Psilocybin

Psilocybin
INN: Psilocybine

Kekulé, skeletal formula of canonical psilocybin
Ball-and-stick model of canonical psilocybin
Clinical data
Pronunciation	/ˌsaɪləˈsaɪbɪn/ sy-lə-SY-bin, /ˌsɪl-/
Other names	Psilocybine; Psilocibin; Psylocybin; Psilocybinum; Psilotsibin; Psilocin phosphate; Psilocin phosphate ester; Indocybin; O-Phosphoryl-4-hydroxy-N,N-dimethyltryptamine; 4-Phosphoryloxy-N,N-dimethyltryptamine; 4-Phosphoryl-N,N-dimethyltryptamine; 4-PO-DMT; 4-PO-N,N-DMT; COMP-360; COMP360, Psilocybin (USAN US)
Dependence liability	Low [1] [2] [3] [4] [5]
Addiction liability	Low [1] [6]
Routes of administration	By mouth, intravenous [7]
Drug class	Serotonergic psychedelic (hallucinogen) [8]
ATC code	None
Legal status
Legal status	AU:S9/S8 (Controlled Drug) BR: Class F2 (Prohibited psychotropics) [9] CA: Schedule III UK: Class A US: Schedule I
Pharmacokinetic data
Bioavailability	Oral: 52.7 ± 20.4% (as psilocin) (n=3) [10] [11] [12]
Protein binding	66% [13]
Metabolism	Liver, other tissues: [11] [10] [7] [14] • Dephosphorylation (ALP Tooltip alkaline phosphatase) • Demethylation and deamination (MAO Tooltip monoamine oxidase) • Oxidation (ALDH Tooltip aldehyde dehydrogenase) • Glucuronidation (UGTs)
Metabolites	• Psilocin [11] [10] [7] • Psilocin-O-glucuronide [10] [7] • 4-Hydroxyindole-3-acetaldehyde [10] [7] • 4-Hydroxyindole-3-acetic acid (4-HIAA) [10] [7] • 4-Hydroxytryptophol [10] [7]
Onset of action	Oral: 20–40 min [11]
Elimination half-life	Oral (as psilocin): 2.1–3.7 hours (range 1.5–18.6 hours) [10] IV Tooltip Intravenous administration (as psilocin): 1.2 hours (range 1.8–4.5 hours) [10] [2]
Duration of action	Oral: 4–6 hours (range 3–12 hours) [11] [15] IV Tooltip Intravenous injection: 15–30 minutes (1 mg, n=6) [2] [12]
Excretion	Urine (mainly as psilocin-O-glucuronide, 2–4% as unchanged psilocin) [10] [7] [16]
Identifiers
IUPAC name [3-[2-(dimethylamino)ethyl]-1H-indol-4-yl] dihydrogen phosphate
CAS Number	520-52-5  Y
PubChem CID	10624
DrugBank	DB11664
ChemSpider	10178  Y
UNII	2RV7212BP0
KEGG	D12881  Y
ChEBI	CHEBI:8614  Y
ChEMBL	ChEMBL194378  Y
CompTox Dashboard (EPA)	DTXSID0048898
ECHA InfoCard	100.007.542
Chemical and physical data
Formula	C12H17N2O4P
Molar mass	284.252 g·mol−1
3D model (JSmol)	Interactive image
Melting point	220–228 °C (428–442 °F) [17]
SMILES CN(C)CCC1=CNC2=C1C(=CC=C2)OP(=O)(O)O
InChI InChI=1S/C12H17N2O4P/c1-14(2)7-6-9-8-13-10-4-3-5-11(12(9)10)18-19(15,16)17/h3-5,8,13H,6-7H2,1-2H3,(H2,15,16,17) Y Key:QVDSEJDULKLHCG-UHFFFAOYSA-N Y
(verify)

Psilocybin, also known as 4-phosphoryloxy-N,N-dimethyltryptamine (4-PO-DMT), and formerly sold under the brand name Indocybin, ^[a] is a naturally occurring psychedelic prodrug compound produced by more than 200 species of fungi. Psilocybin is itself biologically inactive but is quickly converted by the body to psilocin, which has mind-altering effects similar, in some aspects, to those of other classical psychedelics. Effects include euphoria, hallucinations, changes in perception, a distorted sense of time, ^[19] and perceived spiritual experiences. It can also cause adverse reactions such as nausea and panic attacks.

Imagery in cave paintings and rock art of modern-day Algeria and Spain suggests that human use of psilocybin mushrooms predates recorded history. ^[20] 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 (spirituality-enhancing agent) grew in the next decade, owing largely to the increased availability of information on how to cultivate psilocybin mushrooms.

The intensity and duration of psilocybin's effects vary, depending on species or cultivar of mushrooms, dosage, individual physiology, and set and setting, as shown in experiments led by Timothy Leary at Harvard University in the early 1960s. Once ingested, psilocybin is rapidly metabolized to psilocin, which then acts on serotonin receptors in the brain. Psilocybin's mind-altering effects typically last two to six hours, although to people under the influence of psilocybin, they may seem to last much longer, since the drug can distort the perception of time. 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.

History

Early

Mayan "mushroom stones" of Guatemala.

