Psilocybin, also known as 4-phosphoryloxy- N, N-dimethyltryptamine ( 4-PO-DMT), is a natural product tryptamine alkaloid and investigational drug found in more than 200 species of , with and Serotonin effects. Effects include euphoria, changes in perception, a distorted sense of time (via brain desynchronization), and perceived spiritual experiences. It can also cause such as nausea and . Its effects depend on set and setting and one's expectations.
Psilocybin is a prodrug of psilocin. That is, the compound itself is biologically inactive but quickly converted by the body to psilocin. Psilocybin is transformed into psilocin by dephosphorylation mediated via phosphatase . Psilocin is chemically related to the neurotransmitter serotonin and acts as a non-selective agonist of the serotonin receptors. Activation of one serotonin receptor, the serotonin 5-HT2A receptor, is specifically responsible for the hallucinogenic effects of psilocin and other serotonergic psychedelics. Psilocybin is usually taken orally. By this route, its onset is about 20 to 50minutes, peak effects occur after around 60 to 90minutes, and its duration is about 4 to 6hours.
Imagery in and rock art of modern-day Algeria and Spain suggests that human use of psilocybin mushrooms predates recorded history. In Mesoamerica, the mushrooms had long been consumed in spiritual and divinatory ceremonies before Spanish chroniclers first documented their use in the 16th century. In 1958, the Swiss chemist Albert Hofmann isolated psilocybin and psilocin from the mushroom Psilocybe mexicana. His employer, Sandoz, marketed and sold pure psilocybin to physicians and clinicians worldwide for use in psychedelic therapy. Increasingly restrictive drug laws of the 1960s and the 1970s curbed scientific research into the effects of psilocybin and other hallucinogens, but its popularity as an entheogen grew in the next decade, owing largely to the increased availability of information on how to cultivate psilocybin mushrooms.
Possession of psilocybin-containing mushrooms has been outlawed in most countries, and psilocybin has been classified as a Schedule I controlled substance under the 1971 United Nations Convention on Psychotropic Substances. Psilocybin is being studied as a possible medicine in the treatment of psychiatric disorders such as depression, substance use disorders, obsessive–compulsive disorder, and other conditions such as . It is in late-stage for treatment-resistant depression.
When psilocybin is used in the form of psilocybin-containing mushrooms, microdoses are 0.1g to 0.3g and psychedelic doses are 1.0g to 3.5–5.0g in the case of dried mushrooms. The preceding 1.0 to 5.0g range corresponds to psilocybin doses of about 10 to 50mg. Psilocybin-containing mushrooms vary in their psilocybin and psilocin content, but are typically around 1% of the dried weight of the mushrooms (in terms of total or combined psilocybin and psilocin content). Psilocin is about 1.4 times as potent as psilocybin because of the two compounds' difference in Molar mass.
Psilocybin is known to strongly affect the subjective experience of the time perception.
Users having a pleasant experience can feel a sense of connection to others, nature, and the universe; other perceptions and emotions are also often intensified. Users having an unpleasant experience (a "bad trip") describe a reaction accompanied by fear, other unpleasant feelings, and occasionally by dangerous behavior. The term "bad trip" is generally used to describe a reaction characterized primarily by fear or other unpleasant emotions, not just a transitory experience of such feelings. A variety of factors may contribute to a bad trip, including "tripping" during an emotional or physical low or in a non-supportive environment (see: set and setting). Ingesting psilocybin in combination with other drugs, including alcohol, can also increase the likelihood of a bad trip. Other than the duration of the experience, the effects of psilocybin are similar to comparable dosages of lysergic acid diethylamide (LSD) or mescaline. But in the Psychedelics Encyclopedia, author Peter Stafford writes: "The psilocybin experience seems to be warmer, not as forceful and less isolating. It tends to build connections between people, who are generally much more in communication than when they use LSD."
Group therapies using "classic" psychedelics are becoming more commonly used in the Western world in clinical practice. This is speculated to grow, provided the evidence remains indicative of their safety and efficacy. In social sense, the group is shaped by their experiences surrounding psilocybin and how they view the fungus collectively. As mentioned in the anthropology article, the group partakes in a "journey" together, thus adding to the spiritual, social body where roles, hierarchies and gender are subjectively understood.
Psychedelic drugs can induce states of consciousness that have lasting personal meaning and spiritual significance in religious or spiritually inclined people; these states are called mystical experiences. Some scholars have proposed that many of the qualities of a drug-induced mystical experience are indistinguishable from mystical experiences achieved through non-drug techniques such as meditation or holotropic breathwork. In the 1960s, Walter Pahnke and colleagues systematically evaluated mystical experiences (which they called "mystical consciousness") by categorizing their common features. According to Pahnke, these categories "describe the core of a universal psychological experience, free from culturally determined philosophical or theological interpretations", and allow researchers to assess mystical experiences on a qualitative, numerical scale.
