Psilocybin

Psilocybin,also known as4-phosphoryloxy-N,N-dimethyltryptamine(4-PO-DMT)is anaturally occurringpsychedeliccompoundproduced by more than200 speciesofmushrooms.Effects includeeuphoria,hallucinations,changes inperception,a distortedsense of time,and perceivedspiritual experiences.It can also causeadverse reactionssuch asnauseaandpanic attacks.Its effects depend onset and settingand one's expectations.

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; Psilotsibin; Psilocin phosphate; Psilocin phosphate ester;O-Phosphoryl-4-hydroxy-N,N-dimethyltryptamine; 4-Phosphoryloxy-N,N-dimethyltryptamine; 4-Phosphoryl-N,N-dimethyltryptamine; 4-PO-DMT; COMP360; COMP-360, Psilocybin (USANUS)
Dependence liability	Low
Addiction liability	Low
Routes of administration	By mouth, intravenous
Drug class	Serotonergic psychedelic;Hallucinogen;Serotonin receptor agonist;Serotonin5-HT2Areceptoragonist
ATC code	None
Legal status
Legal status	AU:S9/S8 (Controlled Drug) BR:Class F2(Prohibited psychotropics) CA:Schedule III UK:Class A US:Schedule I
Pharmacokineticdata
Bioavailability	Oral:52.7 ± 20.4% (aspsilocin) (n=3)
Protein binding	66%
Metabolism	Liver,othertissues: •Dephosphorylation(ALPTooltip alkaline phosphatase) •Demethylationanddeamination(MAOTooltip monoamine oxidase) •Oxidation(ALDHTooltip aldehyde dehydrogenase) •Glucuronidation(UGTs)
Metabolites	•Psilocin • Psilocin-O-glucuronide • 4-Hydroxyindole-3-acetaldehyde • 4-Hydroxyindole-3-acetic acid (4-HIAA) • 4-Hydroxytryptophol
Onset of action	Oral:20–50min
Eliminationhalf-life	Oral(aspsilocin): 2.1–4.7h (range 1.2–18.6h) IVTooltip Intravenous administration(as psilocin): 1.2h (range 1.8–4.5h)
Duration of action	Oral:4–6h (range 3–12h) IVTooltip Intravenous injection:15–30min (1mg)
Excretion	Urine(mainly as psilocin-O-glucuronide, 2–4% as unchanged psilocin)
Identifiers
IUPAC name [3-[2-(dimethylamino)ethyl]-1H-indol-4-yl] dihydrogen phosphate
CAS Number	520-52-5Y
PubChemCID	10624
DrugBank	DB11664
ChemSpider	10178Y
UNII	2RV7212BP0
KEGG	D12881Y
ChEBI	CHEBI:8614Y
ChEMBL	ChEMBL194378Y
CompTox Dashboard(EPA)	DTXSID0048898
ECHA InfoCard	100.007.542
Chemical and physical data
Formula	C12H17N2O4P
Molar mass	284.252g·mol−1
3D model (JSmol)	Interactive image
Melting point	220–228 °C (428–442 °F)
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-NY
(verify)

Psilocybin is aprodrugofpsilocin.That is, the compound itself is biologically inactive but quickly converted by the body to psilocin.Psilocybin is transformed into psilocin bydephosphorylationmediated viaphosphataseenzymes.Psilocin ischemically relatedto theneurotransmitterserotoninand acts as anon-selectiveagonistof theserotonin receptors.Activation of one serotonin receptor, the serotonin5-HT_2Areceptor,is specifically responsible for the hallucinogenic effects of psilocin and otherserotonergic psychedelics.Psilocybin is usually takenorally.By thisroute,itsonsetis about 20 to 50minutes,peak effectsoccur after around 60 to 90minutes, and itsdurationis about 4 to 6hours.

Imagery incave paintingsandrock artof modern-dayAlgeriaandSpainsuggests that human use ofpsilocybin mushroomspredates recorded history.InMesoamerica,the mushrooms had long been consumed in spiritual anddivinatoryceremonies before Spanish chroniclers first documented their use in the 16th century. In 1958, the Swiss chemistAlbert Hofmannisolated 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 the1960sand the1970scurbed 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.

Possession of psilocybin-containing mushroomshas been outlawedin most countries, and psilocybin has been classified as aSchedule I controlled substanceunder the 1971 United NationsConvention on Psychotropic Substances.Psilocybin is being studied as a possible medicine in the treatment ofpsychiatric disorderssuch asdepressionandobsessive–compulsive disorderand otherconditionssuch ascluster headaches.It is in late-stageclinical trialsfortreatment-resistant depression.

History

Early

Mayan"mushroom stones" ofGuatemala.

There is evidence to suggest that psychoactive mushrooms have been used by humans in religious ceremonies for thousands of years. TheTassili Mushroom Figurewas 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.

6,000-year-oldpictographsdiscovered near the Spanish town ofVillar del Humoillustrate several mushrooms that have been tentatively identified asPsilocybe hispanica,a hallucinogenic species native to the area.

Some scholars have also interpreted archaeologicalartifactsfromMexicoand the so-calledMayan"mushroom stones" ofGuatemalaas evidence of ritual and ceremonial use of psychoactive mushrooms in theMayanandAzteccultures ofMesoamerica.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.After Spanish explorers of theNew Worldarrived in the 16th century, chroniclers reported the use of mushrooms by the natives for ceremonial and religious purposes. According to theDominicanfriarDiego DuráninThe 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. TheFranciscanfriarBernardino de Sahagúnwrote of witnessing mushroom use in theFlorentine Codex(published 1545–1590),and described how some merchants would celebrate upon returning from a successful business trip by consuming mushrooms to evoke revelatory visions.After 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 ofMesoamericahid their use ofentheogensfrom the Spanish authorities.

