Psilocybin

Source: Wikipedia, the free encyclopedia.

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 namesPsilocybine; 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 (USAN US)
Dependence
liability		Low[1][2][3][4][5]
Addiction
liability		Low[1][6]
Routes of
administration
Serotonergic psychedelic; Hallucinogen; Serotonin receptor agonist; Serotonin 5-HT2A receptor agonist[8]
ATC code
  • None
Legal status
Legal status
IVTooltip Intravenous injection: 15–30 min (1 mg)[2][12]
ExcretionUrine (mainly as psilocin-O-glucuronide, 2–4% as unchanged psilocin)[10][7][19]
Identifiers
  • [3-[2-(dimethylamino)ethyl]-1H-indol-4-yl] dihydrogen phosphate
JSmol)
Melting point220–228 °C (428–442 °F) [21]
SMILES
  • CN(C)CCC1=CNC2=C1C(=CC=C2)OP(=O)(O)O
  • 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) checkY
  • Key:QVDSEJDULKLHCG-UHFFFAOYSA-N checkY
  (verify)

Psilocybin, also known as 4-phosphoryloxy-N,N-dimethyltryptamine (4-PO-DMT),

adverse reactions such as nausea and panic attacks. Its effects depend on set and setting and one's expectations.[11][24]

Psilocybin is a

duration is about 4 to 6 hours.[11][17][18][14]

Imagery in

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.

Possession of psilocybin-containing mushrooms

conditions such as cluster headaches.[27] It is in late-stage clinical trials for treatment-resistant depression.[28][29][30]

Uses

See also: Psychedelic drug § Uses

Psilocybin is used

routes of administration
are also employed.

Dosage

See also: Psychedelic drug § Dosage, and Psilocybin mushroom § Dosage

Psilocybin is used as a psychedelic at doses of 5 to 40 mg

ego-dissolution doses are 30 to 40 mg.[14][31] Microdosing involves the use of subthreshold psilocybin doses of less than 2.5 mg.[14][31]

When psilocybin is used in the form of

psilocybin-containing mushrooms, microdoses are 0.1 g to 0.3 g and psychedelic doses are 1.0 g to 3.5–5.0 g in the case of dried mushrooms.[32][33][7] The preceding 1.0 to 5.0 g range corresponds to psilocybin doses of about 10 to 50 mg.[7] Psilocybin-containing mushrooms vary in their psilocybin and psilocin content, but are typically around 1% of the dried weight of the mushrooms (in terms of total or combined psilocybin and psilocin content).[33][34][19][7][25][35][36][37] Psilocin is about 1.4 times as potent as psilocybin because of the two compounds' difference in molecular weight.[19][38][39]

Available forms

Psilocybin is most commonly consumed in the form of

gummies, which may be purchased at psychedelic mushroom stores
.

Effects

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

Psilocybin produces a variety of

physical effects.[14]

Psychological and perceptual effects

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

After ingesting psilocybin, the user may experience a wide range of emotional effects, which can include 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.[41] In studies at Johns Hopkins, among those given a moderate dose (but 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.[45][46] Low doses can induce hallucinatory effects. Closed-eye hallucinations may occur, where the affected person sees multicolored geometric shapes and vivid imaginative sequences.[47] Some people report synesthesia, such as tactile sensations when viewing colors.[48]: 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".[49] Open-eye visual hallucinations are common and may be very detailed, although rarely confused with reality.[47]

Psilocybin is known to strongly affect the subjective experience of the passage of time.[50][23] Users often feel as if time is slowed down, resulting in the perception that "minutes appear to be hours" or "time is standing still".[51] 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.[51][52] These results are consistent with the drug's role in affecting prefrontal cortex activity[53] and the role that the prefrontal cortex plays in time perception,[54] but the neurochemical basis of psilocybin's effects on perception of time is not known with certainty.[55]

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 "

lysergic acid diethylamide (LSD) or mescaline. But in the Psychedelics Encyclopedia, author Peter Stafford writes: "The psilocybin experience seems to be warmer, not as forceful and less isolating. It tends to build connections between people, who are generally much more in communication than when they use LSD."[57]
: 273 