In the 1962 Marsh Chapel Experiment, run by Pahnke at the Harvard Divinity School under Leary's supervision, almost all the graduate degree seminary student volunteers who received psilocybin reported profound religious experiences. One of the participants was religious scholar Huston Smith, author of several textbooks on comparative religion; he called his experience "the most powerful cosmic homecoming I have ever experienced." In a 25-year followup to the experiment, all the subjects given psilocybin said their experience had elements of "a genuine mystical nature and characterized it as one of the high points of their spiritual life". Psychedelic researcher Rick Doblin considered the study partially flawed due to incorrect implementation of the double-blind procedure and several imprecise questions in the mystical experience questionnaire. Nevertheless, he said that the study cast "considerable doubt on the assertion that mystical experiences catalyzed by drugs are in any way inferior to non-drug mystical experiences in both their immediate content and long-term effects". Psychiatrist William A. Richards echoed this sentiment, writing in a 2007 review, "psychedelic mushroom use may constitute one technology for evoking revelatory experiences that are similar, if not identical, to those that occur through so-called spontaneous alterations of brain chemistry."
A group of researchers from Johns Hopkins School of Medicine led by Roland Griffiths conducted a study to assess the immediate and long-term psychological effects of the psilocybin experience, using a modified version of the mystical experience questionnaire and a rigorous double-blind procedure. When asked in an interview about the similarity of his work to Leary's, Griffiths explained the difference: "We are conducting rigorous, systematic research with psilocybin under carefully monitored conditions, a route which Dr. Leary abandoned in the early 1960s." Experts have praised the National Institute of Drug Abuse-funded study, published in 2006, for the soundness of its experimental design. In the experiment, 36 volunteers with no experience with hallucinogens were given psilocybin and methylphenidate (Ritalin) in separate sessions; the methylphenidate sessions served as a control and psychoactive placebo. The degree of mystical experience was measured using a questionnaire developed by Ralph W. Hood; 61% of subjects reported a "complete mystical experience" after their psilocybin session, while only 13% reported such an outcome after their experience with methylphenidate. Two months after taking psilocybin, 79% of the participants reported moderately to greatly increased life satisfaction and sense of well-being. About 36% of participants also had a strong to extreme "experience of fear" or dysphoria (i.e., a "bad trip") at some point during the psilocybin session (which was not reported by any subject during the methylphenidate session); about one-third of these (13% of the total) reported that this dysphoria dominated the entire session. These negative effects were reported to be easily managed by the researchers and did not have a lasting negative effect on the subject's sense of well-being.
A follow-up study 14months later confirmed that participants continued to attribute deep personal meaning to the experience. Almost a third of the subjects reported that the experience was the single most meaningful or spiritually significant event of their lives, and over two-thirds reported it was among their five most spiritually significant events. About two-thirds said the experience increased their sense of well-being or life satisfaction. Even after 14 months, those who reported mystical experiences scored on average 4 percentage points higher on the personality trait of Openness/Intellect; personality traits are normally stable across the lifespan for adults. Likewise, in a 2010 web-based questionnaire study designed to investigate user perceptions of the benefits and harms of hallucinogenic drug use, 60% of the 503 psilocybin users reported that their use of psilocybin had a long-term positive impact on their sense of well-being.
While many recent studies have concluded that psilocybin can cause mystical-type experiences of substantial and sustained personal meaning and spiritual significance, the medical community does not unanimously agree. Former director of the Johns Hopkins Department of Psychiatry and Behavioral Science Paul R. McHugh wrote in a book review: "The unmentioned fact in The Harvard Psychedelic Club is that LSD, psilocybin, mescaline, and the like produce not a 'higher consciousness' but rather a particular kind of 'lower consciousness' known well to psychiatrists and neurologists—namely, 'toxic delirium.'"
Psilocybin is also considered to be contraindicated in women who are pregnancy or breastfeeding due to insufficient research in this population. There are transient increases in heart rate and blood pressure with psilocybin, and hence uncontrolled cardiovascular conditions are a relative contraindication for psilocybin. Serotonin 5-HT2A receptor antagonists such as atypical antipsychotics and certain may block psilocybin's hallucinogenic effects and hence may be considered contraindicated in this sense. Monoamine oxidase inhibitors (MAOIs) may potentiate psilocybin's effects and augment its risks.
The similarity of psilocybin-induced symptoms to those of schizophrenia has made the drug a useful research tool in behavioral and neuroimaging studies of schizophrenia. In both cases, psychotic symptoms are thought to arise from a "deficient gating of sensory and cognitive information" in the brain that leads to "cognitive fragmentation and psychosis". Flashbacks (spontaneous recurrences of a previous psilocybin experience) can occur long after psilocybin use. Hallucinogen persisting perception disorder (HPPD) is characterized by a continual presence of visual disturbances similar to those generated by psychedelic substances. Neither flashbacks nor HPPD are commonly associated with psilocybin usage, and correlations between HPPD and psychedelics are further obscured by polydrug use and other variables.
Repeated use of psilocybin does not lead to physical dependence. A 2008 study concluded that, based on U.S. data from 2000 to 2002, adolescent-onset (defined here as ages 11–17) usage of hallucinogenic drugs (including psilocybin) did not increase the risk of drug dependence in adulthood; this was in contrast to adolescent usage of cannabis, cocaine, , anxiolytic medicines, and , all of which were associated with "an excess risk of developing clinical features associated with drug dependence". Likewise, a 2010 Dutch study ranked the relative harm of psilocybin mushrooms compared to a selection of 19 recreational drugs, including alcohol, cannabis, cocaine, MDMA, heroin, and tobacco. Psilocybin mushrooms were ranked as the illicit drug with the lowest harm, corroborating conclusions reached earlier by expert groups in the United Kingdom.
