Imagery incave paintings androck art of modern-dayAlgeria andSpain suggests that human use ofpsilocybin mushrooms predates recorded history.[26] InMesoamerica, the mushrooms had long been consumed in spiritual anddivinatory ceremonies before Spanish chroniclers first documented their use in the 16th century. In 1958, the Swiss chemistAlbert Hofmann isolated psilocybin and psilocin from the mushroomPsilocybe mexicana. His employer,Sandoz, marketed and sold pure psilocybin to physicians and clinicians worldwide for use inpsychedelic therapy. Increasingly restrictive drug laws of the1960s and the1970s curbed scientific research into the effects of psilocybin and other hallucinogens, but its popularity as anentheogen (spirituality-enhancing agent) grew in the next decade, owing largely to the increased availability of information on how to cultivate psilocybin mushrooms.
Psilocybin is used as a psychedelic at doses of 5 to 40mgorally.[14][31] Low doses are 5 to 10mg, an intermediate or "good effect" dose is 20mg, and high orego-dissolution doses are 30 to 40mg.[14][31]Microdosing involves the use of subthreshold psilocybin doses of less than 2.5mg.[14][31]
When psilocybin is used in the form ofpsilocybin-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.[32][33][7] The preceding 1.0 to 5.0g range corresponds to psilocybin doses of about 10 to 50mg.[7] Psilocybin-containing mushrooms vary in their psilocybin andpsilocin content, but are typically around 1% of the dried weight of the mushrooms (in terms of total or combined psilocybin and psilocin content).[33][34][19][7][25][35][36][37] Psilocybin and psilocin are fairly similar inpotency and dose, with psilocin being slightly more potent.[19][38]
American psychologist andcounterculture figureTimothy Leary conducted early experiments into the effects of psychedelic drugs, including psilocybin (1989 photo).
The ability of psilocybin to cause perceptual distortions is linked to its influence on the activity of theprefrontal cortex.
After ingesting psilocybin, the user may experience a wide range of emotional effects which can include: feelings of disorientation, lethargy, giddiness,euphoria, joy, anddepression. In one study, 31% of volunteers given a high dose reported feelings of significant fear and 17% experienced transientparanoia.[40] In studies atJohns Hopkins, among those given a moderate dose (but still enough to "give a high probability of a profound and beneficial experience"), negative experiences were rare, whereas one-third of those given a high dose experienced anxiety or paranoia.[44][45] Low doses can induce hallucinatory effects.Closed-eye hallucinations may occur, where the affected individual sees multicolored geometric shapes and vivid imaginative sequences.[46] Some individuals reportsynesthesia, such as tactile sensations when viewing colors.[47]: 175 At higher doses, psilocybin can lead to "intensification ofaffective responses, enhanced ability for introspection,regression to primitive and childlike thinking, and activation of vivid memory traces with pronounced emotional undertones".[48] Open-eye visualhallucinations are common, and may be very detailed, althoughrarely confused with reality.[46]
Psilocybin is known to strongly influence the subjective experience of thepassage of time.[49][23] Users often feel as if time is slowed down, resulting in the perception that "minutes appear to be hours" or "time is standing still".[50] Studies have demonstrated that psilocybin significantly impairs subjects' ability to gauge time intervals longer than 2.5 seconds, impairs their ability to synchronize to inter-beat intervals longer than 2 seconds, and reduces their preferredtapping rate.[50][51] These results are consistent with the drug's role in affectingprefrontal cortex activity,[52] and the role that the prefrontal cortex is known to play in time perception.[53] However, the neurochemical basis of psilocybin's effects on the perception of time are not known with certainty.[54]
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. In general, the phrase "bad trip" is used to describe a reaction that is characterized primarily by fear or other unpleasant emotions, not just a transitory experience of such feelings. A variety of factors may contribute to a psilocybin user experiencing 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, includingalcohol, can also increase the likelihood of a bad trip.[40][55] Other than theduration of the experience, the effects of psilocybin are similar to comparable dosages oflysergic acid diethylamide (LSD) ormescaline. However, in thePsychedelics Encyclopedia, authorPeter Stafford noted, "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."[56]: 273
The effects of psilocybin are highly variable and depend on the mindset and environment in which the user has the experience: factors commonly referred to asset and setting. In the early 1960s,Timothy Leary and colleagues at Harvard University investigated the role of set and setting on the effects of psilocybin. They administered the drug to 175 volunteers (from various backgrounds) in an environment intended to be similar to a comfortable living room. 98 of the subjects were given questionnaires to assess their experiences and the contribution of background and situational factors. Individuals who had experience with psilocybin prior to the study reported more pleasant experiences than those for whom the drug was novel. Group size, dosage, preparation, and expectancy were important determinants of the drug response. In general, those in groups of more than eight felt that the groups were less supportive, and their experiences less pleasant. Conversely, smaller groups (fewer than six) were seen as more supportive and reported more positive reactions to the drug in those groups. Leary and colleagues proposed that psilocybin heightens suggestibility, making an individual more receptive to interpersonal interactions and environmental stimuli.[57] These findings were affirmed in a later review by Jos ten Berge (1999), who concluded that dosage, set, and setting were fundamental factors in determining the outcome of experiments that tested the effects of psychedelic drugs on artists' creativity.[58]
Psychedelics, including psilocybin, have been shown to affect different clusters of brain regions known as the "theory of mind network" (ToMN) and thedefault mode network (DMN).[59] The ToMN involves making inferences and understanding social situations based on patterns[60] whereas, the DMN relates more to introspection and one's sense of self.[59] The DMN in particular is related to increased rumination and worsening self-image in patients with major depressive disorder (MDD).[61] In studies done with single use psilocybin, areas of the DMN showed decreased functional connectivity (communication between areas of the brain). This provides functional insight into the work of psilocybin in increasing one's sense of connection to one's surroundings, as the areas of the brain involved in introspection decrease in functionality under the effects of the drug.[62] Conversely, areas of the brain involved in the ToMN showed increased activity and functional activation in response to psychedelics. These results were not unique to psilocybin and there was no significant difference in brain activation found in similar trials of mescaline and LSD. Information and studies into the DMN and ToMN are relatively sparse and their connections to other psychiatric illnesses and the use of psychedelics is still largely unknown.[59]
Through furtheranthropological studies regarding "personal insights"[63] and the psychosocial effects of psilocybin, it can be seen in many traditional societies that powerful mind-active substances such as psilocybin are regularly "consumed ritually for therapeutic purposes or for transcending normal, everyday reality".[64] Positive effects that psilocybin has on individuals can be observed by taking on an anthropological approach and moving away from the Western biomedical view; this is aided by the studies done by Leary.[65] Within certain traditional societies, where the use of psilocybin is frequent for shamanic healing rituals, group collectives praise their guide, healer and shaman for helping alleviate their pains, aches and hurt. They do this through a group ritual practice where the group, or just the guide, ingests psilocybin to help extract any "toxic psychic residues or sorcerous implants"[64] found in one's body.
Group therapies using "classic" psychedelics are becoming more commonly used in the Western world in clinical practice.[66] This is speculated to grow, provided the evidence remains indicative of their safety and efficacy.[67] In social sense, the group is shaped by their experiences surrounding psilocybin and how they view the plant collectively. As mentioned in the anthropology article,[64] the group partakes in a "journey" together, thus adding to the spiritual, social body where roles, hierarchies and gender are subjectively understood.[64]
In their studies on the psilocybin experience, Johns Hopkins researchers use peaceful music and a comfortable room to help ensure a comfortable setting, and experienced guides to monitor and reassure the volunteers.