Dozens of species of psychedelic mushrooms are found in Europe, but there is little documented usage of them inOld Worldhistory besides the use ofAmanita muscariaamong Siberian peoples.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 ruralHungaryto prepare love potions. English botanistJohn Parkinsonincluded details about a "foolish mushroom" in his 1640herbalTheatricum Botanicum.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.

Modern

Albert Hofmann (shown here in 1993) purified psilocybin and psilocin fromPsilocybe mexicanain the late 1950s.

The increasing availability of information on growing techniques eventually made it possible for amateurs to grow psilocybin mushrooms (Psilocybe cubensispictured) without access to laboratory equipment.

American banker and amateurethnomycologistR. Gordon Wassonand his wife,Valentina P. Wasson,a physician, studied the ritual use of psychoactive mushrooms by the native population in theMazatecvillageHuautla de Jiménez,Mexico. In 1957, Wasson described thepsychedelic visionshe experienced during these rituals in "Seeking the Magic Mushroom",an article published in the American weeklyLifemagazine.Later the same year they were accompanied on a follow-up expedition by French mycologistRoger Heim,who identified several of the mushrooms asPsilocybespecies.

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.The team was aided in the discovery process by Hofmann's willingness to ingest mushroom extracts to help verify the presence of the active compounds.

Next, Hofmann's team synthesized severalstructural analogsof these compounds to examine how these structural changes affect psychoactivity. This research led to the development ofethocybinandCZ-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.Sandoz also marketed and sold pure psilocybin under the name Indocybin to clinicians and researchers worldwide.There were no reports of serious complications when psilocybin was used in this way.

In the early 1960s,Harvard Universitybecame a testing ground for psilocybin through the efforts of Timothy Leary and his associatesRalph Metznerand 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.But according to a 2008 review of safety guidelines in human hallucinogenic research, Leary's and Alpert's well-publicized termination from Harvard and later advocacy of hallucinogen use "further undermined an objective scientific approach to studying these compounds".In response to concerns about the increase in unauthorized use of psychedelic drugs by the general public, psilocybin and other hallucinogenic drugs were unfavorably covered in the press and faced increasingly restrictive laws. In the U.S., laws passed in 1966 that prohibited the production, trade, or ingestion of hallucinogenic drugs; Sandoz stopped producing LSD and psilocybin the same year.In 1970, Congress passed "The Federal Comprehensive Drug Abuse Prevention and Control Act" that made LSD, peyote, psilocybin, and other hallucinogens illegal to use for any purpose, including scientific research.United States politicians' agenda against LSD usage had swept psilocybin along with it into theSchedule I categoryof illicit drugs. Such restrictions on the use of these drugs in human research made funding for such projects difficult to obtain, and scientists who worked with psychedelic drugs faced being "professionally marginalized".Although Hofmann tested these 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.

Despite the legal restrictions on psilocybin use, the 1970s witnessed the emergence of psilocybin as the "entheogen of choice".This was due in large part to wide dissemination of information on the topic, which included works such as those byCarlos Castanedaand 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.As ethnobiologistJonathan Ottexplains, "These authors adapted San Antonio's technique (for producing edible mushrooms by casingmycelialcultures 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. "San Antonio's technique describes a method to grow the common edible mushroomAgaricus bisporus.

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 insmartshopsin the Netherlands, the UK, and online. Several websitesemerged that contributed to the accessibility of information on the mushrooms' description, use, and effects, and users exchanged mushroom experiences. Since 2001, sixEUcountries have tightened their legislation on psilocybin mushrooms in response to concerns about their prevalence and increasing usage.In the 1990s, hallucinogens and their effects on human consciousness were again the subject of scientific study, particularly in Europe. Advances inneuropharmacologyandneuropsychologyand the availability of brain imaging techniques have provided impetus for using drugs like psilocybin to probe the "neural underpinnings of psychotic symptom formation including ego disorders and hallucinations".Recent studies in the U.S. have attracted attention from the popular press and brought psilocybin back into the limelight.

Reported effects

American psychologist andcounterculturefigureTimothy Learyconducted 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 asset and setting.In the early 1960s,Timothy Learyand 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.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.

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.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.Low doses can induce hallucinatory effects.Closed-eye hallucinationsmay occur, where the affected individual sees multicolored geometric shapes and vivid imaginative sequences.Some individuals reportsynesthesia,such as tactile sensations when viewing colors.At higher doses, psilocybin can lead to "intensification ofaffectiveresponses, enhanced ability for introspection,regressionto primitive and childlike thinking, and activation of vivid memory traces with pronounced emotional undertones ".Open-eye visualhallucinationsare common, and may be very detailed, althoughrarely confused with reality.

Physical effects

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).The temporary increases in blood pressure caused by the drug can be a risk factor for users with pre-existing hypertension.These qualitative somatic effects caused by psilocybin have been corroborated by several early clinical studies.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.In one study, administration of gradually increasing dosages of psilocybin daily for 21 days had no measurable effect onelectrolytelevels,blood sugarlevels, orliver toxicity tests.

Psychiatric effects and perceptual disturbances

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

Psilocybin is known to strongly influence the subjective experience of thepassage of time.Users often feel as if time is slowed down, resulting in the perception that "minutes appear to be hours" or "time is standing still".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.These results are consistent with the drug's role in affectingprefrontal cortexactivity,and the role that the prefrontal cortex is known to play in time perception.However, the neurochemical basis of psilocybin's effects on the perception of time are not known with certainty.

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.Other than the duration of the experience, the effects of psilocybin are similar to comparable dosages oflysergic acid diethylamide(LSD) or mescaline. However, in thePsychedelics Encyclopedia,authorPeter Staffordnoted, "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."

