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The Prescription Drug Marketing Act (PDMA) of 1987 (P.L. 100-293, 102 Stat. 95) is a law of the United States federal government. It establishes legal safeguards for prescription drug distribution to ensure safe and effective pharmaceuticals and is designed to discourage the sale of counterfeit, adulterated, misbranded, sub potent, and expired prescription drugs. It was passed in response to the development of a wholesale sub-market (known as the "diversion market") for prescription drugs. The PDMA was modified by the Prescription Drug Amendments of 1992 (P.L. 102-353, 106 Stat. 941) on August 26, 1992. The U.S. Food and Drug Administration (FDA) issued regulations implementing the PDMA in 1990 (21 C.F.R. Part 205) and 1999 (21 C.F.R. Part 203). == See also == Food and Drug Administration (FDA, USA) Drug distribution Inverse benefit law Regulation of therapeutic goods == External links == PDMA article	Wikipedia/Prescription_Drug_Marketing_Act
In the United States, prescription monitoring programs (PMPs) or prescription drug monitoring programs (PDMPs) are state-run programs which collect and distribute data about the prescription and dispensation of federally controlled substances and, depending on state requirements, other potentially abusable prescription drugs. PMPs are meant to help prevent adverse drug-related events such as opioid overdoses, drug diversion, and substance abuse by decreasing the amount and/or frequency of opioid prescribing, and by identifying those patients who are obtaining prescriptions from multiple providers (i.e., "doctor shopping") or those physicians overprescribing opioids. Most US health care workers support the idea of PMPs, which intend to assist physicians, physician assistants, nurse practitioners, dentists and other prescribers, the pharmacists, chemists and support staff of dispensing establishments. The database, whose use is required by State law, typically requires prescribers and pharmacies dispensing controlled substances to register with their respective state PMPs and (for pharmacies and providers who dispense from their offices) to report the dispensation of such prescriptions to an electronic online database. The majority of PMPs are authorized to notify law enforcement agencies or licensing boards or physicians when a prescriber, or patients receiving prescriptions, exceed thresholds established by the state or prescription recipient exceeds thresholds established by the State. All states have implemented PDMPs, although evidence for the effectiveness of these programs is mixed. While prescription of opioids has decreased with PMP use, overdose deaths in many states have actually increased, with those states sharing data with neighboring jurisdictions or requiring reporting of more drugs experiencing highest increases in deaths. This may be because those declined opioid prescriptions turn to street drugs, whose potency and contaminants carry greater overdose risk. == History == Prescription drug monitoring programs, or PDMPs, are an example of one initiative proposed to alleviate effects of the opioid crisis. The programs are designed to restrict prescription drug abuse by limiting a patient's ability to obtain similar prescriptions from multiple providers (i.e. “doctor shopping”) and reducing diversion of controlled substances. This is meant to reduce risk of fatal overdose caused by high doses of opioids or interactions between opioids and benzodiazepenes, and to enable better decision making on the part of healthcare providers who may be unaware of a patient's prescription drug use, history or other prescriptions. PDMPs have been implemented in state legislations since 1939 in California, a time before electronic medical records, though implementation increased with s awareness of overprescribing of opioids and overdose. A later New York state program was struck down by the U.S. Supreme Court in Whalen v. Roe. But, by 2019, 49 states, the District of Columbia, and Guam had enacted PDMP legislation. In 2021 Missouri, the last State to not use a PMP, adopted legislation to create one. PMPs are constantly being updated to increase speed of data collection, sharing of data across States, and ease of interpretation. This is being done by integrating PDMP reports with other health information technologies such as health information exchanges (HIE), electronic health record (EHR) systems, and/ or pharmacy dispensing software systems. One program that has been implemented in nine states is called the PDMP Electronic Health Records Integration and Interoperability Expansion, also known as PEHRIIE. Another software, marketed by Bamboo Health and integrated with PMPs in 43 states, uses an algorithm to track factors thought to increase risk of diversion, abuse or overdose, and assigns patients a three digit score based on presumed indicators of risk. While some studies have suggested that PDMP-HIT integration and sharing of interstate data brings benefits such as reduced opioid-related inpatient morbidity, others have found no or negative impact on mortality compared to states without PMP data sharing. Patient and media reports suggest need for testing and evaluation of algorithmic software used to score risk, with some patients reporting denial of prescriptions without c explanation or clarity of data. == Goals == Most health care workers support PMPs which intend to assist physicians, physician assistants, nurse practitioners, dentists and other prescribers, the pharmacists, chemists and support staff of dispensing establishments, as well as law-enforcement agencies. The collaboration supports the legitimate medical use of controlled substances while limiting their abuse and diversion. Pharmacies dispensing controlled substances and prescribers typically must register with their respective state PMPs and (for pharmacies and providers who dispense controlled substances from their offices) report the dispensation to an electronic online database. Some pharmacy software can submit these reports automatically to multiple states. == Usage == === List of programs by state === === Software systems === NarxCare is a prescription drug monitoring program (PDMP) run by Bamboo Health. Bamboo Health was formerly known as Appriss. It is widely used across the United States by pharmacies including Rite Aid as well as those at Walmart and Sam’s Club. The NarxCare software allows doctors to view data about a patient, combining data from the prescription registries of various U.S. states to make the registries interoperable nationally. It also uses machine learning to generate an "Overdose Risk Score" that potentially includes EMS and criminal justice data; these scores have been criticized by researchers and patient advocates for the lack of transparency in the process as well as the potential for disparate treatment of women and minority groups. Advertised as an "analytics tool and care management platform", the NarxCare software allows doctors to view data about a patient including how many pharmacies they have visited and the combinations of medication they are prescribed. It combines data from the prescription registries of various U.S. states, making the registries interoperable nationally. It additionally uses machine learning to generate various three-digit "risk scores" and an overall "Overdose Risk Score", collectively referred to as Narx Scores, in a process that potentially includes EMS and criminal justice data as well as court records. == Controversy == Many doctors and researchers support the idea of PDMPs as a tool in combatting the opioid epidemic. Opioid prescribing, opioid diversion and supply, opioid misuse, and opioid-related morbidity and mortality are common elements in data entered into PDMPs. Prescription Monitoring Programs are purported to offer economic benefits for the states who implement them by decreasing overall health care costs, lost productivity, and investigation times. However, there are many studies that conclude the impact of PDMPs is unclear. While use of PMPs has been accompanied by decrease in opioid prescribing, few analyses consider corresponding use of street opioids, extramedical use, or diversion, which might provide a more holistic method for evaluation of PMP intent and efficacy. Evidence for PDMP impact on fatal overdoses is decidedly mixed, with multiple studies finding increased overdose rates in some states, decreases in others, or no clear impact. Interestingly, an increase in heroin overdoses after PDMP implementation has been commonly reported, presumably as denial of prescription opioids sends patients in search of street drugs. Narx Scores have been criticized by researchers and patient advocates for the lack of transparency in the generation process as well as the potential for disparate treatment of women and minority groups. Writing in Duke Law Journal, Jennifer Oliva stated that "black-box algorithms" are used to generate the scores. == References == == Further reading ==	Wikipedia/Prescription_drug_monitoring_program
The Drug Enforcement Administration (DEA) is a United States federal law enforcement agency under the U.S. Department of Justice tasked with combating illicit drug trafficking and distribution within the U.S. It is the lead agency for domestic enforcement of the Controlled Substances Act, sharing concurrent jurisdiction with the Federal Bureau of Investigation and U.S. Customs and Border Protection. The DEA is responsible for coordinating and pursuing U.S. drug investigations both domestically and internationally. It was established in 1973 as part of the U.S. government's war on drugs. The DEA has an intelligence unit that is also a member of the U.S. Intelligence Community. While the unit is part of the DEA chain-of-command, it also reports to the director of national intelligence. The DEA has been criticized for scheduling drugs that have medicinal uses, and for focusing on operations that allow it to seize money rather than those involving drugs that cause more harm. == History and mandate == The Drug Enforcement Administration was established on July 1, 1973, by Reorganization Plan No. 2 of 1973, signed by President Richard Nixon on July 28. It proposed the creation of a single federal agency to enforce the federal drug laws as well as consolidate and coordinate the government's drug control activities. Congress accepted the proposal, as they were concerned with the growing availability of drugs. As a result, the Bureau of Narcotics and Dangerous Drugs (BNDD), the Office of Drug Abuse Law Enforcement (ODALE); approximately 600 Special Agents of the Bureau of Customs, Customs Agency Service, and other federal offices merged to create the DEA. The DEA is the primary federal agency charged with implementing and enforcing the Controlled Substances Act (CSA), which is Title II of a larger Federal Act called the Comprehensive Drug Abuse Prevention and Control Act of 1970. The DEA is responsible for drugs listed in the CSA's five drug Schedules, categories that rank drugs by their potential for harm, and whether they have a medical use. The CSA seeks to ensure legitimate access to controlled pharmaceuticals, while preventing illicit use of controlled drugs. To these ends, the DEA implements two intersecting legal schemes created by the CSA, registration provisions for entities involved in legal activities, violations of which are not usually criminal offenses, and trafficking provisions for illegal activities, violations of which are criminal offenses. From the early 1970s, DEA headquarters was located at 1405 I ("Eye") Street NW in downtown Washington, D.C. With the overall growth of the agency in the 1980s (owing to the increased emphasis on federal drug law enforcement efforts) and concurrent growth in the headquarters staff, the DEA began to search for a new headquarters location; locations in Arkansas, Mississippi and various abandoned military bases around the United States were considered. However, then–attorney general Edwin Meese determined that the headquarters had to be located close to the attorney general's office. Thus, in 1989, the headquarters relocated to 600–700 Army-Navy Drive in the Pentagon City area of Arlington County, Virginia, near the eponymous Metro station. On April 19, 1995, Timothy McVeigh carried out a terrorist attack on the Alfred P. Murrah Federal Building in Oklahoma City. He was targeting regional offices for the Federal Bureau of Investigation (FBI), Bureau of Alcohol, Tobacco, Firearms and Explosives (ATF) and DEA, all of which had carried out raids that he viewed as unjustified intrusions on the rights of the people. This attack caused the deaths of two DEA employees, one task force member and two contractors in the Oklahoma City bombing. Subsequently, the DEA headquarters complex was classified as a Level IV installation under United States federal building security standards, meaning it was to be considered a high-risk law enforcement target for terrorists. Security measures include hydraulic steel roadplates to enforce standoff distance from the building, metal detectors and guard stations. In February 2003, the DEA established a Digital Evidence Laboratory within its Office of Forensic Sciences. == Organization == The DEA is headed by an administrator of the Drug Enforcement Administration appointed by the president of the United States and confirmed by the U.S. Senate. The Administrator reports to the attorney general through the deputy attorney general. The administrator is assisted by a deputy administrator, the chief of operations, the chief inspector, and three assistant administrators (for the Operations Support, Intelligence, and Human Resources divisions). Other senior staff includes the chief financial officer and the chief counsel. The administrator and deputy administrator are the only presidentially appointed personnel in the DEA; all other DEA officials are career government employees. DEA's headquarters is located in Arlington County, Virginia, across from the Pentagon. It maintains its own DEA Academy located on the Marine Corps Base Quantico at Quantico, Virginia, alongside the FBI Academy. As of 2024, it maintains 241 domestic offices in 23 divisions, and 93 foreign offices in 69 countries. With a budget exceeding $3 billion, DEA employs 10,169 people, including 4,924 special agents and 800 intelligence analysts. c. 2015 its headquarters and the DEA Museum were in 503,776 square feet (46,802.3 m2) in Lincoln Place, a rented office building in Pentagon City in Arlington County, Virginia. In September 2018 this lease was scheduled to end. The General Services Administration (GSA), circa 2015, was checking to see where in Northern Virginia the DEA could be headquartered. In 2018 the government of the United States extended the lease at Lincoln Place, now to expire circa 2033. The DEA administration favored retaining the original location. === Structure === Administrator Deputy Administrator Human Resource Division Career Board Board of Professional Conduct Office of Training Operations Division Aviation Division Office of Operations Management Special Operations Division Office of Diversion Control Office of Global Enforcement Office of Financial Operations Intelligence Division Office of National Security Intelligence (ONSI) Office of Strategic Intelligence Office of Special Intelligence El Paso Intelligence Center OCDETF Fusion Center Financial Management Division Office of Acquisition and Relocation Management Office of Finance Office of Resource Management Operational Support Division Office of Administration Office of Information System Office of Forensic Science Office of Investigative Technology Inspection Division Office of Inspections Office of Professional Responsibility Office of Security Programs Field Divisions and Offices === Special agents === As of 2017, there were 4,650 special agents employed by the Drug Enforcement Administration. DEA agents' starting salary is $49,746–$55,483. After four years, the salary rises to above $92,592. This figure doesn’t include Cost of living allowance (COLA) or LEAP which rated at 25% of base pay including COLA. Special Agents at the 13 step 5 level in high cost of living areas of the United States make near the federal pay cap of $191,000. After receiving a conditional offer of employment, recruits must then complete an 18-week rigorous training which includes lessons in firearms proficiency (including basic marksmanship), weapons safety, tactical shooting, and deadly-force decision training. To graduate, students must maintain an academic average of 80 percent on academic examinations, pass the firearms qualification test, successfully demonstrate leadership and sound decision-making in practical scenarios, and pass rigorous physical-task tests. Upon graduation, recruits earn the title of DEA Special Agent. Because the DEA is responsible for enforcing the Controlled Substances Act, it excludes from consideration job applicants who use or have a recent history of using narcotics or illicit drugs. As of June 27, 2024, DEA applicants cannot have used cannabis or marijuana within three years of submitting their application and cannot have used any other narcotic substance within seven years of applying, although allowances are made for the use of marijuana prior to an applicant's 18th birthday. Background investigations usually include a polygraph test for special-agent, diversion-investigator, and intelligence research specialist positions. The DEA's relatively firm stance on personal drug use contrasts with those of the Central Intelligence Agency and the Federal Bureau of Investigation, which in 2023 considered further relaxing their eligibility guidelines so as to combat dwindling recruitment rates. === Aviation Division === The DEA Aviation Division or Office of Aviation Operations (OA) (formerly Aviation Section) is an airborne division based in Perot Field Fort Worth Alliance Airport, Texas. The current OA fleet consists of 106 aircraft and 124 DEA pilots. The DEA shares a communications system with the Department of Defense for communication with state and regional enforcement independent of the Department of Justice and police information systems and is coordinated by an information command center called the El Paso Intelligence Center (EPIC) near El Paso, Texas. === Special Response Teams === Rapid Response Teams (RRT), previously known as Foreign-Deployed Advisory and Support Teams (FAST), were decommissioned by DEA acting administrator Chuck Rosenburg in March 2017 via memorandum. A need for domestic high-risk service teams led to the hybrid creation of specialized tactical units residing within various geographical regions throughout the United States. DEA officially created and standardized its Special Response Team (SRT) program in 2016. The SRT was designed as a stop-gap between tactical operations conducted by field agents and those necessitating specialized tactics as a result of elevated risks. SRT operators are highly trained in various weapons systems and entry tactics/maneuvers. Because of the clandestine nature of the DEA mission, SRT training protocols and activation requirements are highly sensitive and not available to the public. Some of the SRT missions consist of high-risk arrests, vehicle assaults, air assault/infiltration, specialized surveillance, custody of high-profile individuals, dignitary and witness protection, tactical surveillance and interdiction, advanced breaching, tactical training to other police units, and urban and rural fugitive searches. Covertly located throughout the nation, DEA SRT teams are available to respond to practically any CONUS geographical area with little to no preparation or notification. The DEA SRT has been involved in several high-profile operations in recent years, however, DEA involvement is often not publicized due to operational and intelligence considerations. Considered one of the most covert outfits in federal law enforcement, very little is known about DEA SRT capabilities and its operator selection process. In the past, DEA had other tactical teams like the High-risk Entry Apprehension Teams (HEAT) in some Field Divisions, and Operation Snowcap Teams (predecessor of FAST). The teams administered by the Mobile Enforcement Section, the Mobile Enforcement Teams (MET), and Regional Enforcement Teams (RET), were mobile investigative units intended to deploy resources to state and local agencies (MET) or DEA Field Divisions (RET) in need of assistance with a particular investigation or trafficking group. These programs ended in the early 2000s. === Special Operations Division === The DEA Special Operations Division (SOD) is a division within the DEA, which forwards information from wiretaps, intercepts, and databases from various sources to federal agents and local law enforcement officials. The SOD came under scrutiny following the 2010s global surveillance disclosures. === Domestic Cannabis Eradication/Suppression Program === The Domestic Cannabis Eradication/Suppression Program (DCE/SP) began funding eradication programs in Hawaii and California in 1979. The program rapidly expanded to include programs in 25 states by 1982. By 1985, all 50 states were participating in the DCE/SP. In 2015, the DCE/SP was responsible for the eradication of 3,932,201 cultivated outdoor cannabis plants and 325,019 indoor plants for a total of 4,257,220 marijuana plants. In addition, the DCE/SP accounted for 6,278 arrests and the seizure in excess of $29.7 million of cultivator assets. In 2014, the DEA spent $73,000 to eradicate marijuana plants in Utah, though they did not find a single marijuana plant. Federal documents obtained by journalist Drew Atkins detail the DEA's continuing efforts to spend upwards of $14 million per year to completely eradicate marijuana within the United States despite the government funding allocation reports showing that the Marijuana Eradication Program often leads to the discovery of no marijuana plants. This prompted twelve members of Congress to push for the elimination of the program and use the money instead to fund domestic-violence prevention and deficit-reduction programs. == Budget == In 2018, the DEA budget was $2.086 billion. $445 million was spent on international enforcement and $1.627 billion was spent on domestic enforcement. Breaking foreign and domestic sources of supply ($1.0149 billion) via domestic cannabis eradication/suppression; domestic enforcement; research, engineering, and technical operations; the Foreign Cooperative Investigations Program; intelligence operations (financial intelligence, operational intelligence, strategic intelligence, and the El Paso Intelligence Center); and drug and chemical diversion control. Reduction of drug-related crime and violence ($181.8 million) funding state and local teams and mobile enforcement teams. Demand reduction ($3.3 million) via anti-legalization education, training for law enforcement personnel, youth programs, support for community-based coalitions, and sports drug awareness programs. == Firearms == DEA agents' primary service weapons are the Glock 17 and Glock 19, Remington 870 12-gauge shotgun, and Rock River Arms LAR-15 semi-automatic carbine in 5.56×45mm NATO. Agents may also qualify to carry a firearm listed on an authorized carry list maintained and updated by the Firearms Training Unit (FTU), Quantico, Virginia. Special Agents may qualify with their own personally-owned handguns, rifle, and shotgun, and certain handguns are allowed to be used with permission from the FTU. Agents are required to attend tactical and firearms proficiency training quarterly, and to qualify with their handguns twice per year. The DEA has one of the most challenging handgun qualification courses in all of the federal law enforcement. Failure to achieve a passing qualification score is the reason for most Academy dismissals and special agents in the field may have their authority to carry a firearm revoked for failure to qualify. Basic Agent Trainees (BATs) who fail the initial pistol qualification course of fire are placed in a remedial program to receive additional training. In remedial training, BATs receive five extra two-hour range sessions, for a total of 10 more hours of live fire training on their issued sidearm, to further aid them in helping pass the pistol qualification. After passing their pistol qualification, Basic Agent Trainees move on to receive formal training on the DEA's standard-issue long guns and will continue to frequently shoot the agency-issued sidearms that they have already qualified on. In all, BATs receive a total of 32 firearms training sessions, when combining classroom instruction, gear issue, and pistol, rifle, and shotgun live fire training at the DEA Academy. They will shoot the qualification courses for all three weapons systems during their initial training but must pass their final qualification attempts only on their Glock pistols to become a Special Agent. Agents are trained to use shoulder-fired weapons, such as the Rock River LAR-15, adopted in 2004, and the LWRC M6A2, the standard carbine of DEA. The Colt 9mm SMG was previously issued, but no longer in service. Agents are required to complete a two-day (16-hour) proficiency course to carry a shoulder weapon on enforcement operations. They may carry a Rock River LAR-15 or LWRC carbine as authorized, personally-owned weapons, provided they meet the same training and proficiency standards. == Impact on the drug trade == In 2005, the DEA seized a reported $1.4 billion in drug trade related assets and $477 million worth of drugs. According to the White House's Office of Drug Control Policy, the total value of all of the drugs sold in the U.S. is as much as $64 billion a year, giving the DEA an efficiency rate of less than 1% at intercepting the flow of drugs into and within the United States. Critics of the DEA (including recipient of the Nobel Memorial Prize in Economic Sciences, Milton Friedman, prior to his death a member of Law Enforcement Against Prohibition) point out that demand for illegal drugs is inelastic; the people who are buying drugs will continue to buy them with little regard to price, often turning to crime to support expensive drug habits when the drug prices rise. One recent study by the DEA showed that the price of cocaine and methamphetamine is the highest it has ever been while the quality of both is at its lowest point ever. This is contrary to a collection of data done by the Office of National Drug Control Policy, which states that purity of street drugs has increased, while price has decreased. In contrast to the statistics presented by the DEA, the United States Department of Justice released data in 2003 showing that purity of methamphetamine was on the rise. === Registration and licensing === The DEA has a registration system in place which authorizes anyone to manufacture, import, export, and distribute by filing DEA form 225 Archived November 8, 2015, at the Wayback Machine along with medical professionals, researchers and manufacturers access to "Schedule I" drugs, as well as Schedules 2, 3, 4 and 5. Authorized registrants apply for and, if granted, receive a "DEA number". An entity that has been issued a DEA number is authorized to manufacture (drug companies), distribute research, prescribe (doctors, pharmacists, nurse practitioners and physician assistants, etc.), or dispense (pharmacy) a controlled substance. === Diversion control system === Many problems associated with substance use disorders are the result of legitimately manufactured controlled substances being diverted from their lawful purpose into the illicit drug traffic. Many of the analgesics, depressants and stimulants manufactured for legitimate medical use can often carry the potential for addiction. Therefore, those scheduled substances have been brought under legal control for prevention and population safety. The goal of controls is to ensure that these "controlled substances" are readily available for medical use while preventing their distribution for illicit distribution and non-medical use. This can be a difficult task, sometimes providing difficulty for legitimate patients and healthcare providers while circumventing illegal trade and consumption of scheduled drugs. Under federal law, all businesses which manufacture or distribute controlled drugs, all health professionals entitled to dispense, administer or prescribe them, and all pharmacies entitled to fill prescriptions must register with the DEA. Registrants must comply with a series of regulatory requirements relating to drug security, records accountability, and adherence to standards. All of these investigations are conducted by Diversion Investigators (DIs). DIs conduct investigations to uncover and investigate suspected sources of diversion and take appropriate civil and administrative actions. Prescription Database Management Programs (PDMP) aid and facilitate investigation and surveillance. === Fentanyl overdose crisis === In 2019 and 2020, record overdoses from illicit fentanyl tablets or as a deadly adulterant in heroin have ravaged North America. An estimated 19,416 individuals died of a drug overdose in the United States in the first 3 months of 2020 compared with 16,682 in the same 3-month period in 2019; this trend was fueled by synthetic opioids (especially illicitly manufactured fentanyl and analogs). Furthermore, between May 2020 and April 2021, the estimated number of drug overdose deaths in the United States exceeded 100,000 over this time period, with 64.0% of deaths involving synthetic opioids other than methadone (the same illicitly manufactured fentanyls and analogs). In contrast, Europe has seen a decrease from heroin overdoses, and a practical absence of illicit, synthetic opioids. Fentanyl, originally developed in the 1970s by Janssen Pharmaceutica, is a potent anesthetic primarily used in hospital or hospice settings. In Europe, heroin is mainly supplied from Western Asia (from Afghanistan and neighboring countries), and less likely to be contaminated with fentanyl. In North America, there are now fewer deaths involving heroin than either meth or cocaine, a striking change that has taken place over the last two years as heroin has all but disappeared from some regions. Due to the absence of heroin from Asian sources, fentanyl-laced heroin powder or tablets have filled that void. In October 2021, the US reported another record in fentanyl deaths, as federal agencies were unable to stem the tide of illicit, synthetic drugs entering the US. Originally, introduced to replace much of the white powder heroin in the Eastern United States, the drug continues to move further west. Between July 2019–December 2020, illicitly manufactured fentanyl involved deaths increased sharply in midwestern (33.1%), southern (64.7%), and western (93.9%) jurisdictions. === MDMA DEA scheduling overturn === In 1985 MDMA and its analogues were under review by the American government as a drug with a potential for addiction. During this time, several public hearings on the new drug were held by the DEA. Based on all of the evidence and facts presented at the time, the DEA's administrative law judge did not see MDMA and its analogues as being of large concern and recommended that they be placed in Schedule III. The DEA administrator, expressing concern for addictive potential, overruled the recommendation and ruled that MDMA be put in Schedule I, the Controlled Substances Act's most restrictive category. == Rank structure == The following is a listing of the rank structure found within the DEA (in ascending order): Agents Agent Trainee Special Agent Senior Special Agent Supervising Special Agent Assistant Special Agent in Charge (ASAC) Special Agent in Charge (SAC) Management Assistant Administrator Associate Deputy Administrator Deputy Administrator Principal Deputy Administrator Chief of Staff Administrator == Line of duty deaths == 54 DEA agents have been killed in the line of duty. == Criticism and controversies == The DEA has been criticized for placing highly restrictive schedules on a few drugs that researchers in the fields of pharmacology and medicine regard as having medical uses. Critics assert that some such decisions are motivated primarily by political factors stemming from the U.S. government's war on drugs and that many benefits of such substances remain unrecognized due to the difficulty of conducting scientific research. A counterpoint to that criticism is that under the Controlled Substances Act it is the Department of Health and Human Services (through the Food and Drug Administration and the National Institute on Drug Abuse), not the DEA, which has the legal responsibility to make scientific and medical determinations with respect to drug scheduling; no drug can be scheduled if the secretary of health and human services recommends against it on a scientific or medical basis, and no drug can be placed in the most restrictive schedule (Schedule I) if DHHS finds that the drug has an accepted medical use. Jon Gettman's essay Science and the End of Marijuana Prohibition describes the DEA as "a fall guy to deflect responsibility from the key decision-makers" and opines, "HHS calls the shots when it comes to marijuana prohibition, and the cops at DEA and the general over at ONDCP take the heat." The DEA is also criticized for focusing on the operations from which it can seize the most money, namely the organized cross-border trafficking of marijuana. Some individuals contemplating the nature of the DEA's charter advise that, based on danger, the DEA should be most focused on cocaine. Others suggest that, based on opiate popularity, the DEA should focus much more on prescription opiates used recreationally, which critics contend comes first before users switch to heroin. Practitioners who legally prescribe medicine however must possess a valid DEA license. According to federal law, the budget of the DEA Diversion Control Program is to be paid by these license fees. In 1984 a three-year license cost $25. In 2009 the fee for a three-year license was $551. Some have likened this approach to license fees unreasonable, "like making pilot licenses support the entire Federal Aviation Administration (FAA) budget." The renewal fee for 2020 as of October 1, 2020, is $888 for a three-year license. In 2005, the DEA estimated that it had over 4,000 informants without which they "could not effectively enforce the controlled substances laws of the United States." To gather information, agents permitted their informants to buy and sell drugs, engage in Medicaid fraud rings, and other illicit acts. Despite this, the DEA claims that they are "in compliance" with the rules for using informants to gather information about illicit activities. === Costs === The total budget of the DEA from 1972 to 2014, according to the agency website, was $50.6 billion. The agency had 11,055 employees in 2014. For the year 2014 the average cost per arrest made was $97,325. === Civil liberties === Others, such as former Republican congressman Ron Paul, the Cato Institute, The Libertarian Party and the Drug Policy Alliance criticize the very existence of the DEA and the war on drugs as both hostile, and contrary, to the concept of civil liberties by arguing that anybody should be free to put any substance they choose into their own bodies for any reason, particularly when legal drugs such as alcohol, tobacco and prescription drugs are also open to addiction, and that any harm caused by a drug user or addict to the general public is a case of conflicting civil rights. Recurrently, billions of dollars are spent yearly, focusing largely on criminal law and demand reduction campaigns, which has resulted in the imprisonment of thousands of U.S. citizens. Demand for recreational drugs is somewhat static as the market for most illegal drugs has been saturated, forcing the cartels to expand their market to Europe and other areas than the United States. United States federal law registers cannabis as a Schedule I drug. === Incarceration of Daniel Chong === In April 2012 in San Diego, California, DEA agents detained a student, Daniel Chong, and left him locked in a holding room for five days. The cell contained no food, water or bathroom facilities. When he was found, he had to be hospitalized for several days for a variety of medical problems. The incident touched off a national furor, resulting in several investigations. The incident has been described as a "Kafkaesque nightmare," a "debacle," and "one of the worst cases of its kind." Chong subsequently sued the DEA; the government settled the suit for $4.1 million. === Department of Justice Smart on Crime Program === On August 12, 2013, at the American Bar Association's House of Delegates meeting, Attorney General Eric Holder announced the "Smart on Crime" program, which is "a sweeping initiative by the Justice Department that in effect renounces several decades of tough-on-crime anti-drug legislation and policies." Holder said the program "will encourage U.S. attorneys to charge defendants only with crimes "for which the accompanying sentences are better suited to their individual conduct, rather than excessive prison terms more appropriate for violent criminals or drug kingpins..." Running through Holder's statements, the increasing economic burden of over-incarceration was stressed. As of August 2013, the Smart on Crime program is not a legislative initiative but an effort "limited to the DOJ's policy parameters." === International events === David Coleman Headley (born Daood Sayed Gilani, June 30, 1960) who was working as an informant for the U.S. Drug Enforcement Administration (DEA) simultaneously made periodic trips to Pakistan for LeT training and was one of the main conspirators in the 2008 Mumbai attacks. On January 24, 2013, Headley, then 52 years old, was sentenced by U.S. district judge Harry Leinenweber of the United States District Court for the Northern District of Illinois in Chicago to 35 years in prison for his part in the 2008 Mumbai attacks, in which at least 164 victims (civilians and security personnel) and nine attackers were killed. Among the dead were 28 foreign nationals from 10 countries. One attacker was captured. The bodies of many of the dead hostages showed signs of torture or disfigurement. A number of those killed were notable figures in business, media, and security services. The DEA was accused in 2005 by the Venezuelan government of collaborating with drug traffickers, after which President Hugo Chávez decided to end any collaboration with the agency. In 2007, after the U.S. State Department criticized Venezuela in its annual report on drug trafficking, the Venezuelan Minister of Justice reiterated the accusations: "A large quantity of drug shipments left the country through that organization. We were in the presence of a new drug cartel." In his 1996 series of articles and subsequent 1999 book, both titled Dark Alliance, journalist Gary Webb asserts that the DEA helped harbor Nicaraguan drug traffickers. Notably, they allowed Oscar Danilo Blandón political asylum in the USA despite knowledge of his cocaine-trafficking organization. The government of Bolivia has also taken similar steps to ban the DEA from operating in the country. In September 2008, Bolivia drastically reduced diplomatic ties with the United States, withdrawing its ambassador from the US and expelling the US ambassador from Bolivia. This occurred soon after Bolivian president Evo Morales expelled all DEA agents from the country due to a revolt in the traditional coca-growing Chapare Province. The Bolivian government claimed that it could not protect the agents, and Morales further accused the agency of helping incite the violence, which claimed 30 lives. National agencies were to take over control of drug management. Three years later, Bolivia and the US began to restore full diplomatic ties. However, Morales maintained that the DEA would remain unwelcome in the country, characterising it as an affront to Bolivia's "dignity and sovereignty". In the Netherlands, both the Dutch government and the DEA have been criticized for violations of Dutch sovereignty in drug investigations. According to Peter R. de Vries, a Dutch journalist present at the 2005 trial of Henk Orlando Rommy, the DEA has admitted to activities on Dutch soil. Earlier, then Minister of Justice Piet Hein Donner, had denied to the Dutch parliament that he had given permission to the DEA for any such activities, which would have been a requirement by Dutch law in order to allow foreign agents to act within the territory. The DEA conducted a covert operation over several years in which undercover operatives were sent to Venezuela to build drug-trafficking cases against Venezuela's leadership, including Nicholas Maduro. The plan was part of "Operation Money Badger", which the DEA and prosecutors in Miami created in 2013. It potentially breached Venezuelan and international law and therefore required the approval of the Sensitive Activity Review Committee, a secretive panel of senior State and Justice Department officials that oversees the most sensitive DEA cases involving tricky ethical, legal or foreign policy considerations. Following the Colombian peace process, which brought an end to the Colombian conflict between the Colombian government and the Revolutionary Armed Forces of Colombia (FARC–EP), the Special Jurisdiction for Peace found that the DEA had plotted with Colombian Attorney General Néstor Humberto Martínez to fabricate drug trafficking charges against Jesús Santrich, in a bid to jeopardize the peace agreement by inciting the FARC to take up arms again. === Special Operations Division fabricated evidence trails === In 2013, Reuters published a report about the DEA's Special Operations Division (SOD) stating that it conceals where an investigative trail about a suspect truly originates from and creates a parallel set of evidence given to prosecutors, judges, and defense lawyers. This DEA program mainly affects common criminals such as drug dealers. The concealment of evidence means the defendant is unaware of how his or her investigation began and will be unable to request a review of possible sources of exculpatory evidence. Exculpatory evidence may include biased witnesses, mistakes, or entrapment. Nancy Gertner, a former federal judge who had served from 1994 to 2011 and a Harvard Law School professor, stated that "It is one thing to create special rules for national security. Ordinary crime is entirely different. It sounds like they are phonying up investigations." Andrew O'Hehir of Salon wrote that "It's the first clear evidence that the “special rules” and disregard for constitutional law that have characterized the hunt for so-called terrorists have crept into the domestic criminal justice system on a significant scale." === Cannabis rescheduling === A 2014 report by the Multidisciplinary Association for Psychedelic Studies and the Drug Policy Alliance accuses the DEA of unfairly blocking the removal of cannabis from Schedule I. The report alleges that the methods employed by the DEA to achieve this include: delaying rescheduling petitions for years, overruling DEA administrative law judges, and systematically impeding scientific research. The DEA continues to refuse the removal of cannabis from Schedule I despite wide-scale acceptance of the substance among the medical community, including 76% of doctors, for the treatment of various diseases. === Domestic anti-drug advocacy === The DEA, in addition to enforcement, also regularly engage in advocacy, specifically against rescheduling marijuana, by publishing policy-based papers on certain drugs. Figures such as Ifetayo Harvey, founder and executive of the People of Color Psychedelic Collective, have criticized the DEA for using tax dollars in what they call an attempt to change public opinion, a practice they call an overreach from the scope of the agency's job of enforcement. They claim that the DEA releasing such non-peer-reviewed reports is a transparent attempt to justify its own activities and that since it is not by law an advocacy group but rather a legal enforcement group, those press releases are tantamount to what they consider domestic propaganda. === Insufficient monitoring of David Headley === The DEA faced a major setback for not keeping stringent observation on Pakistani-American informant David Headley, for involvement in the November 2008 terror attacks in Mumbai, as well as conspiring a terror attack on the Danish newspaper Jyllands-Posten for the cartoons of Muhammad. Headley, while working with the DEA, took part in the plot by providing reconnaissance to the Pakistan based terror outfit Lashkar-e-Taiba, which he was introduced to while visiting Pakistan. On January 24, 2013, a U.S. federal court eventually sentenced Headley to 35 years in prison for his role in Mumbai and Copenhagen. == Raids on medical marijuana dispensaries == The DEA has taken a particularly strong stance on enforcement of the Controlled Substances Act on persons and organizations acting within state laws that allow medical cannabis cultivation and distribution. DEA chief Chuck Rosenberg has made negative comments on patients who use medical marijuana, saying he considers medical marijuana to be a "joke". As a reaction against the negative statements made by Rosenberg towards medical marijuana, an international online petition has been formed. More than 159,737 signatures have been gathered globally with the intention that Rosenberg be fired or forced to resign as head of DEA. "The people of California and the County of Santa Cruz have overwhelmingly supported the provision of medical marijuana for people who have serious illnesses," county Supervisor Mardi Wormhoudt told the San Francisco Chronicle. "These people (blocking the road) are people with AIDS and cancer and other grave illnesses. To attack these people, who work collectively and have never taken money for their work, is outrageous." As a result, the Wo/Men's Alliance for Medical Marijuana, with the City and County of Santa Cruz, had sued the DEA, Attorney General Michael Mukasey, and the ONDCP. The most recent court decision rejected the government's motion to dismiss, which allowed discovery to move forward. The American Civil Liberties Union hailed the decision as "a first-of-its-kind ruling." More recently, the DEA has escalated its enforcement efforts on the recently proliferated Los Angeles area medical cannabis collectives. On July 25, 2007, the DEA raided the California Patients Group, Hollywood Compassionate Collective, and Natural Hybrid (NHI Caregivers) in Hollywood, California. Earlier that day, the operators of those collectives participated in a press conference with LA City Council members announcing the city's intention to regulate the collectives and asking the DEA to halt raids on collectives while the City drafted regulations. The dispensary operator of Natural Hybrid (NHI Caregivers) was forced to close down the collective due to the tremendous loss caused by the DEA conducted joint task force raid against them. == Project Cassandra == In 2008 the Special Operations part of the agency launched a multi-agency effort named Project Cassandra to investigate Hezbollah for allegations of illicit drug trafficking and terrorist financing. The investigation identified an Iranian cell in the U.S. which worked in concert with a Lebanese bank called the Lebanese Canadian Bank to launder money using the purchase of used automobiles exported to Africa. Project Cassandra also identified hemispheric drug syndicates involved in cocaine trafficking in order to finance Hezbollah activities. The Department of Justice issued several sealed indictments but declined to seize, prosecute, extradite, or further investigate likely targets of these alleged foreign criminal activities operating in the United States due to White House diplomatic objectives involving the international nuclear agreement with Iran. On December 22, 2017, Attorney General Jeff Sessions ordered a review of prior cases in the project. == DEA Museum == In 1999, the DEA opened the Drug Enforcement Administration Museum in Arlington County, Virginia. The original permanent exhibit – Illegal Drugs in America: A Modern History – remains the museum's centerpiece. The exhibit features "the more than 150 year history of drugs and drug abuse and the DEA," including a considerable collection of drug paraphernalia and an image of a smiling drug vendor under the heading "Jimmy's Joint". == In popular culture == The DEA are commonly featured in crime drama films and TV, as both protagonists and antagonists. Hank Schrader is one of the main protagonists in AMC's Breaking Bad. He is both a DEA agent (later promoted to ASAC) and brother-in-law to drug kingpin Walter White, unknowingly investigating Walt's alter-ego Heisenberg for the duration of the show. Javier Peña and Stephen Murphy are two of the main protagonists in Netflix's Narcos. They are responsible for the capture and killing of the Colombian drug lord Pablo Escobar on December 2, 1993, of which the show was based on. Norman Stansfield leads a team of corrupt DEA agents, who along with the NYPD, hunt an assassin in the 1994 movie Léon: The Professional. In the film Sabotage, a group of special agents with the DEA's Special Operations Team, are hunted down after stealing a large amount of cartel cash during a raid. == See also == DEA Purple Heart Award Departamento Administrativo de Seguridad (former Colombian counterpart) Diplomatic Security Service (DSS), U.S. State Department Federal Bureau of Investigation (FBI) Federal Drug Control Service (Russian former counterpart) Immigration and Customs Enforcement (ICE) List of United States federal law enforcement agencies Main Directorate for Drugs Control (Russian counterpart) Office of Criminal Investigations Operation Money Badger Operation Panama Express Operation Tiburon (most successful counter-drug operation) Regulation of therapeutic goods in the United States Title 21 of the Code of Federal Regulations U.S. Customs and Border Protection (CBP) == References == == Further reading == Harry J. Anslinger and Will Oursler (1961). The Murderers: The Story of the Narcotic Gangs. New York: Farrar, Straus and Cudahy. Edward Jay Epstein (1977). Agency of Fear: Opiates and Political Power in America. New York: Putnam. King, Rufus (1972). The Drug Hang-Up: America's Fifty Year Folly Luno, Nathan Results of America's Drug War; Archived January 14, 2009, at the Wayback Machine. TheDEA.og. "98 Percent of All Domestically Eradicated Marijuana Is 'Ditchweed,' DEA Admits". NORML. September 7, 2006. Archived from the original on September 27, 2011. Retrieved March 27, 2007. Major Studies of Drugs and Drug Policy—Schaffer Library of Drug Policy Smith, Wayne (2012). Waffle House Diaries. Chattanooga, TN: Bluehotel Press. == External links == Official website Archives of late 1990s websites (usdoj.gov/dea/) at the Wayback Machine (archive index) DEA Tip Line Drug Enforcement Administration in the Federal Register List of former DEA Administrators Office of Diversion Control A response to the DEA web site DEA Watch DrugEnforcementEdu.org Get Smart About Drugs – A DEA Resource for Parents DEA Demand Reduction – Street Smart Prevention DEA Museum	Wikipedia/Drug_Enforcement_Administration
The Sunday Telegraph is a British broadsheet newspaper, first published on 5 February 1961 and published by the Telegraph Media Group, a division of Press Holdings. It is the sister paper of The Daily Telegraph, also published by the Telegraph Media Group. The Sunday Telegraph was originally a separate operation with a different editorial staff, but since 2013 the Telegraph has been a seven-day operation. However, The Sunday Telegraph still has its own editor, different from that of The Daily Telegraph. According to the Audit Bureau of Circulations, the Sunday Telegraph had an average circulation of 214,711 copies per week in the first half of 2021. == See also == Journalism portal == References == == External links == Official website	Wikipedia/The_Sunday_Telegraph
Any product defined as a drug under the Canadian Food and Drugs Act must have an associated drug identification number (or DIN). A DIN also pertains to veterinary drugs permitted for sale in Canada. The drug identification number (DIN) is the 8 digit number located on the label of prescription and over-the-counter drug products that have been evaluated by the Therapeutic Products Directorate (TPD) and approved for sale in Canada. Once a drug has been approved, the Therapeutic Products Directorate issues a DIN, which permits the manufacturer to market the drug in Canada. For drugs, where there is minimal market history in Canada, there is a more stringent review and the drug is required to have a Notice of Compliance and a DIN in order to be marketed in Canada. A DIN lets the user know that the product has undergone and passed a review of its formulation, labeling, and instructions for use. A drug product sold in Canada without a DIN is not in compliance with Canadian law, with limited exceptions, such as foreign drug products imported under emergency authorization. The DIN is also a tool to help in the follow-up of products on the market, recall of products, inspections, and quality monitoring. A drug product can be looked up via its DIN with the Health Canada's Drug Product Database (DPD) to find specific information of drugs approved by the Ministry. == See also == National Drug Code United States Pharmaceutical code == References == == External links == Health Canada DIN fact sheet Drug Product Database (DPD)	Wikipedia/Drug_identification_number
The term “dormant therapy” refers to a new drug or a new biological product which was made the subject of a request for designation in compliance with the Dormant Therapies Act. According to the legislation, the assignment of dormant therapy is given to a drug or new biological product that has been determined to have insufficient patent protection and meets an unmet medical need, improves outcomes, or reduces risks compared to an existing treatment. Many drugs may be abandoned due to their failure to meet a clinical endpoint. Over time, manufacturers wanting to re-investigate the abandoned drug will not because the patent for the drug has expired or will expire prior to the completion of research and the federal approval process. Weak or no patent protection is a disincentive for drug development as it hinders a manufacturer’s ability to recoup the investment in expensive clinical trials. This disincentive is even more pronounced for treatments for more complex conditions such as Alzheimer’s, which require more clinical data than conditions which currently have existing treatments. == References ==	Wikipedia/Dormant_therapy
A combination drug is a combination of two or more pharmaceutical drugs as active ingredients combined into a single dosage form, typically as a fixed-dose combination, with each constituent standardized to specifications of a fixed dose. Fixed-dose combinations are mass-produced and mass marketed, intended to serve as a near universal treatment for a large patient population with diverse medical histories, conditions, predisposition thereof, and treatment requirements. A polypill is a pharmacy or capsule containing four or more active ingredients, often needing to be compounded at a specialized pharmacy in order to satisfy the specifications of a patient's personalized prescription and treatment plan, including dosage form, medicinal dosing, and/or mechanism of release. Polypills encompass approved prescription drugs and over the counter drugs, at times including nutritional supplements, amino acids, vitamins, minerals, and hormones. Fixed-dose combination drugs were initially developed to target a single disease, as with antiretroviral FDCs indicated for treating AIDS and HIV. Over time, the concept of combination drugs has come to include reducing pill burden for patients, thereby encouraging patient compliance, and generally simplifying treatment plan with one product containing easily accessible (often available over the counter without a prescription requirement), relatively affordable (often generic drugs) ingredients with established therapeutic efficacy and a broad capacity for treating a variety of symptoms and conditions, thus ensuring maximum appeal to a majority of patients amongst a large population with varying needs. == Current prescription combination drugs == The combination drugs listed below are typically available by prescription only, but specific circumstances regarding a given combination's legal accessibility, or any specific regulation pertinent to ingredient quality, quantities, production standards, sourcing, etc. will vary by jurisdictions, and include: amitriptyline/perphenazine, brand brand Triavil amlodipine/benazepril: Lotrel amitriptyline/chlordiazepoxide: brandLimbitrol in India, Limbix (Bangladesh) amlodipine/atorvastatin brand Conduet Amlodipine/celecoxib: brand Consensai amlodipine/olmesartan: brand Azor amlodipine/valsartan: brand Exforge bupropion/naltrexone, 450 mg bupropion hydrochloride and naltrexone, brand Contrave butalbital/acetaminophen, brand Butapap butalbital and caffeine, branded Fioricet butalbital combined with aspirin and caffeine, branded Fiorinal butalbital, caffeine, acetaminophen, and codeine: Fioricet with Codeine chlordiazepoxide combined with clidinium bromide: ephedrine/ethylmorphine: Lephotan lisinopril/amlodipine: Lisonorm' lisinopril/hydrochlorothiazide: Zestorenic Paxlovid: combination of nirmatrelvir and ritonavir for treatment and management of COVID-19. hydrocodone/acetaminophen, common brands Norco and Vicodin Deanxit by Lundbeck, available in India and Bangladesh: combination of flupentixol and melitracen hydrocodone/aspirin: Azdone hydrocodone/guaifenesin: Obedron hydrocodone/ibuprofen: Ibudone omeprazole/amoxicillin/rifabutin, brand Talicia olanzapine/fluoxetine, branded Symbyax oxycodone/acetaminophen, common brand Percocet oxycodone/aspirin: Percodan oxycodone/ibuprofen: Combunol phentermine/topiramate, under patent as Qsymia: combination of 37.5 mg phentermine hydrochloride and 150 mg topiramate phenylephrine/ketorolac brand Omidria Amphetamine mixed salts of the racemic: dextroamphetamine sulfate, dextroamphetamine saccharate, levoamphetamine aspartate monohydrate, levoamphetaminee sulfate, commonly Adderall and Mydayis pseudoephedrine/carbinoxamine, Rondec syrup == Combination drugs accessible over the counter (OTC) == Fixed-dose combination drugs for sale over the counter (OTC) exist around the world, constituting doses that are tolerable to a mainstream consumer population. In the United States, items containing ephedrine, pseudoephedrine, or phenylpropanolamine can be purchased without a prescription, albeit under strict oversight and from behind the pharmacy counter, per the U.S. Federal drug law titled the Combat Methamphetamine Epidemic Act of 2005. Fixed-dose combination drugs for sale over the counter internationally, including medicine indicated for various purposes: Bayer Anacin: pill available since 1916, constituting 400 mg aspirin and 32 mg caffeine. Bayer Coricidin: a product line sold OTC combinations at least 2 mg of an antihistamine (chlorpheniramine dextromethorphan hydrobromide: Coricidin Cold + Cough: antihistamine chlorpheniramine combined with 200 mg guaifenesin (expectorant) and acetaminophen; and Coricidin High Blood Pressure is a combination of chlorpheniramine, guaifenisin or phenylephrine, 325 mg. diphenhydramine + 8-chlorotheophylline produces dimenhydrinate, generally branded Dramamine. fexofenadine/pseudoephedrine by GlaxoSmithKline: combination of 12 mg fexofenadine and 120 mg pseudoephedrine hydrochloride, Allegra-D glucose/fructose/phosphoric acid, Emetrol for Nausea: combines glucose with fructose and phosphoric acid aspirin/paracetamol/caffeine (primary brand Excedrin) b: product line combining 250 mg aspirin, 400 mg acetaminophen, and 35 mg caffeine ibuprofen/famotidine: combination of ibuprofen and famotidine, brand Duexis. ibuprofen/diphenhydramine: combination of 400 mg ibuprofen with 25 mg diphenhydramine citrate Advil PM loratadine/pseudoephedrine: combination of 10 mg loratadine and pseudoephedrine hydrochloride, Claritin-D naproxen/diphenhydramine by Bayer: combination of 220 mg naproxen sodiuum and 25 mg diphenhydramine hydrochloride naproxen/pseudoephedrine (branded Aleve-D): 220 mg naproxen sodium and 120 mg pseudoephedrine hydrochloride oxomemazine/guaifenesin (primarily branded Toplexil by Aventis): most frequently taken orally in liquid syrup dosage form, but generically is also available in suppository and pill dosage forms. Aventis' fixed-dose preparation, Toplexil, constitutes oxomemazine exactified to a dose of 1.65 mg/5ml and guaifenesin exactified to 33.3 mg/5ml. Utilized in France, Algeria, Morocco, oxomemazine itself has never been FDA-approved for medical use in the United States. Robitussin: a product line of cough medicines containing an antitussive/cough suppressant (usually dextromethorphan), a fever reducer and/or analgesic (e.g. acetaminophen, NSAID), anthistamine (chlorpheniramine, doxylamine), and a cough expectorant (usually guaifenesin or phenylephrine) Sudafed PE: combination of 300 mg guaifenesin and 50mg phenylephrine hydrochloride Tylenol PM by Johnson & Johnson: combination of 500 mg acetaminophen and 25 mg diphenhydramine Vernate by Tutag Pharmaceuticals is an injectable elixir or liquid: 8mg chlorpheniramine maleate and 50 mg phenylpropanolamine per serving. Tri-Nefrin for tablet forms; Altec Syrup (primary brand name for liquid tincture formulation) available in Asia Vernate Liquid, injectable liquid formulation by Tutag Pharmaceuticals == Combination drugs under development, not yet approved for medical use == MDMA/citalopram: an empathogen called "Ecstasy" combined with citalopram (SSRI); currently under development in FDA Phase II clinical trials. == Combinations drugs for veterinary use == Temaril-P: alimemazine and prednisolone; indicated as antitussive and antipruritic in dogs, generic since 2024. The generic alternative to the brand version substitutes alimemazine with trimeprazine, but is otherwise identical in terms of formulation and efficacy. Titzeol: combination of tiletamine and zolazepam both major tranquilizers, intended to sedate large animals == Combination drugs no longer widely available == Acutran by G.W. Carnrick Laboratories: amfecloral, a chemical compound constituting dextroamphetamine sulfate and chloral hydrate, discontinued 1973 Ambar by Wyeth: combination of methamphetamine hydrochloride and phenobarbital sodium; Ambar Extentab is the extended-release formulation Amphaplex 10 and Amphaplex 20 by Laderle Laboratories: combination of 2.5 mg methamphetamine saccharate, 2.5 mg methamphetamine hydrochloride, 2.5 mg levoamphetamine sulfate, and 2.5 mg dextroamphetamine sulfate; the latter comprised 20 mg in aggregate: combining 5 mg methamphetamine saccharate, 5 mg methamphetamine hydrochloride, 5 mg levoamphetamine sulfate, and 5 mg dextroamphetamine sulfate. Amplus Now by Roehrig Laboratories, Inc.–combined 5 mg dextroamphetamine sulfate and 5 mg hydroxyzine Amvicel by Roehrig Laboratories: 10 mg dextroamphetamine sulfate, 30 mg nicotinamide, 40 mg amobarbital, 15 mg phenobarbital sodium, and essential vitamins and minerals Artogesic (alternatively Artigesic) by Cole Pharmaceuticals: combination of dextroamphetamine, mephobarbital, phenacetin, and salicylamide. Name since recycled by Glenmark of India for a brand of ibuprofen. Apamead by Lederle Laboratories: combination of dextroamphetamine sulfate, amobarbital sodium, aspirin, and phenacetin Anox by Winston-Salem Pharmaceuticals, capsule polypill combining 7.5 mg each of two amphetamine salts: methamphetamine hydrochloride and dextroamphetamine sulfate, alongside 20 mg each of three barbiturate salts: phenobarbital, butabarbital, and secobarbital. Anxine by Behlen Manufacturing: combination of 120 mg mephenesin, 35 mg cyclobarbital sodium, and 2.5 mg dextroamphetamine sulfate, and BamaDex by Behlen: combination of 5 mg dextroamphetamine and 400 mg meprobamate Biphetamine T-12.5 and Biphetamine T-20 by Fisons: combination of 6.25 mg levoamphetamine and 6.25 mg dextroamphetamine (1/2.5 mg racemic amphetamine; 10 mg levoamphetamine and 10 mg dextroamphetamine (20 mg racemic amphetamine) Delcobese by the Lemmon Drug Company: combination of mixed salts of amphetamine sulfate and adipate: 50% levoamphetamine sulfate and adipate combined with 50% dextroamphetamine sulfate and adipate, voluntarily withdrawn from production by the Lemmon Company in 1984 Tanphetamin by Neisler: levoamphetamine and dextroamphetamine, both bonded to a tannic acid molecule. Bontril Timed product line by Carnrick: Bontril Timed No. 1 combined 2.5 mg dextroamphetamine and 7.5 mg butabarbital sodium; Bontril Timed No. 2 5 mg dexamphetamine and 15 mg butabarbital; Bontril Timed No. 3 10 mg dexamphetamine with 30 mg butabarbital; and Bontril Timed No. 4 15 mg dexamphetamine with 60 mg butabarbital. Desbutal: combination 5 mg methamphetamine hydrochloride and 30 mg pentobarbital sodium, discontinued 1973 Dexamyl by Smith, Kline & French (tablets) and Dexytal by Eli Lilly & Co. (liquid elixir): dextroamphetamine and amobarbital sodium, discontinued 1982 Durophet M by/ Neisler Labs: combination of 6.5 mg levoamphetamine and 6.5 mg dextroamphetamine (13 mg racemic amphetamine) with 400 mg methaqualone hydrochloride; available in the United Kingdom until 1984, amidst international crackdown on methaqualone Durabond by Neisler Laboratories: Daprisal by GlaxoSmithKline: dextroamphetamine sulfate, 32.5 mg amobarbital sodium, and 162.5 mg aspirin Direcel combined dextroamphetamine, butabarbital, and carboxymethylcellulose; Direcel-T added thyroid hormone Duodex: combination of 16.25 mg aloin, 15 mg amphetamine sulfate, 16.25 mg pentobarbital, and thyroid hormone Dysonil: combination of methamphetamine hydrochloride, pentobarbital sodium, and salicylamide Edrisal: combination 160 mg aspirin and 160 mg phenacetin with 2.5 mg amphetamine sulfate; a formulation containing 16 mg codeine as an additional active ingredient was branded Edrisal with Codeine Elpanal Lamital by Teva Pharmaceuticals: combination of 500 mg acetaminophen, 15 mg amobarbital sodium, and 2.5 mg methamphetamine hydrochloride Esbelcap (fenproporex/diazepam): combination of 20 mg fenproporex with 6 mg diazepam; never approved foruse in the JU.S., but is available over the counter in [[Central America Central]] and South American countries until 2020 Eskatrol by Smith, French & Kline: combination of dextroamphetamine and prochlorperazine; discontinued 1981 Euphoramin: 5 mg methamphetamine hydrochloride and 300 mg meprobamate NalerTan by Neisler: combination of 12.5 mg dextroamphetamine tannate, 8 mg chlorpheniramine tannate, and 25 mg pyrilamine tannate Mandrax by Lemmon Company: methaqualone hydrochloride and diphenhydramine, commercially available in South Africa until 1990s Mediatric by Janssenr: combination of two hormones, 0.25 mg Premarin (Conjugated Estrogens USP) and 2.5 mg methyltestosterone, along with 100 mg vitamin c, b vitamins, and 1 mg methamphetamine hydrochloride Nexorin: combination of dextroamphetamine sulfate, amobarbital sodium, methylcellulose, and supplements Obocell by Neisler: combination of 5 mg dextroamphetamine phosphate and 25 mg methapyrilene phosphate; Obocell-TF was nearly identical but with an additional 160 mg high-viscosity methylcellulose Obetrol by Abbott Laboratories: combination of various mixed salts of the substances, methamphetamine and dextroamphetamine; discontinued in 1973 Obolip: dextroamphetamine and phenobarbital, with choline bitartrate, di-methionine, and methylcellulose Phelantin by Parke-Davis: combination of 100 mg phenytoin sodium, 32 mg pentobarbital sodium, and 2.5 mg methamphetamine hydrochloride. Phenephen: by A.H. Robins: combination of hyoscamine sulfate, phenacetin, and aspirin, Phenephen with Codeine by A.H. Robins: combination of hyoscamine sulfate, phenacetin, aspirin, codeine Pondimin (Fen-Phen): combination of fenfluramine and phentermine, discontinued 1997 SynaTan-S by Neisler Laboratories: combined 10 mg dextroamphetamine tannate with 35 mg secobarbital sodium, since 1955 OboTan-S: formerly SynaTan-S by Mallinckrodt: combination 10 mg dexamphetamine tannate and secobarbital sodium Pre M.T. by Behlen Manufacturing, a polypill and tablet containing: levoamphetamine sulfate, dextroamphetamine sulfate, pentobarbital sodium, pyrilamine maleate, and a micro-dose of theobromine. Reladorm by unknown domestic Russian manufacturer: combination of 100 mg cyclobarbital sodium and 10 mg diazepam, available in Russia until 2019 Tuinal by Abott: combination of two barbiturate salts, amobarbital and secobarbital; discontinued 1999 == Medical use and justification of discontinued combination drugs == Most of the combination drugs which have been discontinued since the twentieth century were simultaneously indicated and utilized for treatment of various conditions, with medical use justified as part of a multifaceted, comprehensive approach to patient health care and medical treatment. Central nervous system stimulants (colloquially called "uppers") were used as appetite suppressants, antidepressants, and wakefulness-promoting agents, and further effects include increased mental alertness and concentration/focus, as well as physical energy and motivation. The addition of a central nervous system depressant mitigated the stimulant's adverse effects without eliminating therapeutic benefits. In most cases, the "upper" component of these combination drugs was a salt, or mixed salts, of racemic amphetamine, dextroamphetamine, or methamphetamine, while the "downer" was typically one or more barbiturates (most commonly amobarbital, phenobarbital, pentobarbital, and/or secobarbital) or similar GABAergic, non-barbiturate tranquilizers or sedatives, frequently meprobamate or methaqualone, respectively, which provided anxiolytic, muscle relaxant, and hypnotic effects. Upper and downer combination drugs were often capable of substituting for Monoamine Oxidase Inhibitors (MAOIs) in patients with treatment-resistant depression where MAOIs are indicated, but where MAOI-related dietary restrictions would impact patient's life. Combination drugs offer the advantage over polypharmacy by decreasing patients' pill burden. Overall, giving patients the ability to take control and alleviate symptoms, and potentially treat or cure multiple conditions by consuming all of their medical treatments efficacious treatment options by the ingestion of a single pill, which consistently improves patient medication compliance by reducing their pill burden. The American Association of Orthodontists asserts that fixed-dose combinations "limit clinicians' ability to customize dosing regimens." Scientists formulating combination drugs face challenges in the development stages of multi-drug formulations such as compatibility issues among active ingredients and excipients affecting solubility and dissolution For prescribers, if one constituent of the combination is contraindicated for a patient, the product cannot be prescribed. === Limitations of currently-available combinations === The limitations of combination formulations currently available for treating a widely-inclusive collection of symptoms such as Tourette's is highlighted by there not being a polypill or any combination formula period approved for treating the condition. Medication available, and sometimes used in the context of polypharmacy involves various individual medicines for treating tics and/or generalized anxiety or social anxiety disorder and/or obsessive-compulsive anxieties with use of individual benzodiazepines or SSRIs for the former two conditions, and fluvoxamine or clomipramine first-line treatments for OCD and related disorders, such as hoarding or compulsive decluttering. But, where Attention-Deficit Hyperactivity Disorder, depression, or insomnia become a primary concern to the patient, it is only through polypharmacy (in this case, adding another antidepressant or a "booster, alongside a hypnotic soporific agent, and/or psychostimulants to both treat ADHD and counteract the sleep inertia, grogginess or hangover caused by the other evening medications). Tourette syndrome is a neurological tic disorder whose only FDA-approved treatment is the neuroleptic pimozide, a drug only used for tics due Tourette's disorder; every other treatment is an off-label use. While Tourette's is typically identified by chronic motor and vocal tics–"semi-voluntary" movements and noises made in response to a "premonitory urge," an internal buildup of compulsive tension that can only be temporarily upon performing/making the motion/sound demanded by compulsion. Tourette's, however, is an all-encompassing umbrella term that includes not just chronic physical and phonic tics, but also presents with such comorbid symptoms as anxiety (often OCD, social anxiety, schizoid personality, avoidant personality disorder, or generalized anxiety), ADHD, insomnia, depression, and traits of high-functioning autism formerly called Asperger syndrome. == Illicit streets as de facto drug combinations == === Illicit stimulants === Illicit combination drugs are often formulated as a powder, paste, or counterfeit "pressed" pills intended to resemble their pharmaceutical-grade counterparts. Since 2018, ABC News of Houston reports that product described as "powder cocaine" originating from a clandestine laboratory are increasingly analyzed and found to contain other stimulants, in order to mimic cocaine's effects in a cost-effective, deceptive manner; many of the batches analyzed did not contain any cocaine or coca alkaloids whatsoever; instead, they were blends of various designer drugs and research chemicals, typically synthetic cathinones, MDMA, methamphetamine, caffeine powder, ephedrine or pseudoephedrine; and in recent years, the flesh-eating veterinary antibiotic levamisole === Illicit depressants and opiates === Due to the crackdown of pill mills between 2007 and 2012, the opioid epidemic frequently includes drug deals whereby a substance may often be sold as "heroin" or legitimate pharmaceutical pills ("pressed," counterfeit, often adulterated pills). Mandrax in South Africa is now produced via clandestine chemistry as a free base form of methaqualone, which is smoked for a quick high. The proportion of cutting agents as part of a product's overall composition has increased greatly since 2013. Powder sold as "heroin" is often found to be "cut" or "adulterated" with central nervous system depressants as diverse as major tranquilizers and antipsychotics (e.g. quetiapine), first-generation antihistamines (e.g. diphenhydramine, meclizine, promethazine, pyrilamene, doxylamine, hydroxyzine), or benzodiazepine, barbiturate, or opiate derivative and analogs, often research chemicals, including clobromazolam and etizolam. Since 2020, there has been a noticeable rise amongst active ingredients in opioid combinations containing fentanyl. Since 2023, worldwide samples of illicit combinations featuring opioids have contained substances classified as nitazene. have been found in these opioid samples– all of which mimic the muscle relaxant, anxiolytic, and analgesic properties of pharmaceutical-grade opioid medications. U.S. Attorney General has indicated interested in federally regulating the relative mild veterinary sedative xylazine, which is currently available by prescription only, as a federally-controlled Schedule III controlled substance per the Controlled Substances Act, a direct response to its implication in overdose deaths featured in products alongside fentanyl and other power central nervous system depressants; xylazine is currently a controlled substance at the state level in Michigan and New York. == See also == Codrugs Synergy#Drug synergy == References == == External links == Media related to Combination drugs at Wikimedia Commons	Wikipedia/Combination_drug
Combination therapy or polytherapy is therapy that uses more than one medication or modality. Typically, the term refers to using multiple therapies to treat a single disease, and often all the therapies are pharmaceutical (although it can also involve non-medical therapy, such as the combination of medications and talk therapy to treat depression). 'Pharmaceutical' combination therapy may be achieved by prescribing/administering separate drugs, or, where available, dosage forms that contain more than one active ingredient (such as fixed-dose combinations). Polypharmacy is a related term, referring to the use of multiple medications (without regard to whether they are for the same or separate conditions/diseases). Sometimes "polymedicine" is used to refer to pharmaceutical combination therapy. Most of these kinds of terms lack a universally consistent definition, so caution and clarification are often advisable. == Uses == Conditions treated with combination therapy include tuberculosis, leprosy, cancer, malaria, and HIV/AIDS. One major benefit of combination therapies is that they reduce development of drug resistance since a pathogen or tumor is less likely to have resistance to multiple drugs simultaneously. Artemisinin-based monotherapies for malaria are explicitly discouraged to avoid the problem of developing resistance to the newer treatment. Combination therapy may seem costlier than monotherapy in the short term, but when it is used appropriately, it causes significant savings: lower treatment failure rate, lower case-fatality ratios, fewer side-effects than monotherapy, slower development of resistance, and thus less money needed for the development of new drugs. === In oncology === Combination therapy has gained momentum in oncology in recent years, with various studies demonstrating higher response rates with combinations of drugs compared to monotherapies, and the FDA recently approving therapeutic combination regimens that demonstrated superior safety and efficacy to monotherapies. In a recent study about solid cancers, Martin Nowak, Bert Vogelstein, and colleagues showed that in most clinical cases, combination therapies are needed to avoid the evolution of resistance to targeted drugs. Furthermore, they find that the simultaneous administration of multiple targeted drugs minimizes the chance of relapse when no single mutation confers cross-resistance to both drugs. Various systems biology methods must be used to discover combination therapies to overcome drug resistance in select cancer types. Recent precision medicine approaches have focused on targeting multiple biomarkers found in individual tumors by using combinations of drugs. However, with 300 FDA-approved cancer drugs on the market, there almost 45,000 possible two-drug combinations and almost 4.5 million three-drug combinations for to choose from. That level of complexity is one of the primary impediments to the growth of combination therapy in oncology. The National Cancer Institute has recently highlighted combination therapy as a top research priority in oncology. === Bacterial infections === Combination therapy with two or more antibiotics are often used in an effort to treat multi-drug resistant Gram-negative bacteria. == Contrast to monotherapy == Monotherapy, or the use of a single therapy, can be applied to any therapeutic approach, but it is most commonly used to describe the use of a single medication. Normally, monotherapy is selected because a single medication is adequate to treat the medical condition. However, monotherapies may also be used because of unwanted side effects or dangerous drug interactions. == See also == Polypill, a medication which contains a combination of multiple active ingredients Combination drug == References == == External links == Drug combination database. covers information on more than 1300 drug combinations in either clinical use or different testing stages. Perturbation biology method for the discovery of anti-resistance drug combinations with network pharmacology.	Wikipedia/Polytherapy
Psychotherapy (also psychological therapy, talk therapy, or talking therapy) is the use of psychological methods, particularly when based on regular personal interaction, to help a person change behavior, increase happiness, and overcome problems. Psychotherapy aims to improve an individual's well-being and mental health, to resolve or mitigate troublesome behaviors, beliefs, compulsions, thoughts, or emotions, and to improve relationships and social skills. Numerous types of psychotherapy have been designed either for individual adults, families, or children and adolescents. Some types of psychotherapy are considered evidence-based for treating diagnosed mental disorders; other types have been criticized as pseudoscience. There are hundreds of psychotherapy techniques, some being minor variations; others are based on very different conceptions of psychology. Most approaches involve one-to-one sessions, between the client and therapist, but some are conducted with groups, including couples and families. Psychotherapists may be mental health professionals such as psychiatrists, psychologists, mental health nurses, clinical social workers, marriage and family therapists, or licensed professional counselors. Psychotherapists may also come from a variety of other backgrounds, and depending on the jurisdiction may be legally regulated, voluntarily regulated or unregulated (and the term itself may be protected or not). It has shown general efficacy across a range of conditions, although its effectiveness varies by individual and condition. While large-scale reviews support its benefits, debates continue over the best methods for evaluating outcomes, including the use of randomized controlled trials versus individualized approaches. A 2022 umbrella review of 102 meta-analyses found that effect sizes for both psychotherapies and medications were generally small, leading researchers to recommend a paradigm shift in mental health research. Although many forms of therapy differ in technique, they often produce similar outcomes, leading to theories that common factors—such as the therapeutic relationship—are key drivers of effectiveness. Challenges include high dropout rates, limited understanding of mechanisms of change, potential adverse effects, and concerns about therapist adherence to treatment fidelity. Critics have raised questions about psychotherapy’s scientific basis, cultural assumptions, and power dynamics, while others argue it is underutilized compared to pharmacological treatments. == Definitions == The term psychotherapy is derived from Ancient Greek psyche (ψυχή meaning "breath; spirit; soul") and therapeia (θεραπεία "healing; medical treatment"). The Oxford English Dictionary defines it as "The treatment of disorders of the mind or personality by psychological means...", however, in earlier use, it denoted the treatment of disease through hypnotic suggestion. Psychotherapy is often dubbed as a "talking therapy" or "talk therapy", particularly for a general audience, though not all forms of psychotherapy rely on verbal communication. Children or adults who do not engage in verbal communication (or not in the usual way) are not excluded from psychotherapy; indeed some types are designed for such cases. The American Psychological Association adopted a resolution on the effectiveness of psychotherapy in 2012 based on a definition developed by American psychologist John C. Norcross: "Psychotherapy is the informed and intentional application of clinical methods and interpersonal stances derived from established psychological principles for the purpose of assisting people to modify their behaviors, cognitions, emotions, and/or other personal characteristics in directions that the participants deem desirable". Influential editions of a work by psychiatrist Jerome Frank defined psychotherapy as a healing relationship using socially authorized methods in a series of contacts primarily involving words, acts and rituals—which Frank regarded as forms of persuasion and rhetoric. Historically, psychotherapy has sometimes meant "interpretative" (i.e. Freudian) methods, namely psychoanalysis, in contrast with other methods to treat psychiatric disorders such as behavior modification. Some definitions of counseling overlap with psychotherapy (particularly in non-directive client-centered approaches), or counseling may refer to guidance for everyday problems in specific areas, typically for shorter durations with a less medical or "professional" focus. Somatotherapy refers to the use of physical changes as injuries and illnesses, and sociotherapy to the use of a person's social environment to effect therapeutic change. Psychotherapy may address spirituality as a significant part of someone's mental / psychological life, and some forms are derived from spiritual philosophies, but practices based on treating the spiritual as a separate dimension are not necessarily considered as traditional or 'legitimate' forms of psychotherapy. == Delivery == Psychotherapy may be delivered in person (one on one, or with couples, with families, or, in groups) or via telephone counseling or online counseling (see also § Telepsychotherapy). There have also been developments in computer-assisted therapy, such as virtual reality therapy for behavioral exposure, multimedia programs to teach cognitive techniques, and handheld devices for improved monitoring or putting ideas into practice (see also § Computer-supported). Most forms of psychotherapy use spoken conversation. Some also use various other forms of communication such as the written word, artwork, drama, narrative story or music. Psychotherapy with children and their parents often involves play, dramatization (i.e. role-play), and drawing, with a co-constructed narrative from these non-verbal and displaced modes of interacting. == Regulation == Psychotherapists traditionally may be mental health professionals like psychologists and psychiatrists; professionals from other backgrounds (family therapists, social workers, nurses, etc.) who have trained in a specific psychotherapy; or (in some cases) academic or scientifically trained professionals. In addition to the training, many countries require psychotherapist to register with a professional body in order to be permitted to offer services. Psychiatrists are trained first as physicians, and as such they may prescribe prescription medication; and specialist psychiatric training begins after medical school in psychiatric residencies: however, their specialty is in mental disorders or forms of mental illness. Clinical psychologists have specialist doctoral degrees in psychology with some clinical and research components. Other clinical practitioners, social workers, mental health counselors, pastoral counselors, and nurses with a specialization in mental health, also often conduct psychotherapy. Many of the wide variety of psychotherapy training programs and institutional settings are multi-professional. In most countries, psychotherapy training is completed at a postgraduate level, often at a master's degree (or doctoral) level, over four years, with significant clinical supervision and clinical placements. Mental health professionals that choose to specialize in psychotherapeutic work also require a program of continuing professional education after basic professional training. A listing of the extensive professional competencies of a European psychotherapist was developed by the European Association of Psychotherapy (EAP) in 2013. As sensitive and deeply personal topics are often discussed during psychotherapy, therapists are expected, and usually legally bound, to respect client or patient confidentiality. The critical importance of client confidentiality—and the limited circumstances in which it may need to be broken for the protection of clients or others—is enshrined in the regulatory psychotherapeutic organizations' codes of ethical practice. Examples of when it is typically accepted to break confidentiality include when the therapist has knowledge that a child or elder is being physically abused; when there is a direct, clear and imminent threat of serious physical harm to self or to a specific individual. In some countries psychotherapists are required by law to be mandated reporters. === Europe === As of 2015, there are still a lot of variations between different European countries about the regulation and delivery of psychotherapy. Several countries have no regulation of the practice or no protection of the title. Some have a system of voluntary registration, with independent professional organizations, while other countries attempt to restrict the practice of psychotherapy to 'mental health professionals' (psychologists and psychiatrists) with state-certified training. The titles that are protected also vary. The European Association for Psychotherapy (EAP) established the 1990 Strasbourg Declaration on Psychotherapy, which is dedicated to establishing an independent profession of psychotherapy in Europe, with pan-European standards. The EAP has already made significant contacts with the European Union & European Commission towards this end. Given that the European Union has a primary policy about the free movement of labor within Europe, European legislation can overrule national regulations that are, in essence, forms of restrictive practices. In Germany, the practice of psychotherapy for adults is restricted to qualified psychologists and physicians (including psychiatrists) who have completed several years of specialist practical training and certification in psychotherapy. As psychoanalysis, psychodynamic therapy, cognitive behavioral therapy, and systemic therapy meet the requirements of German health insurance companies, mental health professionals regularly opt for one of these four specializations in their postgraduate training. For psychologists, this includes three years of full-time practical training (4,200 hours), encompassing a year-long internship at an accredited psychiatric institution, six months of clinical work at an outpatient facility, 600 hours of supervised psychotherapy in an outpatient setting, and at least 600 hours of theoretical seminars. Social workers may complete the specialist training for child and teenage clients. Similarly in Italy, the practice of psychotherapy is restricted to graduates in psychology or medicine who have completed four years of recognised specialist training. Sweden has a similar restriction on the title "psychotherapist", which may only be used by professionals who have gone through a post-graduate training in psychotherapy and then applied for a licence, issued by the National Board of Health and Welfare. Legislation in France restricts the use of the title "psychotherapist" to professionals on the National Register of Psychotherapists, which requires a training in clinical psychopathology and a period of internship which is only open to physicians or titulars of a master's degree in psychology or psychoanalysis. Austria and Switzerland (2011) have laws that recognize multi-disciplinary functional approaches. In the United Kingdom, the government and Health and Care Professions Council considered mandatory legal registration but decided that it was best left to professional bodies to regulate themselves, so the Professional Standards Authority for Health and Social Care (PSA) launched an Accredited Voluntary Registers scheme. Counseling and psychotherapy are not protected titles in the United Kingdom. Counsellors and psychotherapists who have trained and qualify to a certain standard (usually a level 4 Diploma) can apply to be members of the professional bodies who are listed on the PSA Accredited Registers. === United States === In some states, counselors or therapists must be licensed to use certain words and titles on self-identification or advertising. In some other states, the restrictions on practice are more closely associated with the charging of fees. Licensing and regulation are performed by various states. Presentation of practice as licensed, but without such a license, is generally illegal. Without a license, for example, a practitioner cannot bill insurance companies. Information about state licensure of psychologists is provided by the American Psychological Association. In addition to state laws, the American Psychological Association requires its members to adhere to its published Ethical Principles of Psychologists and Code of Conduct. The American Board of Professional Psychology examines and certifies "psychologists who demonstrate competence in approved specialty areas in professional psychology". === Canada === Regulation of psychotherapy is in the jurisdiction of, and varies among, the provinces and territories. In Quebec, psychotherapy is a regulated activity which is restricted to psychologists, medical doctors, and holders of a psychotherapy permit issued by the Ordre des psychologues du Québec, the Quebec order of psychologists. Members of certain specified professions, including social workers, couple and family therapists, occupational therapists, guidance counsellors, criminologists, sexologists, psychoeducators, and registered nurses may obtain a psychotherapy permit by completing certain educational and practice requirements; their professional oversight is provided by their own professional orders. Some other professionals who were practising psychotherapy before the current system came into force continue to hold psychotherapy permits alone. On 1 July 2019, Ontario's Missing Persons Act came into effect, with the purpose of giving police more power to investigate missing persons. It allows police to require (as opposed to permit) health professionals, including psychotherapists, to share otherwise confidential documents about their client, if there is reason to believe their client is missing. Some have expressed concern that this legislation undermines psychotherapy confidentiality and could be abused maliciously by police, while others have praised the act for how it respects privacy and includes checks and balances. == History == Psychotherapy can be said to have been practiced through the ages, as medics, philosophers, spiritual practitioners and people in general used psychological methods to heal others. In the Western tradition, by the 19th century, a moral treatment movement (then meaning morale or mental) developed based on non-invasive non-restraint therapeutic methods. Another influential movement was started by Franz Mesmer (1734–1815) and his student Armand-Marie-Jacques de Chastenet, Marquis of Puységur (1751–1825). Called Mesmerism or animal magnetism, it would have a strong influence on the rise of dynamic psychology and psychiatry as well as theories about hypnosis. In 1853, Walter Cooper Dendy introduced the term "psycho-therapeia" regarding how physicians might influence the mental states of patients and thus their bodily ailments, for example by creating opposing emotions to promote mental balance. Daniel Hack Tuke cited the term and wrote about "psycho-therapeutics" in 1872 in his book Illustrations of the Influence of the Mind upon the Body in Health and Disease, in which he also proposed making a science of animal magnetism. Hippolyte Bernheim and colleagues in the "Nancy School" developed the concept of "psychotherapy" in the sense of using the mind to heal the body through hypnotism, yet further. Charles Lloyd Tuckey's 1889 work, Psycho-therapeutics, or Treatment by Hypnotism and Suggestion popularized the work of the Nancy School in English. Also in 1889 a clinic used the word in its title for the first time, when Frederik van Eeden and Albert Willem van Renterghem in Amsterdam renamed theirs "Clinique de Psycho-thérapeutique Suggestive" after visiting Nancy. During this time, travelling stage hypnosis became popular, and such activities added to the scientific controversies around the use of hypnosis in medicine. Also in 1892, at the second congress of experimental psychology, van Eeden attempted to take the credit for the term psychotherapy and to distance the term from hypnosis. In 1896, the German journal Zeitschrift für Hypnotismus, Suggestionstherapie, Suggestionslehre und verwandte psychologische Forschungen changed its name to Zeitschrift für Hypnotismus, Psychotherapie sowie andere psychophysiologische und psychopathologische Forschungen, which is probably the first journal to use the term. Thus psychotherapy initially meant "the treatment of disease by psychic or hypnotic influence, or by suggestion". Sigmund Freud visited the Nancy School and his early neurological practice involved the use of hypnotism. However following the work of his mentor Josef Breuer—in particular a case where symptoms appeared partially resolved by what the patient, Bertha Pappenheim, dubbed a "talking cure"—Freud began focusing on conditions that appeared to have psychological causes originating in childhood experiences and the unconscious mind. He went on to develop techniques such as free association, dream interpretation, transference and analysis of the id, ego and superego. His popular reputation as the father of psychotherapy was established by his use of the distinct term "psychoanalysis", tied to an overarching system of theories and methods, and by the effective work of his followers in rewriting history. Many theorists, including Alfred Adler, Carl Jung, Karen Horney, Anna Freud, Otto Rank, Erik Erikson, Melanie Klein and Heinz Kohut, built upon Freud's fundamental ideas and often developed their own systems of psychotherapy. These were all later categorized as psychodynamic, meaning anything that involved the psyche's conscious/unconscious influence on external relationships and the self. Sessions tended to number into the hundreds over several years. Behaviorism developed in the 1920s, and behavior modification as a therapy became popularized in the 1950s and 1960s. Notable contributors were Joseph Wolpe in South Africa, M.B. Shapiro and Hans Eysenck in Britain, and John B. Watson and B.F. Skinner in the United States. Behavioral therapy approaches relied on principles of operant conditioning, classical conditioning and social learning theory to bring about therapeutic change in observable symptoms. The approach became commonly used for phobias, as well as other disorders. Some therapeutic approaches developed out of the European school of existential philosophy. Concerned mainly with the individual's ability to develop and preserve a sense of meaning and purpose throughout life, major contributors to the field (e.g., Irvin Yalom, Rollo May) and Europe (Viktor Frankl, Ludwig Binswanger, Medard Boss, R.D.Laing, Emmy van Deurzen) attempted to create therapies sensitive to common "life crises" springing from the essential bleakness of human self-awareness, previously accessible only through the complex writings of existential philosophers (e.g., Søren Kierkegaard, Jean-Paul Sartre, Gabriel Marcel, Martin Heidegger, Friedrich Nietzsche). The uniqueness of the patient-therapist relationship thus also forms a vehicle for therapeutic inquiry. A related body of thought in psychotherapy started in the 1950s with Carl Rogers. Based also on the works of Abraham Maslow and his hierarchy of human needs, Rogers brought person-centered psychotherapy into mainstream focus. The primary requirement was that the client receive three core "conditions" from his counselor or therapist: unconditional positive regard, sometimes described as "prizing" the client's humanity; congruence [authenticity/genuineness/transparency]; and empathic understanding. This type of interaction was thought to enable clients to fully experience and express themselves, and thus develop according to their innate potential. Others developed the approach, like Fritz and Laura Perls in the creation of Gestalt therapy, as well as Marshall Rosenberg, founder of Nonviolent Communication, and Eric Berne, founder of transactional analysis. Later these fields of psychotherapy would become what is known as humanistic psychotherapy today. Self-help groups and books became widespread. During the 1950s, Albert Ellis originated rational emotive behavior therapy (REBT). Independently a few years later, psychiatrist Aaron T. Beck developed a form of psychotherapy known as cognitive therapy. Both of these included relatively short, structured and present-focused techniques aimed at identifying and changing a person's beliefs, appraisals and reaction-patterns, by contrast with the more long-lasting insight-based approach of psychodynamic or humanistic therapies. Beck's approach used primarily the socratic method, and links have been drawn between ancient stoic philosophy and these cognitive therapies. Cognitive and behavioral therapy approaches were increasingly combined and grouped under the umbrella term cognitive behavioral therapy (CBT) in the 1970s. Many approaches within CBT are oriented towards active/directive yet collaborative empiricism (a form of reality-testing), and assessing and modifying core beliefs and dysfunctional schemas. These approaches gained widespread acceptance as a primary treatment for numerous disorders. A "third wave" of cognitive and behavioral therapies developed, including acceptance and commitment therapy and dialectical behavior therapy, which expanded the concepts to other disorders and/or added novel components and mindfulness exercises. However the "third wave" concept has been criticized as not essentially different from other therapies and having roots in earlier ones as well. Counseling methods developed include solution-focused therapy and systemic coaching. Postmodern psychotherapies such as narrative therapy and coherence therapy do not impose definitions of mental health and illness, but rather see the goal of therapy as something constructed by the client and therapist in a social context. Systemic therapy also developed, which focuses on family and group dynamics—and transpersonal psychology, which focuses on the spiritual facet of human experience. Other orientations developed in the last three decades include feminist therapy, brief therapy, somatic psychology, expressive therapy, applied positive psychology and the human givens approach. A survey of over 2,500 US therapists in 2006 revealed the most utilized models of therapy and the ten most influential therapists of the previous quarter-century. == Types == There are hundreds of psychotherapy approaches or schools of thought. By 1980 there were more than 250; by 1996 more than 450; and at the start of the 21st century there were over a thousand different named psychotherapies—some being minor variations while others are based on very different conceptions of psychology, ethics (how to live) or technique. In practice therapy is often not of one pure type but draws from a number of perspectives and schools—known as an integrative or eclectic approach. The importance of the therapeutic relationship, also known as therapeutic alliance, between client and therapist is often regarded as crucial to psychotherapy. Common factors theory addresses this and other core aspects thought to be responsible for effective psychotherapy. Sigmund Freud (1856–1939), a Viennese neurologist who studied with Jean-Martin Charcot in 1885, is often considered the father of modern psychotherapy. His methods included analyzing his patient's dreams in search of important hidden insights into their unconscious minds. Other major elements of his methods, which changed throughout the years, included identification of childhood sexuality, the role of anxiety as a manifestation of inner conflict, the differentiation of parts of the psyche (id, ego, superego), transference and countertransference (the patient's projections onto the therapist, and the therapist's emotional responses to that). Some of his concepts were too broad to be amenable to empirical testing and invalidation, and he was critiqued for this by Jaspers. Numerous major figures elaborated and refined Freud's therapeutic techniques including Melanie Klein, Donald Winnicott, and others. Since the 1960s, however, the use of Freudian-based analysis for the treatment of mental disorders has declined substantially. Different types of psychotherapy have been created along with the advent of clinical trials to test them scientifically. These incorporate subjective treatments (after Beck), behavioral treatments (after Skinner and Wolpe) and additional time-constrained and centered structures, for example, interpersonal psychotherapy. In youth issue and in schizophrenia, the systems of family treatment hold esteem. A portion of the thoughts emerging from therapy are presently pervasive and some are a piece of the tool set of ordinary clinical practice. They are not just medications, they additionally help to understand complex conduct. Therapy may address specific forms of diagnosable mental illness, or everyday problems in managing or maintaining interpersonal relationships or meeting personal goals. A course of therapy may happen before, during or after pharmacotherapy (e.g. taking psychiatric medication). Psychotherapies are categorized in several different ways. A distinction can be made between those based on a medical model and those based on a humanistic model. In the medical model, the client is seen as unwell and the therapist employs their skill to help the client back to health. The extensive use of the DSM-IV, the diagnostic and statistical manual of mental disorders in the United States is an example of a medically exclusive model. The humanistic or non-medical model in contrast strives to depathologise the human condition. The therapist attempts to create a relational environment conducive to experiential learning and help build the client's confidence in their own natural process resulting in a deeper understanding of themselves. The therapist may see themselves as a facilitator/helper. Another distinction is between individual one-to-one therapy sessions, and group psychotherapy, including couples therapy and family therapy. Therapies are sometimes classified according to their duration; a small number of sessions over a few weeks or months may be classified as brief therapy (or short-term therapy), others, where regular sessions take place for years, may be classified as long-term. Some practitioners distinguish between more "uncovering" (or "depth") approaches and more "supportive" psychotherapy. Uncovering psychotherapy emphasizes facilitating the client's insight into the roots of their difficulties. The best-known example is classical psychoanalysis. Supportive psychotherapy by contrast stresses strengthening the client's coping mechanisms and often providing encouragement and advice, as well as reality-testing and limit-setting where necessary. Depending on the client's issues and situation, a more supportive or more uncovering approach may be optimal. === Humanistic === These psychotherapies, also known as "experiential", are based on humanistic psychology and emerged in reaction to both behaviorism and psychoanalysis, being dubbed the "third force". They are primarily concerned with the human development and needs of the individual, with an emphasis on subjective meaning, a rejection of determinism, and a concern for positive growth rather than pathology. Some posit an inherent human capacity to maximize potential, "the self-actualizing tendency"; the task of therapy is to create a relational environment where this tendency might flourish. Humanistic psychology can, in turn, be rooted in existentialism—the belief that human beings can only find meaning by creating it. This is the goal of existential therapy. Existential therapy is in turn philosophically associated with phenomenology. Person-centered therapy, also known as client-centered, focuses on the therapist showing openness, empathy and "unconditional positive regard", to help clients express and develop their own self. Humanistic Psychodrama (HPD) is based on the human image of humanistic psychology. So all rules and methods follow the axioms of humanistic psychology. The HPD sees itself as development-oriented psychotherapy and has completely moved away from the psychoanalytic catharsis theory. Self-awareness and self-realization are essential aspects in the therapeutic process. Subjective experiences, feelings and thoughts and one's own experiences are the starting point for a change or reorientation in experience and behavior in the direction of more self-acceptance and satisfaction. Dealing with the biography of the individual is closely related to the sociometry of the group. Gestalt therapy, originally called "concentration therapy", is an existential/experiential form that facilitates awareness in the various contexts of life, by moving from talking about relatively remote situations to action and direct current experience. Derived from various influences, including an overhaul of psychoanalysis, it stands on top of essentially four load-bearing theoretical walls: phenomenological method, dialogical relationship, field-theoretical strategies, and experimental freedom. A briefer form of humanistic therapy is the human givens approach, introduced in 1998–99. It is a solution-focused intervention based on identifying emotional needs—such as for security, autonomy and social connection—and using various educational and psychological methods to help people meet those needs more fully or appropriately. === Insight-oriented === Insight-oriented psychotherapies focus on revealing or interpreting unconscious processes. Most commonly referring to psychodynamic therapy, of which psychoanalysis is the oldest and most intensive form, these applications of depth psychology encourage the verbalization of all the patient's thoughts, including free associations, fantasies, and dreams, from which the analyst formulates the nature of the past and present unconscious conflicts which are causing the patient's symptoms and character problems. There are six main schools of psychoanalysis, which all influenced psychodynamic theory: Freudian, ego psychology, object relations theory, self psychology, interpersonal psychoanalysis, and relational psychoanalysis. Techniques for analytic group therapy have also developed. === Cognitive-behavioral === Behavior therapies use behavioral techniques, including applied behavior analysis (also known as behavior modification), to change maladaptive patterns of behavior to improve emotional responses, cognitions, and interactions with others. Functional analytic psychotherapy is one form of this approach. By nature, behavioral therapies are empirical (data-driven), contextual (focused on the environment and context), functional (interested in the effect or consequence a behavior ultimately has), probabilistic (viewing behavior as statistically predictable), monistic (rejecting mind-body dualism and treating the person as a unit), and relational (analyzing bidirectional interactions). Cognitive therapy focuses directly on changing the thoughts, in order to improve the emotions and behaviors. Cognitive behavioral therapy attempts to combine the above two approaches, focused on the construction and reconstruction of people's cognitions, emotions and behaviors. Generally in CBT, the therapist, through a wide array of modalities, helps clients assess, recognize and deal with problematic and dysfunctional ways of thinking, emoting and behaving. The concept of "third wave" psychotherapies reflects an influence of Eastern philosophy in clinical psychology, incorporating principles such as meditation into interventions such as mindfulness-based cognitive therapy, acceptance and commitment therapy, and dialectical behavior therapy for borderline personality disorder. Interpersonal psychotherapy (IPT) is a relatively brief form of psychotherapy (deriving from both CBT and psychodynamic approaches) that has been increasingly studied and endorsed by guidelines for some conditions. It focuses on the links between mood and social circumstances, helping to build social skills and social support. It aims to foster adaptation to current interpersonal roles and situations. Exposure and response prevention (ERP) is primarily deployed by therapists in the treatment of OCD. The American Psychiatric Association (APA) state that CBT drawing primarily on behavioral techniques (such as ERP) has the "strongest evidence base" among psychosocial interventions. By confronting feared scenarios (i.e., exposure) and refraining from performing rituals (i.e., responsive prevention), patients may gradually feel less distress in confronting feared stimuli, while also feeling less inclination to use rituals to relieve that distress. Typically, ERP is delivered in "hierarchical fashion", meaning patients confront increasingly anxiety-provoking stimuli as they progress through a course of treatment. Other types include reality therapy/choice theory, multimodal therapy, and therapies for specific disorders including PTSD therapies such as cognitive processing therapy, substance abuse therapies such as relapse prevention and contingency management; and co-occurring disorders therapies such as Seeking Safety. === Systemic === Systemic therapy seeks to address people not just individually, as is often the focus of other forms of therapy, but in relationship, dealing with the interactions of groups, their patterns and dynamics (includes family therapy and marriage counseling). Community psychology is a type of systemic psychology. The term group therapy was first used around 1920 by Jacob L. Moreno, whose main contribution was the development of psychodrama, in which groups were used as both cast and audience for the exploration of individual problems by reenactment under the direction of the leader. The more analytic and exploratory use of groups in both hospital and out-patient settings was pioneered by a few European psychoanalysts who emigrated to the US, such as Paul Schilder, who treated severely neurotic and mildly psychotic out-patients in small groups at Bellevue Hospital, New York. The power of groups was most influentially demonstrated in Britain during the Second World War, when several psychoanalysts and psychiatrists proved the value of group methods for officer selection in the War Office Selection Boards. A chance to run an Army psychiatric unit on group lines was then given to several of these pioneers, notably Wilfred Bion and Rickman, followed by S. H. Foulkes, Main, and Bridger. The Northfield Hospital in Birmingham gave its name to what came to be called the two "Northfield Experiments", which provided the impetus for the development since the war of both social therapy, that is, the therapeutic community movement, and the use of small groups for the treatment of neurotic and personality disorders. Today group therapy is used in clinical settings and in private practice settings. === Expressive === Expressive psychotherapy is a form of therapy that utilizes artistic expression (via improvisational, compositional, re-creative, and receptive experiences) as its core means of treating clients. Expressive psychotherapists use the different disciplines of the creative arts as therapeutic interventions. This includes the modalities dance therapy, drama therapy, art therapy, music therapy, writing therapy, among others. This may include techniques such as affect labeling. Expressive psychotherapists believe that often the most effective way of treating a client is through the expression of imagination in creative work and integrating and processing what issues are raised in the act. === Postmodernist === Also known as post-structuralist or constructivist. Narrative therapy gives attention to each person's "dominant story" through therapeutic conversations, which also may involve exploring unhelpful ideas and how they came to prominence. Possible social and cultural influences may be explored if the client deems it helpful. Coherence therapy posits multiple levels of mental constructs that create symptoms as a way to strive for self-protection or self-realization. Feminist therapy does not accept that there is one single or correct way of looking at reality and therefore is considered a postmodernist approach. === Other === Transpersonal psychology addresses the client in the context of a spiritual understanding of consciousness. Positive psychotherapy (PPT) (since 1968) is a method in the field of humanistic and psychodynamic psychotherapy and is based on a positive image of humans, with a health-promoting, resource-oriented and conflict-centered approach. Hypnotherapy is undertaken while a subject is in a state of hypnosis. Hypnotherapy is often applied in order to modify a subject's behavior, emotional content, and attitudes, as well as a wide range of conditions including: dysfunctional habits, anxiety, stress-related illness, pain management, and personal development. Psychedelic therapy are therapeutic practices involving psychedelic drugs, such as LSD, psilocybin, DMT, and MDMA. In psychedelic therapy, in contrast to conventional psychiatric medication taken by the patient regularly or as needed, patients generally remain in an extended psychotherapy session during the acute psychedelic activity with additional sessions both before and after in order to help integrate experiences with the psychedelics. Psychedelic therapy has been compared with the shamanic healing rituals of indigenous people. Researchers identified two main differences: the first is the shamanic belief that multiple realities exist and can be explored through altered states of consciousness, and second the belief that spirits encountered in dreams and visions are real. The charitable initiative Founders Pledge has written a research report on cost-effective giving opportunities for funding psychedelic-assisted mental health treatments. Body psychotherapy, part of the field of somatic psychology, focuses on the link between the mind and the body and tries to access deeper levels of the psyche through greater awareness of the physical body and emotions. There are various body-oriented approaches, such as Reichian (Wilhelm Reich) character-analytic vegetotherapy and orgonomy; neo-Reichian bioenergetic analysis; somatic experiencing; integrative body psychotherapy; Ron Kurtz's Hakomi psychotherapy; sensorimotor psychotherapy; Biosynthesis psychotherapy; and Biodynamic psychotherapy. These approaches are not to be confused with body work or body-therapies that seek to improve primarily physical health through direct work (touch and manipulation) on the body, rather than through directly psychological methods. Some non-Western indigenous therapies have been developed. In African countries this includes harmony restoration therapy, meseron therapy and systemic therapies based on the Ubuntu philosophy. Integrative psychotherapy is an attempt to combine ideas and strategies from more than one theoretical approach. These approaches include mixing core beliefs and combining proven techniques. Forms of integrative psychotherapy include multimodal therapy, the transtheoretical model, cyclical psychodynamics, systematic treatment selection, cognitive analytic therapy, internal family systems model, multitheoretical psychotherapy and conceptual interaction. In practice, most experienced psychotherapists develop their own integrative approach over time. === Child === Psychotherapy needs to be adapted to meet the developmental needs of children. Depending on age, it is generally held to be one part of an effective strategy to help the needs of a child within the family setting. Child psychotherapy training programs necessarily include courses in human development. Since children often do not have the ability to articulate thoughts and feelings, psychotherapists will use a variety of media such as musical instruments, sand and toys, crayons, paint, clay, puppets, bibliocounseling (books), or board games. The use of play therapy is often rooted in psychodynamic theory, but other approaches also exist. In addition to therapy for the child, sometimes instead of it, children may benefit if their parents work with a therapist, take parenting classes, attend grief counseling, or take other action to resolve stressful situations that affect the child. Parent management training is a highly effective form of psychotherapy that teaches parenting skills to reduce their child's behavior problems. In many cases a different psychotherapist will work with the care taker of the child, while a colleague works with the child. Therefore, contemporary thinking on working with the younger age group has leaned towards working with parent and child simultaneously, as well as individually as needed. == Computer-supported == Research on computer-supported and computer-based interventions has increased significantly over the course of the last two decades. The following applications frequently have been investigated: Virtual reality: VR is a computer-generated scenario that simulates experience. The immersive environment, used for simulated exposure, can be similar to the real world or it can be fantastical, creating a new experience. Computer-based interventions (or online interventions or internet interventions): These interventions can be described as interactive self-help. They usually entail a combination of text, audio or video elements. Computer-supported therapy (or blended therapy): Classical psychotherapy is supported by means of online or software application elements. The feasibility of such interventions has been investigated for individual and group therapy. === Telepsychotherapy === == Effects == === Efficacy === There is considerable controversy about whether, or when, psychotherapy efficacy is best evaluated by randomized controlled trials or more individualized idiographic methods. One issue with trials is what to use as a placebo treatment group or non-treatment control group. Often, this group includes patients on a waiting list, or those receiving some kind of regular non-specific contact or support. Researchers must consider how best to match the use of inert tablets or sham treatments in placebo-controlled studies in pharmaceutical trials. Several interpretations and differing assumptions and language remain. Another issue is the attempt to standardize and manualize therapies and link them to specific symptoms of diagnostic categories, making them more amenable to research. Some report that this may reduce efficacy or gloss over individual needs. Fonagy and Roth's opinion is that the benefits of the evidence-based approach outweighs the difficulties. There are several formal frameworks for evaluating whether a psychotherapist is a good fit for a patient. One example is the Scarsdale Psychotherapy Self-Evaluation (SPSE). However, some scales, such as the SPS, elicit information specific to certain schools of psychotherapy alone (e.g. the superego). Many psychotherapists believe that the nuances of psychotherapy cannot be captured by questionnaire-style observation, and prefer to rely on their own clinical experiences and conceptual arguments to support the type of treatment they practice. Psychodynamic therapists increasingly believe that evidence-based approaches are appropriate to their methods and assumptions, and have increasingly accepted the challenge to implement evidence-based approaches in their methods. A pioneer in investigating the results of different psychological therapies was psychologist Hans Eysenck, who argued that psychotherapy does not produce any improvement in patients. He held that behavior therapy is the only effective one. However, it was revealed that Eysenck (who died in 1997) falsified data in his studies about this subject, fabricating data that would indicate that behavioral therapy enables achievements that are impossible to believe. Fourteen of his papers were retracted by journals in 2020, and journals issued 64 statements of concern about publications by him. Rod Buchanan, a biographer of Eysenck, has argued that 87 publications by Eysenck should be retracted. The response rate of psychotherapy varies, no reliable changes due to psychotherapy can be found in up to 33% of patients. ==== Comparison with other treatments ==== Large-scale international reviews of scientific studies have concluded that psychotherapy is effective for numerous conditions. A 2022 umbrella review of 102 meta-analyses found that most effect sizes reported for both psychotherapies and pharmacotherapies, compared to treatment-as-usual or placebo, were small for most disorders and treatments, and concluded that a "paradigm shift in research" was needed to advance the field and improve treatment strategies for mental disorders. One line of research consistently found that supposedly different forms of psychotherapy show similar effectiveness. According to the 2008 edition of The Handbook of Counseling Psychology: "Meta-analyses of psychotherapy studies have consistently demonstrated that there are no substantial differences in outcomes among treatments". The handbook stated that "little evidence suggests that any one treatment consistently outperforms any other for any specific psychological disorders". This is sometimes called the Dodo bird verdict after a scene/section in Alice in Wonderland where every competitor in a race was called a winner and is given prizes. Further analyses seek to identify the factors that the psychotherapies have in common that seem to account for this, known as common factors theory; for example the quality of the therapeutic relationship, interpretation of problem, and the confrontation of painful emotions. Outcome studies have been critiqued for being too removed from real-world practice in that they use carefully selected therapists who have been extensively trained and monitored, and patients who may be non-representative of typical patients by virtue of strict inclusionary/exclusionary criteria. Such concerns impact the replication of research results and the ability to generalize from them to practicing therapists. However, specific therapies have been tested for use with specific disorders, and regulatory organizations in both the UK and US make recommendations for different conditions. The Helsinki Psychotherapy Study was one of several large long-term clinical trials of psychotherapies that have taken place. Anxious and depressed patients in two short-term therapies (solution-focused and brief psychodynamic) improved faster, but five years long-term psychotherapy and psychoanalysis gave greater benefits. Several patient and therapist factors appear to predict suitability for different psychotherapies. Meta-analyses have established that cognitive behavioural therapy (CBT) and psychodynamic psychotherapy are equally effective in treating depression. A 2014 meta analysis over 11,000 patients reveals that Interpersonal Psychotherapy (IPT) is of comparable effectiveness to CBT for depression but is inferior to the latter for eating disorders. For children and adolescents, interpersonal psychotherapy and CBT are the best methods according to a 2014 meta analysis of almost 4000 patients. === Adverse effects === Research on adverse effects of psychotherapy has been limited, yet worsening of symptoms may be expected to occur in 3% to 15% of patients, with variability across patient and therapist characteristics. Potential problems include deterioration of symptoms or developing new symptoms, strains in other relationships, social stigma, and therapy dependence. Some techniques or therapists may carry more risks than others, and some client characteristics may make them more vulnerable. Side-effects from properly conducted therapy should be distinguished from harms caused by malpractice. === Adherence === Patient adherence to a course of psychotherapy—continuing to attend sessions or complete tasks—is a major issue. The dropout level—early termination—ranges from around 30% to 60%, depending partly on how it is defined. The range is lower for research settings for various reasons, such as the selection of clients and how they are inducted. Early termination is associated on average with various demographic and clinical characteristics of clients, therapists and treatment interactions. The high level of dropout has raised some criticism about the relevance and efficacy of psychotherapy. Most psychologists use between-session tasks in their general therapy work, and cognitive behavioral therapies in particular use and see them as an "active ingredient". It is not clear how often clients do not complete them, but it is thought to be a pervasive phenomenon. From the other side, the adherence of therapists to therapy protocols and techniques—known as "treatment integrity" or "fidelity"—has also been studied, with complex mixed results. In general, however, it is a hallmark of evidence-based psychotherapy to use fidelity monitoring as part of therapy outcome trials and ongoing quality assurance in clinical implementation. === Mechanisms of change === It is not yet understood how psychotherapies can succeed in treating mental illnesses. Different therapeutic approaches may be associated with particular theories about what needs to change in a person for a successful therapeutic outcome. In general, processes of emotional arousal and memory have long been held to play an important role. One theory combining these aspects proposes that permanent change occurs to the extent that the neuropsychological mechanism of memory reconsolidation is triggered and is able to incorporate new emotional experiences. === General critiques === Some critics are skeptical of the healing power of psychotherapeutic relationships. Some dismiss psychotherapy altogether in the sense of a scientific discipline requiring professional practitioners, instead favoring either nonprofessional help or biomedical treatments. Others have pointed out ways in which the values and techniques of therapists can be harmful as well as helpful to clients (or indirectly to other people in a client's life). Many resources available to a person experiencing emotional distress—the friendly support of friends, peers, family members, clergy contacts, personal reading, healthy exercise, research, and independent coping—all present considerable value. Critics note that humans have been dealing with crises, navigating severe social problems and finding solutions to life problems long before the advent of psychotherapy. On the other hand, some argue psychotherapy is under-utilized and under-researched by contemporary psychiatry despite offering more promise than stagnant medication development. In 2015, the US National Institute of Mental Health allocated only 5.4% of its budget to new clinical trials of psychotherapies (medication trials are largely funded by pharmaceutical companies), despite plentiful evidence they can work and that patients are more likely to prefer them. Further critiques have emerged from feminist, constructionist and discourse-analytical sources. Key to these is the issue of power. In this regard there is a concern that clients are persuaded—both inside and outside the consulting room—to understand themselves and their difficulties in ways that are consistent with therapeutic ideas. This means that alternative ideas (e.g., feminist, economic, spiritual) are sometimes implicitly undermined. Critics suggest that we idealize the situation when we think of therapy only as a helping relationship—arguing instead that it is fundamentally a political practice, in that some cultural ideas and practices are supported while others are undermined or disqualified, and that while it is seldom intended, the therapist–client relationship always participates in society's power relations and political dynamics. A noted academic who espoused this criticism was Michel Foucault. == See also == Improving Access to Psychological Therapies – United Kingdom initiative to improve access to psychological therapiesPages displaying wikidata descriptions as a fallback List of psychotherapy journals Physical therapy – Profession that helps a disabled person function in everyday life Psychosomatic medicine – Interdisciplinary medical field exploring various influences on bodily processes == References == == Further reading == Bartlett, Steven J. (1987). When You Don't Know Where to Turn: A Self-diagnosing Guide to Counseling and Therapy. Contemporary Books. ISBN 9780809248292. Bloch, Sidney (2006). Introduction to the Psychotherapies (4th ed.). Oxford University Press. ISBN 0198520921. Carter, Robert T., ed. (2005). Handbook of Racial-Cultural Psychology and Counseling. OCLC 54905669. Two volumes. Corey, Gerald (2015). Theory and Practice of Counseling and Psychotherapy (10th ed.). Cengage Learning. ISBN 9781305263727. Cozolino, Louis (2017). The Neuroscience of Psychotherapy: Healing the Social Brain (3rd ed.). National Geographic Books. ISBN 9780393712643. DeBord, Kurt A.; Fischer, Ann R.; Bieschke, Kathleen J.; Perez, Ruperto M., eds. (2017). Handbook of Sexual Orientation and Gender Diversity in Counseling and Psychotherapy. American Psychological Association. ISBN 9781433823060. Foschi, Renato; Innamorati, Marco (2023). A Critical History of Psychotherapy. Routledge, Taylor & Francis. ISBN 9781032364025. Two volumes. Hofmann, Stefan G., ed. (2017). International Perspectives on Psychotherapy. Springer. ISBN 9783319561936. Jongsma, Arthur E.; Peterson, L. Mark; Bruce, Timothy J. (2021). The Complete Adult Psychotherapy Treatment Planner (6th ed.). John Wiley & Sons. ISBN 978-1118067864. McAuliffe, Garrett J., ed. (2021). Culturally Alert Counseling: A Comprehensive Introduction (3rd ed.). SAGE Publications. ISBN 9781483378213. Prochaska, James O.; Norcross, John C. (2018). Systems of Psychotherapy: A Transtheoretical Analysis (9th ed.). Oxford University Press. ISBN 9780190880415. Rastogi, Mudita; Wieling, Elizabeth, eds. (2005). Voices of Color: First-Person Accounts of Ethnic Minority Therapists. ISBN 0761928901. Slavney, Phillip R. (2005). Psychotherapy: An Introduction for Psychiatry Residents and Other Mental Health Trainees. JHU Press. ISBN 0801880963. Wampold, Bruce E. (2019). The Basics of Psychotherapy: An Introduction to Theory and Practice (2nd ed.). American Psychological Association. ISBN 9781433830198.	Wikipedia/Talk_therapy
PKPD modeling (pharmacokinetic pharmacodynamic modeling) (alternatively abbreviated as PK/PD or PK-PD modeling) is a technique that combines the two classical pharmacologic disciplines of pharmacokinetics and pharmacodynamics. It integrates a pharmacokinetic and a pharmacodynamic model component into one set of mathematical expressions that allows the description of the time course of effect intensity in response to administration of a drug dose. PKPD modeling is related to the field of pharmacometrics. Central to PKPD models is the concentration-effect or exposure-response relationship. A variety of PKPD modeling approaches exist to describe exposure-response relationships. PKPD relationships can be described by simple equations such as linear model, Emax model or sigmoid Emax model. However, if a delay is observed between the drug administration and the drug effect, a temporal dissociation needs to be taken into account and more complex models exist: Direct vs Indirect link PKPD models Direct vs Indirect response PKPD models Time variant vs time invariant Cell lifespan models Complex response models PKPD modeling has its importance at each step of the drug development and it has shown its usefulness in many diseases. The Food and Drug Administration also provides guidances for Industry to recommend how exposure-response studies should be performed. == References ==	Wikipedia/PK/PD_models
Toxicodynamics, termed pharmacodynamics in pharmacology, describes the dynamic interactions of a toxicant with a biological target and its biological effects. A biological target, also known as the site of action, can be binding proteins, ion channels, DNA, or a variety of other receptors. When a toxicant enters an organism, it can interact with these receptors and produce structural or functional alterations. The mechanism of action of the toxicant, as determined by a toxicant’s chemical properties, will determine what receptors are targeted and the overall toxic effect at the cellular level and organismal level. Toxicants have been grouped together according to their chemical properties by way of quantitative structure-activity relationships (QSARs), which allows prediction of toxic action based on these properties. endocrine disrupting chemicals (EDCs) and carcinogens are examples of classes of toxicants that can act as QSARs. EDCs mimic or block transcriptional activation normally caused by natural steroid hormones. These types of chemicals can act on androgen receptors, estrogen receptors and thyroid hormone receptors. This mechanism can include such toxicants as dichlorodiphenyltrichloroethane (DDE) and polychlorinated biphenyls (PCBs). Another class of chemicals, carcinogens, are substances that cause cancer and can be classified as genotoxic or nongenotoxic carcinogens. These categories include toxicants such as polycyclic aromatic hydrocarbon (PAHs) and carbon tetrachloride (CCl4). The process of toxicodynamics can be useful for application in environmental risk assessment by implementing toxicokinetic-toxicodynamic (TKTD) models. TKTD models include phenomenas such as time-varying exposure, carry-over toxicity, organism recovery time, effects of mixtures, and extrapolation to untested chemicals and species. Due to their advantages, these types of models may be more applicable for risk assessment than traditional modeling approaches. == Overview == While toxicokinetics describes the changes in the concentrations of a toxicant over time due to the uptake, biotransformation, distribution and elimination of toxicants, toxicodynamics involves the interactions of a toxicant with a biological target and the functional or structural alterations in a cell that can eventually lead to a toxic effect. Depending on the toxicant’s chemical reactivity and vicinity, the toxicant may be able to interact with the biological target. Interactions between a toxicant and the biological target may also be more specific, where high-affinity binding sites increase the selectivity of interactions. For this reason, toxicity may be expressed primarily in certain tissues or organs. The targets are often receptors on the cell surface or in the cytoplasm and nucleus. Toxicants can either induce an unnecessary response or inhibit a natural response, which can cause damage. If the biological target is critical and the damage is severe enough, irreversible injury can occur first at the molecular level, which will translate into effects at higher levels of organization. == Endocrine disruptors == EDCs are generally considered to be toxicants that either mimic or block the transcriptional activation normally caused by natural steroid hormones. These chemicals include those acting on androgen receptors, estrogen receptors and thyroid hormone receptors. === Effects of endocrine disruptors === Endocrine disrupting chemicals can interfere with the endocrine system in a number of ways including hormone synthesis, storage/release, transport and clearance, receptor recognition and binding, and postreceptor activation. In wildlife, exposure to EDCs can result in altered fertility, reduced viability of offspring, impaired hormone secretion or activity and modified reproductive anatomy. The reproductive anatomy of offspring can particularly be affected if maternal exposure occurs. In females, this includes mammary glands, fallopian tubes, uterus, cervix, and vagina. In males, this includes the prostate, seminal vesicles, epididymitis and testes. Exposure of fish to EDCs has also been associated with abnormal thyroid function, decreased fertility, decreased hatching success, de-feminization and masculinization of female fish and alteration of immune function. Endocrine disruption as a mode of action for xenobiotics was brought into awareness by Our Stolen Future by Theo Colborn. Endocrine disrupting chemicals are known to accumulate in body tissue and are highly persistent in the environment. Many toxicants are known EDCs including pesticides, phthalates, phytoestrogens, some industrial/commercial products, and pharmaceuticals. These chemicals are known to cause endocrine disruption via a few different mechanisms. While the mechanism associated with the thyroid hormone receptor is not well understood, two more established mechanisms involve the inhibition of the androgen receptor and activation of the estrogen receptor. === Androgen-receptor mediated === Certain toxicants act as endocrine disruptors by interacting with the androgen receptor. DDE is one example of a chemical that acts via this mechanism. DDE is a metabolite of DDT that is widespread in the environment. Although production of DDT has been banned in the Western world, this chemical is extremely persistent and is still commonly found in the environment along with its metabolite DDE. DDE is an antiandrogen, which means it alters the expression of specific androgen-regulated genes, and is an androgen receptor (AR)-mediated mechanism. DDE is a lipophilic compound which diffuses into the cell and binds to the AR. Through binding, the receptor is inactivated and cannot bind to the androgen response element on DNA. This inhibits the transcription of androgen-responsive genes which can have serious consequences for exposed wildlife. In 1980, there was a spill in Lake Apopka, Florida which released the pesticide dicofol and DDT along with its metabolites. The neonatal and juvenile alligators present in this lake have been extensively studied and observed to have altered plasma hormone concentrations, decreased clutch viability, increased juvenile mortality, and morphological abnormalities in the testis and ovary. === Estrogen-receptor mediated === Toxicants may also cause endocrine disruption through interacting with the estrogen receptor. This mechanism has been well-studied with PCBs. These chemicals have been used as coolants and lubricants in transformers and other electrical equipment due to their insulating properties. A purely anthropogenic substance, PCBs are no longer in production in the United States due to the adverse health effects associated with exposure, but they are highly persistent and are still widespread in the environment. PCBs are a xenoestrogen, which elicit an enhancing (rather than inhibiting) response, and are mediated by the estrogen receptor. These are often referred to as estrogen mimics because they mimic the effects of estrogen. PCBs often build up in sediments and bioaccumulate in organisms. These chemicals diffuse into the nucleus and bind to the estrogen receptor. The estrogen receptor is kept in an inactive conformation through interactions with proteins such as heat shock proteins 59, 70, and 90. After the toxicant binding occurs, the estrogen receptor is activated and forms a homodimer complex which seeks out estrogen response elements in the DNA. The binding of the complex to these elements causes a rearrangement of the chromatin and transcription of the gene, resulting in production of a specific protein. In doing this, PCBs elicit an estrogenic response which can affect numerous functions within the organism. These effects are observed in various aquatic species. The levels of PCBs in marine mammals are often very high as a result of bioaccumulation. Studies have demonstrated that PCBs are responsible for reproductive impairment in the harbor seal (Phoca vitulina). Similar effects have been found in the grey seal (Halichoerus grypus), the ringed seal (Pusa hispida) and the California sea lion (Zalophys californianus). In the grey seals and ringed seals, uterine occlusions and stenosis were found which led to sterility. If exposed to a xenoestrogen such as PCBs, male fish have also been seen to produce vitellogenin. Vitellogenin is an egg protein female fish normally produce but is not usually present in males except at very low concentrations. This is often used as a biomarker for EDCs. == Carcinogens == Carcinogens are defined as any substance that causes cancer. The toxicodynamics of carcinogens can be complex due to the varying mechanisms of action for different carcinogenic toxicants. Because of their complex nature, carcinogens are classified as either genotoxic or nongenotoxic carcinogens. === Effects of carcinogens === The effects of carcinogens are most often related to human exposures but mammals are not the only species that can be affected by cancer-causing toxicants. Many studies have shown that cancer can develop in fish species as well. Neoplasms occurring in epithelial tissue such as the liver, gastrointestinal tract, and the pancreas have been linked to various environmental toxicants. Carcinogens preferentially target the liver in fish and develop hepatocellular and biliary lesions. === Genotoxic carcinogens === Genotoxic carcinogens interact directly with DNA and genetic material or indirectly by their reactive metabolites. Toxicants such as PAHs can be genotoxic carcinogens to aquatic organisms. PAHs are widely spread throughout the environment through the incomplete burning of coal, wood, or petroleum products. Although PAHs do not bioaccumulate in vertebrate tissue, many studies have confirmed that certain PAH compounds such as benzo(a)pyrene, benz(a)anthracene, and Benzofluoranthene, are bioavailable and responsible for liver diseases like cancer in wild fish populations. One mechanism of action for genotoxic carcinogens includes the formation of DNA adducts. Once the PAH compound enters an organism, it becomes metabolized and available for biotransformation. The biotransformation process can activate the PAH compound and transform it into a diol epoxide, which is a very reactive intermediate. These diol-epoxides covalently bind with DNA base pairs, most often with guanine and adenine to form stable adducts within the DNA structure. The binding of diol epoxides and DNA base pairs blocks polymerase replication activity. This blockage ultimately contributes to an increase in DNA damage by reducing repair activity. Due to these processes, PAH compounds are thought to play a role in the initiation and early promotion stage of carcinogenesis. Fish exposed to PAHs develop a range of liver lesions, some of which are characteristic of hepatocarcinogenicity. === Nongenotoxic carcinogens === Nongenotoxic, or epigenetic carcinogens are different and slightly more ambiguous than genotoxic carcinogens since they are not directly carcinogenic. Nongenotoxic carcinogens act by secondary mechanisms that do not directly damage genes. This type of carcinogenesis does not change the sequence of DNA; instead it alters the expression or repression of certain genes by a wide variety of cellular processes. Since these toxicants do not directly act on DNA, little is known about the mechanistic pathway. It has been proposed that modification of gene expression from nongenotoxic carcinogens can occur by oxidative stress, peroxisome proliferation, suppression of apoptosis, alteration of intercellular communication, and modulation of metabolizing enzymes. Carbon tetrachloride is an example of a probable nongenotoxic carcinogen to aquatic vertebrates. Historically, carbon tetrachloride has been used in pharmaceutical production, petroleum refining, and as an industrial solvent. Due to its widespread industrial use and release into the environment, carbon tetrachloride has been found in drinking water and therefore, has become a concern for aquatic organisms. Because of its high hepatotoxic properties, carbon tetrachloride could potentially be linked to liver cancer. Experimental cancer studies have shown that carbon tetrachloride may cause benign and malignant liver tumors to rainbow trout. carbon tetrachloride works as a nongenotoxic carcinogen by formulating free radicals which induce oxidative stress. It has been proposed that once carbon tetrachloride enters the organism, it is metabolized to trichloromethyl and trichloromethyl peroxy radicals by the CYP2E1 enzyme. The more reactive radical, trichloromethyl peroxy, can attack polyunsaturated fatty acids in the cellular membrane to form fatty acid free radicals and initiate lipid peroxidation. The attack on the cellular membrane increases its permeability, causing a leakage of enzymes and disrupts cellular calcium homeostasis. This loss of calcium homeostasis activates calcium dependent degradative enzymes and cytotoxicity, causing hepatic damage. The regenerative and proliferative changes that occur in the liver during this time could increase the frequency of genetic damage, resulting in a possible increase of cancer. == Applications == Toxicodynamics can be used in combination with toxicokinetics in environmental risk assessment to determine the potential effects of releasing a toxicant into the environment. The most widely used method of incorporating this are TKTD models. === Setup of TKTD models === Both toxicokinetics and toxicodynamics have now been described, and using these definitions models were formed, where the internal concentration (TK) and damage (TD) are simulated in response to exposure. TK and TD are separated in the model to allow for the identification of properties of toxicants that determine TK and those that determine TD. To use this type of model, parameter values for TK processes need to be obtained first. Second, the TD parameters need to be estimated. Both of these steps require a large database of toxicity information for parameterization. After establishing all the parameter values for the TKTD model, and using basic scientific precautions, the model can be used to predict toxic effects, calculate recovery times for organisms, or establish extrapolations from the model to toxicity of untested toxicants and species. === History of TKTD models === It has been argued that the current challenges facing risk assessments can be addressed with TKTD modeling. TKTD models were derived in response to a couple of factors. One is the lack of time being considered as a factor in toxicity and risk assessment. Some of the earliest developed TKTD models, such as the Critical Body Residue (CBR) model and Critical Target Occupation (CTO) model, have considered time as a factor but a criticism has been that they are for very specific circumstances such as reversibly acting toxicants or irreversibly acting toxicants. Further extrapolation of the CTO and CBR models are DEBtox, which can model sublethal endpoints, and hazard versions of the CTO, which takes into account stochastic death as opposed to individual tolerance. Another significant step to developing TKTD models was the incorporation of a state variable for damage. By using damage as a toxicodynamic state-variable, modeling intermediate recovery rates can be accomplished for toxicants that act reversibly with their targets, without the assumptions of instant recovery (CBR model) or irreversible interactions (CTO model). TKTD models that incorporate damage are the Damage Assessment Model (DAM) and the Threshold Damage Model (TDM). For what may seem like straightforward endpoints, a variety of different TKTD approaches exist. A review of the assumptions and hypotheses of each was previously published in the creation of a general unified threshold model of survival (GUTS). === Advantages for risk assessment === As referenced above, TKTD models have several advantages to traditional models for risk assessments. The principal advantages to using TKTD models are: The consequences of time-varying or repeated exposures can be explained and simulated by the TKTD model. Carry-over toxicity as well as delayed effects can be simulated, whether the carry-over toxicity is due to TK or TD or both. In this way, TKTD models can quantify risks from pulsed or fluctuating exposures. Organism recovery time depends on the time course of TK and TD, which makes the TKTD models suitable for calculating organism recovery time. TKTD models have the potential to predict effects of mixtures, including both environmental and chemical stressors and also be used as mechanism-based extrapolation to untested toxicants or untested species. Linking TKTD models with Individual Based Models (IBM) may improve risk assessment of toxicants by simulating temporal aspects as well as ecological aspects. Due to its advantages, TKTD models may be more powerful than the traditional dose-response models because of their incorporation of chemical concentrations as well as temporal dimensions. Toxicodynamic modeling (such as TKTD models) has been shown to be a useful tool for toxicological research, with increasing opportunities to use these results in risk assessment to permit a more scientifically based risk assessment that is less reliable on animal testing. Overall, these types of models can formalize knowledge about the toxicity of toxicants and organism sensitivity, create new hypotheses, and simulate temporal aspects of toxicity, making them useful tools for risk assessment. == See also == Ecotoxicology == Notes == == References == Ashauer, Roman; Escher, Beate I. (2010). "Advantages of toxicokinetic and toxicodynamic modelling in aquatic ecotoxicology and risk assessment". Journal of Environmental Monitoring. 12 (11): 2056–2061. doi:10.1039/c0em00234h. PMID 20862435. Ashauer, Roman; Hintermeister, Anita; Caravatti, Ivo; Kretschmann, Andreas; Escher, Beate I (15 May 2010). "Toxicokinetic and Toxicodynamic Modeling Explains Carry-over Toxicity from Exposure to Diazinon by Slow Organism Recovery". Environmental Science & Technology. 44 (10): 3963–3971. Bibcode:2010EnST...44.3963A. doi:10.1021/es903478b. PMID 20397634. Ashauer R, Albert C, Augustine S, Cedergreen N, Charles, S, Ducrot V, Focks A, Gabsi, F, Gergs, A, Goussen, B, Jager, T, Kramer, N. I, Nyman, A.-M, Poulsen, V, Reichenberger, S, Schäfer, R.B, Van den Brink, P.J, Veltman, K, Vogel, S, Zimmer, E.I, Preuss, T. G. 2016. Modelling survival: exposure pattern, species sensitivity and uncertainty. Scientific Reports 6:29178 doi:10.1038/srep29178 ATSDR. Agency for Toxic Substances and Disease Registry. ToxFAQs™ for Polychlorinated Biphenyls (PCBs). Web. <https://wwwn.cdc.gov/TSP/ToxFAQs/ToxFAQsLanding.aspx?id=140&tid=26>. Blaauboer B. 2003. Biokinetic and Toxicodynamic modeling and its role in toxicological research and risk assessment. Alternatives to Laboratory Animals 31: 277-281. Boelsterli, Urs. Mechanistic Toxicology: The molecular basis of how chemicals disrupt biological targets. New York: Taylor & Francis, 2003. 258-263. Print. Choi, S.M., Yoo, S.D., Lee, B.M. 2010. Toxicological Characteristics of Endocrine-Disrupting Chemicals: Developmental Toxicity, Carcinogenicity, and Mutagenicity. Journal of Toxicology and Environmental Health, Part B: Critical Reviews, 7:1, 1-23 Clotfelter, Ethan D.; Bell, Alison M.; Levering, Kate R. (October 2004). "The role of animal behaviour in the study of endocrine-disrupting chemicals". Animal Behaviour. 68 (4): 665–676. doi:10.1016/j.anbehav.2004.05.004. S2CID 51690424. Colborn, T., Saal, F.S.V. and Soto, A.M. 1993. Developmental effects of endocrine-disrupting chemicals in wildlife and humans. Environmental Health Perspectives 101, 378-384. Goussen, B., Rendal, C., Sheffield, D., Butler, E., Price, O.R. and Ashauer, R. 2020. Bioenergetics modelling to analyse and predict the joint effects of multiple stressors: Meta-analysis and model corroboration. Science of the Total Environment 749, 141509 DOI: doi:10.1016/j.scitotenv.2020.141509 Guillette, L.J., Crain, D.A., Gunderson, M.P., Kools, S.A.E., Milnes, M.R., Orlando, E.F., Rooney, A.A. and Woodward, A.R. 2000. *Alligators and endocrine disrupting contaminants: A current perspective. American Zoologist 40, 438-452. Jager T, Albert C, Preuss T, Ashauer R. 2011. General unified threshold model of survival – a Toxicokinetic-Toxicodynamic framework for ecotoxicology. Environmental Science and Technology 45: 2529-2540. Manibusan MK, Odin M, Eastmond DA. 2007. Postulated Carbon Tetrachloride Mode of Action: A Review. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 25(3): 185-209. National Toxicology Program (NTP). 2011. Carbon Tetrachloride: Report on Carcinogens (12th ed.). https://ntp.niehs.nih.gov/ntp/roc/content/profiles/carbontetrachloride.pdf Newman, M. C. (2010). Fundamentals of Ecotoxicology (3rd ed.). Boca Raton, FL: CRC Press. Pait, A.S. and J.O. Nelson. 2002. Endocrine Disruption in Fish: An Assessment of Recent Research and Results. NOAA Tech. Memo. NOS NCCOS CCMA 149. Silver Spring, MD:NOAA, NOS, Center for Coastal Monitoring and Assessment. 55. 4-5. Perrin, William. Encyclopedia of Marine Mammals. 2nd ed. New York: Academic Press, 2009. 894. eBook. Rabergh C.M.I. and Lipsky M.M. 1997. Toxicity of Chloroform and Carbon Tetrachloride in Primary Cultures of Rainbow Trout Hepatocytes. Aquat Toxicol. 37: 169-182. Rand, G.M. (1995). Fundamentals of Aquatic Toxicology: Effects, Environmental Fate, and Risk Assessment (2nd ed.). Washington, D.C.: Taylor and Francis. Tabb, M.M. and Blumberg, B. 2006. New modes of action for endocrine-disrupting chemicals. Molecular Endocrinology 20, 475-482. VanDelft J.H.M., Van Agen E, Van Breda S.G.J., Herwijnen M.H., Staal Y.C.M., Kleinjans J.C.S. 2004. Discrimination of Genotoxic from Non-genotoxic Carcinogens by Gene Expression Profiling. Carcinogenesis. 25:1265-1276.	Wikipedia/Toxicodynamics
Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and relies on the science of pharmacology for continual advancement and on pharmacy for appropriate management. Drugs are classified in many ways. One of the key divisions is by level of control, which distinguishes prescription drugs (those that a pharmacist dispenses only on the medical prescription) from over-the-counter drugs (those that consumers can order for themselves). Medicines may be classified by mode of action, route of administration, biological system affected, or therapeutic effects. The World Health Organization keeps a list of essential medicines. Drug discovery and drug development are complex and expensive endeavors undertaken by pharmaceutical companies, academic scientists, and governments. As a result of this complex path from discovery to commercialization, partnering has become a standard practice for advancing drug candidates through development pipelines. Governments generally regulate what drugs can be marketed, how drugs are marketed, and in some jurisdictions, drug pricing. Controversies have arisen over drug pricing and disposal of used medications. == Definition == Medication is a medicine or a chemical compound used to treat or cure illness. According to Encyclopædia Britannica, medication is "a substance used in treating a disease or relieving pain". As defined by the National Cancer Institute, dosage forms of medication can include tablets, capsules, liquids, creams, and patches. Medications can be administered in different ways, such as by mouth, by infusion into a vein, or by drops put into the ear or eye. A medication that does not contain an active ingredient and is used in research studies is called a placebo. In Europe, the term is "medicinal product", and it is defined by EU law as: "Any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or" "Any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting, or modifying physiological functions by exerting a pharmacological, immunological or metabolic action or to making a medical diagnosis.": 36 In the US, a "drug" is: A substance (other than food) intended to affect the structure or any function of the body. A substance intended for use as a component of a medicine but not a device or a component, part, or accessory of a device. A substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease. A substance recognized by an official pharmacopeia or formulary. Biological products are included within this definition and are generally covered by the same laws and regulations, but differences exist regarding their manufacturing processes (chemical process versus biological process). == Usage == Drug use among elderly Americans has been studied; in a group of 2,377 people with an average age of 71 surveyed between 2005 and 2006, 84% took at least one prescription drug, 44% took at least one over-the-counter (OTC) drug, and 52% took at least one dietary supplement; in a group of 2245 elderly Americans (average age of 71) surveyed over the period 2010 – 2011, those percentages were 88%, 38%, and 64%. == Classification == One of the key classifications is between traditional small molecule drugs; usually derived from chemical synthesis and biological medical products; which include recombinant proteins, vaccines, blood products used therapeutically (such as IVIG), gene therapy, and cell therapy (for instance, stem cell therapies). Pharmaceuticals or drugs or medicines are classified into various other groups besides their origin on the basis of pharmacological properties like mode of action and their pharmacological action or activity, such as by chemical properties, mode or route of administration, biological system affected, or therapeutic effects. An elaborate and widely used classification system is the Anatomical Therapeutic Chemical Classification System (ATC system). The World Health Organization keeps a list of essential medicines. A sampling of classes of medicine includes: Antipyretics: reducing fever (pyrexia/pyresis) Analgesics: reducing pain (painkillers) Antimalarial drugs: treating malaria Antibiotics: inhibiting germ growth Antiseptics: prevention of germ growth near burns, cuts, and wounds Mood stabilizers: lithium and valproate Hormone replacements: Premarin Oral contraceptives: Enovid, "biphasic" pill, and "triphasic" pill Stimulants: methylphenidate, amphetamine Tranquilizers: meprobamate, chlorpromazine, reserpine, chlordiazepoxide, diazepam, and alprazolam Statins: lovastatin, pravastatin, and simvastatin Pharmaceuticals may also be described as "specialty", independent of other classifications, which is an ill-defined class of drugs that might be difficult to administer, require special handling during administration, require patient monitoring during and immediately after administration, have particular regulatory requirements restricting their use, and are generally expensive relative to other drugs. == Types of medicines == === For the digestive system === Lower digestive tract: laxatives, antispasmodics, antidiarrhoeals, bile acid sequestrants, opioids. Upper digestive tract: antacids, reflux suppressants, antiflatulents, antidopaminergics, proton pump inhibitors (PPIs), H2-receptor antagonists, cytoprotectants, prostaglandin analogues. === For the cardiovascular system === Affecting blood pressure/(antihypertensive drugs): ACE inhibitors, angiotensin receptor blockers, beta-blockers, α blockers, calcium channel blockers, thiazide diuretics, loop diuretics, aldosterone inhibitors. Coagulation: anticoagulants, heparin, antiplatelet drugs, fibrinolytics, anti-hemophilic factors, haemostatic drugs. General: β-receptor blockers ("beta blockers"), calcium channel blockers, diuretics, cardiac glycosides, antiarrhythmics, nitrate, antianginals, vasoconstrictors, vasodilators. HMG-CoA reductase inhibitors (statins) for lowering LDL cholesterol inhibitors: hypolipidaemic agents. === For the central nervous system === Drugs affecting the central nervous system include psychedelics, hypnotics, anaesthetics, antipsychotics, eugeroics, antidepressants (including tricyclic antidepressants, monoamine oxidase inhibitors, lithium salts, and selective serotonin reuptake inhibitors (SSRIs)), antiemetics, anticonvulsants/antiepileptics, anxiolytics, barbiturates, movement disorder (e.g., Parkinson's disease) drugs, nootropics, stimulants (including amphetamines), benzodiazepines, cyclopyrrolones, dopamine antagonists, antihistamines, cholinergics, anticholinergics, emetics, cannabinoids, and 5-HT (serotonin) antagonists. === For pain === The main classes of painkillers are NSAIDs, opioids, and local anesthetics. For consciousness (anesthetic drugs) Some anesthetics include benzodiazepines and barbiturates. === For musculoskeletal disorders === The main categories of drugs for musculoskeletal disorders are: NSAIDs (including COX-2 selective inhibitors), muscle relaxants, neuromuscular drugs, and anticholinesterases. === For the eye === Anti-allergy: mast cell inhibitors. Anti-fungal: imidazoles, polyenes. Anti-glaucoma: adrenergic agonists, beta-blockers, carbonic anhydrase inhibitors/hyperosmotics, cholinergics, miotics, parasympathomimetics, prostaglandin agonists/prostaglandin inhibitors, nitroglycerin. Anti-inflammatory: NSAIDs, corticosteroids. Antibacterial: antibiotics, topical antibiotics, sulfa drugs, aminoglycosides, fluoroquinolones. Antiviral drugs. Diagnostic: topical anesthetics, sympathomimetics, parasympatholytics, mydriatics, cycloplegics. General: adrenergic neurone blocker, astringent. === For the ear, nose, and oropharynx === Antibiotics, sympathomimetics, antihistamines, anticholinergics, NSAIDs, corticosteroids, antiseptics, local anesthetics, antifungals, and cerumenolytics. === For the respiratory system === Bronchodilators, antitussives, mucolytics, decongestants, inhaled and systemic corticosteroids, beta2-adrenergic agonists, anticholinergics, mast cell stabilizers, leukotriene antagonists. === For endocrine problems === Androgens, antiandrogens, estrogens, gonadotropin, corticosteroids, human growth hormone, insulin, antidiabetics (sulfonylureas, biguanides/metformin, thiazolidinediones, insulin), thyroid hormones, antithyroid drugs, calcitonin, diphosphonate, vasopressin analogues. === For the reproductive system or urinary system === Antifungal, alkalinizing agents, quinolones, antibiotics, cholinergics, anticholinergics, antispasmodics, 5-alpha reductase inhibitor, selective alpha-1 blockers, sildenafils, fertility medications. === For contraception === Hormonal contraception. Ormeloxifene. Spermicide. === For obstetrics and gynecology === NSAIDs, anticholinergics, haemostatic drugs, antifibrinolytics, Hormone Replacement Therapy (HRT), bone regulators, beta-receptor agonists, follicle stimulating hormone, luteinising hormone, LHRH, gamolenic acid, gonadotropin release inhibitor, progestogen, dopamine agonists, oestrogen, prostaglandins, gonadorelin, clomiphene, tamoxifen, diethylstilbestrol. === For the skin === Emollients, anti-pruritics, antifungals, antiseptics, scabicides, pediculicides, tar products, vitamin A derivatives, vitamin D analogues, keratolytics, abrasives, systemic antibiotics, topical antibiotics, hormones, desloughing agents, exudate absorbents, fibrinolytics, proteolytics, sunscreens, antiperspirants, corticosteroids, immune modulators. === For infections and infestations === Antibiotics, antifungals, antileprotics, antituberculous drugs, antimalarials, anthelmintics, amoebicides, antivirals, antiprotozoals, probiotics, prebiotics, antitoxins, and antivenoms. === For the immune system === Vaccines, immunoglobulins, immunosuppressants, interferons, and monoclonal antibodies. === For allergic disorders === Anti-allergics, antihistamines, NSAIDs, corticosteroids. === For nutrition === Tonics, electrolytes and mineral preparations (including iron preparations and magnesium preparations), parenteral nutrition, vitamins, anti-obesity drugs, anabolic drugs, haematopoietic drugs, food product drugs. === For neoplastic disorders === Cytotoxic drugs, therapeutic antibodies, sex hormones, aromatase inhibitors, somatostatin inhibitors, recombinant interleukins, G-CSF, erythropoietin. === For diagnostics === Contrast media. === For euthanasia === A euthanaticum is used for euthanasia and physician-assisted suicide. Euthanasia is not permitted by law in many countries, and consequently, medicines will not be licensed for this use in those countries. == Administration == A single drug may contain single or multiple active ingredients. The administration is the process by which a patient takes medicine. There are three major categories of drug administration: enteral (via the human gastrointestinal tract), injection into the body, and by other routes (dermal, nasal, ophthalmic, otologic, and urogenital). Oral administration, the most common form of enteral administration, can be performed using various dosage forms including tablets or capsules and liquid such as syrup or suspension. Other ways to take the medication include buccally (placed inside the cheek), sublingually (placed underneath the tongue), eye and ear drops (dropped into the eye or ear), and transdermally (applied to the skin). They can be administered in one dose, as a bolus. Administration frequencies are often abbreviated from Latin, such as every 8 hours reading Q8H from Quaque VIII Hora. The drug frequencies are often expressed as the number of times a drug is used per day (e.g., four times a day). It may include event-related information (e.g., 1 hour before meals, in the morning, at bedtime), or complimentary to an interval, although equivalent expressions may have different implications (e.g., every 8 hours versus 3 times a day). == Drug discovery == In the fields of medicine, biotechnology, and pharmacology, drug discovery is the process by which new drugs are discovered. Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by serendipitous discovery. Later chemical libraries of synthetic small molecules, natural products, or extracts were screened in intact cells or whole organisms to identify substances that have a desirable therapeutic effect in a process known as classical pharmacology. Since sequencing of the human genome which allowed rapid cloning and synthesis of large quantities of purified proteins, it has become common practice to use high throughput screening of large compound libraries against isolated biological targets which are hypothesized to be disease-modifying in a process known as reverse pharmacology. Hits from these screens are then tested in cells and then in animals for efficacy. Even more recently, scientists have been able to understand the shape of biological molecules at the atomic level and to use that knowledge to design (see drug design) drug candidates. Modern drug discovery involves the identification of screening hits, medicinal chemistry, and optimization of those hits to increase the affinity, selectivity (to reduce the potential of side effects), efficacy/potency, metabolic stability (to increase the half-life), and oral bioavailability. Once a compound that fulfills all of these requirements has been identified, it will begin the process of drug development prior to clinical trials. One or more of these steps may, but not necessarily, involve computer-aided drug design. Despite advances in technology and understanding of biological systems, drug discovery is still a lengthy, "expensive, difficult, and inefficient process" with a low rate of new therapeutic discovery. In 2010, the research and development cost of each new molecular entity (NME) was approximately US$1.8 billion. Drug discovery is done by pharmaceutical companies, sometimes with research assistance from universities. The "final product" of drug discovery is a patent on the potential drug. The drug requires very expensive Phase I, II, and III clinical trials, and most of them fail. Small companies have a critical role, often then selling the rights to larger companies that have the resources to run the clinical trials. Drug discovery is different from Drug Development. Drug Discovery is often considered the process of identifying new medicine. At the same time, Drug development is delivering a new drug molecule into clinical practice. In its broad definition, this encompasses all steps from the basic research process of finding a suitable molecular target to supporting the drug's commercial launch. == Development == Drug development is the process of bringing a new drug to the market once a lead compound has been identified through the process of drug discovery. It includes pre-clinical research (microorganisms/animals) and clinical trials (on humans) and may include the step of obtaining regulatory approval to market the drug. Drug Development Process Discovery: The Drug Development process starts with Discovery, a process of identifying a new medicine. Development: Chemicals extracted from natural products are used to make pills, capsules, or syrups for oral use. Injections for direct infusion into the blood drops for eyes or ears. Preclinical research: Drugs go under laboratory or animal testing, to ensure that they can be used on Humans. Clinical testing: The drug is used on people to confirm that it is safe to use. FDA Review: drug is sent to FDA before launching the drug into the market. FDA post-Market Review: The drug is reviewed and monitored by FDA for the safety once it is available to the public. == Regulation == The regulation of drugs varies by jurisdiction. In some countries, such as the United States, they are regulated at the national level by a single agency. In other jurisdictions, they are regulated at the state level, or at both state and national levels by various bodies, as is the case in Australia. The role of therapeutic goods regulation is designed mainly to protect the health and safety of the population. Regulation is aimed at ensuring the safety, quality, and efficacy of the therapeutic goods which are covered under the scope of the regulation. In most jurisdictions, therapeutic goods must be registered before they are allowed to be marketed. There is usually some degree of restriction on the availability of certain therapeutic goods depending on their risk to consumers. Depending upon the jurisdiction, drugs may be divided into over-the-counter drugs (OTC) which may be available without special restrictions, and prescription drugs, which must be prescribed by a licensed medical practitioner in accordance with medical guidelines due to the risk of adverse effects and contraindications. The precise distinction between OTC and prescription depends on the legal jurisdiction. A third category, "behind-the-counter" drugs, is implemented in some jurisdictions. These do not require a prescription, but must be kept in the dispensary, not visible to the public, and be sold only by a pharmacist or pharmacy technician. Doctors may also prescribe prescription drugs for off-label use – purposes which the drugs were not originally approved for by the regulatory agency. The Classification of Pharmaco-Therapeutic Referrals helps guide the referral process between pharmacists and doctors. The International Narcotics Control Board of the United Nations imposes a world law of prohibition of certain drugs. They publish a lengthy list of chemicals and plants whose trade and consumption (where applicable) are forbidden. OTC drugs are sold without restriction as they are considered safe enough that most people will not hurt themselves accidentally by taking it as instructed. Many countries, such as the United Kingdom have a third category of "pharmacy medicines", which can be sold only in registered pharmacies by or under the supervision of a pharmacist. Medical errors include over-prescription and polypharmacy, mis-prescription, contraindication and lack of detail in dosage and administration instructions. In 2000 the definition of a prescription error was studied using a Delphi method conference; the conference was motivated by ambiguity in what a prescription error is and a need to use a uniform definition in studies. == Drug pricing == In many jurisdictions, drug prices are regulated. === United Kingdom === In the UK, the Pharmaceutical Price Regulation Scheme is intended to ensure that the National Health Service is able to purchase drugs at reasonable prices. The prices are negotiated between the Department of Health, acting with the authority of Northern Ireland and the UK Government, and the representatives of the Pharmaceutical industry brands, the Association of the British Pharmaceutical Industry (ABPI). For 2017 this payment percentage set by the PPRS will be 4,75%. === Canada === In Canada, the Patented Medicine Prices Review Board examines drug pricing and determines if a price is excessive or not. In these circumstances, drug manufacturers must submit a proposed price to the appropriate regulatory agency. Furthermore, "the International Therapeutic Class Comparison Test is responsible for comparing the National Average Transaction Price of the patented drug product under review" different countries that the prices are being compared to are the following: France, Germany, Italy, Sweden, Switzerland, the United Kingdom, and the United States === Brazil === In Brazil, the prices are regulated through legislation under the name of Medicamento Genérico (generic drugs) since 1999. === India === In India, drug prices are regulated by the National Pharmaceutical Pricing Authority. === United States === In the United States, drug costs are partially unregulated, but instead are the result of negotiations between drug companies and insurance companies. High prices have been attributed to monopolies given to manufacturers by the government. New drug development costs continue to rise as well. Despite the enormous advances in science and technology, the number of new blockbuster drugs approved by the government per billion dollars spent has halved every 9 years since 1950. == Blockbuster drug == A blockbuster drug is a drug that generates more than $1 billion in revenue for a pharmaceutical company in a single year. Cimetidine was the first drug ever to reach more than $1 billion a year in sales, thus making it the first blockbuster drug. In the pharmaceutical industry, a blockbuster drug is one that achieves acceptance by prescribing physicians as a therapeutic standard for, most commonly, a highly prevalent chronic (rather than acute) condition. Patients often take the medicines for long periods. == History == === Prescription drug history === Antibiotics first arrived on the medical scene in 1932 thanks to Gerhard Domagk; and were coined the "wonder drugs". The introduction of the sulfa drugs led to the mortality rate from pneumonia in the U.S. to drop from 0.2% each year to 0.05% (i.e., 1⁄4 as much) by 1939. Antibiotics inhibit the growth or the metabolic activities of bacteria and other microorganisms by a chemical substance of microbial origin. Penicillin, introduced a few years later, provided a broader spectrum of activity compared to sulfa drugs and reduced side effects. Streptomycin, found in 1942, proved to be the first drug effective against the cause of tuberculosis and also came to be the best known of a long series of important antibiotics. A second generation of antibiotics was introduced in the 1940s: aureomycin and chloramphenicol. Aureomycin was the best known of the second generation. Lithium was discovered in the 19th century for nervous disorders and its possible mood-stabilizing or prophylactic effect; it was cheap and easily produced. As lithium fell out of favor in France, valpromide came into play. This antibiotic was the origin of the drug that eventually created the mood stabilizer category. Valpromide had distinct psychotrophic effects that were of benefit in both the treatment of acute manic states and in the maintenance treatment of manic depression illness. Psychotropics can either be sedative or stimulant; sedatives aim at damping down the extremes of behavior. Stimulants aim at restoring normality by increasing tone. Soon arose the notion of a tranquilizer which was quite different from any sedative or stimulant. The term tranquilizer took over the notions of sedatives and became the dominant term in the West through the 1980s. In Japan, during this time, the term tranquilizer produced the notion of a psyche-stabilizer and the term mood stabilizer vanished. Premarin (conjugated estrogens, introduced in 1942) and Prempro (a combination estrogen-progestin pill, introduced in 1995) dominated hormone replacement therapy (HRT) regimens during the 1990s. Though not designed to cure any disease, HRT is prescribed to improve quality of life and as a preventative measure, such as treating post-menopausal symptoms. In the 1960s and early 1970s, more physicians began to prescribe estrogen for their female patients. Between 1991 and 1999, Premarin was listed as the most popular prescription and best-selling drug in America. The first oral contraceptive, Enovid, was approved by FDA in 1960. Oral contraceptives inhibit ovulation and so prevent conception. Enovid was known to be much more effective than alternatives including the condom and the diaphragm. As early as 1960, oral contraceptives were available in several different strengths by every manufacturer. In the 1980s and 1990s, an increasing number of options arose including, most recently, a new delivery system for the oral contraceptive via a transdermal patch. In 1982, a new version of "the pill" was introduced, known as the biphasic pill. By 1985, a new triphasic pill was approved. Physicians began to think of "the pill" as an excellent means of birth control for young women. Stimulants such as Ritalin (methylphenidate) came to be pervasive tools for behavior management and modification in young children. Ritalin was first marketed in 1955 for narcolepsy; its potential users were middle-aged and the elderly. It was not until some time in the 1980s along with hyperactivity in children that Ritalin came onto the market. Medical use of methylphenidate is predominantly for symptoms of attention deficit hyperactivity disorder (ADHD). Consumption of methylphenidate in the U.S. out-paced all other countries between 1991 and 1999. Significant growth in consumption was also evident in Canada, New Zealand, Australia, and Norway. Currently, 85% of the world's methylphenidate is consumed in America. The first minor tranquilizer was meprobamate. Only fourteen months after it was made available, meprobamate had become the country's largest-selling prescription drug. By 1957, meprobamate had become the fastest-growing drug in history. The popularity of meprobamate paved the way for Librium and Valium, two minor tranquilizers that belonged to a new chemical class of drugs called the benzodiazepines. These were drugs that worked chiefly as anti-anxiety agents and muscle relaxants. The first benzodiazepine was Librium. Three months after it was approved, Librium had become the most prescribed tranquilizer in the nation. Three years later, Valium hit the shelves and was ten times more effective as a muscle relaxant and anti-convulsant. Valium was the most versatile of the minor tranquilizers. Later came the widespread adoption of major tranquilizers such as chlorpromazine and the drug reserpine. In 1970, sales began to decline for Valium and Librium, but sales of new and improved tranquilizers, such as Xanax, introduced in 1981 for the newly created diagnosis of panic disorder, soared. Mevacor (lovastatin) is the first and most influential statin in the American market. The 1991 launch of Pravachol (pravastatin), the second available in the United States, and the release of Zocor (simvastatin) made Mevacor no longer the only statin on the market. In 1998, Viagra was released as a treatment for erectile dysfunction. === Ancient pharmacology === Using plants and plant substances to treat all kinds of diseases and medical conditions is believed to date back to prehistoric medicine. The Kahun Gynaecological Papyrus, the oldest known medical text of any kind, dates to about 1800 BC and represents the first documented use of any kind of drug. It and other medical papyri describe Ancient Egyptian medical practices, such as using honey to treat infections and the legs of bee-eaters to treat neck pains. Ancient Babylonian medicine demonstrated the use of medication in the first half of the 2nd millennium BC. Medicinal creams and pills were employed as treatments. On the Indian subcontinent, the Atharvaveda, a sacred text of Hinduism whose core dates from the second millennium BC, although the hymns recorded in it are believed to be older, is the first Indic text dealing with medicine. It describes plant-based drugs to counter diseases. The earliest foundations of ayurveda were built on a synthesis of selected ancient herbal practices, together with a massive addition of theoretical conceptualizations, new nosologies and new therapies dating from about 400 BC onwards. The student of Āyurveda was expected to know ten arts that were indispensable in the preparation and application of his medicines: distillation, operative skills, cooking, horticulture, metallurgy, sugar manufacture, pharmacy, analysis and separation of minerals, compounding of metals, and preparation of alkalis. The Hippocratic Oath for physicians, attributed to fifth century BC Greece, refers to the existence of "deadly drugs", and ancient Greek physicians imported drugs from Egypt and elsewhere. The pharmacopoeia De materia medica, written between 50 and 70 CE by the Greek physician Pedanius Dioscorides, was widely read for more than 1,500 years. === Medieval pharmacology === Al-Kindi's ninth century AD book, De Gradibus and Ibn Sina (Avicenna)'s The Canon of Medicine, covers a range of drugs known to the practice of medicine in the medieval Islamic world. Medieval medicine of Western Europe saw advances in surgery compared to previously, but few truly effective drugs existed, beyond opium (found in such extremely popular drugs as the "Great Rest" of the Antidotarium Nicolai at the time) and quinine. Folklore cures and potentially poisonous metal-based compounds were popular treatments. Theodoric Borgognoni, (1205–1296), one of the most significant surgeons of the medieval period, responsible for introducing and promoting important surgical advances including basic antiseptic practice and the use of anaesthetics. Garcia de Orta described some herbal treatments that were used. === Modern pharmacology === For most of the 19th century, drugs were not highly effective, leading Oliver Wendell Holmes Sr. to famously comment in 1842 that "if all medicines in the world were thrown into the sea, it would be all the better for mankind and all the worse for the fishes".: 21 During the First World War, Alexis Carrel and Henry Dakin developed the Carrel-Dakin method of treating wounds with an irrigation, Dakin's solution, a germicide which helped prevent gangrene. In the inter-war period, the first anti-bacterial agents such as the sulpha antibiotics were developed. The Second World War saw the introduction of widespread and effective antimicrobial therapy with the development and mass production of penicillin antibiotics, made possible by the pressures of the war and the collaboration of British scientists with the American pharmaceutical industry. Medicines commonly used by the late 1920s included aspirin, codeine, and morphine for pain; digitalis, nitroglycerin, and quinine for heart disorders, and insulin for diabetes. Other drugs included antitoxins, a few biological vaccines, and a few synthetic drugs. In the 1930s, antibiotics emerged: first sulfa drugs, then penicillin and other antibiotics. Drugs increasingly became "the center of medical practice".: 22 In the 1950s, other drugs emerged including corticosteroids for inflammation, rauvolfia alkaloids as tranquilizers and antihypertensives, antihistamines for nasal allergies, xanthines for asthma, and typical antipsychotics for psychosis.: 23–24 As of 2007, thousands of approved drugs have been developed. Increasingly, biotechnology is used to discover biopharmaceuticals. Recently, multi-disciplinary approaches have yielded a wealth of new data on the development of novel antibiotics and antibacterials and on the use of biological agents for antibacterial therapy. In the 1950s, new psychiatric drugs, notably the antipsychotic chlorpromazine, were designed in laboratories and slowly came into preferred use. Although often accepted as an advance in some ways, there was some opposition, due to serious adverse effects such as tardive dyskinesia. Patients often opposed psychiatry and refused or stopped taking the drugs when not subject to psychiatric control. Governments have been heavily involved in the regulation of drug development and drug sales. In the U.S., the Elixir Sulfanilamide disaster led to the establishment of the Food and Drug Administration, and the 1938 Federal Food, Drug, and Cosmetic Act required manufacturers to file new drugs with the FDA. The 1951 Humphrey-Durham Amendment required certain drugs to be sold by prescription. In 1962, a subsequent amendment required new drugs to be tested for efficacy and safety in clinical trials.: 24–26 Until the 1970s, drug prices were not a major concern for doctors and patients. As more drugs became prescribed for chronic illnesses, however, costs became burdensome, and by the 1970s nearly every U.S. state required or encouraged the substitution of generic drugs for higher-priced brand names. This also led to the 2006 U.S. law, Medicare Part D, which offers Medicare coverage for drugs.: 28–29 As of 2008, the United States is the leader in medical research, including pharmaceutical development. U.S. drug prices are among the highest in the world, and drug innovation is correspondingly high. In 2000, U.S.-based firms developed 29 of the 75 top-selling drugs; firms from the second-largest market, Japan, developed eight, and the United Kingdom contributed 10. France, which imposes price controls, developed three. Throughout the 1990s, outcomes were similar.: 30–31 == Controversies == Controversies concerning pharmaceutical drugs include patient access to drugs under development and not yet approved, pricing, and environmental issues. === Access to unapproved drugs === Governments worldwide have created provisions for granting access to drugs prior to approval for patients who have exhausted all alternative treatment options and do not match clinical trial entry criteria. Often grouped under the labels of compassionate use, expanded access, or named patient supply, these programs are governed by rules which vary by country defining access criteria, data collection, promotion, and control of drug distribution. Within the United States, pre-approval demand is generally met through treatment IND (investigational new drug) applications (INDs), or single-patient INDs. These mechanisms, which fall under the label of expanded access programs, provide access to drugs for groups of patients or individuals residing in the US. Outside the US, Named Patient Programs provide controlled, pre-approval access to drugs in response to requests by physicians on behalf of specific, or "named", patients before those medicines are licensed in the patient's home country. Through these programs, patients are able to access drugs in late-stage clinical trials or approved in other countries for a genuine, unmet medical need, before those drugs have been licensed in the patient's home country. Patients who have not been able to get access to drugs in development have organized and advocated for greater access. In the United States, ACT UP formed in the 1980s, and eventually formed its Treatment Action Group in part to pressure the US government to put more resources into discovering treatments for AIDS and then to speed release of drugs that were under development. The Abigail Alliance was established in November 2001 by Frank Burroughs in memory of his daughter, Abigail. The Alliance seeks broader availability of investigational drugs on behalf of terminally ill patients. In 2013, BioMarin Pharmaceutical was at the center of a high-profile debate regarding expanded access of cancer patients to experimental drugs. === Access to medicines and drug pricing === Essential medicines, as defined by the World Health Organization (WHO), are "those drugs that satisfy the health care needs of the majority of the population; they should therefore be available at all times in adequate amounts and in appropriate dosage forms, at a price the community can afford." Recent studies have found that most of the medicines on the WHO essential medicines list, outside of the field of HIV drugs, are not patented in the developing world, and that lack of widespread access to these medicines arise from issues fundamental to economic development – lack of infrastructure and poverty. Médecins Sans Frontières also runs a Campaign for Access to Essential Medicines campaign, which includes advocacy for greater resources to be devoted to currently untreatable diseases that primarily occur in the developing world. The Access to Medicine Index tracks how well pharmaceutical companies make their products available in the developing world. World Trade Organization negotiations in the 1990s, including the TRIPS Agreement and the Doha Declaration, have centered on issues at the intersection of international trade in pharmaceuticals and intellectual property rights, with developed world nations seeking strong intellectual property rights to protect investments made to develop new drugs, and developing world nations seeking to promote their generic pharmaceuticals industries and their ability to make medicine available to their people via compulsory licenses. Some have raised ethical objections specifically with respect to pharmaceutical patents and the high prices for drugs that they enable their proprietors to charge, which poor people around the world, cannot afford. Critics also question the rationale that exclusive patent rights and the resulting high prices are required for pharmaceutical companies to recoup the large investments needed for research and development. One study concluded that marketing expenditures for new drugs often doubled the amount that was allocated for research and development. Other critics claim that patent settlements would be costly for consumers, the health care system, and state and federal governments because it would result in delaying access to lower cost generic medicines. Novartis fought a protracted battle with the government of India over the patenting of its drug, Gleevec, in India, which ended up in a Supreme Court in a case known as Novartis v. Union of India & Others. The Supreme Court ruled narrowly against Novartis, but opponents of patenting drugs claimed it as a major victory. === Environmental issues === Pharmaceutical medications are commonly described as "ubiquitous" in nearly every type of environmental medium (i.e. lakes, rivers, streams, estuaries, seawater, and soil) worldwide. Their chemical components are typically present at relatively low concentrations in the ng/L to μg/L ranges. The primary avenue for medications reaching the environment are through the effluent of wastewater treatment plants, both from industrial plants during production, and from municipal plants after consumption. Agricultural pollution is another significant source derived from the prevalence of antibiotic use in livestock. Scientists generally divide environmental impacts of a chemical into three primary categories: persistence, bioaccumulation, and toxicity. Since medications are inherently bio-active, most are naturally degradable in the environment, however they are classified as "pseudopersistent" because they are constantly being replenished from their sources. These Environmentally Persistent Pharmaceutical Pollutants (EPPPs) rarely reach toxic concentrations in the environment, however they have been known to bioaccumulate in some species. Their effects have been observed to compound gradually across food webs, rather than becoming acute, leading to their classification by the US Geological Survey as "Ecological Disrupting Compounds." == See also == == References == == External links == Drug Reference Site Directory – OpenMD Drugs & Medications Directory – Curlie European Medicines Agency NHS Medicines A–Z U.S. Food & Drug Administration: Drugs WHO Model List of Essential Medicines	Wikipedia/Drug_administration
