Medical cannabis ,  medicinal cannabis  or  medical marijuana  ( MMJ ) refers to  cannabis products  and  cannabinoid molecules  that are  prescribed  by  physicians  for their patients. [ 1 ] [ 2 ] [ 3 ] [ 4 ]  The use of cannabis as medicine has a long history, but has not been as rigorously tested as other medicinal plants due to legal and governmental restrictions, resulting in limited  clinical research  to define the safety and efficacy of using cannabis to treat diseases. [ 5 ]


Preliminary evidence has indicated that cannabis might reduce  nausea  and  vomiting  during  chemotherapy  and reduce  chronic pain  and  muscle spasms . [ 6 ] [ 7 ]  Regarding non-inhaled cannabis or cannabinoids, a 2021 review found that it provided little relief against chronic pain and sleep disturbance, and caused several transient  adverse effects , such as cognitive impairment,  nausea , and  drowsiness . [ 8 ]


Short-term use increases the risk of minor and major adverse effects. [ 7 ]  Common side effects include  dizziness , feeling tired, vomiting, and  hallucinations . [ 7 ]  Long-term effects of cannabis are not clear. [ 7 ]  Concerns include memory and cognition problems, risk of addiction,  schizophrenia  in young people, and the risk of children taking it by accident. [ 6 ]


Many cultures have used cannabis for therapeutic purposes for thousands of years. [ 9 ]  Some American medical organizations have requested removal of cannabis from the list of  Schedule I controlled substances  maintained by the United States federal government, followed by regulatory and scientific review. [ 10 ] [ 11 ]  Others oppose its legalization, such as the  American Academy of Pediatrics . [ 12 ]


Medical cannabis can be administered through various methods, including  capsules ,  lozenges ,  tinctures ,  dermal patches , oral or dermal sprays,  cannabis edibles , and  vaporizing  or  smoking dried buds . Synthetic cannabinoids are available for prescription use in some countries, such as  synthetic delta-9-THC  and  nabilone . Countries that  allow the medical use of whole-plant cannabis  include Argentina, Australia, Canada, Chile, Colombia, Germany, Greece, Israel, Italy, the Netherlands, Peru, Poland, Portugal, Spain, and Uruguay. In the United States, 38 states and the District of Columbia have legalized cannabis for medical purposes, beginning with the passage of California's  Proposition 215  in 1996. [ 13 ]  Although cannabis remains prohibited for any use at the federal level, the  Rohrabacher–Farr amendment  was enacted in December 2014, limiting the ability of federal law to be enforced in states where medical cannabis has been legalized.


In the U.S., the  National Institute on Drug Abuse  defines medical cannabis as "using the whole, unprocessed marijuana plant or its basic extracts to treat symptoms of illness and other conditions". [ 14 ]


A cannabis plant includes more than 400 different chemicals, of which about 70 are  cannabinoids . [ 15 ]  In comparison, typical government-approved medications contain only one or two chemicals. [ 15 ]  The number of active chemicals in cannabis is one reason why treatment with cannabis is difficult to classify and study. [ 15 ]


A 2014 review stated that the variations in ratio of CBD-to-THC in botanical and pharmaceutical preparations determines the therapeutic vs psychoactive effects (CBD attenuates THC's psychoactive effects [ 16 ] ) of cannabis products. [ 17 ]


Overall, research into the health effects of medical cannabis has been of low quality and it is not clear whether it is a useful treatment for any condition, or whether harms outweigh any benefit. [ 18 ]  There is no consistent evidence that it helps with  chronic pain  and  muscle spasms . [ 18 ]


Low quality evidence suggests its use for reducing  nausea  during  chemotherapy , improving appetite in  HIV/AIDS , improving sleep, and improving  tics  in  Tourette syndrome . [ 7 ]  When usual treatments are ineffective,  cannabinoids  have also been recommended for  anorexia ,  arthritis ,  glaucoma , [ 19 ]  and  migraine . [ 20 ]


It is unclear whether American states might be able to mitigate the adverse effects of the  opioid epidemic  by prescribing medical cannabis as an alternative pain management drug. [ 21 ]


Cannabis should not be used in  pregnancy . [ 22 ]


Research analyzing data from the National Health and Nutrition Examination Survey (NHANES) did not find significant differences in sleep duration between cannabis users and non-users. This suggests that while some individuals may perceive benefits from cannabis use in terms of sleep, it may not significantly change overall sleep patterns across the general population. [ 23 ]


A review of literature up to 2018 indicates that cannabidiol (CBD) may have therapeutic potential for the treatment of insomnia. CBD, a non-psychoactive component of cannabis, is of particular interest due to its potential to influence sleep without the psychoactive effects associated with tetrahydrocannabinol (THC). [ 24 ]


Medical cannabis is somewhat effective in  chemotherapy-induced nausea and vomiting  (CINV) [ 6 ] [ 19 ]  and may be a reasonable option in those who do not improve following preferential treatment. [ 25 ]  Comparative studies have found cannabinoids to be more effective than some conventional antiemetics such as  prochlorperazine ,  promethazine , and  metoclopramide  in controlling CINV, [ 26 ]  but these are used less frequently because of side effects including dizziness, dysphoria, and hallucinations. [ 27 ] [ 28 ]  Long-term cannabis use may cause nausea and vomiting, a condition known as  cannabinoid hyperemesis syndrome  (CHS). [ 29 ]


A 2016  Cochrane review  said that cannabinoids were "probably effective" in treating chemotherapy-induced nausea in children, but with a high side-effect profile (mainly drowsiness, dizziness, altered moods, and increased appetite). Less common side effects were "ocular problems, orthostatic hypotension, muscle twitching, pruritus, vagueness, hallucinations, lightheadedness and dry mouth". [ 30 ]


Evidence is lacking for both efficacy and safety of cannabis and cannabinoids in treating patients with  HIV/AIDS  or for  anorexia  associated with AIDS. As of 2013, current studies suffer from the effects of bias, small sample size, and lack of long-term data. [ 31 ]


A 2021 review found little effect of using non-inhaled cannabis to relieve chronic pain. [ 8 ]  According to a 2019 systematic review, there have been inconsistent results of using cannabis for neuropathic pain, spasms associated with  multiple sclerosis  and pain from  rheumatic  disorders, but was not effective treating chronic cancer pain. The authors state that additional  randomized controlled trials  of different cannabis products are necessary to make conclusive recommendations. [ 18 ]


When cannabis is inhaled to relieve pain, blood levels of cannabinoids rise faster than when oral products are used, peaking within three minutes and attaining an analgesic effect in seven minutes. [ 32 ]


A 2011 review considered cannabis to be generally safe, [ 33 ]  and it appears safer than  opioids  in palliative care. [ 34 ]


A 2022 review concluded the pain relief experienced after using medical cannabis is due to the  placebo effect , especially given widespread media attention that sets the expectation for pain relief. [ 35 ]


Cannabis' efficacy is not clear in treating neurological problems, including  multiple sclerosis  (MS) and movement problems. [ 17 ]  Evidence also suggests that oral cannabis extract is effective for reducing patient-centered measures of spasticity. [ 17 ]  A trial of cannabis is deemed to be a reasonable option if other treatments have not been effective. [ 6 ] [ by whom? ]  Its use for MS is approved in ten countries. [ 6 ] [ 36 ] [ conflicted source? ]  A 2012 review found no problems with tolerance, abuse, or addiction. [ 37 ]   In the United States,  cannabidiol , one of the cannabinoids found in the marijuana plant, has been approved for treating two severe forms of epilepsy,  Lennox-Gastaut syndrome  and  Dravet syndrome . [ 38 ]


A 2019 systematic review found that there is a lack of evidence that cannabinoids are effective in treating  depressive  or  anxiety disorders ,  attention-deficit hyperactivity disorder  (ADHD),  Tourette syndrome ,  post-traumatic stress disorder , or  psychosis . [ 39 ]


Research indicates that cannabis, particularly CBD, may have anxiolytic (anxiety-reducing) effects. A study found that CBD significantly reduced anxiety during a simulated public speaking test for individuals with social anxiety disorder. However, the relationship between cannabis use and anxiety symptoms is complex, and while some users report relief, the overall evidence from observational studies and clinical trials remains inconclusive. Cannabis is often used by people to cope with anxiety, yet the efficacy and safety of cannabis for treating anxiety disorders is yet to be researched. [ 40 ] [ 41 ]


Cannabis use, especially at high doses, is associated with a higher risk of psychosis, particularly in individuals with a genetic predisposition to psychotic disorders like schizophrenia. Some studies have shown that cannabis can trigger a temporary psychotic episode, which may increase the risk of developing a psychotic disorder later. [ 42 ]


The impact of cannabis on depression is less clear. Some studies suggest a potential increase in depression risk among adolescents who use cannabis, though findings are inconsistent across studies. [ 42 ]


There is insufficient data to draw strong conclusions about the safety of medical cannabis. [ 43 ]  Typically, adverse effects of medical cannabis use are not serious; [ 6 ]  they include tiredness, dizziness, increased appetite, and cardiovascular and psychoactive effects. Other effects can include impaired short-term memory; impaired motor coordination; altered judgment; and paranoia or psychosis at high doses. [ 44 ]  Tolerance to these effects develops over a period of days or weeks. The amount of cannabis normally used for medicinal purposes is not believed to cause any permanent cognitive impairment in adults, though long-term treatment in adolescents should be weighed carefully as they are more susceptible to these impairments. Withdrawal symptoms are rarely a problem with controlled medical administration of cannabinoids. The ability to drive vehicles or to operate machinery may be impaired until a tolerance is developed. [ 25 ]   Although supporters of medical cannabis say that it is safe, [ 43 ]  further research is required to assess the long-term safety of its use. [ 27 ] [ 45 ]


Recreational use of cannabis is associated with cognitive deficits, especially for those who begin to use cannabis in adolescence. As of 2021 [update]  there is a lack of research into long-term cognitive effects of medical use of cannabis, but one 12-month observational study reported that "MC patients demonstrated significant improvements on measures of  executive function  and clinical state over the course of 12 months". [ 46 ]


Exposure to THC can cause acute transient psychotic symptoms in healthy individuals and people with schizophrenia. [ 16 ]


A 2007 meta analysis concluded that cannabis use reduced the average age of onset of psychosis by 2.7 years relative to non-cannabis use. [ 47 ]   A 2005 meta analysis concluded that adolescent use of cannabis increases the risk of psychosis, and that the risk is dose-related. [ 48 ]  A 2004 literature review on the subject concluded that cannabis use is associated with a two-fold increase in the risk of psychosis, but that cannabis use is "neither necessary nor sufficient" to cause psychosis. [ 49 ]  A French review from 2009 came to a conclusion that cannabis use, particularly that before age 15, was a factor in the development of schizophrenic disorders. [ 50 ]


The  genus   Cannabis  contains two species which produce useful amounts of psychoactive cannabinoids:  Cannabis indica  and  Cannabis sativa , which are listed as Schedule I medicinal plants in the US; [ 6 ]  a third species,  Cannabis ruderalis , has few psychogenic properties. [ 6 ]  Cannabis contains more than 460 compounds; [ 9 ]  at least 80 of these are  cannabinoids [ 51 ] [ 52 ]  –  chemical compounds  that interact with  cannabinoid receptors  in the brain. [ 6 ]  As of 2012, more than 20 cannabinoids were being studied by the U.S. FDA. [ 53 ]


The most psychoactive cannabinoid found in the cannabis plant is  tetrahydrocannabinol  (or delta-9-tetrahydrocannabinol, commonly known as THC). [ 9 ]  Other cannabinoids include  delta-8-tetrahydrocannabinol ,  cannabidiol  (CBD),  cannabinol  (CBN),  cannabicyclol  (CBL),  cannabichromene  (CBC) and  cannabigerol  (CBG); they have less psychotropic effects than THC, but may play a role in the overall effect of cannabis. [ 9 ]  The most studied are THC, CBD and CBN. [ 54 ]


CB1 and CB2 are the primary cannabinoid receptors responsible for several of the effects of cannabinoids, although other receptors may play a role as well. Both belong to a group of receptors called G protein-coupled receptors (GPCRs). CB1 receptors are found in very high levels in the brain and are thought to be responsible for psychoactive effects. [ 55 ]  CB2 receptors are found peripherally throughout the body and are thought to modulate pain and inflammation. [ 56 ]


Cannabinoid absorption is dependent on its route of administration.


