Psilocybin

Psychedelic, Serotonergic psychedelic, Tryptamine

Psilocybin

COMP360 (Compass Pathways, investigational synthesized clinical formulation)

Psilocybin, chemically 4-phosphoryloxy-N,N-dimethyltryptamine, is a tryptamine alkaloid produced by approximately two hundred species of mushrooms across several genera, of which Psilocybe is the most widely studied. Psilocybin is itself biologically inactive; gastric and intestinal alkaline phosphatases dephosphorylate it within minutes of absorption to psilocin, the psychoactive metabolite. The mushrooms have been used ceremonially across Mesoamerica for at least two thousand years, and in their Mesoamerican context were known by the Mexica (Aztec) name teonanácatl, conventionally translated "flesh of the gods."[citation needed] The compound was isolated and named by Albert Hofmann at Sandoz Laboratories in Basel in 1958, three years after R. Gordon Wasson, a New York banker and amateur ethnomycologist, attended a velada with the Mazatec curandera María Sabina in Huautla de Jiménez, Oaxaca, and brought back the first samples from which the chemistry could be worked out. The compound entered Western clinical psychiatry in the 1960s through the Harvard Psilocybin Project and was placed in Schedule I of the Controlled Substances Act in 1970 and Schedule I of the United Nations Convention on Psychotropic Substances in 1971. Formal research effectively ended in most jurisdictions for approximately twenty-five years. Beginning in the late 1990s, regulatory approval for new clinical studies was incrementally restored. Modern clinical investigation has focused on treatment-resistant depression, major depressive disorder, cancer-related psychological distress, substance use disorders including tobacco and alcohol, cluster headache, and obsessive-compulsive disorder. Compass Pathways' COMP360 program completed its phase IIb trial in 2022 and is in pivotal phase III for treatment-resistant depression; the medicine is not yet approved for any indication by major regulatory agencies. Multiple United States states and cities have decriminalized possession and use of psilocybin since 2019, and Oregon's Measure 109 created the country's first state-regulated psilocybin services program in 2020, with services beginning in 2023.[citation needed]

History

The compound that became psilocybin was first separated from dried mushroom samples that Roger Heim, director of the National Museum of Natural History in Paris, sent to Albert Hofmann at Sandoz Laboratories in Basel in 1958. Heim had identified the mushrooms three years earlier as Psilocybe mexicana, Psilocybe cubensis, and several related species, after a 1955 expedition led by R. Gordon Wasson, an amateur ethnomycologist who worked as a vice president at J.P. Morgan in New York. Wasson and his photographer Allan Richardson had attended a velada with the Mazatec curandera María Sabina in Huautla de Jiménez, in the mountains of Oaxaca, on the night of 29-30 June 1955.[citation needed] They were the first non-indigenous outsiders to participate in a Mazatec mushroom ceremony and publish the experience.

The mushrooms had been used ceremonially in the Mesoamerican highlands for at least two thousand years before the Spanish conquest. Mushroom-shaped stone effigies dated to between approximately 1000 BCE and 500 CE have been recovered from sites in the Guatemalan highlands and Chiapas; these are conventionally interpreted as cult objects associated with mushroom ceremonies, though the interpretation is not universal.[citation needed] In the post-conquest period the most extensive documentation came from the Franciscan friar Bernardino de Sahagún, whose Florentine Codex (Historia General de las Cosas de Nueva España, completed in the 1570s and 1580s) described the use of nanácatl by Mexica priests and merchants as part of feasts and ceremonies. The Mexica name teonanácatl carries the same theological framing as the Spanish friars' alarmed accounts: the mushrooms were not eaten as foods or as medicines in the European pharmacological sense but as sources of contact with the sacred.[citation needed]

The terminology used for the mushrooms and for the compound that drives their effects has shifted across several frames. The earliest Western framing, from the conquest-era chronicles, classified them as forms of inebriation and intoxication. Twentieth-century clinical psychiatry adopted the term "hallucinogen," which presupposes that the experiences they occasion are false perceptions of a kind with pathology. Humphry Osmond proposed "psychedelic," from the Greek for "mind-manifesting," in 1957, in a letter to Aldous Huxley, on the grounds that the earlier terms imposed a clinical frame inadequate to the experiences themselves.[citation needed] Carl Ruck, R. Gordon Wasson, Albert Hofmann, and others proposed "entheogen," from the Greek for "generating the divine within," in 1979, to mark the ceremonial and religious dimension that "psychedelic" had come to neglect through its association with the counterculture.[citation needed] Each term encodes a stance toward what the medicine does: hallucinogen is the pathological frame, psychedelic the experiential frame, entheogen the sacred frame. The current academic and clinical literature uses "psychedelic" most widely, with "entheogen" as a recognized alternative in contexts where the religious or ceremonial dimension is foregrounded.