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 thedefault mode network(DMN).The ToMN involves making inferences and understanding social situations based on patternswhereas, the DMN relates more to introspection and one's sense of self.The DMN in particular is related to increased rumination and worsening self-image in patients with major depressive disorder (MDD).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.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.

Group perceptions

Through furtheranthropologicalstudies regarding "personal insights"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".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.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"found in one's body.

Group therapies using "classic" psychedelics are becoming more commonly used in the Western world in clinical practice.This is speculated to grow, provided the evidence remains indicative of their safety and efficacy.In social sense, the group is shaped by their experiences surrounding psilocybin and how they view the plant collectively. As mentioned in the anthropology article,the group partakes in a "journey" together, thus adding to the spiritual, social body where roles, hierarchies and gender are subjectively understood.

Adverse effects

Most of the comparatively few fatal incidents that are associated with psychedelic mushroom usage involve the simultaneous use of other drugs, especiallyalcohol.A commonadverse effectresulting from psilocybin mushroom use involves "bad trips" orpanic reactions,in which affected individuals become anxious, confused, agitated, or disoriented.Accidents,self-injury,orsuicideattempts can result from serious cases of acutepsychotic episodes.Although no studies have linked psilocybin withbirth defects,it is recommended that pregnant women avoid its usage.

Toxicity

Psilocybin has lowtoxicity,indicating that it has low potential for inducing life-threatening events like breathing or heart problems.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.

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.One analysis of people hospitalized from psilocybin poisoning found high urine concentrations ofphenethylamine(PEA), indicating that PEA may contribute to the effects of psilocybin poisoning.

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 administeredintravenouslyin mice is 285mg/kg and in rats is 280 mg/kg.When administeredintravenouslyin rabbits, psilocybin's LD₅₀is approximately 12.5 mg/kg.Psilocybin comprises approximately 1% of the weight ofPsilocybe cubensismushrooms, 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 LD₅₀value of rats.Based on the results of animal studies, thelethal doseof psilocybin has been extrapolated to be 6 grams, 1000 times greater than theeffective doseof 6 milligrams.TheRegistry of Toxic Effects of Chemical Substancesassigns psilocybin a relatively hightherapeutic indexof 641 (higher values correspond to a better safety profile); for comparison, the therapeutic indices ofaspirinandnicotineare 199 and 21, respectively.The lethal dose from psilocybin toxicity alone is unknown, and has rarely been documented—as of 2011,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.

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,schizophrenia-likepsychosis,andconvulsionshave 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.Other adverse effects, less frequently reported, include paranoia,confusion,prolongedderealization(disconnection from reality), andmania.Psilocybin usage can temporarily induce a state ofdepersonalization disorder.Usage by those withschizophreniacan induce acute psychotic states requiring hospitalization.

The similarity of psilocybin-induced symptoms to those of schizophrenia has made the drug a useful research tool in behavioral andneuroimagingstudies of this psychotic disorder.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".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,and correlations between HPPD and psychedelics are further obscured bypolydrug useand other variables.

Tolerance and dependence

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

Toleranceto 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.Across-tolerancecan develop between psilocybin and the pharmacologically similar LSD,and between psilocybin andphenethylaminessuch asmescalineandDOM.

Repeated use of psilocybin does not lead tophysical dependence.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 ofdrug dependencein adulthood; this was in contrast to adolescent usage ofcannabis,cocaine,inhalants,anxiolyticmedicines, andstimulants,all of which were associated with "an excess risk of developing clinical features associated with drug dependence".Likewise, a 2010 Dutch study ranked the relative harm of psilocybin mushrooms compared to a selection of 19recreational drugs,including alcohol, cannabis, cocaine,ecstasy,heroin,andtobacco.Psilocybin mushrooms were ranked as the illicit drug with the lowest harm,corroborating conclusions reached earlier by expert groups in the United Kingdom.

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 inIndigenous Americancultures in religious,divinatory,orspiritualcontexts. Reflecting the meaning of the wordentheogen( "the god within" ), the mushrooms are revered as powerful spiritualsacramentsthat provide access to sacred worlds. Typically used in small group community settings, they enhancegroup cohesionand reaffirm traditional values.Terence McKennadocumented the worldwide practices of psilocybin mushroom usage as part of a culturalethosrelating to the Earth and mysteries of nature, and suggested that mushrooms enhancedself-awarenessand a sense of contact with a "Transcendent Other" —reflecting a deeper understanding of our connectedness with nature.

Psychedelic drugs can induce states ofconsciousnessthat have lasting personal meaning and spiritual significance in individuals who are religious or spiritually inclined; 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.In the 1960s,Walter Pahnkeand 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.

In the 1962Marsh Chapel Experiment,which was run by Pahnke at theHarvard Divinity Schoolunder the supervision of Timothy Leary,almost all of the graduate degreedivinitystudent volunteers who received psilocybin reported profound religious experiences.One of the participants was religious scholarHuston Smith,author of several textbooks oncomparative religion;he later described his experience as "the most powerful cosmic homecoming I have ever experienced."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".Psychedelic researcherRick Doblinconsidered the study partially flawed due to incorrect implementation of thedouble-blindprocedure, 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".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."

