Most drugs were discovered by empirical means, including observation, accident, and trial and error. [ 6 ]  One famous example is the  discovery of penicillin , the first  antibiotic  in the world. The substance was discovered by  Alexander Fleming  in 1928 after a combination of unanticipated events occurred in his laboratory during his summer vacation. [ 8 ]  The  Penicillium  mold on the  petri dish  was believed to secrete a substance (later named "penicillin") that inhibited bacterial growth. [ 8 ]  Large pharmaceutical companies then started to establish their microbiological departments and search for new antibiotics. [ 9 ]  The screening program for antimicrobial compounds also led to the discovery of drugs with other pharmacological properties, such as  immunosuppressants  like  Cyclosporin A . [ 9 ]


The discovery of  penicillin  was a  serendipitous  (i.e. chance) discovery. Another, more advanced approach to drug discovery is  rational drug design . The method is underpinned by an understanding of the biological targets of the drugs, including  enzymes ,  receptors , and other proteins. In the late 19th century,  Paul Ehrlich  observed the selective affinity of dyes for different  tissues  and proposed the existence of  chemoreceptors  in our bodies. [ 9 ] [ 10 ]  Receptors were believed to be the specific binding sites for drugs. [ 9 ]  The drug-receptor recognition was described as a key-and-lock interplay by  Emil Fischer  in the early 1890s. [ 11 ]  It was later found that the receptors can either be stimulated or inhibited by chemotherapeutic agents to attain the desired physiological response. [ 9 ]  Once the  ligand  interacting with the target macromolecule is identified, drug candidates can be designed and optimized based on the  structure-activity relationship . [ 11 ]  Nowadays, artificial intelligence is employed in drug design to predict drug-protein interactions, drug activity, the 3D configuration of  proteins , etc. [ 11 ]


Evidence-based medicine  is defined as deploying the best current scientific evidence that is available to give the best treatment and make the best decision effectively and efficiently. [ 12 ]  Clinical guidelines are developed based on scientific evidence; for example, the  ACC / AHA  guidelines (for  cardiovascular diseases ), the GOLD guidelines (for  chronic obstructive pulmonary disease ), the GINA guidelines (for  asthma ), etc. They convert and classify the evidence using a systematic method, aiming to provide care with quality. [ 13 ]  The guidelines cannot substitute clinical judgment, as they cannot meet all the circumstances. [ 13 ]  Healthcare professionals can use the  clinical guidelines  as references or evidence to support their clinical judgement when prescribing therapy to patients.


Example: Clinical Guideline for controlling blood pressure ( hypertension )


If there is an Asian male patient who is 40 years old and has recently been diagnosed with high blood pressure (with a blood pressure of 140/90) and without any other  chronic diseases  ( comorbidities ), such as  type-2 diabetes ,  gout ,  benign prostatic hyperplasia , etc. His estimated 10-year risk of cardiovascular disease is 15%.


According to the  NICE  2019 Hypertension guideline, the healthcare professional can consider starting anti-hypertensive therapy after a discussion with the patient. [ 14 ]  The first-line therapy will be either an  Angiotensin Converting Enzyme Inhibitor (ACEi)  or an  Angiotensin receptor blocker (ARB)  (if the patient cannot tolerate ACEi). [ 14 ]  If the blood pressure of the patient is not well controlled, the healthcare professionals can consider adding a  calcium channel blocker (CCB) [ 15 ]  or a  Thiazide-like diuretic  to the previous therapy, i,e, ACEi or ARBs with a CCB or a thiazide-like diuretic. [ 14 ]


Every patient has their own body condition, for example, kidney function, liver function, genetic variations, medical history, etc. These are all the factors that should be considered by healthcare professionals before giving any pharmacological therapy. Most importantly, the advancing technology in  genetics  guides us to have more insight into the linkage between health and genes. [ 16 ]  In pharmacological therapy, two areas of study are evolving:  pharmacogenetics  and  pharmacogenomics .  Age will affect the  pharmacokinetics  and  pharmacodynamics  of drugs, and hence the efficacy of the therapy. The effect of age causes deterioration of organ function, [ 17 ]  like liver function and kidney function.  Pharmacokinetics  is the study of drugs' effects on absorption, distribution, metabolism, and elimination.  Pharmacodynamics  is the study of drugs' effects on our body and their mechanisms.


Pharmacogenetics  is defined as the study of inherited genes causing different  drug metabolisms  that vary from each other, such as the rate of metabolism and metabolites. [ 18 ]   Pharmacogenomics  is defined as the study of associating the drug response with one's  gene . [ 19 ]  Both terms are similar in nature, so they are used interchangeably.


Multiple  alleles  can contribute together to a change in response to a drug by expressing a different form of an  enzyme  that responds differently than the normal ones. [ 18 ]  The different forms of  enzymes  ( phenotypes ) include ultra-rapid metabolizers, moderate metabolizers, no-enzyme activity, etc. The  genetic variations  can also be used to match the particular  adverse drug reaction  in order to prevent the patient from suffering the unfavorable outcomes. [ 20 ]  The genetic make-up can affect the  pharmacokinetics .


Azathioprine  is an  immunomodulator  for  inflammatory bowel disease , for instance. Its  metabolite  relies on two different  enzymes  ( TPMT  and  NUDT15 ) to eliminate its effect on our body during its  metabolism . If the patient has the  phenotype  of the  enzymes  that metabolize it poorly, i.e., the poor metabolizer, more toxic metabolites are accumulated in the body. Thus, the patient has a greater risk of the related side-effect. [ 21 ]  The side effect causes the adjustment of dosage [ 21 ]  or switching to another drug.


Omalizumab  is a  humanized monoclonal antibody  for the treatment of various  allergic diseases , including  asthma ,  urticaria , and  allergic rhinitis . [ 22 ]  It targets the  immunoglobulin E  (IgE) in human body, which plays an important role in  allergic reactions . [ 23 ]  The efficacy of  omalizumab  may vary among patients. To identify responders to  omalizumab , the level of several  biomarkers  can be measured, including serum  eosinophils , fractional exhaled nitric oxide, and serum IgE. [ 23 ] [ 24 ]  For instance, patients with higher baseline  eosinophil  counts are likely to respond better to  omalizumab  therapy. [ 24 ]


Medication compliance  is defined as the degree to which the patient follows the therapy that is recommended by healthcare professionals. [ 2 ]  There are  direct and indirect methods to evaluate compliance. Direct method refers to the measurement that the healthcare professionals observed  or measure the patient's drug-taking behavior. Indirect method refers to the healthcare professionals do not observe or measure the drug-taking behavior of the patient but use the other source of information to evaluate the compliance.


The direct method includes measurement of drug (or the corresponding  metabolite ) concentration, [ 2 ] [ 25 ]  while the indirect method includes pill counting [ 2 ] [ 25 ]  and the self-report from the patient. [ 2 ] [ 25 ]  The direct method is more time-consuming, more expensive, more invasive, but it is more accurate. [ 2 ]  The indirect method has a lower accuracy but is easier to administer to the patient. [ 2 ]  If the patient fails to comply with treatment, for example, by not taking the medication according to the instructions, it leads to risk and a poor treatment outcome.


For  tuberculosis  patients, directly observed therapy is still part of the treatment. [ 26 ]  This is to increase  medication compliance . [ 27 ]  This is to prevent treatment failure, relapse, and transmission in the community. [ 28 ]  Apart from the traditional direct observed therapy (DOT), there is another method proposed to try increasing medication compliance.  Video-observed therapy (VOT)  is one of the methods. It has some advantages and disadvantages. It reduces the cost of healthcare and the travel costs for the patient. [ 27 ]  The downside of the intervention is the need for quality control training as it would be hard to confirm the patient's adherence. [ 27 ]


Pharmacists  are experts in pharmacotherapy and are responsible for ensuring the safe, appropriate, and economical use of pharmaceutical drugs. The skills required to function as a pharmacist require knowledge, training and experience in biomedical, pharmaceutical and  clinical sciences . [ 29 ]   Pharmacology  is the science that aims to continually improve pharmacotherapy. The  pharmaceutical industry  and  academia  use  basic science ,  applied science , and  translational science  to create new pharmaceutical drugs.


As pharmacotherapy specialists and pharmacists have responsibility for direct  patient care , often functioning as a member of a multidisciplinary team, and acting as the primary source of drug-related information for other  healthcare professionals . A pharmacotherapy specialist is an individual who is specialized in administering and prescribing medication, and requires extensive academic knowledge in pharmacotherapy. [ 30 ]


In the US, a pharmacist can gain Board Certification in the area of pharmacotherapy upon fulfilling eligibility requirements and passing a certification examination. [ 31 ] [ 32 ]  While pharmacists provide valuable information about medications for patients and healthcare professionals, they are not typically considered covered pharmacotherapy providers by insurance companies.


Photosensitivity  is the amount to which an object reacts upon receiving  photons , especially  visible light . In medicine, the term is principally used for abnormal reactions of the skin, and two types are distinguished,  photoallergy  and  phototoxicity . [ 1 ] [ 2 ]  The  photosensitive ganglion cells  in the mammalian eye are a separate class of light-detecting cells from the  photoreceptor cells  that function in vision.


Sensitivity of the  skin  to a light source can take various forms. People with particular skin types are more sensitive to  sunburn . Particular medications make the skin more sensitive to sunlight; these include most of the  tetracycline antibiotics , heart drugs  amiodarone , and  sulfonamides .
Some dietary supplements, such as  St. John's Wort , include photosensitivity as a possible side effect.


Particular conditions lead to increased light sensitivity. Patients with  systemic lupus erythematosus  experience skin symptoms after sunlight exposure; some types of  porphyria  are aggravated by sunlight. A rare hereditary condition  xeroderma pigmentosum  (a defect in DNA repair) is thought to increase the risk of UV-light-exposure-related cancer by increasing photosensitivity.


Photosensitivity occurs in multiple species including  sheep ,  bovine , and  horses . They are classified as primary if an ingested plant contains a photosensitive substance, like  hypericin  in  St John's wort  poisoning and ingestion of biserrula ( Biserrula pelecinus ) [ 3 ]  in sheep, or  buckwheat plants  (green or dried) in horses. [ 4 ]


In  hepatogenous photosensitization , the photosensitzing substance is  phylloerythrin , a normal end-product of  chlorophyll  metabolism.  [ 5 ]  It accumulates in the body because of liver damage, reacts with UV light on the skin, and leads to free radical formation. These free radicals damage the skin, leading to ulceration, necrosis, and sloughing. Non-pigmented skin is most commonly affected.