Inhaled and vaporized THC have similar absorption profiles to smoked THC, with a  bioavailability  ranging from 10 to 35%. Oral administration has the lowest bioavailability of approximately 6%, variable absorption depending on the vehicle used, and the longest time to peak plasma levels  (2 to 6 hours) compared to smoked or vaporized THC. [ 57 ]


Similar to THC, CBD has poor oral bioavailability, approximately 6%. The low bioavailability is largely attributed to significant first-pass metabolism in the liver and erratic absorption from the gastrointestinal tract. However, oral administration of CBD has a faster time to peak concentrations (2 hours) than THC. [ 57 ]


Due to the poor bioavailability of oral preparations, alternative routes of administration have been studied, including sublingual and rectal. These alternative formulations maximize bioavailability and reduce first-pass metabolism. Sublingual administration in rabbits yielded bioavailability of 16% and time to peak concentration of 4 hours. [ 58 ]  Rectal administration in monkeys doubled bioavailability to 13.5% and achieved peak blood concentrations within 1 to 8 hours after administration. [ 59 ]


Like cannabinoid absorption, distribution is also dependent on route of administration. Smoking and inhalation of vaporized cannabis have better absorption than do other routes of administration, and therefore also have more predictable distribution. [ 59 ] [ 60 ]  THC is highly protein bound once absorbed, with only 3% found unbound in the plasma. It distributes rapidly to highly vascularized organs such as the heart, lungs, liver, spleen, and kidneys, as well as to various glands. Low levels can be detected in the brain, testes, and unborn fetuses, all of which are protected from systemic circulation via barriers. [ 61 ]  THC further distributes into fatty tissues a few days after administration due to its high lipophilicity, and is found deposited in the spleen and fat after redistribution. [ 60 ] [ 62 ] [ 63 ]


Delta-9-THC is the primary molecule responsible for the effects of cannabis. Delta-9-THC is metabolized in the liver and turns into 11-OH-THC. [ 64 ]  11-OH-THC is the first metabolic product in this pathway. Both Delta-9-THC and 11-OH-THC are psychoactive. The metabolism of THC into 11-OH-THC plays a part in the heightened psychoactive effects of edible cannabis. [ 65 ]


Next, 11-OH-THC is metabolized in the liver into 11-COOH-THC, which is the second metabolic product of THC. [ 66 ]  11-COOH-THC is not psychoactive. [ 64 ]


Ingestion of edible cannabis products lead to a slower onset of effect than the inhalation of it because the THC travels to the liver first through the blood before it travels to the rest of the body. Inhaled cannabis can result in THC going directly to the brain, where it then travels from the brain back to the liver in recirculation for metabolism. [ 64 ]  Eventually, both routes of metabolism result in the metabolism of psychoactive THC to inactive 11-COOH-THC.


Due to substantial metabolism of THC and CBD, their metabolites are excreted mostly via  feces , rather than by urine. [ 57 ] [ 67 ]  After delta-9-THC is hydroxylated into 11-OH-THC via CYP2C9, CYP2C19, and CYP3A4, it undergoes phase II metabolism into more than 30 metabolites, a majority of which are products of  glucuronidation . Approximately 65% of THC is excreted in feces and 25% in the urine, while the remaining 10% is excreted by other means. [ 57 ]  The terminal half-life of THC is 25 to 36 hours, [ 68 ]  whereas for CBD it is 18 to 32 hours. [ 67 ]


CBD is hydroxylated by P450 liver enzymes into 7-OH-CBD. Its metabolites are products of primarily CYP2C19 and CYP3A4 activity, with potential activity of CYP1A1, CYP1A2, CYP2C9, and CYP2D6. [ 69 ]  Similar to delta-9-THC, a majority of CBD is excreted in feces and some in the urine. [ 57 ]  The terminal half-life is approximately 18–32 hours. [ 70 ]


Smoking  has been the means of administration of cannabis for many users, but it is not suitable for the use of cannabis as a medicine. [ 71 ]  It was the most common method of medical cannabis consumption in the US as of 2013 [update] . [ 6 ]  It is difficult to predict the pharmacological response to cannabis because concentration of cannabinoids varies widely, as there are different ways of preparing it for consumption (smoked, applied as oils, eaten, infused into other foods,  or drunk) and a lack of production controls. [ 6 ]  The potential for adverse effects from smoke inhalation makes smoking a less viable option than oral preparations. [ 71 ]   Cannabis vaporizers  have gained popularity because of a perception among users that fewer harmful chemicals are ingested when components are inhaled via aerosol rather than smoke. [ 6 ]  Cannabinoid medicines are available in pill form ( dronabinol  and  nabilone ) and liquid extracts formulated into an oromucosal spray ( nabiximols ). [ 6 ]  Oral preparations are "problematic due to the uptake of cannabinoids into fatty tissue, from which they are released slowly, and the significant first-pass liver metabolism, which breaks down Δ9THC and contributes further to the variability of plasma concentrations". [ 71 ]


The US Food and Drug Administration (FDA) has not approved smoked cannabis for any condition or disease, as it deems that evidence is lacking concerning safety and efficacy. [ 72 ]  The FDA issued a 2006 advisory against  smoked  medical cannabis stating: "marijuana has a high potential for abuse, has no currently accepted medical use in treatment in the United States, and has a lack of accepted safety for use under medical supervision." [ 72 ]


Cannabis, called  má   麻  (meaning "hemp; cannabis; numbness") or  dàmá   大麻  (with "big; great") in Chinese, was used in  Taiwan  for fiber starting about 10,000 years ago. [ 73 ]  The botanist  Hui-lin Li  wrote that in China, "The use of Cannabis in medicine was probably a very early development. Since ancient humans used hemp seed as food, it was quite natural for them to also discover the medicinal properties of the plant." [ 74 ]  Emperor  Shen-Nung , who was also a pharmacologist, wrote a book on treatment methods in 2737 BCE that included the medical benefits of cannabis. He recommended the substance for many ailments, including constipation, gout, rheumatism, and absent-mindedness. [ 75 ]  Cannabis is one of the  50 "fundamental" herbs  in  traditional Chinese medicine . [ 76 ]


The  Ebers Papyrus  ( c.  1550 BCE ) from  Ancient Egypt  describes medical cannabis. [ 77 ]  The ancient Egyptians used hemp (cannabis) in  suppositories  for relieving the pain of  hemorrhoids . [ 78 ]


Surviving texts from  ancient India  confirm that cannabis' psychoactive properties were recognized, and doctors used it for treating a variety of illnesses and ailments, including insomnia, headaches, gastrointestinal disorders, and pain, including during childbirth. [ 79 ]


The  Ancient Greeks  used cannabis to dress wounds and sores on their horses, [ 80 ]  and in humans, dried leaves of cannabis were used to treat nose bleeds, and cannabis seeds were used to expel tapeworms. [ 80 ]


In the  medieval Islamic world ,  Arabic physicians  made use of the  diuretic ,  antiemetic ,  antiepileptic ,  anti-inflammatory ,  analgesic  and  antipyretic  properties of  Cannabis sativa , and used it extensively as medication from the 8th to 18th centuries. [ 81 ]


Cannabis seeds may have been used for food, rituals or religious practices in ancient Europe and China. [ 82 ] : 19–22   Harvesting the plant led to the spread of cannabis throughout  Eurasia  about 10,000 to 5,000 years ago, with further distribution to the  Middle East  and Africa about 2,000 to 500 years ago. [ 82 ] : 18–19   A  landrace   strain  of cannabis developed over centuries. [ 83 ]  They are cultivars of the plant that originated in one specific region.


Widely cultivated strains of cannabis, such as "Afghani" or "Hindu Kush", are indigenous to the  Pakistan  and  Afghanistan  regions, while "Durban Poison" is native to Africa. [ 82 ] : 45–48   There are approximately 16 landrace strains of cannabis identified from Pakistan, Jamaica, Africa, Mexico, Central America and Asia. [ 84 ]


An Irish physician,  William Brooke O'Shaughnessy , is credited with introducing cannabis to Western medicine. [ 85 ]  O'Shaughnessy discovered cannabis in the 1830s while living abroad in  India , where he conducted numerous experiments investigating the drug's medical utility (noting in particular its  analgesic  and  anticonvulsant  effects). [ 86 ]   He returned to  England  with a supply of cannabis in 1842, after which its use spread through Europe and the United States. [ 87 ]   In 1845 French physician  Jacques-Joseph Moreau  published a book about the use of cannabis in psychiatry. [ 88 ]   In 1850 cannabis was entered into the  United States Pharmacopeia . [ 86 ]  An anecdotal report of  Cannabis indica  as a treatment for  tetanus  appeared in  Scientific American  in 1880. [ 89 ]


The use of cannabis in medicine began to decline by the end of the 19th century, due to difficulty in controlling dosages and the rise in popularity of synthetic and  opium -derived drugs. [ 87 ]   Also, the advent of the hypodermic  syringe  allowed these drugs to be injected for immediate effect, in contrast to cannabis which is not water-soluble and therefore cannot be injected. [ 87 ]


In the United States, the medical use of cannabis further declined with the passage of the  Marihuana Tax Act of 1937 , which imposed new regulations and fees on physicians prescribing cannabis. [ 90 ]   Cannabis was removed from the U.S. Pharmacopeia in 1941, and officially banned for any use with the passage of the  Controlled Substances Act  of 1970. [ 87 ]


Cannabis began to attract renewed interest as medicine in the 1970s and 1980s, in particular due to its use by cancer and AIDS patients who reported relief from the effects of  chemotherapy  and  wasting syndrome . [ 91 ]   In 1996,  California  became the first U.S. state to legalize medical cannabis in defiance of federal law. [ 92 ]   In 2001,  Canada  became the first country to adopt a system regulating the medical use of cannabis. [ 93 ]