There is evidence to suggest that psychoactive mushrooms have been used by humans in religious ceremonies for thousands of years. The Tassili Mushroom Figure was discovered in Tassili, 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. ^[21]

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. ^[22]

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. ^{[23] : 11} In Nahuatl, the language of the Aztecs, the mushrooms were called teonanácatl—literally "divine mushroom": the agglutinative form of teō(tl) ("god", "sacred") and nanācatl ("mushroom") in Nahuatl.^{[ citation needed ]} 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 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), ^{[24] : 164} and described how some merchants would celebrate upon returning from a successful business trip by consuming mushrooms to evoke revelatory visions. ^{[25] : 118} 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. ^{[24] : 165}

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. ^{[26] [27]} The few existing accounts that mention psilocybin mushrooms typically lack sufficient information to allow species identification, focusing on their effects. For example, Flemish botanist Carolus Clusius (1526–1609) described the bolond gomba ("crazy mushroom"), used in rural Hungary to prepare love potions. English botanist John Parkinson included details about a "foolish mushroom" in his 1640 herbal Theatricum Botanicum. ^{[28] : 10–12} The first reliably documented report of intoxication with Psilocybe 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's Green Park. ^{[28] : 16}

Modern

Albert Hofmann (shown here in 1993) purified psilocybin and psilocin from Psilocybe 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.

American banker and amateur ethnomycologist R. Gordon Wasson and his wife, Valentina P. Wasson, a physician, studied the ritual use of psychoactive mushrooms by the native population in the Mazatec village Huautla de Jiménez, Mexico. In 1957, Wasson described the psychedelic visions he experienced during these rituals in "Seeking the Magic Mushroom", an article published in the American weekly Life magazine. ^[29] Later the same year they were accompanied on a follow-up expedition by French mycologist Roger Heim, who identified several of the mushrooms as Psilocybe species. ^[30]

Heim cultivated the mushrooms in France and sent samples for analysis to Albert Hofmann, a chemist employed by the Swiss pharmaceutical company Sandoz (now Novartis). 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. ^{[25] : 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. ^{[25] : 126–127}

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. ^{[31] : 237} Sandoz also marketed and sold pure psilocybin under the name Indocybin to clinicians and researchers worldwide. ^{[24] : 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 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. ^{[32] [33]} 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". ^[34] 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. ^[35] 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. ^[36] 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". ^[37] 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. ^{[25] : 79–116}

Despite the legal restrictions on psilocybin use, the 1970s witnessed the emergence of psilocybin as the "entheogen of choice". ^{[38] : 276} This was due in large part to wide dissemination of information on the topic, which included works such as those by Carlos 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. ^[39] As ethnobiologist Jonathan Ott explains, "These authors adapted San Antonio's technique (for producing edible mushrooms by casing mycelial cultures on a rye grain substrate; San Antonio 1971) to the production of Psilocybe [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." ^{[38] : 290} San Antonio's technique describes a method to grow the common edible mushroom Agaricus bisporus . ^[40]

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 smartshops in the Netherlands, the UK, and online. Several websites ^[b] 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. ^[41] 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". ^[42] Recent studies in the U.S. have attracted attention from the popular press and brought psilocybin back into the limelight. ^{[43] [44]}

Reported effects

American psychologist and counterculture figure Timothy Leary conducted early experiments into the effects of psychedelic drugs, including psilocybin (1989 photo).

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 as set 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. ^[32] 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. ^[45]

After ingesting psilocybin, the user may experience a wide range of emotional effects which can include: feelings of disorientation, lethargy, giddiness, euphoria, joy, and depression. In one study, 31% of volunteers given a high dose reported feelings of significant fear and 17% experienced transient paranoia. ^[46] In studies at Johns 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. ^{[47] [48]} Low doses can induce hallucinatory effects. Closed-eye hallucinations may occur, where the affected individual sees multicolored geometric shapes and vivid imaginative sequences. ^[49] Some individuals report synesthesia, such as tactile sensations when viewing colors. ^{[50] : 175} At higher doses, psilocybin can lead to "intensification of affective responses, enhanced ability for introspection, regression to primitive and childlike thinking, and activation of vivid memory traces with pronounced emotional undertones". ^[42] Open-eye visual hallucinations are common, and may be very detailed, although rarely confused with reality. ^[49]

Physical effects

Common responses include pupil dilation (93%); changes in heart rate (100%), including increases (56%), decreases (13%), and variable responses (31%); changes in blood pressure (84%), including hypotension (34%), hypertension (28%), and general instability (22%); changes in stretch reflex (86%), including increases (80%) and decreases (6%); nausea (44%); tremor (25%); and dysmetria (16%) (inability to properly direct or limit motions). ^[c] The temporary increases in blood pressure caused by the drug can be a risk factor for users with pre-existing hypertension. ^[49] These qualitative somatic effects caused by psilocybin have been corroborated by several early clinical studies. ^[52] A 2005 magazine survey of clubgoers in the UK found that nausea or vomiting was experienced by over a quarter of those who had used psilocybin mushrooms in the last year, although this effect is caused by the mushroom rather than psilocybin itself. ^[46] In one study, administration of gradually increasing dosages of psilocybin daily for 21 days had no measurable effect on electrolyte levels, blood sugar levels, or liver toxicity tests. ^[2]

Psychiatric effects and perceptual disturbances

The ability of psilocybin to cause perceptual distortions is linked to its influence on the activity of the prefrontal cortex.