A  pill organiser  (or  pill organizer ),  pill container ,  dosette box ,  pillcase  or  pillbox  is a multicompartment  compliance  aid for storing scheduled doses of  medications . Pill organisers usually have square-shaped compartments for each day of the week, although other more compact and discreet versions have come to market, including cylindrical and pen-shaped cases. [ 1 ] [ 2 ]  Some organisers have sections corresponding to times of the day. Pill organisers are viewed as a way to prevent or reduce medication errors on the part of the patient, though evidence of effectiveness is not strong and they have been linked to medication errors. [ 3 ]


The first pill organizer was invented by Phil Cherrin of Cherrin Brothers Corporation in Detroit, Michigan.  The brothers patent was filed July 21, 1966, US-3432951-A, and approved on March 18, 1969.  This patent for "a compartmented container made of clear plastic for use in dispensing medicinal pills at periodic intervals such as daily on a mistake-proof basis" has been cited as the first, seminal patent for all subsequent pill organizer patent filings. [ 4 ]  Cherrin Brothers Corporation, a distributor of candy, tobacco and personal care paper products was a pioneer in the design of plastics for packaging consumables that preserved freshness and bundled multi-packs including but not limited to seminal patents for the clear invoice/packing slip envelope used by Fedex/UPS/USPS etc today as well as the adhesive tape dispenser.  [ 5 ] [ 6 ]


Pill organisers are useful for all types of  patients , including the  elderly , those who have  memory deficiencies , and those taking multiple medications as an aid in remembering to take proper doses of their medications in  compliance  with their doctor's recommended dose. They allow a patient to know whether or not they have taken a particular dose of their medication; if a pill still remains in its compartment, it is apparent that it has not yet been taken, whereas if it is missing, it has already been taken. [ 7 ]


Pill organisers often have various features to make them easier for special-needs patients to use, such as  color-coding ,  Braille  for the  blind , or a locking mechanism to prevent double dosing. [ 8 ]  Some organisers used for  diabetes  patients have sections for  insulin  and  hypodermic syringes .


Some pharmacists will pre-load pills into pill organisers for their patients, as a convenient service. [ 9 ]


Electronic pill organisers,  pill dispensers , and  pill reminders  have been developed that alert patients when their  prescription medication ,  OTC medication , or daily  food supplements  must be taken. [ 8 ]  These devices have been credited with saving lives and saving money in the health care system. [ 10 ]  Advanced models can be linked via the Internet to a medical facility, to aid in monitoring and reminding a patient to take his/her medications. [ 11 ]


A  pill reminder  is any device that reminds users to take medications.  Traditional pill reminders are  pill containers  with electric timers attached, which can be preset for certain times of the day to set off an alarm.  More sophisticated pill reminders can also detect when they have been opened, and therefore when the user is away during the time they were supposed to take their medication, they will be reminded of it when they return.  This reminder can be in the form of a light, which also helps for deaf or hearing-impaired users.


A newer type of pill reminder is a  mobile app  that reminds the owner to take the medication. [ 1 ]  Some of these applications might effectively support  adherence  to taking medications. [ 2 ] [ 3 ]


This article related to  medical equipment  is a  stub . You can help Wikipedia by  expanding it .


Polysubstance dependence  refers to a type of  substance use disorder  in which an individual uses at least three different classes of substances indiscriminately and does not have a favorite substance that qualifies for dependence on its own. Although any combination of three substances can be used, studies have shown that  alcohol  is commonly used with another substance. [ 1 ]  One study on polysubstance use categorized participants who used multiple substances according to their substance of preference. The results of a  longitudinal study  on substance use led the researchers to observe that excessively using or relying on one substance increased the probability of excessively using or relying on another substance. [ 2 ]


The three substances were  cocaine , alcohol, and  heroin , which implies that those three are very popular. [ 3 ]  Other studies have found that opiates, cannabis, amphetamines, hallucinogens, inhalants, and benzodiazepines are often used in combination as well. [ 4 ]


Cognition refers to what happens in the mind, such as mental functions like " perception , attention, memory, language, problem solving, reasoning, and decision making." [ 5 ]  Although many studies have looked at the cognitive impairments of individuals who are dependent on one substance, there are few researchers who have tried to determine the problems with cognitive functioning that are caused by dependence on multiple substances. [ 6 ]  Therefore, what is known about the effects of polysubstance dependence on mental abilities is based on the results of a few studies.


The effect of polysubstance dependence on learning ability is one area of interest to researchers. A study involving 63 polysubstance dependent women and 46 controls (participants who were not using substances) used the  Benton Visual Retention Test  (BVRT) and the  California Verbal Learning Test  (CVLT) to look at visual memory and verbal ability. [ 7 ]  This study showed that in polysubstance dependent women, verbal learning ability was significantly decreased, though visual memory was not affected. In addition, alcohol and cocaine use led to more severe issues with verbal learning, recall, and recognition. [ 7 ]


Sometimes studies about specific groups in the general population can be informative. One study decided to test the cognitive abilities of participants in  rave  parties who used multiple substances. To do this, they compared 25 rave party attenders with 27 control participants who were not using substances. The results of this study indicated that in general, the rave attender group did not perform as well on tasks that tested speed of information processing,  working memory , knowledge of similarities between words, ability to attend to a task with interference in the background, and decision making. [ 3 ]  Certain substances were associated with particular mental functions, but the researchers suggested that the impairments for working memory and reasoning were caused by the misuse of multiple substances. [ 3 ]


Another study that tried to find differences between the effects of particular substances focused on people with polysubstance use who were seeking treatment for addictions to  cannabis , cocaine, and heroin. They studied a group of people with polysubstance use and a group that was not dependent on any substances. Because alcohol was a common co-substance for nearly all of the people in the polysubstance use group, it was difficult to tell exactly which substances were affecting certain cognitive functions. The researchers found that the difference in the two groups' performance levels on  executive function , or higher-level cognitive processing tasks were consistently showing that the polysubstance group scored lower than the control group. [ 8 ]  In general, this meant that multiple substances negatively affected the polysubstance group's cognitive functioning. More specifically, the researchers found that the amount of cannabis and cocaine affected the verbal part of working memory, the reasoning task, and decision making, while cocaine and heroin had a similar negative effect on visual and spatial tasks, but cannabis particularly affected visual and spatial working memory. [ 8 ]  These results suggest that the combined use of cannabis, cocaine, and heroin impair more cognitive functions more severely than if used separately. [ 8 ]


Alcohol's negative effects on learning, spatial abilities and memory has been shown in many studies. [ 9 ]  This raises a question: does using alcohol in combination with other substances impair cognitive functioning even more? One study decided to try to determine if people with polysubstance use who also recreationally use alcohol would display poorer performance on a verbal learning and memory test in comparison to those who consumed excessive amounts of alcohol specifically. [ 10 ]  The California Verbal Learning Test (CVLT) was used due to its ability to "quantify small changes in verbal learning and memory" by evaluating errors made during the test and the strategies used to make those errors. [ 10 ]  The results of this study showed that the group of people with polysubstance and alcohol use performed poorly on the CVLT recall and recognition tests compared to the group of people who exclusively consumed excessive alcohol only, which implies that polysubstance use impaired the memory and learning in a different way than the effects of alcohol alone can explain. [ 10 ]


To examine whether abstinence for long periods of time helps people with polysubstance use recover their cognitive function, a group of researchers tested 207 polysubstance dependent men, of whom 73.4% were dependent on three or more substances. [ 6 ]  The researchers were interested in six areas of cognitive functioning, which included visual memory, verbal memory, knowledge of words, abstract reasoning, inhibition (interference), and attention. [ 6 ]  The study used the Benton Visual Retention Test (BVRT) for testing visual memory, the California Verbal Learning Test (CVLT) for verbal memory, the  Wechsler Adult Intelligence Scale  vocabulary portion for knowledge of words, the Booklet Category Test for abstract reasoning, the  Stroop  Neuropsychological Screening task for inhibition, and the  Trail Making Test  for attention. [ 6 ]  The results showed that neuropsychological ability did not improve with increases in the length of time abstinent. This suggests that polysubstance dependence leads to serious impairment which cannot be recovered much over the span of a year. [ 6 ]


There is data to support that some genes contribute to substance dependence. [ 11 ]  Some studies have focused on finding genes that predispose the person to be dependent on marijuana, cocaine, or heroin by studying genes that control a person's  dopamine  and  opioid  receptors, but no conclusive findings were reported. [ 12 ]  Other researchers found a connection between dopamine receptor genes and dependency on a substance. [ 12 ]  A potential problem with this study was that alcohol is commonly used with another substance, so the results of the study may not have been caused by dependency on a single substance. This means that multiple substances may have been contributing to the results, but the researchers suggested that further research should be done. [ 12 ]


However, there are studies that have found evidence of the influence of genes on vulnerability to substance dependence. [ 13 ]  These studies often use genotype, or the genetic information found on a person's chromosomes, and phenotype, which consists of the visible features of a person, to look at genetic patterns. [ 14 ]  One study examined the phenotype and genotype of 1,858 participants from 893 families to look at differences in three  nicotinic acetylcholine receptor  genes found within these individuals. [ 13 ]  The experimenters found significant connections between receptor genes for nicotine and polysubstance dependence, which indicated that differences in these genes can create the risk of being dependent on multiple substances. [ 13 ]


A 1985 study conducted by Khantzian and Treece found that 65% of their opioid-dependent sample met criteria for a  personality disorder  diagnosis. In the same study, 93% of the sample had a  comorbid  disorder, implying that the comorbid disorder plays some role in the addiction. [ 15 ] [ 16 ]  It has also been shown that depression and polysubstance dependence are often both present at the same time. If a person is genetically predisposed to be depressed then they are at a higher risk of having polysubstance dependence. [ 17 ]


Possibly the most widely accepted cause of addictions is the  self-medication  hypothesis, that views substance addiction as a form of coping with stress through  negative reinforcement , by temporarily alleviating awareness of or concerns over the stressor. [ 18 ]  People who use substances learn that the effects of each type of substance works to relieve or better painful states. They use substances as a form of self-medication to deal with difficulties of self-esteem, relationships, and self-care. Individuals with substance use disorders often are overwhelmed with emotions and painful situations and turn to substances as a coping method. [ 19 ]


The sociocultural causes are areas in a person's life that might have influenced their decision to start and continue using multiple substances. Sociocultural causes can be divided into social causes and cultural causes.