A membrane transport protein is a membrane protein involved in the movement of ions, small molecules, and macromolecules, such as another protein, across a biological membrane. Transport proteins are integral transmembrane proteins; that is they exist permanently within and span the membrane across which they transport substances. The proteins may assist in the movement of substances by facilitated diffusion, active transport, osmosis, or reverse diffusion. The two main types of proteins involved in such transport are broadly categorized as either channels or carriers (a.k.a. transporters, or permeases). Examples of channel/carrier proteins include the GLUT 1 uniporter, sodium channels, and potassium channels. The solute carriers and atypical SLCs are secondary active or facilitative transporters in humans. Collectively membrane transporters and channels are known as the transportome. Transportomes govern cellular influx and efflux of not only ions and nutrients but drugs as well. == Difference between channels and carriers == A carrier is not open simultaneously to both the extracellular and intracellular environments. Either its inner gate is open, or outer gate is open. In contrast, a channel can be open to both environments at the same time, allowing the molecules to diffuse without interruption. Carriers have binding sites, but pores and channels do not. When a channel is opened, millions of ions can pass through the membrane per second, but only 100 to 1000 molecules typically pass through a carrier molecule in the same time. Each carrier protein is designed to recognize only one substance or one group of very similar substances. Research has correlated defects in specific carrier proteins with specific diseases. == Active transport == Active transport is the movement of a substance across a membrane against its concentration gradient. This is usually to accumulate high concentrations of molecules that a cell needs, such as glucose or amino acids. If the process uses chemical energy, such as adenosine triphosphate (ATP), it is called primary active transport. Membrane transport proteins that are driven directly by the hydrolysis of ATP are referred to as ATPase pumps. These types of pumps direct the exergonic hydrolysis of ATP to the unfavorable movement of molecules against their concentration gradient. Examples of ATPase pumps include P-type ATPase's, V-type ATPases, F-type ATPases, and ABC binding cassettes. Secondary active transport involves the use of an electrochemical gradient, and does not use energy produced in the cell. Secondary active transport commonly uses types of carrier proteins, typically symporters and antiporters. Symporter proteins couple the transport of one molecule down its concentration gradient to the transport of another molecule against its concentration gradient, and both molecules diffuse in the same direction. Antiporter proteins transport one molecule down its concentration gradient to transport another molecule against its concentration gradient, but the molecules diffuse in opposite directions. As symporters and antiporters are involved in coupling the transport of two molecules, they are commonly referred to as cotransporters. Unlike channel proteins which only transport substances through membranes passively, carrier proteins can transport ions and molecules either passively through facilitated diffusion, or via secondary active transport. A carrier protein is required to move particles from areas of low concentration to areas of high concentration. These carrier proteins have receptors that bind to a specific molecule (substrate) needing transport. The molecule or ion to be transported (the substrate) must first bind at a binding site at the carrier molecule, with a certain binding affinity. Following binding, and while the binding site is facing the same way, the carrier will capture or occlude (take in and retain) the substrate within its molecular structure and cause an internal translocation so that the opening in the protein now faces the other side of the plasma membrane. The carrier protein substrate is released at that site, according to its binding affinity there. == Facilitated diffusion == Facilitated diffusion is the passage of molecules or ions across a biological membrane through specific transport proteins and requires no energy input. Facilitated diffusion is used especially in the case of large polar molecules and charged ions; once such ions are dissolved in water they cannot diffuse freely across cell membranes due to the hydrophobic nature of the fatty acid tails of the phospholipids that make up the bilayers. The type of carrier proteins used in facilitated diffusion is slightly different from those used in active transport. They are still transmembrane carrier proteins, but these are gated transmembrane channels, meaning they do not internally translocate, nor require ATP to function. The substrate is taken in one side of the gated carrier, and without using ATP the substrate is released into the cell. Facilitated diffusion does not require the use of ATP as facilitated diffusion, like simple diffusion, transports molecules or ions along their concentration gradient. == Osmosis == Osmosis is the passive diffusion of water across a cell membrane from an area of high concentration to an area of low concentration. Since Osmosis is a passive process, like facilitated diffusion and simple diffusion, it does not require the use of ATP. Osmosis is important in regulating the balance of water and salt within cells, thus it plays a critical role in maintaining homeostasis. Aquaporins are integral membrane proteins that allow for the rapid passage of water and glycerol through membranes. The aquaporin monomers consist of six transmembrane alpha-helix domains and these monomers can assemble to form the aquaporin proteins. As four of these monomers come together to form the aquaporin protein, it is known as a homotetramer, meaning it is made up of four identical subunits. All aquaporins are tetrameric membrane integral proteins, and the water passes through each individual monomer channel rather than between all of the four channels. Since aquaporins are transmembrane channels for the diffusion of water, the channels that make up the aquaporin are typically lined with hydrophilic side chains to allow water to pass through. == Reverse diffusion == Reverse transport, or transporter reversal, is a phenomenon in which the substrates of a membrane transport protein are moved in the opposite direction to that of their typical movement by the transporter. Transporter reversal typically occurs when a membrane transport protein is phosphorylated by a particular protein kinase, which is an enzyme that adds a phosphate group to proteins. == Types == (Grouped by Transporter Classification database categories) === 1: Channels/pores === α-helical protein channels such as voltage-gated ion channel (VIC), ligand-gated ion channels(LGICs) β-barrel porins such as aquaporin channel-forming toxins, including colicins, diphtheria toxin, and others Nonribosomally synthesized channels such as gramicidin Holins; which function in export of enzymes that digest bacterial cell walls in an early step of cell lysis. Facilitated diffusion occurs in and out of the cell membrane via channels/pores and carriers/porters. Note: Channels: Channels are either in open state or closed state. When a channel is opened with a slight conformational switch, it is open to both environment simultaneously (extracellular and intracellular) Pores: Pores are continuously open to these both environment, because they do not undergo conformational changes. They are always open and active. === 2: Electrochemical potential-driven transporters === Also named carrier proteins or secondary carriers. 2.A: Porters (uniporters, symporters, antiporters), SLCs. Excitatory amino acid transporters (EAATs) EAAT1 EAAT2 EAAT3 EAAT4 EAAT5 Glucose transporter Monoamine transporters, including: Dopamine transporter (DAT) Norepinephrine transporter (NET) Serotonin transporter (SERT) Vesicular monoamine transporters (VMAT) Adenine nucleotide translocator (ANT) 2.B: Nonribosomally synthesized porters, such as: The Nigericin family The Ionomycin family 2.C: Ion-gradient-driven energizers === 3: Primary Active Transporters === 3.A: P-P-bond-hydrolysis-driven transporters (a.k.a. ATP-driven pumps, or transport ATPases): ATP-binding cassette transporter (ABC transporter), such as MDR, CFTR V-type ATPase ; ( "V" related to vacuolar ). P-type ATPase ; ( "P" related to phosphorylation), such as: Na+/K+-ATPase Plasma membrane Ca2+ ATPase Proton pump F-type ATPase; ("F" related to factor), including: mitochondrial ATP synthase, chloroplast ATP synthase1 3.B: Decarboxylation-driven transporters 3.C: Methyltransfer-driven transporters 3.D: Oxidoreduction-driven transporters 3.E: Light absorption-driven transporters, such as rhodopsin === 4: Group translocators === The group translocators provide a special mechanism for the phosphorylation of sugars as they are transported into bacteria (PEP group translocation) === 5: Electron carriers === The transmembrane electron transfer carriers in the membrane include two-electron carriers, such as the disulfide bond oxidoreductases (DsbB and DsbD in E. coli) as well as one-electron carriers such as NADPH oxidase. Often these redox proteins are not considered transport proteins. == Relevant Examples == === GLUT 1 === Every carrier protein, especially within the same cell membrane, is specific to one type or family of molecules. GLUT1 is a named carrier protein found in almost all animal cell membranes that transports glucose across the bilayer. This protein is a uniporter, meaning it transports glucose along its concentration in a singular direction. It is an integral membrane protein carrier with a hydrophilic interior, which allows it to bind to glucose. As GLUT 1 is a type of carrier protein, it will undergo a conformational change to allow glucose to enter the other side of the plasma membrane. GLUT 1 is commonly found in the red blood cell membranes of mammals. === Sodium/Potassium Channels === While there are many examples of channels within the human body, two notable ones are sodium and potassium channels. Potassium channels are typically involved in the transport of potassium ions across the cell membrane to the outside of the cell, which helps maintain the negative membrane potential of cells. As there are more potassium channels than sodium channels, more potassium flows out of the cell than sodium into a cell, thus why the membrane potential is negative. Sodium channels are typically involved in the transport of sodium ions across the cell membrane into the cell. These channels are commonly associated with excitable neurons, as an influx of sodium can trigger depolarization, which in turn propagates an action potential. As these proteins are types of channel proteins, they do not undergo a change of conformation after binding their respective substrates. === Other Examples === Other specific carrier proteins also help the body function in important ways. Cytochromes operate in the electron transport chain as carrier proteins for electrons. == Pathology == A number of inherited diseases involve defects in carrier proteins in a particular substance or group of cells. Cysteinuria (cysteine in the urine and the bladder) is such a disease involving defective cysteine carrier proteins in the kidney cell membranes. This transport system normally removes cysteine from the fluid destined to become urine and returns this essential amino acid to the blood. When this carrier malfunctions, large quantities of cysteine remain in the urine, where it is relatively insoluble and tends to precipitate. This is one cause of urinary stones. Some vitamin carrier proteins have been shown to be overexpressed in patients with malignant disease. For example, levels of riboflavin carrier protein (RCP) have been shown to be significantly elevated in people with breast cancer. == See also == Cotransport Cotransporter C14orf102, a 3810bp protein-encoding gene Ion channel Permease P-loop Solute carrier family (classification) TC number (classification) Translocase Flippases Vesicular transport protein Endocytosis == References == == Sources == Sadava, David E; Hillis, David M; Heller, H Craig; Berenbaum, May (2011). Life: The Science of Biology. Macmillan. ISBN 978-1-4292-4644-6. Han, Seong S.; Ashley, Ruth; Hann, Gary (1974). Cell Biology. University of Michigan. OCLC 1532651. == External links == "Transport protein" at Dorland's Medical Dictionary	Wikipedia/Carrier-protein
Persister cells are subpopulations of cells that resist treatment, and become antimicrobial tolerant by changing to a state of dormancy or quiescence. Persister cells in their dormancy do not divide. The tolerance shown in persister cells differs from antimicrobial resistance in that the tolerance is not inherited and is reversible. When treatment has stopped the state of dormancy can be reversed and the cells can reactivate and multiply. Most persister cells are bacterial, and there are also fungal persister cells, yeast persister cells, and cancer persister cells that show tolerance for cancer drugs. == History == Recognition of bacterial persister cells dates back to 1944 when Joseph Warwick Bigger, an Irish physician working in England, was experimenting with the recently discovered penicillin. Bigger used penicillin to lyse a suspension of bacteria and then inoculate a culture medium with the penicillin-treated liquid. Colonies of bacteria were able to grow after antibiotic exposure. The important observation that Bigger made was that this new population could again be almost eliminated by the use of penicillin except for a small residual population. Hence the residual organisms were not antibiotic resistant mutants but rather a subpopulation of what he called ‘persisters’. The formation of bacterial persisters is now known to be a common phenomenon that can occur by the formation of persister cells prior to the antibiotic treatment or in response to a variety of antibiotics. == Relevance to chronic infections == Antimicrobial tolerance is achieved by a small subpopulation of microbial cells termed persisters. Persisters are not mutants, but rather are dormant cells that can survive the antimicrobials that effectively eliminate their much greater number. Persister cells have entered a non-growing, or extremely slow-growing physiological state which makes them tolerant (insensitive or refractory) to the action of antimicrobials. When such persisting pathogenic microbes cannot be eliminated by the immune system, they become a reservoir from which recurrence of infection will develop. Such non-growing bacteria have been observed to persist during infections from Salmonella. Persister cells are the main cause of relapsing and chronic infections. The bacteria species Listeria monocytogenes, the main causal agent of listeriosis, has been shown to demonstrate persistence during infection in hepatocyte and trophoblast cells. The usual active lifestyle can change and the bacteria can remain in intracellular vacuoles entering into a slow non-growing state of persistence thus promoting their survival from antibiotics. Fungal persister cells are a common cause of recurring infections due to Candida albicans a common biofilm infection of implants. == Medical importance == Antibiotic tolerance poses medically important challenges. It is largely responsible for the inability to eradicate bacterial infections with antibiotic treatment. Persister cells are highly enriched in biofilms, and this makes biofilm-related diseases difficult to treat. Examples are chronic infections of implanted medical devices such as catheters and artificial joints, urinary tract infections, middle ear infections and fatal lung disease. == Resistance vs tolerance == Unlike multiple drug resistance, and antimicrobial resistance, antimicrobial tolerance is transient, and not inherited. Antibiotic tolerant persister cells are not antibiotic resistant mutants. Resistance is caused by newly acquired genetic traits (by mutation or horizontal gene transfer) that are heritable and confer the ability to grow at elevated concentrations of antibiotics. In contrast, tolerant bacteria have the same minimum inhibitory concentration (MIC) as susceptible bacteria, and differ in the duration of the treatment that they can survive. Antibiotic tolerance can be caused by a reversible physiological state in a small subpopulation of genetically identical cells, similar to a differentiated cell type. It enables this small subpopulation of bacteria to survive their complete elimination by antibiotic use. Persisting cells resume growth when the antibiotic is removed, and their progeny is sensitive to antibiotics. == Molecular mechanisms == The molecular mechanisms that underlie persister cell formation, and antimicrobial tolerance are largely unknown. Persister cells are thought to arise spontaneously in a growing microbial population by a stochastic genetic switch, although inducible mechanisms of persister cell formation have been described. For instance, toxin-antitoxin systems, and a number of different stress responses such as the SOS response, the envelope stress response, and the starvation response have also been associated with persister cell formation in biofilms. Owing to their transient nature and relatively low abundance, it is hard to isolate persister cells in sufficient numbers for experimental characterization, and only a few relevant genes have been identified to date. The best-understood persistence factor is the E. coli high persistence gene, commonly abbreviated as hipA. Although tolerance is widely considered a passive state, there is evidence indicating it can be an energy-dependent process. Persister cells in E. coli can transport intracellular accumulations antibiotic using an energy requiring efflux pump called TolC. A persister subpopulation has also been demonstrated in budding yeast Saccharomyces cerevisiae. Yeast persisters are triggered in a small subset of unperturbed exponentially growing cells by spontaneously occurring DNA damage, which leads to the activation of a general stress response and protection against a range of harsh drug and stress environments. As a result of the DNA damage, yeast persisters are also enriched for random genetic mutations that occurred prior to the stress, and are unrelated to the stress survival. In response to antifungals, fungal persister cells activate stress-response pathways, and two stress-protective molecules – glycogen, and trehalose accumulate in large amounts. == Potential treatment == A study has shown that adding certain metabolites to aminoglycosides could enable bacterial persisters to be eliminated. This study was carried out on a number of bacterial species including E. coli and S. aureus. Phage therapy, where applicable, is thought to entirely circumvent antibiotic tolerance, though phages themselves may be capable of inducing the persister state. == See also == Founder effect Population bottleneck == References == == External links == "Persister cells and mode of action of HipA". Archived from the original on March 28, 2010.	Wikipedia/Multidrug_tolerance
Directed therapy refers to the treatment of infections based on specific knowledge of what the causal agent is able to be treated with. It is the opposite to empiric therapy, which refers to the treatment of infections based on the clinical suspicion about what the agent should be able to be treated with, based on experience or guidelines. Information that directs therapy may medical tests that isolate the cause of an infection, such as microbiological culture, or polymerase chain reaction testing, as well as testing for antimicrobial sensitivities. Often, directed therapy occurs after initial empiric therapy. Empiric therapy is often commenced first, particularly important when antimicrobial sensitivities are not known, or when a severe infection such as one causing sepsis has been identified. In this circumstance, the decision may be made for empiric therapy first. A change to directed therapy may be associated with a change in antimicrobials, a change in the duration of treatment, or the cessation of unnecessary antimicrobials. Directed therapy is considered important because it ensures a person is completely treated for an infection, and because it can help lower the rate of antimicrobial resistance. == References ==	Wikipedia/Directed_therapy
Multidrug-resistant tuberculosis (MDR-TB) is a form of tuberculosis (TB) infection caused by bacteria that are resistant to treatment with at least two of the most powerful first-line anti-TB medications (drugs): isoniazid and rifampicin. Some forms of TB are also resistant to second-line medications, and are called extensively drug-resistant TB (XDR-TB). Tuberculosis is caused by infection with the bacterium Mycobacterium tuberculosis. Almost one in four people in the world are infected with TB bacteria. Only when the bacteria become active do people become ill with TB. Bacteria become active as a result of anything that can reduce the person's immunity, such as HIV, advancing age, diabetes or other immunocompromising illnesses. TB can usually be treated with a course of four standard, or first-line, anti-TB drugs (i.e., isoniazid, rifampicin, pyrazinamide and ethambutol). However, beginning with the first antibiotic treatment for TB in 1943, some strains of the TB bacteria developed resistance to the standard drugs through genetic changes (see mechanisms.) This process accelerates if incorrect or inadequate treatments are used, leading to the development and spread of multidrug-resistant TB (MDR-TB). Incorrect or inadequate treatment may be due to use of the wrong medications, use of only one medication (standard treatment is at least two drugs), or not taking medication consistently or for the full treatment period (treatment is required for several months). Treatment of MDR-TB requires treatment with second-line drugs, (i.e., fluoroquinolones, aminoglycosides, and others), which in general are less effective, more toxic and much more expensive than first-line drugs. Treatment regimes can run for two years, compared to the six months of first-line drug treatment. If these second-line drugs are prescribed or taken incorrectly, further resistance can develop leading to XDR-TB. MDR-TB can be directly transmitted from an infected person to an uninfected person. In this case a previously untreated person develops a new case of MDR-TB. This is known as primary MDR-TB, and is responsible for up to 75% of cases. Acquired MDR-TB develops when a person with a non-resistant strain of TB is treated inadequately, resulting in the development of antibiotic resistance in the TB bacteria infecting them. These people can in turn infect other people with MDR-TB. MDR-TB caused an estimated 600,000 new TB cases and 240,000 deaths in 2016 and MDR-TB accounts for 4.1% of all new TB cases and 19% of previously treated cases worldwide. Globally, most MDR-TB cases occur in South America, Southern Africa, India, China, and the former Soviet Union. == Origin == Researchers hypothesize that an ancestor of Mycobacterium tuberculosis first originated in the East African region approximately 3 million years ago, with modern strains mutating and arising 20,000 years ago. As migration out of East Africa increased, so did the spread of the disease, starting in Asia and then spreading towards the West and South America. Multidrug-resistant tuberculosis has a variety of causes, but resistance is usually due to treatment failure, drug combinations, coinfections, prior use of anti-TB medications, inadequate absorption of medication, underlying disease, and noncompliance with anti-TB drugs. == Mechanism of drug resistance == The TB bacterium has natural defenses against some drugs, and can acquire drug resistance through genetic mutations. The bacterium does not have the ability to transfer genes for resistance between organisms through plasmids (see horizontal transfer). Some mechanisms of drug resistance include: Cell wall: The cell wall of M. tuberculosis (TB) contains complex lipid molecules which act as a barrier to stop drugs from entering the cell. In order to lessen its vulnerability, M. tuberculosis can also stop medications from penetrating its cells. RIF resistance is linked to numerous genes and proteins that are involved in the formation of cell walls. Maintaining the M. tuberculosis cell wall is a major function of the PE11 protein. It is hypothesized that upregulating the production of PE11 protein can decrease the quantity of antibiotics that enter M. tuberculosis. The expression of M. tuberculosis PE11 protein in M. smegmatis can generate raised resistance levels to several antibiotics, including RIF. Drug modifying & inactivating enzymes: The TB genome codes for enzymes (proteins) that inactivate drug molecules. These enzymes are usually phosphorylate, acetylate, or adenylate drug compounds. Drug efflux systems: The TB cell contains molecular systems that actively pump drug molecules out of the cell. Mutations: Spontaneous mutations in the TB genome can alter proteins which are the target of drugs, making the bacteria drug-resistant. One example is a mutation in the rpoB gene, which encodes the beta subunit of the bacterium's RNA polymerase enzyme. In non-resistant TB, rifampin binds the beta subunit of RNA polymerase and disrupts transcription elongation. Mutation in the rpoB gene changes the sequence of amino acids and eventual conformation, or arrangement, of the beta subunit. In this case, rifampin can no longer bind or prevent transcription, and the bacterium is resistant. Other mutations make the bacterium resistant to other drugs. For example, there are many mutations that confer resistance to isoniazid (INH), including in the genes katG, inhA, ahpC and others. Amino acid replacements in the NADH binding site of InhA apparently result in INH resistance by preventing the inhibition of mycolic acid biosynthesis, which the bacterium uses in its cell wall. Mutations in the katG gene make the enzyme catalase peroxidase unable to convert INH to its biologically active form. Hence, INH is ineffective and the bacterium is resistant. The discovery of new molecular targets is essential to overcome drug-resistance problems. In some TB bacteria, the acquisition of these mutations can be explained by other mutations in the DNA recombination, recognition and repair machinery. Mutations in these genes allow the bacteria to have a higher overall mutation rate and to accumulate mutations that cause drug resistance more quickly. == Extensively drug-resistant TB == MDR-TB can become resistant to the major second-line TB drug groups: fluoroquinolones (moxifloxacin, ofloxacin) and injectable aminoglycoside or polypeptide drugs (amikacin, capreomycin, kanamycin). When MDR-TB is resistant to at least one drug from each group, it is classified as extensively drug-resistant tuberculosis (XDR-TB). WHO has revised the definitions of pre-XDR-TB and XDR-TB in 2021 as following: Pre-XDR-TB: TB caused by Mycobacterium tuberculosis (M. tuberculosis) strains that fulfill the definition of MDR/RR-TB and which are also resistant to any fluoroquinolone. XDR-TB: TB caused by Mycobacterium tuberculosis (M. tuberculosis) strains that fulfill the definition of MDR/RR-TB and which are also resistant to any fluoroquinolone and at least one additional Group A drug. The Group A drugs are currently levofloxacin or moxifloxacin, bedaquiline and linezolid, therefore XDR-TB is MDR/RR-TB that is resistant to a fluoroquinolone and at least one of bedaquiline or linezolid (or both). In a study of MDR-TB patients from 2005 to 2008 in various countries, 43.7% had resistance to at least one second-line drug. About 9% of MDR-TB cases are resistant to a drug from both classes and classified as XDR-TB. In the past 10 years TB strains have emerged in Italy, Iran, India, and South Africa which are resistant to all available first and second line TB drugs, classified as totally drug-resistant tuberculosis, though there is some controversy over this term. Increasing levels of resistance in TB strains threaten to complicate the current global public health approaches to TB control. New drugs are being developed to treat extensively resistant forms but major improvements in detection, diagnosis, and treatment will be needed. There have been reports of totally drug-resistant tuberculosis, but such strains of TB are not recognized by the WHO. == Prevention == There are several ways that drug resistance to TB, and drug resistance in general, can be prevented: Rapid diagnosis & treatment of TB: One of the greatest risk factors for drug-resistant TB is problems in treatment and diagnosis, especially in developing countries. If TB is identified and treated soon, drug resistance can be avoided. Completion of treatment: Previous treatment of TB is an indicator of MDR TB. If the patient does not complete their antibiotic treatment, or if the physician does not prescribe the proper antibiotic regimen, resistance can develop. Also, drugs that are of poor quality or less in quantity, especially in developing countries, contribute to MDR TB. Identifying and diagnosing patients with HIV/AIDS as soon as possible. They lack the immunity to fight the TB infection and are at great risk of developing drug resistance. Identifying contacts who could have contracted TB: family members, people in close contact, etc. Research: Much research and funding is needed in the diagnosis, prevention and treatment of TB and MDR TB. "Opponents of a universal tuberculosis treatment, reasoning from misguided notions of cost-effectiveness, fail to acknowledge that MDRTB is not a disease of poor people in distant places. The disease is infectious and airborne. Treating only one group of patients looks inexpensive in the short run, but will prove disastrous for all in the long run." Paul Farmer === DOTS-Plus === Community-based treatment programs such as DOTS-Plus, a MDR-TB-specialized treatment using the popular Directly Observed Therapy – Short Course (DOTS) initiative, have shown considerable success in the world. In these locales, these programs have proven to be a good option for proper treatment of MDR-TB in poor, rural areas. A successful example has been in Lima, Peru, where the program has seen cure rates of over 80%. However, the DOTS program administered in the Republic of Georgia uses passive case finding. This means that the system depends on patients coming to health care providers, without conducting compulsory screenings. As medical anthropologists like Erin Koch have shown, this form of implementation does not suit all cultural structures. They urge that the DOTS protocol be constantly reformed in the context of local practices, forms of knowledge and everyday life. == Treatment == Usually, multidrug-resistant tuberculosis can be cured with long treatments of second-line drugs, but these are more expensive than first-line drugs and have more adverse effects. The treatment and prognosis of MDR-TB are much more akin to those for cancer than to those for infection. MDR-TB has a mortality rate of about 15% with treatment, which further depends on a number of factors, including: How many drugs the organism is resistant to (the fewer the better) How many drugs the patient is given (patients treated with five or more drugs do better) The expertise and experience of the physician responsible How co-operative the patient is with treatment (treatment is arduous and long, and requires persistence and determination on the part of the patient) Whether the patient is HIV-positive or not (HIV co-infection is associated with increased mortality). The majority of patients with multidrug-resistant tuberculosis do not receive treatment, as they are found in underdeveloped countries or in poverty. Denial of treatment remains a difficult human rights issue, as the high cost of second-line medications often precludes those who cannot afford therapy. A study of cost-effective strategies for tuberculosis control supported three major policies. First, the treatment of smear-positive cases in DOTS programs must be the foundation of any tuberculosis control approach, and should be a basic practice for all control programs. Second, there is a powerful economic case for treating smear-negative and extra-pulmonary cases in DOTS programs along with treating smear-negative and extra-pulmonary cases in DOTS programs as a new WHO "STOP TB" approach and the second global plan for tuberculosis control. Last but not least, the study shows that a significant scaling-up of all interventions is needed in the next 10 years if the millennium development goal and related goals for tuberculosis control are to be achieved. If the case detection rate can be improved, this will guarantee that people who gain access to treatment facilities are covered and that coverage is widely distributed to people who do not now have access. In general, treatment courses are measured in months to years; MDR-TB may require surgery, and death rates remain high despite optimal treatment. However, good outcomes for patients are still possible. The treatment of MDR-TB must be undertaken by physicians experienced in the treatment of MDR-TB. Mortality and morbidity in patients treated in non-specialist centers are significantly higher than those of patients treated in specialist centers. Treatment of MDR-TB must be done on the basis of sensitivity testing: it is impossible to treat such patients without this information. When treating a patient with suspected MDR-TB, pending the result of laboratory sensitivity testing, the patient could be started on SHREZ (Streptomycin+ isonicotinyl Hydrazine+ Rifampicin+Ethambutol+ pyraZinamide) and moxifloxacin with cycloserine. There is evidence that previous therapy with a drug for more than a month is associated with diminished efficacy of that drug regardless of in vitro tests indicating susceptibility. Hence, a detailed knowledge of the treatment history of each patient is essential. In addition to the obvious risks (i.e., known exposure to a patient with MDR-TB), risk factors for MDR-TB include HIV infection, previous incarceration, failed TB treatment, failure to respond to standard TB treatment, and relapse following standard TB treatment. A gene probe for rpoB is available in some countries. This serves as a useful marker for MDR-TB, because isolated RMP resistance is rare (except when patients have a history of being treated with rifampicin alone). If the results of a gene probe (rpoB) are known to be positive, then it is reasonable to omit RMP and to use SHEZ+MXF+cycloserine. The reason for maintaining the patient on INH is that INH is so potent in treating TB that it is foolish to omit it until there is microbiological proof that it is ineffective (even though isoniazid resistance so commonly occurs with rifampicin resistance). For treatment of RR- and MDT-TB, WHO treatment guidelines are as follows: "a regimen with at least five effective TB medicines during the intensive phase is recommended, including pyrazinamide and four core second-line TB medicines – one chosen from Group A, one from Group B, and at least two from Group C3 (conditional recommendation, very low certainty in the evidence). If the minimum number of effective TB medicines cannot be composed as given above, an agent from Group D2 and other agents from Group D3 may be added to bring the total to five. It is recommended that the regimen be further strengthened with high-dose isoniazid and/or ethambutol (conditional recommendation, very low certainty in the evidence)." Medicines recommended are the following: Group A: Fluoroquinolones (levofloxacin, moxifloxicin), linezolid, bedaquiline Group B: Clofazimine, cycloserine/terizidone Group C: Other core second-line agents (ethambutol, delamanid, pyrazinamide, imipenem-cilastatin/meropenem, amikacin/streptomycin, ethionamide/prothionamide, p-aminosalicylic acid) For patients with RR-TB or MDR-TB, "not previously treated with second-line drugs and in whom resistance to fluoroquinolones and second-line injectable agents was excluded or is considered highly unlikely, a shorter MDR-TB regimen of 9–12 months may be used instead of the longer regimens (conditional recommendation, very low certainty in the evidence)." In general, resistance to one drug within a class means resistance to all drugs within that class, but a notable exception is rifabutin: Rifampicin-resistance does not always mean rifabutin-resistance, and the laboratory should be asked to test for it. It is possible to use only one drug within each drug class. If it is difficult finding five drugs to treat then the clinician can request that high-level INH-resistance be looked for. If the strain has only low-level INH-resistance (resistance at 0.2 mg/L INH, but sensitive at 1.0 mg/L INH), then high dose INH can be used as part of the regimen. When counting drugs, PZA and interferon count as zero; that is to say, when adding PZA to a four-drug regimen, another drug must be chosen to make five. It is not possible to use more than one injectable (STM, capreomycin or amikacin), because the toxic effect of these drugs is additive: If possible, the aminoglycoside should be given daily for a minimum of three months (and perhaps thrice weekly thereafter). Ciprofloxacin should not be used in the treatment of tuberculosis if other fluoroquinolones are available. As of 2008, Cochrane reports that trials of other fluoroquinolones are ongoing. While Rifampin is an effective drug, lack of adherence has led to relapse. This is why the use of various first-line drugs, along with developing new drugs that are specific towards drug-resistant strains, is essential. There are a number of new anti-TB medications that are currently in the developmental stage that are directed to treat drug resistant strains; a few of these drugs are PA-824 (now pretomanid), OPC-67683 (now delamanid), and R207910 (now bedaquiline), all of which are in Phase II of development. Pretomanid and delamanid are both in the nitroimidazole class and have mechanisms involving bioactive reductive activation. Bedaquiline is a diarylquinoline that has a different mechanism; this drug directly inhibits energy production, so this drug may be a better option because it may not require as long of a treatment course as other drugs. When it is not possible to find five drugs from the lists above; the drugs imipenem, co-amoxiclav, clofazimine, prochlorperazine, metronidazole have been used in desperation, though it is not certain whether they are effective at all. There is no intermittent regimen validated for use in MDR-TB, but clinical experience is that giving injectable drugs for five days a week (because there is no-one available to give the drug at weekends) does not seem to result in inferior results. Directly observed therapy helps to improve outcomes in MDR-TB and should be considered an integral part of the treatment of MDR-TB. Patients with MDR-TB should be isolated in negative-pressure rooms, if possible. Patients with MDR-TB should not be accommodated on the same ward as immunosuppressed patients (HIV-infected patients, or patients on immunosuppressive drugs). Careful monitoring of compliance with treatment is crucial to the management of MDR-TB (and some physicians insist on hospitalisation if only for this reason). Some physicians will insist that these patients remain isolated until their sputum is smear-negative, or even culture-negative (which may take many months, or even years). Keeping these patients in hospital for weeks (or months) on end may be a practical or physical impossibility, and the final decision depends on the clinical judgement of the physician treating that patient. The attending physician should make full use of therapeutic drug monitoring (in particular, of the aminoglycosides) both to monitor compliance and to avoid toxic effects. Response to treatment must be obtained by repeated sputum cultures (monthly if possible). Some supplements may be useful as adjuncts in the treatment of tuberculosis, but, for the purposes of counting drugs for MDR-TB, they count as zero (if four drugs are already in the regimen, it may be beneficial to add arginine or vitamin D or both, but another drug will be needed to make five). Supplements include: arginine (peanuts are a good source), vitamin D, Dzherelo, V5 Immunitor. On 28 December 2012, the U.S. Food and Drug Administration (FDA) approved bedaquiline (marketed as Sirturo by Johnson & Johnson) to treat multidrug-resistant tuberculosis, the first new treatment in 40 years. Sirturo is to be used in a combination therapy for patients who have failed standard treatment and have no other options. Sirturo is an adenosine triphosphate synthase (ATP synthase) inhibitor. The resurgence of tuberculosis in the United States, the advent of HIV-related tuberculosis, and the development of strains of TB resistant to the first-line therapies developed in recent decades serve to reinforce the thesis that Mycobacterium tuberculosis, the causative organism, makes its own preferential option for the poor. The simple truth is that almost all tuberculosis deaths result from a lack of access to existing effective therapy. Treatment success rates remain unacceptably low globally with variation between regions. 2016 data published by the WHO reported treatment success rates of multidrug-resistant TB globally. For those started on treatment for multidrug-resistant TB 56% successfully completed treatment, either treatment course completion or eradication of disease; 15% of those died while in treatment; 15% were lost to follow-up; 8% had treatment failure and there was no data on the remaining 6%. Treatment success rate was highest in the World Health Organization Mediterranean region at 65%. Treatment success rates were lower than 50% in Ukraine, Mozambique, Indonesia and India. Areas with poor TB surveillance infrastructure had higher rates of loss to follow-up of treatment. 57 countries reported outcomes for patients started on extreme-drug resistant TB, this included 9258 patients. 39% completed treatment successfully, 26% of patients died and treatment failed for 18%. 84% of the extreme drug resistant cohort was made up of only three countries; India, Russian Federation and Ukraine. Shorter treatment regimes for MDR-TB have been found to be beneficial having higher treatment success rates. === Surgery === In cases of extremely resistant disease, surgery to remove infection portions of the lung is, in general, the final option. Early surgical treatments beginning in the 19th century include inducing lung collapse, as standing tissue heals faster than tissue in use, called artificial pneumothorax. Shrinking the lung cavity, thoracoplasty, to fill void space caused by tuberculosis damage was done by either removing ribs, raising the diaphragm, or implanting fluids or solid materials into lung cavity as a less invasive alternative to artificial pneumothorax. These treatments fell out of favor with the invention anti-tuberculosis drugs in the mid-20th century and have not seen a revival with MDR-TB, except for thoracoplasty done with implanted muscle tissue. Surgically removing portions of the lung, called lung resectioning, was a mostly theoretical possibility until the improved surgical tools and techniques of the mid-20th century. As of 2016, surgery is typically performed after 6–8 months of unsuccessful anti-TB treatment by other means. Surgical treatment has a high success rate, upwards of 80%, but a similarly high failure rate of upwards of 10% including the risk of death. Surgery is first focused on stabilizing cavities, or "destroyed lung", caused by the disease, followed by the removal of tuberculomas, and then the removal of fluid and pus build up. Tuberculosis and lung cancer can coexist in patients as a possible complication, however the surgical therapies are similar as lung cancer surgery has its roots in aforementioned tuberculosis treatments. == Epidemiology == Cases of MDR tuberculosis have been reported in every country surveyed. MDR-TB most commonly develops in the course of TB treatment, and is most commonly due to doctors giving inappropriate treatment, or patients missing doses or failing to complete their treatment. Because MDR tuberculosis is an airborne pathogen, persons with active, pulmonary tuberculosis caused by a multidrug-resistant strain can transmit the disease through coughing. TB strains are often less fit and less transmissible, and outbreaks occur more readily in people with weakened immune systems (e.g., patients with HIV). Outbreaks among non-immunocompromised healthy people do occur, but are less common. As of 2013, 3.7% of new tuberculosis cases have MDR-TB. Levels are much higher in those previously treated for tuberculosis – about 20%. WHO estimates that there were about 0.5 million new MDR-TB cases in the world in 2011. About 60% of these cases occurred in Brazil, China, India, the Russian Federation and South Africa alone. In Moldova, the crumbling health system has led to the rise of MDR-TB. In 2013, the Mexico–United States border was noted to be "a very hot region for drug resistant TB", though the number of cases remained small. A study in Los Angeles, California, found that only 6% of cases of MDR-TB were clustered. Likewise, the appearance of high rates of MDR-TB in New York City in the early 1990s was associated with the explosion of AIDS in that area. In New York City, a report issued by city health authorities states that fully 80 percent of all MDR-TB cases could be traced back to prisons and homeless shelters. When patients have MDR-TB, they require longer periods of treatment. Several of the less powerful second-line drugs, which are required to treat MDR-TB, are also more toxic, with side effects such as nausea, abdominal pain, and even psychosis. The Partners in Health team had treated patients in Peru who were sick with strains that were resistant to ten and even twelve drugs. Most such patients require adjuvant surgery for any hope of a cure. === Somalia === MDR-TB is widespread in Somalia, where 8.7% of newly discovered TB cases are resistant to Rifampicin and Isoniazid, in patients which were treated previously the share was 47%. Refugees from Somalia brought an until then unknown variant of MDR tuberculosis with them to Europe. A few number of cases in four different countries were considered by the European Centre for Disease Prevention and Control to pose no risk to the native population. === Russian prisons === One of the so-called "hot-spots" of drug-resistant tuberculosis is within the Russian prison system. Infectious disease researchers Nachega & Chaisson report that 10% of the one million prisoners within the system have active TB. One of their studies found that 75% of newly diagnosed inmates with TB are resistant to at least one drug; 40% of new cases are multidrug-resistant. In 1997, TB accounted for almost half of all Russian prison deaths, and as Bobrik et al. point out in their public health study, the 90% reduction in TB incidence contributed to a consequential fall in the prisoner death rate in the years following 1997. Baussano et al. articulate that concerning statistics like these are especially worrisome because spikes in TB incidence in prisons are linked to corresponding outbreaks in surrounding communities. Additionally, rising rates of incarceration, especially in Central Asian and Eastern European countries like Russia, have been correlated with higher TB rates in civilian populations. Even as the DOTS program is expanded throughout Russian prisons, researchers such as Shin et al. have noted that wide-scale interventions have not had their desired effect, especially with regard to the spread of drug-resistant strains of TB. ==== Contributing factors ==== There are several elements of the Russian prison system that enable the spread of MDR-TB and heighten its severity. Overcrowding in prisons is especially conducive to the spread of tuberculosis; an inmate in a prison hospital has (on average) 3 meters of personal space, and an inmate in a correctional colony has 2 meters. Specialized hospitals and treatment facilities within the prison system, known as TB colonies, are intended to isolate infected prisoners to prevent transmission; however, as Ruddy et al. demonstrate, there are not enough of these colonies to sufficiently protect staff and other inmates. Additionally, many cells lack adequate ventilation, which increases likelihood of transmission. Bobrik et al. have also noted food shortages within prisons, which deprive inmates of the nutrition necessary for healthy functioning. Comorbidity of HIV within prison populations has also been shown to worsen health outcomes. Nachega & Chaisson articulate that while HIV-infected prisoners are not more susceptible MDR-TB infection, they are more likely to progress to serious clinical illness if infected. According to Stern, HIV infection is 75 times more prevalent in Russian prison populations than in the civilian population. Therefore, prison inmates are both more likely to become infected with MDR-TB initially and to experience severe symptoms because of previous exposure to HIV. Shin et al. emphasize another factor in MDR-TB prevalence in Russian prisons: alcohol and substance use. Ruddy et al. showed that risk for MDR-TB is three times higher among recreational drug users than non-users. Shin et al.'s study demonstrated that alcohol usage was linked to poorer outcomes in MDR-TB treatment; they also noted that a majority of subjects within their study (many of whom regularly used alcohol) were nevertheless cured by their aggressive treatment regimen. Non-compliance with treatment plans is often cited as a contributor to MDR-TB transmission and mortality. Indeed, of the 80 newly released TB-infected inmates in Fry et al.'s study, 73.8% did not report visiting a community dispensary for further treatment. Ruddy et al. cite release from facilities as one of the main causes of interruption in prisoner's TB treatment, in addition to non-compliance within the prison and upon reintegration into civilian life. Fry et al.'s study also listed side effects of TB treatment medications (especially in HIV positive individuals), financial worries, housing insecurities, family problems, and fear of arrest as factors that prevented some prisoners from properly adhering to TB treatment. They also note that some researchers have argued that the short-term gains TB-positive prisoners receive, such as better food or work exclusion, may dis-incentivize becoming cured. In their World Health Organization article, Gelmanova et al. posit that non-adherence to TB treatment indirectly contributes to bacterial resistance. Although ineffective or inconsistent treatment does not "create" resistant strains, mutations within the high bacterial load in non-adherent prisoners can cause resistance. Nachega & Chaisson argue that inadequate TB control programs are the strongest driver of MDR-TB incidence. They note that prevalence of MDR-TB is 2.5 times higher in areas of poorly controlled TB. Russian-based therapy (i.e., not DOTS) has been criticized by Kimerling et al. as "inadequate" in properly controlling TB incidence and transmission. Bobrik et al. note that treatment for MDR-TB is equally inconsistent; the second-line drugs used to treat the prisoners lack specific treatment guidelines, infrastructure, training, or follow-up protocols for prisoners reentering civilian life. ==== Policy impacts ==== As Ruddy et al. note, Russia's early 2000s penal reforms could greatly reduce the number of inmates inside prison facilities and thus increase the number of ex-convicts integrated into civilian populations. Because the incidence of MDR-TB is strongly predicted by past imprisonment, the health of Russian society will be greatly impacted by this change. Formerly incarcerated Russians will re-enter civilian life and remain within that sphere; as they live as civilians, they will infect others with the contagions they were exposed to in prison. Researcher Vivian Stern argues that the risk of transmission from prison populations to the general public calls for an integration of prison healthcare and national health services to better control both TB and MDR-TB. While second-line drugs necessary for treating MDR-TB are arguably more expensive than a typical regimen of DOTS therapy, infectious disease specialist Paul Farmer posits that the outcome of leaving infected prisoners untreated could cause a massive outbreak of MDR-TB in civilian populations, thereby inflicting a heavy toll on society. Additionally, as MDR-TB spreads, the threat of the emergence of totally-drug-resistant TB becomes increasingly apparent. == See also == 2007 tuberculosis scare Drug resistance MRSA Vancomycin-resistant enterococcus (VRE) Totally drug-resistant tuberculosis (TDR-TB) Medicines Patent Pool == References == Notes Farmer, Paul (1999). Infections and inequalities : the modern plagues. Berkeley, California, United States: University of California Press. ISBN 978-0-520-22913-6. Farmer, Paul (2005). Pathologies of Power: health, human rights, and the new war on the poor. Berkeley, California, United States: University of California Press. ISBN 978-0-520-93147-3. Garrett, Laurie (1994). The coming plague : newly emerging diseases in a world out of balance. New York, New York, United States: Farrar, Straus and Giroux. ISBN 978-0-374-12646-9. Garrett, Laurie (2000). Betrayal of trust: the collapse of global public health. New York, New York, United States: Hyperion Books. ISBN 978-0-7868-6522-2. == Further reading == American Lung Association (April 2007). "Multidrug Resistant Tuberculosis Fact Sheet". Archived from the original on 30 November 2006. Retrieved 29 November 2007. == External links == Video: Drug-Resistant TB in Russia 24 July 2007, Woodrow Wilson Center event featuring Salmaan Keshavjee and Murray Feshbach MDR-TB (DOTS Plus) protocol followed under RNTCP in India (PDF) "The Strange, Isolated Life of a Tuberculosis Patient in the 21st Century", Buzzfeed	Wikipedia/Multi-drug-resistant_tuberculosis
In molecular biology and genetics, transformation is the genetic alteration of a cell resulting from the direct uptake and incorporation of exogenous genetic material from its surroundings through the cell membrane(s). For transformation to take place, the recipient bacterium must be in a state of competence, which might occur in nature as a time-limited response to environmental conditions such as starvation and cell density, and may also be induced in a laboratory. Transformation is one of three processes that lead to horizontal gene transfer, in which exogenous genetic material passes from one bacterium to another, the other two being conjugation (transfer of genetic material between two bacterial cells in direct contact) and transduction (injection of foreign DNA by a bacteriophage virus into the host bacterium). In transformation, the genetic material passes through the intervening medium, and uptake is completely dependent on the recipient bacterium. As of 2014 about 80 species of bacteria were known to be capable of transformation, about evenly divided between Gram-positive and Gram-negative bacteria; the number might be an overestimate since several of the reports are supported by single papers. "Transformation" may also be used to describe the insertion of new genetic material into nonbacterial cells, including animal and plant cells; however, because "transformation" has a special meaning in relation to animal cells, indicating progression to a cancerous state, the process is usually called "transfection". == History == Transformation in bacteria was first demonstrated in 1928 by the British bacteriologist Frederick Griffith. Griffith was interested in determining whether injections of heat-killed bacteria could be used to vaccinate mice against pneumonia. However, he discovered that a non-virulent strain of Streptococcus pneumoniae could be made virulent after being exposed to heat-killed virulent strains. Griffith hypothesized that some "transforming principle" from the heat-killed strain was responsible for making the harmless strain virulent. In 1944 this "transforming principle" was identified as being genetic by Oswald Avery, Colin MacLeod, and Maclyn McCarty. They isolated DNA from a virulent strain of S. pneumoniae and using just this DNA were able to make a harmless strain virulent. They called this uptake and incorporation of DNA by bacteria "transformation" (See Avery-MacLeod-McCarty experiment) The results of Avery et al.'s experiments were at first skeptically received by the scientific community and it was not until the development of genetic markers and the discovery of other methods of genetic transfer (conjugation in 1947 and transduction in 1953) by Joshua Lederberg that Avery's experiments were accepted. It was originally thought that Escherichia coli, a commonly used laboratory organism, was refractory to transformation. However, in 1970, Morton Mandel and Akiko Higa showed that E. coli may be induced to take up DNA from bacteriophage λ without the use of helper phage after treatment with calcium chloride solution. Two years later in 1972, Stanley Norman Cohen, Annie Chang and Leslie Hsu showed that CaCl2 treatment is also effective for transformation of plasmid DNA. The method of transformation by Mandel and Higa was later improved upon by Douglas Hanahan. The discovery of artificially induced competence in E. coli created an efficient and convenient procedure for transforming bacteria which allows for simpler molecular cloning methods in biotechnology and research, and it is now a routinely used laboratory procedure. Transformation using electroporation was developed in the late 1980s, increasing the efficiency of in-vitro transformation and increasing the number of bacterial strains that could be transformed. Transformation of animal and plant cells was also investigated with the first transgenic mouse being created by injecting a gene for a rat growth hormone into a mouse embryo in 1982. In 1897 a bacterium that caused plant tumors, Agrobacterium tumefaciens, was discovered and in the early 1970s the tumor-inducing agent was found to be a DNA plasmid called the Ti plasmid. By removing the genes in the plasmid that caused the tumor and adding in novel genes, researchers were able to infect plants with A. tumefaciens and let the bacteria insert their chosen DNA into the genomes of the plants. Not all plant cells are susceptible to infection by A. tumefaciens, so other methods were developed, including electroporation and micro-injection. Particle bombardment was made possible with the invention of the Biolistic Particle Delivery System (gene gun) by John Sanford in the 1980s. == Definitions == Transformation is one of three forms of horizontal gene transfer that occur in nature among bacteria, in which DNA encoding for a trait passes from one bacterium to another and is integrated into the recipient genome by homologous recombination; the other two are transduction, carried out by means of a bacteriophage, and conjugation, in which a gene is passed through direct contact between bacteria. In transformation, the genetic material passes through the intervening medium, and uptake is completely dependent on the recipient bacterium. Competence refers to a temporary state of being able to take up exogenous DNA from the environment; it may be induced in a laboratory. It appears to be an ancient process inherited from a common prokaryotic ancestor that is a beneficial adaptation for promoting recombinational repair of DNA damage, especially damage acquired under stressful conditions. Natural genetic transformation appears to be an adaptation for repair of DNA damage that also generates genetic diversity. Transformation has been studied in medically important Gram-negative bacteria species such as Helicobacter pylori, Legionella pneumophila, Neisseria meningitidis, Neisseria gonorrhoeae, Haemophilus influenzae and Vibrio cholerae. It has also been studied in Gram-negative species found in soil such as Pseudomonas stutzeri, Acinetobacter baylyi, and Gram-negative plant pathogens such as Ralstonia solanacearum and Xylella fastidiosa. Transformation among Gram-positive bacteria has been studied in medically important species such as Streptococcus pneumoniae, Streptococcus mutans, Staphylococcus aureus and Streptococcus sanguinis and in Gram-positive soil bacterium Bacillus subtilis. It has also been reported in at least 30 species of Pseudomonadota distributed in several different classes. The best studied Pseudomonadota with respect to transformation are the medically important human pathogens Neisseria gonorrhoeae, Haemophilus influenzae, and Helicobacter pylori. "Transformation" may also be used to describe the insertion of new genetic material into nonbacterial cells, including animal and plant cells; however, because "transformation" has a special meaning in relation to animal cells, indicating progression to a cancerous state, the process is usually called "transfection". == Natural competence and transformation == Naturally competent bacteria carry sets of genes that provide the protein machinery to bring DNA across the cell membrane(s). The transport of the exogenous DNA into the cells may require proteins that are involved in the assembly of type IV pili and type II secretion system, as well as DNA translocase complex at the cytoplasmic membrane. Due to the differences in structure of the cell envelope between Gram-positive and Gram-negative bacteria, there are some differences in the mechanisms of DNA uptake in these cells, however most of them share common features that involve related proteins. The DNA first binds to the surface of the competent cells on a DNA receptor, and passes through the cytoplasmic membrane via DNA translocase. Only single-stranded DNA may pass through, the other strand being degraded by nucleases in the process. The translocated single-stranded DNA may then be integrated into the bacterial chromosomes by a RecA-dependent process. In Gram-negative cells, due to the presence of an extra membrane, the DNA requires the presence of a channel formed by secretins on the outer membrane. Pilin may be required for competence, but its role is uncertain. The uptake of DNA is generally non-sequence specific, although in some species the presence of specific DNA uptake sequences may facilitate efficient DNA uptake. === Natural transformation === Natural transformation is a bacterial adaptation for DNA transfer that depends on the expression of numerous bacterial genes whose products appear to be responsible for this process. In general, transformation is a complex, energy-requiring developmental process. In order for a bacterium to bind, take up and recombine exogenous DNA into its chromosome, it must become competent, that is, enter a special physiological state. Competence development in Bacillus subtilis requires expression of about 40 genes. The DNA integrated into the host chromosome is usually (but with rare exceptions) derived from another bacterium of the same species, and is thus homologous to the resident chromosome. In B. subtilis the length of the transferred DNA is greater than 1271 kb (more than 1 million bases). The length transferred is likely double stranded DNA and is often more than a third of the total chromosome length of 4215 kb. It appears that about 7-9% of the recipient cells take up an entire chromosome. The capacity for natural transformation appears to occur in a number of prokaryotes, and thus far 67 prokaryotic species (in seven different phyla) are known to undergo this process. Competence for transformation is typically induced by high cell density and/or nutritional limitation, conditions associated with the stationary phase of bacterial growth. Transformation in Haemophilus influenzae occurs most efficiently at the end of exponential growth as bacterial growth approaches stationary phase. Transformation in Streptococcus mutans, as well as in many other streptococci, occurs at high cell density and is associated with biofilm formation. Competence in B. subtilis is induced toward the end of logarithmic growth, especially under conditions of amino acid limitation. Similarly, in Micrococcus luteus (a representative of the less well studied Actinomycetota phylum), competence develops during the mid-late exponential growth phase and is also triggered by amino acids starvation. By releasing intact host and plasmid DNA, certain bacteriophages are thought to contribute to transformation. === Transformation, as an adaptation for DNA repair === Competence is specifically induced by DNA damaging conditions. For instance, transformation is induced in Streptococcus pneumoniae by the DNA damaging agents mitomycin C (a DNA cross-linking agent) and fluoroquinolone (a topoisomerase inhibitor that causes double-strand breaks). In B. subtilis, transformation is increased by UV light, a DNA damaging agent. In Helicobacter pylori, ciprofloxacin, which interacts with DNA gyrase and introduces double-strand breaks, induces expression of competence genes, thus enhancing the frequency of transformation Using Legionella pneumophila, Charpentier et al. tested 64 toxic molecules to determine which of these induce competence. Of these, only six, all DNA damaging agents, caused strong induction. These DNA damaging agents were mitomycin C (which causes DNA inter-strand crosslinks), norfloxacin, ofloxacin and nalidixic acid (inhibitors of DNA gyrase that cause double-strand breaks), bicyclomycin (causes single- and double-strand breaks), and hydroxyurea (induces DNA base oxidation). UV light also induced competence in L. pneumophila. Charpentier et al. suggested that competence for transformation probably evolved as a DNA damage response. Natural transformation in the extraordinarily radiation resistant bacterium Deinococcus radiodurans is associated with the repair of DNA damage under stressful conditions. Logarithmically growing bacteria differ from stationary phase bacteria with respect to the number of genome copies present in the cell, and this has implications for the capability to carry out an important DNA repair process. During logarithmic growth, two or more copies of any particular region of the chromosome may be present in a bacterial cell, as cell division is not precisely matched with chromosome replication. The process of homologous recombinational repair (HRR) is a key DNA repair process that is especially effective for repairing double-strand damages, such as double-strand breaks. This process depends on a second homologous chromosome in addition to the damaged chromosome. During logarithmic growth, a DNA damage in one chromosome may be repaired by HRR using sequence information from the other homologous chromosome. Once cells approach stationary phase, however, they typically have just one copy of the chromosome, and HRR requires input of homologous template from outside the cell by transformation. To test whether the adaptive function of transformation is repair of DNA damages, a series of experiments were carried out using B. subtilis irradiated by UV light as the damaging agent (reviewed by Michod et al. and Bernstein et al.) The results of these experiments indicated that transforming DNA acts to repair potentially lethal DNA damages introduced by UV light in the recipient DNA. The particular process responsible for repair was likely HRR. Transformation in bacteria can be viewed as a primitive sexual process, since it involves interaction of homologous DNA from two individuals to form recombinant DNA that is passed on to succeeding generations. Bacterial transformation in prokaryotes may have been the ancestral process that gave rise to meiotic sexual reproduction in eukaryotes (see Evolution of sexual reproduction; Meiosis.) == Methods and mechanisms of transformation in laboratory == === Bacterial === Artificial competence can be induced in laboratory procedures that involve making the cell passively permeable to DNA by exposing it to conditions that do not normally occur in nature. Typically the cells are incubated in a solution containing divalent cations (often calcium chloride) under cold conditions, before being exposed to a heat pulse (heat shock). Calcium chloride partially disrupts the cell membrane, which allows the recombinant DNA to enter the host cell. Cells that are able to take up the DNA are called competent cells. It has been found that growth of Gram-negative bacteria in 20 mM Mg reduces the number of protein-to-lipopolysaccharide bonds by increasing the ratio of ionic to covalent bonds, which increases membrane fluidity, facilitating transformation. The role of lipopolysaccharides here are verified from the observation that shorter O-side chains are more effectively transformed – perhaps because of improved DNA accessibility. The surface of bacteria such as E. coli is negatively charged due to phospholipids and lipopolysaccharides on its cell surface, and the DNA is also negatively charged. One function of the divalent cation therefore would be to shield the charges by coordinating the phosphate groups and other negative charges, thereby allowing a DNA molecule to adhere to the cell surface. DNA entry into E. coli cells is through channels known as zones of adhesion or Bayer's junction, with a typical cell carrying as many as 400 such zones. Their role was established when cobalamine (which also uses these channels) was found to competitively inhibit DNA uptake. Another type of channel implicated in DNA uptake consists of poly (HB):poly P:Ca. In this poly (HB) is envisioned to wrap around DNA (itself a polyphosphate), and is carried in a shield formed by Ca ions. It is suggested that exposing the cells to divalent cations in cold condition may also change or weaken the cell surface structure, making it more permeable to DNA. The heat-pulse is thought to create a thermal imbalance across the cell membrane, which forces the DNA to enter the cells through either cell pores or the damaged cell wall. Electroporation is another method of promoting competence. In this method the cells are briefly shocked with an electric field of 10-20 kV/cm, which is thought to create holes in the cell membrane through which the plasmid DNA may enter. After the electric shock, the holes are rapidly closed by the cell's membrane-repair mechanisms. === Yeast === Most species of yeast, including Saccharomyces cerevisiae, may be transformed by exogenous DNA in the environment. Several methods have been developed to facilitate this transformation at high frequency in the lab. Yeast cells may be treated with enzymes to degrade their cell walls, yielding spheroplasts. These cells are very fragile but take up foreign DNA at a high rate. Exposing intact yeast cells to alkali cations such as those of caesium or lithium allows the cells to take up plasmid DNA. Later protocols adapted this transformation method, using lithium acetate, polyethylene glycol, and single-stranded DNA. In these protocols, the single-stranded DNA preferentially binds to the yeast cell wall, preventing plasmid DNA from doing so and leaving it available for transformation. Electroporation: Formation of transient holes in the cell membranes using electric shock; this allows DNA to enter as described above for bacteria. Enzymatic digestion or agitation with glass beads may also be used to transform yeast cells. Efficiency – Different yeast genera and species take up foreign DNA with different efficiencies. Also, most transformation protocols have been developed for baker's yeast, S. cerevisiae, and thus may not be optimal for other species. Even within one species, different strains have different transformation efficiencies, sometimes different by three orders of magnitude. For instance, when S. cerevisiae strains were transformed with 10 ug of plasmid YEp13, the strain DKD-5D-H yielded between 550 and 3115 colonies while strain OS1 yielded fewer than five colonies. === Plants === A number of methods are available to transfer DNA into plant cells. Some vector-mediated methods are: Agrobacterium-mediated transformation is the easiest and most simple plant transformation. Plant tissue (often leaves) are cut into small pieces, e.g. 10x10mm, and soaked for ten minutes in a fluid containing suspended Agrobacterium. The bacteria will attach to many of the plant cells exposed by the cut. The plant cells secrete wound-related phenolic compounds which in turn act to upregulate the virulence operon of the Agrobacterium. The virulence operon includes many genes that encode for proteins that are part of a Type IV secretion system that exports from the bacterium proteins and DNA (delineated by specific recognition motifs called border sequences and excised as a single strand from the virulence plasmid) into the plant cell through a structure called a pilus. The transferred DNA (called T-DNA) is piloted to the plant cell nucleus by nuclear localization signals present in the Agrobacterium protein VirD2, which is covalently attached to the end of the T-DNA at the Right border (RB). Exactly how the T-DNA is integrated into the host plant genomic DNA is an active area of plant biology research. Assuming that a selection marker (such as an antibiotic resistance gene) was included in the T-DNA, the transformed plant tissue can be cultured on selective media to produce shoots. The shoots are then transferred to a different medium to promote root formation. Once roots begin to grow from the transgenic shoot, the plants can be transferred to soil to complete a normal life cycle (make seeds). The seeds from this first plant (called the T1, for first transgenic generation) can be planted on a selective (containing an antibiotic), or if an herbicide resistance gene was used, could alternatively be planted in soil, then later treated with herbicide to kill wildtype segregants. Some plants species, such as Arabidopsis thaliana can be transformed by dipping the flowers or whole plant, into a suspension of Agrobacterium tumefaciens, typically strain C58 (C=Cherry, 58=1958, the year in which this particular strain of A. tumefaciens was isolated from a cherry tree in an orchard at Cornell University in Ithaca, New York). Though many plants remain recalcitrant to transformation by this method, research is ongoing that continues to add to the list the species that have been successfully modified in this manner. Viral transformation (transduction): Package the desired genetic material into a suitable plant virus and allow this modified virus to infect the plant. If the genetic material is DNA, it can recombine with the chromosomes to produce transformant cells. However, genomes of most plant viruses consist of single stranded RNA which replicates in the cytoplasm of infected cell. For such genomes this method is a form of transfection and not a real transformation, since the inserted genes never reach the nucleus of the cell and do not integrate into the host genome. The progeny of the infected plants is virus-free and also free of the inserted gene. Some vector-less methods include: Gene gun: Also referred to as particle bombardment, microprojectile bombardment, or biolistics. Particles of gold or tungsten are coated with DNA and then shot into young plant cells or plant embryos. Some genetic material will stay in the cells and transform them. This method also allows transformation of plant plastids. The transformation efficiency is lower than in Agrobacterium-mediated transformation, but most plants can be transformed with this method. Electroporation: Formation of transient holes in cell membranes using electric pulses of high field strength; this allows DNA to enter as described above for bacteria. === Fungi === There are some methods to produce transgenic fungi most of them being analogous to those used for plants. However, fungi have to be treated differently due to some of their microscopic and biochemical traits: A major issue is the dikaryotic state that parts of some fungi are in; dikaryotic cells contain two haploid nuclei, one of each parent fungus. If only one of these gets transformed, which is the rule, the percentage of transformed nuclei decreases after each sporulation. Fungal cell walls are quite thick hindering DNA uptake so (partial) removal is often required; complete degradation, which is sometimes necessary, yields protoplasts. Mycelial fungi consist of filamentous hyphae, which are, if at all, separated by internal cell walls interrupted by pores big enough to enable nutrients and organelles, sometimes even nuclei, to travel through each hypha. As a result, individual cells usually cannot be separated. This is problematic as neighbouring transformed cells may render untransformed ones immune to selection treatments, e.g. by delivering nutrients or proteins for antibiotic resistance. Additionally, growth (and thereby mitosis) of these fungi exclusively occurs at the tip of their hyphae which can also deliver issues. As stated earlier, an array of methods used for plant transformation do also work in fungi: Agrobacterium is not only capable of infecting plants but also fungi, however, unlike plants, fungi do not secrete the phenolic compounds necessary to trigger Agrobacterium so that they have to be added, e.g. in the form of acetosyringone. Thanks to development of an expression system for small RNAs in fungi the introduction of a CRISPR/CAS9-system in fungal cells became possible. In 2016 the USDA declared that it will not regulate a white button mushroom strain edited with CRISPR/CAS9 to prevent fruit body browning causing a broad discussion about placing CRISPR/CAS9-edited crops on the market. Physical methods like electroporation, biolistics ("gene gun"), sonoporation that uses cavitation of gas bubbles produced by ultrasound to penetrate the cell membrane, etc. are also applicable to fungi. === Animals === Introduction of DNA into animal cells is usually called transfection, and is discussed in the corresponding article. == Practical aspects of transformation in molecular biology == The discovery of artificially induced competence in bacteria allow bacteria such as Escherichia coli to be used as a convenient host for the manipulation of DNA as well as expressing proteins. Typically plasmids are used for transformation in E. coli. In order to be stably maintained in the cell, a plasmid DNA molecule must contain an origin of replication, which allows it to be replicated in the cell independently of the replication of the cell's own chromosome. The efficiency with which a competent culture can take up exogenous DNA and express its genes is known as transformation efficiency and is measured in colony forming unit (cfu) per μg DNA used. A transformation efficiency of 1×108 cfu/μg for a small plasmid like pUC19 is roughly equivalent to 1 in 2000 molecules of the plasmid used being transformed. In calcium chloride transformation, the cells are prepared by chilling cells in the presence of Ca2+ (in CaCl2 solution), making the cell become permeable to plasmid DNA. The cells are incubated on ice with the DNA, and then briefly heat-shocked (e.g., at 42 °C for 30–120 seconds). This method works very well for circular plasmid DNA. Non-commercial preparations should normally give 106 to 107 transformants per microgram of plasmid; a poor preparation will be about 104/μg or less, but a good preparation of competent cells can give up to ~108 colonies per microgram of plasmid. Protocols, however, exist for making supercompetent cells that may yield a transformation efficiency of over 109. The chemical method, however, usually does not work well for linear DNA, such as fragments of chromosomal DNA, probably because the cell's native exonuclease enzymes rapidly degrade linear DNA. In contrast, cells that are naturally competent are usually transformed more efficiently with linear DNA than with plasmid DNA. The transformation efficiency using the CaCl2 method decreases with plasmid size, and electroporation therefore may be a more effective method for the uptake of large plasmid DNA. Cells used in electroporation should be prepared first by washing in cold double-distilled water to remove charged particles that may create sparks during the electroporation process. === Selection and screening in plasmid transformation === Because transformation usually produces a mixture of relatively few transformed cells and an abundance of non-transformed cells, a method is necessary to select for the cells that have acquired the plasmid. The plasmid therefore requires a selectable marker such that those cells without the plasmid may be killed or have their growth arrested. Antibiotic resistance is the most commonly used marker for prokaryotes. The transforming plasmid contains a gene that confers resistance to an antibiotic that the bacteria are otherwise sensitive to. The mixture of treated cells is cultured on media that contain the antibiotic so that only transformed cells are able to grow. Another method of selection is the use of certain auxotrophic markers that can compensate for an inability to metabolise certain amino acids, nucleotides, or sugars. This method requires the use of suitably mutated strains that are deficient in the synthesis or utility of a particular biomolecule, and the transformed cells are cultured in a medium that allows only cells containing the plasmid to grow. In a cloning experiment, a gene may be inserted into a plasmid used for transformation. However, in such experiment, not all the plasmids may contain a successfully inserted gene. Additional techniques may therefore be employed further to screen for transformed cells that contain plasmid with the insert. Reporter genes can be used as markers, such as the lacZ gene which codes for β-galactosidase used in blue-white screening. This method of screening relies on the principle of α-complementation, where a fragment of the lacZ gene (lacZα) in the plasmid can complement another mutant lacZ gene (lacZΔM15) in the cell. Both genes by themselves produce non-functional peptides, however, when expressed together, as when a plasmid containing lacZ-α is transformed into a lacZΔM15 cells, they form a functional β-galactosidase. The presence of an active β-galactosidase may be detected when cells are grown in plates containing X-gal, forming characteristic blue colonies. However, the multiple cloning site, where a gene of interest may be ligated into the plasmid vector, is located within the lacZα gene. Successful ligation therefore disrupts the lacZα gene, and no functional β-galactosidase can form, resulting in white colonies. Cells containing successfully ligated insert can then be easily identified by its white coloration from the unsuccessful blue ones. Other commonly used reporter genes are green fluorescent protein (GFP), which produces cells that glow green under blue light, and the enzyme luciferase, which catalyzes a reaction with luciferin to emit light. The recombinant DNA may also be detected using other methods such as nucleic acid hybridization with radioactive RNA probe, while cells that expressed the desired protein from the plasmid may also be detected using immunological methods. == References == == External links == Bacterial Transformation (a Flash Animation) "Ready, aim, fire!" At the Max Planck Institute for Molecular Plant Physiology in Potsdam-Golm plant cells are 'bombarded' using a particle gun	Wikipedia/DNA_transfer
An animal drug (also veterinary drug) refers to a drug intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in animals. == Regulation == === United States === The U.S. Food and Drug Administration (FDA) has the broad mandate under the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321 et seq.) to assure the safety and effectiveness of animal drugs and their use in all animals, including farm animals. The division of the FDA responsible for this is the Center for Veterinary Medicine (CVM). The equivalents of the Investigational New Drug and New Drug Application are known as the Investigational New Animal Drug and New Animal Drug Application, respectively. The FDA enumerates veterinary drug approvals in the FDA Green Book. Drugs approved by the FDA for use in veterinary medicine are structurally similar to drugs approved for use in humans, owing to highly conserved physiology across species, and half of drugs approved for animals are separately approved for use in humans.[1] Before CVM formally approves an animal drug, the sponsor or manufacturer of the drug must document in scientific testing that the drug has been found "safe and effective". The testing data also must demonstrate that a methodology is available to detect and measure any residue left in edible animal products. Farmers and veterinarians using drugs on farm animals must adhere to guidelines about how much time must elapse before a treated animal can be slaughtered, and any other use constraints or warnings stated on the drug label. Animal biologics (e.g., vaccines and tests) are regulated by the Animal and Plant Health Inspection Service. == See also == Drug packaging List of veterinary drugs Veterinary medicine Veterinary pathology == References == This article incorporates public domain material from Jasper Womach. Report for Congress: Agriculture: A Glossary of Terms, Programs, and Laws, 2005 Edition (PDF). Congressional Research Service. == External links == Approved Animal Drugs at FDA website Animal drugs at DailyMed website	Wikipedia/Animal_drug
Expanded access or compassionate use is the use of an unapproved drug or medical device under special forms of investigational new drug applications (IND) or IDE application for devices, outside of a clinical trial, by people with serious or life-threatening conditions who do not meet the enrollment criteria for the clinical trial in progress. These programs go under various names, including early access, special access, or managed access program, compassionate use, compassionate access, named-patient access, temporary authorization for use, cohort access, and pre-approval access. In general the person and their doctor must apply for access to the investigational product, the company has to choose to cooperate, and the medicine's regulatory agency needs to agree that the risks and possible benefits of the drug or device are understood well enough to determine if putting the person at risk has sufficient potential benefit. In some countries the government will pay for the drug or device, but in many countries the person must pay for the drug or device, as well as medical services necessary to receive it. In the US, compassionate use started with the provision of investigational medicine to certain patients in the late 1970s, and a formal program was established in 1987 in response to HIV/AIDS patients requesting access to drugs in development. An important legal case was Abigail Alliance v. von Eschenbach, in which the Abigail Alliance, a group that advocates for access to investigational drugs for people who are terminally ill, tried to establish such access as a legal right. The Supreme Court declined to hear the case, effectively upholding previous cases that have maintained that there is not a constitutional right to unapproved medical products. == Programs == As of 2016, regulation of access to pharmaceuticals that were not approved for marketing was handled on a country by country basis, including in the European Union, where the European Medicines Agency issued guidelines for national regulatory agencies to follow. In the US, Europe, and the EU, no company could be compelled to provide a drug or device that it was developing. Companies sometimes provide drugs under these programs to people who were in clinical trials and who responded to the drug, after the clinical trial ends. === United States === In the US as of 2018, people could try obtain unapproved drugs or medical devices that were in development under specific conditions. These conditions were: The person wanting the drug or device and a licensed physician are both willing to participate. The person's physician determines that there is no comparable or satisfactory therapy available to diagnose, monitor, or treat the patient's disease or condition. That the probable risk to the person from the investigational product is not greater than the probable risk from the disease or condition. The FDA determines that there is sufficient evidence of the safety and effectiveness of the investigational product to support its use in the particular circumstance; The FDA determines that providing the investigational product will not interfere with the initiation, conduct, or completion of clinical investigations to support marketing approval; The sponsor (generally the company developing the investigational product for commercial use) or the clinical investigator (or the patient's physician in the case of a single patient expanded access request) submits a clinical protocol (a document that describes the treatment plan for the patient) that is consistent with FDA's statute and applicable regulations for INDs or investigational device exemption applications (IDEs), describing the use of the investigational product; and The person is unable to obtain the investigational drug or device under another IND application (for drugs), IDE application (for devices), or to participate in a clinical trial. Drugs can be made available to individuals, small groups, or large groups. In the US, actual provision of the drug depends on the manufacturer's willingness to provide it, as well as the person's ability to pay for it; it is the company's decision whether to require payment or to provide the drug or device for free. The manufacturer can only charge direct costs for individual INDs; it can add some but not all indirect costs for small group or larger expanded access programs. To the extent that a doctor or clinic is required for use of the drug or device, they too may require payment. In some cases, it may be in the manufacturer's commercial interest to provide access under an EA program; this is a way, for example, for a company to make money before the drug or device is approved. Companies must provide data collected from people getting the drug or device under EA programs to the FDA annually; this data may be helpful with regard to getting the drug or device approved, or may be harmful, should unexpected adverse events occur. The manufacturer remains legally liable as well. If the manufacturer chooses to charge for the investigational product, that price influences later discussions about the price if the product is approved for marketing. ==== State law ==== As of February 2019, 41 states have passed right-to-try laws that permit manufacturers to provide experimental medicines to terminally ill people without US FDA authorization. Legal, medical, and bioethics scholars, including Jonathan Darrow and Arthur Caplan, have argued that these state laws have little practical significance because people can already obtain pre-approval access through the FDA's expanded access program, and because the FDA is generally not the limiting factor in obtaining pre-approval access. === Europe === In Europe, the European Medicines Agency issued guidelines that members may follow. Each country has its own regulations, and they vary. In the UK, for example, the program is called "early access to medicine scheme" or EAMS and was established in 2014. If a company that wants to provide a drug under EAMS, it must submit its Phase I data to the Medicines and Healthcare products Regulatory Agency and apply for what is called a "promising innovative medicine" (PIM) designation. If that designation is approved, the data is reviewed, if that review is positive, the National Health Service is obligated to pay for people who fit the criteria to have access to the drug. As of 2016, governments also paid for early access to drugs in Austria, Germany, Greece, and Spain. Since 2021, France has a system of early and expanded access separated in two systems: AAC and AAP. Companies sometimes make use of expanded programs in Europe even after they receive EMA approval to market a drug, because drugs also must go through regulatory processes in each member state, and in some countries this process can take nearly a year; companies can start making sales earlier under these programs. === Philippines === In the Philippines, the usage of unregistered drugs may be allowed through a doctor, a specialist, or health institution or society obtaining a specific compassionate use permit (CSP) from the country's Food and Drug Administration for the treatment of their terminally or seriously ill patients. The issuance of CSP is stated under Department of Health Administrative Order No. 4 of 1992. Those seeking CSP are required to provide the following information; estimated amount of the unregistered drug the patient, the "licensed drug/device establishment through which the unregistered drug may be procured", and "the names and address of the specialists qualified and authorized to use the product." A CSP may also be obtained for processed medical cannabis despite cannabis in general being illegal in the Philippines. == History == In the US, one of the earliest expanded access programs was a compassionate use IND that was established in 1978, which allowed a limited number of people to use medical cannabis grown at the University of Mississippi, under the direction of Marijuana Research Project Director Dr. Mahmoud ElSohly. It is administered by the National Institute on Drug Abuse. The program was started after Robert C. Randall brought a lawsuit (Randall v. United States) against the FDA, the Drug Enforcement Administration, the National Institute on Drug Abuse, the Department of Justice, and the Department of Health, Education & Welfare. Randall, who had glaucoma, had successfully used the Common Law doctrine of necessity to argue against criminal charges of marijuana cultivation that had been brought against him, because his use of cannabis was deemed a medical necessity (U.S. v. Randall). On November 24, 1976, federal Judge James Washington ruled in his favor.: 142 The settlement in Randall v. U.S. became the legal basis for the FDA's compassionate IND program. People were only allowed to use cannabis under the program who had certain conditions, like glaucoma, known to be alleviated with cannabis. The scope was later expanded to include people with AIDS in the mid-1980s. At its peak, fifteen people received the drug. 43 people were approved for the program, but 28 of the people whose doctors completed the necessary paperwork never received any cannabis. The program stopped accepting new people in 1992 after public health authorities concluded there was no scientific value to it, and due to President George H. W. Bush administration's policies. As of 2011, four people continued to receive cannabis from the government under the program. The closure of the program during the height of the AIDS epidemic led to the formation of the medical cannabis movement in the United States, a movement which initially sought to provide cannabis for treating anorexia and wasting syndrome in people with AIDS. In November 2001 the Abigail Alliance for Better Access to Developmental Drugs was established by Frank Burroughs in memory of his daughter, Abigail. The Alliance seeks broader availability of investigational drugs on behalf of people with terminal illnesses. It is best known for a legal case, which it lost, Abigail Alliance v. von Eschenbach, in which it was represented by the Washington Legal Foundation. On August 7, 2007, in an 8–2 ruling, the U.S. Court of Appeals for the District of Columbia Circuit reversed an earlier ruling in favor of the Alliance. In 2008, the Supreme Court of the United States declined to hear their appeal. This decision left standing the appellate court decision that people who are terminal ill patients have no legal right to demand "a potentially toxic drug with no proven therapeutic benefit". In March 2014, Josh Hardy, a 7-year-old boy from Virginia, made national headlines that sparked a conversation on pediatric access to investigational drugs when his family's request for brincidofovir was declined by the drug manufacturer, Chimerix. The company reversed its decision after pressure from cancer advocacy organizations, and Josh received the drug that saved his life. Hardy later passed away in September 2016 due to complications related to his underlying cancer diagnosis. In 2016 Kids v Cancer, a pediatric cancer advocacy organization, launched the Compassionate Use Navigator to assist physicians and guide families about the application process. Since then, FDA simplified the application process, but stressed that it cannot require a manufacturer to provide a product. FDA receives about 1,500 expanded access requests per year and authorizes 99% of it. == See also == Orphan drug Right-to-try law Emergency Use Authorization == References == === Citations === == External links == Europeans Medicines Agency Food and Drug Administration U.S FDA Personal Importation and EMA Named Patient Import The Socialmedwork as a named patient import Provider myTomorrows Expanded Access as an Expanded Access Provider === Sources ===	Wikipedia/Abigail_Alliance_for_Better_Access_to_Developmental_Drugs
A biologics license application (BLA) is defined by the U.S. Food and Drug Administration (FDA) as follows: The biologics license application is a request for permission to introduce, or deliver for introduction, a biologic product into interstate commerce (21 CFR 601.2). The BLA is regulated under 21 CFR 600 – 680. A BLA is submitted by any legal person or entity who is engaged in manufacture or an applicant for a license who takes responsibility for compliance with product and establishment standards. Form 356h specifies the requirements for a BLA. This includes: Applicant information Product/manufacturing information Pre-clinical studies Clinical studies Labeling Some biological products are regulated by the Center for Drug Evaluation and Research (CDER) while others are regulated by the Center for Biologics Evaluation and Research (CBER). A BLA is submitted after the investigational new drug (IND) phase, once the clinical investigations are completed. If the Form 356h is missing information, the FDA will reply within 74 days. A BLA asserts that the product is "safe, pure, and potent", the manufacturing facilities are inspectable, and each package of the product bears the license number. Statutory standards for BLA approval are largely the same as those for New Drug Application approval. According to 21 CFR 600.3, FDA interprets "potency" to include effectiveness of the biologic. After approval, annual reports, reports on adverse events, manufacturing changes, and labeling changes must be submitted. == See also == New drug application Investigational new drug == References ==	Wikipedia/Biologics_license_application
The Anthrax Vaccine Immunization Program (AVIP), is the name of the policy set forth by the U.S. federal government to immunize its military and certain civilian personnel with BioThrax, an anthrax vaccine manufactured by Emergent BioSolutions Inc. It was set up by the Clinton administration. In June 2001, the program was halted by the DoD due to changes in the manufacturing process not approved by the Food and Drug Administration (FDA). In the wake of the 2001 anthrax attacks and long after the 2003 invasion of Iraq, all military personnel were required to receive the anthrax vaccine. In Court, it was ruled that vaccination could not be forced on military personnel without a special order by the president. Thereafter it ran into and judicial obstacles (mainly concerning the methods and viability of the vaccine). Between March 1998 and December 2008, nearly 8 million doses of BioThrax were administered to over 2 million U.S. military personnel as part of the program. In December 2008, the FDA approved a new version of BioThrax which requires five intramuscular doses instead of six subcutaneous doses. == Overview == The vaccination requirement was instituted in 1998 because of concerns that anthrax could be used as a biological weapon (see anthrax weaponization). Secretary of Defense William Cohen stated that "anthrax poses a clear and present danger to our armed forces. It is the weapon of choice for germ warfare because it is easy to weaponize and is as lethal as the Ebola virus." Anthrax had previously been used in warfare as early as World War I, against livestock, and was also tested during World War II by Japan, against Chinese civilian populations, and by the US, Canada, and Great Britain on sheep at Gruinard Island. The Japanese attack was part of a larger program of biological warfare and human experimentation that is estimated to have killed 580,000 people. The Soviet Union weaponized anthrax, and 64 people were killed in an accident at Sverdlovsk in 1979. The Japanese doomsday cult Aum Shinrikyo had carried out a successful attack using sarin and an unsuccessful one in 1993 using anthrax. Iraq was found in 1995 to have a biological weapons program that included anthrax. In 2001, shortly after 9/11, five people were killed in an anthrax attack delivered by mail to the US Senate. The US armed forces had a longstanding custom of mandating various vaccines for service members, so the leadership expected that the vaccination requirement would be a matter of routine. But according to the director of the program, "Things have changed. They used to stand you in line, give you two or three shots, and off you went. Nobody asked what they were for. [...] There has been a ... shift in the relationship between health care providers and patients. No longer do you just put a patient in a doctor’s office or in a shot line." The program included the National Guard and Reserve, whose members had less of an expectation of being subject to such a requirement or of being exposed to biological warfare. Service members began to complain about side effects of the vaccine, and debate ensued about whether these problems were really vaccine-related. The DOD maintained that the vaccine was safe, but surveys showed that many service members did not believe the information that was being given to them about it. Treatment of troops who refused or hesitated was up to the discretion of their commanding officers, and therefore varied widely. Some were not punished at all, others acquiesced after further counseling, while still others received serious penalties such as dishonorable discharges. Following the 9/11 attacks, an exemption requested by marine James Muhammad led to his court martial, with his lawyer advising him to plead guilty because he would not be allowed to present his religious reasons and might be subject to the death penalty. The legal situation was complicated by the fact that the vaccine was experimental. Although service members are required to obey orders, it is also illegal under US law to use an experimental drug on patients without their consent. In the reserves, the requirement led many members to quit, switch to inactive status, or move to another unit. In the Air Force Reserve, a GAO report cited a negative effect on "retention of trained and experienced guard and reserve pilots." Legal challenges and questions about safety led to the cancellation of the program in 2008. == History == === 1990s === In 1998, the Clinton administration required the inoculation of all military members with the anthrax vaccine known as Anthrax Vaccine Adsorbed (AVA) and by the trade name BioThrax. In 1999 at Offutt Air Force Base, the first ever Anthrax refusal court-martial in the United States Air Force was prosecuted. In the case of U.S. v. Bickley, Captain Jeffrey A. Lustick, USAF, prosecuted an airman's refusal to submit to the immunization. The airman was convicted and later administratively separated from the U.S. Air Force. === 2000s === In June 2001, the DoD halted vaccinations due to non-FDA approved changes in BioPort's manufacturing process. On October 15, 2001, military members filed a FDA Citizen Petition highlighting the fact that the license for AVA had never formally been finalized by the FDA in accordance with the requirements of 21 CFR § 10.30 as Docket # 01P-0471. The Petition was later utilized as the foundational basis for a Preliminary Injunction by a Federal Court to temporarily halt the program [Doe v. Rumsfeld, 297 F. Supp. 2d 119 (D.D.C. 2003)]. On June 28, 2002, in the wake of the 2001 anthrax attacks and leading up to the 2003 invasion of Iraq, all military personnel were required to receive AVA in addition to their other vaccinations of smallpox. The military does give this vaccination regularly as well as Japanese encephalitis (JEV) when the service member is to be deployed to Southeast Asia, and other vaccines such as pneumococcal, tetanus, among others. While some military personnel had questions about the safety of the vaccine, it was considered a lawful order at that time, and this made refusing the vaccine at peril of the subordinate, including possible discharge (i.e., losing their job and any benefits depending on the type of discharge). This pressure, at least for the National Guard and Reserve pilots and crewmembers, became a deciding retention factor. Later that month, the DOD made it policy to include any personnel spending 15 days or more in high anthrax-risk areas, such as the Persian Gulf or the Korean peninsula. In December 2003, Judge Emmet G. Sullivan of the U.S. District Court for the District of Columbia ruled that the Department of Defense could not force military personnel to take the vaccine unless through a special order by the president. In October 2004, for about 8 days in (October 20–28), anthrax vaccinations were resumed, but then an injunction against mandatory vaccination was filed on the basis that AVA was not proven to work against inhalation anthrax. The ruling held that the mandatory program was illegal. The DoD was now required to either let the individual member choose under an informed consent policy, or allowed the president to bypass this requirement by executive order (Doe v. Rumsfeld, 341 F. Supp. 2d 1, 6 (D.D.C. 2004)). For military members who had started the vaccination (which usually takes build-up and booster shots), they tended to continue the vaccination program under informed consent. For those who had a choice, they usually decided against it. The government stated that they will resume the vaccination program under informed consent in April 2005. On December 15, 2005, the FDA re-issued a Final Rule & Order on the license status of AVA, clearing the way for mandatory vaccination reinstatement. After reviewing extensive scientific evidence and carefully considering comments from the public, the FDA again determined that the vaccine is licensed for the prevention of anthrax, regardless of the route of exposure. Pertaining to the previous ruling, the DC District Federal Appeals Court declined to vacate or overturn the injunction in 2006, instead mooting the case based on the FDA's new 2005 licensing of the vaccine.[Doe v. Rumsfeld, 127 Fed. App'x 327 (D.C. Cir. 2006)] On October 16, 2006 the military announced intentions to resume vaccinations for select personnel again, but the vaccinations remained voluntary until further guidance by the DoD. The DoD's official resumption status of the program awaited publication of service messages. On December 13, 2006, a new class-action lawsuit, filed on behalf of six unnamed plaintiffs, revived the legal battle over the military's mandatory anthrax immunization program. According to court documents, the basic premise of the lawsuit is the plaintiffs' claim that the vaccine is "unapproved for its applied/intended use." The lawsuit says that "plaintiffs will suffer substantial and irreparable injury if they are forced to take the vaccine," which the suit says has not been properly approved by the government, despite the FDA issuing its "final rule" on the vaccine on December 15, 2005. The suit also says the DOD has failed to follow presidential orders and federal laws that require the government to obtain informed consent before giving an unapproved and experimental vaccine to anyone. On February 8, 2007, the military has resumed mandatory vaccinations of certain troops. Specific policies and troop selection varies according to branch of service. By August 2007, the original court affirmed that the AVIP was not substantially justified prior to the consequent FDA licensure and requisite rule making for the vaccine in December 2005. The Court ultimately granted "prevailing party" status for the plaintiffs against defendants DoD and FDA [Doe v. Rumsfeld, 501 F. Supp. 2d 186, 188 (D.D.C. 2007)]. By March 2008, a different Federal Judge affirmed the prior ruling in its opinion regarding corrections of records writing, "Taken as a whole, Judge Sullivan's decisions in Doe v. Rumsfeld conclude that, prior to the FDA's December 2005 rulemaking, it was a violation of federal law for military personnel to be subjected to involuntary AVA inoculation because the vaccine was neither the subject of a presidential waiver nor licensed for use against inhalation anthrax." By August 6, 2008, an FBI press briefing theorized that the "failing" anthrax vaccine immunization program led as the primary motivator in the fall 2001 anthrax letter attacks allegedly perpetrated by U.S. Army scientist Bruce Ivins. FBI documents reveal the FDA "suspended further production" of anthrax vaccine just prior to the attacks (Ivins' emails and FBI analysis available on pp. 12–16 of affidavit). Failed potency tests prevented FDA approval. FBI released emails by Ivins showing the vaccine "isn't passing the potency test" and that "no approved lots" were available just prior to the letter attacks. The FBI explained Ivins' involvement with the failed potency tests. FBI affidavits also documented Ivins receiving the highest Defense Department honors for "getting the anthrax vaccine back into production". The U.S. Department of Justice press statements theorized Ivins’ anthrax letter attack motive: "by launching these attacks, he creates a situation, a scenario, where people all of a sudden realize the need to have this vaccine." On October 1, 2008, Michael O. Leavitt, Secretary of Health and Human Services, declared a need "to provide targeted liability protections for anthrax countermeasures" because "I have determined there is a credible risk that the threat of exposure of B. anthracis and the resulting disease constitutes a public health emergency" until the year 2015. Emergent BioSolutions immediately prepared to supply 14.5 million doses of anthrax vaccine by 2011. In December 2008, the FDA approved a new version of BioThrax which requires five intramuscular doses instead of six subcutaneous doses. The vaccine is required for US military members who are deployed to the Middle East, although some have objected to the vaccine because of side effects. === 2010s === On February 19, 2010, the FBI released its final summary on the Amerithrax investigation. The "motive", according to the FBI, was detailed on page 8 of the report: "Motive. According to his e-mails and statements to friends, in the months leading up to the anthrax attacks in the fall of 2001, Dr. Ivins was under intense personal and professional pressure. The anthrax vaccine program to which he had devoted his entire career of more than 20 years was failing. The anthrax vaccines were receiving criticism in several scientific circles, because of both potency problems and allegations that the anthrax vaccine contributed to Gulf War syndrome. Short of some major breakthrough or intervention, he feared that the vaccine research program was going to be discontinued. Following the anthrax attacks, however, his program was suddenly rejuvenated." The FBI continued on page 39 finding, "within a few months of the anthrax attacks, the FDA fast-tracked the approval process and approved the Anthrax Vaccine Adsorbed ("AVA"), even though it didn't meet the original potency standards. This was a significant development for the anthrax researchers." To date, the DOD has not announced a reevaluation of the AVIP, nor consideration of correcting the records of previously punished soldiers, in light of the above-mentioned legislative, legal and criminal findings related to the anthrax vaccine. == Pamphlet == This is a pamphlet distributed to military members regarding their vaccinations after the Emergency Use Authorization from the FDA after April 4, 2005. == See also == Anthrax == References == == Further reading == Donegan S, Bellamy R, Gamble CL (2009). "Vaccines for preventing anthrax". Cochrane Database Syst Rev (2): CD006403. doi:10.1002/14651858.CD006403.pub2. PMC 6532564. PMID 19370633. == External links == Official U.S. Department of Defense web site for AVIP. Vaccination Timeline at Stars and Stripes. The Military Vaccine Resource Directory maintained by Kathryn D. Hubbell, former Air Force parent. Q&A from the Navy regarding anthrax vaccination from 2002.	Wikipedia/Anthrax_Vaccine_Immunization_Program
Expanded access or compassionate use is the use of an unapproved drug or medical device under special forms of investigational new drug applications (IND) or IDE application for devices, outside of a clinical trial, by people with serious or life-threatening conditions who do not meet the enrollment criteria for the clinical trial in progress. These programs go under various names, including early access, special access, or managed access program, compassionate use, compassionate access, named-patient access, temporary authorization for use, cohort access, and pre-approval access. In general the person and their doctor must apply for access to the investigational product, the company has to choose to cooperate, and the medicine's regulatory agency needs to agree that the risks and possible benefits of the drug or device are understood well enough to determine if putting the person at risk has sufficient potential benefit. In some countries the government will pay for the drug or device, but in many countries the person must pay for the drug or device, as well as medical services necessary to receive it. In the US, compassionate use started with the provision of investigational medicine to certain patients in the late 1970s, and a formal program was established in 1987 in response to HIV/AIDS patients requesting access to drugs in development. An important legal case was Abigail Alliance v. von Eschenbach, in which the Abigail Alliance, a group that advocates for access to investigational drugs for people who are terminally ill, tried to establish such access as a legal right. The Supreme Court declined to hear the case, effectively upholding previous cases that have maintained that there is not a constitutional right to unapproved medical products. == Programs == As of 2016, regulation of access to pharmaceuticals that were not approved for marketing was handled on a country by country basis, including in the European Union, where the European Medicines Agency issued guidelines for national regulatory agencies to follow. In the US, Europe, and the EU, no company could be compelled to provide a drug or device that it was developing. Companies sometimes provide drugs under these programs to people who were in clinical trials and who responded to the drug, after the clinical trial ends. === United States === In the US as of 2018, people could try obtain unapproved drugs or medical devices that were in development under specific conditions. These conditions were: The person wanting the drug or device and a licensed physician are both willing to participate. The person's physician determines that there is no comparable or satisfactory therapy available to diagnose, monitor, or treat the patient's disease or condition. That the probable risk to the person from the investigational product is not greater than the probable risk from the disease or condition. The FDA determines that there is sufficient evidence of the safety and effectiveness of the investigational product to support its use in the particular circumstance; The FDA determines that providing the investigational product will not interfere with the initiation, conduct, or completion of clinical investigations to support marketing approval; The sponsor (generally the company developing the investigational product for commercial use) or the clinical investigator (or the patient's physician in the case of a single patient expanded access request) submits a clinical protocol (a document that describes the treatment plan for the patient) that is consistent with FDA's statute and applicable regulations for INDs or investigational device exemption applications (IDEs), describing the use of the investigational product; and The person is unable to obtain the investigational drug or device under another IND application (for drugs), IDE application (for devices), or to participate in a clinical trial. Drugs can be made available to individuals, small groups, or large groups. In the US, actual provision of the drug depends on the manufacturer's willingness to provide it, as well as the person's ability to pay for it; it is the company's decision whether to require payment or to provide the drug or device for free. The manufacturer can only charge direct costs for individual INDs; it can add some but not all indirect costs for small group or larger expanded access programs. To the extent that a doctor or clinic is required for use of the drug or device, they too may require payment. In some cases, it may be in the manufacturer's commercial interest to provide access under an EA program; this is a way, for example, for a company to make money before the drug or device is approved. Companies must provide data collected from people getting the drug or device under EA programs to the FDA annually; this data may be helpful with regard to getting the drug or device approved, or may be harmful, should unexpected adverse events occur. The manufacturer remains legally liable as well. If the manufacturer chooses to charge for the investigational product, that price influences later discussions about the price if the product is approved for marketing. ==== State law ==== As of February 2019, 41 states have passed right-to-try laws that permit manufacturers to provide experimental medicines to terminally ill people without US FDA authorization. Legal, medical, and bioethics scholars, including Jonathan Darrow and Arthur Caplan, have argued that these state laws have little practical significance because people can already obtain pre-approval access through the FDA's expanded access program, and because the FDA is generally not the limiting factor in obtaining pre-approval access. === Europe === In Europe, the European Medicines Agency issued guidelines that members may follow. Each country has its own regulations, and they vary. In the UK, for example, the program is called "early access to medicine scheme" or EAMS and was established in 2014. If a company that wants to provide a drug under EAMS, it must submit its Phase I data to the Medicines and Healthcare products Regulatory Agency and apply for what is called a "promising innovative medicine" (PIM) designation. If that designation is approved, the data is reviewed, if that review is positive, the National Health Service is obligated to pay for people who fit the criteria to have access to the drug. As of 2016, governments also paid for early access to drugs in Austria, Germany, Greece, and Spain. Since 2021, France has a system of early and expanded access separated in two systems: AAC and AAP. Companies sometimes make use of expanded programs in Europe even after they receive EMA approval to market a drug, because drugs also must go through regulatory processes in each member state, and in some countries this process can take nearly a year; companies can start making sales earlier under these programs. === Philippines === In the Philippines, the usage of unregistered drugs may be allowed through a doctor, a specialist, or health institution or society obtaining a specific compassionate use permit (CSP) from the country's Food and Drug Administration for the treatment of their terminally or seriously ill patients. The issuance of CSP is stated under Department of Health Administrative Order No. 4 of 1992. Those seeking CSP are required to provide the following information; estimated amount of the unregistered drug the patient, the "licensed drug/device establishment through which the unregistered drug may be procured", and "the names and address of the specialists qualified and authorized to use the product." A CSP may also be obtained for processed medical cannabis despite cannabis in general being illegal in the Philippines. == History == In the US, one of the earliest expanded access programs was a compassionate use IND that was established in 1978, which allowed a limited number of people to use medical cannabis grown at the University of Mississippi, under the direction of Marijuana Research Project Director Dr. Mahmoud ElSohly. It is administered by the National Institute on Drug Abuse. The program was started after Robert C. Randall brought a lawsuit (Randall v. United States) against the FDA, the Drug Enforcement Administration, the National Institute on Drug Abuse, the Department of Justice, and the Department of Health, Education & Welfare. Randall, who had glaucoma, had successfully used the Common Law doctrine of necessity to argue against criminal charges of marijuana cultivation that had been brought against him, because his use of cannabis was deemed a medical necessity (U.S. v. Randall). On November 24, 1976, federal Judge James Washington ruled in his favor.: 142 The settlement in Randall v. U.S. became the legal basis for the FDA's compassionate IND program. People were only allowed to use cannabis under the program who had certain conditions, like glaucoma, known to be alleviated with cannabis. The scope was later expanded to include people with AIDS in the mid-1980s. At its peak, fifteen people received the drug. 43 people were approved for the program, but 28 of the people whose doctors completed the necessary paperwork never received any cannabis. The program stopped accepting new people in 1992 after public health authorities concluded there was no scientific value to it, and due to President George H. W. Bush administration's policies. As of 2011, four people continued to receive cannabis from the government under the program. The closure of the program during the height of the AIDS epidemic led to the formation of the medical cannabis movement in the United States, a movement which initially sought to provide cannabis for treating anorexia and wasting syndrome in people with AIDS. In November 2001 the Abigail Alliance for Better Access to Developmental Drugs was established by Frank Burroughs in memory of his daughter, Abigail. The Alliance seeks broader availability of investigational drugs on behalf of people with terminal illnesses. It is best known for a legal case, which it lost, Abigail Alliance v. von Eschenbach, in which it was represented by the Washington Legal Foundation. On August 7, 2007, in an 8–2 ruling, the U.S. Court of Appeals for the District of Columbia Circuit reversed an earlier ruling in favor of the Alliance. In 2008, the Supreme Court of the United States declined to hear their appeal. This decision left standing the appellate court decision that people who are terminal ill patients have no legal right to demand "a potentially toxic drug with no proven therapeutic benefit". In March 2014, Josh Hardy, a 7-year-old boy from Virginia, made national headlines that sparked a conversation on pediatric access to investigational drugs when his family's request for brincidofovir was declined by the drug manufacturer, Chimerix. The company reversed its decision after pressure from cancer advocacy organizations, and Josh received the drug that saved his life. Hardy later passed away in September 2016 due to complications related to his underlying cancer diagnosis. In 2016 Kids v Cancer, a pediatric cancer advocacy organization, launched the Compassionate Use Navigator to assist physicians and guide families about the application process. Since then, FDA simplified the application process, but stressed that it cannot require a manufacturer to provide a product. FDA receives about 1,500 expanded access requests per year and authorizes 99% of it. == See also == Orphan drug Right-to-try law Emergency Use Authorization == References == === Citations === == External links == Europeans Medicines Agency Food and Drug Administration U.S FDA Personal Importation and EMA Named Patient Import The Socialmedwork as a named patient import Provider myTomorrows Expanded Access as an Expanded Access Provider === Sources ===	Wikipedia/Compassionate_Investigational_New_Drug_program
Druggability is a term used in drug discovery to describe a biological target (such as a protein) that is known to or is predicted to bind with high affinity to a drug. Furthermore, by definition, the binding of the drug to a druggable target must alter the function of the target with a therapeutic benefit to the patient. The concept of druggability is most often restricted to small molecules (low molecular weight organic substances) but also has been extended to include biologic medical products such as therapeutic monoclonal antibodies. Drug discovery comprises a number of stages that lead from a biological hypothesis to an approved drug. Target identification is typically the starting point of the modern drug discovery process. Candidate targets may be selected based on a variety of experimental criteria. These criteria may include disease linkage (mutations in the protein are known to cause a disease), mechanistic rationale (for example, the protein is part of a regulatory pathway that is involved in the disease process), or genetic screens in model organisms. Disease relevance alone however is insufficient for a protein to become a drug target. In addition, the target must be druggable. == Prediction of druggability == If a drug has already been identified for a target, that target is by definition druggable. If no known drugs bind to a target, then druggability is implied or predicted using different methods that rely on evolutionary relationships, 3D-structural properties or other descriptors. === Precedence-based === A protein is predicted to be "druggable" if it is a member of a protein family for which other members of the family are known to be targeted by drugs (i.e., "guilt" by association). While this is a useful approximation of druggability, this definition has limitations for two main reasons: (1) it highlights only historically successful proteins, ignoring the possibility of a perfectly druggable, but yet undrugged protein family; and (2) assumes that all protein family members are equally druggable. === Structure-based === This relies on the availability of experimentally determined 3D structures or high quality homology models. A number of methods exist for this assessment of druggability but all of them consist of three main components: Identifying cavities or pockets on the structure Calculating physicochemical and geometric properties of the pocket Assessing how these properties fit a training set of known druggable targets, typically using machine learning algorithms Early work on introducing some of the parameters of structure-based druggability came from Abagyan and coworkers and then Fesik and coworkers, the latter by assessing the correlation of certain physicochemical parameters with hits from an NMR-based fragment screen. There has since been a number of publications reporting related methodologies. There are several commercial tools and databases for structure-based druggability assessment. A publicly available database of pre-calculated druggability assessments for all structural domains within the Protein Data Bank (PDB) is provided through the ChEMBL's DrugEBIlity portal. Structure-based druggability is usually used to identify suitable binding pocket for a small molecule; however, some studies have assessed 3D structures for the availability of grooves suitable for binding helical mimetics. This is an increasingly popular approach in addressing the druggability of protein-protein interactions. === Predictions based on other properties === As well as using 3D structure and family precedence, it is possible to estimate druggability using other properties of a protein such as features derived from the amino-acid sequence (feature-based druggability) which is applicable to assessing small-molecule based druggability or biotherapeutic-based druggability or the properties of ligands or compounds known to bind the protein (Ligand-based druggability). === The importance of training sets === All methods for assessing druggability are highly dependent on the training sets used to develop them. This highlights an important caveat in all the methods discussed above: which is that they have learned from the successes so far. The training sets are typically either databases of curated drug targets; screened targets databases (ChEMBL, BindingDB, PubChem etc.); or on manually compiled sets of 3D structure known by the developers to be druggable. As training sets improve and expand, the boundaries of druggability may also be expanded. == Undruggable targets == About 3% of human proteins are known to be "mode of action" drug targets, i.e., proteins through which approved drugs act. Another 7% of the human proteins interact with small molecule chemicals. Based on DrugCentral, 1795 human proteins annotated to interact with 2455 approved drugs. Furthermore, it is estimated that only 10-15% of human proteins are disease modifying while only 10-15% are druggable (there is no correlation between the two), meaning that only between 1 and 2.25% of disease modifying proteins are likely to be druggable. Hence it appears that the number of new undiscovered drug targets is very limited. A potentially much larger percentage of proteins could be made druggable if protein–protein interactions could be disrupted by small molecules. However the majority of these interactions occur between relatively flat surfaces of the interacting protein partners and it is very difficult for small molecules to bind with high affinity to these surfaces. Hence these types of binding sites on proteins are generally thought to be undruggable but there has been some progress (by 2009) targeting these sites. Chemoproteomics techniques have recently expanded the scope of what is deemed a druggable target through the identification of covalently modifiable sites across the proteome. == References == == Further reading == == External links == "DrugEBIlity". ChEMBL. "The Drug Gene Interaction Database (DGIdb)". Washington University School of Medicine. "TDR Targets Database". The TDR Drug Targets Network.	Wikipedia/Druggable
Pharmaceutical Drugs Directorate (PDD), previously called the Therapeutic Products Directorate (TPD), is a Canadian federal authority that regulates small molecule pharmaceutical drugs for human use. Prior to being given market authorization, a manufacturer must present substantive scientific evidence of a product's safety, efficacy, and quality as required by the Food and Drugs Act and Regulations. It is one of the ten operational directorates of the Health Products and Food Branch, a branch of Health Canada. == See also == European Medicines Agency Good Manufacturing Practice Good clinical practice Informed consent Institutional review board International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Investigational product Investigator's Brochure == References ==	Wikipedia/Therapeutic_Products_Directorate
The Controlled Drugs and Substances Act (French: Loi réglementant certaines drogues et autres substances) is Canada's federal drug control statute. Passed in 1996 under Prime Minister Jean Chrétien's government, it repeals the Narcotic Control Act and Parts III and IV of the Food and Drugs Act, and establishes eight Schedules of controlled substances and two Classes of precursors. It provides that "The Governor in Council may, by order, amend any of Schedules I to VIII by adding to them or deleting from them any item or portion of an item, where the Governor in Council deems the amendment to be necessary in the public interest." The Act serves as the implementing legislation for the Single Convention on Narcotic Drugs, the Convention on Psychotropic Substances, and the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances. == Amendments to the act == In November 2007, the Justice Minister Rob Nicholson introduced Bill C-26, which proposed a number of mandatory minimum penalties imposed on those who commit drug offences. On 27 February 2009, Bill C-15, a re-introduction of C-26 received first reading in the second session of the 40th Parliament of Canada. On 9 June 2009, the House of Commons passed Bill C-15 and it went to the Senate for study and approval. On 14 December 2009, the Senate passed Bill C-15, with some amendments, for approval by the House of Commons. When the Canadian Parliament dissolved in a prorogation on 31 January 2010, Bill C-15, along with all unpassed legislation then tabled before the Commons, fell. Early in 2012, the next parliament passed the Safe Streets and Communities Act, which received Royal Assent in March. The final legislation sees changes made to four areas of the Act, outlining mandatory minimum sentences for offences relating to the trafficking and production of various controlled substances. Mandatory minimum sentencing does not apply to simple possession and trafficking in smaller amounts. On 17 October 2018, the federal Cannabis Act came into effect, legalizing the possession, sale and production of cannabis. Everyone with a criminal record for cannabis possession became eligible to apply for a pardon on this date. == List of drugs == The list below reflects the list of drugs scheduled in Canada's Controlled Drugs and Substances Act. === Schedule I === Opium Poppy (Papaver somniferum), its preparations, derivatives, alkaloids and salts, including: Opium Codeine (methylmorphine) Morphine (7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol) Thebaine (paramorphine)and the salts, derivatives and salts of derivatives of the substances set out in subitems (1) to (4), including: Acetorphine (acetyletorphine) Acetyldihydrocodeine (4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol acetate) Benzylmorphine (7,8-didehydro-4,5-epoxy-17-methyl-3-(phenylmethoxy) morphinan-6-ol) Codoxime (dihydrocodeinone O-(carboxymethyl) oxime) Desomorphine (dihydrodeoxymorphine) Diacetylmorphine (heroin) Dihydrocodeine (4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol) Dihydromorphine (4,5-epoxy-17-methylmorphinan-3,6-diol) Ethylmorphine (7,8-didehydro-4,5-epoxy-3-ethoxy-17-methylmorphinan-6-ol) Etorphine (tetrahydro-7α-(1-hydroxy-1-methyl-butyl)-6,14-endo-ethenooripavine) Hydrocodone (dihydrocodeinone) Hydromorphinol (dihydro-14-hydroxymorphine) Hydromorphone (dihydromorphinone) Methyldesorphine (Δ6-deoxy-6-methylmorphine) Methyldihydromorphine (dihydro-6-methylmorphine) Metopon (dihydromethylmorphinone) Morphine-N-oxide (morphine oxide) Myrophine (benzylmorphine myristate) Nalorphine (N-allylnormorphine) Nicocodine (6-nicotinylcodeine) Nicomorphine (dinicotinylmorphine) Norcodeine (N-desmethylcodeine) Normorphine (N-desmethylmorphine) Oxycodone (dihydrohydroxycodeinone) Oxymorphone (dihydrohydroxymorphinone) Pholcodine (3-[2-(4-morpholinyl)ethyl]morphine) Thebacon (acetyldihydrocodeinone)but not including: Apomorphine (5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo[de,g]quinoline-10,11-diol) and its salts Cyprenorphine (N-(cyclopropylmethyl)-6,7,8,14-tetrahydro-7α-(1-hydroxy-1-methylethyl)-6,14-endo-ethenonororipavine) and its salts Nalmefene (17-(cyclopropylmethyl)-4,5α-epoxy-6-methylenemorphinan-3,14-diol) and its salts Naloxone (4,5α-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-one) and its salts Naltrexone (17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one) and its salts Methylnaltrexone (17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxy-17-methyl-6-oxomorphinanium) and its salts Naloxegol (4,5α-epoxy-6α-(3,6,9,12,15,18,21-heptaoxadocos-1-yloxy)-17-(2-propenyl)morphinan-3,14-diol) and its salts Narcotine (6,7-dimethoxy-3-(5,6,7,8-tetra-hydro-4-methoxy-6-methyl-1,3-dioxolos [4,5-g]isoquinolin-5-yl)-1(3H)-isobenzofuranone) and its salts Papaverine (1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxyisoquinoline) and its salts Poppy seed Coca (Erythroxylon), its preparations, derivatives, alkaloids and salts, including: Coca leaves Cocaine (benzoylmethylecgonine) Ecgonine (3-hydroxy-2-tropane carboxylic acid) but not including: 123l-ioflupane Phenylpiperidines, their intermediates, salts, derivatives and analogues and salts of intermediates, derivatives and analogues, including: Allylprodine (3-allyl-1-methyl-4-phenyl-4-piperidinol propionate) Alphameprodine (α-3-ethyl-1-methyl-4-phenyl-4-piperidinol propionate) Alphaprodine (α-1,3-dimethyl-4-phenyl-4-piperidinol propionate) Anileridine (ethyl 1-[2-(p-aminophenyl)ethyl]-4-phenylpiperidine-4-carboxylate) Betameprodine (β-3-ethyl-1-methyl-4-phenyl-4-piperidinol propionate) Betaprodine (β-1,3-dimethyl-4-phenyl-4-piperidinol propionate) Benzethidine (ethyl 1-(2-benzyloxyethyl)-4-phenylpiperidine-4-carboxylate) Diphenoxylate (ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate) Difenoxin (1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate) Etoxeridine (ethyl 1-[2-(2-hydroxyethoxy) ethyl]-4-phenylpiperidine-4-carboxylate) Furethidine (ethyl 1-(2-tetrahydrofurfury loxyethyl)-4-phenylpiperidine-4-carboxylate) Hydroxypethidine (ethyl 4-(m-hydroxyphenyl)-1-methylpiperidine-4-carboxylate) Ketobemidone (1-[4-(m-hydroxyphenyl)-1-methyl-4-piperidyl]-1-propanone) Methylphenylisonipecotonitrile (4-cyano-1-methyl-4-phenylpiperidine) Morpheridine (ethyl 1-(2-morpholinoethyl)-4-phenylpiperidine-4-carboxylate) Norpethidine (ethyl 4-phenylpiperidine-4-carboxylate) Pethidine (ethyl 1-methyl-4-phenylpiperidine-4-carboxylate) Phenoperidine (ethyl 1-(3-hydroxy-3-phenylpropyl)-4-phenylpiperidine-4-carboxylate) Piminodine (ethyl 1-[3-(phenylamino)propyl]-4-phenylpiperidine-4-carboxylate) Properidine (isopropyl 1-methyl-4-phenylpiperidine-4-carboxylate) Trimeperidine (1,2,5-trimethyl-4-phenyl-4-piperidinol propionate) Pethidine Intermediate C (1-methyl-4-phenylpiperidine-4-carboxylate)but not including: Carbamethidine (ethyl 1-(2-carbamylethyl)-4-phenylpiperidine-4-carboxylate) and its salts Oxpheneridine (ethyl 1-(2-hydroxy-2-phenylethyl)-4-phenylpiperidine-4-carboxylate) and its salts Phenazepines, their salts, derivatives and salts of derivatives including: Proheptazine (hexahydro-1,3-dimethyl-4-phenyl-1H-azepin-4-ol propionate)but not including: Ethoheptazine (ethyl hexahydro-1-methyl-4-phenyl-azepine-4-carboxylate) and its salts Metethoheptazine (ethyl hexahydro-1,3-dimethyl-4-phenylazepine-4-carboxylate) and its salts Metheptazine (methyl hexahydro-1,2-dimethyl-4-phenylazepine-4-carboxylate) and its salts Amidones, their intermediates, salts, derivatives and salts of intermediates and derivatives including: Dimethylaminodiphenylbutanonitrile (4-cyano-2-dimethylamino-4,4-diphenylbutane) Dipipanone (4,4-diphenyl-6-piperidino-3-heptanone) Isomethadone (6-dimethylamino-5-methyl-4,4-diphenyl-3-hexanone) Methadone (6-dimethylamino-4,4-diphenyl-3-heptanone) Normethadone (6-dimethylamino-4,4-diphenyl-3-hexanone) Norpipanone (4,4-diphenyl-6-piperidino-3-hexanone) Phenadoxone (6-morpholino-4,4-diphenyl-3-heptanone) Methadols, their salts, derivatives and salts of derivatives including: Acetylmethadol (6-dimethylamino-4,4-diphenyl-3-heptanol acetate) Alphacetylmethadol (α-6-dimethylamino-4,4-diphenyl-3-heptanol acetate) Alphamethadol (α-6-dimethylamino-4,4-diphenyl-3-heptanol) Betacetylmethadol (β-6-dimethylamino-4,4-diphenyl-3-heptanol acetate) Betamethadol (β-6-dimethylamino-4,4-diphenyl-3-heptanol) Dimepheptanol (6-dimethylamino-4,4-diphenyl-3-heptanol) Noracymethadol (α-6-methylamino-4,4-diphenyl-3-heptanol acetate) Phenalkoxams, their salts, derivatives and salts of derivatives including: Dimenoxadol (dimethylaminoethyl 1-ethoxy-1,1-diphenylacetate) Dioxaphetyl butyrate (ethyl 2,2-diphenyl-4-morpholinobutyrate) Dextropropoxyphene ([S-(R,S)]-α-[2-(dimethylamino)-1-methylethyl]-α-phenylbenzeneethanol, propanoate ester) Thiambutenes, their salts, derivatives and salts of derivatives including: Diethylthiambutene (N,N-diethyl-1-methyl-3,3-di-2-thienylallylamine) Dimethylthiambutene (N,N,1-trimethyl-3,3-di-2-thienylallylamine) Ethylmethylthiambutene (N-ethyl-N,1-dimethyl-3,3-di-2-thienylallylamine) Moramides, their intermediates, salts, derivatives and salts of intermediates and derivatives including: Dextromoramide (d-1-(3-methyl-4-morpholino-2,2-diphenylbutyryl)pyrrolidine) Diphenylmorpholinoisovaleric acid (2-methyl-3-morpholino-1,1-diphenylpropionic acid) Levomoramide (l-1-(3-methyl-4-morpholino-2,2-diphenylbutyryl)pyrrolidine) Racemoramide (d,l-1-(3-methyl-4-morpholino-2,2-diphenylbutyryl) pyrrolidine) Morphinans, their salts, derivatives and salts of derivatives including: Buprenorphine (17-(cyclopropylmethyl)-α-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-α-methyl-6,14-ethenomorphinan-7-methanol) Drotebanol (6β,14-dihydroxy-3,4-dimethoxy-17-methylmorphinan) Levomethorphan (l-3-methoxy-17-methylmorphinan) Levorphanol (l-3-hydroxy-17-methylmorphinan) Levophenacylmorphan (l-3-hydroxy-17-phenacylmorphinan) Norlevorphanol (l-3-hydroxymorphinan) Phenomorphan (3-hydroxy-17-(2-phenylethyl)morphinan) Racemethorphan (d,1-3-methoxy-17-methylmorphinan) Racemorphan (d,l-3-hydroxy-N-methylmorphinan)but not including: Dextromethorphan (d-1,2,3,9,10,10a-hexahydro-6-methoxy-11-methyl-4H-10,4a-iminoethano-phenanthren) and its salts Dextrorphan (d-1,2,3,9,10,10a-hexahydro-11-methyl-4H-10,4a-iminoethanophenanthren-6-ol) and its salts Levallorphan (l-11-allyl-1,2,3,9,10,10a-hexahydro-4H-10,4a-iminoethanophenanthren-6-ol) and its salts Levargorphan (l-11-propargyl-1,2,3,9,10,10a-hexahydro-4H-10,4a-iminoethanophenanthren-6-ol) and its salts Butorphanol (17-(cyclobutylmethyl)morphinan-3,14-diol) and its salts Nalbuphine (17-(cyclobutylmethyl)-4,5α-epoxymorphinan-3,6α, 14-triol) and its salts Benzazocines, their salts, derivatives and salts of derivatives including: Phenazocine (1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-phenethyl-2,6-methano-3-benzazocin-8-ol) Metazocine (1,2,3,4,5,6-hexahydro-3,6,11-trimethyl-2,6-methano-3-benzazocin-8-ol) Pentazocine (1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol)but not including: Cyclazocine (1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(cyclopropylmethyl)-2,6-methano-3-benzazocin-8-ol) and its salts Ampromides, their salts, derivatives and salts of derivatives including: Diampromide (N-[2-(methylphenethylamino)propyl] propionanilide) Phenampromide (N-(1-methyl-2-piperidino) ethyl) propionanilide) Propiram (N-(1-methyl-2-piperidinoethyl)-N-2-pyridylpropionamide) Benzimidazoles, their salts, derivatives and salts of derivatives including: Clonitazene (2-(p-chlorobenzyl)-1-diethylaminoethyl-5-nitrobenzimidazole) Etonitazene (2-(p-ethoxybenzyl)-1-diethylaminoethyl-5-nitrobenzimidazole) Bezitramide (1-(3-cyano-3,3-diphenylpropyl)-4-(2-oxo-3-propionyl-1-benzimidazolinyl)-piperidine) Phencyclidine (1-(1-phenylcyclohexyl)piperidine), its salts, derivatives and analogues and salts of derivatives and analogues, including: Ketamine (2-(2-chlorophenyl)-2-(methylamino)cyclohexanone) Piritramide (1-(3-cyano-3,3-diphenylpropyl)-4-(1-piperidino)piperidine-4-carboxylic acid amide), its salts, derivatives and salts of derivatives Fentanyls, their salts, derivatives, and analogues and salts of derivatives and analogues, including: Acetyl-α-methylfentanyl (N-[1-(α-methylphenethyl)-4-piperidyl] acetanilide) Alfentanil (N-[1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl]-4-(methoxymethyl)-4-piperidyl]propionanilide) Carfentanil (methyl 4-[(1-oxopropyl)phenylamino]-1-(2-phenethyl)-4-piperidinecarboxylate) p-Fluorofentanyl (4′fluoro-N-(1-phenethyl-4-piperidyl) propionanilide) Fentanyl (N-(1-phenethyl-4-piperidyl) propionanilide) β-Hydroxyfentanyl (N-[1-(β-hydroxyphenethyl)-4-piperidyl] propionanilide) β-Hydroxy-3-methylfentanyl (N-[1-(β-hydroxyphenethyl)-3-methyl-4-piperidyl] propionanilide) α-Methylfentanyl (N-[1-(α-methylphenethyl)-4-piperidyl] propionanilide) α-Methylthiofentanyl (N-[1-[1-methyl-2-(2-thienyl) ethyl]-4-piperidyl] propionanilide) 3-Methylfentanyl (N-(3-methyl-1-phenethyl-4-piperidyl) propionanilide) 3-Methylthiofentanyl (N-[3-methyl-1-[2-(2-thienyl) ethyl]-4-piperidyl] propionanilide) Remifentanil (dimethyl 4-carboxy-4-(N-phenylpropionamido)-1-piperidinepropionate) Sufentanil (N-[4-(methoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidyl] propionanilide) Thiofentanyl (N-[1-[2-(2-thienyl)ethyl]-4-piperidyl] propionanilide) Tilidine (ethyl2-(dimethylamino)-1-phenyl-3-cyclohexene-1-carboxylate), its salts, derivatives and salts of derivatives Methylenedioxypyrovalerone (MDPV), its salts, derivatives, isomers and analogues and salts of derivatives, isomers and analogues Methamphetamine (N,α-dimethylbenzeneethanamine), its salts, derivatives, isomers and analogues and salts of derivatives, isomers and analogues Amphetamines, their salts, derivatives, isomers and analogues and salts of derivatives, isomers and analogues including: Amphetamine (α-methylbenzene-ethanamine) N-ethylamphetamine (N-ethyl-α-methylbenzeneethanamine) 4-methyl-2,5-dimethoxyamphetamine (STP) (2,5-dimethoxy-4,α-dimethylbenzeneethanamine) 3,4-Methylenedioxyamphetamine (MDA) (α-methyl-1,3-benzodioxole-5-ethanamine) 2,5-dimethoxyamphetamine (2,5-dimethoxy-α-methylbenzene-ethanamine) 4-methoxyamphetamine (4-methoxy-α-methylbenzeneethanamine) 2,4,5-trimethoxyamphetamine (2,4,5-trimethoxy-α-methylbenzeneethanamine) N-methyl-3,4-methylenedioxy- amphetamine (N,α-dimethyl-1,3-benzodioxole-5-ethanamine) 4-ethoxy-2,5-dimethoxyamphetamine (4-ethoxy-2,5-dimethoxy-α-methylbenzeneethanamine) 5-methoxy-3,4-methylenedioxy- amphetamine (7-methoxy-α-methyl-1,3-benzodioxole-5-ethanamine) N,N-dimethyl-3,4-methylenedioxyamphetamine (N,N, α-trimethyl-1,3-benzodioxole-5-ethanamine) N-ethyl-3,4-methylenedioxyamphetamine (N-ethyl-α-methyl-1,3-benzodioxole-5-ethanamine) 4-ethyl-2,5-dimethoxyamphetamine (DOET) (4-ethyl-2,5-dimethoxy-α-methylbenzeneethanamine) 4-bromo-2,5-dimethoxyamphetamine (4-bromo-2,5-dimethoxy-α-methylbenzeneethanamine) 4-chloro-2,5-dimethoxyamphetamine (4-chloro-2,5-dimethoxy-α-methyl-benzeneethanamine) 4-ethoxyamphetamine (4-ethoxy-α-methylbenzeneethanamine) Benzphetamine (N-benzyl-N,α-dimethylbenzeneethanamine) N-Propyl-3,4-methylenedioxy- amphetamine (α-methyl-N-propyl-1,3-benzodioxole-5-ethanamine) N-(2-Hydroxyethyl)-α-meth-ylbenzeneethanamine N-hydroxy-3,4-methylenedioxy- amphetamine (N-[α-methyl-3,4-(methylenedioxy)phenethyl]hydroxylamine) 3,4,5-trimethoxyamphetamine (3,4,5-trimethoxy-α-methylbenzeneethanamine) Flunitrazepam (5-(o-fluorophenyl)-1,3-dihydro-1-methyl-7-nitro-2H-1,4-benzodiazepin-2-one) and any of its salts or derivatives 4-hydroxybutanoic acid (GHB) and any of its salts Tapentadol (3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]-phenol), its salts, derivatives and isomers and salts of derivatives and isomers AH-7921 (1-(3,4-dichlorobenzamidomethyl)cyclohexyldimethylamine), its salts, isomers and salts of isomers MT-45 (1-cyclohexyl-4-(1,2-diphenylethyl)piperazine), its salts, derivatives, isomers and analogues and salts of derivatives, isomers and analogues, including: Diphenidine (DEP) (1-(1,2-diphenylethyl)piperidine) Methoxphenidine (2-MeO-Diphenidine, MXP) (1-[1-(2-methoxyphenyl)-2-phenylethyl]piperidine) Ephenidine (NEDPA, EPE) (N-ethyl-1,2-diphenylethylamine) Isophenidine (NPDPA) (N-isopropyl-1,2-diphenylethylamine)but not including: Lefetamine ((-)-N,N-dimethyl-α-phenylbenzeneethanamine), its salts, derivatives and isomers and salts of derivatives and isomers W-18 (-chloro-N-[1-[2-(4-nitrophenyl)ethyl]-2-piperidinylidene]benzenesulfonamide), its salts, derivatives, isomers and analogues and salts of derivatives, isomers and analogues U-47700 (3,4-dichloro-N-(2-(dimethylamino)cyclohexyl)-N-methylbenzamide), its salts, derivatives, isomers and analogues, and salts of derivatives, isomers and analogues, including: Bromadoline (4-bromo-N-(2-(dimethylamino)cyclohexyl)benzamide) U-47109 (3,4-dichloro-N-(2-(dimethylamino)cyclohexyl)benzamide) U-48520 (4-chloro-N-(2-(dimethylamino)cyclohexyl)-N-methylbenzamide) U-50211 (N-(2-(dimethylamino)cyclohexyl)-4-hydroxy-N-methylbenzamide) U-77891 (3,4-dibromo-N-methyl-N-(1-methyl-1-azaspiro[4.5]decan-6-yl)benzamide) Tramadol (2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol), its salts, isomers and salts of isomers and the following derivatives of tramadol and the salts, isomers and salts of isomers of those derivatives: O-desmethyltramadol (3-[2-[(dimethylamino)methyl]-1-hydroxycyclohexyl]-phenol) N,O-didesmethyltramadol (3-[1-hydroxy-2-[(methylamino)methyl]cyclohexyl]-phenol) === Schedule II === Synthetic cannabinoid receptor type 1 agonists, their salts, derivatives, isomers, and salts of derivatives and isomers — with the exception of any substance that is identical to any phytocannabinoid and with the exception of ((3S)-2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl)-1-naphthalenyl-methanone (WIN 55,212-3) and its salts — including those that fall within the following core chemical structure classes: Any substance that has a 2-(cyclohexyl)phenol structure with substitution at the 1-position of the benzene ring by a hydroxy, ether or ester group and further substituted at the 5-position of the benzene ring, whether or not further substituted on the benzene ring to any extent, and substituted at the 3’-position of the cyclohexyl ring by an alkyl, carbonyl, hydroxyl, ether or ester, and whether or not further substituted on the cyclohexyl ring to any extent, including Nabilone ((±)-trans-3-(1,1-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-one) Parahexyl (3-hexyl-6,6,9-trimethyl-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran-1-ol) 3-(1,2-dimethylheptyl)-7,8,9,10-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol (DMHP) 5-(1,1-dimethylheptyl)-2-(5-hydroxy-2-(3-hydroxypropyl)cyclohexyl)phenol (CP 55,940) 5-(1,1-dimethylheptyl)-2-(3-hydroxycyclohexyl)phenol (CP 47,497) Any substance that has a 3-(1-naphthoyl)indole structure with substitution at the nitrogen atom of the indole ring, whether or not further substituted on the indole ring to any extent and whether or not substituted on the naphthyl ring to any extent, including 1-pentyl-3-(1-naphthoyl)indole (JWH-018) 1-butyl-3-(1-naphthoyl)indole (JWH-073) 1-pentyl-3-(4-methyl-1-naphthoyl)indole (JWH-122) 1-hexyl-3-(1-naphthoyl)indole (JWH-019) 1-(4-pentenyl)-3-(1-naphthoyl)indole (JWH-022) 1-butyl-3-(4-methoxy-1-naphthoyl)indole (JWH-080) 1-pentyl-3-(4-methoxy-1-naphthoyl)indole (JWH-081) 1-(2-morpholin-4-ylethyl)-3-(1-naphthoyl)indole (JWH-200) 1-pentyl-3-(4-ethyl-1-naphthoyl)indole (JWH-210) 1-pentyl-3-(2-methoxy-1-naphthoyl)indole (JWH-267) 1-[(N-methylpiperidin-2-yl)methyl]-3-(1-naphthoyl)indole (AM-1220) 1-(5-fluoropentyl)-3-(1-naphthoyl)indole (AM-2201) 1-(5-fluoropentyl)-3-(4-methyl-1-naphthoyl)indole (MAM-2201) 1-(5-fluoropentyl)-3-(4-ethyl-1-naphthoyl)indole (EAM-2201) ((3R)-2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl)-1-naphthalenyl-methanone (WIN 55,212-2) Any substance that has a 3-(1-naphthoyl)pyrrole structure with substitution at the nitrogen atom of the pyrrole ring, whether or not further substituted on the pyrrole ring to any extent and whether or not substituted on the naphthyl ring to any extent, including 1-pentyl-5-(2-fluorophenyl)-3-(1-naphthoyl)pyrrole (JWH-307) Any substance that has a 3-phenylacetylindole structure with substitution at the nitrogen atom of the indole ring, whether or not further substituted on the indole ring to any extent and whether or not substituted on the phenyl ring to any extent, including 1-pentyl-3-(2-methoxyphenylacetyl)indole (JWH-250) 1-pentyl-3-(2-methylphenylacetyl)indole (JWH-251) 1-pentyl-3-(3-methoxyphenylacetyl)indole (JWH-302) Any substance that has a 3-benzoylindole structure with substitution at the nitrogen atom of the indole ring, whether or not further substituted on the indole ring to any extent and whether or not substituted on the phenyl ring to any extent, including 1-(1-methylpiperidin-2-ylmethyl)-3-(2-iodobenzoyl)indole (AM-2233) Any substance that has a 3-methanone(cyclopropyl)indole structure with substitution at the nitrogen atom of the indole ring, whether or not further substituted on the indole ring to any extent and whether or not substituted on the cyclopropyl ring to any extent, including (1-pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)-methanone (UR-144) (1-(5-fluoropentyl)-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)-methanone (5F-UR-144) (1-(2-(4-morpholinyl)ethyl)-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)-methanone (A-796,260) Any substance that has a quinolin-8-yl 1H-indole-3-carboxylate structure with substitution at the nitrogen atom of the indole ring, whether or not further substituted on the indole ring to any extent and whether or not substituted on the quinolin-8-yl ring to any extent, including 1-pentyl-8-quinolinyl ester-1H-indole-3-carboxylic acid (PB-22) 1-(5-fluoropentyl)-8-quinolinyl ester-1H-indole-3-carboxylic acid (5F-PB-22) Any substance that has a 3-carboxamideindazole structure with substitution at the nitrogen atom of the indazole ring, whether or not further substituted on the indazole ring to any extent and whether or not substituted at the carboxamide group to any extent, including N-(adamantan-1-yl)-1-pentyl-1H-indazole-3-carboxamide (AKB48) N-(adamantan-1-yl)-1-(5-fluoropentyl)-1H-indazole-3-carboxamide (5F-AKB48) N-(1-(aminocarbonyl)-2-methylpropyl)-1-(4-fluorobenzyl)-1H-indazole-3-carboxamide (AB-FUBINACA) N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide (AB-PINACA) Any substance that has a 3-carboxamideindole structure with substitution at the nitrogen atom of the indole ring, whether or not further substituted on the indole ring to any extent and whether or not substituted at the carboxamide group to any extent, including N-(adamantan-1-yl)-1-fluoropentylindole-3-carboxamide (STS-135) N-(adamantan-1-yl)-1-pentylindole-3-carboxamide (APICA) === Schedule III === Methylphenidate (α-phenyl-2-piperidineacetic acid methyl ester) and any salts, derivatives, isomers, and analogues and salts of derivatives, isomers, and analogues, including: Ethylphenidate (ethyl 2-phenyl-2-(piperidin-2-yl)acetate) Isopropylphenidate (isopropyl 2-phenyl-2-(piperidin-2-yl)acetate) Propylphenidate (propyl 2-phenyl-2-(piperidin-2-yl)acetate) 3,4-Dichloromethylphenidate (methyl 2-(3,4-dichlorophenyl)-2-(piperidin-2-yl)acetate) 4-Methylmethylphenidate (methyl 2-(4-methylphenyl)-2-(piperidin-2-yl)acetate) 4-Fluoromethylphenidate (methyl 2-(4-fluorophenyl)-2-(piperidin-2-yl)acetate) Methylnaphthidate (methyl 2-(naphthalen-2-yl)-2-(piperidin-2-yl)acetate) Ethylnaphthidate (ethyl 2-(naphthalen-2-yl)-2-(piperidin-2-yl)acetate) Methaqualone (2-methyl-3-(2-methylphenyl)-4(3H)-quinazolinone) and any salt thereof Mecloqualone (2-methyl-3-(2-chlorophenyl)-4(3H)-quinazolinone) and any salt thereof 11 LSD (lysergic acid diethylamide) (N,N-diethyllysergamide) and any salt thereof DET (N,N-Diethyltryptamine) (3-[(2-diethylamino) ethyl]indole) and any salt thereof DMT (N,N-Dimethyltryptamine) (3-[(2-dimethylamino) ethyl]indole) and any salt thereof JB-336 (N-Methyl-3-piperidyl benzilate or LBJ) (3-[(hydroxydiphenylacetyl)oxy]-1-methylpiperidine) and any salt thereof Harmaline (4,9-dihydro-7-methoxy-1-methyl-3H-pyrido(3,4-b)indole) and any salt thereof Harmalol (4,9-dihydro-1-methyl-3H-pyrido(3,4-b)indol-7-ol) and any salt thereof Psilocin (3-[2-(dimethylamino)ethyl]-4-hydroxyindole) and any salt thereof Psilocybin (3-[2-(dimethylamino)ethyl]-4-phosphoryloxyindole) and any salt thereof PCE (N-(1-phenylcyclohexyl)ethylamine) and any salt thereof TCP (1-[1-(2-Thienyl) cyclohexyl]piperidine) and any salt thereof PCPr (1-Phenyl-N-propylcyclohexanamine) and any salt thereof Rolicyclidine (1-(1-phenylcyclohexyl) pyrrolidine) and any salt thereof Mescaline (3,4,5-trimethoxybenzeneethanamine) and any salt thereof, but not peyote (lophophora) 4-Methylaminorex (4,5-dihydro-4-methyl-5-phenyl-2-oxazolamine) and any salt thereof Cathinone ((-)-α-aminopropiophenone) and any salt thereof Fenetylline (d,l-3,7-dihydro-1,3-dimethyl-7-(2-[(1-methyl-2-phenethyl)amino]ethyl)-1H-purine-2, 6-dione) and any salt thereof Methcathinone (2-Methylamino-1-phenyl-1-propanone) and any salt thereof Benzylcyclidine (1-[1-(Phenylmethyl)cyclohexyl]piperidine) and any salt thereof 4-Methyl-PCP (1-[1-(4-Methylphenyl)cyclohexyl]piperidine) and any salt thereof [Repealed, SOR/2016-73, s. 1] [Repealed, 2012, c. 1, s. 46] [Repealed, 2012, c. 1, s. 46] Aminorex (4,5-dihydro-5-phenyl-2-oxazolamine) and any salt thereof Etryptamine (3-(2-aminobutyl)indole) and any salt thereof Lefetamine ((-)-N,N-dimethyl-α-phenylbenzeneethanamine) and any salt thereof Mesocarb (3-(α-methylphenethyl)-N-(phenylcarbamoyl)sydnone imine) and any salt thereof Zipeprol (4-(2-methoxy-2-phenylethyl)-α-(methoxyphenylmethyl)-1-piperazineethanol) and any salt thereof Amineptine (7-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)amino]heptanoic acid) and any salt thereof BZP (Benzylpiperazine) (1-benzylpiperazine) and its salts, isomers and salts of isomers TFMPP (Trifluoromethylphenylpiperazine) (1-(3-trifluoromethylphenyl)piperazine) and its salts, isomers and salts of isomers 2C-phenethylamines and their salts, derivatives, isomers and salts of derivatives and isomers that correspond to the following chemical description: any substance that has a 1-amino-2-phenylethane structure substituted at the 2' and 5' or 2' and 6' positions of the benzene ring by an alkoxy or haloalkoxy group, or substituted at two adjacent carbon atoms of the benzene ring which results in the formation of a furan, dihydrofuran, pyran, dihydropyran or methylenedioxy group—whether or not further substituted on the benzene ring to any extent, whether or not substituted at the amino group by one or two, or a combination of, methyl, ethyl, propyl, isopropyl, hydroxyl, benzyl (or benzyl substituted to any extent) or benzylene (or benzylene substituted to any extent) groups and whether or not substituted at the 2-ethyl (beta carbon) position by a hydroxyl, oxo or alkoxy group—and its salts and derivatives and salts of derivatives, including: 4-bromo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25B-NBOMe) 4-chloro-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25C-NBOMe) 4-iodo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25I-NBOMe) 4-bromo-2,5-dimethoxybenzeneethanamine (2C-B) === Schedule IV === Barbiturates, their salts and derivatives including Allobarbital (5,5-diallylbarbituric acid) Alphenal (5-allyl-5-phenylbarbituric acid) Amobarbital (5-ethyl-5-(3-methylbutyl)barbituric acid) Aprobarbital (5-allyl-5-isopropylbarbituric acid) Barbital (5,5-diethylbarbituric acid) [Repealed, SOR/2017-13, s. 7] Butabarbital (5-sec-butyl-5-ethylbarbituric acid) Butalbital (5-allyl-5-isobutylbarbituric acid) Butallylonal (5-(2-bromoallyl)-5-sec-butylbarbituric acid) Butethal (5-butyl-5-ethylbarbituric acid) Cyclobarbital (5-(1-cyclohexen-1-yl)-5-ethylbarbituric acid) Cyclopal (5-allyl-5-(2-cyclopenten-1-yl)barbituric acid) Heptabarbital (5-(1-cyclohepten-1-yl)-5-ethylbarbituric acid) Hexethal (5-ethyl-5-hexylbarbituric acid) Hexobarbital (5-(1-cyclohexen-1-yl)-1,5-dimethylbarbituric acid) Mephobarbital (5-ethyl-1-methyl-5-phenylbarbituric acid) Methabarbital (5,5-diethyl-1-methylbarbituric acid) Methylphenobarbital (5-ethyl-1-methyl-5-phenylbarbituric acid) Propallylonal (5-(2-bromoallyl)-5-isopropylbarbituric acid) Pentobarbital (5-ethyl-5-(1-methylbutyl)barbituric acid) Phenobarbital (5-ethyl-5-phenylbarbituric acid) Probarbital (5-ethyl-5-isopropylbarbituric acid) Phenylmethylbarbituric acid (5-methyl-5-phenylbarbituric acid) Secobarbital (5-allyl-5-(1-methylbutyl)barbituric acid) Sigmodal (5-(2-bromoallyl)-5-(1-methylbutyl) barbituric acid) Talbutal (5-allyl-5-sec-butylbarbituric acid) Vinbarbital (5-ethyl-5-(1-methyl-1-butenyl)barbituric acid) Vinylbital (5-(1-methylbutyl)-5-vinylbarbituric acid)but not including: Barbituric acid (2,4,6(1H,3H,5H)-pyrimidinetrione) and its salts 1,3-dimethylbarbituric acid (1,3-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione) and its salts Thiobarbiturates, their salts and derivatives including: Thialbarbital (5-allyl-5-(2-cyclohexen-1-yl)-2-thiobarbituric acid) Thiamylal (5-allyl-5-(1-methylbutyl)-2-thiobarbituric acid) Thiobarbituric acid (2-thiobarbituric acid) Thiopental (5-ethyl-5-(1-methylbutyl)-2-thiobarbituric acid) Chlorphentermine (1-(p-chlorophenyl)-2-methyl-2-aminopropane) and any salt thereof Diethylpropion (2-(diethylamino)propiophenone) and any salt thereof Phendimetrazine (d-3,4-dimethyl-2-phenylmorpholine) and any salt thereof Phenmetrazine (3-methyl-2-phenylmorpholine) and any salt thereof Pipradrol (α,α-diphenyl-2-piperidinemethanol) and any salt thereof Phentermine (α,α-dimethylbenzeneethanamine) and any salt thereof Butorphanol (l-N-cyclobutylmethyl-3,14-dihydroxymorphinan) and any salt thereof Nalbuphine (N-cyclobutylmethyl-4,5-epoxy-morphinan-3,6,14-triol) and any salt thereof Glutethimide (2-ethyl-2-phenylglutarimide) Clotiazepam (5-(o-chlorophenyl)-7-ethyl-1,3-dihydro-1-methyl-2H-thieno[2,3-e]-1,4-diazepin-2-one) and any salt thereof Ethchlorvynol (ethyl-2-chlorovinyl ethynyl carbinol) Ethinamate (1-ethynylcyclohexanol carbamate) Mazindol (5-(p-chlorophenyl)-2,5-dihydro-3H-imidazo[2,1-a]isoindol-5-ol) Meprobamate (2-methyl-2-propyl-1,3-propanediol dicarbamate) Methyprylon (3,3-diethyl-5-methyl-2,4-piperidinedione) Benzodiazepines, their salts and derivatives, including: Alprazolam (8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4] benzodiazepine) Bromazepam (7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1, 4-benzodiazepin-2-one) Brotizolam (2-bromo-4-(o-chlorophenyl)-9-methyl-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine) Camazepam (7-chloro-1,3-dihydro-3-(N,N- dimethylcarbamoyl)-1-methyl-5-phenyl-2H-1, 4-benzodiazepin-2-one) Chlordiazepoxide (7-chloro-2-(methylamino)-5-phenyl-3H-1,4-benzodiazepine-4-oxide) Clobazam (7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione) Clonazepam (5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one) Clorazepate (7-chloro-2,3-dihydro-2,2-dihydroxy-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid) Cloxazolam (10-chloro-11b-(o-chlorophenyl)-2,3, 7,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin 6-(5H)-one) Delorazepam (7-chloro-5-(o-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one) Diazepam (7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one) Estazolam (8-chloro-6-phenyl-4H-s-triazolo [4,3-a][1,4]benzodiazepine) Ethyl Loflazepate (ethyl 7-chloro-5-(o-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-carboxylate) Fludiazepam (7-chloro-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one) [Repealed, SOR/98-173, s. 2] Flurazepam (7-chloro-1-[2-(diethylamino) ethyl]-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one) Halazepam (7-chloro-1,3-dihydro-5-phenyl-1-(2,2,2-trifluoroethyl)-2H-1,4-benzodiazepin-2-one) Haloxazolam (10-bromo-11b-(o-fluorophenyl)-2,3,7,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(5H)-one) Ketazolam (11-chloro-8,12b-dihydro-2,8-dimethyl-12b-phenyl-4H-[1,3]-oxazino-[3,2-d][1,4] benzodiazepine-4,7(6H)-dione) Loprazolam (6-(o-chlorophenyl)-2,4-dihydro-2-[(4-methyl-1-piperazinyl)methylene]-8-nitro-1H-imidazo[1,2-a][1,4]benzodiazepin-1-one) Lorazepam (7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one) Lormetazepam (7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-1-methyl-2H-1,4-benzodiazepin-2-one) Medazepam (7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine) Midazolam (8-chloro-6-(o-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine) Nimetazepam (1,3-dihydro-1-methyl-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one) Nitrazepam (1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one) Nordazepam (7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one) Oxazepam (7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one) Oxazolam (10-chloro-2,3,7,11b-tetrahydro-2-methyl-11b-phenyloxazolo[3,2-d] [1,4]benzodiazepin-6(5H)-one) Pinazepam (7-chloro-1,3-dihydro-5-phenyl-1-(2-propynyl)-2H-1,4-benzodiazepin-2-one) Prazepam (7-chloro-1-(cyclopropylmethyl)-1, 3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one) Quazepam (7-chloro-5-(o-fluorophenyl)-1,3-dihydro-1-(2,2,2-trifluoroethyl)-2H-1,4-benzodiazepine-2-thione) Temazepam (7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one) Tetrazepam (7-chloro-5-(cyclohexen-1-yl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one) Triazolam (8-chloro-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine)but not including: Clozapine (8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine) and any salt thereof Flunitrazepam (5-(o-fluorophenyl)-1,3-dihydro-1-methyl-7-nitro-2H-1,4-benzodiazepin-2-one) and any salts or derivatives thereof Olanzapine (2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine) and its salts Clozapine N-oxide (8-chloro-11-(4-methyl-4-oxido-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine) and its salts Catha edulis Forsk., its preparations, derivatives, alkaloids and salts, including: Cathine (d-threo-2-amino-1-hydroxy-1-phenylpropane) Fencamfamin (d,l-N-ethyl-3-phenylbicyclo[2,2,1] heptan-2-amine) and any salt thereof Fenproporex (d,l-3-[(α-methylphenethyl)amino]propionitrile) and any salt thereof Mefenorex (d,l-N-(3-chloropropyl)-α-methylbenzeneethanamine) and any salt thereof Anabolic steroids and their derivatives including: Androisoxazole (17ß-hydroxy-17α-methylandrostano [3,2-c]isoxazole) Androstanolone (17ß-hydroxy-5α-androstan-3-one) Androstenediol (androst-5-ene-3ß,17ß-diol) Bolandiol (estr-4-ene-3ß,17ß-diol) Bolasterone (17ß-hydroxy-7α,17-dimethylandrost-4-en-3-one) Bolazine (17ß-hydroxy-2α-methyl-5α-androstan-3-one azine) Boldenone (17ß-hydroxyandrosta-1,4-dien-3-one) Bolenol (19-nor-17α-pregn-5-en-17-ol) Calusterone (17ß-hydroxy-7ß,17-dimethylandrost-4-en-3-one) Clostebol (4-chloro-17ß-hydroxyandrost-4-en-3-one) Drostanolone (17ß-hydroxy-2α-methyl-5α-androstan-3-one) Enestebol (4, 17ß-dihydroxy-17-methylandrosta-1,4-dien-3-one) Epitiostanol (2α, 3α-epithio-5α-androstan-17ß-ol) Ethylestrenol (19-nor-17α-pregn-4-en-17-ol) 4-Hydroxy-19-nor testosterone (4-HO-Nandrolone) Fluoxymesterone (9-fluoro-11ß,17ß-dihydroxy-17-methylandrost-4-en-3-one) Formebolone (11α, 17ß-dihydroxy-17-methyl-3-oxoandrosta-1,4 di-en-2-carboxaldehyde) Furazabol (17-methyl-5α-androstano[2,3-c] furazan-17ß-ol) Mebolazine (17ß-hydroxy-2α,17-dimethyl-5α-androstan-3-one azine) Mesabolone (17ß-[(1-methoxycyclohexyl)oxy]-5α-androst-1-en-3-one) Mesterolone (17ß-hydroxy-1α-methyl-5α-androstan-3-one) Metandienone (17ß-hydroxy-17-methylandrosta-1,4-dien-3-one) Metenolone (17ß-hydroxy-1-methyl-5α-androst-1-en-3-one) Methandriol (17α-methylandrost-5-ene-3ß,17ß-diol) Methyltestosterone (17ß-hydroxy-17-methylandrost-4-en-3-one) Metribolone (17ß-hydroxy-17-methylestra-4, 9,11-trien-3-one) Mibolerone (17ß-hydroxy-7α,17-dimethylestr-4-en-3-one) Nandrolone (17ß-hydroxyestr-4-en-3-one) Norboletone (13-ethyl-17ß-hydroxy-18, 19-dinorpregn-4-en-3-one) Norclostebol (4-chloro-17ß-hydroxyestr-4-en-3-one) Norethandrolone (17α-ethyl-17ß-hydroxyestr-4-en-3-one) Oxabolone (4,17ß-dihydroxyestr-4-en-3-one) Oxandrolone (17ß-hydroxy-17-methyl-2-oxa-5α-androstan-3-one) Oxymesterone (4,17ß-dihydroxy-17-methylandrost-4-en-3-one) Oxymetholone (17ß-hydroxy-2-(hydroxymethylene)-17-methyl-5α-androstan-3-one) Prasterone (3ß-hydroxyandrost-5-en-17-one) Quinbolone (17ß-(1-cyclopenten-1-yloxy) androsta-1,4-dien-3-one) Stanozolol (17ß-hydroxy-17-methyl-5α-androstano [3,2-c]pyrazole) Stenbolone (17ß-hydroxy-2-methyl-5α-androst-1-en-3-one) Testosterone (17ß-hydroxyandrost-4-en-3-one) Tibolone ((7α,17α)-17-hydroxy-7-methyl-19-norpregn-5(10) en-20-yn-3-one) Tiomesterone (1α,7α-bis(acetylthio)-17ß -hydroxy-17-methylandrost-4-en-3-one) Trenbolone (17ß-hydroxyestra-4,9,11-trien-3-one) Zeranol (3,4,5,6,7,8,9,10,11,12-decahydro-7,14,16-trihydroxy-3-methyl-1H-2-benzoxacyclotetradecin-1-one) Zolpidem (N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide) and any salt thereof Pemoline (2-amino-5-phenyl-oxazolin-4-one) and any salt thereof Pyrovalerone (4′-methyl-2-(1-pyrrolidinyl)valerophenone) and any salt thereof Salvia divinorum (S. divinorum), its preparations and derivatives, including: Salvinorin A ((2S,4aR,6aR,7R,9S,10aS,10bR)-9-(acetyloxy)-2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-naphtho[2,1-c]pyran-7-carboxylic acid methyl ester) === Schedule V === (Sections 2, 5 to 7.1, 10, 55 and 60.1) 1996, c. 19, Sch. V; SOR/2002-361, s. 1; SOR/2003-32, s. 7; 2017, c. 7, s. 50. === Schedule VI (Precursors) === ==== PART 1 ==== Class A Precursors Acetic anhydride N-Acetylanthranilic acid (2-acetamidobenzoic acid) and its salts Anthranilic acid (2-aminobenzoic acid) and its salts Ephedrine (erythro-2-(methylamino)-1-phenylpropan-1-ol), its salts and any plant containing ephedrine or any of its salts Ergometrine (9,10-didehydro-N-(2-hydroxy-1-methylethyl)-6-methylergoline-8-carboxamide) and its salts Ergotamine (12′-hydroxy-2′-methyl-5′-(phenylmethyl)ergotaman-3′,6′,18-trione) and its salts Isosafrole (5-(1-propenyl)-1,3-benzodioxole) Lysergic acid (9,10-didehydro-6-methylergoline-8-carboxylic acid) and its salts 3,4-Methylenedioxyphenyl-2-propanone (1-(1,3-benzodioxole)-2-propanone), its derivatives and analogues and salts of derivatives and analogues, including: methyl 3-(1,3 benzodioxol-5-yl)-2-methyloxirane-2-carboxylate (MMDMG) Norephedrine (Phenylpropanolamine) and its salts 1-Phenyl-2-propanone, its derivatives and analogues and salts of derivatives and analogues, including: methyl 2-methyl-3-phenyloxirane-2-carboxylate (BMK methyl glycidate) 3-oxo-2-phenylbutanamide (α- phenylacetoacetamide-APAA) Phenylacetic acid and its salts Piperidine and its salts Piperonal (1,3-benzodioxole-5-carboxaldehyde) Potassium permanganate Pseudoephedrine (threo-2-(methylamino)-1-phenylpropan-1-ol), its salts and any plant containing pseudoephedrine or any of its salts Safrole (5-(2-propenyl)-1,3-benzodioxole) and any essential oil containing more than 4% safrole Gamma-butyrolactone (dihydro-2(3H)-furanone) 1,4-butanediol Red Phosphorus White Phosphorus Hypophosphorous acid, its salts and derivatives Hydriodic acid Alpha-phenylacetoacetonitrile and its salts, isomers and salts of isomers Propionyl chloride 1-Phenethyl-4-piperidone and its salts 4-Piperidone and its salts Norfentanyl (N-phenyl-N-piperidin-4-ylpropanamide), its salts, derivatives and analogues and salts of derivatives and analogues 1-Phenethylpiperidin-4-ylidenephenylamine and its salts N-Phenyl-4-piperidinamine (N-phenylpiperidin-4-amine), its salts, derivatives and analogues and salts of derivatives and analogues, including: 4-anilino-1-boc-piperidine (tert-butyl 4-(phenylamino)piperidine-1-carboxylate) 4-fluoro anilino-1-boc-piperidine (tert-butyl 4-((4-fluorophenyl)amino)piperidine-1-carboxylate) N-(4-fluorophenyl)-4-piperidinamine (N-(4-fluorophenyl)piperidin-4-amine) 4-bromo anilino-1-boc-piperidine (tert-butyl 4-((4-bromophenyl)amino)piperidine-1-carboxylate) N1,N1,N2-trimethylcyclohexane-1,2-diamine and its salts Benzylfentanyl (N-(1-benzylpiperidin-4-yl)-N-phenylpropionamide), its salts, derivatives and analogues and salts of derivatives and analogues ==== PART 2 ==== Class B Precursors Acetone Diethyl ether Hydrochloric acid Methyl ethyl ketone Sulfuric acid Toluene ==== PART 3 ==== Preparations and Mixtures Any preparation or mixture that contains a precursor set out in Part 1, except items 20 to 23 [Red Phosphorus; White Phosphorus; Hypophosphorous acid, its salts and derivatives; Hydriodic acid], or in Part 2. === Schedule VII === [Repealed, 2018, c. 16, s. 205] === Schedule VIII === [Repealed, 2018, c. 16, s. 205] === Schedule IX === Manual, semi-automatic or fully automatic device that may be used to compact or mould powdered, granular or semi-solid material to produce coherent solid tablets Manual, semi-automatic or fully automatic device that may be used to fill capsules with any powdered, granular, semi-solid or liquid material == Laws – Penalties == === Possession === If tried as an indictable offence, the defendant is liable to: Schedule I: Maximum 3 years' imprisonment Schedule II: Maximum 2 years' imprisonment Schedule III: Maximum 1 years' imprisonment Schedule IV: It is not an indictable offence to possess a Schedule IV substance for personal use. If tried as a summary conviction offence, the defendant is liable to: Schedule I, II, or III: Maximum $1000 fine for the first offence and/or a maximum 6-month term of imprisonment, increasing to a maximum fine of $2000 for each subsequent offense and/or a maximum of 1 year in prison. Schedule IV: It is not a summary offence to possess a Schedule IV substance for personal use. Section (4), Subsection (2) of the CDSA reads that any person who obtains or who makes any attempt to obtain a Schedule I through IV substance from a physician without fully disclosing the details of any previous instances of obtaining a Schedule I through IV substance in the preceding thirty (30) days, a practice often referred to as "doctor shopping", is guilty of a summary or indictable offense, as per Section (4), Subsection (7)(a) and (b). These drugs are considered lawful (and thus without penalty) if the person from whom the substance, precursor or property was seized came into possession of it lawfully and continued to deal with it lawfully, such as through a prescription by a prescribing practitioner. === Trafficking/Possession for the Purpose of === If tried as an indictable offence, the defendant is liable to: Schedule I or Schedule II: Maximum 4 years' imprisonment Schedule III: Maximum 4 years' imprisonment Schedule IV: Maximum 2 years' imprisonment Or, if tried as a summary conviction, the defendant is liable to: Schedule III: Maximum 9 months' imprisonment Schedule IV: Maximum 6 months' imprisonment === Smuggling/Possession for the Purpose of Distribution === If tried as an indictable offence, the defendant is liable to: Schedule I or Schedule II: Maximum 4 years' imprisonment Mandatory minimum 1 year's imprisonment for exporting a Schedule I drug under 1 kg (2 lb), 2 years if amount exceeds 1 kg (2 lb) Schedule III or Schedule IV: Maximum 4 years' imprisonment Schedule V or Schedule VI: Maximum 2 years' imprisonment Or, if tried as a summary conviction, the defendant is liable to: Schedule III or Schedule IV: Maximum 9 months' imprisonment Schedule V or Schedule VI: Maximum 6 months' imprisonment === Production === If tried as an indictable offence, the defendant is liable to: Schedule I or Schedule II: Maximum 4 years imprisonment minimum 2 years' imprisonment Schedule III: Maximum 4 years' imprisonment Schedule IV: Maximum 2 years' imprisonment Or, if tried as a summary conviction, the defendant is liable to: Schedule III: Maximum 9 months' imprisonment Schedule IV: Maximum 6 months' imprisonment == See also == Controlled Substances Act (US) Misuse of Drugs Act 1971 (UK) == Notes == == References == [1] [2] == External links == Controlled Drugs and Substances Act. Amendments to the Controlled Drugs and Substances Act [Bill C-10, Part 2, Clauses 32-33, 39-48 and 50-51 (Former Bill S-10)]	Wikipedia/Controlled_Drugs_and_Substances_Act