“Pendell's corner

Entheogenic, manifesting god within. And yet that doesn't say it. Psychedelic, revealing the soul. And yet that doesn't say it. Hallucinogenic, generating visions. And yet that doesn't say it, either.

— Dale Pendell, Pharmako/Gnosis, p. 28

The Mexican Inquisition, established in Mexico City in 1571, took a series of formal positions against the use of native inebriating plants and mushrooms. The most consequential of these came in a 1620 edict that classified the use of peyote, teonanácatl, and ololiuhqui (the seeds of Turbina corymbosa) as superstition associated with the invocation of demons, making their use punishable as a heretical practice.[citation needed] The decree forced public ceremonial use underground in the regions where Inquisition reach was effective. In remote mountain communities, including the Sierra Mazateca, the ceremonies continued at the perimeter of colonial authority, transmitted within particular families and lineages of practice. The three centuries between the 1620 edict and Wasson's 1955 expedition were continuous ceremonial activity, not interrupted tradition.

“Pendell's corner

In 1620 the Holy Office of the Inquisition in Mexico City formally decreed that ingestion of inebriating plants was heresy. The War on Drugs is still a religious war.

— Dale Pendell, Pharmako/Gnosis, p. 31

In the Mazatec tradition that survived into the twentieth century, the mushrooms are addressed and spoken with as a being. They are an interlocutor whose voice the curandera transmits, not an object that produces an effect. The term niños santos ("holy children") is used in some Mazatec communities; the mushrooms are referred to in the diminutive plural and treated as ally, witness, and teacher rather than as substance. The framing is not metaphorical for the practitioners. The disjunction between this framing and the chemistry-and-receptor framing of twentieth-century pharmacology is one of the recurring themes in the modern revival of psilocybin medicine, and a question that the clinical literature has handled with varying degrees of attention.

“Pendell's corner

The great gift of the mushroom ally is a special clarity and intelligence, a special and compassionate healing presence. The experts, the people who kept the ally alive for four hundred years while the rest of the world pursued more destructive visions, say that matters relating to the mushroom allies are muy delicado.

— Dale Pendell, Pharmako/Gnosis, p. 29

Wasson's account of the velada with María Sabina was published in Life magazine on 13 May 1957, under the title "Seeking the Magic Mushroom."[citation needed] The article carried color plates of the mushrooms and a detailed first-person account of the ceremony, and was the first widely circulated description of Mesoamerican mushroom use to reach a non-specialist audience. The Life article and Wasson's subsequent ethnographic publications brought a steady flow of outside seekers to Huautla de Jiménez and to Sabina personally. The seekers ranged from clinical researchers to celebrities to recreational tourists; Wasson himself came to regret the publicity, and Sabina, in interviews near the end of her life, said that the mushrooms had lost their force because they had been used by the wrong people for the wrong reasons.[citation needed] The Sabina story has become part of the basic ethical literature of modern psychedelic medicine: it is the case in which Western engagement with an indigenous tradition damaged the tradition that had been the source of the engagement.

Heim sent dried mushroom samples to Hofmann at Sandoz beginning in 1957. Hofmann, who had thirteen years earlier discovered the psychoactivity of LSD-25, isolated the principal psychoactive constituent from Psilocybe mexicana by 1958 and named it psilocybin, with the closely related psilocin as the active dephosphorylated form. Hofmann confirmed activity by ingesting the isolated compound himself; the dose-response and duration characterizations in the foundational papers came from his self-experiments and from a small group of Sandoz colleagues. Hofmann visited Huautla de Jiménez in 1962 with Wasson to present synthesized psilocybin tablets to Sabina; she confirmed that the synthesized compound carried the same spirit as the mushrooms.[citation needed]