For most of these disorders, in relation to polysubstance dependence, there is a vicious cycle that those with a dependence go through. First, ingesting the substance creates a need for more, which creates a dopamine surge, which then creates pleasure. As the dopamine subsides, the pleasure adds to the emotional and physical pain and triggers stress transmitters, which in turn creates a craving, which must then be medicated, and thus the cycle begins again. However, the next time they use, more of the substance will need to be used to get to the same degree of intoxication . [ 21 ] [ 22 ]


Scientists have hypothesized that the use of a substance either causes a mood disorder such as depression or at least attributes to a pre-existing one. Additionally, the substances that people with depression use can be a misguided method of self-medication in order to manage their depression. [ 23 ]  This is the classic  chicken or egg  hypothesis, does the pre-existing condition cause dependence or does dependence cause the condition? The underlying mental illness needs to be identified and treated in conjunction with treating the polysubstance dependence in order to increase the success rate of treatment and decrease the probability of relapse. [ 17 ]  One specific study focused on alcohol and depression, because they are so commonly inter-related. Researchers have discovered that depression continues for several weeks after a patient had been rehabilitated and those who relapsed developed depression again. This means that the onset of depression happens after alcohol dependence occurs, which means that alcohol is a major contributor to depression. [ 17 ]


One study showed that patients who are recovering from an addiction, who have had an eating disorder in the past, often use food to try to replace the substance that they are no longer getting. Or they obsess over controlling their weight and appearance. Some rehabilitation centers have licensed nutritionists to help patients develop healthy eating habits to help them cope while recovering from their addictions. It is important that those who have a former eating disorder be taught how to eat healthfully, so they don't continuously switch from one addiction back to another. [ 22 ]


According to the DSM-IV, a diagnosis of polysubstance dependence must include a person who has used at least three different substances (not including caffeine or nicotine) indiscriminately, but does not have a preference to any specific one. In addition they must show a minimum of three of the following symptoms listed below, all within the past twelve months. [ 24 ]  There is a distinct difference between a person having three separate dependence issues and having Polysubstance dependence the main difference is polysubstance dependence means that they are not specifically addicted to one particular substance. This is often confused with multiple specific dependences present at the same time. To elaborate, if a person is addicted to three separate substance such as cocaine, methamphetamines and alcohol and is dependent on all three then they would be diagnosed with three separate dependence disorders existing together (cocaine dependence, methamphetamine dependence and  alcohol dependence ,) not polysubstance dependence. [ 24 ]  In addition to using three different substances without a preference to one, there has to be a certain level of dysfunction in a person's life to qualify for a diagnosis of polysubstance dependence. [ 25 ]  One of the bigger challenges that often occurs when trying to diagnose is the fact that people don't always report what they are taking because they are afraid of getting into legal trouble. [ 20 ]  When coding polysubstance Dependence in a DSM-IV it would be a  multiaxial diagnosis  304.80- Polysubstance Dependence", next to the classification, it is accompanied by a list of other types of  Substance dependence  (e.g. "305.00 Alcohol Abuse" or "305.60 Cocaine Abuse"). [ 26 ]


The DSM-IV requires at least three of the following symptoms present during a 12-month period for a diagnoses of polysubstance dependence. [ 27 ]


DSM-5  eliminated polysubstance disorder; there the substances must be specified, among other related changes. [ 28 ]


Treatment for polysubstance dependence has many critical aspects.  Substance rehabilitation  is a lengthy and difficult process. Treatment must be individualized and last a sufficient amount of time to ensure the patient has kicked the addictions and to ensure the prevention of relapse. The most common forms of treatment for polysubstance dependence include: inpatient and outpatient treatment centers, counseling and behavioral treatments, and medications. It is important that treatments be carried on throughout the patient's life in order to  prevent relapse . It is a good idea that recovering addicts continue to attend social support groups or meet with counselors to ensure they do not relapse. [ 29 ]


Inpatient treatment centers are treatment centers where addicts move to the facility while they are undergoing treatment. Inpatient treatment centers offer a safe environment where patients will not be exposed to potentially harmful situations during their treatments as they would on the outside. Inpatients usually undergo the process of  detoxification . Detox involves withdrawing the user (usually medically) from all substances of concern. During their stay in the treatment facility, patients often are learning to manage and identify their substance addictions and to find alternate ways to cope with whatever is the cause of their addiction. [ 30 ]


Outpatient treatments include many of the same activities offered in an inpatient treatment facility, [ 31 ]  but the patient is not protected by the secure and safe environment of an inpatient treatment center. For this reason, they are significantly less effective. The patient usually continues to hold a job and goes to treatment nightly. [ 30 ]


Both in-patient and out-patient treatments can offer introductions to  Twelve-step programs  such as  Alcoholics Anonymous  and  Narcotics Anonymous . They offer regular meetings where members can discuss their experiences in a non-judgmental and supportive place. [ 32 ]


Also offered to patients are one-on-one  counseling sessions  and  cognitive behavioral therapy (CBT) . [ 30 ]  When looked at through a cognitive-behavioral perspective, addictions are the result of learned behaviors developed through positive experiences. In other words, when an individual uses a substance and receives desired results (happiness, reduced stress, etc.) it may become the preferred way of attaining those results, leading to addictions. The goal of CBT is to identify the needs that the addictions are being used to meet and to develop skills and alternative ways of meeting those needs. The therapist will work with the patient to educate them on their addictions and give them the skills they need to change their cognitions and behaviors. Addicts will learn to identify and correct problematic behavior. They will be taught how to identify harmful thoughts and substance cravings. CBT is an effective treatment for addictions. [ 33 ]


Medications can be very helpful in the long-term treatment of polysubstance dependence. Medications are a useful aid in helping to prevent or reducing substance cravings. Another benefit of medications is helping to preventing relapse. Since substance use disorders affect brain functioning, medications assist in returning to normal brain functioning. People who use multiple substances require medications for each substance they use, as the current medications do not treat all substance use disorders simultaneously. Medications are a useful aid in treatments, but are not effective when they are the sole treatment method. [ 29 ]


There are not very many studies that have examined how often polysubstance dependence occurs or how many people are dependent on multiple substances. However, according to a study that analyzed the results from the National Epidemiological Survey on Alcohol and Related Conditions, approximately 215.5 out of a total of 43,093 individuals in the United States (0.5%) met the requirements for polysubstance use disorder. [ 36 ]  Another study suggested that the number of new cases of polysubstance dependence has been going up. [ 37 ]  This idea was supported by a study that took place in  Munich ,  Germany . A group of researchers chose to look at responses to a survey using the M-Composite International Diagnostic Interview (M-CIDI). The M-CIDI is a version of the  Composite International Diagnostic Interview  (CIDI). [ 38 ]  The researchers collected data from 3,021 participants, all between the ages of 14 and 24, to estimate the  prevalence , or total number of cases, of substance use and of polysubstance use/dependence. [ 39 ]  The results of this study indicated that of the 17.3% who said that they regularly used substances, 40% said that they used more than one substance, but 3.9% specifically reported using three or more substances, indicating that there is a lot of overlap in the use of different substances. [ 39 ]  The researchers compared their results to earlier German studies and found that substance dependence seems to be increasing, at least in Germany. [ 39 ]


Women and men differ in various ways when it comes to addictions. Research has shown that women are more likely to be polysubstance dependent. It has been noted that a larger percentage of women use licit (legal) substances such as tranquilizers, sedatives, and stimulants. On the other hand, men are more likely to use illicit (illegal) substances such as cocaine, methamphetamine, and other illicit substances. Research suggests that women addicts more frequently have a family history of substance use. When asked to describe their onset of addictions, women more frequently describe their addiction as sudden where as men describe them as gradual. Females have a higher percentage of fatty tissues and a lower percentage of body water than men. Therefore, women absorb substances more slowly. This means these substances are at a higher concentration in a woman's bloodstream. Female addicts are known to be at greater risk for fatty liver disease, hypertension, anemia, and other disorders. [ 40 ]


The  rebound effect , or  rebound phenomenon , is the emergence or re-emergence of  symptoms  that were either absent or controlled while taking a medication, but appear when that same medication is discontinued, or reduced in dosage. In the case of re-emergence, the severity of the symptoms is often worse than pretreatment levels.


The rebound effect, or  pharmaceutical  rebound phenomenon, is the emergence or re-emergence of  symptoms  that were either absent or controlled while taking a medication, but appear when that same medication is discontinued, or reduced in dosage. In the case of re-emergence, the severity of the symptoms is often worse than pretreatment levels. [ citation needed ]


Rebound insomnia is  insomnia  that occurs following discontinuation of  sedative  substances taken to relieve primary insomnia. Regular use of these substances can cause a person to become  dependent  on its effects in order to fall asleep. Therefore, when a person has stopped taking the medication and is 'rebounding' from its effects, they may experience insomnia as a symptom of  withdrawal . Occasionally, this insomnia may be worse than the insomnia the drug was intended to treat. [ 1 ]  Common medicines known to cause this problem are  eszopiclone ,  zolpidem , and  anxiolytics  such as  benzodiazepines  and which are prescribed to people having difficulties falling or staying asleep.


Rebound depression may appear to arise in patients previously free of such an illness. [ 2 ]


Daytime rebound effects of anxiety, metallic taste, perceptual disturbances which are typical  benzodiazepine withdrawal symptoms  can occur the next day after a short-acting  benzodiazepine  hypnotic wears off. Rebound phenomena do not necessarily only occur on discontinuation of a prescribed dosage. Another example is early morning rebound insomnia which may occur when a rapidly eliminated hypnotic wears off which leads to rebounding awakeness forcing the person to become wide awake before he or she has had a full night's sleep. One drug which seems to be commonly associated with these problems is  triazolam , due to its high potency and ultra short half life, but these effects can occur with other short-acting  hypnotic drugs . [ 3 ] [ 4 ] [ 5 ]   Quazepam , due to its selectivity for type1 benzodiazepine receptors and long half-life, does not cause daytime anxiety rebound effects during treatment, showing that half-life is very important for determining whether a nighttime  hypnotic  will cause next-day rebound withdrawal effects or not. [ 6 ]  Daytime rebound effects are not necessarily mild but can sometimes produce quite marked psychiatric and psychological disturbances. [ 7 ]


Rebound effects from  stimulants  such as  methylphenidate  or  dextroamphetamine  include  stimulant psychosis ,  depression  and a return of ADHD symptoms but in a temporarily exaggerated form. [ 8 ] [ 9 ] [ 10 ]  Up to a third of ADHD children experience a rebound effect when methylphenidate is withdrawn. [ 11 ]


Many  antidepressants , including  SSRIs , can cause rebound  depression ,  panic attacks ,  anxiety , and  insomnia  when discontinued. [ 12 ]


Sudden and severe emergence [ 13 ]   or re-emergence [ 14 ]  of psychosis may appear when  antipsychotics  are  switched  or  discontinued  too rapidly.


Rebound hypertension, above pre-treatment level, was observed after  clonidine , [ 15 ]  and  guanfacine [ 16 ]  discontinuation.


Continuous usage of  topical decongestants  ( nasal sprays ) can lead to constant  nasal congestion , known as  rhinitis medicamentosa .