A review of the management of psychedelic overdoses suggested that psilocybin-related overdose management should prioritize managing the immediate adverse effects, such as anxiety and paranoia, rather than specific pharmacological interventions, as psilocybin's physiological toxicity tends to be rather limited. One analysis of people hospitalized for psilocybin poisoning found high urine concentrations of phenethylamine (PEA), indicating that PEA may contribute to the effects of psilocybin poisoning.
In rats, the median lethal dose (LD50) of psilocybin when administered orally is 280mg/kg, approximately 1.5times that of caffeine. The lethal dose of psilocybin when administered intravenously in mice is 285mg/kg, in rats is 280mg/kg, and in rabbits is 12.5mg/kg. Psilocybin comprises approximately 1% of the weight of Psilocybe cubensis mushrooms, and so nearly of dried mushrooms, or of fresh mushrooms, would be required for a person to reach the 280mg/kg LD50 value of rats. Based on the results of animal studies and limited human , the human lethal dose of psilocybin has been extrapolated to be 2,000 to 6,000mg, which is around 1,000 times greater than its effective dose of 6mg and 200times the typical recreational dose of 10 to 30mg. The Registry of Toxic Effects of Chemical Substances assigns psilocybin a relatively high therapeutic index of 641 (higher values correspond to a better safety profile); for comparison, the therapeutic indices of aspirin and nicotine are 199 and 21, respectively. The lethal dose from psilocybin toxicity alone is unknown, and has rarely been documented—, only two cases attributed to overdosing on hallucinogenic mushrooms (without concurrent use of other drugs) have been reported in the scientific literature, and those may involve factors other than psilocybin.
The serotonin 5-HT1A receptor partial agonist buspirone has been found to markedly reduce psilocybin's hallucinogenic effects in humans. Conversely, the serotonin 5-HT1A receptor antagonist pindolol has been found to potentiate the hallucinogenic effects of the related psychedelic dimethyltryptamine (DMT) by 2- to 3-fold in humans. Selective serotonin reuptake inhibitors (SSRIs) may modify psilocybin's effects. One clinical trial found that psilocybin's hallucinogenic and "good drug" effects were not modified by the SSRI escitalopram, but that its "bad drug effects" such as anxiety, as well as ego dissolution, were reduced, among other changes.
such as diazepam, alprazolam, clonazepam, and lorazepam, as well as alcohol, which act as GABAA receptor positive allosteric modulators, have been limitedly studied in combination with psilocybin and other psychedelics and are not known to directly interact with them. But these GABAergic drugs produce effects such as anxiolytic, sedation, and amnesia, and may therefore diminish or otherwise oppose psychedelics' effects. Because of this, recreational users often use benzodiazepines and alcohol as "trip killers" to manage difficult hallucinogenic experiences with psychedelics, such as experiences with prominent anxiety. This strategy's drug safety is not entirely clear and might have risks, but benzodiazepines have been used to manage psychedelics' adverse psychological effects in clinical studies and in Emergency Rooms.
Psilocin, the active form of psilocybin, is a substrate of the monoamine oxidase (MAO) enzyme MAO-A. The exact extent to which psilocin (and by extension psilocybin) is drug metabolism by MAO-A is not fully clear, but has ranged from 4% to 33% in different studies based on metabolite excretion. Circulating levels of psilocin's deamination metabolite are far higher than those of free unmetabolized psilocin with psilocybin administration. Combination of MAO-substrate psychedelics with monoamine oxidase inhibitors (MAOIs) can result in overdose and toxicity. Examples of MAOIs that may potentiate psychedelics behaving as MAO-A substrates, such as psilocin, include phenelzine, tranylcypromine, isocarboxazid, and moclobemide, as well as like harmine and harmaline and chronic tobacco smoking. An early clinical study of psilocybin in combination with short-term tranylcypromine pretreatment found that tranylcypromine marginally potentiated psilocybin's human body effects, including pressor effects and mydriasis, but overall did not significantly modify its psychoactive and hallucinogenic effects, although some of its emotional effects were said to be reduced and some of its perceptual effects were said to be amplified.
Psilocin may be metabolized to a minor extent by the cytochrome P450 (CYP450) CYP2D6 and/or CYP3A4 and appears unlikely to be metabolized by other CYP450 enzymes. The role of CYP450 enzymes in psilocin's metabolism seems to be small, and so considerable with CYP450 enzyme inhibitor and/or enzyme inducer may not be expected. Psilocin's major metabolic pathway is glucuronidation by UDP-glucuronosyltransferase enzymes including UGT1A10 and UGT1A9. Diclofenac and probenecid are inhibitors of these enzymes that theoretically might inhibit the metabolism of and thereby potentiate psilocybin's effects, but no clinical research or evidence on this possible interaction exists. Few other drugs are known to influence UGT1A10 or UGT1A9 function.