A group of researchers fromJohns Hopkins School of Medicineled byRoland Griffithsconducted a study to assess the immediate and long-term psychological effects of the psilocybin experience, using a modified version of the mystical experience questionnaire and a rigorous double-blind procedure.When asked in an interview about the similarity of his work 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."TheNational Institute of Drug Abuse-funded study, published in 2006, has been praised by experts for the soundness of its experimental design.In the experiment, 36 volunteers without prior experience with hallucinogens were given psilocybin andmethylphenidate(Ritalin) in separate sessions; the methylphenidate sessions served as acontroland psychoactiveplacebo.The degree of mystical experience was measured using a questionnaire developed by Ralph W. Hood;61% of subjects reported a "complete mystical experience" after their psilocybin session, while only 13% reported such an outcome after their experience with methylphenidate. Two months after taking psilocybin, 79% of the participants reported moderately to greatly increasedlife satisfactionand 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.

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.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 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.

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 inThe Harvard Psychedelic Clubis 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.' "

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 anherbal tea,or by combining with other foods to mask the bitter taste.In rare cases people have injected mushroom extractsintravenously.

Chemistry

Physical properties

The neurotransmitterserotoninis structurally similar to psilocybin.

Psilocybin is a naturally-occurringsubstituted tryptaminethat features anindolering linked to anaminoethylsubstituent.It is structurally related toserotonin,amonoamine neurotransmitterwhich is a derivative of theamino acidtryptophan.Psilocybin is a member of the general class of tryptophan-based compounds that originally functioned asantioxidantsin earlier life forms before assuming more complex functions in multicellular organisms, including humans.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.

Psilocybin is a white, crystalline solid that is soluble in water,methanolandethanolbut insoluble in nonpolar organicsolventssuch aschloroformandpetroleum ether.It has amelting pointbetween 220 and 228 °C (428 and 442 °F),and anammonia-like taste.ItspKavalues are estimated to be 1.3 and 6.5 for the two successivephosphatehydroxy groupsand 10.4 for thedimethylaminenitrogen, so it typically exists as azwitterionicstructure.There are two known crystalline polymorphs of psilocybin, as well as reportedhydrated phases.Psilocybin rapidly oxidizes upon exposure to light—an important consideration when using it as an analyticalstandard.

Structural analogues

Structural analoguesof psilocybin (4-PO-DMT;O-phosphorylpsilocin) andpsilocin(4-HO-DMT) includedimethyltryptamine(DMT),5-hydroxytryptamine(5-HT),bufotenin(5-HO-DMT),4-AcO-DMT(psilacetin;O-acetylpsilocin),4-PrO-DMT(O-propionylpsilocin),psilomethoxin(4-HO-5-MeO-DMT; 5-methoxypsilocin),ethocybin(4-PO-DET),baeocystin(4-PO-NMT),aeruginascin(4-PO-TMT), andnorbaeocystin(4-PO-T), among others.

Laboratory synthesis

Albert Hofmannet 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 requirechromatographicpurification. 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.

Biosynthesis

Isotopic labelingexperiments from the 1960s suggested that thebiosynthesisof psilocybin was a four-step process:

1. Decarboxylationoftryptophantotryptamine
2. N,N-Dimethylation of tryptamine at the N⁹position todimethyltryptamine
3. 4-Hydroxylationof dimethyltryptamine topsilocin
4. O-Phosphorylationof psilocin to psilocybin

This process can be seen in the following diagram:

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.

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.The sequence of the intermediate steps has been shown to involve four enzymes (PsiD, PsiH, PsiK, and PsiM) inP. cubensisandP. cyanescens,although it is possible that the biosynthetic pathway differs between species.These enzymes are encoded ingene clustersinPsilocybe, Panaeolus,andGymnopilus.

Escherichia colihas been genetically modified to manufacture large amounts of psilocybin.Psilocybin can be producedde novoin GM yeast.

Pharmacology

Pharmacodynamics

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 (EC50Tooltip half-maximal effective concentration) 16–98% (EmaxTooltip 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–β2	>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) 920–2,700 (EC50) (rodent) >30,000 (EC50) (human)
SERTTooltip Serotonin transporter	3,800–>10,000 (Ki) 662–3,900 (IC50Tooltip half-maximal inhibitory concentration) 561 (EC50) 54% (Emax)
NETTooltip Norepinephrine transporter	13,000 (Ki) 14,000 (IC50) >10,000 (EC50)
DATTooltip 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:

Psilocybin is aserotonergic psychedelicthat acts as aprodrugofpsilocin,theactive formof the drug.Psilocin is a closeanalogueof themonoamine neurotransmitterserotoninand, like serotonin, acts as anon-selectiveagonistof theserotonin receptors,including behaving as apartial agonistof the serotonin5-HT_2Areceptor.It shows highaffinityfor most of the serotonin receptors, with the notable exception of the serotonin5-HT₃receptor.Psilocin's affinity for the serotonin 5-HT_2Areceptor is 15-fold higher in humans than in rats due to species differences.In addition to interacting with the serotonin receptors, psilocin is apartialserotonin releasing agentwith lowerpotency.Unlike certain other psychedelics such asLSD,it appears to show little affinity for many othertargets,such asdopamine receptors.Psilocin is an agonist of the mouse and rat but not humantrace amine-associated receptor 1(TAAR1).

Psilocybin's and psilocin's psychedelic effects are mediated specifically by agonism of the serotonin 5-HT_2Areceptor.Selectiveserotonin 5-HT_2Areceptorantagonistslikevolinanserinblock 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-HT_2Areceptorknockout mice.There is a significant relationship between psilocybin's hallucinogenic effects and serotonin 5-HT_2Areceptoroccupancyin humans.Psilocybin's psychedelic effects can be blocked by serotonin 5-HT_2Areceptor antagonists likeketanserinandrisperidonein humans.Activation of serotonin 5-HT_2Areceptors inlayer Vof themedial prefrontal cortex(mPFC) and consequentglutamaterelease in this area has been especially implicated in the hallucinogenic effects of psilocybin and other serotonergic psychedelics.In addition, region-dependent alterations in brain glutamate levels may be related to the experience ofego dissolution.Serotonin5-HT_1Areceptoractivation seems to inhibit the hallucinogenic effects of psilocybin and other psychedelics.