Denosumab  inhibits osteoclast recycling, which results in the accumulation of pre-osteoclasts and osteomorphs. When denosumab therapy is discontinued, the induced cells quite quickly and abundantly differentiate into osteoclasts causing  bone resorption  (rebound effect) and increasing the risk of fractures. For improving mineral bone density and preventing fractures after denosumab discontinuation,  bisphosphonate  administration is recommended. [ 17 ]


Another example of  pharmaceutical  rebound is a  rebound headache  from painkillers when the dose is lowered, the medication wears off, or the drug is abruptly discontinued. [ 18 ]


In 2022, reports of viral RNA and symptom rebound in people with  COVID-19  treated with  Paxlovid  were published. In May, CDC even issued a health alert informing physicians about "Paxlovid rebounds", which received attention when US president  Joe Biden  experienced a rebound. The cause of the rebound is unclear however, since around a third of people with COVID-19 experience a symptom rebound regardless of treatment. [ 19 ]


Abrupt withdrawal of highly potent  corticosteroids , such as  clobetasol  for  psoriasis  can cause a much more severe case of the psoriasis to develop. Therefore, withdrawal should be gradual, until very little actual medication is being applied. [ citation needed ]


Research on Adverse Drug Events and Reports (RADAR)  is a  pharmacovigilance  team of 25 doctors who receive calls about possible  adverse drug reactions  (ADR) and investigate.  RADAR is based at  Northwestern 's  Feinberg School of Medicine . RADAR is led by Dennis West. Though it was without funding for its first four years, RADAR has raised about $12 million through grants from the  National Institutes of Health , the  American Cancer Society  and other such institutions. Its work has identified safety problems with 33 drugs.   Adverse drug events  are a serious health problem.


The aims of RADAR are to disseminate safety reports for serious adverse drug reactions (sADRs) and to identify barriers to identification and reporting of these clinical events. Investigators have developed a well-coordinated system to accurately compile case report information on sADRs and to identify milestones associated with identification and reporting of the relevant ADR information. This ADR identification system allows us to amass pertinent sADR information from a diverse set of data sources in order to identify and report sADRs in a timely and thorough manner. With increasingly shortened review periods,  postmarketing surveillance  for sADRs has become very important. In some instances, initial cases are identified at hospital case conferences and reported to the  U.S. Food and Drug Administration  (FDA) or to the  pharmaceutical manufacturer . The RADAR methodology relies on initial recognition of these “sentinel” cases that then prompts hypothesis–driven inquiries as to whether an unrecognized  adverse drug event  signal is present in the population of those exposed to that drug.


Between 1998 and 2007, 33 serious adverse drug or device reactions have been reported by RADAR investigators. The  toxicities  involved multiple  biological system  and included  thrombotic thrombocytopenic purpura  (TTP) ( ticlopidine  and  clopidogrel ),  thromboembolism  ( thalidomide  and  lenalidomide ),  liver failure  ( gemtuzumab  and  nevirapine ),  hypersensitivity  ( drug eluting coronary arterial stents ),  pure red-cell aplasia  (PRCA) ( epoetin ), vision changes ( amiodarone ,  sildenafil , and  tadalafil ), late  thrombotic events  ( drug eluting cardiac stents ),  leukemia  ( G-CSF ), and  interstitial pneumonitis  ( gemcitabine ). For each individual ADR, the number of unique event reports collected by RADAR ranged from 0 to 96. Twenty-seven sADRs were associated with drugs and four were associated with a device.


The success of the RADAR program has previously been largely based on the use of diverse data sources to identify, clarify, and verify ADRs.   Databases ,  registries ,  clinical trials , referral centers, and case reports have all been utilized as sites of detection. In particular, RADAR has made use of reports submitted to  MedWatch  as well as more focused databases such as the  Medicare -SEER database. Hypothesis-driven active surveillance of a few hundred safety reports serves as the underlying conceptual framework of RADAR  pharmacovigilance . Fewer than 20 individual ADR reports led to RADAR investigators identifying safety signals for the majority of the ADRs described to date. Despite a small number of reports for each ADR,  causality  assessments have been supported by  pathology  studies,  antibody  studies, and  autopsies . For example, the initial description of  thrombotic thrombocytopenic purpura  associated with  clopidogrel  included only 11 cases.


RADAR has also identified key barriers to timely and efficiently identifying ADRs and to comprehensively reporting these findings. In particular, we identified quality concerns with MedWatch reports (the FDA's primary source of adverse event reports) and poor quality of dissemination of adverse event findings from the FDA and the  pharmaceutical  sponsor. Our efforts have found that RADAR sADR identification and dissemination efforts can be as rapid as one to two years after FDA approval, in contrast to the seven years generally seen with safety efforts from the FDA and pharmaceutical sponsors. Thus, the RADAR project has developed into an important adjunct to the current pharmaceutical drug and device safety system.


RADAR has analyzed historical data on many drugs from their initial inception, through approval by the FDA, and to the
present.  These analyses synthesize the various sources of statistical information on the presence of adverse reactions to these drugs and assess whether the actual risk is in line with studies.


Serotonin syndrome  ( SS ) is a group of symptoms that may occur with the use of certain  serotonergic  medications or  drugs . [ 1 ]  The symptoms can range from mild to severe, and are potentially fatal. [ 4 ] [ 5 ] [ 2 ]  Symptoms in mild cases include  high blood pressure  and a  fast heart rate ; usually without a  fever . [ 2 ]  Symptoms in moderate cases include  high body temperature , agitation,  increased reflexes ,  tremor ,  sweating ,  dilated pupils , and  diarrhea . [ 1 ] [ 2 ]  In severe cases,  body temperature  can increase to greater than 41.1 °C (106.0 °F). [ 2 ]  Complications may include  seizures  and  extensive muscle breakdown . [ 2 ]


Serotonin syndrome is typically caused by the use of two or more serotonergic medications or drugs. [ 2 ]  This may include  selective serotonin reuptake inhibitor  (SSRI),  serotonin norepinephrine reuptake inhibitor  (SNRI),  monoamine oxidase inhibitor  (MAOI),  tricyclic antidepressants  (TCAs),  amphetamines ,  pethidine  (meperidine),  tramadol ,  dextromethorphan ,  buspirone ,  L-tryptophan ,  5-hydroxytryptophan ,  St. John's wort ,  triptans ,  MDMA ,  ondansetron ,  metoclopramide , or  cocaine . [ 2 ]  It occurs in about 15% of SSRI overdoses. [ 3 ]  It is a predictable consequence of excess  serotonin  on the  central nervous system . [ 6 ]  Onset of symptoms is typically within a day of the extra serotonin. [ 2 ]


Diagnosis is based on a person's symptoms and history of medication use. [ 2 ]  Other conditions that can produce similar symptoms such as  neuroleptic malignant syndrome ,  malignant hyperthermia ,  anticholinergic toxicity ,  heat stroke , and  meningitis  should be ruled out. [ 2 ]  No laboratory tests can confirm the diagnosis. [ 2 ]


Initial treatment consists of discontinuing medications which may be contributing. [ 1 ]  In those who are agitated,  benzodiazepines  may be used. [ 1 ]  If this is not sufficient, a  serotonin antagonist  such as  cyproheptadine  may be used. [ 1 ]  In those with a high body temperature,  active cooling  measures may be needed. [ 1 ]  The number of cases of SS that occur each year is unclear. [ 3 ]  With appropriate medical intervention the risk of death is low, likely less than 1%. [ 7 ]  The high-profile  case of Libby Zion , who is generally accepted to have died from SS, resulted in changes to graduate medical school education in  New York State . [ 6 ] [ 8 ]


Symptom onset is usually relatively rapid, and SS encompasses a wide range of clinical findings. Mild symptoms may consist of  increased heart rate , shivering,  sweating ,  dilated pupils ,  myoclonus  (intermittent jerking or twitching), as well as  hyperreflexia  (overresponsive reflexes). [ 6 ]  Many of these symptoms may be side effects of the drug or drug interaction causing excessive levels of serotonin rather than an effect of elevated serotonin itself.


Tremor  is a common side effect of  MDMA 's action on  dopamine , whereas hyperreflexia is symptomatic of exposure to  serotonin agonists . Moderate intoxication includes additional abnormalities such as hyperactive bowel sounds,  high blood pressure  and  hyperthermia ; a temperature as high as 40 °C (104 °F). The overactive reflexes and  clonus  in moderate cases may be greater in the lower limbs than in the  upper limbs . Mental changes include  hypervigilance  or  insomnia  and  agitation . [ 6 ]  Severe symptoms include severe increases in heart rate and blood pressure. Temperature may rise to above 41.1 °C (106.0 °F) in life-threatening cases. Other abnormalities include  metabolic acidosis ,  rhabdomyolysis ,  seizures ,  kidney failure , and  disseminated intravascular coagulation ; these effects usually arising as a consequence of hyperthermia. [ 6 ] [ 9 ]


The symptoms are often present as a clinical triad of abnormalities: [ 6 ] [ 10 ]


Numerous medications and street drugs can cause SS when taken alone at high doses or in combination with other serotonergic agents. The table below lists some of these.