Countries that have legalized the medical use of cannabis include  Argentina , [ 94 ]   Australia , [ 95 ]   Brazil , [ 96 ]   Canada , [ 97 ]   Chile , [ 97 ]   Colombia , [ 97 ]   Costa Rica , [ 98 ]   Croatia , [ 99 ]   Cyprus , [ 100 ]   Czech Republic , [ 97 ]   Finland , [ 101 ]   Germany , [ 102 ]   Greece , [ 103 ]   Israel , [ 104 ]   Italy , [ 105 ]   Jamaica , [ 106 ]   Lebanon , [ 107 ]   Luxembourg , [ 108 ]   Malta , [ 109 ]   Morocco , [ 110 ]  the  Netherlands , [ 97 ]   New Zealand , [ 111 ]   North Macedonia , [ 112 ]   Panama , [ 113 ]   Peru , [ 114 ]   Poland , [ 115 ]   Portugal , [ 116 ]   Rwanda , [ 117 ]   Sri Lanka , [ 118 ]   Switzerland , [ 119 ]   Thailand , [ 120 ]  the  United Kingdom , [ 121 ]  and  Uruguay . [ 97 ]   Other countries have more restrictive laws that allow only the use of isolated cannabinoid drugs such as  Sativex  or  Epidiolex . [ 122 ] [ 123 ]   Countries with the most relaxed policies include Canada, [ 124 ]  the Netherlands, [ 97 ]  Thailand, [ 125 ]  and Uruguay, [ 97 ]  where cannabis can be purchased without need for a prescription.  In  Mexico , THC content of medical cannabis is limited to one percent. [ 126 ]   In the  United States , the legality of medical cannabis varies by state. [ 13 ]


However, in many of these countries, access may not always be possible under the same conditions.


Cannabis and its derivatives are subject to regulation under three  United Nations   drug control treaties : the 1961  Single Convention on Narcotic Drugs , the 1971  Convention on Psychotropic Substances , and the 1988  Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances . [ 127 ]


Cannabis and cannabis resin are classified as a Schedule I drug under the Single Convention treaty, meaning that medical use is considered "indispensible for the relief of pain and suffering" but that it is considered to be an addictive medication with risks of abuse. [ 128 ]  Countries have an obligation to provide access and sufficient availability of drugs listed in Schedule I for the purposes of medical uses. [ 129 ] [ 130 ]


Prior to December 2020 cannabis and cannabis resin were also included in Schedule IV, a more restrictive level of control, which is for only the most dangerous drugs such as heroin and fentanyl. [ 131 ]  They were removed after an independent scientific assessment by the  World Health Organization  in 2018-1029.


Member nations of the  UN Commission on Narcotic Drugs  voted 27–25 to remove it from Schedule IV on 2 December 2020, [ 132 ]  following a  World Health Organization  recommendation for removal in January 2019. [ 133 ] [ 134 ]


In the United States, the use of cannabis for medical purposes is legal in 38 states, four out of five permanently inhabited  U.S. territories , and the  District of Columbia . [ 13 ]   An additional 10 states have more restrictive laws allowing the use of low-THC products. [ 13 ]   Cannabis remains illegal at the federal level under the  Controlled Substances Act , which classifies it as a Schedule I drug with a high potential for abuse and no accepted medical use.  In December 2014, however, the  Rohrabacher–Farr amendment  was signed into law, prohibiting the  Justice Department  from prosecuting individuals acting in accordance with state medical cannabis laws. [ 135 ]


In the US, the FDA has approved two oral cannabinoids for use as medicine in 1985: [ 136 ]   dronabinol  (pure delta-9-THC; brand name Marinol) and  nabilone  (a  synthetic neocannabinoid ; brand name Cesamet). [ 6 ]  In the US, they are both listed as Schedule II, indicating high potential for side effects and addiction. [ 53 ] [ 137 ]


The method of obtaining medical cannabis varies by region and by legislation. In the US, most consumers grow their own or buy it from  cannabis dispensaries  in states where it is legal. [ 6 ] [ 138 ]   Marijuana vending machines  for selling or dispensing cannabis are in use in the United States and are planned to be used in Canada. [ 139 ]  In 2014, the startup Meadow began offering on-demand delivery of medical marijuana in the San Francisco Bay Area, through their mobile app. [ 140 ]


Almost 70% of medical cannabis is exported from the United Kingdom, according to a 2017 United Nations report, with much of the remaining amount coming from Canada and the Netherlands. [ 141 ]


In the United States, health insurance companies may not pay for a medical marijuana prescription as the  Food and Drug Administration  must approve any substance for medicinal purposes. Before this can happen, the FDA must first permit the study of the medical benefits and drawbacks of the substance, which it has not done since it was placed on Schedule I of the Controlled Substances Act in 1970. Therefore, all expenses incurred fulfilling a medical marijuana prescription will possibly be incurred as out-of-pocket. [ 142 ]   However, the  New Mexico Court of Appeals  has ruled that  workers' compensation  insurance must pay for prescribed marijuana as part of the state's Medical Cannabis Program. [ 143 ]


Medical organizations that have issued statements in support of allowing access to medical cannabis include the  American Nurses Association , [ 10 ]   American Public Health Association , [ 144 ]   American Medical Student Association , [ 145 ]   National Multiple Sclerosis Society , [ 146 ]   Epilepsy Foundation , [ 147 ]  and  Leukemia & Lymphoma Society . [ 148 ]


Organizations that oppose the legalization of medical cannabis include the  American Academy of Pediatrics  (AAP) [ 12 ]  and  American Psychiatric Association . [ 149 ]   However, the AAP also supports rescheduling for the purpose of facilitating research. [ 12 ]


The  American Medical Association [ 150 ]  and  American College of Physicians [ 151 ]  do not take a position on the legalization of medical cannabis, but have called for the Schedule I classification to be reviewed. The  American Academy of Family Physicians [ 11 ]  and  American Society of Addiction Medicine [ 152 ]  also do not take a position, but do support rescheduling to better facilitate research. The  American Heart Association  says that "many of the concerning health implications of cannabis include cardiovascular diseases" but that it supports rescheduling to allow "more nuanced ... marijuana legislation and regulation" and to "reflect the existing science behind cannabis". [ 153 ]   The  American Cancer Society [ 154 ]  and  American Psychological Association [ 155 ]  have noted the obstacles that exist for conducting research on cannabis, and have called on the federal government to better enable scientific study of the drug.


Cancer Research UK  say that while cannabis is being studied for therapeutic potential, "claims that there is solid "proof" that cannabis or cannabinoids can cure cancer is highly misleading to patients and their families, and builds a false picture of the state of progress in this area". [ 156 ]


There are three  International Nonproprietary Name  (INN) granted for cannabinoids: two plant-derived  phytocannabinoids  and one  neocannabinoid :


Nabiximols  is the generic name (but not recognized as an INN) of a mixture of Cannabidiol and Dronabinol. Its most common form is the oromucosal spray derived from two strains of  Cannabis sativa  and containing THC and CBD traded under the brand name Sativex®. [ 53 ]  It is not approved in the United States, but is approved in several European countries, Canada, and New Zealand as of 2013. [ 6 ]


As an  antiemetic , these medications are usually used when conventional treatment for nausea and vomiting associated with cancer chemotherapy fail to work. [ 6 ]


Nabiximols  is used for treatment of spasticity associated with MS when other therapies have not worked, and when an initial trial demonstrates "meaningful improvement". [ 6 ]  Trials for FDA approval in the US are underway. [ 6 ]  It is also approved in several European countries for overactive bladder and  vomiting . [ 53 ]  When sold under the trade name Sativex as a mouth spray, the prescribed daily dose in Sweden delivers a maximum of 32.4 mg of  THC  and 30 mg of  CBD ; mild to moderate dizziness is common during the first few weeks. [ 162 ]


Relative to inhaled consumption, peak concentration of oral THC is delayed, and it may be difficult to determine optimal dosage because of variability in patient absorption. [ 6 ]


In 1964, Albert Lockhart and  Manley West  began studying the health effects of traditional cannabis use in  Jamaican  communities. They developed, and in 1987 gained permission to market, the pharmaceutical "Canasol", one of the first cannabis extracts. [ 163 ]


A 2022 review concluded that "oral, synthetic cannabis products with high THC-to-CBD ratios and sublingual, extracted cannabis products with comparable THC-to-CBD ratios may be associated with short-term improvements in chronic pain and increased risk for dizziness and sedation." [ 164 ]


, links to websites about medical cannabis


The  Medicines Discovery Catapult  ( MDC ) is the United Kingdom's  catapult centre  for medicine research and innovation, headquartered at  Alderley Park  in  Cheshire .


The intention to form the company was announced by the Chancellor on 13 July 2015 with funding of £5m, on a visit to Cheshire. It would be part of the  Northern Powerhouse  initiative. [ 1 ]


The Medicines Technologies Catapult was established in December 2015, [ 2 ]  funded by a £10m grant from  Innovate UK  and based at the Alderley Park science park in Cheshire. [ 3 ]  On 1 March 2016 its name changed to the Medicines Discovery Catapult. [ 2 ]  Further funding of approximately £10m per year was secured from Innovate UK for the years 2018 to 2023. [ 3 ]


The PMC was based in Cambridge and had regional centres of excellence at Belfast, Glasgow, Cardiff, Oxford, Leeds and Manchester. It worked with  precision medicine . It started from April 2015, and worked with regional parts of the Diagnostic Evidence Cooperative and  Academic Health Science Networks  (AHSN). [ citation needed ]


On 26 June 2017 it was announced that the PMC would close, with most of its functions transferred to the MDC. [ 4 ]  The Leeds site is now the Leeds Centre for Personalised Medicine and Health.


A not-for-profit company, the MDC works with a range of UK innovators to advance projects and products towards clinical impact. In 2019, the company stated that it worked in four sectors: [ 3 ]


In the same year, the number of staff increased from 40 to 75, and the company reported that its income comprised £8.5m from Innovate UK and £152,000 from collaborative research and development. After charging £7.1m to administrative expenses, the company reported a loss for the year of £16,000. [ 3 ]


In 2020, the company was given the task of setting up one of the first PCR analysis centres for COVID-19 tests – known as  Lighthouse labs  – elsewhere at the Alderley Park site. [ 5 ] [ 6 ]  By 2021, this centre employed over 700 staff and had a stated capacity of 80,000 test samples per day. [ citation needed ]


Dr Robin Brown has been the company's chairman since July 2018; [ 3 ]  he has a PhD in molecular biology and has worked in  venture capital  at  Advent Healthcare . [ 7 ]  The company has no shareholders. [ 3 ]


Previously, Professor Graham Boulnois was chairman from January 2016; he was head of research from 1992 to 2000 at  Zeneca Pharmaceuticals  in Cheshire, and Professor of Microbiology from 1984 to 1992 at the  University of Leicester . [ 8 ]


The  Nine Herbs Charm ,  Nigon Wyrta Galdor ,  Lay of the Nine Healing Herbs , or  Nine Wort Spell  (among other names) is an  Old English charm  recorded in the tenth century CE. [ 1 ]  It is part of the Anglo-Saxon medical compilation known as  Lacnunga , which survives in the manuscript Harley MS 585 in the British Library. [ 2 ]  The charm involves the preparation of nine plants.