Although serotonin 5-HT_2Areceptor agonism mediates thehallucinogeniceffects of psilocybin and psilocin, activation of other serotonin receptors also appears to contribute to these compounds'psychoactiveand behavioral effects.Some of psilocybin's non-hallucinogenic behavioral effects in animals can be reversed by antagonists of the serotonin 5-HT_1A,5-HT_2B,and5-HT_2Creceptors.Psilocybin produces profoundlydecreased locotomotorandinvestigatory behaviorin rodents, and this appears to be dependent on serotonin 5-HT_1Areceptor activation but not on activation of the serotonin 5-HT_2Aor 5-HT_2Creceptors.In addition, the serotonin5-HT_1Breceptorhas been found to be required for psilocybin's persistingantidepressant- andanxiolytic-like effects as well as acute hypolocomotion in animals.In humans, ketanserin blocked psilocybin's hallucinogenic effects but not all of its cognitive and behavioral effects.Serotonin 5-HT_2Creceptor activation and downstream inhibition of themesolimbic dopamine pathwaymay be involved in the limitedaddictive potentialof serotonergic psychedelics like psilocybin.

In addition to its psychedelic effects, psilocin has been found to producepsychoplastogeniceffects in animals, includingdendritogenesis,spinogenesis,andsynaptogenesis.It has been found to promoteneuroplasticityin the brain in a rapid, robust, and sustained manner with a single dose.These effects appear to be mediated byintracellularserotonin 5-HT_2Areceptor activation.The psychoplastogenic effects of psilocybin and other serotonergic psychedelics may be involved in their potential therapeutic benefits in the treatment ofpsychiatric disorderssuch asdepression.They may also be involved in the effects ofmicrodosing.Psilocin has also been reported to act as a highlypotentpositive allosteric modulatorof thetropomyosin receptor kinase B(TrkB), one of thereceptorsofbrain-derived neurotrophic factor(BDNF).But psilocybin has been found to inhibithippocampalneurogenesisin rodents.

Psilocybin produces profoundanti-inflammatoryeffects mediated by serotonin 5-HT_2Areceptor activation inpreclinical studies.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.Psilocybin's anti-inflammatory effects might be involved in its potential antidepressant benefits and might also have other therapeutic applications, such as treatment ofasthmaandneuroinflammation.They may also be involved in microdosing effects.But psychedelics have been found to have anti-inflammatory effects only in the setting of preexistinginflammationand may bepro-inflammatoryoutside that context.Psilocybin has been found to have a large, long-lasting impact on theintestinal microbiomeand to influence thegut–brain axisin animals.These effects are partially but not fully dependent on its activation of the serotonin 5-HT_2Aand/or 5-HT_2Creceptors.Some of psilocybin's behavioral and potential therapeutic effects may be mediated by changes to the gut microbiome.Transplantation of intestinal contents of psilocybin-treated rodents to untreated rodents resulted in behavioral changes consistent with those of psilocybin administration.

Psilocybin and other psychedelics producesympathomimeticeffects, such as increasedheart rateandblood pressure,by activating the serotonin 5-HT_2Areceptor.Long-term repeated use of psilocybin may result in risk ofcardiac valvulopathyand othercomplicationsby activating serotonin 5-HT_2Breceptors.

There is little or no acutetolerancewith psilocybin, and hence itsdurationis dictated bypharmacokineticsrather than bypharmacodynamics.Conversely, tolerance andtachyphylaxisrapidly develop to psilocybin's psychedelic effects with repeated administration in humans.In addition, there iscross-tolerancewith the hallucinogenic effects of other psychedelics such as LSD.Psilocybin producesdownregulationof the serotonin 5-HT_2Areceptor in the brain in animals, an effect thought to be responsible for the development of tolerance to its psychedelic effects.Serotonin 5-HT_2Areceptors appear to slowly return over the course of days to weeks after psilocybin administration.

Pharmacokinetics

Absorption

There has been little research on psilocybin'sbioavailability.Itsoralbioavailability, as itsactive formpsilocin,was about 55.0% (± ~20%) relative tointravenous administrationin one small older study (n=3).After oral administration, psilocybin is detectable in the blood circulation within 20 to 40minutes, and psilocin is detectable after 30minutes.The meantime to peaklevels for psilocin is 1.05 to 3.71hours in different studies, with most around 2hours and the upper limit of 3.71hours being anoutlier.

Psilocybin, in terms of psilocin, shows clear linear ordose-dependentpharmacokinetics.Maximal concentrations of psilocin were 11ng/mL, 17ng/mL, and 21ng/mL with oral psilocybin doses of 15, 25, and 30mg psilocybin, respectively.The maximal levels of psilocin have been found to range from 8.2ng/mL to 37.6ng/mL across a dose range of 14 to 42mg.The dose-normalized peak concentration of psilocin is about 0.8ng/mL/mg.Theinterindividual variabilityin the pharmacokinetics of psilocybin is relatively small.There is a very strong positive correlation between dose and psilocin peak levels (R²= 0.95).The effects of food on the pharmacokinetics of psilocybin have not been reported and are unknown, but no clear sign of food effects has been observed in preliminary analyses.It has also been said that food might delayabsorption,reduce peak levels, and reduce bioavailability.

Distribution

Psilocin, the active form of psilocybin, is extensivelydistributedto alltissuesthrough thebloodstream.Itsvolume of distributionis 505 to 1,267L.Psilocybin itself ishydrophilicdue to itsphosphategroupand cannot easily cross theblood–brain barrier.Conversely, psilocin islipophilicand readily crosses the blood–brain barrier to exert effects in thecentral nervous system.Theplasma protein bindingof psilocybin is 66% and hence it is moderately plasma protein-bound.