Many cases of serotonin toxicity occur in people who have ingested drug combinations that synergistically increase synaptic serotonin. [ 10 ]  It may also occur due to an overdose of a single serotonergic agent. [ 29 ]  The combination of  monoamine oxidase inhibitors  (MAOIs) with precursors such as  L-tryptophan  or  5-hydroxytryptophan  pose a particularly acute risk of life-threatening serotonin syndrome. [ 30 ]  The case of combination of MAOIs with tryptamine agonists (commonly known as  ayahuasca ) can present similar dangers as their combination with precursors, but this phenomenon has been described in general terms as the  cheese effect . Many MAOIs irreversibly inhibit  monoamine oxidase . It can take at least four weeks for this enzyme to be replaced by the body in the instance of irreversible inhibitors. [ 31 ]  With respect to tricyclic antidepressants, only clomipramine and imipramine have a risk of causing SS. [ 32 ]


Many medications may have been incorrectly thought to cause SS. For example, some case reports have implicated  atypical antipsychotics  in SS, but it appears based on their pharmacology that they are unlikely to cause the syndrome. [ 33 ]  It has also been suggested that  mirtazapine  has no significant serotonergic effects and is therefore not a dual action drug. [ 34 ]  Bupropion has also been suggested to cause SS, [ 35 ] [ 36 ]  although as there is no evidence that it has any significant serotonergic activity, it is thought unlikely to produce the syndrome. [ 37 ]  In 2006 the US  Food and Drug Administration  (FDA) issued an alert suggesting that the combined use of either SSRIs or SNRIs with triptan medications or sibutramine could potentially lead to severe cases of SS. [ 38 ]  This has been disputed by other researchers, as none of the cases reported by the FDA met the Hunter criteria for SS. [ 38 ] [ 39 ]  The condition has however occurred in surprising clinical situations, and because of phenotypic variations among individuals, it has been associated with unexpected drugs, including mirtazapine. [ 40 ] [ 41 ]


The relative risk and severity of serotonergic side effects and serotonin toxicity, with individual drugs and combinations, is complex. SS has been reported in patients of all ages, including the elderly, children, and even newborn infants due to  in utero  exposure. [ 42 ] [ 43 ] [ 44 ] [ 45 ]  The serotonergic toxicity of SSRIs increases with dose, but even in overdose, it is insufficient to cause fatalities from SS in healthy adults. [ 46 ] [ 47 ]  Elevations of  central nervous system  (CNS) serotonin will typically only reach potentially fatal levels when drugs with different  mechanisms of action  are mixed together. [ 9 ]  Various drugs, other than SSRIs, also have clinically significant potency as serotonin reuptake inhibitors, (such as  tramadol ,  amphetamine , and MDMA) and are associated with severe cases of the syndrome. [ 6 ] [ 48 ]


Although the most significant health risk associated with  opioid overdoses  is  respiratory depression , [ 49 ]  it is still possible for an individual to develop SS from certain opioids without the  loss of consciousness . However, most cases of opioid-related SS involve the concurrent use of a  serotergenic drug  such as  antidepressants . [ 50 ]  Nonetheless, it is not uncommon for individuals taking opioids to also be taking antidepressants due to the comorbidity of pain and depression. [ 51 ]


Cases where opioids alone are the cause of SS are typically seen with tramadol, because of its dual mechanism as a  serotonin-norepinephrine reuptake inhibitor . [ 52 ] [ 53 ]  SS caused by tramadol can be particularly problematic if an individual taking the drug is unaware of the risks associated with it and attempts to self-medicate symptoms such as headache, agitation, and tremors with more opioids, further exacerbating the condition.


Serotonin is a  neurotransmitter  involved in multiple complex biological processes including aggression, pain, sleep, appetite, anxiety, depression, migraine, and vomiting. [ 10 ]  In humans the effects of excess serotonin were first noted in 1960 in patients receiving an MAOI and  tryptophan . [ 54 ]  The syndrome is caused by increased serotonin in the CNS. [ 6 ]  It was originally suspected that  agonism  of  5-HT 1A  receptors  in  central grey  nuclei and the  medulla oblongata  was responsible for the development of the syndrome. [ 55 ]  Further study has determined that overstimulation of primarily the  5-HT 2A  receptors  appears to contribute substantially to the condition. [ 55 ]  The 5-HT 1A  receptor may still contribute through a  pharmacodynamic  interaction in which increased synaptic concentrations of a serotonin agonist saturate all receptor subtypes. [ 6 ]  Additionally, noradrenergic CNS hyperactivity may play a role as CNS  norepinephrine  concentrations are increased in SS and levels appear to correlate with the clinical outcome. Other neurotransmitters may also play a role;  NMDA receptor  antagonists and  γ-aminobutyric acid  have been suggested as affecting the development of the syndrome. [ 6 ]  Serotonin toxicity is more pronounced following supra-therapeutic doses and  overdoses , and they merge in a continuum with the toxic effects of overdose. [ 46 ] [ 56 ]


A postulated "spectrum concept" of serotonin toxicity emphasises the role that progressively increasing serotonin levels play in mediating the clinical picture as side effects merge into toxicity. The  dose-response relationship  is the effect of progressive elevation of serotonin, either by raising the dose of one drug, or combining it with another serotonergic drug which may produce large elevations in serotonin levels. [ 57 ] [ 58 ]  Some experts prefer the terms serotonin toxicity or serotonin toxidrome, to more accurately reflect that it is a form of  poisoning . [ 9 ] [ 58 ]


There is no specific test for SS. Diagnosis is by symptom observation and investigation of the person's history. [ 6 ]  Several criteria have been proposed. The first evaluated criteria were introduced in 1991 by Harvey Sternbach. [ 6 ] [ 31 ] [ 59 ]  Researchers later developed the Hunter Toxicity Criteria Decision Rules, which have better  sensitivity and specificity , 84% and 97%, respectively, when compared with the gold standard of diagnosis by a medical toxicologist. [ 6 ] [ 10 ]  As of 2007, Sternbach's criteria were still the most commonly used. [ 9 ]


The most important symptoms for diagnosing SS are tremor, extreme aggressiveness,  akathisia , or clonus (spontaneous, inducible and ocular). [ 10 ]   Physical examination  of the patient should include assessment of  deep tendon reflexes  and muscle rigidity, the dryness of the  mucosa of the mouth , the size and reactivity of the pupils, the intensity of bowel sounds, skin color, and the presence or absence of sweating. [ 6 ]  The patient's history also plays an important role in diagnosis, investigations should include inquiries about the use of prescription and  over-the-counter drugs , illicit substances, and  dietary supplements , as all these agents have been implicated in the development of SS. [ 6 ]  To fulfill the Hunter Criteria, a patient must have taken a  serotonergic agent  and meet one of the following conditions: [ 10 ]


Serotonin toxicity has a characteristic picture which is generally hard to confuse with other  medical conditions , but in some situations it may go unrecognized because it may be mistaken for a  viral illness ,  anxiety disorders ,  neurological disorder ,  anticholinergic  poisoning,  sympathomimetic  toxicity, or worsening psychiatric condition. [ 6 ] [ 9 ] [ 60 ]  The condition most often confused with serotonin syndrome is  neuroleptic malignant syndrome  (NMS). [ 61 ] [ 62 ]  The clinical features of neuroleptic malignant syndrome and SS share some features which can make differentiating them difficult. [ 63 ]  In both conditions,  autonomic  dysfunction and altered  mental status  develop. [ 55 ]  However, they are actually very different conditions with different underlying dysfunction (serotonin excess vs dopamine blockade). Both the time course and the clinical features of NMS differ significantly from those of serotonin toxicity. [ 10 ]  Serotonin toxicity has a rapid onset after the administration of a serotonergic drug and responds to serotonin blockade such as drugs like  chlorpromazine  and  cyproheptadine .  Dopamine receptor  blockade (NMS) has a slow onset, typically evolves over several days after administration of a  neuroleptic  drug, and responds to dopamine agonists such as  bromocriptine . [ 6 ] [ 55 ]


Differential diagnosis  may become difficult in patients recently exposed to both serotonergic and neuroleptic drugs.  Bradykinesia  and  extrapyramidal  "lead pipe" rigidity are classically present in NMS, whereas SS causes  hyperkinesia  and clonus; these distinct symptoms can aid in differentiation. [ 24 ] [ 64 ]


Management is based primarily on stopping the usage of the precipitating drugs, the administration of  serotonin antagonists  such as  cyproheptadine  (with a regimen of 12 mg for the initial dose followed by 2 mg every 2 hours until clinical, while some claim that a higher initial dose up to 32 mg has more benefit [ 65 ] ), [ 66 ]  and supportive care including the control of agitation, the control of autonomic instability, and the control of hyperthermia. [ 6 ] [ 67 ] [ 68 ]  Additionally, those who ingest large doses of serotonergic agents may benefit from gastrointestinal decontamination with  activated charcoal  if it can be administered within an hour of overdose. [ 9 ]  The intensity of therapy depends on the severity of symptoms. If the symptoms are mild, treatment may only consist of discontinuation of the offending medication or medications, offering supportive measures, giving  benzodiazepines  for myoclonus, and waiting for the symptoms to resolve. Moderate cases should have all thermal and cardiorespiratory abnormalities corrected and can benefit from serotonin antagonists. The serotonin antagonist cyproheptadine is the recommended initial therapy, although there have been no  controlled trials  demonstrating its efficacy for SS. [ 9 ] [ 69 ] [ 70 ]  Despite the absence of controlled trials, there are a number of case reports detailing apparent improvement after people have been administered cyproheptadine. [ 9 ]  Animal experiments also suggest a benefit from serotonin antagonists. [ 71 ]  Cyproheptadine is only available as tablets and therefore can only be administered orally or via a  nasogastric tube ; it is unlikely to be effective in people administered activated charcoal and has limited use in severe cases. [ 9 ]  Cyproheptadine can be stopped when the person is no longer experiencing symptoms and the half life of serotonergic medications already passed. [ 2 ]


Additional pharmacological treatment for severe case includes administering atypical antipsychotic drugs with serotonin antagonist activity such as  olanzapine  or  asenapine . [ 6 ]  Critically ill people should receive the above therapies as well as sedation or neuromuscular paralysis. [ 6 ]  People who have autonomic instability such as low  blood pressure  require treatment with direct-acting sympathomimetics such as  epinephrine , norepinephrine, or  phenylephrine . [ 6 ]  Conversely, hypertension or tachycardia can be treated with short-acting  antihypertensive  drugs such as  nitroprusside  or  esmolol ; longer acting drugs such as  propranolol  should be avoided as they may lead to hypotension and shock. [ 6 ]  The cause of serotonin toxicity or accumulation is an important factor in determining the course of treatment. Serotonin is catabolized by  monoamine oxidase A  in the presence of  oxygen , so if care is taken to prevent an unsafe spike in body temperature or metabolic acidosis, oxygenation will assist in dispatching the excess serotonin. The same principle applies to alcohol intoxication. In cases of SS caused by MAOIs, oxygenation will not help to dispatch serotonin. In such instances, hydration is the main concern until the enzyme is regenerated.