Psilocybin is known to strongly influence the subjective experience of the passage of time. ^{[53] [19]} Users often feel as if time is slowed down, resulting in the perception that "minutes appear to be hours" or "time is standing still". ^[54] 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 preferred tapping rate. ^{[54] [55]} These results are consistent with the drug's role in affecting prefrontal cortex activity, ^[56] and the role that the prefrontal cortex is known to play in time perception. ^[57] However, the neurochemical basis of psilocybin's effects on the perception of time are not known with certainty. ^[58]

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, including alcohol, can also increase the likelihood of a bad trip. ^{[46] [59]} Other than the duration of the experience, the effects of psilocybin are similar to comparable dosages of lysergic acid diethylamide (LSD) or mescaline. However, in the Psychedelics Encyclopedia, author Peter 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." ^{[31] : 273}

Theory of mind network and default mode network

Psychedelics, including psilocybin, have been shown to affect different clusters of brain regions known as the "theory of mind network" (ToMN) and the default mode network (DMN). ^[60] The ToMN involves making inferences and understanding social situations based on patterns ^[61] whereas, the DMN relates more to introspection and one's sense of self. ^[60] The DMN in particular is related to increased rumination and worsening self-image in patients with major depressive disorder (MDD). ^[62] 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. ^[63] 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. ^[60]

Group perceptions

Through further anthropological studies regarding "personal insights" ^[64] 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". ^[65] 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. ^[66] 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" ^[65] found in one's body.

Group therapies using "classic" psychedelics are becoming more commonly used in the Western world in clinical practice. ^[67] This is speculated to grow, provided the evidence remains indicative of their safety and efficacy. ^[68] 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, ^[65] the group partakes in a "journey" together, thus adding to the spiritual, social body where roles, hierarchies and gender are subjectively understood. ^[65]

Adverse effects

Most of the comparatively few fatal incidents that are associated with psychedelic mushroom usage involve the simultaneous use of other drugs, especially alcohol. A common adverse effect resulting from psilocybin mushroom use involves "bad trips" or panic reactions, in which affected individuals become anxious, confused, agitated, or disoriented. ^[69] Accidents, self-injury, or suicide attempts can result from serious cases of acute psychotic episodes. ^[46] Although no studies have linked psilocybin with birth defects, ^[70] it is recommended that pregnant women avoid its usage. ^[71]

Toxicity

Psilocybin has low toxicity, indicating that it has low potential for inducing life-threatening events like breathing or heart problems. ^[69] Research shows that health risks may develop with use of psilocybin. Nonetheless, hospitalizations from it are rare, and overdoses are generally mild and self-limiting. ^[69]

A review regarding 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. ^[72] One analysis of people hospitalized from psilocybin poisoning found high urine concentrations of phenethylamine (PEA), indicating that PEA may contribute to the effects of psilocybin poisoning. ^[72]

In rats, the median lethal dose (LD₅₀) when administered orally is 280 milligrams per kilogram (mg/kg), approximately one and a half times that of caffeine. The lethal dose of psilocybin when administered intravenously in mice is 285 mg/kg and in rats is 280 mg/kg. ^[17] When administered intravenously in rabbits, psilocybin's LD₅₀ is approximately 12.5 mg/kg. ^[73] Psilocybin comprises approximately 1% of the weight of Psilocybe 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. ^[46] Based on the results of animal studies, the lethal dose of psilocybin has been extrapolated to be 6 grams, 1000 times greater than the effective dose of 6 milligrams. ^[74] 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. ^[75] 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 may involve other factors aside from psilocybin. ^{[46] [d]}

Psychiatric

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, ^[78] schizophrenia-like psychosis, ^{[79] [80]} and convulsions ^[81] 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. ^{[46] [ failed verification ]} Other adverse effects, less frequently reported, include paranoia, confusion, prolonged derealization (disconnection from reality), and mania. ^[82] Psilocybin usage can temporarily induce a state of depersonalization disorder. ^[83] Usage by those with schizophrenia can induce acute psychotic states requiring hospitalization. ^[84]

The similarity of psilocybin-induced symptoms to those of schizophrenia has made the drug a useful research tool in behavioral and neuroimaging studies of this psychotic disorder. ^{[85] [86] [87]} In both cases, psychotic symptoms are thought to arise from a "deficient gating of sensory and cognitive information" in the brain that ultimately lead to "cognitive fragmentation and psychosis". ^[86] Flashbacks (spontaneous recurrences of a previous psilocybin experience) can occur long after having used psilocybin mushrooms. 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, ^[46] and correlations between HPPD and psychedelics are further obscured by polydrug use and other variables. ^[88]

Tolerance and dependence

Chart of dependence potential and effective dose/lethal dose ratio of several psychoactive drugs.