Psilocybin's and psilocin's psychedelic effects are mediated specifically by agonism of the serotonin 5-HT2A receptor. Selective serotonin 5-HT2A receptor antagonists like volinanserin block the head-twitch response (HTR), a behavioral proxy of psychedelic-like effects, induced by psilocybin in rodents, and the HTR is similarly absent in serotonin 5-HT2A receptor knockout mice. There is a significant relationship between psilocybin's hallucinogenic effects and serotonin 5-HT2A receptor occupancy in humans. Psilocybin's psychedelic effects can be blocked by serotonin 5-HT2A receptor antagonists like ketanserin and risperidone in humans.
Although serotonin 5-HT2A receptor agonism mediates the effects of psilocybin and psilocin, activation of other serotonin receptors also appears to contribute to these compounds' psychoactive and behavioral effects. Serotonin 5-HT1A receptor activation seems to inhibit the hallucinogenic effects of psilocybin and other psychedelics. Some of psilocybin's non-hallucinogenic behavioral effects in animals can be reversed by antagonists of the serotonin 5-HT1A, 5-HT2B, and 5-HT2C receptors. Psilocybin produces profoundly hypolocomotion and exploration in rodents, and this appears to be dependent on serotonin 5-HT1A receptor activation but not on activation of the serotonin 5-HT2A or 5-HT2C receptors.
In addition to its psychedelic effects, psilocin has been found to produce effects in animals, including dendritogenesis, spinogenesis, and synaptogenesis. It has been found to promote neuroplasticity in the brain in a rapid, robust, and sustained manner with a single dose. These effects appear to be mediated by intracellular serotonin 5-HT2A receptor activation. The psychoplastogenic effects of psilocybin and other serotonergic psychedelics may be involved in their potential therapeutic benefits in the treatment of psychiatric disorders such as depression. They may also be involved in the effects of microdosing. Psilocin has also been reported to act as a highly potent positive allosteric modulator of the tropomyosin receptor kinase B (TrkB), one of the receptors of brain-derived neurotrophic factor (BDNF). But psilocybin has been found to inhibit hippocampus neurogenesis in rodents.
Psilocybin produces profound anti-inflammatory effects mediated by serotonin 5-HT2A receptor activation in preclinical studies.
Psilocybin and other psychedelics produce sympathomimetic effects, such as increased heart rate and blood pressure, by activating the serotonin 5-HT2A receptor. Long-term repeated use of psilocybin may result in risk of cardiac valvulopathy and other complications by activating serotonin 5-HT2B receptors.
There is little or no acute drug tolerance with psilocybin, and hence its duration is dictated by pharmacokinetics rather than by pharmacodynamics. Conversely, tolerance and tachyphylaxis rapidly develop to psilocybin's psychedelic effects with repeated administration in humans. In addition, there is cross-tolerance with the hallucinogenic effects of other psychedelics such as LSD. Psilocybin produces downregulation of the serotonin 5-HT2A receptor in the brain in animals, an effect thought to be responsible for the development of tolerance to its psychedelic effects. Serotonin 5-HT2A receptors appear to slowly return over the course of days to weeks after psilocybin administration.
Psilocybin, in terms of psilocin, shows clear linear or dose dependence pharmacokinetics. Maximal concentrations of psilocin were 11ng/mL, 17ng/mL, and 21ng/mL with oral psilocybin doses of 15, 25, and 30mg psilocybin, respectively. The maximal levels of psilocin have been found to range from 8.2ng/mL to 37.6ng/mL across a dose range of 14 to 42mg. The dose-normalized peak concentration of psilocin is about 0.8ng/mL/mg. The interindividual variability in the pharmacokinetics of psilocybin is relatively small. There is a very strong positive correlation between dose and psilocin peak levels (R2 = 0.95). The effects of food on the pharmacokinetics of psilocybin have not been reported and are unknown, but no clear sign of food effects has been observed in preliminary analyses. It has also been said that food might delay absorption, reduce peak levels, and reduce bioavailability.
Psilocin (4-HO-DMT) is a close positional isomer of bufotenin (5-HO-DMT), which shows peripheral selectivity, and might be expected to have similarly restricted lipophilicity and blood–brain barrier permeability. But psilocin appears to form a tricyclic pseudo-ring system wherein its hydroxyl group and amine interact through . This in turn makes psilocin much less polar, more lipophilic, and more able to cross the blood–brain barrier and exert central actions than it would be otherwise. It may also protect psilocin from metabolism by monoamine oxidase (MAO). In contrast, bufotenin is not able to achieve this pseudo-ring system. Accordingly, bufotenin is less lipophilic than psilocin in terms of partition coefficient. But bufotenin does still show significant central permeability and, like psilocybin, can produce robust hallucinogenic effects in humans.