Specific treatment for some symptoms may be required. One of the most important treatments is the control of agitation due to the extreme possibility of injury to the person themselves or caregivers, benzodiazepines should be administered at first sign of this. [ 6 ]   Physical restraints  are not recommended for agitation or delirium as they may contribute to mortality by enforcing isometric  muscle contractions  that are associated with severe  lactic acidosis  and hyperthermia. If physical restraints are necessary for severe agitation they must be rapidly replaced with pharmacological  sedation . [ 6 ]  The agitation can cause a large amount of muscle breakdown. This breakdown can cause severe damage to the kidneys through a condition called  rhabdomyolysis . [ 72 ]


Treatment for hyperthermia includes reducing muscle overactivity via sedation with a benzodiazepine. More severe cases may require muscular paralysis with  vecuronium ,  intubation , and artificial ventilation. [ 6 ] [ 9 ]   Suxamethonium  is not recommended for muscular paralysis as it may increase the risk of cardiac dysrhythmia from hyperkalemia associated with rhabdomyolysis. [ 6 ]   Antipyretic  agents are not recommended as the increase in  body temperature  is due to muscular activity, not a  hypothalamic  temperature set point abnormality. [ 6 ]


Upon the discontinuation of serotonergic drugs, most cases of SS resolve within 24 hours, [ 6 ] [ 9 ] [ 73 ] [ 74 ]  although in some cases  delirium  may persist for a number of days. [ 31 ]  Symptoms typically persist for a longer time frame in patients taking drugs which have a long elimination  half-life , active metabolites, or a protracted duration of action. [ 6 ]


Cases have reported persisting chronic symptoms, [ 75 ]  and  antidepressant discontinuation  may contribute to ongoing features. [ 76 ]  Following appropriate medical management, SS is generally associated with a favorable prognosis. [ 77 ]


Epidemiological studies of SS are difficult as many physicians are unaware of the diagnosis or they may miss the syndrome due to its variable manifestations. [ 6 ] [ 78 ]  In 1998 a survey conducted in England found that 85% of the  general practitioners  that had prescribed the antidepressant  nefazodone  were unaware of SS. [ 43 ]  The incidence may be increasing as a larger number of pro-serotonergic drugs (drugs which increase serotonin levels) are now being used in clinical practice. [ 69 ]  One  postmarketing surveillance  study identified an incidence of 0.4 cases per 1000 patient-months for patients who were taking nefazodone. [ 43 ]  Additionally, around 14–16% of persons who overdose on SSRIs are thought to develop SS. [ 46 ]


The most widely recognized example of SS was the death of  Libby Zion  in 1984. [ 79 ]  Zion was a freshman at  Bennington College  at her death on March 5, 1984, at age 18. She died within 8 hours of her emergency admission to the  New York Hospital Cornell Medical Center . She had an ongoing history of depression, and came to the Manhattan hospital on the evening of March 4, 1984, with a fever, agitation and "strange jerking motions" of her body. She also seemed  disoriented  at times. The emergency room physicians were unable to diagnose her condition definitively but admitted her for  hydration  and observation. Her death was caused by a combination of  pethidine  and  phenelzine . [ 80 ]  A medical intern prescribed the pethidine. [ 81 ]  The case influenced graduate medical education and residency work hours. Limits were set on  working hours for medical postgraduates , commonly referred to as interns or residents, in hospital training programs, and they also now require closer senior physician supervision. [ 8 ]


Creutzfeldt–Jakob disease


In  medicine , a  side effect  is an effect of the use of a medicinal  drug  or other treatment, usually  adverse  but sometimes beneficial,  that is unintended. Herbal and  traditional medicines  also have side effects.


A drug or procedure usually used for a specific effect may be used specifically because of a beneficial side-effect; this is termed " off-label use " until such use is approved. [ 1 ]  For instance,  X-rays  have long been used as  an imaging technique ; the discovery of their oncolytic capability led to their use in  radiotherapy  for ablation of  malignant   tumours .


The  World Health Organization  and other health organisations characterise the probability of experiencing side effects as: [ 4 ] [ 5 ]


The  European Commission  recommends that the list should contain only effects where there is "at least a reasonable possibility" that they are caused by the drug and the frequency "should represent crude incidence rates (and not differences or relative risks calculated against placebo or other comparator)". [ 6 ]  The frequency describes how often symptoms appear  after  taking the drug, without assuming that they were necessarily  caused by  the drug. Both healthcare providers [ 7 ]  and lay people [ 8 ]  misinterpret the frequency of side effects as describing the increase in frequency caused by the drug.


Most drugs and procedures have a multitude of reported adverse side effects; the information leaflets provided with virtually all drugs list possible side effects. Beneficial side effects are less common; some examples, in many cases of side-effects that ultimately gained regulatory approval as intended effects, are:


Structured intermittent therapy  (SIT) was coined in early 2000 by  Mark Dybul ,  Anthony Fauci , and other research scientists from the  National Institute of Health , as a form of reduced treatment for patients with  HIV .  HIV+ patients took anti-HIV drugs for seven days, and then took no drugs for seven days. [ citation needed ]


Generally, patients with HIV who were being treated aggressively with continuous  highly active antiretroviral therapy  (HAART) lived longer lives, but they were not able to eliminate the HIV  virus  altogether and experienced many undesirable side effects. The long-term toxicity and financial expense of HAART makes it undesirable as the standard, long-term treatment for HIV patients. Consequently, a short study on administering medications in a structured intermittent manner was designed.  The hope of this 2001 study was that alternating weeks of drug-taking with weeks of drug abstinence would both reduce toxicity and cost to the patients. [ 1 ]


This small, uncontrolled study found that a structured intermittent therapy (SIT) approach may help to maintain health while also reducing cost and toxicity of antiretroviral therapy. This approach might have had particular applicability in resource-poor settings where access to therapy is limited by the cost of antiretroviral agents. [ 1 ]


The Strategies for the Management of Antiretroviral Therapy (SMART) trial was intended to provide good information on whether this approach worked for HIV+ people.  The double-blind controlled study began in 2002 and enrolled 5,472 participants in 33 countries.  Unfortunately for proponents of SIT, the study had to be stopped in 2006 because of the excessive number of "interrupted" patients who died or got much sicker. [1]   People on the SIT protocol were more than twice as likely to die during the study than people who took HAART drugs continuously. [ citation needed ]


In  medicine ,  tapering  is the practice of gradually reducing the dosage of a medication to reduce or discontinue it. Generally, tapering is done is to avoid or minimize withdrawal symptoms that arise from neurobiological adaptation to the drug. [ 1 ] [ 2 ]


Prescribed psychotropic drugs that may require tapering due to this physical dependence include  opioids , [ 3 ] [ 4 ] [ 5 ]   selective serotonin reuptake inhibitors , [ 6 ]   antipsychotics , [ 7 ]   anticonvulsants , [ 8 ]  and  benzodiazepines . [ 9 ] [ 10 ]


Cross-tapering refers to the practice of reducing one drug, while introducing a new medication that is  titrated  to an effective dose. This can be used, for example, when changing  antipsychotic medications . [ 11 ] : 156


Peer support groups , such as  survivingantidepressants.org , provide a medium where those tapering medication can discuss approaches and withdrawal symptoms. [ 12 ]   Surviving antidepressants  advocate for a slower rate of tapering than that used in standard medical practice. [ 13 ] : 4   Many such groups exist on Facebook and other social media platforms. [ 14 ]  Along with sharing tapering tips, members of the groups discuss the risks of  prescription cascade , where withdrawal symptoms or the side effects of a  psychotropic medication  result in further medication, and the risk of neurobiological  "kindling"  effects where repeated unsuccessful withdrawal attempts yield progressively poor results upon drug reinstatement or, later, may increase the risk of withdrawal symptoms. [ 15 ] [ 16 ] [ 13 ] : 5


A  therapeutic interfering particle  is an antiviral preparation that reduces the replication rate and pathogenesis of a particular viral infectious disease. A therapeutic interfering particle is typically a biological agent (i.e., nucleic acid) engineered from portions of the viral genome being targeted. Similar to  Defective Interfering Particles (DIPs) , the agent competes with the pathogen within an infected cell for critical viral replication resources, reducing the viral replication rate and resulting in reduced pathogenesis. [ 1 ] [ 2 ]  But, in contrast to DIPs, TIPs are engineered to have an in vivo  basic reproductive ratio  ( R 0 ) that is greater than 1 ( R 0 >1). [ 3 ]  The term "TIP" was first introduced in 2011 [ 4 ]  based on models of its mechanism-of-action from 2003. [ 3 ]  Given their unique  R 0 >1 mechanism of action, TIPs exhibit high barriers to the evolution of antiviral resistance [ 5 ]  and are predicted to be resistance proof. [ 4 ]  Intervention with therapeutic interfering particles can be prophylactic (to prevent or ameliorate the effects of a future infection), or a single-administration therapeutic (to fight a disease that has already occurred, such as HIV or COVID-19). [ 6 ] [ 4 ] [ 3 ] [ 7 ] [ 5 ]  Synthetic DIPs that rely on stimulating innate antiviral immune responses (i.e., interferon) were proposed for influenza in 2008 [ 8 ]  and shown to protect mice to differing extents  [ 9 ] [ 10 ] [ 11 ]  but are technically distinct from TIPs due to their alternate molecular mechanism of action which has not been predicted to have a similarly high barrier to resistance. [ 12 ]   Subsequent work tested the pre-clinical efficacy of TIPs against HIV, [ 6 ]  a synthetic DIP for SARS-CoV-2 (in vitro), [ 7 ]  and a TIP for SARS-CoV-2 (in vivo). [ 5 ] [ 13 ]


Therapeutic Interfering Particles, often referred to as TIPs, are typically synthetic, engineered versions of naturally occurring  defective interfering particles  (DIPs), in which critical portions of the virus genome are deleted rendering the TIP unable to replicate on its own. Often a TIP has the vast majority of the virus genome deleted. [ 5 ]  However, TIPs are engineered to retain specific elements of the genome that allow them to efficiently compete with the wild-type virus for critical replication resources inside an infected cell. TIPs thereby deprive wild-type virus of replication material through  competitive inhibition , [ 14 ]  and therapeutically reduce viral load. [ 6 ]  Competitive inhibition enables TIPs to conditionally replicate and efficiently mobilize between cells, essentially "piggybacking" on wild-type virus, to act as single-administration antivirals with a high genetic barrier to the evolution of resistance. [ 15 ]  TIPs have been engineered for HIV [ 6 ] [ 14 ]  and SARS-CoV-2, [ 7 ]  and do not induce innate immune responses such as  interferon [ 5 ]


Three mechanistic criteria define a TIP:


As a result of these mechanistic criteria, TIPs have been referred to as "piggyback" [ 17 ]  or alternatively as "virus hijackers". [ 18 ] [ 19 ]


TIPs do not stimulate or function through the induction of innate cellular immune responses (such as interferon). In fact, stimulation of innate cellular antiviral mechanisms has been shown to contravene criterion (#3) (i.e.,  R 0 >1), as innate immune mechanisms inhibit efficient mobilization of TIPs. [ 3 ]  As such, several VLP-based therapy proposals for influenza and other viruses [ 20 ]  that do not satisfy these criteria are DIPs, but not TIPs.


TIPs are built off the phenomenon of  defective interfering particles  (DIPs) discovered by  Preben Von Magnus  in the early 1950s, during his work on influenza viruses. [ 21 ] [ 22 ] [ 23 ] [ 2 ]  DIPs are spontaneously arising virus mutants, first described by von Magnus as "incomplete" viruses, in which a critical portion of the viral genome has been lost. Direct evidence for DIPs was only found in the 1960s by Hackett, who observed the presence of "stumpy" particles of vesicular stomatitis virus in electron micrographs, [ 24 ]  and the DIP terminology was formalized in 1970 by Huang and Baltimore. [ 25 ]  DIPs have been reported for many classes of DNA and RNA viruses in clinical and laboratory settings.