Theoreticalintramolecularhydrogen bondandpseudo-ring systemoccurring withpsilocin(4-HO-DMT) but not withbufotenin(5-HO-DMT).

Psilocin (4-HO-DMT) is a closepositional isomerofbufotenin(5-HO-DMT), which showsperipheral selectivity,and might be expected to have similarly restricted lipophilicity and blood–brain barrier permeability.But psilocin appears to form atricyclicpseudo-ring systemwherein itshydroxyl groupandamineinteract throughhydrogen bonding.This in turn makes psilocin much lesspolar,more lipophilic, and more able to cross the blood–brain barrier and exert central actions than it would be otherwise.It may also protect psilocin from metabolism bymonoamine oxidase(MAO).In contrast, bufotenin is not able to achieve this pseudo-ring system.Accordingly, bufotenin is less lipophilic than psilocin in terms ofpartition coefficient.But bufotenin does still show significant central permeability and, like psilocybin, can produce robust hallucinogenic effects in humans.

Metabolism

Metabolismof psilocybin andpsilocinin humans and mice.

Psilocybin isdephosphorylatedinto itsactive formpsilocinin the body.Psilocybin ismetabolizedin theintestines,liver,kidneys,blood,and othertissuesandbodily fluids.There is significantfirst-pass metabolismof psilocybin and psilocin withoral administration.No psilocybin has been detected in the blood in humans after oral administration, suggesting virtually complete dephosphorylation into psilocin with the first pass.Thecompetitivephosphatase inhibitorβ-glycerolphosphate, which inhibits psilocybin dephosphorylation, greatly attenuates the behavioral effects of psilocybin in rodents.Psilocybin undergoes dephosphorylation into psilocin via theacidicenvironment of thestomachor the actions ofalkaline phosphatase(ALP) and non-specificesterasesin tissues and fluids.

Psilocin isdemethylatedandoxidatively deaminatedbymonoamine oxidase(MAO), specificallymonoamine oxidase A(MAO-A), into 4-hydroxyindole-3-acetaldehyde (4-HIAL or 4-HIA).4-HIAL is then further oxidated into 4-hydroxyindole-3-acetic acid (4-HIAA) byaldehyde dehydrogenase(ALDH) or into 4-hydroxytryptophol (4-HTOL or 4-HTP) byalcohol dehydrogenase(ALD).Deamination of psilocin by MAO-A appears to be responsible for about 4% or 33% of its metabolism in different studies.In contrast to psilocin, its metabolites 4-HIAA and 4-HTP showed no affinity for or activation of multiple serotonin receptors and are considered inactive.Based onin vitrostudies, it has been estimated that MAO-A is responsible for about 81% of psilocin'sphase Ihepatic metabolism.Psilocin and its metabolites are alsoglucuronidatedbyUDP-glucuronyltransferases(UGTs).UGT1A10andUGT1A9appear to be the most involved.Psilocybin's glucuronidated metabolites include psilocin-O-glucuronide and 4-HIAA-O-glucuronide.Approximately 80% of psilocin inblood plasmais inconjugatedform, and conjugated psilocin levels are about fourfold higher than levels of free psilocin.Plasma 4-HIAA levels are also much higher than those of free psilocin.

Norpsilocin(4-HO-NMT), formed from psilocin via demethylation mediated by thecytochrome P450enzymeCYP2D6,is known to occur in micein vivoand with human recombinant CYP2D6in vitrobut was not detected in humansin vivo.An oxidized psilocin metabolite of unknownchemical structureis also formed by hydroxyindole oxidase activity of CYP2D6.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).Additional metabolites formed by CYP2D6 may also be present.Besides CYP2D6,CYP3A4showed minor activity in metabolizing psilocin, though the produced metabolite is unknown.Othercytochrome P450enzymesbesides CYP2D6 and CYP3A4 appear unlikely to be involved in psilocin metabolism.CYP2D6metabolizer phenotypesdo not modify psilocin exposure in humans, suggesting that CYP2D6 is not critically involved in psilocin metabolism and is unlikely to result in interindividual differences in psilocin kinetics or effects.Psilocybin and psilocin might inhibitCYP3A4andCYP2A6to some extent, respectively.

Elimination

Psilocybin iseliminated80 to 85% inurineand 15 to 20% inbile.It isexcretedmainly in urine as psilocin-O-glucuronide.The drug was eliminated approximately 20% and 80% as psilocinO-glucuronide in different studies.The amountexcretedas unchanged psilocin in urine is 1.5 to 3.4%.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-HTOLand another that psilocybin is excreted 33% in urine as 4-HIAA.Findings also conflict on whether psilocybin can be detected in urine.A majority of psilocybin and its metabolites is excreted within 3hours with oral administration and elimination is almost complete within 24hours.

Theelimination half-lifeof psilocybin, as psilocin, is 2.1 to 4.7hours on average (range 1.2–18.6hours)orallyand 1.2hours (range 1.8–4.5hours)intravenously.Psilocin's elimination half-life in mice is 0.9hours, much faster than in humans.PsilocinO-glucuronide's half-life is about 4hours in humans and approximately 1hour in mice.

No dose adjustment of psilocin is thought to be required as psilocin is inactivated mainly via metabolism as opposed to renal elimination.Accordingly,glomerular filtration rate(GFR) did not affect the pharmacokinetics of psilocybin.