Sandoz supplied psilocybin tablets, under the trade name Indocybin, to researchers in psychiatry and psychology through the 1960s. The Harvard Psilocybin Project, established by Timothy Leary and Richard Alpert (later Ram Dass) in 1960, was the most prominent of the American programs; it produced the Concord Prison Experiment, in which psilocybin sessions were administered to incarcerated men with the aim of reducing recidivism, and the Marsh Chapel Good Friday Experiment, conducted by Walter Pahnke on 20 April 1962, in which divinity students received psilocybin or active placebo before a Good Friday service and were assessed for mystical-type experiences. Pahnke's doctoral thesis from this experiment is the foundational empirical document for the mystical-experience research paradigm later revived in modern psilocybin trials.[citation needed] Leary and Alpert were dismissed from Harvard in 1963, ostensibly for administering psilocybin to undergraduates without supervision, and their later activities became increasingly tied to the broader counterculture. Sandoz withdrew its clinical supply of psilocybin in 1965, citing both the diversion of supplies into non-clinical channels and the broader regulatory pressure.[citation needed]

The United States placed psilocybin in Schedule I of the Controlled Substances Act on 27 October 1970, the most restrictive schedule for substances classified as having no accepted medical use and high abuse potential.[citation needed] The United Nations Convention on Psychotropic Substances, opened for signature on 21 February 1971, placed psilocybin in Schedule I of the international treaty system, requiring signatory states to maintain equivalent domestic prohibitions. Most national legal regimes followed within the decade. Formal clinical research on psilocybin in human subjects effectively ended in 1970 in the United States and in similar windows elsewhere; the gap in legitimate clinical investigation lasted approximately twenty-five years. Underground continuation of psilocybin sessions in psychotherapeutic settings, particularly in California and on the East Coast of the United States, occurred through this period and provided a thread of clinical experience that informed the design of the modern revival trials.[citation needed]

The modern psilocybin clinical literature began in earnest with the publication in 2006 of the Roland Griffiths group's Johns Hopkins study, which demonstrated that a high oral dose of psilocybin administered under structured conditions could occasion experiences indistinguishable, by phenomenological measures, from naturally occurring mystical experiences, and that these experiences were associated with lasting positive changes in mood, attitudes, and behavior reported at follow-up. Successive trials extended the work to specific clinical populations. The 2016 Griffiths and Ross trials enrolled patients with cancer and clinically significant depression or anxiety; both studies reported large effect sizes that were sustained at six-month follow-up. The Carhart-Harris group at Imperial College London published an open-label feasibility study of psilocybin for treatment-resistant depression in 2016 and a randomized comparison against escitalopram in 2021. Davis and colleagues at Johns Hopkins published a randomized controlled trial for major depressive disorder in 2021. Compass Pathways' COMP360 phase IIb dose-finding trial for treatment-resistant depression, published in 2022, established a single 25 mg dose with psychological support as the primary regimen now in pivotal trials. Smaller programs have addressed tobacco use disorder, alcohol use disorder, anorexia nervosa, and obsessive-compulsive disorder; psilocybin and LSD have also been reported to abort or shorten cluster headache cycles.

The psilocybin experience has a recognizable somatic component that the early Mesoamerican accounts and the modern phenomenological literature share. The come-up, typically thirty to sixty minutes after oral ingestion, is often accompanied by nausea, body load, yawning, and a generalized sense of physical discomfort. The pre-conquest Mexica accounts described episodes of vomiting at the beginning of the experience as part of the ceremonial transit; modern clinical sessions manage the somatic phase through reclined positioning, eye masks, curated music, fasting for several hours before the session, and the option of antiemetic pretreatment where appropriate. The somatic dimension is part of what distinguishes psilocybin from LSD (which has a more diffuse somatic profile, longer duration, and less reliable nausea), and from the smoked tryptamines such as 5-MeO-DMT (which produce abrupt, brief experiences with a different somatic register). The body load typically resolves over the first hour of the experience; the visual and cognitive features peak in the second through fourth hours and decline through the fifth and sixth.[citation needed]

“Pendell's corner

The poison can get stuck. Sometimes it sticks in the teeth and makes the gums ache. Sometimes the poison gets stuck in the stomach and you feel some nausea. If you can let the power go, if you can let the spirit take over and let the power flow on to wherever it is going, these physical symptoms usually pass.