The Food and Drugs Act (French: Loi sur les aliments et drogues) is an act of the Parliament of Canada regarding the production, import, export, transport across provinces and sale of food, drugs, contraceptive devices and cosmetics (including personal cleaning products such as soap and toothpaste). It was first passed in 1920 and most recently revised in 1985. It attempts to ensure that these products are safe, that their ingredients are disclosed and that drugs are effective and are not sold as food or cosmetics. It also states that cures for disease listed in Schedule A (including cancer, obesity, anxiety, asthma, depression, appendicitis, and sexually transmitted diseases), cannot be advertised to the general public. == Background == After the launch of the Federal Department of Health in 1919, the Food and Drugs Act was presented in late 1920. Rules and regulations developed under the Act established the requirements for licensing and creating drugs in Canada. The law granted the Minister of Health the right to cancel or suspend licenses of companies failing to comply with the requirements. The Food and Drugs Act was not significantly modified until 1947 when the foundations were laid for the current market today. In 1951, drug manufacturers were required to submit a file for each new drug prior to marketing their product. However, during the early 1960s, the drug thalidomide, which had been approved to enter the market, resulted in the deaths of thousands of infants and severe birth defects in others when the drug was taken by women in early stages of pregnancy. As a result of the problems caused by the drug thalidomide, the Act was revisited and strengthened by Health Canada. The revised version placed new requirements on manufacturers to provide evidence for efficacy in seeking a Notice of Compliance, which must be obtained before any drug could be sold. The manufacturer must meet all the requirements before making any drug available to the public, but once the drug passes with no adverse reactions and without any changes needed to the drug's formula, it may never be subjected to review by Health Canada again. Some health advocates want post-approval surveillance to watch for unexpected problems. == Part I == Part I provides general interpretations of the terms, and provides details of each of the topics discussed on what the Act entails: Food Drugs Cosmetics Devices == Part II == Part II of the Act focuses the administration and the Enforcement that allows the government to intervene with the manufacturer. It entails: Inspection, Seizure and forfeiture Analysis Power of the Minister Incorporation by Reference Regulations Interim Orders Marketing Authorization Offense and Punishment Exports == Parts III and IV == Parts III (enacted in 1961) and IV (enacted in 1969) provided for implementation of controls required by the Convention on Psychotropic Substances. Part III dealt with "controlled" drugs such as amphetamine, methaqualone, and phenmetrazine, which have legitimate medical uses. Part IV focused on Schedule H "restricted drugs", those whose only legitimate use is for scientific research, such as the hallucinogens LSD, DMT, and MDMA. These parts established eight classes of regulated substances, ranging from Schedules A to H. The 1996 Controlled Drugs and Substances Act repealed Parts III and IV. == 2008 proposed amendment == In April 2008, an amendment to the Food and Drugs Act, Canadian Bill C-51 was tabled in the House of Commons. The purpose of this bill was to modernize the regulatory system for foods and therapeutic products, to strengthen the oversight of the benefits and risks of therapeutic products throughout their life cycle, to support effective compliance and enforcement actions and to enable a greater transparency and openness of the regulatory system. Some of the proposed amendments are as follows: Illegalize the sale and importation of products that have knowingly been adulterated. Illegalize the sale of counterfeit therapeutic products. Clarify in the Food and Drugs Act the requirement of therapeutic products to have market authorization, which has been required by Health Canada for many years. The bill has been subject to criticism due to a perception that the bill would illegalize all food and Natural Health Products by categorizing them as drug products. Natural health products in Canada have been regulated as a subset of drugs since the Natural Health Products Regulations were put into place on January 1, 2004. Health Canada has stated "The Natural Health Product Regulations, introduced in 2004, will continue to operate the same way under Bill C-51. Canadians will continue to have access to natural health products that are safe, effective and of high quality. In spite of this claim, The Natural Health Industry remained skeptical. A watchdog group was employed to investigate the concerns and a number of hidden camera videos surfaced that further aggravated the NHP industry concerns. == Regulations Amending the Food and Drug Regulations (Nutrition Symbols, Other Labelling Provisions, Vitamin D and Hydrogenated Fats or Oils) == === Overview === Frequent consumption of foods rich in sodium, sugars, or saturated fats is associated with elevated health risks, including but not limited to: Stroke Obesity Heart disease Type 2 diabetes High blood pressure Certain types of cancers To address this concern, a front-of-package nutrition symbol has been introduced. This symbol serves the dual purpose of aiding consumers in making informed choices while grocery shopping and assisting health professionals in educating the public about the nutritional content of foods high in sodium, sugars, and saturated fat. === Front-of-Package Nutrition Labelling === The front-of-package nutrition symbol is mandatory for prepackaged foods that meet or exceed specified levels for sodium, sugars, or saturated fat. However, certain foods are exempt from displaying this symbol, including: Packaged individual portions intended for restaurant or commercial consumption Milk and cream sold in refillable glass containers - Foods in very small packages Raw, single-ingredient whole cuts of meat, poultry, and fish without a nutrition facts table Additionally, certain foods with health-promoting properties, such as fruits, vegetables without added sodium, sugars, or saturated fats, plain dairy products, and specific dairy items contributing to bone health, are exempt from the requirement. Certain products, such as butter, sugar, salt, honey, celery salt, maple syrup, vegetable oils, and seasoning salt, used for the same purpose, are also exempt from displaying the front-of-package nutrition symbol. === Appearance of the Front-of-Package Nutrition Symbol === The front-of-package nutrition symbol is depicted in black and white and features a magnifying glass, emphasizing whether the food product is high in sodium, sugars, saturated fat, or a combination of these components. === Symbol Selection Process === The selection of the front-of-package nutrition symbol was informed by feedback from Canadian residents and consumer research, ensuring its relevance and comprehensibility. === Placement Requirements === For uniformity and ease of identification, the nutrition symbol must adhere to specific requirements concerning size, location, and language: Size: The size of the symbol is determined by the package size to ensure visibility on packages of varying dimensions. Location: Generally, the symbol appears in the upper half of the label for most package shapes. However, on wider-than-tall labels, it is situated on the right half. Language: The front-of-package nutrition symbol is presented in both English and French. It may manifest as two separate symbols, each in one language, or as a combined symbol featuring both languages. == See also == Therapeutic Products Directorate Food safety Medical device Food Bill 160-2 of New Zealand Food Safety Modernization Act Pledge to Africa Act == References == == External links == Food and Drugs Act Justice Canada Canada's Previous Drug Laws (before the Controlled Drugs and Substances Act came into force in May 1997), Canadian Foundation for Drug Policy. Cannabis Canada Issue 7. Co-operation between Canada and other countries and territories to promote countermeasures against illicit drug trafficking, 1987. Debates of the House of Commons of Canada, Oct. 30, 1995. Official Government of Canada webpage for information on Bill C-51 Complete transcript of C51 Bill C-51 and the Regulation of Natural Health Products – Fast Facts Brief History of Drug Regulation in Canada	Wikipedia/Food_and_Drug_Act
Very-low-density lipoprotein (VLDL), density relative to extracellular water, is a type of lipoprotein made by the liver. VLDL is one of the five major groups of lipoproteins (chylomicrons, VLDL, intermediate-density lipoprotein, low-density lipoprotein, high-density lipoprotein) that enable fats and cholesterol to move within the water-based solution of the bloodstream. VLDL is assembled in the liver from triglycerides, cholesterol, and apolipoproteins. VLDL is converted in the bloodstream to low-density lipoprotein (LDL) and intermediate-density lipoprotein (IDL). VLDL particles have a diameter of 30–80 nanometers (nm). VLDL transports endogenous products, whereas chylomicrons transport exogenous (dietary) products. In the early 2010s both the lipid composition and protein composition of this lipoprotein were characterised in great detail. == Physical properties == Very-low-density lipoprotein size is variable, with diameters ranging from approximately 35 to 70 nm. Some researchers further classify VLDL particles into VLDL1 and VLDL2 based on size (as measured by Svedberg flotation units), where VLDL1 particles are larger and contain more triglycerides, while other researchers create a tripartite system by subdividing VLDL1 into larger VLDL1 and smaller VLDL2 and relabeling VLDL2 as VLDL3. == Function == Very-low-density lipoproteins transport endogenous triglycerides, phospholipids, cholesterol, and cholesteryl esters. They function as the body's internal transport mechanism for lipids. In addition they can assist in long-range transport of hydrophobic intercellular messengers, like the morphogen Indian hedgehog (protein). == Changes during circulation == Nascent VLDL released from the liver contains apolipoprotein B100, apolipoprotein C1 (apoC1), apolipoprotein E (apoE), cholesterol, cholesteryl esters, and triglycerides. As it circulates in blood, it picks up apolipoprotein C-II (apoC-II) and additional apoE donated from high-density lipoprotein (HDL). At this point, nascent VLDL becomes a mature VLDL. Once in circulation, VLDL will come in contact with lipoprotein lipase (LPL) in the capillary beds in the body (adipose, cardiac, and skeletal muscle). LPL will remove triglycerides from VLDL for storage or energy production. VLDL now meets back up with HDL where apoC-II is transferred back to HDL (but keeps apoE). HDL also transfers cholesteryl esters to the VLDL in exchange for phospholipids and triglycerides via cholesterylester transfer protein (CETP). As more and more triglycerides are removed from the VLDL because of the action of LPL and CETP enzymes, the composition of the molecule changes, and it becomes intermediate-density lipoprotein (IDL). Fifty percent of IDLs are recognized by receptors in the liver cells because of the apolipoprotein B-100 (apoB-100) and apoE they contain and are endocytosed. The other 50% of IDL lose apoE; when their cholesterol content becomes greater than the content of triglyceride, they become LDL, with apoB-100 as the primary apolipoprotein. The LDL is taken into a cell via the LDL receptor via endocytosis, where the contents are either stored, used for cell membrane structure, or converted into other products such as steroid hormones or bile acids. == See also == Combined hyperlipidemia Lipid profile == Notes and references ==	Wikipedia/Very_low-density_lipoprotein
Microsomal triglyceride transfer protein large subunit is a protein that in humans is encoded by the MTTP, also known as MTP, gene. MTTP encodes the large subunit of the heterodimeric microsomal triglyceride transfer protein (MTP). Protein disulfide isomerase (PDI) completes the heterodimeric MTP, which has been shown to play a central role in lipoprotein assembly. Mutations in MTTP can cause abetalipoproteinemia. Apolipoprotein B48 on chylomicra and Apolipoprotein B100 on LDL, IDL, and VLDL are important for MTP binding. MTP adds triglycerides to nascent chylomicrons in the intestine, and to VLDL in the liver. == Structure == The large subunit of MTP, also known as the alpha subunit, contains an N-terminal half beta barrel, an alpha helix and a C-terminal lipid binding site that lies between two beta pleated sheets. It is a member of the large lipid transfer protein family, like apolipoprotein B (apo B), with which it interacts, but unlike apo B, it is not secreted. The heterodimer is instead retained in the endoplasmic reticulum due to the presence of a C-terminal KDEL motif on the PDI beta subunit. == Interactive pathway map == Click on genes, proteins and metabolites below to link to respective articles. == Pharmacology == Drugs that inhibit MTTP prevent the assembly of apo B-containing lipoproteins thus inhibiting the synthesis of chylomicrons and VLDL and leading to decrease in plasma levels of LDL-C. Lomitapide (Juxtapid) was approved by the US FDA for adjunctive treatment of homozygous familial hypercholesterolemia. Dirlotapide (Slentrol) and mitratapide (Yarvitan) are veterinary drugs for the management of obesity in dogs. == References == == Further reading ==	Wikipedia/Microsomal_triglyceride_transfer_protein
ATP citrate synthase (also ATP citrate lyase (ACLY)) is an enzyme that in animals catalyzes an important step in fatty acid biosynthesis. By converting citrate to acetyl-CoA, the enzyme links carbohydrate metabolism, which yields citrate as an intermediate, with fatty acid biosynthesis, which consumes acetyl-CoA. In plants, ATP citrate lyase generates cytosolic acetyl-CoA precursors of thousands of specialized metabolites, including waxes, sterols, and polyketides. == Function == ATP citrate lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. The enzyme is a tetramer of apparently identical subunits. In animals, the product, acetyl-CoA, is used in several important biosynthetic pathways, including lipogenesis and cholesterogenesis. It is activated by insulin. In plants, ATP citrate lyase generates acetyl-CoA for cytosolically-synthesized metabolites; Acetyl-CoA is not transported across subcellular membranes of plants. Such metabolites include: elongated fatty acids (used in seed oils, membrane phospholipids, the ceramide moieties of sphingolipids, cuticle, cutin, and suberin); flavonoids; malonic acid; acetylated phenolics, alkaloids, isoprenoids, anthocyanins, and sugars; and, mevalonate-derived isoprenoids (e.g., sesquiterpenes, sterols, brassinosteroids); malonyl and acyl-derivatives (d-amino acids, malonylated flavonoids, acylated, prenylated and malonated proteins). De novo fatty acid biosynthesis in plants occurs in plastids; thus, ATP citrate lyase is not relevant to this pathway. == Reaction == ATP citrate lyase is responsible for catalyzing the conversion of citrate and Coenzyme A (CoA) to acetyl-CoA and oxaloacetate, driven by hydrolysis of ATP. In the presence of ATP and CoA, citrate lyase catalyzes the cleavage of citrate to yield acetyl CoA, oxaloacetate, adenosine diphosphate (ADP), and orthophosphate (Pi): citrate + ATP + CoA → oxaloacetate + Acetyl-CoA + ADP + Pi This enzyme was formerly given the EC number 4.1.3.8. == Location == The enzyme is cytosolic in plants and animals. == Structure == The enzyme is composed of two subunits in green plants (including Chlorophyceae, Marchantimorpha, Bryopsida, Pinaceae, monocotyledons, and eudicots), species of fungi, glaucophytes, Chlamydomonas, and prokaryotes. Animal ACL enzymes are homomeric; a fusion of the ACLA and ACLB genes probably occurred early in the evolutionary history of this kingdom. The mammalian ATP citrate lyase has a N-terminal citrate-binding domain that adopts a Rossmann fold, followed by a CoA binding domain and CoA-ligase domain and finally a C-terminal citrate synthase domain. The cleft between the CoA binding and citrate synthase domains forms the active site of the enzyme, where both citrate and acetyl-coenzyme A bind. In 2010, a structure of truncated human ATP citrate lyase was determined using X-ray diffraction to a resolution of 2.10 Å. In 2019, a full length structure of human ACLY in complex with the substrates coenzyme A, citrate and Mg.ADP was determined by X-ray crystallography to a resolution of 3.2 Å. Moreover, in 2019 a full length structure of ACLY in complex with an inhibitor was determined by cryo-EM methods to a resolution of 3.7 Å. Additional structures of heteromeric ACLY-A/B from the green sulfur bacteria Chlorobium limicola and the archaeon Methanosaeta concilii show that the architecture of ACLY is evolutionarily conserved. Full length ACLY structures showed that the tetrameric protein oligomerizes via its C-terminal domain. The C-terminal domain had not been observed in the previously determined truncated crystal structures. The C-terminal region of ACLY assembles in a tetrameric module that is structurally similar to citryl-CoA lyase (CCL) found in deep branching bacteria. This CCL module catalyses the cleavage of the citryl-CoA intermediate into the products acetyl-CoA and oxaloacetate. In 2019, cryo-EM structures of human ACLY, alone or bound to substrates or products were reported as well. ACLY forms a homotetramer with a rigid citrate synthase homology (CSH) module, flanked by four flexible acetyl-CoA synthetase homology (ASH) domains; CoA is bound at the CSH–ASH interface in mutually exclusive productive or unproductive conformations. The structure of a catalytic mutant of ACLY in the presence of ATP, citrate and CoA substrates reveals a CoA and phosphor-citrate intermediate in the N-terminal domain. Cryo-EM structures of products bound ACLY and substrates bound ACLY were also determined at 3.0 Å and 3.1 Å. An EM structure of mutant E599Q in complex with CoA and phospho-citrate intermediate was determined at resolution of 2.9 Å. Comparison between these structures of apo-ACLY and ligands bound ACLY demonstrated conformational changes on ASH domain (N-terminal domain) when different ligands bind. == Pharmacology == The enzyme's action can be inhibited by the coenzyme A-conjugate of bempedoic acid, a compound which lowers LDL cholesterol in humans. The drug was approved by the Food and Drug Administration in February 2020 for use in the United States. == References == == Further reading == Lill U, Schreil A, Eggerer H (July 1982). "Isolation of enzymically active fragments formed by limited proteolysis of ATP citrate lyase". European Journal of Biochemistry. 125 (3): 645–50. doi:10.1111/j.1432-1033.1982.tb06731.x. PMID 6749502. Srere PA, Lipmann F (1953). "An enzymatic reaction between citrate, adenosine triphosphate and coenzyme A". Journal of the American Chemical Society. 75 (19): 4874. doi:10.1021/ja01115a547. == External links == ATP Citrate Lyase at the U.S. National Library of Medicine Medical Subject Headings (MeSH) This article incorporates text from the United States National Library of Medicine, which is in the public domain.	Wikipedia/ATP_citrate_lyase
Bezafibrate (marketed as Bezalip and various other brand names) is a fibrate drug used as a lipid-lowering agent to treat hyperlipidaemia. It helps to lower LDL cholesterol and triglyceride in the blood, and increase HDL. It was patented in 1971 and approved for medical use in 1978. == Medical uses == Bezafibrate improves markers of combined hyperlipidemia, effectively reducing LDL and triglycerides and improving HDL levels. The main effect on cardiovascular morbidity is in patients with the metabolic syndrome, the features of which are attenuated by bezafibrate. Studies show that in patients with impaired glucose tolerance, bezafibrate may delay progress to diabetes, and in those with insulin resistance it slowed progress in the HOMA severity marker. In addition, a prospective observational study of dyslipidemic patients with diabetes or hyperglycemia showed that bezafibrate significantly reduces haemoglobin A1c (HbA1c) concentration as a function of baseline HbA1c levels, regardless of concurrent use of antidiabetic drugs. == Side-effects == The main toxicity is hepatic (abnormal liver enzymes); myopathy and on rare occasions rhabdomyolysis have been reported. == Other uses == The Australian biotech company Giaconda combines bezafibrate with chenodeoxycholic acid in an anti-hepatitis C drug combination called Hepaconda. Bezafibrate has been shown to reduce tau protein hyperphosphorylation and other signs of tauopathy in transgenic mice having human tau mutation. The combination of a cholesterol-lowering drug, bezafibrate, and a contraceptive steroid, medroxyprogesterone acetate, could be an effective, non-toxic treatment for a range of cancers, researchers at the University of Birmingham have found. == Mode of action == Like the other fibrates, bezafibrate is an agonist of PPARα; some studies suggest it may have some activity on PPARγ and PPARδ as well. == Synthesis == Further evidence that substantial bulk tolerance is available in the para position is given by the lipid lowering agent bezafibrate. The p-chlorobenzamide of tyramine undergoes a Williamson ether synthesis with ethyl 2-bromo-2-methylpropionate to complete the synthesis. The ester group is hydrolyzed in the alkaline reaction medium. == History == Bezafibrate was first introduced by Boehringer Mannheim in 1977. == References ==	Wikipedia/Bezafibrate
Fenofibrate/simvastatin, sold under the brand name Cholib, is a fixed-dose combination medication used to treat abnormal blood lipid levels when used in combination with a low-fat diet and exercise. It contains fenofibrate and simvastatin. It was approved for use in the European Union in August 2013. == Medical uses == Fenofibrate/simvastatin is indicated as adjunctive therapy to diet and exercise in high cardiovascular risk adults with mixed dyslipidemia to reduce triglycerides and increase HDL C levels when LDL C levels are adequately controlled with the corresponding dose of simvastatin monotherapy. == Adverse effects == == References == == Further reading == Filippatos TD, Elisaf MS (2015). "Safety considerations with fenofibrate/simvastatin combination". Expert Opin Drug Saf. 14 (9): 1481–93. doi:10.1517/14740338.2015.1056778. PMID 26134595. S2CID 207488283. Tarantino N, Santoro F, De Gennaro L, Correale M, Guastafierro F, Gaglione A, et al. (2017). "Fenofibrate/simvastatin fixed-dose combination in the treatment of mixed dyslipidemia: safety, efficacy, and place in therapy". Vasc Health Risk Manag. 13: 29–41. doi:10.2147/VHRM.S95044. PMC 5317328. PMID 28243111.{{cite journal}}: CS1 maint: overridden setting (link)	Wikipedia/Fenofibrate/simvastatin
An adverse drug reaction (ADR) is a harmful, unintended result caused by taking medication.: 1.1 Adverse Drug Reaction (ADR) ADRs may occur following a single dose or prolonged administration of a drug or may result from the combination of two or more drugs. The meaning of this term differs from the term "side effect" because side effects can be beneficial as well as detrimental. The study of ADRs is the concern of the field known as pharmacovigilance. An adverse event (AE) refers to any unexpected and inappropriate occurrence at the time a drug is used, whether or not the event is associated with the administration of the drug.: 1.2 Adverse Event (AE) An ADR is a special type of AE in which a causative relationship can be shown. ADRs are only one type of medication-related harm. Another type of medication-related harm type includes not taking prescribed medications, known as non-adherence. Non-adherence to medications can lead to death and other negative outcomes. Adverse drug reactions require the use of a medication. == Classification == === Traditional === Type A: augmented pharmacological effects, which are dose-dependent and predictable Type A reactions, which constitute approximately 80% of adverse drug reactions, are usually a consequence of the drug's primary pharmacological effect (e.g., bleeding when using the anticoagulant warfarin) or a low therapeutic index of the drug (e.g., nausea from digoxin), and they are therefore predictable. They are dose-related and usually mild, although they may be serious or even fatal (e.g. intracranial bleeding from warfarin). Such reactions are usually due to inappropriate dosage, especially when drug elimination is impaired. The term side effects may be applied to minor type A reactions. Type B: Type B reactions are not dose-dependent and are not predictable, and so may be called idiosyncratic. These reactions can be due to particular elements within the person or the environment. Types A and B were proposed in the 1970s, and the other types were proposed subsequently when the first two proved insufficient to classify ADRs. Other types of adverse drug reactions are Type C, Type D, Type E, and Type F. Type C was categorized for chronic adverse drug reactions, Type D for delayed adverse drug reactions, Type E for withdrawal adverse drug reactions, and Type F for failure of therapy as an adverse drug reaction. Adverse drug reactions can also be categorized using time-relatedness, dose-relatedness, and susceptibility, which collectively are called the DoTS classification. === Seriousness === The U.S Food and Drug Administration defines a serious adverse event as one when the patient outcome is one of the following: Death Life-threatening Hospitalization (initial or prolonged) Disability — significant, persistent, or permanent change, impairment, damage or disruption in the patient's body function/structure, physical activities or quality of life. Congenital abnormality Requires intervention to prevent permanent impairment or damage Severity is a measure of the intensity of the adverse event in question. The terms "severe" and "serious", when applied to adverse events, are technically very different. They are easily confused but can not be used interchangeably, requiring care in usage. Seriousness usually indicates patient outcome (such as negative outcomes including disability, long-term effects, and death). In adverse drug reactions, the seriousness of the reaction is important for reporting. == Location == Some ocular antihypertensives cause systemic effects, although they are administered locally as eye drops, since a fraction escapes to the systemic circulation. == Mechanisms == === Abnormal pharmacokinetics === ==== Comorbid disease states ==== Various diseases, especially those that cause renal or hepatic insufficiency, may alter drug metabolism. Resources are available that report changes in a drug's metabolism due to disease states. The Medication Appropriateness Tool for Comorbid Health Conditions in Dementia (MATCH-D) criteria warns that people with dementia are more likely to experience adverse effects, and that they are less likely to be able to reliably report symptoms. ==== Genetic factors ==== Pharmacogenomics includes how genes can predict potential adverse drug reactions. However, pharmacogenomics is not limited to adverse events (of any type), but also looks at how genes may impact other responses to medications, such as low/no effect or expected/normal responses (especially based on drug metabolism). Abnormal drug metabolism may be due to inherited factors of either Phase I oxidation or Phase II conjugation. ===== Phase I reactions ===== Phase I reactions include metabolism by cytochrome P450. Patients have abnormal metabolism by cytochrome P450 due to either inheriting abnormal alleles or due to drug interactions. Tables are available to check for drug interactions due to P450 interactions. Inheriting abnormal butyrylcholinesterase (pseudocholinesterase) may affect metabolism of drugs such as succinylcholine. ===== Phase II reactions ===== Inheriting abnormal N-acetyltransferase which conjugated some drugs to facilitate excretion may affect the metabolism of drugs such as isoniazid, hydralazine, and procainamide. Inheriting abnormal thiopurine S-methyltransferase may affect the metabolism of the thiopurine drugs mercaptopurine and azathioprine. ===== Protein binding ===== Protein binding interactions are usually transient and mild until a new steady state is achieved. These are mainly for drugs without much first-pass liver metabolism. The principal plasma proteins for drug binding are: albumin α1-acid glycoprotein lipoproteins Some drug interactions with warfarin are due to changes in protein binding. === Drug interactions === The risk of drug interactions is increased with polypharmacy, especially in older adults. ==== Additive drug effects ==== Two or more drugs that contribute to the same mechanism in the body can have additive toxic or adverse effects. One example of this is multiple medications administered concurrently that prolong the QT interval, such as antiarrhythmics like sotalol and some macrolide antibiotics, such as systemic azithromycin. Another example of additive effects for adverse drug reactions is in serotonin toxicity (serotonin syndrome). If medications that cause increased serotonin levels are combined, they can cause serotonin toxicity (though therapeutic doses of one agent that increases serotonin levels can cause serotonin toxicity in certain cases and individuals). Some of the medications that can contribute to serotonin toxicity include MAO inhibitors, SSRIs, and tricyclic antidepressants. ==== Altered metabolism ==== Some medications can either inhibit or induce key drug metabolizing enzymes or drug transporters, which when combined with other medications that utilize the same proteins can lead to either toxic or sub-therapeutic adverse effects. One example of this is a patient taking a cytochrome P450 3A4 (CYP3A4) inhibitor such as the antibiotic clarithromycin, as well as another medication metabolized by CYP3A4 such as the anticoagulant apixaban, which results in elevated blood concentrations of apixaban and greater risk of serious bleeds. Additionally, Clarithromycin is a permeability glycoprotein (P-gp) efflux pump inhibitor, which when given with apixaban (a substrate for P-gp) will lead to increased absorption of apixaban, resulting in the same adverse effects as with CYP3A4 inhibition. == Management == === Assessing causality === Causality assessment is used to determine the likelihood that a drug caused a suspected ADR. There are a number of different methods used to judge causation, including the Naranjo algorithm, the Venulet algorithm and the WHO causality term assessment criteria. Each have pros and cons associated with their use and most require some level of expert judgement to apply. An ADR should not be labeled as 'certain' unless the ADR abates with a challenge-dechallenge-rechallenge protocol (stopping and starting the agent in question). The chronology of the onset of the suspected ADR is important, as another substance or factor may be implicated as a cause; co-prescribed medications and underlying psychiatric conditions may be factors in the ADR. Assigning causality to a specific agent often proves difficult, unless the event is found during a clinical study or large databases are used. Both methods have difficulties and can be fraught with error. Even in clinical studies, some ADRs may be missed as large numbers of test individuals are required to find a specific adverse drug reaction, especially for rare ADRs. Psychiatric ADRs are often missed as they are grouped together in the questionnaires used to assess the population. === Monitoring bodies === Many countries have official bodies that monitor drug safety and reactions. On an international level, the WHO runs the Uppsala Monitoring Centre. The European Union runs the European Medicines Agency (EMA). In the United States, the Food and Drug Administration (FDA) is responsible for monitoring post-marketing studies. The FDA has a reporting system called the FDA Adverse Event Reporting System, where individuals can report adverse drug events. Healthcare professionals, consumers, and the pharmaceutical industry can all submit information to this system. For health products marketed in Canada, a branch of Health Canada called The Canada Vigilance Program is responsible for surveillance. Both healthcare professionals and consumers can report to this program. In Australia, the Therapeutic Goods Administration (TGA) conducts postmarket monitoring of therapeutic products. In the UK, a monitoring system called the Yellow Card Scheme was established in 1964. The Yellow Card Scheme was set up to surveil medications and other health products. == Epidemiology == A study by the Agency for Healthcare Research and Quality (AHRQ) found that in 2011, sedatives and hypnotics were a leading source for adverse drug events seen in the hospital setting. Approximately 2.8% of all ADEs present on admission and 4.4% of ADEs that originated during a hospital stay were caused by a sedative or hypnotic drug. A second study by AHRQ found that in 2011, the most common specifically identified causes of adverse drug events that originated during hospital stays in the U.S. were steroids, antibiotics, opiates/narcotics, and anticoagulants. Patients treated in urban teaching hospitals had higher rates of ADEs involving antibiotics and opiates/narcotics compared to those treated in urban nonteaching hospitals. Those treated in private, nonprofit hospitals had higher rates of most ADE causes compared to patients treated in public or private, for-profit hospitals. Medication related harm (MRH) is common after hospital discharge in older adults, but methodological inconsistencies between studies and a paucity of data on risk factors limits clear understanding of the epidemiology. There was a wide range in incidence, from 0.4% to 51.2% of participants, and 35% to 59% of harm was preventable. Medication related harm incidence within 30 days after discharge ranged from 167 to 500 events per 1,000 individuals discharged (17–51% of individuals). In the U.S., females had a higher rate of ADEs involving opiates and narcotics than males in 2011, while male patients had a higher rate of anticoagulant ADEs. Nearly 8 in 1,000 adults aged 65 years or older experienced one of the four most common ADEs (steroids, antibiotics, opiates/narcotics, and anticoagulants) during hospitalization. A study showed that 48% of patients had an adverse drug reaction to at least one drug, and pharmacist involvement helps to pick up adverse drug reactions. In 2012, McKinsey & Company concluded that the cost of the 50-100 million preventable error-related adverse drug events would be between US$18–115 billion. An article published in The Journal of the American Medical Association (JAMA) in 2016 reported adverse drug event statistics from emergency departments around the United States in 2013-2014. From this article, an estimated prevalence of adverse drug events that were presented to the emergency department (ED) was 4 events out of every 1000 people. This article reported that 57.1% of these adverse drug events presented to the ED were in females. As well, out of all of the adverse drug events presented to the emergency department documented in this article, 17.6% were from anticoagulants, 16.1% were from antibiotics, and 13.3% from diabetic agents. == See also == == References == == Further reading == Incidence of adverse drug reactions in human immune deficiency virus-positive patients using highly active antiretroviral therapy PMC 3312730 == External links ==	Wikipedia/Drug_toxicity
Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall density naming convention), very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL). LDL delivers fat molecules to cells. LDL has been associated with the progression of atherosclerosis. == Overview == Lipoproteins transfer lipids (fats) around the body in the extracellular fluid, making fats available to body cells for receptor-mediated endocytosis. Lipoproteins are complex particles composed of multiple proteins, typically 80–100 proteins per particle (organized by a single apolipoprotein B for LDL and the larger particles). A single LDL particle is about 22–27.5 nanometers in diameter, typically transporting 3,000 to 6,000 fat molecules per particle and varying in size according to the number and mix of fat molecules contained within. The lipids carried include all fat molecules with cholesterol, phospholipids, and triglycerides dominant; amounts of each vary considerably. A good clinical interpretation of blood lipid levels is that high LDL, in combination with a low amount of HDL, is associated with an increased risk of cardiovascular diseases. == Biochemistry == === Structure === Each native LDL particle enables emulsification, i.e. surrounding the fatty acids being carried, enabling these fats to move around the body within the water outside cells. Each particle contains a single apolipoprotein B-100 molecule (Apo B-100, a protein that has 4536 amino acid residues and a mass of 514 kDa), along with 80 to 100 additional ancillary proteins. Each LDL has a highly hydrophobic core consisting of polyunsaturated fatty acid known as linoleate and hundreds to thousands (about 1500 commonly cited as an average) of esterified and unesterified cholesterol molecules. This core also carries varying numbers of triglycerides and other fats and is surrounded by a shell of phospholipids and unesterified cholesterol, as well as the single copy of Apo B-100. LDL particles are approximately 22 nm (0.00000087 in.) to 27.5 nm in diameter and have a mass of about 3 million daltons. Since LDL particles contain a variable and changing number of fatty acid molecules, there is a distribution of LDL particle mass and size. Determining the structure of LDL has been difficult for biochemists because of its heterogeneous structure. However, the structure of LDL at human body temperature in native condition, with a resolution of about 16 Angstroms using cryogenic electron microscopy, has been described in 2011. == Physiology == LDL particles are formed when triglycerides are removed from VLDL by the lipoprotein lipase enzyme (LPL), and they become smaller and denser (i.e., fewer fat molecules with the same protein transport shell), containing a higher proportion of cholesterol esters. === Transport into the cell === When a cell requires more cholesterol than its HMG-CoA pathway can produce, it synthesizes the necessary LDL receptors as well as PCSK9, a proprotein convertase that marks the LDL receptor for degradation. LDL receptors are inserted into the plasma membrane and diffuse freely until they associate with clathrin-coated pits. When LDL receptors bind LDL particles in the bloodstream, the clathrin-coated pits are endocytosed into the cell. Vesicles containing LDL receptors bound to LDL are delivered to the endosome. In the presence of low pH, such as that found in the endosome, LDL receptors undergo a conformation change, releasing LDL. LDL is then shipped to the lysosome, where cholesterol esters in the LDL are hydrolysed. LDL receptors are typically returned to the plasma membrane, where they repeat this cycle. If LDL receptors bind to PCSK9, however, transport of LDL receptors is redirected to the lysosome, where they are degraded. === Role in the innate immune system === LDL interferes with the quorum sensing system that upregulates genes required for invasive Staphylococcus aureus infection. The mechanism of antagonism entails binding apolipoprotein B to a S. aureus autoinducer pheromone, preventing signaling through its receptor. Mice deficient in apolipoprotein B are more susceptible to invasive bacterial infection. === LDL size patterns === LDL can be grouped based on its size: large low-density LDL particles are described as pattern A, and small high-density ("small dense") LDL particles are pattern B. Pattern B has been associated by some with a higher risk for Coronary artery disease.: 1–10 This is thought to be because the smaller particles are more easily able to penetrate the endothelium of arterial walls. Pattern I, or intermediate, indicates that most LDL particles are very close in size to the normal gaps in the endothelium (26 nm). According to one study, sizes 19.0–20.5 nm were designated as pattern B and LDL sizes 20.6–22 nm were designated as pattern A. Some evidence suggests the correlation between pattern B and coronary artery disease is stronger than the correspondence between the LDL number measured in the standard lipid profile test. Tests to measure these LDL subtype patterns have been more expensive and not widely available, so the standard lipid profile test is used more often. There has also been noted a correspondence between higher triglyceride levels and higher levels of smaller, denser LDL particles and alternately lower triglyceride levels and higher levels of the larger, less dense ("buoyant") LDL. With continued research, decreasing cost, greater availability, and wider acceptance of other lipoprotein subclass analysis assay methods, including NMR spectroscopy, research studies have shown a stronger correlation between clinically evident human cardiovascular events and quantitatively measured particle concentrations. === Oxidized LDL === Oxidized LDL (oxLDL) is a general term for LDL particles with oxidatively modified structural components. As a result, from free radical attack, both lipid and protein parts of LDL can be oxidized in the vascular wall. Besides the oxidative reactions in the vascular wall, oxidized lipids in LDL can also be derived from oxidized dietary lipids. Oxidized LDL is known to associate with the development of atherosclerosis, and it is therefore widely studied as a potential risk factor of cardiovascular diseases. Atherogenicity of oxidized LDL has been explained by lack of recognition of oxidation-modified LDL structures by the LDL receptors, preventing the normal metabolism of LDL particles and leading eventually to the development of atherosclerotic plaques. Of the lipid material contained in LDL, various lipid oxidation products are known as the ultimate atherogenic species. Acting as a transporter of these injurious molecules is another mechanism by which LDL can increase the risk of atherosclerosis. The LOX-1 scavenge receptor does take up oxLDL, but the liver does not naturally express it. It is instead expressed by endothelial cells, platelets, macrophages, smooth muscle cells, and cardiomyocytes as an innate immune scavenge receptor. When activated, pro-inflammatory signals are generated in the cell, and damaging compounds are released as well. As a result, these cells are most sensitive to the effects of oxLDL. SR-BI and CD36, two class B scavenge receptors, also take up oxLDL into the macrophage. Despite lower recognition efficacy by the LDLR, the liver does remove oxLDLs from the circulation. This is achieved by Kupffer cells and liver sinusoidal endothelial cells (LSECs). In LSECs, stabilin-1 and stabilin-2 mediate most of the uptake. Uptake of oxLDLs causes visible disruption to the structure of the LSEC in rats. Doing the same also damages human LSEC cultures. === Acetyl LDL === Acetyl LDL (acLDL) is a construct generated in vitro. When scientists produced such a modified version of LDL, they found that a class of scavenge receptors, now called SR-A, can recognize them and take them up. Because scavenge receptors work much faster than the downregulated native LDL receptor of a macrophage, oxLDL and acLDL can both fill up a macrophage quickly, turning it into a foam cell. == Testing == Blood tests commonly report LDL-C: the amount of cholesterol that is estimated to be contained with LDL particles, on average, using a formula, the Friedewald equation. In a clinical context, mathematically calculated estimates of LDL-C are commonly used to estimate how much low-density lipoproteins drive the progression of atherosclerosis. The problem with this approach is that LDL-C values are commonly discordant with both direct measurements of LDL particles and actual rates of atherosclerosis progression. Direct LDL measurements are also available and better reveal individual issues but are less often promoted or done due to slightly higher costs and are available from only a couple of laboratories in the United States. In 2008, the ADA and ACC recognized direct LDL particle measurement by NMR as superior for assessing individual risk of cardiovascular events. === Estimation of LDL particles via cholesterol content === Chemical measures of lipid concentration have long been the most-used clinical measurement, not because they have the best correlation with individual outcomes but because these lab methods are less expensive and more widely available. The lipid profile does not measure LDL particles. It only estimates them using the Friedewald equation by subtracting the amount of cholesterol associated with other particles, such as HDL and VLDL, assuming a prolonged fasting state, etc.: L ≈ C − H − k T {\displaystyle L\approx C-H-kT} where H is HDL cholesterol, L is LDL cholesterol, C is total cholesterol, T is triglycerides, and k is 0.20 if the quantities are measured in mg/dL and 0.45 in mmol/L. There are limitations to this method, most notably that samples must be obtained after a 12 to 14 h fast and that LDL-C cannot be calculated if plasma triglyceride is >4.52 mmol/L (400 mg/dL). Even at triglyceride levels of 2.5 to 4.5 mmol/L, this formula is considered inaccurate. If both total cholesterol and triglyceride levels are elevated then a modified formula, with quantities in mg/dL, may be used L = C − H − 0.16 T {\displaystyle L=C-H-0.16T} This formula provides an approximation with fair accuracy for most people, assuming the blood was drawn after fasting for about 14 hours or longer, but does not reveal the actual LDL particle concentration because the percentage of fat molecules within the LDL particles, which are cholesterol, varies as much as 8:1 variation. There are several formulas published addressing the inaccuracy in LDL-C estimation. The inaccuracy is based on the assumption that VLDL-C (Very low density lipoprotein cholesterol) is always one-fifth of the triglyceride concentration. Other formulae address this issue by using an adjustable factor or using a regression equation. There are few studies which have compared the LDL-C values derived from this formula and values obtained by direct enzymatic method. Direct enzymatic methods are found to be accurate and must be the test of choice in clinical situations. In resource-poor settings, the option to use the formula has to be considered. However, the concentration of LDL particles, and to a lesser extent, their size, has a stronger and consistent correlation with individual clinical outcomes than the amount of cholesterol within LDL particles, even if the LDL-C estimation is approximately correct. There is increasing evidence and recognition of the value of more targeted and accurate measurements of LDL particles. Specifically, LDL particle number (concentration) and, to a lesser extent, size have shown slightly stronger correlations with atherosclerotic progression and cardiovascular events than obtained using chemical measures of the amount of cholesterol carried by the LDL particles. It is possible that the LDL cholesterol concentration can be low, yet LDL particle number high and cardiovascular events rates are high. Correspondingly, it is possible that LDL cholesterol concentration can be relatively high, yet LDL particle number is low, and cardiovascular events are also low. ==== Normal ranges ==== In the US, the American Heart Association, NIH, and NCEP provide a set of guidelines for fasting LDL-Cholesterol levels, estimated or measured, and risk for heart disease. As of about 2005, these guidelines were: Over time, with more clinical research, these recommended levels keep being reduced because LDL reduction, including to abnormally low levels, was the most effective strategy for reducing cardiovascular death rates in one large double blind, randomized clinical trial of men with hypercholesterolemia; far more effective than coronary angioplasty/stenting or bypass surgery. The 2004 updated American Heart Association, NIH, and NCEP recommendations for people with known atherosclerosis diseases are for lowering LDL levels to less than 70 mg/dL. This low level of less than 70 mg/dL was recommended for primary prevention of 'very-high risk patients' and secondary prevention as a 'reasonable further reduction'. This position was disputed. Statin drugs involved in such clinical trials have numerous physiological effects beyond simply the reduction of LDL levels. From longitudinal population studies following the progression of atherosclerosis-related behaviors from early childhood into adulthood, the usual LDL in childhood, before the development of fatty streaks, is about 35 mg/dL. However, all the above values refer to chemical measures of lipid/cholesterol concentration within LDL, not measured low-density lipoprotein concentrations, which is the accurate approach. A study was conducted measuring the effects of guideline changes on LDL cholesterol reporting and control for diabetes visits in the US from 1995 to 2004. It was found that although LDL cholesterol reporting and control for diabetes and coronary heart disease visits improved continuously between 1995 and 2004, neither the 1998 ADA guidelines nor the 2001 ATP III guidelines increased LDL cholesterol control for diabetes relative to coronary heart disease. === Direct measurement of LDL particle concentrations === There are several competing methods for measuring lipoprotein particle concentrations and size. The evidence is that the NMR methodology (developed, automated & significantly reduced in costs while improving accuracy as pioneered by Jim Otvos and associates) results in a 22-25% reduction in cardiovascular events within one year, contrary to the longstanding claims by many in the medical industry that the superiority over existing methods was weak, even by statements of some proponents. Since the later 1990s, because of the development of NMR measurements, it has been possible to clinically measure lipoprotein particles at lower cost [under $80 US (including shipping) & is decreasing versus the previous costs of >$400 to >$5,000] and higher accuracy. There are two other assays for LDL particles; however, most estimate only LDL particle concentrations like LDL-C. The ADA and ACC mentioned direct LDL particle measurement by NMR in a 28 March 2008 joint consensus statement, as having advantages for predicting individual risk of atherosclerosis disease events, but the statement noted that the test is less widely available, is more expensive [about $13.00 US (2015 without insurance coverage) from some labs which use the Vantera Analyzer]. Debate continues that it is "...unclear whether LDL particle size measurements add value to the measurement of LDL-particle concentration", though outcomes have continuously tracked LDL particle, not LDL-C, concentrations. Using NMR, the total LDL particle concentrations in nmol/L plasma are typically subdivided by percentiles referenced to the 5,382 men and women participating in the MESA trial who are not on any lipid medications. LDL particle concentration can also be measured by measuring the concentration of the protein ApoB, based on the generally accepted principle that each LDL or VLDL particle carries one ApoB molecule. ==== Optimal ranges ==== The LDL particle concentrations are typically categorized by percentiles, <20%, 20–50%, 50th–80th%, 80th–95%, and >95% groups of the people participating and being tracked in the MESA trial, a medical research study sponsored by the United States National Heart, Lung, and Blood Institute. Over time, the lowest incidence of atherosclerotic events occurs within the <20% group, with increased rates for the higher groups. Multiple other measures, including particle sizes, small LDL particle concentrations, large total and HDL particle concentrations, along with estimations of insulin resistance pattern and standard cholesterol lipid measurements (for comparison of the plasma data with the estimation methods discussed above) are also routinely provided. == Lowering LDL-cholesterol == The mevalonate pathway serves as the basis for the biosynthesis of many molecules, including cholesterol. The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) is an essential component and performs the first of 37 steps within the cholesterol production pathway, and is present in every animal cell. Statins block this first step. LDL-C is not a count of actual LDL particles. LDL-C represents how much cholesterol is being transported by all LDL particles, which is either a smaller concentration of large particles or a high concentration of small particles. LDL-C itself can be estimated by subtraction (Friedewald's method) or directly measured; see the section #Testing above to see how it's measured. LDL particles carry many lipid molecules (typically 3,000 to 6,000 lipid molecules per LDL particle); this includes cholesterol, triglycerides, phospholipids and others. An LDL-C measurement cannot account for differences in size and composition between types of LDL. === Pharmaceutical === PCSK9 inhibitors, in clinical trials, by several companies, are more effective for LDL reduction than the statins, including statins alone at high dose (though not necessarily the combination of statins plus ezetimibe). They have been approved and are recommended in patients not receiving enough reduction from their maximally tolerated dose of statins + ezetimibe. Statins reduce high levels of LDL particles by inhibiting the enzyme HMG-CoA reductase in cells, the rate-limiting step of cholesterol synthesis. To compensate for the decreased cholesterol availability, synthesis of LDL receptors (including hepatic) is increased, resulting in an increased clearance of LDL particles from the extracellular water, including of the blood. Ezetimibe reduces intestinal absorption of cholesterol, thus can reduce LDL particle concentrations when combined with statins. Niacin (nicotinic acid), lowers LDL by selectively inhibiting hepatic diacylglycerol acyltransferase 2, reducing triglyceride synthesis and VLDL secretion through a receptor HM74 and HM74A or GPR109A. Introduced in 1955. Clofibrate is effective at lowering cholesterol levels, but has been associated with significantly increased cancer and stroke mortality, despite lowered cholesterol levels. Other developed and tested fibrates, e.g. fenofibric acid have had a better track record and are primarily promoted for lowering VLDL particles (triglycerides), not LDL particles, yet can help some in combination with other strategies. Probucol, introduced in the 1970s. Now known to work through, among other ways, changing the shape and size of the LDL particle so they can be taken up by the liver without involving the LDL receptor. It has been discontinued in the west due to HDL-C decreases that were not explainable at the time. It's now known that it enhances the reverse cholesterol transport and antioxidant functions of HDL despite decreasing HDL-C. ==== Not approved as drugs ==== Several CETP inhibitors have been researched to improve HDL concentrations, but so far, despite dramatically increasing HDL-C, have not had a consistent track record in reducing atherosclerosis disease events. Some have increased mortality rates compared with placebo. Some tocotrienols, especially delta- and gamma-tocotrienols, are being promoted as statin alternative non-prescription agents to treat high cholesterol, having been shown in vitro to have an effect. In particular, gamma-tocotrienol appears to be another HMG-CoA reductase inhibitor, and can reduce cholesterol production. As with statins, this decrease in intra-hepatic (liver) LDL levels may induce hepatic LDL receptor up-regulation, also decreasing plasma LDL levels. As always, a key issue is how benefits and complications of such agents compare with statins—molecular tools that have been analyzed in large numbers of human research and clinical trials since the mid-1970s. Phytosterols are widely recognized as having a proven LDL cholesterol lowering efficacy' A 2018 review found a dose-response relationship for phytosterols, with intakes of 1.5 to 3 g/day lowering LDL-C by 7.5% to 12%, but reviews as of 2017 had found no data indicating that the consumption of phytosterols may reduce the risk of CVD. Current supplemental guidelines for reducing LDL recommend doses of phytosterols in the 1.6-3.0 grams per day range (Health Canada, EFSA, ATP III, FDA) with a 2009 meta-analysis demonstrating an 8.8% reduction in LDL-cholesterol at a mean dose of 2.15 gram per day. === Lifestyle === LDL cholesterol can be lowered through dietary intervention by limiting foods with saturated fat and avoiding foods with trans fat. Saturated fats are found in meat products (including poultry), full-fat dairy, eggs, and refined tropical oils like coconut and palm. Added trans fat (in the form of partially hydrogenated oils) has been banned in the US since 2021. However, trans fat can still be found in red meat and dairy products as it is produced in small amounts by ruminants such as sheep and cows. LDL cholesterol can also be lowered by increasing consumption of soluble fiber and plant-based foods. Another lifestyle approach to reduce LDL cholesterol has been minimizing total body fat, in particular fat stored inside the abdominal cavity (visceral body fat). Visceral fat, which is more metabolically active than subcutaneous fat, has been found to produce many enzymatic signals, e.g. resistin, which increase insulin resistance and circulating VLDL particle concentrations, thus both increasing LDL particle concentrations and accelerating the development of diabetes mellitus. == Research == Some studies dispute the benefits of low LDL in elderly people, but not in other age groups. === Gene editing === In 2021, scientists demonstrated that CRISPR gene editing can decrease blood levels of LDL cholesterol in Macaca fascicularis monkeys for months by 60% via knockout of PCSK9 in the liver. == See also == == Notes and references == == External links == Fat (LDL) Degradation: PMAP The Proteolysis Map-animation Adult Treatment Panel III Full Report ATP III Update 2004 O'Keefe JH, Cordain L, Harris WH, Moe RM, Vogel R (June 2004). "Optimal low-density lipoprotein is 50 to 70 mg/dL: lower is better and physiologically normal". Journal of the American College of Cardiology. 43 (11): 2142–6. doi:10.1016/j.jacc.2004.03.046. PMID 15172426.	Wikipedia/Low-density_lipoprotein
High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are typically composed of 80–100 proteins per particle (organized by one, two or three ApoA). HDL particles enlarge while circulating in the blood, aggregating more fat molecules and transporting up to hundreds of fat molecules per particle. HDL particles are commonly referred to as "good cholesterol", because they transport fat molecules out of artery walls, reduce macrophage accumulation, and thus help prevent or even regress atherosclerosis. == Overview == Lipoproteins are divided into five subgroups, by density/size (an inverse relationship), which also correlates with function and incidence of cardiovascular events. Unlike the larger lipoprotein particles, which deliver fat molecules to cells, HDL particles remove fat molecules from cells. The lipids carried include cholesterol, phospholipids, and triglycerides, amounts of each are variable. HDL particles remove fats and cholesterol from cells, including within artery wall atheroma, and transport it back to the liver for excretion or re-use. Increasing concentrations of HDL particles in the blood are associated with decreasing accumulation of atherosclerosis within the walls of arteries, reducing the risk of sudden plaque ruptures, cardiovascular disease, stroke and other vascular diseases. People with higher levels of HDL-C tend to have fewer problems with cardiovascular diseases, while those with low HDL-C cholesterol levels (especially less than 40 mg/dL or about 1 mmol/L) have increased rates for heart disease. Higher native HDL levels are correlated with lowered risk of cardiovascular disease in healthy people. However, a higher blood level of HDL is not necessarily protective against cardiovascular disease and may even be harmful in extremely high quantities, with an increased cardiovascular risk, especially in hypertensive patients. == Testing == Because of the high cost of directly measuring HDL particles, blood tests commonly measure a surrogate value, HDL-cholesterol (HDL-C), i.e. the cholesterol associated with HDL particles. HDL-C is often contrasted with the amount of cholesterol estimated to be carried within low-density lipoprotein particles, known as LDL-C, with HDL-C being nicknamed "good cholesterol" and LDL-C "bad cholesterol". In healthy individuals, about 30% of blood cholesterol, along with other fats, is carried by HDL. This is often contrasted with the amount of cholesterol estimated to be carried within low-density lipoprotein particles, LDL, and called LDL-C. HDL particles remove fats and cholesterol from cells, including within artery wall atheroma, and transport it back to the liver for excretion or re-utilization; thus the cholesterol carried within HDL particles (HDL-C) is sometimes called "good cholesterol". Those with higher levels of HDL-C tend to have fewer problems with cardiovascular diseases, while those with low HDL-C cholesterol levels (especially less than 40 mg/dL or about 1 mmol/L) have increased rates for heart disease. Higher native HDL levels are correlated with lowered risk of cardiovascular disease in healthy people. The remainder of the serum cholesterol after subtracting the HDL is the non-HDL cholesterol. The concentration of these other components, which may cause atheroma, is known as the non-HDL-C. This is now preferred to LDL-C as a secondary marker as it has been shown to be a better predictor and it is more easily calculated. == Structure and function == With a size ranging from 5 to 17 nm, HDL is the smallest of the lipoprotein particles. It is the densest because it contains the highest proportion of protein to lipids. Its most abundant apolipoproteins are apo A-I and apo A-II. A rare genetic variant, ApoA-1 Milano, has been documented to be far more effective in both protecting against and regressing arterial disease, atherosclerosis. The liver synthesizes these lipoproteins as complexes of apolipoproteins and phospholipid, which resemble cholesterol-free flattened spherical lipoprotein particles, whose NMR structure was published; the complexes are capable of picking up cholesterol, carried internally, from cells by interaction with the ATP-binding cassette transporter A1 (ABCA1). A plasma enzyme called lecithin-cholesterol acyltransferase (LCAT) converts the free cholesterol into cholesteryl ester (a more hydrophobic form of cholesterol), which is then sequestered into the core of the lipoprotein particle, eventually causing the newly synthesized HDL to assume a spherical shape. HDL particles increase in size as they circulate through the blood and incorporate more cholesterol and phospholipid molecules from cells and other lipoproteins, such as by interaction with the ABCG1 transporter and the phospholipid transport protein (PLTP). HDL transports cholesterol mostly to the liver or steroidogenic organs such as adrenals, ovary, and testes by both direct and indirect pathways. HDL is removed by HDL receptors such as scavenger receptor BI (SR-BI), which mediate the selective uptake of cholesterol from HDL. In humans, probably the most relevant pathway is the indirect one, which is mediated by cholesteryl ester transfer protein (CETP). This protein exchanges triglycerides of VLDL against cholesteryl esters of HDL. As the result, VLDLs are processed to LDL, which are removed from the circulation by the LDL receptor pathway. The triglycerides are not stable in HDL, but are degraded by hepatic lipase so that, finally, small HDL particles are left, which restart the uptake of cholesterol from cells. The cholesterol delivered to the liver is excreted into the bile and, hence, intestine either directly or indirectly after conversion into bile acids. Delivery of HDL cholesterol to adrenals, ovaries, and testes is important for the synthesis of steroid hormones. Several steps in the metabolism of HDL can participate in the transport of cholesterol from lipid-laden macrophages of atherosclerotic arteries, termed foam cells, to the liver for secretion into the bile. This pathway has been termed reverse cholesterol transport and is considered as the classical protective function of HDL toward atherosclerosis. HDL carries many lipid and protein species, several of which have very low concentrations but are biologically very active. For example, HDL and its protein and lipid constituents help to inhibit oxidation, inflammation, activation of the endothelium, coagulation, and platelet aggregation. All these properties may contribute to the ability of HDL to protect from atherosclerosis, and it is not yet known which are the most important. In addition, a small subfraction of HDL lends protection against the protozoan parasite Trypanosoma brucei brucei. This HDL subfraction, termed trypanosome lytic factor (TLF), contains specialized proteins that, while very active, are unique to the TLF molecule. In the stress response, serum amyloid A, which is one of the acute-phase proteins and an apolipoprotein, is under the stimulation of cytokines (interleukin 1, interleukin 6), and cortisol produced in the adrenal cortex and carried to the damaged tissue incorporated into HDL particles. At the inflammation site, it attracts and activates leukocytes. In chronic inflammations, its deposition in the tissues manifests itself as amyloidosis. It has been postulated that the concentration of large HDL particles more accurately reflects protective action, as opposed to the concentration of total HDL particles. This ratio of large HDL to total HDL particles varies widely and is measured only by more sophisticated lipoprotein assays using either electrophoresis (the original method developed in the 1970s) or newer NMR spectroscopy methods (See also nuclear magnetic resonance and spectroscopy), developed in the 1990s. === Subfractions === Five subfractions of HDL have been identified. From largest (and most effective in cholesterol removal) to smallest (and least effective), the types are 2a, 2b, 3a, 3b, and 3c. == Epidemiology == Men tend to have noticeably lower HDL concentrations, with smaller size and lower cholesterol content, than women. Men also have a greater incidence of atherosclerotic heart disease. Studies confirm the fact that HDL has a buffering role in balancing the effects of the hypercoagulable state in type 2 diabetics and decreases the high risk of cardiovascular complications in these patients. Also, the results obtained in this study revealed that there was a significant negative correlation between HDL and activated partial thromboplastin time (APTT). Epidemiological studies have shown that high concentrations of HDL (over 60 mg/dL) have protective value against cardiovascular diseases such as ischemic stroke and myocardial infarction. Low concentrations of HDL (below 40 mg/dL for men, below 50 mg/dL for women) increase the risk for atherosclerotic diseases. Data from the landmark Framingham Heart Study showed that, for a given level of LDL, the risk of heart disease increases 10-fold as the HDL varies from high to low. On the converse, however, for a fixed level of HDL, the risk increases 3-fold as LDL varies from low to high. Even people with very low LDL levels achieved by statin treatment are exposed to increased risk if their HDL levels are not high enough. Very high HDL-C levels (≥80 mg/dL in men, ≥100 mg/dL in women) appears to be detrimental to cardiovascular outcomes. Several genetic conditions cause abnormally low or high HDL-C levels, often without the expected change in cardiovascular disease rates. In fact, when many known correlates of CVD risks are controlled for, HDL-C does not have any correlation with cardiovascular event risks. In this way, HDL-C only seems to serve as an imperfect, but easy-to-measure, proxy for a healthy lifestyle. What does correlate well with CVD risks even when these factors are controlled for is a direct measure of the capability for reverse cholesterol transport in a person's blood serum, the cholesterol efflux capacity (CEC). == Estimating HDL via associated cholesterol == Clinical laboratories formerly measured HDL cholesterol by separating other lipoprotein fractions using either ultracentrifugation or chemical precipitation with divalent ions such as Mg2+, then coupling the products of a cholesterol oxidase reaction to an indicator reaction. The reference method still uses a combination of these techniques. Most laboratories now use automated homogeneous analytical methods in which lipoproteins containing apo B are blocked using antibodies to apo B, then a colorimetric enzyme reaction measures cholesterol in the non-blocked HDL particles. HPLC can also be used. Subfractions (HDL-2C, HDL-3C) can be measured, but clinical significance of these subfractions has not been determined. The measurement of apo-A reactive capacity can be used to measure HDL cholesterol but is thought to be less accurate. === Recommended ranges === The American Heart Association, NIH and NCEP provide a set of guidelines for fasting HDL levels and risk for heart disease. High LDL with low HDL level is an additional risk factor for cardiovascular disease. == Measuring HDL concentration and sizes == As technology has reduced costs and clinical trials have continued to demonstrate the importance of HDL, methods for directly measuring HDL concentrations and size (which indicates function) at lower costs have become more widely available and increasingly regarded as important for assessing individual risk for progressive arterial disease and treatment methods. === Electrophoresis measurements === Since the HDL particles have a net negative charge and vary by density & size, ultracentrifugation combined with electrophoresis have been utilized since before 1950 to enumerate the concentration of HDL particles and sort them by size with a specific volume of blood plasma. Larger HDL particles are carrying more cholesterol. === NMR measurements === Concentration and sizes of lipoprotein particles can be estimated using nuclear magnetic resonance fingerprinting. ==== Optimal total and large HDL concentrations ==== The HDL particle concentrations are typically categorized by event rate percentiles based on the people participating and being tracked in the MESA trial, a medical research study sponsored by the United States National Heart, Lung, and Blood Institute. The lowest incidence of atherosclerotic events over time occurs within those with both the highest concentrations of total HDL particles (the top quarter, >75%) and the highest concentrations of large HDL particles. Multiple additional measures, including LDL particle concentrations, small LDL particle concentrations, VLDL concentrations, estimations of insulin resistance and standard cholesterol lipid measurements (for comparison of the plasma data with the estimation methods discussed above) are routinely provided in clinical testing. == Increasing HDL levels == While higher HDL levels are correlated with lower risk of cardiovascular diseases, no medication used to increase HDL has been proven to improve health. As of 2017, numerous lifestyle changes and drugs to increase HDL levels were under study. HDL lipoprotein particles that bear apolipoprotein C3 are associated with increased, rather than decreased, risk for coronary heart disease. === Diet and exercise === Certain changes in diet and exercise may have a positive impact on raising HDL levels: Decreased intake of simple carbohydrates. Aerobic exercise Weight loss Avocado consumption Magnesium supplements raise HDL-C. Addition of soluble fiber to diet Consumption of omega-3 fatty acids such as fish oil or flax oil Increased intake of unsaturated fats Removal of trans fatty acids from the diet Most saturated fats increase HDL cholesterol to varying degrees but also raise total and LDL cholesterol. === Recreational drugs === HDL levels can be increased by smoking cessation, or mild to moderate alcohol intake. Cannabis in unadjusted analyses, past and current cannabis use was not associated with higher HDL-C levels. A study performed in 4635 patients demonstrated no effect on the HDL-C levels (P=0.78) [the mean (standard error) HDL-C values in control subjects (never used), past users and current users were 53.4 (0.4), 53.9 (0.6) and 53.9 (0.7) mg/dL, respectively]. Exogenous anabolic androgenic steroids, particularly 17α-alkylated anabolic steroids and others administered orally, can reduce HDL-C by 50 percent or more. Other androgen receptor agonists such as selective androgen receptor modulators can also lower HDL. As there is some evidence that the HDL reduction is caused by increased reverse cholesterol transport, it is unknown if AR agonists' HDL-lowering effect is pro- or anti-atherogenic. === Pharmaceutical drugs and niacin === Pharmacological therapy to increase the level of HDL cholesterol includes use of fibrates and niacin. Fibrates have not been proven to have an effect on overall deaths from all causes, despite their effects on lipids. Niacin (nicotinic acid, a form of vitamin B3) increases HDL by selectively inhibiting hepatic diacylglycerol acyltransferase 2, reducing triglyceride synthesis and VLDL secretion through a receptor HM74 otherwise known as niacin receptor 2 and HM74A / GPR109A, niacin receptor 1. Pharmacologic (1- to 3-gram/day) niacin doses increase HDL levels by 10–30%, making it the most powerful agent to increase HDL-cholesterol. A randomized clinical trial demonstrated that treatment with niacin can significantly reduce atherosclerosis progression and cardiovascular events. Niacin products sold as "no-flush", i.e. not having side-effects such as "niacin flush", do not, however, contain free nicotinic acid and are therefore ineffective at raising HDL, while products sold as "sustained-release" may contain free nicotinic acid, but "some brands are hepatotoxic"; therefore the recommended form of niacin for raising HDL is the cheapest, immediate-release preparation. Both fibrates and niacin increase artery toxic homocysteine, an effect that can be counteracted by also consuming a multivitamin with relatively high amounts of the B-vitamins, but multiple European trials of the most popular B-vitamin cocktails, trial showing 30% average reduction in homocysteine, while not showing problems have also not shown any benefit in reducing cardiovascular event rates. A 2011 extended-release niacin (Niaspan) study was halted early because patients adding niacin to their statin treatment showed no increase in heart health, but did experience an increase in the risk of stroke. In contrast, while the use of statins is effective against high levels of LDL cholesterol, most have little or no effect in raising HDL cholesterol. Rosuvastatin and pitavastatin, however, have been demonstrated to significantly raise HDL levels. Lovaza has been shown to increase HDL-C. However, the best evidence to date suggests it has no benefit for primary or secondary prevention of cardiovascular disease. The PPAR modulator GW501516 has shown a positive effect on HDL-C and an antiatherogenic where LDL is an issue. However, research on the drug has been discontinued after it was discovered to cause rapid cancer development in several organs in rats. == See also == Asymmetric dimethylarginine Cardiovascular disease Cholesteryl ester storage disease Endothelium Lipid profile Lysosomal acid lipase deficiency == References ==	Wikipedia/High-density_lipoprotein
Fenofibrate/pravastatin, sold under the brand name Pravafenix, is a combination medication used for the treatment of hypercholesterolemia (high blood cholesterol levels) in adults whose low-density lipoprotein (LDL) cholesterol is already being controlled with pravastatin alone but who still need to improve their cholesterol levels and to reduce their levels of triglycerides. It contains fenofibrate and pravastatin. It is taken by mouth. The most common side effects are abdominal distension (bloating), abdominal pain (stomach ache), constipation, diarrhea, dry mouth, dyspepsia (heartburn), eructation (belching), flatulence (gas), nausea (feeling sick), abdominal discomfort, vomiting and raised blood levels of liver enzymes. Fenofibrate is a peroxisome proliferator-activated receptor (PPAR) agonist. It activates a type of receptor called the peroxisome proliferator-activated receptor alpha, which is involved in breaking down fat from the diet, especially triglycerides. When the receptors are activated, the breakdown of fats is accelerated, and this helps clear the blood of cholesterol and triglycerides. Pravastatin belongs to the group called statins. It reduces total blood cholesterol by blocking the action of 3-hydroxy-3-methyl-glutaryl-coenzyme-A (HMG-CoA) reductase, an enzyme in the liver involved in the production of cholesterol. As the liver needs cholesterol to produce bile, the reduced blood cholesterol level causes the liver cells to produce receptors that draw cholesterol from the blood, reducing its level even further. The cholesterol drawn out of the blood in this way is the LDL cholesterol. == Medical uses == Fenofibrate/pravastatin is indicated for the treatment of high-coronary-heart-disease (CHD)-risk adults with mixed dyslipidemia characterized by high triglycerides and low HDL-cholesterol (C) levels whose LDL-C levels are adequately controlled while on a treatment with pravastatin 40 mg monotherapy. == Society and culture == === Legal status === In January 2011, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Pravafenix, fenofibrate/pravastatin, 160 mg/40 mg, hard capsule, intended the treatment of high coronary heart disease (CHD)-risk adult patients with mixed dyslipidemia characterized by high triglycerides and low HDL-cholesterol levels whose LDL-C levels are adequately controlled while on a treatment with pravastatin 40 mg monotherapy. The applicant for this medicinal product is Laboratoires S.M.B. S.A. Fenofibrate/pravastatin was approved for use in the European Union in April 2011. == References == == Further reading == Farnier M (May 2012). "Pravastatin and fenofibrate in combination (Pravafenix) for the treatment of high-risk patients with mixed hyperlipidemia". Expert Rev Cardiovasc Ther. 10 (5): 565–75. doi:10.1586/erc.12.37. PMID 22651832. S2CID 12767763. Hernández Mijares A (July 2014). "[Combination of pravastatin and fenofibrate (Pravafenix). Safety studies]". Clin Investig Arterioscler (in Spanish). 26 Suppl 1: 25–30. doi:10.1016/S0214-9168(14)70023-3. PMID 25043544.	Wikipedia/Fenofibrate/pravastatin
Drugs used in diabetes treat types of diabetes mellitus by decreasing glucose levels in the blood. With the exception of insulin, most GLP-1 receptor agonists (liraglutide, exenatide, and others), and pramlintide, all diabetes medications are administered orally and are thus called oral hypoglycemic agents or oral antihyperglycemic agents. There are different classes of hypoglycemic drugs, and selection of the appropriate agent depends on the nature of diabetes, age, and situation of the person, as well as other patient factors. Type 1 diabetes or Diabetes mellitus is an endocrine disorder characterized by hyperglycemia due to autoimmune destruction of insulin-secreting pancreatic beta cells or from variable degrees of insulin resistance and deficiency. Chronic hyperglycemia of diabetes can lead to multiorgan damage, resulting in renal, neurologic, cardiovascular, and other serious complications. The treatment for Type 1 diabetes is insulin injection. Type 2 diabetes is the most common type of diabetes. Type 2 diabetes occurs because the body doesn’t use the hormone insulin properly. Insulin helps your body absorb glucose and use it for energy. If your body doesn’t make enough insulin or doesn’tuse insulin properly, you have a condition called insulin resistance. Insulin resistance requires the body to produce higher levels of insulin. Over time, the body cannot keep up with the demand for extra insulin and type 2 diabetes develops. Treatments include agents that (1) increase the amount of insulin secreted by the pancreas, (2) increase the sensitivity of target organs to insulin, (3) decrease the rate at which glucose is absorbed from the gastrointestinal tract, and (4) increase the loss of glucose through urination. Several drug classes are indicated for use in type 2 diabetes and are often used in combination. Therapeutic combinations may include several insulin isoforms or varying classes of oral antihyperglycemic agents. As of 2020, 23 unique antihyperglycemic drug combinations were approved by the FDA. The first triple combination of oral anti-diabetics was approved in 2019, consisting of metformin, saxaglipti, and dapagliflozin. Another triple combination approval for metformin, linagliptin, and empagliflozin followed in 2020. == Mechanisms of action == Diabetes medications have four main mechanisms of action: Insulin sensitization: Increased sensitivity of insulin receptors on cells leading to decreased insulin resistance, and higher effects of insulin on blood glucose levels. Stimulation of beta cells: This stimulation increases insulin secretion from beta cells of pancreas. Alpha-glucosidase inhibition: Inhibition of the alpha-glucosidase enzyme, decreases the rate at which glucose is absorbed from the gastrointestinal tract. Alpha-amylase inhibition: Inhibition of the alpha-amylase enzyme, decreasing the digestion of starch. SGLT2 inhibition: Inhibition of sodium-glucose transport protein 2 (SGLT2) decreases glucose reabsorption in the renal tubules of nephrons, thus increasing the amount of glucose excreted in urine. == Insulin == Insulin is usually given subcutaneously, either by injections or by an insulin pump. In acute care settings, insulin may also be given intravenously. Insulins are typically characterized by the rate at which they are metabolized by the body, yielding different peak times and durations of action. Faster-acting insulins peak quickly and are subsequently metabolized, while longer-acting insulins tend to have extended peak times and remain active in the body for more significant periods. Examples of rapid-acting insulins (peak at ~1 hour) are: Insulin lispro (Humalog) Insulin aspart (Novolog) Insulin glulisine (Apidra) Examples of short-acting insulins (peak 2–4 hours) are: Regular insulin (Humulin R, Novolin R) Prompt insulin zinc (Semilente) Examples of intermediate-acting insulins (peak 4–10 hours) are: Isophane insulin, neutral protamine Hagedorn (NPH) (Humulin N, Novolin N) Insulin zinc (Lente) Examples of long-acting insulins (duration 24 hours, often without peak) are: Extended insulin zinc insulin (Ultralente) Insulin glargine (Lantus) Insulin detemir (Levemir) Insulin degludec (Tresiba) Insulin degludec is sometimes classed separately as an "ultra-long" acting insulin due to its duration of action of about 42 hours, compared with 24 hours for most other long-acting insulin preparations. As a systematic review of studies comparing insulin detemir, insulin glargine, insulin degludec and NPH insulin did not show any clear benefits or serious adverse effects for any particular form of insulin for nocturnal hypoglycemia, severe hypoglycemia, glycated hemoglobin A1c, non-fatal myocardial infarction/stroke, health-related quality of life or all-cause mortality. The same review did not find any differences in effects of using these insulin analogues between adults and children. Most oral anti-diabetic agents are contraindicated in pregnancy, in which case insulin is preferred. Insulin is not administered by other routes, although this has been studied. An inhaled form was briefly licensed but was subsequently withdrawn. == Sensitizers == Insulin sensitizers address the core problem in type 2 diabetes – insulin resistance. === Biguanides === Biguanides reduce hepatic glucose output and increase uptake of glucose by the periphery, including skeletal muscle. Although it must be used with caution in patients with impaired liver or kidney function, Metformin, a biguanide, has become the most commonly used agent for type 2 diabetes in children and teenagers. Among common diabetic drugs, Metformin is the only widely used oral drug that does not cause weight gain. Typical reduction in glycated hemoglobin (A1C) values for Metformin is 1.5–2.0% Metformin (Glucophage) may be the best choice for patients who also have heart failure, but it should be temporarily discontinued before any radiographic procedure involving intravenous iodinated contrast, as patients are at an increased risk of lactic acidosis. Phenformin (DBI) was used from 1960s through 1980s, but was withdrawn due to lactic acidosis risk. Buformin also was withdrawn due to lactic acidosis risk. Metformin is a first-line medication used for treatment of type 2 diabetes. It is generally prescribed at initial diagnosis in conjunction with exercise and weight loss, as opposed to the past, where it was prescribed after diet and exercise had failed. There is an immediate-release as well as an extended-release formulation, typically reserved for patients experiencing gastrointestinal side-effects. It is also available in combination with other oral diabetic medications. === Thiazolidinediones === Thiazolidinediones (TZDs), also known as "glitazones," bind to PPARγ, peroxisome proliferator activated receptor γ, a type of nuclear regulatory protein involved in the transcription of genes that regulate glucose and fat metabolism. These PPARs act on peroxisome proliferator responsive elements (PPRE). The PPREs influence insulin-sensitive genes, which enhance production of mRNAs of insulin-dependent enzymes. The final result is better use of glucose by the cells. These drugs also enhance PPAR-α activity and hence lead to a rise in HDL and some larger components of LDL. Typical reductions in glycated hemoglobin (A1C) values are 1.5–2.0%. Some examples are: Rosiglitazone (Avandia): the European Medicines Agency recommended in September 2010 that it be suspended from the EU market due to elevated cardiovascular risks. Pioglitazone (Actos): remains on the market but has also been associated with increased cardiovascular risks. Troglitazone (Rezulin): used in 1990s, withdrawn due to hepatitis and liver damage risk. Multiple retrospective studies have resulted in a concern about rosiglitazone's safety, although it is established that the group, as a whole, has beneficial effects on diabetes. The greatest concern is an increase in the number of severe cardiac events in patients taking it. The ADOPT study showed that initial therapy with drugs of this type may prevent the progression of disease, as did the DREAM trial. The American Association of Clinical Endocrinologists (AACE), which provides clinical practice guidelines for management of diabetes, retains thiazolidinediones as recommended first, second, or third line agents for type 2 diabetes mellitus, as of their 2019 executive summary, over sulfonylureas and α-glucosidase inhibitors. However, they are less preferred than GLP-1 agonists or SGLT2 inhibitors, especially in patients with cardiovascular disease (which liraglutide, empagliflozin, and canagliflozin are all FDA approved to treat). Concerns about the safety of rosiglitazone arose when a retrospective meta-analysis was published in the New England Journal of Medicine. There have been a significant number of publications since then, and a Food and Drug Administration panel voted, with some controversy, 20:3 that available studies "supported a signal of harm", but voted 22:1 to keep the drug on the market. The meta-analysis was not supported by an interim analysis of the trial designed to evaluate the issue, and several other reports have failed to conclude the controversy. This weak evidence for adverse effects has reduced the use of rosiglitazone, despite its important and sustained effects on glycemic control. Safety studies are continuing. In contrast, at least one large prospective study, PROactive 05, has shown that pioglitazone may decrease the overall incidence of cardiac events in people with type 2 diabetes who have already had a heart attack. === LYN Kinase Activators === The LYN kinase activator Tolimidone has been reported to potentiate insulin signaling in a manner that is distinct from the glitazones. The compound has demonstrated positive results in a Phase 2a clinical study involving 130 diabetic subjects. == Secretagogues == Secretagogues are drugs that increase output from a gland, in the case of insulin from the pancreas. === Sulfonylureas === Sulfonylureas were the first widely used oral anti-hyperglycemic medications. They are insulin secretagogues, triggering insulin release by inhibiting the KATP channel of the pancreatic beta cells. Eight types of these pills have been marketed in North America, but not all remain available. The "second-generation" sulfonylureas are now more commonly used. They are more effective than first-generation drugs and have fewer side-effects. All may cause weight gain. Current clinical practice guidelines from the AACE rate sulfonylureas (as well as glinides) below all other classes of antidiabetic drugs in terms of suggested use as first, second, or third line agents - this includes Bromocriptine, the bile acid sequestrant Colesevelam, α-glucosidase inhibitors, Thiazolidinediones (glitazones), and DPP-4 inhibitors (gliptins). The low cost of most sulfonylureas, however, especially when considering their significant efficacy in blood glucose reduction, tends to keep them as a more feasible option in many patients - neither SGLT2 inhibitors nor GLP-1 agonists, the classes most favored by the AACE guidelines after metformin, are currently available as generics. Sulfonylureas bind strongly to plasma proteins. Sulfonylureas are useful only in type 2 diabetes, as they work by stimulating endogenous release of insulin. They work best with patients over 40 years old who have had diabetes mellitus for under ten years. They cannot be used with type 1 diabetes, or diabetes of pregnancy. They can be safely used with metformin or glitazones. The primary side-effect is hypoglycemia, which appears to happen more commonly with sulfonylureas than with other treatments. A Cochrane systematic review from 2011 showed that treatment with Sulfonylureas did not improve control of glucose levels more than insulin at 3 nor 12 months of treatment. This same review actually found evidence that treatment with Sulfonylureas could lead to earlier insulin dependence, with 30% of cases requiring insulin at 2 years. When studies measured fasting C-peptide, no intervention influenced its concentration, but insulin maintained concentration better compared to Sulphonylurea. Still, it is important to highlight that the studies available to be included in this review presented considerable flaws in quality and design. Typical reductions in glycated hemoglobin (A1C) values for second-generation sulfonylureas are 1.0–2.0%. First-generation agents tolbutamide acetohexamide tolazamide chlorpropamide Second-generation agents glipizide glyburide or glibenclamide glimepiride gliclazide glyclopyramide gliquidone === Meglitinides === Meglitinides help the pancreas produce insulin and are often called "short-acting secretagogues." They act on the same potassium channels as sulfonylureas, but at a different binding site. By closing the potassium channels of the pancreatic beta cells, they open the calcium channels, thereby enhancing insulin secretion. They are taken with or shortly before meals to boost the insulin response to each meal. If a meal is skipped, the medication is also skipped. Typical reductions in glycated hemoglobin (A1C) values are 0.5–1.0%. repaglinide nateglinide Adverse reactions include weight gain and hypoglycemia. == Alpha-glucosidase inhibitors == Alpha-glucosidase inhibitors are a class of diabetes drugs found in plants/herbs like cinnamon; however, they are technically not hypoglycemic agents because they do not have a direct effect on insulin secretion or sensitivity. These agents slow the digestion of starch in the small intestine, such that glucose from the starch enters the bloodstream at a slower rate, and can be matched more effectively by an impaired insulin response or sensitivity. The intake of a single dose before a meal containing complex carbohydrates clearly suppresses the glucose spike and may decrease the postprandial hyperglycemia (higher than 140 mg/dL; >7.8 mmol/L) in patients with type II diabetes. These agents are effective by themselves only in the earliest stages of impaired glucose tolerance, but can be helpful in combination with other agents in type 2 diabetes. Typical reductions in glycated hemoglobin (A1C) values are 0.5–1.0%. miglitol acarbose voglibose These medications are rarely used in the United States because of the severity of their side-effects (flatulence and bloating). They are more commonly prescribed in Europe. They do have the potential to cause weight loss by lowering the amount of sugar metabolized. == Peptide analogs == === Injectable incretin mimetics === Incretins are also insulin secretagogues. The two main candidate molecules that fulfill criteria for being an incretin are glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (glucose-dependent insulinotropic peptide, GIP). Both GLP-1 and GIP are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4). ==== Injectable glucagon-like peptide analogs and agonists ==== Glucagon-like peptide (GLP) agonists bind to a membrane GLP receptor. As a consequence, insulin release from the pancreatic beta cells is increased. Endogenous GLP has a half-life of only a few minutes, thus an analogue of GLP would not be practical. As of 2019, the AACE lists GLP-1 agonists, along with SGLT2 inhibitors, as the most preferred anti-diabetic agents after metformin. Liraglutide in particular may be considered first-line in diabetic patients with cardiovascular disease, as it has received FDA approval for reduction of risk of major adverse cardiovascular events in patients with type 2 diabetes. In a 2011 Cochrane review, GLP-1 agonists showed approximately a 1% reduction in HbA1c when compared to placebo. GLP-1 agonists also show improvement of beta-cell function, but this effect does not last after treatment is stopped. Due to shorter duration of studies, this review did not allow for long-term positive or negative effects to be assessed. Exenatide (also Exendin-4, marketed as Byetta) is the first GLP-1 agonist approved for the treatment of type 2 diabetes. Exenatide is not an analogue of GLP but rather a GLP agonist. Exenatide has only 53% homology with GLP, which increases its resistance to degradation by DPP-4 and extends its half-life. A 2011 Cochrane review showed a HbA1c reduction of 0.20% more with Exenatide 2 mg compared to insulin glargine, exenatide 10 μg twice daily, sitagliptin and pioglitazone. Exenatide, together with liraglutide, led to greater weight loss than glucagon-like peptide analogues. Liraglutide, a once-daily human analogue (97% homology), has been developed by Novo Nordisk under the brand name Victoza. The product was approved by the European Medicines Agency (EMEA) on July 3, 2009, and by the U.S. Food and Drug Administration (FDA) on January 25, 2010. A 2011 Cochrane review showed a HbA1c reduction of 0.24% more with liraglutide 1.8 mg compared to insulin glargine, 0.33% more than exenatide 10 μg twice daily, sitagliptin and rosiglitazone. Liraglutide, together with exenatide, led to greater weight loss than glucagon-like peptide analogues. Taspoglutide is presently in Phase III clinical trials with Hoffman-La Roche. Lixisenatide (Lyxumia) Sanofi Aventis Semaglutide (Ozempic) (oral version is Rybelsus) Dulaglutide (Trulicity) - once weekly Albiglutide (Tanzeum) - once weekly Tirzepatide (dual GLP-1 and GIP agonist; manufactured by Eli Lilly, and approved in 2022. It is Marketed under brandname Mounjaro for type II diabetes, and Zepbound for obesity These agents may also cause a decrease in gastric motility, responsible for the common side-effect of nausea, which tends to subside with time. ==== Gastric inhibitory peptide analogs ==== ==== Dipeptidyl peptidase-4 inhibitors ==== GLP-1 analogs resulted in weight loss and had more gastrointestinal side-effects, while in general dipeptidyl peptidase-4 (DPP-4) inhibitors were weight-neutral and are associated with increased risk for infection and headache. Both classes appear to present an alternative to other antidiabetic drugs. However, weight gain and/or hypoglycemia have been observed when dipeptidyl peptidase-4 inhibitors were used with sulfonylureas; effects on long-term health and morbidity rates are still unknown. DPP-4 inhibitors increase blood concentration of the incretin GLP-1 by inhibiting its degradation by DPP-4. Examples are: vildagliptin (Galvus) EU Approved 2008 sitagliptin (Januvia) FDA approved Oct 2006 saxagliptin (Onglyza) FDA Approved July 2009 linagliptin (Tradjenta) FDA Approved May 2, 2011 alogliptin septagliptin teneligliptin gemigliptin (Zemiglo) DPP-4 inhibitors lowered hemoglobin A1C values by 0.74%, comparable to other antidiabetic drugs. A result in one RCT comprising 206 patients aged 65 or older (mean baseline HgbA1c of 7.8%) receiving either 50 or 100 mg/d of sitagliptin was shown to reduce HbA1c by 0.7% (combined result of both doses). A combined result of 5 RCTs enlisting a total of 279 patients aged 65 or older (mean baseline HbA1c of 8%) receiving 5 mg/d of saxagliptin was shown to reduce HbA1c by 0.73%. A combined result of 5 RCTs enlisting a total of 238 patients aged 65 or older (mean baseline HbA1c of 8.6%) receiving 100 mg/d of vildagliptin was shown to reduce HbA1c by 1.2%. Another set of 6 combined RCTs involving alogliptin (approved by FDA in 2013) was shown to reduce HbA1c by 0.73% in 455 patients aged 65 or older who received 12.5 or 25 mg/d of the medication. === Injectable amylin analogues === Amylin agonist analogues slow gastric emptying and suppress glucagon. They have all the incretins actions except stimulation of insulin secretion. As of 2007, pramlintide is the only clinically available amylin analogue. Like insulin, it is administered by subcutaneous injection. The most frequent and severe adverse effect of pramlintide is nausea, which occurs mostly at the beginning of treatment and gradually reduces. Typical reductions in A1C values are 0.5–1.0%. == SGLT2 inhibitors == SGLT2 inhibitors block the sodium-glucose linked transporter 2 proteins in renal tubules of nephrons in kidneys, reabsorption of glucose in into the renal tubules, promoting excretion of glucose in the urine. This causes both mild weight loss, and a mild reduction in blood sugar levels with little risk of hypoglycemia. Oral preparations may be available alone or in combination with other agents. Along with GLP-1 agonists, they are considered preferred second or third agents for type 2 diabetics sub-optimally controlled with metformin alone, according to most recent clinical practice guidelines. Because they are taken by mouth, rather than injected (like GLP-1 agonists), patients who are injection-averse may prefer these agents over the former. They may be considered first line in diabetic patients with cardiovascular disease, especially heart failure, as these medications have been shown to reduce the risk of hospitalization in patients with such comorbidities. Because they are not available as generic medications, however, cost may limit their feasibility for many patients. Furthermore, there has been growing evidence that the effectiveness and safety of this drug class could depend on genetic variability of the patients. Examples include: Dapagliflozin Canagliflozin Empagliflozin Remogliflozin The side effects of SGLT2 inhibitors are derived directly from their mechanism of action; these include an increased risk of: ketoacidosis, urinary tract infections, candidal vulvovaginitis, and hypoglycemia. == Comparison == The following table compares some common anti-diabetic agents, generalizing classes, although there may be substantial variation in individual drugs of each class. When the table makes a comparison such as "lower risk" or "more convenient" the comparison is with the other drugs on the table. == Generics == Many anti-diabetes drugs are available as generics. These include: Sulfonylureas – glimepiride, glipizide, glyburide Biguanides – metformin Thiazolidinediones (Tzd) – pioglitazone, Actos generic Alpha-glucosidase inhibitors – Acarbose Meglitinides – nateglinide Combination of sulfonylureas plus metformin – known by generic names of the two drugs No generics are available for dipeptidyl peptidase-4 inhibitors (Onglyza), the glifozins, the incretins and various combinations. Sitagliptin patent expired in July 2022, leading to launch of generic sitagliptin brands . This lowered the cost of therapy for type 2 diabetes using sitagliptin . == Alternative Medicine == The effect of Ayurvedic treatments has been researched, however due to methodological flaws of relevant studies and research, it has not been possible to draw conclusions regarding efficacy of these treatments and there is insufficient evidence to recommend them. == References == == Further reading == Lebovitz, Harold E. (2004). Therapy For Diabetes Mellitus and Related Disorders (4th ed.). Alexandria, VA: American Diabetes Association. ISBN 978-1-58040-187-6. Adams, Michael Ian, Holland, Norman Norwood (2003). Core Concepts in Pharmacology. Englewood Cliffs, NJ: Prentice Hall. ISBN 978-0-13-089329-1.	Wikipedia/Anti-diabetic_drug
Fenofibrate, sold under the brand name Tricor among others, is an oral medication of the fibrate class used to treat abnormal blood lipid levels. It is less commonly used compared to statins because it treats a different type of cholesterol abnormality to statins. While statins have strong evidence for reducing heart disease and death, there is evidence to suggest that fenofibrate also reduces the risk of heart disease and death. However, this seems only to apply to specific populations of people with elevated triglyceride levels and reduced high-density lipoprotein (HDL) cholesterol. Its use is recommended together with dietary changes. Common side effects include liver problems, breathing problems, abdominal pain, muscle problems, and nausea. Serious side effects may include toxic epidermal necrolysis, rhabdomyolysis, gallstones, and pancreatitis. Use during pregnancy and breastfeeding is not recommended. It works by multiple mechanisms. It was patented in 1969, and came into medical use in 1975. It is available as a generic medication. In 2022, it was the 88th most commonly prescribed medication in the United States, with more than 7 million prescriptions. == Medical uses == Fenofibrate is mainly used for primary hypercholesterolemia or mixed dyslipidemia. Fenofibrate may slow the progression of diabetic retinopathy and the need for invasive treatment such as laser therapy in patients with type 2 diabetes with pre-existing retinopathy. It was initially indicated for diabetic retinopathy in patients with type 2 diabetes and diabetic retinopathy in Australia. The large scale, international FIELD and ACCORD-Eye trials found that fenofibrate therapy reduced required laser treatment for diabetic retinopathy by 1.5% over 5 years, as well as reducing progression by 3.7% over 4 years. Further studies looking at the role of fenofibrate in the progression of diabetic retinopathy as the primary outcome is warranted to understand its role in this condition. Although no statistically significant cardiovascular risk benefits were identified in these trials, benefits may accrue to add on therapy to patients with high triglyceride dyslipidaemia currently taking statin medications. Fenofibrate appears to reduce the risk of below ankle amputations in patients with Type 2 diabetes without microvascular disease. The FIELD study reported that fenofibrate at doses of 200 mg daily, reduced the risk for any amputation by 37% independent of glycaemic control, presence or absence of dyslipidaemia and its lipid-lowering mechanism of action. However, the cohort of participants who underwent amputations were more likely to have had previous cardiovascular disease (e.g. angina, myocardial infarction), longer duration of diabetes and had baseline neuropathy. Fenofibrate has an off-label use as an added therapy of high blood uric acid levels in people who have gout. It is used in addition to diet to reduce elevated low-density lipoprotein cholesterol (LDL), total cholesterol, triglycerides (TG), and apolipoprotein B (apo B), and to increase high-density lipoprotein cholesterol (HDL) in adults with primary hypercholesterolemia or mixed dyslipidemia. === Severe hypertriglyceridemia type IV or V === It is used in tandem with diet for treatment of adults with severe hypertriglyceridemia. Improving glycemic control in diabetics showing fasting chylomicronemia usually reduces the need for pharmacologic intervention. Statins remain the first line for treatment of blood cholesterol. AHA guidelines from 2013 did not find evidence for routine use of additional medications. Additionally, in 2016, the FDA filed "Withdrawal of Approval of Indications Related to the Coadministration With Statins in Applications for Niacin Extended-Release Tablets and Fenofibric Acid Delayed Release Capsules" noting "the Agency has concluded that the totality of the scientific evidence no longer supports the conclusion that a drug-induced reduction in triglyceride levels and/or increase in HDL cholesterol levels in statin-treated patients results in a reduction in the risk of cardiovascular events. Consistent with this conclusion, FDA has determined that the benefits of niacin ER tablets and fenofibric acid DR capsules for coadministration with statins no longer outweigh the risks, and the approvals for this indication should be withdrawn." == Contraindications == Fenofibrate is contraindicated in: Patients with severe renal impairment, including those receiving dialysis (2.7-fold increase in exposure, and increased accumulation during chronic dosing in patients with estimated glomerular filtration rate < 30 mL/min) Patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function test abnormalities Patients with preexisting gallbladder disease Nursing mothers Hypothyroidism Patients with known hypersensitivity to fenofibrate or fenofibric acid == Adverse effects == The most common adverse events (>3% of patients with coadministered statins) are === Precautions === When fenofibrate and a statin are given as combination therapy, it is recommended that fenofibrate be given in the morning and the statin at night, so that the peak dosages do not overlap. Musculoskeletal Myopathy and rhabdomyolysis; increased risk when coadminstered with a statin, particularly in the elderly and patients with diabetes, kidney failure, hypothyroidism Hepatotoxicity Can increase serum transaminases; liver tests should be monitored periodically Nephrotoxicity Can increase serum creatinine levels; renal function should be monitored periodically in patients with chronic kidney disease Biliary Can increase cholesterol excretion into the bile, leading to risk of cholelithiasis; if suspected, gallbladder studies are indicated. See "Interaction" section under Bile acid sequestrant Coagulation/Bleeding Exercise caution in concomitant treatment with oral Coumadin anticoagulants (e.g. warfarin). Adjust the dosage of Coumadin to maintain the prothrombin time/INR at desired level to prevent bleeding complications. == Overdose == "There is no specific treatment for overdose with fenofibric acid delayed-release capsules. General supportive care is indicated, including monitoring of vital signs and observation of clinical status". Additionally, hemodialysis should not be considered as an overdose treatment option because fenofibrate heavily binds to plasma proteins and does not dialyze well. == Interactions == These drug interactions with fenofibrate are considered major and may need therapy modifications: Bile acid sequestrants (e.g. cholestyramine, colestipol, etc.): If taken together, bile acid resins may bind to fenofibrate, resulting in a decrease in fenofibrate absorption. To maximize absorption, patients need to separate administration by at least 1 h before or 4 h to 6 h after taking the bile acid sequestrant. Immunosuppressants (e.g. ciclosporin or tacrolimus): An increased risk of renal dysfunction exists with concomitant use of immunosuppressants and fenofibrate. Approach with caution when coadministering additional medications that decrease renal function. Vitamin K antagonists (e.g. warfarin): As previously mentioned, fenofibrate interacts with coumadin anticoagulants to increase the risk of bleeding. Dosage adjustment of vitamin K antagonist may be necessary. Statins: Combination of statins and fenofibrate may increase the risk of rhabdomyolysis or myopathy. == Mechanism of action == "In summary, enhanced catabolism of triglyceride-rich particles and reduced secretion of VLDL underlie the hypotriglyceridemic effect of fibrates, whereas their effect on HDL metabolism is associated with changes in HDL apolipoprotein expression." Fenofibrate is a fibrate derivative, a prodrug comprising fenofibric acid linked to an isopropyl ester. It lowers lipid levels by activating peroxisome proliferator-activated receptor alpha (PPARα). PPARα activates lipoprotein lipase and reduces apoprotein CIII, which increases lipolysis and elimination of triglyceride-rich particles from plasma. PPARα also increases apoproteins AI and AII, reduces VLDL- and LDL-containing apoprotein B, and increases HDL-containing apoprotein AI and AII. == Formulations == Fenofibrate is available in several formulations and is sold under several brand names. The formulations may differ in terms of pharmacokinetic properties, particularly bioavailability; some must be taken with meals, whereas others may be taken without regard to food. The choline salt of fenofibrate is available in the United States, sold as Trilipix, and may be taken without regard to meals. == Environmental presence == Fenofibric acid was one of the 12 compounds identified in sludge samples taken from 12 wastewater treatment plants in California that were associated with estrogenic activity in in vitro. == History == Fenofibrate was first synthesized in 1974, as a derivative of clofibrate, and was initially offered in France. It was initially known as procetofen, and was later renamed fenofibrate to comply with World Health Organization International Nonproprietary Name guidelines. Fenofibrate was developed by Groupe Fournier SA of France. == Society and culture == In the United States, Tricor was reformulated in 2005. This reformulation was controversial, seen as an attempt to stifle competition from generic equivalents, and was the subject of antitrust litigation by Teva. === Brand names === Tricor by AbbVie Lipofen by Kowa Pharmaceuticals America Inc Lofibra by Teva Lipanthyl, Lipidil, Lipantil micro and Supralip by Abbott Laboratories Fenocor-67 by Ordain Health Care Fenogal by SMB Laboratories Antara by Oscient Pharmaceuticals Tricheck by Zydus (CND) Atorva TG by Zydus Medica Golip by GolgiUSA Stanlip by Sun Pharma (India) == Research == A systematic review and meta-analysis found that fenofibrate might be a safe adjunct to neonatal phototherapy. However, the certainty of evidence was very low. == References ==	Wikipedia/Fenofibrate
Clofibrate (trade name Atromid-S) is a lipid-lowering agent used for controlling the high cholesterol and triacylglyceride level in the blood. It belongs to the class of fibrates. It increases lipoprotein lipase activity to promote the conversion of VLDL to LDL, and hence reduce the level of VLDL. It can increase the level of HDL as well. It was patented in 1958 by Imperial Chemical Industries and approved for medical use in 1963. Clofibrate was discontinued in 2002 due to adverse effects. == Complications and controversies == It can induce SIADH, syndrome of inappropriate secretion of antidiuretic hormone ADH (vasopressin). Clofibrate can also result in formation of cholesterol stones in the gallbladder. The World Health Organization Cooperative Trial on Primary Prevention of Ischaemic Heart Disease using clofibrate to lower serum cholesterol observed excess mortality in the clofibrate-treated group despite successful cholesterol lowering (47% more deaths during treatment with clofibrate and 5% after treatment with clofibrate) than the non-treated high cholesterol group. These deaths were due to a wide variety of causes other than heart disease, and remain "unexplained". == References ==	Wikipedia/Clofibrate
An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces the coagulation of blood, prolonging the clotting time. Some occur naturally in blood-eating animals, such as leeches and mosquitoes, which help keep the bite area unclotted long enough for the animal to obtain blood. As a class of medications, anticoagulants are used in therapy for thrombotic disorders. Oral anticoagulants (OACs) are taken by many people in pill or tablet form, and various intravenous anticoagulant dosage forms are used in hospitals. Some anticoagulants are used in medical equipment, such as sample tubes, blood transfusion bags, heart–lung machines, and dialysis equipment. One of the first anticoagulants, warfarin, was initially approved as a rodenticide. Anticoagulants are closely related to antiplatelet drugs and thrombolytic drugs by manipulating the various pathways of blood coagulation. Specifically, antiplatelet drugs inhibit platelet aggregation (clumping together), whereas anticoagulants inhibit specific pathways of the coagulation cascade, which happens after the initial platelet aggregation but before the formation of fibrin and stable aggregated platelet products. Common anticoagulants include warfarin and heparin. == Medical uses == The use of anticoagulants is a decision based on the risks and benefits of anticoagulation. The biggest risk of anticoagulation therapy is the increased risk of bleeding. In otherwise healthy people, the increased risk of bleeding is minimal, but those who have had recent surgery, cerebral aneurysms, and other conditions may have too great a risk of bleeding. Generally, the benefit of anticoagulation is preventing or reducing the progression of a thromboembolic disease. Some indications for anticoagulant therapy that are known to have benefit from therapy include: Atrial fibrillation – commonly forms an atrial appendage clot Coronary artery disease Deep vein thrombosis – can lead to pulmonary embolism Ischemic stroke Hypercoagulable states (e.g., Factor V Leiden) – can lead to deep vein thrombosis Mechanical heart valves Myocardial infarction Pulmonary embolism Restenosis from stents Cardiopulmonary bypass (or any other surgeries requiring temporary aortic occlusion) Heart failure In these cases, anticoagulation therapy prevents the formation or growth of dangerous clots. The decision to begin therapeutic anticoagulation often involves the use of multiple bleeding risk predictable outcome tools as non-invasive pre-test stratifications due to the potential for bleeding while on blood thinning agents. Among these tools are HAS-BLED, ATRIA, HEMORR2HAGES, and CHA2DS2-VASc. The risk of bleeding using the risk assessment tools above must then be weighed against thrombotic risk to formally determine the patient's overall benefit in starting anticoagulation therapy. There is no evidence to indicate that adding anticoagulant therapy to standard treatment has a benefit for people with cerebral small vessel disease but not dementia, and there is an increased risk of a person with this disease experiencing a bleed with this approach. == Adverse effects == The most serious and common adverse side effects associated with anticoagulants are increased risk of bleeding, both nonmajor and major bleeding events. The bleeding risk depends on the class of anticoagulant agent used, the patient's age, and pre-existing health conditions. Warfarin has an estimated incidence of bleeding of 15–20% per year and a life-threatening bleeding rate of 1–3% per year. Newer non-vitamin K antagonist oral anticoagulants appear to have fewer life-threatening bleeding events than warfarin. Additionally, patients aged 80 years or more may be especially susceptible to bleeding complications, with a rate of 13 bleeds per 100 person-years. Bleeding risk is especially important to consider in patients with renal impairment and NOAC therapy because all NOACs, to some extent, are excreted by the kidneys. Thus, patients with renal impairment may be at higher risk of increased bleeding. In people with cancer, a systematic review has found warfarin had no effect on death rate or the risk of blood clots. However, it did increase the risk of major bleeding in 107 more people per 1000 population and minor bleeding in 167 more people per 1000 population. Apixaban had no effect on mortality, recurrence of blood clots in blood vessels, or major or minor bleeding. However, this finding comes only from one study. Nonhemorrhagic adverse events are less common than hemorrhagic adverse events but should still be monitored closely. Nonhemorrhagic adverse events of warfarin include skin necrosis, limb gangrene, and purple toe syndrome. Skin necrosis and limb gangrene are most commonly observed on the third to eighth day of therapy. The exact pathogenesis of skin necrosis and limb gangrene is not completely understood but it is believed to be associated with warfarin's effect on inhibiting the production of protein C and protein S. Purple toe syndrome typically develops three to eight weeks after initiation of warfarin therapy. Other adverse effects of warfarin are associated with depletion of vitamin K, which can lead to inhibition of G1a proteins and growth arrest-specific gene 6, which can lead to increased risk of arterial calcification and heart valve, especially if too much Vitamin D is present. Warfarin's interference with G1a proteins has also been linked to abnormalities in fetal bone development in mothers who were treated with warfarin during pregnancy. Long-term warfarin and heparin usage have also been linked to osteoporosis. Another potentially severe complication associated with heparin use is called heparin-induced thrombocytopenia (HIT). There are two distinct types: HIT 1) immune-mediated and 2) non-immune-mediated. Immune-mediated HIT most commonly arises five to ten days after exposure to heparin. Pathogenesis of immune-mediated HIT is believed to be caused by heparin-dependent immunoglobulin antibodies binding to platelet factor 4/heparin complexes on platelets, leading to widespread platelet activation. == Interactions == Foods and food supplements with blood-thinning effects include nattokinase, lumbrokinase, beer, bilberry, celery, cranberries, fish oil, garlic, ginger, ginkgo, ginseng, green tea, horse chestnut, licorice, niacin, onion, papaya, pomegranate, red clover, soybean, St. John's wort, turmeric, wheatgrass, and willow bark. Many herbal supplements have blood-thinning properties, such as danshen and feverfew. Multivitamins that do not interact with clotting are available for patients on anticoagulants. However, some foods and supplements encourage clotting. These include alfalfa, avocado, cat's claw, coenzyme Q10, and dark leafy greens such as spinach. Excessive intake of the food mentioned above should be avoided while taking anticoagulants, or if coagulability is being monitored, their intake should be kept approximately constant so that anticoagulant dosage can be maintained at a level high enough to counteract this effect without fluctuations in coagulability. Grapefruit interferes with some anticoagulant drugs, increasing the time it takes for them to be metabolized out of the body, and should be eaten with caution when on anticoagulant drugs. Anticoagulants are often used to treat acute deep-vein thrombosis. People using anticoagulants to treat this condition should avoid using bed rest as a complementary treatment because there are clinical benefits to continuing to walk and remaining mobile while using anticoagulants in this way. Bed rest while using anticoagulants can harm patients in circumstances in which it is not medically necessary. == Types == Several anticoagulants are available. Warfarin, other coumarins, and heparins have long been used. Since the 2000s, several agents have been introduced that are collectively referred to as direct oral anticoagulants (DOACs), previously named novel oral anticoagulants (NOACs) or non-vitamin K antagonist oral anticoagulants. These agents include direct thrombin inhibitor (dabigatran) and factor Xa inhibitor (rivaroxaban, apixaban, betrixaban and edoxaban), and they have been shown to be as good or possibly better than the coumarins with less serious side effects. The newer anticoagulants (NOACs/DOACs) are more expensive than the traditional ones and should be used in caring for patients with kidney problems. === Coumarins (vitamin K antagonists) === These oral anticoagulants are derived from coumarin found in many plants. A prominent member of this class, warfarin (Coumadin), was found to be the anticoagulant most prescribed in a large multispecialty practice. The anticoagulant effect takes at least 48 to 72 hours to develop. Where an immediate effect is required, heparin is given concomitantly. These anticoagulants are used to treat patients with deep-vein thrombosis (DVT) and pulmonary embolism (PE) and to prevent emboli in patients with atrial fibrillation (AF), and mechanical prosthetic heart valves. Other examples are acenocoumarol, phenprocoumon, atromentin, and phenindione. The coumarins brodifacoum and difenacoum are used as mammalicides (particularly as rodenticides) but are not used medically. === Heparin and derivative substances === Heparin is the most widely used intravenous clinical anticoagulant worldwide. Heparin is a naturally occurring glycosaminoglycan. There are three major categories of heparin: unfractionated heparin (UFH), low molecular weight heparin (LMWH), and ultra-low-molecular weight heparin (ULMWH). Unfractionated heparin is usually derived from pig intestines and bovine lungs. UFH binds to the enzyme inhibitor antithrombin III (AT), causing a conformational change that results in its activation. The activated AT then inactivates factor Xa, thrombin, and other coagulation factors. Heparin can be used in vivo (by injection), and also in vitro to prevent blood or plasma clotting in or on medical devices. In venipuncture, Vacutainer brand blood collecting tubes containing heparin usually have a green cap. ==== Low molecular weight heparin (LMWH) ==== Low molecular weight heparin (LMWH) is produced through a controlled depolymerization of unfractionated heparin. LMWH exhibits a higher anti-Xa/anti-IIa activity ratio and is useful as it does not require monitoring of the APTT coagulation parameter and has fewer side effects. === Synthetic pentasaccharide inhibitors of factor Xa === Fondaparinux is a synthetic sugar composed of the five sugars (pentasaccharides) in heparin that bind to antithrombin. It is a smaller molecule than low molecular-weight heparin. Idraparinux Idrabiotaparinux === Direct oral === The direct oral anticoagulants (DOACs) were introduced in and after 2008. There are five DOACs currently on the market: dabigatran, rivaroxaban, apixaban, edoxaban and betrixaban. They were also previously referred to as "new/novel" and "non-vitamin K antagonist" oral anticoagulants (NOACs). Compared to warfarin, DOACs have a rapid onset action and relatively short half-lives; hence, they carry out their function more rapidly and effectively, allowing drugs to reduce their anticoagulation effects quickly. Routine monitoring and dose adjustments of DOACs are less important than for warfarin, as they have better predictable anticoagulation activity. DOAC monitoring, including laboratory monitoring and a complete medication review, should generally be conducted before initiation of a DOAC, 1–3 months after initiation, and then every 6–12 months afterwards. Both DOACs and warfarin are equivalently effective, but compared to warfarin, DOACs have fewer drug interactions, no known dietary interactions, a wider therapeutic index, and have conventional dosing that does not require dose adjustments with constant monitoring. However, there is no countermeasure for most DOACs, unlike for warfarin; nonetheless, the short half-lives of DOACs will allow their effects to recede swiftly. A reversal agent for dabigatran, idarucizumab, is currently available and approved for use by the FDA. Rates of adherence to DOACs are only modestly higher than adherence to warfarin among patients prescribed these drugs. Thus, adherence to anticoagulation is often poor despite hopes that DOACs would lead to higher adherence rates. DOACs are significantly more expensive than warfarin, but the patients on DOACs may experience reduced lab costs as they do not need to monitor their INR. ==== Direct factor Xa inhibitors ==== Drugs such as rivaroxaban, apixaban and edoxaban work by inhibiting factor Xa directly (unlike heparins and fondaparinux, which work via antithrombin activation). Also included in this category are betrixaban from Portola Pharmaceuticals, the discontinued darexaban (YM150) from Astellas, and, more recently, the discontinued letaxaban (TAK-442) from Takeda and eribaxaban (PD0348292) from Pfizer. Betrixaban is significant as it was in 2018, the only oral factor Xa inhibitor approved by the FDA for use in acutely medically ill patients. Darexaban development was discontinued in September 2011; in a trial for prevention of recurrences of myocardial infarction in addition to dual antiplatelet therapy (DAPT), the drug did not demonstrate effectiveness, and the risk of bleeding was increased by approximately 300%. The development of letaxaban for acute coronary syndrome was discontinued in May 2011 following negative results from a Phase II study. ==== Direct thrombin inhibitors ==== Another type of anticoagulant is the direct thrombin inhibitor. Current members of this class include the bivalent drugs hirudin, lepirudin, and bivalirudin and the monovalent drugs argatroban and dabigatran. An oral direct thrombin inhibitor, ximelagatran (Exanta), was denied approval by the Food and Drug Administration (FDA) in September 2004 and was pulled from the market entirely in February 2006 after reports of severe liver damage and heart attacks. In November 2010, dabigatran etexilate was approved by the FDA to prevent thrombosis in atrial fibrillation. ==== Relevance to dental treatments ==== As in any invasive procedure, patients on anticoagulation therapy have an increased risk for bleeding, and caution should be used along with local hemostatic methods to minimize bleeding risk during the operation as well as postoperatively. However, with regards to DOACs and invasive dental treatments, there has not been enough clinical evidence and experience to prove any reliable adverse effects, relevance or interaction between these two. Further clinical prospective studies on DOACs are required to investigate the bleeding risk and hemostasis associated with surgical and dental procedures. Recommendations of modifications to the usage/dosage of DOACs before dental treatments are made based on the balance of the bleeding risk of each procedure and also the individual's own bleeding risks and renal functionality. With low-bleeding-risk dental procedures, it is recommended that DOACs be continued by the patient to avoid any increase in the risk of a thromboembolic event. For dental procedures with a higher risk of bleeding complications (i.e. complex extractions, adjacent extractions leading to a large wound, or more than three extractions), the recommended practice is for the patient to miss or delay a dose of their DOAC before such procedures to minimize the effect on bleeding risk. === Antithrombin protein therapeutics === The antithrombin protein is used as a protein therapeutic that can be purified from human plasma or produced recombinantly (for example, Atryn, produced in the milk of genetically modified goats). The FDA approves Antithrombin as an anticoagulant for preventing clots before, during, or after surgery or birthing in patients with hereditary antithrombin deficiency. === Other === Many other anticoagulants exist in research and development, diagnostics, or as drug candidates. Batroxobin, a toxin from snake venom, clots platelet-rich plasma without affecting platelet functions (cleaves fibrinogen). Hementin is an anticoagulant protease from the salivary glands of the giant Amazon leech, Haementeria ghilianii. Vitamin E Alcoholic beverage == Reversal agents == With the growing number of patients taking oral anticoagulation therapy, studies into reversal agents are gaining increasing interest due to major bleeding events and the need for urgent anticoagulant reversal therapy. Reversal agents for warfarin are more widely studied, and established guidelines for reversal exist due to a longer history of use of warfarin and the ability to get a more accurate measurement of anticoagulation effect in a patient via measuring the INR (International Normalized Ratio). In general, vitamin K is most commonly used to reverse the effect of warfarin in non-urgent settings. However, in urgent settings or settings with extremely high INR (INR >20), hemostatic reversal agents such as fresh frozen plasma (FFP), recombinant factor VIIa, and prothrombin complex concentrate (PCC) have been utilized with proven efficacy. Specifically with warfarin, four-factor PCC (4F-PCC) has been shown to have superior safety and mortality benefits compared to FPP in lowering INR levels. Although specific antidotes and reversal agents for DOACs are not as widely studied, idarucizumab (for dabigatran) and andexanet alfa (for factor Xa inhibitor) have been used in clinical settings with varying efficacy. Idarucizumab is a monoclonal antibody, approved by the US FDA in 2015, that reverses the effect of dabigatran by binding to both free and thrombin-bound dabigatran. Andexanet alfa is a recombinant modified human factor Xa decoy that reverses the effect of factor Xa inhibitors by binding at the active sites of factor Xa inhibitor and making it catalytically inactive. Andexanet alfa was approved by the US FDA in 2018. Another drug called ciraparantag, a potential reversal agent for direct factor Xa inhibitors, is still under investigation. Additionally, hemostatic reversal agents have also been used with varying efficacy to reverse the effects of DOACs. == Coagulation inhibitor measurement == A Bethesda unit (BU) is a measure of blood coagulation inhibitor activity. It is the amount of inhibitor that will inactivate half of a coagulant during the incubation period. It is the standard measure used in the United States and is so named because it was adopted as a standard at a conference in Bethesda, Maryland. == Laboratory use == If blood is allowed to clot, laboratory instruments, blood transfusion bags, and medical and surgical equipment will get clogged up and non-operational. In addition, test tubes used for laboratory blood tests will have chemicals added to stop blood clotting. Besides heparin, most of these chemicals bind calcium ions, preventing the coagulation proteins from using them. Ethylenediaminetetraacetic acid (EDTA) strongly and irreversibly chelates (binds) calcium ions, preventing blood from clotting. Citrate is in liquid form in the tube and is used for coagulation tests and blood transfusion bags. It binds calcium but not as strongly as EDTA. The correct proportion of this anticoagulant to blood is crucial because of the dilution, which can be reversed with the addition of calcium. Formulations include plain sodium citrate, acid-citrate-dextrose, and more. Oxalate has a mechanism similar to that of citrate. It is the anticoagulant used in fluoride/oxalate tubes to determine glucose and lactate levels. The fluoride inhibits glycolysis, which can throw off blood sugar measurements. Citrate/fluoride/EDTA tubes work better in this regard. == Dental considerations for long-term users == Dental practitioners play an important role in the early detection of anticoagulant overdose through oral manifestations, as the patient does not show any symptoms. Dental treatment of patients taking anticoagulant or antiplatelet medication raises safety concerns in terms of the potential risk of bleeding complications following invasive dental procedures. Therefore, certain guidelines for the dental care of patients taking these drugs are needed. Detecting overdose An overdose of anticoagulants usually occurs in people who have heart problems and need to take anticoagulants in the long term to reduce the risk of stroke from their high blood pressure. An International Normalised Ratio (INR) test would be recommended to confirm the overdose so that the dosage can be adjusted to an acceptable standard. The INR test measures the time it takes for a clot to form in a blood sample relative to a standard. An INR value of 1 indicates a level of coagulation equivalent to that of an average patient not taking warfarin, and values greater than 1 indicate a longer clotting time and, thus, a longer bleeding time. Assessing bleeding risk There are two main parts to the assessment of bleeding risk: Assessment of the likely risk of bleeding associated with the required dental procedure Assessment of the patient's individual-level bleeding risk Managing bleeding risk A patient who is on anticoagulants or antiplatelet medications may undergo dental treatments which are unlikely to cause bleeding, such as local anesthesia injection, basic gum charting, removal of plaque, calculus and stain above the gum level, direct or indirect fillings which are above the gingiva, root canal treatment, taking impression for denture or crown and fitting or adjustment of orthodontic appliances. For all these procedures, it is recommended that the dentist treat the patient following the normal standard procedure and taking care to avoid any bleeding. For a patient who needs to undergo dental treatments which are more likely to cause bleeding, such as simple tooth extractions (1-3 teeth with small wound size), drainage of swelling inside the mouth, periodontal charting, root planing, direct or indirect filling which extends below the gingiva, complex filling, flap raising procedure, gingival recontouring and biopsies, the dentist needs to take extra precautions apart from the standard procedure. The recommendations are as follows: if the patient has another medical condition or is taking other medication that may increase bleeding risk, consult the patient's general medical practitioner or specialist if the patient is on a short course of anticoagulant or antiplatelet therapy, delay the non-urgent, invasive procedure until the medication has been discontinued plan treatment for early in the day and week, where possible, to allow time for the management of prolonged bleeding or re-bleeding if it occurs perform the procedure as traumatically as possible, use appropriate local measures and only discharge the patient once hemostasis has been confirmed if travel time to emergency care is a concern, place particular emphasis at the time of the initial treatment on the use of measures to avoid complications advise the patient to take paracetamol, unless contraindicated, for pain relief rather than NSAIDs such as aspirin, ibuprofen, diclofenac or naproxen provide the patient with written post-treatment advice and emergency contact details follow the specific recommendations and advice given for the management of patients taking different anticoagulants or antiplatelet drugs There is general agreement that in most cases, treatment regimens with older anticoagulants (e.g., warfarin) and antiplatelet agents (e.g., clopidogrel, ticlopidine, prasugrel, ticagrelor, and/or aspirin) should not be altered before dental procedures. The risks of stopping or reducing these medication regimens (i.e., thromboembolism, stroke, myocardial infarction) far outweigh the consequences of prolonged bleeding, which can be controlled with local measures. In patients with other existing medical conditions that can increase the risk of prolonged bleeding after dental treatment or receiving other therapy that can increase bleeding risk, dental practitioners may wish to consult the patient's physician to determine whether care can safely be delivered in a primary care office. Any suggested modification to the medication regimen before dental surgery should be done in consultation and on the advice of the patient's physician. Based on limited evidence, the consensus appears to be that in most patients who are receiving the newer direct-acting oral anticoagulants (i.e., dabigatran, rivaroxaban, apixaban, or edoxaban) and undergoing dental treatment (in conjunction with usual local measures to control bleeding), no change to the anticoagulant regimen is required. In patients deemed to be at higher risk of bleeding (e.g., patients with other medical conditions or undergoing more extensive procedures associated with higher bleeding risk), consideration may be given, in consultation with and on advice of the patient's physician, to postponing the timing of the daily dose of the anticoagulant until after the procedure; timing the dental intervention as late as possible after last dose of anticoagulant; or temporarily interrupting drug therapy for 24 to 48 hours. == Research == A substantial number of compounds are being investigated for use as anticoagulants. The most promising ones act on the contact activation system (factor XIIa and factor XIa); it is anticipated that this may provide agents that prevent thrombosis without conferring a risk of bleeding. As of November 2021, the direct factor XIa inhibitor milvexian is in Phase II clinical trials for the prevention of an embolism after surgery. === Utilization === Research has been conducted on changes in anticoagulant drug supply for hospitals in the US during the COVID-19 pandemic from 2018–2022. According to researchers, "there was a 43.4% decline in the total volume of anticoagulants and antiplatelets at US hospitals in March 2020, driven by a decrease in heparin volume." Furthermore, it has been found that "Therapeutic AC [Anticoagulation] use declined from 32% in 2020 to 12% in 2022, especially after December 2021" and the introduction of the Omicron variant. == See also == CHADS2 score Direct factor Xa inhibitors Hypercoagulability in pregnancy == References == == External links == Staying Active and Healthy with Blood Thinners by the Agency for Healthcare Research and Quality	Wikipedia/Anticoagulant_drug
In medicine, glycoprotein IIb/IIIa inhibitors, also GpIIb/IIIa inhibitors, is a class of antiplatelet agents. Several GpIIb/IIIa inhibitors exist: abciximab (abcixifiban) (ReoPro) eptifibatide (Integrilin) tirofiban (Aggrastat) roxifiban orbofiban == Use == Glycoprotein IIb/IIIa inhibitors are frequently used during percutaneous coronary intervention (angioplasty with or without intracoronary stent placement). They work by preventing platelet aggregation and thrombus formation. They do so by inhibition of the GpIIb/IIIa receptor on the surface of the platelets. They may also be used to treat acute coronary syndromes, without percutaneous coronary intervention, depending on TIMI risk. They should be given intravenously. The oral form is associated with increased mortality and hence should not be given. In integrin nomenclature glycoprotein IIb/IIIa is called αIIbβ3. == History == Their development arose from the understanding of Glanzmann's thrombasthenia, a condition in which the GpIIb/IIIa receptor is deficient or dysfunctional. == References ==	Wikipedia/Glycoprotein_IIB/IIIA_inhibitor
Von Willebrand disease (VWD) is the most common hereditary blood-clotting disorder in humans. An acquired form can sometimes result from other medical conditions. It arises from a deficiency in the quality or quantity of von Willebrand factor (VWF), a multimeric protein that is required for platelet adhesion. It is known to affect several breeds of dogs as well as humans. The three forms of VWD are hereditary, acquired, and pseudo or platelet type. The three types of hereditary VWD are VWD type 1, VWD type 2, and VWD type 3. Type 2 contains various subtypes. Platelet type VWD is also an inherited condition. In 2008 a new diagnostic category of "Low VWF" was proposed to include those individuals whose von Willebrand factor levels were in the 30–50 IU/dL range, below the normal reference range but not low enough to be von Willebrand disease. Patients with low VWF were sometimes noted to experience bleeding, despite mild reductions in VWF levels. The 2021 ASH/ISTH guidelines re-classified patients with levels in the 30–50 IU/dl range as "Low VWF" if they have no bleeding, but as having VWD if they have bleeding. VWD type 1 is the most common type of the disorder, with mild bleeding symptoms such as nosebleeds, though occasionally more severe symptoms can occur. Blood type can affect the presentation and severity of symptoms of VWD. VWD type 2 is the second most common type of the disorder and has mild to moderate symptoms. The factor is named after the Finnish physician Erik Adolf von Willebrand who first described the condition in 1926. Guidelines for the diagnosis and management of VWD were updated in 2021. == Signs and symptoms == The various types of VWD present with varying degrees of bleeding tendency, usually in the form of easy bruising, nosebleeds, and bleeding gums. Women may experience heavy menstrual periods and blood loss during childbirth. Severe internal bleeding and bleeding into joints are uncommon in all but the most severe type, VWD type 3. == Genetics == The VWF gene is located on the short arm p of chromosome 12 (12p13.2). It has 52 exons spanning 178 kbp. Types 1 and 2 are inherited as autosomal dominant traits. Occasionally, type 2 also inherits recessively. Type 3 is inherited as autosomal recessive. However, some individuals heterozygous for type 3 may be diagnosed with VWD type 1, indicating an intermediate inheritance in those cases. VWD occurs in approximately 1% of the population and affects men and women equally. Genetic testing is typically not part of the initial workup for von Willebrand disease, and is not needed for people diagnosed with type 1 VWD based on clinical history and laboratory tests. It is mainly useful for: Evaluating family members of individuals who have known variants. Differentiating between type 2B and platelet-type VWD, as well as between type 2N VWD and hemophilia A. == Pathophysiology == Von Willebrand factor is mainly active in conditions of high blood flow and shear stress. Deficiency of VWF, therefore, shows primarily in organs with extensive small vessels, such as skin, gastrointestinal tract, and uterus. In angiodysplasia, a form of telangiectasia of the colon, shear stress is much higher than in average capillaries, and the risk of bleeding is increased concomitantly. In more severe cases of type 1 VWD, genetic changes are common within the VWF gene and are highly penetrant. In milder cases of type 1 VWD, a complex spectrum of molecular pathology may exist in addition to polymorphisms of the VWF gene alone. The individual's ABO blood group can influence presentation and pathology of VWD. Those individuals with blood group O have a lower mean level than individuals with other blood groups. Unless ABO group-specific VWF:antigen reference ranges are used, normal group O individuals can be diagnosed as type I VWD, and some individuals of blood group AB with a genetic defect of VWF may have the diagnosis overlooked because VWF levels are elevated due to blood group. == Diagnosis == Basic tests performed in any patient with bleeding problems are a complete blood count-CBC (especially platelet counts), activated partial thromboplastin time-APTT, prothrombin time with International Normalized Ratio-PTINR, thrombin time-TT, and fibrinogen level. Patients with abnormal tests typically undergo further testing for hemophilias. Other coagulation factor assays may be performed depending on the results of a coagulation screen. Patients with von Willebrand disease typically display a normal prothrombin time and a variable prolongation of APTT, depending on whether sufficient VWF is available to perform its carrier function for factor VIII. When VWD is suspected, blood plasma of a patient must be investigated for quantitative and qualitative deficiencies of VWF. This is achieved by measuring the amount of VWF in a VWF antigen assay and the functionality of VWF with a glycoprotein (GP)Ib binding assay, VWF antibody assay, or a ristocetin cofactor activity (RiCof) assay. Factor VIII levels are also performed because factor VIII is bound to VWF which protects the factor VIII from rapid breakdown within the blood. Deficiency of VWF can then lead to a reduction in factor VIII levels, which explains the elevation in PTT. Normal levels do not exclude all forms of VWD, particularly type 2, which may only be revealed by investigating platelet interaction with subendothelium under flow, a highly specialized coagulation study not routinely performed in most medical laboratories. Ristocetin-induced platelet agglutination (RIPA), collagen binding, and/or VWF multimer assays may be performed to follow up abnormal screening tests. A platelet aggregation assay will show an abnormal response to ristocetin with normal responses to the other agonists used: A platelet function assay may give an abnormal collagen/epinephrine closure time, and in most cases, a normal collagen/ADP time. Type 2N may be considered if factor VIII levels are disproportionately low, but confirmation requires a "factor VIII binding" assay. Additional laboratory tests that help classify sub-types of VWD include von Willebrand multimer analysis, modified ristocetin induced platelet aggregation assay and VWF propeptide to VWF propeptide antigen ratio. In cases of suspected acquired von Willebrand syndrome, a mixing study (analysis of patient plasma along with pooled normal plasma/PNP and a mixture of the two tested immediately, at one hour, and at two hours) should be performed. Detection of VWD is complicated by VWF being an acute-phase reactant with levels rising in infection, pregnancy, and stress. The testing for VWD can be influenced by laboratory procedures. Numerous variables exist in the testing procedure that may affect the validity of the test results and may result in a missed or erroneous diagnosis. The chance of procedural errors are typically greatest during the preanalytical phase (during collecting storage and transportation of the specimen) especially when the testing is contracted to an outside facility and the specimen is frozen and transported long distances. Diagnostic errors are not uncommon, and the rate of testing proficiency varies amongst laboratories, with error rates ranging from 7 to 22% in some studies to as high as 60% in cases of misclassification of VWD subtype. To increase the probability of a proper diagnosis, testing should be done at a facility with immediate on-site processing in a specialized coagulation laboratory. === Types === The four hereditary types of VWD described are type 1, type 2, type 3, and pseudo- or platelet-type. Most cases are hereditary, but acquired forms of VWD have been described. The International Society on Thrombosis and Haemostasis's classification depends on the definition of qualitative and quantitative defects. ==== Type 1 ==== Type 1 VWD (40-80% of all VWD cases) is a quantitative defect which is heterozygous for the defective gene. It arises from failure to secrete VWF into the circulation or, in the case of Type 1C, from VWF being cleared more quickly than normal. If VWF levels are greater than 50%, VWD can be ruled out. If VWF activity is below 30%, VWD is present. Patients with VWF activity between 0.30-0.50 IU/mL are classified based on their bleeding phenotype. If they have bleeding symptoms, they have VWD. If they have no bleeding, they are considered to have "Low VWF". Many patients are asymptomatic or may have mild symptoms and not have clearly impaired clotting, which might suggest a bleeding disorder. Often, the discovery of low VWF occurs incidentally to other medical procedures requiring a blood work-up. Most cases of low VWF are never diagnosed due to its asymptomatic or mild presentation, and most people with type I VWD end up leading a normal life free of complications, with many being unaware that they have the disorder. Trouble may, however, arise in some patients in the form of bleeding following surgery (including dental procedures), noticeable easy bruising, or menorrhagia (heavy menstrual periods). The minority of cases of type 1 may present with severe hemorrhagic symptoms. ==== Type 1C ==== Type 1C VWD indicates patients with quantitative deficiency due to an enhanced VWF clearance, accounting for ~15% to 20% of cases. Such patients may require VWF concentrate to treat/prevent bleeds. ==== Type 2 ==== Type 2 VWD (15-50% of cases) is a qualitative defect and the bleeding tendency can vary between individuals. Four subtypes exist: 2A, 2B, 2M, and 2N. These subtypes depend on the presence and behavior of the underlying multimers. Type 2 VWD (other than 2N) features an activity-to-antigen ratio of less than 0.7. This ratio is obtained by dividing the VWF activity by the VWF antigen. ===== Type 2A ===== VWD Type 2A results from a loss-of-function mutation in von Willebrand factor (VWF), leading to reduced binding of VWF with Platelet GP1b receptors. This disorder follows an autosomal dominant inheritance pattern with only occasional cases following autosomal recessive pattern. It accounts for 10-15% of all VWD cases. It manifests with moderate to moderately severe bleeding. Diagnostic features of VWD Type 2A include greater reduction in VWF activity (measured by a functional assay) compared to VWF antigen (quantity). This results in a decreased VWF Activity to Antigen ratio. Additionally, high molecular weight multimers are either absent or very low on electrophoresis due to impaired multimer assembly or increased susceptibility to ADAMTS13 (a protease that cleaves VWF). Factor VIII activity can be normal or low. Ristocetin-induced platelet aggregation (RIPA) is typically low. ===== Type 2B ===== This is a "gain of function" defect. The ability of the qualitatively defective VWF to bind to glycoprotein Ib (GPIb) receptor on the platelet membrane is abnormally enhanced, leading to its spontaneous binding to platelets and subsequent rapid clearance of the bound platelets and of the large VWF multimers. Thrombocytopenia may occur. Large VWF multimers are reduced or absent from the circulation. The ristocetin cofactor activity is low when the patient's platelet-poor plasma is assayed against formalin-fixed, normal donor platelets. However, when the assay is performed with the patient's own platelets (platelet-rich plasma), a lower-than-normal amount of ristocetin causes aggregation to occur. This is due to the large VWF multimers remaining bound to the patient's platelets. Patients with this subtype are unable to use desmopressin as a treatment for bleeding, because it can lead to unwanted platelet aggregation and aggravation of thrombocytopenia. ===== Type 2M ===== VWD Type 2M results from a loss-of-function mutation in von Willebrand factor (VWF). This mutation leads to reduced binding of VWF with GP1b (similar to VWD Type 2A) or with collagen. Like other Type 2 VWD subtypes, there is a decreased ratio of VWF Activity to antigen. Differentiating VWD Type 2M from Type 2A involves analyzing VWF multimers through electrophoresis. In VWD Type 2M, all multimers are identified but uniformly decreased in quantity, resembling the pattern seen in VWD Type 1. Conversely, in VWD Type 2A, high molecular weight multimers are either absent or present in very low quantities. VWD Type 2M can be further differentiated from VWD Type 1 based on the VWF Activity to antigen ratio. In Type 1, the ratio is >0.7. In Type 2M, the ratio is <0.7. In Type 2M, factor VIII activity can be normal or low while the ristocetin-induced platelet aggregation (RIPA) is typically low. It is uncommon and manifests with moderate to severe bleeding. The disease may follow either an autosomal dominant or recessive pattern of inheritance. ===== Type 2N (Normandy) ===== Type 2N VWD results from a loss-of-function mutation that reduces the binding of von Willebrand factor (VWF) to factor VIII. Although VWF antigen (quantity) and activity levels (Ristocetin cofactor assay) remain normal, factor VIII levels are typically low (usually 5-15%) due to impaired VWF binding. This vulnerability to proteolysis in the circulation leads to clinical manifestations resembling those of Hemophilia A. The significantly reduced factor VIII levels in VWD Type 2N can sometimes lead to misdiagnosis as mild Hemophilia A. Like Hemophilia A, VWD Type 2N presents with joint and soft tissue bleeds. It is an autosomal recessive disorder, requiring either homozygosity or double heterozygosity for disease manifestation. Diagnostic tools include assessing the ratio of VWF binding to VWF antigen levels. A ratio <0.3 indicates homozygous or double heterozygous VWD Type 2N, while a ratio <0.5 suggests heterozygous VWD Type 2N. Conversely, a VWF antigen-to-binding ratio >3 confirms the diagnosis of VWD Type 2N. Ristocetin-Induced Platelet Agglutination (RIPA) and VWF multimer analysis are typically normal. ==== Type 3 ==== VWD type 3 is a rare but the most severe form of VWD. It occurs in individuals who are homozygous for the defective gene, resulting in a severe quantitative deficiency or complete absence of von Willebrand factor (VWF) production. In VWD type 3, VWF is undetectable in the VWF antigen assay. Since VWF normally protects coagulation factor VIII from proteolytic degradation, the total absence of VWF leads to extremely low factor VIII levels (typically 1-10%). These low levels are equivalent to those seen in severe hemophilia A, with clinical manifestations of life-threatening external and internal hemorrhages. The inheritance pattern of VWD type 3 is autosomal recessive, meaning that both parents must carry the defective gene for their child to be affected. In contrast, hemophilia A follows an X-linked recessive inheritance pattern. Additional diagnostic tools for VWD type 3 include assessing VWF activity using the Ristocetin cofactor assay and Collagen binding assay. In VWD type 3, VWF activity is either absent or approaching undetectable. VWF multimer analysis reveals no bands or very faint bands on electrophoresis. Additionally, Ristocetin-Induced Platelet Agglutination (RIPA) is typically absent or severely low. ==== Comparison ==== ==== Platelet-type ==== Platelet-type VWD (also known as pseudo-VWD) is an autosomal dominant genetic defect of the platelets. The VWF is qualitatively normal and genetic testing of the von Willebrand gene and VWF protein reveals no mutational alteration. The defect lies in the qualitatively altered GPIb receptor on the platelet membrane which increases its affinity to bind to the VWF. Large platelet aggregates and high molecular weight VWF multimers are removed from the circulation resulting in thrombocytopenia and diminished or absent large VWF multimers. The ristocetin cofactor activity and loss of large VWF multimers are similar to VWD type 2B. ==== Acquired ==== Acquired Von Willebrand syndrome can occur due to autoantibodies, either interfering with platelet or collagen binding; increasing VWF clearance from the plasma; adsorption to myeloma cells or platelets; or proteolytic cleavage of VWF after shear stress-induced unfolding. A form of acquired VWD occurs in patients with aortic valve stenosis, leading to gastrointestinal bleeding (Heyde's syndrome). This form of acquired VWD may be more prevalent than is presently thought. In 2003, Vincentelli et al. noted that patients with acquired VWD and aortic stenosis who underwent valve replacement experienced a correction of their hemostatic abnormalities, but that the hemostatic abnormalities can recur after 6 months when the prosthetic valve is a poor match with the patient. Similarly, acquired VWD contributes to the bleeding tendency in people with an implant of a left ventricular assist device (a pump that pumps blood from the left ventricle of the heart into the aorta). == Treatment == For patients with VWD type 1 and VWD type 2A, desmopressin is available as different preparations, recommended for use in cases of minor trauma, or in preparation for dental or minor surgical procedures. Desmopressin stimulates the release of VWF from the Weibel–Palade bodies of endothelial cells, thereby increasing the levels of VWF (as well as coagulant factor VIII) three- to five-fold. Desmopressin is also available as a preparation for intranasal administration (Stimate) and as a preparation for intravenous administration. Desmopressin is contraindicated in VWD type 2b because of the risk of aggravated thrombocytopenia and thrombotic complications. Desmopressin is probably not effective in VWD type 2M and is rarely effective in VWD type 2N. It is totally ineffective in VWD type 3. For women with heavy menstrual bleeding, estrogen-containing oral contraceptive medications are effective in reducing the frequency and duration of the menstrual periods. Estrogen and progesterone compounds available for use in the correction of menorrhagia include ethinylestradiol,levonorgestrel, drospirenone and cyproterone. Administration of ethinylestradiol diminishes the secretion of luteinizing hormone and follicle-stimulating hormone from the pituitary, leading to stabilization of the endometrial surface of the uterus. Desmopressin is a synthetic analog of the natural antidiuretic hormone vasopressin. Its overuse can lead to water retention and dilutional hyponatremia with consequent convulsion. For patients with VWD scheduled for surgery and cases of VWD disease complicated by clinically significant hemorrhage, human-derived medium purity factor VIII concentrates, which also contain von Willebrand factors, are available for prophylaxis and treatment. Humate P, Alphanate, Wilate and Koate HP are commercially available for prophylaxis and treatment of VWD, and have varying levels of factor VIII. Products with higher VWF:RCo/FVIII ratios allow for more frequent dosing of VWF if needed, without the risk of accumulation to supranormal levels of FVIII. Recombinant factor VIII products contain insignificant quantity of VWF, so are not clinically useful as standalone therapy for VWD. Risks of thrombosis, development of alloantibodies, and allergic reactions including anaphylaxis must be considered when administering these preparations. Such risks have emerged as the main concerns in factor replacement therapies as infectious risks have diminished. Blood transfusions are given as needed to correct anemia and hypotension secondary to hypovolemia. Infusion of platelet concentrates is recommended for correction of hemorrhage associated with platelet-type VWD. Vonicog alfa is a recombinant von Willebrand factor that was approved for use in the United States in December 2015, and for use in the European Union in August 2018. If baseline factor VIII activity is >40%, rVWF may be administered as a standalone product when immediate response is needed, but if Factor VIII activity is <40% and immediate response is needed, rVWF must be administered in conjunction with FVIII replacement therapy. == Epidemiology == The prevalence of VWD is about one in 100 individuals. However, the majority of these people do not have symptoms. The prevalence of clinically significant cases is one per 10,000. Because most forms are rather mild, they are detected more often in women, whose bleeding tendency shows during menstruation. It may be more severe or apparent in people with blood type O. == History == In 1924, a 5-year-old girl from Föglö, Åland, Finland, was brought to the Deaconess Hospital in Helsinki, where she was seen by Finnish physician Erik Adolf von Willebrand. He ultimately assessed 66 members of her family and reported in a 1926 Swedish-language article that this was a previously undescribed bleeding disorder that differed from hemophilia. He published another article on the disorder in 1931, in the German language, which attracted international attention in the disease. The eponymous name was assigned to the disease between the late 1930s and the early 1940s, in recognition of von Willebrand's extensive research. In the 1950s, it became clear that a "plasma factor", factor VIII, was decreased in these persons and that Cohn fraction I-0 could correct both the plasma deficiency of FVIII and the prolonged bleeding time. Since this time, the factor causing the long bleeding time was called the "von Willebrand factor" in honor of Erik Adolf von Willebrand. Variant forms of VWF were recognized in the 1970s, and these variations are now recognized as the result of synthesis of an abnormal protein. During the 1980s, molecular and cellular studies distinguished hemophilia A and VWD more precisely. Persons who had VWD had a normal FVIII gene on the X chromosome, and some had an abnormal VWF gene on chromosome 12. Gene sequencing identified many of these persons as having a VWF gene mutation. The genetic causes of milder forms of low VWF are still under investigation, and these forms may not always be caused by an abnormal VWF gene. == Other animals == VWD can also affect dogs, pigs, and mice. Furthermore, cases have been reported in cats, horses, cattle, and rabbits. The causal mutation for VWD type 1 was identified in dogs of the breeds Doberman Pinscher, German Pinscher, Bernese Mountain Dog, Manchester Terrier, Kerry Blue Terrier, Cardigan Welsh Corgi, Poodle, Coton de Tulear, Drentse Patrijshond, Papillon, and Stabyhoun. Causal mutations for type 2 were identified in dogs of the breeds German Wirehaired Pointer, German Shorthaired Pointer, and Chinese Crested; and for type 3 in dogs of the breeds Kooikerhondje, Scottish Terrier and Shetland Sheepdog. In dogs affected by type 1 VWD, the causal mutation was the same across all breeds and the same mutation was also detected in some human VWD type 1 patients. In contrast, the mutations causing VWD type 3 in dogs are specific to each breed. Genetic screening is offered for known breeds. In pigs, the causal mutation for VWD type 3 has also been identified. It is a large duplication within the VWF gene and causes serious damage to the gene function, so that virtually no VWF protein is produced. The clinical picture in pigs is most similar to that in humans with VWD type 3. Therefore, those pigs are valuable models for clinical and pharmacological research. Mice affected by VWD type 3 were produced by genetic engineering to obtain a small sized model for the human disease. In these strains, the VWF gene has been knocked out. In animals of other species affected by VWD, the causal mutations have not yet been identified. == Oral manifestations == In the case of severe deficiency, there may be spontaneous gingival bleeding, ecchymosis, and epistaxis. Symptoms of VWD include postoperative bleeding, bleeding after dental extraction, gingival bleeding, epistaxis and easy bruising. The intake of oral contraceptives as the first-line treatment for menorrhagia may lead to gingival enlargement and bleeding in women. Platelet or coagulation disorders with severely altered hemostasis can cause spontaneous gingival bleeding, as seen in conjunction with hyperplastic hyperemic gingival enlargements in leukemic patients. Deposition of hemosiderin and other blood degradation products on the tooth surfaces turning them brown can occur with continuous oral bleeding over long periods. The location of oral bleeds was as follows: labial frenum, 60%; tongue, 23%; buccal mucosa, 17% and gingiva and palate, 0.5%. Severe hemophilia will have most frequent bleeding occurrences, followed by moderate and then mild hemophilia. They mostly come from traumatic injuries. Bleeding will also be induced by iatrogenic factors and poor oral hygiene practices. The frequency of oral hemorrhage by location in people with deficiency of F VIII and F IX is: gingiva, 64%; dental pulp, 13%; tongue, 7.5%; lip, 7%; palate, 2% and buccal mucosa, 1%. == Dental considerations == The protocols suggest the use of factor concentrate along with the use of local hemostatic techniques, such as suturing, and local measures, such as the use of oxidized cellulose, for example, Surgicel or fibrin glue in conjunction with post-operatively administered antifibrinolytic agents where appropriate. The use of any non-steroidal anti-inflammatory drug (NSAID) must be discussed beforehand with the patient's hematologist because of their effect on platelet aggregation. There are no restrictions regarding the type of local anaesthetic agent used although those with vasoconstrictors may provide additional local hemostasis. == See also == Bernard–Soulier syndrome, caused by a deficiency in the VWF receptor, GPIb List of hematologic conditions Purpura == References == == Further reading == == External links ==	Wikipedia/Von_Willebrand's_disease
Thrombolysis, also called fibrinolytic therapy, is the breakdown (lysis) of blood clots formed in blood vessels, using medication. It is used in ST elevation myocardial infarction, stroke, and in cases of severe venous thromboembolism (massive pulmonary embolism or extensive deep vein thrombosis). The main complication is bleeding (which can be dangerous), and in some situations thrombolysis may therefore be unsuitable. Thrombolysis can also play an important part in reperfusion therapy that deals specifically with blocked arteries. == Medical uses == Diseases where thrombolysis is used: ST elevation myocardial infarction: Large trials have shown that mortality can be reduced using thrombolysis (particularly fibrinolysis) in treating heart attacks. It works by stimulating secondary fibrinolysis by plasmin through infusion of analogs of tissue plasminogen activator (tPA), the protein that normally activates plasmin. Stroke: Thrombolysis reduces major disability or death when given within 3 hours (or perhaps even 6 hours) of ischaemic stroke onset when there are no contraindications to treatment. Massive pulmonary embolism. For the treatment of a massive pulmonary embolism, catheter-directed therapy is a safer and more effective alternative to systemic thrombolysis. This involves the injecting of drugs directly into the clot. Severe deep vein thrombosis (DVT), such as phlegmasia cerulea dolens, which threatens limb loss, or iliofemoral DVT, where clots involve at a minimum the common iliac vein Acute limb ischaemia Clotted hemothorax Thrombolysis is usually intravenous. It may also be used directly into the affected blood vessel during an angiogram (intra-arterial thrombolysis), e.g. when patients present with stroke beyond three hours or in severe deep vein thrombosis (catheter-directed thrombolysis). Thrombolysis is performed by many types of medical specialists, including interventional radiologists, vascular surgeons, cardiologists, interventional neuroradiologists, and neurosurgeons. In some countries such as the United States of America, emergency medical technicians may administer thrombolytics for heart attacks in prehospital settings, by on-line medical direction. In countries with more extensive and independent qualifications, prehospital thrombolysis (fibrinolysis) may be initiated by the emergency care practitioner (ECP). Other countries which employ ECP's include, South Africa, the United Kingdom, and New Zealand. Prehospital thrombolysis is always the result of a risk-benefit calculation of the heart attack, thrombolysis risks, and primary percutaneous coronary intervention (pPCI) availability. == Contraindications == Thrombolysis is not without risks. Therefore, clinicians must select patients who are to be best suited for the procedure, and those who have the least risk of having a fatal complication. An absolute contraindication is in itself enough to avoid thrombolysis, while a relative contraindication needs to be considered in relation to the overall clinical situation. === Myocardial infarction === Absolute contraindications: Any previous history of hemorrhagic stroke, ischemic stroke within 3 months. History of stroke, dementia, or central nervous system damage within 1 year Head trauma within 3 weeks or brain surgery within 6 months Known intracranial neoplasm Suspected aortic dissection Internal bleeding within 6 weeks Active bleeding or known bleeding disorder Traumatic cardiopulmonary resuscitation within 3 weeks Relative contraindications: Oral anticoagulant therapy Acute pancreatitis Pregnancy or within 1 week postpartum Active peptic ulceration Transient ischemic attack within 6 months Dementia Infective endocarditis Active cavitating pulmonary tuberculosis Advanced liver disease Intracardiac thrombi Uncontrolled hypertension (systolic blood pressure >180 mm Hg, diastolic blood pressure >110 mm Hg) Puncture of noncompressible blood vessel within 2 weeks Previous streptokinase therapy Major surgery, trauma, or bleeding within 2 weeks === Stroke === Absolute contraindications: Uncertainty about time of stroke onset (e.g. patients awakening from sleep). Coma or severe obtundation with fixed eye deviation and complete hemiplegia. Hypertension: systolic blood pressure ≥ 185mmHg; or diastolic blood pressure >110mmHg on repeated measures prior to study (if reversed, patient can be treated). Clinical presentation suggestive of subarachnoid haemorrhage even if the CT scan is normal. Presumed septic embolus. Patient having received a heparin medication within the last 48 hours and has an elevated Activated Prothrombin Time (APTT) or has a known hereditary or acquired haemorrhagic diathesis INR >1.7 Known advanced liver disease, advanced right heart failure, or anticoagulation, and INR > 1.5 (no need to wait for INR result in the absence of the former three conditions). Known platelet count <100,000 uL. Serum glucose is < 2.8 mmol/L or >22.0 mmol/L. Relative contraindications: Severe neurological impairment with NIHSS score >22. Age >80 years. CT evidence of extensive middle cerebral artery (MCA) territory infarction (sulcal effacement or blurring of grey-white junction in greater than 1/3 of MCA territory). Stroke or serious head trauma within the past three months where the risks of bleeding are considered to outweigh the benefits of therapy. Major surgery within the last 14 days (consider intra-arterial thrombolysis). Patient has a known history of intracranial haemorrhage, subarachnoid haemorrhage, known intracranial arteriovenous malformation or previously known intracranial neoplasm Suspected recent (within 30 days) myocardial infarction. Recent (within 30 days) biopsy of a parenchymal organ or surgery that, in the opinion of the responsible clinician, would increase the risk of unmanageable (e.g. uncontrolled by local pressure) bleeding. Recent (within 30 days) trauma with internal injuries or ulcerative wounds. Gastrointestinal or urinary tract haemorrhage within the last 30 days or any active or recent haemorrhage that, in the opinion of the responsible clinician, would increase the risk of unmanageable (e.g. by local pressure) bleeding. Arterial puncture at non-compressible site within the last 7 days. Concomitant serious, advanced or terminal illness or any other condition that, in the opinion of the responsible clinician would pose an unacceptable risk. Minor or Rapidly improving deficit. Seizure: If the presenting neurological deficit is deemed due to a seizure. Pregnancy is not an absolute contraindication. Consider intra-arterial thrombolysis. == Side-effects == Hemorrhagic stroke is a rare but serious complication of thrombolytic therapy. If a patient has had thrombolysis before, an allergy against the thrombolytic drug may have developed (especially after streptokinase). If the symptoms are mild, the infusion is stopped and the patient is commenced on an antihistamine before infusion is recommenced. Anaphylaxis generally requires immediate cessation of thrombolysis. == Agents == Thrombolysis therapy uses thrombolytic drugs that dissolve blood clots. Most of these drugs target fibrin (one of the main constituent of blood clots) and are therefore called fibrinolytics. All currently approved thrombolytic drugs are biologics, either derived from Streptococcus species, or, more recently, using recombinant biotechnology whereby tPA is manufactured using cell culture, resulting in a recombinant tissue plasminogen activator or rtPA. Some fibrinolytics are: Streptokinase (Kabikinase) Urokinase Recombinant tissue plasminogen activators (rtPA) Alteplase (Activase or Actilyse) Reteplase (Retavase) Tenecteplase Anistreplase (Eminase) == Catheter-directed thrombolysis == A 2023 meta-analysis of 44 studies compared treatments for pulmonary embolism including thrombolytic therapy delivered through a catheter. Catheter-directed thrombolysis (CDT) methods included fragmentation and ultrasound use. CDT was associated with better outcomes than anticoagulation alone or systemic thrombolysis, but the studies were mostly small and observational. In people who receive CDT, there is a risk of hemorrhage as a side effect. Scientists have studied whether measuring fibrinogen in blood can be used as a biomarker to predict hemorrhage. As of 2017 it was not known if this works or not. == Research == Researchers showed a 10-fold variation in the proportion of patients who received thrombolysis after stroke in England and Wales, ranging from 1 in 50 (2%) to 1 in 4 (24%). The team also showed that most of the variation was explained by hospital processes (such as how quickly people can have a brain scan) and in doctors’ decision-making (who they think should or should not receive thrombolysis) rather than knowledge of the time of stroke. Prospective, randomized clinical trials to evaluate the utility of catheter-directed thrombolysis in pulmonary embolism include HI-PEITHO (Higher-Risk Pulmonary Embolism Thrombolysis). == See also == TIMI – thrombolysis in myocardial infarction == References ==	Wikipedia/Thrombolytic_therapy
In medicine, glycoprotein IIb/IIIa inhibitors, also GpIIb/IIIa inhibitors, is a class of antiplatelet agents. Several GpIIb/IIIa inhibitors exist: abciximab (abcixifiban) (ReoPro) eptifibatide (Integrilin) tirofiban (Aggrastat) roxifiban orbofiban == Use == Glycoprotein IIb/IIIa inhibitors are frequently used during percutaneous coronary intervention (angioplasty with or without intracoronary stent placement). They work by preventing platelet aggregation and thrombus formation. They do so by inhibition of the GpIIb/IIIa receptor on the surface of the platelets. They may also be used to treat acute coronary syndromes, without percutaneous coronary intervention, depending on TIMI risk. They should be given intravenously. The oral form is associated with increased mortality and hence should not be given. In integrin nomenclature glycoprotein IIb/IIIa is called αIIbβ3. == History == Their development arose from the understanding of Glanzmann's thrombasthenia, a condition in which the GpIIb/IIIa receptor is deficient or dysfunctional. == References ==	Wikipedia/Glycoprotein_IIb/IIIa_inhibitors
The Cannabis Act (German: Cannabisgesetz) is a bill passed by the German Bundestag in February 2024, and the Bundesrat in March, that legalised the adult (18-years-old and over) use of cannabis in Germany, as well as the personal possession and cultivation of limited amounts of cannabis by adults in Germany, beginning on 1 April 2024. Adults in Germany are allowed to possess up to 25 grams of cannabis in public and up to 50 grams of dried cannabis at home. Each individual adult in Germany may also have up to three of their own cannabis plants at home. As part of the bill, adult-only non-profit cannabis social clubs with a maximum of 500 members became legal in Germany on 1 July 2024. == 2015 proposal == Entwurf eines Cannabiskontrollgesetzes (CannKG; "Draft of a cannabis control law") was a bill proposed in 2015 that would remove cannabis from the list of scheduled drugs in Germany's Narcotic Drugs Act. The issue was proposed by Alliance 90/The Greens (the German Green Party) on 20 March 2015. It would regulate cannabis in a manner similar to alcohol, with adults 18 years old permitted to buy and possess up to 30 grams in regulated stores. == 2022 proposal == A new regulatory framework that would legalise cannabis in Germany was brought out with an Eckpunktepapier ("cornerstone paper", or framework paper), introduced on 26 October 2022 by Minister of Health and member of the Bundestag, Karl Lauterbach, who is a physician and epidemiologist trained in the United States and Germany. The 2022 deregulation proposal was leaked around 19 October 2022. == 2023 proposal == In March 2023, the former health minister, Karl Lauterbach, reported a positive reaction from European Commission on the plan, and intended to bring a bill forward soon. The finalised bill received approval of the governing parties on 2 February 2024. The Bundestag passed the bill on 23 February 2024, and the Bundesrat approved it on 22 March, with the national legalisation to follow by 1 April. The final bill legislates that adults in Germany (those aged 18 and over) can legally use cannabis, possess and carry up to 25 grams (7⁄8 oz) of cannabis for personal possession in public and have up to 50 grams (1+3⁄4 oz) of dried cannabis at home. The legislation states that adults have a maximum purchase limit of 25 grams of cannabis a day and a monthly maximum purchase limit of 50 grams of cannabis. Each individual adult in Germany can also have up to three of their own cannabis plants at home. From 1 July 2024, adult residents of Germany will be allowed to join adult-only non-profit cannabis social clubs in Germany, with a maximum membership of 500. These cannabis social clubs will require permits. Consumption of cannabis inside and in a radius of less of 100 m from the entrances of schools, kindergartens, public playgrounds, public sports facilities, as well as in presence of minors and, between 7 am and 8 pm, in pedestrian zones in city centers will not be allowed. === Development === Details of a leaked version of a new scaled-back plan were published by German newspaper Die Zeit in late March. The new plan would have experimental controlled legalization in sub-national areas. The new plan was officially announced on 12 April. Provisions included legal possession of up to 25 grams of cannabis, and home- or club-grown cannabis, but did not allow large-scale commercial production and sale of the plant. The proposal was accepted by the federal cabinet on 16 August to be submitted to parliament. If it goes through as planned by the health ministry, the law could be in effect as early as the beginning of 2024. It survived a challenges by German states in the Bundesrat in late September, prior to its being taken up by the Bundestag. A version of the bill agreed to by the then German governing coalition, the traffic light coalition, was released on 27 November 2023, with a vote planned soon to allow for legal possession by adults by 1 April 2024. A vote on the bill was considered likely to pass by 1 December. Health minister Lauterbach said in January 2024 that the bill would be passed by the Bundestag in the week between 19 and 23 February and then go into force on 1 April. According to a YouGov poll in February 2024, 42% of Germans stated that they either somewhat or completely support the bill, while 47% of respondents said they somewhat or completely oppose the bill. === Reception === The issuance of the draft regulations by the Ministry of Health was called "decisive step toward legalization" by Politico. The Deutscher Hanfverband (German Hemp Association) criticised the 15% THC limit in the leaked draft. The bill has been criticised by many in the Social Democratic Party of Germany (SPD) because it does not allow for the control of cannabis via sales from licensed stores, which they state would tackle organised crime and reduce the burden on the police. A 2021 study from the University of Düsseldorf concluded that legal sales of recreational cannabis in Germany could raise over $5.3 billion in additional yearly tax revenue and create 27,000 jobs in the country. Those from the opposition CDU/CSU said if they form a government after the next German federal election they will completely scrap the bill. The conservative CSU government of Bavaria wanted to see if it could take a legal route to stop the implementation of the bill. === Provisions === Provisions of the October 2022 framework paper include sales in licensed establishments, and personal possession by adults over 18 years of 20 to 30 grams of cannabis without THC content limit. There may be sales limitations regarding persons under 21 years of age. === Effect === The ministry document is intended to have direct effect under Directive (EU) 2015/1535. Germany said it would present the framework paper to the European Union before implementing legislation. == See also == Cannabis in Germany Drug policy of Germany Hanfparade Legality of cannabis Outline of cannabis == References == == Further reading == Dr. Harald Terpe; et al., Entwurf eines Cannabiskontrollgesetzes [Design of a cannabis control law] (PDF), 18/4204 at Bundestag Wahlperiode 18 (18th German parliament) Stellungnahme der Bundespsychotherapeutenkammer [Opinion of the Federal Chamber of Psychotherapists] (PDF), Bundespsychotherapeutenkammer (Federal Chamber of Psychotherapists), 14 March 2016 – via Deutsche Bundestag (German Parliament) Karen Gilchrist (22 March 2023). "'Cannabis in Germany will be a success story': Europe's biggest economy moves closer to weed legalization". CNBC. Timothy Jones; Matthias von Hein (16 August 2023), Germany unveils bill to legalize cannabis, Deutsche Welle	Wikipedia/German_cannabis_control_bill
The Andean Trade Promotion and Drug Eradication Act (ATPDEA) is a trade preference system by which the United States grants duty-free access to a wide range of exports from four Andean countries: Bolivia, Colombia, Ecuador and Peru. It was enacted on October 31, 2002 as a replacement for the similar Andean Trade Preference Act (ATPA). The purpose of this preference system is to foster economic development in the Andean countries to provide alternatives to coca production. Bolivia has installed capacity to industrialize coca production and its derivatives, since coca has no narcotic effects, but the United States does not make any difference between coca and cocaine. Thus, the U.S. government eliminated this "preference". == History == On December 4, 1991, under the George H. W. Bush administration, the United States enacted the Andean Trade Preference Act (ATPA), eliminating tariffs on a number of products from Bolivia, Colombia, Ecuador, and Peru. Its objective was the strengthening of legal industries in these countries as alternatives to drug production and trafficking. The program was renewed on October 31, 2002 by the George W. Bush administration as the Andean Trade Promotion and Drug Eradication Act (ATPDEA). Under the renewed act, Andean products exempted from tariffs increased from around 5,600 to some 6,300. ATPDEA was set to expire on December 31, 2006, but was renewed by Congress for six months, up to June 30, 2007. An extension was granted on June 28, 2007, this time for eight months, until February 29, 2008. The U.S. Congress passed a third renewal for ten months on February 28, 2008, up to December 31, 2008. In November 2008, U.S. President George W. Bush asked Congress to remove Bolivia from the agreement due to failure to cooperate in counternarcotics efforts. On December 14, 2009, the United States House of Representatives approved the extension of such plan for a period of one year. The final version of the agreement, covering Ecuadorian products only, lapsed on July 31, 2013 after Ecuador became ineligible. == Impact == The Andean Trade Promotion and Drug Eradication Act has fostered rapid growth in trade between the United States and the four Andean nations; U.S. exports to the region rose from $6.46 billion in 2002 to $11.64 billion in 2006, while imports grew from $9.61 billion to $22.51 billion in the same period. As of 2006 main Andean exports to the United States under ATPDEA were oil, apparel, copper cathodes, cut flowers, gold jewelry, asparagus, and sugar. Of the 2006 total of U.S. imports under ATPDEA, Ecuador accounted for 39%, Colombia for 36%, Peru for 24%, and Bolivia for 1%. According to a September 2006 report by the United States International Trade Commission, ATPDEA has had a negative effect on the U.S. economy and consumers as well as a small positive effect on drug-crop reduction and export-related job creation in the Andean region. A 2006 report by the United States Department of Labor stated that ATPDEA does not appear to have had a negative impact on U.S. employment with the possible exception of some sectors of the cut flower industry. == See also == Colombia Trade Promotion Agreement United States-Peru Trade Promotion Agreement == Notes == == Bibliography == Office of the United States Trade Representative. New Andean Trade Benefits. September 25, 2002. Office of the United States Trade Representative. "Third Report to the Congress on the Operation of the Andean Trade Preference Act" (PDF). Archived from the original (PDF) on 2008-06-05. (181 KiB), January 31, 2001. Office of the United States Trade Representative. "Third Report to the Congress on the Operation of the Andean Trade Preference Act as Amended" (PDF). Archived from the original (PDF) on 2008-09-20. (310 KiB). April 30, 2007. Reuters. Congress extends Andean trade benefits 10 months. February 28, 2008. Reuters. US Senate OKs 8-month Andean trade pact extension. June 28, 2007. The White House. Andean Trade Promotion and Drug Eradication Act. October 31, 2002. == External links == (in Spanish) Colombian Ministry of Trade site on the ATPDEA (in Spanish) Peruvian Ministry of Trade site on the ATPDEA United States Trade Representative site on the ATPDEA	Wikipedia/Andean_Trade_Promotion_and_Drug_Eradication_Act