Miscellaneous

Theonset of actionof psilocybin taken orally is about 20 to 50minutes and peak subjective effects occur at about 1.0 to 2.2hours (60–130minutes).The time to offset of psilocybin orally is about 6 to 7hours on average.Theduration of actionof psilocybin is about 4 to 6hours (range 3–12hours) orally.A small dose of 1mg byintravenous injectionhad a duration of 15 to 30minutes.The psychoactive effects and duration of psilocybin are strongly correlated with psilocin levels.

Single doses of psilocybin of 3 to 30mg have been found to dose-dependently occupy the serotonin 5-HT_2Areceptor in humans as assessed byimagingstudies.TheEC₅₀Tooltip half-maximal effective concentrationfor occupancy of the serotonin 5-HT_2Areceptor by psilocin in terms of circulating levels has been found to be 1.97ng/mL.

Body weightandbody mass indexdo not appear to affect the pharmacokinetics of psilocybin.This suggests that body weight-adjusted dosing of psilocybin is unnecessary and may actually be counterproductive and that fixed-dosing should be preferred.Similarly,agedoes not affect the pharmacokinetics of psilocybin.Sexhas not been tested.

Analytical methods

Several relatively simplechemical tests—commercially available asreagent testingkits—can be used to assess the presence of psilocybin inextractsprepared from mushrooms. The drug reacts in theMarquis testto produce a yellow color, and a green color in theMandelin reagent.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 containingprimary aminogroups and unsubstitutedbenzene rings,includingamphetamineandmethamphetamine.Ehrlich's reagentandDMACA reagentare used as chemical sprays to detect the drug afterthin layer chromatography.Many modern techniques ofanalytical chemistryhave been used to quantify psilocybin levels in mushroom samples. Although the earliest methods commonly usedgas chromatography,the high temperature required tovaporizethe 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. Inforensic toxicology,techniques involvinggas 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.These techniques includeion mobility spectrometry,capillary zone electrophoresis,ultraviolet spectroscopy,andinfrared spectroscopy.High-performance liquid chromatography(HPLC) is used with ultraviolet,fluorescence,electrochemical,andelectrospraymass spectrometric detection methods.

Various chromatographic methods have been developed to detect psilocin inbody fluids:the rapid emergency drug identification system (REMEDi HS), adrug screeningmethod based on HPLC;HPLC with electrochemical detection;GC–MS;andliquid chromatography coupled to mass spectrometry.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 inplasmaorserumrequires a preliminaryextraction,followed byderivatizationof the extracts in the case of GC–MS. A specificimmunoassayhas also been developed to detect psilocin in whole blood samples.A 2009 publication reported using HPLC to quickly separate forensically important illicit drugs including psilocybin and psilocin, which were identifiable within about half a minute of analysis time.These analytical techniques to determine psilocybin concentrations in body fluids are, however, not routinely available, and not typically used inclinicalsettings.

Natural occurrence

Maximum reported psilocybin concentrations (% dry weight) in 12Psilocybespecies

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 ofBasidiomycotamushrooms. In a 2000 review on the worldwide distribution of hallucinogenic mushrooms,Gastón Guzmánand 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).Guzmán increased his estimate of the number of psilocybin-containingPsilocybeto 144 species in a 2005 review. The majority of these are found in Mexico (53 species), with the remainder distributed in the United States and Canada (22), Europe (16), Asia (15), Africa (4), and Australia and associated islands (19).The diversity of psilocybin mushrooms is reported to have been increased by horizontal transfer of the psilocybingene clusterbetween unrelated mushroom species.In general, psilocybin-containing species are dark-spored,gilledmushrooms that grow in meadows and woods of thesubtropicsandtropics,usually in soils rich inhumusand plant debris.Psilocybin mushrooms occur on all continents, but the majority of species are found insubtropical humid forests.Psilocybespecies commonly found in the tropics includeP. cubensisandP. subcubensis.P. semilanceata—considered by Guzmán to be the world's most widely distributed psilocybin mushroom—is found in Europe, North America, Asia, South America, Australia and New Zealand, but is entirely absent from Mexico.Although the presence or absence of psilocybin is not of much use as achemotaxonomicalmarker at thefamiliallevel or higher, it is used to classifytaxaof lower taxonomic groups.

Global distribution of over 100 psychoactive species of genusPsilocybemushrooms.

Psilocybin was first isolated fromPsilocybe mexicana.

P. semilanceatais common in Europe, Canada, and the United States.

Both thecapsand thestemscontain psychoactive compounds, although the caps consistently contain more. Thesporesof these mushrooms do not contain psilocybin or psilocin.The totalpotencyvaries greatly between species and even between specimens of a species collected or grown from the same strain.Because most psilocybin biosynthesis occurs early in the formation offruit bodiesorsclerotia,younger, smaller mushrooms tend to have a higher concentration of the drug than larger, mature mushrooms.In general, the psilocybin content of mushrooms is quite variable (ranging from almost nothing to 2.5% of thedry weight)and depends on species, strain, growth and drying conditions, and mushroom size.Cultivated mushrooms have less variability in psilocybin content than wild mushrooms.The drug is more stable in dried than fresh mushrooms; dried mushrooms retain their potency for months or even years,while mushrooms stored fresh for four weeks contain only traces of the original psilocybin.

The psilocybin contents of driedherbariumspecimens ofPsilocybe semilanceatain 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.Maturemyceliacontain some psilocybin, while young mycelia (recentlygerminatedfrom spores) lack appreciable amounts.Many species of mushrooms containing psilocybin also contain lesser amounts of the analog compoundsbaeocystinandnorbaeocystin,chemicals thought to be biogenicprecursors.Although most species of psilocybin-containing mushrooms bruise blue when handled or damaged due to theoxidizationof phenolic compounds, this reaction is not a definitive method of identification or determining a mushroom's potency.