Psilocin is demethylation and oxidatively deaminated by monoamine oxidase (MAO), specifically monoamine oxidase A (MAO-A), into 4-hydroxyindole-3-acetaldehyde (4-HIAL or 4-HIA). 4-HIAL is then further oxidated into 4-hydroxyindole-3-acetic acid (4-HIAA) by aldehyde dehydrogenase (ALDH) or into 4-hydroxytryptophol (4-HTOL or 4-HTP) by alcohol dehydrogenase (ALD). Deamination of psilocin by MAO-A appears to be responsible for about 4% or 33% of its metabolism in different studies. In contrast to psilocin, its metabolites 4-HIAA and 4-HTP showed no affinity for or activation of multiple serotonin receptors and are considered inactive. Based on in vitro studies, it has been estimated that MAO-A is responsible for about 81% of psilocin's phase I hepatic metabolism. Psilocin and its metabolites are also glucuronidation by UDP-glucuronyltransferases (UGTs). UGT1A10 and UGT1A9 appear to be the most involved. Psilocybin's glucuronidated metabolites include psilocin- O-glucuronide and 4-HIAA- O-glucuronide. Approximately 80% of psilocin in blood plasma is in conjugated form, and conjugated psilocin levels are about fourfold higher than levels of free psilocin. Plasma 4-HIAA levels are also much higher than those of free psilocin.
Norpsilocin (4-HO-NMT), formed from psilocin via demethylation mediated by the cytochrome P450 enzyme CYP2D6, is known to occur in mice in vivo and with human recombinant CYP2D6 in vitro but was not detected in humans in vivo. An oxidized psilocin metabolite of unknown chemical structure is also formed by hydroxyindole oxidase activity of CYP2D6. Oxidized psilocin is possibly a quinone-type structure like psilocin iminoquinone (4-hydroxy-5-oxo- N, N-DMT) or psilocin hydroquinone (4,5-dihydroxy- N, N-DMT). Additional metabolites formed by CYP2D6 may also be present. Besides CYP2D6, CYP3A4 showed minor activity in metabolizing psilocin, though the produced metabolite is unknown. Other cytochrome P450 besides CYP2D6 and CYP3A4 appear unlikely to be involved in psilocin metabolism. CYP2D6 pharmacogenomics do not modify psilocin exposure in humans, suggesting that CYP2D6 is not critically involved in psilocin metabolism and is unlikely to result in interindividual differences in psilocin kinetics or effects. Psilocybin and psilocin might inhibit CYP3A4 and CYP2A6 to some extent, respectively.
The elimination half-life of psilocybin, as psilocin, is 2.1 to 4.7hours on average (range 1.2–18.6hours) orally and 1.2hours (range 1.8–4.5hours) intravenously. Psilocin's elimination half-life in mice is 0.9hours, much faster than in humans. Psilocin O-glucuronide's half-life is about 4hours in humans and approximately 1hour in mice.
No dose adjustment of psilocin is thought to be required as psilocin is inactivated mainly via metabolism as opposed to renal elimination. Accordingly, glomerular filtration rate (GFR) did not affect the pharmacokinetics of psilocybin.
Psilocybin's psychoactive effects and duration are strongly correlated with psilocin levels.
Single doses of psilocybin of 3 to 30mg have been found to dose-dependently occupy the serotonin 5-HT2A receptor in humans as assessed by medical imaging studies. The for occupancy of the serotonin 5-HT2A receptor by psilocin in terms of circulating levels has been found to be 1.97ng/mL.
Body weight and body mass index do not appear to affect psilocybin's pharmacokinetics. This suggests that body weight-adjusted dosing of psilocybin is unnecessary and may actually be counterproductive, and that fixed-dosing should be preferred. Similarly, age does not affect psilocybin's pharmacokinetics. The influence of sex on psilocybin's pharmacokinetics has not been tested.
Psilocybin is a white, crystalline solid that is soluble in water, methanol and ethanol but insoluble in nonpolar organic such as chloroform and petroleum ether. It has a melting point between , and an ammonia-like taste. Its pKa values are estimated to be 1.3 and 6.5 for the two successive phosphate and 10.4 for the dimethylamine nitrogen, so it typically exists as a structure. There are two known crystalline polymorphs of psilocybin, as well as reported hydrated phases. Psilocybin rapidly oxidizes upon exposure to light—an important consideration when using it as an analytical standard.
Various chromatographic methods have been developed to detect psilocin in body fluids: the rapid emergency drug identification system (REMEDi HS), a drug screening method based on HPLC; HPLC with electrochemical detection; GC–MS; and liquid chromatography coupled to mass spectrometry. Although the determination of psilocin levels in urine can be performed without sample cleanup (i.e., removing potential contaminants that make it difficult to accurately assess concentration), the analysis in blood plasma or blood serum requires preliminary extraction followed by derivatization of the extracts in the case of GC–MS. A specific immunoassay has also been developed to detect psilocin in whole blood samples. A 2009 publication reported using HPLC to quickly separate forensically important illicit drugs including psilocybin and psilocin, which were identifiable within about 30 seconds of analysis time. But these analytical techniques to determine psilocybin concentrations in body fluids are not routinely available and not typically used in clinical settings.