Set and setting and moderating factors

The effects of psilocybin are highly variable and depend on the mindset and environment in which the user has the experience. factors commonly called set and setting. In the early 1960s, Timothy Leary and his Harvard colleagues investigated the role of set and setting in psilocybin's effects. 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. Those who had prior experience with psilocybin 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 a user more receptive to interpersonal interactions and environmental stimuli.[58] These findings were affirmed in a later review by Jos ten Berge (1999), who concluded that dosage, set, and setting are fundamental factors in determining the outcome of experiments that tested the effects of psychedelic drugs on artists' creativity.[59]

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 fungus 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]

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

group cohesion and reaffirm traditional values.[69] 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.[70]

Psychedelic drugs can induce states of

holotropic breathwork.[71][72] In the 1960s, Walter Pahnke and colleagues systematically evaluated mystical experiences (which they called "mystical consciousness") by categorizing their common features. According to Pahnke, these categories "describe the core of a universal psychological experience, free from culturally determined philosophical or theological interpretations", and allow researchers to assess mystical experiences on a qualitative, numerical scale.[73]

In the 1962

double-blind procedure and several imprecise questions in the mystical experience questionnaire. Nevertheless, he said that the study cast "considerable doubt on the assertion that mystical experiences catalyzed by drugs are in any way inferior to non-drug mystical experiences in both their immediate content and long-term effects".[77]: 24  Psychiatrist William A. Richards echoed this sentiment, writing in a 2007 review, "[psychedelic] mushroom use may constitute one technology for evoking revelatory experiences that are similar, if not identical, to those that occur through so-called spontaneous alterations of brain chemistry."[78]

A group of researchers from

National Institute of Drug Abuse-funded study, published in 2006, for the soundness of its experimental design.[b] In the experiment, 36 volunteers with no experience with hallucinogens were given psilocybin 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;[81] 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.[82]

A follow-up study 14 months later confirmed that participants continued to attribute deep personal meaning to the experience. Almost a third of the subjects reported that the experience was the single most meaningful or spiritually significant event of their lives, and over two-thirds reported it was among their five most spiritually significant events. About two-thirds said the experience increased their sense of well-being or life satisfaction.[75] Even after 14 months, those who reported mystical experiences scored on average 4 percentage points higher on the personality trait of Openness/Intellect; personality traits are normally stable across the lifespan for adults. Likewise, in a 2010 web-based questionnaire study designed to investigate user perceptions of the benefits and harms of hallucinogenic drug use, 60% of the 503 psilocybin users reported that their use of psilocybin had a long-term positive impact on their sense of well-being.[41][83]

While many recent studies have concluded that psilocybin can cause mystical-type experiences of substantial and sustained personal meaning and spiritual significance, the medical community does not unanimously agree. Former director of the Johns Hopkins Department of Psychiatry and Behavioral Science

toxic delirium.'"[84]

Physical effects

Common responses include

blood sugar levels, or liver toxicity tests.[2]

Onset and duration

The

intravenous injection had a duration of 15 to 30 minutes.[2][12]

Contraindications

safety information about the use of psilocybin in people with such conditions.[11] It is notable in this regard that psilocybin and other psychedelics are being studied for the potential treatment of all the preceding conditions.[90][91][92][93][94][95]

Psilocybin is also considered to be contraindicated in women who are

cardiovascular conditions are a relative contraindication for psilocybin.[11] Serotonin 5-HT2A receptor antagonists such as atypical antipsychotics and certain antidepressants may block psilocybin's hallucinogenic effects and hence may be considered contraindicated in this sense.[96][97] Monoamine oxidase inhibitors (MAOIs) may potentiate psilocybin's effects and augment its risks.[96]

Adverse effects

Most of the comparatively few fatal incidents associated with psychedelic mushroom usage involve the simultaneous use of other drugs, especially

birth defects,[99] but it is recommended that pregnant women avoid its usage.[100]

Psychiatric adverse effects

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,[101] schizophrenia-like psychosis,[102][103] and convulsions[104] 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.[41] [failed verification] Less frequently reported adverse effects include paranoia, confusion, prolonged derealization (disconnection from reality), and mania.[83] Psilocybin usage can temporarily induce a state of depersonalization disorder.[105] Usage by those with schizophrenia can induce acute psychotic states requiring hospitalization.[106]

The similarity of psilocybin-induced symptoms to those of schizophrenia has made the drug a useful research tool in behavioral and

polydrug use and other variables.[110]