Psilocybin mushrooms have been and continue to be used inIndigenous American cultures in religious,divinatory, orspiritual contexts. Reflecting the meaning of the wordentheogen ("the god within"), the mushrooms are revered as powerful spiritualsacraments that provide access to sacred worlds. Typically used in small group community settings, they enhancegroup cohesion and reaffirm traditional values.[68]Terence McKenna documented the worldwide practices of psilocybin mushroom usage as part of a culturalethos relating to the Earth and mysteries of nature, and suggested that mushrooms enhancedself-awareness and a sense of contact with a "Transcendent Other"—reflecting a deeper understanding of our connectedness with nature.[69]
Psychedelic drugs can induce states ofconsciousness that have lasting personal meaning and spiritual significance in religious or spiritually inclined people; these states are calledmystical experiences. Some scholars have proposed that many of the qualities of a drug-induced mystical experience are indistinguishable from mystical experiences achieved throughnon-drug techniques such as meditation orholotropic breathwork.[70][71] 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.[72]
In the 1962Marsh Chapel Experiment, run by Pahnke at theHarvard Divinity School under Leary's supervision ,[73] almost all the graduate degreedivinity student volunteers who received psilocybin reported profound religious experiences.[74] One of the participants was religious scholarHuston Smith, author of several textbooks oncomparative religion; he called his experience "the most powerful cosmic homecoming I have ever experienced."[75] 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".[76]: 13 Psychedelic researcherRick Doblin considered the study partially flawed due to incorrect implementation of thedouble-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".[76]: 24 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."[77]
A group of researchers fromJohns Hopkins School of Medicine led byRoland 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.[78] 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."[79] Experts have praised theNational Institute of Drug Abuse-funded study, published in 2006, for the soundness of its experimental design.[b] In the experiment, 36 volunteers with no experience with hallucinogens were given psilocybin andmethylphenidate (Ritalin) in separate sessions; the methylphenidate sessions served as acontrol and psychoactiveplacebo. The degree of mystical experience was measured using a questionnaire developed by Ralph W. Hood;[80] 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 increasedlife satisfaction and sense of well-being. About 36% of participants also had a strong to extreme "experience of fear" ordysphoria (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.[81]
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.[74] Even after 14 months, those who reported mystical experiences scored on average 4 percentage points higher on the personality trait ofOpenness/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.[40][82]
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 SciencePaul R. McHugh wrote in a book review: "The unmentioned fact inThe 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, 'toxicdelirium.'"[83]
Common responses includepupil dilation (93%); changes inheart rate (100%), including increases (56%), decreases (13%), and variable responses (31%); changes inblood pressure (84%), includinghypotension (34%),hypertension (28%), and general instability (22%); changes instretch reflex (86%), including increases (80%) and decreases (6%); nausea (44%);tremor (25%); anddysmetria (16%) (inability to properly direct or limit motions).[2][c] Psilocybin'ssympathomimetic orcardiovascular effects, including increasedheart rate andblood pressure, are usually mild.[24][2] On average, peak heart rate is increased by 5bpm, peaksystolic blood pressure is increased by 10 to 15mmHg, and peakdiastolic blood pressure is increased by 5 to 10mmHg.[24][2] But temporary increases in blood pressure can be a risk factor for users with preexisting hypertension.[46] Psilocybin's somatic effects have been corroborated by several early clinical studies.[85] A 2005 magazine survey of clubgoers in the UK found that over a quarter of those who had used psilocybin mushrooms in the preceding year experienced nausea or vomiting, although this was caused by the mushroom rather than psilocybin itself.[40] In one study, administration of gradually increasing dosages of psilocybin daily for 21 days had no measurable effect onelectrolyte levels,blood sugar levels, orliver toxicity tests.[2]
Most of the comparatively few fatal incidents associated with psychedelic mushroom usage involve the simultaneous use of other drugs, especiallyalcohol. A commonadverse effect resulting from psilocybin mushroom use involves "bad trips" orpanic reactions, in which people become anxious, confused, agitated, or disoriented.[97] Accidents,self-injury, orsuicide attempts can result from serious cases of acutepsychotic episodes.[40] No studies have linked psilocybin withbirth defects,[98] but it is recommended that pregnant women avoid its usage.[99]
Panic reactions can occur after consumption of psilocybin-containing mushrooms, especially if the ingestion is accidental or otherwise unexpected. Reactions characterized by violent behavior, suicidal thoughts,[100] schizophrenia-likepsychosis,[101][102] andconvulsions[103] have been reported in the literature. A 2005 survey conducted in the United Kingdom found that almost a quarter of those who had used psilocybin mushrooms in the past year had experienced a panic attack.[40][failed verification] Less frequently reported adverse effects include paranoia,confusion, prolongedderealization (disconnection from reality), andmania.[82] Psilocybin usage can temporarily induce a state ofdepersonalization disorder.[104] Usage by those withschizophrenia can induce acute psychotic states requiring hospitalization.[105]
The similarity of psilocybin-induced symptoms to those of schizophrenia has made the drug a useful research tool in behavioral andneuroimaging studies of schizophrenia.[106][107][108] 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".[107]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,[40] and correlations between HPPD and psychedelics are further obscured bypolydrug use and other variables.[109]
Chart of dependence potential and effective dose/lethal dose ratio of severalpsychoactive drugs.[110]
Tolerance to psilocybin builds and dissipates quickly; ingesting it more than about once a week can lead to diminished effects. Tolerance dissipates after a few days, so doses can be spaced several days apart to avoid the effect.[6] Across-tolerance can develop between psilocybin and LSD,[111] and between psilocybin andphenethylamines such asmescaline andDOM.[112]
Repeated use of psilocybin does not lead tophysical dependence.[2] 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 ofdrug dependence in adulthood; this was in contrast to adolescent usage ofcannabis,cocaine,inhalants,anxiolytic medicines, andstimulants, all of which were associated with "an excess risk of developing clinical features associated with drug dependence".[3] Likewise, a 2010 Dutch study ranked the relative harm of psilocybin mushrooms compared to a selection of 19recreational drugs, including alcohol, cannabis, cocaine,ecstasy,heroin, andtobacco. Psilocybin mushrooms were ranked as the illicit drug with the lowest harm,[4] corroborating conclusions reached earlier by expert groups in the United Kingdom.[5]
A potential risk of frequent repeated use of psilocybin and other psychedelics iscardiac fibrosis andvalvulopathy caused byserotonin5-HT2B receptor activation.[113][114] But single high doses or widely spaced doses (e.g., months apart) are thought to be safe, and concerns about cardiac toxicity apply more to chronicpsychedelic microdosing or very frequent intermittent use (e.g., weekly).[113][114]
Psilocybin has lowtoxicity, meaning that it has a low risk of inducing life-threatening events like breathing or heart problems.[97] Research shows that health risks may develop with use of psilocybin. Nonetheless,hospitalizations from it are rare, andoverdoses are generally mild and self-limiting.[97]
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.[115] One analysis of people hospitalized for psilocybin poisoning found high urine concentrations ofphenethylamine (PEA), indicating that PEA may contribute to the effects of psilocybin poisoning.[115]
In rats, themedian lethal dose (LD50) when administered orally is 280 milligrams per kilogram (mg/kg), approximately one and a half times that ofcaffeine. The lethal dose of psilocybin when administeredintravenously in mice is 285mg/kg and in rats is 280 mg/kg.[21] When administeredintravenously in rabbits, psilocybin's LD50 is approximately 12.5 mg/kg.[116] Psilocybin comprises approximately 1% of the weight ofPsilocybe cubensis mushrooms, and so nearly 1.7 kilograms (3.7 lb) of dried mushrooms, or 17 kilograms (37 lb) of fresh mushrooms, would be required for a 60-kilogram (130 lb) person to reach the 280 mg/kg LD50 value of rats.[40] Based on the results of animal studies, thelethal dose of psilocybin has been extrapolated to be 6 grams, 1,000 times greater than theeffective dose of 6 milligrams.[117] TheRegistry of Toxic Effects of Chemical Substances assigns psilocybin a relatively hightherapeutic index of 641 (higher values correspond to a better safety profile); for comparison, the therapeutic indices ofaspirin andnicotine are 199 and 21, respectively.[118] The lethal dose from psilocybin toxicity alone is unknown, and has rarely been documented—as of 2011[update], 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.[40][d]