Whereas DIPs had been proposed as potential therapeutics that would act via stimulation of the immune system [ 20 ]  – a concept [ 8 ]   [ 26 ]   tested in influenza with mixed results [ 9 ]   [ 10 ]  – the TIP R 0 >1 mechanism of action was first proposed in 2003 [ 3 ]  with the term “TIP” and the unique benefits of the R 0 >1 mechanism shown in 2011. [ 4 ]


In 2016 the US government launched a major funding initiative ( DARPA  INTERCEPT, [ 26 ] [ 27 ] [ 28 ]  ) to discover and engineer antiviral TIPs for diverse viruses, based on prior investments from the US  National Institutes of Health . [ 29 ]  This program led to renewed interest in the concept of interfering particles as therapies with the development of technologies to isolate DIPs for influenza [ 30 ] [ 31 ] [ 32 ]  and engineer TIPs for HIV and Zika virus. [ 14 ]  The first successful experimental demonstration of the TIP concept was reported in 2019 [ 6 ]  for HIV, and the discovery of a TIP for SARS-CoV-2 was reported in 2020 [ 7 ]  and results on the effect on hamsters in 2021. [ 33 ]  In 2020, the US government funded first-in-human clinical trials of TIPs. [ 34 ] [ 35 ]


Threshold dose  is the minimum dose of drug that triggers minimal detectable biological effect in an animal. [ 1 ]  At extremely low doses, biological responses are absent for some of the drugs. The increase in dose above threshold dose induces an increase in the percentage of biological responses. [ 2 ]  Several benchmarks have been established to describe the effects of a particular dose of drug in a particular species, such as NOEL(no-observed-effect-level),  NOAEL (no-observed-adverse-effect-level) and  LOAEL (lowest-observed-adverse-effect-level). [ 3 ]  They are established by reviewing the available studies and  animal studies . [ 1 ]  The application of threshold dose in risk assessment safeguards the participants in human clinical trials and evaluates the risks of chronic exposure to certain substances. [ 4 ]  However, the nature of animal studies also limits the applicability of experimental results in the human population and its significance in evaluating potential risk of certain substances. [ 5 ]  In toxicology, there are some other safety factors including  LD50 ,  LC50  and  EC50 .


Threshold dose is a dose of drug barely adequate to produce a biological effect in an animal. In dose-response assessment, the term ‘threshold dose’ is refined into several terminologies, such as NOEL,  NOAEL , and  LOAEL . They define the limits of doses resulting in biological responses or toxic effects. [ 3 ]  Common responses are alterations in structures, growth, development and average lifespan of the treated group of organisms. [ 6 ]  The changes are found by comparing the observations between the  treated and control groups . Both groups are of the same species and have the same environment of exposure in the trial. The only difference is that the treated group receives the experimental substance while the control group does not. [ 7 ]


For the drugs administered by  oral  and  dermal route , the units of threshold dose are mg/kg body-weight/day (dose of the drug in mg per body weight in kg per day) or  ppm  (parts per million), while the threshold dose of drugs by inhalation delivery has the unit of mg/L 6h/day (amount of drug in mg in 1L of air, for 6 hours per day). [ 8 ]


NOEL is no-observed-effect-level. It is the maximum dose of a substance that has no observable effect on the treated group in human clinical trials or animal experimental trials. [ 3 ]  In some literature, NOEL is the only dose level referred by the terminology ‘threshold dose’. [ 9 ]


NOAEL  is no-observed-adverse-effect-level. It is the maximum dose of a substance that has no observable adverse effect on the treated group in human clinical trials or animal experimental trials. [ 3 ]


LOAEL  is lowest-observed-adverse-effect-level. It is the minimum dose of a substance that produces an observable adverse effect on the treated group in human clinical trials or animal experimental trials. [ 3 ]  There is a biologically or  statistically significant  increase in the prevalence of adverse effect in the treated group above this level. [ 10 ]


The  dose-response relationship  is dependent on various factors. They include the physicochemical properties of the drug,  route of administration  or exposure, duration of exposure, population size, and the characteristics of the studied organism such as their species, sex, ages, etc. [ 3 ]  The type of biological responses is also a significant factor for the variations of a dose-response relationship. Each response corresponds to one unique relationship. [ 16 ]  As it is not practical to establish the  dose-response relationships  for all possible responses, the studies usually narrow down the scopes to a few responses. All available studies examining the correlation between the target drug and its biological responses will be reviewed. The selection criteria for the critical responses for assessment is that the dose required to produce that particular response is the lowest. [ 1 ]  The precursor of a biological effect can also be the response for assessment. [ 1 ]  For instance, the risk factors of a disease may eventually precipitate the disease. In the study of the relationship between a drug and the development of a particular  cardiovascular disease , the risk factors of the disease can be considered as the responses for measurement as well.


A two-step process is adopted to evaluate the specific dose levels,  NOAEL  and  LOAEL . The first step is to carry out reviews of available studies or  animal studies  to obtain data on the effect of different doses of the target drug. [ 1 ]  They allow the establishment of  dose-response relationships  over the range of doses reported in the data collected. Often the data collected is inadequate to produce a range wide enough to observe the dose in which biological responses are not induced in humans. [ 17 ]  The dose which is sufficiently low to prevent the occurrence of the response in humans cannot be evaluated and therefore paves the way to the second step, extrapolation of the  dose-response relationship . [ 17 ]  The results beyond the range covered by the available data are estimated. It attempts to make inferences of the region that the critical dose levels such as  NOAEL  and  LOAEL  fell within. [ 18 ]  Thus the doses starting to trigger adverse effects in humans can be evaluated.


For step one, the two common approaches for evaluating threshold doses are qualitative examination of available studies and animal studies.


The effects of the target drug at different doses are obtained from available studies. The  dose-response relationship  will be identified and extrapolation is often required to make inferences about the dose levels below the range of data collected. [ 4 ] [ 18 ]


Animal studies  are conducted when the data collected from qualitative examination of available studies is scarce. It is for expanding the range of doses. [ 19 ]  Also, animal studies allow the manipulation of the study design, such as the age and gender of treated animals. Animal study is therefore less susceptible to the influences of  confounders  than  observational studies  and therefore contributes to a more rigorous dose-response assessment. [ 1 ]  As the assessed animals exhibit variation in characteristics with humans such as body size,  extrapolation  should be carried out to estimate the dose-response relationship in humans. [ 20 ]


A common animal study is repeated dose toxicity testing. The participating species are divided into 4 groups, receiving  placebo , low dose, mid-dose and high dose of the drugs respectively. [ 21 ]  Within the same group, the same dose is given on a daily basis for a specified period, such as 28 days or 90 days. [ 22 ]  Subsequent to the specified period,  necropsy  or tissue samples collection allows identification of the dose levels bring about certain effects and therefore establishment of  NOAEL  and  LOAEL . [ 21 ]


The threshold doses such as NOAEL, LOAEL and NOEL are essential values in risk assessment. The maximum safe starting doses of different drugs can be obtained from them prior to human clinical trials. [ 23 ]   Another application is to assess the safe dose for chronic exposure. They are utilized to estimate the daily exposure which does not induce detrimental effects in humans in their lifetime, which is also known as the  Reference Dose  (RfD). [ 1 ]


The variations between different species and the extrapolation of dose-response relationship generated from animal studies to that for humans introduce uncertainties into the analysis of dose-response. Humans also manifest intra-variation of sensitivity towards a particular substance among the population. [ 20 ]  As a result, 10-fold uncertainty factors (UF) are applied to convert NOAEL to the reference dose. The UFinter and UFintra account for the inter- and intra-species variation respectively. [ 20 ]


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 {\displaystyle RfD=NOAEL\div (UFinter\times (UFintra))}

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For carcinogenic substances, theoretically NOAEL and LOAEL do not exist as there is no safe dose for the  carcinogens . A  linear no-threshold model  is commonly used for illustrating the probability of  cancer  development from  radiation . There is no threshold value at which stochastic health effects start emerging. [ 25 ]  Only for non-cancer health outcomes, there is an assumption of the presence of a safety margin below which no negative biological effect is expected. [ 25 ]


Most dose-response models are obtained from animal experiments out of ethical concerns. Therefore, the results might not be consistent with that of the human population. [ 5 ]  Individual differences also arise among people in terms of age, weight, gender, health status, etc. [ 20 ]  Thus, in most circumstances, the threshold dose serves as a reference to evaluate the probable outcome of a certain dosage of a substance for the general population, while great deviations might exist in special populations such as  immunocompromised  patients, pregnant women and young children. [ 26 ]


The threshold dose is only a measure of  acute toxicity  since the drug or toxic substance investigated is administered at once. The consequence of long-term administration remains unknown. [ 27 ]  As the threshold dose is the measured minimal response, its accuracy heavily depends on the machinery used. It is possible that further refinement is needed. [ 28 ]  Furthermore, the threshold dose only reflects the dose required for a minimum detectable response but it should not be misunderstood that health effects are absolutely absent in the doses below the threshold dose. [ 25 ]


The median lethal dose ( LD50 ) of a substance is defined as the dose that leads to death in 50% of the tested population. It is a significant parameter in toxicology study and indicates the  acute toxicity  of a particular substance. LD50 is usually expressed in the weight of the chemical administered in milligram per unit of body weight (mg/kg). [ 29 ]  In the discussion of  environmental toxins , as there is no direct administration of toxic materials, a similar parameter  LC50  will be mentioned instead. LC50 is the concentration of substance in air that kills half of the tested population during the experimental period. [ 30 ]


The median effective concentration ( EC50 ) is the concentration of a drug required to reach 50% of the maximal biological effect the drug can exert. It is a reflection of the potency of a drug and is expressed in  molar units  such as mol/L. [ 31 ]  The value of EC50 greatly depends on the  affinity  of the drug for its  receptor , as well as the  efficacy  of the drug, which conveys receptor occupancy and the ability of the drug to trigger a biological response. [ 32 ]  EC50 is incorporated in the  Hill's Equation , a function that demonstrates the relationship between  agonist  concentration and  ligand  binding. EC50 is mathematically given as the  inflection point  of the equation. [ 33 ]


Zoopharmacognosy  is a behaviour in which non-human  animals   self-medicate  by selecting and  ingesting  or  topically applying   plants ,  soils  and  insects  with medicinal properties, to prevent or reduce the harmful effects of pathogens, toxins, and even other animals. [ 1 ] [ 2 ]   The term derives from Greek roots  zoo  ("animal"),  pharmacon  ("drug, medicine"), and  gnosy  ("knowing").