The poem contains one of two clear Old English mentions of the god  Woden  in Old English poetry; the other is  Maxims I  of the  Exeter Book .  Robert K. Gordon's  translation of the section reads as follows:


A snake came crawling, it bit a man.
Then Woden took nine glory-twigs,
Smote the serpent so that it flew into nine parts.
There apple brought this pass against poison,
That she nevermore would enter her house. [ 1 ]


Nine and three,  numbers significant in Germanic paganism  and later  Germanic folklore , are mentioned frequently throughout the charm. [ 2 ]


Scholars have proposed that this passage describes Woden coming to the assistance of the herbs through his use of nine twigs, each twig inscribed with the  runic  first-letter initial of a plant. [ 3 ]


According to Gordon, the poem is "clearly an old heathen thing which has been subjected to Christian censorship." [ 1 ]  Malcolm Laurence Cameron states that chanting the poem aloud results in a "marvellously incantatory effect". [ 4 ]


Paphiopedilum callosum  is a species of  orchid  found from  Vietnam  to northwestern  Peninsular Malaysia . It has been investigated and shown promising results in the treatment of cancer. [ 2 ]


This  Cypripedioideae -related article is a  stub . You can help Wikipedia by  expanding it .


Pharmacognosy Communications  is a  peer-reviewed   open-access  pharmacy journal published by  EManuscript Services  on behalf of Pharmacognosy Network Worldwide. It is a quarterly publication edited by pharmacognosist Ian Edwin Cock,  Griffith University ,  Australia . It publishes articles on the subjects of  pharmacognosy ,  natural products ,  phytochemistry , and  phytomedicine .


The journal is indexed with CAB Abstracts,  Chemical Abstracts ,  EBSCO ,  Google Scholar , Index Copernicus, OpenJGate,  ProQuest , and  Ulrich's Periodicals Directory .


Phcog.net (Pharmacognosy Network Worldwide) appeared on Beall's list from October 2012 [ 1 ]  through September 12, 2015. [ 2 ]


Pharmacognosy Research  is a  peer-reviewed   open-access   medical journal  published on behalf of the  Pharmacognosy Network Worldwide . The journal publishes articles on the subject of  pharmacognosy , natural products, and  phytochemistry  and is indexed with  CASPUR ,  EBSCO ,  ProQuest , and  Scopus .


Pharmacognosy Reviews  is a  peer-reviewed   open-access   medical journal  published by Pharmacognosy Network Worldwide (Phcog.net). The journal publishes articles on the subject of  pharmacognosy , natural products, and  phytochemistry . It is indexed with Caspur,  EBSCO ,  ProQuest , and  Scopus .


Phcog.net appeared on  Beall's list  of predatory open-access journals from October 2012 [ 1 ]  through September 12, 2015. [ 2 ]


Phytochemistry  is the study of  phytochemicals , which are chemicals derived from  plants . Phytochemists strive to describe the structures of the large number of  secondary metabolites  found in plants, the functions of these compounds in human and plant biology, and the biosynthesis of these compounds. Plants synthesize phytochemicals for many reasons, including to protect themselves against  insect  attacks and  plant diseases . The compounds found in plants are of many kinds, but most can be grouped into four major biosynthetic classes:  alkaloids ,  phenylpropanoids ,  polyketides , and  terpenoids .


Phytochemistry can be considered a subfield of  botany  or  chemistry . Activities can be led in  botanical gardens  or in the wild with the aid of  ethnobotany . Phytochemical studies directed toward human (i.e. drug discovery) use may fall under the discipline of  pharmacognosy , whereas phytochemical studies focused on the ecological functions and evolution of phytochemicals likely fall under the discipline of  chemical ecology . Phytochemistry also has relevance to the field of  plant physiology .


Techniques commonly used in the field of phytochemistry are  extraction , isolation, and  structural elucidation  ( MS ,1D and 2D NMR) of  natural products , as well as various  chromatography  techniques (MPLC,  HPLC , and LC-MS).


Many plants produce chemical compounds  for defence against herbivores . The major classes of pharmacologically active  phytochemicals  are described below, with examples of medicinal plants that contain them. [ 1 ]  Human settlements are often surrounded by weeds containing phytochemicals, such as  nettle ,  dandelion  and  chickweed . [ 2 ] [ 3 ]


Many phytochemicals, including  curcumin ,  epigallocatechin gallate ,  genistein , and  resveratrol  are  pan-assay interference compounds  and are not useful in  drug discovery . [ 4 ] [ 5 ]


Alkaloids  are bitter-tasting chemicals, widespread in nature, and often toxic. There are several classes with different modes of action as drugs, both recreational and pharmaceutical. Medicines of different classes include  atropine ,  scopolamine , and  hyoscyamine  (all from  nightshade ), [ 6 ]  the traditional medicine  berberine  (from plants such as  Berberis  and  Mahonia ),  caffeine  ( Coffea ),  cocaine  ( Coca ),  ephedrine  ( Ephedra ),  morphine  ( opium poppy ),   nicotine  ( tobacco ),  reserpine  ( Rauvolfia serpentina ),  quinidine  and  quinine  ( Cinchona ),  vincamine  ( Vinca minor ), and  vincristine  ( Catharanthus roseus ). [ 7 ]


Anthraquinone   glycosides  are found in  senna , [ 9 ]   rhubarb , and  Aloe . [ 10 ]


The  cardiac glycosides  are phytochemicals from plants including  foxglove  and  lily of the valley . They include  digoxin  and  digitoxin  which act as  diuretics . [ 11 ]


Polyphenols  of several classes are widespread in plants, including  anthocyanins ,  phytoestrogens , and  tannins . [ 13 ]  Polyphenols are secondary metabolites produced by almost every part of plants, including fruits, flowers, leaves and bark. [ 13 ]


Terpenes  and  terpenoids  of many kinds are found in  resinous  plants such as the  conifers . They are aromatic and serve to repel herbivores. Their scent makes them useful in  essential oils , whether for  perfumes  such as  rose  and  lavender , or for  aromatherapy . [ 14 ] [ 15 ]  Some have had medicinal uses:  thymol  is an antiseptic and was once used as a  vermifuge  (anti-worm medicine). [ 16 ] [ 17 ]


Contrary to bacteria and fungi, most plant  metabolic pathways  are not grouped into  biosynthetic gene clusters , but instead are scattered as individual genes. Some exceptions have been discovered:  steroidal glycoalkaloids  in  Solanum ,  polyketides  in  Pooideae , benzoxazinoids in  Zea mays ,  triterpenes  in  Avena sativa ,  Cucurbitaceae ,  Arabidopsis , and momilactone diterpenes in  Oryza sativa . [ 18 ]


Plant manufactured Pharmaceuticals  are pharmaceuticals derived from genetically modified plants used as therapeutic compounds. This can be used as the replacement for the traditional method of inoculating animals for  Cell Culture  production. We can use plants to cure and prevent diseases that may have once been deemed incurable. Through biotechnological advancements, we are able to produce complex therapeutic proteins from plant cells. [ 1 ]   Such  Therapeutic Proteins  are seen in brands like Enevrel and  Remicade  for rheumatoid arthritis, Herceptin, a breast cancer treatment. Plants like tobacco are hosts for protein production for applications such as; anemia, hepatitis C & B, hypertension, antimicrobial, and liver disease. [ 1 ] [ 2 ]


With the advancement of Plant Manufactured Pharmaceuticals, comes the advancements of a new type production in industry. Companies such as  ZEA Biosciences  are developing cost-effective and scalable pharmaceutical ingredients using plants instead of cell culture. Unlike cell culture, plants can have a much larger production capacity, a mass quantity of plant hosts on site, and the ability to make specific antibodies that is used as a bio-reactor for specific patient needs. [ 1 ]  Indirectly, the need to grow plants that are being used as Plant Manufactured Pharmaceuticals will increase in geographic areas where certain plants naturally grow, for instance in developing countries. Increasing the need for agricultural societies in developing countries will help certain countries to export and make trade alliance with other countries and with the development of the therapies that can control diseases like  Cholera  and  HIV/AIDS . [ 1 ]


Landscape Gardens that must be grown for the production of the therapeutic proteins brings a new time of recovery for certain patients. Professor Roger Ulrich of Texas A&M University believes that  Therapeutic Gardens  can help the spiritual needs of patients and enhance stress recovery. This relieves the patient of stress and gives the patient a feeling of tranquility during their recovery. [ 1 ]


Many corporations are allowed to create  genetically modified organisms  and secure them through  intellectual property  rights creating monopolies, a fact that continues to evoke criticism . Awareness and education is needed for the public to understand how even GM plants have helped medical research. For instance, in 1992, a group of American students produced a  Hepatitis B  vaccine from a genetically modified  tobacco  plant showing the ability of produce pharmaceutical compounds. [ 1 ]


Stomachic  is a historic term for a medicine that serves to  tone  the  stomach , improving its function and increase appetite.  While many  herbal remedies  claim stomachic effects, modern  pharmacology  does not have an equivalent term for this type of action.


Herbs with putative stomachic effects include: [ citation needed ]


The purported stomachic  mechanism of action  of these substances is to stimulate the appetite by increasing the gastric secretions of the stomach; however, the actual therapeutic value of some of these compounds is dubious.  Some other important agents used are:


Swedish bitters , also called Swedish tincture, is a  bitter  and a traditional herbal tonic, the use of which dates back to the 15th century. [ 1 ]


Swedish bitters is said to have been formulated in a similar way to ancient  bitters  by  Paracelsus  and rediscovered by 18th century Swedish medics Dr.  Klaus Samst  and Dr.  Urban Hjärne , though this appears to be mistaking the latter for his son, Kristian Henrik Hjärne, who himself invented a bitter. [ 2 ]


In modern times, Swedish bitters have been popularized by  Maria Treben , an Austrian herbalist. [ 2 ]  The tonic is claimed to cure a large number of ailments, and to aid digestion. These claims are presented with little in the way of scientific evidence to support them, though  empirical evidence  provides for a very large database of positive results. [ 1 ] [ better source needed ]


The alcoholic  Swedish bitters  is purported to have a similar flavor to   Angostura bitters , though perhaps drier. Nowadays, it is more common to prepare  Swedish bitters  from a dry herbs mixture


The following herbs are added to alcohol to make Swedish bitters:


There are variations on this recipe and herbal shops supply  alcoholic  and non-alcoholic versions of the drink. [ 3 ]


Maria Treben 's book contains nine pages on this bitter, with a description of many ailments and their cures. [ 1 ]


Christophe Wiart  (born August 12, 1967) is a French scientist.