Psilocybin's and psilocin's psychedelic effects are mediated specifically by agonism of the serotonin 5-HT2A receptor.[14][10]Selective serotonin 5-HT2A receptorantagonists likevolinanserin block thehead-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 receptorknockout mice.[10][19][156][155] There is a significant relationship between psilocybin's hallucinogenic effects and serotonin 5-HT2A receptoroccupancy in humans.[14][112][157] Psilocybin's psychedelic effects can be blocked by serotonin 5-HT2A receptor antagonists likeketanserin andrisperidone in humans.[158][14][10][112][101] Activation of serotonin 5-HT2A receptors inlayer V of themedial prefrontal cortex (mPFC) and consequentglutamate release in this area has been especially implicated in the hallucinogenic effects of psilocybin and other serotonergic psychedelics.[159][160][161][162][163] In addition, region-dependent alterations in brain glutamate levels may be related to the experience ofego dissolution.[164] Serotonin5-HT1A receptor activation seems to inhibit the hallucinogenic effects of psilocybin and other psychedelics.[95][124][125][126]
Although serotonin 5-HT2A receptor agonism mediates thehallucinogenic effects of psilocybin and psilocin, activation of other serotonin receptors also appears to contribute to these compounds'psychoactive and behavioral effects.[112][10][19][165][166][167] Some of psilocybin's non-hallucinogenic behavioral effects in animals can be reversed by antagonists of the serotonin 5-HT1A,5-HT2B, and5-HT2C receptors.[10][19] Psilocybin produces profoundlydecreased locotomotor andinvestigatory behavior 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.[161][162][168] In addition, the serotonin5-HT1B receptor has been found to be required for psilocybin's persistingantidepressant- andanxiolytic-like effects as well as acute hypolocomotion in animals.[169] In humans, ketanserin blocked psilocybin's hallucinogenic effects but not all of its cognitive and behavioral effects.[112] Serotonin 5-HT2C receptor activation and downstream inhibition of themesolimbic dopamine pathway may be involved in the limitedaddictive potential of serotonergic psychedelics like psilocybin.[170]
Psilocybin produces profoundanti-inflammatory effects mediated by serotonin 5-HT2A receptor activation inpreclinical studies.[179][180][181] These effects have a potency similar to that of(R)-DOI, and its anti-inflammatory effects occur at far lower doses than those that produce hallucinogen-like effects in animals.[182][179][180][183] Psilocybin's anti-inflammatory effects might be involved in its potential antidepressant benefits and might also have other therapeutic applications, such as treatment ofasthma andneuroinflammation.[179][180][184] They may also be involved in microdosing effects.[185][181] But psychedelics have been found to have anti-inflammatory effects only in the setting of preexistinginflammation and may bepro-inflammatory outside that context.[186] Psilocybin has been found to have a large, long-lasting impact on theintestinal microbiome and to influence thegut–brain axis in animals.[187][188][189][166][190][191] These effects are partially but not fully dependent on its activation of the serotonin 5-HT2A and/or 5-HT2C receptors.[166] Some of psilocybin's behavioral and potential therapeutic effects may be mediated by changes to the gut microbiome.[166][189][191] Transplantation of intestinal contents of psilocybin-treated rodents to untreated rodents resulted in behavioral changes consistent with those of psilocybin administration.[166]
There is little or no acutetolerance with psilocybin, and hence itsduration is dictated bypharmacokinetics rather than bypharmacodynamics.[14][86] Conversely, tolerance andtachyphylaxis rapidly develop to psilocybin's psychedelic effects with repeated administration in humans.[18][194][161][112] In addition, there iscross-tolerance with the hallucinogenic effects of other psychedelics such as LSD.[18][194][161][112] Psilocybin producesdownregulation 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.[18][194][161][112] Serotonin 5-HT2A receptors appear to slowly return over the course of days to weeks after psilocybin administration.[18]
There has been little research on psilocybin'sbioavailability.[15] Itsoral bioavailability, as itsactive formpsilocin, was about 55.0% (± ~20%) relative tointravenous administration in one small older study (n=3).[15][10][11][12] After oral administration, psilocybin is detectable in the blood circulation within 20 to 40minutes, and psilocin is detectable after 30minutes.[11][19] The meantime to peak levels for psilocin is 1.05 to 3.71hours in different studies, with most around 2hours and the upper limit of 3.71hours being anoutlier.[15][16][19]
Psilocybin, in terms of psilocin, shows clear linear ordose-dependentpharmacokinetics.[15][14][10][11][86][195] Maximal concentrations of psilocin were 11ng/mL, 17ng/mL, and 21ng/mL with oral psilocybin doses of 15, 25, and 30mg psilocybin, respectively.[86] 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.[16] The dose-normalized peak concentration of psilocin is about 0.8ng/mL/mg.[15] Theinterindividual variability in the pharmacokinetics of psilocybin is relatively small.[86] There is a very strong positive correlation between dose and psilocin peak levels (R2 = 0.95).[16] 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.[15] It has also been said that food might delayabsorption, reduce peak levels, and reduce bioavailability.[24]
Psilocin isdemethylated andoxidatively deaminated bymonoamine oxidase (MAO), specificallymonoamine oxidase A (MAO-A), into 4-hydroxyindole-3-acetaldehyde (4-HIAL or 4-HIA).[10][7][204] 4-HIAL is then further oxidated into 4-hydroxyindole-3-acetic acid (4-HIAA) byaldehyde dehydrogenase (ALDH) or into 4-hydroxytryptophol (4-HTOL or 4-HTP) byalcohol dehydrogenase (ALD).[10][7] Deamination of psilocin by MAO-A appears to be responsible for about 4% or 33% of its metabolism in different studies.[137][86][19] 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.[10][24][137] Based onin vitro studies, it has been estimated that MAO-A is responsible for about 81% of psilocin'sphase I hepatic metabolism.[204] Psilocin and its metabolites are alsoglucuronidated byUDP-glucuronyltransferases (UGTs).[15][10][7][137]UGT1A10 andUGT1A9 appear to be the most involved.[15][10][19] Psilocybin's glucuronidated metabolites include psilocin-O-glucuronide and 4-HIAA-O-glucuronide.[10][7][137] Approximately 80% of psilocin inblood plasma is inconjugated form, and conjugated psilocin levels are about fourfold higher than levels of free psilocin.[137][19] Plasma 4-HIAA levels are also much higher than those of free psilocin.[10]
Norpsilocin (4-HO-NMT), formed from psilocin via demethylation mediated by thecytochrome P450enzymeCYP2D6, is known to occur in micein vivo and with human recombinant CYP2D6in vitro but was not detected in humansin vivo.[137] An oxidized psilocin metabolite of unknownchemical structure is also formed by hydroxyindole oxidase activity of CYP2D6.[137][19] Oxidized psilocin is possibly aquinone-type structure like psilocin iminoquinone (4-hydroxy-5-oxo-N,N-DMT) or psilocin hydroquinone (4,5-dihydroxy-N,N-DMT).[137][19] Additional metabolites formed by CYP2D6 may also be present.[137] Besides CYP2D6,CYP3A4 showed minor activity in metabolizing psilocin, though the produced metabolite is unknown.[137] Othercytochrome P450enzymes besides CYP2D6 and CYP3A4 appear unlikely to be involved in psilocin metabolism.[137] CYP2D6metabolizer phenotypes 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.[24][137] Psilocybin and psilocin might inhibitCYP3A4 andCYP2A6 to some extent, respectively.[16]
Psilocybin iseliminated 80% to 85% inurine and 15 to 20% inbile.[24] It isexcreted mainly in urine as psilocin-O-glucuronide.[24][201] The drug was eliminated approximately 20% and 80% as psilocinO-glucuronide in different studies.[15][201][19][86] The amountexcreted as unchanged psilocin in urine is 1.5 to 3.4%.[15][201][10][86] Studies conflict on the deaminated metabolites of psilocin, with one study finding that only 4% of psilocin is metabolized into 4-HIAA, 4-HIAL, and 4-HTOL[19] and another that psilocybin is excreted 33% in urine as 4-HIAA.[137][86] Findings also conflict on whether psilocybin can be detected in urine, with either no psilocybin excreted or 3% to 10% excreted as unchanged psilocybin.[202][2][15][7][19] A majority of psilocybin and its metabolites is excreted within three hours with oral administration and elimination is almost complete within 24hours.[19][7][86]
Theelimination 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.[15][16][10][19] Psilocin's elimination half-life in mice is 0.9hours, much faster than in humans.[137] PsilocinO-glucuronide's half-life is about 4hours in humans and approximately 1hour in mice.[137]
No dose adjustment of psilocin is thought to be required as psilocin is inactivated mainly via metabolism as opposed to renal elimination.[15][24][86] Accordingly,glomerular filtration rate (GFR) did not affect the pharmacokinetics of psilocybin.[15][24][86]
Single doses of psilocybin of 3 to 30mg have been found to dose-dependently occupy the serotonin 5-HT2A receptor in humans as assessed byimaging studies.[10] TheEC50Tooltip half-maximal effective concentration for occupancy of the serotonin 5-HT2A receptor by psilocin in terms of circulating levels has been found to be 1.97ng/mL.[10]
Body weight andbody mass index do not appear to affect the pharmacokinetics of psilocybin.[14][24][86] This suggests that body weight-adjusted dosing of psilocybin is unnecessary and may actually be counterproductive and that fixed-dosing should be preferred.[24][86] Similarly,age does not affect the pharmacokinetics of psilocybin.[15] The influence ofsex on psilocybin pharmacokinetics has not been tested.[15]
The neurotransmitterserotonin is structurally similar to psilocybin.