Renewable energy commercialization involves the deployment of three generations of renewable energy technologies dating back more than 100 years. First-generation technologies, which are already mature and economically competitive, include biomass, hydroelectricity, geothermal power and heat. Second-generation technologies are market-ready and are being deployed at the present time; they include solar heating, photovoltaics, wind power, solar thermal power stations, and modern forms of bioenergy. Third-generation technologies require continued R&D efforts in order to make large contributions on a global scale and include advanced biomass gasification, hot-dry-rock geothermal power, and ocean energy. In 2019, nearly 75% of new installed electricity generation capacity used renewable energy and the International Energy Agency (IEA) has predicted that by 2025, renewable capacity will meet 35% of global power generation. Public policy and political leadership helps to "level the playing field" and drive the wider acceptance of renewable energy technologies. Countries such as Germany, Denmark, and Spain have led the way in implementing innovative policies which has driven most of the growth over the past decade. As of 2014, Germany has a commitment to the "Energiewende" transition to a sustainable energy economy, and Denmark has a commitment to 100% renewable energy by 2050. There are now 144 countries with renewable energy policy targets. Renewable energy continued its rapid growth in 2015, providing multiple benefits. There was a new record set for installed wind and photovoltaic capacity (64GW and 57GW) and a new high of US$329 Billion for global renewables investment. A key benefit that this investment growth brings is a growth in jobs. The top countries for investment in recent years were China, Germany, Spain, the United States, Italy, and Brazil. Renewable energy companies include BrightSource Energy, First Solar, Gamesa, GE Energy, Goldwind, Sinovel, Targray, Trina Solar, Vestas, and Yingli. Climate change concerns are also driving increasing growth in the renewable energy industries. According to a 2011 projection by the IEA, solar power generators may produce most of the world's electricity within 50 years, reducing harmful greenhouse gas emissions. == Background == === Rationale for renewables === Climate change, pollution, and energy insecurity are significant problems, and addressing them requires major changes to energy infrastructures. Renewable energy technologies are essential contributors to the energy supply portfolio, as they contribute to world energy security, reduce dependency on fossil fuels, and some also provide opportunities for mitigating greenhouse gases. Climate-disrupting fossil fuels are being replaced by clean, climate-stabilizing, non-depletable sources of energy: ...the transition from coal, oil, and gas to wind, solar, and geothermal energy is well under way. In the old economy, energy was produced by burning something — oil, coal, or natural gas — leading to the carbon emissions that have come to define our economy. The new energy economy harnesses the energy in wind, the energy coming from the sun, and heat from within the earth itself. In international public opinion surveys there is strong support for a variety of methods for addressing the problem of energy supply. These methods include promoting renewable sources such as solar power and wind power, requiring utilities to use more renewable energy, and providing tax incentives to encourage the development and use of such technologies. It is expected that renewable energy investments will pay off economically in the long term. EU member countries have shown support for ambitious renewable energy goals. In 2010, Eurobarometer polled the twenty-seven EU member states about the target "to increase the share of renewable energy in the EU by 20 percent by 2020". Most people in all twenty-seven countries either approved of the target or called for it to go further. Across the EU, 57 percent thought the proposed goal was "about right" and 16 percent thought it was "too modest." In comparison, 19 percent said it was "too ambitious". As of 2011, new evidence has emerged that there are considerable risks associated with traditional energy sources, and that major changes to the mix of energy technologies is needed: Several mining tragedies globally have underscored the human toll of the coal supply chain. New EPA initiatives targeting air toxics, coal ash, and effluent releases highlight the environmental impacts of coal and the cost of addressing them with control technologies. The use of fracking in natural gas exploration is coming under scrutiny, with evidence of groundwater contamination and greenhouse gas emissions. Concerns are increasing about the vast amounts of water used at coal-fired and nuclear power plants, particularly in regions of the country facing water shortages. Events at the Fukushima nuclear plant have renewed doubts about the ability to operate large numbers of nuclear plants safely over the long term. Further, cost estimates for "next generation" nuclear units continue to climb, and lenders are unwilling to finance these plants without taxpayer guarantees. The 2014 REN21 Global Status Report says that renewable energies are no longer just energy sources, but ways to address pressing social, political, economic and environmental problems: Today, renewables are seen not only as sources of energy, but also as tools to address many other pressing needs, including: improving energy security; reducing the health and environmental impacts associated with fossil and nuclear energy; mitigating greenhouse gas emissions; improving educational opportunities; creating jobs; reducing poverty; and increasing gender equality... Renewables have entered the mainstream. === Growth of renewables === In 2008 for the first time, more renewable energy than conventional power capacity was added in both the European Union and United States, demonstrating a "fundamental transition" of the world's energy markets towards renewables, according to a report released by REN21, a global renewable energy policy network based in Paris. In 2010, renewable power consisted about a third of the newly built power generation capacities. By the end of 2011, total renewable power capacity worldwide exceeded 1,360 GW, up 8%. Renewables producing electricity accounted for almost half of the 208 GW of capacity added globally during 2011. Wind and solar photovoltaics (PV) accounted for almost 40% and 30%. Based on REN21's 2014 report, renewables contributed 19 percent to our energy consumption and 22 percent to our electricity generation in 2012 and 2013, respectively. This energy consumption is divided as 9% coming from traditional biomass, 4.2% as heat energy (non-biomass), 3.8% hydro electricity and 2% electricity from wind, solar, geothermal, and biomass. During the five-years from the end of 2004 through 2009, worldwide renewable energy capacity grew at rates of 10–60 percent annually for many technologies, while actual production grew 1.2% overall. In 2011, UN under-secretary general Achim Steiner said: "The continuing growth in this core segment of the green economy is not happening by chance. The combination of government target-setting, policy support and stimulus funds is underpinning the renewable industry's rise and bringing the much needed transformation of our global energy system within reach." He added: "Renewable energies are expanding both in terms of investment, projects and geographical spread. In doing so, they are making an increasing contribution to combating climate change, countering energy poverty and energy insecurity". According to a 2011 projection by the International Energy Agency, solar power plants may produce most of the world's electricity within 50 years, significantly reducing the emissions of greenhouse gases that harm the environment. The IEA has said: "Photovoltaic and solar-thermal plants may meet most of the world's demand for electricity by 2060 – and half of all energy needs – with wind, hydropower and biomass plants supplying much of the remaining generation". "Photovoltaic and concentrated solar power together can become the major source of electricity". In 2013, China led the world in renewable energy production, with a total capacity of 378 GW, mainly from hydroelectric and wind power. As of 2014, China leads the world in the production and use of wind power, solar photovoltaic power and smart grid technologies, generating almost as much water, wind and solar energy as all of France and Germany's power plants combined. China's renewable energy sector is growing faster than its fossil fuels and nuclear power capacity. Since 2005, production of solar cells in China has expanded 100-fold. As Chinese renewable manufacturing has grown, the costs of renewable energy technologies have dropped. Innovation has helped, but the main driver of reduced costs has been market expansion. See also renewable energy in the United States for US-figures. === Economic trends === Renewable energy technologies are getting cheaper, through technological change and through the benefits of mass production and market competition. A 2011 IEA report said: "A portfolio of renewable energy technologies is becoming cost-competitive in an increasingly broad range of circumstances, in some cases providing investment opportunities without the need for specific economic support," and added that "cost reductions in critical technologies, such as wind and solar, are set to continue." As of 2011, there have been substantial reductions in the cost of solar and wind technologies: The price of PV modules per MW has fallen by 60 percent since the summer of 2008, according to Bloomberg New Energy Finance estimates, putting solar power for the first time on a competitive footing with the retail price of electricity in a number of sunny countries. Wind turbine prices have also fallen – by 18 percent per MW in the last two years – reflecting, as with solar, fierce competition in the supply chain. Further improvements in the levelised cost of energy for solar, wind and other technologies lie ahead, posing a growing threat to the dominance of fossil fuel generation sources in the next few years. Hydro-electricity and geothermal electricity produced at favourable sites are now the cheapest way to generate electricity. Renewable energy costs continue to drop, and the levelised cost of electricity (LCOE) is declining for wind power, solar photovoltaic (PV), concentrated solar power (CSP) and some biomass technologies. Renewable energy is also the most economic solution for new grid-connected capacity in areas with good resources. As the cost of renewable power falls, the scope of economically viable applications increases. Renewable technologies are now often the most economic solution for new generating capacity. Where "oil-fired generation is the predominant power generation source (e.g. on islands, off-grid and in some countries) a lower-cost renewable solution almost always exists today". As of 2012, renewable power generation technologies accounted for around half of all new power generation capacity additions globally. In 2011, additions included 41 gigawatt (GW) of new wind power capacity, 30 GW of PV, 25 GW of hydro-electricity, 6 GW of biomass, 0.5 GW of CSP, and 0.1 GW of geothermal power. === Three generations of technologies === Renewable energy includes a number of sources and technologies at different stages of commercialization. The International Energy Agency (IEA) has defined three generations of renewable energy technologies, reaching back over 100 years: "First-generation technologies emerged from the industrial revolution at the end of the 19th century and include hydropower, biomass combustion, geothermal power and heat. These technologies are quite widely used. Second-generation technologies include solar heating and cooling, wind power, modern forms of bioenergy, and solar photovoltaics. These are now entering markets as a result of research, development and demonstration (RD&D) investments since the 1980s. Initial investment was prompted by energy security concerns linked to the oil crises of the 1970s but the enduring appeal of these technologies is due, at least in part, to environmental benefits. Many of the technologies reflect significant advancements in materials. Third-generation technologies are still under development and include advanced biomass gasification, biorefinery technologies, concentrating solar thermal power, hot-dry-rock geothermal power, and ocean energy. Advances in nanotechnology may also play a major role". First-generation technologies are well established, second-generation technologies are entering markets, and third-generation technologies heavily depend on long-term research and development commitments, where the public sector has a role to play. == First-generation technologies == First-generation technologies are widely used in locations with abundant resources. Their future use depends on the exploration of the remaining resource potential, particularly in developing countries, and on overcoming challenges related to the environment and social acceptance. === Biomass === Biomass, the burning of organic materials for heat and power, is a fully mature technology. Unlike most renewable sources, biomass (and hydropower) can supply stable base load power generation. Biomass produces CO2 emissions on combustion, and the issue of whether biomass is carbon neutral is contested. Material directly combusted in cook stoves produces pollutants, leading to severe health and environmental consequences. Improved cook stove programs are alleviating some of these effects. The industry remained relatively stagnant over the decade to 2007, but demand for biomass (mostly wood) continues to grow in many developing countries, as well as Brazil and Germany. The economic viability of biomass is dependent on regulated tariffs, due to high costs of infrastructure and ingredients for ongoing operations. Biomass does offer a ready disposal mechanism by burning municipal, agricultural, and industrial organic waste products. First-generation biomass technologies can be economically competitive, but may still require deployment support to overcome public acceptance and small-scale issues. As part of the food vs. fuel debate, several economists from Iowa State University found in 2008 "there is no evidence to disprove that the primary objective of biofuel policy is to support farm income." === Hydroelectricity === Hydroelectricity is the term referring to electricity generated by hydropower; the production of electrical power through the use of the gravitational force of falling or flowing water. In 2015 hydropower generated 16.6% of the worlds total electricity and 70% of all renewable electricity and is expected to increase about 3.1% each year for the next 25 years. Hydroelectric plants have the advantage of being long-lived and many existing plants have operated for more than 100 years. Hydropower is produced in 150 countries, with the Asia-Pacific region generating 32 percent of global hydropower in 2010. China is the largest hydroelectricity producer, with 721 terawatt-hours of production in 2010, representing around 17 percent of domestic electricity use. There are now three hydroelectricity plants larger than 10 GW: the Three Gorges Dam in China, Itaipu Dam across the Brazil/Paraguay border, and Guri Dam in Venezuela. The cost of hydroelectricity is low, making it a competitive source of renewable electricity. The average cost of electricity from a hydro plant larger than 10 megawatts is 3 to 5 U.S. cents per kilowatt-hour. === Geothermal power and heat === Geothermal power plants can operate 24 hours per day, providing baseload capacity. Estimates for the world potential capacity for geothermal power generation vary widely, ranging from 40 GW by 2020 to as much as 6,000 GW. Geothermal power capacity grew from around 1 GW in 1975 to almost 10 GW in 2008. The United States is the world leader in terms of installed capacity, representing 3.1 GW. Other countries with significant installed capacity include the Philippines (1.9 GW), Indonesia (1.2 GW), Mexico (1.0 GW), Italy (0.8 GW), Iceland (0.6 GW), Japan (0.5 GW), and New Zealand (0.5 GW). In some countries, geothermal power accounts for a significant share of the total electricity supply, such as in the Philippines, where geothermal represented 17 percent of the total power mix at the end of 2008. Geothermal (ground source) heat pumps represented an estimated 30 GWth of installed capacity at the end of 2008, with other direct uses of geothermal heat (i.e., for space heating, agricultural drying and other uses) reaching an estimated 15 GWth. As of 2008, at least 76 countries use direct geothermal energy in some form. == Second-generation technologies == Second-generation technologies have gone from being a passion for the dedicated few to a major economic sector in countries such as Germany, Spain, the United States, and Japan. Many large industrial companies and financial institutions are involved and the challenge is to broaden the market base for continued growth worldwide. === Solar heating === Solar heating systems are a well known second-generation technology and generally consist of solar thermal collectors, a fluid system to move the heat from the collector to its point of usage, and a reservoir or tank for heat storage. The systems may be used to heat domestic hot water, swimming pools, or homes and businesses. The heat can also be used for industrial process applications or as an energy input for other uses such as cooling equipment. In many warmer climates, a solar heating system can provide a very high percentage (50 to 75%) of domestic hot water energy. As of 2009, China has 27 million rooftop solar water heaters. === Photovoltaics === Photovoltaic (PV) cells, also called solar cells, convert light into electricity. In the 1980s and early 1990s, most photovoltaic modules were used to provide remote-area power supply, but from around 1995, industry efforts have focused increasingly on developing building integrated photovoltaics and photovoltaic power stations for grid connected applications. Many plants are integrated with agriculture and some use innovative tracking systems that follow the sun's daily path across the sky to generate more electricity than conventional fixed-mounted systems. There are no fuel costs or emissions during operation of the power stations. === Wind power === Some of the second-generation renewables, such as wind power, have high potential and have already realised relatively low production costs. Wind power could become cheaper than nuclear power. Global wind power installations increased by 35,800 MW in 2010, bringing total installed capacity up to 194,400 MW, a 22.5% increase on the 158,700 MW installed at the end of 2009. The increase for 2010 represents investments totalling €47.3 billion (US$65 billion) and for the first time more than half of all new wind power was added outside of the traditional markets of Europe and North America, mainly driven, by the continuing boom in China which accounted for nearly half of all of the installations at 16,500 MW. China now has 42,300 MW of wind power installed. Wind power accounts for approximately 19% of electricity generated in Denmark, 9% in Spain and Portugal, and 6% in Germany and the Republic of Ireland. In Australian state of South Australia wind power, championed by Premier Mike Rann (2002–2011), now comprises 26% of the state's electricity generation, edging out coal fired power. At the end of 2011 South Australia, with 7.2% of Australia's population, had 54% of the nation's installed wind power capacity. Wind power's share of worldwide electricity usage at the end of 2014 was 3.1%. The wind industry is able to produce more power at lower cost by using taller wind turbines with longer blades, capturing the faster winds at higher elevations. This has opened up new opportunities and in Indiana, Michigan, and Ohio, the price of power from wind turbines built 300 feet to 400 feet above the ground can now compete with conventional fossil fuels like coal. Prices have fallen to about 4 cents per kilowatt-hour in some cases and utilities have been increasing the amount of wind energy in their portfolio, saying it is their cheapest option. === Solar thermal power stations === Solar thermal power stations include the 354 megawatt (MW) Solar Energy Generating Systems power plant in the US, Solnova Solar Power Station (Spain, 150 MW), Andasol solar power station (Spain, 100 MW), Nevada Solar One (USA, 64 MW), PS20 solar power tower (Spain, 20 MW), and the PS10 solar power tower (Spain, 11 MW). The 370 MW Ivanpah Solar Power Facility, located in California's Mojave Desert, is the world's largest solar-thermal power plant project currently under construction. Many other plants are under construction or planned, mainly in Spain and the USA. In developing countries, three World Bank projects for integrated solar thermal/combined-cycle gas-turbine power plants in Egypt, Mexico, and Morocco have been approved. === Modern forms of bioenergy === Global ethanol production for transport fuel tripled between 2000 and 2007 from 17 billion to more than 52 billion litres, while biodiesel expanded more than tenfold from less than 1 billion to almost 11 billion litres. Biofuels provide 1.8% of the world's transport fuel and recent estimates indicate a continued high growth. The main producing countries for transport biofuels are the US, Brazil, and the EU. Brazil has one of the largest renewable energy programs in the world, involving production of ethanol fuel from sugar cane, and ethanol now provides 18 percent of the country's automotive fuel. As a result of this and the exploitation of domestic deep water oil sources, Brazil, which for years had to import a large share of the petroleum needed for domestic consumption, recently reached complete self-sufficiency in liquid fuels. Nearly all the gasoline sold in the United States today is mixed with 10 percent ethanol, a mix known as E10, and motor vehicle manufacturers already produce vehicles designed to run on much higher ethanol blends. Ford, DaimlerChrysler, and GM are among the automobile companies that sell flexible-fuel cars, trucks, and minivans that can use gasoline and ethanol blends ranging from pure gasoline up to 85% ethanol (E85). The challenge is to expand the market for biofuels beyond the farm states where they have been most popular to date. The Energy Policy Act of 2005, which calls for 7.5 billion US gallons (28,000,000 m3) of biofuels to be used annually by 2012, will also help to expand the market. The growing ethanol and biodiesel industries are providing jobs in plant construction, operations, and maintenance, mostly in rural communities. According to the Renewable Fuels Association, "the ethanol industry created almost 154,000 U.S. jobs in 2005 alone, boosting household income by $5.7 billion. It also contributed about $3.5 billion in tax revenues at the local, state, and federal levels". == Third-generation technologies == Third-generation renewable energy technologies are still under development and include advanced biomass gasification, biorefinery technologies, hot-dry-rock geothermal power, and ocean energy. Third-generation technologies are not yet widely demonstrated or have limited commercialization. Many are on the horizon and may have potential comparable to other renewable energy technologies, but still depend on attracting sufficient attention and research and development funding. === New bioenergy technologies === According to the International Energy Agency, cellulosic ethanol biorefineries could allow biofuels to play a much bigger role in the future than organizations such as the IEA previously thought. Cellulosic ethanol can be made from plant matter composed primarily of inedible cellulose fibers that form the stems and branches of most plants. Crop residues (such as corn stalks, wheat straw and rice straw), wood waste, and municipal solid waste are potential sources of cellulosic biomass. Dedicated energy crops, such as switchgrass, are also promising cellulose sources that can be sustainably produced in many regions. === Ocean energy === Ocean energy is all forms of renewable energy derived from the sea including wave energy, tidal energy, river current, ocean current energy, offshore wind, salinity gradient energy and ocean thermal gradient energy. The Rance Tidal Power Station (240 MW) is the world's first tidal power station. The facility is located on the estuary of the Rance River, in Brittany, France. Opened on 26 November 1966, it is currently operated by Électricité de France, and is the largest tidal power station in the world, in terms of installed capacity. First proposed more than thirty years ago, systems to harvest utility-scale electrical power from ocean waves have recently been gaining momentum as a viable technology. The potential for this technology is considered promising, especially on west-facing coasts with latitudes between 40 and 60 degrees: In the United Kingdom, for example, the Carbon Trust recently estimated the extent of the economically viable offshore resource at 55 TWh per year, about 14% of current national demand. Across Europe, the technologically achievable resource has been estimated to be at least 280 TWh per year. In 2003, the U.S. Electric Power Research Institute (EPRI) estimated the viable resource in the United States at 255 TWh per year (6% of demand). There are currently nine projects, completed or in-development, off the coasts of the United Kingdom, United States, Spain and Australia to harness the rise and fall of waves by Ocean Power Technologies. The current maximum power output is 1.5 MW (Reedsport, Oregon), with development underway for 100 MW (Coos Bay, Oregon). === Enhanced geothermal systems === As of 2008, geothermal power development was under way in more than 40 countries, partially attributable to the development of new technologies, such as Enhanced Geothermal Systems. The development of binary cycle power plants and improvements in drilling and extraction technology may enable enhanced geothermal systems over a much greater geographical range than "traditional" Geothermal systems. Demonstration EGS projects are operational in the US, Australia, Germany, France, and the United Kingdom. === Advanced solar concepts === Beyond the already established solar photovoltaics and solar thermal power technologies are such advanced solar concepts as the solar updraft tower or space-based solar power. These concepts have yet to (if ever) be commercialized. The Solar updraft tower (SUT) is a renewable-energy power plant for generating electricity from low temperature solar heat. Sunshine heats the air beneath a very wide greenhouse-like roofed collector structure surrounding the central base of a very tall chimney tower. The resulting convection causes a hot air updraft in the tower by the chimney effect. This airflow drives wind turbines placed in the chimney updraft or around the chimney base to produce electricity. Plans for scaled-up versions of demonstration models will allow significant power generation, and may allow development of other applications, such as water extraction or distillation, and agriculture or horticulture. To view a study on the solar updraft tower and its affects click here A more advanced version of a similarly themed technology is the Vortex engine (AVE) which aims to replace large physical chimneys with a vortex of air created by a shorter, less-expensive structure. Space-based solar power (SBSP) is the concept of collecting solar power in space (using an "SPS", that is, a "solar-power satellite" or a "satellite power system") for use on Earth. It has been in research since the early 1970s. SBSP would differ from current solar collection methods in that the means used to collect energy would reside on an orbiting satellite instead of on Earth's surface. Some projected benefits of such a system are a higher collection rate and a longer collection period due to the lack of a diffusing atmosphere and night time in space. == Renewable energy industry == Total investment in renewable energy reached $211 billion in 2010, up from $160 billion in 2009. The top countries for investment in 2010 were China, Germany, the United States, Italy, and Brazil. Continued growth for the renewable energy sector is expected and promotional policies helped the industry weather the 2009 economic crisis better than many other sectors. === Wind power companies === As of 2010, Vestas (from Denmark) is the world's top wind turbine manufacturer in terms of percentage of market volume, and Sinovel (from China) is in second place. Together Vestas and Sinovel delivered 10,228 MW of new wind power capacity in 2010, and their market share was 25.9 percent. GE Energy (USA) was in third place, closely followed by Goldwind, another Chinese supplier. German Enercon ranks fifth in the world, and is followed in sixth place by Indian-based Suzlon. === Photovoltaic market trends === The solar PV market has been growing for the past few years. According to solar PV research company, PVinsights, worldwide shipment of solar modules in 2011 was around 25 GW, and the shipment year over year growth was around 40%. The top 5 solar module players in 2011 in turns are Suntech, First Solar, Yingli, Trina, and Sungen. The top 5 solar module companies possessed 51.3% market share of solar modules, according to PVinsights' market intelligence report. The PV industry has seen drops in module prices since 2008. In late 2011, factory-gate prices for crystalline-silicon photovoltaic modules dropped below the $1.00/W mark. The $1.00/W installed cost, is often regarded in the PV industry as marking the achievement of grid parity for PV. These reductions have taken many stakeholders, including industry analysts, by surprise, and perceptions of current solar power economics often lags behind reality. Some stakeholders still have the perspective that solar PV remains too costly on an unsubsidized basis to compete with conventional generation options. Yet technological advancements, manufacturing process improvements, and industry re-structuring, mean that further price reductions are likely in coming years. == Non-technical barriers to acceptance == Many energy markets, institutions, and policies have been developed to support the production and use of fossil fuels. Newer and cleaner technologies may offer social and environmental benefits, but utility operators often reject renewable resources because they are trained to think only in terms of big, conventional power plants. Consumers often ignore renewable power systems because they are not given accurate price signals about electricity consumption. Intentional market distortions (such as subsidies), and unintentional market distortions (such as split incentives) may work against renewables. Benjamin K. Sovacool has argued that "some of the most surreptitious, yet powerful, impediments facing renewable energy and energy efficiency in the United States are more about culture and institutions than engineering and science". The obstacles to the widespread commercialization of renewable energy technologies are primarily political, not technical, and there have been many studies which have identified a range of "non-technical barriers" to renewable energy use. These barriers are impediments which put renewable energy at a marketing, institutional, or policy disadvantage relative to other forms of energy. Key barriers include: Difficulty overcoming established energy systems, which includes difficulty introducing innovative energy systems, particularly for distributed generation such as photovoltaics, because of technological lock-in, electricity markets designed for centralized power plants, and market control by established operators. As the Stern Review on the Economics of Climate Change points out: "National grids are usually tailored towards the operation of centralised power plants and thus favour their performance. Technologies that do not easily fit into these networks may struggle to enter the market, even if the technology itself is commercially viable. This applies to distributed generation as most grids are not suited to receive electricity from many small sources. Large-scale renewables may also encounter problems if they are sited in areas far from existing grids." Lack of government policy support, which includes the lack of policies and regulations supporting deployment of renewable energy technologies and the presence of policies and regulations hindering renewable energy development and supporting conventional energy development. Examples include subsidies for fossil-fuels, insufficient consumer-based renewable energy incentives, government underwriting for nuclear plant accidents, and complex zoning and permitting processes for renewable energy. Lack of information dissemination and consumer awareness. Higher capital cost of renewable energy technologies compared with conventional energy technologies. Inadequate financing options for renewable energy projects, including insufficient access to affordable financing for project developers, entrepreneurs and consumers. Imperfect capital markets, which includes failure to internalize all costs of conventional energy (e.g., effects of air pollution, risk of supply disruption) and failure to internalize all benefits of renewable energy (e.g., cleaner air, energy security). Inadequate workforce skills and training, which includes lack of adequate scientific, technical, and manufacturing skills required for renewable energy production; lack of reliable installation, maintenance, and inspection services; and failure of the educational system to provide adequate training in new technologies. Lack of adequate codes, standards, utility interconnection, and net-metering guidelines. Poor public perception of renewable energy system aesthetics. Lack of stakeholder/community participation and co-operation in energy choices and renewable energy projects. With such a wide range of non-technical barriers, there is no "silver bullet" solution to drive the transition to renewable energy. So ideally there is a need for several different types of policy instruments to complement each other and overcome different types of barriers. A policy framework must be created that will level the playing field and redress the imbalance of traditional approaches associated with fossil fuels. The policy landscape must keep pace with broad trends within the energy sector, as well as reflecting specific social, economic and environmental priorities. Some resource-rich countries struggle to move away from fossil fuels and have failed thus far to adopt regulatory frameworks necessary for developing renewable energy (e.g. Russia). == Public policy landscape == Public policy has a role to play in renewable energy commercialization because the free market system has some fundamental limitations. As the Stern Review points out: "In a liberalised energy market, investors, operators and consumers should face the full cost of their decisions. But this is not the case in many economies or energy sectors. Many policies distort the market in favour of existing fossil fuel technologies." The International Solar Energy Society has stated that "historical incentives for the conventional energy resources continue even today to bias markets by burying many of the real societal costs of their use". Fossil-fuel energy systems have different production, transmission, and end-use costs and characteristics than do renewable energy systems, and new promotional policies are needed to ensure that renewable systems develop as quickly and broadly as is socially desirable. Lester Brown states that the market "does not incorporate the indirect costs of providing goods or services into prices, it does not value nature's services adequately, and it does not respect the sustainable-yield thresholds of natural systems". It also favors the near term over the long term, thereby showing limited concern for future generations. Tax and subsidy shifting can help overcome these problems, though is also problematic to combine different international normative regimes regulating this issue. === Shifting taxes === Tax shifting has been widely discussed and endorsed by economists. It involves lowering income taxes while raising levies on environmentally destructive activities, in order to create a more responsive market. For example, a tax on coal that included the increased health care costs associated with breathing polluted air, the costs of acid rain damage, and the costs of climate disruption would encourage investment in renewable technologies. Several Western European countries are already shifting taxes in a process known there as environmental tax reform. In 2001, Sweden launched a new 10-year environmental tax shift designed to convert 30 billion kroner ($3.9 billion) of income taxes to taxes on environmentally destructive activities. Other European countries with significant tax reform efforts are France, Italy, Norway, Spain, and the United Kingdom. Asia's two leading economies, Japan and China, are considering carbon taxes. === Shifting subsidies === Just as there is a need for tax shifting, there is also a need for subsidy shifting. Subsidies are not an inherently bad thing as many technologies and industries emerged through government subsidy schemes. The Stern Review explains that of 20 key innovations from the past 30 years, only one of the 14 was funded entirely by the private sector and nine were totally publicly funded. In terms of specific examples, the Internet was the result of publicly funded links among computers in government laboratories and research institutes. And the combination of the federal tax deduction and a robust state tax deduction in California helped to create the modern wind power industry. At the same time specifically US tax credits systems for renewable energy have been described as an "opaque" financial instrument dominated by large investors to reduce their tax payments while greenhouse gas reduction targets are being treated as a side effect. Lester Brown has argued that "a world facing the prospect of economically disruptive climate change can no longer justify subsidies to expand the burning of coal and oil. Shifting these subsidies to the development of climate-benign energy sources such as wind, solar, biomass, and geothermal power is the key to stabilizing the earth's climate." The International Solar Energy Society advocates "leveling the playing field" by redressing the continuing inequities in public subsidies of energy technologies and R&D, in which the fossil fuel and nuclear power receive the largest share of financial support. Some countries are eliminating or reducing climate-disrupting subsidies and Belgium, France, and Japan have phased out all subsidies for coal. Germany is reducing its coal subsidy. The subsidy dropped from $5.4 billion in 1989 to $2.8 billion in 2002, and in the process Germany lowered its coal use by 46 percent. China cut its coal subsidy from $750 million in 1993 to $240 million in 1995 and more recently has imposed a high-sulfur coal tax. However, the United States has been increasing its support for the fossil fuel and nuclear industries. In November 2011, an IEA report entitled Deploying Renewables 2011 said "subsidies in green energy technologies that were not yet competitive are justified in order to give an incentive to investing into technologies with clear environmental and energy security benefits". The IEA's report disagreed with claims that renewable energy technologies are only viable through costly subsidies and not able to produce energy reliably to meet demand. A fair and efficient imposition of subsidies for renewable energies and aiming at sustainable development, however, require coordination and regulation at a global level, as subsidies granted in one country can easily disrupt industries and policies of others, thus underlining the relevance of this issue at the World Trade Organization. === Renewable energy targets === Setting national renewable energy targets can be an important part of a renewable energy policy and these targets are usually defined as a percentage of the primary energy and/or electricity generation mix. For example, the European Union has prescribed an indicative renewable energy target of 12 percent of the total EU energy mix and 22 percent of electricity consumption by 2010. National targets for individual EU Member States have also been set to meet the overall target. Other developed countries with defined national or regional targets include Australia, Canada, Israel, Japan, Korea, New Zealand, Norway, Singapore, Switzerland, and some US States. National targets are also an important component of renewable energy strategies in some developing countries. Developing countries with renewable energy targets include China, India, Indonesia, Malaysia, the Philippines, Thailand, Brazil, Egypt, Mali, and South Africa. The targets set by many developing countries are quite modest when compared with those in some industrialized countries. Renewable energy targets in most countries are indicative and nonbinding but they have assisted government actions and regulatory frameworks. The United Nations Environment Program has suggested that making renewable energy targets legally binding could be an important policy tool to achieve higher renewable energy market penetration. === Levelling the playing field === The IEA has identified three actions which will allow renewable energy and other clean energy technologies to "more effectively compete for private sector capital". "First, energy prices must appropriately reflect the "true cost" of energy (e.g. through carbon pricing) so that the positive and negative impacts of energy production and consumption are fully taken into account". Example: New UK nuclear plants cost £92.50/MWh, whereas offshore wind farms in the UK are supported with €74.2/MWh at a price of £150 in 2011 falling to £130 per MWh in 2022. In Denmark, the price can be €84/MWh. "Second, inefficient fossil fuel subsidies must be removed, while ensuring that all citizens have access to affordable energy". "Third, governments must develop policy frameworks that encourage private sector investment in lower-carbon energy options". === Green stimulus programs === In response to the Great Recession, major governments made "green stimulus" programs one of their main policy instruments for supporting economic recovery. Some US$188 billion in green stimulus funding had been allocated to renewable energy and energy efficiency, to be spent mainly in 2010 and in 2011. === Energy sector regulation === Public policy determines the extent to which renewable energy (RE) is to be incorporated into a developed or developing country's generation mix. Energy sector regulators implement that policy—thus affecting the pace and pattern of RE investments and connections to the grid. Energy regulators often have authority to carry out a number of functions that have implications for the financial feasibility of renewable energy projects. Such functions include issuing licenses, setting performance standards, monitoring the performance of regulated firms, determining the price level and structure of tariffs, establishing uniform systems of accounts, arbitrating stakeholder disputes (like interconnection cost allocations), performing management audits, developing agency human resources (expertise), reporting sector and commission activities to government authorities, and coordinating decisions with other government agencies. Thus, regulators make a wide range of decisions that affect the financial outcomes associated with RE investments. In addition, the sector regulator is in a position to give advice to the government regarding the full implications of focusing on climate change or energy security. The energy sector regulator is the natural advocate for efficiency and cost-containment throughout the process of designing and implementing RE policies. Since policies are not self-implementing, energy sector regulators become a key facilitator (or blocker) of renewable energy investments. === Energy transition in Germany === The Energiewende (German for energy transition) is the transition by Germany to a low carbon, environmentally sound, reliable, and affordable energy supply. The new system will rely heavily on renewable energy (particularly wind, photovoltaics, and biomass) energy efficiency, and energy demand management. Most if not all existing coal-fired generation will need to be retired. The phase-out of Germany's fleet of nuclear reactors, to be complete by 2022, is a key part of the program. Legislative support for the Energiewende was passed in late 2010 and includes greenhouse gas (GHG) reductions of 80–95% by 2050 (relative to 1990) and a renewable energy target of 60% by 2050. These targets are ambitious. The Berlin-based policy institute Agora Energiewende noted that "while the German approach is not unique worldwide, the speed and scope of the Energiewende are exceptional". The Energiewende also seeks a greater transparency in relation to national energy policy formation. Germany has made significant progress on its GHG emissions reduction target, achieving a 27% decrease between 1990 and 2014. However Germany will need to maintain an average GHG emissions abatement rate of 3.5% per annum to reach its Energiewende goal, equal to the maximum historical value thus far. Germany spends €1.5 billion per annum on energy research (2013 figure) in an effort to solve the technical and social issues raised by the transition. This includes a number of computer studies that have confirmed the feasibility and a similar cost (relative to business-as-usual and given that carbon is adequately priced) of the Energiewende. These initiatives go well beyond European Union legislation and the national policies of other European states. The policy objectives have been embraced by the German federal government and has resulted in a huge expansion of renewables, particularly wind power. Germany's share of renewables has increased from around 5% in 1999 to 22.9% in 2012, surpassing the OECD average of 18% usage of renewables. Producers have been guaranteed a fixed feed-in tariff for 20 years, guaranteeing a fixed income. Energy co-operatives have been created, and efforts were made to decentralize control and profits. The large energy companies have a disproportionately small share of the renewables market. However, in some cases poor investment designs have caused bankruptcies and low returns, and unrealistic promises have been shown to be far from reality. Nuclear power plants were closed, and the existing nine plants will close earlier than planned, in 2022. One factor that has inhibited efficient employment of new renewable energy has been the lack of an accompanying investment in power infrastructure to bring the power to market. It is believed 8,300 km of power lines must be built or upgraded. The different German States have varying attitudes to the construction of new power lines. Industry has had their rates frozen and so the increased costs of the Energiewende have been passed on to consumers, who have had rising electricity bills. == Voluntary market mechanisms for renewable electricity == Voluntary markets, also referred to as green power markets, are driven by consumer preference. Voluntary markets allow a consumer to choose to do more than policy decisions require and reduce the environmental impact of their electricity use. Voluntary green power products must offer a significant benefit and value to buyers to be successful. Benefits may include zero or reduced greenhouse gas emissions, other pollution reductions or other environmental improvements on power stations. The driving factors behind voluntary green electricity within the EU are the liberalized electricity markets and the RES Directive. According to the directive, the EU Member States must ensure that the origin of electricity produced from renewables can be guaranteed and therefore a "guarantee of origin" must be issued (article 15). Environmental organisations are using the voluntary market to create new renewables and improving sustainability of the existing power production. In the US the main tool to track and stimulate voluntary actions is Green-e program managed by Center for Resource Solutions. Globally available voluntary tool used by the NGOs to promote sustainable electricity production is EKOenergy label. == Recent developments == A number of events in 2006 pushed renewable energy up the political agenda, including the US mid-term elections in November, which confirmed clean energy as a mainstream issue. Also in 2006, the Stern Review made a strong economic case for investing in low carbon technologies now, and argued that economic growth need not be incompatible with cutting energy consumption. According to a trend analysis from the United Nations Environment Programme, climate change concerns coupled with recent high oil prices and increasing government support are driving increasing rates of investment in the renewable energy and energy efficiency industries. Investment capital flowing into renewable energy reached a record US$77 billion in 2007, with the upward trend continuing in 2008. The OECD still dominates, but there is now increasing activity from companies in China, India and Brazil. Chinese companies were the second largest recipient of venture capital in 2006 after the United States. In the same year, India was the largest net buyer of companies abroad, mainly in the more established European markets. New government spending, regulation, and policies helped the industry weather the 2009 economic crisis better than many other sectors. Most notably, U.S. President Barack Obama's American Recovery and Reinvestment Act of 2009 included more than $70 billion in direct spending and tax credits for clean energy and associated transportation programs. This policy-stimulus combination represents the largest federal commitment in U.S. history for renewables, advanced transportation, and energy conservation initiatives. Based on these new rules, many more utilities strengthened their clean-energy programs. Clean Edge suggests that the commercialization of clean energy will help countries around the world deal with the current economic malaise. Once-promising solar energy company, Solyndra, became involved in a political controversy involving U.S. President Barack Obama's administration's authorization of a $535 million loan guarantee to the Corporation in 2009 as part of a program to promote alternative energy growth. The company ceased all business activity, filed for Chapter 11 bankruptcy, and laid-off nearly all of its employees in early September 2011. In his 24 January 2012, State of the Union address, President Barack Obama restated his commitment to renewable energy. Obama said that he "will not walk away from the promise of clean energy." Obama called for a commitment by the Defense Department to purchase 1,000 MW of renewable energy. He also mentioned the long-standing Interior Department commitment to permit 10,000 MW of renewable energy projects on public land in 2012. As of 2012, renewable energy plays a major role in the energy mix of many countries globally. Renewables are becoming increasingly economic in both developing and developed countries. Prices for renewable energy technologies, primarily wind power and solar power, continued to drop, making renewables competitive with conventional energy sources. Without a level playing field, however, high market penetration of renewables is still dependent on robust promotional policies. Fossil fuel subsidies, which are far higher than those for renewable energy, remain in place and quickly need to be phased out. United Nations' Secretary-General Ban Ki-moon has said that "renewable energy has the ability to lift the poorest nations to new levels of prosperity". In October 2011, he "announced the creation of a high-level group to drum up support for energy access, energy efficiency and greater use of renewable energy. The group is to be co-chaired by Kandeh Yumkella, the chair of UN Energy and director general of the UN Industrial Development Organisation, and Charles Holliday, chairman of Bank of America". Worldwide use of solar power and wind power continued to grow significantly in 2012. Solar electricity consumption increased by 58 percent, to 93 terawatt-hours (TWh). Use of wind power in 2012 increased by 18.1 percent, to 521.3 TWh. Global solar and wind energy installed capacities continued to expand even though new investments in these technologies declined during 2012. Worldwide investment in solar power in 2012 was $140.4 billion, an 11 percent decline from 2011, and wind power investment was down 10.1 percent, to $80.3 billion. But due to lower production costs for both technologies, total installed capacities grew sharply. This investment decline, but growth in installed capacity, may again occur in 2013. Analysts expect the market to triple by 2030. In 2015, investment in renewables exceeded fossils. == 100% renewable energy == The incentive to use 100% renewable energy for electricity, transport, or even total primary energy supply globally, has been motivated by global warming and other ecological as well as economic concerns. In the Intergovernmental Panel on Climate Change's reviews of scenarios of energy usage that would keep global warming to approximately 1.5 degrees, the proportion of primary energy supplied by renewables increases from 15% in 2020 to 60% in 2050 (median values across all published pathways). The proportion of primary energy supplied by biomass increases from 10% to 27%, with effective controls on whether land use is changed in the growing of biomass. The proportion from wind and solar increases from 1.8% to 21%. At the national level, at least 30 nations around the world already have renewable energy contributing more than 20% of energy supply. Mark Z. Jacobson, professor of civil and environmental engineering at Stanford University and director of its Atmosphere and Energy Program says producing all new energy with wind power, solar power, and hydropower by 2030 is feasible and existing energy supply arrangements could be replaced by 2050. Barriers to implementing the renewable energy plan are seen to be "primarily social and political, not technological or economic". Jacobson says that energy costs with a wind, solar, water system should be similar to today's energy costs. Renewable projects must be sited at distant locations due to high land prices in urban areas or for the renewable resource itself which require transmission construction costs. Similarly, in the United States, the independent National Research Council has noted that "sufficient domestic renewable resources exist to allow renewable electricity to play a significant role in future electricity generation and thus help confront issues related to climate change, energy security, and the escalation of energy costs … Renewable energy is an attractive option because renewable resources available in the United States, taken collectively, can supply significantly greater amounts of electricity than the total current or projected domestic demand." The most significant barriers to the widespread implementation of large-scale renewable energy and low carbon energy strategies are primarily political and not technological. According to the 2013 Post Carbon Pathways report, which reviewed many international studies, the key roadblocks are: climate change denial, the fossil fuels lobby, political inaction, unsustainable energy consumption, outdated energy infrastructure, and financial constraints. == Energy efficiency == Moving towards energy sustainability will require changes not only in the way energy is supplied, but in the way it is used, and reducing the amount of energy required to deliver various goods or services is essential. Opportunities for improvement on the demand side of the energy equation are as rich and diverse as those on the supply side, and often offer significant economic benefits. A sustainable energy economy requires commitments to both renewables and efficiency. Renewable energy and energy efficiency are said to be the "twin pillars" of sustainable energy policy. The American Council for an Energy-Efficient Economy has explained that both resources must be developed in order to stabilize and reduce carbon dioxide emissions: Efficiency is essential to slowing the energy demand growth so that rising clean energy supplies can make deep cuts in fossil fuel use. If energy use grows too fast, renewable energy development will chase a receding target. Likewise, unless clean energy supplies come online rapidly, slowing demand growth will only begin to reduce total emissions; reducing the carbon content of energy sources is also needed. The IEA has stated that renewable energy and energy efficiency policies are complementary tools for the development of a sustainable energy future, and should be developed together instead of being developed in isolation. == See also == === Lists === === Topics === === People === == References == == Bibliography == == External links == Investing: Green technology has big growth potential, LA Times, 2011 Global Renewable Energy: Policies and Measures Missing the Market Meltdown Bureau of Land Management 2012 Renewable Energy Priority Projects	Wikipedia/Renewable_energy_policy
The Agreement for the Control of Opium Smoking in the Far East, also known as the Agreement concerning the Suppression of Opium Smoking, was a treaty concluded in Bangkok on 27 November 1931 and at Lake Success, New York on 11 December 1946. The treaty was signed and ratified by the State of Vietnam, France, British India, Japan, Laos, Netherlands, Thailand, and United Kingdom. Article I provided that retail sale and distribution of opium would be limited to Government shops. Fixed salaries were mandated for retailers; sales commissions were abolished. A system of licensing and rationing smokers was permitted as an alternative to the Government retail provisions. Article II prohibited minors under the age of 21 from smoking opium or entering smoking establishments, and mandated prison sentences for inducing minors to smoke opium, to enter an opium-smoking establishment, or to procure opium. Other provisions mandated that opium be sold for cash only, allowed governments to establish monopolies on opium production, and limited the application of the agreement to the Far East. The Agreement was superseded by the 1961 Single Convention on Narcotic Drugs. == References == Agreement concerning the Suppression of Opium Smoking, United Nations Treaty Collection. Ratifications. Unification of Conventions on Narcotic Drugs, Bulletin on Narcotics, 1950.	Wikipedia/Agreement_for_the_Control_of_Opium_Smoking_in_the_Far_East
Get Your Drugs Tested is a free public drug checking service located in Vancouver, Canada. It was founded by Dana Larsen in May 2019, accepting samples in person at their storefront and by mail from all across Canada. Dana Larsen said: "I want to help save lives, I want people to be informed and I wish they could buy clean, pre-tested drugs" since "the whole war on drug users is a genocide of the poor." Get Your Drugs Tested receives no public funding, and is entirely supported by The Medicinal Cannabis Dispensary. They use FTIR Spectrometers in conjunction with fentanyl, Lysergamides and Benzodiazepine test strips to offer free analysis of any drug or substance at their storefront or by mail. In January 2021 they announced they had analyzed over 10,000 samples. In June 2021 they announced they had analyzed 15,000 samples. In March 2022 they announced they had analyzed 25,000 samples. In July 2022 they announced they had analyzed 30,000 samples. By October 2023, the service had analyzed over 50,000 samples. All of their drug analysis results are posted to their website in a searchable database. The service has received extensive media coverage. == See also == Counterfeit drug Drug education Drug test Harm reduction Reagent testing == External links == Get Your Drugs Tested website == References ==	Wikipedia/Get_Your_Drugs_Tested
Industrial policy is proactive government-led encouragement and development of specific strategic industries for the growth of all or part of the economy, especially in absence of sufficient private sector investments and participation. Historically, it has often focused on the manufacturing sector, militarily important sectors, or on fostering an advantage in new technologies. In industrial policy, the government takes measures "aimed at improving the competitiveness and capabilities of domestic firms and promoting structural transformation". A country's infrastructure (including transportation, telecommunications and energy industry) is a major enabler of industrial policy. Industrial policies are interventionist measures typical of mixed economy countries. Many types of industrial policies contain common elements with other types of interventionist practices such as trade policy. Industrial policy is usually seen as separate from broader macroeconomic policies, such as tightening credit and taxing capital gains. Traditional examples of industrial policy include subsidizing export industries and import-substitution-industrialization (ISI), where trade barriers are temporarily imposed on some key sectors, such as manufacturing. By selectively protecting certain industries, these industries are given time to learn (learning by doing) and upgrade. Once competitive enough, these restrictions are lifted to expose the selected industries to the international market. More contemporary industrial policies include measures such as support for linkages between firms and support for upstream technologies. Economists have debated the role of industrial policy in fostering industrialization and economic development. They have also debated concerns that industrial policy threatens free trade and international cooperation. == History == The traditional arguments for industrial policies go back as far as the 18th century. Prominent early arguments in favor of selective protection of industries were contained in the 1791 Report on the Subject of Manufactures of US statesman Alexander Hamilton, as well as the work of German economist Friedrich List. List's views on free trade were in explicit contradiction to those of Adam Smith, who, in The Wealth of Nations, said that "the most advantageous method in which a landed nation can raise up artificers, manufacturers, and merchants of its own is to grant the most perfect freedom of trade to the artificers, manufacturers, and merchants of all other nations." According to NYU historians Prince & Taylor, "The relationship between government and industry in the United States has never been a simple one, and the labels used in categorizing these relationships at different times are often misleading if not false. In the early nineteenth century, for example, it is quite clear that the laissez faire label is an inappropriate one." In the US, an industrial policy was explicitly presented for the first time by the Jimmy Carter administration in August 1980, but it was subsequently dismantled with the election of Ronald Reagan the following year. Historically, there is a growing consensus that most developed countries, including United Kingdom, United States, Germany, and France, have intervened actively in their domestic economy through industrial policies. These early examples are followed by interventionist ISI strategies pursued in Latin American countries such as Brazil, Mexico or Argentina. More recently, the rapid growth of East Asian economies, or the newly industrialized countries (NICs), has also been associated with active industrial policies that selectively promoted manufacturing and facilitated technology transfer and industrial upgrading. The success of these state-directed industrialization strategies are often attributed to developmental states and strong bureaucracies such as the Japanese MITI. According to Princeton's Atul Kohli, the reason Japanese colonies such as South Korea developed so rapidly and successfully was down to Japan exporting to its colonies the same centralised state development that it had used to develop itself. Precisely speaking, South Korea's development can be explained by the fact that it followed the similar industrial policies that UK, US and Germany implemented, and South Korea adopted Export-Oriented Industrialization (EOI) policy from 1964 based on its own decision contrary to the Import Substitution Industrialization (ISI) policy touted by international aid organizations and experts at that time. Many of these domestic policy choices, however, are now seen as detrimental to free trade and are hence limited by various international agreements such as WTO TRIMs or TRIPS. Instead, the recent focus for industrial policy has shifted towards the promotion of local business clusters and the integration into global value chains. During the Reagan administration, an economic development initiative called Project Socrates was initiated to address US decline in ability to compete in world markets. Project Socrates, directed by Michael Sekora, resulted in a computer-based competitive strategy system that was made available to private industry and all other public and private institutions that impact economic growth, competitiveness and trade policy. A key objective of Socrates was to utilize advanced technology to enable US private institutions and public agencies to cooperate in the development and execution of competitive strategies without violating existing laws or compromising the spirit of "free market". President Reagan was satisfied that this objective was fulfilled in the Socrates system. Through the advances of innovation age technology, Socrates would provide "voluntary" but "systematic" coordination of resources across multiple "economic system" institutions including industry clusters, financial service organizations, university research facilities and government economic planning agencies. While the view of one US President and the Socrates team was that technology made it virtually possible for both to exist simultaneously, the industrial policy vs. free market debate continued as later under the George H. W. Bush administration, Socrates was labeled as industrial policy and de-funded. After the 2008 financial crisis, countries including the US, UK, Australia, Japan and most countries of the European Union adopted industry policies. However contemporary industry policy generally accepts globalization as a given, and focuses less on the decline of older industries, and more on the growth of emergent industries. It often involves the government working collaboratively with industry to respond to challenges and opportunities. China is a prominent case where the central and subnational governments participate in nearly all economic sectors and processes. Even though market mechanisms have gained importance, state guidance through state-directed investment and indicative planning plays a substantial role in the economy. In order to catch-up and even overtake industrialized countries technologically, China's "state activities even extend to efforts to prevent the dominance of foreign investors and technologies in areas considered to be of key significance such as the strategic industries and the new technologies" including robotics and new energy vehicles. == Criticism == Some criticize industrial policy based on the concept of government failure. Industrial policy is seen as harmful as governments lack the required information, capabilities, and incentives to successfully determine whether the benefits of promoting certain sectors above others exceeds the costs and in turn implement the policies. While the East Asian Tigers provided successful examples of heterodox interventions and protectionist industrial policies, industrial policies such as import-substitution-industrialization (ISI) have failed in many other regions such as Latin America and Sub-Saharan Africa. Governments, in making decisions with regard to electoral or personal incentives, can be captured by vested interests, leading to industrial policies supporting local rent-seeking political elites while distorting the efficient allocation of resources by market forces. == Debates on process == Despite criticism, there is a consensus in recent development theory that says state interventions may be necessary when market failures occur. Market failures often exist in the form of externalities and natural monopolies. Some economists argue that public action can boost certain development factors "beyond what market forces on their own would generate." In practice, these interventions are often aimed at regulating networks, public infrastructure, R&D or correcting information asymmetries. Many countries are now seeing a revival of industrial policy. One question is which kinds of industrial policy are most effective in promoting economic development. For example, economists debate whether developing countries should focus on their comparative advantage by promoting mostly resource- and labor-intensive products and services, or invest in higher-productivity industries, which may only become competitive in the longer term. Debate also surrounds the issue of whether government failures are more pervasive and severe than market failures. Some argue that the lower the government accountability and capabilities, the higher the risk of political capture of industrial policies, which may be economically more harmful than existing market failures. Of particular relevance for developing countries are the conditions under which industrial policies may also contribute to poverty reduction, such as a focus on specific industries or the promotion of linkages between larger companies and smaller local enterprises. == Effects == A study conducted by Réka Juhász investigated the economic effect of the Continental Blockade on the French empire. It concluded that the regions of the French empire which were more protected from trade with the United Kingdom had an higher increase in mechanized cotton spinning than other regions. During the 2000s, China had implemented an industrial policy targeting its shipbuilding industry. The policy consisted in subsidizing entry, investment and production. It increased sectoral investment and entry rate by 270% and 200% respectively. It led to the entry of small and less productive firms and created excess capacity. The gain in producer or consumer surplus was lower than the cost of the subsidies. The policy was therefore welfare-reducing. A 2025 study challenged that industrial policy under the most favorable circumstances in the textbook cases for industrial policy (sectors with relatively large external economies of scale) had transformative economic effects. According to the authors, "our estimates imply that even under the optimistic assumption that governments maximize welfare and have full knowledge of the underlying economy, gains from optimal industrial policy are hardly transformative, ranging from an average across countries of 1.08% of GDP in our baseline analysis to 4.06% in the general environment with physical capital and input-output linkages." == See also == Green industrial policy Chaebol Developmental state Import substitution industrialization Infant industry argument Ministry of International Trade and Industry The Lucas Plan == References == == Sources == == External links == New Industrial and Innovation Policy, The World Bank Institute China's Political System, Mercator Institute for China Studies Interview with US secretary of commerce Penny Pritzke by the McKinsey Global Institute	Wikipedia/Industrial_policy
The illegal drug trade, drug trafficking, or narcotrafficking is a global black market dedicated to the cultivation, manufacture, distribution and sale of prohibited drugs. Most jurisdictions prohibit trade, except under license, of many types of drugs through the use of drug prohibition laws. The think tank Global Financial Integrity's Transnational Crime and the Developing World report estimates the size of the global illicit drug market between US$426 and US$652 billion in 2014, which is equal to the UK's national debt alone. With a world GDP of US$78 trillion in the same year, the illegal drug trade may be estimated as nearly 1% of total global trade. Consumption of illegal drugs is widespread globally, and it remains very difficult for local authorities to reduce the rates of drug consumption. == History == Prior to the 20th century, governments rarely made a major effort to proscribe recreational drug use, though several smoking bans were passed by authorities in Europe and Asia during the early modern era. Tobacco and opium were the two first drugs to be subject to prohibitory government legislation, with officials in New Spain, the Ottoman Empire, Germany, Austria and the Russian Empire passing laws against smoking tobacco; the government of the Qing dynasty issued edicts banning opium smoking in 1730, 1796 and 1800. Beginning in the 18th century, the East India Company (EIC) began to smuggle Indian opium to Chinese merchants, resulting in the creation of an illegal drug trade in China. By 1838, there were between four and 12 million opium addicts in China, and Qing officials responded by strengthening their suppression of the illegal opium trade. Incidents such as the destruction of opium at Humen led to the outbreak of the First Opium War between China and Britain in 1839; the 1842 Treaty of Nanking ending the war did not legalize the importation of opium into China, but Western merchants continued to smuggle the drug to Chinese merchants in ever-increasing amounts. The 1858 Treaty of Tianjin, which ended the Second Opium War, stipulated that the Qing government would open several ports to foreign trade, including opium. Western governments began prohibiting addictive drugs during the late 19th and early 20th centuries. In 1868, as a result of the increased use of opium in Britain, the British government restricted the sale of opium by implementing the 1868 Pharmacy Act. In the United States, control of opium remained under the control of individual US states until the introduction of the Harrison Act in 1914, after 12 international powers signed the International Opium Convention in 1912. Between 1920 and c. 1933, the Eighteenth Amendment to the United States Constitution banned alcohol in the United States. Prohibition proved almost impossible to enforce and resulted in the rise of organized crime, including the modern American Mafia, which identified enormous business opportunities in the manufacturing, smuggling and sale of illicit liquor. The beginning of the 21st century saw drug use increase in North America and Europe, with a particularly increased demand for marijuana and cocaine. As a result, international organized crime syndicates such as the Sinaloa Cartel and 'Ndrangheta have increased cooperation among each other in order to facilitate trans-Atlantic drug-trafficking. Use of another illicit drug, hashish, has also increased in Europe. Drug trafficking is widely regarded by lawmakers as a serious offense around the world. Penalties often depend on the type of drug (and its classification in the country into which it is being trafficked), the quantity trafficked, where the drugs are sold and how they are distributed. If the drugs are sold to underage people, then the penalties for trafficking may be harsher than in other circumstances. Drug smuggling carries severe penalties in many countries. Sentencing may include lengthy periods of incarceration, flogging and even the death penalty (in Singapore, Malaysia, Indonesia and elsewhere). In December 2005, Van Tuong Nguyen, a 25-year-old Australian drug smuggler, was hanged in Singapore after being convicted in March 2004. In 2010, two people were sentenced to death in Malaysia for trafficking 1 kilogram (2.2 lb) of cannabis into the country. Execution is mostly used as a deterrent, and many have called upon much more effective measures to be taken by countries to tackle drug trafficking; for example, targeting specific criminal organisations that are often also active in the smuggling of other goods (i.e. wildlife) and even people. In many cases, links between politicians and the criminal organisations have been proven to exist. In June 2021, Interpol revealed an operation in 92 countries that shut down 113,000 websites and online marketplaces selling counterfeit or illicit medicines and medical products a month earlier, led to the arrests of 227 people worldwide, recovered pharmaceutical products worth $23 million, and led to the seizure of approximately nine million devices and drugs, including large quantities of fake COVID-19 tests and face masks. == Societal effects == The countries of drug production and transit are some of the most affected by the trade, though countries receiving the illegally imported substances are also adversely affected. For example, Ecuador has absorbed up to 300,000 refugees from Colombia who are running from guerrillas, paramilitaries and drug lords. While some applied for asylum, others are still illegal immigrants. The drugs that pass from Colombia through Ecuador to other parts of South America create economic and social problems. Honduras, through which an estimated 79% of cocaine passes on its way to the United States, had, as of 2011, the highest murder rate in the world. According to the International Crisis Group, the most violent regions in Central America, particularly along the Guatemala–Honduras border, are highly correlated with an abundance of drug trafficking activity. === Violent crime === In several countries, the illegal drug trade is thought to be directly linked to violent crimes such as murder and gun violence. This is especially true in all developing countries, such as Honduras, but is also an issue for many developed countries worldwide. In the late 1990s in the United States, the Federal Bureau of Investigation estimated that 5% of murders were drug-related. In Colombia, drug violence can be caused by factors such as the economy, poor governments, and no authority within law enforcement. After a crackdown by US and Mexican authorities in the first decade of the 21st century as part of tightened border security in the wake of the September 11 attacks, border violence inside Mexico surged. The Mexican government estimated that 90% of the killings were drug-related. A report by the UK government's Drug Strategy Unit that was leaked to the press, stated that due to the expensive price of highly addictive drugs heroin and cocaine, drug use was responsible for the great majority of crime, including 85% of shoplifting, 70–80% of burglaries and 54% of robberies. It concluded "[t]he cost of crime committed to support illegal cocaine and heroin habits amounts to £16 billion a year in the UK" == Drug trafficking routes == === Africa === ==== East and South ==== Heroin is increasingly trafficked from Afghanistan to Europe and America through eastern and southern African countries. This path is known as the "southern route" or "smack track". Repercussions of this trade include burgeoning heroin use and political corruption among intermediary African nations. ==== West ==== Cocaine produced in Colombia and Bolivia has increasingly been shipped via West Africa (especially in Nigeria, Cape Verde, Guinea-Bissau, Cameroon, Mali, Benin, Togo, and Ghana). The money is often laundered in countries such as Nigeria, Ghana, and Senegal. According to the Africa Economic Institute, the value of illicit drug smuggling in Guinea-Bissau is almost twice the value of the country's GDP. Police officers are often bribed. A police officer's normal monthly wage of $93 is less than 2% of the value of 1 kilogram (2.2 lb) of cocaine (€7000 or $8750). The money can also be laundered using real estate. A house is built using illegal funds, and when the house is sold, legal money is earned. When drugs are sent over land, through the Sahara, the drug traders have been forced to cooperate with terrorist organizations, such as Al-Qaeda in Islamic Maghreb. === Asia === Drugs in Asia traditionally traveled the southern routes – the main caravan axes of Southeast Asia and Southern China – and include the former opium-producing countries of Thailand, Iran, and Pakistan. After the 1990s, particularly after the end of the Cold War (1991), borders were opened and trading and customs agreements were signed so that the routes expanded to include China, Central Asia, and Russia. There are, therefore, diversified drug trafficking routes available today, particularly in the heroin trade and these thrive due to the continuous development of new markets. A large amount of drugs are smuggled into Europe from Asia. The main sources of these drugs are Afghanistan, along with countries that constituted the so-called Golden Crescent. From these producers, drugs are smuggled into the West and Central Asia to its destinations in Europe and the United States. Iran is now a common route for smugglers, having been previously a primary trading route, due to its large-scale and costly war against drug trafficking. The Border Police Chief of Iran said that his country "is a strong barrier against the trafficking of illegal drugs to Caucasus, especially the Republic of Azerbaijan." The drugs produced by the Golden Triangle of Myanmar, Laos, and Thailand, on the other hand, pass through the southern routes to feed the Australian, US, and Asian markets. === South America === Venezuela has been a path to the United States and Europe for illegal drugs originating in Colombia, through Central America, Mexico and Caribbean countries such as Haiti, the Dominican Republic, and Puerto Rico. According to the United Nations, cocaine trafficking through Venezuela increased from 2002 to 2008. In 2005, the government of Hugo Chávez severed ties with the United States Drug Enforcement Administration (DEA), accusing its representatives of spying. Following the departure of the DEA from Venezuela and the expansion of DEA's partnership with Colombia in 2005, Venezuela became more attractive to drug traffickers. Between 2008 and 2012, Venezuela's cocaine seizure ranking among other countries declined, going from being ranked fourth in the world for cocaine seizures in 2008 to sixth in the world in 2012. On 18 November 2016, following what was known as the Narcosobrinos incident, Venezuelan President Nicolás Maduro's two nephews were found guilty of trying to ship drugs into the United States so they could "obtain a large amount of cash to help their family stay in power". According to a research conducted by the Israel-based Abba Eban Institute as part of an initiative called Janus Initiative, the main routes that Hezbollah uses for smuggling drugs are from Colombia, Venezuela and Brazil into West Africa and then transported through northern Africa into Europe. This route serves Hezbollah in making a profit in the cocaine smuggling market in order to leverage it for their activities. == Online trafficking == Drugs are increasingly traded online on the dark web on darknet markets. Internet-based drug trafficking is the global distribution of narcotics, making extensive use of technology. Similarly, the use of the Internet for the illegal trafficking of two controlled categories of drugs can also be identified as Internet-related drug trafficking. The platform Silk Road provided goods and services to 100,000 buyers before being shut down in October 2013. This prompted the creation of new platforms such as Silk Road 2.0, which were also shut down. == Profits == Statistics about profits from the drug trade are largely unknown due to its illicit nature. An online report published by the UK Home Office in 2007 estimated the illicit drug market in the UK at £4–6.6 billion a year. In December 2009, United Nations Office on Drugs and Crime Executive Director Antonio Maria Costa claimed illegal drug money saved the banking industry from collapse. He claimed he had seen evidence that the proceeds of organized crime were "the only liquid investment capital" available to some banks on the brink of collapse during 2008. He said that a majority of the $352 billion (£216bn) of drug profits was absorbed into the economic system as a result: "In many instances, the money from drugs was the only liquid investment capital. In the second half of 2008, liquidity was the banking system's main problem and hence liquid capital became an important factor ... Inter-bank loans were funded by money that originated from the drugs trade and other illegal activities...there were signs that some banks were rescued that way". Costa declined to identify countries or banks that may have received any drug money, saying that would be inappropriate because his office is supposed to address the problem, not apportion blame. Though street-level drug sales are widely viewed as lucrative, a study by Sudhir Venkatesh suggested that many low-level employees receive low wages. In a study he made in the 1990s working closely with members of the Black Gangster Disciple Nation in Chicago, he found that one gang (essentially a franchise) consisted of a leader (a college graduate named J.T.), three senior officers, and 25 to 75 street level salesmen ('foot soldiers') depending on season. Selling crack cocaine, they took in approximately $32,000 per month over a six-year period. This was spent as follows: $5,000 to the board of twenty directors of the Black Gangster Disciple Nation, who oversaw 100 such gangs for approximately $500,000 in monthly income. Another $5,000 monthly was paid for cocaine, and $4,000 for other non-wage expenses. J.T. took $8,500 monthly for his own salary. The remaining $9,500 monthly went to pay the employees a $7 per hour wage for officers and a $3.30 per hour wage for foot soldiers. Contrary to a popular image of drug sales as a lucrative profession, many of the employees were living with their mothers by necessity. Despite this, the gang had four times as many unpaid members who dreamed of becoming foot soldiers. == Impact of free trade == There are several arguments on whether or not free trade has a correlation to an increased activity in the illicit drug trade. Currently, the structure and operation of the illicit drug industry is described mainly in terms of an international division of labor. Free trade can open new markets to domestic producers who would otherwise resort to exporting illicit drugs. Additionally, extensive free trade among states increases cross-border drug enforcement and coordination between law enforcement agencies in different countries. However, free trade also increases the sheer volume of legal cross-border trade and provides cover for drug smuggling—by providing ample opportunity to conceal illicit cargo in legal trade. While international free trade continues to expand the volume of legal trade, the ability to detect and interdict drug trafficking is severely diminished. Towards the late 1990s, the top ten seaports in the world processed 33.6 million containers. Free trade has fostered integration of financial markets and has provided drug traffickers with more opportunities to launder money and invest in other activities. This strengthens the drug industry while weakening the efforts of law enforcement to monitor the flow of drug money into the legitimate economy. Cooperation among cartels expands their scope to distant markets and strengthens their abilities to evade detection by local law enforcement. Additionally, criminal organizations work together to coordinate money-laundering activities by having separate organizations handle specific stages of laundering process. One organization structures the process of how financial transactions will be laundered, while another criminal group provides the "dirty" money to be cleaned. By fostering expansion of trade and global transportation networks, free trade encourages cooperation and formation of alliances among criminal organizations across different countries. The drug trade in Latin America emerged in the early 1930s. It saw significant growth in the Andean countries, including Peru, Bolivia, Chile, Ecuador, Colombia and Venezuela. The underground market in the early half of the 20th century mainly had ties to Europe. After World War II, the Andean countries saw an expansion of trade, specifically with cocaine. == Drug trafficking by country == === Syria === The Ba'athist government of Syria ruled by the Al-Assad family is known for its extensive involvement in drug trade since the 1970s. As of 2022, the Syrian government financed the biggest multi-billion dollar drug trade in the world, mostly focused on an illegal drug known as Captagon, making it the world's largest narco-state. Its revenues from Captagon smuggling alone is estimated to worth 57 billion dollars annually in 2022, which is approximately thrice the total trade of all Mexican cartels. General Maher al-Assad, younger brother of Syrian dictator Bashar al-Assad and commander of the Fourth Armoured Division, directly supervised the production, smuggling and profiteering of the drug business. Already suffering from severe financial problems as a result of corruption and civil war, profits from Captagon are said to be the "lifeline" of the Assad regime, through which it earned more than 90% of its total revenue. The smugglers receive direct training from Syrian military to successfully conduct trafficking operations. Republican Guard, commanded by Maher al-Assad was one of the main Ba'athist military divisions that was engaged in perpetrating brutal crackdowns and mass violence against protestors across the country. In 2018, Bashar al-Assad assigned Maher as the commander of the 4th Armoured Division, a military unit that supervised the Assad regime's criminal enterprises like smuggling, drug trafficking, narcotics production and plunder of goods and resources. Under Maher's supervision, the 4th Armoured Division expanded captagon production and trafficking from Syria into a "business model controlled by the regime". In 2022, 90% of all captagon pills manufactured in Syria exported by drug cartels affiliated with Assad regime arrived at its customer destinations across the world. Although hundreds of millions of pills were intercepted and seized by police forces, these accounted only for 10% of the total captagon exports of the drug cartels linked to the Assad regime. In 2020, Italian police seized 84 million captagon pills originating from Syrian ports while intercepting a single shipment. In June 2023, US State Department's Bureau of Near Eastern Affairs published a detailed report to the US Congress, elucidating a strategy to eliminate the narcotics production, drug trafficking and drug cartel networks affiliated with the Assad regime and Hezbollah. A joint investigation conducted by Organized Crime and Corruption Reporting Project (OCCRP) and BBC News Arabic published a documentary in June 2023, revealing further details about the activities of regime officials, Ba'athist military commanders and Assad family members in their involvement in Syria's drug cartel. The investigation found that Lebanese criminal and drug kingpin Hassan Daqou collaborated with Syria's Fourth Armoured Division on trafficiking billions of dollars of drugs, under the command of General Ghassan Bilal, the right-hand man of Maher al-Assad. The report also unearthed Hezbollah's close participation in the drug production and smuggling networks. The Fourth Armoured Division, being an elite military unit permitted to move freely across Assad regime's checkpoints, oversees the smuggling operations from Syria, including the trafficking of cash, weapons, illegal drugs, etc. Days after the publication of the joint BBC-OCCRP documentary; Assad government banned all activities of BBC media outlets and entry of affiliated media personnel in Syria. The extensive involvement of Syrian Armed Forces in sponsorship of drug production and trade has led to pervasive drug addiction problems amongst pro-Assad soldiers. In many instances, military officials encourage the soldiers to consume Captagon and other illegal drugs, leading to overdose or drug abuse. Pro-Assad fighters in the National Defence Forces and Hezbollah also consume illegal drugs in large quantities. In July 2023, German police busted a major captagon network run by two Syrian-born men in southern German state of Bavaria. Assad regime sponsors the largest Captagon production network in Syria; which is the source of about 80% of total captagon supply in the world. In an investigative report published by The Insider news-outlet in 2024, journalist Yuriy Matsarsky stated:"...Captagon produced in underground labs—and in actual Syrian pharmaceutical facilities—is distributed to the fighters of Bashar Assad's army. Interestingly, however, the quantities the country produces far exceed its own military’s demand. ... By some estimates, this business gives Syria more money than its entire legal export, and the regime constantly works to increase its profits, primarily by expanding its market reach. To this end, criminal gangs associated with Damascus or Hezbollah have built distribution networks for Captagon in countries where the drug was not previously popular." === United States === ==== Background ==== The effects of the illegal drug trade in the United States can be seen in a range of political, economic and social aspects. Increasing drug related violence can be tied to the racial tension that arose during the late 20th century along with the political upheaval prevalent throughout the 1960s and 70s. The second half of the 20th century was a period when increased wealth, and increased discretionary spending, increased the demand for illicit drugs in certain areas of the United States. Large-scale drug trafficking is one of the capital crimes, and may result in a death sentence prescribed at the federal level when it involves murder. ==== Political impact ==== A large generation, the baby boomers, came of age in the 1960s. Their social tendency to confront the law on specific issues, including illegal drugs, overwhelmed the understaffed judicial system. The federal government attempted to enforce the law, but with meager effect. Marijuana was a popular drug seen through the Latin American trade route in the 1960s. Cocaine became a major drug product in the later decades. Much of the cocaine is smuggled from Colombia and Mexico via Jamaica. This led to several administrations combating the popularity of these drugs. Due to the influence of this development on the US economy, the Reagan administration began "certifying" countries for their attempts at controlling drug trafficking. This allowed the United States to intervene in activities related to illegal drug transport in Latin America. Continuing into the 1980s, the United States instated stricter policy pertaining to drug transit through sea. As a result, there was an influx in drug-trafficking across the Mexico–US border, which increased the drug cartel activity in Mexico. By the early 1990s, so much as 50% of the cocaine available in the United States market originated from Mexico, and by the 2000s, over 90% of the cocaine in the United States was imported from Mexico. In Colombia, however, there was a fall of the major drug cartels in the mid-1990s. Visible shifts occurred in the drug market in the United States. Between 1996 and 2000, US cocaine consumption dropped by 11%. In 2008, the US government initiated another program, known as the Merida Initiative, to help combat drug trafficking in Mexico. This program increased US security assistance to $1.4 billion over several years, which helped supply Mexican forces with "high-end equipment from helicopters to surveillance technology". Despite US aid, Mexican "narcogangs" continue to outnumber and outgun the Mexican Army, allowing for continued activities of drug cartels across the US–Mexico border. ==== Social impacts ==== Although narcotics are illegal in the US, they have become integrated into the nation's culture and are seen as a recreational activity by sections of the population. Illicit drugs are considered to be a commodity with strong demand, as they are typically sold at a high value. This high price is caused by a combination of factors that include the potential legal ramifications that exist for suppliers of illicit drugs and their high demand. Despite the constant effort by politicians to win the war on drugs, the US is still the world's largest importer of illegal drugs. Throughout the 20th century, narcotics other than cocaine also crossed the Mexican border, meeting the US demand for alcohol during the 1920s Prohibition, opiates in the 1940s, marijuana in the 1960s, and heroin in the 1970s. Most of the US imports of drugs come from Mexican drug cartels. In the United States, around 195 cities have been infiltrated by drug trafficking that originated in Mexico. An estimated $10bn of the Mexican drug cartel's profits come from the United States, not only supplying the Mexican drug cartels with the profit necessary for survival, but also furthering America's economic dependence on drugs. ===== Demographics ===== With a large wave of immigrants in the 1960s and onwards, the United States saw an increased heterogeneity in its public. In the 1980s and 1990s, drug-related homicide was at a record high. This increase in drug violence became increasingly tied to these ethnic minorities. Though the rate of violence varied tremendously among cities in America, it was a common anxiety in communities across urban America. An example of this could be seen in Miami, a city with a host of ethnic enclaves. Between 1985 and 1995, the homicide rate in Miami was one of the highest in the nation—four times the national homicide average. This crime rate was correlated with regions with low employment and was not entirely dependent on ethnicity. The baby boomer generation also felt the effects of the drug trade in their increased drug use from the 1960s to 1980s. Along with substance use, criminal involvement, suicide and murder were also on the rise. Due to the large amount of baby boomers, commercial marijuana use was on the rise. This increased the supply and demand for marijuana during this time period. === Mexico === ==== Political influences ==== Corruption in Mexico has contributed to the domination of Mexican cartels in the illicit drug trade. Since the beginning of the 20th century, Mexico's political environment allowed the growth of drug-related activity. The loose regulation over the transportation of illegal drugs and the failure to prosecute known drug traffickers and gangs increased the growth of the drug industry. Toleration of drug trafficking has undermined the authority of the Mexican government and has decreased the power of law enforcement officers in regulation over such activities. These policies of tolerance fostered the growing power of drug cartels in the Mexican economy and have made drug traders wealthier. Many states in Mexico lack policies that establish stability in governance. There also is a lack of local stability, as mayors cannot be re-elected. This requires electing a new mayor each term. Drug gangs have manipulated this, using vacuums in local leadership to their own advantage. In 1929, the Institutional Revolutionary Party (PRI) was formed to resolve the chaos resulting from the Mexican Revolution. Over time, this party gained political influence and had a major impact on Mexico's social and economic policies. The party created ties with various groups as a power play in order to gain influence, and as a result created more corruption in the government. One such power play was an alliance with drug traffickers. This political corruption obscured justice, making it difficult to identify violence when it related to drugs. By the 1940s, the tie between the drug cartels and the PRI had solidified. This arrangement created immunity for the leaders of the drug cartels and allowed drug trafficking to grow under the protection of the government officials. During the 1990s, the PRI lost some elections to the new National Action Party (PAN). Chaos again emerged as elected government in Mexico changed drastically. As the PAN party took control, drug cartel leaders took advantage of the ensuing confusion and used their existing influence to further gain power. Instead of negotiating with the central government as was done with the PRI party, drug cartels utilized new ways to distribute their supply and continued operating through force and intimidation. As Mexico became more democratized, the corruption fell from a centralized power to the local authorities. Cartels began to bribe local authorities, thus eliminating the structure and rules placed by the government—giving cartels more freedom. As a response, Mexico saw an increase in violence caused by drug trafficking. The corruption cartels created resulted in distrust of government by the Mexican public. This distrust became more prominent after the collapse of the PRI party. In response, the presidents of Mexico, in the late twentieth century and early twenty-first century, implemented several different programs relating to law enforcement and regulation. In 1993, President Salinas created the National Institute for the Combat of Drugs in Mexico. From 1995 to 1998, President Zedillo established policies regarding increased punishment of organized crime, allowing "[wire taps], protected witnesses, covert agents and seizures of goods", and increasing the quality of law enforcement at the federal level. From 2001 to 2005, President Vicente Fox created the Federal Agency of Investigation. These policies resulted in the arrests of major drug-trafficking bosses: ==== Mexico's economy ==== Over the past few decades, drug cartels have become integrated into Mexico's economy. Approximately 500 cities are directly engaged in drug trafficking and nearly 450,000 people are employed by drug cartels. Additionally, the livelihood of 3.2 million people is dependent on the drug cartels. Between local and international sales, such as to Europe and the United States, drug cartels in Mexico see a $25–30 bn yearly profit, a great deal of which circulates through international banks such as HSBC. Drug cartels are fundamental in local economics. A percentage of the profits seen from the trade are invested in the local community. Such profits contribute to the education and healthcare of the community. While these cartels bring violence and hazards into communities, they create jobs and provide income for its many members. ==== Culture of drug cartels ==== Major cartels saw growth due to a prominent set culture of Mexican society that created the means for drug capital. One of the sites of origin for drug trafficking within Mexico, was the state of Michoacán. In the past, Michoacán was mainly an agricultural society. This provided an initial growth of trade. Industrialization of rural areas of Mexico facilitated a greater distribution of drugs, expanding the drug market into different provinces. Once towns became industrialized, cartels such as the Sinaloa Cartel started to form and expand. The proliferation of drug cartel culture largely stemmed from the ranchero culture seen in Michoacán. Ranchero culture values the individual as opposed to the society as a whole. This culture fostered the drug culture of valuing the family that is formed within the cartel. This ideal allowed for greater organization within the cartels. Gangs play a major role in the activity of drug cartels. MS-13 and the 18th Street gang are notorious for their contributions and influence over drug trafficking throughout Latin America. MS-13 has controlled much of the activity in the drug trade spanning from Mexico to Panama. Female involvement is present in the Mexican drug culture. Although females are not treated as equals to males, they typically hold more power than their culture allows and acquire some independence. The increase in power has attracted females from higher social classes. Financial gain has also prompted women to become involved in the illegal drug market. Many women in the lower levels of major drug cartels belong to a low economic class. Drug trafficking offers women an accessible way to earn income. Females from all social classes have become involved in the trade due to outside pressure from their social and economic environments. === Colombia === ==== Political ties ==== It was common for smugglers in Colombia to import liquor, alcohol, cigarettes and textiles, while exporting cocaine. Personnel with knowledge of the terrain were able to supply the local market while also exporting a large amount of product. The established trade initially involved Peru, Bolivia, Colombia, Venezuela and Cuba. Peasant farmers produced coca paste in Peru and Bolivia, while Colombian smugglers would process the coca paste into cocaine in Colombia, and trafficked product through Batista's Cuba. This trade route established ties between Cuban and Colombian organized crime. From Cuba, cocaine would be transported to Miami, Florida; and Union City, New Jersey. Quantities of the drug were then smuggled throughout the US. The international drug trade created political ties between the involved countries, encouraging the governments of the countries involved to collaborate and instate common policies to eradicate drug cartels. Cuba stopped being a center for transport of cocaine following the Cuban Revolution and the establishment of Fidel Castro's communist government in 1959. As a result, Miami and Union City became the sole locations for trafficking. The relations between Cuban and Colombian organized crime remained strong until the 1970s, when Colombian cartels began to vie for power. In the 1980s and 90s, Colombia emerged as a key contributor of the drug trade industry in the Western Hemisphere. While the smuggling of drugs such as marijuana, poppy, opium and heroin became more ubiquitous during this time period, the activity of cocaine cartels drove the development of the Latin American drug trade. The trade emerged as a multinational effort as supplies (i.e. coca plant substances) were imported from countries such as Bolivia and Peru, were refined in Colombian cocaine labs and smuggled through Colombia, and exported to countries such as the US. ==== Colombia's economy ==== Colombia has had a significant role in the illegal drug trade in Latin America. While active in the drug trade since the 1930s, Colombia's role in the drug trade did not truly become dominant until the 1970s. When Mexico eradicated marijuana plantations, demand stayed the same. Colombia met much of the demand by growing more marijuana. Grown in the strategic northeast region of Colombia, marijuana soon became the leading cash crop in Colombia. This success was short-lived due to anti-marijuana campaigns that were enforced by the US military throughout the Caribbean. Instead, drug traffickers in Colombia continued their focus on exporting cocaine. Having been an export of Colombia since the early 1950s, cocaine remained popular for a host of reasons. Colombia's location facilitated its transportation from South America into Central America, and then to its destination of North America. This continued into the 1990s, when Colombia remained the chief exporter of cocaine. The business of drug trafficking can be seen in several stages in Colombia towards the latter half of the 20th century. Colombia served as the dominant force in the distribution and sale of cocaine by the 1980s. As drug producers gained more power, they became more centralized and organized into what became drug cartels. Cartels controlled the major aspects of each stage in the traffic of their product. Their organization allowed cocaine to be distributed in great amounts throughout the United States. By the late 1980s, intra-industry strife arose within the cartels. This stage was marked by increased violence as different cartels fought for control of export markets. Despite this strife, this power struggle led to then having multiple producers of coca leaf farms. This in turn caused an improvement in quality control and reduction of police interdiction in the distribution of cocaine. This also led to cartels attempting to repatriate their earnings which would eventually make up 5.5% of Colombia's GDP. This drive to repatriate earnings led to the pressure of legitimizing their wealth, causing an increase in violence throughout Colombia. Throughout the 1980s, estimates of illegal drug value in Colombia ranged from $2bn to $4bn. This made up about 7–10% of the $36bn estimated Gross National Product (GNP) of Colombia during this decade. In the 1990s, the estimates of the illegal drug value remained roughly within the same range (~$2.5bn). As the Colombian GNP rose throughout the 1990s ($68.5bn in 1994 and $96.3bn in 1997), illegal drug values began to comprise a decreasing fraction of the national economy. By the early 1990s, although Colombia led in the exportation of cocaine, it found increasing confrontations within its state. These confrontations were primarily between cartels and government institutions. This led to a decrease in the drug trade's contribution to the GDP of Colombia; dropping from 5.5% to 2.6%. Though a contributor of wealth, the distribution of cocaine has had negative effects on the socio-political situation of Colombia and has weakened its economy as well. ==== Social impacts ==== By the 1980s, Colombian cartels became the dominant cocaine distributors in the US. This led to the spread of increased violence throughout both Latin America and Miami. In the 1980s, two major drug cartels emerged in Colombia: the Medellín and Cali groups. Throughout the 1990s however, several factors led to the decline of these major cartels and to the rise of smaller Colombian cartels. The US demand for cocaine dropped while Colombian production rose, pressuring traffickers to find new drugs and markets. In this time period, there was an increase in activity of Caribbean cartels that led to the rise of an alternate route of smuggling through Mexico. This led to the increased collaboration between major Colombian and Mexican drug traffickers. Such drastic changes in the execution of drug trade in Colombia paired with the political instabilities and rise of drug wars in Medellin and Cali, gave way for the rise of the smaller Colombian drug trafficking organizations (and the rise of heroin trade). As the drug trade's influence over the economy increased, drug lords and their networks grew in their power and influence in society. The occurrences in drug-related violence increased during this time period as drug lords fought to maintain their control in the economy. Typically, a drug cartel had support networks that consisted of a number of individuals. These people individuals ranged from those directly involved in the trade (such as suppliers, chemists, transporters, smugglers, etc.) as well as those involved indirectly in the trade (such as politicians, bankers, police, etc.). As these smaller Colombian drug cartels grew in prevalence, several notable aspects of the Colombian society gave way for further development of the Colombian drug industry. For example, until the late 1980s, the long-term effects of the drug industry were not realized by much of society. Additionally, there was a lack of regulation in prisons where captured traffickers were sent. These prisons were under-regulated, under-funded, and under-staffed, which allowed for the formation of prison gangs, for the smuggling of arms/weapons/etc., for feasible escapes, and even for captured drug lords to continue running their businesses from prison. === Western Balkans === Since the beginning of the 21st century, the global drug trade network witnessed the emergence of criminal groups from the Western Balkans as crucial players. These groups have moved up from being small-time crooks to major drug distributors. Most of these organized crime groups belonged to Albania, Bosnia and Herzegovina, Kosovo, Montenegro, North Macedonia and Serbia. The illicit trade activities of the Balkans primarily involved Latin America, Western Europe, South Africa, Australia and Turkey. These groups keep their operations outside the Western Balkans, while staying connected to their homeland. Within the network of these groups, the dealmakers operate in a proximity of supply sources and the distribution networks are managed by foot soldiers. However, the bosses of the organized criminal groups stay and keep their wealth in the United Arab Emirates (UAE). The UAE is amongst the enablers of global corruption and illicit financial flows. Analysts have claimed that criminal actors across the world either operate from or through the Emirates. It was a haven for criminals, where the risk for illicit activities remains low. For the Balkan criminals, a growing trend was to relocate to the UAE, which became an attraction to dirty money and kingpins from several European nations and the United Kingdom. Besides, Dubai was also dubbed as the "new Costa del Crime", replacing the crime hideaway of Spain, the Costa del Sol. The UAE had poor regulations for money laundering and for screening of suspicious transactions. The lack of regulations against illicit financial activities prompted the Financial Action Task Force (FATF) to place the Gulf country on its grey list in March 2022. Consequently, the Emirates' remained a safe option for the criminals. Nearly two-thirds of the Albanian criminal groups, who were active in trade of drugs like cocaine, were believed to be hiding in the UAE. One of such individuals, Eldi Dizdari was accused of international drug trafficking and was living in Dubai. Research revealed that these criminals invested huge amounts in the Emirates' real estate and other economical sectors to live there. Another trafficker of cocaine from Bosnia, Edin Gačanin was living in the UAE using his extensive profits to buy property and protection in the country. Dubbed as the "European Escobar", he connected the supply network between production markets of Latin America and consumer markets of Western European. He was able to evade the arrest and investigations, including by the US Drug Enforcement Administration, by seeking shelter in the Emirates. == Trade in specific drugs == === Cannabis === While the recreational use of (and consequently the distribution of) cannabis is illegal in most countries throughout the world, recreational distribution is legal in some countries, such as Canada, and medical distribution is permitted in some places, such as 38 of the 50 US states (although importation and distribution is still federally prohibited). Beginning in 2014, Uruguay became the first country to legalize cultivation, sale, and consumption of cannabis for recreational use for adult residents. In 2018, Canada became the second country to legalize use, sale and cultivation of cannabis. The first few weeks were met with extremely high demand, most shops being out of stock after operating for only four days. Cannabis use is tolerated in some areas, most notably the Netherlands, which has legalized the possession and licensed sale (but not cultivation) of the drug. Many nations have decriminalized the possession of small amounts of marijuana. Due to the hardy nature of the cannabis plant, marijuana is grown all across the world; today, it is the world's most popular illegal drug with the highest level of availability. Cannabis is grown legally in many countries for industrial, non-drug use (known as hemp) as well. Cannabis-hemp may also be planted for other non-drug domestic purposes, such as seasoning that occurs in Aceh. The demand for cannabis around the world, coupled with the drug's relative ease of cultivation, makes the illicit cannabis trade one of the primary ways in which organized criminal groups finance many of their activities. In Mexico, for example, the illicit trafficking of cannabis is thought to constitute the majority of many of the cartels' earnings, and the main way in which the cartels finance many other illegal activities; including the purchase of other illegal drugs for trafficking, and for acquiring weapons that are ultimately used to commit murders (causing a burgeoning in the homicide rates of many areas of the world, but particularly Latin America). Some studies show that the increased legalization of cannabis in the United States (beginning in 2012 with Washington Initiative 502 and Colorado Amendment 64) has led Mexican cartels to smuggle less cannabis in exchange for more heroin. === Alcohol === Alcohol, in the context of alcoholic beverages rather than denatured alcohol, is illegal in a number of Muslim countries, such as Saudi Arabia; this has resulted in a thriving illegal trade in alcohol. The manufacture, sale, transportation, import, and export of alcoholic beverages were illegal in the United States during the time known as the Prohibition in the 1920s and early 1930s. === Heroin === In the 1950s and 1960s, most heroin was produced in Turkey and transshipped in France via the French Connection crime ring, with much of it arriving in the United States. This resulted in the record setting April 26, 1968 seizure of 246 lb (111.6 kg) of heroin smuggled in a vehicle on the SS France (1960) ocean liner. By the time of The French Connection (1971 film), this route was being supplanted. Then, until c. 2004, the majority of the world's heroin was produced in an area known as the Golden Triangle. However, by 2007, 93% of the opiates on the world market originated in Afghanistan. This amounted to an export value of about US$4 billion, with a quarter being earned by opium farmers and the rest going to district officials, insurgents, warlords and drug traffickers. Another significant area where poppy fields are grown for the manufacture of heroin is Mexico. In November 2023, a U.N report showed that in the entirety of Afghanistan, poppy cultivation dropped by over 95%, removing it from its place as being the world's largest opium producer. According to the United States Drug Enforcement Administration, the price of heroin is typically valued 8 to 10 times that of cocaine on American streets, making it a high-profit substance for smugglers and dealers. In Europe (except the transit countries Portugal and the Netherlands), for example, a purported gram of street heroin, usually consisting of 700–800 mg of a light to dark brown powder containing 5–10% heroin base, costs €30–70, making the effective value per gram of pure heroin €300–700. Heroin is generally a preferred product for smuggling and distribution—over unrefined opium due to the cost-effectiveness and increased efficacy of heroin. Because of the high cost per volume, heroin is easily smuggled. A US quarter-sized (2.5 cm) cylindrical vial can contain hundreds of doses. From the 1930s to the early 1970s, the so-called French Connection supplied the majority of US demand. Allegedly, during the Vietnam War, drug lords such as Ike Atkinson used to smuggle hundreds of kilograms of heroin to the US in coffins of dead American soldiers (see Cadaver Connection). Since that time it has become more difficult for drugs to be imported into the US than it had been in previous decades, but that does not stop the heroin smugglers from getting their product across US borders. Purity levels vary greatly by region with Northeastern cities having the most pure heroin in the United States. On 17 October 2018 police in Genoa, Italy discovered 270 kg (600 lb) of heroin hidden in a ship coming from the Iranian southern port of Bandar Abbas. The ship had already passed and stopped at Hamburg in Germany and Valencia in Spain. Penalties for smuggling heroin or morphine are often harsh in most countries. Some countries will readily hand down a death sentence (e.g. Singapore) or life in prison for the illegal smuggling of heroin or morphine, which are both internationally Schedule I drugs under the Single Convention on Narcotic Drugs. In May 2021, Romania seized 1.4 tonnes of heroin at Constanța port of a shipment from Iran that was headed for Western Europe. === Methamphetamine === Methamphetamine is another popular drug among distributors. Three common street names are "meth", "crank", and "ice". According to the Community Epidemiology Work Group, the number of clandestine methamphetamine laboratory incidents reported to the National Clandestine Laboratory Database decreased from 1999 to 2009. During this period, methamphetamine lab incidents increased in mid-western States (Illinois, Michigan, Missouri, and Ohio), and in Pennsylvania. In 2004, more lab incidents were reported in Missouri (2,788) and Illinois (1,058) than in California (764). In 2003, methamphetamine lab incidents reached new highs in Georgia (250), Minnesota (309), and Texas (677). There were only seven methamphetamine lab incidents reported in Hawaii in 2004, though nearly 59 percent of substance use treatment admissions (excluding alcohol) were for primary methamphetamine use during the first six months of 2004. As of 2007, Missouri leads the United States in drug-lab seizures, with 1,268 incidents reported. Often canine units are used for detecting rolling meth labs which can be concealed on large vehicles, or transported on something as small as a motorcycle. These labs are more difficult to detect than stationary ones, and can often be obscured among legal cargo in big trucks. Methamphetamine is sometimes used intravenously, placing users and their partners at risk for transmission of HIV and hepatitis C. "Meth" can also be inhaled, most commonly vaporized on aluminum foil or in a glass pipe. This method is reported to give "an unnatural high" and a "brief intense rush". In South Africa, methamphetamine is called "tik" or "tik-tik". Known locally as "tik", the substance was virtually unknown as late as 2003. Now, it is the country's main addictive substance, even when alcohol is included. Children as young as eight are abusing the substance, smoking it in crude glass vials made from light bulbs. Since methamphetamine is easy to produce, the substance is manufactured locally in staggering quantities. The government of North Korea currently operates methamphetamine production facilities. There, the drug is used as medicine because no alternatives are available; it also is smuggled across the Chinese border. The Australian Crime Commission's illicit drug data report for 2011–2012 stated that the average strength of crystal methamphetamine doubled in most Australian jurisdictions within a 12-month period, and the majority of domestic laboratory closures involved small "addict-based" operations. === Temazepam === Temazepam, a strong hypnotic benzodiazepine, is illicitly manufactured in clandestine laboratories (called jellie labs) to supply the increasingly high demand for the drug internationally. Many clandestine temazepam labs are in Eastern Europe. The labs manufacture temazepam by chemically altering diazepam, oxazepam or lorazepam. "Jellie labs" have been identified and shut down in Russia, Ukraine, Latvia and Belarus. === Cocaine === Cocaine is a highly trafficked drug. In 2017 the value of the global market for illicit cocaine was estimated at between $94 and $143 billion. In 2022, illicit sales in Europe were estimated at $11.1 billion. In 2020, almost 2,000 tons of cocaine were produced for distribution through illicit markets. === Fentanyl === Fentanyl, a synthetic opioid, is 20 to 40 times more potent than heroin and 100 times more potent than morphine; its primary clinical utility is in pain management for cancer patients and those recovering from painful surgeries. Illicit use of fentanyl continues to fuel an epidemic of synthetic opioid drug overdose deaths in the US. From 2011 to 2021, synthetic opioid deaths per year increased from 2,600 overdoses to 70,601. Since 2018, fentanyl and its analogues have been responsible for most drug overdose deaths in the US, causing over 71,238 deaths in 2021. Fentanyl is often mixed, cut, or ingested alongside other drugs, including cocaine and heroin. The fentanyl epidemic has erupted in a highly acrimonious dispute between the US and Mexican governments. While US officials blame the flood of fentanyl crossing the border primarily on Mexican crime groups, President Andrés Manuel López Obrador insists that the main source of this synthetic drug is Asia. He believes that the crisis of a lack of family values in the US drives people to use the drug. == See also == Allegations of CIA drug trafficking Arguments for and against drug prohibition Corruption Counterfeit medications Counterfeit money Environmental impact of illicit drug production Rum running Illicit cigarette trade Human trafficking Arms trafficking Wildlife trafficking Illegal organ trade Drug liberalization Drug trafficking organizations Golden Crescent Golden Triangle (Southeast Asia) Illegal drug trade in the Indian Ocean region Maritime drug smuggling into Australia Narco-capitalism Narco-state Narcoterrorism Organized crime Operation Show Me How === International coordination === International Day Against Drug Abuse and Illicit Trafficking Interpol United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances == References == == External links == Official website of the United Nations Office on Drugs and Crime (UNODC) Illicit drug issues by country, by the CIA. Archived 2010-12-29 at the Wayback Machine.	Wikipedia/Drug-dealers
Feminist legal theory, also known as feminist jurisprudence, is based on the belief that the law has been fundamental in women's historical subordination. Feminist jurisprudence the philosophy of law is based on the political, economic, and social inequality of the sexes and feminist legal theory is the encompassment of law and theory connected. The project of feminist legal theory is twofold. First, feminist jurisprudence seeks to explain ways in which the law played a role in women's subordinate status. Feminist legal theory was directly created to recognize and combat the legal system built primarily by the and for male intentions, often forgetting important components and experiences women and marginalized communities face. The law perpetuates a male valued system at the expense of female values. Through making sure all people have access to participate in legal systems as professionals to combating cases in constitutional and discriminatory law, feminist legal theory is utilized for it all. Second, feminist legal theory is dedicated to changing women's status through a rework of the law and its approach to gender. It is a critique of American law that was created to change the way women were treated and how judges had applied the law to keep women in the same position they had been in for years. The women who worked in this area viewed the law as holding women in a lower place in society than men based on gender assumptions, and judges have therefore relied on these assumptions to make their decisions. This movement originated in the 1960s and 1970s to achieve equality for women by challenging laws that made distinctions based on sex. One example of this sex-based discrimination during these times was the struggles for equal admission and access to their desired education. The women's experiences and persistence to fight for equal access led to low rates of retention and mental health issues, including anxiety disorders. Through their experiences, they were influenced to create new legal theory that fought for their rights and those that came after them in education and broader marginalized communities which led to the creation of the legal scholarship feminist legal theory in the 1970s and 1980s. It was crucial to allowing women to become their own people through becoming financially independent and having the ability to find real jobs that were not available to them before due to discrimination in employment. The foundation of feminist legal theory reflects these second and third-wave feminist struggles. However, feminist legal theorists today extend their work beyond overt discrimination by employing a variety of approaches to understand and address how the law contributes to gender inequality. == History == The first known use of the term feminist jurisprudence was in the late 1970s by Ann Scales during the planning process for Celebration 25, a party and conference held in 1978 to celebrate the twenty-fifth anniversary of the first women graduating from Harvard Law School. The term was first published in 1978 in the first issue of the Harvard Women's Law Journal. This feminist critique of American law was developed as a reaction to the fact that the legal system was too gender-prioritized and patriarchal. In 1984 Martha Fineman founded the Feminism and Legal Theory Project at the University of Wisconsin Law School to explore the relationships between feminist theory, practice, and law, which has been instrumental in the development of feminist legal theory. The foundation of the feminist legal theory was laid by women who challenged the laws that were in place to keep women in their respective places in the home. A driving force of this new movement was the need for women to start becoming financially independent. Women who were working in law started to focus on this idea more and started to work on achieving reproductive freedom, stopping gender discrimination in the law and workforce, and stopping the allowance of sexual abuse. == Main approaches == Some approaches to feminist jurisprudence are: the liberal equality model; the sexual difference model; the dominance model; the anti-essentialist model; and the postmodern model. Each model provides a distinct view of the legal mechanisms that contribute to women's subordination, and each offers a distinct method for changing legal approaches to gender. === The liberal equality model === The liberal equality model operates from within the liberal legal paradigm and generally embraces liberal values and the rights-based approach to law, though it takes issue with how the liberal framework has operated in practice. This model focuses on ensuring that women are afforded genuine equality including race, sexual orientation, and gender—as opposed to the nominal equality often given them in the traditional liberal framework—and seeks to achieve this either by way of a more thorough application of liberal values to women's experiences or the revision of liberal categories to take gender into account. The liberal equality model applies Kimberlé Crenshaw's theoretical framework of intersectionality in relation to a person's lived experience. For example, when black women are only provided legal relief when the case is against their race or gender. === The sexual difference model === The difference model emphasizes the significance of gender discrimination and holds that this discrimination should not be obscured by the law, but should be taken into account by it. Only by taking into account differences can the law provide adequate remedies for women's situation, which is in fact distinct from men's. The difference model suggests that differences between women and men put one sex at a disadvantage; therefore, the law should compensate women and men for their differences and disadvantages. These differences between women and men may be biological or culturally constructed. The difference model is in direct opposition to the sameness account which holds that women's sameness with men should be emphasized. To the sameness feminist, employing women's differences in an attempt to garner greater rights is ineffectual to that end and places emphasis on the very characteristics of women that have historically precluded them from achieving equality with men. The sameness feminist also argued that there was already special treatment for these so-called "differences" in the law, which is what was oppressing women. The idea of there being differences between the sexes led to the classical thought that feminist legal theory was trying to get rid of. It forced women to prove that they were like men by comparing their experiences to those of men, all in an attempt to gain legal protection. This all only led to women trying to meet norms that were made by men without questioning why these were accepted as the norm for equality. Men and women cannot be seen or defined as equal because they have completely different lived experiences. Understanding that access must be equal, but difference must still be recognized to diffract fairness and power struggle including unpaid societal standards like caring for children and the home, rather than feminine characteristics. === The dominance model === The dominance model rejects liberal feminism and views the legal system as a mechanism for the perpetuation of male dominance. By recognizing the foundation of law, scholars are able to conceptualize how women and marginalized communities were not written into the foundation of many structures limiting access and equal rights in all areas of life. Further, dominance theorists reject the difference model because it uses men as the benchmark of equality. While the liberal equality model and difference theory aim to achieve equality for women and men, the dominance model's end goal is to liberate women from men. Dominance theorists understand gender inequality as a result of an imbalance of power between women and men and believe the law contributes to this subordination of women. It thus joins certain strands of critical legal theory, which also consider the potential for law to act as an instrument for domination. This theory focuses on how male dominate females, but it also talks about other groups being oppressed such as how legal aid is not often offered to the transgender population. Also, any white female would have good legal representation compared to minority groups. In the account of dominance proposed by Catharine MacKinnon, sexuality is central to dominance. MacKinnon argues that women's sexuality is socially constructed by male dominance and the sexual domination of women by men is a primary source of the general social subordination of women. According to MacKinnon, the legal system perpetuates inequalities between women and men by creating laws about women using a male perspective. Additionally, MacKinnon further applies her dominance model of feminist legal theory to transgender sex equality. She criticizes the libertarian Textual and Literal Approach for exacerbating, rather than eliminating, the discrimination faced by lesbians, gay men, and transgender men and women. MacKinnon argues that the liberal Anti-Stereotyping Approach benefits only those who do not conform to stereotypes and yet meet the dominant standards while offering no help to those who face discrimination based on subordinated stereotypes. She asserts that only by adopting the Substantive Approach, inspired by her dominance model and focusing on the gender hierarchy driven by sexualized misogyny, can intersectionality be properly addressed, ultimately benefiting all women. === The anti-essentialist model === Anti-essentialist feminist legal theory was created by women of color and lesbians in the 1980s who felt feminist legal theory was excluding their perspectives and experiences. Anti-essentialist and intersectionalist critiques of feminists have objected to the idea that there can be any universal women's voice and have criticized feminists, as did Black feminism, for implicitly basing their work on the experiences of white, middle class, heterosexual women. The anti-essentialist and intersectionalist project has been to explore the ways in which race, class, sexual orientation, and other axes of subordination interplay with gender and to uncover the implicit, detrimental assumptions that have often been employed in feminist theory. This model challenges feminist legal theorists who only address how the law affects heterosexual, middle-class white women. Anti-essentialist feminist legal theory recognizes that the identities of individual women shape their experiences, so the law does not influence all women in the same ways. It is about building actual equality for all regardless or gender, race, sexual orientation, class, or disability. When feminist legal theory practices under an essentialist lens, women of color are often dismissed as they would in historical legal theory. While race is an important factor in feminist legal theory, it can also be misconstrued in a way that silences women of color, furthering racism in a system created to build more access. For this reason, Crenshaw's "Mapping the Margins: Intersectionality, Identity Politics, and Violence against Women of Color" should remain a canonical to this topic to continue to support and challenge the gender essentialism within feminism culture and ideology the marginalized women of color by protection them further in legal implications through support. Kimberlé Crenshaw's formation of intersectionality within feminist legal theory has given more women and people living multifaceted lives more representation in an arguable essentialist legal arena. Mari Matsuda created the term "multiple consciousness" to explain a person's ability to take on the perspective of an oppressed group. Anti-essentialist feminist legal theorists use multiple consciousness to understand how the law is affecting women belonging to groups other than their own. Feminist legal theory is still evolving to diminish gender and race essentialism to recognize how oppression and privilege work together to create a person's life experiences. === The postmodern model === Postmodern feminist legal theorists reject the liberal equality idea that women are like men as well as the difference theory idea that women are inherently different from men. This is because they do not believe in singular truths and instead see truths as multiple and based on experience and perspective. Feminists from the postmodern camp use a method known as deconstruction in which they look at laws to find hidden biases within them. Postmodern feminists use deconstruction to demonstrate that laws should not be unchangeable since they are created by people with biases and may therefore contribute to female oppression. More recent scholarship has focused on sex/gender as manipulable tools of state policy, showing that state definitions of male and female often depend on the use of the category in furthering particular state projects. == Hedonic Jurisprudence == Feminist legal theory produced a new idea of using hedonic jurisprudence to show that women's experiences of assault and rape was a product of laws that treated them as less human and gave them fewer rights than men. With this feminist legal theorists argued that given examples were not only a description of possible scenarios but also a sign of events that have actually occurred, relying on them to support statements that the law ignores the interests and disrespects the existence of women. == Influence on judicial decisions == Over half of cases involving feminist issues in the Supreme Court of the United Kingdom included elements of feminist jurisprudence in their judgements.: 17 The most common form of feminist legal reasoning was placing the case within a wider context of the experience of those involved or another wider context, which could involve showing empathy for women involved in cases.: 18 Judges also considered the impact of judgments on disadvantaged groups, challenged gendered bias, and commented on historic injustice.: 20 Some feminist facts entered into the courts reasoning as common knowledge with feminist scholars being referred to.: 22 Lady Hale has used Intersectional arguments,: 23 arguments that extend the concept of violence in cases that domestic violence outside of physical violence.: 24 == Notable scholars == Paisley Currah Martha Fineman Mary Joe Frug Catharine MacKinnon Mari Matsuda Kimberlé Crenshaw Dean Spade Ann Scales Robin West == See also == Critical race theory Feminist political theory Gender mainstreaming Women in law Feminist interventions in the philosophy of law == Notes == == References == Baer, Judith A. Our Lives Before the Law: Constructing a Feminist Jurisprudence. Princeton University Press, 2001. Berkeley Journal Of Gender Law (2013). "Difference, Dominance, Differences: Feminist Theory, Equality, and the Law". Berkeley Journal of Gender, Law & Justice. 5 (1). doi:10.15779/Z388C4M. Cain, Patricia A. "Feminist Jurisprudence: Grounding the Theories." Berkeley Journal of Gender, Law & Justice, vol. 4, no. 2, September 2013, Accessed 3 October 2017. Crenshaw, Kimberlé (7 December 2015). "Demarginalizing the Intersection of Race and Sex: A Black Feminist Critique of Antidiscrimination Doctrine, Feminist Theory and Antiracist Politics". University of Chicago Legal Forum. 1989 (1). Ehrenreich, Nancy. (2013). On "Having fun and raising hell": Symposium honoring the work of professor ann scales. Denver University law review. 91. 1–11. "Feminism and Legal Theory Project \| Emory University School of Law \| Atlanta, GA." Emory University School of Law, law.emory.edu/faculty-and-scholarship/centers/feminism-and-legal-theory-project.html. Accessed 2 October 2017. Levit, Nancy, and Robert R.M. Verchick. "Feminist Legal Theories." Feminist Legal Theory (Second Edition): A Primer., 2nd ed., NYU Press, 2015, pp. 11–41. MacKinnon, Catharine A. (1983). "Feminism, Marxism, Method, and the State: Toward Feminist Jurisprudence". Signs. 8 (4): 635–658. doi:10.1086/494000. JSTOR 3173687. S2CID 145125690. Matsuda, Mari (1989). "When the First Quail Calls: Multiple Consciousness as Jurisprudential Method". Women's Rights Law Reporter. hdl:10125/65954. Minda, Gary. "Feminist Legal Theory." In Postmodern Legal Movements: Law and Jurisprudence At Century's End, 128–48. New York; London: NYU Press, 1995. Scales, Ann. Legal feminism: activism, lawyering, and legal theory. New York, New York University Press, 2006. Spade, Dean (1 January 2010). "Be Professional!". Harvard Journal of Law and Gender. SSRN 1585388. Warner, J Cali. Proposal: the alignment of oppressed groups as post-Modern development. 2016. == Further reading == Applications of Feminist Legal Theory: Sex, Violence, Work and Reproduction (Women in the Political Economy), ed. by D. Kelly Weisberg, Temple University Press, 1996, ISBN 1-56639-424-4 Feminist Legal Theory: An Anti-Essentialist Reader, ed. by Nancy E. Dowd and Michelle S. Jacobs, New York Univ Press, 2003, ISBN 0-8147-1913-9 Nancy Levit, Robert R. M. Verchick: Feminist Legal Theory: A Primer (Critical America (New York University Paperback)), New York University Press 2006, ISBN 0-8147-5199-7 == External links == "Feminist Jurisprudence". Internet Encyclopedia of Philosophy. Feminism and Legal Theory Project	Wikipedia/Feminist_legal_theory
Heroin-assisted treatment (HAT), or diamorphine-assisted treatment, refers to a type of Medication-Assisted Treatment (MAT) where semi-synthetic heroin is prescribed to opioid addicts who do not benefit from, or cannot tolerate, treatment with one of the established drugs used in opioid replacement therapy such as methadone or buprenorphine/naloxone (brand name Suboxone). For this group of patients, heroin-assisted treatment has proven superior in improving their social and health situation. Heroin-assisted treatment is fully a part of the national health system in Switzerland, Germany, the Netherlands, Canada, and Denmark. Additional trials are being carried out in the United Kingdom, Norway, and Belgium. == History == The British have had a system of heroin maintenance since the 1920s. For decades it supplied a few hundred addicts nationwide, most of whom were doctors themselves. It was de-emphasized considerably during the 1960s-1980s as a result of the U.S.-led war on drugs. In the 1980s and early 1990s, Dr John Marks ran heroin-prescribing clinics in Liverpool, Widnes and Warrington that were highly controversial. Because of the lack of large-scale trials, only anecdotal evidence existed as to the efficacy of the treatment. This changed in 1994 when Switzerland, faced with one of the largest open drug scenes in Europe at the time, started large-scale trials on the potential use of diamorphine as a maintenance drug. They proved diamorphine to be a viable maintenance drug which has shown equal or better rates of success than methadone in terms of assisting long-term users establish stable, crime-free lives. These results encouraged countries like Germany and the Netherlands to conduct their own trials and finally to include heroin-assisted treatment fully as a part of the national health system in 2009. In Switzerland, heroin has been made available under supervision to addicts since around 1994. Several studies have been conducted between 1994 and 1996. == Positions == === Favor === In recent years the British have begun moving towards the inclusion of heroin maintenance programs as a legitimate component of their National Health Service. In 2013 European Union's European Monitoring Centre for Drugs and Drug Addiction issued guidelines for the years 2013–2020; for the first time since the EMCDDA's 1995 inception, the group advocated "reducing the health and social risks and harms caused by drugs" in addition to longstanding policies of lessening demand and supply. Groups such as United Nations Office on Drugs and Crime and the Transnational Institute have released documents advocating harm-reduction strategies, though only the latter mentions heroin-assisted therapy. === Opposition === Groups such as the Drug Free America Foundation, have criticized heroin-assisted treatment along with other harm reduction strategies for allegedly creating the perception that certain behaviors can be partaken safely, such as illicit drug use, claiming that this may lead to an increase in that behavior by people who would otherwise be deterred. We oppose so-called `harm reduction´ strategies as endpoints that promote the false notion that there are safe or responsible ways to use drugs. That is, strategies in which the primary goal is to enable drug users to maintain addictive, destructive, and compulsive behavior by misleading users about some drug risks while ignoring others. Such shortcomings arguably exist with some harm reduction measures, such as supervised injection facilities. These facilities provide users with the information and equipment necessary to avoid infection with diseases such as HIV, but leave them dependent on the black market. So users still face the health risk associated with the injection of impure street drugs and they still face the enormous financial strain of financing their addiction. In the case of heroin-assisted treatment however, users are provided with a form of pharmaceutical-grade heroin injection solution which doctors consider fit for injection. And as doctors refrain from drastic changes in dose and provide post-injection monitoring, overdoses are rare and can be quickly treated with opioid antagonists like naloxone. Thus, patients in heroin-assisted treatment are relieved from the major complex of problems that defines illicit heroin use. Synthetic heroin taken under the aforementioned conditions is not neurotoxic and has few long-term side effects beside constipation and dependency. And while it had been speculated that the availability of such treatment options might change public perception of the risks associated with drug use and might lead to an increase in illicit drug use, the incidence of heroin abuse in Switzerland has declined sharply since the introduction of heroin-assisted treatment. As a study published in The Lancet concluded: The harm reduction policy of Switzerland and its emphasis on the medicalisation of the heroin problem seems to have contributed to the image of heroin as unattractive for young people." Also, the notion that patients in such treatment programs are enabled to maintain "destructive behavior" contradicts the findings that patients significantly recover in terms of both their social and health situation. A clinical follow-up report on the German study on this matter found that 40% of all patients and 68% of those able to work had found employment after four years of treatment. Some even started a family after years of homelessness and delinquency. == See also == Opioid agonist therapy Drug policy of Switzerland Drug policy of the Netherlands == References ==	Wikipedia/Heroin-assisted_treatment
Corporate law (also known as company law or enterprise law) is the body of law governing the rights, relations, and conduct of persons, companies, organizations and businesses. The term refers to the legal practice of law relating to corporations, or to the theory of corporations. Corporate law often describes the law relating to matters which derive directly from the life-cycle of a corporation. It thus encompasses the formation, funding, governance, and death of a corporation. While the minute nature of corporate governance as personified by share ownership, capital market, and business culture rules differ, similar legal characteristics and legal problems exist across many jurisdictions. Corporate law regulates how corporations, investors, shareholders, directors, employees, creditors, and other stakeholders such as consumers, the community, and the environment interact with one another. Whilst the term company or business law is colloquially used interchangeably with corporate law, the term business law mostly refers to wider concepts of commercial law, that is the law relating to commercial and business related purposes and activities. In some cases, this may include matters relating to corporate governance or financial law. When used as a substitute for corporate law, business law means the law relating to the business corporation (or business enterprises), including such activity as raising capital, company formation, and registration with the government. == Overview == Academics identify four legal characteristics universal to business enterprises. These are: Separate legal personality of the corporation (access to tort and contract law in a manner similar to a person) Limited liability of the shareholders (a shareholder's personal liability is limited to the value of their shares in the corporation) Transferable shares (if the corporation is a "public company", the shares are publicly listed and traded) Delegated management under a board structure; the board of directors delegates day-to-day management of the company to executives. Widely available and user-friendly corporate law enables business participants to possess these four legal characteristics and thus transact as businesses. Thus, corporate law is a response to three endemic opportunism: conflicts between managers and shareholders, between controlling and non-controlling shareholders; and between shareholders and other contractual counterparts (including creditors and employees). A corporation may accurately be called a company; however, a company should not necessarily be called a corporation, which has distinct characteristics. In the United States, a company may or may not be a separate legal entity, and is often used synonymous with "firm" or "business." According to Black's Law Dictionary, in America a company means "a corporation — or, less commonly, an association, partnership or union — that carries on industrial enterprise." Other types of business associations can include partnerships (in the UK governed by the Partnership Act 1890), or trusts (such as a pension fund), or companies limited by guarantee (like some community organizations or charities). Corporate law deals with companies that are incorporated or registered under the corporate or company law of a sovereign state or their sub-national states. The defining feature of a corporation is its legal independence from the shareholders that own it. Under corporate law, corporations of all sizes have separate legal personality, with limited or unlimited liability for its shareholders. Shareholders control the company through a board of directors which, in turn, typically delegates control of the corporation's day-to-day operations to a full-time executive. Shareholders' losses, in the event of liquidation, are limited to their stake in the corporation, and they are not liable for any remaining debts owed to the corporation's creditors. This rule is called limited liability, and it is why the names of corporations end with "Ltd." or some variant such as "Inc." or "plc." Under almost all legal systems corporations have much the same legal rights and obligations as individuals. In some jurisdictions, this extends to allow corporations to exercise human rights against real individuals and the state, and they may be responsible for human rights violations. Just as they are "born" into existence through its members obtaining a certificate of incorporation, they can "die" when they lose money into insolvency. Corporations can even be convicted of criminal offences, such as corporate fraud and corporate manslaughter. === History === Although some forms of companies are thought to have existed during Ancient Rome and Ancient Greece, the closest recognizable ancestors of the modern company did not appear until the 16th century. With increasing international trade, Royal charters were granted in Europe (notably in England and Holland) to merchant adventurers. The Royal charters usually conferred special privileges on the trading company (including, usually, some form of monopoly). Originally, traders in these entities traded stock on their own account, but later the members came to operate on joint account and with joint stock, and the new Joint stock company was born. Early companies were purely economic ventures; it was only a belatedly established benefit of holding joint stock that the company's stock could not be seized for the debts of any individual member. The development of company law in Europe was hampered by two notorious "bubbles" (the South Sea Bubble in England and the Tulip Bulb Bubble in the Dutch Republic) in the 17th century, which set the development of companies in the two leading jurisdictions back by over a century in popular estimation. Companies returned to the forefront of commerce, although in England to circumvent the Bubble Act 1720 investors had reverted to trading the stock of unincorporated associations, until it was repealed in 1825. However, the process of obtaining Royal charters was insufficient to keep up with demand. In England there was a lively trade in the charters of defunct companies. It was not until the Joint Stock Companies Act 1844 that the first equivalent of modern companies, formed by registration, appeared. Soon after came the Limited Liability Act 1855, which in the event of a company's bankruptcy limited the liability of all shareholders to the amount of capital they had invested. The beginning of modern company law came when the two pieces of legislation were codified under the Joint Stock Companies Act 1856 at the behest of the then Vice President of the Board of Trade, Mr Robert Lowe. That legislation shortly gave way to the railway boom, and from there the numbers of companies formed soared. In the later nineteenth century depression took hold, and just as company numbers had boomed, many began to implode and fall into insolvency. Much strong academic, legislative and judicial opinion was opposed to the notion that businessmen could escape accountability for their role in the failing businesses. The last significant development in the history of companies was the decision of the House of Lords in Salomon v. Salomon & Co. where the House of Lords confirmed the separate legal personality of the company, and that the liabilities of the company were separate and distinct from those of its owners. == Corporate structure == The law of business organizations originally derived from the common law of England, and has evolved significantly in the 20th century. In common law countries today, the most commonly addressed forms are: Corporation Limited company Unlimited company Limited liability partnership Limited partnership Not-for-profit corporation Company limited by guarantee Partnership Sole proprietorship Privately held company The proprietary limited company is a statutory business form in several countries, including Australia. Many countries have forms of business entity unique to that country, although there are equivalents elsewhere. Examples are the limited liability company (LLC) and the limited liability limited partnership (LLLP) in the United States. Other types of business organizations, such as cooperatives, credit unions and publicly owned enterprises, can be established with purposes that parallel, supersede, or even replace the profit maximization mandate of business corporations. There are various types of company that can be formed in different jurisdictions, but the most common forms of company are: a company limited by guarantee. Commonly used where companies are formed for non-commercial purposes, such as clubs or charities. The members guarantee the payment of certain (usually nominal) amounts if the company goes into insolvent liquidation, but otherwise they have no economic rights in relation to the company . a company limited by guarantee with a share capital. A hybrid entity, usually used where the company is formed for non-commercial purposes, but the activities of the company are partly funded by investors who expect a return. a company limited by shares. The most common form of company used for business ventures. an unlimited company either with or without a share capital. This is a hybrid company, a company similar to its limited company (Ltd.) counterpart but where the members or shareholders do not benefit from limited liability should the company ever go into formal liquidation. There are, however, many specific categories of corporations and other business organizations which may be formed in various countries and jurisdictions throughout the world. === Corporate legal personality === One of the key legal features of corporations are their separate legal personality, also known as "personhood" or being "artificial persons". However, the separate legal personality was not confirmed under English law until 1895 by the House of Lords in Salomon v. Salomon & Co. Separate legal personality often has unintended consequences, particularly in relation to smaller, family companies. In B v. B [1978] Fam 181 it was held that a discovery order obtained by a wife against her husband was not effective against the husband's company as it was not named in the order and was separate and distinct from him. And in Macaura v. Northern Assurance Co Ltd a claim under an insurance policy failed where the insured had transferred timber from his name into the name of a company wholly owned by him, and it was subsequently destroyed in a fire; as the property now belonged to the company and not to him, he no longer had an "insurable interest" in it and his claim failed. Separate legal personality allows corporate groups flexibility in relation to tax planning, and management of overseas liability. For instance in Adams v. Cape Industries plc it was held that victims of asbestos poisoning at the hands of an American subsidiary could not sue the English parent in tort. Whilst academic discussion highlights certain specific situations where courts are generally prepared to "pierce the corporate veil", to look directly at, and impose liability directly on the individuals behind the company; the actual practice of piercing the corporate veil is, at English law, non-existent. However, the court will look beyond the corporate form where the corporation is a sham or perpetuating a fraud. The most commonly cited examples are: where the company is a mere façade where the company is effectively just the agent of its members or controllers where a representative of the company has taken some personal responsibility for a statement or action where the company is engaged in fraud or other criminal wrongdoing where the natural interpretation of a contract or statute is as a reference to the corporate group and not the individual company where permitted by statute (for example, many jurisdictions provide for shareholder liability where a company breaches environmental protection laws) ==== Capacity and powers ==== Historically, because companies are artificial persons created by operation of law, the law prescribed what the company could and could not do. Usually this was an expression of the commercial purpose which the company was formed for, and came to be referred to as the company's objects, and the extent of the objects are referred to as the company's capacity. If an activity fell outside the company's capacity it was said to be ultra vires and void. By way of distinction, the organs of the company were expressed to have various corporate powers. If the objects were the things that the company was able to do, then the powers were the means by which it could do them. Usually expressions of powers were limited to methods of raising capital, although from earlier times distinctions between objects and powers have caused lawyers difficulty. Most jurisdictions have now modified the position by statute, and companies generally have capacity to do all the things that a natural person could do, and power to do it in any way that a natural person could do it. However, references to corporate capacity and powers have not quite been consigned to the dustbin of legal history. In many jurisdictions, directors can still be liable to their shareholders if they cause the company to engage in businesses outside its objects, even if the transactions are still valid as between the company and the third party. And many jurisdictions also still permit transactions to be challenged for lack of "corporate benefit", where the relevant transaction has no prospect of being for the commercial benefit of the company or its shareholders. As artificial persons, companies can only act through human agents. The main agent who deals with the company's management and business is the board of directors, but in many jurisdictions other officers can be appointed too. The board of directors is normally elected by the members, and the other officers are normally appointed by the board. These agents enter into contracts on behalf of the company with third parties. Although the company's agents owe duties to the company (and, indirectly, to the shareholders) to exercise those powers for a proper purpose, generally speaking third parties' rights are not impugned if it transpires that the officers were acting improperly. Third parties are entitled to rely on the ostensible authority of agents held out by the company to act on its behalf. A line of common law cases reaching back to Royal British Bank v Turquand established in common law that third parties were entitled to assume that the internal management of the company was being conducted properly, and the rule has now been codified into statute in most countries. Accordingly, companies will normally be liable for all the act and omissions of their officers and agents. This will include almost all torts, but the law relating to crimes committed by companies is complex, and varies significantly between countries. ==== Corporate crime ==== Corporate Manslaughter and Corporate Homicide Act 2007 === Corporate governance === Corporate governance is primarily the study of the power relations among a corporation's senior executives, its board of directors and those who elect them (shareholders in the "general meeting" and employees), as well as other stakeholders, such as creditors, consumers, the environment and the community at large. One of the main differences between different countries in the internal form of companies is between a two-tier and a one tier board. The United Kingdom, the United States, and most Commonwealth countries have single unified boards of directors. In Germany, companies have two tiers, so that shareholders (and employees) elect a "supervisory board", and then the supervisory board chooses the "management board". There is the option to use two tiers in France, and in the new European Companies (Societas Europaea). Recent literature, especially from the United States, has begun to discuss corporate governance in the terms of management science. While post-war discourse centred on how to achieve effective "corporate democracy" for shareholders or other stakeholders, many scholars have shifted to discussing the law in terms of principal–agent problems. On this view, the basic issue of corporate law is that when a "principal" party delegates his property (usually the shareholder's capital, but also the employee's labour) into the control of an "agent" (i.e. the director of the company) there is the possibility that the agent will act in his own interests, be "opportunistic", rather than fulfill the wishes of the principal. Reducing the risks of this opportunism, or the "agency cost", is said to be central to the goal of corporate law. ==== Constitution ==== The rules for corporations derive from two sources. These are the country's statutes: in the US, usually the Delaware General Corporation Law (DGCL); in the UK, the Companies Act 2006 (CA 2006); in Germany, the Aktiengesetz (AktG) and the Gesetz betreffend die Gesellschaften mit beschränkter Haftung (GmbH-Gesetz, GmbHG). The law will set out which rules are mandatory, and which rules can be derogated from. Examples of important rules which cannot be derogated from would usually include how to fire the board of directors, what duties directors owe to the company or when a company must be dissolved as it approaches bankruptcy. Examples of rules that members of a company would be allowed to change and choose could include, what kind of procedure general meetings should follow, when dividends get paid out, or how many members (beyond a minimum set out in the law) can amend the constitution. Usually, the statute will set out model articles, which the corporation's constitution will be assumed to have if it is silent on a bit of particular procedure. The United States, and a few other common law countries, split the corporate constitution into two separate documents (the UK got rid of this in 2006). The memorandum of association (or articles of incorporation) is the primary document, and will generally regulate the company's activities with the outside world. It states which objects the company is meant to follow (e.g. "this company makes automobiles") and specifies the authorised share capital of the company. The articles of association (or by-laws) is the secondary document, and will generally regulate the company's internal affairs and management, such as procedures for board meetings, dividend entitlements etc. In the event of any inconsistency, the memorandum prevails and in the United States only the memorandum is publicised. In civil law jurisdictions, the company's constitution is normally consolidated into a single document, often called the charter. It is quite common for members of a company to supplement the corporate constitution with additional arrangements, such as shareholders' agreements, whereby they agree to exercise their membership rights in a certain way. Conceptually a shareholders' agreement fulfills many of the same functions as the corporate constitution, but because it is a contract, it will not normally bind new members of the company unless they accede to it somehow. One benefit of shareholders' agreement is that they will usually be confidential, as most jurisdictions do not require shareholders' agreements to be publicly filed. Another common method of supplementing the corporate constitution is by means of voting trusts, although these are relatively uncommon outside the United States and certain offshore jurisdictions. Some jurisdictions consider the company seal to be a part of the "constitution" (in the loose sense of the word) of the company, but the requirement for a seal has been abrogated by legislation in most countries. ==== Balance of power ==== The most important rules for corporate governance are those concerning the balance of power between the board of directors and the members of the company. Authority is given or "delegated" to the board to manage the company for the success of the investors. Certain specific decision rights are often reserved for shareholders, where their interests could be fundamentally affected. There are necessarily rules on when directors can be removed from office and replaced. To do that, meetings need to be called to vote on the issues. How easily the constitution can be amended and by whom necessarily affects the relations of power. It is a principle of corporate law that the directors of a company have the right to manage. This is expressed in statute in the DGCL, where §141(a) states, (a) The business and affairs of every corporation organized under this chapter shall be managed by or under the direction of a board of directors, except as may be otherwise provided in this chapter or in its certificate of incorporation. In Germany, §76 AktG says the same for the management board, while under §111 AktG the supervisory board's role is stated to be to "oversee" (überwachen). In the United Kingdom, the right to manage is not laid down in law, but is found in Part.2 of the Model Articles. This means it is a default rule, which companies can opt out of (s.20 CA 2006) by reserving powers to members, although companies rarely do. UK law specifically reserves shareholders right and duty to approve "substantial non cash asset transactions" (s.190 CA 2006), which means those over 10% of company value, with a minimum of £5,000 and a maximum of £100,000. Similar rules, though much less stringent, exist in §271 DGCL and through case law in Germany under the so-called Holzmüller-Doktrin. Probably the most fundamental guarantee that directors will act in the members' interests is that they can easily be sacked. During the Great Depression, two Harvard scholars, Adolf Berle and Gardiner Means wrote The Modern Corporation and Private Property, an attack on American law which failed to hold directors to account, and linked the growing power and autonomy of directors to the economic crisis. In the UK, the right of members to remove directors by a simple majority is assured under s.168 CA 2006 Moreover, Art.21 of the Model Articles requires a third of the board to put themselves up for re-election every year (in effect creating maximum three year terms). 10% of shareholders can demand a meeting any time, and 5% can if it has been a year since the last one (s.303 CA 2006). In Germany, where employee participation creates the need for greater boardroom stability, §84(3) AktG states that management board directors can only be removed by the supervisory board for an important reason (ein wichtiger Grund) though this can include a vote of no-confidence by the shareholders. Terms last for five years, unless 75% of shareholders vote otherwise. §122 AktG lets 10% of shareholders demand a meeting. In the US, Delaware lets directors enjoy considerable autonomy. §141(k) DGCL states that directors can be removed without any cause, unless the board is "classified", meaning that directors only come up for re-appointment on different years. If the board is classified, then directors cannot be removed unless there is gross misconduct. Director's autonomy from shareholders is seen further in §216 DGCL, which allows for plurality voting and §211(d) which states shareholder meetings can only be called if the constitution allows for it. The problem is that in America, directors usually choose where a company is incorporated and §242(b)(1) DGCL says any constitutional amendment requires a resolution by the directors. By contrast, constitutional amendments can be made at any time by 75% of shareholders in Germany (§179 AktG) and the UK (s.21 CA 2006). Countries with co-determination employ the practice of workers of an enterprise having the right to vote for representatives on the board of directors in a company. === Director duties === In most jurisdictions, directors owe strict duties of good faith, as well as duties of care and skill, to safeguard the interests of the company and the members. In many developed countries outside the English speaking world, company boards are appointed as representatives of both shareholders and employees to "codetermine" company strategy. Corporate law is often divided into corporate governance (which concerns the various power relations within a corporation) and corporate finance (which concerns the rules on how capital is used). Directors also owe strict duties not to permit any conflict of interest or conflict with their duty to act in the best interests of the company. This rule is so strictly enforced that, even where the conflict of interest or conflict of duty is purely hypothetical, the directors can be forced to disgorge all personal gains arising from it. In Aberdeen Ry v. Blaikie (1854) 1 Macq HL 461 Lord Cranworth stated in his judgment that, However, in many jurisdictions the members of the company are permitted to ratify transactions which would otherwise fall foul of this principle. It is also largely accepted in most jurisdictions that this principle should be capable of being abrogated in the company's constitution. The standard of skill and care that a director owes is usually described as acquiring and maintaining sufficient knowledge and understanding of the company's business to enable him to properly discharge his duties. This duty enables the company to seek compensation from its director if it can be proved that a director has not shown reasonable skill or care which in turn has caused the company to incur a loss. In many jurisdictions, where a company continues to trade despite foreseeable bankruptcy, the directors can be forced to account for trading losses personally. Directors are also strictly charged to exercise their powers only for a proper purpose. For instance, were a director to issue a large number of new shares, not for the purposes of raising capital but in order to defeat a potential takeover bid, that would be an improper purpose. == Company law theory == Ronald Coase has pointed out, all business organizations represent an attempt to avoid certain costs associated with doing business. Each is meant to facilitate the contribution of specific resources - investment capital, knowledge, relationships, and so forth - towards a venture which will prove profitable to all contributors. Except for the partnership, all business forms are designed to provide limited liability to both members of the organization and external investors. Business organizations originated with agency law, which permits an agent to act on behalf of a principal, in exchange for the principal assuming equal liability for the wrongful acts committed by the agent. For this reason, all partners in a typical general partnership may be held liable for the wrongs committed by one partner. Those forms that provide limited liability are able to do so because the state provides a mechanism by which businesses that follow certain guidelines will be able to escape the full liability imposed under agency law. The state provides these forms because it has an interest in the strength of the companies that provide jobs and services therein, but also has an interest in monitoring and regulating their behaviour. == Litigation == Members of a company generally have rights against each other and against the company, as framed under the company's constitution. However, members cannot generally claim against third parties who cause damage to the company which results in a diminution in the value of their shares or others membership interests because this is treated as "reflective loss" and the law normally regards the company as the proper claimant in such cases. In relation to the exercise of their rights, minority shareholders usually have to accept that, because of the limits of their voting rights, they cannot direct the overall control of the company and must accept the will of the majority (often expressed as majority rule). However, majority rule can be iniquitous, particularly where there is one controlling shareholder. Accordingly, a number of exceptions have developed in law in relation to the general principle of majority rule. Where the majority shareholder(s) are exercising their votes to perpetrate a fraud on the minority, the courts may permit the minority to sue members always retain the right to sue if the majority acts to invade their personal rights, e.g. where the company's affairs are not conducted in accordance with the company's constitution (this position has been debated because the extent of a personal right is not set in law). Macdougall v Gardiner and Pender v Lushington present irreconcilable differences in this area. in many jurisdictions it is possible for minority shareholders to take a representative or derivative action in the name of the company, where the company is controlled by the alleged wrongdoers == Corporate finance == Through the operational life of the corporation, perhaps the most crucial aspect of corporate law relates to raising capital for the business to operate. The law, as it relates to corporate finance, not only provides the framework for which a business raises funds - but also provides a forum for principles and policies which drive the fundraising, to be taken seriously. Two primary methods of financing exists with regard to corporate financing, these are: Equity financing; and Debt financing Each has relative advantages and disadvantages, both at law and economically. Additional methods of raising capital necessary to finance its operations is that of retained profits Various combinations of financing structures have the capacity to produce fine-tuned transactions which, using the advantages of each form of financing, support the limitations of the corporate form, its industry, or economic sector. A mix of both debt and equity is crucial to the sustained health of the company, and its overall market value is independent of its capital structure. One notable difference is that interest payments to debt is tax deductible whilst payment of dividends are not, this will incentivise a company to issue debt financing rather than preferred stock in order to reduce their tax exposure. === Shares and share capital === A company limited by shares, whether public or private, must have at least one issued share; however, depending on the corporate structure, the formatting may differ. If a company wishes to raise capital through equity, it will usually be done by issuing shares (sometimes called "stock" (not to be confused with stock-in-trade)) or warrants. In the common law, whilst a shareholder is often colloquially referred to as the owner of the company - it is clear that the shareholder is not an owner of the company but makes the shareholder a member of the company and entitles them to enforce the provisions of the company's constitution against the company and against other members. A share is an item of property, and can be sold or transferred. Shares also normally have a nominal or par value, which is the limit of the shareholder's liability to contribute to the debts of the company on an insolvent liquidation. Shares usually confer a number of rights on the holder. These will normally include: voting rights rights to dividends (or payments made by companies to their shareholders) declared by the company rights to any return of capital either upon redemption of the share, or upon the liquidation of the company in some countries, shareholders have preemption rights, whereby they have a preferential right to participate in future share issues by the company Companies may issue different types of shares, called "classes" of shares, offering different rights to the shareholders depending on the underlying regulatory rules pertaining to corporate structures, taxation, and capital market rules. A company might issue both ordinary shares and preference shares, with the two types having different voting and/or economic rights. It might provide that preference shareholders shall each receive a cumulative preferred dividend of a certain amount per annum, but the ordinary shareholders shall receive everything else. Corporations will structure capital raising in this way in order to appeal to different lenders in the market by providing different incentives for investment. The total value of issued shares in a company is said to represent its equity capital. Most jurisdictions regulate the minimum amount of capital which a company may have, although some jurisdictions prescribe minimum amounts of capital for companies engaging in certain types of business (e.g. banking, insurance etc.). Similarly, most jurisdictions regulate the maintenance of equity capital, and prevent companies returning funds to shareholders by way of distribution when this might leave the company financially exposed. Often this extends to prohibiting a company from providing financial assistance for the purchase of its own shares. == Dissolution == Events such as mergers, acquisitions, insolvency, or the commission of a crime affect the corporate form. In addition to the creation of the corporation, and its financing, these events serve as a transition phase into either dissolution, or some other material shift. === Mergers and acquisitions === A merger or acquisition can often mean the altering or extinguishing of the corporation. === Corporate insolvency === If unable to discharge its debts in a timely manner, a corporation may end up on bankruptcy liquidation. Liquidation is the normal means by which a company's existence is brought to an end. It is also referred to (either alternatively or concurrently) in some jurisdictions as winding up or dissolution. Liquidations generally come in two forms — either compulsory liquidations (sometimes called creditors' liquidations) and voluntary liquidations (sometimes called members' liquidations, although a voluntary liquidation where the company is insolvent will also be controlled by the creditors, and is properly referred to as a creditors' voluntary liquidation). Where a company goes into liquidation, normally a liquidator is appointed to gather in all the company's assets and settle all claims against the company. If there is any surplus after paying off all the creditors of the company, this surplus is then distributed to the members. As its names imply, applications for compulsory liquidation are normally made by creditors of the company when the company is unable to pay its debts. However, in some jurisdictions, regulators have the power to apply for the liquidation of the company on the grounds of public good, i.e., where the company is believed to have engaged in unlawful conduct, or conduct which is otherwise harmful to the public at large. Voluntary liquidations occur when the company's members decide voluntarily to wind up the affairs of the company. This may be because they believe that the company will soon become insolvent, or it may be on economic grounds if they believe that the purpose for which the company was formed is now at an end, or that the company is not providing an adequate return on assets and should be broken up and sold off. Some jurisdictions also permit companies to be wound up on "just and equitable" grounds. Generally, applications for just and equitable winding-up are brought by a member of the company who alleges that the affairs of the company are being conducted in a prejudicial manner, and asking the court to bring an end to the company's existence. For obvious reasons, in most countries, the courts have been reluctant to wind up a company solely on the basis of the disappointment of one member, regardless of how well-founded that member's complaints are. Accordingly, most jurisdictions that permit just and equitable winding up also permit the court to impose other remedies, such as requiring the majority shareholder(s) to buy out the disappointed minority shareholder at a fair value. === Insider dealing === Insider trading is the trading of a corporation's stock or other securities (e.g., bonds or stock options) by individuals with potential access to non-public information about the company. In most countries, trading by corporate insiders such as officers, key employees, directors, and large shareholders may be legal if this trading is done in a way that does not take advantage of non-public information. However, the term is frequently used to refer to a practice in which an insider or a related party trades based on material non-public information obtained during the performance of the insider's duties at the corporation, or otherwise in breach of a fiduciary or other relationship of trust and confidence or where the non-public information was misappropriated from the company. Illegal insider trading is believed to raise the cost of capital for securities issuers, thus decreasing overall economic growth. In the United States and several other jurisdictions, trading conducted by corporate officers, key employees, directors, or significant shareholders (in the United States, defined as beneficial owners of ten percent or more of the firm's equity securities) must be reported to the regulator or publicly disclosed, usually within a few business days of the trade. Many investors follow the summaries of these insider trades in the hope that mimicking these trades will be profitable. While "legal" insider trading cannot be based on material non-public information, some investors believe corporate insiders nonetheless may have better insights into the health of a corporation (broadly speaking) and that their trades otherwise convey important information (e.g., about the pending retirement of an important officer selling shares, greater commitment to the corporation by officers purchasing shares, etc.) == Trends and developments == Most case law on the matter of corporate governance dates to the 1980s and primarily addresses hostile takeovers, however, current research considers the direction of legal reforms to address issues of shareholder activism, institutional investors and capital market intermediaries. Corporations and boards are challenged to respond to these developments. Shareholder demographics have been effected by trends in worker retirement, with more institutional intermediaries like mutual funds playing a role in employee retirement. These funds are more motivated to partner with employers to have their fund included in a company's retirement plans than to vote their shares – corporate governance activities only increase costs for the fund, while the benefits would be shared equally with competitor funds. Shareholder activism prioritizes wealth maximization and has been criticized as a poor basis for determining corporate governance rules. Shareholders do not decide corporate policy, that is done by the board of directors, but shareholders may vote to elect board directors and on mergers and other changes that have been approved by directors. They may also vote to amend corporate bylaws. Broadly speaking there have been three movements in 20th century American law that sought a federal corporate law: the Progressive Movement, some aspects of proposals made in the early stages of the New Deal and again in the 1970s during a debate about the effect of corporate decision making on states. However, these movements did not establish federal incorporation. Although there has been some federal involvement in corporate governance rules as a result, the relative rights of shareholders and corporate officers is still mostly regulated by state laws. There is no federal legislation like there is for corporate political contributions or regulation of monopolies and federal laws have developed along different lines than state laws. == By region == === Europe === ==== Germany ==== ==== United Kingdom ==== === United States === In the United States, most corporations are incorporated, or organized, under the laws of a particular state. The laws of the state of incorporation normally governs a corporation's internal operations, even if the corporation's operations take place outside that state. Corporate law differs from state to state. Because of these differences, some businesses will benefit from having a corporate lawyer determine the most appropriate or advantageous state in which to incorporate. Business entities may also be regulated by federal laws and in some cases by local laws and ordinances. ==== Delaware ==== A majority of publicly traded companies in the U.S. are Delaware corporations. Some companies choose to incorporate in Delaware because the Delaware General Corporation Law offers lower corporate taxes than many other states. Many venture capitalists prefer to invest in Delaware corporations. Also, the Delaware Court of Chancery is widely recognized as a good venue for the litigation of business disputes. == See also == == References == == External links == Media related to Corporate law at Wikimedia Commons A Comparative Bibliography: Regulatory Competition on Corporate Law The Samuel and Ronnie Heyman Center on Corporate Governance Benjamin N. Cardozo School of Law The Delaware Journal of Corporate Law International Financial Law Review	Wikipedia/Corporate_law