Tolerance and dependence

Chart of dependence potential and effective dose/lethal dose ratio of several psychoactive drugs.[111]

DOM.[113]

Repeated use of psilocybin does not lead to

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]

Long-term effects

A potential risk of frequent repeated use of psilocybin and other psychedelics is cardiac fibrosis and valvulopathy caused by serotonin 5-HT2B receptor activation.[114][115] But single high doses or widely spaced doses (e.g., months apart) are thought to be safe, and concerns about cardiac toxicity apply more to chronic psychedelic microdosing or very frequent intermittent use (e.g., weekly).[114][115]

Overdose

Psilocybin has low

overdoses are generally mild and self-limiting.[98]

A review of the management of psychedelic overdoses suggested that psilocybin-related overdose management should prioritize managing the immediate adverse effects, such as anxiety and paranoia, rather than specific pharmacological interventions, as psilocybin's physiological toxicity tends to be rather limited.[116] One analysis of people hospitalized for psilocybin poisoning found high urine concentrations of phenethylamine (PEA), indicating that PEA may contribute to the effects of psilocybin poisoning.[116]

In rats, the

intravenously in rabbits, psilocybin's LD50 is approximately 12.5 mg/kg.[117] 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.[41] Based on the results of animal studies, the lethal dose of psilocybin has been extrapolated to be 6 grams, 1,000 times greater than the effective dose of 6 milligrams.[118] 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.[119] 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 those may involve factors other than psilocybin.[41][d]

Interactions

See also: Psychedelic drug § Interactions, Trip killer § Serotonergic psychedelic antidotes, and Head-twitch response § Modulators of the head-twitch response

Serotonin 5-HT2A receptor antagonists can block the hallucinogenic effects of serotonergic psychedelics like psilocybin.[96][122] Numerous drugs act as serotonin 5-HT2A receptor antagonists, including antidepressants like trazodone and mirtazapine, antipsychotics like quetiapine, olanzapine, and risperidone, and other agents like ketanserin, pimavanserin, cyproheptadine, and pizotifen.[96][97] Such drugs are sometimes called "trip killers" because they can prevent or abort psychedelics' hallucinogenic effects.[123][97][124] Serotonin 5-HT2A receptor antagonists that have been specifically shown in clinical studies to diminish or abolish psilocybin's effects include ketanserin, risperidone, and chlorpromazine.[96][122]

The serotonin

ego dissolution, were reduced, among other changes.[122][96][128]

impaired memory of the experience.[134][135] Benzodiazepines might interfere with the therapeutic effects of psychedelics like psilocybin, such as sustained antidepressant effects.[136][137]

overdose and toxicity.[96] Examples of MAOIs that may potentiate psychedelics behaving as MAO-A substrates, such as psilocin, include phenelzine, tranylcypromine, isocarboxazid, and moclobemide, as well as harmala alkaloids like harmine and harmaline and chronic tobacco smoking.[96][139]

Psilocin may be metabolized to a minor extent by the

UDP-glucuronosyltransferase enzymes including UGT1A10 and UGT1A9.[122] Diclofenac and probenecid are inhibitors of these enzymes that theoretically might inhibit the metabolism of and thereby potentiate psilocybin's effects,[122] but no clinical research or evidence on this possible interaction exists.[122] Few other drugs are known to influence UGT1A10 or UGT1A9 function.[122]

Pharmacology

Pharmacodynamics

See also: Psychedelic drug § Pharmacology
Psilocin at molecular targets
Target Affinity (Ki, nM)
5-HT1A 49–567 (Ki)
853–>3,160 (
Emax
Tooltip maximal efficacy)
5-HT1B 31–305
5-HT1D 19–36
5-HT1E 44–52
5-HT1F ND
5-HT2A 6.0–340 (Ki)
2.4–3,836 (EC50)
16–98% (Emax)
5-HT2B 4.6–410 (Ki)
2.4–>20,000 (EC50)
38–84% (Emax)
5-HT2C 10–141 (Ki)
30.3 (EC50)
95.1% (Emax)
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 1,379–2,044
α2B 1,271–1,894
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
H4
 >10,000
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 (
IC50
Tooltip 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: [140][141][142][143][14][10][19][144][145][146][147][148][149][150][151][152][153][154]

Psilocybin is a

trace amine-associated receptor 1 (TAAR1).[154][145][156]

Psilocybin's and psilocin's psychedelic effects are mediated specifically by agonism of the serotonin 5-HT2A receptor.