His fields of expertise are  Asian   ethnopharmacology ,  chemotaxonomy  and  ethnobotany . [ 1 ]
He has collected, identified and classified several hundred species of medicinal plants of  India ,  Southeast Asia  and  China . [ 1 ]


Ethnopharmacology of medicinal plants in Asia Pacific; [ 2 ]   bioprospection , collection and identification of medicinal botanical samples and  phytochemical  and  pharmacological  study for the identification of lead compounds as novel  antibacterial ,  anticancer , and  antioxidant  principles from rare plants from the  rainforest  of Southeast Asia. [ 1 ]


Christophe Wiart has authored several books of which:


Dr. Christophe Wiart appeared on HBO's  Vice  in season 3, episode 6 (episode 28 of the series), titled "The Post-Antibiotic World & Indonesia's Palm Bomb." This episode aired on April 17, 2015. [ 5 ]  This episode highlighted the need to find new treatments for infections that were previously treatable with antibiotics, but are now resistant to multiple drugs. “The last hope for the human race’s survival, I believe, is in the rainforests of tropical Asia,” said ethnopharmacologist Dr. Christophe Wiart. “The pharmaceutical wealth of this land is immense.”  [ 6 ]


Pharmacology  is the science of drugs and medications, [ 1 ]  including a substance's origin, composition,  pharmacokinetics ,  pharmacodynamics , therapeutic use, and  toxicology . More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal  biochemical  function. [ 2 ]  If substances have medicinal properties, they are considered  pharmaceuticals .


The field encompasses drug composition and properties, functions, sources, synthesis and  drug design , molecular and cellular  mechanisms , organ/systems mechanisms, signal transduction/cellular communication,  molecular diagnostics ,  interactions ,  chemical biology , therapy, and medical applications and antipathogenic capabilities. The two main areas of pharmacology are  pharmacodynamics  and  pharmacokinetics . Pharmacodynamics studies the effects of a drug on biological systems, and pharmacokinetics studies the effects of biological systems on a drug. In broad terms, pharmacodynamics discusses the chemicals with biological  receptors , and pharmacokinetics discusses the  absorption , distribution,  metabolism , and  excretion  (ADME) of chemicals from the biological systems.


Pharmacology is not synonymous with  pharmacy  and the two terms are frequently confused. Pharmacology, a  biomedical science , deals with the research, discovery, and characterization of chemicals which show biological effects and the elucidation of cellular and organismal function in relation to these chemicals. In contrast, pharmacy, a health services profession, is concerned with the application of the principles learned from pharmacology in its clinical settings; whether it be in a dispensing or clinical care role. In either field, the primary contrast between the two is their distinctions between direct-patient care, pharmacy practice, and the science-oriented research field, driven by pharmacology.


The word  pharmacology  is derived from  Greek  word  φάρμακον ,   pharmakon , meaning "drug" or " poison ", together with another Greek word  -λογία ,  logia  with the meaning of "study of" or "knowledge of" [ 3 ] [ 4 ]  (cf. the  etymology of  pharmacy ). Pharmakon is related to  pharmakos , the ritualistic sacrifice or exile of a human  scapegoat  or victim in  Ancient Greek religion .


The modern term  pharmacon  is used more broadly than the term  drug  because it includes  endogenous  substances, and biologically active substances which are not used as drugs.  Typically it includes pharmacological  agonists  and  antagonists , but also  enzyme  inhibitors (such as  monoamine oxidase  inhibitors). [ 5 ]


The origins of  clinical pharmacology  date back to the  Middle Ages , with  pharmacognosy  and  Avicenna 's  The Canon of Medicine ,  Peter of Spain 's  Commentary on Isaac , and  John of St Amand 's  Commentary on the Antedotary of Nicholas . [ 9 ]  Early pharmacology focused on  herbalism  and natural substances, mainly plant extracts. Medicines were compiled in books called  pharmacopoeias .  Crude drugs  have been used since prehistory as a preparation of substances from natural sources. However, the  active ingredient  of crude drugs are not purified and the substance is adulterated with other substances.


Traditional medicine  varies between cultures and may be specific to a particular culture, such as in traditional  Chinese ,  Mongolian ,  Tibetan  and  Korean medicine . However much of this has since been regarded as  pseudoscience . Pharmacological substances known as  entheogens  may have spiritual and religious use and historical context.


In the 17th century, the English physician  Nicholas Culpeper  translated and used pharmacological texts. Culpeper detailed plants and the conditions they could treat. In the 18th century, much of clinical pharmacology was established by the work of  William Withering . [ 10 ]  Pharmacology as a scientific discipline did not further advance until the mid-19th century amid the great biomedical resurgence of that period. [ 11 ]  Before the second half of the nineteenth century, the remarkable potency and specificity of the actions of drugs such as  morphine ,  quinine  and  digitalis  were explained vaguely and with reference to extraordinary chemical powers and affinities to certain organs or tissues. [ 12 ]  The first pharmacology department was set up by  Rudolf Buchheim  in 1847, at University of Tartu, in recognition of the need to understand how therapeutic drugs and poisons produced their effects. [ 11 ]  Subsequently, the first  pharmacology department  in  England  was set up in 1905 at  University College London .


Pharmacology developed in the 19th century as a biomedical science that applied the principles of scientific experimentation to therapeutic contexts. [ 13 ]  The advancement of research techniques propelled pharmacological research and understanding. The development of the  organ bath  preparation, where tissue samples are connected to recording devices, such as a  myograph , and physiological responses are recorded after drug application, allowed analysis of drugs' effects on tissues. The development of the  ligand binding assay  in 1945 allowed quantification of the  binding affinity  of drugs at chemical targets. [ 14 ]  Modern pharmacologists use techniques from  genetics ,  molecular biology ,  biochemistry , and other advanced tools to transform information about molecular mechanisms and targets into therapies directed against disease, defects or pathogens, and create methods for preventive care, diagnostics, and ultimately  personalized medicine .


The discipline of pharmacology can be divided into many sub disciplines each with a specific focus.


Pharmacology can also focus on specific  systems  comprising the body. Divisions related to bodily systems study the effects of drugs in different systems of the body. These include  neuropharmacology , in the  central  and  peripheral nervous systems ;  immunopharmacology  in the immune system. Other divisions include  cardiovascular ,  renal  and  endocrine  pharmacology.  Psychopharmacology  is the study of the use of drugs that affect the  psyche , mind and behavior (e.g. antidepressants) in treating mental disorders (e.g. depression). [ 15 ] [ 16 ]  It incorporates approaches and techniques from neuropharmacology, animal behavior and behavioral neuroscience, and is interested in the behavioral and neurobiological mechanisms of action of psychoactive drugs. [ citation needed ]  The related field of  neuropsychopharmacology  focuses on the effects of drugs at the overlap between the nervous system and the psyche.


Pharmacometabolomics , also known as pharmacometabonomics, is a field which stems from  metabolomics , the quantification and analysis of  metabolites  produced by the body. [ 17 ] [ 18 ]  It refers to the direct measurement of  metabolites  in an individual's bodily fluids, in order to predict or evaluate the  metabolism  of  pharmaceutical  compounds, and to better understand the pharmacokinetic profile of a drug. [ 17 ] [ 18 ]  Pharmacometabolomics can be applied to measure  metabolite  levels following the administration of a drug, in order to monitor the effects of the drug on metabolic pathways.  Pharmacomicrobiomics  studies the effect of microbiome variations on drug disposition, action, and toxicity. [ 19 ]  Pharmacomicrobiomics is concerned with the interaction between drugs and the gut  microbiome .  Pharmacogenomics  is the application of genomic technologies to  drug discovery  and further characterization of drugs related to an organism's entire genome. [ citation needed ]  For pharmacology regarding individual genes,  pharmacogenetics  studies how genetic variation gives rise to differing responses to drugs. [ citation needed ]   Pharmacoepigenetics  studies the underlying  epigenetic  marking patterns that lead to variation in an individual's response to medical treatment. [ 20 ]


Pharmacology can be applied within clinical sciences.  Clinical pharmacology  is the application of pharmacological methods and principles in the study of drugs in humans. [ 21 ]  An example of this is posology, which is the study of dosage of medicines. [ 22 ]


Pharmacology is closely related to  toxicology . Both pharmacology and toxicology are scientific disciplines that focus on understanding the properties and actions of chemicals. [ 23 ]  However, pharmacology emphasizes the therapeutic effects of chemicals, usually drugs or compounds that could become drugs, whereas toxicology is the study of chemical's adverse effects and risk assessment. [ 23 ]


Pharmacological knowledge is used to advise  pharmacotherapy  in  medicine  and  pharmacy .


Drug discovery  is the field of study concerned with creating new drugs. It encompasses the subfields of  drug design  and  development . [ 24 ]  Drug discovery starts with drug design, which is the  inventive  process of finding new drugs. [ 25 ]  In the most basic sense, this involves the design of molecules that are complementary in  shape  and  charge  to a given biomolecular target. [ 26 ]  After a  lead compound  has been identified through drug discovery, drug development involves bringing the drug to the market. [ 24 ]  Drug discovery is related to  pharmacoeconomics , which is the sub-discipline of  health economics  that considers the value of drugs [ 27 ] [ 28 ]  Pharmacoeconomics evaluates the cost and benefits of drugs in order to guide optimal healthcare resource allocation. [ 29 ]  The techniques used for the  discovery ,  formulation , manufacturing and quality control of drugs discovery is studied by  pharmaceutical engineering , a branch of  engineering . [ 30 ]   Safety pharmacology  specialises in detecting and investigating potential undesirable effects of drugs. [ 31 ]


Development of medication  is a vital concern to  medicine , but also has strong  economical  and  political  implications. To protect the  consumer  and prevent abuse, many governments regulate the manufacture, sale, and administration of medication. In the  United States , the main body that regulates pharmaceuticals is the  Food and Drug Administration ; they enforce  standards  set by the  United States Pharmacopoeia . In the  European Union , the main body that regulates pharmaceuticals is the  EMA , and they enforce standards set by the  European Pharmacopoeia .


The metabolic stability and the reactivity of a library of candidate drug compounds have to be assessed for drug metabolism and toxicological studies. Many methods have been proposed for quantitative predictions in drug metabolism; one example of a recent computational method is SPORCalc. [ 32 ]  A slight alteration to the chemical structure of a medicinal compound could alter its medicinal properties, depending on how the alteration relates to the structure of the substrate or receptor site on which it acts: this is called the structural activity relationship (SAR). When a useful activity has been identified, chemists will make many similar compounds called analogues, to try to maximize the desired medicinal effect(s). This can take anywhere from a few years to a decade or more, and is very expensive. [ 33 ]  One must also determine how safe the medicine is to consume, its stability in the human body and the best form for delivery to the desired organ system, such as tablet or aerosol. After extensive testing, which can take up to six years, the new medicine is ready for marketing and selling. [ 33 ]


Because of these long timescales, and because out of every 5000 potential new medicines typically only one will ever reach the open market, this is an expensive way of doing things, often costing over 1 billion dollars. To recoup this outlay pharmaceutical companies may do a number of things: [ 33 ]


The  inverse benefit law  describes the relationship between a drugs therapeutic benefits and its marketing.