Tolerance to psilocybin builds and dissipates quickly; ingesting psilocybin 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] A cross-tolerance can develop between psilocybin and the pharmacologically similar LSD, ^[90] and between psilocybin and phenethylamines such as mescaline and DOM. ^[91]

Repeated use of psilocybin does not lead to physical dependence. ^[2] A 2008 study concluded that, based on US data from the period 2000–2002, 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, inhalants, anxiolytic medicines, and stimulants, 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 19 recreational drugs, including alcohol, cannabis, cocaine, ecstasy, heroin, and tobacco. 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]

Cultural significance and "mystical" experiences

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 in Indigenous American cultures in religious, divinatory, or spiritual contexts. Reflecting the meaning of the word entheogen ("the god within"), the mushrooms are revered as powerful spiritual sacraments that provide access to sacred worlds. Typically used in small group community settings, they enhance group cohesion and reaffirm traditional values. ^[92] Terence McKenna documented the worldwide practices of psilocybin mushroom usage as part of a cultural ethos relating to the Earth and mysteries of nature, and suggested that mushrooms enhanced self-awareness and a sense of contact with a "Transcendent Other"—reflecting a deeper understanding of our connectedness with nature. ^[93]

Psychedelic drugs can induce states of consciousness that have lasting personal meaning and spiritual significance in individuals who are religious or spiritually inclined; 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. ^{[94] [95]} In the 1960s, Walter Pahnke and colleagues systematically evaluated mystical experiences (which they called "mystical consciousness") by categorizing their common features. These categories, according to Pahnke, "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. ^[96]

In the 1962 Marsh Chapel Experiment, which was run by Pahnke at the Harvard Divinity School under the supervision of Timothy Leary, ^[97] almost all of the graduate degree divinity student volunteers who received psilocybin reported profound religious experiences. ^[98] One of the participants was religious scholar Huston Smith, author of several textbooks on comparative religion; he later described his experience as "the most powerful cosmic homecoming I have ever experienced." ^[99] In a 25-year followup to the experiment, all of the subjects given psilocybin described their experience as having elements of "a genuine mystical nature and characterized it as one of the high points of their spiritual life". ^{[100] : 13} 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 "a 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". ^{[100] : 24} This sentiment was echoed by psychiatrist William A. Richards, who in a 2007 review stated "[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." ^[101]

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. ^[102] When asked in an interview about the similarity of his work with 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." ^[103] The National Institute of Drug Abuse-funded study, published in 2006, has been praised by experts for the soundness of its experimental design. ^[e] In the experiment, 36 volunteers without prior 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; ^[104] 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. ^[105]

A follow-up study conducted 14 months after the original psilocybin session confirmed that participants continued to attribute deep personal meaning to the experience. Almost one-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 among their five most spiritually significant events. About two-thirds indicated that the experience increased their sense of well-being or life satisfaction. ^[98] 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 recent (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. ^{[46] [82]}

While many recent studies have concluded that psilocybin can cause mystical-type experiences having substantial and sustained personal meaning and spiritual significance, not all the medical community agree. Paul R. McHugh, formerly director of the Department of Psychiatry and Behavioral Science at Johns Hopkins, responded as follows 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.'" ^[106]

Available forms

Although psilocybin may be prepared synthetically, outside of the research setting it is not typically used in this form. The psilocybin present in certain species of mushrooms can be ingested in several ways: by consuming fresh or dried fruit bodies, by preparing an herbal tea, or by combining with other foods to mask the bitter taste. ^[41] In rare cases people have injected mushroom extracts intravenously. ^[46]

Chemistry

Physical properties

Psilocybin is a naturally-occurring substituted tryptamine that features an indole ring linked to an aminoethyl substituent. It is structurally related to serotonin, a monoamine neurotransmitter which is a derivative of the amino acid tryptophan. Psilocybin is a member of the general class of tryptophan-based compounds that originally functioned as antioxidants in earlier life forms before assuming more complex functions in multicellular organisms, including humans. ^[107] Other related indole-containing psychedelic compounds include dimethyltryptamine, found in many plant species and in trace amounts in some mammals, and bufotenin, found in the skin of certain amphibians, especially the Colorado River toad. ^{[108] : 10–13}

Psilocybin is a white, crystalline solid that is soluble in water, methanol and ethanol but insoluble in nonpolar organic solvents such as chloroform and petroleum ether. ^{[108] : 15} It has a melting point between 220 and 228 °C (428 and 442 °F), ^[73] and an ammonia-like taste. ^[109] Its pKa values are estimated to be 1.3 and 6.5 for the two successive phosphate hydroxy groups and 10.4 for the dimethylamine nitrogen, so it typically exists as a zwitterionic structure. ^[109] There are two known crystalline polymorphs of psilocybin, as well as reported hydrated phases. ^[110] Psilocybin rapidly oxidizes upon exposure to light—an important consideration when using it as an analytical standard. ^[111]

Laboratory synthesis

Albert Hofmann et al. were the first team to synthesize psilocybin in 1958. Since that time, various chemists have improved the methods for the 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 require chromatographic 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. ^[112]

Biosynthesis

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.