Bryan L. Roth and colleagues.[166][167]

Although serotonin 5-HT2A receptor agonism mediates the

addictive potential of serotonergic psychedelics like psilocybin.[173]

In addition to its psychedelic effects, psilocin has been found to produce

positive allosteric modulator of the tropomyosin receptor kinase B (TrkB), one of the receptors of brain-derived neurotrophic factor (BDNF).[174][24][181] But psilocybin has been found to inhibit hippocampal neurogenesis in rodents.[174]

Psilocybin produces profound

intestinal microbiome and to influence the gut–brain axis in animals.[190][191][192][169][193][194] These effects are partially but not fully dependent on its activation of the serotonin 5-HT2A and/or 5-HT2C receptors.[169] Some of psilocybin's behavioral and potential therapeutic effects may be mediated by changes to the gut microbiome.[169][192][194] Transplantation of intestinal contents of psilocybin-treated rodents to untreated rodents resulted in behavioral changes consistent with those of psilocybin administration.[169]

Psilocybin and other psychedelics produce

complications by activating serotonin 5-HT2B receptors.[18][114][115][151][195]

There is little or no acute

downregulation of the serotonin 5-HT2A receptor in the brain in animals, an effect thought to be responsible for the development of tolerance to its psychedelic effects.[18][197][162][113] Serotonin 5-HT2A receptors appear to slowly return over the course of days to weeks after psilocybin administration.[18]

Pharmacokinetics

Absorption

There has been little research on psilocybin's

time to peak levels for psilocin is 1.05 to 3.71 hours in different studies, with most around 2 hours and the upper limit of 3.71 hours being an outlier.[15][16][19]

Psilocybin, in terms of psilocin, shows clear linear or

absorption, reduce peak levels, and reduce bioavailability.[24]

Distribution

Psilocin, the active form of psilocybin, is extensively

lipophilic and readily crosses the blood–brain barrier to exert effects in the central nervous system.[11] The plasma protein binding of psilocybin is 66% and hence it is moderately plasma protein-bound.[13]

Theoretical intramolecular hydrogen bond and pseudo-ring system occurring with psilocin (4-HO-DMT) but not with bufotenin (5-HO-DMT).[199][200]

Psilocin (4-HO-DMT) is a close

hydroxyl group and amine interact through hydrogen bonding.[199][200][147][201] This in turn makes psilocin much less polar, more lipophilic, and more able to cross the blood–brain barrier and exert central actions than it would be otherwise.[199][200][147][201] It may also protect psilocin from metabolism by monoamine oxidase (MAO).[199] In contrast, bufotenin is not able to achieve this pseudo-ring system.[199][200][147][201] Accordingly, bufotenin is less lipophilic than psilocin in terms of partition coefficient.[199][200] But bufotenin does still show significant central permeability and, like psilocybin, can produce robust hallucinogenic effects in humans.[200][147][202][203]

Metabolism

Metabolism of psilocybin and psilocin in humans and mice.[138][24]

Psilocybin is

phosphatase inhibitor β-glycerolphosphate, which inhibits psilocybin dephosphorylation, greatly attenuates the behavioral effects of psilocybin in rodents.[19][138][206] Psilocybin undergoes dephosphorylation into psilocin via the acidic environment of the stomach or the actions of alkaline phosphatase (ALP) and non-specific esterases in tissues and fluids.[34][204][19]

Psilocin is

conjugated form, and conjugated psilocin levels are about fourfold higher than levels of free psilocin.[138][19] Plasma 4-HIAA levels are also much higher than those of free psilocin.[10]