When designing drugs, the  placebo  effect must be considered to assess the drug's true therapeutic value.


Drug development uses techniques from  medicinal chemistry  to chemically design drugs. This overlaps with the biological approach of finding targets and physiological effects.


Pharmacology can be studied in relation to wider contexts than the physiology of individuals. For example,  pharmacoepidemiology  concerns the variations of the effects of drugs in or between populations, it is the bridge between  clinical pharmacology  and  epidemiology . [ 34 ] [ 35 ]   Pharmacoenvironmentology  or environmental pharmacology is the study of the effects of used pharmaceuticals and personal care products (PPCPs) on the environment after their elimination from the body. [ 36 ]  Human health and ecology are intimately related so environmental pharmacology studies the environmental effect of drugs and  pharmaceuticals and personal care products in the environment . [ 37 ]


Drugs may also have ethnocultural importance, so  ethnopharmacology  studies the ethnic and cultural aspects of pharmacology. [ 38 ]


Photopharmacology  is an emerging approach in  medicine  in which drugs are activated and deactivated with  light . The energy of light is used to change for shape and chemical properties of the drug, resulting in different biological activity. [ 39 ]  This is done to ultimately achieve control when and where drugs are active in a reversible manner, to prevent  side effects  and pollution of drugs into the environment. [ 40 ] [ 41 ]


The study of chemicals requires intimate knowledge of the biological system affected. With the knowledge of  cell biology  and  biochemistry  increasing, the field of pharmacology has also changed substantially. It has become possible, through molecular analysis of  receptors , to design chemicals that act on specific cellular signaling or  metabolic pathways  by affecting sites directly on cell-surface receptors (which modulate and mediate cellular signaling pathways controlling cellular function).


Chemicals can have pharmacologically relevant properties and effects.  Pharmacokinetics  describes the effect of the body on the chemical (e.g.  half-life  and  volume of distribution ), and  pharmacodynamics  describes the chemical's effect on the body (desired or  toxic ).


Pharmacology is typically studied with respect to particular systems, for example endogenous  neurotransmitter systems . The major systems studied in pharmacology can be categorised by their  ligands  and include  acetylcholine ,  adrenaline ,  glutamate ,  GABA ,  dopamine ,  histamine ,  serotonin ,  cannabinoid  and  opioid .


Molecular targets in pharmacology include  receptors ,  enzymes  and  membrane transport proteins . Enzymes can be targeted with  enzyme inhibitors . Receptors are typically categorised based on structure and function. Major receptor types studied in pharmacology include  G protein coupled receptors ,  ligand gated ion channels  and  receptor tyrosine kinases .


Network pharmacology is a subfield of pharmacology that combines principles from pharmacology, systems biology, and network analysis to study the complex interactions between drugs and targets (e.g., receptors or enzymes etc.) in biological systems. The topology of a biochemical reaction network determines the shape of drug  dose-response curve [ 42 ]  as well as the type of drug-drug interactions, [ 43 ]  thus can help designing efficient and safe therapeutic strategies. The topology Network pharmacology utilizes computational tools and network analysis algorithms to identify drug targets, predict drug-drug interactions, elucidate signaling pathways, and explore the polypharmacology of drugs.


Pharmacodynamics is defined as how the body reacts to the drugs. Pharmacodynamics theory often investigates the  binding affinity  of  ligands  to their receptors. Ligands can be  agonists , partial agonists or  antagonists  at specific receptors in the body. Agonists bind to receptors and produce a biological response, a partial agonist produces a biological response lower than that of a full agonist, antagonists have affinity for a receptor but do not produce a biological response.


The ability of a ligand to produce a biological response is termed  efficacy , in a dose-response profile it is indicated as percentage on the y-axis, where 100% is the maximal efficacy (all receptors are occupied).


Binding affinity is the ability of a ligand to form a ligand-receptor complex either through  weak attractive forces  (reversible) or  covalent bond  (irreversible), therefore efficacy is dependent on binding affinity.


Potency  of drug is the measure of its effectiveness,  EC 50  is the drug concentration of a drug that produces an efficacy of 50% and the lower the concentration the higher the potency of the drug therefore EC 50  can be used to compare potencies of drugs.


Medication is said to have a narrow or wide  therapeutic index ,   certain safety factor  or  therapeutic window . This describes the ratio of desired effect to toxic effect. A compound with a narrow therapeutic index (close to one) exerts its desired effect at a dose close to its toxic dose. A compound with a wide therapeutic index (greater than five) exerts its desired effect at a dose substantially below its toxic dose. Those with a narrow margin are more difficult to dose and administer, and may require  therapeutic drug monitoring  (examples are  warfarin , some  antiepileptics ,  aminoglycoside   antibiotics ). Most anti- cancer  drugs have a narrow therapeutic margin: toxic side-effects are almost always encountered at doses used to kill  tumors .


The effect of drugs can be described with  Loewe additivity  which is one of several common reference models. [ 43 ]


Other models include the  Hill equation ,  Cheng-Prusoff equation  and  Schild regression .


Pharmacokinetics  is the study of the bodily absorption, distribution, metabolism, and excretion of drugs. [ 44 ]


When describing the pharmacokinetic properties of the chemical that is the active ingredient or  active pharmaceutical ingredient  (API), pharmacologists are often interested in  L-ADME :


Drug metabolism  is assessed in pharmacokinetics and is important in drug research and prescribing.


Pharmacokinetics is the movement of the drug in the body, it is usually described as 'what the body does to the drug' the physico-chemical properties of a drug will affect the rate and extent of absorption, extent of distribution, metabolism and elimination. The drug needs to have the appropriate molecular weight, polarity etc. in order to be absorbed, the fraction of a drug the reaches the systemic circulation is termed bioavailability, this is simply a ratio of the peak plasma drug levels after oral administration and the drug concentration after an IV administration(first pass effect is avoided and therefore no amount drug is lost). A drug must be lipophilic (lipid soluble) in order to pass through biological membranes this is true because biological membranes are made up of a lipid bilayer (phospholipids etc.) Once the drug reaches the blood circulation it is then distributed throughout the body and being more concentrated in highly perfused organs.


In the  United States , the  Food and Drug Administration  (FDA) is responsible for creating guidelines for the approval and use of drugs. The FDA requires that all approved drugs fulfill two requirements:


Gaining FDA approval usually takes several years. Testing done on animals must be extensive and must include several species to help in the evaluation of both the effectiveness and toxicity of the drug. The dosage of any drug approved for use is intended to fall within a range in which the drug produces a  therapeutic effect  or desired outcome. [ 45 ]


The safety and effectiveness of prescription drugs in the U.S. are regulated by the federal  Prescription Drug Marketing Act of 1987 .


The  Medicines and Healthcare products Regulatory Agency  (MHRA) has a similar role in the UK.


Medicare Part D  is a prescription drug plan in the U.S.


The  Prescription Drug Marketing Act (PDMA)  is an act related to drug policy.


Prescription drugs  are drugs regulated by legislation.


The  International Union of Basic and Clinical Pharmacology ,  Federation of European Pharmacological Societies  and  European Association for Clinical Pharmacology and Therapeutics  are organisations representing standardisation and regulation of clinical and scientific pharmacology.


Systems for  medical classification  of drugs with  pharmaceutical codes  have been developed. These include the  National Drug Code  (NDC), administered by  Food and Drug Administration .; [ 46 ]   Drug Identification Number  (DIN), administered by  Health Canada  under the  Food and Drugs Act ;  Hong Kong Drug Registration , administered by the Pharmaceutical Service of the  Department of Health (Hong Kong)  and  National Pharmaceutical Product Index  in South Africa. Hierarchical systems have also been developed, including the  Anatomical Therapeutic Chemical Classification System  (AT, or ATC/DDD), administered by  World Health Organization ;  Generic Product Identifier  (GPI), a hierarchical classification number published by MediSpan and  SNOMED , C axis. Ingredients of drugs have been categorised by  Unique Ingredient Identifier .


The study of pharmacology overlaps with  biomedical sciences  and is the study of the effects of drugs on living organisms. Pharmacological research can lead to new drug discoveries, and promote a better understanding of human  physiology . Students of pharmacology must have a detailed working knowledge of aspects in physiology, pathology, and chemistry. They may also require knowledge of plants as sources of pharmacologically active compounds. [ 38 ]   Modern pharmacology is interdisciplinary and involves biophysical and computational sciences, and analytical chemistry. A pharmacist needs to be well-equipped with knowledge on pharmacology for application in pharmaceutical research or pharmacy practice in hospitals or commercial organisations selling to customers. Pharmacologists, however, usually work in a laboratory undertaking research or development of new products. Pharmacological research is important in academic research (medical and non-medical), private industrial positions, science writing, scientific patents and law, consultation, biotech and pharmaceutical employment, the alcohol industry, food industry, forensics/law enforcement, public health, and environmental/ecological sciences. Pharmacology is often taught to pharmacy and medicine students as part of a  Medical School  curriculum.


An  active ingredient  is any  ingredient  that provides  biologically active  or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the body of humans or animals. [ 1 ]


The similar terms  active pharmaceutical ingredient  (abbreviated as  API ) and  bulk active  are also used in medicine. [ 2 ] [ 3 ]  The term  active substance  may be used to describe the effective chemical used to control bacteria or pests. [ 4 ]


Some medication products can contain more than one active ingredient. The traditional word for the active pharmaceutical agent is  pharmacon  or  pharmakon  (from  Greek :  φάρμακον , adapted from  pharmacos ) which originally denoted a  magical substance  or drug. [ citation needed ]


The terms  active constituent  or  active principle  are often chosen when referring to the active  substance  of interest in a plant (such as  salicylic acid  in  willow  bark or  arecoline  in  areca nuts ), since the word "ingredient" can be taken to  connote  a sense of human agency (that is, something that a person combines with other substances), whereas the natural products present in plants were not added by any human agency but rather occurred naturally ("a plant doesn't have ingredients").


In contrast with the active ingredients, the inactive ingredients are usually called  excipients  in pharmaceutical contexts. The main excipient that serves as a medium for conveying the active ingredient is usually called the  vehicle . For example,  petrolatum  and  mineral oil  are common vehicles. The term 'inactive' should not, however, be misconstrued as meaning  inert . [ 5 ]


The  dosage form  for a pharmaceutical contains the active pharmaceutical ingredient, which is the drug substance itself, and  excipients , which are the ingredients of the tablet, or the liquid in which the active agent is suspended, or other material that is pharmaceutically inert. Drugs are chosen primarily for their active ingredients.