+ Maximum reported psilocybin concentrations (% dry weight) in 12 Psilocybe species ! scope="col" | Species ! scope="col" | % psilocybin |
P. azurescens | 1.78 | |
P. serbica | 1.34 | |
P. semilanceata | 0.98 | |
P. baeocystis | 0.85 | |
P. cyanescens | 0.85 | |
P. tampanensis | 0.68 | |
P. cubensis | 0.63 | |
Psilocybe weilii | 0.61 | |
P. hoogshagenii | 0.60 | |
P. stuntzii | 0.36 | |
P. cyanofibrillosa | 0.21 | |
P. liniformans | 0.16 |
Psilocybin is present in varying concentrations in over 200 species of Basidiomycota mushrooms. In a 2000 review on the worldwide distribution of hallucinogenic mushrooms, Gastón Guzmán and colleagues considered these to be distributed amongst the following genera: Psilocybe (116 species), Gymnopilus (14), Panaeolus (13), Copelandia (12), Hypholoma (6), Pluteus (6), Inocybe (6), Conocybe (4), Panaeolina (4), Gerronema (2), and Galerina (1 species). Guzmán increased his estimate of the number of psilocybin-containing Psilocybe to 144 species in a 2005 review. The majority of these are found in Mexico (53 species), with the remainder distributed in the United States and Canada (22), Europe (16), Asia (15), Africa (4), and Australia and associated islands (19). The diversity of psilocybin mushrooms is reported to have been increased by horizontal transfer of the psilocybin gene cluster between unrelated mushroom species. In general, psilocybin-containing species are dark-spored, gilled mushrooms that grow in meadows and woods of the and tropics, usually in soils rich in humus and plant debris. Psilocybin mushrooms occur on all continents, but the majority of species are found in subtropical humid forests. Psilocybe species commonly found in the tropics include P. cubensis and P. subcubensis. P. semilanceata—considered by Guzmán to be the world's most widely distributed psilocybin mushroom—is found in Europe, North America, Asia, South America, Australia and New Zealand, but is entirely absent from Mexico. Although the presence or absence of psilocybin is not of much use as a chemotaxonomy marker at the familial level or higher, it is used to classify taxa of lower taxonomic groups.
Both the caps and the stems contain psychoactive compounds, although the caps consistently contain more. The of these mushrooms do not contain psilocybin or psilocin. The total potency varies greatly between species and even between specimens of a species collected or grown from the same strain. Because most psilocybin biosynthesis occurs early in the formation of basidiocarp or sclerotia, younger, smaller mushrooms tend to have a higher concentration of the drug than larger, mature mushrooms. In general, the psilocybin content of mushrooms is quite variable (ranging from almost nothing to 2.5% of the dry matter) and depends on species, strain, growth and drying conditions, and mushroom size. Cultivated mushrooms have less variability in psilocybin content than wild mushrooms. The drug is more stable in dried than fresh mushrooms; dried mushrooms retain their potency for months or even years, while mushrooms stored fresh for four weeks contain only traces of the original psilocybin.
The psilocybin contents of dried herbarium specimens of Psilocybe semilanceata in one study were shown to decrease with the increasing age of the sample: collections dated 11, 33, or 118 years old contained 0.84%, 0.67%, and 0.014% (all dry weight), respectively. Mature mycelia contain some psilocybin, while young mycelia (recently germinated from spores) lack appreciable amounts. Many species of mushrooms containing psilocybin also contain lesser amounts of the analog compounds baeocystin and norbaeocystin, chemicals thought to be biogenic precursors. Although most species of psilocybin-containing mushrooms bruise blue when handled or damaged due to the Redox of phenolic compounds, this reaction is not a definitive method of identification or determining a mushroom's potency.
This process can be seen in the following diagram:
More recent research has demonstrated that—at least in P. cubensis— O-phosphorylation is in fact the third step, and that neither dimethyltryptamine nor psilocin are intermediates. The sequence of the intermediate steps has been shown to involve four enzymes (PsiD, PsiH, PsiK, and PsiM) in P. cubensis and P. cyanescens, although it is possible that the biosynthetic pathway differs between species. These enzymes are encoded in gene clusters in Psilocybe, Panaeolus, and Gymnopilus.
Escherichia coli has been genetically modified to manufacture large amounts of psilocybin. Psilocybin can be produced de novo in GM yeast.
6,000-year-old pictographs discovered near the Spanish town of Villar del Humo illustrate several mushrooms that have been tentatively identified as Psilocybe hispanica, a hallucinogenic species native to the area.
Some scholars have also interpreted archaeological artifacts from Mexico and the so-called Mayan "mushroom stones" of Guatemala as evidence of ritual and ceremonial use of psychoactive mushrooms in the Mayan and Aztec cultures of Mesoamerica.
After Spanish explorers of the New World arrived in the 16th century, chroniclers reported the use of mushrooms by the natives for ceremonial and religious purposes. According to the Dominican Order friar Diego Durán in The History of the Indies of New Spain (published c. 1581), mushrooms were eaten in festivities conducted on the occasion of Aztec emperor Moctezuma II's accession to the throne in 1502. The Franciscan friar Bernardino de Sahagún wrote of witnessing mushroom use in the Florentine Codex (published 1545–1590), and described how some merchants would celebrate upon returning from a successful business trip by consuming mushrooms to evoke revelatory visions. After the defeat of the Aztecs, the Spanish forbade traditional religious practices and rituals that they considered "pagan idolatry", including ceremonial mushroom use. For the next four centuries, the Indians of Mesoamerica hid their use of entheogens from the Spanish authorities.