Psilocybin is a naturally occurringsubstituted tryptamine that features anindole ring linked to anaminoethylsubstituent. It is structurally related toserotonin, amonoamine neurotransmitter that is a derivative of theamino acidtryptophan. Psilocybin is a member of the general class of tryptophan-based compounds that originally functioned asantioxidants in earlier life forms before assuming more complex functions in multicellular organisms, including humans.[205] Other related indole-containing psychedelic compounds includedimethyltryptamine, found in many plant species and in trace amounts in some mammals, andbufotenin, found in the skin of certain amphibians, especially theColorado River toad.[206]: 10–13
Albert Hofmann et al. were the first to synthesize psilocybin, in 1958. Since then, various chemists have improved the methods for laboratory synthesis and purification of psilocybin. In particular, Shirota et al. reported a novel method in 2003 for the synthesis of psilocybin at the gram scale from 4-hydroxyindole that does not requirechromatographic purification. Fricke et al. described an enzymatic pathway for the synthesis of psilocybin and psilocin, publishing their results in 2017. Sherwood et al. significantly improved upon Shirota's method (producing at the kilogram scale while employing less expensive reagents), publishing their results in 2020.[210]
Various chromatographic methods have been developed to detect psilocin inbody fluids: the rapid emergency drug identification system (REMEDi HS), adrug screening method based on HPLC;[222] HPLC with electrochemical detection;[220][223] GC–MS;[224][222] andliquid chromatography coupled to mass spectrometry.[225] 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 inplasma orserum requires preliminaryextraction followed byderivatization of the extracts in the case of GC–MS. A specificimmunoassay has also been developed to detect psilocin in whole blood samples.[226] 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.[227] But these analytical techniques to determine psilocybin concentrations in body fluids are not routinely available and not typically used inclinical settings.[55]
Psilocybin is present in varying concentrations in over 200 species ofBasidiomycota mushrooms. In a 2000 review on the worldwide distribution of hallucinogenic mushrooms,Gastón Guzmán and colleagues considered these to be distributed amongst the followinggenera:Psilocybe (116 species),Gymnopilus (14),Panaeolus (13),Copelandia (12),Hypholoma (6),Pluteus (6),Inocybe (6),Conocybe (4),Panaeolina (4),Gerronema (2), andGalerina (1 species).[229] Guzmán increased his estimate of the number of psilocybin-containingPsilocybe 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).[230] The diversity of psilocybin mushrooms is reported to have been increased by horizontal transfer of the psilocybingene cluster between unrelated mushroom species.[231][232] In general, psilocybin-containing species are dark-spored,gilled mushrooms that grow in meadows and woods of thesubtropics andtropics, usually in soils rich inhumus and plant debris.[206]: 5 Psilocybin mushrooms occur on all continents, but the majority of species are found insubtropical humid forests.[229]Psilocybe species commonly found in the tropics includeP. cubensis andP. subcubensis.P. semilanceata—considered by Guzmán to be the world's most widely distributed psilocybin mushroom[233]—is found in Europe, North America, Asia, South America, Australia and New Zealand, but is entirely absent from Mexico.[230] Although the presence or absence of psilocybin is not of much use as achemotaxonomical marker at thefamilial level or higher, it is used to classifytaxa of lower taxonomic groups.[234]
Global distribution of over 100 psychoactive species of genusPsilocybe mushrooms.[235]
P. semilanceata is common in Europe, Canada, and the United States.
Both thecaps and thestems contain psychoactive compounds, although the caps consistently contain more. Thespores of these mushrooms do not contain psilocybin or psilocin.[215][236][237] The totalpotency varies greatly between species and even between specimens of a species collected or grown from the same strain.[238] Because most psilocybin biosynthesis occurs early in the formation offruit bodies orsclerotia, younger, smaller mushrooms tend to have a higher concentration of the drug than larger, mature mushrooms.[239] In general, the psilocybin content of mushrooms is quite variable (ranging from almost nothing to 2.5% of thedry weight)[240][56]: 248 and depends on species, strain, growth and drying conditions, and mushroom size.[228]: 36–41, 52 Cultivated mushrooms have less variability in psilocybin content than wild mushrooms.[241] The drug is more stable in dried than fresh mushrooms; dried mushrooms retain their potency for months or even years,[228]: 51–5 while mushrooms stored fresh for four weeks contain only traces of the original psilocybin.[40]
The psilocybin contents of driedherbarium specimens ofPsilocybe 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.[242] Maturemycelia contain some psilocybin, while young mycelia (recentlygerminated from spores) lack appreciable amounts.[243] Many species of mushrooms containing psilocybin also contain lesser amounts of the analog compoundsbaeocystin andnorbaeocystin,[228]: 38 chemicals thought to be biogenicprecursors.[47]: 170 Although most species of psilocybin-containing mushrooms bruise blue when handled or damaged due to theoxidization of phenolic compounds, this reaction is not a definitive method of identification or determining a mushroom's potency.[238][228]: 56–58
This process can be seen in the following diagram:[245]
Biosynthetic route previously thought to lead to psilocybin. It has recently been shown that 4-hydroxylation and O-phosphorylation immediately follow decarboxylation, and neither dimethyltryptamine nor psilocin are intermediates, although spontaneously generated psilocin can be converted back to psilocybin.[245]
More recent research has demonstrated that—at least inP. cubensis—O-phosphorylation is in fact the third step, and that neither dimethyltryptamine nor psilocin are intermediates.[245] The sequence of the intermediate steps has been shown to involve four enzymes (PsiD, PsiH, PsiK, and PsiM) inP. cubensis andP. cyanescens, although it is possible that the biosynthetic pathway differs between species.[206]: 12–13 [245] These enzymes are encoded ingene clusters inPsilocybe, Panaeolus, andGymnopilus.[232]
Escherichia coli has been genetically modified to manufacture large amounts of psilocybin.[246] Psilocybin can be producedde novo in GM yeast.[247][248]
There is evidence to suggest that psychoactive mushrooms have been used by humans in religious ceremonies for thousands of years. TheTassili Mushroom Figure was discovered inTassili,Algeria, and is believed to depict psychedelic mushrooms and the transformation of the user under their influence. The paintings are said to date back to 9000-7000 BC.[249]
6,000-year-oldpictographs discovered near the Spanish town ofVillar del Humo illustrate several mushrooms that have been tentatively identified asPsilocybe hispanica, a hallucinogenic species native to the area.[250]
Some scholars have also interpreted archaeologicalartifacts fromMexico and the so-calledMayan "mushroom stones" ofGuatemala as evidence of ritual and ceremonial use of psychoactive mushrooms in theMayan andAztec cultures ofMesoamerica.[228]: 11 InNahuatl, the language of the Aztecs, the mushrooms were calledteonanácatl—literally "divine mushroom": the agglutinative form of teō(tl) ("god", "sacred") and nanācatl ("mushroom") in Nahuatl.[citation needed] After Spanish explorers of theNew World arrived in the 16th century, chroniclers reported the use of mushrooms by the natives for ceremonial and religious purposes. According to theDominican friarDiego Durán inThe History of the Indies of New Spain (published c. 1581), mushrooms were eaten in festivities conducted on the occasion of Aztec emperorMoctezuma II's accession to the throne in 1502. TheFranciscan friarBernardino de Sahagún wrote of witnessing mushroom use in theFlorentine Codex (published 1545–1590),[251]: 164 and described how some merchants would celebrate upon returning from a successful business trip by consuming mushrooms to evoke revelatory visions.[252]: 118 After thedefeat 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 ofMesoamerica hid their use ofentheogens from the Spanish authorities.[251]: 165
Dozens of species of psychedelic mushrooms are found in Europe, but there is little documented usage of them inOld World history besides the use ofAmanita muscaria among Siberian peoples.[253][254] The few existing accounts that mention psilocybin mushrooms typically lack sufficient information to allow species identification, focusing on their effects. For example, Flemish botanistCarolus Clusius (1526–1609) described thebolond gomba ("crazy mushroom"), used in ruralHungary to prepare love potions. English botanistJohn Parkinson included details about a "foolish mushroom" in his 1640herbalTheatricum Botanicum.[255]: 10–12 The first reliably documented report of intoxication withPsilocybe semilanceata—Europe's most common and widespread psychedelic mushroom—involved a British family in 1799, who prepared a meal with mushrooms they had picked in London'sGreen Park.[255]: 16
Albert Hofmann (shown here in 1993) purified psilocybin and psilocin fromPsilocybe mexicana in the late 1950s.The increasing availability of information on growing techniques eventually made it possible for amateurs to grow psilocybin mushrooms (Psilocybe cubensis pictured) without access to laboratory equipment.