Isotopic labeling experiments from the 1960s suggested that the biosynthesis of psilocybin was a four-step process: ^[114]

1. decarboxylation of tryptophan to tryptamine
2. N,N-dimethylation of tryptamine at the N⁹ position to dimethyltryptamine
3. 4-hydroxylation of dimethyltryptamine to psilocin
4. O-phosphorylation of psilocin to psilocybin

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. ^[113] 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. ^{[108] : 12–13  [113]} These enzymes are encoded in gene clusters in Psilocybe, Panaeolus, and Gymnopilus. ^[115]

Escherichia coli has been genetically modified to manufacture large amounts of psilocybin. ^[116] Psilocybin can be produced de novo in GM yeast. ^{[117] [118]}

Pharmacology

Pharmacodynamics

The neurotransmitter serotonin is structurally similar to psilocybin.

Psilocin at molecular targets

Target	Affinity (Ki, nM)
5-HT1A	49–567
5-HT1B	31–305
5-HT1D	19–36
5-HT1E	44
5-HT1F	ND
5-HT2A	6.0–340 (Ki) 2.4–721 (EC50 Tooltip half-maximal effective concentration) 16–98% (Emax Tooltip maximal efficacy)
5-HT2B	4.6–410 (Ki) 2.4–>20,000 (EC50) 38–84% (Emax)
5-HT2C	10–141
5-HT3	>10,000
5-HT4	ND
5-HT5A	70–84
5-HT6	57–72
5-HT7	3.5–72
α1A–α1B	>10,000
α2A	2,044
α2B	1,271
α2C	4,404
β1–α2	>10,000
D1	20–>14,000
D2	3,700–>10,000
D3	101–8,900
D4	>10,000
D5	>10,000
H1	1,600–>10,000
H2–H4	>10,000
M1–M5	>10,000
σ1	>10,000
σ2	>10,000
I2	792
TAAR1	1,400 (Ki) (rat) 17,000 (Ki) (mouse) >30,000 (EC50) (human)
SERT Tooltip Serotonin transporter	3,800–>10,000 (Ki) 662–3,900 (IC50 Tooltip half-maximal inhibitory concentration) 561 (EC50)
NET Tooltip Norepinephrine transporter	13,000 (Ki) 14,000 (IC50) >10,000 (EC50)
DAT Tooltip Dopamine transporter	6,000–>30,000 (Ki) >100,000 (IC50) >10,000 (EC50)
Notes: The smaller the value, the more avidly psilocin interacts with the site. Sources: [119] [120] [121] [122] [123] [10] [16] [124] [125] [126] [127] [128] [129]

Psilocybin is a psychoplastogen, ^{[130] [131] [132]} which refers to a compound capable of promoting rapid and sustained neuroplasticity.

Psilocybin is rapidly dephosphorylated in the body to psilocin, which is an agonist for several serotonin receptors, which are also known as 5-hydroxytryptamine (5-HT) receptors. In rats, psilocin binds with high affinity to 5-HT_2A receptors and low affinity to 5-HT₁ receptors, including 5-HT_1A and 5-HT_1D; effects are also mediated via 5-HT_2C receptors. ^[2] The psychotomimetic (mimicking the mind distortion present in psychosis) effects of psilocin can be blocked in a dose-dependent fashion by the 5-HT_2A antagonist drug ketanserin. ^[79] Various lines of evidence have shown that interactions with non-5-HT₂ receptors also contribute to the subjective and behavioral effects of the drug. ^{[91] [f]} For example, psilocin indirectly increases the concentration of the neurotransmitter dopamine in the basal ganglia, and some psychotomimetic symptoms of psilocin are reduced by haloperidol, a non-selective dopamine receptor antagonist. Taken together, these suggest that there may be an indirect dopaminergic contribution to psilocin's psychotomimetic effects. ^[58] Psilocybin and psilocin have no affinity for dopamine D₂ receptor, unlike another common 5-HT receptor agonist, lysergic acid diethylamide (LSD). ^[2] Psilocin antagonizes histamine H₁ receptors with moderate affinity, compared to LSD which has lower affinity. ^[134]

Serotonin receptors are located in numerous parts of the brain, including the cerebral cortex, and are involved in a wide range of functions, including regulation of mood, motivation, body temperature, appetite and libido. ^[135]

Psilocybin induces region-dependent alterations in glutamate that may be associated with subjective experiences of ego dissolution. ^[136]

Pharmacokinetics

Psilocybin is converted in the liver to the pharmacologically active psilocin, which is then either glucuronidated to be excreted in the urine or further converted to various psilocin metabolites.