In Colorado, cannabis has been legal for medical use since 2000 and for recreational use since late 2012. On November 7, 2000, 54% of Colorado voters approved Amendment 20, which amended the State Constitution to allow the use of marijuana in the state for approved patients with written medical consent. Under this law, patients may possess up to 2 ounces (57 g) of medical marijuana and may cultivate no more than six marijuana plants (no more than three of these mature flowering plants at a time). Patients who were caught with more than this in their possession could argue "affirmative defense of medical necessity" but were not protected under state law with the rights of those who stayed within the guidelines set forth by the state. The Colorado Amendment 64, which was passed by voters on November 6, 2012, led to recreational legalization in December 2012 and state-licensed retail sales in January 2014. The policy has led to cannabis tourism. There are two sets of policies in Colorado relating to cannabis use: those for medicinal cannabis and for recreational drug use along with a third set of rules governing hemp. == History == === Prohibition (1917) (1929) and (1937) === Amidst an early 20th century trend of limiting the drug, Colorado first restricted cannabis on March 30, 1917. This made the use and cultivation of cannabis a misdemeanor, which was subject to a fine of between $10 and $100 (equivalent to $200 and $2,500 in 2024) and up to a month in jail. In 1929, the Colorado Legislature passed a law making the second offense of sale, possession and distribution of marijuana a felony by one to five years in prison. Shortly after the 1937 Marihuana Tax Act went into effect on October 1, 1937, the Federal Bureau of Narcotics and Denver Police Department arrested Moses Baca for possession and Samuel Caldwell for dealing. Baca and Caldwell's arrest made them the first marijuana convictions under U.S. federal law for not paying the marijuana tax. Judge Foster Symes sentenced Baca to 18 months and Caldwell to four years in Leavenworth Penitentiary for violating the 1937 Marihuana Tax Act. === Decriminalization (1975) === In 1975, during a short-lived wave of decriminalization in the country, Colorado decriminalized possession of cannabis of up to one ounce (28 g), which was made a petty offense with a maximum fine of $100 (equivalent to $584 in 2024). That amount was increased to two ounces (57 g) in 2010, still with a maximum fine of $100 (equivalent to $144 in 2024). A contributing factor in the favor of decriminalization was the work on behalf of NORML by Pitkin County Deputy District Attorney Jay Moore, who helped win over the legislature's Republican leadership with arguments as to money wasted on needless enforcement of marijuana laws. === Medical marijuana (2000) === On November 7, 2000, 54% of Colorado voters approved Amendment 20, which amended the State Constitution to allow the use of marijuana in the state for approved patients with written medical consent. Under this law, patients may possess up to 2 ounces (57 g) of medical marijuana and may cultivate no more than six marijuana plants (no more than three of these mature flowering plants at a time). Patients who are caught with more than this in their possession may argue "affirmative defense of medical necessity" but are not protected under state law with the rights of those who stay within the guidelines set forth by the state. Furthermore, doctors, when making a patient recommendation to the state can recommend the rights to possess additional medicine and grow additional plants, because of the patient's specific medical needs. Conditions recognized for medical marijuana in Colorado include: cachexia; cancer; chronic pain; chronic nervous system disorders; epilepsy and other disorders characterized by seizures; glaucoma; HIV or AIDS; multiple sclerosis and other disorders characterized by muscle spasticity; and nausea. Additionally, patients may not use medical marijuana in public places or in any place where they are in plain view, or in any manner which may endanger others (this includes operating a vehicle or machinery after medicating). Colorado medical marijuana patients cannot fill prescriptions at a pharmacy because under federal law, marijuana is classified as a schedule I drug. Instead, patients may get medicine from a recognized caregiver or a non-state-affiliated club or organization, usually called a dispensary. Dispensaries in Colorado offer a range of marijuana strains with different qualities, as well as various "edibles" or food products that contain marijuana extracts. Certain dispensaries also offer patients seeds and "clones" for those who want to grow their own medicine. In April 2013, the Colorado Court of Appeals held in Coats v. Dish Network that since marijuana remains against federal law, employers can use that standard rather than state law as a rationale for banning off-the-job worker use, and are not bound by Colorado's Lawful Activities Statute: The primary question before us is whether federally prohibited but state-licensed medical marijuana use is "lawful activity" under section 24-34-402.5, C.R.S. 2012, Colorado's Lawful Activities Statute. If it is, employers in Colorado would be effectively prohibited from discharging an employee for off-the-job use of medical marijuana, regardless of the fact that such use was in violation of federal law.On June 10, 2016, Governor John Hickenlooper signed House Bill 16–1359. This bill stated that the court shall not prohibit the use or possession of medical marijuana as a condition of probation unless the individual is sentenced to probation for a conviction under Article 43.3 of Title 12, C.R.S.; or if the court determines based upon any material evidence that such a prohibition is necessary and appropriate to accomplish the goals of sentencing stated in 18-1-102.5, C.R.S. === Recreational marijuana (2012) === Since the enactment of Colorado Amendment 64 in November 2012, adults aged 21 or older can grow up to six marijuana plants (with no more than half being mature flowering plants) privately in a locked space, legally possess all marijuana from the plants they grow (as long as it stays where it was grown), legally possess up to one ounce (28 g) of marijuana while traveling, and give as a gift up to one ounce (28 g) to other citizens 21 years of age or older. Any adult in Colorado's territory may possess up to one ounce (28 g) of marijuana at any time, regardless of whether they are an in-state resident or an out-of-state visitor, as of 2016. Retail concentrate/edible limits are as follows: 8 grams (1⁄4 oz) of retail concentrate will be equal to 1 ounce (28 g) of flower, and therefore 800 mg of THC in the form of retail edibles will be equal to 1oz of retail flower. Consumption is permitted in a manner similar to alcohol, with equivalent offenses prescribed for driving. Consumption in public was recently passed in Denver under Ordinance 300 with a vote of 53% for legal public consumption, and a 46% vote against. Within 60 days the new rules will be written and should be similar to current public alcohol consumption rules and regulations. Amendment 64 also provides for licensing of cultivation facilities, product manufacturing facilities, testing facilities, and retail stores. Visitors and tourists in Colorado can purchase marijuana and use it in the state. Denver airport has banned all possession of marijuana but admits it has not charged a single person with possession nor has the airport seized any marijuana since the ban went into effect. Governor Hickenlooper signed several bills into law on May 28, 2013, implementing the recommendations of the Task Force on the Implementation of Amendment 64. On September 9, 2013, the Colorado Department of Revenue adopted final regulations for recreational marijuana establishments, implementing the Colorado Retail Marijuana Code (HB 13–1317). On September 16, 2013, the Denver City Council adopted an ordinance for retail marijuana establishments. The state prepared for an influx of tourists with extra police officers posted in Denver. Safety fears led to officials seeking to limit use of the drug in popular ski resorts. According to a Quinnipiac University poll released July 21, 2014, Coloradans continued to support the state's legalization of marijuana for recreational use by a margin of 54–43 percent. At the same time, the poll indicated 66 percent of voters there think marijuana use should be legal in private homes and in members-only clubs, but should not be legal in bars, clubs or entertainment venues where alcohol is served. Sixty-one percent of respondents also said laws regulating marijuana use should be as strict as laws regulating alcohol use. During 2014, the first year of implementation of Colorado Amendment 64, Colorado's legal marijuana market (both medical and recreational) reached total sales of $700 million. In September 2014, legislation was submitted by Alabama senator Jeff Sessions to ensure that Electronic Benefit Transfer cards could not be used to purchase marijuana, as the United States Department of Health and Human Services stated that their usage in marijuana shops was not prohibited. By April 2018, revenue from legalized marijuana only amounted to 2% of the state's education budget, with some calling it "a drop in a bucket." During this month, sales records showed that marijuana sales were flat and were about the same as they were the previous year. In mid-2019, Governor Jared Polis signed a law that would allow licensed businesses to have social marijuana use areas. == Regulation == General regulations for the legal commercial production and vending of marijuana in the state, which continue to be updated by the General Assembly, are published through the Marijuana Enforcement Division of the Department of Revenue. In July 2021, the Governor of Colorado established the Colorado Cannabis Business Office. Hemp is defined as any form of the cannabis plant which has less than "3/10's of one percent" delta-9-THC. The state department of agriculture regulates hemp production. Colorado was one of the first states to legalize marijuana which means they were very careful when outlining how they would regulate it. There are multiple forms of marijuana such as smoking the plant, concentrates and edible making it difficult for Colorado to regulate. The Governors' office worked and is still working hand in hand with individuals involved in law enforcement, public and environmental health, human services, and education to find solutions. Marijuana causes impaired judgment and lack of coordination making it unsafe to drive at certain levels. This is problematic due to the rest of the population being at risk on the roads. Colorado has created legislation that states it is unlawful for one to operate a vehicle when intoxicated at a blood THC level of 5 nanograms/milliliter or more. Colorado put in place legislation stating that only persons 21 and older can possess one ounce (28 g) of weed or less on hand. In May 2021 the lawful possession limit for adults was doubled to two ounces (57 g) per person. === Impaired driving === Like other states, driving while impaired by any drug is illegal in Colorado, though it took the legislature six attempts and three years to pass marijuana intoxication measures. Ultimately the legislators decided on a nanogram limit in the bloodstream, though the number they picked was scoffed at by activists. Today Colorado law states that juries may convict a person of marijuana intoxication if they have five or more nanograms of THC per milliliter of blood, but defendants are allowed to argue that they were not intoxicated despite having such levels of THC in their bloodstream. ==== Testing limitations ==== Since the legalization of recreational Marijuana in the state of Colorado testing an individual's level of intoxication has proven to be a challenge. “There is no one blood or oral fluid concentration that can differentiate impaired and not impaired,” (Berger, 2018). == Results == The Colorado amendment 64, which was passed by voters on November 6, 2012, led to legalization in January 2014. The annual number of teenager (13 to 21 years old) visits to emergency rooms involving a cannabis related diagnostic code or positive for marijuana from a urine drug screen more than quadrupled during the decade (2005-2014) leading to the legalization. Two thirds of these cases involving marijuana were about mental health problems, and more than half of these cases also tested positive for other drugs. A national survey conducted between 2014 and 2016 alleged that adolescent abuse of marijuana has fallen to the lowest level it has been in years after legalization. This has been attributed to both additional funding raised from taxation and law enforcement's increasing involvement in the oversight of production and sales. The biannual Healthy Kids Colorado Survey provides data on marijuana usage and attitudes among public middle or high schools students. According to the 2015 survey, Colorado's youth marijuana use rate dipped slightly in 2015 and was lower than the national average. The percentage of teenagers who have "used marijuana one or more times during the past 30 days" had dropped to 21% in 2015, down from 25% in 2009. The 2019 survey showed that the percentage of students who had "used marijuana one or more times during the past 30 days" stayed stable, between 19.4 and 21.2 percent, from 2013 until 2019, and there was no clear trend. In 2014, Colorado invested $2 million generated from marijuana sales tax revenue on campaigns aimed at anti-marijuana education of minors and the state has plans to spend double that amount, $4 million in 2015 (out of a total projected marijuana sales tax revenue of $125 million). The current campaigns provide information on marijuana laws, the impacts of youth use, the dangers of driving under the influence of any drug, and the harmful side effects of using marijuana. In 2017, the government of Colorado collected over $247 million in taxes, fees, and licensing costs. By 2018, there was $905 million in total recreational cannabis sales since the legalization in 2014. == See also == Colorado Amendment 44 (2006) Colorado Amendment 64 (2012) Law of Colorado Cannabis Law Reform Prohibition of drugs Washington Initiative 502 Colorado Badged Network == References == == External links == History of Cannabis in Colorado Denver Marijuana Info at Colorado.gov	Wikipedia/Drug_policy_of_Colorado
The term magistrate is used in a variety of systems of governments and laws to refer to a civilian officer who administers the law. In ancient Rome, a magistratus was one of the highest ranking government officers, and possessed both judicial and executive powers. In other parts of the world, such as China, magistrate is a word applied to a person responsible for administration over a particular geographic area. Today, in some jurisdictions, a magistrate is a judicial officer who hears cases in a lower court, and typically deals with more minor or preliminary matters. In other jurisdictions (e.g., England and Wales), magistrates are typically trained volunteers appointed to deal with criminal and civil matters in their local areas. == Original meaning == In ancient Rome, the word magistratus referred to one of the highest offices of state. Analogous offices in the local authorities, such as municipium, were subordinate only to the legislature of which they generally were members, ex officio, often a combination of judicial and executive power, constituting one jurisdiction. In Rome itself, the highest magistrates were members of the so-called cursus honorum, 'course of honors'. They held both judicial and executive power within their sphere of responsibility (hence the modern use of the term "magistrate" to denote both judicial and executive officers), and also had the power to issue ius honorarium, or magisterial law. The Consul was the highest Roman magistrate. The Praetor (the office was later divided into two, the Urban and Peregrine Praetors) was the highest judge in matters of private law between individual citizens, while the Curule Aediles, who supervised public works in the city, exercised a limited civil jurisdiction in relation to the market. Roman magistrates were not lawyers, but were advised by jurists who were experts in the law. The term was maintained in most feudal successor states to the western Roman Empire. However, it was used mainly in Germanic kingdoms, especially in city-states, where the term magistrate was also used as an abstract generic term denoting the highest office, regardless of the formal titles (e.g. Consul, Mayor, Doge), even when that was actually a council. The term "chief magistrate" applied to the highest official, in sovereign entities the head of state and/or head of government. == Continental Europe and its former colonies == Under the civil law systems of European countries, such as Belgium, France, Italy and the Netherlands, magistrat (French), magistrato (Italian) and magistraat (Dutch) are generic terms which comprise both prosecutors and judges, distinguished as the 'standing' versus 'sitting' magistrature, respectively. In France and Italy, and several other European countries, examining magistrate judges have represented the victim and are part of overseeing investigations from the beginning of a case, in consultation with police and prosecutors. In France they are titled investigative judge (juge d'instruction, "judge of inquiry"). Italy and some other nations have ended this practice. In Portugal, besides being used in the scope of the judiciary to designate prosecutors and judges, the term magistrado was also used to designate certain government officials, like the former civil governors of district. These were referred as "administrative magistrates", to distinguish them from the judiciary magistrates. The President of Portugal is considered the Supreme Magistrate of the Nation. In Finland, maistraatti (the Finnish-language cognate of "magistrate", officially translated as "local register office") is a state-appointed local administrative office whose responsibilities include keeping population information and public registers, acting as a public notary and conducting civil marriages. === Mexico === In Mexico's Federal Law System, a magistrado (magistrate) is a superior judge (and the highest-ranking State judge), hierarchically beneath the Supreme Court Justices (Ministros de la Corte Suprema). The magistrado reviews the cases seen by a judge in a second term if any of the parties disputes the verdict. For special cases, there are magistrados superiores (superior magistrates) who review the verdicts of special court and tribunal magistrates. === Germany === In Germany, the magistrational roles of the judge were transferred to a newly established legal body of the judiciary in 1942, which is that of the Rechtspfleger or judicial magistrate. == English common law tradition == === United Kingdom === ==== England and Wales ==== Magistrates hear 'summary offences' and some 'triable-either-way offences' in the Courts of England and Wales. In 2021, there were 12,651 magistrates, a number that has fallen steadily in recent years, decreasing by 50% from 25,170 since 2012. Magistrates have a maximum sentencing power of up to 12 months' imprisonment, and/or an unlimited fine. In practice, magistrates have a wide range of sentencing options, which include issuing fines, imposing community orders, or dealing with offences by means of a discharge. In more serious cases, where magistrates consider that their sentencing powers are insufficient, they can send 'either-way' offenders to the Crown Court for sentencing. All criminal cases begin in a magistrates' court. The most serious cases (for example murder, rape, etc) are sent to the Crown Court, although magistrates' will often decide on issues such as bail and any preliminary matters. Lesser offences, including all summary only offences and some either-way offences will be dealt with entirely in the magistrates' court. A wide range of other legal matters are within the remit of magistrates, such as matters relating to licensing and debt collection, for example. In the past, magistrates have been responsible for granting licences to sell alcohol; this function is now exercised by local councils, although there is a right of appeal to the magistrates' court. Magistrates are also responsible for granting orders such as search warrants to the police and other authorities. It used to be a requirement that they live within a 15-mile (24 km) radius of the area they preside over (the commission area) in case they are needed to sign a warrant after hours. However, commission areas were replaced with Local Justice Areas by the Courts Act 2003, meaning magistrates no longer need to live within 15 miles (24 km), although, in practice, many still do. Section 7 of the Courts Act 2003 states that "There shall be a commission of the peace for England and Wales—…b) addressed generally, and not by name, to all such persons as may from time to time hold office as justices of the peace for England and Wales". Thus, every magistrate in England and Wales may act as a magistrate anywhere in England or Wales. There are two types of magistrates in England and Wales: Justices of the Peace, and District Judges (formerly known as stipendiary magistrates). Justices of the peace (JPs) are trained volunteers appointed from the local community; the nature of their role means that it is not necessary for them to be legally qualified, but they do have the assistance of a legally qualified adviser in Court. JPs require intelligence, common sense, integrity, and the capacity to act fairly. They are selected by a local advisory committee and only recommended to the Lord Chancellor for appointment if they can demonstrate the six key qualities required of a judicial office holder, these are: (a) good character, (b) commitment and reliability, (c) social awareness, (d) sound judgement, (e) understanding and communication and (f) maturity and sound temperament. Membership is widely spread throughout the area covered and drawn from all walks of life. Police officers, traffic wardens, RSPCA employees and certain other categories of employees, as well as their close relatives, will not be appointed, nor will those convicted of certain criminal offences including recent minor offences. All new justices of the peace undergo comprehensive training before sitting. There is a mentoring programme to help guide new appointees (mentors are magistrates with at least three years' service). The training, delivered by the Judicial College, covers the necessary law and procedure required for their role. They continue to receive training throughout their judicial career, and are appraised every four years (every two years for a Presiding Justice) to check that they continue to remain competent in their role. Additional training is given to justices choosing to sit in the Youth Court or those dealing with family matters. New JPs sit with mentors on at least six occasions during their first eighteen months. Justices of the peace are unpaid appointees, but they may receive allowances to cover travelling expenses, subsistence and loss of earnings for those not paid by their employer while sitting as a magistrate, up to a maximum of £116.78 a day. A justice of the peace may sit at any magistrates' court in England and Wales, but in practice, they are appointed to their local bench (a colloquial and legal term for the local court). Justices of the peace will normally sit as a panel of three, with two as a minimum in most cases, except those cases dealt with under the single justice procedure. Many are members of the Magistrates' Association, which provides advice and training and also represents magistrates. The other type of magistrate is known as a district judge (magistrates' courts). Unlike justices of the peace, district judges (magistrates' courts) usually sit alone, although still have the benefit of a legal adviser. They are paid Judges appointed by open competition through a process administered by the Judicial Appointments Commission (JAC) and are required to be qualified solicitors, barristers, or chartered legal executives. Some also sit in the family court. Questions have been raised by the Magistrates' Association as to the legal safeguards of a single district judge allowed to hear a case, decide the outcome, and pass sentence without reference to another party, however the criminal procedure rules do require some cases to be heard by a district judge, such as those matters relating to extradition or where the contested issue is a disputed point of law. According to the official statistics for diversity of the judiciary in April 2021, 56% of sitting magistrates were women, 13% were Black, Asian and minority ethnic and 82% per aged above 50. ==== Scotland ==== In the courts of Scotland, the office of stipendiary magistrate was established by Section 5 of the District Courts (Scotland) Act 1975,: Section 5 and was replaced by the office of summary sheriff by Section 218 of the Courts Reform (Scotland) Act 2014. In Scotland, the lowest level of law-court, a justice of the peace court, is presided over by a justice of the peace, who like in England and Wales are trained volunteers. Stipendiary magistrates are, ex officio, justices of the peace, and when sitting in a JP court had the summary criminal jurisdiction and powers of a sheriff.: Section 5 === Australia === ==== Federal magistrate ==== A federal magistrate was an office created on 23 December 1999 along with the establishment of the Federal Magistrates' Court by the Australian Government as a result of royal assent of the Federal Magistrates Act 1999 (Cth). Its first judicial officers were appointed in 2000; it first applications were filed on 23 June 2000 and the Court's first sittings were conducted on 3 July 2000 in Adelaide, Brisbane, Canberra, Melbourne, Newcastle, Parramatta and Townsville. The Federal Magistrates' Court of Australia dealt with more minor Commonwealth law matters which had previously been heard by the Federal Court of Australia (administrative law, bankruptcy, consumer protection, trade practices, human rights, and copyright) or the Family Court (divorce, residence [or custody], and contact with [or access to] the children, property division upon divorce, maintenance, and child support). In some areas, such as bankruptcy and copyright, the court had virtually unlimited jurisdiction. The federal magistrates would hear shorter or less complex matters or matters in which the monetary sum in disputes does not exceed given amounts. For instance, property divisions where the total assets are A$700,000 or less and consumer law matters (trade practices) where the amount claimed is less than $750,000. The first Chief Federal Magistrate, Diana Bryant left the court in 2004 when she was appointed Chief Justice of the Family Court of Australia, the third person to be appointed that position since the establishment of the Family Court. Eventually, the Federal Magistrates' Court assumed a significant part of the workload of the Federal Court and the Family Court. By May 2004, the court was dealing with 73% of the total number of applications made in the three courts). The Federal Magistrates' Court was exercising jurisdiction well in excess of that of the state magistrates' courts, and similar to that of the District and County courts of the Australian states. On 12 April 2013, in recognition of its increased jurisdiction and its role as an intermediate court servicing regional centres as well as capital cities throughout Australia, the Federal Magistrates' Court was renamed the Federal Circuit Court of Australia, the Act renamed as the Federal Circuit Court of Australia Act 1999, and its judicial officers received the title "judge" instead of "federal magistrate". ==== State magistrate ==== The state magistrates in Australia derive from the English magistrates. All magistrates are salaried officers. The jurisdiction of the magistrates varies from state-to-state. They preside over courts which are, depending on the state, called magistrates' courts, Local Court, or courts of petty sessions. Magistrates hear bail applications, motor licensing applications, applications for orders restraining a given individual from approaching a specific person ("intervention orders" or "apprehended violence orders"), summary criminal matters, the least serious indictable criminal matters, and civil matters where the disputed amount does not exceed A$40,000 to A$100,000 (depending on the state). In some states, such as Queensland and NSW, the magistrate may appear robed; although, some magistrates are known to prefer a business suit. Magistrates presiding in the Koori Court (which deals with Aboriginal defendants) were originally of a mind not to appear robed; however, elders within the Indigenous community urged magistrates to continue wearing robes to mark the solemnity of the court process to defendants. Robing is being considered for magistrates in other states; however, neither counsel nor solicitors appear robed in any Australian magistrates' court. Robing in summary courts is unlikely to extend to the legal profession. Historically, magistrates in Australia have been referred to as "Your Worship". (From Old English weorthscipe, meaning being worthy of respect.) However, members of the magistracy are now addressed as "Your Honour" in all states. This was partly to recognize the increasing role magistrates play in the administration of justice, but also to recognize the archaic nature of "Your Worship", and the tendency for witnesses and defendants to incorrectly use "Your Honour" in any event. It is also acceptable to address a magistrate simply as Sir or Madam. === Hong Kong === As of 2024, there are seven magistrates' courts in Hong Kong. Magistrates are appointed by the Chief Executive on the recommendation of the Judicial Officers Recommendation Commission and must be qualified barristers. Magistrates exercise criminal jurisdiction over a wide range of offences. Although there is a general limit of two years' imprisonment or a fine of HK$100,000, certain statutory provisions give Magistrates the power to sentence up to three years' imprisonment and to impose a fine up to HK$5,000,000. === Bangladesh === According to the Code of Criminal Procedure (CrPC), 1898, there are two classes of magistrates in Bangladesh, namely judicial magistrate and executive magistrate. There are four classes of judicial magistrate (chief metropolitan magistrate in metropolitan areas and chief judicial magistrate in other areas, magistrate of the first class, metropolitan magistrate in metropolitan areas), magistratem of the second class and magistrates of the third class. ==== Executive magistrate ==== According to section 10(6 )of the Code of Criminal Procedure (CrPC) 1898, members of the Bangladesh Civil Service (Administration) Cadre in the capacity of assistant commissioner, upozila mirbahi officer and additional deputy commissioner shall be executive magistrates and may exercise the power of executive magistrates within their existing respective local areas. Besides this, according to the provision of the section 10(5), the government may, if it thinks it expedient or necessary, appoint any persons employed in the Bangladesh Civil Service (Administration) to be an executive magistrate and confer the powers of an executive magistrate on any such member. Every administrative district has the following executive magistrates: District magistrate: In every district and in every metropolitan area, the government shall appoint as many persons as it thinks fit to be executive magistrates and shall appoint one of them to be the district magistrate. Additional district magistrate : The government may also appoint any executive magistrate to be an additional district magistrate who shall have all or any of the powers of a district magistrate under the code or under any other law for the time being in force, as the government may direct. Additional deputy commissioner:, all of whom are executive magistrates. Upazila nirbahi officer or sub-district executive officer Assistant commissioner including senior assistant commissioner and assistant commissioner (land). === India === There are two classifications of magistrates: judicial magistrates, who are part of the judiciary (court), and executive magistrates, who are government administrative officials and belong to the executive branch of the government. ==== Judicial magistrates ==== There are four categories of magistrates in the judiciary of India. This classification is given in the Criminal Procedure Code, 1973 (CrPC). It stipulates that in each sessions district, there shall be: a chief judicial magistrate a sub-divisional judicial magistrate (SD-JM) a judicial magistrates first class (JFCM/JM-FC) The chief judicial magistrate [CJM] (including additional chief judicial magistrates) hear all types of criminal cases. All magistrates' courts are controlled by the CJM. who looks over the work of judicial magistrates, but cannot take any action against them. The CJM can only report the misbehavior of judicial magistrates to the High Court. A court of chief judicial magistrates can sentence a person to jail for up to seven years and impose fines up to any amount. The CJM is the most senior magistrate in their district. There is a sub-divisional judicial magistrate (SDJM) in every subdivision. They hear cases related to the Dowry Act, EC Act, and other criminal cases. They also maintain and control the judicial court below them. A court of sub-divisional judicial magistrates may sentence a person to imprisonment for up to three years and impose a fine of up to ₹10,000 (US$120). Judicial magistrates can try criminal cases. A judicial magistrate of first class (also known as judicial first class magistrate) can sentence a person to jail for up to three years and impose a fine of up to ₹10,000 (US$120). ==== Executive magistrates ==== An executive magistrate is an officer of the executive branch of the state government (e.g., government department, typically the land revenue department) rather than the Judicial branch. The primary mandate of an Executive Magistrate is to preserve public tranquility and prevent any actions that may disrupt peace and order. They are vested with specific powers under both the Bharatiya Nagarik Suraksha Sanhita (BNSS - the "Indian Citizen Safety Code") and the Bharatiya Nyaya Sanhita (BNS - the "Indian Justice Code"). These powers are conferred by Sections 125–129, 152, 163, 164 and 166 of the BNSS. They are distinct from Judicial Magistrates, who preside over courts, conduct trials and try criminal cases. These officers cannot try any accused nor pass verdicts. A person arrested on the orders of a court located outside the local jurisdiction should be produced before an executive magistrate who can also set the bail amount for the arrested individual to avoid police custody, depending on the terms of the warrant. The executive magistrate also can pass orders restraining persons from committing a particular act or preventing persons from entering an area (Section 163, BNSS). There is no specific provision to order a "curfew". The executive magistrates alone are authorised to use force against people. In plain language, they alone can disperse an "unlawful assembly". Technically, the police are to assist the executive magistrate. Executive magistrates can dictate to the police the manner of force (baton charge, tear gas, blank fire, firing) and how much force should be used. They can also seek the assistance of the armed forces to quell a riot. There are, in each revenue district (as opposed to a sessions district) the following kinds of executive magistrates: a district magistrate (DM) two or more additional district magistrates (ADM) four or more sub-divisional magistrates (SDM) at least ten executive magistrates All of the executive magistrates of the district, except the ADM, are under the control of the DM. These magistrates are normally conferred on the officers of the Revenue Department, although an officer can be appointed exclusively as an executive magistrate. Normally, the collector of the district is appointed as the DM. Similarly, the sub-collectors/sub divisional officers are appointed as the SDMs. Tehsildars and deputy/additional tehsildars are appointed as executive magistrates. In some metropolitan areas, the government has conferred specific or full powers of an Executive Magistrate upon Police Commissioners and their deputies within the police commissionerate system. The BNSS, 2023 (Section 15) allows state governments to appoint "Special Executive Magistrates." These can be either existing Executive Magistrates or senior police officers (Superintendent of Police or higher). They are appointed for specific areas or duties and are granted certain powers of Executive Magistrates, as determined by the state government. Their appointment is for a term decided by the state. Under the old CrPC, there was no distinction between the executive and judicial magistrates and some states still follow the old CrPC. === New Zealand === The position of stipendiary magistrate in New Zealand was renamed in 1980 to that of district court judge. The position was often known simply as "magistrate" or with the postnominal initials "SM" in newspapers' court reports. In the late 1990s, a position of community magistrate was created for District Courts on a trial basis. A community magistrate sits in the hierarchy just below a district court judge. They only have criminal case jurisdiction. They are lay judicial officers, not needing to hold a law degree, although many do. === Sri Lanka === In Sri Lanka, a magistrate is a judicial officer appointed to preside over a magistrate's court to a particular jurisdiction under the Judicature Act No 02 of 1978. The post was formally known as police magistrate when the courts were known as police magistrate courts. Magistrates have jurisdiction over the criminal cases filed under the penal code. They carry out first mortem and post mortem examinations, issue search warrants and arrest warrants, produce suspected persons and grant bail. In many cases, magistrates preside over primary courts Unofficial magistrates can be appointed from among the senior lawyers of the local bar. There are four types of magistrate Chief magistrate (only of the metropolitan area of Colombo) Magistrate/municipal magistrate Additional magistrate (found when there are more than one Magistrate in one station) Unofficial magistrate === United States === Magistrates are somewhat less common in the United States than in Europe, but the position does exist in some state jurisdictions and in federal courts. The term "magistrate" is often used (chiefly in judicial opinions) as a generic term for any independent judge who is capable of issuing warrants, reviewing arrests, etc. When used in this way, it does not denote a judge with a particular office. Instead, it denotes (somewhat circularly) a judge or judicial officer who is capable of hearing and deciding a particular matter. That capability is defined by state statute or by common law. In Virginia, for example, the Constitution of 1971 created the office of magistrate to replace the use in cities and counties of the justice of the peace, which is common in many states for this function. As noted above, the terms "magistrate" or "chief magistrate" were sometimes used in the early days of the republic to refer to the president of the United States, as in President John Adams's message to the U.S. Senate upon the death of George Washington: "His example is now complete, and it will teach wisdom and virtue to magistrates, citizens, and men, not only in the present age, but in future generations, as long as our history shall be read" (19 December 1799). ==== Federal courts ==== In the United States federal courts, a magistrate judge is a judicial officer authorized by 28 U.S.C. § 631 et seq. They were formerly known as U.S. commissioners, and then as magistrates. Magistrate judges, as they have been designated since 1990, are appointed by the federal district judges of a particular court, serving terms of eight years if full-time, or four years if part-time, and may be reappointed. Magistrate judges conduct a wide range of judicial proceedings to expedite the disposition of the civil and criminal caseloads of the United States district courts. Congress set forth in the statute the powers and responsibilities that could be delegated by district court judges to magistrate judges. To achieve maximum flexibility in meeting the needs of each court, however, Congress left to the individual courts the actual determination of which duties to assign to magistrate judges. ==== State courts ==== In many state court systems in the United States, magistrate courts are the successor to Justice of the Peace courts, and frequently have authority to handle the trials of civil cases up to a certain dollar amount at issue, applications for bail, arrest and search warrants, and the adjudication of petty or misdemeanor criminal offences. In Ohio, magistrates are subordinate to the judge or judges who appoint them, and all of their decisions are subject to the review, amendment, approval, or reversal by a judge. In some states, including West Virginia and Georgia, magistrates are elected and not appointed. == Other traditions == === China === Magistrate, or chief magistrate, is also a common translation of the Chinese xianzhang (县长/縣長 literally: county leader) the political head of a county or xiàn/hsien (县/縣) which ranks in the third level of the administrative hierarchy of China. Magistrates are also the administrative heads of government of counties during the Republican era. The county magistrate elections are heavily and sometimes bitterly contested, and are often a stepping-stone to higher office. The translation dates from imperial China in which the county magistrate was the lowest official in the imperial Chinese bureaucracy and had judicial in addition to administrative functions. After losing the Chinese Civil War, county magistrate elections in the Republic of China were first open to election in the 1960s and, before the end of martial law in 1991, were the highest elected position of any real power, and hence, the focus of election campaigns by the Tangwai movement. The magistrates became the first level head of government after the central government reduced provincial powers in 1998. In the People's Republic of China, the county leader is elected by the local people's congress but the process is controlled by the Communist Party. === Russia === In Russia, magistrates (justices of the peace) handle minor criminal cases where imprisonment is for less than three years such as slander, petty hooliganism, public drunkenness, and serious traffic violations of a non-criminal nature, minor civil cases such as simple divorces, some property cases, disputes over land, and some labor cases, as well as some federal administrative law cases. The magistrates are the only judges of the regional level within the judiciary of Russia. All other courts, including the district courts, are federal, as they are financed from the federal budget and their judges are appointed by the president of Russia, while the magistrates are financed from the regional budgets and are usually appointed by regional legislatures or elected by the population of a judicial district . === Switzerland === In Switzerland, magistrate is a designation for the persons holding the most senior executive and judicial offices. On the federal level, the members of the Federal Council, the Federal Chancellor, and the judges on the Federal Supreme Court are called magistrates. The designation of magistrate is not a title or style. It does not, by itself, confer any particular privileges. === Siam === In Siam, the position of yakkrabutr (ยกกระบัตร) is similar to that of the magistrate and was given to palace officials sent to provincial capitals to administers law and ensure justice on behalf of the monarch. The position was phased out and reformed into the position of prosecutor in 1916 during the reign of Rama VI. === Kenya === In Kenya, there are five categories of magistrates, namely resident magistrate, senior resident magistrate, principal magistrate, senior principal magistrate and chief magistrate. Chief magistrate is the highest ranking among magistrates and also assumes administrative control of magistrate courts in his or her jurisdiction. A chief magistrate has jurisdiction in a dispute that does not exceed seven million Kenya shillings. For senior principal magistrates, the limit is in disputes not exceeding five million Kenya shillings; for principal magistrates it is disputes not exceeding four million Kenya shillings. Senior resident magistrates have jurisdiction in disputes not exceeding three million Kenya shillings and resident magistrates in disputes not exceeding two million Kenya shillings. == In popular culture == The British humorist P.G. Wodehouse wrote in one of his Jeeves and Wooster stories, "Jeeves and the Feudal Spirit" (1955), "Well, you know what magistrates are. The lowest form of pond life. When a fellow hasn't the brains and initiative to sell jellied eels, they make him a magistrate." Bertie Wooster often appeared before magistrates when he was arrested for minor offences. A plump and foolish magistrate is a key character in Amy Tan's children's book (and the related PBS television show) Sagwa, the Chinese Siamese Cat. In the post-colonial novel Waiting for the Barbarians by J. M. Coetzee, the story is told from the narrative perspective of the magistrate of one of the settlements in what is presumed to be Africa. In the Walt Disney movie Davy Crockett: King of the Wild Frontier, Crockett is appointed magistrate of the local community. Magistrates appear in the Star Trek universe as well. On Star Trek: Deep Space Nine, Constable Odo often threatens detainees or those he suspects are guilty of various crimes and violations that he will send them to the magistrate, or tells them sarcastically, in response to their pleas of innocence, to "Tell it to the magistrate." In the first installment of the popular StarCraft real-time strategy series, one plays as a magistrate working for the Confederacy, a cruel government. One later joins the Sons of Korhal, aiding in the rebellion. In the videogame series Ace Attorney, there is a fictional children's television show called The Steel Samurai, which is referenced in many cases. The main antagonist of the show is the Evil Magistrate. == See also == Agoranomi Chief magistrate Executive Magistrate of Bangladesh Justice in Eyre Lawspeaker Resident magistrate Roman magistrate == Notes == == References == Etymology Online Van Wert County, Ohio Court Personnel == External links == Quotations related to Magistrate at Wikiquote The dictionary definition of magistrate at Wiktionary Media related to Magistrates at Wikimedia Commons Become a magistrate (GOV.UK, England and Wales) Criminal courts – magistrates' courts (GOV.UK, England and Wales) How sentencing works: You be the Judge Archived 7 December 2018 at the Wayback Machine	Wikipedia/Magistrate
In law, a trial is a coming together of parties to a dispute, to present information (in the form of evidence) in a tribunal, a formal setting with the authority to adjudicate claims or disputes. One form of tribunal is a court. The tribunal, which may occur before a judge, jury, or other designated trier of fact, aims to achieve a resolution to their dispute. == Types by finder of fact == Where the trial is held before a group of members of the community, it is called a jury trial. Where the trial is held solely before a judge, it is called a bench trial. Hearings before administrative bodies may have many of the features of a trial before a court, but are typically not referred to as trials. An appeal (appellate proceeding) is also generally not deemed a trial, because such proceedings are usually restricted to a review of the evidence presented before the trial court, and do not permit the introduction of new evidence. == Types by dispute == === Criminal === A criminal trial is designed to resolve accusations brought (usually by a government) against a person accused of a crime. In common law systems, most criminal defendants are entitled to a trial held before a jury. Because the state is attempting to use its power to deprive the accused of life, liberty, or property, the rights of the accused afforded to criminal defendants are typically broad. The rules of criminal procedure provide rules for criminal trials. === Civil === A civil trial is generally held to settle lawsuits or civil claims—non-criminal disputes. In some countries, the government can both sue and be sued in a civil capacity. The rules of civil procedure provide rules for civil trials. === Administrative === Although administrative hearings are not ordinarily considered trials, they retain many elements found in more "formal" trial settings. When the dispute goes to a judicial setting, it is called an administrative trial, to revise the administrative hearing, depending on the jurisdiction. The types of disputes handled in these hearings are governed by administrative law and auxiliarily by civil trial law. === Labor === Labor law (also known as employment law) is the body of laws, administrative rulings, and precedents which address the legal rights of, and restrictions on, working people and their organizations. Collective labour law relates to the tripartite relationship between employee, employer, and union. Individual labour law concerns employees' rights at work also through the contract for work. Employment standards are social norms (in some cases also technical standards) for the minimum socially acceptable conditions under which employees or contractors are allowed to work. Government agencies (such as the former US Employment Standards Administration) enforce labour law (legislature, regulatory, or judicial). == Systems == === Adversarial === In common law systems, an adversarial or accusatory approach is used to adjudicate guilt or innocence. The assumption is that the truth is more likely to emerge from the open contest between the prosecution and the defense in presenting the evidence and opposing legal arguments, with a judge acting as a neutral referee and as the arbiter of the law. In several jurisdictions in more serious cases, there is a jury to determine the facts, although some common law jurisdictions have abolished the jury trial. This polarizes the issues, with each competitor acting in its own self-interest, and so presenting the facts and interpretations of the law in a deliberately biased way. The intention is that through a process of argument and counter-argument, examination-in-chief and cross-examination, each side will test the truthfulness, relevancy, and sufficiency of the opponent's evidence and arguments. To maintain fairness, there is a presumption of innocence, and the burden of proof lies on the prosecution. Critics of the system argue that the desire to win is more important than the search for truth. Further, the results are likely to be affected by structural inequalities. Those defendants with resources can afford to hire the best lawyers. Some trials are—or were—of a more summary nature, as certain questions of evidence were taken as resolved (see handhabend and backberend). === Inquisitorial === In civil law legal systems, the responsibility for supervising the investigation by the police into whether a crime has been committed falls on an examining magistrate or judge who then conducts the trial. The assumption is that the truth is more likely to emerge from an impartial and exhaustive investigation, both before and during the trial itself. The examining magistrate or judge acts as an inquisitor who directs the fact-gathering process by questioning witnesses, interrogating the suspect, and collecting other evidence. The lawyers who represent the interests of the state and the accused have a limited role to offer legal arguments and alternative interpretations to the facts that emerge during the process. All the interested parties are expected to cooperate in the investigation by answering the magistrate or judge's questions and, when asked, supplying all relevant evidence. The trial only takes place after all the evidence has been collected and the investigation is completed. Thus, most of the factual uncertainties will already be resolved, and the examining magistrate or judge will already have resolved that there is prima facie of guilt. Critics argue that the examining magistrate or judge has too much power with the responsibilities of both investigating and adjudicating on the merits of the case. Although lay assessors do sit as a form of jury to offer advice to the magistrate or judge at the conclusion of the trial, their role is subordinate. Further, because a professional has been in charge of all aspects of the case to the conclusion of the trial, there are fewer opportunities to appeal the conviction alleging some procedural error. == Mistrials == A judge may cancel a trial prior to the return of a verdict; legal parlance designates this as a "mistrial". A judge may declare a mistrial due to: The court determining that it lacks jurisdiction over a case. Evidence being admitted improperly, or new evidence that might seriously affect the outcome of the trial being discovered. Misconduct by a party, juror, or an outside actor, if it prevents due process. A hung jury which cannot reach a verdict with the required degree of unanimity. In a criminal trial, if the jury is able to reach a verdict on some charges but not others, the defendant may be retried on the charges that led to the deadlock, at the discretion of the prosecution. Disqualification of a juror after the jury is empaneled, if no alternative juror is available and the litigants do not agree to proceed with the remaining jurors, or the remaining jurors not meeting the required number for a trial. The illness or death of a juror or attorney. Either side may submit a motion for a mistrial; on occasion, the presiding judge may declare one on a motion of their own. If a mistrial is declared, the case at hand may be retried at the discretion of the plaintiff or prosecution, as long as double jeopardy does not bar that party from doing so. == Other types == Some other kinds of processes for resolving conflicts are also expressed as trials. For example, the United States Constitution requires that, following the impeachment of the president, a judge, or another federal officer by the House of Representatives, the subject of the impeachment may only be removed from office by an impeachment trial in the Senate, a practice which evolved from the British parliament's powers of impeachment, wherein the House of Lords would also try public officials. In earlier times, disputes were often settled through a trial by ordeal, where parties would have to endure physical suffering in order to prove their righteousness; or through a trial by combat, in which the winner of a physical fight was deemed righteous in their cause. == See also == Brought to trial Legal process Trial graphics Trial of the century == References == == External links == Famous trials by the University of Missouri–Kansas City	Wikipedia/Trial
A drug policy is the policy regarding the control and regulation of psychoactive substances (commonly referred to as drugs), particularly those that are addictive or cause physical and mental dependence. While drug policies are generally implemented by governments, entities at all levels (from international organisations, national or local government, administrations, or public places) may have specific policies related to drugs. Drug policies are usually aimed at combatting drug addiction or dependence addressing both demand and supply of drugs, as well as mitigating the harm of drug use, and providing medical assistance and treatment. Demand reduction measures include voluntary treatment, rehabilitation, substitution therapy, overdose management, alternatives to incarceration for drug related minor offenses, medical prescription of drugs, awareness campaigns, community social services, and support for families. Supply side reduction involves measures such as enacting foreign policy aimed at eradicating the international cultivation of plants used to make drugs and interception of drug trafficking, fines for drug offenses, incarceration for persons convicted for drug offenses. Policies that help mitigate the dangers of drug use include needle syringe programs, drug substitution programs, and free facilities for testing a drug's purity. The concept of "drugs" –a substance subject to control– varies from jurisdiction to jurisdiction. For example, heroin is regulated almost everywhere; substances such as khat, codeine, or alcohol are regulated in some places, but not others. Most jurisdictions also regulate prescription drugs, medicinal drugs not considered dangerous but that can only be supplied to holders of a medical prescription, and sometimes drugs available without prescription but only from an approved supplier such as a pharmacy, but this is not usually described as a "drug policy". There are however some international standards as to which substances are under certain controls, in particular via the three international drug control conventions. == International drug control treaties == === History === The first international treaty to control a psychoactive substance was adopted at the Brussels Conference in 1890 in the context of the regulations against slave trade, and concerned alcoholic beverages. It was followed by the final act of the Shanghai Opium Commission of 1909 which attempted to settle peace and arrange the trade in opium, after the Opium Wars in the 19th Century. In 1912 at the First International Opium Conference held in the Hague, the multilateral International Opium Convention was adopted; it ultimately got incorporated into the Treaty of Versailles in 1919. A number of international treaties related to drugs followed in subsequent decades: the 1925 Agreement concerning the Manufacture of, Internal Trade in and Use of Prepared Opium (which introduced some restrictions—but no total prohibition—on the export of "Indian hemp" pure extracts), the 1931 Convention for Limiting the Manufacture and Regulating the Distribution of Narcotic Drugs and Agreement for the Control of Opium Smoking in the Far East, the 1936 Convention for the Suppression of the Illicit Traffic in Dangerous Drugs, among others. After World War II, a series of Protocols signed at Lake Success brought into the mandate of the newly created United Nations these pre-war treaties which had been handled by the League of Nations and the Office international d'hygiène publique. In 1961 the nine previous drug-control treaties in force were superseded by the 1961 Single Convention, which rationalized global control on drug trading and use. Countries commit to "protecting the health and welfare of [hu]mankind" and to combat substance abuse and addiction. The treaty is not a self-enforcing agreement: countries have to pass their own legislation aligned with the framework of the Convention. The 1961 Convention was supplemented by the 1971 Convention and the 1988 Convention, forming the three international drug control treaties upon which other legal instruments rely. Their implementation has been led by the United States, in particular after the Nixon administration's declaration of "War on drugs" in 1971, and the creation of the Drug Enforcement Administration (DEA) as a U.S. federal law enforcement agency in 1973. Since the early 2000s the European Union (EU) has developed several comprehensive and multidisciplinary strategies as part of its drug policy to prevent the diffusion of recreational drug use and abuse among the European population and raise public awareness on the adverse effects of drugs among all member states of the European Union, as well as conjoined efforts with European law enforcement agencies, such as Europol and EMCDDA, to counter organized crime and illegal drug trade in Europe. === Current treaties === The core drug control treaties currently in force internationally are: the Single Convention on Narcotic Drugs, 1961 (1961 Convention or Single Convention) composed of: the original Single Convention concluded at New York City (United States), 30 March 1961, and its amendement, the Protocol amending the Single Convention on Narcotic Drugs which was adopted in Geneva (Switzerland), 25 March 1972, the Convention on Psychotropic Substances (1971 Convention), concluded at Vienna, 21 February 1971, and the UN Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances (1988 Convention) concluded at Vienna (Austria), 20 December 1988. There are other treaties that address drugs under international control, such as: the UN Convention on the Law of the Sea (UNCLOS), concluded on 10 December 1982 in Montego Bay (Jamaica), the Convention on the Rights of the Child (CRC), concluded on 20 November 1989 in New York City, the International Convention Against Doping in Sport concluded in Paris (France) on 19 October 2005. Additionally, other pieces of international law enter into play, like the international human rights treaties protecting the right to health or the rights of indigenous peoples, and, in the case of plants considered as drug crops (coca plant, cannabis, opium poppy), treaties protecting the right to land, farmers' of peasants' rights, and treaties on plant genetic resources or traditional knowledge. === Treaty-mandated organizations === There are four bodies mandated under the international drug control conventions (1961, 1971 and 1988): The Commission on Narcotic Drugs (CND), a subsidiary body of the United Nations ECOSOC, the CND is acting as a Conference of the parties to the three core Conventions, the UN Secretary-General, whose mandate is de facto carried on by the United Nations Office on Drugs and Crime (UNODC), the World Health Organization (WHO), in charge of the scientific review of substances for inclusion under, changes in, or withdrawal from control (scheduling assessment), the International Narcotics Control Board (INCB), the treaty-body monitoring implementation and collecting statistical data. == Drug policy by country == === Australia === Australian drug laws are criminal laws and mostly exist at the state and territory level, not the federal, and are therefore different, which means an analysis of trends and laws for Australia is complicated. The federal jurisdiction has enforcement powers over national borders. In October 2016, Australia legislated for some medicinal use cannabis. === Bolivia === Like Colombia, the Bolivian government signed onto the ATPA in 1991 and called for the forced eradication of the coca plant in the 1990s and early 2000s. Until 2004, the government allowed each residential family to grow 1600m2 of coca crop, enough to provide the family with a monthly minimum wage. In 2005, Bolivia saw another reformist movement. The leader of a coca grower group, Evo Morales, was elected President in 2005. Morales ended any U.S. backed War on Drugs. President Morales opposed the decriminalization of drugs but saw the coca crop as an important piece of indigenous history and a pillar of the community because of the traditional use of chewing coca leaves. In 2009, the Bolivian Constitution backed the legalization and industrialization of coca products. Bolivia first proposed an amendment to the Single Convention on Narcotic Drugs in 2009. After its failure, Bolivia left the convention and re-accessed with a reservation for coca leaf in its natural form. === Canada === === China === === Colombia === Under President Ronald Reagan, the United States declared War on Drugs in the late 1980s; the Colombian drug lords were widely viewed as the root of the cocaine issue in America. In the 1990s, Colombia was home to the world's two largest drug cartels: the Cali cartel and the Medellín cartel. It became Colombia's priority, as well as the priority of the other countries in the Andean Region, to extinguish the cartels and drug trafficking from the region. In 1999, under President Andrés Pastrana, Colombia passed Plan Colombia. Plan Colombia funded the Andean Region's fight against the drug cartels and drug trafficking. With the implementation of Plan Colombia, the Colombian government aimed to destroy the coca crop. This prohibitionist regime has had controversial results, especially on human rights. Colombia has seen a significant decrease in coca cultivation. In 2001, there were 362,000 acres of coca crop in Colombia; by 2011, fewer than 130,000 acres remained. However, farmers who cultivated the coca crop for uses other than for the creation of cocaine, such as the traditional use of chewing coca leaves, became impoverished. Since 1994, consumption of drugs has been decriminalized. However, possession and trafficking of drugs are still illegal. In 2014, Colombia further eased its prohibitionist stance on the coca crop by ceasing aerial fumigation of the coca crop and creating programs for addicts. President Juan Manuel Santos (2010–2018), has called for the revision of Latin American drug policy, and was open to talks about legalization. === Ecuador === In the mid-1980s, under President León Febres-Cordero, Ecuador adopted the prohibitionist drug policy recommended by the United States. By cooperating with the United States, Ecuador received tariff exemptions from the United States. In February 1990, the United States held the Cartagena Drug Summit, in the hopes of continuing progress on the War on Drugs. Three of the four countries in the Andean Region were invited to the Summit: Peru, Colombia and Bolivia, with the notable absence of Ecuador. Two of those three countries—Colombia and Bolivia—joined the Andean Trade Preference Act, later called the Andean Trade Promotion and Drug Eradication Act, in 1992. Ecuador, along with Peru, would eventually join the ATPA in 1993. The Act united the region in the War on Drugs as well as stimulated their economies with tariff exemptions. In 1991, President Rodrigo Borja Cevallos passed Law 108, a law that decriminalized drug use, while continuing to prosecute drug possession. In reality, Law 108 set a trap that snared many citizens. Citizens confused the legality of use with the illegality of carrying drugs on their person. This led to a large increase in prison populations, as 100% of drug crimes were processed. In 2007, 18,000 prisoners were kept in a prison built to hold up to 7,000. In urban regions of Ecuador as many as 45% of male inmates were serving time for drug charges; this prison demographic rises to 80% of female inmates. In 2008, under Ecuador's new Constitution, current prisoners serving time were allowed the "smuggler pardon" if they were prosecuted for purchasing or carrying up to 2 kg of any drug, and they already served 10% of their sentence. Later, in 2009, Law 108 was replaced by the Organic Penal Code (COIP). The COIP contains many of the same rules and regulations as Law 108, but it established clear distinctions among large, medium and small drug traffickers, as well as between the mafia and rural growers, and prosecutes accordingly. In 2013, the Ecuadorian government left the Andean Trade Promotion and Drug Eradication Act. === Germany === Compared with other EU countries, Germany's drug policy is considered progressive, but still stricter than, for example, the Netherlands. In 1994 the Federal Constitutional Court ruled that drug addiction was not a crime, nor was the possession of small amounts of drugs for personal use. In 2000, Germany changed the narcotic law ("BtmG") to allow supervised drug injection rooms. In 2002, they started a pilot study in seven German cities to evaluate the effects of heroin-assisted treatment on addicts, compared to methadone-assisted treatment. The positive results of the study led to the inclusion of heroin-assisted treatment into the services of the mandatory health insurance in 2009. In 2017, Germany re-allowed medical cannabis; after the 2021 German federal election, the new government announced in their coalition agreement their intention to legalise cannabis for all other purposes (including recreational). This was implemented on 1 April 2024. Cannabis can be legally acquired from Cannabis Social Clubs which however have periodic membership fees and a maximum 500 of members as of 2024 or be grown by consumers themselves who can have up to three plants. === India === === Indonesia === Like many other governments in Southeast Asia, the Indonesian government applies severe laws to discourage drug use. === Liberia === Liberia prohibits drugs such as cocaine and marijuana. Its drug laws are enforced by the Liberia Drug Enforcement Agency. === Netherlands === Drug policy in the Netherlands is based on two principles: that drug use is a health issue, not a criminal issue, and that there is a distinction between hard and soft drugs. It was also one of the first countries to introduce heroin-assisted treatment and safe injection sites. From 2008, a number of town councils have closed many so called coffee shops that sold cannabis or implemented other new restrictions for sale of cannabis, e.g. for foreigners. Importing and exporting of any classified drug is a serious offence. The penalty can run up to 12 to 16 years if it is for hard drugs, or a maximum of 4 years for importing or exporting large quantities of cannabis. Investment in treatment and prevention of drug addiction is high when compared to the rest of the world. The Netherlands spends significantly more per capita than all other countries in the EU on drug law enforcement. 75% of drug-related public spending is on law enforcement. Drug use remains at average Western European levels and slightly lower than in English speaking countries. === Peru === According to article 8 of the Constitution of Peru, the state is responsible for battling and punishing drug trafficking. Likewise, it regulates the use of intoxicants. Consumption of drugs is not penalized and possession is allowed for small quantities only. Production and distribution of drugs are illegal. In 1993, Peru, along with Ecuador, signed the Andean Trade Preference Agreement with the United States, later replaced with the Andean Trade Promotion and Drug Eradication Act. Bolivia and Colombia had already signed the ATPA in 1991, and began enjoying its benefits in 1992. By agreeing to the terms of this Agreement, these countries worked in concert with the United States to fight drug trafficking and production at the source. The Act aimed to substitute the production of the coca plant with other agricultural products. In return for their efforts towards eradication of the coca plant, the countries were granted U.S. tariff exemptions on certain products, such as certain types of fruit. Peru ceased complying with the ATPA in 2012, and lost all tariff exemptions previously granted by the United States through the ATPA. By the end of 2012, Peru overtook Colombia as the world's largest cultivator of the coca plant. === Poland === === Portugal === In July 2001, a law maintained the status of illegality for using or possessing any drug for personal use without authorization. The offense was however changed from a criminal one, with prison a possible punishment, to an administrative one if the possessing was no more than up to ten days' supply of that substance. This was in line with the de facto Portuguese drug policy before the reform. Drug addicts were then aggressively targeted with therapy or community service rather than fines or waivers. Even if there are no criminal penalties, these changes did not legalize drug use in Portugal. Possession has remained prohibited by Portuguese law, and criminal penalties are still applied to drug growers, dealers and traffickers. === Russia === Drugs became popular in Russia among soldiers and the homeless, particularly due to the First World War. This included morphine-based drugs and cocaine, which were readily available. The government under Tsar Nicholas II of Russia had outlawed alcohol in 1914 (including vodka) as a temporary measure until the conclusion of the War. Following the Russian Revolution and in particular the October Revolution and the Russian Civil War, the Bolsheviks emerged victorious as the new political power in Russia. The Soviet Union inherited a population with widespread drug addiction, and in the 1920s, tried to tackle it by introducing a 10-year prison sentence for drug-dealers. The Bolsheviks also decided in August 1924 to re-introduce the sale of vodka, which, being more readily available, led to a drop in drug-use. === Sweden === Sweden's drug policy has gradually turned from lenient in the 1960s with an emphasis on drug supply towards a policy of zero tolerance against all illicit drug use (including cannabis). The official aim is a drug-free society. Drug use became a punishable crime in 1988. Personal use does not result in jail time if not combined with driving a car. Prevention includes widespread drug testing, and penalties range from fines for minor drug offenses up to a 10-year prison sentence for aggravated offenses. The condition for suspended sentences could be regular drug tests or submission to rehabilitation treatment. Drug treatment is free of charge and provided through the health care system and the municipal social services. Drug use that threatens the health and development of minors could force them into mandatory treatment if they don't apply voluntarily. If the use threatens the immediate health or the security of others (such as a child of an addict) the same could apply to adults. Among 9th year students, drug experimentation was highest in the early 1970s, falling towards a low in the late 1980s, redoubling in the 1990s to stabilize and slowly decline in 2000s. Estimates of heavy drug addicts have risen from 6000 in 1967 to 15000 in 1979, 19000 in 1992 and 26000 in 1998. According to inpatient data, there were 28000 such addicts in 2001 and 26000 in 2004, but these last two figures may represent the recent trend in Sweden towards out-patient treatment of drug addicts rather than an actual decline in drug addictions. The United Nations Office on Drugs and Crime (UNODC) reports that Sweden has one of the lowest drug use rates in the Western world, and attributes this to a drug policy that invests heavily in prevention and treatment as well as strict law enforcement. The general drug policy is supported by all political parties and, according to opinion polls made in the mid 2000s, the restrictive approach received broad support from the public at that time. === Switzerland === The national drug policy of Switzerland was developed in the early 1990s and comprises the four elements of prevention, therapy, harm reduction and prohibition. In 1994 Switzerland was one of the first countries to try heroin-assisted treatment and other harm reduction measures like supervised injection rooms. In 2008 a popular initiative by the right wing Swiss People's Party aimed at ending the heroin program was rejected by more than two-thirds of the voters. A simultaneous initiative aimed at legalizing marijuana was rejected at the same ballot. Between 1987 and 1992, illegal drug use and sales were permitted in Platzspitz park, Zurich, in an attempt to counter the growing heroin problem. However, as the situation grew increasingly out of control, authorities were forced to close the park. In 2022, Switzerland initiated pilot trials for the non-medical use of cannabis. === Thailand === Thailand has a strict drug policy. The use, storage, transportation and distribution of drugs is illegal. In 2021, Thailand unified all the laws on narcotic, psychoactive substances, and inhalants into the Narcotic Code 2564 BE (2021 AD) with more relaxing policy. The sentence of many criminal offenses relating to narcotic was reduced as the new law focuses more on drug rehabilitation. According to the Narcotic Code, narcotic substances are divided into 5 categories. Category I – highly addictive narcotic such as heroin, amphetamines, methamphetamines, etc. Category II – highly addictive narcotic with medical use such as morphine, cocaine, ketamine, codeine, medicinal opium (opium extracts or products), etc. Category III – drug formularies that legally contain the category II narcotic, etc. Category IV – chemicals used for synthesizing the categories I and II narcotic such as acetic anhydride, acetyl chloride, etc. Category V – narcotic plants such as opium poppy, magic mushroom, cannabis extracts with THC higher than 0.2% by weight and cannabis seed extracts. With the current law, kratom and cannabis plant no longer belong to the category V narcotic. They are no longer considered narcotic plants. However, plantation, possession, distribution, and use of these plants are still controlled by certain level of permission and regulations. It is also illegal to import more than 200 cigarettes per person to Thailand. Control takes place at customs at the airport. If the limit has been exceeded, the owner can be fined up to ten times the cost of cigarettes. In January 2018, Thai authorities imposed a ban on smoking on beaches in some tourist areas. Those who smoke in public places can be punished with a fine of 100,000 Baht or imprisonment for up to one year. It is forbidden to import electronic cigarettes into Thailand. These items are likely to be confiscated, and you can be fined or sent to prison for up to 10 years. The sale or supply of electronic cigarettes and similar devices is also prohibited and is punishable by a fine or imprisonment of up to 5 years. It is worth noting that most people arrested for possessing a small amount of substances from the V-th category are fined and not imprisoned. At present, in Thailand, the anti-drug police are considering methamphetamines as a more serious and dangerous problem. On 9 February 2024 the Public Health Ministry published possession limits for many illicit drugs. This means if you possess a small amount of an illegal drug, you have to go to a rehabilitation program, instead of imprisonment. This marks another progressive step in Thailand's drug policy. === Ukraine === Crimes in the sphere of trafficking in narcotic, psychotropic substances and crimes against health are classified using the 13th section of the Criminal Code of Ukraine; articles from 305 to 327. According to official statistics for 2016, 53% of crimes in the field of drugs fall on art. 309 of the Criminal Code of Ukraine: "illegal production, manufacture, acquisition, storage, transportation or shipment of narcotic drugs, psychotropic substances or their analogues without the purpose of sale". Sentence for crime: fine of fifty to one hundred non-taxable minimum incomes of citizens; or correctional labor for up to two years; or arrest for up to six months, or restriction of liberty for up to three years; or imprisonment for the same term. On 28 August 2013, the Cabinet of Ministers of Ukraine adopted a strategy for state policy on drugs until 2020. This is the first document of this kind in Ukraine. The strategy developed by the State Drug Control Service, involves strengthening criminal liability for distributing large amounts of drugs, and easing the penalty for possession of small doses. Thanks to this strategy, it is planned to reduce the number of injecting drug users by 20% by 2020, and the number of drug overdose deaths by 30%. In October 2018, the State Service of Ukraine on Drugs and Drug Control issued the first license for the import and re-export of raw materials and products derived from cannabis. The corresponding licenses were obtained by the USA company C21. She is also in the process of applying for additional licenses, including the cultivation of hemp. === United Kingdom === Drugs considered addictive or dangerous in the United Kingdom (with the exception of tobacco and alcohol) are called "controlled substances" and regulated by law. Until 1964 the medical treatment of dependent drug users was separated from the punishment of unregulated use and supply. This arrangement was confirmed by the Rolleston Committee in 1926. This policy on drugs, known as the "British system", was maintained in Britain, and nowhere else, until the 1960s. Under this policy drug use remained low; there was relatively little recreational use and few dependent users, who were prescribed drugs by their doctors as part of their treatment. From 1964 drug use was increasingly criminalised, with the framework still in place as of 2014 largely determined by the 1971 Misuse of Drugs Act.: 13–14 === United States === Modern US drug policy still has roots in the war on drugs started by president Richard Nixon in 1971. In the United States, illegal drugs fall into different categories and punishment for possession and dealing varies on amount and type. Punishment for marijuana possession is light in most states, but punishment for dealing and possession of hard drugs can be severe, and has contributed to the growth of the prison population. US drug policy is also heavily invested in foreign policy, supporting military and paramilitary actions in South America, Central Asia, and other places to eradicate the growth of coca and opium. In Colombia, U.S. president Bill Clinton dispatched military and paramilitary personnel to interdict the planting of coca, as a part of the Plan Colombia. The project is often criticized for its ineffectiveness and its negative impact on local farmers, but it has been effective in destroying the once-powerful drug cartels and guerrilla groups of Colombia. President George W. Bush intensified anti-drug efforts in Mexico, initiating the Mérida Initiative, but has faced criticisms for similar reasons. 21 May 2012 the U.S Government published an updated version of its Drug Policy The director of ONDCP stated simultaneously that this policy is something different from "War on Drugs": The U.S Government see the policy as a "third way" approach to drug control one that is based on the results of a huge investment in research from some of the world's preeminent scholars on disease of substance abuse. The policy does not see drug legalization as the "silver bullet" solution to drug control. It is not a policy where success is measured by the number of arrests made or prisons built. The U.S. government generates grants to develop and disseminate evidence based addiction treatments. These grants have developed several practices that NIDA endorses, such as community reinforcement approach and community reinforcement and family training approach, which are behavior therapy interventions. == See also == == References ==	Wikipedia/Drug_control_treaties
Behaviour therapy or behavioural psychotherapy is a broad term referring to clinical psychotherapy that uses techniques derived from behaviourism and/or cognitive psychology. It looks at specific, learned behaviours and how the environment, or other people's mental states, influences those behaviours, and consists of techniques based on behaviorism's theory of learning: respondent or operant conditioning. Behaviourists who practice these techniques are either behaviour analysts or cognitive-behavioural therapists. They tend to look for treatment outcomes that are objectively measurable. Behaviour therapy does not involve one specific method, but it has a wide range of techniques that can be used to treat a person's psychological problems. Behavioural psychotherapy is sometimes juxtaposed with cognitive psychotherapy. While cognitive behavioural therapy integrates aspects of both approaches, such as cognitive restructuring, positive reinforcement, habituation (or desensitisation), counterconditioning, and modelling. Applied behaviour analysis (ABA) is the application of behaviour analysis that focuses on functionally assessing how behaviour is influenced by the observable learning environment and how to change such behaviour through contingency management or exposure therapies, which are used throughout clinical behaviour analysis therapies or other interventions based on the same learning principles. Cognitive-behavioural therapy views cognition and emotions as preceding overt behaviour and implements treatment plans in psychotherapy to lessen the issue by managing competing thoughts and emotions, often in conjunction with behavioural learning principles. A 2013 Cochrane review comparing behaviour therapies to psychological therapies found them to be equally effective, although at the time the evidence base that evaluates the benefits and harms of behaviour therapies was weak. == History == Precursors of certain fundamental aspects of behaviour therapy have been identified in various ancient philosophical traditions, particularly Stoicism. For example, Wolpe and Lazarus wrote, While the modern behavior therapist deliberately applies principles of learning to this therapeutic operations, empirical behavior therapy is probably as old as civilization – if we consider civilization as having started when man first did things to further the well-being of other men. From the time that this became a feature of human life there must have been occasions when a man complained of his ills to another who advised or persuaded him of a course of action. In a broad sense, this could be called behavior therapy whenever the behavior itself was conceived as the therapeutic agent. Ancient writings contain innumerable behavioral prescriptions that accord with this broad conception of behavior therapy. The first use of the term behaviour modification appears to have been by Edward Thorndike in 1911. His article Provisional Laws of Acquired Behavior or Learning makes frequent use of the term "modifying behavior". Through early research in the 1940s and the 1950s the term was used by Joseph Wolpe's research group. The experimental tradition in clinical psychology used it to refer to psycho-therapeutic techniques derived from empirical research. It has since come to refer mainly to techniques for increasing adaptive behaviour through reinforcement and decreasing maladaptive behaviour through extinction or punishment (with emphasis on the former). Two related terms are behaviour therapy and applied behaviour analysis. Since techniques derived from behavioural psychology tend to be the most effective in altering behaviour, most practitioners consider behaviour modification along with behaviour therapy and applied behaviour analysis to be founded in behaviourism. While behaviour modification and applied behaviour analysis typically uses interventions based on the same behavioural principles, many behaviour modifiers who are not applied behaviour analysts tend to use packages of interventions and do not conduct functional assessments before intervening. Possibly the first occurrence of the term "behavior therapy" was in a 1953 research project by B.F. Skinner, Ogden Lindsley, Nathan Azrin and Harry C. Solomon. The paper talked about operant conditioning and how it could be used to help improve the functioning of people who were diagnosed with chronic schizophrenia. Early pioneers in behaviour therapy include Joseph Wolpe and Hans Eysenck. In general, behaviour therapy is seen as having three distinct points of origin: South Africa (Wolpe's group), the United States (Skinner), and the United Kingdom (Rachman and Eysenck). Each had its own distinct approach to viewing behaviour problems. Eysenck in particular viewed behaviour problems as an interplay between personality characteristics, environment, and behaviour. Skinner's group in the United States took more of an operant conditioning focus. The operant focus created a functional approach to assessment and interventions focused on contingency management such as the token economy and behavioural activation. Skinner's student Ogden Lindsley is credited with forming a movement called precision teaching, which developed a particular type of graphing program called the standard celeration chart to monitor the progress of clients. Skinner became interested in the individualising of programs for improved learning in those with or without disabilities and worked with Fred S. Keller to develop programmed instruction. Programmed instruction had some clinical success in aphasia rehabilitation. Gerald Patterson used programme instruction to develop his parenting text for children with conduct problems. (see Parent management training.) With age, respondent conditioning appears to slow but operant conditioning remains relatively stable. While the concept had its share of advocates and critics in the west, its introduction in the Asian setting, particularly in India in the early 1970s and its grand success were testament to the famous Indian psychologist H. Narayan Murthy's enduring commitment to the principles of behavioural therapy and biofeedback. While many behaviour therapists remain staunchly committed to the basic operant and respondent paradigm, in the second half of the 20th century, many therapists coupled behaviour therapy with the cognitive therapy, of Aaron Beck, Albert Ellis, and Donald Meichenbaum to form cognitive behaviour therapy. In some areas the cognitive component had an additive effect (for example, evidence suggests that cognitive interventions improve the result of social phobia treatment.) but in other areas it did not enhance the treatment, which led to the pursuit of third generation behaviour therapies. Third generation behaviour therapy uses basic principles of operant and respondent psychology but couples them with functional analysis and a clinical formulation/case conceptualisation of verbal behaviour more inline with view of the behaviour analysts. Some research supports these therapies as being more effective in some cases than cognitive therapy, but overall the question is still in need of answers. == Theoretical basis == The behavioural approach to therapy assumes that behaviour that is associated with psychological problems develops through the same processes of learning that affects the development of other behaviours. Therefore, behaviourists see personality problems in the way that personality was developed. They do not look at behaviour disorders as something a person has, but consider that it reflects how learning has influenced certain people to behave in a certain way in certain situations. Behaviour therapy is based upon the principles of classical conditioning developed by Ivan Pavlov and operant conditioning developed by B.F. Skinner. Classical conditioning happens when a neutral stimulus comes right before another stimulus that triggers a reflexive response. The idea is that if the neutral stimulus and whatever other stimulus that triggers a response is paired together often enough that the neutral stimulus will produce the reflexive response. Operant conditioning has to do with rewards and punishments and how they can either increase or decrease certain behaviours. Contingency management programs are a direct product of research from operant conditioning. == Current forms == Behavioural therapy based on operant and respondent principles has considerable evidence base to support its usage. This approach remains a vital area of clinical psychology and is often termed clinical behavior analysis. Behavioral psychotherapy has become increasingly contextual in recent years. Behavioral psychotherapy has developed greater interest in recent years in personality disorders as well as a greater focus on acceptance and complex case conceptualizations. === Functional analytic psychotherapy === One current form of behavioural psychotherapy is functional analytic psychotherapy. Functional analytic psychotherapy is a longer duration behaviour therapy. Functional analytic therapy focuses on in-session use of reinforcement and is primarily a relationally-based therapy. As with most of the behavioural psychotherapies, functional analytic psychotherapy is contextual in its origins and nature. and draws heavily on radical behaviourism and functional contextualism. Functional analytic psychotherapy holds to a process model of research, which makes it unique compared to traditional behaviour therapy and cognitive behavioural therapy. Functional analytic psychotherapy has a strong research support. Recent functional analytic psychotherapy research efforts are focusing on management of aggressive inpatients. == Assessment == Behaviour therapists complete a functional analysis or a functional assessment that looks at four important areas: stimulus, organism, response and consequences. The stimulus is the condition or environmental trigger that causes behaviour. An organism involves the internal responses of a person, like physiological responses, emotions and cognition. A response is the behaviour that a person exhibits and the consequences are the result of the behaviour. These four things are incorporated into an assessment done by the behaviour therapist. Most behaviour therapists use objective assessment methods like structured interviews, objective psychological tests or different behavioural rating forms. These types of assessments are used so that the behaviour therapist can determine exactly what a client's problem may be and establish a baseline for any maladaptive responses that the client may have. By having this baseline, as therapy continues this same measure can be used to check a client's progress, which can help determine if the therapy is working. Behaviour therapists do not typically ask the why questions but tend to be more focused on the how, when, where and what questions. Tests such as the Rorschach inkblot test or personality tests like the MMPI (Minnesota Multiphasic Personality Inventory) are not commonly used for behavioural assessment because they are based on personality trait theory assuming that a person's answer to these methods can predict behaviour. Behaviour assessment is more focused on the observations of a person's behaviour in their natural environment. Behavioural assessment specifically attempts to find out what the environmental and self-imposed variables are. These variables are the things that are allowing a person to maintain their maladaptive feelings, thoughts and behaviours. In a behavioural assessment "person variables" are also considered. These "person variables" come from a person's social learning history and they affect the way in which the environment affects that person's behaviour. An example of a person variable would be behavioural competence. Behavioural competence looks at whether a person has the appropriate skills and behaviours that are necessary when performing a specific response to a certain situation or stimuli. When making a behavioural assessment the behaviour therapist wants to answer two questions: (1) what are the different factors (environmental or psychological) that are maintaining the maladaptive behaviour and (2) what type of behaviour therapy or technique that can help the individual improve most effectively. The first question involves looking at all aspects of a person, which can be summed up by the acronym BASIC ID. This acronym stands for behaviour, affective responses, sensory reactions, imagery, cognitive processes, interpersonal relationships and drug use. == Clinical applications == Behaviour therapy based its core interventions on functional analysis. Just a few of the many problems that behaviour therapy have functionally analyzed include intimacy in couples relationships, forgiveness in couples, chronic pain, stress-related behaviour problems of being an adult child of a person with an alcohol use disorder, anorexia, chronic distress, substance abuse, depression, anxiety, insomnia and obesity. Functional analysis has even been applied to problems that therapists commonly encounter like client resistance, partially engaged clients and involuntary clients. Applications to these problems have left clinicians with considerable tools for enhancing therapeutic effectiveness. One way to enhance therapeutic effectiveness is to use positive reinforcement or operant conditioning. Although behaviour therapy is based on the general learning model, it can be applied in a lot of different treatment packages that can be specifically developed to deal with problematic behaviours. Some of the more well known types of treatments are: Relaxation training, systematic desensitization, virtual reality exposure, exposure and response prevention techniques, social skills training, modelling, behavioural rehearsal and homework, and aversion therapy and punishment. Relaxation training involves clients learning to lower arousal to reduce their stress by tensing and releasing certain muscle groups throughout their body. Systematic desensitization is a treatment in which the client slowly substitutes a new learned response for a maladaptive response by moving up a hierarchy of situations involving fear. Systematic desensitization is based in part on counter conditioning. Counter conditioning is learning new ways to change one response for another and in the case of desensitization it is substituting that maladaptive behaviour for a more relaxing behaviour. Exposure and response prevention techniques (also known as flooding and response prevention) is the general technique in which a therapist exposes an individual to anxiety-provoking stimuli while keeping them from having any avoidance responses. Virtual reality therapy provides realistic, computer-based simulations of troublesome situations. The modelling process involves a person being subjected to watching other individuals who demonstrate behaviour that is considered adaptive and that should be adopted by the client. This exposure involves not only the cues of the "model person" as well as the situations of a certain behaviour that way the relationship can be seen between the appropriateness of a certain behaviour and situation in which that behaviour occurs is demonstrated. With the behavioural rehearsal and homework treatment a client gets a desired behaviour during a therapy session and then they practice and record that behaviour between their sessions. Aversion therapy and punishment is a technique in which an aversive (painful or unpleasant) stimulus is used to decrease unwanted behaviours from occurring. It is concerned with two procedures: 1) the procedures are used to decrease the likelihood of the frequency of a certain behaviour and 2) procedures that will reduce the attractiveness of certain behaviours and the stimuli that elicit them. The punishment side of aversion therapy is when an aversive stimulus is presented at the same time that a negative stimulus and then they are stopped at the same time when a positive stimulus or response is presented. Examples of the type of negative stimulus or punishment that can be used is shock therapy treatments, aversive drug treatments as well as response cost contingent punishment which involves taking away a reward. Applied behaviour analysis is using behavioural methods to modify certain behaviours that are seen as being important socially or personally. There are four main characteristics of applied behaviour analysis. First behaviour analysis is focused mainly on overt behaviours in an applied setting. Treatments are developed as a way to alter the relationship between those overt behaviours and their consequences. Another characteristic of applied behaviour analysis is how it (behaviour analysis) goes about evaluating treatment effects. The individual subject is where the focus of study is on, the investigation is centred on the one individual being treated. A third characteristic is that it focuses on what the environment does to cause significant behaviour changes. Finally the last characteristic of applied behaviour analysis is the use of those techniques that stem from operant and classical conditioning such as providing reinforcement, punishment, stimulus control and any other learning principles that may apply. Social skills training teaches clients skills to access reinforcers and lessen life punishment. Operant conditioning procedures in meta-analysis had the largest effect size for training social skills, followed by modelling, coaching, and social cognitive techniques in that order. Social skills training has some empirical support particularly for schizophrenia. However, with schizophrenia, behavioural programs have generally lost favour. Some other techniques that have been used in behaviour therapy are contingency contracting, response costs, token economies, biofeedback, and using shaping and grading task assignments. Shaping and graded task assignments are used when behaviour that needs to be learned is complex. The complex behaviours that need to be learned are broken down into simpler steps where the person can achieve small things gradually building up to the more complex behaviour. Each step approximates the eventual goal and helps the person to expand their activities in a gradual way. This behaviour is used when a person feels that something in their lives can not be changed and life's tasks appear to be overwhelming. Another technique of behaviour therapy involves holding a client or patient accountable of their behaviours in an effort to change them. This is called a contingency contract, which is a formal written contract between two or more people that defines the specific expected behaviours that you wish to change and the rewards and punishments that go along with that behaviour. In order for a contingency contract to be official it needs to have five elements. First it must state what each person will get if they successfully complete the desired behaviour. Secondly those people involved have to monitor the behaviours. Third, if the desired behaviour is not being performed in the way that was agreed upon in the contract the punishments that were defined in the contract must be done. Fourth if the persons involved are complying with the contract they must receive bonuses. The last element involves documenting the compliance and noncompliance while using this treatment in order to give the persons involved consistent feedback about the target behaviour and the provision of reinforcers. Token economies is a behaviour therapy technique where clients are reinforced with tokens that are considered a type of currency that can be used to purchase desired rewards, like being able to watch television or getting a snack that they want when they perform designated behaviours. Token economies are mainly used in institutional and therapeutic settings. In order for a token economy to be effective there must be consistency in administering the program by the entire staff. Procedures must be clearly defined so that there is no confusion among the clients. Instead of looking for ways to punish the patients or to deny them of rewards, the staff has to reinforce the positive behaviours so that the clients will increase the occurrence of the desired behaviour. Over time the tokens need to be replaced with less tangible rewards such as compliments so that the client will be prepared when they leave the institution and won't expect to get something every time they perform a desired behaviour. Closely related to token economies is a technique called response costs. This technique can either be used with or without token economies. Response costs is the punishment side of token economies where there is a loss of a reward or privilege after someone performs an undesirable behaviour. Like token economies this technique is used mainly in institutional and therapeutic settings. Considerable policy implications have been inspired by behavioural views of various forms of psychopathology. One form of behaviour therapy, habit reversal training, has been found to be highly effective for treating tics. === In rehabilitation === Currently, there is a greater call for behavioural psychologists to be involved in rehabilitation efforts. === Treatment of mental disorders === Two large studies done by the Faculty of Health Sciences at Simon Fraser University indicate that both behaviour therapy and cognitive-behavioural therapy (CBT) are equally effective for OCD. CBT is typically considered the "first-line" treatment for OCD. CBT has also been shown to perform slightly better at treating co-occurring depression. Considerable policy implications have been inspired by behavioural views of various forms of psychopathology. One form of behaviour therapy (habit reversal training) has been found to be highly effective for treating tics. There has been a development towards combining techniques to treat psychiatric disorders. Cognitive interventions are used to enhance the effects of more established behavioural interventions based on operant and classical conditioning. An increased effort has also been placed to address the interpersonal context of behaviour. Behaviour therapy can be applied to a number of mental disorders and in many cases is more effective for specific disorders as compared to others. Behaviour therapy techniques can be used to deal with any phobias that a person may have. Desensitization has also been successfully applied to other issues such as dealing with anger, if a person has trouble sleeping and certain speech disorders. Desensitization does not occur over night, there is a process of treatment. Desensitization is done on a hierarchy and happens over a number of sessions. The hierarchy goes from situations that make a person less anxious or nervous up to things that are considered to be extreme for the patient. Modelling has been used in dealing with fears and phobias. Fears are thought to develop through observational learning, and so positive modelling, when a person's behaviour is imitated, can used to counter these effects. In a systematic review of 1,677 papers, positive modelling was found to lower fear levels. Modelling has been used in the treatment of fear of snakes as well as a fear of water. Aversive therapy techniques have been used to treat sexual deviations, as well as alcohol use disorder. Exposure and prevention procedure techniques can be used to treat people who have anxiety problems as well as any fears or phobias. These procedures have also been used to help people dealing with any anger issues as well as pathological grievers (people who have distressing thoughts about a deceased person). Virtual reality therapy deals with fear of heights, fear of flying, and a variety of other anxiety disorders. VRT has also been applied to help people with substance abuse problems reduce their responsiveness to certain cues that trigger their need to use drugs. Shaping and graded task assignments has been used in dealing with suicide and depressed or inhibited individuals. This is used when a patient feel hopeless and they have no way of changing their lives. This hopelessness involves how the person reacts and responds to someone else and certain situations and their perceived powerlessness to change that situation that adds to the hopelessness. For a person with suicidal ideation, it is important to start with small steps. Because that person may perceive everything as being a big step, the smaller you start the easier it will be for the person to master each step. This technique has also been applied to people dealing with agoraphobia, or fear of being in public places or doing something embarrassing. Contingency contracting has been used to effectively deal with behaviour problems in delinquents and when dealing with on task behaviours in students. Token economies are used in controlled environments and are found mostly in psychiatric hospitals. They can be used to help patients with different mental illnesses but it doesn't focus on the treatment of the mental illness but instead on the behavioural aspects of a patient. The response cost technique has been used to successfully address a variety of behaviours such as smoking, overeating, stuttering, and psychotic talk. === Treatment outcomes === Systematic desensitization has been shown to successfully treat phobias about heights, driving, insects as well as any anxiety that a person may have. Anxiety can include social anxiety, anxiety about public speaking as well as test anxiety. It has been shown that the use of systematic desensitization is an effective technique that can be applied to a number of problems that a person may have. When using modelling procedures this technique is often compared to another behavioural therapy technique. When compared to desensitization, the modelling technique does appear to be less effective. However it is clear that the greater the interaction between the patient and the subject he is modelling the greater the effectiveness of the treatment. While undergoing exposure therapy, a person typically needs five sessions to assess the treatment's effectiveness. After five sessions, exposure treatment has been shown to provide benefit to the patient. However, it is still recommended treatment continue beyond the initial five sessions. Virtual reality therapy (VRT) has shown to be effective for a fear of heights. It has also been shown to help with the treatment of a variety of anxiety disorders. Due to the costs associated with VRT in 2007, therapists were still awaiting results of controlled trials investigating VRT, to assess which applications demonstrate the best results. For those with suicidal ideation, treatment depends on how severe the person's depression and sense of hopelessness is. If these things are severe, the person's response to completing small steps will not be of importance to them, because they don't consider the success an accomplishment. Generally, in those without severe depression or fear, this technique has been successful, as completion of simpler activities builds their confidences and allows them to progress to more complex situations. Contingency contracts have been seen to be effective in changing any undesired behaviours of individuals. It has been seen to be effective in treating behaviour problems in delinquents regardless of the specific characteristics of the contract. Token economies have been shown to be effective when treating patients in psychiatric wards who had chronic schizophrenia. The results showed that the contingent tokens were controlling the behaviour of the patients. Response costs has been shown to work in suppressing a variety of behaviours such as smoking, overeating or stuttering with a diverse group of clinical populations ranging from sociopaths to school children. These behaviours that have been suppressed using this technique often do not recover when the punishment contingency is withdrawn. Also undesirable side effects that are usually seen with punishment are not typically found when using the response cost technique. == "Third generation" == Since the 1980s, a series of new behavioral therapies have been developed. These have been later labeled by Steven C. Hayes as "the third-generation" of behavioural therapy. Under this classification, the first generation of behavioural therapy is that independently developed in the 1950s by Joseph Wolpe, Ogden Lindsley and Hans Eysenck, while the second generation is the cognitive therapy developed by Aaron Beck in the 1970s. Other authors object to the term "third generation" or "third wave" and incorporate many of the "third wave" therapeutic techniques under the general umbrella term of modern cognitive behavioural therapies. This "third wave" of behavioural therapy has sometimes been called clinical behaviour analysis because it has been claimed that it represents a movement away from cognitivism and back toward radical behaviourism and other forms of behaviourism, in particular functional analysis and behavioural models of verbal behaviour. This area includes acceptance and commitment therapy (ACT), cognitive behavioural analysis system of psychotherapy (CBASP) (McCullough, 2000), behavioural activation (BA), dialectical behaviour therapy, functional analytic psychotherapy (FAP), integrative behavioural couples therapy, metacognitive therapy and metacognitive training. These approaches are squarely within the applied behaviour analysis tradition of behaviour therapy. Acceptance and Commitment Therapy (ACT) may be the most well-researched of all the third-generation behaviour therapy models. It is based on relational frame theory. As of March 2022, there are over 900 randomized trials of Acceptance and Commitment Therapy and 60 mediational studies of the ACT literature. ACT has been included in over 275 meta-analyses and systematic reviews. As the result of multiple randomized trials of ACT by the World Health Organization, WHO now distribute ACT-based self-help for "anyone who experiences stress, wherever they live, and whatever their circumstances." As of March 2022, a number of different organizations have stated that Acceptance and Commitment Therapy is empirically supported in certain areas or as a whole according to their standards. These include: American Psychological Association, Society of Clinical Psychology (Div. 12), The World Health Organization, The United Kingdom National Institute for Health and Care Excellence (NICE), Australian Psychological Society, Netherlands Institute of Psychologists: Sections of Neuropsychology and Rehabilitation, Sweden Association of Physiotherapists, SAMHSA's National Registry of Evidence-based Programs and Practices, California Evidence-Based Clearinghouse for Child Welfare, and the U.S. Veterans Affairs/DoD. Functional analytic psychotherapy is based on a functional analysis of the therapeutic relationship. It places a greater emphasis on the therapeutic context and returns to the use of in-session reinforcement. In general, 40 years of research supports the idea that in-session reinforcement of behaviour can lead to behavioural change. Behavioural activation emerged from a component analysis of cognitive behaviour therapy. Researchers hope to prove that it can be complete treatment in its own right. Behavioural activation is based on a matching model of reinforcement. A recent review of the research, supports the notion that the use of behavioural activation is clinically important for the treatment of depression. Integrative behavioural couples therapy developed from dissatisfaction with traditional behavioural couples therapy. Integrative behavioural couples therapy looks to Skinner (1966) for the difference between contingency-shaped and rule-governed behaviour. It couples this analysis with a thorough functional assessment of the couple's relationship. Recent efforts have used radical behavioural concepts to interpret a number of clinical phenomena including forgiveness. A review study published in 2008, concluded that at the time, third-generation behavioral psychotherapies did not meet the criteria for empirically supported treatments. == Organisations == Many organisations exist for behaviour therapists around the world. In the United States, the American Psychological Association's Division 25 is the division for behaviour analysis. The Association for Contextual Behavioral Science is another professional organisation. ACBS is home to many clinicians with specific interest in third generation behaviour therapy. Doctoral-level behaviour analysts who are psychologists belong to American Psychological Association's Division 25 – behaviour analysis. APA offers a diploma in behavioural psychology. The Association for Behavioral and Cognitive Therapies (formerly the Association for the Advancement of Behavior Therapy) is for those with a more cognitive orientation. The ABCT also has an interest group in behaviour analysis, which focuses on clinical behaviour analysis. In addition, the Association for Behavioral and Cognitive Therapies has a special interest group on addictions. == Characteristics == By nature, behavioural therapies are empirical (data-driven), contextual (focused on the environment and context), functional (interested in the effect or consequence a behaviour ultimately has), probabilistic (viewing behaviour as statistically predictable), monistic (rejecting mind–body dualism and treating the person as a unit), and relational (analysing bidirectional interactions). Behavioural therapy develops, adds and provides behavioural intervention strategies and programs for clients, and training to people who care to facilitate successful lives in various communities. == Training == Recent efforts in behavioural psychotherapy have focused on the supervision process. A key point of behavioural models of supervision is that the supervisory process parallels the behavioural psychotherapy provided. == See also == == References == == Sources == Bellack, A.S.; Hersen, M. (1985). Dictionary of Behavior Therapy Techniques. General Psychology Series. Pergamon Press. ISBN 978-0-08-030168-6. Boyle, S.W. (2006). "Knowledge and Skills for Intervention". Direct Practice in Social Work (1st ed.). Pearson/Allyn & Bacon. ISBN 978-0-205-40162-8. O'Leary, K.D.; Wilson, G.T. (1975). Behavior Therapy: Application and Outcome. Prentice-Hall series on social learning theory. Prentice-Hall. ISBN 978-0-13-073890-5. Rimm, David; Masters, John C. (1974). Behavior therapy: techniques and empirical findings. New York: Academic Press. ISBN 0-12-588850-3. OCLC 793562. Schaefer, H.H.; Martin, P.L. (1969). Behavioral Therapy. Blakiston Division, McGraw-Hill. == External links == Library resources in your library and in other libraries about Behaviour therapy	Wikipedia/Behavior_therapy
An unenforced law (also symbolic law, dead letter law) is a law which is formally in effect (de jure), but is usually (de facto) not penalized by a jurisdiction. Such laws are usually ignored by law enforcement, and therefore there are few or no practical consequences for breaking them. The existence of unenforced laws has been criticized for undermining the legal system in general, as such laws may be selectively enforced. == Overview == Unenforced laws may be enacted purely for symbolic reasons, with little or no intention of enforcement. There are also circumstances in which an otherwise enforced law is not; for example, speeding in a motor vehicle is illegal in most jurisdictions, however law enforcement may choose to ignore motorists who only slightly exceed the legal speed limit. Automated traffic enforcement cameras may still issue fines in these circumstances in some jurisdictions. Symbolic laws typically attempt to persuade rather than enforce, punish or prevent. For example, until the relevant statute was repealed in 2013, adultery was prohibited by law in the US state of Colorado, but no criminal penalty was specified. In Maryland, adultery is prohibited, however the statutory criminal penalty is limited to a $10 fine. In the United Kingdom, under the Treason Felony Act 1848, it is a crime punishable by life imprisonment to advocate for the creation of a republic in print, even peacefully. The Law Lords' interpretation of the later Human Rights Act 1998, however, has ensured that this law is unenforced, on the grounds that peaceful advocacy of a republic is protected speech. == See also == Decriminalization Desuetude Expressive function of law Statute Law Revision Act Unenforceable Victimless crime == References ==	Wikipedia/Unenforced_law
Pharmacotherapy, also known as pharmacological therapy or drug therapy, is defined as medical treatment that utilizes one or more pharmaceutical drugs to improve ongoing symptoms (symptomatic relief), treat the underlying condition, or act as a prevention for other diseases (prophylaxis). It can be distinguished from therapy using surgery (surgical therapy), radiation (radiation therapy), movement (physical therapy), or other modes. Among physicians, sometimes the term medical therapy refers specifically to pharmacotherapy as opposed to surgical or other therapy; for example, in oncology, medical oncology is thus distinguished from surgical oncology. Today's pharmacological therapy has evolved from a long history of medication use, and it has changed most rapidly in the last century due to advancements in drug discovery. The therapy is administered and adjusted by healthcare professionals according to the evidence-based guidelines and the patient's health condition. Personalized medicine also plays a crucial role in pharmacological therapy. Personalized medicine, or precision medicine, takes account of the patient's genetic variation, liver function, kidney function, etc, to provide a tailor-made treatment for a patient. In pharmacological therapy, pharmacists will also consider medication compliance. Medication compliance, or medication adherence, is defined as the degree to which the patient follows the therapy that is recommended by the healthcare professionals. == History == === From natural compounds to pharmaceutical drugs === The use of medicinal substances can be traced back to 4000 BC in the Sumer civilization. Healers at the time (called apothecaries), for example, understood the application of opium for pain relief. The history of natural remedies can also be found in other cultures, including traditional Chinese medicine in China and Ayurvedic medicine in India, which are still in use nowadays. Dioscorides, a 1st -century Greek surgeon, described more than six hundred animals, plants, and their derivatives in his medical botany, which remained the most influential pharmacopeia for fourteen hundred years. Besides substances derived from living organisms, metals, including copper, mercury, and antimony, were also used as medical therapies. They were said to cure various diseases during the late Renaissance. In 1657, tartar emetic, which is an antimony compound, was credited with curing Louis XIV of typhoid fever. The drug was also administered intravenously for the treatment of schistosomiasis in the 20th century. However, due to the concern over acute and chronic antimony poisoning, the role of tartar emetic as an antischistosomal agent was gradually replaced after the advent of praziquantel. Other than using natural products, humans also learned to compound medicine by themselves. The first pharmaceutical text was found on clay tablets from the Mesopotamians, who lived around 2100 BC. Later in the 2nd century AD, compounding was formally introduced by Galen as “a process of mixing two or more medicines to meet the individual needs of a patient”. Initially, compounding was only done by individual pharmacists, but in the post-World War II period, pharmaceutical manufacturers surged in number and took over the role of making medicine. Meanwhile, there was a marked increase in pharmaceutical research, which led to a growing number of new drugs. Most drug discovery milestones were made in the last hundred years, from antibiotics to biologics, contributing to the foundation of current pharmacological therapy. === Drug discovery === Most drugs were discovered by empirical means, including observation, accident, and trial and error. One famous example is the discovery of penicillin, the first antibiotic in the world. The substance was discovered by Alexander Fleming in 1928 after a combination of unanticipated events occurred in his laboratory during his summer vacation. The Penicillium mold on the petri dish was believed to secrete a substance (later named "penicillin") that inhibited bacterial growth. Large pharmaceutical companies then started to establish their microbiological departments and search for new antibiotics. The screening program for antimicrobial compounds also led to the discovery of drugs with other pharmacological properties, such as immunosuppressants like Cyclosporin A.The discovery of penicillin was a serendipitous (i.e. chance) discovery. Another, more advanced approach to drug discovery is rational drug design. The method is underpinned by an understanding of the biological targets of the drugs, including enzymes, receptors, and other proteins. In the late 19th century, Paul Ehrlich observed the selective affinity of dyes for different tissues and proposed the existence of chemoreceptors in our bodies. Receptors were believed to be the specific binding sites for drugs. The drug-receptor recognition was described as a key-and-lock interplay by Emil Fischer in the early 1890s. It was later found that the receptors can either be stimulated or inhibited by chemotherapeutic agents to attain the desired physiological response. Once the ligand interacting with the target macromolecule is identified, drug candidates can be designed and optimized based on the structure-activity relationship. Nowadays, artificial intelligence is employed in drug design to predict drug-protein interactions, drug activity, the 3D configuration of proteins, etc. == Evidence-based medicine == Evidence-based medicine is defined as deploying the best current scientific evidence that is available to give the best treatment and make the best decision effectively and efficiently. Clinical guidelines are developed based on scientific evidence; for example, the ACC/AHA guidelines (for cardiovascular diseases), the GOLD guidelines (for chronic obstructive pulmonary disease), the GINA guidelines (for asthma), etc. They convert and classify the evidence using a systematic method, aiming to provide care with quality. The guidelines cannot substitute clinical judgment, as they cannot meet all the circumstances. Healthcare professionals can use the clinical guidelines as references or evidence to support their clinical judgement when prescribing therapy to patients. Example: Clinical Guideline for controlling blood pressure (hypertension) If there is an Asian male patient who is 40 years old and has recently been diagnosed with high blood pressure (with a blood pressure of 140/90) and without any other chronic diseases (comorbidities), such as type-2 diabetes, gout, benign prostatic hyperplasia, etc. His estimated 10-year risk of cardiovascular disease is 15%. According to the NICE 2019 Hypertension guideline, the healthcare professional can consider starting anti-hypertensive therapy after a discussion with the patient. The first-line therapy will be either an Angiotensin Converting Enzyme Inhibitor (ACEi) or an Angiotensin receptor blocker (ARB) (if the patient cannot tolerate ACEi). If the blood pressure of the patient is not well controlled, the healthcare professionals can consider adding a calcium channel blocker (CCB) or a Thiazide-like diuretic to the previous therapy, i,e, ACEi or ARBs with a CCB or a thiazide-like diuretic. == Personalized medicine == Every patient has their own body condition, for example, kidney function, liver function, genetic variations, medical history, etc. These are all the factors that should be considered by healthcare professionals before giving any pharmacological therapy. Most importantly, the advancing technology in genetics guides us to have more insight into the linkage between health and genes. In pharmacological therapy, two areas of study are evolving: pharmacogenetics and pharmacogenomics. Age will affect the pharmacokinetics and pharmacodynamics of drugs, and hence the efficacy of the therapy. The effect of age causes deterioration of organ function, like liver function and kidney function. Pharmacokinetics is the study of drugs' effects on absorption, distribution, metabolism, and elimination. Pharmacodynamics is the study of drugs' effects on our body and their mechanisms. === Pharmacogenetics and pharmacogenomics === Pharmacogenetics is defined as the study of inherited genes causing different drug metabolisms that vary from each other, such as the rate of metabolism and metabolites. Pharmacogenomics is defined as the study of associating the drug response with one's gene. Both terms are similar in nature, so they are used interchangeably. Multiple alleles can contribute together to a change in response to a drug by expressing a different form of an enzyme that responds differently than the normal ones. The different forms of enzymes (phenotypes) include ultra-rapid metabolizers, moderate metabolizers, no-enzyme activity, etc. The genetic variations can also be used to match the particular adverse drug reaction in order to prevent the patient from suffering the unfavorable outcomes. The genetic make-up can affect the pharmacokinetics. === Example: Azathioprine Therapy === Azathioprine is an immunomodulator for inflammatory bowel disease, for instance. Its metabolite relies on two different enzymes (TPMT and NUDT15) to eliminate its effect on our body during its metabolism. If the patient has the phenotype of the enzymes that metabolize it poorly, i.e., the poor metabolizer, more toxic metabolites are accumulated in the body. Thus, the patient has a greater risk of the related side-effect. The side effect causes the adjustment of dosage or switching to another drug. === Example: Omalizumab Therapy === Omalizumab is a humanized monoclonal antibody for the treatment of various allergic diseases, including asthma, urticaria, and allergic rhinitis. It targets the immunoglobulin E (IgE) in human body, which plays an important role in allergic reactions. The efficacy of omalizumab may vary among patients. To identify responders to omalizumab, the level of several biomarkers can be measured, including serum eosinophils, fractional exhaled nitric oxide, and serum IgE. For instance, patients with higher baseline eosinophil counts are likely to respond better to omalizumab therapy. == Medication compliance == Medication compliance is defined as the degree to which the patient follows the therapy that is recommended by healthcare professionals. There are direct and indirect methods to evaluate compliance. Direct method refers to the measurement that the healthcare professionals observed or measure the patient's drug-taking behavior. Indirect method refers to the healthcare professionals do not observe or measure the drug-taking behavior of the patient but use the other source of information to evaluate the compliance. The direct method includes measurement of drug (or the corresponding metabolite) concentration, while the indirect method includes pill counting and the self-report from the patient. The direct method is more time-consuming, more expensive, more invasive, but it is more accurate. The indirect method has a lower accuracy but is easier to administer to the patient. If the patient fails to comply with treatment, for example, by not taking the medication according to the instructions, it leads to risk and a poor treatment outcome. === Example: Tuberculosis treatment === For tuberculosis patients, directly observed therapy is still part of the treatment. This is to increase medication compliance. This is to prevent treatment failure, relapse, and transmission in the community. Apart from the traditional direct observed therapy (DOT), there is another method proposed to try increasing medication compliance. Video-observed therapy (VOT) is one of the methods. It has some advantages and disadvantages. It reduces the cost of healthcare and the travel costs for the patient. The downside of the intervention is the need for quality control training as it would be hard to confirm the patient's adherence. == Role of Pharmacists == Pharmacists are experts in pharmacotherapy and are responsible for ensuring the safe, appropriate, and economical use of pharmaceutical drugs. The skills required to function as a pharmacist require knowledge, training and experience in biomedical, pharmaceutical and clinical sciences. Pharmacology is the science that aims to continually improve pharmacotherapy. The pharmaceutical industry and academia use basic science, applied science, and translational science to create new pharmaceutical drugs. As pharmacotherapy specialists and pharmacists have responsibility for direct patient care, often functioning as a member of a multidisciplinary team, and acting as the primary source of drug-related information for other healthcare professionals. A pharmacotherapy specialist is an individual who is specialized in administering and prescribing medication, and requires extensive academic knowledge in pharmacotherapy. In the US, a pharmacist can gain Board Certification in the area of pharmacotherapy upon fulfilling eligibility requirements and passing a certification examination. While pharmacists provide valuable information about medications for patients and healthcare professionals, they are not typically considered covered pharmacotherapy providers by insurance companies. == See also == == References ==	Wikipedia/Drug_therapy
Trial advocacy is the branch of knowledge concerned with making attorneys and other advocates more effective in trial proceedings. Trial advocacy is an essential trade skill for litigators and is taught in law schools and continuing legal education programs. It may also be taught in primary, secondary, and undergraduate schools, usually as a mock trial elective. The skills of trial advocacy can be broken into two categories: skills that accomplish individual tasks (tactical skills) such as selecting jurors, delivering opening statements and closing arguments, and examining witnesses, and those skills that integrate the individual actions to achieve greater effects and to drive unfolding events toward the advocate's desired outcome (strategy) . Most law school trial advocacy courses focus on tactical skills, though some integrate basic strategic planning methods. Some academics have expressed disfavor with advanced strategic techniques because of the imbalance they create, especially against attorneys who are unaware of them. Proponents of advanced strategic techniques argue that these methods are the only effective means to counter the already-existing imbalances in the system, as between indigent defendants and the state, and between working-class plaintiffs and well-resourced, wealthy corporations. == History == Like most legal skills, trial advocacy evolved through the apprenticeship and practice of attorneys. Even after 1900 (when the education of attorneys shifted to law schools,) most law schools offered little education in advocacy. In 1969, in response to criticism within the judicial system that law schools were not properly preparing attorneys for trial practice, a group of lawyers and law professors combined to form the National Institute for Trial Advocacy (NITA). Since then, many law schools have added or improved their instruction in trial advocacy, and numerous Continuing Legal Education organizations have offered classes surveying the subject area, and on specific topics within the field. Nearly one dozen law schools in the United States offer Master of Law (LL.M.) degrees in trial advocacy. Trial advocacy originally focused on individual actions within the trial, proposing improved juror selection, argument delivery, and direct and cross-examination methods. However, in the 1970s, NITA advanced the concepts of theme and theory as methods of integrating the various components into a cohesive whole. More recently, litigation strategy has blossomed with the importation of concepts from economic game theory, complexity theory, Gestalt psychology, and the application of maneuver warfare as a means not only of integrating the various actions within the trial into a comprehensive case but also as a means of gaining a decisive advantage over opposing counsel. == Topics == The topics commonly encompassed within Trial Advocacy are: === Jury selection or voir dire === The selection of jurors that will be receptive to the argument the attorney intends to make. === Opening statement === Presenting a non-argumentative overview of what the jury will see, often in the context of the attorney's theme, theory, and story. === Direct examination === Eliciting evidence from one's witnesses through non-leading questions. Because studies have shown that people best remember the first and the most recent (last) information heard (methods referred to as primacy and recency), the preferred method is to start with an engaging and favorable topic, move through more mundane matters, and to finish on a strong, favorable point. === Cross examination === Working with witnesses offered by the opposing party who may be hostile or uncooperative. === Closing argument === Using argument to create within the jurors a perception of what they have seen and heard that influences them to find in favor of the attorney's client. === Persuasion === The general principles that enable an advocate to make the jurors more receptive to his or her claims. === Mock trial === In mock trials, students take responsibility for the prosecution/plaintiff or defense case in a trial presented using fabricated evidence, and role-players as witnesses and faculty or volunteers as judge or jury. It evaluates the participants' skills in argument, evidence handling, and examination of witnesses but omits jury selection and strategic matters. Mock trial differs from moot court in that moot court practices appellate argument and so involves no handling of witnesses or evidence, but instead is an exercise in legal research and oral advocacy. === Basic trial strategy === The means of organizing a case into a clear and complete presentation. Case Diagrams: The attorney charts the elements they intend to prove (or attack) and the evidence supporting each. These ensures the case is comprehensively addressed. Theme and Theory: The theme is a sound bite that captures the emotional appeal of the case, and the theory is an explanation of events. These serve as strategic focal points, allowing individual actions (opening, examination of each witness, etc.) to be united with a common focus and in a way that clarifies and reinforces the perception of the case the attorney wants the jury or judge to adopt. === Advanced trial strategy === The means of organizing a case to maximize the combined impact of every element and to overwhelm or outmaneuver the opposing counsel while presenting a clear, decisive argument to the jury (or judge, in the case of bench trials). Advanced strategic skills, based upon psychology and military maneuver philosophy, are generally learned outside the classroom, as few law schools teach them. In fact, academics have criticized advanced strategic techniques for tipping verdicts through means unrelated to the merits of the case. For example, these techniques may cause an unfamiliar advocate to take actions that unwittingly undermine his client's interests. There is particular concern regarding the use of advanced strategic techniques by prosecutors, who already wield the substantial power of the state against often poorly resourced defendants. The counterargument is that strategy can correct already-existing imbalances in the justice system, such as when inexperienced advocates must face highly experienced ones, when small firms oppose large ones, and when poor clients must litigate their rights against wealthy ones. Under the current system, without a well-developed strategy, a small firm with an impoverished client stands almost no chance of success against a large firm with more significant resources, regardless of the case's merits. Maneuver strategy: An alternative to arguing the evidence or the law, maneuver strategies pursue solutions such as redirecting the focus of the trial, reshaping the way events are perceived, or disrupting or surprising the opposing counsel, rendering him ineffective at responding to unfolding events. While these methods are practiced widely, even by advocates not educated in strategy, some object to this as improper even when practiced ethically, as it subordinates the importance of the evidence and the law in determining a trial's outcome. One proponent of maneuver strategy, however, has noted that regardless of whether the attorney intends to leverage the tools of maneuver strategy, the attorney must understand the methods, or they will be ill-equipped to identify and counter them. Gestalt psychology: This branch of psychology focuses on how things are perceived as a whole instead of how individual components appear. It aids in ensuring the jury (or judge in bench trials) perceives events as the attorney desires. It also offers a way of shaping how witnesses and opposing counsel will perceive the problems an attorney raises for them during the trial. When coupled with game theory, shaping perception allows an attorney to influence or shape the hostile witness or counsel's actions. Game theory: Game theory offers models of how people make decisions. In trial practice, game theory is useful in predicting witnesses' likely actions when presented with a decision. Because decisions are framed according to how they perceive a situation, when game theory is coupled with Gestalt psychology, attorneys can present problems to witnesses or opposing counsel to increase the likelihood of them making decisions about their responses that improve the attorney's strategic position. Lines of effort: In the way a case diagram matches evidence to elements, the line of effort matches actions to specific effects the attorney intends to the various results that achieve their goal. == References == === Bibliography === Dreier, A.S. Strategy, Planning & Litigating to Win. Boston MA: Conatus, 2012. ISBN 9780615676951 Korzen, John Make Your Argument: Succeeding in Moot Court and Mock Trial. New York NY: Kaplan 2010. ISBN 9781607144953 Lubet, Steven Modern Trial Advocacy. South Bend IN. NITA, 2004. ISBN 1556818866	Wikipedia/Trial_advocacy
Opioid use disorder (OUD) is a substance use disorder characterized by cravings for opioids, continued use despite physical and/or psychological deterioration, increased tolerance with use, and withdrawal symptoms after discontinuing opioids. Opioid withdrawal symptoms include nausea, muscle aches, diarrhea, trouble sleeping, agitation, and a low mood. Addiction and dependence are important components of opioid use disorder. Risk factors include a history of opioid misuse, current opioid misuse, young age, socioeconomic status, race, untreated psychiatric disorders, and environments that promote misuse (social, family, professional, etc.). Complications may include opioid overdose, suicide, HIV/AIDS, hepatitis C, and problems meeting social or professional responsibilities. Diagnosis may be based on criteria by the American Psychiatric Association in the DSM-5. Opioids include substances such as heroin, morphine, fentanyl, codeine, dihydrocodeine, oxycodone, and hydrocodone. A useful standard for the relative strength of different opioids is morphine milligram equivalents (MME). It is recommended for clinicians to refer to daily MMEs when prescribing opioids to decrease the risk of misuse and adverse effects. Long-term opioid use occurs in about 4% of people following their use for trauma or surgery-related pain. In the United States, most heroin users begin by using prescription opioids that may also be bought illegally. People with opioid use disorder are often treated with opioid replacement therapy using methadone or buprenorphine. Such treatment reduces the risk of death. Additionally, they may benefit from cognitive behavioral therapy, other forms of support from mental health professionals such as individual or group therapy, twelve-step programs, and other peer support programs. The medication naltrexone may also be useful to prevent relapse. Naloxone is useful for treating an opioid overdose and giving those at risk naloxone to take home is beneficial. This disorder is much more prevalent than first realized. In 2020, the CDC estimated that nearly 3 million people in the U.S. were living with OUD and more than 65,000 people died by opioid overdose, of whom more than 15,000 overdosed on heroin. In 2022, the U.S. reported 81,806 deaths caused by opioid-related overdoses. Canada reported 32,632 opioid-related deaths between January 2016 and June 2022. == History == === Historical misuse === Opiate misuse has been recorded at least since 300 BC. Greek mythology describes Nepenthe ("free from sorrow") and its use by the hero of the Odyssey. Opioids have been used in the Near East for centuries. The purification and isolation of opiates occurred in the early 19th century. In the early 2000s, buprenorphine was one of the first opioid dependence drugs approved in the U.S. to combat opioid abuse, after decades of research led to the development of drugs to fight opioid use disorder. === Historical treatment === Levacetylmethadol (LAAM) was formerly used to treat opioid dependence. In 2003, its manufacturer discontinued production. There are no available generic versions. LAAM produced long-lasting effects, which allowed the person receiving treatment to visit a clinic only three times per week, as opposed to daily as with methadone. In 2001, LAAM was removed from the European market due to reports of life-threatening ventricular rhythm disorders. In 2003, Roxane Laboratories, Inc. discontinued it in the U.S. == Diagnosis == The DSM-5 guidelines for the diagnosis of opioid use disorder require that the individual has a significant impairment or distress related to opioid uses. To make the diagnosis two or more of 11 criteria must be present in a given year: More opioids are taken than intended The individual is unable to decrease the number of opioids used Large amounts of time are spent trying to obtain opioids, use opioids, or recover from taking them The individual has cravings for opioids Difficulty fulfilling professional duties at work or school Continued use of opioids leading to social and interpersonal consequences Decreased social or recreational activities Using opioids despite being in physically dangerous settings Continued use despite opioids worsening physical or psychological health (i.e. depression, constipation) Tolerance Withdrawal The severity can be classified as mild, moderate, or severe based on the number of criteria present. The tolerance and withdrawal criteria are not considered to be met for individuals taking opioids solely under appropriate medical supervision. Addiction and dependence are components of a substance use disorder; addiction is the more severe form. == Signs and symptoms == === Opioid intoxication === Signs and symptoms of opioid intoxication include: === Opioid overdose === Signs and symptoms of opioid overdose include, but are not limited to: Pin-point pupils may occur. Patient presenting with dilated pupils may still be experiencing an opioid overdose. Decreased heart rate Decreased body temperature Decreased breathing Altered level of consciousness. People may be unresponsive or unconscious. Pulmonary edema (fluid accumulation in the lungs) Shock Death === Withdrawal === Opioid withdrawal can occur with a sudden decrease in, or cessation of, opioids after prolonged use. Onset of withdrawal depends on the half-life of the opioid that was used last. With heroin this typically occurs five hours after use. With methadone, it may take two days. The length of time that major symptoms occur also depends on the opioid used. For heroin withdrawal, symptoms are typically greatest at two to four days and can last up to two weeks. Less significant symptoms may remain longer, in which case the withdrawal is known as post-acute-withdrawal syndrome. Treatment of withdrawal may include methadone and buprenorphine. Medications for nausea or diarrhea may also be used. == Cause == Opioid use disorder can develop for many reasons, including systemic failures such as pervasive marketing strategies, over-prescribing, and self-medication. Scoring systems have been derived to assess the likelihood of opiate addiction in chronic pain patients. Healthcare practitioners have long been aware that despite the effective use of opioids for managing pain, empirical evidence supporting long-term opioid use is minimal. Many studies of patients with chronic pain have failed to show any sustained improvement in their pain or ability to function with long-term opioid use. A 2024 literature review suggests that adverse childhood experiences (ACEs) are significantly associated with opioid use disorder later in life. ACEs include witnessing violence, experiencing abuse and neglect, and growing up with a family member with a mental health or substance abuse problem. == Mechanism == === Addiction === Addiction is a chronic brain disorder characterized by compulsive drug use despite adverse consequences. Addiction involves the overstimulation of the brain's mesocorticolimbic reward circuit (reward system), essential for motivating behaviors linked to survival and reproductive fitness, like seeking food and sex. This reward system encourages associative learning and goal-directed behavior. In addiction, substances overactivate this circuit, causing compulsive behavior due to changes in brain synapses. In the brain's mesolimbic region, Nucleus Accumbens (NAc) accepts releases of dopamine triggered by the neurotransmitters. The brain reward circuitry is rooted in these networks, interacting between the mesolimbic and prefrontal cortex; these systems link motivation, anti-stress, incentive salience, and wellbeing. The incentive-sensitization theory differentiates between "wanting" (driven by dopamine in the reward circuit) and "liking" (related to brain pleasure centers). This explains the addictive potential of non-pleasurable substances and the persistence of opioid addiction despite tolerance to their euphoric effects. Addiction surpasses mere avoidance of withdrawal, involving cues and stress that reactivate reward-driven behaviors. This is thought to be an important reason detoxification alone is unsuccessful 90% of the time. Overexpression of the gene transcription factor ΔFosB in the nucleus accumbens plays a crucial role in the development of an addiction to opioids and other addictive drugs by sensitizing drug reward and amplifying compulsive drug-seeking behavior. Like other addictive drugs, overuse of opioids leads to increased ΔFosB expression in the nucleus accumbens. Opioids affect dopamine neurotransmission in the nucleus accumbens via the disinhibition of dopaminergic pathways as a result of inhibiting the GABA-based projections to the ventral tegmental area (VTA) from the rostromedial tegmental nucleus (RMTg), which negatively modulates dopamine neurotransmission. In other words, opioids inhibit the projections from the RMTg to the VTA, which in turn disinhibits the dopaminergic pathways that project from the VTA to the nucleus accumbens and elsewhere in the brain. The differences in the genetic regions encoding the dopamine receptors for each individual may help to elucidate part of the risk for opioid addiction and general substance abuse. Studies of the D2 Dopamine Receptor, in particular, have shown some promising results. One specific SNP is at the TaqI RFLP (rs1800497). In a 2014 study of 530 Han Chinese heroin-addicted individuals from a Methadone Maintenance Treatment Program, those with the specific genetic variation showed higher mean heroin consumption by around double those without the SNP. This study helps to show the contribution of dopamine receptors to substance addiction and more specifically to opioid abuse. Neuroimaging has shown functional and structural alterations in the brain. Chronic intake of opioids such as heroin may cause long-term effects in the orbitofrontal area (OFC), which is essential for regulating reward-related behaviors, emotional responses, and anxiety. Moreover, neuroimaging and neuropsychological studies demonstrate dysregulation of circuits associated with emotion, stress and high impulsivity. === Dependence === Opioid dependence can occur as physical dependence, psychological dependence, or both. Drug dependence is an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake). Dependence is a component of a substance use disorder. Opioid dependence can manifest as physical dependence, psychological dependence, or both. Increased brain-derived neurotrophic factor (BDNF) signaling in the ventral tegmental area (VTA) has been shown to mediate opioid-induced withdrawal symptoms via downregulation of insulin receptor substrate 2 (IRS2), protein kinase B (AKT), and mechanistic target of rapamycin complex 2 (mTORC2). As a result of downregulated signaling through these proteins, opiates cause VTA neuronal hyperexcitability and shrinkage (specifically, the size of the neuronal soma is reduced). It has been shown that when an opiate-naive person begins using opiates in concentrations that induce euphoria, BDNF signaling increases in the VTA. Upregulation of the cyclic adenosine monophosphate (cAMP) signal transduction pathway by cAMP response element binding protein (CREB), a gene transcription factor, in the nucleus accumbens is a common mechanism of psychological dependence among several classes of drugs of abuse. Upregulation of the same pathway in the locus coeruleus is also a mechanism responsible for certain aspects of opioid-induced physical dependence. A scale was developed to compare the harm and dependence liability of 20 drugs. The scale uses a rating of zero to three to rate physical dependence, psychological dependence, and pleasure to create a mean score for dependence. Selected results can be seen in the chart below. Heroin and morphine both scored highest, at 3.0. === Opioid receptors === A genetic basis for the efficacy of opioids in the treatment of pain has been demonstrated for several specific variations, but the evidence for clinical differences in opioid effects is not clear. There is an estimated 50% genetic contribution to opioid use disorder. The pharmacogenomics of the opioid receptors and their endogenous ligands have been the subject of intensive activity in association studies. These studies test broadly for a number of phenotypes, including opioid dependence, cocaine dependence, alcohol dependence, methamphetamine dependence/psychosis, response to naltrexone treatment, personality traits, and others. Major and minor variants have been reported for every receptor and ligand coding gene in both coding sequences, as well as regulatory regions. Research on endogenous opioid receptors has focused around the OPRM1 gene, which encodes the μ-opioid receptor, and the OPRK1 and OPRD1 genes, which encode the κ and δ receptors, respectively. Newer approaches shift away from analysis of specific genes and regions to screen the entire genome. These GWAS studies have yielded a number of implicated genes, although many of them code for seemingly unrelated proteins in processes such as cell adhesion, transcriptional regulation, cell structure determination, and RNA, DNA, and protein handling/modifying. ==== 118A>G variant ==== While over 100 variants have been identified for the opioid mu-receptor, the most studied mu-receptor variant is the non-synonymous 118A>G variant, which results in functional changes to the receptor, including lower binding site availability, reduced mRNA levels, altered signal transduction, and increased affinity for beta-endorphin. In theory, all these functional changes would reduce the impact of exogenous opioids, requiring a higher dose to achieve the same therapeutic effect. This points to a potential for greater addictive capacity in individuals who require higher dosages to achieve pain control. Evidence linking the 118A>G variant to opioid dependence is mixed, with associations shown in some study groups but negative results in other groups. One explanation for the mixed results is the possibility of other variants that are in linkage disequilibrium with the 118A>G variant and thus contribute to different haplotype patterns more specifically associated with opioid dependence. ==== Non-opioid receptor genes ==== While opioid receptors have been the most widely studied, a number of other genes have been implicated in OUD. Higher numbers of (CA) repeats flanking the preproenkephalin gene, PENK, have been associated with opiate dependence. There have been mixed results for the MCR2 gene, encoding melanocortin receptor type 2, implicating both protection and risk to heroin addiction. A number of enzymes in the cytochrome P450 family may also play a role in dependence and overdose due to variance in breakdown of opioids and their receptors. There are also multiple potential complications with combining opioids with antidepressants and antiepileptic drugs (both common drugs for chronic pain patients) because of their effects on inducing CYP enzymes. Genotyping of CYP2D6 in particular may play a role in helping patients with individualized treatment for OUD and other drug addictions. == Prevention == Prevention approaches for opioid use disorder must consider clinical recommendations for prescribing/starting to take opioids, when they are clinically appropriate to use, and risks associated with opioid therapy. Improving opioid prescribing guidelines and practices can help reduce unnecessary exposure to opioids, which lowers the risk of developing OUD (opioid use disorder). Healthcare providers should strictly follow evidence-based guidelines to ensure safe and appropriate use. Another way to prevent OUD is by educating the public about the risks of prescription opioids and illegal substances like fentanyl. Awareness campaigns, community outreach programs, and school-based education initiatives can help people make informed decisions about opioid use and recognize the signs of addiction early. A strong association between adverse childhood experiences and opioid abuse later in life has been identified, suggesting that a high adverse childhood experiences score should be considered a risk factor for opioid abuse. Screening for adverse childhood experiences before prescribing or implementing interventions involving opioids can mitigate the potential for misuse. === Opioid overdose === Naloxone is used for the emergency treatment of an overdose. It can be given by many routes (e.g., intramuscular (IM), intravenous (IV), subcutaneous, intranasal, and inhalation) and acts quickly by displacing opioids from opioid receptors and preventing the activation of these receptors. Naloxone kits are recommended for laypersons who may witness an opioid overdose, for people with large prescriptions for opioids, those in substance use treatment programs, and those recently released from incarceration. Since naloxone is a life-saving medication, many areas of the U.S. have implemented standing orders for law enforcement to carry and give it as needed. In addition, naloxone can be used to challenge a person's opioid abstinence status before starting a medication such as naltrexone, which is used in the management of opioid addiction. Good Samaritan laws typically protect bystanders who administer naloxone. In the U.S., at least 40 states have Good Samaritan laws to encourage bystanders to take action without fear of prosecution. As of 2019, 48 states give pharmacists the authority to distribute naloxone without an individual prescription. Homicide, suicide, accidents and liver disease are also opioid-related causes of death for those with OUD. Many of these causes of death are unnoticed due to the often limited information on death certificates. Other risk factors for overdose mortality related to opioids at the individual level include clinical factors such as cardiovascular disease, comorbid mental disorders and psychological stress (e.g., depression), a history of substance use disorders, economic and community distress (e.g., low education, high unemployment), and characteristics such as male sex and middle age. === U.S. prevention strategies === The CDC Clinical Practice Guideline for Prescribing Opioids for Pain was developed to help guide healthcare professinals toward safe and evidence-based use of opioid therapy. Large U.S. retail pharmacy chains are implementing protocols, guidelines, and initiatives to take back unused opioids, providing naloxone kits, and being vigilant about suspicious prescriptions. Insurance programs can help limit opioid use by setting quantity limits on prescriptions or requiring prior authorizations for certain medications. Many U.S. officials and government leaders have become involved in implementing preventative measures to decrease opioid usage in the U.S. Targeted education of medical providers and government officials can lead to provisions affecting opioid distribution by healthcare providers. == Mitigation == The "CDC Clinical Practice Guideline for Prescribing Opioids for Pain-United States, 2022" provides recommendations related to opioid misuse, OUD, and opioid overdoses. It reports a lack of clinical evidence that "abuse-deterrent" opioids (e.g., OxyContin), as labeled by the U.S. Food and Drug Administration, are effective for OUD risk mitigation. CDC guidance suggests the prescription of immediate-release opioids instead of opioids that have a long duration (long-acting) or opioids that are released over time (extended release). Other recommendations include prescribing the lowest opioid dose that successfully addresses the pain in opioid-naïve patients and collaborating with patients who already take opioid therapy to maximize the effect of non-opioid analgesics. While receiving opioid therapy, patients should be periodically evaluated for opioid-related complications and clinicians should review state prescription drug monitoring program systems. The latter should be assessed to reduce the risk of overdoses in patients due to their opioid dose or medication combinations. For patients receiving opioid therapy in whom the risks outweigh the benefits, clinicians and patients should develop a treatment plan to decrease their opioid dose incrementally. Compartmental models are mathematical frameworks used to assess and describe complex topics such as the opioid crisis. Applied compartmental models are used in public health to assess the effectiveness of interventions in opioid use disorder. Most overdoses in 2020 were due to synthetic opioids, highlighting a need to incorporate synthetic opioid data in the models. For more specific mitigation strategies regarding opioid overdoses, see opioid overdose § Prevention. == Management == Opioid use disorders typically require long-term treatment and care with the goal of reducing the person's risks and improving their long-term physical and psychological condition. First-line management involves the use of opioid replacement therapies, particularly methadone, naltrexone, and buprenorphine/naloxone. Withdrawal management alone is strongly discouraged, because of its association with elevated risks of HIV and hepatitis C transmission, high rates of overdose deaths, and nearly universal relapse. This approach is seen as ineffective without plans for transition to long-term evidence-based addiction treatment, such as opioid agonist treatment. Though treatment reduces mortality rates, the first four weeks after treatment begins and the four weeks after treatment ceases are the riskiest times for drug-related deaths. These periods of increased vulnerability are significant because many of those in treatment leave programs during these periods. There is evidence that people with opioid use disorder who are dependent on pharmaceutical opioids may require a different management approach from those who take heroin. === Medication === Opioid replacement therapy (ORT), also known as opioid substitution therapy (OST), Medication for Addiction Treatment (MAT), or Medications for Opioid Use Disorder (MOUD), involves replacing an opioid, such as heroin. Commonly used drugs for ORT are methadone and buprenorphine/naloxone (Suboxone), which are taken under medical supervision. Buprenorphine/naloxone is usually preferred over methadone because of its safety profile, which is considered significantly better, primarily with regard to its risk of overdose and effects on the heart (QTc prolongation). Buprenorphine/naloxone, methadone, and naltrexone are approved by the U.S. Food and Drug Administration (FDA) for medication-assisted treatment (MAT). In the U.S., the Substance Abuse and Mental Health Services Administration (SAMHSA) certifies opioid treatment programs (OTPs), where methadone can be dispensed at methadone clinics. As of 2023, the Waiver Elimination (MAT Act), also known as the "Omnibus Bill", removed the federal requirement for medical providers to obtain a waiver to prescribe buprenorphine, in an attempt to increase access to OUD treatment. The driving principle behind ORT is the patient's reclamation of a self-directed life. ORT facilitates this process by reducing symptoms of drug withdrawal and drug cravings. In some countries (not the U.S. or Australia), regulations enforce a limited time for people on ORT programs that conclude when a stable economic and psychosocial situation is achieved. (People with HIV/AIDS or hepatitis C are usually excluded from this requirement.) In practice, 40–65% of patients maintain abstinence from additional opioids while receiving opioid replacement therapy and 70–95% can reduce their use significantly. Medical (improper diluents, non-sterile injecting equipment), psychosocial (mental health, relationships), and legal (arrest and imprisonment) issues that can arise from the use of illegal opioids are concurrently eliminated or reduced. Clonidine or lofexidine can help treat the symptoms of withdrawal. The period when initiating methadone and the time immediately after discontinuing treatment with both drugs are periods of particularly increased mortality risk, which should be dealt with by both public health and clinical strategies. ORT has proved to be the most effective treatment for improving the health and living condition of people experiencing illegal opiate use or dependence, including mortality reduction and overall societal costs, such as the economic loss from drug-related crime and healthcare expenditure. A review of UK hospital policies found that local guidelines delayed access to substitute opioids, for instance by requiring lab tests to demonstrate recent use or input from specialist drug teams before prescribing. Delays to access can increase people's risk of discharging themselves early against medical advice. ORT is endorsed by the World Health Organization, United Nations Office on Drugs and Crime, and UNAIDS as effective at reducing injection, lowering risk for HIV/AIDS, and promoting adherence to antiretroviral therapy. Buprenorphine and methadone work by reducing opioid cravings, easing withdrawal symptoms, and blocking the euphoric effects of opioids via cross-tolerance, and in the case of buprenorphine, a high-affinity partial opioid agonist, also due to opioid receptor saturation. ==== Buprenorphine and buprenorphine/naloxone ==== Buprenorphine can be administered either as a standalone product or in combination with the opioid antagonist naloxone. This inclusion is strategic: it deters misuse by preventing the crushing and injecting of the medication, encouraging instead the prescribed sublingual (under the tongue) route. Buprenorphine/naloxone formulations are available as tablets and films; these formulations operate efficiently when taken sublingually. In this form, buprenorphine's bioavailability remains robust (35–55%), while naloxone's is significantly reduced (~10%). Buprenorphine's role as a partial opioid receptor agonist sets it apart from full agonists like methadone. Its unique pharmacological profile makes it less likely to cause respiratory depression, thanks to its "ceiling effect". While the risk of misuse or overdose is higher with buprenorphine alone compared to the buprenorphine/naloxone combination or methadone, its usage is linked to a decrease in mortality. Approved in the U.S. for opioid dependence treatment in 2002, buprenorphine has since expanded in form, with the FDA approving a month-long injectable version in 2017. When initiating buprenorphine/naloxone therapy, several critical factors must be considered. These include the severity of withdrawal symptoms, the time elapsed since the last opioid use, and the type of opioid involved (long-acting vs. short-acting). A standard induction method involves waiting until the patient exhibits moderate withdrawal symptoms, as measured by a Clinical Opiate Withdrawal Scale, achieving a score of around 12. Alternatively, "microdosing" commences with a small dose immediately, regardless of withdrawal symptoms, offering a more flexible approach to treatment initiation. "Macrodosing" starts with a larger dose of Suboxone, a different induction strategy with its own set of considerations. ==== Methadone ==== Methadone is a commonly used full-opioid agonist in the treatment of opioid use disorder. It is effective in relieving withdrawal symptoms and cravings in people with opioid addiction, and can also be used in pain control in certain situations. While methadone is a widely prescribed form of OAT, it often requires more frequent clinical visits compared to buprenorphine/naloxone, which also has a better safety profile and lower risk of respiratory depression and overdose. Important considerations when initiating methadone include the patient's opioid tolerance, the time since last opioid use, the type of opioid used (long-acting vs. short-acting), and the risk of methadone toxicity. Methadone comes in different forms: tablet, oral solution, or an injection. One of methadone's benefits is that it can last up to 56 hours in the body, so if a patient misses a daily dose, they will not typically struggle with withdrawal symptoms. Other advantages of methadone include reduction in infectious disease related to injection drug use, and reduced mortality. Methadone has a number of potential side effects, including slowed breathing, nausea, vomiting, restlessness, and headache. ==== Naltrexone ==== Naltrexone is an opioid receptor antagonist used for the treatment of opioid addiction. It is not as widely used as buprenorphine or methadone for OUD due to low rates of patient acceptance, non-adherence due to daily dosing, and difficulty achieving abstinence from opioids before beginning treatment. Dosing naltrexone after recent opioid use can lead to precipitated withdrawal. Conversely, naltrexone antagonism at the opioid receptor can be overcome with higher doses of opioids. Naltrexone monthly IM injections received FDA approval in 2010 for the treatment of opioid dependence in abstinent opioid users. ==== Other opioids ==== Evidence of effects of heroin maintenance compared to methadone are unclear as of 2010. A Cochrane review found some evidence in opioid users who had not improved with other treatments. In Switzerland, Germany, the Netherlands, and the United Kingdom, long-term injecting drug users who do not benefit from methadone and other medication options may be treated with injectable heroin that is administered under the supervision of medical staff. Other countries where it is available include Spain, Denmark, Belgium, Canada, and Luxembourg. Dihydrocodeine in both extended-release and immediate-release form is also sometimes used for maintenance treatment as an alternative to methadone or buprenorphine in some European countries. Dihydrocodeine is an opioid agonist. It may be used as a second-line treatment. A 2020 systematic review found low-quality evidence that dihydrocodeine may be no more effective than other routinely used medication interventions in reducing illicit opiate use.An extended-release morphine confers a possible reduction of opioid use and with fewer depressive symptoms but overall more adverse effects compared to other forms of long-acting opioids. Retention in treatment was not found to be significantly different. It is used in Switzerland and Canada. ==== In pregnancy ==== Pregnant women with opioid use disorder can also receive treatment with methadone, naltrexone, or buprenorphine. Buprenorphine appears to be associated with more favorable outcomes compared to methadone for treating opioid use disorder (OUD) in pregnancy. Studies show that buprenorphine is linked to lower risks of preterm birth, greater birth weight, and larger head circumference without increased harm. Compared to methadone, it consistently results in improved birth weight and gestational age, though these findings should be interpreted with caution due to potential biases. Buprenorphine use correlates with a lower risk of adverse neonatal outcomes, with similar risks of adverse maternal outcomes as methadone. Infants born to buprenorphine-treated mothers generally have higher birth weights, fewer withdrawal symptoms, and a lower likelihood of premature birth. They often require less treatment for neonatal abstinence syndrome and have mothers who are more likely to start treatment earlier in pregnancy, leading to longer gestations and larger infants. === Behavioral therapy === Paralleling the variety of medical treatments, there are many forms of psychotherapy and community support for treating OUD. The primary evidence-based psychotherapies include cognitive behavioral therapy (CBT), motivational enhancement therapy (MET), contingency management (CM), and twelve-step programs. Community-based support such as support groups (e.g., Narcotics Anonymous) and therapeutic housing for those with OUD is also an important aspect of healing. ==== Cognitive behavioral therapy ==== Cognitive behavioral therapy (CBT) is a form of psychosocial intervention that systematically evaluates thoughts, feelings, and behaviors about a problem and works to develop coping strategies to work through those problems. This intervention has demonstrated success in many psychiatric conditions (e.g., depression) and substance use disorders (e.g., tobacco). The use of CBT alone for OUD has declined due to lack of efficacy, and many rely on medication therapy or medication therapy with CBT, since both were found to be more efficacious than CBT alone. CBT has been shown to be more successful in relapse prevention than treatment of ongoing drug use. It is particularly known for its durability. ==== Motivational Enhancement Therapy ==== Motivational enhancement therapy (MET) is the manualized form of motivational interviewing (MI). MI leverages one's intrinsic motivation to recover through education, formulation of relapse prevention strategies, reward for adherence to treatment guidelines, and positive thinking to keep motivation high—which are based on a person's socioeconomic status, gender, race, ethnicity, sexual orientation, and readiness to recover. Like CBT, MET alone has not shown convincing efficacy for OUD. There is stronger support for combining it with other therapies. ==== Contingency Management Therapy ==== Contingency Management Therapy (CMT) employs similar principles as operant behavioral conditioning, such as using incentives to reach certain goals (e.g., verified abstinence, usually in the form of urine drug testing). This form of psychotherapy has the strongest, most robust empirical support for treating drug addiction. Outpatient clients are shown to have improved medication compliance, retention, and abstinence when using voucher-based incentives. One way this is implemented is to offer take-home privileges for methadone programs. Despite its effectiveness during treatment, effects tend to wane once terminated. Additionally, the cost barrier limits its application in the clinical community. ==== Twelve-step programs ==== While medical treatment may help with the initial symptoms of opioid withdrawal, once the first stages of withdrawal are through, a method for long-term preventative care is attendance at 12-step groups such as Narcotics Anonymous (NA). NA's 12-step process is based on the 12-step facilitation of Alcoholic Anonymous (AA) and centers on peer support, self-help, and spiritual connectedness. Some evidence also supports the use of these programs for adolescents. Multiple studies have shown increased abstinence for those in NA compared to those who are not. Members report a median abstinence length of 5 years. === Novel experimental treatments === Though medications and behavioral treatments are effective forms for treating OUD, relapse remains a common problem. The medical community has looked to novel technologies and traditional alternative medicines for new ways to approach the issues of continued cravings and impaired executive functioning. While consensus on their efficacy has not been reached, a number of reviews have shown promising results for the use of non-invasive brain stimulation (NIBS) for reducing cravings in OUD. These results are consistent with the use of NIBS for reducing cravings of other substances. Investigations into the anecdotal evidence of psychedelics like ibogaine have also shown the possibility of decreased cravings and withdrawal symptoms. Ibogaine is illegal in the U.S. but is unregulated in Mexico, Costa Rica, and New Zealand, where many clinics use it for addiction treatment. Research has shown a minor mortality risk due to its cardiotoxic and neurotoxic effects. In 2024 the FDA approved the NET (NeuroElectric Therapy) device, which reduces withdrawal symptoms by neurostimulation. Used for three to five days of continuous treatment, NET delivers alternating current via surface electrodes placed trans-cranially at the base of the skull on each side of the head. == Treatment challenges == The stigma surrounding addiction can heavily influence opioid addicts not to seek help. Many people view addiction as a moral failing rather than a medical condition, which can lead to feelings of shame and isolation. This stigma can affect family members, making it difficult for them to support their loved ones effectively. According to position papers on the treatment of opioid dependence published by the United Nations Office on Drugs and Crime and the World Health Organization, care providers should not treat opioid use disorder as the result of a weak moral character or will but as a medical condition. Some evidence suggests the possibility that opioid use disorders occur due to genetic or other chemical mechanisms that may be difficult to identify or change, such as dysregulation of brain circuitry involving reward and volitional experience. It has also been hypothesized that endocrine and autonomic nervous system abnormalities can be opioid-induced. Critically, the endogenous opioid system is involved in reward; changes to this system affect experience and subsequent behavior. The exact mechanisms are unclear, leading to debate over the influence of biology and free will. Accessing appropriate treatment is often a significant barrier. Factors include: Availability of services: Many areas, especially rural regions, lack treatment facilities or qualified healthcare providers who specialize in opioid use disorder. Insurance coverage: People without insurance or those whose plans do not cover substance use disorder treatment may struggle to find affordable care. Transportation: For many, getting to treatment facilities can be challenging due to a lack of transportation options. Public stigma: Many communities may advocate against establishing treatment programs in their area due to stigma and perceptions of people with substance use disorders. The United States passed the Comprehensive Addiction and Recovery Act (CARA) in 2016, with the aim to remove treatment barriers by allocating federal funds to increase accessibility to Medication Opioid Use Disorder (MOUD) treatment in rural areas. Telehealth could be a beneficial treatment alternative, especially for people in rural areas with limited access to MOUD treatment. The variety of treatment modalities available for OUD—such as medication-assisted treatment (MAT), counseling, and residential programs—can be overwhelming. Patients may have difficulty understanding which option best suits them, leading to confusion and potential disengagement from the treatment process. Withdrawal symptoms can be severe and uncomfortable, leading many people to relapse before they complete detoxification or engage fully in recovery programs. The fear of withdrawal often prevents people from seeking help altogether. == Epidemiology == Globally, the number of people with opioid dependence increased from 10.4 million in 1990 to 15.5 million in 2010. In 2016, the numbers rose to 27 million people who experienced this disorder. Opioid use disorders resulted in 122,000 deaths worldwide in 2015, up from 18,000 deaths in 1990. Deaths from all causes rose from 47.5 million in 1990 to 55.8 million in 2013. === United States === The current epidemic of opioid abuse is the most lethal drug epidemic in U.S. history. The crisis can be distinguished by waves of opioid overdose deaths as described by the Centers of Disease Control and Prevention. The first wave began in the 1990s, related to the rise in prescriptions of natural opioids (such as codeine and morphine), semisynthetic opioids (oxycodone, hydrocodone, hydromorphone, and oxymorphone), and synthetic opioids like methadone. In the U.S., "the age-adjusted drug poisoning death rate involving opioid analgesics increased from 1.4 to 5.4 deaths per 100,000 population between 1999 and 2010". The second wave dates to around 2010 with the rapid increase in opioid overdoses due to heroin. By this time, there were already four times as many deaths by overdose than in 1999. The age-adjusted drug poisoning death rate involving heroin doubled from 0.7 to 1.4 deaths per 100,000 people between 1999 and 2011 and continued to increase to 4.1 in 2015. The third wave of overdose deaths began in 2013, related to synthetic opioids, particularly illicitly produced fentanyl. While the illicit fentanyl market has continuously changed, the drug is generally sold as an adulterant in heroin. Research suggests that the rapid increase of fentanyl into the illicit opioid market has been largely supply-side-driven and dates to 2006. Decreasing heroin purity, competition from increased access to prescription medications, and dissemination of "The Siegfried Method" (a relatively simple and cost-effective method of fentanyl production) were major factors in street suppliers' inclusion of fentanyl in their products. The current, fourth wave, which began in 2016, has been characterized by polysubstance overdose due to synthetic opioids like fentanyl mixed with stimulants such as methamphetamine or cocaine. In 2010, around 0.5% of opioid-related deaths were attributed to mixture with stimulants. This figure increased more than 50-fold by 2021, when about a third of opioid-related deaths, or 34,000, involved stimulant use. In 2017, the U.S. Department of Health and Human Services (HHS) announced a public health emergency due to an increase in the misuse of opioids. The administration introduced a strategic framework called the Five-Point Opioid Strategy, which includes providing access recovery services, increasing the availability of reversing agents for overdose, funding opioid misuse and pain research, changing treatments of people managing pain, and updating public health reports related to combating opioid drug misuse. Studies done in the U.S. from 2010 to 2019 revealed that about 86.6% of people in the U.S. who could have benefited from opioid use disorder treatment were not receiving it. Over the past decade, the uptake of medications for opioid use disorder has increased, but there are still many regions with a prevalence of opioid use disorder and lack of medical support. The U.S. epidemic in the 2000s is related to a number of factors. Rates of opioid use and dependency vary by age, sex, race, and socioeconomic status. With respect to race, the discrepancy in deaths is thought to be due to an interplay between physician prescribing and lack of access to healthcare and certain prescription drugs. Men are at higher risk for opioid use and dependency than women, and men also account for more opioid overdoses than women, although this gap is closing. Women are more likely to be prescribed pain relievers, be given higher doses, use them for longer durations, and become dependent upon them faster. Deaths due to opioid use also tend to skew at older ages than deaths from use of other illicit drugs. This does not reflect opioid use as a whole, which includes younger people. Overdoses from opioids are highest among people between the ages of 40 and 50, in contrast to heroin overdoses, which are highest among people between the ages of 20 and 30. 21- to 35-year-olds represent 77% of people who enter treatment for opioid use disorder, but the average age of first-time use of prescription painkillers was 21.2 years in 2013. Among the middle class, means of acquiring funds include elder financial abuse and international dealers noticing a lack of enforcement in their transaction scams throughout the Caribbean. Since 2018, with the federal government's passing of the SUPPORT (Substance Use-Disorder Prevention That Promotes Opioid Recovery and Treatment for Patients and Communities Act) Act, federal restrictions on methadone use for patients receiving Medicare have been lifted. Since March 2020, as a result of the COVID-19 pandemic, buprenorphine may be dispensed via telemedicine in the U.S. In October 2021, New York Governor Kathy Hochul signed legislation to combat the opioid crisis. This included establishing a program for the use of medication-assisted substance use disorder treatment for incarcerated individuals in state and local correctional facilities, decriminalizing the possession and sale of hypodermic needles and syringes, establishing an online directory for distributors of opioid antagonists, and expanding the number of eligible crimes committed by individuals with a substance use disorder that may be considered for diversion to a substance use treatment program. Until these laws were signed, incarcerated New Yorkers did not reliably have access to medication-assisted treatment. Syringe possession was still a class A misdemeanor despite New York authorizing and funding syringe exchange and access programs. This legislation acknowledges the ways New York State laws have contributed to opioid deaths: in 2020 more than 5,112 people died from overdoses in New York State, with 2,192 deaths in New York City. In 2023, the Waiver Elimination (MAT Act), as part of Section 1262 of the Consolidated Appropriations Act, 2023 (or "Omnibus Bill"), removed the federal requirement for medical providers to obtain a waiver to prescribe buprenorphine, in an attempt to increase access to OUD treatment. Before this bill, practitioners were required to receive a Drug Addiction Treatment Act of 2000 (DATA) waiver, also known as "x-waiver", before prescribing buprenorphine. There is also now no longer any limit to the number of patients to whom a provider may prescribe buprenorphine for OUD. Charts of deaths involving specific opioids and classes of opioids - US National Institute on Drug Abuse == Canada == Canada recorded 32,632 opioid-related deaths between January 2016 and June 2022. The marked increase in opioid toxicity deaths is largely attributed to the COVID-19 pandemic. === Effects of COVID-19 on opioid overdose and telehealth treatment === Epidemiological research has shown that the COVID-19 pandemic accelerated the opioid crisis. The overarching trend of opioid overdose data has shown a plateau in deaths around 2017–18, with a sudden and acute rise in 2019 primarily attributed to synthetic opioids like fentanyl. In 2020, there were 93,400 drug overdoses in the U.S. with >73% (approximately 69,000) due to opioid overdose. One JAMA review by Gomes et al. showed that estimated years of life loss (YLL) due to opioid toxicity in the U.S. increased by 276%. This increase was particularly felt by those ages 15 to 19, whose YLL increased nearly threefold. Younger male adults had the largest effect size. Other reviews of U.S. and Canadian opioid data coinciding with the onset of COVID-19 suggested significant increases in opioid-related emergency medicine utilization, increased positivity for opioids, and surprisingly no to decreased change in naloxone dispensation. Telehealth played a large role in OUD treatment access, and legislation on telehealth continues to evolve. A study of Medicare beneficiaries with new-onset OUD showed that those who received telehealth services had a 33% lower risk of death by overdose. Minority groups such as Black and Hispanic Americans have also been shown to benefit from the increased access due to telehealth programs introduced during the pandemic, despite increasing disparity gaps in other OUD-related outcomes. The DEA and HHS have extended telemedicine flexibility in regard to prescribing controlled substances such as buprenorphine for OUD through 31 December 2024.\\ == China == China's relationship with opioids, particularly opium, dates back centuries, with significant use for medicinal purposes by the 7th century and increased demand in the 17th century due to smoking practices from Southeast Asia. The Opium Wars in the 19th century exacerbated the problem, leading to social and health crises. After 1949, under the Communist regime, strict legislation and punishment significantly reduced opioid use, creating a drug-free atmosphere by the 1950s. But with the economic reforms and open-door policies of the 1980s, drug abuse, including opiate dependence, reemerged as a major public health issue. From 2000 to 2020, the prevalence of OUD in China showed significant trends, though exact figures are hard to obtain due to underreporting. In 2004, Tang et al. reported approximately 1.14 million registered drug addicts, with over 75% being heroin addicts, suggesting a substantial burden, though the actual number is likely higher due to the hidden nature of drug use. This figure aligns with the understanding that official statistics often undercount, as noted in later reports like a 2019 Associated Press article that discussed pain pill addiction and suggested undercounting problems. Opioid abuse has been linked to significant health implications, particularly the spread of HIV/AIDS. In 2004, intravenous drug use was the most prevalent route of HIV transmission, accounting for 51.2% of cases, underscoring the public health threat. This suggests OUD and associated infectious illness therapies are needed. == References == == Further reading == == External links == Heroin information from the National Institute on Drug Abuse Opioid Dependence Treatment and Guidelines Bill Kinkle Recovery From Opioid Use Disorder	Wikipedia/Substitution_therapy