An example of zoopharmacognosy occurs when dogs eat grass to induce vomiting. However, the behaviour is more diverse than this.  Animals ingest or apply non-foods such as  clay ,  charcoal  and even  toxic  plants and invertebrates, apparently to prevent  parasitic  infestation or  poisoning . [ 3 ]


Whether animals truly self-medicate remains a somewhat controversial subject because early evidence is mostly circumstantial or anecdotal. [ 4 ]  However, more recent examinations have adopted an experimental, hypothesis-driven approach.


The methods by which animals self-medicate vary, but can be classified according to function as prophylactic (preventative, before infection or poisoning) or therapeutic (after infection, to combat the pathogen or poisoning). [ 4 ]  The behaviour is believed to have widespread adaptive significance. [ 5 ]


In 1978, Janzen suggested that vertebrate  herbivores  might benefit medicinally from the  secondary metabolites  in their plant food. [ 6 ]


In 1993, the term "zoopharmacognosy" was coined, derived from the Greek roots  zoo  ("animal"),  pharma  ("drug"), and  gnosy  ("knowing"). [ 7 ]  The term gained popularity from academic works [ 4 ]  and in a book by Cindy Engel entitled  Wild Health: How Animals Keep Themselves Well and What We Can Learn from Them . [ 8 ]


The  anti-parasitic  effect of zoopharmacognosy could occur by at least two mechanisms, namely demonstrated through the modes of  deglutition  or  ingestion .  First, ingested material may have pharmacological antiparasitic properties, such as  phytochemicals  decreasing the ability of worms to attach to the mucosal lining of the intestines or  chemotaxis  attracting worms into the folds of leaves. Additionally, many plants have  trichomes , often presented as hooked and spiky hairs, that can attach to parasites and dislodge them from the intestines. Another possible mode of action is that the ingested material may initiate a purging response of the gastrointestinal tract by rapidly inducing diarrhoea. This substantially decreases gut transit time, causing worm expulsion and interruption in the life cycle of parasites. This, or a similar, mechanism could explain undigested materials in the faeces of various animals such as birds, carnivores and primates. [ 9 ]


The  topical application  of materials is often used by animals to treat wounds or repel insects. [ 10 ]  When plant leaves are chewed and then directly rubbed onto fur, compounds from said leaves are released for use. These compounds can often be analgesic or antiparasitic in nature. In regards to an insect repellant, the  secondary metabolites  traditionally used by plants to deter herbivores and insects from eating them [ 11 ]  can be used by animals as a protective measure. By interfering with neuroreceptors, these secondary metabolites can specifically act as olfactory cues for insects to avoid a certain source. [ 12 ]


The three reported methods of self-medication are deglutition, ingestion, and topical application. When using one of these methods while appearing well, an animal may be using self-medication as a  prophylactic  measure. When it is unwell, the animal could be using self-medication as a  curative  measure.


Some examples of zoopharmacognosy are demonstrated when animals, namely apes, swallow materials whole instead of chewing and ingesting them.


Wild chimpanzees sometimes seek leaves of the  Aspilia  plant.  These contain thiarubrine-A, a chemical active against intestinal  nematode  parasites. Because this compound is quickly broken down by the stomach, chimpanzees will pick up the  Aspilia  leaves and, rather than chewing them, they roll them around in their mouths, sometimes for as long as 25 seconds. They then swallow the capsule-like leaves whole. Afterwards, the trichomes of the leaves can attach to any intestinal parasites, namely the nodular worm ( Oesophagostomum stephanostomum ) and tapeworm ( Bertiella studeri ), and allow the chimpanzee to physically expel the parasites. [ 13 ]  As many as 15 to 35  Aspilia  leaves may be used in each bout of this behaviour, particularly in the rainy season when there is an abundance of many parasitic larvae that can cause an increased risk of infection. [ 14 ]


Chimpanzees sometimes eat the leaves of the herbaceous  Desmodium gangeticum .  Undigested, non-chewed leaves were recovered in 4% of faecal samples of wild chimpanzees and clumps of sharp-edged grass leaves in 2%. The leaves have a rough surface or sharp-edges and the fact they were not chewed and excreted whole indicates they were not ingested for nutritional purposes. Furthermore, this leaf-swallowing was restricted to the rainy season when parasite re-infections are more common, and parasitic worms ( Oesophagostomum stephanostomum ) were found together with the leaves. [ 9 ]


Bonobos sometimes swallow non-chewed stem-strips of  Manniophyton fulvum .  Despite the plant being abundantly available all year,  M. fulvum  is ingested only at specific times, in small amounts, and by a small proportion of bonobos in each group, demonstrating that it is indeed only utilized when the bonobos are unwell. [ 15 ]


Tamarins  were observed swallowing the large seeds of the fruit they regularly ingest. Although they are consumed along with the rest of the fruit, these seeds have no nutritional value for the monkeys. Since tamarins are routinely infected by trematodes, cestodes, nematodes, and acanthocephalans, there is speculation that the deliberate swallowing of these large seeds can help dislodge the parasites from the monkey's body. [ 16 ]


Similar to the wild chimpanzees,  Alaskan brown bears  will swallow whole  Carex  leaves in the springtime to ensure the complete expulsion of parasites during their hibernation. [ 17 ]  Specifically, as tapeworms thrive off previously digested nutrients in the gut, the rough  Carex  leaves will lacerate their scolices, facilitating the defecation process. The proactive swallowing of these leaves will ensure low levels of active parasites within a hibernating bear.


Many examples of zoopharmacognosy involve an animal ingesting a substance with (potential) medicinal properties.


Many  parrot  species in the Americas, Africa, and Papua New Guinea consume  kaolin  or  clay , which both releases minerals and absorbs toxic compounds from the  gut . [ 18 ]


Great bustards  eat  blister beetles  of the genus  Meloe  maybe to decrease parasite load in the digestive system; [ 19 ]   cantharidin , the toxic compound in blister beetles, can kill a great bustard if too many beetles are ingested. [ 20 ]  Great bustards may eat toxic  blister beetles  of the genus  Meloe  to increase the sexual arousal of males. [ 21 ]  Some plants selected in the mating season showed in-vitro activity against laboratory models of parasites and pathogens. [ 22 ]


Woolly bear  caterpillars ( Grammia incorrupta ) are sometimes lethally  endoparasitised  by  tachinid  flies.  The caterpillars ingest plant toxins called  pyrrolizidine alkaloids , which improve survival by conferring resistance against the flies.  Crucially, parasitised caterpillars are more likely than non-parasitised caterpillars to specifically ingest large amounts of pyrrolizidine alkaloids, and excessive ingestion of these toxins reduces the survival of non-parasitised caterpillars.  These three findings are all consistent with the adaptive plasticity theory. [ 6 ]


The  tobacco hornworm  ingests  nicotine  which reduces colony growth and toxicity of  Bacillus thuringiensis , leading to increased survival of the hornworm. [ 14 ]


Ants infected with  Beauveria bassiana , a fungus, selectively consume harmful substances (reactive oxygen species, ROS) upon exposure to a fungal pathogen, yet avoid these in the absence of infection. [ 23 ]


Great apes often consume plants that have no nutritional values but which have beneficial effects on gut acidity or combat intestinal parasitic infection. [ 1 ]


Chimpanzees  sometimes select bitter leaves for chewing. Parasite infection drops noticeably after chimpanzees chew leaves of pith ( Vernonia amygdalina ), which contain  sesquiterpene lactones  and steroid glucosides that are particularly effective against  schistosoma ,  plasmodium  and  Leishmania . [ 25 ]  Specifically, these compounds can induce paralysis within the parasites and impair its ability to absorb nutrients, move, and reproduce. [ 26 ]  Chimpanzees do not consume bitter on a regular basis, but when they do, it is often in small amounts by individuals that appear ill. [ 27 ]   Jane Goodall  witnessed  chimpanzees  eating particular bushes, apparently to make themselves vomit. [ citation needed ]


Chimpanzees ,  bonobos , and  gorillas  eat the fruits of  Aframomum   angustifolium . Laboratory assays of homogenized fruit and seed extracts show significant  anti-microbial  activity. [ 28 ]
Illustrating the medicinal knowledge of some species, apes have been observed selecting a particular part of a medicinal plant by taking off leaves and breaking the stem to suck out the juice. [ 29 ]


Anubis baboons  ( Papio anubis ) and  hamadryas baboons  ( Papio hamadryas ) in Ethiopia use fruits and leaves of  Balanites aegyptiaca  to control  schistosomiasis . [ 30 ]  Its fruits contain  diosgenin , a hormone precursor that presumably hinders the development of schistosomes. [ 4 ]


African elephants  ( Loxodonta africana ) apparently self-medicate to induce labour by chewing on the leaves of a particular tree from the family  Boraginaceae ;  Kenyan  women brew a tea from this tree for the same purpose. [ 31 ]


White-nosed  coatis  ( Nasua narica ) in Panama take the menthol-scented resin from freshly scraped bark of  Trattinnickia aspera  ( Burseraceae ) and vigorously rub it into their own fur or that of other coatis, possibly to kill  ectoparasites  such as fleas, ticks, and lice, as well as biting insects such as mosquitoes; [ 32 ]  the resin contains  triterpenes  α- and β-amyrin, the eudesmane derivative β-selinene, and the  sesquiterpene  lactone 8β-hydroxyasterolide. [ 28 ]


Domestic cats and dogs often select and ingest plant material either to induce vomiting [ 33 ]  or for anti-parasitic purposes. [ 34 ]


Indian wild boars selectively dig up and eat the roots of  pigweed  which humans use as an  anthelmintic .  Mexican folklore indicates that pigs eat  pomegranate  roots because they contain an alkaloid that is toxic to tapeworms. [ 35 ]


A study on  domestic sheep  ( Ovis aries ) has provided clear experimental proof of self-medication via individual learning. [ 6 ]  Lambs in a treatment group were allowed to consume foods and toxins (grain, tannins, oxalic acid) that lead to  malaise  (negative internal states) and then allowed to eat a substance known to alleviate each malaise ( sodium bentonite ,  polyethylene glycol  and  dicalcium phosphate , respectively). Control lambs ate the same foods and medicines, but this was disassociated temporally so they did not recuperate from the illness. After the conditioning, lambs were fed grain or food with tannins or oxalates and then allowed to choose the three medicines. The treatment animals preferred to eat the specific compound known to rectify the state of malaise induced by the food previously ingested. However, control animals did not change their pattern of use of the medicines, irrespective of the food consumed before the choice. [ 36 ]  Other  ruminants  learn to self-medicate against gastrointestinal parasites by increasing consumption of plant secondary compounds with antiparasitic actions. [ 24 ]