— Dale Pendell, Pharmako/Gnosis, p. 29

Contemporary settings of psilocybin use span a range that the Western clinical-versus-recreational binary does not fully capture. Formal clinical trials of synthesized psilocybin with psychological support continue under FDA-approved IND protocols in the United States, under MHRA approvals in the United Kingdom, and under national equivalents elsewhere. Oregon's Measure 109 (2020) established a regulated psilocybin services framework under which adults can access psilocybin sessions facilitated by licensed practitioners in licensed service centers; services began in 2023.[citation needed] Colorado's Proposition 122 (2022) authorizes a similar framework. The cities of Denver (May 2019), Oakland (June 2019), Santa Cruz (January 2020), Washington, D.C. (November 2020), Somerville, Cambridge, Northampton, and Easthampton in Massachusetts (2021), Seattle (October 2021), Detroit (November 2021), and others have passed measures decriminalizing personal possession.[citation needed] Underground therapeutic practice continues in lineages descended from the mid-century Esalen and Stanislav Grof and Myron Stolaroff circles and from independent traditions. The Mazatec ceremonial continuity in Sierra Mazateca persists alongside a substantial commodified mushroom-tourism economy in Huautla de Jiménez and nearby towns. Recreational use in festival and small-group settings is common in jurisdictions where prosecution risk is low. Microdosing, the practice of taking sub-perceptual doses (approximately 0.1 to 0.3 grams of dried mushroom or 1 to 3 mg of synthesized psilocybin) at intervals of two to four days, became broadly popular after approximately 2015; controlled trials of microdosing have not consistently demonstrated effects beyond placebo on cognition or mood, though anecdotal reports of benefit continue.[citation needed]

“Pendell's corner

Indoors, at night, in a circle. Outdoors, in the forest, wandering. In the desert. On the prairie. In Madrid. In London. In Germany. In Florida, at a Grateful Dead show, in tie-dye. Alone, when you must speak with the spirit yourself, one on one.

— Dale Pendell, Pharmako/Gnosis, p. 27

Experience

👥 No personal reports yet

⚕ No clinical reports yet

Log in to add your own experience.

Problems

Treatment-Resistant Depression★★★★★★★★★★★★★★★—××

Investigational. Compass Pathways' COMP360 psilocybin (a synthesized formulation) is in pivotal phase III trials for treatment-resistant depression following the 2022 phase IIb dose-finding study, in which a single 25 mg dose with psychological support produced a significantly greater reduction in MADRS score at three weeks compared with 10 mg or 1 mg control doses. FDA Breakthrough Therapy designation was granted in 2018.

Major Depressive Disorder★★★★★★★★★★★★★★★—××

Investigational. Davis and colleagues' 2021 randomized trial reported substantial reductions in depressive symptoms in patients with MDD that were sustained at follow-up. Carhart-Harris and colleagues' 2021 trial against escitalopram found psilocybin non-inferior to a six-week course of escitalopram by the QIDS-SR-16 primary endpoint, with secondary measures favoring psilocybin.

Cancer-Related Distress★★★★★★★★★★★★★★★—××

Investigational. Two simultaneously published 2016 trials by the Griffiths group at Johns Hopkins and the Ross group at NYU demonstrated large effect sizes for psilocybin in the treatment of clinically significant depression and anxiety in patients with life-threatening cancer; effects were sustained at six-month follow-up in both studies. The cancer-related distress indication is among the most robust in the modern psilocybin clinical literature.

Tobacco Use Disorder★★★★★★★★★★★★★★★—××

Investigational. Johnson and colleagues' 2014 open-label pilot reported 80% biologically confirmed smoking abstinence at six months in fifteen long-term smokers who completed a structured psilocybin-assisted smoking cessation protocol, a higher rate than observed in standard pharmacological cessation programs. Randomized trials are ongoing.

Alcohol Use Disorder★★★★★★★★★★★★★★★—××

Investigational. Modern small-scale randomized trials of psilocybin-assisted treatment for alcohol use disorder have reported significant reductions in heavy drinking days at follow-up.[citation needed] The medicine is not approved for this indication.