The effects of the drug begin 10–40 minutes after ingestion, and last 2–6 hours depending on dose, species, and individual metabolism. ^{[23] : 36–41} The half life of psilocybin is 163 ± 64 minutes when taken orally, or 74.1 ± 19.6 minutes when injected intravenously. ^[2]

Psilocybin is metabolized mostly in the liver. As it becomes converted to psilocin, it undergoes a first-pass effect, whereby its concentration is greatly reduced before it reaches the systemic circulation. Psilocin is broken down by the enzyme monoamine oxidase (MAO) to produce several metabolites that can circulate in the blood plasma, including 4-hydroxyindole-3-acetaldehyde (4-HIAL), 4-hydroxyindole-3-acetic acid (4-HIAA), and 4-hydroxytryptophol (4-HTOL). ^[2] Some psilocin is not broken down by enzymes and instead forms a glucuronide; this is a biochemical mechanism animals use to eliminate substances by linking them with glucuronic acid, which can then be excreted in the urine. ^{[137] [138]} Psilocin is glucuronidated by the glucuronosyltransferase enzymes UGT1A9 in the liver, and by UGT1A10 in the small intestine. ^[139] Based on studies using animals, about 50% of ingested psilocybin is absorbed through the stomach and intestine. About 80% of psilocin is glucuronidated into psilocin-O-glucuronide and about 4% is demethylated and oxidatively deaminated via MAO into 4-HIAL. ^[14] 4-HIAL is subsequently oxidized by aldehyde dehydrogenase (ALDH) into 4-HIAA or can be converted by alcohol dehydrogenase (ADH) into 4-HTOL. ^{[14] [140]} Within 24 hours, about 65% of the absorbed psilocybin is excreted into the urine, and a further 15–20% is excreted in the bile and feces. Although most of the remaining drug is eliminated in this way within 8 hours, it is still detectable in the urine after 7 days. ^[35] Clinical studies show that psilocin concentrations in the plasma of adults average about 8 μg/liter within 2 hours after ingestion of a single 15 mg oral psilocybin dose; ^[141] psychological effects occur with a blood plasma concentration of 4–6 μg/liter. ^[2] Psilocybin is approximately 1/100 the potency of LSD on a weight per weight basis, and the physiological effects last about half as long. ^{[50] : 171}

Monoamine oxidase inhibitors (MAOI) have been known to prolong and enhance the effects of dimethyltryptamine (DMT) and one study assumed that the effect on psilocybin would be similar since it is a structural analogue of DMT. ^[142] However, only a small portion of psilocin appears to be metabolized by MAO. ^[14] Alcohol consumption may enhance the effects of psilocybin, because acetaldehyde, one of the primary breakdown metabolites of consumed alcohol, reacts with biogenic amines present in the body to produce MAOIs related to tetrahydroisoquinoline and β-carboline. ^[46] Tobacco smokers may also experience more powerful effects with psilocybin, ^[46] because tobacco smoke exposure decreases the activity of MAO in the brain and peripheral organs. ^[143]

Analytical methods

Several relatively simple chemical tests—commercially available as reagent testing kits—can be used to assess the presence of psilocybin in extracts prepared from mushrooms. The drug reacts in the Marquis test to produce a yellow color, and a green color in the Mandelin reagent. ^[144] Neither of these tests, however, is specific for psilocybin; for example, the Marquis test will react with many classes of controlled drugs, such as those containing primary amino groups and unsubstituted benzene rings, including amphetamine and methamphetamine. ^[145] Ehrlich's reagent and DMACA reagent are used as chemical sprays to detect the drug after thin layer chromatography. ^[146] Many modern techniques of analytical chemistry have been used to quantify psilocybin levels in mushroom samples. Although the earliest methods commonly used gas chromatography, the high temperature required to vaporize the psilocybin sample prior to analysis causes it to spontaneously lose its phosphoryl group and become psilocin—making it difficult to chemically discriminate between the two drugs. In forensic toxicology, techniques involving gas chromatography coupled to mass spectrometry (GC–MS) are the most widely used due to their high sensitivity and ability to separate compounds in complex biological mixtures. ^[147] These techniques include ion mobility spectrometry, ^[148] capillary zone electrophoresis, ^[149] ultraviolet spectroscopy, ^[150] and infrared spectroscopy. ^[151] High-performance liquid chromatography (HPLC) is used with ultraviolet, ^[111] fluorescence, ^[152] electrochemical, ^[153] and electrospray mass spectrometric detection methods. ^[154]

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; ^[155] HPLC with electrochemical detection; ^{[153] [156]} GC–MS; ^{[137] [155]} and liquid chromatography coupled to mass spectrometry. ^[157] Although the determination of psilocin levels in urine can be performed without sample clean-up (i.e., removing potential contaminants that make it difficult to accurately assess concentration), the analysis in plasma or serum requires a 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. ^[158] A 2009 publication reported using HPLC to quickly separate forensically important illicit drugs including psilocybin and psilocin, which were identifiable within about half a minute of analysis time. ^[159] These analytical techniques to determine psilocybin concentrations in body fluids are, however, not routinely available, and not typically used in clinical settings. ^[59]

Natural occurrence

Maximum reported psilocybin concentrations (% dry weight) in 12 Psilocybe species ^{[23] : 39}

Species	% 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
P. 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). ^[160] 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). ^[161] The diversity of psilocybin mushrooms is reported to have been increased by horizontal transfer of the psilocybin gene cluster between unrelated mushroom species. ^{[162] [115]} In general, psilocybin-containing species are dark-spored, gilled mushrooms that grow in meadows and woods of the subtropics and tropics, usually in soils rich in humus and plant debris. ^{[108] : 5} Psilocybin mushrooms occur on all continents, but the majority of species are found in subtropical humid forests. ^[160] 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 ^[163] —is found in Europe, North America, Asia, South America, Australia and New Zealand, but is entirely absent from Mexico. ^[161] Although the presence or absence of psilocybin is not of much use as a chemotaxonomical marker at the familial level or higher, it is used to classify taxa of lower taxonomic groups. ^[164]

Global distribution of over 100 psychoactive species of genus Psilocybe mushrooms.