Patients often have difficulty identifying the active ingredients in their medication, as well as being unaware of the notion of an active ingredient. When patients are on multiple medications, active ingredients can interfere with each other, often resulting in severe or life-threatening complications. [ 6 ]


Many online services can help identify the active ingredient of most medications, such as the Medicines Database providing information on medications available in Australia. [ 7 ]


In phytopharmaceutical or  herbal medicine , the active ingredient may be either unknown or may require  cofactors  in order to achieve therapeutic goals. This leads to complications in labelling. One way manufacturers have attempted to indicate strength is to engage in  standardization  to a  marker  compound. Standardization has not been achieved yet, however, with different companies using different markers, or different levels of the same markers, or different methods of testing for marker compounds. For example,  St John's wort  is often standardized to the  hypericin  that is now known not to be the "active ingredient" for  antidepressant  use.  Other companies standardize to  hyperforin  or both, ignoring some 24 known additional possible active constituents. Many herbalists believe that the active ingredient in a plant is the plant itself. [ 8 ]


Additive effect  in  pharmacology  describes the situation when the combining effects of two drugs equal the sum of the effects of the two drugs acting independently. [ 1 ] [ 2 ]  The concept of additive effect is derived from the concept of  synergy . It was introduced by the scientists in pharmacology and  biochemistry  fields in the process of understanding the synergistic interaction between drugs and chemicals over the century.


Additive effect often occurs when two similar drugs are taken together to achieve the same degree of therapeutic effect while reducing the specific  adverse effect  of one particular drug. For example,  aspirin, paracetamol, and caffeine  are formulated together to treat pain caused by tension headaches and  migraine .


Additive effect can be used to detect synergy as it can be considered as the baseline effect in methods determining whether drugs have synergistic effect. Synergistic effect is similar to additive effect, having a combination effect greater than additive effect. It can produce an effect of 2+2 > 4 when two drugs are used together. Additive effect can also be found in a majority of  combination therapies , although synergistic effect is more common. If the combination of two drugs in combination therapy has an effect lower than the sum of the effects of the two drugs acting independently, also known as  antagonistic effect , the drugs will seldom be prescribed together in the same therapy.


Drug or chemical combinations with additive effects can cause adverse effects. For example, co-administration of  non-steroidal anti-inflammatory drugs  (NSAIDs) and  glucocorticoids  increases the risk of gastric bleeding. [ 3 ]


The concept of additive effect is derived from the concept of drug synergy. Thus, the origin of additive effect dates back to the early twentieth century when the search for synergy started. During the search for synergy, the models of  Loewe additivity  and  Bliss independence  were proposed. [ 4 ]  These models are capable of measuring the effects of drug combinations. Hence, Loewe additivity and Bliss independence were developed to determine whether an effect of a drug combination is synergistic or antagonistic. During the construction of these models, the concept of additive effect was introduced as the baseline for the determination of synergy and antagonism.


Additive effects can occur with drugs with either equivalent or overlapping actions, or independent actions.


Many of the drugs in the same class exert additive effect as they have a similar therapeutic  mechanism of action . For example, the  calcium carbonate ,  magnesium , and  aluminium  salts are all  antacids  with the mechanism of using the  negative ion  to  neutralize  the acid in the stomach. [ 5 ]  The antacids have no interaction between them, so they would be considered to have additive effect when taken together.


Drugs that are in the same class, but do not have the same target, may also act additively by interacting with different targets in the same pathway. For example,  propofol  and  sevoflurane  can both produce  anesthetic effects . [ 6 ]  Propofol can potentiate the activity of  GABA A  receptor  and act on α, β and γ subunits, [ 7 ] [ 8 ] [ 9 ]  while sevoflurane enhances the response of the GABA A  receptor to endogenous GABA by binding to the α1-subunit. [ 10 ]  By using Dixon up-down method, a trial has shown that the effect in producing anesthetic effects between propofol and sevoflurane is additive. [ 11 ]


Two drugs having different targets in unrelated pathways that ultimately result in the desired therapeutic result are considered to have additive effects with independent actions. For example,  artemisinin  and  curcumin  both exert  antimalarial  effects. Artemisinin works by being metabolized in the body into active metabolites. The metabolites would then create  reactive oxygen species(ROS)  that damage the parasites and kill them. [ 12 ]  The mechanism of action of curcumin remains largely unknown, but the antiparasitic effect is believed to be associated with the potentiation of innate and adaptive  immunological responses . [ 13 ] [ 14 ]  The combined effects of artemisinin and curcumin each contribute to the death of parasites via different mechanisms and the effect is shown to be additive by fractional inhibitory concentrations. [ 15 ]


Drugs with the same target in different sites that produce additive effects are also considered as independent action. For example,  doxorubicin  and  trabectedin  can both produce  anticancer effect . [ 16 ]  Doxorubicin is a  DNA intercalator  that prefers to bind to AT regions, [ 17 ]  while trabectedin forms  guanine  adduct in DNA to disrupt DNA repair system. [ 18 ]  A recent study has shown that doxorubicin and trabectedin do not hinder each other and could produce an additive anticancer effect. [ 19 ]


The concept of additive effect is analogous to the concept of simple addition in mathematics. However, the additive effect is not simply the  arithmetic summation  of two (or more) drugs in most cases. [ 20 ]  For an additive inhibition effect, drug A and drug B could each inhibit 20% individually, but the additive effect is not 40%. The effect cannot be simply arithmetic because if drug A and drug B each inhibits 60% cannot theoretically exert an inhibitory effect of 120%. With 60% inhibitory effect each, the remaining function would be at (1-60%)×(1-60%)=16%, meaning the additive inhibitory effect would be 84%. Since the application of additive effect is commonly seen in clinical practice, avoiding the common misconceptions of additive effect is crucial to understanding the clinical significance of additive effect. [ citation needed ]


One of the typical uses of additive effect is to detect synergy. [ 21 ]  Additive effect can be considered as the baseline effect in methods of determining the presence of synergistic effect between two or more drugs. Synergistic effect is similar to additive effect. The only difference is it has a combination effect greater than additive effect. To be brief, synergy can produce an effect of 2 + 2 > 4 when drugs are used in combination. [ 22 ]  The combination of  angiotensin II receptor antagonist (ARB) ,  Candesartan-cilexetil , and  angiotensin-converting enzyme inhibitor (ACEI) , Ramipril, demonstrates a synergistic effect in reducing  systolic blood pressure . [ 23 ]


The other use of additive effect is to detect antagonism. Similarly, additive effect can be considered as the baseline effect in methods of determining the presence of antagonistic effect between drugs. Pharmacists can confirm the presence of antagonism when the combination effect of drugs is less than additive effect. The combination of  acetylsalicylic acid  and  ibuprofen  demonstrates an antagonistic effect in relieving pain and  inflammation . [ 3 ]


The most common clinical usage of additive effect in pharmacology is combination therapy. Two or more therapeutic agents are used in combination therapy to treat a single disease. Different drugs in the same combination therapy act on different biological and biochemical pathways in the body to produce an additive effect.


An example of combination therapy demonstrating additive effect is the use of  β-2 adrenergic receptor agonists  together with  inhaled corticosteroids . This is a treatment for two commonly seen  pulmonary diseases ,  asthma  and  chronic obstructive pulmonary disease . β-2 adrenergic receptor agonists act as  bronchodilators , having an effect of inducing bronchodilation to relieve bronchoconstriction; Inhaled corticosteroids act as anti-inflammatory drugs to decrease the inflammatory response. The two drugs act on different sites in the body. The corticosteroids also reverse and restore the function and number of β-2 adrenergic receptors in patients’ lungs  in vivo . Meanwhile, the combined activity of two drugs resolves the problem of reduced sensitivity in some patients with chronic obstructive pulmonary disease towards inhaled corticosteroids. [ 24 ]  A common drug from this example can be found is  Seretide® , containing a long-acting β-2 adrenergic receptor agonist named as  Salmeterol  and a corticosteroid named as  Fluticasone . [ 25 ]


Additive interaction can also be found in combination therapy for treating  hypertension . The combination of angiotensin II receptor blockers (ARBs) and  calcium channel blockers  (CCBs) is one of the suggested antihypertensive therapies. ARBs inhibit the action of  angiotensin II  to decrease fluid retention and blood volume to decrease blood pressure, reduce  vasoconstriction  to decrease  peripheral vascular resistance , and prevent vascular  fibrosis  to decrease vascular stiffness. CCBs are  vasodilators  inhibiting  L-type voltage-operated calcium channels  in the blood vessels to alleviate vasoconstriction resulting in a decrease in peripheral vascular resistance. The two types of drugs act on different pathways to produce an additive effect on lowering blood pressure without any increase in adverse effects. [ 26 ]  This combination, with ARB,  valsartan , and CCB,  amlodipine , is a common treatment in high-risk hypertensive patients, especially the elderly. [ 27 ]


The treatment for another common disease, primary  hypercholesterolemia , also demonstrates additive effect. Plant sterol-ester margarine and a common type of  antihyperlipidaemic  drug,  cerivastatin , have an additive effect in reducing  LDL cholesterol , without significant interaction between the two drugs. [ 28 ]  Another drug combination with additive effect for hypercholesterolemia is  niacin  ( vitamin B3 ) and  simvastatin . This drug combination is also known as  Simcor  commercially. Niacin can reduce the secretion of LDL cholesterol and very-low-density lipoprotein cholesterol (VLDL cholesterol). On the other hand, simvastatin can reduce the synthesis of LDL cholesterol and  triglycerides , and increase the level of  high-density lipoprotein cholesterol (HDL cholesterol) . Together, niacin and simvastatin reduce the level of LDL cholesterol and increases the level of HDL cholesterol, [ 23 ]  therefore managing hypercholesterolemia effectively.


Additive interaction or additive effect can be found in the treatment of the majority of common diseases. The combination of drugs with different effects has the benefit of using each drug at its optimal dose. [ 29 ]  This decreases the possibility of using a higher dose of a single medication if the previous dose is ineffective in treating diseases or relieving symptoms. The significance of using drugs with optimal dose is lowering the occurrence of intolerable side effects, adverse reactions, and possible  drug toxicity  in patient's body. This increases the safe use of drugs and increases patient compliance with the therapy. [ 30 ]


One of the examples is the use of calcium channel blocker and beta-blocker. They are drugs that can be used to treat stable  angina . They can both decrease the frequency of angina, aiming to relieve the symptoms of angina. There are controlled, double blind clinical trials and studies involving patients with preserved left ventricular function demonstrating that the combination of calcium channel blocker and beta blocker has an additive cardio depressant effects when comparing with either drug class alone. [ 31 ]  The combination therapy is used when a single medication fails to produce a therapeutic effect. Choosing the optimal dose of the two medications in the combination therapy prevents the use of an extreme high dose of a single medication alone, leading to adverse effects.


Drug combinations with additive effects have the potential to cause adverse effects. Adverse effects induced by drug combinations are not uncommon. The risk of having adverse effects is increased when the drug combination with additive effect has the same adverse effect. Thus, some drug combinations with additive effect are avoided. Below are commonly seen drug combinations with additive effect causing adverse effects.


An example demonstrating how drug combination with additive effect can cause adverse effects is the co-administration of ACEI and  potassium-sparing diuretics . [ 3 ]  Despite having different mechanisms of action, the drugs are able to reduce potassium excretion from the body. Hence, both ACEI and potassium-sparing diuretics have the side effect of  hyperkalemia . When two drugs are used together, the risk of having hyperkalemia is doubled. Since hyperkalemia has the potential to cause  arrhythmia  and  metabolic acidosis , the combination of ACEI and potassium-sparing diuretics is avoided.