Cluster headache★★★★★★★★★★★★★★★—××

Off-label, case-series evidence only. Sewell, Halpern, and Pope's 2006 case series reported aborted or substantially shortened cluster headache cycles in patients self-administering psilocybin or LSD in chronic cluster headache. Subsequent open-label and small randomized trials have continued the line of investigation; the medicine is not approved for this indication and no major regulatory submission is pending.

Obsessive-Compulsive Disorder★★★★★★★★★★★★★★★—××

Investigational, early-stage. Small pilot studies have explored psilocybin in obsessive-compulsive disorder. The evidence base remains thin.

+ Add a problem

Titration strategies

Modern clinical trial dosing▲0▼×

The standard modern clinical-trial dose for psilocybin-assisted therapy is a single oral dose of 25 mg synthesized psilocybin, administered with psychological support before, during, and after the experience. The 25 mg figure was established as the optimal dose for treatment-resistant depression by the COMP360 phase IIb dose-finding trial, which compared 1 mg, 10 mg, and 25 mg single doses; the 25 mg arm produced the largest reduction in depressive symptoms. Dose-response findings in non-resistant MDD and in cancer-related distress have generally placed the active clinical range at 20 to 30 mg.

Reported dose magnitudes▲0▼×

Dose magnitudes reported in the modern clinical and historical literature span:

• Sub-perceptual ("microdose"): 1-3 mg synthesized psilocybin (approximately 0.1-0.3 g dried Psilocybe cubensis)
• Threshold to mild: 5-10 mg (approximately 0.5-1 g dried mushroom)
• Moderate: 15-20 mg (approximately 1.5-2 g)
• Strong, including standard clinical trial dose: 25-30 mg (approximately 2.5-3 g)
• High, ceremonial or psychotherapeutic: 35-50 mg (approximately 3.5-5 g)

The mushroom-to-synthesized-compound equivalence is approximate. Dried mushrooms of the same species and strain vary in psilocybin content by a factor of two to four, and different species and strains vary further; mushroom material does not permit dose precision comparable to synthesized capsules. Onset after oral ingestion is typically 20 to 45 minutes (faster on an empty stomach), peak effects at 90 to 180 minutes, and total duration approximately 4 to 6 hours.

Harm reduction considerations▲0▼×

Psilocybin is a Schedule I controlled substance in most jurisdictions with no legal recreational supply chain. Mushrooms purchased outside regulated programs are subject to species misidentification (some inactive look-alikes are toxic), dose imprecision (potency variation factor of two to four within a species), and adulteration. Combinations with serotonergic medicines (SSRIs, SNRIs, MAOIs, tramadol, dextromethorphan) carry serotonin syndrome risk and should be avoided; MAOI co-administration is particularly dangerous and produces both serotonin syndrome risk and substantial potentiation of psilocybin effect. Lithium is a separate concern: combined with classical psychedelics including psilocybin, lithium is associated with a markedly elevated risk of seizures and severe adverse reactions, distinct from serotonin syndrome and documented in multiple case reports.[citation needed] Combinations with psychostimulants increase cardiovascular load. Personal or family history of psychotic-spectrum illness or bipolar disorder is a relative contraindication in most clinical research programs; the long-standing concern that psilocybin can precipitate psychotic episodes in predisposed individuals is supported by case reports but not by population-level data. The general harm-reduction principles for psychedelic experiences (set, setting, sober companion, prior experience with the dose range, fasting for several hours before the session, advance arrangement of a trusted post-session contact) apply.

+ Add a titration strategy

Effects

Physical

• Neurogenesis👤 no reports yet⚕️ no reports yetRate×
• Somnolence / sedation👤 no reports yet⚕️ no reports yetRate×
• Spontaneous bodily sensations👤 no reports yet⚕️ no reports yetRate×
• Perception of bodily heaviness👤 no reports yet⚕️ no reports yetRate×
• Tactile intensification👤 no reports yet⚕️ no reports yetRate×
• Changes in felt bodily form👤 no reports yet⚕️ no reports yetRate×
• Pain relief👤 no reports yet⚕️ no reports yetRate×
• Nausea👤 no reports yet⚕️ no reports yetRate×
• Changes in felt gravity👤 no reports yet⚕️ no reports yetRate×
• Excessive yawning👤 no reports yet⚕️ no reports yetRate×
• Watery eyes👤 no reports yet⚕️ no reports yetRate×
• Frequent urination👤 no reports yet⚕️ no reports yetRate×
• Muscle contractions👤 no reports yet⚕️ no reports yetRate×
• Olfactory hallucination👤 no reports yet⚕️ no reports yetRate×
• Pupil dilation👤 no reports yet⚕️ no reports yetRate×
• Runny nose👤 no reports yet⚕️ no reports yetRate×
• Increased salivation👤 no reports yet⚕️ no reports yetRate×
• Brain zaps👤 no reports yet⚕️ no reports yetRate×
• Seizure/Epileptic fit👤 no reports yet⚕️ no reports yetRate×