Multiple drug resistance (MDR), multidrug resistance or multiresistance is antimicrobial resistance shown by a species of microorganism to at least one antimicrobial drug in three or more antimicrobial categories. Antimicrobial categories are classifications of antimicrobial agents based on their mode of action and specific to target organisms. The MDR types most threatening to public health are MDR bacteria that resist multiple antibiotics; other types include MDR viruses, parasites (resistant to multiple antifungal, antiviral, and antiparasitic drugs of a wide chemical variety). Recognizing different degrees of MDR in bacteria, the terms extensively drug-resistant (XDR) and pandrug-resistant (PDR) have been introduced. Extensively drug-resistant (XDR) is the non-susceptibility of one bacteria species to all antimicrobial agents except in two or less antimicrobial categories. Within XDR, pandrug-resistant (PDR) is the non-susceptibility of bacteria to all antimicrobial agents in all antimicrobial categories. The definitions were published in 2011 in the journal Clinical Microbiology and Infection and are openly accessible. == Common multidrug-resistant organisms (MDROs) == Common multidrug-resistant organisms, typically bacteria, include: Vancomycin-Resistant Enterococci (VRE) Methicillin-resistant Staphylococcus aureus (MRSA) Extended-spectrum β-lactamase (ESBLs) producing Gram-negative bacteria Klebsiella pneumoniae carbapenemase (KPC) producing Gram-negatives Multidrug-resistant Gram negative rods (MDR GNR) MDRGN bacteria such as Enterobacter species, E.coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa Multi-drug-resistant tuberculosis Overlapping with MDRGN, a group of Gram-positive and Gram-negative bacteria of particular recent importance have been dubbed as the ESKAPE group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species). == Bacterial resistance to antibiotics == Various microorganisms have survived for thousands of years by their ability to adapt to antimicrobial agents. They do so via spontaneous mutation or by DNA transfer. This process enables some bacteria to oppose the action of certain antibiotics, rendering the antibiotics ineffective. These microorganisms employ several mechanisms in attaining multi-drug resistance: No longer relying on a glycoprotein cell wall Enzymatic deactivation of antibiotics Decreased cell wall permeability to antibiotics Altered target sites of antibiotic Efflux mechanisms to remove antibiotics Increased mutation rate as a stress response Many different bacteria now exhibit multi-drug resistance, including staphylococci, enterococci, gonococci, streptococci, salmonella, as well as numerous other Gram-negative bacteria and Mycobacterium tuberculosis. Antibiotic resistant bacteria are able to transfer copies of DNA that code for a mechanism of resistance to other bacteria even distantly related to them, which then are also able to pass on the resistance genes, resulting in generations of antibiotics resistant bacteria. This initial transfer of DNA is called horizontal gene transfer. == Bacterial resistance to bacteriophages == Phage-resistant bacteria variants have been observed in human studies. As for antibiotics, horizontal transfer of phage resistance can be acquired by plasmid acquisition. == Antifungal resistance == Yeasts such as Candida species can become resistant under long-term treatment with azole preparations, requiring treatment with a different drug class. Lomentospora prolificans infections are often fatal because of their resistance to multiple antifungal agents. == Antiviral resistance == HIV is the prime example of MDR against antivirals, as it mutates rapidly under monotherapy. Influenza virus has become increasingly MDR; first to amantadines, then to neuraminidase inhibitors such as oseltamivir, (2008-2009: 98.5% of Influenza A tested resistant), also more commonly in people with weak immune systems. Cytomegalovirus can become resistant to ganciclovir and foscarnet under treatment, especially in immunosuppressed patients. Herpes simplex virus rarely becomes resistant to acyclovir preparations, mostly in the form of cross-resistance to famciclovir and valacyclovir, usually in immunosuppressed patients. == Antiparasitic resistance == The prime example for MDR against antiparasitic drugs is malaria. Plasmodium vivax has become chloroquine and sulfadoxine-pyrimethamine resistant a few decades ago, and as of 2012 artemisinin-resistant Plasmodium falciparum has emerged in western Cambodia and western Thailand. Toxoplasma gondii can also become resistant to artemisinin, as well as atovaquone and sulfadiazine, but is not usually MDR Antihelminthic resistance is mainly reported in the veterinary literature, for example in connection with the practice of livestock drenching and has been recent focus of FDA regulation. == Preventing the emergence of antimicrobial resistance == To limit the development of antimicrobial resistance, it has been suggested to: Use the appropriate antimicrobial for an infection; e.g. no antibiotics for viral infections Identify the causative organism whenever possible Select an antimicrobial which targets the specific organism, rather than relying on a broad-spectrum antimicrobial Complete an appropriate duration of antimicrobial treatment (not too short and not too long) Use the correct dose for eradication; subtherapeutic dosing is associated with resistance, as demonstrated in food animals. More thorough education of and by prescribers on their actions' implications globally. Vaccination to prevent drug resistance for instance pneumococcus vaccine or flu vaccine The medical community relies on education of its prescribers, and self-regulation in the form of appeals to voluntary antimicrobial stewardship, which at hospitals may take the form of an antimicrobial stewardship program. It has been argued that depending on the cultural context government can aid in educating the public on the importance of restrictive use of antibiotics for human clinical use, but unlike narcotics, there is no regulation of its use anywhere in the world at this time. Antibiotic use has been restricted or regulated for treating animals raised for human consumption with success, in Denmark for example. Infection prevention is the most efficient strategy of prevention of an infection with a MDR organism within a hospital, because there are few alternatives to antibiotics in the case of an extensively resistant or panresistant infection; if an infection is localized, removal or excision can be attempted (with MDR-TB the lung for example), but in the case of a systemic infection only generic measures like boosting the immune system with immunoglobulins may be possible. The use of bacteriophages (viruses which kill bacteria) is a developing area of possible therapeutic treatments. It is necessary to develop new antibiotics over time since the selection of resistant bacteria cannot be prevented completely. This means with every application of a specific antibiotic, the survival of a few bacteria which already have a resistance gene against the substance is promoted, and the concerning bacterial population amplifies. Therefore, the resistance gene is farther distributed in the organism and the environment, and a higher percentage of bacteria means they no longer respond to a therapy with this specific antibiotic. In addition to developing new antibiotics, new strategies entirely must be implemented in order to keep the public safe from the event of total resistance. New strategies are being tested such as UV light treatments and bacteriophage utilization, however more resources must be dedicated to this cause. == See also == Drug resistance MDRGN bacteria Xenobiotic metabolism NDM1 enzymatic resistance Herbicide resistance P-glycoprotein == References == == Further reading == == External links == BURDEN of Resistance and Disease in European Nations - An EU project to estimate the financial burden of antibiotic resistance in European Hospitals European Centre of Disease Prevention and Control and (ECDC): Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: An international expert proposal for interim standard definitions for acquired resistance Disease Programmes Unit State of Connecticut Department of Public Health MDRO information MultidrugResistant Organisms MDROs What Are They	Wikipedia/Multidrug_resistance
Some fruit juices and fruits can interact with numerous drugs, in many cases causing adverse effects. The effect is most studied with grapefruit and grapefruit juice, but similar effects have been observed with certain other citrus fruits. One whole grapefruit, or a small glass (200 mL, 6.8 US fl oz) of grapefruit juice, can cause drug overdose toxicity. Fruit consumed three days before the medicine can still have an effect. The relative risks of different types of citrus fruit have not been systematically studied. Affected drugs typically have an auxiliary label saying "Do not take with grapefruit" on the container, and the interaction is elaborated upon in the package insert. People are advised to ask their physician or pharmacist about drug interactions. However, some experts believe that for the majority of patients, complete avoidance of grapefruit is unwarranted. Although a prospective cohort study of middle-aged women indicated that some flavonoid-rich foods are associated with a reduction in all-cause mortality, frequent grapefruit consumption was associated with a small increase in all-cause mortality, possibly because of the clinically significant drug interactions of the non-flavonoid components. == History == The effect of grapefruit juice with regard to drug absorption was originally discovered in 1989 by a group led by pharmacologist David Bailey. Their first published clinical report on grapefruit drug interactions was in 1991. The effect was first discovered accidentally in 1989, when a test of drug interactions with alcohol used grapefruit juice to hide the taste of the ethanol. A 2005 medical review advised patients to avoid all citrus juices until further research clarifies the risks. It was reported in 2008 that similar effects had been observed with apple juice. == Polyphenols == Citrus fruits contain various polyphenols, which may include furanocoumarins and naringin, such as bergamottin, dihydroxybergamottin, and bergapten. Grapefruit, Seville oranges, and bergamot contain naringin. Furanocoumarins may have a stronger effect than naringin. == Mechanism == The effects are caused by furanocoumarins (and, to a lesser extent, flavonoids) which are compounds produced by many plants including but not limited to grapefruit. These chemicals inhibit key drug metabolizing enzymes, such as cytochrome P450 3A4 (CYP3A4). CYP3A4 is a metabolizing enzyme for almost 50% of drugs, and is found in the liver and small intestinal epithelial cells. Organic derivatives of furanocoumarin interfere with liver and intestinal enzyme CYP3A4 and may be responsible for the effects of grapefruit on the enzyme. Cytochrome isoforms affected by grapefruit components include CYP1A2, CYP2C9, and CYP2D6, but CYP3A4 is the major CYP enzyme in the intestine. Inhibition of enzymes can have two different effects: grapefruit juice-mediated inhibition of enzymes that metabolize the drug to an inactive metabolite leads to too high doses of the drug in the body grapefruit juice-mediated inhibition of membrane transport proteins from the intestine to the blood, or inhibition of enzymes that activates a prodrug to an active metabolite leads to insufficient doses of the drug in the body resulting in loss of theurapeutic effect Grapefruit or grapefruit juice can reduce the absorption of many drugs by inhibiting transport across cell membranes by the transporters P-glycoprotein (a member of the superfamily of ATP-binding cassette (ABC) transporters) and members of the organo anion transporter family. These transporters appear to have a minimal effect on systemic exposure of the drugs they affect, however. Many drugs are affected by consumption of citrus juice. When the metabolizing enzyme is inhibited, less of the drug will be metabolized by it in the epithelial cells. This interaction is particularly dangerous when the drug in question has a low therapeutic index, so that a small increase in blood concentration can be the difference between therapeutic effect and toxicity. Citrus juice inhibits the enzyme only within the intestines if consumed in small amounts. When larger amounts are consumed they may in addition inhibit the enzyme in the liver. The hepatic enzyme inhibition may cause an additional increase in potency and a prolonged metabolic half-life (prolonged metabolic half-life for all ways of drug administration). == Duration and timing == === Metabolism interactions === Grapefruit–drug interactions that affect the pre-systemic metabolism (i.e., the metabolism that occurs before the drug enters the blood) of drugs have a different duration of action than interactions that work by other mechanisms, such as on absorption, discussed below. The interaction is greatest when the juice is ingested with the drug or up to 4 hours before the drug. The location of the inhibition occurs in the lining of the intestines, not within the liver. The effects last because grapefruit-mediated inhibition of drug metabolizing enzymes, like CYP3A4, is irreversible; that is, once the grapefruit has "broken" the enzyme, the intestinal cells must produce more of the enzyme to restore their capacity to metabolize drugs that the enzyme is used to metabolize. It takes around 24 hours to regain 50% of the cell's baseline enzyme activity and it can take 72 hours for the enzyme activity to completely return to baseline. For this reason, simply separating citrus consumption and medications taken daily does not avoid the drug interaction. === Absorption interactions === For medications that interact due to inhibition of OATP (organic anion-transporting polypeptides), a relative short period of time is needed to avoid this interaction, and a four-hour interval between grapefruit consumption and the medication should suffice. For drugs recently sold on the market, drugs have information pages (monographs) that provide information on any potential interaction between a medication and grapefruit juice. Because there is a growing number of medications that are known to interact with citrus, patients should consult a pharmacist or physician before consuming citrus while taking their medications. == Affected fruit == Grapefruit is not the only citrus fruit that can interact with medications. One medical review advised patients to avoid all citrus. There are three ways to test if a fruit interacts with drugs: Test a drug–fruit combination in humans Test a fruit chemically for the presence of the interacting polyphenol compounds Test a fruit genetically for the genes needed to make the interacting polyphenol compounds The first approach involves risk to trial volunteers. The first and second approaches have another problem: the same fruit cultivar could be tested twice with different results. Depending on growing and processing conditions, concentrations of the interacting polyphenol compounds can vary dramatically. The third approach is hampered by a paucity of knowledge of the genes in question. === Citrus genetics and interactions === A descendant of citrus cultivars that cannot produce the problematic polyphenol compounds would presumably also lack the genes to produce them. Many citrus cultivars are hybrids of a small number of ancestral species, which have now been fully genetically sequenced. Many traditional citrus groups, such as true sweet oranges and lemons, seem to be bud sports, mutant descendants of a single hybrid ancestor. In theory, cultivars in a bud sport group would be either all safe or all problematic. Nonetheless, new citrus varieties arriving on the market are increasingly likely to be sexually created hybrids, not asexually created sports. The ancestry of a hybrid cultivar may not be known. Even if it is known, it is not possible to be certain that a cultivar will not interact with drugs on the basis of taxonomy, as it is not known which ancestors lack the capacity to make the problematic polyphenol compounds. Nonetheless, many of the citrus cultivars known to be problematic seem to be closely related. ==== Ancestral species ==== Pomelo (the Asian fruit that was crossed with an orange to produce grapefruit) contains high amounts of furanocoumarin derivatives. Grapefruit relatives and other varieties of pomelo have variable amounts of furanocoumarin. The Dancy cultivar has a small amount of pomelo ancestry, but is genetically close to a non-hybrid true mandarin (unlike most commercial mandarins, which may have much more extensive hybridization). Eight Dancy fruits, all picked at one time from one tree, have been blended and tested for furanocoumarins; none were detectable. ==== Hybrid cultivars ==== Both sweet oranges and bitter oranges are mandarin-pomelo hybrids. Bitter oranges (such as the Seville oranges often used in marmalade) can interfere with drugs including etoposide, a chemotherapy drug, some beta blocker drugs used to treat high blood pressure, and cyclosporine, taken by transplant patients to prevent rejection of their new organs. Evidence on sweet oranges is more mixed. Tests on some tangelos (hybrids of mandarins/tangerines and pomelo or grapefruit) have not shown significant amounts of furanocoumarin; these studies were also conducted on eight fruit all picked at one time from one tree. Common lemons are the product of orange/citron hybridization, and hence have pomelo ancestry, and although Key limes are papeda/citron hybrids, the more commercially prevalent Persian limes and similar varieties are crosses of the Key lime with lemons, and hence likewise have pomelo ancestry. These limes can also inhibit drug metabolism. Other less-common citrus species also referred to as lemons or limes are genetically distinct from the more common varieties, with different proportions of pomelo ancestry. ==== Inaccurate labeling ==== Marketing classifications often do not correspond to taxonomic ones. The "Ambersweet" cultivar is marketed and sold as an orange, but does not descend from the same common ancestor as sweet oranges; it has grapefruit, orange, and mandarin ancestry. Fruits are often sold as mandarin, tangerine, or satsuma (which may be synonyms). Fruit sold under these names include many that are, like Sunbursts and Murcotts, hybrids with grapefruit ancestry. === Other fruit and vegetables === The discovery that flavonoids are responsible for some interactions make it plausible that other fruit and vegetables are affected. ==== Apple juice ==== Apple juice, especially commercially produced products, interferes with the action of OATPs. This interference can decrease the absorption of a variety of commonly used medications, including beta blockers like atenolol, antibiotics like ciprofloxacin, and antihistamines like montelukast. ==== Pomegranate juice ==== Pomegranate juice inhibits the action of the drug metabolizing enzymes CYP2C9 and CYP3A4. As of 2014, the currently available literature does not appear to indicate a clinically relevant impact of pomegranate juice on drugs that are metabolized by CYP2C9 and CYP3A4. == Affected drugs == Researchers have identified over 85 drugs with which grapefruit reacts adversely. According to a review done by the Canadian Medical Association, there is an increase in the number of potential drugs that can interact with grapefruit juice, and of the number of fruit types that can interact with those drugs. From 2008 to 2012, the number of drugs known to potentially interact with grapefruit, with risk of harmful or even dangerous effects (gastrointestinal bleeding, nephrotoxicity), increased from 17 to 43. === Traits === The interaction between citrus and medication depends on the individual drug, and not the class of the drug. Drugs that interact usually share three common features: they are taken orally, normally only a small amount enters systemic blood circulation, and they are metabolized by CYP3A4. The effects on the CYP3A4 in the liver could, in principle, cause interactions with non-CYP3A4-mediated effects. Cytochrome isoforms affected by grapefruit components include CYP3A4, CYP1A2, CYP2C9, and CYP2D6. Drugs that are metabolized by these enzymes may have interactions with components of grapefruit. An easy way to tell if a medication may be affected by grapefruit juice is by researching whether another known CYP3A4 inhibitor drug is already contraindicated with the active drug of the medication in question. Examples of such known CYP3A4 inhibitors include cisapride (Propulsid), erythromycin, itraconazole (Sporanox), ketoconazole (Nizoral), and mibefradil (Posicor). === Incomplete list of affected drugs === ==== By enzyme ==== Drugs that interact with grapefruit compounds at CYP3A4 include: benzodiazepines: triazolam (Halcion), orally administered midazolam (Versed), orally administered nitrazepam (Mogodon), diazepam (Valium), clonazepam (Klonopin), alprazolam (Xanax) and quazepam (Doral, Dormalin) ritonavir (Norvir): Inhibition of CYP3A4 prevents the metabolism of protease inhibitors such as ritonavir. sertraline (Zoloft and Lustral) verapamil (Covera-HS, Calan, Verelan, and Isoptin) Drugs that interact with grapefruit compounds at CYP1A2 include: caffeine Drugs that interact with grapefruit compounds at CYP2D6 include: dextroamphetamine (Dexedrine) dextroamphetamine (75%)/ levoamphetamine (25%) (Adderall) dextromethamphetamine (Desoxyn) Research has been done on the interaction between amphetamines and CYP2D6 enzyme, and researchers concluded that some parts of substrate molecules contribute to the binding of the enzyme. ==== Other interactions ==== Additional drugs affected by grapefruit juice include, but are not limited to: Some statins, including atorvastatin (Lipitor), lovastatin (Mevacor), and simvastatin (Zocor, Simlup, Simcor, Simvacor) In contrast, pravastatin (Pravachol), fluvastatin (Lescol), and rosuvastatin (Crestor) are unaffected by grapefruit. Anti-arrhythmics including amiodarone (Cordarone), dronedarone (Multaq), quinidine (Quinidex, Cardioquin, Quinora), disopyramide (Norpace), propafenone (Rythmol) and carvedilol (Coreg) Amlodipine: Grapefruit increases the available amount of the drug in the blood stream, leading to an unpredictable increase in antihypertensive effects. Anti-migraine drugs ergotamine (Cafergot, Ergomar), amitriptyline (Elavil, Endep, Vanatrip) and nimodipine (Nimotop) Erectile dysfunction drugs sildenafil (Viagra), tadalafil (Cialis) and vardenafil (Levitra) Acetaminophen (also known as paracetamol, brand name Tylenol) concentrations increase in the blood of mice when they consume white and pink grapefruit juice, with the white juice acting faster. "The bioavailability of paracetamol was significantly reduced following multiple GFJ administration" in mice and rats. This suggests that repeated intake of grapefruit juice reduces the efficacy and bioavailability of acetaminophen/paracetamol in comparison with a single dose of grapefruit juice, which conversely increases the efficacy and bioavailability of acetaminophen/paracetamol. Anthelmintics: Used for treating certain parasitic infections; includes praziquantel Buprenorphine: Metabolized into norbuprenorphine by CYP3A4 Buspirone (Buspar): Grapefruit juice increased peak and AUC plasma concentrations of buspirone 4.3- and 9.2-fold, respectively, in a randomized, 2-phase, ten-subject crossover study. Codeine is a prodrug that produces its analgesic properties following metabolism to morphine entirely by CYP2D6. Ciclosporin (cyclosporine, Neoral): Blood levels of ciclosporin are increased if taken with grapefruit juice, orange juice, or apple juice. A plausible mechanism involves the combined inhibition of enteric CYP3A4 and MDR1, which potentially leads to serious adverse events (e.g., nephrotoxicity). Blood levels of tacrolimus (Prograf) can also be equally affected for the same reason as ciclosporin, as both drugs are calcineurin inhibitors. Dihydropyridines including felodipine (Plendil), nicardipine (Cardene), nifedipine, nisoldipine (Sular) and nitrendipine (Bayotensin) Erlotinib (Tarceva) Exemestane, aromasin, and by extension all estrogen-like compounds and aromatase inhibitors that mimic estrogen in function will be increased in effect, causing increased estrogen retention and increased drug retention. Etoposide interferes with grapefruit, orange, and apple juices. Fexofenadine (Allegra) concentrations are decreased rather than increased as is the case with most grapefruit–drug interactions. Fluvoxamine (Luvox, Faverin, Fevarin and Dumyrox) Imatinib (Gleevec): Although no formal studies with imatinib and grapefruit juice have been conducted, the fact that grapefruit juice is a known inhibitor of the CYP 3A4 suggests that co-administration may lead to increased imatinib plasma concentrations. Likewise, although no formal studies were conducted, co-administration of imatinib with another specific type of citrus juice called Seville orange juice (SOJ) may lead to increased imatinib plasma concentrations via inhibition of the CYP3A isoenzymes. Seville orange juice is not usually consumed as a juice because of its sour taste, but it is found in marmalade and other jams. Seville orange juice has been reported to be a possible inhibitor of CYP3A enzymes without affecting MDR1 when taken concomitantly with ciclosporin. Ketamine: After drinking 200 mL of grapefruit juice daily for five days, the overall absorption of orally ingested ketamine was increased three-fold compared to the control group in a clinical trial. The peak blood ketamine concentration was increased over two-fold. Levothyroxine (Eltroxin, Levoxyl, Synthroid): "Grapefruit juice may slightly delay the absorption of levothyroxine, but it seems to have only a minor effect on its bioavailability." Losartan (Cozaar) Methadone: Inhibits the metabolism of methadone and raises serum levels. Omeprazole (Losec, Prilosec) Oxycodone: Grapefruit juice enhances the exposure to oral oxycodone. In a randomized, controlled trial 12 healthy volunteers ingested 200 mL of either grapefruit juice or water three times daily for five days. On the fourth day 10 mg of oxycodone hydrochloride were administered orally. Analgesic and behavioral effects were reported for 12 hours and plasma samples were analyzed for oxycodone metabolites for 48 hours. Grapefruit juice increased the mean area under the oxycodone concentration-time curve (AUC(0-∞)) by 1.7 fold, the peak plasma concentration by 1.5-fold and the half-life of oxycodone by 1.2-fold as compared to water. The metabolite-to-parent ratios of noroxycodone and noroxymorphone decreased by 44% and 45% respectively. Oxymorphone AUC(0-∞) increased by 1.6-fold but the metabolite-to-parent ratio remained unchanged. Quetiapine (Seroquel) Repaglinide (Prandin) Sirolimus (Rapamycin, Rapamune) Tamoxifen (Nolvadex): Tamoxifen is metabolized by CYP2D6 into its active metabolite 4-hydroxytamoxifen. Grapefruit juice may potentially reduce the effectiveness of tamoxifen. Trazodone (Desyrel): Little or no interaction with grapefruit juice. Verapamil (Calan SR, Covera HS, Isoptin SR, Verelan): atrioventricular conduction disorders. Warfarin (coumadin) Zolpidem (Ambien): Little or no interaction with grapefruit juice == References ==	Wikipedia/Grapefruit–drug_interactions
Some fruit juices and fruits can interact with numerous drugs, in many cases causing adverse effects. The effect is most studied with grapefruit and grapefruit juice, but similar effects have been observed with certain other citrus fruits. One whole grapefruit, or a small glass (200 mL, 6.8 US fl oz) of grapefruit juice, can cause drug overdose toxicity. Fruit consumed three days before the medicine can still have an effect. The relative risks of different types of citrus fruit have not been systematically studied. Affected drugs typically have an auxiliary label saying "Do not take with grapefruit" on the container, and the interaction is elaborated upon in the package insert. People are advised to ask their physician or pharmacist about drug interactions. However, some experts believe that for the majority of patients, complete avoidance of grapefruit is unwarranted. Although a prospective cohort study of middle-aged women indicated that some flavonoid-rich foods are associated with a reduction in all-cause mortality, frequent grapefruit consumption was associated with a small increase in all-cause mortality, possibly because of the clinically significant drug interactions of the non-flavonoid components. == History == The effect of grapefruit juice with regard to drug absorption was originally discovered in 1989 by a group led by pharmacologist David Bailey. Their first published clinical report on grapefruit drug interactions was in 1991. The effect was first discovered accidentally in 1989, when a test of drug interactions with alcohol used grapefruit juice to hide the taste of the ethanol. A 2005 medical review advised patients to avoid all citrus juices until further research clarifies the risks. It was reported in 2008 that similar effects had been observed with apple juice. == Polyphenols == Citrus fruits contain various polyphenols, which may include furanocoumarins and naringin, such as bergamottin, dihydroxybergamottin, and bergapten. Grapefruit, Seville oranges, and bergamot contain naringin. Furanocoumarins may have a stronger effect than naringin. == Mechanism == The effects are caused by furanocoumarins (and, to a lesser extent, flavonoids) which are compounds produced by many plants including but not limited to grapefruit. These chemicals inhibit key drug metabolizing enzymes, such as cytochrome P450 3A4 (CYP3A4). CYP3A4 is a metabolizing enzyme for almost 50% of drugs, and is found in the liver and small intestinal epithelial cells. Organic derivatives of furanocoumarin interfere with liver and intestinal enzyme CYP3A4 and may be responsible for the effects of grapefruit on the enzyme. Cytochrome isoforms affected by grapefruit components include CYP1A2, CYP2C9, and CYP2D6, but CYP3A4 is the major CYP enzyme in the intestine. Inhibition of enzymes can have two different effects: grapefruit juice-mediated inhibition of enzymes that metabolize the drug to an inactive metabolite leads to too high doses of the drug in the body grapefruit juice-mediated inhibition of membrane transport proteins from the intestine to the blood, or inhibition of enzymes that activates a prodrug to an active metabolite leads to insufficient doses of the drug in the body resulting in loss of theurapeutic effect Grapefruit or grapefruit juice can reduce the absorption of many drugs by inhibiting transport across cell membranes by the transporters P-glycoprotein (a member of the superfamily of ATP-binding cassette (ABC) transporters) and members of the organo anion transporter family. These transporters appear to have a minimal effect on systemic exposure of the drugs they affect, however. Many drugs are affected by consumption of citrus juice. When the metabolizing enzyme is inhibited, less of the drug will be metabolized by it in the epithelial cells. This interaction is particularly dangerous when the drug in question has a low therapeutic index, so that a small increase in blood concentration can be the difference between therapeutic effect and toxicity. Citrus juice inhibits the enzyme only within the intestines if consumed in small amounts. When larger amounts are consumed they may in addition inhibit the enzyme in the liver. The hepatic enzyme inhibition may cause an additional increase in potency and a prolonged metabolic half-life (prolonged metabolic half-life for all ways of drug administration). == Duration and timing == === Metabolism interactions === Grapefruit–drug interactions that affect the pre-systemic metabolism (i.e., the metabolism that occurs before the drug enters the blood) of drugs have a different duration of action than interactions that work by other mechanisms, such as on absorption, discussed below. The interaction is greatest when the juice is ingested with the drug or up to 4 hours before the drug. The location of the inhibition occurs in the lining of the intestines, not within the liver. The effects last because grapefruit-mediated inhibition of drug metabolizing enzymes, like CYP3A4, is irreversible; that is, once the grapefruit has "broken" the enzyme, the intestinal cells must produce more of the enzyme to restore their capacity to metabolize drugs that the enzyme is used to metabolize. It takes around 24 hours to regain 50% of the cell's baseline enzyme activity and it can take 72 hours for the enzyme activity to completely return to baseline. For this reason, simply separating citrus consumption and medications taken daily does not avoid the drug interaction. === Absorption interactions === For medications that interact due to inhibition of OATP (organic anion-transporting polypeptides), a relative short period of time is needed to avoid this interaction, and a four-hour interval between grapefruit consumption and the medication should suffice. For drugs recently sold on the market, drugs have information pages (monographs) that provide information on any potential interaction between a medication and grapefruit juice. Because there is a growing number of medications that are known to interact with citrus, patients should consult a pharmacist or physician before consuming citrus while taking their medications. == Affected fruit == Grapefruit is not the only citrus fruit that can interact with medications. One medical review advised patients to avoid all citrus. There are three ways to test if a fruit interacts with drugs: Test a drug–fruit combination in humans Test a fruit chemically for the presence of the interacting polyphenol compounds Test a fruit genetically for the genes needed to make the interacting polyphenol compounds The first approach involves risk to trial volunteers. The first and second approaches have another problem: the same fruit cultivar could be tested twice with different results. Depending on growing and processing conditions, concentrations of the interacting polyphenol compounds can vary dramatically. The third approach is hampered by a paucity of knowledge of the genes in question. === Citrus genetics and interactions === A descendant of citrus cultivars that cannot produce the problematic polyphenol compounds would presumably also lack the genes to produce them. Many citrus cultivars are hybrids of a small number of ancestral species, which have now been fully genetically sequenced. Many traditional citrus groups, such as true sweet oranges and lemons, seem to be bud sports, mutant descendants of a single hybrid ancestor. In theory, cultivars in a bud sport group would be either all safe or all problematic. Nonetheless, new citrus varieties arriving on the market are increasingly likely to be sexually created hybrids, not asexually created sports. The ancestry of a hybrid cultivar may not be known. Even if it is known, it is not possible to be certain that a cultivar will not interact with drugs on the basis of taxonomy, as it is not known which ancestors lack the capacity to make the problematic polyphenol compounds. Nonetheless, many of the citrus cultivars known to be problematic seem to be closely related. ==== Ancestral species ==== Pomelo (the Asian fruit that was crossed with an orange to produce grapefruit) contains high amounts of furanocoumarin derivatives. Grapefruit relatives and other varieties of pomelo have variable amounts of furanocoumarin. The Dancy cultivar has a small amount of pomelo ancestry, but is genetically close to a non-hybrid true mandarin (unlike most commercial mandarins, which may have much more extensive hybridization). Eight Dancy fruits, all picked at one time from one tree, have been blended and tested for furanocoumarins; none were detectable. ==== Hybrid cultivars ==== Both sweet oranges and bitter oranges are mandarin-pomelo hybrids. Bitter oranges (such as the Seville oranges often used in marmalade) can interfere with drugs including etoposide, a chemotherapy drug, some beta blocker drugs used to treat high blood pressure, and cyclosporine, taken by transplant patients to prevent rejection of their new organs. Evidence on sweet oranges is more mixed. Tests on some tangelos (hybrids of mandarins/tangerines and pomelo or grapefruit) have not shown significant amounts of furanocoumarin; these studies were also conducted on eight fruit all picked at one time from one tree. Common lemons are the product of orange/citron hybridization, and hence have pomelo ancestry, and although Key limes are papeda/citron hybrids, the more commercially prevalent Persian limes and similar varieties are crosses of the Key lime with lemons, and hence likewise have pomelo ancestry. These limes can also inhibit drug metabolism. Other less-common citrus species also referred to as lemons or limes are genetically distinct from the more common varieties, with different proportions of pomelo ancestry. ==== Inaccurate labeling ==== Marketing classifications often do not correspond to taxonomic ones. The "Ambersweet" cultivar is marketed and sold as an orange, but does not descend from the same common ancestor as sweet oranges; it has grapefruit, orange, and mandarin ancestry. Fruits are often sold as mandarin, tangerine, or satsuma (which may be synonyms). Fruit sold under these names include many that are, like Sunbursts and Murcotts, hybrids with grapefruit ancestry. === Other fruit and vegetables === The discovery that flavonoids are responsible for some interactions make it plausible that other fruit and vegetables are affected. ==== Apple juice ==== Apple juice, especially commercially produced products, interferes with the action of OATPs. This interference can decrease the absorption of a variety of commonly used medications, including beta blockers like atenolol, antibiotics like ciprofloxacin, and antihistamines like montelukast. ==== Pomegranate juice ==== Pomegranate juice inhibits the action of the drug metabolizing enzymes CYP2C9 and CYP3A4. As of 2014, the currently available literature does not appear to indicate a clinically relevant impact of pomegranate juice on drugs that are metabolized by CYP2C9 and CYP3A4. == Affected drugs == Researchers have identified over 85 drugs with which grapefruit reacts adversely. According to a review done by the Canadian Medical Association, there is an increase in the number of potential drugs that can interact with grapefruit juice, and of the number of fruit types that can interact with those drugs. From 2008 to 2012, the number of drugs known to potentially interact with grapefruit, with risk of harmful or even dangerous effects (gastrointestinal bleeding, nephrotoxicity), increased from 17 to 43. === Traits === The interaction between citrus and medication depends on the individual drug, and not the class of the drug. Drugs that interact usually share three common features: they are taken orally, normally only a small amount enters systemic blood circulation, and they are metabolized by CYP3A4. The effects on the CYP3A4 in the liver could, in principle, cause interactions with non-CYP3A4-mediated effects. Cytochrome isoforms affected by grapefruit components include CYP3A4, CYP1A2, CYP2C9, and CYP2D6. Drugs that are metabolized by these enzymes may have interactions with components of grapefruit. An easy way to tell if a medication may be affected by grapefruit juice is by researching whether another known CYP3A4 inhibitor drug is already contraindicated with the active drug of the medication in question. Examples of such known CYP3A4 inhibitors include cisapride (Propulsid), erythromycin, itraconazole (Sporanox), ketoconazole (Nizoral), and mibefradil (Posicor). === Incomplete list of affected drugs === ==== By enzyme ==== Drugs that interact with grapefruit compounds at CYP3A4 include: benzodiazepines: triazolam (Halcion), orally administered midazolam (Versed), orally administered nitrazepam (Mogodon), diazepam (Valium), clonazepam (Klonopin), alprazolam (Xanax) and quazepam (Doral, Dormalin) ritonavir (Norvir): Inhibition of CYP3A4 prevents the metabolism of protease inhibitors such as ritonavir. sertraline (Zoloft and Lustral) verapamil (Covera-HS, Calan, Verelan, and Isoptin) Drugs that interact with grapefruit compounds at CYP1A2 include: caffeine Drugs that interact with grapefruit compounds at CYP2D6 include: dextroamphetamine (Dexedrine) dextroamphetamine (75%)/ levoamphetamine (25%) (Adderall) dextromethamphetamine (Desoxyn) Research has been done on the interaction between amphetamines and CYP2D6 enzyme, and researchers concluded that some parts of substrate molecules contribute to the binding of the enzyme. ==== Other interactions ==== Additional drugs affected by grapefruit juice include, but are not limited to: Some statins, including atorvastatin (Lipitor), lovastatin (Mevacor), and simvastatin (Zocor, Simlup, Simcor, Simvacor) In contrast, pravastatin (Pravachol), fluvastatin (Lescol), and rosuvastatin (Crestor) are unaffected by grapefruit. Anti-arrhythmics including amiodarone (Cordarone), dronedarone (Multaq), quinidine (Quinidex, Cardioquin, Quinora), disopyramide (Norpace), propafenone (Rythmol) and carvedilol (Coreg) Amlodipine: Grapefruit increases the available amount of the drug in the blood stream, leading to an unpredictable increase in antihypertensive effects. Anti-migraine drugs ergotamine (Cafergot, Ergomar), amitriptyline (Elavil, Endep, Vanatrip) and nimodipine (Nimotop) Erectile dysfunction drugs sildenafil (Viagra), tadalafil (Cialis) and vardenafil (Levitra) Acetaminophen (also known as paracetamol, brand name Tylenol) concentrations increase in the blood of mice when they consume white and pink grapefruit juice, with the white juice acting faster. "The bioavailability of paracetamol was significantly reduced following multiple GFJ administration" in mice and rats. This suggests that repeated intake of grapefruit juice reduces the efficacy and bioavailability of acetaminophen/paracetamol in comparison with a single dose of grapefruit juice, which conversely increases the efficacy and bioavailability of acetaminophen/paracetamol. Anthelmintics: Used for treating certain parasitic infections; includes praziquantel Buprenorphine: Metabolized into norbuprenorphine by CYP3A4 Buspirone (Buspar): Grapefruit juice increased peak and AUC plasma concentrations of buspirone 4.3- and 9.2-fold, respectively, in a randomized, 2-phase, ten-subject crossover study. Codeine is a prodrug that produces its analgesic properties following metabolism to morphine entirely by CYP2D6. Ciclosporin (cyclosporine, Neoral): Blood levels of ciclosporin are increased if taken with grapefruit juice, orange juice, or apple juice. A plausible mechanism involves the combined inhibition of enteric CYP3A4 and MDR1, which potentially leads to serious adverse events (e.g., nephrotoxicity). Blood levels of tacrolimus (Prograf) can also be equally affected for the same reason as ciclosporin, as both drugs are calcineurin inhibitors. Dihydropyridines including felodipine (Plendil), nicardipine (Cardene), nifedipine, nisoldipine (Sular) and nitrendipine (Bayotensin) Erlotinib (Tarceva) Exemestane, aromasin, and by extension all estrogen-like compounds and aromatase inhibitors that mimic estrogen in function will be increased in effect, causing increased estrogen retention and increased drug retention. Etoposide interferes with grapefruit, orange, and apple juices. Fexofenadine (Allegra) concentrations are decreased rather than increased as is the case with most grapefruit–drug interactions. Fluvoxamine (Luvox, Faverin, Fevarin and Dumyrox) Imatinib (Gleevec): Although no formal studies with imatinib and grapefruit juice have been conducted, the fact that grapefruit juice is a known inhibitor of the CYP 3A4 suggests that co-administration may lead to increased imatinib plasma concentrations. Likewise, although no formal studies were conducted, co-administration of imatinib with another specific type of citrus juice called Seville orange juice (SOJ) may lead to increased imatinib plasma concentrations via inhibition of the CYP3A isoenzymes. Seville orange juice is not usually consumed as a juice because of its sour taste, but it is found in marmalade and other jams. Seville orange juice has been reported to be a possible inhibitor of CYP3A enzymes without affecting MDR1 when taken concomitantly with ciclosporin. Ketamine: After drinking 200 mL of grapefruit juice daily for five days, the overall absorption of orally ingested ketamine was increased three-fold compared to the control group in a clinical trial. The peak blood ketamine concentration was increased over two-fold. Levothyroxine (Eltroxin, Levoxyl, Synthroid): "Grapefruit juice may slightly delay the absorption of levothyroxine, but it seems to have only a minor effect on its bioavailability." Losartan (Cozaar) Methadone: Inhibits the metabolism of methadone and raises serum levels. Omeprazole (Losec, Prilosec) Oxycodone: Grapefruit juice enhances the exposure to oral oxycodone. In a randomized, controlled trial 12 healthy volunteers ingested 200 mL of either grapefruit juice or water three times daily for five days. On the fourth day 10 mg of oxycodone hydrochloride were administered orally. Analgesic and behavioral effects were reported for 12 hours and plasma samples were analyzed for oxycodone metabolites for 48 hours. Grapefruit juice increased the mean area under the oxycodone concentration-time curve (AUC(0-∞)) by 1.7 fold, the peak plasma concentration by 1.5-fold and the half-life of oxycodone by 1.2-fold as compared to water. The metabolite-to-parent ratios of noroxycodone and noroxymorphone decreased by 44% and 45% respectively. Oxymorphone AUC(0-∞) increased by 1.6-fold but the metabolite-to-parent ratio remained unchanged. Quetiapine (Seroquel) Repaglinide (Prandin) Sirolimus (Rapamycin, Rapamune) Tamoxifen (Nolvadex): Tamoxifen is metabolized by CYP2D6 into its active metabolite 4-hydroxytamoxifen. Grapefruit juice may potentially reduce the effectiveness of tamoxifen. Trazodone (Desyrel): Little or no interaction with grapefruit juice. Verapamil (Calan SR, Covera HS, Isoptin SR, Verelan): atrioventricular conduction disorders. Warfarin (coumadin) Zolpidem (Ambien): Little or no interaction with grapefruit juice == References ==	Wikipedia/Grapefruit_drug_interactions
Selling counterfeit illegal drugs is a crime in many U.S. states' legal codes and in the federal law of the United States. The fake drugs are sometimes termed as imitation controlled substances. == Relation to drug-related crimes == There is a low chance of law punishing fraud among illicit drug traders, however it is likely that informal social control among drug traders reduces the likelihood of fraud between illegal trade partners. For instance, getting robbed or losing a business contact may not justify dealer's increased profits for a short-term from fraudulent behavior. == Legal status == Selling counterfeit illicit drugs is illegal even if the substances used to make the imitation drug are not illegal on themselves. It is illegal to distribute or sell counterfeit fake drugs in many U.S. states including Nevada, Ohio, Illinois, Florida, Michigan and Massachusetts. === U.S. Federal Law === Selling counterfeit illicit drugs is illegal under the U.S. federal law. Relevant parts of the U.S. federal law include 21 U.S.C. Section 331 and 18 U.S. Code § 1001. 21 U.S.C. Section 331 makes it illegal to sell an adulterated or misbranded drug in interstate commerce. 18 U.S. Code § 1001 bans falsifying, concealing or covering up a material fact; making any materially false, fictitious or fraudulent statement or representation; or making or using any false writing or document knowing that it contains materially false, fictitious or fraudulent statements. == Deaths == === Europe === ==== Amsterdam ==== On 25 November 2014 two British tourists aged 20 and 21 died in a hotel room in Amsterdam, after snorting white heroin that was sold as cocaine by a street dealer. The bodies were found less than a month after another British tourist died in similar circumstances. At least 17 other people have had medical treatment after taking the white heroin. ==== Sweden ==== Nine deaths occurred in Sweden during 2010–11 relating to use of Krypton, a mixture of kratom, caffeine and O-desmethyltramadol, a metabolite of the opioid analgesic tramadol. == See also == Unclean hands == References ==	Wikipedia/Counterfeit_illegal_drug_selling
A codrug consists of two drug moieties, generally "active against the same disease", that are joined through one or more covalent chemical bonds to create a single new chemical entity; they can also be described as a mutual prodrug, recognising that a catabolic biosynthetic step is most often required to liberate the two drugs. While acting against the same disease, the two moities may operate via different mechanisms of action, and so display differing specific therapeutic effects. The recognised advantages of a codrug approach to small molecule drug design include the possibilities of (i) combined efficacies of the two drugs that are therapeutically synergistic, (ii) altered properties that improve the pharmacokinetics (e.g., halflife) of the codrug over its individually administered components (iii) improved modes of drug delivery, and (iv) masking of reactive functional groups of each component drug, possibly improving shelf life (as well as pharmacokinetics). == Elements of codrug design == An effective codrug should be pharmacologically inactive in its own right but should release the constituent drugs upon biochemical breakage of the chemical linkage at the target tissue where their therapeutic effects are needed. As such, the chemical linkage (usually a covalent bond) should be subjectable to biodegradation, such as hydrolysis, by an enzymatic or non-enzymatic mechanism. The differential distribution of enzymes capable of catalyzing the breakage of the chemical linkage in different tissues may be exploited to achieve tissue-specific metabolism of the codrug to release the constituent drugs. == Common codrugs == Sulfasalazine: Sulfapyridine linked via an azo group to 5-aminosalicylic acid. Alpha-GPC: Choline linked to glycerophosphate. Benorylate: Paracetamol linked via esterification to acetylsalicylic acid. Cod-THC: THC linked via a carbonate group to codeine. Fenethylline: Amphetamine linked to theophylline. Sultamicillin: ampicillin linked via esterification to sulbactam. Cefilavancin: a vancomycin derived antibiotic linked to a cephalosporin antibiotic. Rifaquizinone: a rifamycin derived antibiotic linked to a quinolone antibiotic. == References == == See also == Combination drug Small molecule drug conjugate Drug synergy Ampicillin/sulbactam	Wikipedia/Codrug
In biochemistry and pharmacology, receptors are chemical structures, composed of protein, that receive and transduce signals that may be integrated into biological systems. These signals are typically chemical messengers which bind to a receptor and produce physiological responses, such as a change in the electrical activity of a cell. For example, GABA, an inhibitory neurotransmitter, inhibits electrical activity of neurons by binding to GABAA receptors. There are three main ways the action of the receptor can be classified: relay of signal, amplification, or integration. Relaying sends the signal onward, amplification increases the effect of a single ligand, and integration allows the signal to be incorporated into another biochemical pathway. Receptor proteins can be classified by their location. Cell surface receptors, also known as transmembrane receptors, include ligand-gated ion channels, G protein-coupled receptors, and enzyme-linked hormone receptors. Intracellular receptors are those found inside the cell, and include cytoplasmic receptors and nuclear receptors. A molecule that binds to a receptor is called a ligand and can be a protein, peptide (short protein), or another small molecule, such as a neurotransmitter, hormone, pharmaceutical drug, toxin, calcium ion or parts of the outside of a virus or microbe. An endogenously produced substance that binds to a particular receptor is referred to as its endogenous ligand. E.g. the endogenous ligand for the nicotinic acetylcholine receptor is acetylcholine, but it can also be activated by nicotine and blocked by curare. Receptors of a particular type are linked to specific cellular biochemical pathways that correspond to the signal. While numerous receptors are found in most cells, each receptor will only bind with ligands of a particular structure. This has been analogously compared to how locks will only accept specifically shaped keys. When a ligand binds to a corresponding receptor, it activates or inhibits the receptor's associated biochemical pathway, which may also be highly specialised. Receptor proteins can be also classified by the property of the ligands. Such classifications include chemoreceptors, mechanoreceptors, gravitropic receptors, photoreceptors, magnetoreceptors and gasoreceptors. == Structure == The structures of receptors are very diverse and include the following major categories, among others: Type 1: Ligand-gated ion channels (ionotropic receptors) – These receptors are typically the targets of fast neurotransmitters such as acetylcholine (nicotinic) and GABA; activation of these receptors results in changes in ion movement across a membrane. They have a heteromeric structure in that each subunit consists of the extracellular ligand-binding domain and a transmembrane domain which includes four transmembrane alpha helices. The ligand-binding cavities are located at the interface between the subunits. Type 2: G protein-coupled receptors (metabotropic receptors) – This is the largest family of receptors and includes the receptors for several hormones and slow transmitters e.g. dopamine, metabotropic glutamate. They are composed of seven transmembrane alpha helices. The loops connecting the alpha helices form extracellular and intracellular domains. The binding-site for larger peptide ligands is usually located in the extracellular domain whereas the binding site for smaller non-peptide ligands is often located between the seven alpha helices and one extracellular loop. The aforementioned receptors are coupled to different intracellular effector systems via G proteins. G proteins are heterotrimers made up of 3 subunits: α (alpha), β (beta), and γ (gamma). In the inactive state, the three subunits associate together and the α-subunit binds GDP. G protein activation causes a conformational change, which leads to the exchange of GDP for GTP. GTP-binding to the α-subunit causes dissociation of the β- and γ-subunits. Furthermore, the three subunits, α, β, and γ have additional four main classes based on their primary sequence. These include Gs, Gi, Gq and G12. Type 3: Kinase-linked and related receptors (see "Receptor tyrosine kinase" and "Enzyme-linked receptor") – They are composed of an extracellular domain containing the ligand binding site and an intracellular domain, often with enzymatic-function, linked by a single transmembrane alpha helix. The insulin receptor is an example. Type 4: Nuclear receptors – While they are called nuclear receptors, they are actually located in the cytoplasm and migrate to the nucleus after binding with their ligands. They are composed of a C-terminal ligand-binding region, a core DNA-binding domain (DBD) and an N-terminal domain that contains the AF1(activation function 1) region. The core region has two zinc fingers that are responsible for recognizing the DNA sequences specific to this receptor. The N terminus interacts with other cellular transcription factors in a ligand-independent manner; and, depending on these interactions, it can modify the binding/activity of the receptor. Steroid and thyroid-hormone receptors are examples of such receptors. Membrane receptors may be isolated from cell membranes by complex extraction procedures using solvents, detergents, and/or affinity purification. The structures and actions of receptors may be studied by using biophysical methods such as X-ray crystallography, NMR, circular dichroism, and dual polarisation interferometry. Computer simulations of the dynamic behavior of receptors have been used to gain understanding of their mechanisms of action. == Binding and activation == Ligand binding is an equilibrium process. Ligands bind to receptors and dissociate from them according to the law of mass action in the following equation, for a ligand L and receptor, R. The brackets around chemical species denote their concentrations. [ L ] + [ R ] ⇌ K d [ LR ] {\displaystyle {[{\ce {L}}]+[{\ce {R}}]{\ce {<=>[{K_{d}}]}}[{\text{LR}}]}} One measure of how well a molecule fits a receptor is its binding affinity, which is inversely related to the dissociation constant Kd. A good fit corresponds with high affinity and low Kd. The final biological response (e.g. second messenger cascade, muscle-contraction), is only achieved after a significant number of receptors are activated. Affinity is a measure of the tendency of a ligand to bind to its receptor. Efficacy is the measure of the bound ligand to activate its receptor. === Agonists versus antagonists === Not every ligand that binds to a receptor also activates that receptor. The following classes of ligands exist: (Full) agonists are able to activate the receptor and result in a strong biological response. The natural endogenous ligand with the greatest efficacy for a given receptor is by definition a full agonist (100% efficacy). Partial agonists do not activate receptors with maximal efficacy, even with maximal binding, causing partial responses compared to those of full agonists (efficacy between 0 and 100%). Antagonists bind to receptors but do not activate them. This results in a receptor blockade, inhibiting the binding of agonists and inverse agonists. Receptor antagonists can be competitive (or reversible), and compete with the agonist for the receptor, or they can be irreversible antagonists that form covalent bonds (or extremely high affinity non-covalent bonds) with the receptor and completely block it. The proton pump inhibitor omeprazole is an example of an irreversible antagonist. The effects of irreversible antagonism can only be reversed by synthesis of new receptors. Inverse agonists reduce the activity of receptors by inhibiting their constitutive activity (negative efficacy). Allosteric modulators: They do not bind to the agonist-binding site of the receptor but instead on specific allosteric binding sites, through which they modify the effect of the agonist. For example, benzodiazepines (BZDs) bind to the BZD site on the GABAA receptor and potentiate the effect of endogenous GABA. Note that the idea of receptor agonism and antagonism only refers to the interaction between receptors and ligands and not to their biological effects. === Constitutive activity === A receptor which is capable of producing a biological response in the absence of a bound ligand is said to display "constitutive activity". The constitutive activity of a receptor may be blocked by an inverse agonist. The anti-obesity drugs rimonabant and taranabant are inverse agonists at the cannabinoid CB1 receptor and though they produced significant weight loss, both were withdrawn owing to a high incidence of depression and anxiety, which are believed to relate to the inhibition of the constitutive activity of the cannabinoid receptor. The GABAA receptor has constitutive activity and conducts some basal current in the absence of an agonist. This allows beta carboline to act as an inverse agonist and reduce the current below basal levels. Mutations in receptors that result in increased constitutive activity underlie some inherited diseases, such as precocious puberty (due to mutations in luteinizing hormone receptors) and hyperthyroidism (due to mutations in thyroid-stimulating hormone receptors). == Theories of drug-receptor interaction == === Occupation === Early forms of the receptor theory of pharmacology stated that a drug's effect is directly proportional to the number of receptors that are occupied. Furthermore, a drug effect ceases as a drug-receptor complex dissociates. Ariëns & Stephenson introduced the terms "affinity" & "efficacy" to describe the action of ligands bound to receptors. Affinity: The ability of a drug to combine with a receptor to create a drug-receptor complex. Efficacy: The ability of drug to initiate a response after the formation of drug-receptor complex. === Rate === In contrast to the accepted Occupation Theory, Rate Theory proposes that the activation of receptors is directly proportional to the total number of encounters of a drug with its receptors per unit time. Pharmacological activity is directly proportional to the rates of dissociation and association, not the number of receptors occupied: Agonist: A drug with a fast association and a fast dissociation. Partial-agonist: A drug with an intermediate association and an intermediate dissociation. Antagonist: A drug with a fast association & slow dissociation === Induced-fit === As a drug approaches a receptor, the receptor alters the conformation of its binding site to produce drug—receptor complex. === Spare Receptors === In some receptor systems (e.g. acetylcholine at the neuromuscular junction in smooth muscle), agonists are able to elicit maximal response at very low levels of receptor occupancy (<1%). Thus, that system has spare receptors or a receptor reserve. This arrangement produces an economy of neurotransmitter production and release. == Receptor regulation == Cells can increase (upregulate) or decrease (downregulate) the number of receptors to a given hormone or neurotransmitter to alter their sensitivity to different molecules. This is a locally acting feedback mechanism. Change in the receptor conformation such that binding of the agonist does not activate the receptor. This is seen with ion channel receptors. Uncoupling of the receptor effector molecules is seen with G protein-coupled receptors. Receptor sequestration (internalization), e.g. in the case of hormone receptors. == Examples and ligands == The ligands for receptors are as diverse as their receptors. GPCRs (7TMs) are a particularly vast family, with at least 810 members. There are also LGICs for at least a dozen endogenous ligands, and many more receptors possible through different subunit compositions. Some common examples of ligands and receptors include: === Ion channels and G protein coupled receptors === Some example ionotropic (LGIC) and metabotropic (specifically, GPCRs) receptors are shown in the table below. The chief neurotransmitters are glutamate and GABA; other neurotransmitters are neuromodulatory. This list is by no means exhaustive. === Enzyme linked receptors === Enzyme linked receptors include Receptor tyrosine kinases (RTKs), serine/threonine-specific protein kinase, as in bone morphogenetic protein and guanylate cyclase, as in atrial natriuretic factor receptor. Of the RTKs, 20 classes have been identified, with 58 different RTKs as members. Some examples are shown below: === Intracellular Receptors === Receptors may be classed based on their mechanism or on their position in the cell. 4 examples of intracellular LGIC are shown below: == Role in health and disease == === In genetic disorders === Many genetic disorders involve hereditary defects in receptor genes. Often, it is hard to determine whether the receptor is nonfunctional or the hormone is produced at decreased level; this gives rise to the "pseudo-hypo-" group of endocrine disorders, where there appears to be a decreased hormonal level while in fact it is the receptor that is not responding sufficiently to the hormone. === In the immune system === The main receptors in the immune system are pattern recognition receptors (PRRs), toll-like receptors (TLRs), killer activated and killer inhibitor receptors (KARs and KIRs), complement receptors, Fc receptors, B cell receptors and T cell receptors. == See also == Ki Database Ion channel linked receptors Neuropsychopharmacology Schild regression for ligand receptor inhibition Signal transduction Stem cell marker List of MeSH codes (D12.776) Receptor theory == Notes == == References == == External links == IUPHAR GPCR Database and Ion Channels Compendium Archived 2019-03-23 at the Wayback Machine Human plasma membrane receptome Archived 2019-09-15 at the Wayback Machine Cell+surface+receptors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)	Wikipedia/Drug_receptors
Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. == Liver diseases == There are more than a hundred different liver diseases. Some of the most common are: Fascioliasis, a parasitic infection of liver caused by a liver fluke of the genus FascioIa, mostly FascioIa hepatica. Hepatitis, inflammation of the liver, is caused by various viruses (viral hepatitis) also by some liver toxins (e.g. alcoholic hepatitis), autoimmunity (autoimmune hepatitis) or hereditary conditions. Alcoholic liver disease is a hepatic manifestation of alcohol overconsumption, including fatty liver disease, alcoholic hepatitis, and cirrhosis. Analogous terms such as "drug-induced" or "toxic" liver disease are also used to refer to disorders caused by various drugs. Fatty liver disease (hepatic steatosis) is a reversible condition where large vacuoles of triglyceride fat accumulate in liver cells. Non-alcoholic fatty liver disease is a spectrum of disease associated with obesity and metabolic syndrome. Hereditary diseases that cause damage to the liver include hemochromatosis, involving accumulation of iron in the body, and Wilson's disease. Liver damage is also a clinical feature of alpha 1-antitrypsin deficiency and glycogen storage disease type II. In transthyretin-related hereditary amyloidosis, the liver produces a mutated transthyretin protein which has severe neurodegenerative or cardiopathic effects. Liver transplantation can be curative. Gilbert's syndrome, a genetic disorder of bilirubin metabolism found in a small percent of the population, can cause mild jaundice. Cirrhosis is the formation of fibrous tissue (fibrosis) in the place of liver cells that have died due to a variety of causes, including viral hepatitis, alcohol overconsumption, and other forms of liver toxicity. Cirrhosis causes chronic liver failure. Primary liver cancer most commonly manifests as hepatocellular carcinoma or cholangiocarcinoma; rarer forms include angiosarcoma and hemangiosarcoma of the liver. (Many liver malignancies are secondary lesions that have metastasized from primary cancers in the gastrointestinal tract and other organs, such as the kidneys, lungs.) Primary biliary cirrhosis is a serious autoimmune disease of the bile capillaries. Primary sclerosing cholangitis is a serious chronic inflammatory disease of the bile duct, which is believed to be autoimmune in origin. Budd–Chiari syndrome is the clinical picture caused by occlusion of the hepatic vein. == Signs and symptoms == Some of the signs and symptoms of a liver disease are the following: Jaundice Confusion and altered consciousness caused by hepatic encephalopathy. Thrombocytopenia and coagulopathy. Risk of bleeding symptoms, particularly taking place in the gastrointestinal tract == Mechanisms == Liver diseases can develop through several mechanisms: === DNA damage === One general mechanism, increased DNA damage, is shared by some of the major liver diseases, including infection by hepatitis B virus or hepatitis C virus, heavy alcohol consumption, and obesity. Viral infection by hepatitis B virus, or hepatitis C virus causes an increase of reactive oxygen species. The increase in intracellular reactive oxygen species is about 10,000-fold with chronic hepatitis B virus infection and 100,000-fold following hepatitis C virus infection. This increase in reactive oxygen species causes inflammation and more than 20 types of DNA damage. Oxidative DNA damage is mutagenic and also causes epigenetic alterations at the sites of DNA repair. Epigenetic alterations and mutations affect the cellular machinery that may cause the cell to replicate at a higher rate or result in the cell avoiding apoptosis, and thus contribute to liver disease. By the time accumulating epigenetic and mutational changes eventually cause hepatocellular carcinoma, epigenetic alterations appear to have an even larger role in carcinogenesis than mutations. Only one gene, TP53, is mutated in more than 20% of liver cancers while 41 genes each have hypermethylated promoters (repressing gene expression) in more than 20% of liver cancers. Alcohol consumption in excess causes a build-up of acetaldehyde. Acetaldehyde and free radicals generated by metabolizing alcohol induce DNA damage and oxidative stress. In addition, activation of neutrophils in alcoholic liver disease contributes to the pathogenesis of hepatocellular damage by releasing reactive oxygen species (which can damage DNA). The level of oxidative stress and acetaldehyde-induced DNA adducts due to alcohol consumption does not appear sufficient to cause increased mutagenesis. However, as reviewed by Nishida et al., alcohol exposure, causing oxidative DNA damage (which is repairable), can result in epigenetic alterations at the sites of DNA repair. Alcohol-induced epigenetic alterations of gene expression appear to lead to liver injury and ultimately carcinoma. Obesity is associated with a higher risk of primary liver cancer. As shown with mice, obese mice are prone to liver cancer, likely due to two factors. Obese mice have increased pro-inflammatory cytokines. Obese mice also have higher levels of deoxycholic acid, a product of bile acid alteration by certain gut microbes, and these microbes are increased with obesity. The excess deoxycholic acid causes DNA damage and inflammation in the liver, which, in turn, can lead to liver cancer. === Other relevant aspects === Several liver diseases are due to viral infection. Viral hepatitides such as Hepatitis B virus and Hepatitis C virus can be vertically transmitted during birth via contact with infected blood. According to a 2012 NICE publication, "about 85% of hepatitis B infections in newborns become chronic". In occult cases, Hepatitis B virus is present by hepatitis B virus DNA, but testing for HBsAg is negative. High consumption of alcohol can lead to several forms of liver disease including alcoholic hepatitis, alcoholic fatty liver disease, cirrhosis, and liver cancer. In the earlier stages of alcoholic liver disease, fat builds up in the liver's cells due to increased creation of triglycerides and fatty acids and a decreased ability to break down fatty acids. Progression of the disease can lead to liver inflammation from the excess fat in the liver. Scarring in the liver often occurs as the body attempts to heal and extensive scarring can lead to the development of cirrhosis in more advanced stages of the disease. Approximately 3–10% of individuals with cirrhosis develop a form of liver cancer known as hepatocellular carcinoma. According to Tilg, et al., gut microbiome could very well have an effect, be involved in the pathophysiology, on the various types of liver disease which an individual may encounter. Insight into the exact causes and mechanisms mediating pathophysiology of the liver is quickly progressing due to the introduction new technological approaches like Single cell sequencing and kinome profiling === Air pollutants === Particulate matter or carbon black are common pollutants. They have a direct toxic effect on the liver; cause inflammation of liver caused by and thereby impact lipid metabolism and fatty liver disease; and can translocate from the lungs to the liver. Because particulate matter and carbon black are very diverse and each has different toxicodynamics, detailed mechanisms of translocation are not clear. Water-soluble fractions of particulate matter are the most important part of translocation to the liver, through extrapulmonary circulation. When particulate matter gets into the bloodstream, it combines with immune cells and stimulates innate immune responses. Pro-inflammatory cytokines are released and cause disease progression. == Epidemiology == Liver diseases, including conditions such as non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease (ALD), and viral hepatitis, are significant public health concerns worldwide. In the United States, NAFLD is the most common chronic liver condition, affecting approximately 24% of the population, with the prevalence rising due to increasing rates of obesity and metabolic syndrome. Alcohol-related liver disease accounts for about 4.5% of liver-related deaths globally, underscoring the substantial burden of alcohol misuse. Viral hepatitis, primarily hepatitis B and hepatitis C, remains a leading cause of liver cirrhosis and liver cancer worldwide, despite advances in antiviral therapies and vaccination efforts. Additionally, recent studies have highlighted lean steatotic liver disease (SLD), a subset of NAFLD, affecting over 12% of U.S. adults even in the absence of obesity. These data emphasize the importance of early detection and targeted interventions to manage liver disease and its associated complications effectively. New research reports the prevalence of lean steatotic liver disease (SLD) in the United States using data from the National Health and Nutrition Examination Survey (2017-2023), researchers estimated the age-adjusted prevalence of lean SLD at 12.8%. This includes 9.3% for lean metabolic dysfunction-associated steatotic liver disease, 1.3% for metabolic dysfunction and alcohol-related steatotic liver disease, and 1.0% for alcohol-related liver disease. == Diagnosis == A number of liver function tests are available to test the proper function of the liver. These test for the presence of enzymes in blood that are normally most abundant in liver tissue, metabolites or products. serum proteins, serum albumin, serum globulin, alanine transaminase, aspartate transaminase, prothrombin time, partial thromboplastin time. Imaging tests such as transient elastography, ultrasound and magnetic resonance imaging can be used to show the liver tissue and the bile ducts. Liver biopsy can be performed to examine liver tissue to distinguish between various conditions; tests such as elastography may reduce the need for biopsy in some situations. In liver disease, prothrombin time is longer than usual. In addition, the amounts of both coagulation factors and anticoagulation factors are reduced as a diseased liver cannot productively synthesize them as it did when healthy. Nonetheless, there are two exceptions in this falling tendency: coagulation factor VIII and von Willebrand factor, a platelet adhesive protein. Both inversely rise in the setting of hepatic insufficiency, thanks to the drop of hepatic clearance and compensatory productions from other sites of the body. Fibrinolysis generally proceeds faster with acute liver failure and advanced stage liver disease, unlike chronic liver disease in which concentration of fibrinogen remains unchanged. A previously undiagnosed liver disease may become evident first after autopsy. Following are gross pathology images: == Treatment == Anti-viral medications are available to treat infections such as hepatitis B. Other conditions may be managed by slowing down disease progression, for example: By using steroid-based drugs in autoimmune hepatitis. Regularly removing a quantity of blood from a vein (venesection) in the iron overload condition, hemochromatosis. Wilson's disease, a condition where copper builds up in the body, can be managed with drugs that bind copper, allowing it to be passed from the body in urine. In cholestatic liver disease, (where the flow of bile is affected due to cystic fibrosis) a medication called ursodeoxycholic acid may be given. == See also == Model for end-stage liver disease (MELD) == References == == Further reading == Friedman LS, Keeffe EB (2011-08-03). Handbook of Liver Disease. Elsevier Health Sciences. ISBN 978-1-4557-2316-4. == External links ==	Wikipedia/Hepatic_disease
Combined drug intoxication (CDI), or multiple drug intake (MDI), is a cause of death by drug overdose from poly drug use, often implicated in polysubstance dependence. == Risk factors == People who engage in polypharmacy are at an elevated risk of death from CDI. Other dangers of combining drugs such as "brain damage, heart problems, seizures, stomach bleeding, liver damage/ liver failure, heatstroke, coma, suppressed breathing, and respiratory failure", along with many other complications. Disorders like depression and anxiety can also stem from polydrug use. Elderly people are at the highest risk of CDI, because of having many age-related and health problems requiring many medications combined with age-impaired judgment, leading to confusion in taking medications. Elderly patients are often prescribed more than one drug within the same drug class, and doctors may treat the side effects of prescribed drugs with even more drugs, which can overwhelm the patient. == Prevention == In general, the use of multiple drugs should be carefully monitored by a qualified individual such as board certified and licensed medical doctor, either an MD or DO. Close association between prescribing physicians and pharmacies, along with the computerization of prescriptions and patients' medical histories, aim to avoid the occurrence of dangerous drug interactions. Lists of contraindications for a drug are usually provided with it, either in monographs, package inserts (accompanying prescribed medications), or in warning labels (for OTC drugs). CDI/MDI might also be avoided by physicians requiring their patients to return any unused prescriptions. Patients should ask their doctors and pharmacists if there are any interactions between the drugs they are taking. == Prevalence == In 2004, there were 3,800 deaths in the US resulting from a fatal medication error involving alcohol, while in 1983 there were fewer than 100 such deaths. It is more of a risk for older patients. == Common combinations == === Alcohol === Alcohol can exacerbate the symptoms and may directly contribute to increased severity of symptoms. The reasons for toxicity vary depending on the mixture of drugs. Usually, most victims die after using two or more drugs in combination that suppress breathing, and the low blood oxygen level causes brain death. == See also == == References == == External links == Drug Interactions Checker at Drugs.com: Drug Information Online Drug Interaction Checker at Medscape (registration required)	Wikipedia/Combined_drug_intoxication
Pharmacy is the science and practice of discovering, producing, preparing, dispensing, reviewing and monitoring medications, aiming to ensure the safe, effective, and affordable use of medicines. It is a miscellaneous science as it links health sciences with pharmaceutical sciences and natural sciences. The professional practice is becoming more clinically oriented as most of the drugs are now manufactured by pharmaceutical industries. Based on the setting, pharmacy practice is either classified as community or institutional pharmacy. Providing direct patient care in the community of institutional pharmacies is considered clinical pharmacy. The scope of pharmacy practice includes more traditional roles such as compounding and dispensing of medications. It also includes more modern services related to health care including clinical services, reviewing medications for safety and efficacy, and providing drug information with patient counselling. Pharmacists, therefore, are experts on drug therapy and are the primary health professionals who optimize the use of medication for the benefit of the patients. An establishment in which pharmacy (in the first sense) is practiced is called a pharmacy (this term is more common in the United States) or chemists (which is more common in Great Britain, though pharmacy is also used). In the United States and Canada, drugstores commonly sell medicines, as well as miscellaneous items such as confectionery, cosmetics, office supplies, toys, hair care products and magazines, and occasionally refreshments and groceries. In its investigation of herbal and chemical ingredients, the work of the apothecary may be regarded as a precursor of the modern sciences of chemistry and pharmacology, prior to the formulation of the scientific method. == Disciplines == The field of pharmacy can generally be divided into various disciplines: Pharmaceutics and Computational Pharmaceutics Pharmacokinetics and Pharmacodynamics Medicinal Chemistry and Pharmacognosy Pharmacology Pharmacy Practice Pharmacoinformatics Pharmacogenomics The boundaries between these disciplines and with other sciences, such as biochemistry, are not always clear-cut. Often, collaborative teams from various disciplines (pharmacists and other scientists) work together toward the introduction of new therapeutics and methods for patient care. However, pharmacy is not a basic or biomedical science in its typical form. Medicinal chemistry is also a distinct branch of synthetic chemistry combining pharmacology, organic chemistry, and chemical biology. Pharmacology is sometimes considered the fourth discipline of pharmacy. Although pharmacology is essential to the study of pharmacy, it is not specific to pharmacy. Both disciplines are distinct. Those who wish to practice both pharmacy (patient-oriented) and pharmacology (a biomedical science requiring the scientific method) receive separate training and degrees unique to either discipline. Pharmacoinformatics is considered another new discipline, for systematic drug discovery and development with efficiency and safety. Pharmacogenomics is the study of genetic-linked variants that effect patient clinical responses, allergies, and metabolism of drugs. == Professionals == The World Health Organization estimates that there are at least 2.6 million pharmacists and other pharmaceutical personnel worldwide. === Pharmacists === Pharmacists are healthcare professionals with specialized education and training who perform various roles to ensure optimal health outcomes for their patients through the quality use of medicines. Pharmacists may also be small business proprietors, owning the pharmacy in which they practice. Since pharmacists know about the mode of action of a particular drug, and its metabolism and physiological effects on the human body in great detail, they play an important role in optimization of drug treatment for an individual. Pharmacists are represented internationally by the International Pharmaceutical Federation (FIP), an NGO linked with World Health Organization (WHO). They are represented at the national level by professional organisations such as the Royal Pharmaceutical Society in the UK, Pharmaceutical Society of Australia (PSA), Canadian Pharmacists Association (CPhA), Indian Pharmacist Association (IPA), Pakistan Pharmacists Association (PPA), American Pharmacists Association (APhA), and the Malaysian Pharmaceutical Society (MPS). In some cases, the representative body is also the registering body, which is responsible for the regulation and ethics of the profession. In the United States, specializations in pharmacy practice recognized by the Board of Pharmacy Specialties include: cardiovascular, infectious disease, oncology, pharmacotherapy, nuclear, nutrition, and psychiatry. The Commission for Certification in Geriatric Pharmacy certifies pharmacists in geriatric pharmacy practice. The American Board of Applied Toxicology certifies pharmacists and other medical professionals in applied toxicology. == Pharmacy support staff == === Pharmacy technicians === Pharmacy technicians support the work of pharmacists and other health professionals by performing a variety of pharmacy-related functions, including dispensing prescription drugs and other medical devices to patients and instructing on their use. They may also perform administrative duties in pharmaceutical practice, such as reviewing prescription requests with medic's offices and insurance companies to ensure correct medications are provided and payment is received. Legislation requires the supervision of certain pharmacy technician's activities by a pharmacist. The majority of pharmacy technicians work in community pharmacies. In hospital pharmacies, pharmacy technicians may be managed by other senior pharmacy technicians. In the UK the role of a PhT in hospital pharmacy has grown and responsibility has been passed on to them to manage the pharmacy department and specialized areas in pharmacy practice allowing pharmacists the time to specialize in their expert field as medication consultants spending more time working with patients and in research. Pharmacy technicians are registered with the General Pharmaceutical Council (GPhC). The GPhC is the regulator of pharmacists, pharmacy technicians, and pharmacy premises. In the US, pharmacy technicians perform their duties under the supervision of pharmacists. Although they may perform, under supervision, most dispensing, compounding and other tasks, they are not generally allowed to perform the role of counseling patients on the proper use of their medications. Some states have a legally mandated pharmacist-to-pharmacy technician ratio. === Dispensing assistants === Dispensing assistants are commonly referred to as "dispensers" and in community pharmacies perform largely the same tasks as a pharmacy technician. They work under the supervision of pharmacists and are involved in preparing (dispensing and labelling) medicines for provision to patients. === Healthcare assistants/medicines counter assistants === In the UK, this group of staff can sell certain medicines (including pharmacy only and general sales list medicines) over the counter. They cannot prepare prescription-only medicines for supply to patients. == History == The earliest known compilation of medicinal substances was the Sushruta Samhita, an Indian Ayurvedic treatise attributed to Sushruta in the 6th century BC. However, the earliest text as preserved dates to the 3rd or 4th century AD. Many Sumerian (4th millennium BC – early 2nd millennium BC) cuneiform clay tablets record prescriptions for medicine. Ancient Egyptian pharmacological knowledge was recorded in various papyri such as the Ebers Papyrus of 1550 BC, and the Edwin Smith Papyrus of the 16th century BC. In Ancient Greece, Diocles of Carystus (4th century BC) was one of several men studying the medicinal properties of plants. He wrote several treatises on the topic. The Greek physician Pedanius Dioscorides is famous for writing a five-volume book in his native Greek Περί ύλης ιατρικής in the 1st century AD. The Latin translation De Materia Medica (Concerning medical substances) was used as a basis for many medieval texts and was built upon by many middle eastern scientists during the Islamic Golden Age, themselves deriving their knowledge from earlier Greek Byzantine medicine. Pharmacy in China dates at least to the earliest known Chinese manual, the Shennong Bencao Jing (The Divine Farmer's Herb-Root Classic), dating back to the 1st century AD. It was compiled during the Han dynasty and was attributed to the mythical Shennong. Earlier literature included lists of prescriptions for specific ailments, exemplified by a manuscript "Recipes for 52 Ailments", found in the Mawangdui, sealed in 168 BC. In Japan, at the end of the Asuka period (538–710) and the early Nara period (710–794), the men who fulfilled roles similar to those of modern pharmacists were highly respected. The place of pharmacists in society was expressly defined in the Taihō Code (701) and re-stated in the Yōrō Code (718). Ranked positions in the pre-Heian Imperial court were established; and this organizational structure remained largely intact until the Meiji Restoration (1868). In this highly stable hierarchy, the pharmacists—and even pharmacist assistants—were assigned status superior to all others in health-related fields such as physicians and acupuncturists. In the Imperial household, the pharmacist was even ranked above the two personal physicians of the Emperor. There is a stone sign for a pharmacy shop with a tripod, a mortar, and a pestle opposite one for a doctor in the Arcadian Way in Ephesus near Kusadasi in Turkey. The current Ephesus dates back to 400 BC and was the site of the Temple of Artemis, one of the seven wonders of the world. In Baghdad the first pharmacies, or drug stores, were established in 754, under the Abbasid Caliphate during the Islamic Golden Age. By the 9th century, these pharmacies were state-regulated. The advances made in the Middle East in botany and chemistry led medicine in medieval Islam substantially to develop pharmacology. Muhammad ibn Zakarīya Rāzi (Rhazes) (865–915), for instance, acted to promote the medical uses of chemical compounds. Abu al-Qasim al-Zahrawi (Abulcasis) (936–1013) pioneered the preparation of medicines by sublimation and distillation. His Liber servitoris is of particular interest, as it provides the reader with recipes and explains how to prepare the "simples" from which were compounded the complex drugs then generally used. Sabur Ibn Sahl (d 869), was, however, the first physician to record his findings in a pharmacopoeia, describing a large variety of drugs and remedies for ailments. Al-Biruni (973–1050) wrote one of the most valuable Islamic works on pharmacology, entitled Kitab al-Saydalah (The Book of Drugs), in which he detailed the properties of drugs and outlined the role of pharmacy and the functions and duties of the pharmacist. Avicenna, too, described no less than 700 preparations, their properties, modes of action, and their indications. He devoted in fact a whole volume to simple drugs in The Canon of Medicine. Of great impact were also the works by al-Maridini of Baghdad and Cairo, and Ibn al-Wafid (1008–1074), both of which were printed in Latin more than fifty times, appearing as De Medicinis universalibus et particularibus by 'Mesue' the younger, and the Medicamentis simplicibus by 'Abenguefit'. Peter of Abano (1250–1316) translated and added a supplement to the work of al-Maridini under the title De Veneris. Al-Muwaffaq's contributions in the field are also pioneering. Living in the 10th century, he wrote The foundations of the true properties of Remedies, amongst others describing arsenious oxide, and being acquainted with silicic acid. He made clear distinction between sodium carbonate and potassium carbonate, and drew attention to the poisonous nature of copper compounds, especially copper vitriol, and also lead compounds. He also describes the distillation of sea-water for drinking. In Europe, pharmacy-like shops began to appear during the 12th century. In 1240, emperor Frederic II issued a decree by which the physician's and the apothecary's professions were separated. There are pharmacies in Europe that have been in operation since medieval times. In Florence, Italy, the director of the museum in the former Santa Maria Novella pharmacy says that the pharmacy there dates back to 1221. In Trier (Germany), the Löwen-Apotheke is in operation since 1241, the oldest pharmacy in Europe in continuous operation. In Dubrovnik (Croatia), a pharmacy that first opened in 1317 is located inside the Franciscan monastery: it is the 2nd oldest pharmacy in Europe that is still operating. In the Town Hall Square of Tallinn (Estonia), there is a pharmacy dating from at least 1422. The medieval Esteve Pharmacy, located in Llívia, a Catalan enclave close to Puigcerdà, is a museum: the building dates back to the 15th century and the museum keeps albarellos from the 16th and 17th centuries, old prescription books and antique drugs. == Practice areas == Pharmacists practice in a variety of areas including community pharmacies, infusion pharmacies, hospitals, clinics, insurance companies, medical communication companies, research facilities, pharmaceutical companies, extended care facilities, psychiatric hospitals, and regulatory agencies. Pharmacists themselves may have expertise in a medical specialty. === Community pharmacy === A pharmacy (also known as a chemist in Australia, New Zealand and the British Isles; or drugstore in North America; retail pharmacy in industry terminology; or apothecary, historically) is where most pharmacists practice the profession of pharmacy. It is the community pharmacy in which the dichotomy of the profession exists; health professionals who are also retailers. Community pharmacies usually consist of a retail storefront with a dispensary, where medications are stored and dispensed. According to Sharif Kaf al-Ghazal, the opening of the first drugstores are recorded by Muslim pharmacists in Baghdad in 754 AD. === Hospital pharmacy === Pharmacies within hospitals differ considerably from community pharmacies. Some pharmacists in hospital pharmacies may have more complex clinical medication management issues, and pharmacists in community pharmacies often have more complex business and customer relations issues. Because of the complexity of medications including specific indications, effectiveness of treatment regimens, safety of medications (i.e., drug interactions) and patient compliance issues (in the hospital and at home), many pharmacists practicing in hospitals gain more education and training after pharmacy school through a pharmacy practice residency, sometimes followed by another residency in a specific area. Those pharmacists are often referred to as clinical pharmacists and they often specialize in various disciplines of pharmacy. For example, there are pharmacists who specialize in hematology/oncology, HIV/AIDS, infectious disease, critical care, emergency medicine, toxicology, nuclear pharmacy, pain management, psychiatry, anti-coagulation clinics, herbal medicine, neurology/epilepsy management, pediatrics, neonatal pharmacists and more. Hospital pharmacies can often be found within the premises of the hospital. Hospital pharmacies usually stock a larger range of medications, including more specialized medications, than would be feasible in the community setting. Most hospital medications are unit-dose, or a single dose of medicine. Hospital pharmacists and trained pharmacy technicians compound sterile products for patients including total parenteral nutrition (TPN), and other medications are given intravenously. That is a complex process that requires adequate training of personnel, quality assurance of products, and adequate facilities. Several hospital pharmacies have decided to outsource high-risk preparations and some other compounding functions to companies who specialize in compounding. The high cost of medications and drug-related technology and the potential impact of medications and pharmacy services on patient-care outcomes and patient safety require hospital pharmacies to perform at the highest level possible. === Clinical pharmacy === Pharmacists provide direct patient care services that optimize the use of medication and promotes health, wellness, and disease prevention. Clinical pharmacists care for patients in all health care settings, but the clinical pharmacy movement initially began inside hospitals and clinics. Clinical pharmacists often collaborate with physicians and other healthcare professionals to improve pharmaceutical care. Clinical pharmacists are now an integral part of the interdisciplinary approach to patient care. They often participate in patient care rounds for drug product selection. In the UK clinical pharmacists can also prescribe some medications for patients on the National Health Services (NHS) or privately, after completing a non-medical prescribers course to become an Independent Prescriber. The clinical pharmacist's role involves creating a comprehensive drug therapy plan for patient-specific problems, identifying goals of therapy, and reviewing all prescribed medications prior to dispensing and administration to the patient. The review process often involves an evaluation of the appropriateness of drug therapy (e.g., drug choice, dose, route, frequency, and duration of therapy) and its efficacy. Research shows that pharmacist led strategies reduce errors related to medication use. The pharmacist must also consider potential drug interactions, adverse drug reactions, and patient drug allergies while they design and initiate a drug therapy plan. === Ambulatory care pharmacy === Since the emergence of modern clinical pharmacy, ambulatory care pharmacy practice has emerged as a unique pharmacy practice setting. Ambulatory care pharmacy is based primarily on pharmacotherapy services that a pharmacist provides in a clinic. Pharmacists in this setting often do not dispense drugs, but rather see patients in-office visits to manage chronic disease states. In the U.S. federal health care system (including the VA, the Indian Health Service, and National Institute of Health (NIH)) ambulatory care pharmacists are given full independent prescribing authority. In some states, such as North Carolina and New Mexico, these pharmacist clinicians are given collaborative prescriptive and diagnostic authority. In 2011 the board of Pharmaceutical Specialties approved ambulatory care pharmacy practice as a separate board certification. The official designation for pharmacists who pass the ambulatory care pharmacy specialty certification exam will be Board Certified Ambulatory Care Pharmacist and these pharmacists will carry the initials BCACP. === Compounding pharmacy/industrial pharmacy === Compounding involves preparing drugs in forms that are different from the generic prescription standard. This may include altering the strength, ingredients, or dosage form. Compounding is a way to create custom drugs for patients who may not be able to take the medication in its standard form, such as due to an allergy or difficulty swallowing. Compounding is necessary for these patients to still be able to properly get the prescriptions they need. One area of compounding is preparing drugs in new dosage forms. For example, if a drug manufacturer only provides a drug as a tablet, a compounding pharmacist might make a medicated lollipop that contains the drug. Patients who have difficulty swallowing the tablet may prefer to suck the medicated lollipop instead. Another form of compounding is by mixing different strengths (g, mg, mcg) of capsules or tablets to yield the desired amount of medication indicated by the physician, physician assistant, nurse practitioner, or clinical pharmacist practitioner. This form of compounding is found at community or hospital pharmacies or in-home administration therapy. Compounding pharmacies specialize in compounding, although many also dispense the same non-compounded drugs that patients can obtain from community pharmacies. === Consultant pharmacy === Consultant pharmacy practice focuses more on medication regimen review (i.e. "cognitive services") than on actual dispensing of drugs. Consultant pharmacists most typically work in nursing homes, but are increasingly branching into other institutions and non-institutional settings. Traditionally consultant pharmacists were usually independent business owners, though in the United States many now work for a large pharmacy management company such as Omnicare, Kindred Healthcare or PharMerica. This trend may be gradually reversing as consultant pharmacists begin to work directly with patients, primarily because many elderly people are now taking numerous medications but continue to live outside of institutional settings. Some community pharmacies employ consultant pharmacists and/or provide consulting services. The main principle of consultant pharmacy was developed by Hepler and Strand in 1990. === Veterinary pharmacy === Veterinary pharmacies, sometimes called animal pharmacies, may fall in the category of hospital pharmacy, retail pharmacy or mail-order pharmacy. Veterinary pharmacies stock different varieties and different strengths of medications to fulfill the pharmaceutical needs of animals. Because the needs of animals, as well as the regulations on veterinary medicine, are often very different from those related to people, in some jurisdictions veterinary pharmacy may be kept separate from regular pharmacies. === Nuclear pharmacy === Nuclear pharmacy focuses on preparing radioactive materials for diagnostic tests and for treating certain diseases. Nuclear pharmacists undergo additional training specific to handling radioactive materials, and unlike in community and hospital pharmacies, nuclear pharmacists typically do not interact directly with patients. === Military pharmacy === Military pharmacy is a different working environment to civilian practise because military pharmacy technicians perform duties such as evaluating medication orders, preparing medication orders, and dispensing medications. This would be illegal in civilian pharmacies because these duties are required to be performed by a licensed registered pharmacist. In the US military, state laws that prevent technicians from counseling patients or doing the final medication check prior to dispensing to patients (rather than a pharmacist solely responsible for these duties) do not apply. === Pharmacy informatics === Pharmacy informatics is the combination of pharmacy practice science and applied information science. Pharmacy informaticists work in many practice areas of pharmacy, however, they may also work in information technology departments or for healthcare information technology vendor companies. As a practice area and specialist domain, pharmacy informatics is growing quickly to meet the needs of major national and international patient information projects and health system interoperability goals. Pharmacists in this area are trained to participate in medication management system development, deployment, and optimization. === Specialty pharmacy === Specialty pharmacies supply high-cost injectable, oral, infused, or inhaled medications that are used for chronic and complex disease states such as cancer, hepatitis, and rheumatoid arthritis. Unlike a traditional community pharmacy where prescriptions for any common medication can be brought in and filled, specialty pharmacies carry novel medications that need to be properly stored, administered, carefully monitored, and clinically managed. In addition to supplying these drugs, specialty pharmacies also provide lab monitoring, adherence counseling, and assist patients with cost-containment strategies needed to obtain their expensive specialty drugs. In the US, it is currently the fastest-growing sector of the pharmaceutical industry with 19 of 28 newly Food and Drug Administration (FDA) approved medications in 2013 being specialty drugs. Due to the demand for clinicians who can properly manage these specific patient populations, the Specialty Pharmacy Certification Board has developed a new certification exam to certify specialty pharmacists. Along with the 100 questions computerized multiple-choice exam, pharmacists must also complete 3,000 hours of specialty pharmacy practice within the past three years as well as 30 hours of specialty pharmacist continuing education within the past two years. == Pharmaceutical sciences == The pharmaceutical sciences are a group of interdisciplinary areas of study concerned with the design, manufacturing, action, delivery, and classification of drugs. They apply knowledge from chemistry (inorganic, physical, biochemical and analytical), biology (anatomy, physiology, biochemistry, cell biology, and molecular biology), epidemiology, statistics, chemometrics, mathematics, physics, and chemical engineering. The pharmaceutical sciences are further subdivided into several specific specialties, with four main branches: Pharmacology: the study of the biochemical and physiological effects of drugs on human beings. Pharmacodynamics: the study of the cellular and molecular interactions of drugs with their receptors. Simply "What the drug does to the body" Pharmacokinetics: the study of the factors that control the concentration of drug at various sites in the body. Simply "What the body does to the drug" Pharmaceutical toxicology: the study of the harmful or toxic effects of drugs. Pharmacogenomics: the study of the inheritance of characteristic patterns of interaction between drugs and organisms. Pharmaceutical chemistry: the study of drug design to optimize pharmacokinetics and pharmacodynamics, and synthesis of new drug molecules (Medicinal Chemistry). Pharmaceutics: the study and design of drug formulation for optimum delivery, stability, pharmacokinetics, and patient acceptance. Pharmacognosy: the study of medicines derived from natural sources. As new discoveries advance and extend the pharmaceutical sciences, subspecialties continue to be added to this list. Importantly, as knowledge advances, boundaries between these specialty areas of pharmaceutical sciences are beginning to blur. Many fundamental concepts are common to all pharmaceutical sciences. These shared fundamental concepts further the understanding of their applicability to all aspects of pharmaceutical research and drug therapy. Pharmacocybernetics (also known as pharma-cybernetics, cybernetic pharmacy, and cyber pharmacy) is an emerging field that describes the science of supporting drugs and medications use through the application and evaluation of informatics and internet technologies, so as to improve the pharmaceutical care of patients. == Society and culture == === Etymology === The word pharmacy is derived from Old French farmacie "substance, such as a food or in the form of a medicine which has a laxative effect" from Medieval Latin pharmacia from Greek pharmakeia (Ancient Greek: φαρμακεία) "a medicine", which itself derives from pharmakon (φάρμακον), meaning "drug, poison, spell" (which is etymologically related to pharmakos). === Separation of prescribing and dispensing === Separation of prescribing and dispensing, also called dispensing separation, is a practice in medicine and pharmacy in which the physician who provides a medical prescription is independent from the pharmacist who provides the prescription drug. In the Western world there are centuries of tradition for separating pharmacists from physicians. In Asian countries, it is traditional for physicians to also provide drugs. In contemporary time researchers and health policy analysts have more deeply considered these traditions and their effects. Advocates for separation and advocates for combining make similar claims for each of their conflicting perspectives, saying that separating or combining reduces conflict of interest in the healthcare industry, unnecessary health care, and lowers costs, while the opposite causes those things. Research in various places reports mixed outcomes in different circumstances. === Environmental impacts === In 2022 the Organisation for Economic Co-operation and Development (OECD) proposed that pharmaceutical companies should be required to collect and destroy unused or expired medicines that they have put on the market in order to reduce public health risks around the misuse of medicines obtained from waste bins, the development of antimicrobial resistant bacteria from the discharge of antibiotics into environmental systems and "economic losses" from wasted healthcare resources. Potentially harmful concentrations of pharmaceutical waste has been detected in more than a quarter of water samples taken from 258 rivers around the world. OECD recommend that medicines should be collected separately from household waste and that "marketplaces and redistribution platforms for unused close-to-expiry-date medicines" should be set up. Such extended producer responsibility schemes are already running in France, Spain and Portugal. === The future of pharmacy === In the coming decades, pharmacists are expected to become more integral within the health care system. Rather than simply dispensing medication, pharmacists are increasingly expected to be compensated for their patient care skills. In particular, Medication Therapy Management (MTM) includes the clinical services that pharmacists can provide for their patients. Such services include a thorough analysis of all medication (prescription, non-prescription, and herbals) currently being taken by an individual. The result is a reconciliation of medication and patient education resulting in increased patient health outcomes and decreased costs to the health care system. This shift has already commenced in some countries; for instance, pharmacists in Australia receive remuneration from the Australian Government for conducting comprehensive Home Medicines Reviews. In Canada, pharmacists in certain provinces have limited prescribing rights (as in Alberta and British Columbia) or are remunerated by their provincial government for expanded services such as medications reviews (Medschecks in Ontario). In the United Kingdom, pharmacists who undertake additional training are obtaining prescribing rights and this is because of pharmacy education. They are also being paid for by the government for medicine use reviews. In Scotland, the pharmacist can write prescriptions for Scottish registered patients of their regular medications, for the majority of drugs, except for controlled drugs, when the patient is unable to see their doctor, as could happen if they are away from home or the doctor is unavailable. In the United States, pharmaceutical care or clinical pharmacy has had an evolving influence on the practice of pharmacy. Moreover, the Doctor of Pharmacy (Pharm. D.) degree is now required before entering practice and some pharmacists now complete one or two years of residency or fellowship training following graduation. In addition, consultant pharmacists, who traditionally operated primarily in nursing homes, are now expanding into direct consultation with patients, under the banner of "senior care pharmacy". In addition to patient care, pharmacies will be a focal point for medical adherence initiatives. There is enough evidence to show that integrated pharmacy based initiatives significantly impact adherence for chronic patients. For example, a study published in National Institute for Health (NIH) shows "pharmacy based interventions improved patients' medication adherence rates by 2.1 percent and increased physicians' initiation rates by 38 percent, compared to the control group". == Pharmacy journals == List of pharmaceutical sciences journals == Symbols == The symbols most commonly associated with pharmacy are the mortar and pestle (North America) and the ℞ (medical prescription) character, which is often written as "Rx" in typed text; the green cross in France, Argentina, the United Kingdom, Belgium, Ireland, Italy, Spain, and India; the Bowl of Hygieia (only) often used in the Netherlands but may be seen combined with other symbols elsewhere. Other common symbols include conical measures, and (in the US) caduceuses, in their logos. A red stylized letter A is used in Germany and Austria (from Apotheke, the German word for pharmacy, from the same Greek root as the English word "apothecary"). The show globe was used in the US until the early 20th century; the Gaper in the Netherlands is increasingly rare. == See also == == Notes == == References == == Sources == Watkins, Elizabeth Siegel (2009). "From History of Pharmacy to Pharmaceutical History". Pharmacy in History. 51 (1): 3–13. PMID 20027914. (in Japanese) Asai, T. (1985). Nyokan Tūkai. Tokyo: Kōdan-Sha. (in French) Titsingh, Isaac, ed. (1834). [Siyun-sai Rin-siyo/Hayashi Gahō, 1652], Nipon o daï itsi ran; ou, Annales des empereurs du Japon. Paris: Oriental Translation Fund of Great Britain and Ireland....Click link for digitized, full-text copy of this book (in French) Pharmacy Consulting Services \| McKesson – A landmark study in hospital pharmacy performance based on an extensive literature review and the collective experience of the Health Systems Pharmacy Executive Alliance. == External links == Navigator History of Pharmacy Collection of internet resources related to the history of pharmacy Soderlund Pharmacy Museum – Information about the history of the American Drugstore The Lloyd Library Library of botanical, medical, pharmaceutical, and scientific books and periodicals, and works of allied sciences American Institute of the History of Pharmacy American Institute of the History of Pharmacy—resources in the history of pharmacy International Pharmaceutical Federation (FIP) Federation representing national associations of pharmacists and pharmaceutical scientists. Information and resources relating to pharmacy education, practice, science and policy	Wikipedia/Pharmaceutical_sciences
Drug fraud is a type of fraud in which drugs, legal or illegal, are cut or altered in such a way that diminishes their value below that which they are sold for. == Illegal drug fraud == This type of drug fraud occurs when the dealer cuts or commingles the pure drug with a similar substance such as baby powder or powdered milk. When this is sold to the user, the user receives less of a high and so must buy more to get the previous high. There may also be adverse health consequences as a result of the cutting substance, such as a bad trip or overdose. This can also be seen in prescription drugs. == Legal drug fraud == Legal drug fraud occurs when a physician prescribes medication for a patient under false pretenses. This may be because the manufacturers of the drug have paid the doctor a fee to dispense their drug. Another cause may be drug pricing fraud, in which a physician prescribes a patient expensive drugs, that they may or may not need, in order to profit from the receipts. Patients too, may participate in this. A common method is the forging of doctor prescriptions to gain access to prescription medications. A somewhat rarer type is a citizen posing as a doctor to, among other things, gain access to the free samples of drugs that some drug manufacturers give out. The samples may also be sold to desperate patients at an exorbitant rate. Actual physicians may do this also. Others may prescribe drugs without sufficient cause. == Legal status == Illegal drug fraud is rarely addressed in court, as victims rarely involve police, but legal drug fraud is on the rise. Its upswing has increased calls for accountability as well as a bill being passed in the United States, 2007 Senate Bill 88. == References == == See also == Quackery Double billing Counterfeit medications Pharmaceutical fraud	Wikipedia/Drug_fraud
In medicine and psychology, clinical significance is the practical importance of a treatment effect—whether it has a real genuine, palpable, noticeable effect on daily life. == Types of significance == === Statistical significance === Statistical significance is used in hypothesis testing, whereby the null hypothesis (that there is no relationship between variables) is tested. A level of significance is selected (most commonly α = 0.05 or 0.01), which signifies the probability of incorrectly rejecting a true null hypothesis. If there is a significant difference between two groups at α = 0.05, it means that there is only a 5% probability of obtaining the observed results under the assumption that the difference is entirely due to chance (i.e., the null hypothesis is true); it gives no indication of the magnitude or clinical importance of the difference. When statistically significant results are achieved, they favor rejection of the null hypothesis, but they do not prove that the null hypothesis is false. Likewise, non-significant results do not prove that the null hypothesis is true; they also give no evidence of the truth or falsity of the hypothesis the researcher has generated. Statistical significance relates only to the compatibility between observed data and what would be expected under the assumption that the null hypothesis is true. === Practical significance === In broad usage, the "practical clinical significance" answers the question, how effective is the intervention or treatment, or how much change does the treatment cause. In terms of testing clinical treatments, practical significance optimally yields quantified information about the importance of a finding, using metrics such as effect size, number needed to treat (NNT), and preventive fraction. Practical significance may also convey semi-quantitative, comparative, or feasibility assessments of utility. Effect size is one type of practical significance. It quantifies the extent to which a sample diverges from expectations. Effect size can provide important information about the results of a study, and are recommended for inclusion in addition to statistical significance. Effect sizes have their own sources of bias, are subject to change based on population variability of the dependent variable, and tend to focus on group effects, not individual changes. Although clinical significance and practical significance are often used synonymously, a more technical restrictive usage denotes this as erroneous. This technical use within psychology and psychotherapy not only results from a carefully drawn precision and particularity of language, but it enables a shift in perspective from group effects to the specifics of change(s) within an individual. === Specific usage === In contrast, when used as a technical term within psychology and psychotherapy, clinical significance yields information on whether a treatment was effective enough to change a patient's diagnostic label. In terms of clinical treatment studies, clinical significance answers the question "Is a treatment effective enough to cause the patient to be normal [with respect to the diagnostic criteria in question]?" For example, a treatment might significantly change depressive symptoms (statistical significance), the change could be a large decrease in depressive symptoms (practical significance- effect size), and 40% of the patients no longer met the diagnostic criteria for depression (clinical significance). It is very possible to have a treatment that yields a significant difference and medium or large effect sizes, but does not move a patient from dysfunctional to functional. Within psychology and psychotherapy, clinical significance was first proposed by Jacobson, Follette, and Revenstorf as a way to answer the question, is a therapy or treatment effective enough such that a client does not meet the criteria for a diagnosis? Jacobson and Truax later defined clinical significance as "the extent to which therapy moves someone outside the range of the dysfunctional population or within the range of the functional population." They proposed two components of this index of change: the status of a patient or client after therapy has been completed, and "how much change has occurred during the course of therapy." Clinical significance is also a consideration when interpreting the results of the psychological assessment of an individual. Frequently, there will be a difference of scores or subscores that is statistically significant, unlikely to have occurred purely by chance. However, not all of those statistically significant differences are clinically significant, in that they do not either explain existing information about the client, or provide useful direction for intervention. Differences that are small in magnitude typically lack practical relevance and are unlikely to be clinically significant. Differences that are common in the population are also unlikely to be clinically significant, because they may simply reflect a level of normal human variation. Additionally, clinicians look for information in the assessment data and the client's history that corroborates the relevance of the statistical difference, to establish the connection between performance on the specific test and the individual's more general functioning. == Calculation of clinical significance == Just as there are many ways to calculate statistical significance and practical significance, there are a variety of ways to calculate clinical significance. Five common methods are the Jacobson-Truax method, the Gulliksen-Lord-Novick method, the Edwards-Nunnally method, the Hageman-Arrindell method, and hierarchical linear modeling. === Jacobson-Truax === Jacobson-Truax is common method of calculating clinical significance. It involves calculating a Reliability Change Index (RCI). The RCI equals the difference between a participant's pre-test and post-test scores, divided by the standard error of the difference. Cutoff scores are established for placing participants into one of four categories: recovered, improved, unchanged, or deteriorated, depending on the directionality of the RCI and whether the cutoff score was met. === Gulliksen-Lord-Novick === The Gulliksen-Lord-Novick method is similar to Jacobson-Truax, except that it takes into account regression to the mean. This is done by subtracting the pre-test and post-test scores from a population mean, and dividing by the standard deviation of the population. === Edwards-Nunnally === The Edwards-Nunnally method of calculating clinical significance is a more stringent alternative to the Jacobson-Truax method. Reliability scores are used to bring the pre-test scores closer to the mean, and then a confidence interval is developed for this adjusted pre-test score. Confidence intervals are used when calculating the change from pre-test to post-test, so greater actual change in scores is necessary to show clinical significance, compared to the Jacobson-Truax method. === Hageman-Arrindell === The Hageman-Arrindell calculation of clinical significance involves indices of group change and of individual change. The reliability of change indicates whether a patient has improved, stayed the same, or deteriorated. A second index, the clinical significance of change, indicates four categories similar to those used by Jacobson-Truax: deteriorated, not reliably changed, improved but not recovered, and recovered. === Hierarchical linear modeling (HLM) === HLM involves growth curve analysis instead of pre-test post-test comparisons, so three data points are needed from each patient, instead of only two data points (pre-test and post-test). A computer program, such as Hierarchical Linear and Nonlinear Modeling is used to calculate change estimates for each participant. HLM also allows for analysis of growth curve models of dyads and groups. == See also == Cohen's h Medical statistics Minimal clinically important difference == References ==	Wikipedia/Clinically_significant
Lacing or cutting, in drug culture, refer to the act of using a substance (referred to as the lacing agent or cutting agent) to adulterate substances independent of the reason. The resulting substance is laced or cut. Some street drugs are commonly laced with other chemicals for various reasons, but it is most commonly done to bulk up the original product or to sell other, cheaper drugs in the place of something more expensive. Individuals sometimes lace their own drugs with another substance to combine or alter the physiological or psychoactive effects. == Overview == The classical model of drug cutting refers to the way that illicit drugs were diluted at each stage of the chain of distribution. Drug markets have changed considerably since the 1980s; greater competition, and a shift from highly structured (and thus controlled) to greatly fragmented markets, has generated competition among dealers in terms of purity. Many drugs that reach the street are now only cut at the manufacture/producer stage, and this may be more a matter of lacing the drug with another substance designed to appeal to the consumer, as opposed to simple diluents that increase the profit for the seller. The extent of cutting can vary significantly over time but for the last 15 years drugs such as cocaine ranged in Europe on average from 32% to 65% in purity. Heroin purity at 50% does not mean 50% cutting agents; other adulterants could include other opiate by-products of making heroin from opium. Furthermore heroin base can only have a max purity of 61% while heroin HCl can be up to 98% pure Coomber, after having street heroin seizures from the UK re-analysed, reported that nearly 50% of the samples had no cutting agents present at all. This means that 50% of street heroin in the UK in 1995 had worked its way from producer to user without being cut at any stage, although other adulterants may have been present. Other research outlined how drug dealers have other ways of making profit without having to resort to cutting the drugs they sell. Cocaine has been cut with various substances ranging from flour and powdered milk to ground drywall, mannitol, baking soda, and other common, easily obtainable substances. Levamisole and other PTHIT substances also remain in frequent use as cutting agent. Most illicit drugs are adulterated to some degree. Some street drugs can be as low as 10–15% of the active drug, with the other (85–90%) not necessarily being the cutting agent. In fact a heroin sample of only 20% purity may have no cutting agents in it at all. The other 80% may be impurities produced in the manufacturing process and substances created as by products of this process and/or degradation of the drug if improperly stored. When choosing a cutting agent, the drug manufacturer or dealer would ideally attempt to find a chemical that is inexpensive, easy to obtain, relatively non-toxic, and mimics the physical attributes of the drug to be adulterated. For example, if a drug is soluble in water, the preferred adulterant would also be water-soluble. Similar melting and boiling points are also important if the drug is to be smoked. == Types of lacing agents == === Non-psychoactive lacing agents === ==== Visually mimics ==== Some fake drugs consist of substances from relatively harmless sources, such as grocery store goods like flour, oregano or allergy pills. Even despite the substances' harmlessness, legal penalties for the crime of selling them can include time in jail. ==== Flavor masker ==== Sometimes a flavor masker is added to give a more pleasant experience. === Psychoactive mimics === Lacing/cutting agents may be psychoactive. Certain fake drugs include other controlled drugs, or they may include synthetic drugs with similar properties. Uncertainty of an identity of the substance may increase the risk of an overdose. A related, yet distinct problem is the trade of counterfeit medications with pills including substances such as fentanyl which can be used recreationally. == Reasons for lacing == === Illegal drug trade === Drugs may be sold to end users who are unaware they have been laced or are unaware what was used to lace them. At various points in the supply chain, in order to maximize profitability, many drugs are adulterated with cutting agents. Substances with similar physical and/or chemical properties can be used so the end product most closely resembles what it is purported to be. Inert substances with similar physical properties can be used to increase weight without changing the look and feel. Less expensive or easier to obtain compounds with similar chemical properties may be used to lace heavily adulterated drugs while still maintaining some psychoactive potency. === Mickey Finn === In slang, a Mickey Finn—or simply a Mickey—is a drink laced with a psychoactive drug or incapacitating agent (especially chloral hydrate) given to someone without their knowledge, with intent to incapacitate them. === Poly drug use === Drugs may also be laced with the end user being made aware of the lacing. In this case, rather than as an adulteration, the lacing is intended to make the product more desirable. Sometimes less potent, often less expensive drugs, are laced with a small amount of a more potent, often more expensive drug. This may be used to facilitate the ingestion of drugs or to allow the simultaneous ingestion of multiple drugs. Cigarettes laced with PCP allow users to take in the liquid PCP through smoking and some multi drug users report intentionally buying marijuana laced with methamphetamine. == Commonly laced substances == === Dietary supplements === ==== CBD ==== Cannabidiol (CBD) is often cut with synthetic cannabinoids. === Street drugs === ==== Depressants ==== ===== Heroin ===== Heroin is commonly cut with quinine, caffeine, dimethocaine, lidocaine, procaine, lactose, inositol, dextrose, mannitol, and starch. Other opioids are sometimes sold as heroin or cut with heroin. Fentanyl sold as or laced into heroin has made the news in the past due to the numerous fatalities it causes when it appears on the market. Recently, Fentanyl and close analogues have been produced in pure powder form for very cheap. Dealers may cut with or sell heroin with Fentanyl due to the street cost of Fentanyl versus the cost of heroin. The potency of such mixtures (especially if made carelessly) can be far above that of pure heroin, and users frequently overdose due to this. Gray death is a street drug in the United States. Samples have been found to contain the designer drug U-47700, heroin and opioids including fentanyl and carfentanil. ====== α-Methylfentanyl ====== In 1976, α-Methylfentanyl ("China White") began to appear mixed with heroin, as an additive, and the mixture was sometimes also called "China White". It was first identified in the bodies of two drug overdose victims in Orange County, California, in December 1979, who appeared to have died from opiate overdose but tested negative for any known drugs of this type. Over the next year, there were 13 more deaths, and eventually the responsible agent was identified as α-methylfentanyl. ==== Stimulants ==== Stimulants are drugs that speed or give a mental boost to the consumer. ===== Cocaine ===== Black cocaine, and cocaine paste, are impure forms of cocaine. The most common cocaine adulterants found in 1998 in samples in Rome, Italy were lidocaine and caffeine. Cocaine is sometimes mixed with methylamphetamine, methylphenidate, and ephedrine, but is usually mixed with non psychoactive chemicals such as mannitol, inositol, pectin, glucose, lactose, saccharin, white rice flour, and maltodextrin. Other of agranulocytosis, including 2 deaths, according to an alert from the Substance Abuse and Mental Health Services Administration (SAMHSA). The emergence of fentanyl-laced cocaine has led to an increase in cocaine overdose fatalities in New York City. ===== Methamphetamine ===== MSM is sometimes used as a cutting agent for illicitly manufactured methamphetamine. ==== Psychedelics ==== ===== Cannabis ===== Cannabis products that are laced are usually laced with synthetic cannabinoids: Counterfeit cannabis-liquid (c-liquid) for e-cigarettes: Synthetic cannabinoids are increasingly offered in e-cigarette form as "c-liquid". Counterfeit cannabis buds: Hemp buds (or low-potency cannabis buds) laced with synthetic cannabinoids. Counterfeit cannabis edible: The Florida Poison Information Center in Jacksonville warned parents in September 2020 that the number of people poisoned by fake marijuana edibles and candies has tripled. Counterfeit hash oil: Several school kids in Greater Manchester collapsed after vaping synthetic cannabinoids mis-sold as THC vape. Counterfeit hashish: In 2020 counterfeit hashish were found to contain 4F-MDMB-BINACA and 5F-MDMB-PINACA (5F-ADB). Less common psychoactive substances used to adulterate cannabis: Erectile dysfunction drugs: In the Netherlands two chemical analogs of sildenafil (Viagra) were found in adulterated marijuana. Methamphetamine: psychiatrist Dr Bill MacEwan believes that drug dealers in British Columbia are intentionally lacing cannabis with methamphetamine to make it more addictive. He had some psychiatric patients that claimed they only smoked pot but their drug tests were positive for methamphetamine use. PCP: Rarely, cannabis (especially that of low quality) is laced with PCP, particularly in the United States. However, it is not always done surreptitiously. Dealers who do so often (but not always) advertise their wares as being "enhanced" with other substances, and charge more money than they would otherwise, even if they do not say exactly what the lacing agents are. Such concoctions are often called "fry", "wet", "illy", "sherm", "water-water", "dust(ed)", "super weed", "grecodine" or other names. Weight cutting agents: Binding substances: Sometimes cannabis is adulterated with other binding substances including industrial glues such as neoprene, tar, ammonia, bitumen, petroleum-derived hydrocarbons, dog food or even human or animal excrement. to make it cheaper, thus being of poorer quality. Sand, sugar, brix fertilizers, hair spray, fertilizers, pesticides and fungicides. Microscopic glass beads: Cannabis buds was found to be contaminated with glass beads in 2007, known as gris weed. Lead: In 2008, 30 German teenagers were hospitalized after the marijuana which they smoked was found to have been contaminated with lead, which was added in order to increase its weight. Shoe polish: Hash has been cut with shoe polish. Vitamin E acetate: Although harmless when used orally, high levels of the substance cause vaping-associated pulmonary injury when inhaled. ===== Ecstasy ===== Black market ecstasy pills are frequently found to contain other drugs in place of or in addition to methylenedioxymethylamphetamine (MDMA). Since the slang term "ecstasy" usually refers only to MDMA, any pill which contains other compounds may be considered adulterated. 3,4-Methylenedioxyamphetamine (MDA), methylenedioxyethamphetamine (MDEA), amphetamine, methylamphetamine, benzylpiperazine (BZP), trifluoromethylphenylpiperazine (TFMPP), caffeine, ephedrine, pseudoephedrine, and dextromethorphan (DXM) are all commonly found in pills being sold as ecstasy. Less common drugs in ecstasy include diphenhydramine, acetaminophen, 5-MeO-DiPT, 2C-B, procaine, and phencyclidine (PCP). Ecstasy pills sometimes contain dimethylamylamine to increase its stimulant effects. Ecstasy pills might also contain a low dose of 2C-I to potentiate its euphoric effects. Pharmaceutical pills are sometimes sold as ecstasy, as well as pills that contain no psychoactive chemicals at all. Ecstasy sometimes contains 10 mg to 20 mg of baclofen to reduce overheating caused by ecstasy. para-Methoxyamphetamine (PMA or "Dr. Death", a drug that causes so much overheating that it can kill within 40 minutes) is sometimes sold as ecstasy. There is one published case of an ecstasy tablet being adulterated with 8 mg of strychnine, a toxic alkaloid which was used in very low doses (less than 1 mg) as a stimulant and performance-enhancing drug in the past. Recently, several groups advocating for drug safety through education have made reagent testing products available to confirm what substances there are. ===== LSD ===== LSD is virtually never laced with other chemicals, but other lysergamides such as ALD-52 are sometimes sold as LSD-25. DOB, DOI, and other closely related drugs are sometimes sold as LSD. Several other highly potent hallucinogens such as Bromo-DragonFLY or 25I-NBOMe can be found in the form of blotters. LSD is also tasteless in normal dosages, so detection is only possible after ingestion or reagent testing. For these reasons, it is not uncommon to find blotters sold as LSD completely devoid of psychoactive substances. === Prescription medication === As the sources of prescription medication on the street are not verifiable through legitimate channels, misrepresentation of prescription medications is a common practice. == Deaths == === Case reports in commercial products === ==== Alcohol ==== In June 2022, the Dutch Food and Consumer Product Safety Authority warned that the 3-liter champagne bottle from Moët & Chandon Ice Impérial contained MDMA, killing a person in Germany. === Polydrug intoxication deaths === A drug called Voodoo that has gained popularity among Egyptian youth, intoxicated seventy-one individuals, and killed two, in 2017. The drug samples contained synthetic cannabinoids, amphetamine, tramadol, methadone, MDA, benzodiazepines, morphine derivatives, and penitrem A (a neurotoxin). == Testing == === Reagent testing === Reagent testing kits are available online and also sold at some head shops. These kits claim to be able to identify common adulterants in ecstasy. === Professional lab tests === There are services available for testing the contents of an ecstasy pill that can tell the user what chemicals are contained in the pill and at what ratio. The results are then posted on their website along with every other pill that they have tested. The tests are considered to be highly accurate. Their services were at one time free, but when they ran out of funding they had to charge a fee for every pill tested. == See also == Darknet market Date rape drug Drug checking Isopropylbenzylamine Pill testing Surrogate alcohol == References == == Further reading == Coomber, R. (1997) Vim in the Veins – Fantasy or Fact: The Adulteration of Illicit Drugs, Addiction Research, Vol 5, No. 3. pp. 195-212 Coomber, R. (1997) ‘Adulteration of Drugs: The Discovery of a Myth', Contemporary Drug Problems, Vol 24, No. 2. pp. 239-271	Wikipedia/Lacing_(drugs)
A hemeprotein (or haemprotein; also hemoprotein or haemoprotein), or heme protein, is a protein that contains a heme prosthetic group. They are a very large class of metalloproteins. The heme group confers functionality, which can include oxygen carrying, oxygen reduction, electron transfer, and other processes. Heme is bound to the protein either covalently or noncovalently or both. The heme consists of iron cation bound at the center of the conjugate base of the porphyrin, as well as other ligands attached to the "axial sites" of the iron. The porphyrin ring is a planar dianionic, tetradentate ligand. The iron is typically Fe2+ or Fe3+. One or two ligands are attached at the axial sites. The porphyrin ring has four nitrogen atoms that bind to the iron, leaving two other coordination positions of the iron available for bonding to the histidine of the protein and a divalent atom. Hemeproteins probably evolved to incorporate the iron atom contained within the protoporphyrin IX ring of heme into proteins. As it makes hemeproteins responsive to molecules that can bind divalent iron, this strategy has been maintained throughout evolution as it plays crucial physiological functions. The serum iron pool maintains iron in soluble form, making it more accessible for cells. Oxygen (O2), nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) bind to the iron atom in heme proteins. Once bound to the prosthetic heme groups, these molecules can modulate the activity/function of those hemeproteins, affording signal transduction. Therefore, when produced in biologic systems (cells), these gaseous molecules are referred to as gasotransmitters. Because of their diverse biological functions and widespread abundance, hemeproteins are among the most studied biomolecules. Data on heme protein structure and function has been aggregated into The Heme Protein Database (HPD), a secondary database to the Protein Data Bank. == Roles == Hemeproteins have diverse biological functions including oxygen transport, which is completed via hemeproteins including hemoglobin, hemocyanin, myoglobin, neuroglobin, cytoglobin, and leghemoglobin. Some hemeproteins—cytochrome P450s, cytochrome c oxidase, ligninases, catalase, and peroxidases—are enzymes. They often activate O2 for oxidation or hydroxylation. Hemeproteins also enable electron transfer as they form part of the electron transport chain. Cytochrome a, cytochrome b, and cytochrome c have such electron transfer functions. It is now known that cytochrome a and cytochrome a3 make up one protein and was deemed the name cytochrome aa3. The sensory system also relies on some hemeproteins including FixL, an oxygen sensor, CooA, a carbon monoxide sensor, and soluble guanylyl cyclase. == Hemoglobin and myoglobin == Hemoglobin and myoglobin are examples of hemeproteins that respectively transport and store of oxygen in mammals and in some fish. Hemoglobin is a quaternary protein that occurs in the red blood cell, whereas, myoglobin is a tertiary protein found in the muscle cells of mammals. Although they might differ in location and size, their function are similar. Being hemeproteins, they both contain a heme prosthetic group. His-F8 of the myoglobin, also known as the proximal histidine, is covalently bonded to the 5th coordination position of the iron. Oxygen interacts with the distal His by way of a hydrogen bond, not a covalent one. It binds to the 6th coordination position of the iron, His-E7 of the myoglobin binds to the oxygen that is now covalently bonded to the iron. The same is true for hemoglobin; however, being a protein with four subunits, hemoglobin contains four heme units in total, allowing four oxygen molecules in total to bind to the protein. Myoglobin and hemoglobin are globular proteins that serve to bind and deliver oxygen using a prosthetic group. These globins dramatically improve the concentration of molecular oxygen that can be carried in the biological fluids of vertebrates and some invertebrates. Differences occur in ligand binding and allosteric regulation. === Myoglobin === Myoglobin is found in vertebrate muscle cells and is a water-soluble globular protein. Muscle cells, when put into action, can quickly require a large amount of oxygen for respiration due to their energy requirements. Therefore, muscle cells use myoglobin to accelerate oxygen diffusion and act as localized oxygen reserves for times of intense respiration. Myoglobin also stores the required amount of oxygen and makes it available for the muscle cell mitochondria. === Hemoglobin === In vertebrates, hemoglobin is found in the cytosol of red blood cells. Hemoglobin is sometimes referred to as the oxygen transport protein, in order to contrast it with myoglobin, which is stationary. In vertebrates, oxygen is taken into the body by the tissues of the lungs, and passed to the red blood cells in the bloodstream where it's used in aerobic metabolic pathways. Oxygen is then distributed to all of the tissues in the body and offloaded from the red blood cells to respiring cells. The hemoglobin then picks up carbon dioxide to be returned to the lungs. Thus, hemoglobin binds and off-loads both oxygen and carbon dioxide at the appropriate tissues, serving to deliver the oxygen needed for cellular metabolism and removing the resulting waste product, CO2. === Neuroglobin === Found in neurons, neuroglobin is responsible for driving nitric oxide to promote neuron cell survival Neuroglobin is believed to increase the oxygen supply for neurons, sustaining ATP production, but they also function as storage proteins. === Peroxidases and catalases === Almost all human peroxidases are hemoproteins, except glutathione peroxidase. They use hydrogen peroxide as a substrate. Metalloenzymes catalyze reactions using peroxide as an oxidant. Catalases are hemoproteins responsible for the catalysis of converting hydrogen peroxide into water and oxygen. They are made up of 4 subunits, each subunit having a Fe3+ heme group. They have an average molecular weight of ~240,000 g/mol. Haloperoxidases involved in the innate immune system also contain a heme prosthetic group. === Electron transport chain and other redox catalysts === Cytochromes, cytochrome c oxidase, and coenzyme Q – cytochrome c reductase are heme-containing proteins or protein subunits embedded in the inner membrane of mitochondria which play an essential role in cellular respiration. Sulfite oxidase, a molybdenum-dependent cytochrome, oxidizes sulfite to sulfate. === Nitric oxide synthase === == Designed heme proteins == Due to the diverse functions of the heme molecule: as an electron transporter, an oxygen carrier, and as an enzyme cofactor, heme binding proteins have consistently attracted the attention of protein designers. Initial design attempts focused on α-helical heme binding proteins, in part, due to the relative simplicity of designing self-assembling helical bundles. Heme binding sites were designed inside the inter-helical hydrophobic grooves. Examples of such designs include: Helichrome Globin-1 Cy-AA-EK Peptides IIa/IId α2 Transmembrane helical designs Later design attempts focused on creating functional heme binding helical bundles, such as: Oxidoreductases Peroxidases Electron transport proteins Oxygen transport proteins Photosensitive proteins Design techniques have matured to such an extent that it is now possible to generate entire libraries of heme binding helical proteins. Recent design attempts have focused on creating all-beta heme binding proteins, whose novel topology is very rare in nature. Such designs include: Pincer-1 β-hairpin peptides β-sheet miniproteins Multi-stranded β-sheet peptides Some methodologies attempt to incorporate cofactors into the hemoproteins who typically endure harsh conditions. In order to incorporate a synthetic cofactor, what must first occur is the denaturing of the holoprotein to remove the heme. The apoprotein is then rebuilt with the cofactor. == References == == External links == Heme Protein Database Hemeproteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)	Wikipedia/Hemeprotein
Concomitant drugs are two or more drugs used or given at or almost at the same time (one after the other, on the same day, etc.). The term has two contextual uses: as used in medicine or as used in drug abuse. == Concomitant drugs in medicine == This designation is used when medicinal drugs are given either at the same time or almost at the same time. This is often the case in medicine. Chemotherapy for cancer applies is an example. The standard of care (sometimes also called the "gold standard") for the adjuvant treatment of stage III colon cancer is the FOLFOX chemotherapy protocol (used in Europe, Japan, Canada, and Australia) and respectively the FLOX chemotherapy protocol (used in the USA). These 2 chemotherapy protocols are very similar in principle. Both consist of 3 medicinal drugs: a) Leucovorin (= folinic acid = calcium folinate), b) 5-Fluorouracil (= 5-FU), and c) Oxaliplatin. Since these 3 medicinal drugs are "concomitant" to each other, such a constellation is called "concomitant drugs". Contrast imaging in medicine is another example. These are imaging procedures in medicine that are performed after giving the patient an iodinated contrast medium (e.g. different types of contrast X-rays, CTs, MRIs). It is well known that such iodinated contrast media can lead to acute allergies in some patients. They may also lead to kidney damage. If the patient is receiving a "concomitant" medicinal drug (prescribed to the patient by another physician), and the radiologist performing the imaging procedure is unaware of this, potentially harmful side-effects can occur and increase the risk of contrast medium-induced nephropathy (i.e. increase the risk of damage to the kidneys). In general, radiologists carefully ask their patients about other medicinal drugs they are "concomitantly" taking before the imaging procedure. Often, they monitor the kidney function and the hydration status of their patients during the imaging procedure, especially whenever a concomitant drug (that is harmful to the kidney) is being used. == Concomitant drugs in drug abuse == If a drug abuser ingests or misuses two or more drugs, either at the same time or almost at the same time, this is also called "concomitant drugs". Whether concomitant drug abuse leads to an increased number of deaths was scientifically analysed in Sheffield, UK. The researchers wanted to find out whether concomitant drug abuse (i.e. an opiate plus another drug of misuse) leads to an increased number of acute accidental opiate-related deaths. The authors showed that at least in the Sheffield area, intravenous (IV) administration of an opiate is the most consistent factor associated with drug abuse deaths. The co-administration of a concomitant drug of misuse appeared to be a feature rather than a risk factor per se in such deaths. == References ==	Wikipedia/Concomitant_drug
Open science is the movement to make scientific research (including publications, data, physical samples, and software) and its dissemination accessible to all levels of society, amateur or professional. Open science is transparent and accessible knowledge that is shared and developed through collaborative networks. It encompasses practices such as publishing open research, campaigning for open access, encouraging scientists to practice open-notebook science (such as openly sharing data and code), broader dissemination and engagement in science and generally making it easier to publish, access and communicate scientific knowledge. Usage of the term varies substantially across disciplines, with a notable prevalence in the STEM disciplines. Open research is often used quasi-synonymously to address the gap that the denotion of "science" might have regarding an inclusion of the Arts, Humanities and Social Sciences. The primary focus connecting all disciplines is the widespread uptake of new technologies and tools, and the underlying ecology of the production, dissemination and reception of knowledge from a research-based point-of-view. As Tennant et al. (2020) note, the term open science "implicitly seems only to regard ‘scientific’ disciplines, whereas open scholarship can be considered to include research from the Arts and Humanities, as well as the different roles and practices that researchers perform as educators and communicators, and an underlying open philosophy of sharing knowledge beyond research communities." Open science can be seen as a continuation of, rather than a revolution in, practices begun in the 17th century with the advent of the academic journal, when the societal demand for access to scientific knowledge reached a point at which it became necessary for groups of scientists to share resources with each other. In modern times there is debate about the extent to which scientific information should be shared. The conflict that led to the Open Science movement is between the desire of scientists to have access to shared resources versus the desire of individual entities to profit when other entities take part of their resources. Additionally, the status of open access and resources that are available for its promotion are likely to differ from one field of academic inquiry to another. == Principles == The six principles of open science are: Open methodology Open source Open data Open access Open peer review Open educational resources == Background == Science is broadly understood as collecting, analyzing, publishing, reanalyzing, criticizing, and reusing data. Proponents of open science identify a number of barriers that impede or dissuade the broad dissemination of scientific data. These include financial paywalls of for-profit research publishers, restrictions on usage applied by publishers of data, poor formatting of data or use of proprietary software that makes it difficult to re-purpose, and cultural reluctance to publish data for fears of losing control of how the information is used. According to the FOSTER taxonomy Open science can often include aspects of Open access, Open data and the open source movement whereby modern science requires software to process data and information. Open research computation also addresses the problem of reproducibility of scientific results. === Types === The term "open science" does not have any one fixed definition or operationalization. On the one hand, it has been referred to as a "puzzling phenomenon". On the other hand, the term has been used to encapsulate a series of principles that aim to foster scientific growth and its complementary access to the public. Two influential sociologists, Benedikt Fecher and Sascha Friesike, have created multiple "schools of thought" that describe the different interpretations of the term. According to Fecher and Friesike ‘Open Science’ is an umbrella term for various assumptions about the development and dissemination of knowledge. To show the term's multitudinous perceptions, they differentiate between five Open Science schools of thought: ==== Infrastructure School ==== The infrastructure school is founded on the assumption that "efficient" research depends on the availability of tools and applications. Therefore, the "goal" of the school is to promote the creation of openly available platforms, tools, and services for scientists. Hence, the infrastructure school is concerned with the technical infrastructure that promotes the development of emerging and developing research practices through the use of the internet, including the use of software and applications, in addition to conventional computing networks. In that sense, the infrastructure school regards open science as a technological challenge. The infrastructure school is tied closely with the notion of "cyberscience", which describes the trend of applying information and communication technologies to scientific research, which has led to an amicable development of the infrastructure school. Specific elements of this prosperity include increasing collaboration and interaction between scientists, as well as the development of "open-source science" practices. The sociologists discuss two central trends in the infrastructure school: 1. Distributed computing: This trend encapsulates practices that outsource complex, process-heavy scientific computing to a network of volunteer computers around the world. The examples that the sociologists cite in their paper is that of the Open Science Grid, which enables the development of large-scale projects that require high-volume data management and processing, which is accomplished through a distributed computer network. Moreover, the grid provides the necessary tools that the scientists can use to facilitate this process. 2. Social and Collaboration Networks of Scientists: This trend encapsulates the development of software that makes interaction with other researchers and scientific collaborations much easier than traditional, non-digital practices. Specifically, the trend is focused on implementing newer Web 2.0 tools to facilitate research related activities on the internet. De Roure and colleagues (2008) list a series of four key capabilities which they believe define a Social Virtual Research Environment (SVRE): The SVRE should primarily aid the management and sharing of research objects. The authors define these to be a variety of digital commodities that are used repeatedly by researchers. Second, the SVRE should have inbuilt incentives for researchers to make their research objects available on the online platform. Third, the SVRE should be "open" as well as "extensible", implying that different types of digital artifacts composing the SVRE can be easily integrated. Fourth, the authors propose that the SVRE is more than a simple storage tool for research information. Instead, the researchers propose that the platform should be "actionable". That is, the platform should be built in such a way that research objects can be used in the conduct of research as opposed to simply being stored. ==== Measurement school ==== The measurement school, in the view of the authors, deals with developing alternative methods to determine scientific impact. This school acknowledges that measurements of scientific impact are crucial to a researcher's reputation, funding opportunities, and career development. Hence, the authors argue, that any discourse about Open Science is pivoted around developing a robust measure of scientific impact in the digital age. The authors then discuss other research indicating support for the measurement school. The three key currents of previous literature discussed by the authors are: The peer-review is described as being time-consuming. The impact of an article, tied to the name of the authors of the article, is related more to the circulation of the journal rather than the overall quality of the article itself. New publishing formats that are closely aligned with the philosophy of Open Science are rarely found in the format of a journal that allows for the assignment of the impact factor. Hence, this school argues that there are faster impact measurement technologies that can account for a range of publication types as well as social media web coverage of a scientific contribution to arrive at a complete evaluation of how impactful the science contribution was. The gist of the argument for this school is that hidden uses like reading, bookmarking, sharing, discussing and rating are traceable activities, and these traces can and should be used to develop a newer measure of scientific impact. The umbrella jargon for this new type of impact measurements is called altmetrics, coined in a 2011 article by Priem et al., (2011). Markedly, the authors discuss evidence that altmetrics differ from traditional webometrics which are slow and unstructured. Altmetrics are proposed to rely upon a greater set of measures that account for tweets, blogs, discussions, and bookmarks. The authors claim that the existing literature has often proposed that altmetrics should also encapsulate the scientific process, and measure the process of research and collaboration to create an overall metric. However, the authors are explicit in their assessment that few papers offer methodological details as to how to accomplish this. The authors use this and the general dearth of evidence to conclude that research in the area of altmetrics is still in its infancy. ==== Public School ==== According to the authors, the central concern of the school is to make science accessible to a wider audience. The inherent assumption of this school, as described by the authors, is that the newer communication technologies such as Web 2.0 allow scientists to open up the research process and also allow scientist to better prepare their "products of research" for interested non-experts. Hence, the school is characterized by two broad streams: one argues for the access of the research process to the masses, whereas the other argues for increased access to the scientific product to the public. Accessibility to the Research Process: Communication technology allows not only for the constant documentation of research but also promotes the inclusion of many different external individuals in the process itself. The authors cite citizen science – the participation of non-scientists and amateurs in research. The authors discuss instances in which gaming tools allow scientists to harness the brain power of a volunteer workforce to run through several permutations of protein-folded structures. This allows for scientists to eliminate many more plausible protein structures while also "enriching" the citizens about science. The authors also discuss a common criticism of this approach: the amateur nature of the participants threatens to pervade the scientific rigor of experimentation. Comprehensibility of the Research Result: This stream of research concerns itself with making research understandable for a wider audience. The authors describe a host of authors that promote the use of specific tools for scientific communication, such as microblogging services, to direct users to relevant literature. The authors claim that this school proposes that it is the obligation of every researcher to make their research accessible to the public. The authors then proceed to discuss if there is an emerging market for brokers and mediators of knowledge that is otherwise too complicated for the public to grasp. ==== Democratic school ==== The democratic school concerns itself with the concept of access to knowledge. As opposed to focusing on the accessibility of research and its understandability, advocates of this school focus on the access of products of research to the public. The central concern of the school is with the legal and other obstacles that hinder the access of research publications and scientific data to the public. Proponents assert that any research product should be freely available. and that everyone has the same, equal right of access to knowledge, especially in the instances of state-funded experiments and data. Two central currents characterize this school: Open Access and Open Data. Open Data: Opposition to the notion that publishing journals should claim copyright over experimental data, which prevents the re-use of data and therefore lowers the overall efficiency of science in general. The claim is that journals have no use of the experimental data and that allowing other researchers to use this data will be fruitful. Only a quarter of researchers agree to share their data with other researchers because of the effort required for compliance. Open Access to Research Publication: According to this school, there is a gap between the creation and sharing of knowledge. Proponents argue that even though scientific knowledge doubles every 5 years, access to this knowledge remains limited. These proponents consider access to knowledge as a necessity for human development, especially in the economic sense. ==== Pragmatic School ==== The pragmatic school considers Open Science as the possibility to make knowledge creation and dissemination more efficient by increasing the collaboration throughout the research process. Proponents argue that science could be optimized by modularizing the process and opening up the scientific value chain. 'Open' in this sense follows very much the concept of open innovation. Take for instance transfers the outside-in (including external knowledge in the production process) and inside-out (spillovers from the formerly closed production process) principles to science. Web 2.0 is considered a set of helpful tools that can foster collaboration (sometimes also referred to as Science 2.0). Further, citizen science is seen as a form of collaboration that includes knowledge and information from non-scientists. Fecher and Friesike describe data sharing as an example of the pragmatic school as it enables researchers to use other researchers' data to pursue new research questions or to conduct data-driven replications. == History == The widespread adoption of the institution of the scientific journal marks the beginning of the modern concept of open science. Before this time societies pressured scientists into secretive behaviors. === Before journals === Before the advent of scientific journals, scientists had little to gain and much to lose by publicizing scientific discoveries. Many scientists, including Galileo, Kepler, Isaac Newton, Christiaan Huygens, and Robert Hooke, made claim to their discoveries by describing them in papers coded in anagrams or cyphers and then distributing the coded text. Their intent was to develop their discovery into something off which they could profit, then reveal their discovery to prove ownership when they were prepared to make a claim on it. The system of not publicizing discoveries caused problems because discoveries were not shared quickly and because it sometimes was difficult for the discoverer to prove priority. Newton and Gottfried Leibniz both claimed priority in discovering calculus. Newton said that he wrote about calculus in the 1660s and 1670s, but did not publish until 1693. Leibniz published "Nova Methodus pro Maximis et Minimis", a treatise on calculus, in 1684. Debates over priority are inherent in systems where science is not published openly, and this was problematic for scientists who wanted to benefit from priority. These cases are representative of a system of aristocratic patronage in which scientists received funding to develop either immediately useful things or to entertain. In this sense, funding of science gave prestige to the patron in the same way that funding of artists, writers, architects, and philosophers did. Because of this, scientists were under pressure to satisfy the desires of their patrons, and discouraged from being open with research which would bring prestige to persons other than their patrons. === Emergence of academies and journals === Eventually the individual patronage system ceased to provide the scientific output which society began to demand. Single patrons could not sufficiently fund scientists, who had unstable careers and needed consistent funding. The development which changed this was a trend to pool research by multiple scientists into an academy funded by multiple patrons. In 1660 England established the Royal Society and in 1666 the French established the French Academy of Sciences. Between the 1660s and 1793, governments gave official recognition to 70 other scientific organizations modeled after those two academies. In 1665, Henry Oldenburg became the editor of Philosophical Transactions of the Royal Society, the first academic journal devoted to science, and the foundation for the growth of scientific publishing. By 1699 there were 30 scientific journals; by 1790 there were 1052. Since then publishing has expanded at even greater rates. === Popular Science Writing === The first popular science periodical of its kind was published in 1872, under a suggestive name that is still a modern portal for the offering science journalism: Popular Science. The magazine claims to have documented the invention of the telephone, the phonograph, the electric light and the onset of automobile technology. The magazine goes so far as to claim that the "history of Popular Science is a true reflection of humankind's progress over the past 129+ years". Discussions of popular science writing most often contend their arguments around some type of "Science Boom". A recent historiographic account of popular science traces mentions of the term "science boom" to Daniel Greenberg's Science and Government Reports in 1979 which posited that "Scientific magazines are bursting out all over. Similarly, this account discusses the publication Time, and its cover story of Carl Sagan in 1980 as propagating the claim that popular science has "turned into enthusiasm". Crucially, this secondary account asks the important question as to what was considered as popular "science" to begin with. The paper claims that any account of how popular science writing bridged the gap between the informed masses and the expert scientists must first consider who was considered a scientist to begin with. === Collaboration among academies === In modern times many academies have pressured researchers at publicly funded universities and research institutions to engage in a mix of sharing research and making some technological developments proprietary. Some research products have the potential to generate commercial revenue, and in hope of capitalizing on these products, many research institutions withhold information and technology which otherwise would lead to overall scientific advancement if other research institutions had access to these resources. It is difficult to predict the potential payouts of technology or to assess the costs of withholding it, but there is general agreement that the benefit to any single institution of holding technology is not as great as the cost of withholding it from all other research institutions. === Coining of term "Open Science" === Steve Mann claimed to have coined the term "Open Science" in 1998. He also registered the domain names openscience.com and openscience.org in 1998, which he sold to degruyter.com in 2011. The term was previously used in a manner that refers to today's 'open science' norms by Daryl E. Chubin in his 1985 essay "Open Science and Closed Science: Tradeoffs in a Democracy". Chubin's essay cited Robert K. Merton's 1942 proposal of what we now refer to as Mertonian Norms for ideal science practices and scientific modes of communication. The term was used sporadically in the 1970s and 1980s in various scholarship to refer to different things. === Internet and the free access to scientific documents === The open science movement, as presented in activist and institutional discourses at the beginning of the 21st century, refers to different ways of opening up science, especially in the Internet age. Its first pillar is free access to scientific publications. The Budapest conference organised by the Open Society Foundations in 2001 was decisive in imposing this issue on the political landscape. The resulting declaration calls for the use of digital tools such as open archives and open access journals, free of charge for the reader. The idea of open access to scientific publications quickly became inseparable from the question of free licenses to guarantee the right to disseminate and possibly modify shared documents, such as the Creative Commons licenses, created in 2002. In 2011, a new text from the Budapest Open Initiative explicitly refers to the relevance of the CC-BY license to guarantee free dissemination and not only free access to a scientific document. The openness promise by the Internet is then extended to research data, which underpins scientific studies in different disciplines, as mentioned already in the Berlin Declaration in 2003. In 2007, the Organisation for Economic Co-operation and Development (OECD) published a report on access to publicly funded research data, in which it defined it as the data that validates research results. Beyond its democratic virtues, open science aims to respond to the replication crisis of research results, notably through the generalization of the opening of data or source code used to produce them or through the dissemination of methodological articles. The open science movement inspired several regulatory and legislative measures. Thus, in 2007, the University of Liège made the deposit of its researchers’ publications in its institutional open repository (Orbi) compulsory. The next year, the NIH Public Access Policy adopted a similar mandate for every paper funded by the National Institutes of Health. In France, the law for a digital Republic enacted in 2016 creates the right to deposit the validated manuscript of a scientific article in an open archive, with an embargo period following the date of publication in the journal. The law also creates the principle of reuse of public data by default. == Politics == In many countries, governments fund some science research. Scientists often publish the results of their research by writing articles and donating them to be published in scholarly journals, which frequently are commercial. Public entities such as universities and libraries subscribe to these journals. Michael Eisen, a founder of the Public Library of Science, has described this system by saying that "taxpayers who already paid for the research would have to pay again to read the results." In December 2011, some United States legislators introduced a bill called the Research Works Act, which would prohibit federal agencies from issuing grants with any provision requiring that articles reporting on taxpayer-funded research be published for free to the public online. Darrell Issa, a co-sponsor of the bill, explained the bill by saying that "Publicly funded research is and must continue to be absolutely available to the public. We must also protect the value added to publicly funded research by the private sector and ensure that there is still an active commercial and non-profit research community." One response to this bill was protests from various researchers; among them was a boycott of commercial publisher Elsevier called The Cost of Knowledge. The Dutch Presidency of the Council of the European Union called out for action in April 2016 to migrate European Commission funded research to Open Science. European Commissioner Carlos Moedas introduced the Open Science Cloud at the Open Science Conference in Amsterdam on 4–5 April. During this meeting also The Amsterdam Call for Action on Open Science was presented, a living document outlining concrete actions for the European Community to move to Open Science. The European Commission continues to be committed to an Open Science policy including developing a repository for research digital objects, European Open Science Cloud (EOSC) and metrics for evaluating quality and impact. In October 2021, the French Ministry of Higher Education, Research and Innovation released an official translation of its second plan for open science spanning the years 2021–2024. === Standard setting instruments === There is currently no global normative framework covering all aspects of Open Science. In November 2019, UNESCO was tasked by its 193 Member States, during their 40th General Conference, with leading a global dialogue on Open Science to identify globally-agreed norms and to create a standard-setting instrument. The multistakeholder, consultative, inclusive and participatory process to define a new global normative instrument on Open Science is expected to take two years and to lead to the adoption of a UNESCO Recommendation on Open Science by Member States in 2021. Two UN frameworks set out some common global standards for application of Open Science and closely related concepts: the UNESCO Recommendation on Science and Scientific Researchers, approved by the General Conference at its 39th session in 2017, and the UNESCO Strategy on Open Access to scientific information and research, approved by the General Conference at its 36th session in 2011. == Open Science and Research Assessment == A central aspect of the Open Science movement is the reform of research assessment. Initiatives such as the Coalition for Advancing Research Assessment (CoARA) and the San Francisco Declaration on Research Assessment (DORA) advocate moving away from traditional quantitative metrics like the Journal Impact Factor (JIF) and the h-Index, as these often exhibit biases and neglect qualitative aspects. Instead, alternative metrics and indicators, such as altmetrics and Open Science indicators, are to be given greater consideration. Open Science indicators include metrics such as the number of open access publications, data management plans, preprints, FAIR-licensed data, and open peer review reports. These approaches aim to promote the transparency and reusability of scientific outcomes, thereby enabling a fairer and more comprehensive evaluation of scientific achievements.While Open Science aims to enhance transparency, accessibility, and collaboration, the introduction of numerous new metrics to measure openness has led to unintended consequences. These metrics often rely on quantitative indicators, which conflict with the holistic and qualitative approaches advocated by initiatives such as CoARA and DORA. The core issue is that these metrics are designed not only to measure but also to influence researchers' behavior. This can result in "metric-driven" practices that undermine research quality. Additionally, Open Science metrics lack standardization and clarity regarding what they truly aim to measure. The risk is that while these metrics may incentivize openness, they could simultaneously distort the overall fairness and effectiveness of research assessment. == Advantages and disadvantages == Arguments in favor of open science generally focus on the value of increased transparency in research, and in the public ownership of science, particularly that which is publicly funded. In January 2014 J. Christopher Bare published a comprehensive "Guide to Open Science". Likewise, in 2017, a group of scholars known for advocating open science published a "manifesto" for open science in the journal Nature. === Advantages === Open access publication of research reports and data allows for rigorous peer-review An article published by a team of NASA astrobiologists in 2010 in Science reported a bacterium known as GFAJ-1 that could purportedly metabolize arsenic (unlike any previously known species of lifeform). This finding, along with NASA's claim that the paper "will impact the search for evidence of extraterrestrial life", met with criticism within the scientific community. Much of the scientific commentary and critique around this issue took place in public forums, most notably on Twitter, where hundreds of scientists and non-scientists created a hashtag community around the hashtag #arseniclife. University of British Columbia astrobiologist Rosie Redfield, one of the most vocal critics of the NASA team's research, also submitted a draft of a research report of a study that she and colleagues conducted which contradicted the NASA team's findings; the draft report appeared in arXiv, an open-research repository, and Redfield called in her lab's research blog for peer review both of their research and of the NASA team's original paper. Researcher Jeff Rouder defined Open Science as "endeavoring to preserve the rights of others to reach independent conclusions about your data and work". Publicly funded science will be publicly available Public funding of research has long been cited as one of the primary reasons for providing Open Access to research articles. Since there is significant value in other parts of the research such as code, data, protocols, and research proposals a similar argument is made that since these are publicly funded, they should be publicly available under a Creative Commons Licence. Open science will make science more reproducible and transparent Increasingly the reproducibility of science is being questioned and for many papers or multiple fields of research was shown to be lacking. This problem has been described as a "reproducibility crisis". For example, psychologist Stuart Vyse notes that "(r)ecent research aimed at previously published psychology studies has demonstrated – shockingly – that a large number of classic phenomena cannot be reproduced, and the popularity of p-hacking is thought to be one of the culprits." Open Science approaches are proposed as one way to help increase the reproducibility of work as well as to help mitigate against manipulation of data. Open science has more impact There are several components to impact in research, many of which are hotly debated. However, under traditional scientific metrics parts Open science such as Open Access and Open Data have proved to outperform traditional versions. Open Science can provide learning opportunities Open science needs to acknowledge and accommodate the heterogeneity of science. It provides an opportunities for different communities to learn from other communities, as well as to inform learning and practice across fields. For example preregistration in quantitative sciences can benefit qualitative researchers to reduce researcher degrees of freedom, whereas positionality statements have been used to contextual researcher and research environment in qualitative can be used in order to combat reproducibility crisis in quantitative research. In addition, journals should be open to publishing these behaviours, using a guide to ease journal editors into open science. Open science will help answer uniquely complex questions Recent arguments in favor of Open Science have maintained that Open Science is a necessary tool to begin answering immensely complex questions, such as the neural basis of consciousness, ecosystem services or pandemics such as the COVID-19 pandemic. The typical argument propagates the fact that these type of investigations are too complex to be carried out by any one individual, and therefore, they must rely on a network of open scientists to be accomplished. By default, the nature of these investigations also makes this "open science" as "big science". It is thought that open science could support innovation and societal benefits, supporting and reinforcing research activities by enabling digital resources that could, for example, use or provide structured open data. === Disadvantages === Arguments against open science tend to focus on the advantages of data ownership and concerns about the misuse of data, but see Potential misuse In 2011, Dutch researchers announced their intention to publish a research paper in the journal Science describing the creation of a strain of H5N1 influenza which can be easily passed between ferrets, the mammals which most closely mimic the human response to the flu. The announcement triggered a controversy in both political and scientific circles about the ethical implications of publishing scientific data which could be used to create biological weapons. These events are examples of how science data could potentially be misused. It has been argued that constraining the dissemination of dual-use knowledge can in certain cases be justified because, for example, "scientists have a responsibility for potentially harmful consequences of their research; the public need not always know of all scientific discoveries [or all its details]; uncertainty about the risks of harm may warrant precaution; and expected benefits do not always outweigh potential harm". Scientists have collaboratively agreed to limit their own fields of inquiry on occasions such as the Asilomar conference on recombinant DNA in 1975,: 111 and a proposed 2015 worldwide moratorium on a human-genome-editing technique. Differential technological development aims to decrease risks by influencing the sequence in which technologies are developed. Relying only on the established form of legislation and incentives to ensure the right outcomes may not be adequate as these may often be too slow. The public may misunderstand science data In 2009 NASA launched the Kepler spacecraft and promised that they would release collected data in June 2010. Later they decided to postpone release so that their scientists could look at it first. Their rationale was that non-scientists might unintentionally misinterpret the data, and NASA scientists thought it would be preferable for them to be familiar with the data in advance so that they could report on it with their level of accuracy. Low-quality science Post-publication peer review, a staple of open science, has been criticized as promoting the production of lower quality papers that are extremely voluminous. Specifically, critics assert that as quality is not guaranteed by preprint servers, the veracity of papers will be difficult to assess by individual readers. This will lead to rippling effects of false science, akin to the recent epidemic of false news, propagated with ease on social media websites. Common solutions to this problem have been cited as adaptations of a new format in which everything is allowed to be published but a subsequent filter-curator model is imposed to ensure some basic quality of standards are met by all publications. Entrapment by platform capitalism For Philip Mirowski open science runs the risk of continuing a trend of commodification of science which ultimately serves the interests of capital in the guise of platform capitalism. WEIRD-focus Open Science is primarily driven by Western, Educated, Industrialized, Rich and Democratic (WEIRD) society that it is challenging for people from the Global South to implement or follow these changes for Open Science. As a result, it perpetuates inequalities found across cultures. However, journal editors have taken note of guidelines for change (e.g.) in order to make sure Open Science is more inclusive with a focus of multi-site studies and value of diversity within Open Science discussion. == Actions and initiatives == === Open-science projects === Different projects conduct, advocate, develop tools for, or fund open science. The Allen Institute for Brain Science conducts numerous open science projects while the Center for Open Science has projects to conduct, advocate, and create tools for open science. Other workgroups have been created in different fields, such as the Decision Analysis in R for Technologies in Health (DARTH) workgroup], which is a multi-institutional, multi-university collaborative effort by researchers who have a common goal to develop transparent and open-source solutions to decision analysis in health. Organizations have extremely diverse sizes and structures. The Open Knowledge Foundation (OKF) is a global organization sharing large data catalogs, running face to face conferences, and supporting open source software projects. In contrast, Blue Obelisk is an informal group of chemists and associated cheminformatics projects. The tableau of organizations is dynamic with some organizations becoming defunct, e.g., Science Commons, and new organizations trying to grow, e.g., the Self-Journal of Science. Common organizing forces include the knowledge domain, type of service provided, and even geography, e.g., OCSDNet's concentration on the developing world. The Allen Brain Atlas maps gene expression in human and mouse brains; the Encyclopedia of Life documents all the terrestrial species; the Galaxy Zoo classifies galaxies; the International HapMap Project maps the haplotypes of the human genome; the Monarch Initiative makes available integrated public model organism and clinical data; and the Sloan Digital Sky Survey which regularizes and publishes data sets from many sources. All these projects accrete information provided by many different researchers with different standards of curation and contribution. Mathematician Timothy Gowers launched open science journal Discrete Analysis in 2016 to demonstrate that a high-quality mathematics journal could be produced outside the traditional academic publishing industry. The launch followed a boycott of scientific journals that he initiated. The journal is published by a nonprofit which is owned and published by a team of scholars. Other projects are organized around completion of projects that require extensive collaboration. For example, OpenWorm seeks to make a cellular level simulation of a roundworm, a multidisciplinary project. The Polymath Project seeks to solve difficult mathematical problems by enabling faster communications within the discipline of mathematics. The Collaborative Replications and Education project recruits undergraduate students as citizen scientists by offering funding. Each project defines its needs for contributors and collaboration. Another practical example for open science project was the first "open" doctoral thesis started in 2012. It was made publicly available as a self-experiment right from the start to examine whether this dissemination is even possible during the productive stage of scientific studies. The goal of the dissertation project: Publish everything related to the doctoral study and research process as soon as possible, as comprehensive as possible and under an open license, online available at all time for everyone. End of 2017, the experiment was successfully completed and published in early 2018 as an open access book. An example promoting accessibility of open-source code for research papers is CatalyzeX, which finds and links both official implementations by authors and source code independently replicated by other researchers. These code implementations are also surfaced on the preprint server arXiv and open peer-review platform OpenReview. The ideas of open science have also been applied to recruitment with jobRxiv, a free and international job board that aims to mitigate imbalances in what different labs can afford to spend on hiring. === Advocacy === Numerous documents, organizations, and social movements advocate wider adoption of open science. Statements of principles include the Budapest Open Access Initiative from a December 2001 conference and the Panton Principles. New statements are constantly developed, such as the Amsterdam Call for Action on Open Science to be presented to the Dutch Presidency of the Council of the European Union in late May 2016. These statements often try to regularize licenses and disclosure for data and scientific literature. Other advocates concentrate on educating scientists about appropriate open science software tools. Education is available as training seminars, e.g., the Software Carpentry project; as domain specific training materials, e.g., the Data Carpentry project; and as materials for teaching graduate classes, e.g., the Open Science Training Initiative. Many organizations also provide education in the general principles of open science. Within scholarly societies there are also sections and interest groups that promote open science practices. The Ecological Society of America has an Open Science Section. Similarly, the Society for American Archaeology has an Open Science Interest Group. === Journal support === Many individual journals are experimenting with the open access model: the Public Library of Science, or PLOS, is creating a library of open access journals and scientific literature. Other publishing experiments include delayed and hybrid models. There are experiments in different fields: F1000Research provides open publishing and open peer review for the life sciences. The Open Library of Humanities is a non-profit open access publisher for the humanities and social sciences. The Journals Library of the National Institute for Health and Care Research (NIHR) publishes all relevant documents and data from the onset of research projects, updating them alongside the progress of the study. Journal support for open-science does not conflict with preprint servers: figshare archives and shares images, readings, and other data; and Open Science Framework preprints, arXiv, and HAL Archives Ouvertes provide electronic preprints across many fields. === Software === A variety of computer resources support open science. These include software like the Open Science Framework from the Center for Open Science to manage project information, data archiving and team coordination; distributed computing services like Ibercivis to use unused CPU time for computationally intensive tasks; and services like Experiment.com to provide crowdsourced funding for research projects. Blockchain platforms for open science have been proposed. The first such platform is the Open Science Organization, which aims to solve urgent problems with fragmentation of the scientific ecosystem and difficulties of producing validated, quality science. Among the initiatives of Open Science Organization include the Interplanetary Idea System (IPIS), Researcher Index (RR-index), Unique Researcher Identity (URI), and Research Network. The Interplanetary Idea System is a blockchain based system that tracks the evolution of scientific ideas over time. It serves to quantify ideas based on uniqueness and importance, thus allowing the scientific community to identify pain points with current scientific topics and preventing unnecessary re-invention of previously conducted science. The Researcher Index aims to establish a data-driven statistical metric for quantifying researcher impact. The Unique Researcher Identity is a blockchain technology based solution for creating a single unifying identity for each researcher, which is connected to the researcher's profile, research activities, and publications. The Research Network is a social networking platform for researchers. A scientific paper from November 2019 examined the suitability of blockchain technology to support open science. === Preprint servers === Preprint Servers come in many varieties, but the standard traits across them are stable: they seek to create a quick, free mode of communicating scientific knowledge to the public. Preprint servers act as a venue to quickly disseminate research and vary on their policies concerning when articles may be submitted relative to journal acceptance. Also typical of preprint servers is their lack of a peer-review process – typically, preprint servers have some type of quality check in place to ensure a minimum standard of publication, but this mechanism is not the same as a peer-review mechanism. Some preprint servers have explicitly partnered with the broader open science movement. Preprint servers can offer service similar to those of journals, and Google Scholar indexes many preprint servers and collects information about citations to preprints. The case for preprint servers is often made based on the slow pace of conventional publication formats. The motivation to start SocArXiv, an open-access preprint server for social science research, is the claim that valuable research being published in traditional venues often takes several months to years to get published, which slows down the process of science significantly. Another argument made in favor of preprint servers like SocArXiv is the quality and quickness of feedback offered to scientists on their pre-published work. The founders of SocArXiv claim that their platform allows researchers to gain easy feedback from their colleagues on the platform, thereby allowing scientists to develop their work into the highest possible quality before formal publication and circulation. The founders of SocArXiv further claim that their platform affords the authors the greatest level of flexibility in updating and editing their work to ensure that the latest version is available for rapid dissemination. The founders claim that this is not traditionally the case with formal journals, which instate formal procedures to make updates to published articles. Perhaps the strongest advantage of some preprint servers is their seamless compatibility with Open Science software such as the Open Science Framework. The founders of SocArXiv claim that their preprint server connects all aspects of the research life cycle in OSF with the article being published on the preprint server. According to the founders, this allows for greater transparency and minimal work on the authors' part. One criticism of pre-print servers is their potential to foster a culture of plagiarism. For example, the popular physics preprint server ArXiv had to withdraw 22 papers when it came to light that they were plagiarized. In June 2002, a high-energy physicist in Japan was contacted by a man called Ramy Naboulsi, a non-institutionally affiliated mathematical physicist. Naboulsi requested Watanabe to upload his papers on ArXiv as he was not able to do so, because of his lack of an institutional affiliation. Later, the papers were realized to have been copied from the proceedings of a physics conference. Preprint servers are increasingly developing measures to circumvent this plagiarism problem. In developing nations like India and China, explicit measures are being taken to combat it. These measures usually involve creating some type of central repository for all available pre-prints, allowing the use of traditional plagiarism detecting algorithms to detect the fraud. Nonetheless, this is a pressing issue in the discussion of pre-print servers, and consequently for open science. == See also == == References == == Sources == Belhajjame, Khalid; et al. (2014). "The Research Object Suite of Ontologies: Sharing and Exchanging Research Data and Methods on the Open Web". arXiv:1401.4307 [cs.DL]. Nielsen, Michael (2011). Reinventing Discovery: The New Era of Networked Science. Princeton, NJ: Princeton University Press. ISBN 978-0691148908. Groen, Frances K. (2007). Access to medical knowledge : libraries, digitization, and the public good. Lanham, Mar.: Scarecrow Press. ISBN 978-0810852723. Kronick, David A. (1976). A history of scientific & technical periodicals : the origins and development of the scientific and technical press, 1665–1790 (2d ed.). Metuchen, NJ: Scarecrow Press. ISBN 978-0810808447. Price, Derek J. de Solla (1986). Little science, big science – and beyond (2nd ed.). New York: Columbia University Press. ISBN 978-0231049566. Suber, Peter (2012). Open access (The MIT Press Essential Knowledge Series ed.). Cambridge, MA: MIT Press. ISBN 978-0262517638. Retrieved 28 July 2016. == External links == TED talk video by Michael Nielsen on open science Cracking Open the Scientific Process	Wikipedia/Open-science