Dozens of species of psychedelic mushrooms are found in Europe, but there is little documented usage of them in Old World history besides the use of Amanita muscaria among Siberian peoples.
Heim cultivated the mushrooms in France and sent samples for analysis to Albert Hofmann, a chemist employed by the Swiss pharmaceutical company Sandoz. Hofmann—who had synthesized lysergic acid diethylamide (LSD) in 1938—led a research group that isolated and identified the psychoactive alkaloids psilocybin and psilocin from Psilocybe mexicana, publishing their results in 1958. The team was aided in the discovery process by Hofmann's willingness to ingest mushroom extracts to help verify the presence of the active compounds.
Next, Hofmann's team synthesized several structural analogs of these compounds to examine how these structural changes affect psychoactivity. This research led to the development of ethocybin and CZ-74. Because these compounds' physiological effects last only about three and a half hours (about half as long as psilocybin's), they proved more manageable for use in psycholytic therapy. Sandoz also marketed and sold pure psilocybin under the name Indocybin to clinicians and researchers worldwide. There were no reports of serious complications when psilocybin was used in this way.
In the early 1960s, Harvard University became a testing ground for psilocybin through the efforts of Timothy Leary and his associates Ralph Metzner and Richard Alpert (who later changed his name to Ram Dass). Leary obtained synthesized psilocybin from Hofmann through Sandoz Pharmaceuticals. Some studies, such as the Concord Prison Experiment, suggested promising results using psilocybin in clinical psychiatry. But according to a 2008 review of safety guidelines in human hallucinogenic research, Leary's and Alpert's well-publicized termination from Harvard and later advocacy of hallucinogen use "further undermined an objective scientific approach to studying these compounds". In response to concerns about the increase in unauthorized use of psychedelic drugs by the general public, psilocybin and other hallucinogenic drugs were unfavorably covered in the press and faced increasingly restrictive laws. In the U.S., laws passed in 1966 that prohibited the production, trade, or ingestion of hallucinogenic drugs; Sandoz stopped producing LSD and psilocybin the same year. In 1970, Congress passed "The Federal Comprehensive Drug Abuse Prevention and Control Act" that made LSD, peyote, psilocybin, and other hallucinogens illegal to use for any purpose, including scientific research. United States politicians' agenda against LSD usage had swept psilocybin along with it into the Schedule I category of illicit drugs. Such restrictions on the use of these drugs in human research made funding for such projects difficult to obtain, and scientists who worked with psychedelic drugs faced being "professionally marginalized". Although Hofmann tested these compounds on himself, he never advocated their legalization or medical use. In his 1979 book LSD—mein Sorgenkind ( LSD—My Problem Child), he described the problematic use of these hallucinogens as inebriants.
Despite the legal restrictions on psilocybin use, the 1970s witnessed the emergence of psilocybin as the "entheogen of choice".
Because of lack of clarity about laws concerning psilocybin mushrooms, specifically in the form of sclerotia (also known as "truffles"), in the late 1990s and early 2000s European retailers commercialized and marketed them in in the Netherlands, the UK, and online. Several websites emerged that contributed to the accessibility of information on the mushrooms' description, use, and effects, and users exchanged mushroom experiences. Since 2001, six EU countries have tightened their legislation on psilocybin mushrooms in response to concerns about their prevalence and increasing usage. In the 1990s, hallucinogens and their effects on human consciousness were again the subject of scientific study, particularly in Europe. Advances in neuropharmacology and neuropsychology and the availability of brain imaging techniques have provided impetus for using drugs like psilocybin to probe the "neural underpinnings of psychotic symptom formation including ego disorders and hallucinations". Recent studies in the U.S. have attracted attention from the popular press and brought psilocybin back into the limelight.
In European countries, the lifetime prevalence estimates of psychedelic mushroom usage among young adults (15–34 years) range from 0.3% to 14.1%.
In modern Mexico, traditional ceremonial use survives among several indigenous groups, including the Nahuas, the Matlatzinca, the Totonacs, the Mazatecs, Mixe people, Zapotec peoples, and the Chatinos. Although hallucinogenic Psilocybe species are abundant in Mexico's low-lying areas, most ceremonial use takes places in mountainous areas of elevations greater than . Guzmán suggests this is a vestige of Spanish colonial influence from several hundred years earlier, when mushroom use was persecuted by the Catholic Church.
From 1 July 2023, the Australian medicines regulator has permitted psychiatrists to prescribe psilocybin for the therapeutic treatment of treatment-resistant depression.
Advocates of legalization argue there is a lack of evidence of harm, and potential use in treating certain mental health conditions. Research is difficult to conduct because of the legal status of psychoactive substances. Advocates of legalization also promote the utility of "ego dissolution" and argue bans are cultural discrimination against traditional users.
In 2024, after calls for regulatory and legal change to expand terminally ill populations' access to controlled substances, two legal cases related to expanded access began moving through the federal courts under right-to-try law. The Advanced Integrative Medicine Science (AIMS) Institute in concert with the NPA filed a series of lawsuits seeking both the rescheduling of and expanded right-to-try access to psilocybin.