Heim cultivated the mushrooms in France and sent samples for analysis toAlbert Hofmann, a chemist employed by the Swiss pharmaceutical companySandoz (now Novartis). Hofmann—who had synthesizedlysergic acid diethylamide (LSD) in 1938—led a research group that isolated and identified the psychoactive alkaloids psilocybin and psilocin fromPsilocybe mexicana, publishing their results in 1958.[252]: 128 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.[252]: 126–127
Next, Hofmann's team synthesized severalstructural analogs of these compounds to examine how these structural changes affect psychoactivity. This research led to the development ofethocybin andCZ-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 inpsycholytic therapy.[56]: 237 Sandoz also marketed and sold pure psilocybin under the name Indocybin to clinicians and researchers worldwide.[251]: 166 There were no reports of serious complications when psilocybin was used in this way.[2]
In the early 1960s,Harvard University became a testing ground for psilocybin through the efforts of Timothy Leary and his associatesRalph Metzner and Richard Alpert (who later changed his name toRam Dass). Leary obtained synthesized psilocybin from Hofmann through Sandoz Pharmaceuticals. Some studies, such as theConcord Prison Experiment, suggested promising results using psilocybin inclinical psychiatry.[57][258] 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".[259] 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.[260] 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.[261] United States politicians' agenda against LSD usage had swept psilocybin along with it into theSchedule 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".[262] Although Hofmann tested these compoundson himself, he never advocated their legalization or medical use. In his 1979 bookLSD—mein Sorgenkind (LSD—My Problem Child), he described the problematic use of these hallucinogens as inebriants.[252]: 79–116
Despite the legal restrictions on psilocybin use, the 1970s witnessed the emergence of psilocybin as the "entheogen of choice".[263]: 276 This was due in large part to wide dissemination of information on the topic, which included works such as those byCarlos Castaneda and several books that taught the technique of growing psilocybin mushrooms. One of the most popular of the latter group,Psilocybin: Magic Mushroom Grower's Guide, was published in 1976 under the pseudonyms O. T. Oss and O. N. Oeric by Jeremy Bigwood,Dennis J. McKenna, K. Harrison McKenna, and Terence McKenna. Over 100,000 copies were sold by 1981.[264] As ethnobiologistJonathan Ott explains, "These authors adapted San Antonio's technique (for producing edible mushrooms by casingmycelial cultures on a rye grain substrate; San Antonio 1971) to the production ofPsilocybe [Stropharia] cubensis. The new technique involved the use of ordinary kitchen implements, and for the first time the layperson was able to produce a potent entheogen in his own home, without access to sophisticated technology, equipment or chemical supplies."[263]: 290 San Antonio's technique describes a method to grow the common edible mushroomAgaricus bisporus.[265]
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 insmartshops in the Netherlands, the UK, and online. Several websites[e] emerged that contributed to the accessibility of information on the mushrooms' description, use, and effects, and users exchanged mushroom experiences. Since 2001, sixEU countries have tightened their legislation on psilocybin mushrooms in response to concerns about their prevalence and increasing usage.[39] In the 1990s, hallucinogens and their effects on human consciousness were again the subject of scientific study, particularly in Europe. Advances inneuropharmacology andneuropsychology 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".[48] Recent studies in the U.S. have attracted attention from the popular press and brought psilocybin back into the limelight.[266][267]
DriedPsilocybe mushrooms showing the characteristic blue bruising on the stems.
A 2009 national survey of drug use by theUS Department of Health and Human Services concluded that the number of first-time psilocybin mushroom users in the United States was roughly equivalent to the number of first-time users of cannabis.[268] A June 2024 report by theRAND Corporation suggests the total number of use days for psychedelics is two orders of magnitude smaller than it is for cannabis, and unlike people who use cannabis and many other drugs, infrequent users of psychedelics account for most of the total days of use.[269] The 2024 report by the RAND Corporation suggests psilocybin mushrooms may be the most prevalent psychedelic drug among adults in the United States.[269]
In European countries, the lifetime prevalence estimates of psychedelic mushroom usage among young adults (15–34 years) range from 0.3% to 14.1%.[270]
In modern Mexico, traditional ceremonial use survives among several indigenous groups, including theNahuas, theMatlatzinca, theTotonacs, theMazatecs,Mixes,Zapotecs, and theChatino. Although hallucinogenicPsilocybe species are abundant in low-lying areas of Mexico, most ceremonial use takes places in mountainous areas of elevations greater than 1,500 meters (4,900 ft). Guzmán suggests this is a vestige of Spanish colonial influence from several hundred years earlier, when mushroom use was persecuted by theCatholic Church.[271]
In some jurisdictions,Psilocybe spores are legal to sell and possess, because they contain neither psilocybin nor psilocin.[278] In other jurisdictions, they are banned because they are items that are used in drug manufacture. A few jurisdictions (such as the US states of California,[279] Georgia,[280] and Idaho[281]) have specifically prohibited the sale and possession of psilocybin mushroom spores. Cultivation of psilocybin mushrooms is considered drug manufacture in most jurisdictions and is often severely penalized, though some countries and one US state (New Mexico) has ruled that growing psilocybin mushrooms does not qualify as "manufacturing" a controlled substance.[282]
Despite being illegal to possess without authorization in many Western countries, such as the UK, Australia, and some U.S. states, less conservative governments nurture the legal possession and supply of psilocybin and other psychedelic drugs. InAmsterdam, authorities provide education on and promote the safe use of psychedelic drugs, such as psilocybin, to reduce public harm.[283] Similarly, religious groups like America's Uniao do Vegetal (UDV)[284] use psychedelics in traditional ceremonies.[285] A report from the U.S. Government Accountability Office (GAO) notes that people may petition the DEA for exemptions to use psilocybin for religious purposes.[286]
From 1 July 2023, the Australian medicines regulator has permitted psychiatrists to prescribe psilocybin for the therapeutic treatment of treatment-resistant depression.[287]
Advocates of legalization argue there is a lack of evidence of harm,[288][289] and potential use in treating certain mental health conditions. Research is difficult to conduct because of the legal status of psychoactive substances.[290] Advocates of legalization also promote the utility of "ego dissolution"[284] and argue bans are cultural discrimination against traditional users.[291]
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 underright-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.[292]
However, some trials have not found psilocybin to significantly outperform placebo in the treatment of depression.[304] In addition, a phase 2 trial found that two 25mg doses of psilocybin 3weeks apart versus daily treatment with theselective serotonin reuptake inhibitor (SSRI)escitalopram (Lexapro) for 6weeks (plus two putatively non-psychoactive 1mg doses of psilocybin 3weeks apart) did not show astatistically significant difference in reduction of depressive symptoms between groups.[304][307] However, reductions in depressive symptoms were numerically greater with psilocybin, somesecondary measures favored psilocybin, and the rate ofremission was statistically higher with psilocybin (57% with psilocybin vs. 28% with escitalopram).[304][307] In any case, the antidepressanteffect size of psilocybin over escitalopram appears to be small.[308]
Functional unblinding by their psychoactive effects andpositive psychological expectancy effects (i.e., theplacebo effect) are major limitations and sources ofbias of clinical trials of psilocybin and other psychedelics for treatment of depression.[309][310][311][312] Relatedly, most of the therapeutic benefit of conventionalantidepressants like the SSRIs for depression appears to be attributable to theplacebo response.[313][314] It has been proposed that psychedelics like psilocybin may in fact act asactive "super placebos" when used for therapeutic purposes.[315][316] As of September 2024, psilocybin and other psychedelics (excludingMDMA) have only been assessed in up to phase 2 clinical trials for psychiatric disorders and have not yet completed larger and more rigorousphase 3 trials or received regulatory approval for medical use.[30][304][89]
^Synonyms and alternate spellings of psilocybin include 4-PO-DMT (PO:phosphate; DMT:dimethyltryptamine), psilocybine, psilocibin, psilocybinum, psilotsibin, and psilocin phosphate ester, among others.[22]
^Percentages are derived from anon-blind clinical study of 30 individuals who were given a dosage of 8–12 milligrams of psilocybin; from Passie (2002),[2] citing Quentin (1960).[84]
^One of the reported fatalities, that of a 22-year-old French man who died in 1993,[119] was later challenged in the literature by Jochen Gartz and colleagues, who concluded "the few reported data concerning the victim are insufficient to exclude other possible causes of the fatality".[120]
^abcdefghijklPassie T, Seifert J, Schneider U, Emrich HM (October 2002)."The pharmacology of psilocybin".Addiction Biology.7 (4):357–364.doi:10.1080/1355621021000005937.PMID14578010.S2CID12656091.An interesting fact may be the much shorter half-life (mean 74.1 ± 19.6 minutes i.v. compared to 163 ± 64 minutes p.o.) and duration of action (subjective effects lasting only 15–30 minutes) when psilocybin is given intravenously, as performed in a recent double-blind placebo controlled trial.29
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^abČampara A, Kovačić D (2024). "Exploring Psilocybin as a Tool for Studying Parkinsonism-Related Psychosis: A Narrative Review Supplemented with a Computational Approach".MEDICON'23 and CMBEBIH'23. IFMBE Proceedings. Vol. 94. Cham: Springer Nature Switzerland. pp. 530–547.doi:10.1007/978-3-031-49068-2_54.ISBN978-3-031-49067-5.With a logS value of −3.009 and a plasma protein binding of 0.66, respectively, psilocybin has poor water solubility and is moderately bound to plasma proteins.