Psilocybin was first isolated from Psilocybe mexicana .

P. semilanceata is common in Europe, Canada, and the United States.

Both the caps and the stems contain psychoactive compounds, although the caps consistently contain more. The spores of these mushrooms do not contain psilocybin or psilocin. ^{[148] [166] [167]} The total potency varies greatly between species and even between specimens of a species collected or grown from the same strain. ^[168] Because most psilocybin biosynthesis occurs early in the formation of fruit bodies or sclerotia, younger, smaller mushrooms tend to have a higher concentration of the drug than larger, mature mushrooms. ^[169] In general, the psilocybin content of mushrooms is quite variable (ranging from almost nothing to 2.5% of the dry weight) ^{[170] [31] : 248} and depends on species, strain, growth and drying conditions, and mushroom size. ^{[23] : 36–41, 52} Cultivated mushrooms have less variability in psilocybin content than wild mushrooms. ^[171] The drug is more stable in dried than fresh mushrooms; dried mushrooms retain their potency for months or even years, ^{[23] : 51–5} while mushrooms stored fresh for four weeks contain only traces of the original psilocybin. ^[46]

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. ^[172] Mature mycelia contain some psilocybin, while young mycelia (recently germinated from spores) lack appreciable amounts. ^[173] Many species of mushrooms containing psilocybin also contain lesser amounts of the analog compounds baeocystin and norbaeocystin, ^{[23] : 38} chemicals thought to be biogenic precursors. ^{[50] : 170} Although most species of psilocybin-containing mushrooms bruise blue when handled or damaged due to the oxidization of phenolic compounds, this reaction is not a definitive method of identification or determining a mushroom's potency. ^{[168] [23] : 56–58}

Societal perception and current usage

Legal status

Further information: Legal status of psilocybin mushrooms and Psilocybin decriminalization in the United States

This section is an excerpt from Legal status of psilocybin mushrooms.[ edit ]

Legality of psilocybin mushrooms by country

  Legal

  Legal for medical use and decriminalized

  Ambiguous/partially legal/decriminalized

  Illegal state with decriminalized cities

  Illegal

  No information

The legal status of unauthorised actions with psilocybin mushrooms varies worldwide. Psilocybin and psilocin are listed as Schedule I drugs under the United Nations 1971 Convention on Psychotropic Substances. ^[174] Schedule I drugs are defined as drugs with a high potential for abuse or drugs that have no recognized medical uses. However, psilocybin mushrooms have had numerous medicinal ^{[175] [176] [177]} and religious uses in dozens of cultures throughout history and have a significantly lower potential for abuse than other Schedule I drugs. ^[178]

Psilocybin mushrooms are not regulated by UN treaties. ^[179] Many countries, however, have some level of regulation or prohibition of psilocybin mushrooms (for example, the US Psychotropic Substances Act, the UK Misuse of Drugs Act 1971, and the Canadian Controlled Drugs and Substances Act).

In some jurisdictions, Psilocybe spores are legal to sell and possess, because they contain neither psilocybin nor psilocin. ^[180] 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, ^[181] Georgia, ^[182] and Idaho ^[183] ) 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. ^[184]

Advocacy for tolerance

Despite being illegal in many typically Western countries, such as the UK, Australia and some US states, less conservative governments opt to nurture the legal use of psilocybin and other psychedelic drugs. In Amsterdam, Netherlands, authorities provide education and promotion on the safe use of psychedelic drugs, such as psilocybin, in an aim to reduce public harm. ^[185] Similarly, religious groups like America's Uniao do Vegetal, UDV, ^[186] use psychedelics in traditional ceremonies. ^[187] 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. ^[188]

From 1 July 2023, the Australian medicines regulator has permitted psychiatrists to prescribe psilocybin for the therapeutic treatment of treatment-resistant depression. ^[189]

Advocates for legalization argue there is a lack of evidence of harm, ^{[190] [191]} and potential use in treating certain mental health conditions. Research is difficult to conduct because of the legal status of psychoactive substances. ^[192] Advocates for legalization also promote the utility of "ego dissolution" ^[186] and argue bans are cultural discrimination against traditional users. ^[193]

Usage

Dried Psilocybe mushrooms showing the characteristic blue bruising on the stems.