Churn rate (also known as attrition rate, turnover, customer turnover, or customer defection) is a measure of the proportion of individuals or items moving out of a group over a specific period. It is one of two primary factors that determine the steady-state level of customers a business will support. Churn is widely applied in business for contractual customer bases. Examples include a subscriber-based service model as used by mobile telephone networks and pay TV operators. Churn rate can also be the input into customer lifetime value modeling and used to measure return on marketing investment with marketing mix modeling. The term comes from the image of agitation of cream in a butter churn. == Calculation == Churn rate is calculated by dividing the total number of individuals, customers, or items lost during a period divided by total number of individuals during the same period. Churn = L T ∗ 100 = Customers lost Total customers during time period ∗ 100 {\displaystyle {\text{Churn}}={\frac {L}{T}}100={\frac {\text{Customers lost}}{\text{Total customers during time period}}}100} For example, if your company lost 50 customers in month, while having a total of 500 customers at the start of the month, the total churn rate is 10% (50/500*100 = 10%). An alternative calculation for churn is to divide by the number of customers acquired during the same time period, rather than total number of customers. == Customer base churn == Churn rate, when applied to a customer base, is the proportion of contractual customers or subscribers who leave a supplier during a given period. It may indicate customer dissatisfaction, cheaper and/or better offers from the competition, more successful sales and/or marketing by the competition, or reasons having to do with the customer life cycle. Churn is closely related to the concept of average customer life time. For example, an annual churn rate of 25 percent implies an average customer life of four years. An annual churn rate of 33 percent implies an average customer life of three years. The churn rate can be minimized by creating barriers which discourage customers to change suppliers (contractual binding periods, use of proprietary technology, value-added services, unique business models, etc.), or through retention activities such as loyalty programs. It is possible to overstate the churn rate, as when a consumer drops the service but then restarts it within the same year. Thus, a clear distinction needs to be made between "gross churn", the total number of absolute disconnections, and "net churn", the overall loss of subscribers or members. The difference between the two measures is the number of new subscribers or members that have joined during the same period. Suppliers may find that if they offer a loss-leader "introductory special", it can lead to a higher churn rate and subscriber abuse, as some subscribers will sign on, let the service lapse, then sign on again to take continuous advantage of current specials. When talking about subscribers or customers, sometimes the expression "survival rate" is used to mean 1 minus the churn rate. For example, for a group of subscribers, an annual churn rate of 25 percent is the same as an annual survival rate of 75 percent. Both imply a customer lifetime of four years because a customer lifetime can be calculated as the inverse of that customer's predicted churn rate. For a group or segment of customers, their customer life (or tenure) is the inverse of their aggregate churn rate. Gompertz distribution models of distribution of customer life times can therefore also predict a distribution of churn rates. For companies with a fast-growing customer base (e.g., digital media companies in a BCG-matrix problem child or star phase), confusion can arise between the statistical analyses associated with what percentage of the whole customer base churns in a given year – What percentage of the base of subscribers in all of 2010 churned out? – versus a particular customer cohort's churn rate. For example: Taking those customers who subscribed in given month, say January 2010 – How many had churned out by January 2011? Examining churn for a fast-growing aggregated customer base will understate the true churn rate compared to cohort based approach to the calculation. The cohort based approach will also allow you to calculate the survival rate and the average customer life, whereas the aggregate approach can not calculate these two metrics. Researchers at Deloitte have argued that social network analysis is a good tool to calculate churn. In recent years, using AI and machine-learning as a means to calculate customer churn has become increasingly common for large retailers and service providers. The phrase "rotational churn" is used to describe the phenomenon where a customer churns and immediately rejoins. This is common in prepaid mobile phone services, where existing customers may take up a new subscription from their current provider in order to avail of special offers only available to new customers. In most circumstances churn is seen as indicating that customers are dissatisfied with a service. However, in some industries whose services delivers on a promise, churn is considered as a positive signal, such as the health care services, weight loss services and online dating platforms. Some researchers have disputed the simple assumption that just dissatisfaction would lead customers to churn, and called for a more nuanced approach. == See also == Turnover (employment) Customer attrition Customer retention == References == == Further reading == Berry and Linoff, Michael J.A. and Gordon S. (2000). Mastering Data Mining: The Art and Science of Customer Relationship Management. John Wiley & Sons. ISBN 0-471-33123-6. Cached Insight paper on churn in the mobile communications industry.	Wikipedia/Attrition_rate
The cost of drug development is the full cost of bringing a new drug (i.e., new chemical entity) to market from drug discovery through clinical trials to approval. Typically, companies spend tens to hundreds of millions of U.S. dollars on drug development. One element of the complexity is that the much-publicized final numbers often not only include the out-of-pocket expenses for conducting a series of Phase I-III clinical trials, but also the capital costs of the long period (10 or more years) during which the company must cover out-of-pocket costs for preclinical drug discovery. Additionally, companies often do not report whether a given figure includes the capitalized cost or comprises only out-of-pocket expenses, or both. One study assessed both capitalized and out-of-pocket costs as about US$1.8 billion and $870 million, respectively. In an analysis of the drug development costs for 98 companies over a decade, the average cost per drug developed and approved by a single-drug company was $350 million. But for companies that approved between eight and 13 drugs over 10 years, the cost per drug went as high as $5.5 billion. A new study in 2020 estimated that the median cost of getting a new drug into the market was $985 million, and the average cost was $1.3 billion, which was much lower compared to previous studies, which have placed the average cost of drug development as $2.8 billion. Alternatives to conventional drug development have the objective for universities, governments and pharmaceutical industry to collaborate and optimize resources. == Research and development == Severin Schwan, the CEO of the Swiss company Roche, reported that Roche's research and development costs amounted to $12.3 billion in 2018, a quarter of the entire National Institutes of Health budget. Given the profit-driven nature of pharmaceutical companies and their research and development expenses, companies use their research and development expenses as a starting point to determine appropriate yet profitable prices. Pharmaceutical companies spend a large amount on research and development before a drug is released to the market and costs can be further divided into three major fields: the discovery into the drug’s specific medical field, clinical trials, and failed drugs. === Discovery === Drug discovery is the area of research and development that amounts to the most time and money. The process can involve scientists to determine the germs, viruses, and bacteria that cause a specific disease or illness. The time frame can range from 3–20 years and costs can range between several billion to tens of billions of dollars. Research teams attempt to break down disease components to find abnormal events/processes taking place in the body. Only then do scientists work on developing chemical compounds to treat these abnormalities with the aid of computer models. After "discovery" and a creation of a chemical compound, pharmaceutical companies move forward with the Investigational New Drug (IND) Application from the FDA. After the investigation into the drug and given approval, pharmaceutical companies can move into pre-clinical trials and clinical trials. === Trials === Drug development and pre-clinical trials focus on non-human subjects and work on animals such as rats. This is the most inexpensive phase of testing. The Food and Drug Administration mandates a 3 phase clinical trial testing that tests for side effects and the effectiveness of the drug with a single phase clinical trial costing upwards of $100 million. After a drug has passed through all three phases, the pharmaceutical company can move forward with a New Drug Application from the FDA. In 2014, the FDA charged between $1 million to $2 million for an NDA. === Failed drugs === The processes of "discovery" and clinical trials amounts to approximately 12 years from research lab to the patient, in which about 10% of all drugs that start pre-clinical trials ever make it to actual human testing.> Each pharmaceutical company (which have hundreds of drugs moving in and out of these phases) will never recuperate the costs of "failed drugs". Thus, profits made from one drug need to cover the costs of previous "failed drugs". === Financial risk === Overall, research and development expenses relating to developing drugs amount to billions of dollars. A 2012 study found that research and development of a drug is riskier than product development in other industries because it is lengthy, costly, and highly uncertain, particularly due to unpredictable human physiological responses to drugs. As an example, in 2018, Roche spent $11 billion for research and developmental expenses, and had two failed Phase III trials for an Alzheimer's drug candidate. == Research on costs == Tufts Center for the Study of Drug Development has published numerous studies estimating the cost of developing new pharmaceutical drugs. In 2001, researchers from the Center estimated that the cost of doing so was $802 million, and in 2014, they released a study estimating that this amount had risen to nearly $2.6 billion. The 2014 study was criticized by Medecins Sans Frontieres, which said it was unreliable because the industry's research and development spending is not made public. Aaron Carroll of the New York Times also criticized the study, saying it "contains a lot of assumptions that tend to favor the pharmaceutical industry." The Center's 2016 estimate, published in the Journal of Health Economics, found the cost to have averaged $2.87 billion (in 2013 dollars). A 2022 study invalidated the common argument as is for high medication costs that research and development investments are reflected in and necessitate the treatment costs, finding no correlation for investments in drugs (for cases where transparency was sufficient) and their costs. == References == == Further reading ==	Wikipedia/Cost_of_drug_development
The United States Food and Drug Administration's Investigational New Drug (IND) program is the means by which a pharmaceutical company obtains permission to start human clinical trials and to ship an experimental drug across state lines (usually to clinical investigators) before a marketing application for the drug has been approved. Regulations are primarily at 21 CFR 312. Similar procedures are followed in the European Union, Japan, and Canada due to regulatory harmonization efforts by the International Council for Harmonisation. == Types == Research or investigator INDs are non-commercial INDs filed by researchers to study an unapproved drug or to study an approved drug for a new indication or in a new patient population. Emergency Use INDs, also called compassionate use or single-patient INDs, are filed for emergency use of an unapproved drug when the clinical situation does not allow sufficient time to submit an IND in accordance with 21 CFR §§ 312.23, 312.24. These are most commonly used for life-threatening conditions for which there is no standard treatment. Treatment INDs are filed to make a drug available for the treatment of serious or immediately life-threatening conditions prior to FDA approval. Serious diseases or conditions are stroke, schizophrenia, rheumatoid arthritis, osteoarthritis, chronic depression, seizures, Alzheimer's dementia, amyotrophic lateral sclerosis (ALS), and narcolepsy. Screening INDs are filed for multiple, closely related compounds in order to screen for the preferred compounds or formulations. The preferred compound can then be developed under a separate IND. Used for screening different salts, esters and other drug derivatives that are chemically different, but pharmacodynamically similar. == Application == The IND application may be divided into the following categories: Preclinical testing consists of animal pharmacology and toxicology studies to assess whether the drug is safe for testing in humans. Also included are any previous experience with the drug in humans (often foreign use). Manufacturing Information includes composition, manufacturer, and stability of, and the controls used for, manufacturing the drug. Used to ensure that the company can adequately produce and supply consistent batches of the drug. Investigator information on the qualifications of clinical investigators, that is, the professionals (generally physicians) who oversee the administration of the experimental drug to the study subjects. Used to assess whether the investigators are qualified to fulfill their clinical trial duties. Clinical trial protocols are the centerpiece of the IND. Detailed protocols for proposed clinical studies to assess whether the initial-phase trials will expose the subjects to unnecessary risks. Other commitments are commitments to obtain informed consent from the research subjects, to obtain a review of the study by an institutional review board (IRB), and to adhere to the investigational new drug regulations. An IND application must also include an Investigator's Brochure intended to educate the trial investigators of the significant facts about the trial drug they need to know to conduct their clinical trial with the least hazard to the subjects or patients. Once an IND application is submitted, the FDA has 30 days to object to the IND or it automatically becomes effective and clinical trials may begin. If the FDA detects a problem, it may place a clinical hold on the IND, prohibiting the start of the clinical studies until the problem is resolved, as outlined in 21 CFR 312.42. An IND must be labeled "Caution: New Drug – Limited by Federal (or United States) law to investigational use," per 21 CFR 312.6 == Prevalence == Approximately two-thirds of both INDs and new drug applications (NDAs) are small-molecule drugs. The rest is biopharmaceuticals. About half of the INDs fail in preclinical and clinical phases of drug development. == Examples == The FDA runs a medical marijuana IND program (the Compassionate Investigational New Drug program). It stopped accepting new patients in 1992 after public health authorities concluded there was no scientific value to it, and due to President George H. W. Bush administration's desire to "get tough on crime and drugs." As of 2011, four patients continue to receive cannabis from the government under the program. Sanctioned by Executive Order 13139, the US Department of Defense employed an anthrax vaccine classified as an investigational new drug (IND) in its Anthrax Vaccine Immunization Program (AVIP). == See also == Abigail Alliance for Better Access to Developmental Drugs Animal drug Biologics license application Drug discovery FDA Fast Track Development Program Good Manufacturing Practice Inverse benefit law Orphan drug TOL101 == References == == External links == Investigational New Drug (IND) Application Process Center for Drug Evaluation and Research, Food and Drug Administration. ICH Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance. BROKEN LINK Troetel, W.M.: Achieving a Successful US IND Filing (1) The Regulatory Affairs Journal. 6: 22–28, January 1995. Troetel, W.M.: Achieving a Successful US IND Filing (2) The Regulatory Affairs Journal. 6: 104–108, February 1995. Henninger, Daniel (2002). "Drug Lag". In David R. Henderson (ed.). Concise Encyclopedia of Economics (1st ed.). Library of Economics and Liberty. OCLC 317650570, 50016270, 163149563 IND Forms and Instructions from the US Food and Drug Administration	Wikipedia/Investigational_new_drug
Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for regulatory status, such as via the United States Food and Drug Administration for an investigational new drug to initiate clinical trials on humans, and may include the step of obtaining regulatory approval with a new drug application to market the drug. The entire process—from concept through preclinical testing in the laboratory to clinical trial development, including Phase I–III trials—to approved vaccine or drug typically takes more than a decade. == New chemical entity development == Broadly, the process of drug development can be divided into preclinical and clinical work. === Pre-clinical === New chemical entities (NCEs, also known as new molecular entities or NMEs) are compounds that emerge from the process of drug discovery. These have promising activity against a particular biological target that is important in disease. However, little is known about the safety, toxicity, pharmacokinetics, and metabolism of this NCE in humans. It is the function of drug development to assess all of these parameters prior to human clinical trials. A further major objective of drug development is to recommend the dose and schedule for the first use in a human clinical trial ("first-in-human" [FIH] or First Human Dose [FHD], previously also known as "first-in-man" [FIM]). In addition, drug development must establish the physicochemical properties of the NCE: its chemical makeup, stability, and solubility. Manufacturers must optimize the process they use to make the chemical so they can scale up from a medicinal chemist producing milligrams, to manufacturing on the kilogram and ton scale. They further examine the product for suitability to package as capsules, tablets, aerosol, intramuscular injectable, subcutaneous injectable, or intravenous formulations. Together, these processes are known in preclinical and clinical development as chemistry, manufacturing, and control (CMC). Many aspects of drug development focus on satisfying the regulatory requirements for a new drug application. These generally constitute a number of tests designed to determine the major toxicities of a novel compound prior to first use in humans. It is a legal requirement that an assessment of major organ toxicity be performed (effects on the heart and lungs, brain, kidney, liver and digestive system), as well as effects on other parts of the body that might be affected by the drug (e.g., the skin if the new drug is to be delivered on or through the skin). Such preliminary tests are made using in vitro methods (e.g., with isolated cells), but many tests can only use experimental animals to demonstrate the complex interplay of metabolism and drug exposure on toxicity. The information is gathered from this preclinical testing, as well as information on CMC, and submitted to regulatory authorities (in the US, to the FDA), as an Investigational New Drug (IND) application. If the IND is approved, development moves to the clinical phase. === Clinical phase === Clinical trials involve four steps: Phase I trials, usually in healthy volunteers, determine safety and dosing. Phase II trials are used to get an initial reading of efficacy and further explore safety in small numbers of patients having the disease targeted by the NCE.a Phase III trials are large, pivotal trials to determine safety and efficacy in sufficiently large numbers of patients with the targeted disease. If safety and efficacy are adequately proved, clinical testing may stop at this step and the NCE advances to the new drug application (NDA) stage. Phase IV trials are post-approval trials that are sometimes a condition attached by the FDA, also called post-market surveillance studies. The process of defining characteristics of the drug does not stop once an NCE is advanced into human clinical trials. In addition to the tests required to move a novel vaccine or antiviral drug into the clinic for the first time, manufacturers must ensure that any long-term or chronic toxicities are well-defined, including effects on systems not previously monitored (fertility, reproduction, immune system, among others). If a vaccine candidate or antiviral compound emerges from these tests with an acceptable toxicity and safety profile, and the manufacturer can further show it has the desired effect in clinical trials, then the NCE portfolio of evidence can be submitted for marketing approval in the various countries where the manufacturer plans to sell it. In the United States, this process is called a "new drug application" or NDA. Most novel drug candidates (NCEs) fail during drug development, either because they have unacceptable toxicity or because they simply do not prove efficacy on the targeted disease, as shown in Phase II–III clinical trials. Critical reviews of drug development programs indicate that Phase II–III clinical trials fail due mainly to unknown toxic side effects (50% failure of Phase II cardiology trials), and because of inadequate financing, trial design weaknesses, or poor trial execution. A study covering clinical research in the 1980–1990s found that only 21.5% of drug candidates that started Phase I trials were eventually approved for marketing. During 2006–2015, the success rate of obtaining approval from Phase I to successful Phase III trials was under 10% on average, and 16% specifically for vaccines. The high failure rates associated with pharmaceutical development are referred to as an "attrition rate", requiring decisions during the early stages of drug development to "kill" projects early to avoid costly failures. == Cost == There are a number of studies that have been conducted to determine research and development costs: notably, recent studies from DiMasi and Wouters suggest pre-approval capitalized cost estimates of $2.6 billion and $1.1 billion, respectively. The figures differ significantly based on methodologies, sampling and timeframe examined. Several other studies looking into specific therapeutic areas or disease types suggest as low as $291 million for orphan drugs, $648 million for cancer drugs or as high as $1.8 billion for cell and gene therapies. The average cost (2013 dollars) of each stage of clinical research was US$25 million for a Phase I safety study, $59 million for a Phase II randomized controlled efficacy study, and $255 million for a pivotal Phase III trial to demonstrate its equivalence or superiority to an existing approved drug, possibly as high as $345 million. The average cost of conducting a 2015–16 pivotal Phase III trial on an infectious disease drug candidate was $22 million. The full cost of bringing a new drug (i.e., new chemical entity) to market—from discovery through clinical trials to approval—is complex and controversial. In a 2016 review of 106 drug candidates assessed through clinical trials, the total capital expenditure for a manufacturer having a drug approved through successful Phase III trials was $2.6 billion (in 2013 dollars), an amount increasing at an annual rate of 8.5%. Over 2003–2013 for companies that approved 8–13 drugs, the cost per drug could rise to as high as $5.5 billion, due mainly to international geographic expansion for marketing and ongoing costs for Phase IV trials for continuous safety surveillance. Alternatives to conventional drug development have the objective for universities, governments, and the pharmaceutical industry to collaborate and optimize resources. An example of a collaborative drug development initiative is COVID Moonshot, an international open-science project started in March 2020 with the goal of developing an un-patented oral antiviral drug to treat SARS-CoV-2. == Valuation == The nature of a drug development project is characterised by high attrition rates, large capital expenditures, and long timelines. This makes the valuation of such projects and companies a challenging task. Not all valuation methods can cope with these particularities. The most commonly used valuation methods are risk-adjusted net present value (rNPV), decision trees, real options, or comparables. The most important value drivers are the cost of capital or discount rate that is used, phase attributes such as duration, success rates, and costs, and the forecasted sales, including cost of goods and marketing and sales expenses. Less objective aspects like quality of the management or novelty of the technology should be reflected in the cash flows estimation. == Success rate == Candidates for a new drug to treat a disease might, theoretically, include from 5,000 to 10,000 chemical compounds. On average about 250 of these show sufficient promise for further evaluation using laboratory tests, mice and other test animals. Typically, about ten of these qualify for tests on humans. A study conducted by the Tufts Center for the Study of Drug Development covering the 1980s and 1990s found that only 21.5 percent of drugs that started Phase I trials were eventually approved for marketing. In the time period of 2006 to 2015, the success rate was 9.6%. The high failure rates associated with pharmaceutical development are referred to as the "attrition rate" problem. Careful decision making during drug development is essential to avoid costly failures. In many cases, intelligent programme and clinical trial design can prevent false negative results. Well-designed, dose-finding studies and comparisons against both a placebo and a gold-standard treatment arm play a major role in achieving reliable data. == Computing initiatives == Novel initiatives include partnering between governmental organizations and industry, such as the European Innovative Medicines Initiative. The US Food and Drug Administration created the "Critical Path Initiative" to enhance innovation of drug development, and the Breakthrough Therapy designation to expedite development and regulatory review of candidate drugs for which preliminary clinical evidence shows the drug candidate may substantially improve therapy for a serious disorder. In March 2020, the United States Department of Energy, National Science Foundation, NASA, industry, and nine universities pooled resources to access supercomputers from IBM, combined with cloud computing resources from Hewlett Packard Enterprise, Amazon, Microsoft, and Google, for drug discovery. The COVID-19 High Performance Computing Consortium also aims to forecast disease spread, model possible vaccines, and screen thousands of chemical compounds to design a COVID-19 vaccine or therapy. In May 2020, the OpenPandemics – COVID-19 partnership between Scripps Research and IBM's World Community Grid was launched. The partnership is a distributed computing project that "will automatically run a simulated experiment in the background [of connected home PCs] which will help predict the effectiveness of a particular chemical compound as a possible treatment for COVID-19". == See also == Drug design Drug repositioning Pharmaceutical engineering Pharmaceutical manufacturing Generic drug International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, a consensus between the U.S. Food and Drug Administration (FDA), EU, and Japan. List of pharmaceutical companies == References == == External links == International Union of Basic and Clinical Pharmacology	Wikipedia/Drug_research
A pivotal trial is typically a Phase III clinical trial in the multi-year process of clinical research intended to demonstrate and confirm the safety and efficacy of a treatment – such as a drug candidate, medical device or clinical diagnostic procedure – and to estimate the incidence of common adverse effects. A successful pivotal trial is required as evidence for drug marketing approval by the relevant approval authorities, such as the European Medicines Agency, Health Canada or United States Food and Drug Administration (FDA). In drug research, a pivotal Phase III trial may be referred to as a "therapeutic confirmatory study", and is conducted in a large number (hundreds to thousands) of subjects. Such pivotal trials are also designed to discover and estimate the prevalence of common adverse events, but based on their size only have the statistical power to establish an adverse effect rate of not less than 1 in 100 subjects. In an analysis of pivotal trials on medical devices conducted between 2006 and 2013, the median duration was three years, with another two years needed for FDA review and approval for marketing. In 2017 in the United States, the median cost of a pivotal trial across all clinical indications was US$19 million. The cost of a pivotal trial increased when more subjects were added to clarify a treatment effect, when active drug comparators were used to improve understanding of the trial drug characteristics, or when specific clinical endpoints were measured rather than using surrogate outcomes. == References ==	Wikipedia/Pivotal_trial
The Tufts Center for the Study of Drug Development is an independent, academic, non-profit research center at Tufts University in Boston, dedicated to researching drug development. It was established in 1976 by American physician Louis Lasagna. The Center develops and publishes information to help researchers, regulators, and policy makers in areas related to the pharmaceutical and biotechnology industries. In any given year, approximately 55% of Tufts CSDD's operating expenses are supported by grants from the private sector and 45% from the public sector. == Research == The Center studies trends in the pharmaceutical industry, maintaining databases pertaining to investigational new drugs, approved drugs, biopharmaceuticals, fast-tracked drugs, and orphan drugs. The Center provides this information with the aim to improve the efficiency of drug development, foster innovation, and increase patient access to medicines. === Drug development costs === The center has published numerous studies estimating the cost of developing new pharmaceutical drugs. In 2001, researchers from the Center estimated that the cost of doing so was $802 million, and in 2014, they released a study estimating that this amount had risen to nearly $2.6 billion. The 2014 study was criticized by Medecins Sans Frontieres, which said it was unreliable because the industry's research and development spending is not made public. Aaron Carroll of the New York Times also criticized the study, saying it "contains a lot of assumptions that tend to favor the pharmaceutical industry." The center's 2016 estimate, published in the Journal of Health Economics, found the cost to have averaged $2.87 billion (in 2013 dollars). == References ==	Wikipedia/Tufts_Center_for_the_Study_of_Drug_Development
Breakthrough therapy is a United States Food and Drug Administration designation that expedites drug development that was created by Congress under Section 902 of the 9 July 2012 Food and Drug Administration Safety and Innovation Act. The FDA's "breakthrough therapy" designation is not intended to imply that a drug is actually a "breakthrough" or that there is high-quality evidence of treatment efficacy for a particular condition; rather, it allows the FDA to grant priority review to drug candidates if preliminary clinical trials indicate that the therapy may offer substantial treatment advantages over existing options for patients with serious or life-threatening diseases. The FDA has other mechanisms for expediting the review and approval process for promising drugs, including fast track designation, accelerated approval, and priority review. == Requirements == A breakthrough therapy designation can be assigned to a drug if "it is a drug which is intended alone or in combination with one or more other drugs to treat a serious or life threatening disease or condition" and if the preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development." Requests are reviewed by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). CDER receives approximately 100 requests per year for breakthrough designation. Historically, about one third were approved. CBER receives 15–30 requests per year. Sponsors must apply for breakthrough status separately for each indication they intend to label the drug for. Breakthrough designation applications are submitted as an amendment to the IND applications, usually prior to end of Phase II meeting. == Incentives == Drugs that have been granted breakthrough status are given priority review. The FDA works with the sponsor of the drug application to expedite the approval process. This expedited process can include rolling reviews, smaller clinical trials, and alternative trial designs. == Issues == Critics have said that the name is misleading and provides companies that obtain a breakthrough designation for a drug candidate with a marketing advantage that may be undeserved. The FDA acknowledges that the name "breakthrough therapy" may be misleading. It was never meant to imply that these drugs are actually "breakthroughs," and it does not ensure that they will provide clinical benefit, but still critics complain that they are based on preliminary evidence, including changes in surrogate markers such as laboratory measurements, that often don't reflect "meaningful clinical benefit." The FDA guidance states: "Not all products designated as breakthrough therapies ultimately will be shown to have the substantial improvement over available therapies suggested by the preliminary clinical evidence at the time of designation. If the designation is no longer supported by subsequent data, FDA may rescind the designation." == See also == List of drugs granted breakthrough therapy designation FDA Fast Track Development Program Priority review (FDA) Orphan drug == References == == External links == Media related to Breakthrough therapy at Wikimedia Commons	Wikipedia/Breakthrough_Therapy
2,5-Dimethoxy-4-iodoamphetamine (DOI) is a psychedelic drug of the amphetamine and 4-substituted-2,5-dimethoxyamphetamine (DOx) families. It is relatively little-used as a recreational drug but is frequently used in scientific research in the study of psychedelics and serotonin receptors. DOI acts as a potent serotonin 5-HT2 receptor agonist, including of the serotonin 5-HT2A and 5-HT2C receptors. The compound has a stereocenter, and R-(−)-DOI is the more active stereoisomer. [125I]-R-(−)-DOI is used as a radioligand and indicator of the presence of serotonin 5-HT2A receptors in studies. DOI's effects have been compared to LSD, although there are differences that experienced users can distinguish. Besides the longer duration of DOI compared to LSD, the trip tends to be more energetic than an LSD trip, with more body load and a different subjective visual experience. The after effects include residual stimulation and difficulty sleeping, which, depending on the dose, may persist for days. While rare, DOI has sometimes been sold as a substitute for LSD, or even sold falsely as LSD, which may be dangerous because DOI does not have the same established safety profile as LSD. DOI was first synthesized in 1973, by Coutts and Malicky. Unlike many other psychedelic drugs, DOI is not an explicitly controlled substance in the United States. However, it could be considered a controlled substance under the Federal Analog Act. In any case, its non-controlled status has made DOI usefully accessible for use in scientific research, which has contributed to its popularity for such uses. In December 2023, the Drug Enforcement Agency (DEA) proposed making DOI a schedule I controlled substance. This proposal has been opposed by psychedelic researchers and the DEA has consequently delayed its June 2024 hearing on the proposal. == Interactions == == Pharmacology == === Pharmacodynamics === ==== Actions ==== DOI is a serotonin 5-HT2A, 5-HT2B and 5-HT2C receptor agonist. It is said to be approximately 5- to 12-fold selective for the serotonin 5-HT2A receptor over the serotonin 5-HT2C receptor. The drug is not a monoamine releasing agent of serotonin or dopamine. DOI is an agonist of the rat trace amine-associated receptor 1 (TAAR1). ==== Effects ==== (R)-DOI and several other serotonergic psychedelics, including TCB-2, LSD, and LA-SS-Az, have been found to show potent inhibition of tumor necrosis factor alpha (TNFα)-induced inflammation. (R)-DOI was the most active of the assessed drugs and showed extremely high potency that was in the picomolar range and was an order of magnitude more potent than its action as a hallucinogen. TNFα may play a mediating role in the pathophysiology of degenerative inflammatory conditions like rheumatoid arthritis and Alzheimer's disease. (R)-DOI has also been found to block pulmonary inflammation, mucus hyperproduction, airway hyperresponsiveness, and to turn off key genes in pulmonary immune response, effects which block the development of allergic asthma in animal models. These findings could make DOI and other serotonin 5-HT2A agonists novel treatments for inflammatory conditions. DOI has been shown to induce rapid growth and reorganization of dendritic spines and synaptic connections with other neurons, processes known to underlie neuroplasticity, and hence to be a psychoplastogen. == Chemistry == DOI, also known as 2,5-dimethoxy-4-iodoamphetamine or as 2,5-dimethoxy-4-iodo-α-methylphenethylamine, is a substituted phenethylamine and amphetamine derivative and a member of the DOx family of drugs. It is structurally related to the naturally occurring phenethylamine psychedelic mescaline (3,4,5-trimethoxyphenethylamine). Other closely related DOx drugs include DOM, DOB, DOC, and DOF, among many others. == History == DOI was first synthesized by Alexander Shulgin. The radioactive iodine-125 form of DOI for PET imaging was first developed in the lab of David E. Nichols. In January 2007, British police reported that three young men had fallen ill, reportedly, after taking DOI at a rave in Biggleswade, near Milton Keynes, and warned others who had taken it to seek medical attention. This would appear to be the first indication that DOI has found more widespread use as a recreational drug in the UK. South Australian man Cody Edwards who brutally murdered Synamin Bell controversially plead guilty to the lesser sentence of manslaughter after attesting that the drug DOI had induced paranoia, and that he had subsequently acted in ‘self-defence’ when he had beaten the mother-of-three to death with a dumbbell, resulting in over fifty wounds. == Society and culture == === Legal status === ==== Australia ==== The Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) of Australia does not list DOI as a prohibited substance. ==== Canada ==== Listed as a Schedule 1 as it is an analogue of amphetamine. The CDSA was updated as a result of the Safe Streets and Communities Act, changing amphetamines from Schedule 3 to Schedule 1. ==== Denmark ==== Illegal since 8 April 2007. ==== Finland ==== DOI is classified as a psychoactive substance banned from the consumer market in Finland. ==== Sweden ==== Sveriges riksdag added DOI to schedule I ("substances, plant materials and fungi which normally do not have medical use") as narcotics in Sweden as of August 30, 2007, published by Medical Products Agency in their regulation LVFS 2007:10 listed as DOI, 4-jod-2,5-dimetoxi-amfetamin. ==== United States ==== As of 2023, DOI is not scheduled in the United States, but it is likely that DOI would be considered an analog (of DOB), in which case, sales or possession could be prosecuted under the Federal Analogue Act. In December 2023, the US Drug Enforcement Administration (DEA) issued a notice of proposed rulemaking that would classify both DOI and 2,5-dimethoxy-4-chloroamphetamine (DOC) as schedule I controlled substances. However, in May 2024, it was reported that the DEA's June 10, 2024 hearing on scheduling of DOI and DOC had been postponed. This followed opposition to the proposal by psychedelic researchers. DOI is frequently used in scientific research due in considerable part to its non-scheduled status, and DOI becoming a controlled substance would cause problems for scientists. DOI is a Schedule I controlled substance in the state of Florida. == See also == 5-HT2A receptor § Anti-inflammatory effects == References == == External links == DOI - Isomer Design DOI - PsychonautWiki DOI - Erowid DOI - Lycaeum DOI - PiHKAL - Erowid DOI - PiHKAL - Isomer Design DOI (2,5-Dimethoxy-4-iodoamphetamine): A Potent & Unique Psychedelic Compound - Tripsitter	Wikipedia/DOI_(drug)
A psychiatric or psychotropic medication is a psychoactive drug taken to exert an effect on the chemical makeup of the brain and nervous system. Thus, these medications are used to treat mental illnesses. These medications are typically made of synthetic chemical compounds and are usually prescribed in psychiatric settings, potentially involuntarily during commitment. Since the mid-20th century, such medications have been leading treatments for a broad range of mental disorders and have decreased the need for long-term hospitalization, thereby lowering the cost of mental health care. The recidivism or rehospitalization of the mentally ill is at a high rate in many countries, and the reasons for the relapses are under research. A 2022 umbrella review of over 100 meta-analyses found that both psychotherapies and pharmacotherapies for adult mental disorders generally yield small effect sizes, suggesting current treatment research may have reached a ceiling and needs a paradigm shift. == History == Several significant psychiatric drugs were developed in the mid-20th century. In 1948, lithium was first used as a psychiatric medicine. One of the most important discoveries was chlorpromazine, an antipsychotic that was first given to a patient in 1952. In the same decade, Julius Axelrod carried out research into the interaction of neurotransmitters, which provided a foundation for the development of further drugs. The popularity of these drugs have increased significantly since then, with millions prescribed annually. The introduction of these drugs brought profound changes to the treatment of mental illness. It meant that more patients could be treated without the need for confinement in a psychiatric hospital. It was one of the key reasons why many countries moved towards deinstitutionalization, closing many of these hospitals so that patients could be treated at home, in general hospitals and smaller facilities. Use of physical restraints such as straitjackets also declined. As of 2013, the 10 most prescribed psychiatric drugs by number of prescriptions were alprazolam, sertraline, citalopram, fluoxetine, lorazepam, trazodone, escitalopram, duloxetine, bupropion XL, and venlafaxine XR. == Administration == Psychiatric medications are prescription medications, requiring a prescription from a physician, such as a psychiatrist, or a psychiatric nurse practitioner, PMHNP, before they can be obtained. Some U.S. states and territories, following the creation of the prescriptive authority for psychologists movement, have granted prescriptive privileges to clinical psychologists who have undergone additional specialised education and training in medical psychology. In addition to the familiar dosage in pill form, psychiatric medications are evolving into more novel methods of drug delivery. New technologies include transdermal, transmucosal, inhalation, suppository or depot injection supplements. == Research == Psychopharmacology studies a wide range of substances with various types of psychoactive properties. The professional and commercial fields of pharmacology and psychopharmacology do not typically focus on psychedelic or recreational drugs, and so the majority of studies are conducted on psychiatric medication. While studies are conducted on all psychoactive drugs by both fields, psychopharmacology focuses on psychoactive and chemical interactions within the brain. Physicians who research psychiatric medications are psychopharmacologists, specialists in the field of psychopharmacology. A 2022 umbrella review of over 100 meta-analyses found that both psychotherapies and pharmacotherapies for adult mental disorders generally yield small effect sizes, suggesting current treatment research may have reached a ceiling and needs a paradigm shift. == Adverse and withdrawal effects == Psychiatric disorders, including depression, psychosis, and bipolar disorder, are common and gaining more acceptance in the United States. The most commonly used classes of medications for these disorders are antidepressants, antipsychotics, and lithium. Unfortunately, these medications are associated with significant neurotoxicities. Psychiatric medications carry risk for neurotoxic adverse effects. The occurrence of neurotoxic effects can potentially reduce drug compliance. Some adverse effects can be treated symptomatically by using adjunct medications such as anticholinergics (antimuscarinics). Some rebound or withdrawal adverse effects, such as the possibility of a sudden or severe emergence or re-emergence of psychosis in antipsychotic withdrawal, may appear when the drugs are discontinued, or discontinued too rapidly. === Medicine combinations with clinically untried risks === While clinical trials of psychiatric medications, like other medications, typically test medicines separately, there is a practice in psychiatry (more so than in somatic medicine) to use polypharmacy in combinations of medicines that have never been tested together in clinical trials (though all medicines involved have passed clinical trials separately). It is argued that this presents a risk of adverse effects, especially brain damage, in real-life mixed medication psychiatry that are not visible in the clinical trials of one medicine at a time (similar to mixed drug abuse causing significantly more damage than the additive effects of brain damages caused by using only one illegal drug). Outside clinical trials, there is evidence for an increase in mortality when psychiatric patients are transferred to polypharmacy with an increased number of medications being mixed. == Types == There are five main groups of psychiatric medications. Antidepressants, which treat disparate disorders such as clinical depression, dysthymia, anxiety disorders, eating disorders and borderline personality disorder. Antipsychotics, which treat psychotic disorders such as schizophrenia and psychotic symptoms occurring in the context of other disorders such as mood disorders. They are also used for the treatment of bipolar disorder. Anxiolytics, which treat anxiety disorders, and include hypnotics and sedatives Mood stabilizers, which treat bipolar disorder and schizoaffective disorder. Stimulants, which treat disorders such as attention deficit hyperactivity disorder and narcolepsy. === Antidepressants === Antidepressants are drugs used to treat clinical depression, and they are also often used for anxiety and other disorders. Most antidepressants will hinder the breakdown of serotonin, norepinephrine, and/or dopamine. A commonly used class of antidepressants are called selective serotonin reuptake inhibitors (SSRIs), which act on serotonin transporters in the brain to increase levels of serotonin in the synaptic cleft. Another is the serotonin-norepinephrine reuptake inhibitors (SNRIs), which increase both serotonin and norepinephrine. Antidepressants will often take 3–5 weeks to have a noticeable effect as the regulation of receptors in the brain adapts. There are multiple classes of antidepressants which have different mechanisms of action. Another type of antidepressant is a monoamine oxidase inhibitor (MAOI), which is thought to block the action of monoamine oxidase, an enzyme that breaks down serotonin and norepinephrine. MAOIs are not used as first-line treatment due to the risk of hypertensive crisis related to the consumption of foods containing the amino acid tyramine. Common antidepressants: Fluoxetine (Prozac), SSRI Paroxetine (Paxil, Seroxat), SSRI Citalopram (Celexa), SSRI Escitalopram (Lexapro), SSRI Sertraline (Zoloft), SSRI Duloxetine (Cymbalta), SNRI Venlafaxine (Effexor), SNRI Bupropion (Wellbutrin), NDRI Mirtazapine (Remeron), NaSSA Isocarboxazid (Marplan), MAOI Phenelzine (Nardil), MAOI Tranylcypromine (Parnate), MAOI Amitriptyline (Elavil), TCA === Antipsychotics === Antipsychotics are drugs used to treat various symptoms of psychosis, such as those caused by psychotic disorders or schizophrenia. Atypical antipsychotics are also used as mood stabilizers in the treatment of bipolar disorder, and they can augment the action of antidepressants in major depressive disorder. Antipsychotics are sometimes referred to as neuroleptic drugs and some antipsychotics are branded "major tranquilizers". There are two categories of antipsychotics: typical antipsychotics and atypical antipsychotics. Most antipsychotics are available only by prescription. Common antipsychotics: === Anxiolytics and hypnotics === Benzodiazepines are effective as hypnotics, anxiolytics, anticonvulsants, myorelaxants and amnesics. Having less proclivity for overdose and toxicity, they have widely supplanted barbiturates, although barbiturates (such as pentobarbital) are still used for euthanasia. Developed in the 1950s onward, benzodiazepines were originally thought to be non-addictive at therapeutic doses, but are now known to cause withdrawal symptoms similar to barbiturates and alcohol. Benzodiazepines are generally recommended for short-term use. Z-drugs are a group of drugs with effects generally similar to benzodiazepines, which are used in the treatment of insomnia. Common benzodiazepines and z-drugs include: === Mood stabilizers === In 1949, the Australian John Cade discovered that lithium salts could control mania, reducing the frequency and severity of manic episodes. This introduced the now popular drug lithium carbonate to the mainstream public, as well as being the first mood stabilizer to be approved by the U.S. Food & Drug Administration. Besides lithium, several anticonvulsants and atypical antipsychotics have mood stabilizing activity. The mechanism of action of mood stabilizers is not well understood. Common non-antipsychotic mood stabilizers include: Lithium (Lithobid, Eskalith), the oldest mood stabilizer Anticonvulsants Carbamazepine (Tegretol) and the related compound oxcarbazepine (Trileptal) Valproic acid, and salts (Depakene, Depakote) Lamotrigine (Lamictal) === Stimulants === A stimulant is a drug that stimulates the central nervous system, increasing arousal, attention and endurance. Stimulants are used in psychiatry to treat attention deficit-hyperactivity disorder. Because the medications can be addictive, patients with a history of drug abuse are typically monitored closely or treated with a non-stimulant. Common stimulants: Methylphenidate (Ritalin, Concerta), a norepinephrine-dopamine reuptake inhibitor Dexmethylphenidate (Focalin), the active dextro-enantiomer of methylphenidate Serdexmethylphenidate/dexmethylphenidate (Azstarys) Mixed amphetamine salts (Adderall), a 3:1 mix of dextro/levo-enantiomers of amphetamine Dextroamphetamine (Dexedrine), the dextro-enantiomer of amphetamine Lisdexamfetamine (Vyvanse), a prodrug containing the dextro-enantiomer of amphetamine Methamphetamine (Desoxyn), a potent but infrequently prescribed amphetamine == Controversies == Professionals, such as David Rosenhan, Peter Breggin, Paula Caplan, Thomas Szasz, Giorgio Antonucci and Stuart A. Kirk, sustain that psychiatry engages "in the systematic medicalization of normality". More recently these concerns have come from insiders who have worked for and promoted the APA (e.g., Robert Spitzer, Allen Frances).: 185 Scholars such as Cooper, Foucalt, Goffman, Deleuze and Szasz believe that pharmacological "treatment" is only a placebo effect, and that administration of drugs is just a religion in disguise and ritualistic chemistry. Other scholars have argued against psychiatric medication in that significant aspects of mental illness are related to the psyche or environmental factors, but medication works exclusively on a pharmacological basis. Antipsychotics have been associated with decreases in brain volume over time, which may indicate a neurotoxic effect. However, untreated psychosis has also been associated with decreases in brain volume and treatments have been shown improve cognitive functioning. == See also == List of long term side effects of antipsychotics Medication Medicine Psychopharmacology == References == == External links == Children and Psychiatric Medication – a multimodal presentation Psychiatric Drugs: Antidepressant, Antipsychotic, Antianxiety, Antimanic Agent, Stimulant Prescription Drugs	Wikipedia/Psychiatric_drug
Psychedelic therapy (or psychedelic-assisted therapy) refers to the proposed use of psychedelic drugs, such as psilocybin, ayahuasca, LSD, psilocin, mescaline (peyote), DMT, 5-MeO-DMT, Ibogaine, MDMA, to treat mental disorders. As of 2021, psychedelic drugs are controlled substances in most countries and psychedelic therapy is not legally available outside clinical trials, with some exceptions. The procedure for psychedelic therapy differs from that of therapies using conventional psychiatric medications. While conventional medications are usually taken without supervision at least once daily, in contemporary psychedelic therapy the drug is administered in a single session (or sometimes up to three sessions) in a therapeutic context. The therapeutic team prepares the patient for the experience beforehand and helps them integrate insights from the drug experience afterwards. After ingesting the drug, the patient normally wears eyeshades and listens to music to facilitate focus on the psychedelic experience, with the therapeutic team interrupting only to provide reassurance if adverse effects such as anxiety or disorientation arise. As of 2022, the body of high-quality evidence on psychedelic therapy remains relatively small and more, larger studies are needed to reliably show the effectiveness and safety of psychedelic therapy's various forms and applications. On the basis of favorable early results, ongoing research is examining proposed psychedelic therapies for conditions including major depressive disorder, anxiety and depression linked to terminal illness, and post-traumatic stress disorder. The United States Food and Drug Administration has granted "breakthrough therapy" status, which expedites the potential approval of promising drug therapies, to psychedelic therapies using psilocybin (for treatment-resistant depression and major depressive disorder) and MDMA (for post-traumatic stress disorder). == History == === Prehistoric use of psychedelic substances === Humans have long consumed psychedelic substances derived from cacti, seeds, bark, and roots of various plants and fungi. Since ancient times, shamans and medicine men have used psychedelics as a way to gain access to the spirit world. Though western culture usually views the practice of shamans and medicine men as predominantly spiritual in nature, elements of psychotherapeutic practice can be read into the entheogenic or shamanic rituals of many cultures. === Research in the mid-20th century === Shortly after Albert Hofmann discovered the psychoactive properties of LSD in 1943, Sandoz Laboratories began widespread distribution of LSD to researchers in 1949. Throughout the 1950s and 1960s, scientists in several countries (e.g., U.S.A.: Langley Porter Psychiatric Institute, MKUltra) conducted extensive research into experimental chemotherapeutic and psychotherapeutic uses of psychedelic drugs. In addition to spawning six international conferences and the release of dozens of books, over 1,000 peer-reviewed clinical papers detailing the use of psychedelic compounds (administered to approximately 40,000 patients) were published by the mid-1960s. Proponents believed that psychedelic drugs facilitated psychoanalytic processes, making them particularly useful for patients with conditions such as alcoholism that are otherwise difficult to treat. However, many of these trials did not meet the methodological standards that are required today. Researchers like Timothy Leary felt psychedelics could alter the fundamental personality structure or subjective value-system of an individual to great potential benefit. Beginning in 1961, he conducted experiments with prison inmates in an attempt to reduce recidivism with short, intense psychotherapy sessions. Participants were administered psilocybin during these sessions weeks apart with regular group therapy sessions in between. Psychedelic therapy was also applied in a number of other specific patient populations including individuals with alcoholism, children with autism, and persons with terminal illness. === Regulation and prohibition in the late 20th century === Throughout the 1960s, concerns raised about the proliferation of unauthorized use of psychedelic drugs by the general public (and, most notably, the counterculture) resulted in the imposition of increasingly severe restrictions on medical and psychiatric research conducted with psychedelic substances. Many countries either banned LSD outright or made it extremely scarce, and, bowing to governmental concerns, Sandoz halted production of LSD in 1965. During a congressional hearing in 1966, Senator Robert F. Kennedy questioned the shift of opinion, stating, "Perhaps to some extent we have lost sight of the fact that (LSD) can be very, very helpful in our society if used properly." In 1968, Dahlberg and colleagues published an article in the American Journal of Psychiatry detailing various forces that had successfully discredited legitimate LSD research. The essay argues that individuals in government and the pharmaceutical industry sabotaged the psychedelic research community by canceling ongoing studies and analysis while labeling genuine scientists as charlatans. Studies on medicinal applications of psychedelics ceased entirely in the United States when the Controlled Substances Act was passed in 1970. LSD and many other psychedelics were placed into the most restrictive "Schedule I" category by the United States Drug Enforcement Administration. Schedule I compounds are claimed to possess "a high potential for abuse and the potential to create severe psychological and/or physical dependence" and have "no currently accepted medical use", effectively rendering them illegal to use in the United States for all purposes. Despite objections from the scientific community, authorized research into therapeutic applications of psychedelic drugs had been discontinued worldwide by the 1980s. Despite broad prohibition, unofficial psychedelic research and therapeutic sessions continued nevertheless in the following decades. Some therapists exploited windows of opportunity preceding scheduling of particular psychedelic drugs. Informal psychedelic therapy was conducted clandestinely in underground networks consisting of sessions carried out both by licensed therapists and autodidacts within the community. Due to the largely illegal nature of psychedelic therapy in this period, little information is available concerning the methods that were used. Individuals having published information between 1980 and 2000 regarding psychedelic psychotherapy include George Greer, Ann and Alexander Shulgin (PiHKAL and TiHKAL), Myron Stolaroff (The Secret Chief, regarding the underground therapy done by Leo Zeff), and Athanasios Kafkalides. === Resurgence in the early 21st century === In the early 2000s, a renewal of interest in the psychiatric use of psychedelics contributed to an increase in clinical research centering on the psychopharmacological effects of these drugs and their subsequent applications. Advances in science and technology allowed researchers to collect and interpret extensive data from animal studies, and the advent of new technologies such as PET and MRI scanning made it possible to examine the sites of action of hallucinogens in the brain. Furthermore, retrospective studies involving users of illicit drugs as voluntary subjects were conducted, allowing data to be collected on how psychedelics affect the human brain while simultaneously sidestepping bureaucratic difficulties associated with providing illegal substances to subjects. The new century also ushered in a broader change in political attitude towards psychedelic medicine—specifically within the Food and Drug Administration. Curtis Wright, then deputy director of the FDA Division of Anesthetic, Critical Care and Addiction Drugs explained a motivation for this change: "the agency was challenged legally in a number of cases and also underwent a process of introspection, asking 'Is it proper to treat this class of drugs differently?'" As of 2014, global treaties listing LSD and psilocybin as "Schedule I" controlled substances continues to inhibit a better understanding of these drugs. Much of the renewed clinical research has been conducted with psilocybin and MDMA in the United States with special permission and breakthrough therapy designations by the FDA, while other studies have investigated the mechanisms and effects of ayahuasca and LSD. MDMA-assisted psychotherapy is being actively researched by MAPS. As of 2023, many new centers for psychedelics research have been launched, including the Centre for Psychedelic Research at Imperial College London, the UC Berkeley Center for the Science of Psychedelics, the Center for Psychedelic and Consciousness Research at Johns Hopkins University, the Center for Psychedelic Research and Therapy at Dell Medical School at the University of Texas at Austin, the Center for Psychedelic Psychotherapy and Trauma Research at the Icahn School of Medicine at Mount Sinai, the Psychae Institute in Melbourne, and the Naut sa mawt Center for Psychedelic Research at Vancouver Island University. Harvard will create a Study of Psychedelics in Society and Culture. A survey published in 2023 found strong support for psychedelic therapy among psychiatrists in the United States, revealing a significant positive shift in attitudes toward this treatment modality in comparison to a previous survey published in 2018. More than half of psychiatrists in the 2023 study expressed intentions to incorporate psychedelic therapy into their practice if regulatory approval is granted. In Australia, authorised psychiatrists can prescribe psilocybin for treatment-resistant depression, and MDMA for post-traumatic stress disorder. In 2024, an FDA advisory panel voted against approving MDMA-assisted therapy for PTSD, "raising questions about the credibility of the research being conducted and the safety of those involved in the trials". The FDA advisors voted 9-2 that the available data didn’t show MDMA was effective in treating PTSD, and 10-1 that the benefits of MDMA-assisted therapy did not outweigh the risks. However, the U.S. Department of Veterans Affairs has since committed $1.5 million to its first study on psychedelic-assisted therapy for PTSD and alcohol use disorder in veterans, signaling growing institutional interest despite FDA skepticism. In addition, veteran-led nonprofits like the Heroic Hearts Project are working with researchers to expand access to psychedelic therapies for military personnel and veterans. In 2025, PsychedeliCare launched a European Citizens’ Initiative aiming to enable the implementation of psychedelic-assisted therapies in the EU to ensure safe and affordable psychedelic-assisted therapies. == Applications == Psychedelic substances which may have therapeutic uses include psilocybin (the main active compound found in "magic" mushrooms), mescaline (the main active compound in the peyote cactus), and LSD. Although the history behind these substances has hindered research into their potential medicinal value, scientists are now able to conduct studies and renew research that was halted in the 1970s. Some research has shown that these substances have helped people with such mental disorders as obsessive-compulsive disorder, post-traumatic stress disorder, alcoholism, depression, and cluster headaches. Some of the well known particular psychedelic substances that have been used to this day are: LSD, DMT, psilocybin, mescaline, 2C-B, 2C-I, 5-MeO-DMT, AMT, ibogaine, and DOM. In general, the mechanism of action of how these drugs have therapeutic effects is poorly understood. Their effects are strongly dependent on the environment in which they are given and on the recipient's state of mind (set and setting). === In substance use disorders === Studies by Humphry Osmond, Betty Eisner, and others examined the possibility that psychedelic therapy could treat alcoholism (or, less commonly, other addictions). Bill Wilson, the founder of Alcoholics Anonymous, used LSD during supervised experiments with Betty Eisner, Gerald Heard, and Aldous Huxley. He ingested LSD for the first time on August 29, 1956. With Wilson's invitation, his wife Lois, his spiritual adviser Father Ed Dowling, and Nell Wing also participated in experimentation of this drug. Later Wilson wrote to Carl Jung, praising the results and recommending it as validation of Jung's spiritual experience. According to Wilson, the session allowed him to re-experience a spontaneous spiritual experience he had had years before, which had enabled him to overcome his own alcoholism. A 1998 review of the effectiveness of psychedelic therapy for treating alcoholism concluded that due to methodological difficulties in the research prior to that time, it was not possible to state whether it was effective. A 2012 meta-analysis found that "In a pooled analysis of six randomized controlled clinical trials, a single dose of LSD had a significant beneficial effect on alcohol misuse at the first reported follow-up assessment, which ranged from 1 to 12 months after discharge from each treatment program. This treatment effect from LSD on alcohol misuse was also seen at 2 to 3 months and at 6 months, but was not statistically significant at 12 months post-treatment. Among the three trials that reported total abstinence from alcohol use, there was also a significant beneficial effect of LSD at the first reported follow-up, which ranged from 1 to 3 months after discharge from each treatment program." In 2022 a systematic review was published on the efficacy of ibogaine/noribogaine, an indole alkaloid with “anti-addictive” properties, to treat substance use disorders looking at studies up to December 2020. Oral ingestion of ibogaine leads to an intense psychedelic experience with effects lasting up to 72 hours that lead participants to insights that may change the way they view life and their ways of thinking; however, the mechanism of how this drug works to reduce substance use is not yet understood. Evidence suggests that ibogaine does have some reduction on opioid and cocaine misuse, but more well designed, larger randomly controlled trials are required to fully understand the therapeutic benefits. Significant adverse reactions were experienced by participants including cardiotoxicity, QT prolongation, ataxia, psychosis, and several fatalities were reported due to toxic adverse events. Analysis of the fatalities concluded that patients with cardiac comorbidities and that those that are taking concurrent medications are at higher risk of a medical emergency. A systematic review completed in 2023, containing studies from the past decade, looked at the ability of psychedelic therapy in combination with psychotherapy to help reduce substance use, cravings, and abstinence of addictions including alcohol, cocaine, opioids, and nicotine. Studies commonly reported reductions in substance misuse, however, the quality of evidence is too low to draw solid conclusions on the efficacy of psychedelic treatments for substance use disorders. However, a systematic review of human and animal studies showed that a single dose of LSD for treatment of AUD led to greater odds of improvement in alcohol consumption than control participants. === In terminal illness === During the early 1950s and 1960s the National Institute of Mental Health sponsored the study of psychedelic drugs such as psilocybin and LSD to alleviate the debilitating anxiety and depression patients with terminal diagnoses may feel. While these early studies are hard to find, the resurgence of interest in psychedelic drugs to treat humans end of life mindset has led to some small studies in the 21st century. The more recently published research strengthens the findings from the 1950s and 1960s showing the drug is extremely effective in reducing anxiety and depression in this patient population once carefully screened and has few adverse effects when administered in a psychotherapy setting and under medical supervision. The psychologists leading psychedelic drug therapy trials found that end of life patients often experience the emotional turmoil of dying more than the physical aspects. This mindset makes it difficult for patients to find meaning and enjoyment in life during their last few months or years. While all patients have completely different experiences on these mind altering drugs the research subjects interviewed all expressed they had, "heightened clarity and confidence about their personal values and priorities, and a renewed or enhanced recognition of intrinsic meaning and value of life." More recently, researchers have argued that psychedelic therapy is beneficial for these patients because it may specifically reduce their fear of dying. As of 2016, Johns Hopkins University and New York University have conducted large randomized, placebo-controlled studies. These two studies are some of the first large controlled studies measuring the effects of psychedelic therapy on depression and anxiety in cancer patients. Across clinician-ratings and self-ratings, the psychedelic treatment produced statistically significant lowered anxiety and depression, with sustenance for at least 6 months. The studies monitored for adverse effects from the drugs but no serious adverse effects were observed. Both studies also attributed the efficacy in part to patients experiencing a "mystical experience". A mystical experience is a very personal introspective experience where some sort of unity or transcendence of time and space is described. More research is necessary to expand generalizability of the conclusions. Also, more research is necessary to understand the biological properties of a mystical experience. Evidence is growing for the use of atypical psychedelics such as ketamine for treating depression in terminally ill patients, with repeated IV administration having the most therapeutic effect. These studies did not have any patients experience any serious adverse effects; however, ketamine-induced ulcerative cystitis is a concern for repeated long-term administration. Qualitative studies are required to better understand the mechanism and thought process changes that lead to therapeutic outcomes. === In post-traumatic stress disorder (PTSD) === The Multidisciplinary Association for Psychedelic Studies (MAPS) is conducting studies in the psychedelic treatment of post-traumatic stress disorder. The Phase 2 trials of these studies, conducted in the U.S., Canada, and Israel, consisted of 107 participants who had chronic, treatment-resistant PTSD, and had had PTSD for an average of 17.8 years. Out of the 107 participants, 61% no longer qualified for PTSD after three sessions of MDMA-assisted psychotherapy two months after the treatment. At the 12-month follow-up session, 68% no longer had PTSD. Phase 2 trials conducted between 2004 and 2010 reported an overall remission rate of 66.2% and low rates of adverse effects for subjects with chronic PTSD. In 2017, MAPS and the FDA reached an agreement on the special protocol for phase 3 trials. Evidence shows that MDMA-assisted psychotherapy versus control shows clinically significant improvement in Clinician-Administered PTSD Scale (CAPS) scores from baseline, with most of the patients no longer meeting the CAPS score for PTSD. Effects of MDMA-assisted psychotherapy can be observed up to 12 months after receiving 2-3 active sessions of moderate to high dose MDMA (75–125 mg). It is important to note that given the difficulties with appropriate blinding in trials of MDMA- and psychedelic-assisted psychotherapy the results are likely overestimated. Furthermore, there are no superiority or non-inferiority clinical trials comparing MDMA-assisted psychotherapy to already existent evidence-based treatments for PTSD, but given the effects reported in clinical trials of MDMA-assisted psychotherapy for PTSD there is no reason to believe that this treatment modality is more effective than existent trauma-focused psychological treatments. In 2024, an FDA advisory panel voted against approving MDMA-assisted therapy for PTSD, "raising questions about the credibility of the research being conducted and the safety of those involved in the trials". The FDA advisors voted 9-2 that the available data didn’t show MDMA was effective in treating PTSD, and 10-1 that the benefits of MDMA-assisted therapy did not outweigh the risks. However, the U.S. Department of Veterans Affairs has since committed $1.5 million to its first study on psychedelic-assisted therapy for PTSD and alcohol use disorder in veterans, signaling growing institutional interest despite FDA skepticism. In addition, veteran-led nonprofits like the Heroic Hearts Project are working with researchers to expand access to psychedelic therapies for military personnel and veterans. === In depressive and anxiety disorders === In 2019, the FDA approved the use of esketamine for intranasal use for major depressive disorder (MDD) and treatment-resistant depression (TRD), in conjunction with an oral antidepressant. Also in 2019, the FDA granted "breakthrough therapy" status to psilocybin for treatment-resistant depression and major depressive disorder in order to hasten the process for potential regulatory approval. The designation of "breakthrough therapy" fast-tracks the study of drugs where preliminary clinical evidence shows that they could be substantially more effective than therapies that are already available. Studies on the clinical effects of ayahuasca have found significant antidepressant and anxiety-reducing effects, leading to calls for further research to overcome methodological limitations in the existing studies. There is some evidence that psilocybin in combination with MDMA could be helpful for treating psychiatric disorders, but only when administered in a controlled clinical setting. There is limited evidence that reductions in suicidality scores can be observed immediately after administration of ayahuasca or psilocybin, observable up to 6 months after administration. === In Obsessive Compulsive Disorder (OCD) === Since 1964, multiple case studies with psychedelic drugs have been performed in patients with either diagnosed OCD or patients exhibiting obsessive and/or compulsive symptoms. In 1964 and 1977, two case studies were published that showed a reduction in symptoms of patients who had previously exhibited obsessive and/or compulsive behaviors after taking Psilocybe mushrooms. In addition, three studies from 1987 to 1997 reported reductions in obsessive and/or compulsive symptoms in patients with diagnosed OCD after taking LSD and psilocybin. In 2014 and 2021, two case studies published by researchers from Arizona and Mexico, respectively, explained how patients taking 2 grams of psilocybin every 2-3 weeks not only saw qualitative improvements in their OCD symptoms, but also sustained this symptom improvement for several weeks after each dose. In 2024, a systematic review was published analyzing the possible therapeutic benefits of psychedelics on OCD and related disorders. Findings include that LSD may be less tolerable than psilocybin due to more potential exacerbations of anxiety and OCD symptoms. Case reports found that psilocybin must be given in repeated doses in order to maintain reduction in OCD symptoms, which differentiates from its effect on depression. In patients diagnosed with body dysmorphic disorder and OCD, a single dose of psilocybin given for OCD symptoms was found to increase insight into the patient's disease, resulting in these patients seeking mental health treatment and recognizing that more effort was needed to tolerate their obsessions and resist their compulsions. This is important because among individuals with OCD, poor insight into their condition is associated with a worse prognosis. Because of existing research showing the efficacy of Exposure and Response Prevention (ERP) in psychiatric disorders, future studies may seek to combine psychedelic therapy, specifically with psilocybin, with ERP as an adjunct for symptom remission, although no such studies have yet been conducted. === In reducing criminal behavior === In 2017, researchers mainly from the University of Birmingham published research suggesting that psilocybin use is correlated with reduced criminal behavior. The researchers analyzed data from 480,000 U.S. adults collected by the National Survey on Drug Use and Health on their past use of psychedelics, including ayahuasca, dimethyltryptamine, LSD, mescaline, peyote, San Pedro, and psilocybin mushrooms. While other illicit drugs have been associated with increased criminal behavior, the researchers found that psychedelic substances were instead associated with reduced criminal behavior. Usage of these substances was associated with a 12% reduction in likelihood of assault, 18% reduction in likelihood of other violent crimes, 27% reduction in likelihood of committing larceny and theft, and 22% reduction in likelihood of committing other property crimes. These findings potentially support the use of psychedelic therapy in forensic and clinical settings. In a prior 2014 study, researchers explored the relationship between recidivism and naturalistic hallucinogens in criminal justice populations with a history of substance use. The results concluded that hallucinogens promoted prosocial behaviors in a population which is typically associated with high recidivism rates. The usage of hallucinogens has been found to reduce supervision failure in ex-convicts. This inherently encourages drug abstinence, including the use of alcohol, resulting in lower rates of recidivism. A 2018 study found that men who had used psychedelic drugs in the past were less likely to commit violence against their current partners compared to those who had not used these substances. The study suggests that the use of psychedelic drugs in men might be associated with a reduced likelihood of committing violence against intimate partners, potentially due to improved emotion regulation. A 2022 U.S. study found that use of classic psychedelics was associated with lowered odds of criminal arrest. The research suggests that 7 of the 11 arrest variables were reduced with lifetime psilocybin use. Peyote use was found to reduce the odds of driving under the influence and vehicle theft. Lastly, mescaline use was found to reduce drug possession/sale. No other substances shared a positive relationship with reducing criminal behavior. == Contraindications == Psychedelic therapy is contraindicated for people who: are pregnant, have a history of epilepsy/other seizure disorder, have severe cardiovascular disease including uncontrolled blood pressure, heart failure, coronary artery disease, or previous heart attack or stroke, use medications like SSRI or MAO-I antidepressants, have a personal or family history of primary psychotic or affective disorders like schizophrenia, schizoaffective disorder, Bipolar I disorder, or psychotic symptoms in the setting of depression. == Criticisms and controversies == Although psychedelic therapy has shown promise in treating a range of mental health conditions—including depression, PTSD, and substance use disorders—it has also generated significant debate across ethical, cultural, and scientific domains. Critics have raised concerns about the overenthusiastic framing of psychedelics as a universal or revolutionary solution, cautioning that such narratives may overshadow limitations in clinical evidence, long-term safety data, and equity in access. Others argue that the rapid commercialization and medicalization of psychedelics risks reproducing existing structural inequalities in mental health care. In response, scholars have called for a more cautious, interdisciplinary approach that considers social context, informed consent, community frameworks, and culturally responsive practices. === Ethical and safety concerns === Critics have raised significant concerns regarding the ethical implications of psychedelic-assisted therapies, particularly focusing on the challenges surrounding informed consent and patient safety. The inherently unpredictable and often ineffable nature of psychedelic experiences can make it difficult for patients to fully comprehend and anticipate potential psychological risks. These challenges complicate the process of obtaining fully informed consent, especially in therapeutic contexts where long-term monitoring or integration support may be limited. In August 2024, the U.S. Food and Drug Administration (FDA) declined to approve the first MDMA-based treatment for post-traumatic stress disorder (PTSD), citing insufficient data and concerns about trial methodology. The agency highlighted issues such as a "striking lack" of documentation regarding participants' prior substance use, problems with trial design, and the necessity for more robust evidence. The FDA requested an additional late-stage trial to further assess the drug's safety and efficacy. Further ethical concerns have emerged from reports of misconduct within clinical trials. For instance, in August 2024, three papers on MDMA-assisted psychotherapy for PTSD were retracted from the journal Psychopharmacology due to ethical violations. These included inappropriate physical contact between a trial participant and an unlicensed therapist, leading to an unethical sexual relationship and alleged sexual assault. The data from this site were not removed from the analyses, raising questions about the integrity of the research. The potential for therapist misconduct is a significant safety concern in psychedelic-assisted therapy. The altered states of consciousness induced by psychedelics can increase patients' suggestibility and vulnerability, necessitating rigorous ethical standards and oversight. Ensuring patient safety requires comprehensive training for therapists, strict adherence to ethical guidelines, and robust mechanisms for reporting and addressing any instances of misconduct. Addressing these ethical and safety concerns is crucial for the responsible development and implementation of psychedelic-assisted therapies. This includes establishing clear protocols for informed consent, ensuring transparency in clinical trial methodologies, implementing stringent ethical standards for therapists, and conducting thorough long-term follow-up studies to monitor patient outcomes. === Methodological and structural limitations === Psychedelic clinical trials have faced recurring criticism for methodological shortcomings, particularly small sample sizes, short follow-up durations, and the exclusion of participants with comorbid or severe psychiatric conditions. These constraints reduce the external validity of findings, limiting their applicability to broader, real-world populations. For instance, many studies prioritize controlled environments and relatively healthy participants, thereby excluding those who may be most in need of innovative mental health treatments, such as individuals with trauma histories, substance use disorders, or severe depression. In addition to these design limitations, demographic homogeneity remains a persistent issue in psychedelic research. A review of 18 psychedelic clinical trials found that 82.3% of participants were non-Hispanic White, with minimal inclusion of Black, Latino, Indigenous, and Asian individuals. More recent analyses suggest that despite growing interest in equitable access, racial and ethnic minorities remain significantly underrepresented in both research studies and clinical practice settings. This underrepresentation has sparked broader concerns about systemic exclusion and the equitable distribution of therapeutic benefits. Historical medical abuses—such as the Tuskegee Syphilis Study and CIA-led MK-Ultra experiments—have contributed to deep mistrust in research institutions among marginalized communities. To address these disparities, scholars and clinicians have called for more inclusive and culturally responsive research practices. Proposed strategies include partnering with community organizations, diversifying research staff, and creating protocols that respect cultural traditions and concerns. Such efforts aim not only to expand access but also to rebuild trust and ensure that psychedelic-assisted therapies are effective and ethical across diverse populations. === Sociological critiques and inequality in access and outcomes === Although psychedelic therapy is often presented as a universally beneficial mental health intervention, emerging sociological and epidemiological research has identified disparities in outcomes across demographic groups. Studies suggest that benefits associated with psychedelic use may be unequally distributed due to structural and social inequalities. Several peer-reviewed studies have documented that racial and ethnic minorities often experience diminished psychological benefits from psychedelics compared to White participants, even when controlling for socioeconomic status, education, and baseline health. Additional research focusing on American Indian Areas has linked geographic and historical disadvantage to more limited mental health improvements following psychedelic use. Gender differences have also been observed. Findings indicate that women may experience more variable or attenuated outcomes than men, particularly in relation to stigma reduction and distress. Other research suggests that education moderates these gender differences, with highly educated men reporting the strongest positive effects. Disparities based on marital and employment status have also been explored. Individuals who are married or employed report greater psychological benefit, potentially due to social support systems and improved access to post-experience integration resources. Variation has been noted in outcomes by religious affiliation and participation. Some studies suggest that individuals with strong religious integration may experience more meaningful or sustained benefits due to the availability of social and interpretive frameworks, while others with rigid or punitive religious backgrounds may experience conflict or distress. LGBTQ+ individuals have also been found to experience unique patterns of benefit and risk in relation to psychedelic use. While some research documents substantial mental health improvements, others point to amplified vulnerability due to minority stress or inadequate therapeutic frameworks. In addition, findings suggest that those from historically marginalized populations are more likely to avoid formal healthcare following psychedelic use due to prior stigma or systemic exclusion, potentially increasing risk or reducing access to integration services. Collectively, this growing body of research challenges assumptions of universal benefit and has contributed to calls for equity-centered approaches in psychedelic science. These include greater attention to structural context, culturally responsive practices, and the inclusion of diverse communities in both research and therapeutic design. === Overmedicalization and commercialization === ==== Marginalization of traditional and community-based healing ==== Scholars and activists have raised concerns that the medicalization of psychedelics risks marginalizing longstanding traditional, spiritual, and community-based approaches to healing. Tightly regulated clinical models—especially those requiring physician oversight and FDA approval—often exclude practices rooted in Indigenous knowledge, harm-reduction communities, or informal peer support structures. Critics argue that this narrowing of acceptable use may replicate colonial dynamics by privileging biomedical authority while disregarding alternative cultural and historical frameworks for psychedelic use. Some researchers note that medical gatekeeping can deter vulnerable populations—especially those with prior trauma or medical mistrust—from seeking care. Others argue that community-first models, such as peer-led integration circles or underground networks, have demonstrated safety and efficacy outside of formal institutions but remain unrecognized in dominant medical discourse. These concerns have fueled calls for pluralistic frameworks that allow coexistence between clinical models and culturally grounded or community-led approaches to psychedelic healing. ==== Organizational influence and conflicts of interest ==== The influence of prominent organizations and individuals in the psychedelic field has raised concerns about transparency, accountability, and potential conflicts of interest. The Multidisciplinary Association for Psychedelic Studies (MAPS), a leading organization in psychedelic research and advocacy, has faced scrutiny regarding its internal governance and handling of ethical violations. In 2019, MAPS publicly disclosed that former clinical sub-investigators in a sponsored trial had violated ethical standards during therapy sessions. While MAPS stated that it responded promptly and transparently, critics questioned the adequacy of the organization's oversight mechanisms. Further concerns emerged from the 2023 Psychedelic Science conference in Denver, Colorado, hosted by MAPS and the Multidisciplinary Association for Psychedelic Studies Public Benefit Corporation (MAPS PBC). The conference featured over 300 speakers, including academic researchers, therapists, entrepreneurs, and policy advocates. Many speakers disclosed financial interests in psychedelic companies, intellectual property claims, or affiliations with private clinics. Notable figures with such disclosures included: - Robin Carhart-Harris, a leading neuroscientist in psychedelic research - Bia Labate, an anthropologist and executive director of the Chacruna Institute - Rick Doblin, founder and president of MAPS - Tim Ferriss, author and investor - Charles Raison, psychiatrist and director of the Center for Compassion Studies at the University of Arizona - Matthew Johnson, professor of psychiatry and behavioral sciences at Johns Hopkins University These conflict of interest disclosures were initially made available through the conference’s mobile app by the Postgraduate Institute for Medicine (PIM) but were later removed. Psymposia, a nonprofit media organization, archived the full list to preserve public access and transparency. Rick Doblin has faced criticism for his dual role as both an advocate and the head of an organization poised to benefit financially from the potential FDA approval of MDMA-assisted therapy. Observers argue that this overlap between activism, research, and commercial interest may compromise objectivity in public discourse and trial reporting. Broader concerns have been raised about how financial entanglements could influence research agendas and regulatory frameworks. In 2024, the Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics at Harvard Law School hosted a panel titled “Disclosed: Conflicts of Interest in the Psychedelics Ecosystem,” which examined how investment structures, private equity, and market speculation are shaping the future of psychedelic medicine. These developments have led to calls for independent oversight, greater funding transparency, and more inclusive governance models to protect the integrity of psychedelic science and practice. ==== Patents, venture capital, and market consolidation ==== As the psychedelic field attracts increasing financial interest, critics have raised alarms about the ethical and structural implications of venture capital investment, aggressive patent strategies, and the potential monopolization of psychedelic therapies. A number of biotechnology companies and investors have moved quickly to patent not only psychedelic compounds—such as psilocybin analogs and synthetic DMT—but also delivery methods, treatment protocols, and even aspects of the therapeutic experience itself. This surge of intellectual property claims has sparked debates over the ethics of commodifying substances that have deep cultural, communal, and spiritual significance. Some researchers and Indigenous advocates argue that patenting naturally occurring substances or ceremonial knowledge represents a form of "biopiracy," in which Western institutions extract and profit from traditional practices without community consent or benefit-sharing mechanisms. The controversy has intensified as corporations such as COMPASS Pathways and MindMed have secured patents on specific synthetic formulations or therapy session structures, prompting concerns about limited access, market exclusivity, and the suppression of innovation. In parallel, the influx of venture capital has raised questions about whether financial incentives may undermine patient well-being. Observers note that the pressure to deliver returns to shareholders could lead to expedited clinical trials, underreporting of adverse effects, or the commercialization of unproven therapies. These dynamics are increasingly seen as misaligned with the values of many early psychedelic researchers, who viewed the field as an opportunity to promote personal transformation, healing, and societal reflection rather than profit maximization. To mitigate these risks, scholars and advocacy groups have called for stronger open-access protections, ethical licensing models, and international standards to prevent monopolistic control. Some propose that non-profit and community-based models be protected or prioritized in future regulatory frameworks to ensure the equitable and culturally sensitive development of psychedelic therapies. == Methods == === Standard psychedelic therapy === The main approach used in the contemporary resurgence of research, often simply called psychedelic therapy, involves the use of moderate-to-high doses of psychedelic drugs. The psychedelic therapy method was initiated by Humphry Osmond and Abram Hoffer (with some influence from Al Hubbard) and replicated by Keith Ditman, and is more closely aligned to transpersonal psychology than to traditional psychoanalysis. Most recent research on psychedelic therapy has used psilocybin or ayahuasca. Patients spend most of the acute period of the drug's activity lying down with eyeshades listening to music selected beforehand and exploring their inner experience. Dialogue with the therapists the drug session(s) but essential during the preparation session before and the integration session afterwards. The therapeutic team normally consists of a man and a woman, who are both present throughout the psychedelic experience. One aspect that occurs in most participants undergoing psychedelic therapy with moderate-to-high doses is transcendental, mystical, or peak experiences. Research has suggested that the strength of these experiences, together with discussion of them soon after in a therapeutic session, could be a major determinant of how great the longer-term effects on symptoms will be. Some studies of psychedelic therapy have incorporated cognitive behavioral therapy (CBT) or motivational enhancement therapy (MET). Within a structured CBT intervention and a dose of psilocybin, patients are given the opportunity to experience cognitive and emotional states that are altered. With these psychedelic effects, cognitive reframing of detrimental schemas and self-identity can be modified positively. In a MET environment, patients are able to reflect on their own behaviors to make changes in problematic manners, such as alcohol use disorder. Additionally, it could potentially enhance motivation to change and decrease possible ambivalence about behavioral changes. Within psychedelic drug sessions, through a reevaluation of the concept of self and reconnecting with core beliefs and values, this can be achieved. Psychedelic-assisted group psychotherapy can be more cost-efficient, because therapists can split the costs among all participants of the group. === Psycholytic therapy === Psycholytic therapy involves the use of low-to-medium doses of psychedelic drugs, repeatedly at intervals of 1–2 weeks. The therapist is present during the peak of the experience to assist the patient in processing material that arises and to offer support. This general form of therapy was mostly used to treat patients with neurotic and psychosomatic disorders. The name psycholytic therapy was coined by Ronald A. Sandison, literally meaning "soul-dissolving", refers to the belief that the therapy can dissolve conflicts in the mind. Psycholytic therapy was historically an important approach to psychedelic psychotherapy in Europe, and was also practiced in the United States by some psychotherapists, including Betty Eisner. In the time since the 1970s, psycholytic therapy has not been a focus of research. Psychedelic drugs are useful for exploring the subconscious because a conscious sliver of the adult ego usually remains active during the experience.: 196 Patients remain intellectually alert throughout the process and remember their experiences vividly afterward.: 196 In this highly introspective state, patients are actively aware of ego defenses such as projection, denial, and displacement as they react to themselves and their choices.: 196 The ultimate goal of the therapy is to provide a safe, mutually compassionate context through which the profound and intense reliving of memories can be filtered through the principles of genuine psychotherapy. Aided by the deeply introspective state attained by the patient, the therapist assists him/her in developing a new life framework or personal philosophy that recognizes individual responsibility for change.: 196 In Germany, Hanscarl Leuner designed a form of psycholytic therapy, which was developed officially but was also used by some socio-politically motivated underground therapists in the 1970s. In Switzerland, Friedericke Meckel Fisher (trained by Stanislav Grof in Breathwork and Samuel Widmer in group psychedelic sessions) practiced group psycholytic therapy mainly from the early 2000s and until 2015. Meckel Fischer developed her own system of psycholytic therapy which she conducted underground, in group weekend sessions of 15 to 19 people, using medium dosages of psychedelic substances. She added and combined into this psycholytic group work, techniques of her own modified family constellation work, cathartic body work, evocative music, and periods of sharing and feedback within the group. === Other variations === ==== Claudio Naranjo ==== The Chilean therapist Claudio Naranjo developed a branch of psychedelic therapy that utilized drugs like MDA, MDMA, harmaline, and ibogaine. ==== Anaclitic therapy ==== The term anaclitic (from the Ancient Greek "ἀνάκλιτος", anaklitos – "for reclining") refers to primitive, infantile needs and tendencies directed toward a pre-genital love object. Developed by two London psychoanalysts, Joyce Martin and Pauline McCririck, this form of treatment is similar to psycholytic approaches as it is based largely on a psychoanalytic interpretation of abreactions produced by the treatment, but it tends to focus on those experiences in which the patient re-encounters carnal feelings of emotional deprivation and frustration stemming from the infantile needs of their early childhood. As a result, the treatment was developed with the aim to directly fulfill or satisfy those repressed, agonizing cravings for love, physical contact, and other instinctual needs re-lived by the patient. Therefore, the therapist is completely engaged with the subject, as opposed to the traditional detached attitude of the psychoanalyst. With the intense emotional episodes that came with the psychedelic experience, Martin and McCririck aimed to sit in as the "mother" role who would enter into close physical contact with the patients by rocking them, giving them milk from a bottle, etc. ==== Hypnodelic therapy ==== Hypnodelic therapy, as the name suggests, was developed with the goal to maximize the power of hypnotic suggestion by combining it with the psychedelic experience. After training the patient to respond to hypnosis, LSD would be administered, and during the onset phase of the drug the patient would be placed into a state of trance. Levine and Ludwig found the combination of these techniques to be more effective than the use of either of these two components separately. == Public interest == A resurgence of public interest in psychedelic drug therapy in the 21st century has been driven in part by articles in The New Yorker, The New York Times, and The Wall Street Journal. === Psychedelic tourism === The first article to bring attention to the uses of psychedelic drugs for mental health was titled, "Seeking the Magic Mushroom", written by Robert Gordon Wasson and published in 1957 by TIME magazine. It detailed his experience traveling to Oaxaca, Mexico, and taking "magic mushrooms" (psilocybin) within the cultural practices that started the "trip" experience. Since that time, there has been growing interest within the United States to travel for these unique psychedelic experiences. The market for psychedelic tourism is currently growing rapidly. While typically the vacation destinations for psychedelics are based in Central and South America, there is a rise in western culture taking over their traditional practices. In the Netherlands, there are psychedelic society retreats ranging in cost from $500–1200 that center on a ceremony in which tourists take magic mushrooms and trip together for around six hours. There are also underground psychedelic "guides" popping up around the United States that include leaders who claim to assist people through their trip similar to shamans in other cultures. An article in The Guardian entitled "Welcome to the trip of your life: the rise of underground LSD guides" details various styles of guides that can be found within the United States. === Psilocybin therapy === Psilocybin therapy is the use of psilocybin (the psychoactive ingredient in psilocybin mushrooms) in treating a range of mental health conditions, such as depression, anxiety, addictions, obsessive compulsive disorder, and psychosis. As of January 1, 2023, psilocybin services facilitator training is available for individuals aged 21 and above who are Oregon residents. To become a psilocybin facilitator, an individual must complete a 120-hour regulated facilitator course, after which they may guide a client through a psilocybin experience. The facilitator may not engage the client in therapy; the therapeutic sessions held before and after the psilocybin experience itself are held by a psychotherapist. As of March 2023, there are currently graduates who can practice as licensed facilitators; however, no licensed service centers are yet operating. == See also == == Notes == == References == == External links == History of LSD Therapy (Ch. 1 of Grof's, LSD Psychotherapy) Reimbursement Pathways for Psychedelic Therapies in Europe Magnetar Access & Blossom The Second International Conference on the Use of LSD in Psychotherapy and Alcoholism Archived 2016-03-05 at the Wayback Machine (1967) (entire book)	Wikipedia/Psychedelic-assisted_therapy
LPH-5 is a psychedelic discovered by Emil Marcher-Rørsted, Jesper L. Kristensen and Anders A. Jensen at Danish biopharmaceutical company Lophora. It is a conformationally-restricted derivative of the phenethylamine 2C-TFM, also a hallucinogen, and acts as a potent agonist of the 5-HT2A receptor (EC50 = 3.2 nM, Emax = 78%). It shows 10- to 100-fold selectivity for the 5-HT2A receptor over the 5-HT2B and 5-HT2C receptors and, along with related compounds like 25CN-NBOH, is said to be one of the few truly selective 5-HT2A receptor agonists. LPH-5 is expected to avoid the cardiac risks of 5-HT2B receptor activation. LPH-48, an analogue of LPH-5 that likewise acts as a selective serotonin 5-HT2A receptor agonist and psychedelic hallucinogen and shows similar characteristics but has a shorter duration of action, is also under development by Lophora. == See also == DEMPDHPCA-2C-D DEMPDHPCA 2C-B-PP 2C-TFM CYB-210010 OSU-6162 TCB-2 ZC-B DMBMPP Z3517967757 == References ==	Wikipedia/LPH-5_(drug)
Fumaric acid or trans-butenedioic acid is an organic compound with the formula HO2CCH=CHCO2H. A white solid, fumaric acid occurs widely in nature. It has a fruit-like taste and has been used as a food additive. Its E number is E297. The salts and esters are known as fumarates. Fumarate can also refer to the C4H2O2−4 ion (in solution). Fumaric acid is the trans isomer of butenedioic acid, while maleic acid is the cis isomer. == Biosynthesis and occurrence == It is produced in eukaryotic organisms from succinate in complex 2 of the electron transport chain via the enzyme succinate dehydrogenase. Fumaric acid is found in fumitory (Fumaria officinalis), bolete mushrooms (specifically Boletus fomentarius var. pseudo-igniarius), lichen, and Iceland moss. Fumarate is an intermediate in the citric acid cycle used by cells to produce energy in the form of adenosine triphosphate (ATP) from food. It is formed by the oxidation of succinate by the enzyme succinate dehydrogenase. Fumarate is then converted by the enzyme fumarase to malate. Human skin naturally produces fumaric acid when exposed to sunlight. Fumarate is also a product of the urea cycle. Click on genes, proteins and metabolites below to link to respective articles. == Uses == === Food === Fumaric acid has been used as a food acidulant since 1946. It is approved for use as a food additive in the EU, USA and Australia and New Zealand. As a food additive, it is used as an acidity regulator and can be denoted by the E number E297. It is generally used in beverages and baking powders for which requirements are placed on purity. Fumaric acid is used in the making of wheat tortillas as a food preservative and as the acid in leavening. It is generally used as a substitute for tartaric acid and occasionally in place of citric acid, at a rate of 1 g of fumaric acid to every ~1.5 g of citric acid, in order to add sourness, similarly to the way malic acid is used. As well as being a component of some artificial vinegar flavors, such as "Salt and Vinegar" flavored potato chips, it is also used as a coagulant in stove-top pudding mixes. The European Commission Scientific Committee on Animal Nutrition, part of DG Health, found in 2014 that fumaric acid is "practically non-toxic" but high doses are probably nephrotoxic after long-term use. === Medicine === Fumaric acid was developed as a medicine to treat the autoimmune condition psoriasis in the 1950s in Germany as a tablet containing 3 esters, primarily dimethyl fumarate, and marketed as Fumaderm by Biogen Idec in Europe. Biogen would later go on to develop the main ester, dimethyl fumarate, as a treatment for multiple sclerosis. In patients with relapsing-remitting multiple sclerosis, the ester dimethyl fumarate (BG-12, Biogen) significantly reduced relapse and disability progression in a phase 3 trial. It activates the Nrf2 antioxidant response pathway, the primary cellular defense against the cytotoxic effects of oxidative stress. === Other uses === Fumaric acid is used in the manufacture of polyester resins and polyhydric alcohols and as a mordant for dyes. Fumaric acid can be used to make 6-methylcoumarin. When fumaric acid is added to their feed, lambs produce up to 70% less methane during digestion. == Synthesis == Fumaric acid is produced based on catalytic isomerisation of maleic acid in aqueous solutions at low pH. It precipitates from the reaction solution. Maleic acid is accessible in large volumes as a hydrolysis product of maleic anhydride, produced by catalytic oxidation of benzene or butane. === Historic and laboratory routes === Fumaric acid was first prepared from succinic acid. A traditional synthesis involves oxidation of furfural (from the processing of maize) using chlorate in the presence of a vanadium-based catalyst. == Reactions == The chemical properties of fumaric acid can be anticipated from its component functional groups. This weak acid forms a diester, it undergoes bromination across the double bond, and it is a good dienophile. == Safety == The oral LD50 is 10g/kg. == See also == Citric acid cycle (TCA cycle) Fumarate reductase Photosynthesis Maleic acid, the cis isomer of fumaric acid Succinic acid == References == == External links == International Chemical Safety Card 1173	Wikipedia/Fumarate
Dissociatives, colloquially dissos, are a subclass of hallucinogens that distort perception of sight and sound and produce feelings of detachment – dissociation – from the environment and/or self. Although many kinds of drugs are capable of such an effect, dissociatives are unique in that they do so in such a way that they produce hallucinogenic effects, which may include dissociation, a general decrease in sensory experience, hallucinations, dream-like states or anesthesia. Despite most dissociatives' main mechanism of action being tied to NMDA receptor antagonism, some of these substances, which are nonselective in action and affect the dopamine and/or opioid systems, may be capable of inducing more direct and repeatable euphoria or symptoms which are more akin to the effects of typical "hard drugs" or common drugs of abuse. This is likely why dissociatives are considered to be addictive with a fair to moderate potential for abuse, unlike psychedelics. Despite some dissociatives, such as phencyclidine (PCP) possessing stimulating properties, most dissociatives seem to have a general depressant effect and can produce sedation, respiratory depression, nausea, disorientation, analgesia, anesthesia, ataxia, cognitive and memory impairment as well as amnesia. Examples of dissociatives include arylcyclohexylamines like ketamine and phencyclidine (PCP); morphinans like dextromethorphan (DXM); inhalants like nitrous oxide (N2O); diarylethylamines like diphenidine; and adamantanes like memantine, among others. == Effects == The effects of dissociatives can include sensory dissociation, hallucinations, mania, catalepsy, analgesia and amnesia. According to Pender (1972), "the state has been designated as dissociative anesthesia since the patient truly seems disassociated from his environment." Both Pender (1970) and Johnstone et al. (1959) reported that patients under anaesthesia due to either ketamine or phencyclidine were prone to purposeless movements and had hallucinations (or "dreams") during and after anaesthesia. Some patients found the hallucinations euphoric while others found them disturbing. At sub-anesthetic doses, dissociatives alter many of the same cognitive and perceptual processes affected by other hallucinogenic drugs such as mescaline, LSD, and psilocybin; hence they are often contrasted and also considered hallucinogenic. Perhaps the most significant subjective differences between dissociatives and the classical hallucinogens (such as LSD and mescaline) are the detaching effects, including: depersonalization, the feeling of being unreal, disconnected from one's self, or unable to control one's actions; and derealization, the feeling that the outside world is unreal or that one is dreaming. == Use == === Medical use === Many dissociatives such as ketamine are used as anesthetics for surgery or pain relief in medical contexts such as in hospitals. However, due to possible psychotomimetic reactions they are sometimes used reluctantly. Certain morphinan dissociatives such as dextromethorphan are also used in sub-psychoactive dosages to suppress coughing. Ketamine is also currently being studied and is showing promising results as a possible fast-acting antidepressant. It may also function as a possible palliative treatment for C-PTSD and chronic pain. === Recreational use === Some dissociative drugs are used recreationally. Ketamine and nitrous oxide are club drugs. Phencyclidine (PCP or angel dust) is available as a street drug. Dextromethorphan-based cough syrups (often labeled DXM) are taken by some users in higher than medically recommended levels for their dissociative effects. Historically, chloroform and diethyl ether have been used recreationally. == See also == Arylcyclohexylamine Morphinan NMDA receptor antagonist Recreational use of nitrous oxide Hallucinogen Deliriant Dissociation (neuropsychology) Dissociation (psychology) Trip report == References == == External links == Media related to Dissociatives at Wikimedia Commons	Wikipedia/Dissociative_drug
Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behavior that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use can alter brain function in synapses similar to natural rewards like food or falling in love in ways that perpetuate craving and weakens self-control for people with pre-existing vulnerabilities. This phenomenon – drugs reshaping brain function – has led to an understanding of addiction as a brain disorder with a complex variety of psychosocial as well as neurobiological factors that are implicated in the development of addiction. While mice given cocaine showed the compulsive and involuntary nature of addiction, for humans this is more complex, related to behavior or personality traits. Classic signs of addiction include compulsive engagement in rewarding stimuli, preoccupation with substances or behavior, and continued use despite negative consequences. Habits and patterns associated with addiction are typically characterized by immediate gratification (short-term reward), coupled with delayed deleterious effects (long-term costs). Examples of substance addiction include alcoholism, cannabis addiction, amphetamine addiction, cocaine addiction, nicotine addiction, opioid addiction, and eating or food addiction. Behavioral addictions may include gambling addiction, shopping addiction, stalking, pornography addiction, internet addiction, social media addiction, video game addiction, and sexual addiction. The DSM-5 and ICD-10 only recognize gambling addictions as behavioral addictions, but the ICD-11 also recognizes gaming addictions. == Signs and symptoms == Signs and symptoms of drug addiction can vary depending on the type of addiction. Symptoms may include: Continuation of drug use despite the knowledge of consequences Disregarding financial status when it comes to drug purchases Ensuring a stable supply of the drug Needing more of the drug over time to achieve similar effects Social and work life impacted due to drug use Unsuccessful attempts to stop drug use Urge to use drug regularly Other signs and symptoms can be categorized across relevant dimensions: == Substance addiction == === Drug addiction === Drug addiction, which belongs to the class of substance-related disorders, is a chronic and relapsing brain disorder that features drug seeking and drug abuse, despite their harmful effects. This form of addiction changes brain circuitry such that the brain's reward system is compromised, causing functional consequences for stress management and self-control. Damage to the functions of the organs involved can persist throughout a lifetime and cause death if untreated. Substances involved with drug addiction include alcohol, nicotine, marijuana, opioids, cocaine, amphetamines, and even foods with high fat and sugar content. Addictions can begin experimentally in social contexts and can arise from the use of prescribed medications or a variety of other measures. Drug addiction has been shown to work in phenomenological, conditioning (operant and classical), cognitive models, and the cue reactivity model. However, no one model completely illustrates substance abuse. Risk factors for addiction include: Aggressive behavior (particularly in childhood) Availability of substance Community economic status Experimentation Epigenetics Impulsivity (attentional, motor, or non-planning) Lack of parental supervision Lack of peer refusal skills Mental disorders Method substance is taken Usage of substance in youth === Food addiction === The diagnostic criteria for food or eating addiction has not been categorized or defined in references such as the Diagnostic and Statistical Manual of Mental Disorders (DSM or DSM-5) and is based on subjective experiences similar to substance use disorders. Food addiction may be found in those with eating disorders, though not all people with eating disorders have food addiction and not all of those with food addiction have a diagnosed eating disorder. Long-term frequent and excessive consumption of foods high in fat, salt, or sugar, such as chocolate, can produce an addiction similar to drugs since they trigger the brain's reward system, such that the individual may desire the same foods to an increasing degree over time. The signals sent when consuming highly palatable foods have the ability to counteract the body's signals for fullness and persistent cravings will result. Those who show signs of food addiction may develop food tolerances, in which they eat more, despite the food becoming less satisfactory. Chocolate's sweet flavor and pharmacological ingredients are known to create a strong craving or feel 'addictive' by the consumer. A person who has a strong liking for chocolate may refer to themselves as a chocoholic. Risk factors for developing food addiction include excessive overeating and impulsivity. The Yale Food Addiction Scale (YFAS), version 2.0, is the current standard measure for assessing whether an individual exhibits signs and symptoms of food addiction. It was developed in 2009 at Yale University on the hypothesis that foods high in fat, sugar, and salt have addictive-like effects which contribute to problematic eating habits. The YFAS is designed to address 11 substance-related and addictive disorders (SRADs) using a 25-item self-report questionnaire, based on the diagnostic criteria for SRADs as per DSM-5. A potential food addiction diagnosis is predicted by the presence of at least two out of 11 SRADs and a significant impairment to daily activities. The Barratt Impulsiveness Scale, specifically the BIS-11 scale, and the UPPS-P Impulsive Behavior subscales of Negative Urgency and Lack of Perseverance have been shown to have relation to food addiction. == Behavioral addiction == The term behavioral addiction refers to a compulsion to engage in a natural reward – which is a behavior that is inherently rewarding (i.e., desirable or appealing) – despite adverse consequences. Preclinical evidence has demonstrated that marked increases in the expression of ΔFosB through repetitive and excessive exposure to a natural reward induces the same behavioral effects and neuroplasticity as occurs in a drug addiction. Addiction can exist without psychotropic drugs, an idea that was popularized by psychologist Stanton Peele. These are termed behavioral addictions. Such addictions may be passive or active, but they commonly contain reinforcing features, which are found in most addictions. Sexual behavior, eating, gambling, playing video games, and shopping are all associated with compulsive behaviors in humans and have been shown to activate the mesolimbic pathway and other parts of the reward system. Based on this evidence, sexual addiction, gambling addiction, video game addiction, and shopping addiction are classified accordingly. == Causes == === Personality theories === Personality theories of addiction are psychological models that associate personality traits or modes of thinking (i.e., affective states) with an individual's proclivity for developing an addiction. Data analysis demonstrates that psychological profiles of drug users and non-users have significant differences and the psychological predisposition to using different drugs may be different. Models of addiction risk that have been proposed in psychology literature include: an affect dysregulation model of positive and negative psychological affects, the reinforcement sensitivity theory of impulsiveness and behavioral inhibition, and an impulsivity model of reward sensitization and impulsiveness. === Neuropsychology === The transtheoretical model of change (TTM) can point to how someone may be conceptualizing their addiction and the thoughts around it, including not being aware of their addiction. Cognitive control and stimulus control, which is associated with operant and classical conditioning, represent opposite processes (i.e., internal vs external or environmental, respectively) that compete over the control of an individual's elicited behaviors. Cognitive control, and particularly inhibitory control over behavior, is impaired in both addiction and attention deficit hyperactivity disorder. Stimulus-driven behavioral responses (i.e., stimulus control) that are associated with a particular rewarding stimulus tend to dominate one's behavior in an addiction. ==== Stimulus control of behavior ==== In operant conditioning, behavior is influenced by outside stimulus, such as a drug. The operant conditioning theory of learning is useful in understanding why the mood-altering or stimulating consequences of drug use can reinforce continued use (an example of positive reinforcement) and why the addicted person seeks to avoid withdrawal through continued use (an example of negative reinforcement). Stimulus control is using the absence of the stimulus or presence of a reward to influence the resulting behavior. ==== Cognitive control of behavior ==== Cognitive control is the intentional selection of thoughts, behaviors, and emotions, based on our environment. It has been shown that drugs alter the way our brains function, and its structure. Cognitive functions such as learning, memory, and impulse control, are affected by drugs. These effects promote drug use, as well as hinder the ability to abstain from it. The increase in dopamine release is prominent in drug use, specifically in the ventral striatum and the nucleus accumbens. Dopamine is responsible for producing pleasurable feelings, as well driving us to perform important life activities. Addictive drugs cause a significant increase in this reward system, causing a large increase in dopamine signaling as well as increase in reward-seeking behavior, in turn motivating drug use. This promotes the development of a maladaptive drug to stimulus relationship. Early drug use leads to these maladaptive associations, later affecting cognitive processes used for coping, which are needed to successfully abstain from them. == Risk factors == A number of genetic and environmental risk factors exist for developing an addiction. Genetic and environmental risk factors each account for roughly half of an individual's risk for developing an addiction; the contribution from epigenetic risk factors to the total risk is unknown. Even in individuals with a relatively low genetic risk, exposure to sufficiently high doses of an addictive drug for a long period of time (e.g., weeks–months) can result in an addiction. Adverse childhood events are associated with negative health outcomes, such as substance use disorder. Childhood abuse or exposure to violent crime is related to developing a mood or anxiety disorder, as well as a substance dependence risk. === Genetic factors === Genetic factors, along with socio-environmental (e.g., psychosocial) factors, have been established as significant contributors to addiction vulnerability. Studies done on 350 hospitalized drug-dependent patients showed that over half met the criteria for alcohol abuse, with a role of familial factors being prevalent. Genetic factors account for 40–60% of the risk factors for alcoholism. Similar rates of heritability for other types of drug addiction have been indicated, specifically in genes that encode the Alpha5 Nicotinic Acetylcholine Receptor. Knestler hypothesized in 1964 that a gene or group of genes might contribute to predisposition to addiction in several ways. For example, altered levels of a normal protein due to environmental factors may change the structure or functioning of specific brain neurons during development. These altered brain neurons could affect the susceptibility of an individual to an initial drug use experience. In support of this hypothesis, animal studies have shown that environmental factors such as stress can affect an animal's genetic expression. In humans, twin studies into addiction have provided some of the highest-quality evidence of this link, with results finding that if one twin is affected by addiction, the other twin is likely to be as well, and to the same substance. Further evidence of a genetic component is research findings from family studies which suggest that if one family member has a history of addiction, the chances of a relative or close family developing those same habits are much higher than one who has not been introduced to addiction at a young age. The data implicating specific genes in the development of drug addiction is mixed for most genes. Many addiction studies that aim to identify specific genes focus on common variants with an allele frequency of greater than 5% in the general population. When associated with disease, these only confer a small amount of additional risk with an odds ratio of 1.1–1.3 percent; this has led to the development the rare variant hypothesis, which states that genes with low frequencies in the population (<1%) confer much greater additional risk in the development of the disease. Genome-wide association studies (GWAS) are used to examine genetic associations with dependence, addiction, and drug use. These studies rarely identify genes from proteins previously described via animal knockout models and candidate gene analysis. Instead, large percentages of genes involved in processes such as cell adhesion are commonly identified. The important effects of endophenotypes are typically not capable of being captured by these methods. Genes identified in GWAS for drug addiction may be involved either in adjusting brain behavior before drug experiences, subsequent to them, or both. === Environmental factors === Environmental risk factors for addiction are the experiences of an individual during their lifetime that interact with the individual's genetic composition to increase or decrease his or her vulnerability to addiction. For example, after the nationwide outbreak of COVID-19, more people quit (vs. started) smoking; and smokers, on average, reduced the quantity of cigarettes they consumed. More generally, a number of different environmental factors have been implicated as risk factors for addiction, including various psychosocial stressors. The National Institute on Drug Abuse (NIDA) and studies cite lack of parental supervision, the prevalence of peer substance use, substance availability, and poverty as risk factors for substance use among children and adolescents. The brain disease model of addiction posits that an individual's exposure to an addictive drug is the most significant environmental risk factor for addiction. Many researchers, including neuroscientists, indicate that the brain disease model presents a misleading, incomplete, and potentially detrimental explanation of addiction. The psychoanalytic theory model defines addiction as a form of defense against feelings of hopelessness and helplessness as well as a symptom of failure to regulate powerful emotions related to adverse childhood experiences (ACEs), various forms of maltreatment and dysfunction experienced in childhood. In this case, the addictive substance provides brief but total relief and positive feelings of control. The Adverse Childhood Experiences Study by the Centers for Disease Control and Prevention has shown a strong dose–response relationship between ACEs and numerous health, social, and behavioral problems throughout a person's lifespan, including substance use disorder. Children's neurological development can be permanently disrupted when they are chronically exposed to stressful events such as physical, emotional, or sexual abuse, physical or emotional neglect, witnessing violence in the household, or a parent being incarcerated or having a mental illness. As a result, the child's cognitive functioning or ability to cope with negative or disruptive emotions may be impaired. Over time, the child may adopt substance use as a coping mechanism or as a result of reduced impulse control, particularly during adolescence. Vast amounts of children who experienced abuse have gone on to have some form of addiction in their adolescence or adult life. This pathway towards addiction that is opened through stressful experiences during childhood can be avoided by a change in environmental factors throughout an individual's life and opportunities of professional help. If one has friends or peers who engage in drug use favorably, the chances of them developing an addiction increases. Family conflict and home management is a cause for one to become engaged in drug use. ==== Social control theory ==== According to Travis Hirschi's social control theory, adolescents with stronger attachments to family, religious, academic, and other social institutions are less likely to engage in delinquent and maladaptive behavior such as drug use leading to addiction. === Age === Adolescence represents a period of increased vulnerability for developing an addiction. In adolescence, the incentive-rewards systems in the brain mature well before the cognitive control center. This consequentially grants the incentive-rewards systems a disproportionate amount of power in the behavioral decision-making process. Therefore, adolescents are increasingly likely to act on their impulses and engage in risky, potentially addicting behavior before considering the consequences. Not only are adolescents more likely to initiate and maintain drug use, but once addicted they are more resistant to treatment and more liable to relapse. Most individuals are exposed to and use addictive drugs for the first time during their teenage years. In the United States, there were just over 2.8 million new users of illicit drugs in 2013 (7,800 new users per day); among them, 54.1% were under 18 years of age. In 2011, there were approximately 20.6 million people in the United States over the age of 12 with an addiction. Over 90% of those with an addiction began drinking, smoking or using illicit drugs before the age of 18. === Comorbid disorders === Individuals with comorbid (i.e., co-occurring) mental health disorders such as depression, anxiety, attention-deficit/hyperactivity disorder (ADHD) or post-traumatic stress disorder are more likely to develop substance use disorders. The NIDA cites early aggressive behavior as a risk factor for substance use. The National Bureau of Economic Research found that there is a "definite connection between mental illness and the use of addictive substances" and a majority of mental health patients participate in the use of these substances: 38% alcohol, 44% cocaine, and 40% cigarettes. === Epigenetic === Epigenetics is the study of stable phenotypic changes that do not involve alterations in the DNA sequence. Illicit drug use has been found to cause epigenetic changes in DNA methylation, as well as chromatin remodeling. The epigenetic state of chromatin may pose as a risk for the development of substance addictions. It has been found that emotional stressors, as well as social adversities may lead to an initial epigenetic response, which causes an alteration to the reward-signalling pathways. This change may predispose one to experience a positive response to drug use. ==== Transgenerational epigenetic inheritance ==== Epigenetic genes and their products (e.g., proteins) are the key components through which environmental influences can affect the genes of an individual: they serve as the mechanism responsible for transgenerational epigenetic inheritance, a phenomenon in which environmental influences on the genes of a parent can affect the associated traits and behavioral phenotypes of their offspring (e.g., behavioral responses to environmental stimuli). In addiction, epigenetic mechanisms play a central role in the pathophysiology of the disease; it has been noted that some of the alterations to the epigenome which arise through chronic exposure to addictive stimuli during an addiction can be transmitted across generations, in turn affecting the behavior of one's children (e.g., the child's behavioral responses to addictive drugs and natural rewards). The general classes of epigenetic alterations that have been implicated in transgenerational epigenetic inheritance include DNA methylation, histone modifications, and downregulation or upregulation of microRNAs. With respect to addiction, more research is needed to determine the specific heritable epigenetic alterations that arise from various forms of addiction in humans and the corresponding behavioral phenotypes from these epigenetic alterations that occur in human offspring. Based on preclinical evidence from animal research, certain addiction-induced epigenetic alterations in rats can be transmitted from parent to offspring and produce behavioral phenotypes that decrease the offspring's risk of developing an addiction. More generally, the heritable behavioral phenotypes that are derived from addiction-induced epigenetic alterations and transmitted from parent to offspring may serve to either increase or decrease the offspring's risk of developing an addiction. == Mechanisms == Addiction is a disorder of the brain's reward system developing through transcriptional and epigenetic mechanisms as a result of chronically high levels of exposure to an addictive stimulus (e.g., eating food, the use of cocaine, engagement in sexual activity, participation in high-thrill cultural activities such as gambling, etc.) over extended time. DeltaFosB (ΔFosB), a gene transcription factor, is a critical component and common factor in the development of virtually all forms of behavioral and drug addictions. Two decades of research into ΔFosB's role in addiction have demonstrated that addiction arises, and the associated compulsive behavior intensifies or attenuates, along with the overexpression of ΔFosB in the D1-type medium spiny neurons of the nucleus accumbens. Due to the causal relationship between ΔFosB expression and addictions, it is used preclinically as an addiction biomarker. ΔFosB expression in these neurons directly and positively regulates drug self-administration and reward sensitization through positive reinforcement, while decreasing sensitivity to aversion. Chronic addictive drug use causes alterations in gene expression in the mesocorticolimbic projection. The most important transcription factors that produce these alterations are ΔFosB, cAMP response element binding protein (CREB), and nuclear factor kappa B (NF-κB). ΔFosB is the most significant biomolecular mechanism in addiction because the overexpression of ΔFosB in the D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient for many of the neural adaptations and behavioral effects (e.g., expression-dependent increases in drug self-administration and reward sensitization) seen in drug addiction. ΔFosB expression in nucleus accumbens D1-type medium spiny neurons directly and positively regulates drug self-administration and reward sensitization through positive reinforcement while decreasing sensitivity to aversion. ΔFosB has been implicated in mediating addictions to many different drugs and drug classes, including alcohol, amphetamine and other substituted amphetamines, cannabinoids, cocaine, methylphenidate, nicotine, opiates, phenylcyclidine, and propofol, among others. ΔJunD, a transcription factor, and G9a, a histone methyltransferase, both oppose the function of ΔFosB and inhibit increases in its expression. Increases in nucleus accumbens ΔJunD expression (via viral vector-mediated gene transfer) or G9a expression (via pharmacological means) reduces, or with a large increase can even block, many of the neural and behavioral alterations that result from chronic high-dose use of addictive drugs (i.e., the alterations mediated by ΔFosB). ΔFosB plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise. Natural rewards, like drugs of abuse, induce gene expression of ΔFosB in the nucleus accumbens, and chronic acquisition of these rewards can result in a similar pathological addictive state through ΔFosB overexpression. Consequently, ΔFosB is the key transcription factor involved in addictions to natural rewards (i.e., behavioral addictions) as well; in particular, ΔFosB in the nucleus accumbens is critical for the reinforcing effects of sexual reward. Research on the interaction between natural and drug rewards suggests that dopaminergic psychostimulants (e.g., amphetamine) and sexual behavior act on similar biomolecular mechanisms to induce ΔFosB in the nucleus accumbens and possess bidirectional cross-sensitization effects that are mediated through ΔFosB. This phenomenon is notable since, in humans, a dopamine dysregulation syndrome, characterized by drug-induced compulsive engagement in natural rewards (specifically, sexual activity, shopping, and gambling), has been observed in some individuals taking dopaminergic medications. ΔFosB inhibitors (drugs or treatments that oppose its action) may be an effective treatment for addiction and addictive disorders. The release of dopamine in the nucleus accumbens plays a role in the reinforcing qualities of many forms of stimuli, including naturally reinforcing stimuli like palatable food and sex. Altered dopamine neurotransmission is frequently observed following the development of an addictive state. In humans and lab animals that have developed an addiction, alterations in dopamine or opioid neurotransmission in the nucleus accumbens and other parts of the striatum are evident. Use of certain drugs (e.g., cocaine) affect cholinergic neurons that innervate the reward system, in turn affecting dopamine signaling in this region. A recent study in Addiction reports that GLP-1 agonist medications, such as semaglutide, which are commonly used for diabetes and weight management, may also reduce the risk of overdose and alcohol intoxication in people with substance use disorders. The study analyzed nearly nine years of health records from 1.3 million individuals across 136 U.S. hospitals, including 500,000 with opioid use disorder and over 800,000 with alcohol use disorder. Researchers found that those who used Ozempic or similar medications had a 40% lower risk of opioid overdose and a 50% lower risk of alcohol intoxication compared to those not using these drugs. === Reward system === ==== Mesocorticolimbic pathway ==== Understanding the pathways in which drugs act and how drugs can alter those pathways is key when examining the biological basis of drug addiction. The reward pathway, known as the mesolimbic pathway, or its extension, the mesocorticolimbic pathway, is characterized by the interaction of several areas of the brain. The projections from the ventral tegmental area (VTA) are a network of dopaminergic neurons with co-localized postsynaptic glutamate receptors (AMPAR and NMDAR). These cells respond when stimuli indicative of a reward are present. The VTA supports learning and sensitization development and releases dopamine (DA) into the forebrain. These neurons project and release DA into the nucleus accumbens, through the mesolimbic pathway. Virtually all drugs causing drug addiction increase the DA release in the mesolimbic pathway. The nucleus accumbens (NAcc) is one output of the VTA projections. The nucleus accumbens itself consists mainly of GABAergic medium spiny neurons (MSNs). The NAcc is associated with acquiring and eliciting conditioned behaviors, and is involved in the increased sensitivity to drugs as addiction progresses. Overexpression of ΔFosB in the nucleus accumbens is a necessary common factor in essentially all known forms of addiction; ΔFosB is a strong positive modulator of positively reinforced behaviors. The prefrontal cortex, including the anterior cingulate and orbitofrontal cortices, is another VTA output in the mesocorticolimbic pathway; it is important for the integration of information which helps determine whether a behavior will be elicited. It is critical for forming associations between the rewarding experience of drug use and cues in the environment. Importantly, these cues are strong mediators of drug-seeking behavior and can trigger relapse even after months or years of abstinence. Other brain structures that are involved in addiction include: The basolateral amygdala projects into the NAcc and is thought to be important for motivation. The hippocampus is involved in drug addiction, because of its role in learning and memory. Much of this evidence stems from investigations showing that manipulating cells in the hippocampus alters DA levels in NAcc and firing rates of VTA dopaminergic cells. ==== Role of dopamine and glutamate ==== Dopamine is the primary neurotransmitter of the reward system in the brain. It plays a role in regulating movement, emotion, cognition, motivation, and feelings of pleasure. Natural rewards, like eating, as well as recreational drug use cause a release of dopamine, and are associated with the reinforcing nature of these stimuli. Nearly all addictive drugs, directly or indirectly, act on the brain's reward system by heightening dopaminergic activity. Excessive intake of many types of addictive drugs results in repeated release of high amounts of dopamine, which in turn affects the reward pathway directly through heightened dopamine receptor activation. Prolonged and abnormally high levels of dopamine in the synaptic cleft can induce receptor downregulation in the neural pathway. Downregulation of mesolimbic dopamine receptors can result in a decrease in the sensitivity to natural reinforcers. Drug seeking behavior is induced by glutamatergic projections from the prefrontal cortex to the nucleus accumbens. This idea is supported with data from experiments showing that drug seeking behavior can be prevented following the inhibition of AMPA glutamate receptors and glutamate release in the nucleus accumbens. === Reward sensitization === Reward sensitization is a process that causes an increase in the amount of reward (specifically, incentive salience) that is assigned by the brain to a rewarding stimulus (e.g., a drug). In simple terms, when reward sensitization to a specific stimulus (e.g., a drug) occurs, an individual's "wanting" or desire for the stimulus itself and its associated cues increases. Reward sensitization normally occurs following chronically high levels of exposure to the stimulus. ΔFosB expression in D1-type medium spiny neurons in the nucleus accumbens has been shown to directly and positively regulate reward sensitization involving drugs and natural rewards. "Cue-induced wanting" or "cue-triggered wanting", a form of craving that occurs in addiction, is responsible for most of the compulsive behavior that people with addictions exhibit. During the development of an addiction, the repeated association of otherwise neutral and even non-rewarding stimuli with drug consumption triggers an associative learning process that causes these previously neutral stimuli to act as conditioned positive reinforcers of addictive drug use (i.e., these stimuli start to function as drug cues). As conditioned positive reinforcers of drug use, these previously neutral stimuli are assigned incentive salience (which manifests as a craving) – sometimes at pathologically high levels due to reward sensitization – which can transfer to the primary reinforcer (e.g., the use of an addictive drug) with which it was originally paired. Research on the interaction between natural and drug rewards suggests that dopaminergic psychostimulants (e.g., amphetamine) and sexual behavior act on similar biomolecular mechanisms to induce ΔFosB in the nucleus accumbens and possess a bidirectional reward cross-sensitization effect that is mediated through ΔFosB. In contrast to ΔFosB's reward-sensitizing effect, CREB transcriptional activity decreases user's sensitivity to the rewarding effects of the substance. CREB transcription in the nucleus accumbens is implicated in psychological dependence and symptoms involving a lack of pleasure or motivation during drug withdrawal. === Neuroepigenetic mechanisms === Altered epigenetic regulation of gene expression within the brain's reward system plays a significant and complex role in the development of drug addiction. Addictive drugs are associated with three types of epigenetic modifications within neurons. These are (1) histone modifications, (2) epigenetic methylation of DNA at CpG sites at (or adjacent to) particular genes, and (3) epigenetic downregulation or upregulation of microRNAs which have particular target genes. As an example, while hundreds of genes in the cells of the nucleus accumbens (NAc) exhibit histone modifications following drug exposure – particularly, altered acetylation and methylation states of histone residues – most other genes in the NAc cells do not show such changes. == Diagnosis == === Classification === ==== DSM-5 ==== The fifth edition of the DSM uses the term substance use disorder to refer to a spectrum of drug use-related disorders. The DSM-5 eliminates the terms abuse and dependence from diagnostic categories, instead using the specifiers of mild, moderate and severe to indicate the extent of disordered use. These specifiers are determined by the number of diagnostic criteria present in a given case. In the DSM-5, the term drug addiction is synonymous with severe substance use disorder. The DSM-5 introduced a new diagnostic category for behavioral addictions. Problem gambling is the only condition included in this category in the fifth edition. Internet gaming disorder is listed as a "condition requiring further study" in the DSM-5. Past editions have used physical dependence and the associated withdrawal syndrome to identify an addictive state. Physical dependence occurs when the body has adjusted by incorporating the substance into its "normal" functioning – i.e., attains homeostasis – and therefore physical withdrawal symptoms occur on cessation of use. Tolerance is the process by which the body continually adapts to the substance and requires increasingly larger amounts to achieve the original effects. Withdrawal refers to physical and psychological symptoms experienced when reducing or discontinuing a substance that the body has become dependent on. Symptoms of withdrawal generally include but are not limited to body aches, anxiety, irritability, intense cravings for the substance, dysphoria, nausea, hallucinations, headaches, cold sweats, tremors, and seizures. During acute physical opioid withdrawal, symptoms of restless legs syndrome are common and may be profound. This phenomenon originated the idiom "kicking the habit". Medical researchers who actively study addiction have criticized the DSM classification of addiction for being flawed and involving arbitrary diagnostic criteria. ==== ICD-11 ==== The eleventh revision of the International Classification of Diseases, commonly referred to as ICD-11, conceptualizes diagnosis somewhat differently. ICD-11 first distinguishes between problems with psychoactive substance use ("Disorders due to substance use") and behavioral addictions ("Disorders due to addictive behaviours"). With regard to psychoactive substances, ICD-11 explains that the included substances initially produce "pleasant or appealing psychoactive effects that are rewarding and reinforcing with repeated use, [but] with continued use, many of the included substances have the capacity to produce dependence. They have the potential to cause numerous forms of harm, both to mental and physical health." Instead of the DSM-5 approach of one diagnosis ("Substance Use Disorder") covering all types of problematic substance use, ICD-11 offers three diagnostic possibilities: 1) Episode of Harmful Psychoactive Substance Use, 2) Harmful Pattern of Psychoactive Substance Use, and 3) Substance Dependence. === Screening and assessment === ==== Addictions Neuroclinical Assessment ==== The Addictions Neuroclinical Assessment is used to diagnose addiction disorders. This tool measures three different domains: executive function, incentive salience, and negative emotionality. Executive functioning consists of processes that would be disrupted in addiction. In the context of addiction, incentive salience determines how one perceives the addictive substance. Increased negative emotional responses have been found with individuals with addictions. ==== Tobacco, Alcohol, Prescription Medication, and Other Substance Use (TAPS) ==== This is a screening and assessment tool in one, assessing commonly used substances. This tool allows for a simple diagnosis, eliminating the need for several screening and assessment tools, as it includes both TAPS-1 and TAPS-2, screening and assessment tools respectively. The screening component asks about the frequency of use of the specific substance (tobacco, alcohol, prescription medication, and other). If an individual screens positive, the second component will begin. This dictates the risk level of the substance. ==== CRAFFT ==== The CRAFFT (Car-Relax-Alone-Forget-Family and Friends-Trouble) is a screening tool that is used in medical centers. The CRAFFT is in version 2.1 and has a version for nicotine and tobacco use called the CRAFFT 2.1+N. This tool is used to identify substance use, substance related driving risk, and addictions among adolescents. This tool uses a set of questions for different scenarios. In the case of a specific combination of answers, different question sets can be used to yield a more accurate answer. After the questions, the DSM-5 criteria are used to identify the likelihood of the person having substance use disorder. After these tests are done, the clinician is to give the "5 RS" of brief counseling. The five Rs of brief counseling includes: REVIEW screening results RECOMMEND to not use RIDING/DRIVING risk counseling RESPONSE: elicit self-motivational statements REINFORCE self-efficacy ==== Drug Abuse Screening Test (DAST-10) ==== The Drug Abuse Screening Test (DAST) is a self-reporting tool that measures problematic substance use. Responses to this test are recorded as yes or no answers, and scored as a number between zero and 28. Drug abuse or dependence, are indicated by a cut off score of 6. Three versions of this screening tool are in use: DAST-28, DAST-20, and DAST-10. Each of these instruments are copyrighted by Dr. Harvey A. Skinner. ==== Alcohol, Smoking, and Substance Involvement Test (ASSIST) ==== The Alcohol, Smoking, and Substance Involvement Test (ASSIST) is an interview-based questionnaire consisting of eight questions developed by the WHO. The questions ask about lifetime use; frequency of use; urge to use; frequency of health, financial, social, or legal problems related to use; failure to perform duties; if anyone has raised concerns over use; attempts to limit or moderate use; and use by injection. == Prevention == === Abuse liability === Abuse or addiction liability is the tendency to use drugs in a non-medical situation. This is typically for euphoria, mood changing, or sedation. Abuse liability is used when the person using the drugs wants something that they otherwise can not obtain. The only way to obtain this is through the use of drugs. When looking at abuse liability there are a number of determining factors in whether the drug is abused. These factors are: the chemical makeup of the drug, the effects on the brain, and the age, vulnerability, and the health (mental and physical) of the population being studied. There are a few drugs with a specific chemical makeup that leads to a high abuse liability. These are: cocaine, heroin, inhalants, marijuana, MDMA (ecstasy), methamphetamine, PCP, synthetic cannabinoids, synthetic cathinones (bath salts), nicotine (e.g. tobacco), and alcohol. === Potential vaccines for addiction to substances === Vaccines for addiction have been investigated as a possibility since the early 2000s. The general theory of a vaccine intended to "immunize" against drug addiction or other substance abuse is that it would condition the immune system to attack and consume or otherwise disable the molecules of such substances that cause a reaction in the brain, thus preventing the addict from being able to realize the effect of the drug. Addictions that have been floated as targets for such treatment include nicotine, opioids, and fentanyl. Vaccines have been identified as potentially being more effective than other anti-addiction treatments, due to "the long duration of action, the certainty of administration and a potential reduction of toxicity to important organs". Specific addiction vaccines in development include: NicVAX, a conjugate vaccine intended to reduce or eliminate physical dependence on nicotine. This proprietary vaccine is being developed by Nabi Biopharmaceuticals of Rockville, MD. with the support from the U.S. National Institute on Drug Abuse. NicVAX consists of the hapten 3'-aminomethylnicotine which has been conjugated (attached) to Pseudomonas aeruginosa exotoxin A. TA-CD, an active vaccine developed by the Xenova Group which is used to negate the effects of cocaine. It is created by combining norcocaine with inactivated cholera toxin. It works in much the same way as a regular vaccine. A large protein molecule attaches to cocaine, which stimulates response from antibodies, which destroy the molecule. This also prevents the cocaine from crossing the blood–brain barrier, negating the euphoric high and rewarding effect of cocaine caused from stimulation of dopamine release in the mesolimbic reward pathway. The vaccine does not affect the user's "desire" for cocaine—only the physical effects of the drug. TA-NIC, used to create human antibodies to destroy nicotine in the human body so that it is no longer effective. As of September 2023, it was further reported that a vaccine "has been tested against heroin and fentanyl and is on its way to being tested against OxyContin". == Treatment == To be effective, treatment for addiction that is pharmacological or biologically based need to be accompanied by other interventions such as cognitive behavioral therapy (CBT) and dialectical behavioral therapy (DBT); individual and group psychotherapy, behavior modification strategies, twelve-step programs, and residential treatment facilities. The transtheoretical model (TTM) can be used to determine when treatment can begin and which method will be most effective. If treatment begins too early, it can cause a person to become defensive and resistant to change. == Epidemiology == Due to cultural variations, the proportion of individuals who develop a drug or behavioral addiction within a specified time period (i.e., the prevalence) varies over time, by country, and across national population demographics (e.g., by age group, socioeconomic status, etc.). Where addiction is viewed as unacceptable, there will be fewer people addicted. === Asia === The prevalence of alcohol dependence is not as high as is seen in other regions. In Asia, not only socioeconomic factors but biological factors influence drinking behavior. Internet addiction disorder is highest in the Philippines, according to both the IAT (Internet Addiction Test) – 5% and the CIAS-R (Revised Chen Internet Addiction Scale) – 21%. === Australia === The prevalence of substance use disorder among Australians was reported at 5.1% in 2009. In 2019 the Australian Institute of Health and Welfare conducted a national drug survey that quantified drug use for various types of drugs and demographics. The survey found that in 2019, 11% of people over 14 years old smoke daily; that 9.9% of those who drink alcohol, which equates to 7.5% of the total population age 14 or older, may qualify as alcohol dependent; that 17.5% of the 2.4 million people who used cannabis in the last year may have hazardous use or a dependence problem; and that 63.5% of about 300000 recent users of meth and amphetamines were at risk for developing problem use. === Europe === In 2015, the estimated prevalence among the adult population was 18.4% for heavy episodic alcohol use (in the past 30 days); 15.2% for daily tobacco smoking; and 3.8% for cannabis use, 0.77% for amphetamine use, 0.37% for opioid use, and 0.35% for cocaine use in 2017. The mortality rates for alcohol and illicit drugs were highest in Eastern Europe. Data shows a downward trend of alcohol use among children 15 years old in most European countries between 2002 and 2014. First-time alcohol use before the age of 13 was recorded for 28% of European children in 2014. === United States === Based on representative samples of the US youth population in 2011, the lifetime prevalence of addictions to alcohol and illicit drugs has been estimated to be approximately 8% and 2–3% respectively. Based on representative samples of the US adult population in 2011, the 12-month prevalence of alcohol and illicit drug addictions were estimated at 12% and 2–3% respectively. The lifetime prevalence of prescription drug addictions is around 4.7%. As of 2021, 43.7 million people aged 12 or older surveyed by the National Survey on Drug Use and Health in the United States needed treatment for an addiction to alcohol, nicotine, or other drugs. The groups with the highest number of people were 18–25 years (25.1%) and "American Indian or Alaska Native" (28.7%). Only about 10%, or a little over 2 million, receive any form of treatments, and those that do generally do not receive evidence-based care. One-third of inpatient hospital costs and 20% of all deaths in the US every year are the result of untreated addictions and risky substance use. In spite of the massive overall economic cost to society, which is greater than the cost of diabetes and all forms of cancer combined, most doctors in the US lack the training to effectively address a drug addiction. Estimates of lifetime prevalence rates in the US are 1–2% for compulsive gambling, 5% for sexual addiction, 2.8% for food addiction, and 5–6% for compulsive shopping. The time-invariant prevalence rate for sexual addiction and related compulsive sexual behavior (e.g., compulsive masturbation with or without pornography, compulsive cybersex, etc.) within the US ranges from 3–6% of the population. According to a 2017 poll conducted by the Pew Research Center, almost half of US adults know a family member or close friend who has struggled with a drug addiction at some point in their life. In 2019, opioid addiction was acknowledged as a national crisis in the United States. An article in The Washington Post stated that "America's largest drug companies flooded the country with pain pills from 2006 through 2012, even when it became apparent that they were fueling addiction and overdoses." The National Epidemiologic Survey on Alcohol and Related Conditions found that from 2012 to 2013 the prevalence of Cannabis use disorder in U.S. adults was 2.9%. === Canada === A Statistics Canada Survey in 2012 found the lifetime prevalence and 12-month prevalence of substance use disorders were 21.6%, and 4.4% in those 15 and older. Alcohol abuse or dependence reported a lifetime prevalence of 18.1% and a 12-month prevalence of 3.2%. Cannabis abuse or dependence reported a lifetime prevalence of 6.8% and a 12-month prevalence of 3.2%. Other drug abuse or dependence has a lifetime prevalence of 4.0% and a 12-month prevalence of 0.7%. Substance use disorder is a term used interchangeably with a drug addiction. In Ontario, Canada between 2009 and 2017, outpatient visits for mental health and addiction increased from 52.6 to 57.2 per 100 people, emergency department visits increased from 13.5 to 19.7 per 1000 people and the number of hospitalizations increased from 4.5 to 5.5 per 1000 people. Prevalence of care needed increased the most among the 14–17 age group overall. === South America === The realities of opioid use and opioid use disorder in Latin America may be deceptive if observations are limited to epidemiological findings. In the United Nations Office on Drugs and Crime report, although South America produced 3% of the world's morphine and heroin and 0.01% of its opium, prevalence of use is uneven. According to the Inter-American Commission on Drug Abuse Control, consumption of heroin is low in most Latin American countries, although Colombia is the area's largest opium producer. Mexico, because of its border with the United States, has the highest incidence of use. == Etymology == The word addiction derives from the Latin "addico", meaning "giving over" with both positive connotations (devotion, dedication) and negative ones (being enslaved to a creditor in Roman law). This dual meaning persisted in traditional English dictionaries, encompassing both legal surrender and personal devotion to habits. Later, 19th century temperance movements narrowed the definition of addiction to just drug-related disease, ignoring behavioral addictions and the possibility of positive or neutral addictions. This restrictive view opposes the current understanding of addiction. Addiction and addictive behavior are polysemes denoting a category of mental disorders, of neuropsychological symptoms, or of merely maladaptive/harmful habits and lifestyles. A common use of the term addiction in medicine is for neuropsychological symptoms denoting pervasive/excessive and intense urges to engage in a category of behavioral compulsions or impulses towards sensory rewards (e.g., alcohol, betel quid, drugs, sex, gambling, video gaming). Addictive disorders or addiction disorders are mental disorders involving high intensities of addictions (as neuropsychological symptoms) that induce functional disabilities (i.e., limit subjects' social/family and occupational activities); the two categories of such disorders are substance-use addictions and behavioral addictions. The etymology of the term addiction throughout history has been misunderstood and has taken on various meanings associated with the word. An example is the usage of the word in the religious landscape of early modern Europe. "Addiction" at the time meant "to attach" to something, giving it both positive and negative connotations. The object of this attachment could be characterized as "good or bad". The meaning of addiction during the early modern period was mostly associated with positivity and goodness; during this early modern and highly religious era of Christian revivalism and Pietistic tendencies, it was seen as a way of "devoting oneself to another". === The suffixes "-holic" and "-holism" === In contemporary modern English "-holic" is a suffix that can be added to a subject to denote an addiction to it. It was extracted from the word alcoholism (one of the first addictions to be widely identified both medically and socially) (correctly the root "alcohol" plus the suffix "-ism") by misdividing or rebracketing it into "alco" and "-holism". There are correct medico-legal terms for such addictions: dipsomania is the medico-legal term for alcoholism; other examples are in this table: == History == Modern research on addiction has led to a better understanding of the disease with research on the topic dating back to 1875, specifically on morphine addiction. This furthered the understanding of addiction being a medical condition. It was not until the 19th century that addiction was seen and acknowledged in the Western world as a disease, being both a physical condition and mental illness. Today, addiction is understood both as a biopsychosocial and neurological disorder that negatively impacts those who are affected by it, most commonly associated with the use of drugs and excessive use of alcohol. The understanding of addiction has changed throughout history, which has impacted and continues to impact the ways it is medically treated and diagnosed. == Addiction and art == The arts can be used in a variety of ways to address issues related to addiction. Art can be used as a form of therapy in the treatment of substance use disorders. Creative activities like painting, sculpting, music, and writing can help people express their feelings and experiences in safe and healthy ways. The arts can be used as an assessment tool to identify underlying issues that may be contributing to a person's substance use disorder. Through art, individuals can gain insights into their own motivations and behaviors that can be helpful in determining a course of treatment. Finally, the arts can be used to advocate for those suffering from a substance use disorder by raising awareness of the issue and promoting understanding and compassion. Through art, individuals can share their stories, increase awareness, and offer support and hope to those struggling with substance use disorders. === As therapy === Addiction treatment is complex and not always effective due to engagement and service availability concerns, so researchers prioritize efforts to improve treatment retention and decrease relapse rates. Characteristics of substance abuse may include feelings of isolation, a lack of confidence, communication difficulties, and a perceived lack of control. In a similar vein, people suffering from substance use disorders tend to be highly sensitive, creative, and as such, are likely able to express themselves meaningfully in creative arts such as dancing, painting, writing, music, and acting. Further evidenced by Waller and Mahony (2002) and Kaufman (1981), the creative arts therapies can be a suitable treatment option for this population especially when verbal communication is ineffective. Primary advantages of art therapy in the treatment of addiction have been identified as: Assess and characterize a client's substance use issues Bypassing a client's resistances, defenses, and denial Containing shame or anger Facilitating the expression of suppressed and/or complicated emotions Highlighting a client's strengths Providing an alternative to verbal communication (via use of symbols) and conventional forms of therapy Providing clients with a sense of control Tackling feelings of isolation Art therapy is an effective method of dealing with substance abuse in comprehensive treatment models. When included in psychoeducational programs, art therapy in a group setting can help clients internalize taught concepts in a more personalized manner. During the course of treatment, by examining and comparing artwork created at different times, art therapists can be helpful in identifying and diagnosing issues, as well as charting the extent or direction of improvement as a person detoxifies. Where increasing adherence to treatment regimes and maintaining abstinence is the target; art therapists can aid by customizing treatment directives (encourage the client to create collages that compare pros and cons, pictures that compare past and present and future, and drawings that depict what happened when a client went off medication). Art therapy can function as a complementary therapy used in conjunction with more conventional therapies and can integrate with harm reduction protocols to minimize the negative effects of drug use. An evaluation of art therapy incorporation within a pre-existing Addiction Treatment Programme based on the 12 step Minnesota Model endorsed by the Alcoholics Anonymous found that 66% of participants expressed the usefulness of art therapy as a part of treatment. Within the weekly art therapy session, clients were able to reflect and process the intense emotions and cognitions evoked by the programme. In turn, the art therapy component of the programme fostered stronger self-awareness, exploration, and externalization of repressed and unconscious emotions of clients, promoting the development of a more integrated 'authentic self'. Despite the large number of randomized control trials, clinical control trials, and anecdotal evidence supporting the effectiveness of art therapies for use in addiction treatment, a systematic review conducted in 2018 could not find enough evidence on visual art, drama, dance and movement therapy, or 'arts in health' methodologies to confirm their effectiveness as interventions for reducing substance misuse. Music therapy was identified to have potentially strong beneficial effects in aiding contemplation and preparing those diagnosed with substance use for treatment. === As an assessment tool === The Formal Elements Art Therapy Scale (FEATS) is an assessment tool used to evaluate drawings created by people suffering from substance use disorders by comparing them to drawings of a control group (consisting of individuals without SUDs). FEATS consists of twelve elements, three of which were found to be particularly effective at distinguishing the drawings of those with SUDs from those without: Person, Realism, and Developmental. The Person element assesses the degree to which a human features are depicted realistically, the Realism element assesses the overall complexity of the artwork, and the Developmental element assesses "developmental age" of the artwork in relation to standardized drawings from children and adolescents. By using the FEATS assessment tool, clinicians can gain valuable insight into the drawings of individuals with SUDs, and can compare them to those of the control group. Formal assessments such as FEATS provide healthcare providers with a means to quantify, standardize, and communicate abstract and visceral characteristics of SUDs to provide more accurate diagnoses and informed treatment decisions. Other artistic assessment methods include the Bird's Nest Drawing: a useful tool for visualizing a client's attachment security. This assessment method looks at the amount of color used in the drawing, with a lack of color indicating an 'insecure attachment', a factor that the client's therapist or recovery framework must take into account. Art therapists working with children of parents suffering from alcoholism can use the Kinetic Family Drawings assessment tool to shed light on family dynamics and help children express and understand their family experiences. The KFD can be used in family sessions to allow children to share their experiences and needs with parents who may be in recovery from alcohol use disorder. Depiction of isolation of self and isolation of other family members may be an indicator of parental alcoholism. === Advocacy === Stigma can lead to feelings of shame that can prevent people with substance use disorders from seeking help and interfere with provision of harm reduction services. It can influence healthcare policy, making it difficult for these individuals to access treatment. Artists attempt to change the societal perception of addiction from a punishable moral offense to instead a chronic illness necessitating treatment. This form of advocacy can help to relocate the fight of addiction from a judicial perspective to the public health system. Artists who have personally lived with addiction or undergone recovery may use art to depict their experiences in a manner that uncovers the "human face of addiction". By bringing experiences of addiction and recovery to a personal level and breaking down the "us and them", the viewer may be more inclined to show compassion, forego stereotypes and stigma of addiction, and label addiction as a social rather than individual problem. According to Santora the main purposes in using art as a form of advocacy in the education and prevention of substance use disorders include: Addiction art exhibitions can come from a variety of sources, but the underlying message of these works is the same: to communicate through emotions without relying on intellectually demanding/gatekept facts and figures. These exhibitions can either stand alone, reinforce, or challenge facts. A powerful educational tool for increasing awareness and understanding of addiction as a medical illness. Exhibitions featuring personal stories and images can help to create lasting impressions on diverse audiences (including addiction scientists/researchers, family/friends of those affected by addiction etc.), highlighting the humanity of the problem and in turn encouraging compassion and understanding. A way to destigmatize substance use disorders and shift public perception from viewing them as a moral failing to understanding them as a chronic medical condition which requires treatment. Provide those who are struggling with addiction assurance and encouragement of healing, and let them know that they are not alone in their struggle. The use of visual arts can help bring attention to the lack of adequate substance use treatment, prevention, and education programs and services in a healthcare system. Messages can encourage policymakers to allocate more resources to addiction treatment and prevention from federal, state, and local levels. The Temple University College of Public Health department conducted a project to promote awareness around opioid use and reduce associated stigma by asking students to create art pieces that were displayed on a website they created and promoted via social media. Quantitative and qualitative data was recorded to measure engagement, and the student artists were interviewed, which revealed a change in perspective and understanding, as well as greater appreciation of diverse experiences. Ultimately, the project found that art was an effective medium for empowering both the artist creating the work and the person interacting with it. Another author critically examined works by contemporary Canadian artists that deal with addiction via the metaphor of a cultural landscape to "unmap" and "remap" ideologies related to Indigenous communities and addiction to demonstrate how colonial violence in Canada has drastically impacted the relationship between Indigenous peoples, their land, and substance abuse. A project known as "Voice" was a collection of art, poetry and narratives created by women living with a history of addiction to explore women's understanding of harm reduction, challenge the effects of stigma and give voice to those who have historically been silenced or devalued. In the project, nurses with knowledge of mainstream systems, aesthetic knowing, feminism and substance use organized weekly gatherings, wherein women with histories of substance use and addiction worked alongside a nurse to create artistic expressions. Creations were presented at several venues, including an International Conference on Drug Related Harm, a Nursing Conference and a local gallery to positive community response. == Social scientific models == === Biopsychosocial–cultural–spiritual === While regarded biomedically as a neuropsychological disorder, addiction is multi-layered, with biological, psychological, social, cultural, and spiritual (biopsychosocial–cultural–spiritual) elements. A biopsychosocial–cultural–spiritual approach fosters the crossing of disciplinary boundaries, and promotes holistic considerations of addiction. A biopsychosocial–cultural–spiritual approach considers, for example, how physical environments influence experiences, habits, and patterns of addiction. Ethnographic engagements and developments in fields of knowledge have contributed to biopsychosocial–cultural–spiritual understandings of addiction, including the work of Philippe Bourgois, whose fieldwork with street-level drug dealers in East Harlem highlights correlations between drug use and structural oppression in the United States. Prior models that have informed the prevailing biopsychosocial–cultural–spiritual consideration of addiction include: === Cultural model === The cultural model, an anthropological understanding of the emergence of drug use and abuse, was developed by Dwight Heath. Heath undertook ethnographic research and fieldwork with the Camba people of Bolivia from June 1956 to August 1957. Heath observed that adult members of society drank 'large quantities of rum and became intoxicated for several contiguous days at least twice a month'. This frequent, heavy drinking from which intoxication followed was typically undertaken socially, during festivals. Having returned in 1989, Heath observed that while much had changed, 'drinking parties' remained, as per his initial observations, and 'there appear to be no harmful consequences to anyone'. Heath's observations and interactions reflected that this form of social behavior, the habitual heavy consumption of alcohol, was encouraged and valued, enforcing social bonds in the Camba community. Despite frequent intoxication, "even to the point of unconsciousness", the Camba held no concept of alcoholism (a form of addiction), and no visible social problems associated with drunkenness, or addiction, were apparent. As noted by Merrill Singer, Heath's findings, when considered alongside subsequent cross-cultural experiences, challenged the perception that intoxication is socially 'inherently disruptive'. Following this fieldwork, Heath proposed the 'cultural model', suggesting that 'problems' associated with heavy drinking, such as alcoholism – a recognised form addiction – were cultural: that is, that alcoholism is determined by cultural beliefs, and therefore varies among cultures. Heath's findings challenged the notion that 'continued use [of alcohol] is inexorably addictive and damaging to the consumer's health'. The cultural model did face criticism by Sociologist Robin Room and others, who felt anthropologists could "downgrade the severity of the problem". Merrill Singer found it notable that the ethnographers working within the prominence of the cultural model were part of the 'wet generation': while not blind to the 'disruptive, dysfunctional and debilitating effects of alcohol consumption', they were products 'socialized to view alcohol consumption as normal'. === Subcultural model === Historically, addiction has been viewed from the etic perspective, defining users through the pathology of their condition. As reports of drug use rapidly increased, the cultural model found application in anthropological research exploring western drug subculture practices. The approach evolved from the ethnographic exploration into the lived experiences and subjectivities of 1960s and 1970s drug subcultures. The seminal publication "Taking care of business", by Edward Preble and John J. Casey, documented the daily lives of New York street-based intravenous heroin users in rich detail, providing unique insight into the dynamic social worlds and activities that surrounded their drug use. These findings challenge popular narratives of immorality and deviance, conceptualizing substance abuse as a social phenomenon. The prevailing culture can have a greater influence on drug taking behaviors than the physical and psychological effects of the drug itself. To marginalized individuals, drug subcultures can provide social connection, symbolic meaning, and socially constructed purpose that they may feel is unattainable through conventional means. The subcultural model demonstrates the complexities of addiction, highlighting the need for an integrated approach. It contends that a biosocial approach is required to achieve a holistic understanding of addiction. === Critical medical anthropology model === Emerging in the early 1980s, the critical medical anthropology model was introduced, and as Merrill Singer offers 'was applied quickly to the analysis of drug use'. Where the cultural model of the 1950s looked at the social body, the critical medical anthropology model revealed the body politic, considering drug use and addiction within the context of macro level structures including larger political systems, economic inequalities, and the institutional power held over social processes. Highly relevant to addiction, the three issues emphasized in the model are: Self-medication The social production of suffering The political economy (Licit and Illicit Drugs) These three key points highlight how drugs may come to be used to self-medicate the psychological trauma of socio-political disparity and injustice, intertwining with licit and illicit drug market politics. Social suffering, "the misery among those on the weaker end of power relations in terms of physical health, mental health and lived experience", is used by anthropologists to analyze how individuals may have personal problems caused by political and economic power. From the perspective of critical medical anthropology heavy drug use and addiction is a consequence of such larger scale unequal distributions of power. The three models developed here – the cultural model, the subcultural model, and the Critical Medical Anthropology Model – display how addiction is not an experience to be considered only biomedically. Through consideration of addiction alongside the biological, psychological, social, cultural and spiritual (biopsychosocial–spiritual) elements which influence its experience, a holistic and comprehensive understanding can be built. == Social learning models == === Social learning theory === Albert Bandura's 1977 social learning theory posits that individuals acquire addictive behaviors by observing and imitating models in their social environment. The likelihood of engaging in and sustaining similar addictive behaviors is influenced by the reinforcement and punishment observed in others. The principle of reciprocal determinism suggests that the functional relationships between personal, environmental, and behavioral factors act as determinants of addictive behavior. Thus, effective treatment targets each dynamic facet of the biopsychosocial disorder. === Transtheoretical model (stages of change model) === The transtheoretical model of change suggests that overcoming an addiction is a stepwise process that occurs through several stages. Precontemplation: This initial stage precedes individuals considering a change in their behavior. They might be oblivious to or in denial of their addiction, failing to recognize the need for change. Contemplation is the stage in which individuals become aware of the problems caused by their addiction and are considering change. Although they may not fully commit, they weigh the costs and benefits of making a shift. Preparation: Individuals in this stage are getting ready to change. They might have taken preliminary steps, like gathering information or making small commitments, in preparation for behavioral change. Action involves actively modifying behavior by making specific, observable changes to address the addictive behavior. The action stage requires significant effort and commitment. Maintenance: After successfully implementing a change, individuals enter the maintenance stage, where they work to sustain the new behavior and prevent relapse. This stage is characterized by ongoing effort and consolidation of gains. Termination/relapse prevention: Recognizing that relapse is a common part of the change process, this stage focuses on identifying and addressing factors that may lead to a return to old behaviors. Relapse is viewed as an opportunity for learning and strategy adjustment, with the ultimate goal of eliminating or terminating the targeted behavior. The transtheoretical model can be helpful in guiding development of tailored behavioral interventions that can promote lasting change. Progression through these stages may not always follow a linear path, as individuals may move back and forth between stages. Resistance to change is recognized as an expected part of the process. Addiction causes an "astoundingly high financial and human toll" on individuals and society as a whole. In the United States, the total economic cost to society is greater than that of all types of diabetes and all cancers combined. These costs arise from the direct adverse effects of drugs and associated healthcare costs (e.g., emergency medical services and outpatient and inpatient care), long-term complications (e.g., lung cancer from smoking tobacco products, liver cirrhosis and dementia from chronic alcohol consumption, and meth mouth from methamphetamine use), the loss of productivity and associated welfare costs, fatal and non-fatal accidents (e.g., traffic collisions), suicides, homicides, and incarceration, among others. The US National Institute on Drug Abuse has found that overdose deaths in the US have almost tripled among males and females from 2002 to 2017, with 72,306 overdose deaths reported in 2017 in the US. 2020 marked the year with the highest number of overdose deaths over a 12-month period, with 81,000 overdose deaths, exceeding the records set in 2017. == See also == == Endnotes == == Notes == Image legend == References == == Further reading == == External links == "The Science of Addiction: Genetics and the Brain". learn.genetics.utah.edu. Learn.Genetics – University of Utah. Why do our brains get addicted? – a TEDMED 2014 talk by Nora Volkow, the director of the National Institute on Drug Abuse at NIH. Kyoto Encyclopedia of Genes and Genomes (KEGG) signal transduction pathways: KEGG – human alcohol addiction KEGG – human amphetamine addiction KEGG – human cocaine addiction	Wikipedia/Drug_addiction