^abcdefManzano-Nunez R, Gomez DA, Toledo-Mendoza C, Perez-Otero M, Matilla IL, Prats C, et al. (2025). "Exploring Psychedelics Pharmacology: A Scoping Review Charting the Course of Psilocybin Pharmacokinetics".Clin Neuropharmacol.48 (1):13–19.doi:10.1097/WNF.0000000000000617.PMID39787428.
^abcdefghijklmnopqrFradet M, Kelly CM, Donnelly AJ, Suppes T (January 2025). "Psilocybin and hallucinogenic mushrooms".CNS Spectr.29 (6):611–632.doi:10.1017/S1092852924002487.PMID39789676.Upon their activation by psilocin, 5-HT2A receptors initiate complex cascades of downstream signaling. The activation of both canonical Gq/11 and β-arrestin-2 seems necessary to produce psychedelic effects,133 and so is the coactivation of Gi/o and Src tyrosine kinase.134 These specific pathways are thought to differentiate 5-HT2A receptor agonists with psychedelic properties from other agonists of the same receptor such as ergoline and lisuride that do not have hallucinogenic effects. [...] Although strong evidence supports that 5-HT2A activity mediates most of psilocin's psychedelic properties, this substituted tryptamine also binds to many other receptors135–137. In fact, psilocin's binding affinity is even higher for some other serotonin receptors such as 5-HT2C, 5-HT1A, and 5-HT2BReference Ray137. It is currently difficult to determine the clinical significance of psilocin's interaction with these receptors. Although they do not seem to contribute to the hallucinogenic properties of psilocin, these other serotonin receptors could potentially play a role in mediating its therapeutic effect.136, 138–140 [...] Psilocin has a very low affinity for the serotonin transporter (SERT), and it does not interact directly with the norepinephrine transporter (NET) or the dopamine transporter (DAT).137 Although it has the potential to bind with D1 and D3 receptors, it has no direct activity on the widespread D2 receptors.137 It does not interact with adrenergic, opioid, muscarinic, histamine, or cannabinoid receptors.137
^abNichols DE (October 2020)."Psilocybin: from ancient magic to modern medicine".J Antibiot (Tokyo).73 (10):679–686.doi:10.1038/s41429-020-0311-8.PMID32398764.Total psilocybin and psilocin levels in species known to be used recreationally varied from 0.1% to nearly 2% by dry weight [8]. The medium oral dose of psilocybin is 4–8 mg, which elicits the same symptoms as the consumption of about 2 g of dried Psilocybe Mexicana [9].
^Kozlowska U, Nichols C, Wiatr K, Figiel M (July 2022). "From psychiatry to neurology: Psychedelics as prospective therapeutics for neurodegenerative disorders".J Neurochem.162 (1):89–108.doi:10.1111/jnc.15509.PMID34519052.One dosing method of psychedelics is the use of so called "microdoses"—very low concentrations of various psychedelics that do not reach the threshold of perceivable behavioral effects. This is usually 10% of active recreational doses (e.g., 10–15 µg of LSD, or 0.1–0.3 g of dry "magic mushrooms") taken up to three times per week.
^abPepe M, Hesami M, de la Cerda KA, Perreault ML, Hsiang T, Jones AM (December 2023). "A journey with psychedelic mushrooms: From historical relevance to biology, cultivation, medicinal uses, biotechnology, and beyond".Biotechnol Adv.69: 108247.doi:10.1016/j.biotechadv.2023.108247.PMID37659744.
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^Wolf G, Singh S, Blakolmer K, Lerer L, Lifschytz T, Heresco-Levy U, et al. (January 2023). "Could psychedelic drugs have a role in the treatment of schizophrenia? Rationale and strategy for safe implementation".Mol Psychiatry.28 (1):44–58.doi:10.1038/s41380-022-01832-z.PMID36280752.
^Sapienza J, Martini F, Comai S, Cavallaro R, Spangaro M, De Gregorio D, et al. (February 2025). "Psychedelics and schizophrenia: a double-edged sword".Mol Psychiatry.30 (2):679–692.doi:10.1038/s41380-024-02743-x.PMID39294303.
^Carrithers BM, Roberts DE, Weiss BM, King JD, Carhart-Harris RL, Gordon AR, et al. (March 2025). "Exploring Serotonergic Psychedelics as a Treatment for Personality Disorders".Neuropharmacology: 110413.doi:10.1016/j.neuropharm.2025.110413.PMID40081794.
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^Nielen RJ, van der Heijden FM, Tuinier S, Verhoeven WM (January 2004). "Khat and mushrooms associated with psychosis".The World Journal of Biological Psychiatry.5 (1):49–53.doi:10.1080/15622970410029908.PMID15048636.S2CID44321700.
^Geyer MA (July 1998). "Behavioral studies of hallucinogenic drugs in animals: implications for schizophrenia research".Pharmacopsychiatry.31 (S2):73–79.doi:10.1055/s-2007-979350.PMID9754837.S2CID24647325.
^abVollenweider FX, Geyer MA (November 2001). "A systems model of altered consciousness: integrating natural and drug-induced psychoses".Brain Research Bulletin.56 (5):495–507.doi:10.1016/S0361-9230(01)00646-3.PMID11750795.S2CID230298.
^Geyer MA, Vollenweider FX (September 2008). "Serotonin research: contributions to understanding psychoses".Trends in Pharmacological Sciences.29 (9):445–453.doi:10.1016/j.tips.2008.06.006.PMID19086254.
^Myers LS, Watkins SS, Carter TJ (1998)."Flashbacks in theory and practice"(PDF).The Heffter Review of Psychedelic Research.1:51–57.Archived(PDF) from the original on September 27, 2011. RetrievedAugust 14, 2011.
^abcTagen M, Mantuani D, van Heerden L, Holstein A, Klumpers LE, Knowles R (September 2023). "The risk of chronic psychedelic and MDMA microdosing for valvular heart disease".J Psychopharmacol.37 (9):876–890.doi:10.1177/02698811231190865.PMID37572027.
^abReinert JP, Colunga K, Etuk A, Richardson V, Dunn RL (August 2020). "Management of overdoses of salvia, kratom, and psilocybin mushrooms: a literature review".Expert Review of Clinical Pharmacology (Review).13 (8):847–856.doi:10.1080/17512433.2020.1794811.PMID32648791.S2CID220472473.
^Gérault A, Picart D (1996). "Intoxication mortelle à la suite de la consommation volontaire et en groupe de champignons hallucinogènes" [Fatal poisoning after a group of people voluntarily consumed hallucinogenic mushrooms].Bulletin de la Société Mycologique de France (in French).112:1–14.
^abcdSuran M (February 2024). "Study Finds Hundreds of Reddit Posts on "Trip-Killers" for Psychedelic Drugs".JAMA.331 (8):632–634.doi:10.1001/jama.2023.28257.PMID38294772.