A 2009 national survey of drug use by the US 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. ^[194] A June 2024 report by the RAND 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. ^[195] The 2024 report by the RAND Corporation suggests psilocybin mushrooms may be the most prevalent psychedelic drug among adults in the United States. ^[195]

In European countries, the lifetime prevalence estimates of psychedelic mushroom usage among young adults (15–34 years) range from 0.3% to 14.1%. ^[196]

In modern Mexico, traditional ceremonial use survives among several indigenous groups, including the Nahuas, the Matlatzinca, the Totonacs, the Mazatecs, Mixes, Zapotecs, and the Chatino. Although hallucinogenic Psilocybe 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 the Catholic Church. ^[197]

Research

See also: Psychedelic therapy

Psilocybin has been a subject of clinical research since the early 1960s, when the Harvard Psilocybin Project evaluated the potential value of psilocybin as a treatment for certain personality disorders. ^[198] Beginning in the 2000s, psilocybin has been investigated for its possible role in the treatment of nicotine dependence, alcohol dependence, obsessive–compulsive disorder (OCD), cluster headache, cancer-related existential distress, ^{[112] [199]} anxiety disorders, and certain mood disorders. ^{[24] : 179–81  [200] [201]} In 2018, the United States Food and Drug Administration (FDA) granted breakthrough therapy designation for psilocybin-assisted therapy for treatment-resistant depression. ^{[202] [203]} A systematic review published in 2021 found that the use of psilocybin as a pharmaceutical substance was associated with reduced intensity of depression symptoms. ^[204] The role of psilocybin as a possible psychoplastogen is also being examined. ^{[130] [131] [132]}

Depression

Clinical trials, including both open-label trials and double-blind randomized controlled trials, have found that single doses of psilocybin produce rapid and long-lasting antidepressant effects outperforming placebo in people with major depressive disorder and treatment-resistant depression. ^[205] Combined with brief psychological support in a phase 2 trial, it has been found to produce dose-dependent improvements in depressive symptoms, with 25 mg (a moderate dose) more effective than 10 mg (a low dose) and 10 mg more effective than 1 mg (non-psychoactive and equivalent to placebo). ^{[205] [206]} The antidepressant effects of psilocybin with psychological support have been found to last at least 6 weeks following a single dose. ^{[205] [206] [207]}

However, some trials have not found psilocybin to significantly outperform placebo in the treatment of depression. ^[205] In addition, a phase 2 trial found that two 25 mg doses of psilocybin 3 weeks apart versus daily treatment with the selective serotonin reuptake inhibitor (SSRI) escitalopram (Lexapro) for 6 weeks (plus two putatively non-psychoactive 1 mg doses of psilocybin 3 weeks apart) did not show a statistically significant difference in reduction of depressive symptoms between groups. ^{[205] [208]} However, reductions in depressive symptoms were numerically greater with psilocybin, some secondary measures favored psilocybin, and the rate of remission was statistically higher with psilocybin (57% with psilocybin vs. 28% with escitalopram). ^{[205] [208]} In any case, the antidepressant effect size of psilocybin over escitalopram appears to be small. ^[209]

Functional 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. ^{[210] [211] [212] [213]} In addition, 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. ^{[214] [205] [215]}

A potential risk of frequent repeated use of psilocybin and other serotonergic psychedelics for psychiatric disorders is cardiac fibrosis and valvulopathy caused by serotonin 5-HT_2B receptor activation. ^{[216] [217]} However, single high doses or widely spaced doses (e.g., months) are widely thought to be safe and concerns about cardiac toxicity apply more to chronic psychedelic microdosing or very frequent use (e.g., weekly). ^{[216] [217]}

See also

• Fungi portal

• List of entheogens
• O-Acetylpsilocin
• Psychedelic microdosing
• Psychoactive plant
• Stoned ape theory
• Soma (drink)

Explanatory notes

1. Synonyms and alternate spellings include 4-PO-DMT (PO: phosphate; DMT: dimethyltryptamine), psilocybine, psilocibin, psilocybinum, psilotsibin, and psilocin phosphate ester, among others. ^[18]
2. The EMCDDA lists the general-purpose websites Erowid, Lycaeum, Mycotopia, The Shroomery, MushroomJohn and The Entheogen Review. Regional sites focusing on hallucinogenic mushrooms listed were Copenhagen Mushroom Link (Denmark), Champis (France), Daath (Hungary), Delysid (Spain), Enteogeneos (Portugal), Kouzelné houbičky (Czech Republic), Norshroom (Norway), Planetahongo (Spain), Svampinfo (Sweden), and Taikasieniforum (Finland). It also listed Magic-Mushrooms.net. The report detailed several additional sites selling spore prints in 2006, but noted that many of these had ceased operation.
3. Percentages are derived from a non-blind clinical study of 30 individuals who were given a dosage of 8–12 milligrams of psilocybin; from Passie (2002), ^[2] citing Quentin (1960). ^[51]
4. One of the reported fatalities, that of a 22-year-old French man who died in 1993, ^[76] 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". ^[77]
5. The academic communities' approval for the methodology employed is exemplified by the quartet of commentaries published in the journal Psychopharmacology titled "Commentary on: Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual experience by Griffiths et al.", by HD Kleber (pp. 291–292), DE Nichols (pp. 284–286), CR Schuster (pp. 289–290), and SH Snyder (pp. 287–288).
6. Subjective effects are "feelings, perceptions, and moods personally experienced by an individual"; they are often assessed using methods of self-report, including questionnaires. Behavioral effects, in contrast, can be observed directly. ^[133]

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External links

• Psilocybin Investigator's Brochure, Version 4.1 (Usona Institute, Madison, Wisconsin, 2021)
• Psilocybin (COMP-360) - COMPASS Pathways - AdisInsight