Norpsilocin (4-HO-NMT), formed from psilocin via demethylation mediated by the cytochrome P450 enzyme CYP2D6, is known to occur in mice in vivo and with human recombinant CYP2D6 in vitro but was not detected in humans in vivo.[138] An oxidized psilocin metabolite of unknown chemical structure is also formed by hydroxyindole oxidase activity of CYP2D6.[138][19] Oxidized psilocin is possibly a quinone-type structure like psilocin iminoquinone (4-hydroxy-5-oxo-N,N-DMT) or psilocin hydroquinone (4,5-dihydroxy-N,N-DMT).[138][19] Additional metabolites formed by CYP2D6 may also be present.[138] Besides CYP2D6, CYP3A4 showed minor activity in metabolizing psilocin, though the produced metabolite is unknown.[138] Other cytochrome P450 enzymes besides CYP2D6 and CYP3A4 appear unlikely to be involved in psilocin metabolism.[138] CYP2D6 metabolizer phenotypes do not modify psilocin exposure in humans, suggesting that CYP2D6 is not critically involved in psilocin metabolism and is unlikely to result in interindividual differences in psilocin kinetics or effects.[24][138] Psilocybin and psilocin might inhibit CYP3A4 and CYP2A6 to some extent, respectively.[16]

Elimination

Psilocybin is eliminated 80% to 85% in urine and 15 to 20% in bile.[24] It is excreted mainly in urine as psilocin-O-glucuronide.[24][204] The drug was eliminated approximately 20% and 80% as psilocin O-glucuronide in different studies.[15][204][19][87] The amount excreted as unchanged psilocin in urine is 1.5 to 3.4%.[15][204][10][87] Studies conflict on the deaminated metabolites of psilocin, with one study finding that only 4% of psilocin is metabolized into 4-HIAA, 4-HIAL, and 4-HTOL[19] and another that psilocybin is excreted 33% in urine as 4-HIAA.[138][87] Findings also conflict on whether psilocybin can be detected in urine, with either no psilocybin excreted or 3% to 10% excreted as unchanged psilocybin.[205][2][15][7][19] A majority of psilocybin and its metabolites is excreted within three hours with oral administration and elimination is almost complete within 24 hours.[19][7][87]

The

intravenously.[15][16][10][19] Psilocin's elimination half-life in mice is 0.9 hours, much faster than in humans.[138] Psilocin O-glucuronide's half-life is about 4 hours in humans and approximately 1 hour in mice.[138]

No dose adjustment of psilocin is thought to be required as psilocin is inactivated mainly via metabolism as opposed to renal elimination.[15][24][87] Accordingly, glomerular filtration rate (GFR) did not affect the pharmacokinetics of psilocybin.[15][24][87]

Miscellaneous

Psilocybin's

duration are strongly correlated with psilocin levels.[14][87][10]

Single doses of psilocybin of 3 to 30 mg have been found to dose-dependently occupy the serotonin 5-HT2A receptor in humans as assessed by

EC50Tooltip half-maximal effective concentration for occupancy of the serotonin 5-HT2A receptor by psilocin in terms of circulating levels has been found to be 1.97 ng/mL.[10]

Body weight and body mass index do not appear to affect psilocybin's pharmacokinetics.[14][24][87] This suggests that body weight-adjusted dosing of psilocybin is unnecessary and may actually be counterproductive, and that fixed-dosing should be preferred.[24][87] Similarly, age does not affect psilocybin's pharmacokinetics.[15] The influence of sex on psilocybin's pharmacokinetics has not been tested.[15]

Chemistry

Physical properties

The neurotransmitter serotonin is structurally similar to psilocybin.

Psilocybin is a naturally occurring

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.[209]
: 10–13 

Psilocybin is a white, crystalline solid that is soluble in water,

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.[210] There are two known crystalline polymorphs of psilocybin, as well as reported hydrated phases.[211] Psilocybin rapidly oxidizes upon exposure to light—an important consideration when using it as an analytical standard.[212]

Structural analogues

See also: Substituted tryptamine and List of psychedelic drugs

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), and norbaeocystin
(4-PO-T), among others.

Laboratory synthesis

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.[213]

Analytical methods

Several relatively simple

electrochemical,[223] and electrospray mass spectrometric detection methods.[224]

Various chromatographic methods have been developed to detect psilocin in

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.[229] A 2009 publication reported using HPLC to quickly separate forensically important illicit drugs including psilocybin and psilocin, which were identifiable within about 30 seconds of analysis time.[230] But these analytical techniques to determine psilocybin concentrations in body fluids are not routinely available and not typically used in clinical settings.[56]

Natural occurrence

Main article:
Psilocybin-containing mushroom
Maximum reported psilocybin concentrations (% dry weight) in 12 Psilocybe species[231]: 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

taxa of lower taxonomic groups.[237]

Global distribution of over 100 psychoactive species of genus Psilocybe mushrooms.[238]
The mushroom Psilocybe mexicana
Psilocybin was first isolated from Psilocybe mexicana.
The mushroom Psilocybe semilanceata
P. semilanceata is common in Europe, Canada, and the United States.