Society and culture

Legal status

Further information:Legal status of psilocybin mushroomsandPsilocybin decriminalization in the United States

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

Legality of activities with psilocybin mushrooms by country

Legal

Legal for medical use and decriminalized

Ambiguous/partially legal/decriminalized

Illegal state with decriminalized cities

Illegal

No information

Thelegal status of unauthorised actions with psilocybin mushroomsvaries worldwide. Psilocybin andpsilocinare listed asSchedule I drugsunder the United Nations 1971Convention on Psychotropic Substances.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 medicinaland religious uses indozens of cultures throughout historyand have a significantly lower potential for abuse than other Schedule I drugs.

Psilocybinmushroomsare not regulated by UN treaties. Many countries, however, have some level of regulation or prohibition of psilocybin mushrooms (for example, the USPsychotropic Substances Act,the UKMisuse of Drugs Act 1971,and the CanadianControlled Drugs and Substances Act).

In some jurisdictions,Psilocybespores are legal to sell and possess, because they contain neither psilocybin nor psilocin.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,Georgia,and Idaho) 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.

Advocacy for tolerance

Despite being illegal to possess without authorisation in many typically Western countries, such as the UK, Australia and some US states, less conservative governments opt to nurture the legal possession and supply 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.Similarly, religious groups like America's Uniao do Vegetal, UDV,use psychedelics in traditional ceremonies.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.

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

Advocates for legalization argue there is a lack of evidence of harm,and potential use in treating certain mental health conditions. Research is difficult to conduct because of our legal status re psychoactive substances.Advocates for legalisation of access also promote the utility of "ego dissolution"and argue bans are cultural discrimination against traditional users.

In 2024, after calls for regulatory and legal change to expand terminally ill populations' access to controlled substances, two legal cases related to expanded access began moving through the federal courts 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.

Usage

DriedPsilocybemushrooms showing the characteristic blue bruising on the stems.

A 2009 national survey of drug use by theUS Department of Health and Human Servicesconcluded 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.A June 2024 report by theRAND Corporationsuggests 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.The 2024 report by the RAND Corporation suggests psilocybin mushrooms may be the most prevalent psychedelic drug among adults in the United States.

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

In modern Mexico, traditional ceremonial use survives among several indigenous groups, including theNahuas,theMatlatzinca,theTotonacs,theMazatecs,Mixes,Zapotecs,and theChatino.Although hallucinogenicPsilocybespecies 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.

Research

See also:Psychedelic therapyandList of investigational hallucinogens and entactogens

Psilocybin has been a subject of clinical research since the early 1960s, when theHarvard Psilocybin Projectevaluated thepotential value of psilocybinas a treatment for certainpersonality disorders.Beginning in the 2000s, psilocybin has been investigated for its possible role in the treatment ofnicotine dependence,alcohol dependence,obsessive–compulsive disorder(OCD),cluster headache,cancer-related existential distress,anxiety disorders,and certainmood disorders.It is also being studied in people withParkinson's disease.In 2018, the United StatesFood and Drug Administration(FDA) grantedbreakthrough therapydesignation for psilocybin-assisted therapy fortreatment-resistant depression.A systematic review published in 2021 found that the use of psilocybin as a pharmaceutical substance was associated with reduced intensity of depression symptoms.The role of psilocybin as a possiblepsychoplastogenis also being examined.It is under development byCompass Pathways,Cybin,and several other companies.

Depression

Clinical trials,including bothopen-label trialsanddouble-blindrandomized controlled trials,have found that single doses of psilocybin produce rapid and long-lastingantidepressanteffects outperformingplaceboin people withmajor depressive disorderandtreatment-resistant depression.Combined with briefpsychological supportin aphase 2trial, it has been found to producedose-dependentimprovements in depressive symptoms, with 25mg (a moderate dose) more effective than 10mg (a low dose) and 10mg more effective than 1mg (non-psychoactive and equivalent toplacebo).The antidepressant effects of psilocybin with psychological support have been found to last at least 6weeks following a single dose.

However, some trials have not found psilocybin to significantly outperform placebo in the treatment of depression.In addition, a phase 2 trial found that two 25mg doses of psilocybin 3weeks apart versus daily treatment with theselective serotonin reuptake inhibitor(SSRI)escitalopram(Lexapro) for 6weeks (plus two putatively non-psychoactive 1mg doses of psilocybin 3weeks apart) did not show astatistically significantdifference in reduction of depressive symptoms between groups.However, reductions in depressive symptoms were numerically greater with psilocybin, somesecondary measuresfavored psilocybin, and the rate ofremissionwas statistically higher with psilocybin (57% with psilocybin vs. 28% with escitalopram).In any case, the antidepressanteffect sizeof psilocybin over escitalopram appears to be small.

Functional unblindingby their psychoactive effects andpositive psychological expectancy effects(i.e., theplacebo effect) are major limitations and sources ofbiasof clinical trials of psilocybin and other psychedelics for treatment of depression.Relatedly, most of the therapeutic benefit of conventionalantidepressantslike the SSRIs for depression appears to be attributable to theplacebo response.It has been proposed that psychedelics like psilocybin may in fact act asactive"superplacebos"when used for therapeutic purposes.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 3trials or received regulatory approval for medical use.

A potential risk of frequent repeated use of psilocybin and other serotonergic psychedelics for psychiatric disorders iscardiac fibrosisandvalvulopathycaused byserotonin5-HT_2Breceptoractivation.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 chronicpsychedelic microdosingor very frequent use (e.g., weekly).

See also

• List of entheogens
• 4-AcO-DMT(psilacetin)
• Mushroom edible
• Psychedelic microdosing
• Psychoactive plant
• Stoned ape theory
• Soma (drink)

External links

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