^abBrandt SD, Kavanagh PV, Twamley B, Westphal F, Elliott SP, Wallach J, et al. (February 2018)."Return of the lysergamides. Part IV: Analytical and pharmacological characterization of lysergic acid morpholide (LSM-775)".Drug Test Anal.10 (2):310–322.doi:10.1002/dta.2222.PMC6230476.PMID28585392.Additionally, pretreatment with the 5‐HT1A agonist buspirone (20 mg p.o.) markedly attenuates the visual effects of psilocybin in human volunteers.59 Although buspirone failed to completely block the hallucinogenic effects of psilocybin, the limited inhibition is not necessarily surprising because buspirone is a low efficacy 5‐HT1A partial agonist.60 The level of 5‐HT1A activation produced by buspirone may not be sufficient to completely counteract the stimulation of 5‐HT2A receptors by psilocin (the active metabolite of psilocybin). Another consideration is that psilocin acts as a 5‐HT1A agonist.30 If 5‐HT1A activation by psilocin buffers its hallucinogenic effects similar to DMT58 then competition between psilocin and a weaker partial agonist such as buspirone would limit attenuation of the hallucinogenic response.
^abcPokorny T, Preller KH, Kraehenmann R, Vollenweider FX (April 2016). "Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience".Eur Neuropsychopharmacol.26 (4):756–766.doi:10.1016/j.euroneuro.2016.01.005.PMID26875114.
^Kaminski D, Reinert JP (August 2024). "The Tolerability and Safety of Psilocybin in Psychiatric and Substance-Dependence Conditions: A Systematic Review".The Annals of Pharmacotherapy.58 (8):811–826.doi:10.1177/10600280231205645.PMID37902038.
^Leikin JB, Krantz AJ, Zell-Kanter M, Barkin RL, Hryhorczuk DO (1989). "Clinical features and management of intoxication due to hallucinogenic drugs".Medical Toxicology and Adverse Drug Experience.4 (5). Springer Science and Business Media LLC:324–350.doi:10.1007/bf03259916.PMID2682130.
^Gartner HT, Wan HZ, Simmons RE, Sollee DR, Sheikh S (November 2024). "Psychedelic mushroom-containing chocolate exposures: Case series".The American Journal of Emergency Medicine.85:208–213.doi:10.1016/j.ajem.2024.09.038.PMID39288500.
^Lima G, Soares C, Teixeira M, Castelo-Branco M (December 2024). "Psychedelic research, assisted therapy and the role of the anaesthetist: A review and insights for experimental and clinical practices".British Journal of Clinical Pharmacology.90 (12):3119–3134.doi:10.1111/bcp.16264.PMID39380091.
^Canal CE (2018)."Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action".Handb Exp Pharmacol. Handbook of Experimental Pharmacology.252:227–260.doi:10.1007/164_2018_107.ISBN978-3-030-10560-0.PMC6136989.PMID29532180.Reports from clinical trials conclude that the psychedelic effects of psilocybin and LSD are mediated by 5-HT2A receptors, because they are blocked by ketanserin (40 mg, P.O.), typically viewed as a selective 5-HT2A antagonist (Kometer et al. 2012; Kraehenmann et al. 2017; Preller et al. 2017; Quednow et al. 2012). Haloperidol, typically viewed as a selective dopamine D2 antagonist, is much less effective than ketanserin at blocking psilocybin's effects, but risperidone, an antipsychotic with combined D2/5-HT2 activity, is as effective as ketanserin (Vollenweider et al. 1998).
^De Gregorio D, Enns JP, Nuñez NA, Posa L, Gobbi G (2018). "D-Lysergic acid diethylamide, psilocybin, and other classic hallucinogens: Mechanism of action and potential therapeutic applications in mood disorders".Psychedelic Neuroscience. Progress in Brain Research. Vol. 242. pp. 69–96.doi:10.1016/bs.pbr.2018.07.008.ISBN978-0-12-814255-4.PMID30471683.Noteworthy, the activation of postsynaptic 5HT2A receptor in layer V of the medial prefrontal cortex (mPFC) is considered to be responsible for the visual hallucinations produced by LSD and other psychedelic drugs such as psilocybin (Jakab and Goldman-Rakic, 1998; Vollenweider and Kometer, 2010) (see Fig. 2). [...] Although the classic hallucinogens LSD and psilocybin do not have a direct affinity for glutamate receptors, several animal studies have highlighted that glutamate carries a significant weight of the overall downstream effects of LSD and hallucinogenic action. The activation of postsynaptic cortical 5HT2A increases extracellular glutamate release in the synaptic cleft which is reversed by selective 5-HT2A antagonists (Vollenweider et al., 1998), AMPA (α-amino-3-hydroxyl-5-methyl4-isoxazole-propionic acid) receptor antagonists (Zhang and Marek, 2008), agonists and positive allosteric modulators of mGluR2 (metabotropic glutamate receptor 2) (Benneyworth et al., 2007), and selective antagonists of the NR2B subunit of NMDA (N-methyl-D-aspartate) receptors (Lambe and Aghajanian, 2006). In particular, microdialysis in rats confirmed that systemic hallucinogen administration leads to a time-dependent increase in prefrontal cortex (PFC) glutamate levels, an effect which is blocked by administration with the selective 5HT2A antagonist M100907 (Muschamp et al., 2004).
^Marek GJ, Schoepp DD (2021). "Cortical influences of serotonin and glutamate on layer V pyramidal neurons".5-HT Interaction with Other Neurotransmitters: Experimental Evidence and Therapeutic Relevance - Part B. Progress in Brain Research. Vol. 261. pp. 341–378.doi:10.1016/bs.pbr.2020.11.002.ISBN978-0-444-64258-5.PMID33785135.
^abHalberstadt AL, Geyer MA (2018)."Effect of Hallucinogens on Unconditioned Behavior"(PDF).Behavioral Neurobiology of Psychedelic Drugs. Current Topics in Behavioral Neurosciences. Vol. 36. pp. 159–199.doi:10.1007/7854_2016_466.ISBN978-3-662-55878-2.PMC5787039.PMID28224459. Archived from the original on August 29, 2017. RetrievedFebruary 7, 2025.Compared with phenylalkylamines, tryptamine hallucinogens produce a disparate profile of effects in the mouse BPM. Administration of psilocin or 5-MeO-DMT produces a profound suppression of locomotor activity, investigatory holepokes and rearings, and center duration in C57BL/6J mice (Halberstadt et al. 2011). Most of these effects are blocked by pretreatment with the 5-HT1A antagonist WAY-100635, whereas the 5-HT2C antagonist SB242084 is ineffective.{{cite book}}: CS1 maint: bot: original URL status unknown (link)
^Willins DL, Meltzer HY (August 1997). "Direct injection of 5-HT2A receptor agonists into the medial prefrontal cortex produces a head-twitch response in rats".J Pharmacol Exp Ther.282 (2):699–706.doi:10.1016/S0022-3565(24)36840-5.PMID9262333.
^abcdeCordner Z, Prandovszky E, Pedicini M, Liu H, Macias L, Pletnikov M, et al. (December 2022)."ACNP 61st Annual Meeting: Poster Abstracts P271-P540: P314. Psilocybin Alters Behavior and the Intestinal Microbiota in a Wild Type Mouse Model by Mechanisms That Are Not Fully Dependent on 5HT2A and 5HT2C Receptors".Neuropsychopharmacology.47 (Suppl 1): 220–370 (245–246).doi:10.1038/s41386-022-01485-0.PMC9714399.PMID36456694.Psilocybin induced a robust head twitch response, increased exploratory behavior in the elevated plus maze, increased social behavior in the social interaction test, and decreased immobility in the forced swim test. Co-administration of ketanserin fully blocked the head twitch response without significantly altering psilocybin's effects on other behavioral outcomes. In a separate cohort, treatment with psilocybin produced broad alteration of the intestinal microbiome, with particularly marked changes in the large intestine that were only partially blocked by pre-treatment with ketanserin. Finally, transplantation of intestinal contents from psilocybin-treated mice to naive untreated mice resulted in behavioral changes consistent with the effects of psilocybin treatment. [...] Our findings demonstrate that a single dose of psilocybin leads to behavioral changes in mice that are relevant for studies of resilience and affective disorders. Our results further indicate that the behavioral changes may not be fully dependent on psilocybin's agonism of 5HT2A and 5HT2C receptors. Further, psilocybin appears to broadly alter the intestinal microbiome and transplantation of intestinal contents reproduces behavioral change associated with psilocybin treatment, suggesting a previously unknown microbiome-gut-brain mechanism of action.