Drug discrimination (DD) is a technique in behavioral neuroscience used to evaluate the discriminative stimulus properties of psychoactive drugs. The discriminative stimulus properties of drugs are believed to reflect their subjective effects. When partial or full stimulus generalization of a test drug to a training drug occurs, the test drug can be assumed to have effects that are subjectively similar to those of the training drug. Drug discrimination tests are usually performed in animals, but have also been conducted in humans. Drug discrimination assays have been employed to assess whether drugs have stimulant-, hallucinogen- or entactogen-like effects, among many other types of drug effects. == See also == Head-twitch response == References == == Further reading == Glennon, R.A.; Young, R. (2011). Drug Discrimination: Applications to Medicinal Chemistry and Drug Studies. Wiley. doi:10.1002/9781118023150. ISBN 978-0-470-43352-2. Retrieved 2 November 2024.	Wikipedia/Drug_discrimination
JRT is a serotonin receptor modulator and putative serotonergic psychedelic and psychoplastogen related to lysergic acid diethylamide (LSD). It is the analogue of LSD in which the embedded tryptamine structure within the ergoline ring system of LSD has been replaced with an isotryptamine structure. It acts as a non-selective serotonin receptor modulator, including as a partial agonist of the serotonin 5-HT2A receptor and as an agonist or antagonist of various other serotonin receptors. The drug has psychedelic-like, psychoplastogenic, antipsychotic-like, antidepressant-like, and pro-cognitive effects in animals and preclinical studies, whilst lacking apparent pro-psychotic-like effects. It has significant but reduced psychedelic-like effects compared to LSD. JRT was first described in the scientific literature by 2022. It was developed by David E. Olson and colleagues in association with Delix Therapeutics. The drug is being investigated as a possible treatment for schizophrenia. == Pharmacology == In contrast to LSD, (+)-JRT is highly selective for a subset of serotonin receptors and does not bind to various dopamine, adrenergic, or histamine receptors. (+)-JRT shows high affinity for the serotonin 5-HT2 receptors, with Ki values ranging from 2.0 to 184 nM. It is a potent partial agonist of the serotonin 5-HT2A and 5-HT2B receptors (EmaxTooltip maximal efficacy = 33–81% and 48–51%, respectively) and a full agonist of the serotonin 5-HT2C receptor (Emax = 89%). The drug is also an agonist of the serotonin 5-HT1A and 5-HT7 receptors, an antagonist of the serotonin 5-HT5A and 5-HT7 receptors, and binds to the serotonin 5-HT6 receptor. It does not have significant affinity for the serotonin 5-HT1B or 5-HT3 receptors, whereas the other serotonin 5-HT1 receptors and the serotonin 5-HT4 receptor were not reported. (+)-JRT is 4.4- to 180-fold less potent than LSD as a serotonin 5-HT2A receptor agonist in vitro (EC50Tooltip half-maximal effective concentration = 0.4–90 nM vs. 0.09–0.5 nM, respectively) and is less efficacious than LSD in activating the receptor (Emax = 33% vs. 44–63%, respectively). (+)-JRT dissociates from the serotonin 5-HT2A receptor approximately 10-fold more quickly than LSD. (+)-JRT produces the head-twitch response (HTR), a behavioral proxy of psychedelic effects, in rodents, and hence would be expected to be hallucinogenic in humans. However, the drug shows a reduced HTR compared to LSD, producing less than half the maximal number of head twitches. It can also antagonize the HTR induced by LSD. Hence, (+)-JRT may be less psychedelic than LSD in humans. LSD and (+)-JRT are of similar potency in this effect, with maximal HTR being achieved at 0.2 mg/kg for both compounds. (+)-JRT does not affect locomotor activity and does not produce any serotonin behavioral syndrome-type effects. It has been found to inhibit dextroamphetamine-induced hyperlocomotion in female but not male mice, does not exacerbate phencyclidine (PCP)-induced hyperlocomotion, does not worsen dizocilpine (MK-801)-induced prepulse inhibition (PPI), and does not induce PPI deficits itself. Some of these findings are in contrast to LSD, and are suggestive that (+)-JRT lacks psychotic-like effects and may have antipsychotic potential. In addition to the preceding findings, (+)-JRT has been reported to increase neuroplasticity and hence to act as a psychoplastogen, to produce antidepressant-like effects, and to promote cognitive flexibility. It was equivalent with LSD in terms of psychoplastogenic effects. == Chemistry == JRT is the analogue of the lysergamide lysergic acid diethylamide (LSD) in which the embedded tryptamine structure within the ergoline ring system of LSD has been replaced with an isotryptamine structure. Hence, JRT is not an ergoline, lysergamide, or tryptamine itself, but could be considered a cyclized isotryptamine. JRT exists as four enantiomers, including (+)-JRT and (–)-JRT, with (+)-JRT being the active enantiomer. == History == JRT was developed by Jeremy R. Tuck (J.R.T.), Lee E. Dunlap, David E. Olson, and other colleagues at Delix Therapeutics and the University of California, Davis. It was first described in the scientific literature by 2022. == Research == JRT is being investigated as a possible treatment for schizophrenia. == See also == List of investigational hallucinogens and entactogens List of miscellaneous 5-HT2A receptor agonists SPT-348 IsoDMT 6-MeO-isoDMT Zalsupindole (DLX-001; AAZ-A-154; (R)-5-MeO-α-methyl-isoDMT) DLX-159 BMB-201 ITI-1549 == References == == External links == LSD-Inspired Drug Reverses Psychosis Brain Damage Without Hallucinations - Neuroscience News Scientists Flip Two Atoms in LSD – And Unlock a Game-Changing Mental Health Treatment - SciTechDaily A New Form of LSD to Treat Schizophrenia - Psychology Today	Wikipedia/JRT_(drug)
Dimethoxybromoamphetamine (DOB), also known as brolamfetamine (INNTooltip International Nonproprietary Name) and bromo-DMA, is a psychedelic drug and substituted amphetamine of the phenethylamine class of compounds. DOB was first synthesized by Alexander Shulgin in 1967. Its synthesis and effects are documented in Shulgin's book PiHKAL: A Chemical Love Story. The drug acts as a serotonin 5-HT2 receptor agonist. == Side effects == Excessively high doses of DOB may cause diffuse arterial spasm. The vasospasm responded readily to intra-arterial and intravenous vasodilators, such as tolazoline. == Interactions == == Pharmacology == === Pharmacodynamics === DOB is a serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptor agonist. Its psychedelic effects are mediated by its agonistic properties at the 5-HT2A receptor. Due to its selectivity, DOB is often used in scientific research when studying the 5-HT2 receptor subfamily. It is a very weak agonist of the human trace amine-associated receptor 1 (TAAR1) and a weak agonist of the rhesus monkey TAAR1. In contrast to the serotonin releasing agent MDMA, DOB does not produce protein kinase C (PKC) activation in the brains of rodents in vivo. The PKC activation by MDMA appears to be dependent on uptake by the serotonin transporter (SERT). DOB has been found to reduce aggression in rats. == Chemistry == The full name of the chemical is 2,5-dimethoxy-4-bromoamphetamine. DOB has a stereocenter and R-(−)-DOB is the eutomer. This is an important finding as it is suggestive that it is targeting different receptors relative to most other phenethylamines (e.g. MDMA) where the R-isomer serves as the distomer. The toxicity of DOB is not fully known, although high doses may cause serious vasoconstriction of the extremities. DOB is one of the most potent compounds in PiHKAL; while the active dose is similar to that of DOI, another psychedelic amphetamine, DOB has been shown to have a higher efficacy in triggering downstream effects mediated by 5-HT2 receptors, making it likely to be slightly more dangerous than DOI in overdose, due to greater vasoconstrictive action. Omission of the amphetamine related α-methyl leads to 2C-B, a compound that possesses a lower affinity for the 5-HT2A receptor and is a weaker receptor agonist which results in drastically reduced vasoconstriction. == History == DOB was first synthesized by Alexander Shulgin in 1967. It was first described in the scientific literature in a paper by Shulgin, Claudio Naranjo, and another colleague in 1971. The INNTooltip International Nonproprietary Name of DOB, brolamfetamine, was proposed and recommended by the World Health Organization (WHO) in 1986. This was the same year that the Multidisciplinary Association for Psychedelic Studies (MAPS) was founded. DOB was registered with the WHO as a supposed "anorexic" (appetite suppressant). == Society and culture == === Legal status === Internationally, DOB is a Schedule I substance under the Convention on Psychotropic Substances and the drug is legal only for medical, industrial or scientific purposes. ==== Canada ==== Listed as a Schedule 1 as it is an analogue of amphetamine. ==== Australia ==== DOB is considered a Schedule 9 prohibited substance in Australia under the Poisons Standard (February 2017). A Schedule 9 substance is a substance which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities. ==== Russia ==== Schedule I, possession of at least 10 mg is a criminal offence. ==== United Kingdom ==== DOB is a Class A drug in the United Kingdom under the Misuse of Drugs Act 1971. ==== United States ==== DOB is a Schedule I controlled substance under federal law in the United States. It was scheduled in 1973. == See also == 2,5-Dimethoxy-4-substituted amphetamines 2C-B – the α-desmethyl derivative of DOB 4C-B – the α-ethyl homologue of DOB β-Methyl-2C-B DOB-FLY == References == == External links == DOB - Isomer Design DOB - PsychonautWiki DOB - Erowid DOB - TripSit The Big & Dandy DOB Thread - Bluelight DOB - PiHKAL - Erowid DOB - PiHKAL - Isomer Design	Wikipedia/DOB_(drug)
2,5-Dimethoxy-4-methylamphetamine (DOM), also known as STP (standing for "Serenity, Tranquility, and Peace" and/or other phrases), is a psychedelic drug of the phenethylamine, amphetamine, and DOx families. It is generally taken orally. DOM was first synthesized by Alexander Shulgin, and later described in his book PiHKAL: A Chemical Love Story (1991). It is classified as a Schedule I controlled substance in the United States, and is similarly controlled in other parts of the world. Internationally, it is a Schedule I drug under the Convention on Psychotropic Substances. == Effects == Effects of this drug include substantial perceptual changes such as blurred vision, multiple images, vibration of objects, visual alterations, distorted shapes, enhancement of details, slowed passage of time, increased sexual drive and pleasure, and increased contrasts. It may cause mystical experiences and changes in consciousness. It may also cause pupillary dilation and a rise in systolic blood pressure. The effects of DOM were assessed in clinical studies in the late 1960s and early 1970s and by other researchers. At low doses, such as 1 to 4 mg, DOM produces effects including stimulation, euphoria, enhanced self-awareness, and mild dose-dependent perceptual disturbances. At higher doses, of above 5 to 7 mg, DOM produces psychedelic effects. == Side effects == Very little is known about the toxicity of DOM. == Interactions == == Pharmacology == === Pharmacodynamics === ==== Actions ==== DOM acts as a selective serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptor full agonist. Its psychedelic effects are mediated by its agonistic properties at the 5-HT2A receptor. Due to its selectivity, DOM is often used in scientific research in studies of the 5-HT2 receptor subfamily. DOM is a chiral molecule, and R-(−)-DOM is the more active enantiomer, functioning as a potent agonist of these receptors. The drug is inactive as a human trace amine-associated receptor 1 (TAAR1) agonist but is an agonist of the rhesus monkey TAAR1. DOM is inactive as a monoamine reuptake inhibitor and releasing agent. It is a very weak monoamine oxidase inhibitor (MAOI), specifically of monoamine oxidase A (MAO-A), whereas it was inactive at monoamine oxidase B (MAO-B). ==== Effects ==== DOM produces the head-twitch response in rodents, a behavioral proxy of psychedelic-like effects. It also substitutes for LSD in rodent drug discrimination tests. DOM is widely used as a psychedelic training drug in rodent drug discrimination assays and many other serotonergic psychedelics have been shown to generalize to it. In contrast to amphetamines like (–)-cathinone but similarly to mescaline, DOM has shown no stimulant-like or reinforcing effects in rhesus monkeys. Conversely however, DOC has shown reinforcing effects, including conditioned place preference (CPP) and self-administration, in rodents similarly to methamphetamine. This is analogous to other findings in which various 2C and NBOMe drugs have been found to produce dopaminergic elevations and reinforcing effects in rodents. === Pharmacokinetics === According to Alexander Shulgin, the effects of DOM typically last 14 to 20 hours, though other clinical trials indicate a duration of 7 to 8 hours. Metabolites of DOM like 2-O-desmethyl-DOM (2-DM-DOM) and 5-O-desmethyl-DOM (5-DM-DOM) are pharmacologically active and show psychedelic-like effects in animal studies. They might contribute to the delayed onset and long duration of DOM. However, these metabolites might also produce metabolism-dependent neurotoxicity. == Chemistry == DOM, also known as 2,5-dimethoxy-4-methylamphetamine or as 2,5-dimethoxy-4-methyl-α-methylphenethylamine, is a substituted phenethylamine and amphetamine and is a member of the DOx group of drugs. It is structurally related to the naturally occurring phenethylamine psychedelic mescaline (3,4,5-trimethoxyphenethylamine). Analogues of DOM include other DOx drugs such as DOET, DOB, DOI, DOC, and TMA, among others. The α-desmethyl or phenethylamine analogue of DOM is 2C-D. Ariadne is the α-ethyl or phenylisobutylamine analogue of DOM. The 2,6-dimethoxy positional isomer of DOM, known as Ψ-DOM, is also mentioned in PiHKAL as being active, as is the α-ethyl homologue Ariadne. Analogues where the methoxy groups at the 2,5- positions of the aromatic ring have been altered have also been synthesised and tested as part of an effort to identify the binding mode of DOM at the serotonin 5-HT2A receptor. Both the 2- and 5- O-desmethyl derivatives 2-DM-DOM and 5-DM-DOM, and the 2- and 5- ethyl analogues 2-Et-DOM and 5-Et-DOM, have been tested, but in all cases were significantly less potent than the corresponding methoxy compound, showing the importance of the oxygen lone pairs in 5-HT2A binding. == History == STP was first synthesized and tested in 1963 by Alexander Shulgin, who was investigating the effect of 4-position substitutions on psychedelic amphetamines. In mid-1967, tablets containing 20 mg (later 10 mg) of STP were widely distributed in the Haight-Ashbury District of San Francisco under the name of STP, having been manufactured by underground chemists Owsley Stanley and Tim Scully. This short-lived appearance of STP on the black market proved disastrous for several reasons. First, the tablets contained an excessively high dose of the chemical. This, combined with DOM's slow onset of action (which encouraged some users, familiar with drugs that have quicker onsets, such as LSD, to re-dose) and its remarkably long duration, caused many users to panic and sent some to the emergency room. Second, treatment of such overdoses was complicated by the fact that no one at the time knew that the tablets called STP were, in fact, DOM, and there was no effective antidote. == Society and culture == === Legal status === ==== Australia ==== DOM is schedule 9 under the Australia Poisons standard. A schedule 9 substance is a "Substances which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities." ==== Canada ==== Listed as a Schedule 1, as it is an analogue of amphetamine. ==== United Kingdom ==== DOM is a Class A drug in the United Kingdom under the Misuse of Drugs Act 1971. ==== United States ==== DOM is Schedule I in the United States. This means it is illegal to manufacture, buy, possess, or distribute (make, trade, own or give) without a DEA license. == See also == ASR-2001 == References == == External links == DOM - Isomer Design DOM - PsychonautWiki Erowid DOM Vault DOM - PiHKAL - Erowid DOM - PiHKAL - Isomer Design What is DOM? The Serenity Psychedelic - Tripsitter	Wikipedia/DOM_(drug)
In cognitive science and neuropsychology, executive functions (collectively referred to as executive function and cognitive control) are a set of cognitive processes that support goal-directed behavior, by regulating thoughts and actions through cognitive control, selecting and successfully monitoring actions that facilitate the attainment of chosen objectives. Executive functions include basic cognitive processes such as attentional control, cognitive inhibition, inhibitory control, working memory, and cognitive flexibility. Higher-order executive functions require the simultaneous use of multiple basic executive functions and include planning and fluid intelligence (e.g., reasoning and problem-solving). Executive functions gradually develop and change across the lifespan of an individual and can be improved at any time over the course of a person's life. Similarly, these cognitive processes can be adversely affected by a variety of events which affect an individual. Both neuropsychological tests (e.g., the Stroop test) and rating scales (e.g., the Behavior Rating Inventory of Executive Function) are used to measure executive functions. They are usually performed as part of a more comprehensive assessment to diagnose neurological and psychiatric disorders. Cognitive control and stimulus control, which is associated with operant and classical conditioning, represent opposite processes (internal vs external or environmental, respectively) that compete over the control of an individual's elicited behaviors; in particular, inhibitory control is necessary for overriding stimulus-driven behavioral responses (stimulus control of behavior). The prefrontal cortex is necessary but not solely sufficient for executive functions; for example, the caudate nucleus and subthalamic nucleus also have a role in mediating inhibitory control. Cognitive control is impaired in addiction, attention deficit hyperactivity disorder, autism, and a number of other central nervous system disorders. Stimulus-driven behavioral responses that are associated with a particular rewarding stimulus tend to dominate one's behavior in an addiction. == Neuroanatomy == Historically, the executive functions have been seen as regulated by the prefrontal regions of the frontal lobes, but it is still a matter of ongoing debate if that really is the case. Even though articles on prefrontal lobe lesions commonly refer to disturbances of executive functions and vice versa, a review found indications for the sensitivity but not for the specificity of executive function measures to frontal lobe functioning. This means that both frontal and non-frontal brain regions are necessary for intact executive functions. Probably the frontal lobes need to participate in basically all of the executive functions, but they are not the only brain structure involved. Neuroimaging and lesion studies have identified the functions which are most often associated with the particular regions of the prefrontal cortex and associated areas. The dorsolateral prefrontal cortex (DLPFC) is involved with "on-line" processing of information such as integrating different dimensions of cognition and behavior. As such, this area has been found to be associated with verbal and design fluency, ability to maintain and shift set, planning, response inhibition, anticipation of conflict stimuli, working memory, organisational skills, reasoning, problem-solving, and abstract thinking. The anterior cingulate cortex (ACC) is involved in emotional drives, experience and integration. Associated cognitive functions include inhibition of inappropriate responses, decision making and motivated behaviors. Lesions in this area can lead to low drive states such as apathy, abulia or akinetic mutism and may also result in low drive states for such basic needs as food or drink and possibly decreased interest in social or vocational activities and sex. The orbitofrontal cortex (OFC) plays a key role in impulse control, maintenance of set, monitoring ongoing behavior and socially appropriate behaviors. The orbitofrontal cortex also has roles in representing the value of rewards based on sensory stimuli and evaluating subjective emotional experiences. Lesions can cause disinhibition, impulsivity, aggressive outbursts, sexual promiscuity and antisocial behavior. Furthermore, in their review, Alvarez and Emory state that:The frontal lobes have multiple connections to cortical, subcortical and brain stem sites. The basis of "higher-level" cognitive functions such as inhibition, flexibility of thinking, problem solving, planning, impulse control, concept formation, abstract thinking, and creativity often arise from much simpler, "lower-level" forms of cognition and behavior. Thus, the concept of executive function must be broad enough to include anatomical structures that represent a diverse and diffuse portion of the central nervous system.The cerebellum also appears to be involved in mediating certain executive functions, as do the ventral tegmental area and the substantia nigra. In humans, high contents of cannabinoid receptor 1 (CB1) is found in frontal neocortical areas, subserving higher cognitive and executive functions, and in the posterior cingulate, a region pivotal for consciousness and higher cognitive processing by its activation. == Hypothesized role == The executive system is thought to be heavily involved in handling novel situations outside the domain of some of our 'automatic' psychological processes that could be explained by the reproduction of learned schemas or set behaviors. Psychologists Don Norman and Tim Shallice have outlined five types of situations in which routine activation of behavior would not be sufficient for optimal performance: Those that involve planning or decision-making Those that involve error correction or troubleshooting Situations where responses are not well-rehearsed or contain novel sequences of actions Dangerous or technically difficult situations Situations that require the overcoming of a strong habitual response or resisting temptation. A prepotent response is a response for which immediate reinforcement (positive or negative) is available or has been previously associated with that response. Executive functions are often invoked when it is necessary to override prepotent responses that might otherwise be automatically elicited by stimuli in the external environment. For example, on being presented with a potentially rewarding stimulus, such as a tasty piece of chocolate cake, a person might have the automatic response to take a bite. However, where such behavior conflicts with internal plans (such as having decided not to eat chocolate cake while on a diet), the executive functions might be engaged to inhibit that response. Although suppression of these prepotent responses is ordinarily considered adaptive, problems for the development of the individual and the culture arise when feelings of right and wrong are overridden by cultural expectations or when creative impulses are overridden by executive inhibitions. == Historical perspective == Although research into the executive functions and their neural basis has increased markedly over recent years, the theoretical framework in which it is situated is not new. In the 1940s, the British psychologist Donald Broadbent drew a distinction between "automatic" and "controlled" processes (a distinction characterized more fully by Shiffrin and Schneider in 1977), and introduced the notion of selective attention, to which executive functions are closely allied. In 1975, the US psychologist Michael Posner used the term "cognitive control" in his book chapter entitled "Attention and cognitive control". The work of influential researchers such as Michael Posner, Joaquin Fuster, Tim Shallice, and their colleagues in the 1980s (and later Trevor Robbins, Bob Knight, Don Stuss, and others) laid much of the groundwork for recent research into executive functions. For example, Posner proposed that there is a separate "executive" branch of the attentional system, which is responsible for focusing attention on selected aspects of the environment. The British neuropsychologist Tim Shallice similarly suggested that attention is regulated by a "supervisory system", which can override automatic responses in favour of scheduling behaviour on the basis of plans or intentions. Throughout this period, a consensus emerged that this control system is housed in the most anterior portion of the brain, the prefrontal cortex (PFC). Psychologist Alan Baddeley had proposed a similar system as part of his model of working memory and argued that there must be a component (which he named the "central executive") that allows information to be manipulated in short-term memory (for example, when doing mental arithmetic). == Development == The executive functions are among the last mental functions to reach maturity. This is due to the delayed maturation of the prefrontal cortex, which is not completely myelinated until well into a person's third decade of life. Development of executive functions tends to occur in spurts, when new skills, strategies, and forms of awareness emerge. These spurts are thought to reflect maturational events in the frontal areas of the brain. Attentional control appears to emerge in infancy and develop rapidly in early childhood. Cognitive flexibility, goal setting, and information processing usually develop rapidly during ages 7–9 and mature by age 12. Executive control typically emerges shortly after a transition period at the beginning of adolescence. It is not yet clear whether there is a single sequence of stages in which executive functions appear, or whether different environments and early life experiences can lead people to develop them in different sequences. === Early childhood === Inhibitory control and working memory act as basic executive functions that make it possible for more complex executive functions like problem-solving to develop. Inhibitory control and working memory are among the earliest executive functions to appear, with initial signs observed in infants, 7 to 12 months old. Then in the preschool years, children display a spurt in performance on tasks of inhibition and working memory, usually between the ages of 3 and 5 years. Also during this time, cognitive flexibility, goal-directed behavior, and planning begin to develop. Nevertheless, preschool children do not have fully mature executive functions and continue to make errors related to these emerging abilities – often not due to the absence of the abilities, but rather because they lack the awareness to know when and how to use particular strategies in particular contexts. === Preadolescence === Preadolescent children continue to exhibit certain growth spurts in executive functions, suggesting that this development does not necessarily occur in a linear manner, along with the preliminary maturing of particular functions as well. During preadolescence, children display major increases in verbal working memory; goal-directed behavior (with a potential spurt around 12 years of age); response inhibition and selective attention; and strategic planning and organizational skills. Additionally, between the ages of 8 and 10, cognitive flexibility in particular begins to match adult levels. However, similar to patterns in childhood development, executive functioning in preadolescents is limited because they do not reliably apply these executive functions across multiple contexts as a result of ongoing development of inhibitory control. === Adolescence === Many executive functions may begin in childhood and preadolescence, such as inhibitory control. Yet, it is during adolescence when the different brain systems become better integrated. At this time, youth implement executive functions, such as inhibitory control, more efficiently and effectively and improve throughout this time period. Just as inhibitory control emerges in childhood and improves over time, planning and goal-directed behavior also demonstrate an extended time course with ongoing growth over adolescence. Likewise, functions such as attentional control, with a potential spurt at age 15, along with working memory, continue developing at this stage. === Adulthood === The major change that occurs in the brain in adulthood is the constant myelination of neurons in the prefrontal cortex. At age 20–29, executive functioning skills are at their peak, which allows people of this age to participate in some of the most challenging mental tasks. These skills begin to decline in later adulthood. Working memory and spatial span are areas where decline is most readily noted. Cognitive flexibility, however, has a late onset of impairment and does not usually start declining until around age 70 in normally functioning adults. Impaired executive functioning has been found to be the best predictor of functional decline in the elderly. Exercise, even at light intensity, significantly improves executive function with the strongest effects seen in children, adolescents, and individuals with ADHD. Low- to moderate-intensity exercise was particularly effective in enhancing these higher-order cognitive processes. == Models == === Top-down inhibitory control === Aside from facilitatory or amplificatory mechanisms of control, many authors have argued for inhibitory mechanisms in the domain of response control, memory, selective attention, theory of mind, emotion regulation, as well as social emotions such as empathy. A recent review on this topic argues that active inhibition is a valid concept in some domains of psychology/cognitive control. === Working memory model === One influential model is Baddeley's multicomponent model of working memory, which is composed of a central executive system that regulates three subsystems: the phonological loop, which maintains verbal information; the visuospatial sketchpad, which maintains visual and spatial information; and the more recently developed episodic buffer that integrates short-term and long-term memory, holding and manipulating a limited amount of information from multiple domains in temporal and spatially sequenced episodes. Researchers have found significant positive effects of biofeedback-enhanced relaxation on memory and inhibition in children. Biofeedback is a mind-body tool where people can learn to control and regulate their body to improve and control their executive functioning skills. To measure one's processes, researchers use their heart rate and or respiratory rates. Biofeedback-relaxation includes music therapy, art, and other mindfulness activities. Executive functioning skills are important for many reasons, including children's academic success and social emotional development. According to the study "The Efficacy of Different Interventions to Foster Children's Executive Function Skills: A Series of Meta-Analyses", researchers found that it is possible to train executive functioning skills. Researchers conducted a meta-analytic study that looked at the combined effects of prior studies in order to find the overarching effectiveness of different interventions that promote the development of executive functioning skills in children. The interventions included computerized and non-computerized training, physical exercise, art, and mindfulness exercises. However, researchers could not conclude that art activities or physical activities could improve executive functioning skills. === Supervisory attentional system (SAS) === Another conceptual model is the supervisory attentional system (SAS). In this model, contention scheduling is the process where an individual's well-established schemas automatically respond to routine situations while executive functions are used when faced with novel situations. In these new situations, attentional control will be a crucial element to help generate new schema, implement these schema, and then assess their accuracy. === Self-regulatory model === Russell Barkley proposed a widely known model of executive functioning that is based on self-regulation. Primarily derived from work examining behavioral inhibition, it views executive functions as composed of four main abilities. One element is working memory that allows individuals to resist interfering information. A second component is the management of emotional responses in order to achieve goal-directed behaviors. Thirdly, internalization of self-directed speech is used to control and sustain rule-governed behavior and to generate plans for problem-solving. Lastly, information is analyzed and synthesized into new behavioral responses to meet one's goals. Changing one's behavioral response to meet a new goal or modify an objective is a higher level skill that requires a fusion of executive functions including self-regulation, and accessing prior knowledge and experiences. According to this model, the executive system of the human brain provides for the cross-temporal organization of behavior towards goals and the future and coordinates actions and strategies for everyday goal-directed tasks. Essentially, this system permits humans to self-regulate their behavior so as to sustain action and problem-solving toward goals specifically and the future more generally. Thus, executive function deficits pose serious problems for a person's ability to engage in self-regulation over time to attain their goals and anticipate and prepare for the future. Teaching children self-regulation strategies is a way to improve their inhibitory control and their cognitive flexibility. These skills allow children to manage their emotional responses. These interventions include teaching children executive function-related skills that provide the steps necessary to implement them during classroom activities and educating children on how to plan their actions before acting upon them. Executive functioning skills are how the brain plans and reacts to situations. Offering new self-regulation strategies allow children to improve their executive functioning skills by practicing something new. It is also concluded that mindfulness practices are shown to be a significantly effective intervention for children to self-regulate. This includes biofeedback-enhanced relaxation. These strategies support the growth of children's executive functioning skills. === Problem-solving model === Yet another model of executive functions is a problem-solving framework where executive functions are considered a macroconstruct composed of subfunctions working in different phases to (a) represent a problem, (b) plan for a solution by selecting and ordering strategies, (c) maintain the strategies in short-term memory in order to perform them by certain rules, and then (d) evaluate the results with error detection and error correction. === Lezak's conceptual model === One of the most widespread conceptual models on executive functions is Lezak's model. This framework proposes four broad domains of volition, planning, purposive action, and effective performance as working together to accomplish global executive functioning needs. While this model may broadly appeal to clinicians and researchers to help identify and assess certain executive functioning components, it lacks a distinct theoretical basis and relatively few attempts at validation. === Miller and Cohen's model === In 2001, Earl Miller and Jonathan Cohen published their article "An integrative theory of prefrontal cortex function", in which they argue that cognitive control is the primary function of the prefrontal cortex (PFC), and that control is implemented by increasing the gain of sensory or motor neurons that are engaged by task- or goal-relevant elements of the external environment. In a key paragraph, they argue: We assume that the PFC serves a specific function in cognitive control: the active maintenance of patterns of activity that represent goals and the means to achieve them. They provide bias signals throughout much of the rest of the brain, affecting not only visual processes but also other sensory modalities, as well as systems responsible for response execution, memory retrieval, emotional evaluation, etc. The aggregate effect of these bias signals is to guide the flow of neural activity along pathways that establish the proper mappings between inputs, internal states, and outputs needed to perform a given task. Miller and Cohen draw explicitly upon an earlier theory of visual attention that conceptualises perception of visual scenes in terms of competition among multiple representations – such as colors, individuals, or objects. Selective visual attention acts to 'bias' this competition in favour of certain selected features or representations. For example, imagine that you are waiting at a busy train station for a friend who is wearing a red coat. You are able to selectively narrow the focus of your attention to search for red objects, in the hope of identifying your friend. Desimone and Duncan argue that the brain achieves this by selectively increasing the gain of neurons responsive to the color red, such that output from these neurons is more likely to reach a downstream processing stage, and, as a consequence, to guide behaviour. According to Miller and Cohen, this selective attention mechanism is in fact just a special case of cognitive control – one in which the biasing occurs in the sensory domain. According to Miller and Cohen's model, the PFC can exert control over input (sensory) or output (response) neurons, as well as over assemblies involved in memory, or emotion. Cognitive control is mediated by reciprocal PFC connectivity with the sensory and motor cortices, and with the limbic system. Within their approach, thus, the term "cognitive control" is applied to any situation where a biasing signal is used to promote task-appropriate responding, and control thus becomes a crucial component of a wide range of psychological constructs such as selective attention, error monitoring, decision-making, memory inhibition, and response inhibition. === Miyake and Friedman's model === Miyake and Friedman's theory of executive functions proposes that there are three aspects of executive functions: updating, inhibition, and shifting. A cornerstone of this theoretical framework is the understanding that individual differences in executive functions reflect both unity (i.e., common EF skills) and diversity of each component (e.g., shifting-specific). In other words, aspects of updating, inhibition, and shifting are related, yet each remains a distinct entity. First, updating is defined as the continuous monitoring and quick addition or deletion of contents within one's working memory. Second, inhibition is one's capacity to supersede responses that are prepotent in a given situation. Third, shifting is one's cognitive flexibility to switch between different tasks or mental states. Miyake and Friedman also suggest that the current body of research in executive functions suggest four general conclusions about these skills. The first conclusion is the unity and diversity aspects of executive functions. Second, recent studies suggest that much of one's EF skills are inherited genetically, as demonstrated in twin studies. Third, clean measures of executive functions can differentiate between normal and clinical or regulatory behaviors, such as ADHD. Last, longitudinal studies demonstrate that EF skills are relatively stable throughout development. === Banich's "cascade of control" model === This model from 2009 integrates theories from other models, and involves a sequential cascade of brain regions involved in maintaining attentional sets in order to arrive at a goal. In sequence, the model assumes the involvement of the posterior dorsolateral prefrontal cortex (DLPFC), the mid-DLPFC, and the posterior and anterior dorsal anterior cingulate cortex (ACC). The cognitive task used in the article is selecting a response in the Stroop task, among conflicting color and word responses, specifically a stimulus where the word "green" is printed in red ink. The posterior DLPFC creates an appropriate attentional set, or rules for the brain to accomplish the current goal. For the Stroop task, this involves activating the areas of the brain involved in color perception, and not those involved in word comprehension. It counteracts biases and irrelevant information, like the fact that the semantic perception of the word is more salient to most people than the color in which it is printed. Next, the mid-DLPFC selects the representation that will fulfill the goal. The task-relevant information must be separated from other sources of information in the task. In the example, this means focusing on the ink color and not the word. The posterior dorsal ACC is next in the cascade, and it is responsible for response selection. This is where the decision is made whether the Stroop task participant will say "green" (the written word and the incorrect answer) or "red" (the font color and correct answer). Following the response, the anterior dorsal ACC is involved in response evaluation, deciding whether one's response were correct or incorrect. Activity in this region increases when the probability of an error is higher. The activity of any of the areas involved in this model depends on the efficiency of the areas that came before it. If the DLPFC imposes a lot of control on the response, the ACC will require less activity. Recent work using individual differences in cognitive style has shown exciting support for this model. Researchers had participants complete an auditory version of the Stroop task, in which either the location or semantic meaning of a directional word had to be attended to. Participants that either had a strong bias toward spatial or semantic information (different cognitive styles) were then recruited to participate in the task. As predicted, participants that had a strong bias toward spatial information had more difficulty paying attention to the semantic information and elicited increased electrophysiological activity from the ACC. A similar activity pattern was also found for participants that had a strong bias toward verbal information when they tried to attend to spatial information. == Assessment == Assessment of executive functions involves gathering data from several sources and synthesizing the information to look for trends and patterns across time and settings. Apart from standardized neuropsychological tests, other measures can and should be used, such as behaviour checklists, observations, interviews, and work samples. From these, conclusions may be drawn on the use of executive functions. There are several different kinds of instruments (e.g., performance based, self-report) that measure executive functions across development. These assessments can serve a diagnostic purpose for a number of clinical populations. == Experimental evidence == The executive system has been traditionally quite hard to define, mainly due to what psychologist Paul W. Burgess calls a lack of "process-behaviour correspondence". That is, there is no single behavior that can in itself be tied to executive function, or indeed executive dysfunction. For example, it is quite obvious what reading-impaired patients cannot do, but it is not so obvious what exactly executive-impaired patients might be incapable of. This is largely due to the nature of the executive system itself. It is mainly concerned with the dynamic, "online" co-ordination of cognitive resources, and, hence, its effect can be observed only by measuring other cognitive processes. In similar manner, it does not always fully engage outside of real-world situations. As neurologist Antonio Damasio has reported, a patient with severe day-to-day executive problems may still pass paper-and-pencil or lab-based tests of executive function. Theories of the executive system were largely driven by observations of patients with frontal lobe damage. They exhibited disorganized actions and strategies for everyday tasks (a group of behaviors now known as dysexecutive syndrome) although they seemed to perform normally when clinical or lab-based tests were used to assess more fundamental cognitive functions such as memory, learning, language, and reasoning. It was hypothesized that, to explain this unusual behaviour, there must be an overarching system that co-ordinates other cognitive resources. Much of the experimental evidence for the neural structures involved in executive functions comes from laboratory tasks such as the Stroop task or the Wisconsin Card Sorting Task (WCST). In the Stroop task, for example, human subjects are asked to name the color that color words are printed in when the ink color and word meaning often conflict (for example, the word "RED" in green ink). Executive functions are needed to perform this task, as the relatively overlearned and automatic behaviour (word reading) has to be inhibited in favour of a less practiced task – naming the ink color. Recent functional neuroimaging studies have shown that two parts of the PFC, the anterior cingulate cortex (ACC) and the dorsolateral prefrontal cortex (DLPFC), are thought to be particularly important for performing this task. === Context-sensitivity of PFC neurons === Other evidence for the involvement of the PFC in executive functions comes from single-cell electrophysiology studies in non-human primates, such as the macaque monkey, which have shown that (in contrast to cells in the posterior brain) many PFC neurons are sensitive to a conjunction of a stimulus and a context. For example, PFC cells might respond to a green cue in a condition where that cue signals that a leftwards fast movement of the eyes and the head should be made, but not to a green cue in another experimental context. This is important, because the optimal deployment of executive functions is invariably context-dependent. One example from Miller & Cohen involves a pedestrian crossing the street. In the United States, where cars drive on the right side of the road, an American learns to look left when crossing the street. However, if that American visits a country where cars drive on the left, such as the United Kingdom, then the opposite behavior would be required (looking to the right). In this case, the automatic response needs to be suppressed (or augmented) and executive functions must make the American look to the right while in the UK. Neurologically, this behavioural repertoire clearly requires a neural system that is able to integrate the stimulus (the road) with a context (US or UK) to cue a behaviour (look left or look right). Current evidence suggests that neurons in the PFC appear to represent precisely this sort of information. Other evidence from single-cell electrophysiology in monkeys implicates ventrolateral PFC (inferior prefrontal convexity) in the control of motor responses. For example, cells that increase their firing rate to NoGo signals as well as a signal that says "don't look there!" have been identified. === Attentional biasing in sensory regions === Electrophysiology and functional neuroimaging studies involving human subjects have been used to describe the neural mechanisms underlying attentional biasing. Most studies have looked for activation at the 'sites' of biasing, such as in the visual or auditory cortices. Early studies employed event-related potentials to reveal that electrical brain responses recorded over left and right visual cortex are enhanced when the subject is instructed to attend to the appropriate (contralateral) side of space. The advent of bloodflow-based neuroimaging techniques such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) has more recently permitted the demonstration that neural activity in a number of sensory regions, including color-, motion-, and face-responsive regions of visual cortex, is enhanced when subjects are directed to attend to that dimension of a stimulus, suggestive of gain control in sensory neocortex. For example, in a typical study, Liu and coworkers presented subjects with arrays of dots moving to the left or right, presented in either red or green. Preceding each stimulus, an instruction cue indicated whether subjects should respond on the basis of the colour or the direction of the dots. Even though colour and motion were present in all stimulus arrays, fMRI activity in colour-sensitive regions (V4) was enhanced when subjects were instructed to attend to the colour, and activity in motion-sensitive regions was increased when subjects were cued to attend to the direction of motion. Several studies have also reported evidence for the biasing signal prior to stimulus onset, with the observation that regions of the frontal cortex tend to come active prior to the onset of an expected stimulus. === Connectivity between the PFC and sensory regions === Despite the growing currency of the 'biasing' model of executive functions, direct evidence for functional connectivity between the PFC and sensory regions when executive functions are used, is to date rather sparse. Indeed, the only direct evidence comes from studies in which a portion of frontal cortex is damaged, and a corresponding effect is observed far from the lesion site, in the responses of sensory neurons. However, few studies have explored whether this effect is specific to situations where executive functions are required. Other methods for measuring connectivity between distant brain regions, such as correlation in the fMRI response, have yielded indirect evidence that the frontal cortex and sensory regions communicate during a variety of processes thought to engage executive functions, such as working memory, but more research is required to establish how information flows between the PFC and the rest of the brain when executive functions are used. As an early step in this direction, an fMRI study on the flow of information processing during visuospatial reasoning has provided evidence for causal associations (inferred from the temporal order of activity) between sensory-related activity in occipital and parietal cortices and activity in posterior and anterior PFC. Such approaches can further elucidate the distribution of processing between executive functions in PFC and the rest of the brain. === Bilingualism and executive functions === A growing body of research demonstrates that bilinguals might show advantages in executive functions, specifically inhibitory control and task switching. A possible explanation for this is that speaking two languages requires controlling one's attention and choosing the correct language to speak. Across development, bilingual infants, children, and elderly show a bilingual advantage when it comes to executive functioning. The advantage does not seem to manifest in younger adults. Bimodal bilinguals, or people who speak one oral language and one sign language, do not demonstrate this bilingual advantage in executive functioning tasks. This may be because one is not required to actively inhibit one language in order to speak the other. Bilingual individuals also seem to have an advantage in an area known as conflict processing, which occurs when there are multiple representations of one particular response (for example, a word in one language and its translation in the individual's other language). Specifically, the lateral prefrontal cortex has been shown to be involved with conflict processing. However, there are still some doubts. In a meta-analytic review, researchers concluded that bilingualism did not enhance executive functioning in adults. == In disease or disorder == The study of executive function in Parkinson's disease suggests subcortical areas such as the amygdala, hippocampus and basal ganglia are important in these processes. Dopamine modulation of the prefrontal cortex is responsible for the efficacy of dopaminergic drugs on executive function, and gives rise to the Yerkes–Dodson Curve. The inverted U represents decreased executive functioning with excessive arousal (or increased catecholamine release during stress), and decreased executive functioning with insufficient arousal. The low activity polymorphism of catechol-O-methyltransferase is associated with slight increase in performance on executive function tasks in healthy persons. Executive functions are impaired in multiple disorders including anxiety disorder, major depressive disorder, bipolar disorder, attention deficit hyperactivity disorder, schizophrenia and autism. Lesions to the prefrontal cortex, such as in the case of Phineas Gage, may also result in deficits of executive function. Damage to these areas may also manifest in deficits of other areas of function, such as motivation, and social functioning. == Future directions == Other important evidence for executive functions processes in the prefrontal cortex have been described. One widely cited review article emphasizes the role of the medial part of the PFC in situations where executive functions are likely to be engaged – for example, where it is important to detect errors, identify situations where stimulus conflict may arise, make decisions under uncertainty, or when a reduced probability of obtaining favourable performance outcomes is detected. This review, like many others, highlights interactions between medial and lateral PFC, whereby posterior medial frontal cortex signals the need for increased executive functions and sends this signal on to areas in dorsolateral prefrontal cortex that actually implement control. Yet there has been no compelling evidence at all that this view is correct, and, indeed, one article showed that patients with lateral PFC damage had reduced ERNs (a putative sign of dorsomedial monitoring/error-feedback) – suggesting, if anything, that the direction of flow of the control could be in the reverse direction. Another prominent theory emphasises that interactions along the perpendicular axis of the frontal cortex, arguing that a 'cascade' of interactions between anterior PFC, dorsolateral PFC, and premotor cortex guides behaviour in accordance with past context, present context, and current sensorimotor associations, respectively. Recent research on network energy in brain functional connectivity reveals that energy is selectively allocated to relevant brain networks during cognitive tasks. Canonical networks involved in executive functions, such as the prefrontal cortex in working memory tasks, exhibit efficient network organization, requiring a smaller share of energy. Advances in neuroimaging techniques have allowed studies of genetic links to executive functions, with the goal of using the imaging techniques as potential endophenotypes for discovering the genetic causes of executive function. == See also == Cognitive neuropsychology Executive dysfunction Metacognition Nonverbal learning disorder Purkinje cell Self-control Conscientiousness == References == == External links == Media related to Executive functions at Wikimedia Commons The National Center for Learning Disabilities	Wikipedia/Executive_function
Afterglow, when used in the context of recreational drug use, refers to positive physical and mental effects that linger after the main effects of a drug have subsided, or after the peak experience has subsided. This state is often characterized by feelings of detachment or increased psychological clarity. The term is most commonly associated with hallucinogens, particularly psychedelics and entactogens. Psychiatrist Walter Pahnke described afterglow as an “elevated and energetic mood with a relative freedom from concerns of the past and from guilt and anxiety.” This phenomenon contrasts with hangovers, a condition that follows the use of various substances, including alcohol. Common effects of afterglow are described by many drug users: Increased confidence State of inner peace Feeling "cleansed" Insomnia Most drugs do not typically cause afterglow, but some (like MDMA) can. Afterglow may also occur after the usage of dissociative drugs, such as the NMDA antagonists, DXM, ketamine and PCP. These forms of afterglows, in contrast to psychedelic afterglows, often leave the user with a decreased mental capacity. Many report that their brain feels like "mush". The trip may leave the user with a bizarre sense of self. Afterglow occurs after the comedown or landing. Afterglow slowly fades, but can last as short as 24-hours, while some positive post-acute phase of psychedelic drug effects (characterized by elevated mood and openness) have been reported to extend between 6 and 8 weeks. == See also == Psychedelic drug § Psychedelic afterglows == References ==	Wikipedia/Afterglow_(drug_culture)
The Grateful Dead was an American rock band formed in Palo Alto, California, in 1965. Known for their eclectic style that fused elements of rock, blues, jazz, folk, country, bluegrass, rock and roll, gospel, reggae, and world music with psychedelia, the band is famous for improvisation during their live performances, and for their devoted fan base, known as "Deadheads". According to the musician and writer Lenny Kaye, the music of the Grateful Dead "touches on ground that most other groups don't even know exists." For the range of their influences and the structure of their live performances, the Grateful Dead are considered "the pioneering godfathers of the jam band world". The Grateful Dead was founded in the San Francisco Bay Area during the rise of the counterculture of the 1960s. The band's founding members were Jerry Garcia (lead guitar and vocals), Bob Weir (rhythm guitar and vocals), Ron "Pigpen" McKernan (keyboards, harmonica, and vocals), Phil Lesh (bass guitar and vocals), and Bill Kreutzmann (drums). Members of the Grateful Dead, originally known as the Warlocks, had played together in various Bay Area ensembles, including the traditional jug band Mother McCree's Uptown Jug Champions. Lesh was the last member to join the Warlocks before they changed their name to Grateful Dead, replacing Dana Morgan Jr., who had played bass for a few gigs. Drummer Mickey Hart and non-performing lyricist Robert Hunter joined in 1967. With the exception of McKernan, who died in 1973, and Hart, who left the band from 1971 to 1974, the core of the band stayed together for its entire 30-year history. Other official members of the band included Tom Constanten (keyboards from 1968 to 1970), John Perry Barlow (non-performing lyricist from 1971 to 1995), Keith Godchaux (keyboards and occasional vocals from 1971 to 1979), Donna Godchaux (vocals from 1972 to 1979), Brent Mydland (keyboards and vocals from 1979 to 1990), and Vince Welnick (keyboards and vocals from 1990 to 1995). Bruce Hornsby (accordion, piano, vocals) was a touring member from 1990 to 1992, as well as a guest with the band on occasion before and after the tours. After Garcia's death in 1995, former members of the band, along with other musicians, toured as The Other Ones in 1998, 2000, and 2002, and as The Dead in 2003, 2004, and 2009. In 2015, the four surviving core members marked the band's 50th anniversary in a series of concerts in Santa Clara, California, and Chicago that were billed as their last performances together. There have also been several spin-offs featuring one or more core members, such as Dead & Company, Furthur, the Rhythm Devils, Phil Lesh and Friends, RatDog, and Billy & the Kids. Despite having only one Top-40 single in their 30-year career, "Touch of Grey" (1987), the Grateful Dead remained among the highest-grossing American touring acts for decades. They gained a committed fanbase by word of mouth and through the free exchange of their live recordings, encouraged by the band's allowance of taping. In 2024, they broke the record for most Top-40 albums on the Billboard 200 chart. Rolling Stone ranked the Grateful Dead number 57 on its 2011 list of the "100 Greatest Artists of All Time". The band was inducted into the Rock and Roll Hall of Fame in 1994, and a recording of their May 8, 1977 performance at Cornell University's Barton Hall was added to the National Recording Registry of the Library of Congress in 2012 for being "culturally, historically, or aesthetically significant". In 2024, Weir, Lesh, Kreutzmann, and Hart were recognized as part of the Kennedy Center Honors. == Formation (1965–1966) == The Grateful Dead began their career as the Warlocks, a group formed in early 1965 from the remnants of a Palo Alto, California jug band called Mother McCree's Uptown Jug Champions and members of The Wildwood Boys (Jerry Garcia, Ron "Pigpen" McKernan, David Nelson, Robert Hunter, and Norm Van Maastricht). As The Wildwood Boys they played regularly at The Tangent, a folk music coffeehouse operated by Stanford Medical Center doctors Stuart "Stu" Goldstein and David "Dave" Shoenstadt on University Avenue in Palo Alto (1963). As the Warlocks, the band's first show was at Magoo's Pizza Parlor, at 639 Santa Cruz Avenue in suburban Menlo Park, on May 5, 1965, now a Harvest furniture store. The band continued playing bar shows, like Frenchy's Bikini-A-Go-Go in Hayward and, importantly, five sets a night, five nights a week, for six weeks, at the In Room in Belmont as the Warlocks, but quickly changed the band's name after finding out that a different band known as the Warlocks had put out a record under that name. (The Velvet Underground also had to change its name from the Warlocks.) The name "Grateful Dead" was chosen from a dictionary. According to Lesh, Garcia "picked up an old Britannica World Language Dictionary ... [and] ... In that silvery elf-voice he said to me, 'Hey, man, how about the Grateful Dead?'" The definition there was "the soul of a dead person, or his angel, showing gratitude to someone who, as an act of charity, arranged their burial." According to Alan Trist, director of the Grateful Dead's music publisher company Ice Nine, Garcia found the name in the Funk & Wagnalls Folklore Dictionary, when his finger landed on that phrase while playing a game of Fictionary. In the Garcia biography Captain Trips, author Sandy Troy states that the band was smoking the psychedelic DMT at the time. The motif of the "grateful dead" appears in folktales from a variety of cultures. The first show under the name Grateful Dead was in San Jose on December 4, 1965, at one of Ken Kesey's Acid Tests. Scholar Michael Kaler has written that the Dead's participation in the Acid Tests was crucial both to the development of their improvisational vocabulary and to their bonding as a band, with the group having set out to foster an intra-band musical telepathy. Kaler has further pointed out that the Dead's pursuit of a new improvisatory rock language in 1965 chronologically coincided with that same goal's adoption by Jefferson Airplane, Pink Floyd and the Velvet Underground. Earlier demo tapes have survived, but the first of over 2,000 concerts known to have been recorded by the band's fans was a show at the Fillmore Auditorium in San Francisco on January 8, 1966. Later that month, the Grateful Dead played at the Trips Festival, a three-day psychedelic rock weekend party and event produced by Ken Kesey, Stewart Brand, and Ramon Sender, that, in conjunction with the Merry Pranksters, brought the nascent hippie movement together for the first time. Other supporting personnel who joined early included Rock Scully, who heard of the band from Kesey and signed on as manager after meeting them at the Big Beat Acid Test; Stewart Brand, "with his side show of taped music and slides of Indian life, a multimedia presentation" at the Big Beat and then, expanded, at the Trips Festival; and Owsley Stanley, the "Acid King" whose LSD supplied the Acid Tests and who, in early 1966, became the band's financial backer, renting them a house on the fringes of Watts, Los Angeles, and buying them sound equipment. "We were living solely off of Owsley's good graces at that time. ... [His] trip was he wanted to design equipment for us, and we were going to have to be in sort of a lab situation for him to do it", said Garcia. == Main career (1967–1995) == === Pigpen era (1967–1972) === One of the group's earliest major performances in 1967 was the Mantra-Rock Dance, a musical event held on January 29, 1967, at the Avalon Ballroom by the San Francisco Hare Krishna temple. The Grateful Dead performed at the event along with the Hare Krishna founder Bhaktivedanta Swami, poet Allen Ginsberg, bands Moby Grape and Big Brother and the Holding Company with Janis Joplin, donating proceeds to the temple. The band's first LP, The Grateful Dead, was released on Warner Brothers in 1967. On May 3, 1968, the band played a free concert at Columbia University during the anti–Vietnam War student protests during which students occupied several campus buildings. In order to play, the band, equipment and all, had to be “smuggled” on campus in the back of a bread delivery truck. “We were already jamming away before the security and police could stop us.” Classically trained trumpeter Phil Lesh performed on bass guitar. Bob Weir, the youngest original member of the group, played rhythm guitar. Ron "Pigpen" McKernan played keyboards, percussion, and harmonica until shortly before his death in 1973 at the age of 27. Garcia, Weir, and McKernan shared the lead vocal duties more or less equally; Lesh sang only a few leads, but his tenor was a key part of the band's three-part vocal harmonies. Bill Kreutzmann played drums, and in September 1967 was joined by a second drummer, New York City native Mickey Hart, who also played a wide variety of other percussion instruments. 1970 included tour dates in New Orleans, where the band performed at The Warehouse for two nights. On January 31, 1970, the local police raided their hotel on Bourbon Street and arrested and charged 19 people with possession of various drugs. The second night's concert was performed as scheduled after bail was posted. Eventually, the charges were dismissed, except those against sound engineer Owsley Stanley, who was already facing charges in California for manufacturing LSD. This event was later memorialized in the lyrics of “Truckin'", a single from American Beauty that reached number 64 on the charts. Hart took time off from the band in February 1971, after his father, an accountant, absconded with much of the band's money; Kreutzmann was once again as the sole percussionist. Hart rejoined the Grateful Dead for good in October 1974. Tom "TC" Constanten was added as a second keyboardist from 1968 to 1970, to help Pigpen keep up with an increasingly psychedelic sound, while Pigpen transitioned into playing various percussion instruments and vocals. After Constanten's departure, Pigpen reclaimed his position as sole keyboardist. Less than two years later, in late 1971, Pigpen was joined by another keyboardist, Keith Godchaux, who played grand piano alongside Pigpen's Hammond B-3 organ. In early 1972, Keith's wife, Donna Jean Godchaux, joined the Grateful Dead as a backing vocalist. Following the Grateful Dead's "Europe '72" tour, Pigpen's health had deteriorated to the point that he could no longer tour with the band. His final concert appearance was June 17, 1972, at the Hollywood Bowl, in Los Angeles; he died on March 8, 1973, of complications from liver damage. === Godchaux era (1972–1979) === Pigpen's death did not slow down the Grateful Dead. With the help of manager Ron Rakow, the band soon formed its own record label, Grateful Dead Records. Later that year, it released its next studio album, the jazz-influenced Wake of the Flood, which became their biggest commercial success thus far. Meanwhile, capitalizing on the album's success, the band soon went back to the studio, and in June 1974 released another album, From the Mars Hotel. Not long after, the Dead decided to take a hiatus from live touring. The band travelled to Europe for a string of shows in September 1974, before performing a series of five concerts at the Winterland Ballroom in San Francisco in October 1974, and delved into various other projects. The Winterland concerts were filmed, and Garcia compiled the footage into The Grateful Dead Movie, a feature-length concert film released in 1977. In September 1975, the Dead released their eighth studio album, Blues for Allah. The band resumed touring in June 1976, playing multiple dates in small theaters, rather than the stadium shows that had become common, and had exhausted them, in 1974. That same year, they signed with Arista Records, and the new contract produced Terrapin Station in July 1977. The band's tour in the spring of that year is held in high regard by its fans, and its concert of May 8 at Cornell University is often considered one of the best performances of its career. Their September 1977 concert at Raceway Park in Old Bridge Township, New Jersey was attended by 107,019 people and held the record for largest-ticketed concert in the United States by a single act for 47 years. Keith and Donna Jean Godchaux left the band in February 1979, citing artistic differences. === Mydland/Welnick era (1979–1995) === Following the Godchauxs' departure, Brent Mydland joined as keyboardist and vocalist and was considered "the perfect fit." The Godchauxs then formed the Heart of Gold Band, before Keith died in a car accident in July 1980. Mydland was the keyboardist for the Grateful Dead for 11 years until his death by narcotics overdose in July 1990, becoming the third keyboardist to die. Shortly after Mydland found his place in the early 1980s, Garcia's health began to decline. He became a frequent smoker of "Persian," a type of heroin, and he gained weight at a rapid pace. He lost his liveliness on stage, his voice was strained, and Deadheads worried for his health. After he began to curtail his opiate usage gradually in 1985, Garcia slipped into a diabetic coma for several days in July 1986, leading to the cancelation of all concerts in the fall of that year. Garcia recovered, the band released In the Dark in July 1987, which became its best-selling studio album and produced its only top-40 single, "Touch of Grey," Also, that year, the group toured with Bob Dylan, as heard on the album Dylan & the Dead. Mydland died in July 1990 and Vince Welnick, former keyboardist for the Tubes, joined as a band member, while Bruce Hornsby, who had a successful career with his band the Range, joined temporarily as a bridge to help Welnick learn songs. Both performed on keyboards and vocals—Welnick until the band's end, and Hornsby mainly from 1990 to 1992. Saxophonist Branford Marsalis played five concerts with the band between 1990 and 1994. The Grateful Dead performed its final concert on July 9, 1995, at Soldier Field in Chicago. == Aftermath (1995–present) == Jerry Garcia died on August 9, 1995. A few months after Garcia's death, the remaining members of the Grateful Dead decided to disband. Since that time, there have been a number of reunions by the surviving members involving various combinations of musicians. Additionally, the former members have also begun or continued individual projects. In 1998, Bob Weir, Phil Lesh, and Mickey Hart, along with several other musicians, formed a band called the Other Ones, and performed a number of concerts that year, releasing a live album, The Strange Remain, the following year. In 2000, the Other Ones toured again, this time with Kreutzmann but without Lesh. After taking another year off, the band toured again in 2002 with Lesh. That year, the Other Ones then included all four living former Grateful Dead members who had been in the band for most or all of its history. At different times the shifting lineup of the Other Ones also included guitarists Mark Karan, Steve Kimock, and Jimmy Herring, keyboardists Bruce Hornsby, Jeff Chimenti, and Rob Barraco, saxophonist Dave Ellis, drummer John Molo, bassist Alphonso Johnson, and vocalist Susan Tedeschi. In 2003, the Other Ones, still including Weir, Lesh, Hart, and Kreutzmann, changed their name to the Dead. The Dead toured the United States in 2003, 2004 and 2009. The band's lineups included Jimmy Herring and Warren Haynes on guitar, Jeff Chimenti and Rob Barraco on keyboards, and Joan Osborne on vocals. In 2008, members of the Dead played two concerts, called "Deadheads for Obama" and "Change Rocks". Following the 2009 Dead tour, Lesh and Weir formed the band Furthur, which debuted in September 2009. Joining Lesh and Weir in Furthur were Chimenti (keyboards), John Kadlecik (guitar), Joe Russo (drums), Jay Lane (drums), Sunshine Becker (vocals), and Zoe Ellis (vocals). Lane and Ellis left the band in 2010, and vocalist Jeff Pehrson joined later that year. Furthur disbanded in 2014. In 2010, Hart and Kreutzmann re-formed the Rhythm Devils, and played a summer concert tour. In the fall of 2015, Hart, Kreutzmann and Weir teamed up with Chimenti, guitarist John Mayer, and bassist Oteil Burbridge to form a band called Dead & Company. Mayer recounted that in 2011 he was listening to Pandora and happened upon the Grateful Dead song "Althea", and that soon Grateful Dead music was all he would listen to. Dead & Company toured every year (except 2020), until announcing that their summer 2023 tour, which saw Kreutzmann replaced by Lane, would be their last. However, they later clarified that it was only their last tour, and they continue to perform concerts. Since 1995, the former members of the Grateful Dead have also pursued solo music careers. Both Bob Weir & RatDog and Phil Lesh and Friends have performed many concerts and released several albums. Mickey Hart and Bill Kreutzmann have also each released a few albums. Hart has toured with his world music percussion ensemble Planet Drum as well as the Mickey Hart Band. Kreutzmann has led several different bands, including BK3, 7 Walkers (with Papa Mali), and Billy & the Kids. Donna Godchaux has returned to the music scene, with the Donna Jean Godchaux Band, and Tom Constanten also continues to write and perform music. All of these groups continue to play Grateful Dead music. In October 2014, it was announced that Martin Scorsese would produce a documentary film about the Grateful Dead, to be directed by Amir Bar-Lev. David Lemieux supervised the musical selection, and Weir, Hart, Kreutzmann, and Lesh agreed to new interviews for the film. Bar-Lev's four-hour documentary, titled Long Strange Trip, was released in 2017. Barlow died in 2018 and Hunter in 2019. Lesh died in 2024. === "Fare Thee Well" === In 2015, Weir, Lesh, Kreutzmann, and Hart reunited for five concerts called "Fare Thee Well: Celebrating 50 Years of the Grateful Dead". The shows were performed on June 27 and 28 at Levi's Stadium in Santa Clara, California, and on July 3, 4 and 5 at Soldier Field in Chicago. The band stated that this would be the final time that Weir, Lesh, Hart, and Kreutzmann would perform together. They were joined by Trey Anastasio of Phish on guitar, Jeff Chimenti on keyboards, and Bruce Hornsby on piano. Demand for tickets was very high. The concerts were simulcast via various media. The Chicago shows have been released as a box set of CDs and DVDs. == Musical style == The Grateful Dead formed during the era when bands such as the Beatles, the Beach Boys and the Rolling Stones were dominating the airwaves. "The Beatles were why we turned from a jug band into a rock 'n' roll band", said Bob Weir. "What we saw them doing was impossibly attractive. I couldn't think of anything else more worth doing." Former folk-scene star Bob Dylan had recently put out a couple of records featuring electric instrumentation. Grateful Dead members have said that it was after attending a concert by the touring New York City band the Lovin' Spoonful that they decided to "go electric" and look for a "dirtier" sound. Jerry Garcia and Bob Weir (both of whom had been immersed in the American folk music revival of the late 1950s and early 1960s), were open-minded about the use of electric guitars. The Grateful Dead's early music (in the mid-1960s) was part of the process of establishing what "psychedelic music" was, but theirs was essentially a "street party" form of it. They developed their "psychedelic" playing as a result of meeting Ken Kesey in Palo Alto, California, and subsequently becoming the house band for the Acid Tests he staged. They did not fit their music to an established category such as pop rock, blues, folk rock, or country & western. Individual tunes within their repertoire could be identified under one of these stylistic labels, but overall their music drew on all of these genres and, more frequently, melded several of them. Bill Graham said of the Grateful Dead, "They're not the best at what they do, they're the only ones that do what they do." Academics Paul Hegarty and Martin Halliwell argued that the Grateful Dead were "not merely as precursors of prog but as essential developments of progressiveness in its early days". Often (both in performance and on recording) the Dead left room for exploratory, spacey soundscapes. Their live shows, fed by an improvisational approach to music, were different from most touring bands. While rock and roll bands often rehearse a standard set, played with minor variations, the Grateful Dead did not prepare in this way. Garcia stated in a 1966 interview, "We don't make up our sets beforehand. We'd rather work off the tops of our heads than off a piece of paper." They maintained this approach throughout their career. For each performance, the band drew material from an active list of a hundred or so songs. The 1969 live album Live/Dead did capture the band in-form, but commercial success did not come until Workingman's Dead and American Beauty, both released in 1970. These records largely featured the band's laid-back acoustic musicianship and more traditional song structures. With their rootsy, eclectic stylings, particularly evident on the latter two albums, the band pioneered the hybrid Americana genre. === Instrumentation and musicianship === As the band and its sound matured over thirty years of touring, playing, and recording, each member's stylistic contribution became more defined, consistent, and identifiable. Garcia's lead lines were fluid, supple and spare, owing a great deal of their character to his experience playing Scruggs style banjo, an approach which often makes use of note syncopation, accenting, arpeggios, staccato chromatic runs, and the anticipation of the downbeat. Garcia had a distinctive sense of timing, often weaving in and out of the groove established by the rest of the band as if he were pushing the beat. His lead lines were also immensely influenced by jazz soloists: Garcia cited Miles Davis, Ornette Coleman, Bill Evans, Pat Martino, George Benson, Al Di Meola, Art Tatum, Duke Ellington, and Django Reinhardt as primary influences, and frequently utilized techniques common to country and blues music in songs that called back to those traditions. Garcia often switched scales in the midst of a solo depending upon the chord changes played underneath, though he nearly always finished phrases by landing on the chord-tones. Jerry most frequently played in the Mixolydian mode, though his solos and phrases often incorporated notes from the Dorian and major/minor pentatonic scales. Particularly in the late 1960s, Garcia occasionally incorporated melodic lines derived from Indian ragas into the band's extended, psychedelic improvisation, likely inspired by John Coltrane and other jazz artists' interest in the sitar music of Ravi Shankar. Lesh was originally a classically trained trumpet player with an extensive background in music theory, but did not tend to play traditional blues-based bass forms. He often played more melodic, symphonic and complex lines, often sounding like a second lead guitar. In contrast to most bassists in popular music, Lesh often avoids playing the root of a chord on the downbeat, instead withholding as a means to build tension. Lesh also rarely repeats the same bassline, even from performance to performance of the same song, and often plays off of or around the other instruments with a syncopated, staccato bounce that contributes to the Dead's unique rhythmic character. Weir, too, was not a traditional rhythm guitarist, but tended to play unique inversions at the upper end of the Dead's sound. Weir modeled his style of playing after jazz pianist McCoy Tyner and attempted to replicate the interplay between John Coltrane and Tyner in his support, and occasional subversion, of the harmonic structure of Garcia's voice leadings. This would often influence the direction the band's improvisation would take on a given night. Weir and Garcia's respective positions as rhythm and lead guitarist were not always strictly adhered to, as Weir would often incorporate short melodic phrases into his playing to support Garcia and occasionally took solos, often played with a slide. Weir's playing is characterized by a "spiky, staccato" sound. The band's two drummers, Mickey Hart and Bill Kreutzmann, developed a unique, complex interplay, balancing Kreutzmann's steady shuffle beat with Hart's interest in percussion styles outside the rock tradition. Kreuzmann has said, "I like to establish a feeling and then add radical or oblique juxtapositions to that feeling." Hart incorporated an 11-count measure to his drumming, bringing a dimension to the band's sound that became an important part of its style. He had studied tabla drumming and incorporated rhythms and instruments from world music, and later electronic music, into the band's live performances. The Dead's live performances featured multiple types of improvisation derived from a vast array of musical traditions. Not unlike many rock bands of their time, the majority of the Dead's songs feature a designated section in which an instrumental break occurs over the chord changes. These sections typically feature solos by Garcia that often originate as variations on the song's melody, but go on to create dynamic phrases that resolve by returning to the chord-tones. Not unlike traditional improvisational jazz, they may occasionally feature several solos by multiple instruments within an undecided number of bars, such as a keyboardist, before returning to the melody. At the same time, Dead shows almost always feature a more collective, modal approach to improvisation that typically occurs during segues between songs before the band modulates to a new tonal center. Some of the Dead's more extended jam vehicles, such as "The Other One", "Dark Star", and "Playing in the Band" almost exclusively make use of modulation between modes to accompany simple two-chord progressions. === Lyrical themes === Following the songwriting renaissance that defined the band's early 1970s period, as reflected in the albums Workingman's Dead and American Beauty, Robert Hunter, Jerry Garcia's primary lyrical partner, frequently made use of motifs common to American folklore including trains, guns, elements, traditional musical instruments, gambling, murder, animals, alcohol, descriptions of American geography, and religious symbolism to illustrate themes involving love and loss, life and death, beauty and horror, and chaos and order. Following in the footsteps of several American musical traditions, these songs are often confessional and feature narration from the perspective of an antihero. Critic Robert Christgau described them as "American myths" that later gave way to "the old karma-go-round". An extremely common feature in both Robert Hunter's lyrics, as well as the band's visual iconography, is the presence of dualistic and opposing imagery illustrating the dynamic range of the human experience (Heaven and hell, law and crime, dark and light, etc.). Hunter and Garcia's earlier, more directly psychedelic-influenced compositions often make use of surreal imagery, nonsense, and whimsey reflective of traditions in English poetry. In a retrospective, The New Yorker described Hunter's verses as "elliptical, by turns vivid and gnomic", which were often "hippie poetry about roses and bells and dew". Grateful Dead biographer Dennis McNally has described Hunter's lyrics as creating "a non-literal hyper-Americana" weaving a psychedelic, kaleidoscopic tapestry in the hopes of elucidating America's national character. At least one of Hunter and Bob Weir's collaborations, "Jack Straw", was inspired by the work of John Steinbeck. == Influence and legacy == Grateful Dead have been called a "symbol of the counterculture movement of the sixties". Beginning in the early 1990s, a new generation of bands became inspired by the Grateful Dead's improvisational ethos and marketing strategy, and began to incorporate elements of the Grateful Dead's live performances into their own shows. These include the nightly alteration of setlists, frequent improvisation, the blending of genres, and the allowance of taping, which would often contribute to the development of a dedicated fanbase. Bands associated with the expansion of the "jam scene" include Phish, The String Cheese Incident, Widespread Panic, Blues Traveler, moe., and the Disco Biscuits. Many of these groups began to look past the American roots music that the Grateful Dead drew inspiration from, and incorporated elements of progressive rock, hard rock, and electronica. At the same time, the Internet gained popularity and provided a medium for fans to discuss these bands and their performances and download MP3s. The Grateful Dead, as well as Phish, were one of the first bands to have a Usenet newsgroup. == Merchandising and representation == Hal Kant was an entertainment industry attorney who specialized in representing musical groups. He spent 35 years as principal lawyer and general counsel for the Grateful Dead, a position in the group that was so strong that his business cards with the band identified his role as "Czar". Kant brought the band millions of dollars in revenue through his management of the band's intellectual property and merchandising rights. At Kant's recommendation, the group was one of the few rock 'n roll pioneers to retain ownership of their music masters and publishing rights. In 2006, the Grateful Dead signed a ten-year licensing agreement with Rhino Entertainment to manage the band's business interests including the release of musical recordings, merchandising, and marketing. The band retained creative control and kept ownership of its music catalog. A Grateful Dead video game titled Grateful Dead Game – The Epic Tour was released in April 2012 and was created by Curious Sense. In November 2022, the children's book The ABCs of The Grateful Dead was released. Authorized by the group, it was written by Howie Abrams, illustrated by Michael "Kaves" McLeer, and published by Simon & Schuster. === Sponsorship of 1992 Lithuanian Olympic basketball team === After Lithuania gained its independence from the USSR, the country announced its withdrawal from the 1992 Olympics due to the lack of any money to sponsor participants. But NBA star Šarūnas Marčiulionis, a native Lithuanian basketball star, wanted to help his native team to compete. His efforts resulted in a call from representatives of the Grateful Dead who set up a meeting with the band members. The band agreed to fund transportation costs for the team (about $5,000) along with Grateful Dead designs for the team's jerseys and shorts. The Lithuanian basketball team won the bronze medal and the Lithuanian basketball/Grateful Dead T-shirts became part of pop culture, especially in Lithuania. The incident was covered by the documentary The Other Dream Team. == Live performances == The Grateful Dead toured constantly throughout their career, playing more than 2,300 concerts. They promoted a sense of community among their fans, who became known as "Deadheads", many of whom followed their tours for months or years on end. Around concert venues, an impromptu communal marketplace known as 'Shakedown Street' was created by Deadheads to serve as centers of activity where fans could buy and sell anything from grilled cheese sandwiches to home-made t-shirts and recordings of Grateful Dead concerts. In their early career, the band also dedicated their time and talents to their community, the Haight-Ashbury area of San Francisco, making available free food, lodging, music, and health care to all. It has been said that the band performed "more free concerts than any band in the history of music". With the exception of 1975, when the band was on hiatus and played only four concerts, Grateful Dead performed many concerts every year, from their formation in April 1965, until July 9, 1995. Initially all their shows were in California, principally in the San Francisco Bay Area and in or near Los Angeles. They also performed, in 1965 and 1966, with Ken Kesey and the Merry Pranksters, as the house band for the Acid Tests. In 1967, they toured nationally, including their first performance in New York City. They appeared at the Monterey Pop Festival in 1967, the Woodstock Festival in 1969 and the Festival Express train tour across Canada in 1970. They were scheduled to appear as the final act at the infamous Altamont Free Concert on December 6, 1969, after the Rolling Stones but withdrew after security concerns. "That's the way things went at Altamont—so badly that the Grateful Dead, prime organizers and movers of the festival, didn't even get to play", staff at Rolling Stone magazine wrote in a detailed narrative on the event. Their first UK performance was at the Hollywood Music Festival in 1970. Their largest concert audience came in 1973 when they played, along with the Allman Brothers Band and the Band, before an estimated 600,000 people at the Summer Jam at Watkins Glen. They played to an estimated total of 25 million people, more than any other band, with audiences of up to 80,000 attending a single show. Many of these concerts were preserved in the band's tape vault, and several dozen have since been released on CD and as downloads. The Dead were known for the tremendous variation in their setlists from night to night—the list of songs documented to have been played by the band exceeds 500. The band has released four concert videos under the name View from the Vault. In 1978, they played three nights at the Great Pyramid of Giza in Egypt. In the 1990s, the Grateful Dead earned a total of $285 million in revenue from their concert tours, the second-highest during the 1990s, with the Rolling Stones earning the most. This figure is representative of tour revenue through 1995, as touring stopped after the death of Jerry Garcia. In a 1991 PBS documentary, segment host Buck Henry attended an August 1991 concert at Shoreline Amphitheatre and gleaned some information from some band members about the Grateful Dead phenomenon and its success. At the time, Jerry Garcia stated, "We didn't really invent the Grateful Dead, the crowd invented the Grateful Dead, you know what I mean? We were sort of standing in line, and uh, it's gone way past our expectations, way past, so it's, we've been going along with it to see what it's gonna do next." Mickey Hart said, "This is one of the last places in America that you can really have this kind of fun, you know, considering the political climate and so forth." Hart also stated that "the transformative power of the Grateful Dead is really the essence of it; it's what it can do to your consciousness. We're more into transportation than we are into music, per se, I mean, the business of the Grateful Dead is transportation." One of the band's largest concerts took place just months before Garcia's death — at their outdoor show with Bob Dylan in Highgate, Vermont, on June 15, 1995. The crowd was estimated to be over 90,000; overnight camping was allowed and about a third of the audience got in without having purchased a ticket. Their numerous studio albums were generally collections of new songs that they had first played in concert. The band was also famous for its extended musical improvisations, having been described as having never played the same song the same way twice. Their concert sets often blended songs, one into the next, often for more than three songs at a time. === Concert sound systems === The Wall of Sound was a large sound system designed specifically for the band. The band was never satisfied with the house system anywhere they played. After the Monterey Pop Festival, the band's crew 'borrowed' some of the other performers' sound equipment and used it to host some free shows in San Francisco. In their early days, soundman Owsley "Bear" Stanley designed a public address (PA) and monitor system for them. Stanley was the Grateful Dead's soundman for many years; he was also one of the largest suppliers of LSD. Stanley's sound systems were delicate and finicky, and frequently brought shows to a halt with technical breakdowns. After Stanley went to jail for manufacturing LSD in 1970, the group briefly used house PAs, but found them to be even less reliable than those built by their former soundman. On February 2, 1970, the group contacted Bob Heil to use his system. In 1971, the band purchased their first solid-state sound system from Alembic Studios. Because of this, Alembic would play an integral role in the research, development, and production of the Wall of Sound. The band also welcomed Dan Healy into the fold on a permanent basis that year. Healy would mix the Grateful Dead's live sound until 1993. Following Jerry Garcia's death and the band's breakup in 1995, their current sound system was inherited by Dave Matthews Band. Dave Matthews Band debuted the sound system April 30, 1996, at the first show of their 1996 tour in Richmond, Virginia. === Tapes === Like several other bands at the time, the Grateful Dead allowed their fans to record their shows. For many years the tapers set up their microphones wherever they could, and the eventual forest of microphones became a problem for the sound crew. Eventually, this was solved by having a dedicated taping section located behind the soundboard, which required a special "tapers" ticket. The band allowed sharing of their shows, as long as no profits were made on the sale of the tapes. Of the approximately 2,350 shows the Grateful Dead played, almost 2,200 were taped, and most of these are available online. The band began collecting and cataloging tapes early on and Dick Latvala was their keeper. "Dick's Picks" is named after Latvala. After his death in 1999, David Lemieux gradually took the post. Concert set lists from a subset of 1,590 Grateful Dead shows were used to perform a comparative analysis between how songs were played in concert and how they are listened online by Last.fm members. In their book Marketing Lessons from the Grateful Dead: What Every Business Can Learn From the Most Iconic Band in History, David Meerman Scott and Brian Halligan identify the taper section as a crucial contributor to increasing the Grateful Dead's fan base. == Iconography == Over the years, a number of iconic images have come to be associated with the Grateful Dead. Many of these images originated as artwork for concert posters or album covers. Skull and Roses The skull and roses design was composed by Alton Kelley and Stanley Mouse, who added lettering and color, respectively, to a black and white drawing by Edmund Joseph Sullivan. Sullivan's drawing was an illustration for a 1913 edition of the Rubaiyat of Omar Khayyam. Earlier antecedents include the custom of exhibiting the relic skulls of Christian martyrs decorated with roses on their feast days. The rose is an attribute of Saint Valentine, who according to one legend, was martyred by decapitation. Accordingly, in Rome, at the church dedicated to him, the observance of his feast day included the display of his skull surrounded by roses. Kelley and Mouse's design originally appeared on a poster for the September 16 and 17, 1966, Dead shows at the Avalon Ballroom. Later, it was used as the cover for the album Grateful Dead (1971). The album is sometimes referred to as Skull and Roses. Jester Another icon of the Dead is a skeleton dressed as a jester and holding a lute. This image was an airbrush painting, created by Stanley Mouse in 1972. It was originally used for the cover of The Grateful Dead Songbook. "Dancing" Bears A series of stylized bears who appear to be dancing was drawn by Bob Thomas as part of the back cover for the album History of the Grateful Dead, Volume One (Bear's Choice) (1973). Thomas reported that he based the bears on a lead sort from an unknown font. The bear is a reference to Owsley "Bear" Stanley, who recorded and produced the album. Bear himself wrote, "the bears on the album cover are not really 'dancing'. I don't know why people think they are; their positions are quite obviously those of a high-stepping march." Steal Your Face Skull Perhaps the best-known Grateful Dead art icon is a red, white, and blue skull with a lightning bolt through it. The lightning bolt skull can be found on the cover of the album Steal Your Face (1976), and the image is sometimes known by that name. It was designed by Owsley Stanley and artist Bob Thomas, and was originally used as a logo to mark the band's equipment. Dancing Terrapins The two dancing terrapins first appeared on the cover of the album Terrapin Station (1977). They were drawn by Kelley and Mouse, based on a drawing by Heinrich Kley. Since then these turtles have become one of the Grateful Dead's most recognizable logos. Uncle Sam Skeleton The Uncle Sam skeleton was devised by Gary Gutierrez as part of the animation for The Grateful Dead Movie (1977). The image combines the Grateful Dead skeleton motif with the character of Uncle Sam, a reference to the then-recently written song "U.S. Blues", which plays during the animation. == Deadheads == Fans and enthusiasts of the band are commonly referred to as Deadheads. While the origin of the term may be unclear, Dead Heads were made canon by the notice placed inside the Skull and Roses (1971) album by manager Jon McIntire: DEAD FREAKS UNITE: Who are you? Where are you? How are you?Send us your name and address and we'll keep you informed.Dead Heads, P.O. Box 1065, San Rafael, California 94901. As each show featured a new setlist and a great deal of improvisation, Deadheads would often follow the band from city to city, attending many shows on a given tour. Many Deadheads speak of being drawn to the culture due to the sense of community that the band's shows tended to foster. Though Deadheads came from a wide array of demographics, many attempted to reproduce the aesthetics and values of the 1960s counterculture and were often stigmatized in the media. Because of the stereotyping of Deadheads as hippies, the band's shows became a common target for officials in the DEA and arrests at shows became common. As a group, the Deadheads were considered very mellow. "I'd rather work nine Grateful Dead concerts than one Oregon football game," Police Det. Rick Raynor said. "They don't get belligerent like they do at the games." Despite this reputation, in the mid-1990s, as the band's popularity grew, there were a series of minor scuffles occurring at shows that peaked with a large scale riot at the Deer Creek Music Center near Indianapolis in July 1995. This gate crashing incident caused the band to cancel the following night's show. Deadheads who appeared on the scene after the band's 1987 hit single "Touch of Grey", were often disparagingly referred to by older fans as "Touchheads". Beginning in the 1980s, a number of definable sects of Deadheads began to appear on the scene. These included the Wharf Rats, as well as the "spinners", named for whirling-style of dancing and their use of the band's music to facilitate mystical experiences. Deadheads, particularly those who collected tapes, were known for keeping close records of the band's setlists and for comparing various live versions of the band's songs, as reflected in publications such as the various editions of "Deadbase" and "The Deadhead's Taping Compendium". This practice continues into the 21st century on digital forums and websites such as the Internet Archive, which features live recordings of nearly every available Grateful Dead show and allows users to discuss and review the site's shows. The band has a number of influential and celebrity fans, including politicians, businesspeople, journalists, and other musicians. == Donation of archives to UC Santa Cruz == On April 24, 2008, members Bob Weir and Mickey Hart, along with Nion McEvoy, CEO of Chronicle Books, UC Santa Cruz chancellor George Blumenthal, and UC Santa Cruz librarian Virginia Steel, held a press conference announcing UCSC's McHenry Library would be the permanent home of the Grateful Dead Archive, which includes a complete archival history from 1965 to the present. The archive includes correspondence, photographs, fliers, posters, and several other forms of memorabilia and records of the band. Also included are unreleased videos of interviews and TV appearances that will be installed for visitors to view, as well as stage backdrops and other props from the band's concerts. Blumenthal stated at the event, "The Grateful Dead Archive represents one of the most significant popular cultural collections of the 20th century; UC Santa Cruz is honored to receive this invaluable gift. The Grateful Dead and UC Santa Cruz are both highly innovative institutions—born the same year—that continue to make a major, positive impact on the world." Guitarist Bob Weir stated "We looked around, and UC Santa Cruz seems the best possible home. If you ever wrote the Grateful Dead a letter, you'll probably find it there!" Professor of music Fredric Lieberman was the key contact between the band and the university, who let the university know about the search for a home for the archive, and who had collaborated with Mickey Hart on three books in the past, Planet Drum (1990), Drumming at the Edge of Magic (1991), and Spirit into Sound (2006). The first large-scale exhibition of materials from the Grateful Dead Archive was mounted at the New-York Historical Society in 2010. == Awards == In 2004, Rolling Stone ranked the Grateful Dead No. 57 on their list of the 100 Greatest Artists of All Time. On February 10, 2007, the Grateful Dead received a Grammy Lifetime Achievement Award. The award was accepted on behalf of the band by Mickey Hart and Bill Kreutzmann. In 2011, a recording of the Grateful Dead's May 8, 1977, concert at Cornell University's Barton Hall was selected for induction into the National Recording Registry of the Library of Congress. Twelve members of the Grateful Dead (the eleven official performing members plus Robert Hunter) were inducted into the Rock and Roll Hall of Fame in 1994, and Bruce Hornsby was their presenter. In 2024 the band was named as one of the recipients of the Kennedy Center Honors. The three living core members (Weir, Hart and Kreutzmann) received the award. As he was named a recipient prior to his death, Lesh received the award posthumously. == Members == === Former members === Jerry Garcia – lead and backing vocals, guitars (1965–1995; his death) Bob Weir – lead and backing vocals, guitars (1965–1995) Phil Lesh – bass guitar, backing and lead vocals (1965–1995; died 2024) Bill Kreutzmann – drums, percussion (1965–1995) Ron "Pigpen" McKernan – lead and backing vocals, keyboards, organ, harmonica, percussion, occasional guitar (1965–1972; died 1973) Mickey Hart – drums, percussion (1967–1971; 1974–1995) Tom Constanten – keyboards (1968–1970) Keith Godchaux – keyboards, backing vocals (1971–1979; died 1980) Donna Jean Godchaux – backing and lead vocals (1971–1979) Brent Mydland – keyboards, backing and lead vocals (1979–1990; his death) Vince Welnick – keyboards, backing and lead vocals (1990–1995; died 2006) === Frequent collaborators === Robert Hunter – lyrics (1967–1995; died 2019) Ned Lagin – keyboards, synthesizers (1970–1975) John Perry Barlow – lyrics (1971–1995; died 2018) Bruce Hornsby – keyboards, vocals (1990–1992) Lead guitarist Jerry Garcia was often viewed both by the public and the media as the leader or primary spokesperson for the Grateful Dead, but was reluctant to be perceived that way, especially since he and the other group members saw themselves as equal participants and contributors to their collective musical and creative output. Garcia, a native of San Francisco, grew up in the Excelsior District. One of his main influences was bluegrass music, and he also performed—on banjo, one of his other great instrumental loves, along with the pedal steel guitar—in bluegrass bands, notably Old & In the Way with mandolinist David Grisman. Ned Lagin, a young MIT student and friend of the band, guested with them many times from 1970 through 1975, providing a second keyboard as well as synthesizers. Upon graduating from MIT, he began touring with the band fulltime in 1974, performing sets of electronic music with Phil Lesh, occasionally with Garcia and Kreutzmann, during the band's intermission. The "Ned and Phil" set became a regular fixture of that era, and was featured nearly every night during their Summer '74 and Europe '74 tours, as well as their five-night residency at the Winterland Ballroom during October 1974. Lagin is also featured in The Grateful Dead Movie. During 1974 and 1975, he would also occasionally play entire sets with the band, usually on Garcia's side of the stage, before ending his touring relationship with the band and focusing on his solo music projects, such as his album Seastones, which features several members of the Dead. Bruce Hornsby never officially joined the band full-time because of his other commitments, but he did play keyboards at most Dead shows between September 1990 and March 1992, and sat in with the band over 100 times in all between 1988 and 1995. He added several Dead songs to his own live shows and Jerry Garcia referred to him as a "floating member" who could come and go as he pleased. Robert Hunter and John Perry Barlow were the band's primary lyricists, starting in 1967 and 1971, respectively, and continuing until the band's dissolution. Hunter collaborated mostly with Garcia and Barlow mostly with Weir, though each wrote with other band members as well. Both are listed as official members at Dead.net, the band's website, alongside the performing members. Barlow was the only member not inducted into the Rock and Roll Hall of Fame. === Timeline === == Discography == == See also == Internet Archive – Copyright issues List of Grateful Dead cover versions == References == == Further reading == == External links == Official website Grateful Dead at AllMusic Grateful Dead discography at Discogs Grateful Dead at IMDb Live recordings by Grateful Dead at the Internet Archive FBI Records: The Vault – The Grateful Dead at vault.fbi.gov	Wikipedia/Grateful_Dead
2C (2C-x) is a general name for the family of psychedelic phenethylamines containing methoxy groups on the 2 and 5 positions of a benzene ring. Most of these compounds also carry lipophilic substituents at the 4 position, usually resulting in more potent and more metabolically stable and longer acting compounds. Most of the currently known 2C compounds were first synthesized by Alexander Shulgin in the 1970s and 1980s and published in his book PiHKAL (Phenethylamines i Have Known And Loved). Shulgin also coined the term 2C, being an acronym for the 2 carbon atoms between the benzene ring and the amino group. 2C-B is the most popular of the 2C drugs. == Use == The 2C drugs are orally active, are used at oral doses of 6 to 150 mg depending on the drug, and have durations of 3 to 48 hours depending on the drug. However, many have doses in the range of 10 to 60 mg and durations in the range of 4 to 12 hours. The 2C drugs produce psychedelic effects. Some, such as 2C-B, have also been reported to have some entactogenic qualities, though findings appear to be mixed. == Pharmacology == === Pharmacodynamics === ==== Actions ==== The 2C drugs act as agonists of the serotonin 5-HT2 receptors, including of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors. They are partial agonists of the serotonin 5-HT2A receptor. Most of the 2C drugs have much lower affinity for the serotonin 5-HT1A receptor than for the serotonin 5-HT2A receptor. Most of the 2C drugs have also shown about 5- to 15-fold higher affinity for the serotonin 5-HT2A receptor over the serotonin 5-HT2C receptor and about 15- to 100-fold higher affinity for the serotonin 5-HT2A receptor over the serotonin 5-HT1A receptor. The psychedelic effects of the 2C drugs are thought to be mediated specifically by activation of the serotonin 5-HT2A receptor. Unlike many other phenethylamines, 2C drugs, including 2C-C, 2C-D, 2C-E, 2C-I, and 2C-T-2 among others, are inactive as monoamine releasing agents and reuptake inhibitors. Most of the 2C drugs are agonists of the rat and mouse trace amine-associated receptor 1 (TAAR1). However, most are inactive as agonists of the human TAAR1. The 2C drugs show very weak monoamine oxidase inhibition, including of monoamine oxidase A (MAO-A) and/or monoamine oxidase B (MAO-B). ==== Effects ==== In accordance with their psychedelic effects in humans, the 2C drugs produce the head-twitch response and wet dog shakes, behavioral proxies of psychedelic effects, in rodents. At least some 2C drugs, such as 2C-D and 2C-E, produce hyperlocomotion at lower doses in rodents. All 2C drugs produce hypolocomotion at higher doses in rodents. 2C drugs, including 2C-C, 2C-D, 2C-E, and 2C-I, substitute partially to fully for psychedelics like DOM, DMT, and LSD and/or for the entactogen MDMA in rodent drug discrimination tests. However, none of the assessed 2C drugs substituted for dextromethamphetamine, suggesting that they lack amphetamine-type or stimulant-like effects. In contrast to most psychedelics, at least two assessed 2C drugs, 2C-C and 2C-P, have shown reinforcing effects in rodents, including conditioned place preference (CPP) and self-administration. The mechanism by which these effects are mediated is unknown. However, it may be related to reduced expression of the dopamine transporter (DAT) and increased DAT phosphorylation, in turn resulting in increased extracellular dopamine levels in certain brain areas. These 2C drugs might have misuse potential in humans. Similar reinforcing effects in animals have been observed for NBOMe analogues of 2C drugs, including 25B-NBOMe, 25D-NBOMe, 25E-NBOMe, 25H-NBOMe, and 25N-NBOMe. Similarly to DOI, tolerance has been found to gradually develop to the head-twitch response induced by 2C-T-7 with chronic administration in rodents. Various 2C drugs show potent anti-inflammatory effects mediated by serotonin 5-HT2A receptor activation. Among these include 2C-I, 2C-B, 2C-H, and 2C-iBu. Others, such as 2C-B-Fly and 2C-T-33, were less effective. 2C-iBu has shown a greater separation between anti-inflammatory effects and psychedelic-like effects in animals than other 2C drugs and is being investigated for possible use as a pharmaceutical drug. === Pharmacokinetics === The 2C drugs are orally active. They are metabolized by O-demethylation and deamination. This is mediated specifically by monoamine oxidase (MAO) enzymes MAO-A and MAO-B, whereas cytochrome P450 enzymes appear to metabolize only some 2C drugs and to have only a very small role. == Interactions == The 2C drugs are metabolized by the monoamine oxidase (MAO) enzymes, including both MAO-A and MAO-B. As a result, they may be potentiated by monoamine oxidase inhibitors (MAOIs), such as phenelzine, tranylcypromine, moclobemide, and selegiline. This may lead to overdose and serious toxicity. == History == 2,4,5-Trimethoxyphenethylamine (2,4,5-TMPEA; 2C-O or "2C-MeO") was first synthesized by Jansen and was found to produce psychedelic effects similar to those of mescaline (3,4,5-trimethoxyphenethylamine). He published his findings in 1931. However, subsequent studies in the 1960s and 1970s suggested that 2,4,5-TMPEA may actually be inactive as a psychedelic in animals and humans. 2C-D (2C-M) was the first of the 2C drugs besides 2C-O to be discovered. It was synthesized and studied in animals by Ho and colleagues and they published their findings in 1970. Alexander Shulgin synthesized 2C-B and 2C-D in 1974 and discovered their psychedelic effects in self-experiments conducted in 1974 and 1975. He published his findings in the scientific literature in 1975. 2C-T was first described by Shulgin and David E. Nichols in 1976. 2C-I was first described by Shulgin and colleagues in 1977 and initial psychoactivity was reported by Shulgin in 1978. Shulgin also first synthesized 2C-E in 1977. He reviewed several of these 2C drugs in 1979. Subsequently, numerous other 2C drugs have been synthesized and characterized. 2C-B gained popularity as a recreational drug and MDMA alternative in the mid-1980s and became a controlled substance in the United States in 1994. It is said to be the most popular of the 2C drugs. == Society and culture == === Legal status === ==== Canada ==== As of October 12, 2016, the 2C-x family of substituted phenethylamines is a controlled substance (Schedule III) in Canada. == List of 2C drugs == == Related compounds == == See also == 25-NB, 3C, DOx, 4C, FLY List of miscellaneous 5-HT2A receptor agonists The Shulgin Index Substituted amphetamines Substituted mescaline analogue Substituted methoxyphenethylamine Substituted methylenedioxyphenethylamines Substituted phenethylamines Substituted tryptamines == References == == External links == 2C Psychedelics - Tripsitter	Wikipedia/2C_drug
Pharmacovigilance (PV, or PhV), also known as drug safety, is the pharmaceutical science relating to the "collection, detection, assessment, monitoring, and prevention" of adverse effects with pharmaceutical products.: 7 The etymological roots for the word "pharmacovigilance" are: pharmakon (Greek for drug) and vigilare (Latin for to keep watch). As such, pharmacovigilance heavily focuses on adverse drug reactions (ADR), which are defined as any response to a drug which is noxious and unintended. That definition includes lack of efficacy: that means that the doses normally used for prevention, diagnosis, or treatment of a disease—or, especially in the case of device, for the modification of physiological disorder function. In 2010, the European Union expanded PV to include medication errors such as overdose, misuse, and abuse of a drug as well as drug exposure during pregnancy and breastfeeding. These are monitored even in the absence of an adverse event, because they may result in an adverse drug reaction. The US FDA has long considered such criteria to conform to reportable and collectible PV standards. Patient and healthcare provider reports (via pharmacovigilance agreements or national mandated reporting laws), as well as other sources such as cases reported in medical literature, play a critical role in providing the data necessary for pharmacovigilance to take place. In order to market or to test a pharmaceutical product in most countries, adverse event data received by the license holder (usually a pharmaceutical company) must be submitted to the national drug regulatory authority. (See Adverse event reporting below.) Ultimately, pharmacovigilance is concerned with identifying the hazards associated with pharmaceutical products and with minimizing the risk of any harm that may come to patients. Companies must conduct a comprehensive drug safety and pharmacovigilance audit to assess their compliance with local, regional, national, or international laws and regulations. This includes ongoing collection of safety data after a product is approved for marketing. == Terms commonly used in drug safety == Pharmacovigilance uses unique terminology. Below are most of the terms used within this article. They are particular to drug safety, although some are used by other disciplines within the pharmaceutical sciences as well. The European Medicines Agency defines terms in its Guideline on good pharmacovigilance practices (GVP): Adverse drug reaction is effects arising when drug given even in therapeutic dose either immunologically mediated reaction or pharmacologically mediated adverse response or idiosyncratic reaction due to the peculiarities of individual. Adverse event (AE) is a side effect occurring with a drug. By definition, the causal relationship between the AE and the drug is unknown. An investigator must establish causality and severity and then report it, especially during clinical trials (not necessarily after marketing is approved). Benefits are the therapeutic good (positive outcome) of a medicine or device, and benefits also include the patient's subjective response. Causal relationship is said to exist when a drug causes or contributes to the occurrence of an adverse drug reaction. Clinical trial (or study) refers to an organised program to determine the safety and/or efficacy of a drug (or drugs) in patients. The design of a clinical trial will depend on the drug and the phase of its development. Some clinical trials are conducted after a device or drug is approved to follow for safety. Control group is a group (or cohort) of individual patients that is used as a standard of comparison within a clinical trial. The control group may be taking a placebo (where no active drug is given) or may be given the standard treatment (“standard of care therapy”) as the comparator. Dechallenge and rechallenge refer to a drug being stopped and restarted in a patient, respectively. A positive dechallenge has occurred, for example, when an adverse event abates or resolves completely following the drug's discontinuation. A positive rechallenge has occurred when the adverse event re-occurs after the drug is restarted. Dechallenge and rechallenge play an important role in determining whether a causal relationship between an event and a drug exists. Effectiveness is the extent to which a drug works under real world circumstances, i.e., clinical practice. Efficacy is the extent to which a drug works under ideal circumstances, i.e., in clinical trials. Event refers to an adverse event. Harm is the nature and extent of the actual damage that could be or has been caused. Implied causality refers to spontaneously reported AE cases where the causality is always presumed to be positive unless the reporter states otherwise. Individual Case Safety Report is an adverse event report for an individual patient. Life-threatening refers to an adverse event that places a patient at the immediate risk of death. Phase refers to the four phases of clinical research and development: I – small safety trials early on in a drug's development; II – medium-sized trials for both safety and efficacy; III – large trials, which includes key (or so-called "pivotal") trials; IV – large, post-marketing trials, typically for safety reasons. There are also intermediate phases designated by an "a" or "b", e.g. Phase IIb. Risk is the probability of harm being caused, usually expressed as a percent or ratio of the treated population. Risk factor is an attribute of a patient that may predispose, or increase the risk, of that patient developing an event that may or may not be drug-related. For instance, obesity is considered a risk factor for a number of different diseases and, potentially, adverse drug reactions. Others would be high blood pressure, diabetes, possessing a specific mutated gene, for example, mutations in the BRCA1 and BRCA2 genes increase propensity to develop breast cancer. Signal is a new safety finding within safety data that requires further investigation. There are three categories of signals: confirmed signals where the data indicate that there is a causal relationship between the drug and the AE; refuted (or false) signals where after investigation the data indicate that no causal relationship exists; and unconfirmed signals which require further investigation (more data) such as the conducting of a post-marketing trial to study the issue. Temporal relationship is said to exist when an adverse event occurs when a patient is taking a given drug. Although a temporal relationship is absolutely necessary in order to establish a causal relationship between the drug and the AE, a temporal relationship does not necessarily in and of itself prove that the event was caused by the drug. Triage refers to the process of placing a potential adverse event report into one of three categories: 1) non-serious case; 2) serious case; or 3) no case (minimum criteria for an AE case are not fulfilled). == Adverse event reporting == The activity that is most commonly associated with pharmacovigilance (PV), and which consumes a significant number of resources for drug regulatory authorities (or similar government agencies) and drug safety departments in pharmaceutical companies, is that of adverse event reporting. Adverse event (AE) reporting involves the receipt, triage, data entry, assessment, distribution, reporting (if appropriate), and archiving of AE data and documentation. The source of AE reports may include: spontaneous reports from healthcare professionals or patients (or other intermediaries); solicited reports from patient support programs; reports from clinical or post-marketing studies; reports from literature sources; reports from the media (including social media and websites); and reports reported to drug regulatory authorities themselves. For pharmaceutical companies, AE reporting is a regulatory requirement in most countries. AE reporting also provides data to these companies and drug regulatory authorities that play a key role in assessing the risk-benefit profile of a given drug. The following are several facets of AE reporting: === Individual Case Safety Report === One of the fundamental principles of adverse event reporting is the determination of what constitutes an individual case safety report. During the triage phase of a potential adverse event report, it is important to determine if the "four elements" of a valid individual case safety report are present: (1) an identifiable patient, (2) an identifiable reporter, (3) a suspect drug, and (4) an adverse event. If one or more of these four elements is missing, the case is not a valid individual case safety report. Although there are no exceptions to this rule there may be circumstances that may require a judgment call. For example, the term "identifiable" may not always be clear-cut. If a physician reports that he/she has a patient X taking drug Y who experienced Z (an AE), but refuses to provide any specifics about patient X, the report is still a valid case even though the patient is not specifically identified. This is because the reporter has first-hand information about the patient and is identifiable (i.e. a real person) to the physician. Identifiability is important so as not only to prevent duplicate reporting of the same case, but also to permit follow-up for additional information. The concept of identifiability also applies to the other three elements. Although uncommon, it is not unheard of for fictitious adverse event "cases" to be reported to a company by an anonymous individual (or on behalf of an anonymous patient, disgruntled employee, or former employee) trying to damage the company's reputation or a company's product. In these and all other situations, the source of the report should be ascertained (if possible). But anonymous reporting is also important, as whistle blower protection is not granted in all countries. In general, the drug must also be specifically named. Note that in different countries and regions of the world, drugs are sold under various tradenames. In addition, there are a large number of generics which may be mistaken for the trade product. Finally, there is the problem of counterfeit drugs producing adverse events. If at all possible, it is best to try to obtain the sample which induced the adverse event, and send it to either the European Medicines Agency, FDA or other government agency responsible for investigating AE reports. If a reporter can't recall the name of the drug they were taking when they experienced an adverse event, this would not be a valid case. This concept also applies to adverse events. If a patient states that they experienced "symptoms", but cannot be more specific, such a report might technically be considered valid, but will be of very limited value to the pharmacovigilance department of the company or to drug regulatory authorities. === Activities involved in pharmacovigilance === 1- Case-control study (Retrospective study) 2- Prospective study (Cohort study). 3- Population statistics. and 4- Intensive event report. 5- The spontaneous report in the case is the population of the single case report. === Coding of adverse events === Adverse event coding is the process by which information from an AE reporter, called the "verbatim", is coded using standardized terminology from a medical coding dictionary, such as MedDRA (the most commonly used medical coding dictionary). The purpose of medical coding is to convert adverse event information into terminology that can be readily identified and analyzed. For instance, Patient 1 may report that they had experienced "a very bad headache that felt like their head was being hit by a hammer" [Verbatim 1] when taking Drug X. Or, Patient 2 may report that they had experienced a "slight, throbbing headache that occurred daily at about two in the afternoon" [Verbatim 2] while taking Drug Y. Neither Verbatim 1 nor Verbatim 2 will exactly match a code in the MedDRA coding dictionary. However, both quotes describe different manifestations of a headache. As a result, in this example both quotes would be coded as PT Headache (PT = Preferred Term in MedDRA). === Seriousness determination === Although somewhat intuitive, there are a set of criteria within pharmacovigilance that are used to distinguish a serious adverse event from a non-serious one. An adverse event is considered serious if it meets one or more of the following criteria: results in death, or is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; results in a congenital anomaly (birth defect); or is otherwise "medically significant" (i.e., that it does not meet preceding criteria, but is considered serious because treatment/intervention would be required to prevent one of the preceding criteria.) Aside from death, each of these categories is subject to some interpretation. Life-threatening, as it used in the drug safety world, specifically refers to an adverse event that places the patient at an immediate risk of death, such as cardiac or respiratory arrest. By this definition, events such as myocardial infarction, which would be hypothetically life-threatening, would not be considered life-threatening unless the patient went into cardiac arrest following the MI. Defining what constitutes hospitalization can be problematic as well. Although typically straightforward, it's possible for a hospitalization to occur even if the events being treated are not serious. By the same token, serious events may be treated without hospitalization, such as the treatment of anaphylaxis may be successfully performed with epinephrine. Significant disability and incapacity, as a concept, is also subject to debate. While permanent disability following a stroke would no doubt be serious, would "complete blindness for 30 seconds" be considered "significant disability"? For birth defects, the seriousness of the event is usually not in dispute so much as the attribution of the event to the drug. Finally, "medically significant events" is a category that includes events that may be always serious, or sometimes serious, but will not fulfill any of the other criteria. Events such as cancer might always be considered serious, whereas liver disease, depending on its Common Terminology Criteria for Adverse Events (CTCAE) grade—Grades 1 or 2 are generally considered non-serious and Grades 3-5 may be considered serious. === Expedited reporting === This refers to individual case safety reports that involve a serious and unlisted event (an event not described in the drug's labeling) that is considered related to the use of the drug (US FDA). (Spontaneous reports are typically considered to have a positive causality, whereas a clinical trial case will typically be assessed for causality by the clinical trial investigator and/or the license holder.) In most countries, the time frame for reporting expedited cases is 7/15 calendar days from the time a drug company receives notification (referred to as "Day 0") of such a case. Within clinical trials such a case is referred to as a SUSAR (a Suspected Unexpected Serious Adverse Reaction). If the SUSAR involves an event that is life-threatening or fatal, it may be subject to a 7-day "clock". Cases that do not involve a serious, unlisted event may be subject to non-expedited or periodic reporting. === Clinical trial reporting === Also known as AE (adverse event) or SAE (serious AE) reporting from clinical trials, safety information from clinical studies is used to establish a drug's safety profile in humans and is a key component that drug regulatory authorities consider in the decision-making as to whether to grant or deny market authorization (market approval) for a drug. AE reporting occurs when study patients (subjects, participants) experience any kind of "untoward" event during the conducting of clinical trials. Non-serious adverse events are typically captured separately at a level lower than pharmacovigilance. AE and SAE information, which may also include relevant information from the patient's medical background, are reviewed and assessed for both causality and degree of seriousness by the study investigator. This information is forwarded to a sponsoring entity (typically a pharmaceutical company or academic medical center) that is responsible for the reporting of this information, as appropriate, to drug regulatory authorities. === Spontaneous reporting === Spontaneous reports are termed spontaneous as they take place during the clinician's normal diagnostic appraisal of a patient, when the clinician is drawing the conclusion that the drug may be implicated in the causality of the event. Spontaneous reporting system (SRS) relies on vigilant physicians and other healthcare professionals who not only generate a suspicion of an adverse drug reaction, but also report it. It is an important source of regulatory actions such as taking a drug off the market or a label change due to safety problems. Spontaneous reporting is the core data-generating system of international pharmacovigilance, relying on healthcare professionals (and in some countries consumers) to identify and report any adverse events to their national pharmacovigilance center, health authority (such as the European Medicines Agency or FDA), or to the drug manufacturer itself. Spontaneous reports are, by definition, submitted voluntarily although under certain circumstances these reports may be encouraged, or "stimulated", by media reports or articles published in medical or scientific publications, or by product lawsuits. In many parts of the world adverse event reports are submitted electronically using a defined message standard. One of the major weaknesses of spontaneous reporting is that of under-reporting, where, unlike in clinical trials, less than 100% of those adverse events occurring are reported. Further complicating the assessment of adverse events, AE reporting behavior varies greatly between countries and in relation to the seriousness of the events, but in general probably less than 10% (some studies suggest less than 5%) of all adverse events that occur are actually reported. The rule-of-thumb is that on a scale of 0 to 10, with 0 being least likely to be reported and 10 being the most likely to be reported, an uncomplicated non-serious event such as a mild headache will be closer to a "0" on this scale, whereas a life-threatening or fatal event will be closer to a "10" in terms of its likelihood of being reported. In view of this, medical personnel may not always see AE reporting as a priority, especially if the symptoms are not serious. And even if the symptoms are serious, the symptoms may not be recognized as a possible side effect of a particular drug or combination thereof. In addition, medical personnel may not feel compelled to report events that are viewed as expected. This is why reports from patients themselves are of high value. The confirmation of these events by a healthcare professional is typically considered to increase the value of these reports. Hence it is important not only for the patient to report the AE to his health care provider (who may neglect to report the AE), but also report the AE to both the biopharmaceutical company and the FDA, European Medicines Agency, ... This is especially important when one has obtained one's pharmaceutical from a compounding pharmacy. As such, spontaneous reports are a crucial element in the worldwide enterprise of pharmacovigilance and form the core of the World Health Organization Database, which includes around 4.6 million reports (January 2009), growing annually by about 250,000. === Aggregate reporting === Aggregate reporting, also known as periodic reporting, plays a key role in the safety assessment of drugs. Aggregate reporting involves the compilation of safety data for a drug over a prolonged period of time (months or years), as opposed to single-case reporting which, by definition, involves only individual AE reports. The advantage of aggregate reporting is that it provides a broader view of the safety profile of a drug. Worldwide, the most important aggregate report is the Periodic Safety Update Report (PSUR) and Development Safety Update Report (DSUR). This is a document that is submitted to drug regulatory agencies in Europe, the US and Japan (ICH countries), as well as other countries around the world. The PSUR was updated in 2012 and is now referred to in many countries as the Periodic Benefit Risk Evaluation report (PBRER). As the title suggests, the PBRER's focus is on the benefit-risk profile of the drug, which includes a review of relevant safety data compiled for a drug product since its development. === Other reporting methods === Some countries legally oblige spontaneous reporting by physicians. In most countries, manufacturers are required to submit, through its Qualified Person for Pharmacovigilance (QPPV), all of the reports they receive from healthcare providers to the national authority. Others have intensive, focused programmes concentrating on new drugs, or on controversial drugs, or on the prescribing habits of groups of doctors, or involving pharmacists in reporting. All of these generate potentially useful information. Such intensive schemes, however, tend to be the exception. A number of countries have reporting requirements or reporting systems specific to vaccine-related events. == Risk management == Risk management is the discipline within pharmacovigilance that is responsible for signal detection and the monitoring of the risk-benefit profile of drugs. Other key activities within the area of risk management are that of the compilation of risk management plans (RMPs) and aggregate reports such as the Periodic Safety Update Report (PSUR), Periodic Benefit-Risk Evaluation Report (PBRER), and the Development Safety Update Report (DSUR). === Causality assessment === One of the most important, and challenging, problems in pharmacovigilance is that of the determination of causality. Causality refers to the relationship of a given adverse event to a specific drug. Causality determination (or assessment) is often difficult because of the lack of clear-cut or reliable data. While one may assume that a positive temporal relationship might "prove" a positive causal relationship, this is not always the case. Indeed, a "bee sting" Adverse Event — where the AE can clearly be attributed to a specific cause — is by far the exception rather than the rule. This is due to the complexity of human physiology as well as that of disease and illnesses. By this reckoning, in order to determine causality between an adverse event and a drug, one must first exclude the possibility that there were other possible causes or contributing factors. If the patient is on a number of medications, it may be the combination of these drugs which causes the AE, and not any one individually. There have been a number of recent high-profile cases where the AE led to the death of an individual. The individuals were not overdosed with any one of the many medications they were taking, but the combination there appeared to cause the AE. Hence it is important to include in your/one's AE report, not only the drug being reported, but also all other drugs the patient was also taking. For instance, if a patient were to start Drug X and then three days later were to develop an AE, one might be tempted to attribute blame Drug X. However, before that can be done, the patient's medical history would need to be reviewed to look for possible risk factors for the AE. In other words, did the AE occur with the drug or because of the drug? This is because a patient on any drug may develop or be diagnosed with a condition that could not have possibly been caused by the drug. This is especially true for diseases, such as cancer, which develop over an extended period of time, being diagnosed in a patient who has been taken a drug for a relatively short period of time. On the other hand, certain adverse events, such as blood clots (thrombosis), can occur with certain drugs with only short-term exposure. Nevertheless, the determination of risk factors is an important step of confirming or ruling-out a causal relationship between an event and a drug. Often the only way to confirm the existence of a causal relationship of an event to a drug is to conduct an observational study where the incidence of the event in a patient population taking the drug is compared to a control group. This may be necessary to determine if the background incidence of an event is less than that found in a group taking a drug. If the incidence of an event is statistically significantly higher in the "active" group versus the placebo group (or other control group), it is possible that a causal relationship may exist to a drug, unless other confounding factors may exist. === Signal detection === Signal detection involves a range of techniques (CIOMS VIII). The WHO defines a safety signal as: "Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously". Usually more than a single report is required to generate a signal, depending upon the event and quality of the information available. Data mining pharmacovigilance databases is one approach that has become increasingly popular with the availability of extensive data sources and inexpensive computing resources. The data sources (databases) may be owned by a pharmaceutical company, a drug regulatory authority, or a large healthcare provider. Individual case safety reports in these databases are retrieved and converted into structured format, and statistical methods (usually a smathematical algorithm) are applied to calculate statistical measures of association. If the statistical measure crosses an arbitrarily set threshold, a signal is declared for a given drug associated with a given adverse event. All signals deemed worthy of investigation, require further analysis using all available data in an attempt to confirm or refute the signal. If the analysis is inconclusive, additional data may be needed such as a post-marketing observational trial. Signal detection is an essential part of drug use and safety surveillance. Ideally, the goal of signal detection is to identify adverse drug reactions that were previously considered unexpected and to be able to provide guidance in the product's labeling as to how to minimize the risk of using the drug in a given patient population. === Risk management plans === A risk management plan is a documented plan that describes the risks (adverse drug reactions and potential adverse reactions) associated with the use of a drug and how they are being handled (warning on drug label or on packet inserts of possible side effects which if observed should cause the patient to inform/see his physician and/or pharmacist and/or the manufacturer of the drug and/or the FDA, European Medicines Agency. The overall goal of a risk management plan is to assure a positive risk-benefit profile once the drug is (has been) marketed. The document is required to be submitted, in a specified format, with all new market authorization requests within the European Union (EU). Although not necessarily required, risk management plans may also be submitted in countries outside the EU. The risks described in a risk management plan fall into one of three categories: identified risks, potential risks, and unknown risks. Also described within a risk management plan are the measures that the Market Authorization Holder, usually a pharmaceutical company, will undertake to minimize the risks associated with the use of the drug. These measures are usually focused on the product's labeling and healthcare professionals. Indeed, the risks that are documented in a pre-authorization risk management plan will inevitably become part of the product's post-marketing labeling. Since a drug, once authorized, may be used in ways not originally studied in clinical trials, this potential "off-label use", and its associated risks, is also described within the risk management plan. Risk management plans can be very lengthy documents, running in some cases hundreds of pages and, in rare instances, up to a thousand pages long. In the US, under certain circumstances, the FDA may require a company to submit a document called a Risk Evaluation and Mitigation Strategy (REMS) for a drug that has a specific risk that FDA believes requires mitigation. While not as comprehensive as a risk management plan, a Risk Evaluation and Mitigation Strategy can require a sponsor to perform certain activities or to follow a protocol, referred to as Elements to Assure Safe Use, to assure that a positive risk-benefit profile for the drug is maintained for the circumstances under which the product is marketed. === Risk/benefit profile of drugs === Pharmaceutical companies are required by law in most countries to perform clinical trials, testing new drugs on people before they are made generally available. This occurs after a drug has been pre-screened for toxicity, sometimes using animals for testing. The manufacturers or their agents usually select a representative sample of patients for whom the drug is designed – at most a few thousand – along with a comparable control group. The control group may receive a placebo and/or another drug, often a so-called "gold standard" that is "best" drug marketed for the disease. The purpose of clinical trials is to determine: if a drug works and how well it works if it has any harmful effects, and if it does more good than harm, and how much more? If it has a potential for harm, how probable and how serious is the harm? Clinical trials do, in general, tell a good deal about how well a drug works. They provide information that should be reliable for larger populations with the same characteristics as the trial group – age, gender, state of health, ethnic origin, and so on though target clinical populations are typically very different from trial populations with respect to such characteristics. The variables in a clinical trial are specified and controlled, but a clinical trial can never tell you the whole story of the effects of a drug in all situations. In fact, nothing could tell you the whole story, but a clinical trial must tell you enough; "enough" being determined by legislation and by contemporary judgements about the acceptable balance of benefit and harm. Ultimately, when a drug is marketed it may be used in patient populations that were not studied during clinical trials (children, the elderly, pregnant women, patients with co-morbidities not found in the clinical trial population, etc.) and a different set of warnings, precautions or contraindications (where the drug should not be used at all) for the product's labeling may be necessary in order to maintain a positive risk/benefit profile in all known populations using the drug. === Pharmacoepidemiology === Pharmacoepidemiology is the study of the incidence of adverse drug reactions in patient populations using drug agents. === Pharmacogenetics and pharmacogenomics === Although often used interchangeably, there are subtle differences between the two disciplines. Pharmacogenetics is generally regarded as the study or clinical testing of genetic variation that gives rise to differing responses to drugs, including adverse drug reactions. It is hoped that pharmacogenetics will eventually provide information as to which genetic profiles in patients will place those patients at greatest risk, or provide the greatest benefit, for using a particular drug or drugs. Pharmacogenomics, on the other hand, is the broader application of genomic technologies to new drug discovery and further characterization of older drugs. == International collaboration == The following organizations play a key collaborative role in the global oversight of pharmacovigilance. === The World Health Organization (WHO) === The principle of international collaboration in the field of pharmacovigilance is the basis for the WHO Programme for International Drug Monitoring, through which over 150 member nations have systems in place that encourage healthcare personnel to record and report adverse effects of drugs in their patients. These reports are assessed locally and may lead to action within the country. Since 1978, the programme has been managed by the Uppsala Monitoring Centre to which member countries send their reports to be processed, evaluated and entered into an international database called VigiBase. Membership in the WHO Programme enables a country to know if similar reports are being made elsewhere. When there are several reports of adverse reactions to a particular drug, this process may lead to the detection of a signal, and an alert about a possible hazard communicated to members countries after detailed evaluation and expert review on the biological stasis and homeostasis of the body. Clb12/2020001 === The International Council for Harmonisation (ICH) === The International Council for Harmonisation is a global organization with members from the European Union, the United States and Japan; its goal is to recommend global standards for drug companies and drug regulatory authorities around the world, with its activities overseen by the Steering Committee overseeing harmonization activities. Established in 1990, each of its six co-sponsors—the EU, the European Federation of Pharmaceutical Industries and Associations, Japan's Ministry of Health, Labor and Welfare, the Japanese Pharmaceutical Manufacturers Association, the U.S. Food and Drug Administration (FDA), and the Pharmaceutical Research and Manufacturers of America (PhRMA)—have two seats on the SC. Other parties have a significant interest in the International Council for Harmonisation and have been invited to nominate Observers to the SC; three current observers are the WHO, Health Canada, and the European Free Trade Association, with the International Federation of Pharmaceutical Manufacturers Association participating as a non-voting member of the SC. === The Council for International Organizations of Medical Science (CIOMS) === The CIOMS, a part of the WHO, is globally oriented think tank that provides guidance on drug safety related topics through its Working Groups. The CIOMS prepares reports that are used as a reference for developing future drug regulatory policy and procedures, and over the years, many of CIOMS' proposed policies have been adopted. Examples of topics these reports have covered include: Current Challenges in Pharmacovigilance: Pragmatic Approaches (CIOMS V); Management of Safety Information from Clinical Trials (CIOMS VI); the Development Safety Update Report (DSUR): Harmonizing the Format and Content for Periodic Safety Reporting During Clinical Trials (CIOMS VII); and Practical Aspects of Signal Detection in Pharmacovigilance: Report of CIOMS Working Group (CIOMS VIII). === The International Society of Pharmacovigilance === The International Society of Pharmacovigilance is an international non-profit scientific organization, which aims to foster pharmacovigilance both scientifically and educationally, and enhance all aspects of the safe and proper use of medicines, in all countries. It was established in 1992 as the European Society of Pharmacovigilance. Society of Pharmacovigilance, India, also established in 1992, is partner member of the International Society of Pharmacovigilance. Other local societies include the Boston Society of Pharmacovigilance Physicians. == Regulatory authorities == Drug regulatory authorities play a key role in national or regional oversight of pharmacovigilance. Some of the agencies involved are listed below (in order of 2011 spending on pharmaceuticals, from the IMS Institute for Healthcare Informatics). === Emerging economies === The "pharmerging", or emerging pharmaceutical market economies, which include Brazil, India, Russia, Argentina, Egypt, Indonesia, Mexico, Pakistan, Poland, Romania, South Africa, Thailand, Turkey, Ukraine and Vietnam, accrued one fifth of global 2011 pharmaceutical expenditures; in future, aggregated data for this set will include China as well. === Africa === ==== Egypt ==== In Egypt, pharmacovigilance is regulated by the Egyptian Pharmacovigilance Center of the Egyptian Ministry of Health. ==== Kenya ==== In Kenya, pharmacovigilance is regulated by the Pharmacy and Poisons Board, which provides a Pharmacovigilance Electronic Reporting System which allows for the online reporting of suspected adverse drug reactions as well as suspected poor quality of medicinal products. The pharmacovigilance activities in Kenya are supported by the School of Pharmacy, University of Nairobi through its Master of Pharmacy in Pharmacoepidemiology & Pharmacovigilance program offered by the Department of Pharmacology and Pharmacognosy. ==== Uganda ==== In Uganda, pharmacovigilance is regulated by the National Drug Authority. === Americas === ==== Canada ==== In Canada, with ~2% of all global 2006 and 2011 pharmaceutical expenditures, pharmacovigilance is regulated by the Marketed Health Products Directorate of the Health Products and Food Branch. Canada was second, following the United States, in holding the highest total prescription drug expenditures per capita in 2011 at around 750 US dollars per person. Canada also pays such a large amount for pharmaceuticals that it was second, next to Switzerland, for the amount of money spent for a certain amount of prescription drugs (around 130 US dollars). It was also accessed that Canada was one of the top countries that increased its yearly average per capita growth on pharmaceutical expenditures the most from 2000 to 2010 with 4 percent a year (with taking inflation into account) The Marketed Health Products Directorate mainly collects adverse drug reaction reports through a network of reporting centers to analyze and issue possible warnings to the public, and currently utilizes newsletters, advisories, adverse reaction centers, as well as electronic mailing lists. However, it does not currently maintain a database or list of drugs removed from Canada as a result of safety concerns. In August 2017, there was a government controversy in which a bill, known as "Vanessa's Law", to protect patients from potentially dangerous prescription drugs was not being fully realized by hospitals; Health Canada only required hospitals to report "unexpected" negative reactions to prescription drugs, rather than any and all adverse reactions, with the justification of managing "administrative overload". ==== Latin America ==== According BioPharm International, as of April 2013 "there is no Latin American equivalent of the European Medicines Agency—no common body with the power to facilitate greater consistency across countries". For simplicity, and per sources, 17 smaller economies are discussed alongside the 4 pharmemerging large economies of Argentina, Brazil, Mexico and Venezuela—Bolivia, Chile, Colombia, Costa Rica, Cuba, Dominican Republic, Ecuador, El Salvador, Guatemala, Haiti, Honduras, Nicaragua, Panama, Paraguay, Peru, Suriname, and Uruguay. As of June 2012, 16 of this total of 21 countries have systems for immediate reporting and 9 have systems for periodic reporting of adverse events for on-market agents, while 10 and 8, respectively, have systems for immediate and periodic reporting of adverse events during clinical trials; most of these have pharmacovigilance requirements that rank as "high or medium...in line with international standards" (ibid.). The WHO's Pan American Network for Drug Regulatory Harmonization seeks to assist Latin American countries in develop harmonized pharmacovigilance regulations. ==== United States ==== In the U.S., with about a third of all global 2011 pharmaceutical expenditures, the drug industry is regulated by the Food and Drug Administration, the largest national drug regulatory authority in the world. FDA authority is exercised through enforcement of regulations derived from legislation, as published in the U.S. Code of Federal Regulations (CFR); the principal drug safety regulations are found in 21 CFR Part 312 (IND regulations) and 21 CFR Part 314 (NDA regulations). While those regulatory efforts address pre-marketing concerns, pharmaceutical manufacturers and academic/non-profit organizations such as Research on Adverse Drug events And Reports (RADAR) and Public Citizen do play a role in pharmacovigilance in the US. The post-legislative rule-making process of the U.S. federal government provides for significant input from both the legislative and executive branches, which also play specific, distinct roles in determining FDA policy. === Asia === ==== Azerbaijan ==== The law on pharmacovigilance in Azerbaijan was revised and implemented as part of the "Regulation of Pharmacovigilance for Medicinal Products" in 2019. This regulation was developed to establish state control over the effectiveness and safety of medicinal products. It outlines measures to detect, evaluate, and prevent adverse reactions and other undesirable effects of medicinal products, applying to marketing authorization holders and all health institutions in Azerbaijan In Azerbaijan, the Ministry of Healthcare and other relevant state authorities play a crucial role in the functioning of the pharmacovigilance system. These organizations implement various regulatory and oversight mechanisms to ensure drug safety. Worldwide company Pharmcontrol offers a full range of pharmacovigilance services in Azerbaijan to ensure the safety and effectiveness of medicines on the market. With a team of highly qualified, certified pharmacists, Pharmcontrol ensures the effective monitoring and management of drug safety. The company aligns with international practices and standards, helping to elevate the country's drug safety levels. The development of pharmacovigilance in Azerbaijan aims to increase public awareness about the safe use of medicines and improve the overall quality of the healthcare system. The integration of international standards and best practices in pharmacovigilance, spearheaded by companies like Pharmcontrol, contributes significantly to this goal, ensuring that the safety of patients is always a top priority. ==== China ==== China's economy is anticipated to pass Japan to become second in the ranking of individual countries' in pharmaceutical purchases by 2015, and so its pharmacovigilance regulation will become increasing important; China's regulation of pharmacovigilance is through its National Center for Adverse Drug Reaction Monitoring, under China's Ministry of Health. ==== India ==== In India, the pharmacovigilance regulatory authority is the Indian Pharmacopoeia Commission, with a National Coordination Centre under the Pharmacovigilance Program of India (PvPI), in the Ministry of Health and Family Welfare. Scientists working on pharmacovigilance share their experiences, findings, innovative ideas and researches during the annual meeting of Society of Pharmacovigilance, India. ==== Iraq ==== In Iraq, pharmacovigilance is regulated by the Iraqi Pharmacovigilance Center of the Iraqi Ministry of Health. ==== Japan ==== In Japan, with ~12% of all global 2011 pharmaceutical expenditures, pharmacovigilance matters are regulated by the Pharmaceuticals and Medical Devices Agency and the Ministry of Health, Labour, and Welfare. ==== South Korea ==== The Republic of Korea, with ~1% of all global 2011 pharmaceutical expenditures, pharmacovigilance matters are regulated in South Korea by the Ministry of Food and Drug Safety. === Australia === === Europe === The European "Big Four" (France, Germany, Italy and the United Kingdom), along with Spain, accrued ~17% of global 2011 pharmaceutical expenditures. The remaining EU and non-EU countries outside of France, Germany, Italy, the United Kingdom and Spain accrued ~7% of global 2011 pharmaceutical expenditures. Regulation of those outside the EU being managed by specific governmental agencies. ==== European Union ==== Pharmacovigilance efforts in the European Union are coordinated by the European Medicines Agency and are conducted by the national competent authorities (NCAs). The main responsibility of the European Medicines Agency is to maintain and develop the pharmacovigilance database consisting of all suspected serious adverse reactions to medicines observed in the European Community; the data processing network and management system is called EudraVigilance and contains separate but similar databases of human and veterinary reactions. The European Medicines Agency requires the individual marketing authorization holders to submit all received adverse reactions in electronic form, except in exceptional circumstances; the reporting obligations of the various stakeholders are defined by EEC legislation, namely regulation (EC) No 726/2004, and for human medicines, European Union Directive 2001/83/EC as amended and Directive 2001/20/EC. In 2002, Heads of Medicines Agencies agreed on a mandate for an ad hoc working group on establishing a European risk management strategy; the working group considered the conduct of a high level survey of EU pharmacovigilance resources to promote the utilization of expertise and encourage collaborative working. In conjunction with this oversight, individual countries maintain their distinct regulatory agencies with pharmacovigilance responsibility. Good Pharmacovigilance Practices (GVP) is a set of set of guidelines that apply to the EU member states. Module I: Pharmacovigilance system and Quality system Module II: Pharmacovigilance system master file Module III: Pharmacovigilance inspection Module IV: Pharmacovigilance audit Module V: Risk management system Module VI: Management and reporting of adverse reactions to medical products Module VII: Periodic safety update report Module VIII: Post authorization safety Module IX : Signal management Module X: Additional monitoring Module XI: Public participation in pharmacovigilance Module XII: Post-marketing authorization: regulatory and procedural guidance for human medicinal products Module XIII: Incident management Module XIV: Referral procedure for safety reasons Module XV: Safety communication Module XVI: Risk minimization measure: Selection of tools and effectiveness indicators ==== Spain ==== In Spain, pharmacovigilance is regulated by the Spanish Agency of Medicines and Medical Devices, which can suspend or withdraw the authorization of pharmaceuticals already on-market if the evidence shows that safety (or quality or efficacy) of an agent are unsatisfactory. ==== Switzerland ==== In Switzerland, pharmacovigilance "inspections" for clinical trials of medicinal products are conducted by the Swiss Agency for Therapeutic Products (Swissmedic). == Pharmacoenvironmentology (Ecopharmacovigilance) == Despite attention from the FDA and regulatory agencies of the European Union, procedures for monitoring drug concentrations and adverse effects in the environment are lacking. Pharmaceuticals, their metabolites, and related substances may enter the environment after patient excretion, after direct release to waste streams during manufacturing or administration, or via terrestrial deposits (e.g., from waste sludges or leachates). A concept combining pharmacovigilance and environmental pharmacology, intended to focus attention on this area, was introduced first as pharmacoenvironmentology in 2006 by Syed Ziaur Rahman and later as ecopharmacology with further concurrent and later terms for the same concept (ecopharmacovigilance, environmental pharmacology, ecopharmacostewardship). The first of these routes to the environment, elimination through living organisms subsequent to pharmacotherapy, is suggested as the principal source of environmental contamination (apart from cases where norms for treatment of manufacturing and other wastes are violated), and ecopharmacovigilance is intended to deal specifically with this impact of pharmacological agents on the environment. Activities of ecopharmacovigilance have been suggested to include: Increasing, generally, the availability of environmental data on medicinal products; Tracking emerging data on environmental exposure, effects and risks after product launch; Using environmental risk management plans to manage risk throughout a drug's life cycle; Following risk identification, promoting further research and environmental monitoring, and In general, promoting a global perspective on ecopharmacovigilance issues. == Related to medical devices == A medical device is an instrument, apparatus, implant, in vitro reagent, or similar or related article that is used to diagnose, prevent, or treat disease or other conditions, and does not achieve its purposes through chemical action within or on the body (which would make it a drug). Whereas medicinal products (also called pharmaceuticals) achieve their principal action by pharmacological, metabolic or immunological means, medical devices act by physical, mechanical, or thermal means. Medical devices vary greatly in complexity and application. Examples range from simple devices such as tongue depressors, medical thermometers, and disposable gloves to advanced devices such as medical robots, cardiac pacemakers, and neuroprosthetics. This modern concept of monitoring and safety of medical devices which is known materiovigilance was quite documented in Unani System of medicine. Given the inherent difference between medicinal products and medical products, the vigilance of medical devices is also different from that of medicinal products. To reflect this difference, a classification system has been adopted in some countries to stratify the risk of failure with the different classes of devices. The classes of devices typically run on a 1-3 or 1-4 scale, with Class 1 being the least likely to cause significant harm with device failure versus Classes 3 or 4 being the most likely to cause significant harm with device failure. An example of a device in the "low risk" category would be contact lenses. An example of a device in the "high risk" category would be cardiac pacemakers. Medical device reporting (MDR), which is the reporting of adverse events with medical devices, is similar to that with medicinal products, although there are differences. In contrast to reporting of medical products reports of side-effects play only a minor role with most medical devices. The vast majority of the medical device reports are related to medical device defects or failures. Other notable differences are in the obligations to report by other actors that aren't manufacturers, in the US user-facilities such as hospitals and nursing homes are legally required to report suspected medical device-related deaths to both FDA and the manufacturer, if known, and serious injuries to the manufacturer or to FDA, if the manufacturer is unknown. This is in contrast to the voluntary reporting of AEs with medicinal products. Similar obligations exist in multiple European countries. The European regulation on medical devices and the European regulation on in vitro diagnostic medical devices (IVDR) obliges other economic operators most notably importers and distributors to inform manufacturers, and in certain instances the authorities, of incidents and safety issues with medical devices that they have distributed or imported in the European market. == For herbal medicines == The safety of herbal medicines has become a major concern to both national health authorities and the general public. The use of herbs as traditional medicines continues to expand rapidly across the world; many people now take herbal medicines or herbal products for their health care in different national health-care settings. However, mass media reports of adverse events with herbal medicines can be incomplete and therefore misleading. Moreover, it can be difficult to identify the causes of herbal medicine-associated adverse events since the amount of data on each event is generally less than for pharmaceuticals formally regulated as drugs (since the requirements for adverse event reporting are either non-existent or are less stringent for herbal supplements and medications). == Novel sources == With the emergence of advanced artificial intelligence methods and social media big data, researchers are now using publicly posted social media data to discover unknown side effects of prescription medications. Natural language processing and machine learning methods are developed and used for identifying non-standard expressions of side effects. == Industry associations == Boston Society of Pharmacovigilance Physicians. == See also == == References == == Further reading == "Current Problems in Pharmacovigilance". Medicines and Healthcare products Regulatory Agency (MHRA). Archived from the original on September 24, 2006. "History of Pharmacovigilance in India: 1983–2022" (PDF). Society of Pharmacovigilance, India. == External links ==	Wikipedia/Drug_safety

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