Both the

sclerotia, younger, smaller mushrooms tend to have a higher concentration of the drug than larger, mature mushrooms.[242] In general, the psilocybin content of mushrooms is quite variable (ranging from almost nothing to 2.5% of the dry weight)[243][57]: 248  and depends on species, strain, growth and drying conditions, and mushroom size.[231]: 36–41, 52  Cultivated mushrooms have less variability in psilocybin content than wild mushrooms.[244] The drug is more stable in dried than fresh mushrooms; dried mushrooms retain their potency for months or even years,[231]: 51–5  while mushrooms stored fresh for four weeks contain only traces of the original psilocybin.[41]

The psilocybin contents of dried

germinated from spores) lack appreciable amounts.[246] Many species of mushrooms containing psilocybin also contain lesser amounts of the analog compounds baeocystin and norbaeocystin,[231]: 38  chemicals thought to be biogenic precursors.[48]: 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.[241][231]
: 56–58 

Biosynthesis

Isotopic labeling experiments from the 1960s suggested that the biosynthesis of psilocybin was a four-step process:[247]

  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

This process can be seen in the following diagram:[248]

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.[248]

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.[248] 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.[209]: 12–13 [248] These enzymes are encoded in gene clusters in Psilocybe, Panaeolus, and Gymnopilus.[235]

Escherichia coli has been genetically modified to manufacture large amounts of psilocybin.[249] Psilocybin can be produced de novo in GM yeast.[250][251]

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, 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.[252]

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.[253]

Some scholars have also interpreted archaeological

entheogens from the Spanish authorities.[254]
: 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.[256][257] 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.[258]: 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.[258]: 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.[259] 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.[260]

Heim cultivated the mushrooms in France and sent samples for analysis to

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.[255]: 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.[255]
: 126–127 

Next, Hofmann's team synthesized several

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.[57]: 237  Sandoz also marketed and sold pure psilocybin under the name Indocybin to clinicians and researchers worldwide.[254]: 166  There were no reports of serious complications when psilocybin was used in this way.[2]

In the early 1960s,

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".[265] 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.[255]
: 79–116 

Despite the legal restrictions on psilocybin use, the 1970s witnessed the emergence of psilocybin as the "entheogen of choice".

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."[266]: 290  San Antonio's technique describes a method to grow the common edible mushroom Agaricus bisporus.[268]

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

EU countries have tightened their legislation on psilocybin mushrooms in response to concerns about their prevalence and increasing usage.[40] 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".[49] Recent studies in the U.S. have attracted attention from the popular press and brought psilocybin back into the limelight.[269][270]

Society and culture

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.[271] 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.[272] The RAND Corporation report suggests psilocybin mushrooms may be the most prevalent psychedelic drug among U.S. adults.[272]

In European countries, the lifetime prevalence estimates of psychedelic mushroom usage among young adults (15–34 years) range from 0.3% to 14.1%.[273]

In modern Mexico, traditional ceremonial use survives among several indigenous groups, including the

Mazatecs, Mixes, Zapotecs, and the Chatino. Although hallucinogenic Psilocybe species are abundant in Mexico's low-lying areas, 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.[274]

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 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

The

Schedule I drugs under the United Nations 1971 Convention on Psychotropic Substances.[275] 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[276][277][278] and religious uses in dozens of cultures throughout history and have a significantly lower potential for abuse than other Schedule I drugs.[279]

Psilocybin mushrooms are not regulated by UN treaties.[280] 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.[281] 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,[282] Georgia,[283] and Idaho[284]) 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.[285]

Advocacy for tolerance

Despite being illegal to possess without authorization in many Western countries, such as the UK, Australia, and some U.S. states, less conservative governments nurture the legal possession and supply of psilocybin and other psychedelic drugs. In Amsterdam, authorities provide education on and promote the safe use of psychedelic drugs, such as psilocybin, to reduce public harm.[286] Similarly, religious groups like America's Uniao do Vegetal (UDV)[287] use psychedelics in traditional ceremonies.[288] 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.[289]