^abcFlanagan TW, Nichols CD (2022). "Psychedelics and Anti-inflammatory Activity in Animal Models".Disruptive Psychopharmacology. Current Topics in Behavioral Neurosciences. Vol. 56. pp. 229–245.doi:10.1007/7854_2022_367.ISBN978-3-031-12183-8.PMID35546383.In our rodent acute asthma model, psilocin, the active metabolite of psilocybin, displays a similar anti-AHR efficacy and potency to that of (R)-DOI. Surprisingly, other tryptamines with very similar structures like N,N-dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) show no efficacy to reduce OVA-induced AHR.
^abcWulff AB, Nichols CD, Thompson SM (June 2023)."Preclinical perspectives on the mechanisms underlying the therapeutic actions of psilocybin in psychiatric disorders".Neuropharmacology.231: 109504.doi:10.1016/j.neuropharm.2023.109504.PMID36921889.Interestingly, the anti-inflammatory effects of psychedelics acting at 5-HT2A receptors do not correlate with activation of either Gαq or β-arrestin recruitment (Flanagan et al., 2020), indicating psychedelics can recruit different effector pathways from those underlying behaviors for biological effects. [...] Psilocybin and certain other psychedelics have potent anti-inflammatory effects in preclinical models of human disease that could contribute to their efficacy. For example, delivery of psilocin directly to the lungs of rats via nebulization potently suppressed inflammation and restored normal breathing in a model of allergic asthma (Flanagan et al., 2020). The amount of psilocybin necessary for full effect was far below the threshold to produce behavioral effects, suggesting that sub-behavioral levels of psilocybin or other psychedelic may represent a new therapeutic strategy to treat inflammatory disorders. Interestingly, as mentioned above, neither the Gαq or β-arrestin signaling pathways seem to be involved in these effects (Flanagan et al., 2020).
^Nichols CD (November 2022)."Psychedelics as potent anti-inflammatory therapeutics".Neuropharmacology.219: 109232.doi:10.1016/j.neuropharm.2022.109232.PMID36007854.Remarkably, the IC50 dose for (R)-DOI in this prophylactic paradigm is ∼0.005 mg/kg, administered via nebulization or by intraperitoneal injection (Flanagan et al., 2021). This is > 50x less than the behavioral threshold dose. We have also shown that the drug psilocin, the active form of the prodrug psilocybin, has virtually the same potency as (R)-DOI (Flanagan et al., 2021), indicating that the effects are not limited to (R)-DOI or are chemotype dependent.
^Flanagan TW, Nichols CD (August 2018)."Psychedelics as anti-inflammatory agents"(PDF).Int Rev Psychiatry.30 (4):363–375.doi:10.1080/09540261.2018.1481827.PMID30102081.We have previously speculated that the anti-inflammatory effects of psychedelics mediated through serotonin 5-HT2A receptor activation are a key component of not only the anti-depressant effects of psilocybin, but also contribute to its long-lasting effects after only a single treatment (Kyzar, Nichols, Gainetdinov, Nichols, & Kalueff, 2017).
^Calder A, Mock S, Friedli N, Pasi P, Hasler G (October 2023). "Psychedelics in the treatment of eating disorders: Rationale and potential mechanisms".Eur Neuropsychopharmacol.75:1–14.doi:10.1016/j.euroneuro.2023.05.008.PMID37352816.Interestingly, both EDs and mood disorders are often comorbid with gastrointestinal symptoms and reduced diversity of the gut microbiome. (Lam et al., 2017) A dysregulated microbiome may constitute a development or maintenance factor for AN in particular. (Butler et al., 2021) It has been suggested that psychedelics exert some of their long-term effects via the microbiome. (Kuypers, 2019) Psilocybin has been shown to diversify the intestinal microbiome in mice, and this diversification appeared to be responsible for lasting antidepressant-like behavioral effects. (Cordner et al., 2022) Normalization of the gut microbiome may thus assist with recovery from both EDs and comorbid mood disorders, and presents an intriguing avenue for future research. (Kleiman et al., 2015)
^abReed F, Foldi CJ (February 2024). "Do the therapeutic effects of psilocybin involve actions in the gut?".Trends Pharmacol Sci.45 (2):107–117.doi:10.1016/j.tips.2023.12.007.PMID38216431.
^abLow ZX, Yong SJ, Alrasheed HA, Al-Subaie MF, Al Kaabi NA, Alfaresi M, et al. (February 2025). "Serotonergic psychedelics as potential therapeutics for post-COVID-19 syndrome (or Long COVID): A comprehensive review".Prog Neuropsychopharmacol Biol Psychiatry.137: 111279.doi:10.1016/j.pnpbp.2025.111279.PMID39909170.
^Brown RT, Nicholas CR, Cozzi NV, Gassman MC, Cooper KM, Muller D, et al. (December 2017). "Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults".Clin Pharmacokinet.56 (12):1543–1554.doi:10.1007/s40262-017-0540-6.PMID28353056.
^abcdefgGumpper RH, Nichols DE (October 2024). "Chemistry/structural biology of psychedelic drugs and their receptor(s)".Br J Pharmacol.doi:10.1111/bph.17361.PMID39354889.In contrast to DMT, psilocybin is orally active. [...] A structurally related molecule, [5-HO-DMT], known as bufotenine, is inactive after oral administration. How does the simple transposition of the hydroxy from the 4 to the 5 position alter the physicochemical properties of the DMT core? We asked that question more than four decades ago. In a study by Migliaccio et al. (1981), the 360 MHz proton NMR, the amine pKa values and the octanol–water Log P values were determined experimentally and compared for both psilocin and bufotenine (Figure 3a). The side chain protons in the NMR for bufotenine were shown to be rapidly rotating with no preference for gauche or trans conformations, whereas the side chain for psilocin was less mobile and was determined to favour a gauche (80%) versus trans (20%) conformation. Because psilocin is a weaker base but is also more lipid soluble, it was proposed that psilocin formed an intramolecular hydrogen bond, as illustrated in Figure 3a. In the energy-minimized structure of this conformation, the length of the hydrogen bond is 1.88 Å. The weaker pKa of psilocin relative to bufotenine means that psilocin is less highly ionized at pH 7.4—that is, 8.5% free base versus 0.53% for bufotenine at pH 7.4. Ionized amines must be unionized and desolvated to cross the blood–brain barrier; the intramolecular H bond in psilocin compensates for that as reflected by the higher lipophilicity of psilocin relative to bufotenine. Finally, the mechanism of deamination by MAO involves either a single electron transfer or a nucleophilic mechanism (Gaweska & Fitzpatrick, 2011; Zapata-Torres et al., 2015), either of which is more enzymically difficult when the amine electrons are hydrogen-bonded by the 4-hydroxy group (Figure 3a). Very recently, Lenz et al. (2022) have confirmed and extended the finding of the potential intramolecular hydrogen bond partially being responsible for slow MAO deamination as well as psilocin's enhanced ability to cross the blood–brain barrier. [...] This would explain why bufotenine is still an agonist at the 5-HT2A receptor but due to its poor physiochemical properties is not psychoactive in humans.
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^van Elk M, Yaden DB (September 2022). "Pharmacological, neural, and psychological mechanisms underlying psychedelics: A critical review".Neurosci Biobehav Rev.140: 104793.doi:10.1016/j.neubiorev.2022.104793.hdl:1887/3515020.PMID35878791.In addition, the strong prior expectations that many people have about psychedelics directly contribute to the psychedelic experience and as a consequence it has been suggested that psychedelics may act as a 'super-placebo' (Hartogsohn, 2016). Specifically, strong prior expectations (e.g., that a specific intervention will likely trigger a mystical experience) will increase the likelihood of having e.g., a mystical-type experience (Maij et al., 2019), and this placebo-effect is further boosted by the psychedelic-induced suggestibility.
Notes: (1) TAAR1 activity of ligands varies significantly between species. Some agents that are TAAR1 ligands in some species are not in other species. This navbox includes all TAAR1 ligands regardless of species. (2) See the individual pages for references, as well as theList of trace amines,TAAR, andTAAR1 pages.See also:Receptor/signaling modulators