However, some trials have not found psilocybin to significantly outperform placebo in the treatment of depression. In addition, a phase 2 trial found that two 25mg doses of psilocybin 3weeks apart versus daily treatment with the selective serotonin reuptake inhibitor (SSRI) escitalopram (Lexapro) for 6weeks (plus two putatively non-psychoactive 1mg doses of psilocybin 3weeks apart) did not show a statistically significant difference in reduction of depressive symptoms between groups. However, reductions in depressive symptoms were numerically greater with psilocybin, some outcome measure favored psilocybin, and the rate of remission was statistically higher with psilocybin (57% with psilocybin vs. 28% with escitalopram). In any case, the antidepressant effect size of psilocybin over escitalopram appears to be small.
Unblinding by their psychoactive effects and positive psychological expectancy effects (i.e., the placebo effect) are major limitations and sources of bias of clinical trials of psilocybin and other psychedelics for treatment of depression. Relatedly, most of the therapeutic benefit of conventional like the SSRIs for depression appears to be attributable to the placebo response. It has been proposed that psychedelics like psilocybin may in fact act as active placebo "" when used for therapeutic purposes. As of September 2024, psilocybin and other psychedelics (excluding MDMA) have only been assessed in up to phase 2 clinical trials for psychiatric disorders and have not yet completed larger and more rigorous phase 3 trials or received regulatory approval for medical use.
In a 2024 meta-analysis of RCTs of psychedelics and escitalopram for treatment of depression, only "high-dose" psilocybin (≥20mg) significantly outperformed escitalopram in improving depressive symptoms. It showed a large effect size over placebo but a small effect size over escitalopram ( = 0.88 vs. 0.31, respectively). A 2025 meta-analysis found a moderate effect size advantage of psilocybin relative to placebo (Hedges' g = 0.62). A 2024 network meta-analysis of RCTs of therapies for treatment-resistant depression, with effectiveness measures being response and , likewise found that psilocybin was more effective than placebo and, considering both effectiveness and tolerability or drug safety, recommended it as a first-line therapy, along with ketamine, esketamine, and electroconvulsive therapy (ECT). However, the quality of evidence was generally rated as low or very low. Meta-analyses of psychedelics for depression and other psychiatric conditions have found that psilocybin has the greatest number of studies and the most evidence of benefit, relative to other psychedelics like ayahuasca and LSD.
Preliminary meta-analyses suggest that improvements in depressive symptoms with psilocybin are dose dependence and that higher doses may result in greater improvements than lower doses. One meta-analysis found that the highest assessed dose in clinical trials, 30 to 35mg per 70kg body weight, was the most effective, with an effect size (Hedges' g) of 3.1 (relative to 1.3 overall), but based on only one study for that dosing subgroup. This meta-analysis included both RCTs and prospective open-label studies, and calculated effect sizes by comparing to the placebo group or by using pre-treatment (baseline) values. Another meta-analysis, which included only RCTs, found that 25mg was the most effective dose, relative to lower doses like 10mg and 0.215mg/kg body weight (~15mg for a 70-kg person). A third meta-analysis found that half of psilocybin's maximal antidepressant effect occurred with a dose of about 10mg per 70kg body weight, while 95% of the maximal effect occurred at a dose of about 41mg per 70kg body weight, and that higher doses might especially be better for treatment-resistant depression. The risk of was also greater with higher doses.
A 2025 network meta-analysis of RCTs of psilocybin for depression found that it did not significantly improve depression scores relative to placebo on day 2 post-dose but did improve them day 8 and day 15 post-dose. Depressive symptoms were improved only slightly more with psilocybin than with placebo. Another 2024 meta-analysis found that depressive symptoms were improved on days 2, 14, and 42, with similar effect sizes. In the previously described dose-ranging phase 2 trial of psilocybin for depression, the time to median depressive event after administration of psilocybin was 92 to 189days for 25mg, 43 to 83days for 10mg, and 21 to 62days for 1mg, depending on the analysis. Repeated dosing of psilocybin is being explored for maximization and maintenance of depressive symptom improvement, with preliminary effectiveness observed.
Most clinical trials of psilocybin for depression have had financial conflicts of interest and significant risk of bias.
In June 2025, Compass Pathways, which is developing psilocybin for treatment-resistant depression, announced the results of a phase 3 clinical trial of single-dose 25mg psilocybin (COMP360) versus placebo. Psilocybin met the primary endpoint of a significant reduction in depressive scores on the Montgomery-Asberg Depression Rating Scale (MADRS) relative to placebo. At the 6-week point, there was a 3.6-point reduction in depressive symptoms on the scale compared to placebo. The degree of improvement over placebo was small and below expectations: a minimum advantage of at least 5 points over placebo had been expected and deemed acceptable, for instance by the company's investors. After Compass Pathways's announcement, the company's stock price fell by 36%. Since October 2024, upon initially delaying the announcement of the results, Compass Pathways has laid off 30% of its staff and stopped all preclinical work unrelated to COMP360. A second phase 3 trial by Compass Pathways involving multiple different doses of psilocybin is also underway, with results expected next year.
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