Another example is the combination of non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids. [ 3 ]  Although NSAIDs and glucocorticoids have different mechanisms of action, the drugs are able to diminish the protective effect of gastric mucosa from gastric acid. [ 32 ] [ 33 ]  As a result, the concomitant use of NSAIDs and glucocorticoids increases the risk of gastric bleeding and worsens  peptic ulcer disease . As a result, the combination of NSAIDs and glucocorticoids is not recommended.


The  Antica Farmacia Sant'Anna  (Italian for “Ancient Pharmacy of Saint Anne”) is a  pharmacy  and  herbal medicine   dispensary  in  Genoa , Italy, located in the quarter of  Castelletto . Founded by the  Discalced Carmelites  friars of the annex  Convent of Sant’Anna  in 1650, it is the oldest commercial establishment still operating in Genoa [ 1 ]  and the only instance in Italy of a fully licensed pharmacy owned and operated by a religious institution. [ 2 ] [ 3 ]  While its ancient furniture and instruments are listed and protected as  cultural heritage , [ 4 ]  its modern  laboratories  are equipped with  state-of-the-art  technology for the preparation of medicines,  Galenic formulations ,  herbal medicine  products,  lotions , cosmetics and  dietary supplements  under the supervision of legally qualified personnel. [ 2 ]


The  Convent of Sant’Anna  is the first foundation of the  Discalced Carmelites  outside of Spain, established in 1584 under the impulse of father Nicolas of Jesus and Mary Doria, a descendant of the prominent Doria family . Returned from Spain twenty years after the reformation of the  Carmelite Order  operated by  Saint Theresa of Avila  and  Saint John of the Cross , Father Doria established a monastery in his native city with the financial support of the noble families Doria,  Cattaneo ,  Spinola  e  Pallavicini .


Soon after the foundation of the convent, the friars opened the pharmacy. [ 5 ]  At the end of the 16th century, one of the  cloisters  of the convent, presently known as 'the Cloister of the Roses', was used for the cultivation of curative  herbs .  Potatoes  imported from the Americas were planted there for the very first time on Italian soil, after the founder Father Doria had seen them at the court of  Philip II King of Spain . [ 5 ]


In the 17th century, noble and wealthy citizens usually resorted to a medical doctor in case of illness, while the underprivileged layers of society would usually seek medical support from religious institutions. By the mid-century Sant'Anna likely had a high influx of patients: testimony thereof is the construction of a large  wing  dedicated to the preparation and dispensation of medicines, separate from the friar's quarters. [ 6 ]


The oldest document mentioning the pharmacy, dated 1650, is stored at the  Vatican Apostolic Archives . [ 2 ]  Another document, dated 1652 and stored in the archives of the Convent of Sant'Anna, shows that the chief  chemist , brother Martino of Saint Anthony (1638–1721), would  "go out every day to procure the ingredients for the medications [...], many patients came to him and not everyone could be healed in the same way [...], hence it was necessary to prepare different potions, medicines,and poultices" . [ 7 ]


According to the historical registers of the pharmacy, a contract redacted in 1778 mentions that the Genoese surgeon and chemist Lorenzo Robello was tasked to procure ingredients for the pharmacy, prepare the medicines and administer them " to the friars and to external patients ". At that time it was not possible to find a friar with the necessary qualifications; the resolve of the Carmelite Order, however, remained that the pharmacy was to be run primarily by friars and, by 1792, the fully-qualified chemist friar Giovanni della Croce assumed the direction of the pharmacy, updated its equipment and furnished the dispensary room with the  boiserie  which is still visible today. [ 2 ]


After the  annexation  of the Republic of Genoa to the  Kingdom of Sardinia  at the beginning of the 19th century, the pharmacy was further refurbished by brother Bernardino di Sant'Anna. [ 2 ]


In those years, the Pharmacy started a cooperation with the famous  Parisian  surgeon Louis Le Roy, author of the  treatise   Healing Medicine, aka Purgation , translated in Italian for the first time in  Bologna  in 1824. Although its content was later superseded by improvement in scientific research, the treatise enjoyed a great success at the time and was reprinted several times. A Genoese reprint in 1885 mentioned the cooperation with Sant'Anna's pharmacy in the back cover. [ 7 ]


A document stored in the library of the Convent shows that brother Modesto, whose lay name was Stefano Montabone, received his diploma of chemist in 1840, granting him permission to practice his profession in Genoa and all other territories of the Kingdom of Sardinia in accordance to  letter patents  issued by King  Victor Emmanuel I of Savoy . In 1882, however, the difficulties in securing chemist friars with appropriate legal  qualifications  appeared insurmountable. Therefore, keen to remain licensed according to the law, the Convent of Sant'Anna decided to enact a compromise solution and appointed a lay chemist " to   ensure the regular preparation and administration of the medicines ", while the  business administration  of the pharmacy remained entrusted to a friar. [ 2 ]


At the end of the 19th century, the pharmacy had several prominent clients, including the main hospital of Genoa, the hospital of Pammatone. At the time, the most sought after products were  white sugar ,  quinine , English  salts ,  cinnamomum ,  rosolio ,  poppyseed  oil, medicines against  parasites  and a medicine against  demodicosis . [ 7 ]


At the end of the 19th century, the construction of the wealthy neighborhood of Circonvallazione a Monte significantly altered the area, when Corso Magenta and the  Sant'Anna funicular  were built immediately to the South of the convent. The religious buildings and the quaint village in which they are located have nonetheless remained intact and quiet to this day. [ 8 ] [ 9 ]


The Pharmacy is still active today. Several ancient recipes are still prepared and updated when necessary. The laboratories have been refurbished to reflect modern needs and the latest regulatory requirements. [ 6 ]


After 1933, the Convent, the church and the pharmacy of Sant'Anna are accessible also with an elevator from the tunnel which connects Corso Magenta with the  Elevator Magenta-Crocco . [ 10 ]


Autopharmacology  relates to the  scientific  study of the  regulation  of body functions by the activity of its naturally existent (or  endogenous ) chemical factors of the  tissues . A more restricted definition would consider substances that were first identified as external agents which had a documented action on  physiological  functions, but later were discovered as existing as endogenous factors. [ 1 ]  The best example is the class of  endorphins , which, as its name implies, were discovered to exist in the  brain  and have specific  receptors  in it, [ 2 ]  by investigations on the mechanism of action of  opioids , such as  morphine .


Historically, the first approach to the concept of autopharmacology began with  British   physiologist  and  pharmacologist   Henry Dale  in the 1910s, discovered the role of  acetylcholine  in  synaptic transmission , [ 3 ]  and later proved by  Austrian  physiologist  Otto Loewi , to be the  neurotransmitter  involved in the proximal synapses of the  autonomic nervous system  (initially named  Vagusstoff  by Loewi, and later identified as acetylcholine). The same happened to another autonomic neurotransmitter,  noradrenaline  ( Akzeleransstoff  by Loewi), which later proved to be chemically similar to a long used pharmacological agent,  adrenaline , a hormone secreted by the  adrenal glands . Both scientists were awarded the 1936  Nobel Prize for Physiology or Medicine  for their pioneering and important contributions.


A research area where autopharmacology principles assumed great importance was that of  pain  and  inflammation , [ 4 ]  due to the great number of endogenous messengers, transmitters and modulators involved in their complex response at molecular and cellular level. The control and regulation mechanisms of the  circulatory system  and  renal  functions and their interactions (such as the  renin/angiotensin system ) are also greatly influenced by autopharmacological agents; One of the autopharmacology pioneers was Professor  Mauricio Rocha e Silva , leader of the team of  Brazilian  researchers who discovered  bradykinin  in 1948, an endogenous substance involved in  hypotension  in  circulatory shock . [ 5 ]  Of course, all these systems are of extreme importance for  clinical practice  and for the discovery of new  therapeutic drugs .


Endogenous substances that could fall under the concept of autopharmacology are:


The main scientific criterion for an autopharmacological agent is the discovery of specific membrane receptors for it and, hopefully, its  transduction  and  cell signaling  mechanisms.


The term was never much of a mainstream concept, and has fallen into disuse, as research on basic mechanisms has advanced. In a  recent literature search  on  PubMed , only six titles refer to the term  autopharmacology .


A  bioassay  is an analytical method to determine the potency or effect of a substance by its effect on  living animals  or plants ( in vivo ), or on living cells or tissues ( in vitro ). [ 1 ] [ 2 ]  A bioassay can be either quantal or quantitative, direct or indirect. [ 3 ]  If the measured response is binary, the assay is  quantal ; if not, it is  quantitative . [ 3 ]


A bioassay may be used to detect biological hazards or to give an assessment of the quality of a mixture. [ 4 ]  A bioassay is often used to monitor  water quality  as well as  wastewater  discharges and its impact on the surroundings. [ 5 ]  It is also used to assess the environmental impact and safety of new technologies and facilities. [ citation needed ]


Bioassays are essential in pharmaceutical, medical and agricultural sciences for development and launching of new drugs, vitamins, etc.


A bioassay is a biochemical test to estimate the potency of a sample compound. Usually this potency can only be measured relative to a standard compound. [ 3 ] [ 1 ]  A typical bioassay involves a  stimulus  (ex. drugs) applied to a  subject  (ex. animals, tissues, plants). The corresponding  response  (ex. death) of the subject is thereby triggered and measured. [ 6 ]


The first use of a bioassay dates back to the late 19th century, when the foundation of bioassays was laid down by German physician Paul Ehrlich. [ 7 ]  He introduced the concept of standardization by the reactions of living matter. [ 7 ] [ 6 ]  His bioassay on  diphtheria  antitoxin was the first bioassay to receive recognition. [ 8 ]  His use of bioassay was able to discover that administration of gradually increasing dose of diphtheria in animals stimulated production of antiserum. [ 9 ]


One well known example of a bioassay is the "canary in the coal mine" experiment. [ 10 ]  To provide advance warning of dangerous levels of methane in the air, miners would take methane-sensitive canaries into coal mines. If the canary died due to a build-up of methane, the miners would leave the area as quickly as possible.


Many early examples of bioassays used animals to test the   carcinogenicity  of chemicals. [ 11 ]  In 1915,  Yamaigiwa Katsusaburo  and Koichi Ichikawa tested the carcinogenicity of coal tar using the inner surface of rabbit's ears. [ 11 ]


From the 1940s to the 1960s, animal bioassays were primarily used to test the toxicity and safety of drugs, food additives, and pesticides. [ 11 ]


Beginning in the late 1960s and 1970s, reliance on bioassays increased as public concern for occupational and environmental hazards increased. [ 11 ]


Bioassay can be classified by how it is applied and how the response is recorded.


One classical bioassay is the  Ames test . A strain of  Salmonella  that requires histidine to grow is put on two plates with growth medium containing minimal amounts of histidine and some rat liver extract (to mimick liver metabolism). A suspected  mutagen  is added to one plate. If the plate with the suspected mutagen grows more visible colonies, it is probably mutagenic: a mutagen might cause the strain of bacterium to regain the ability to make its own histidine. [ 13 ]