From 1 July 2023, the Australian medicines regulator has permitted psychiatrists to prescribe psilocybin for the therapeutic treatment of treatment-resistant depression.[290]

Advocates of legalization argue there is a lack of evidence of harm,

ego dissolution"[287] and argue bans are cultural discrimination against traditional users.[294]

In 2024, after calls for regulatory and legal change to expand terminally ill populations' access to controlled substances, two legal cases related to expanded access began moving through the federal courts under right-to-try law. The Advanced Integrative Medicine Science (AIMS) Institute in concert with the NPA filed a series of lawsuits seeking both the rescheduling of and expanded right-to-try access to psilocybin.[295]

Research

Psychiatric and other disorders

See also: Psychedelic therapy and List of investigational hallucinogens and entactogens

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.[296] 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,[213][297] anxiety disorders, and certain mood disorders.[254]: 179–81 [298][299] It is also being studied in people with Parkinson's disease.[300][301] In 2018, the United States Food and Drug Administration (FDA) granted breakthrough therapy designation for psilocybin-assisted therapy for treatment-resistant depression.[302][303] A systematic review published in 2021 found that the use of psilocybin as a pharmaceutical substance was associated with reduced intensity of depression symptoms.[304] The role of psilocybin as a possible psychoplastogen is also being examined.[177][178][179] It is under development by Compass Pathways, Cybin, and several other companies.[305][306]

Depression

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).[307][308] The antidepressant effects of psilocybin with psychological support have been found to last at least 6 weeks following a single dose.[307][308][309]

However, some trials have not found psilocybin to significantly outperform placebo in the treatment of depression.[307] 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.[307][310] 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).[307][310] In any case, the antidepressant effect size of psilocybin over escitalopram appears to be small.[311]

super placebos" when used for therapeutic purposes.[318][319] 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.[30][307][90]

See also

Notes

  1. dimethyltryptamine), psilocybine, psilocibin, psilocybinum, psilotsibin, and psilocin phosphate ester, among others.[22]
  2. ^ 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).
  3. 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).[85]
  4. ^ One of the reported fatalities, that of a 22-year-old French man who died in 1993,[120] 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".[121]
  5. 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.

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    . Psilocybin induced a robust head twitch response, increased exploratory behavior in the elevated plus maze, increased social behavior in the social interaction test, and decreased immobility in the forced swim test. Co-administration of ketanserin fully blocked the head twitch response without significantly altering psilocybin's effects on other behavioral outcomes. In a separate cohort, treatment with psilocybin produced broad alteration of the intestinal microbiome, with particularly marked changes in the large intestine that were only partially blocked by pre-treatment with ketanserin. Finally, transplantation of intestinal contents from psilocybin-treated mice to naive untreated mice resulted in behavioral changes consistent with the effects of psilocybin treatment. [...] Our findings demonstrate that a single dose of psilocybin leads to behavioral changes in mice that are relevant for studies of resilience and affective disorders. Our results further indicate that the behavioral changes may not be fully dependent on psilocybin's agonism of 5HT2A and 5HT2C receptors. Further, psilocybin appears to broadly alter the intestinal microbiome and transplantation of intestinal contents reproduces behavioral change associated with psilocybin treatment, suggesting a previously unknown microbiome-gut-brain mechanism of action.
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  303. PMID 34451890
    .
  304. PMID 37925136
    .
  305. PMID 40046566
    .
  306. ^
    PMID 38627070
    .
  307. ^
    PMID 36322843
    .
  308. PMID 37651119
    .
  309. ^
    PMID 33852780
    .
  310. PMID 39168500
    .
  311. PMID 34038314
    .
  312. PMID 36193898
    .
  313. PMID 37403379
    .
  314. PMID 38387698
    .
  315. PMID 31249537
    .
  316. S2CID 149608377
    .
  317. PMID 36263513
    .
  318. PMID 35878791
    . In addition, the strong prior expectations that many people have about psychedelics directly contribute to the psychedelic experience and as a consequence it has been suggested that psychedelics may act as a 'super-placebo' (Hartogsohn, 2016). Specifically, strong prior expectations (e.g., that a specific intervention will likely trigger a mystical experience) will increase the likelihood of having e.g., a mystical-type experience (Maij et al., 2019), and this placebo-effect is further boosted by the psychedelic-induced suggestibility.
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