Visual

• Color enhancement👤 no reports yet⚕️ no reports yetRate×
• Pattern recognition enhancement👤 no reports yet⚕️ no reports yetRate×
• Visual acuity enhancement👤 no reports yet⚕️ no reports yetRate×
• Drifting👤 no reports yet⚕️ no reports yetRate×
• Color shifting👤 no reports yet⚕️ no reports yetRate×
• Color tinting👤 no reports yet⚕️ no reports yetRate×
• Visual haze👤 no reports yet⚕️ no reports yetRate×
• Diffraction👤 no reports yet⚕️ no reports yetRate×
• Tracers👤 no reports yet⚕️ no reports yetRate×
• After images👤 no reports yet⚕️ no reports yetRate×
• Symmetrical texture repetition👤 no reports yet⚕️ no reports yetRate×
• Perspective distortion👤 no reports yet⚕️ no reports yetRate×
• Depth perception distortions👤 no reports yet⚕️ no reports yetRate×
• Recursion👤 no reports yet⚕️ no reports yetRate×
• Environmental orbism👤 no reports yet⚕️ no reports yetRate×
• Scenery slicing👤 no reports yet⚕️ no reports yetRate×
• Geometry👤 no reports yet⚕️ no reports yetRate×
• Machinescapes👤 no reports yet⚕️ no reports yetRate×
• Transformations👤 no reports yet⚕️ no reports yetRate×
• Internal hallucination👤 no reports yet⚕️ no reports yetRate×
• External hallucination👤 no reports yet⚕️ no reports yetRate×

Cognitive

• Emotion intensification👤 no reports yet⚕️ no reports yetRate×
• Empathy, affection and sociability enhancement👤 no reports yet⚕️ no reports yetRate×
• Euthymia👤 no reports yet⚕️ no reports yetRate×
• Language depression👤 no reports yet⚕️ no reports yetRate×
• Analysis enhancement👤 no reports yet⚕️ no reports yetRate×
• Enhancement and suppression cycles👤 no reports yet⚕️ no reports yetRate×
• Feelings of impending doom👤 no reports yet⚕️ no reports yetRate×
• Cognitive euphoria👤 no reports yet⚕️ no reports yetRate×
• Autonomous voice communication👤 no reports yet⚕️ no reports yetRate×
• Suggestibility intensification👤 no reports yet⚕️ no reports yetRate×
• Conceptual thinking👤 no reports yet⚕️ no reports yetRate×
• Thought connectivity👤 no reports yet⚕️ no reports yetRate×
• Thought deceleration👤 no reports yet⚕️ no reports yetRate×
• Thought loop👤 no reports yet⚕️ no reports yetRate×
• Thought organization👤 no reports yet⚕️ no reports yetRate×
• Confusion👤 no reports yet⚕️ no reports yetRate×
• Novelty enhancement👤 no reports yet⚕️ no reports yetRate×
• Creativity enhancement👤 no reports yet⚕️ no reports yetRate×
• Delusion👤 no reports yet⚕️ no reports yetRate×
• Déjà vu👤 no reports yet⚕️ no reports yetRate×
• Increased music appreciation👤 no reports yet⚕️ no reports yetRate×
• Immersion intensification👤 no reports yet⚕️ no reports yetRate×
• Memory enhancement👤 no reports yet⚕️ no reports yetRate×
• Memory suppression👤 no reports yet⚕️ no reports yetRate×
• Ego death👤 no reports yet⚕️ no reports yetRate×
• Mindfulness👤 no reports yet⚕️ no reports yetRate×
• Simultaneous emotions👤 no reports yet⚕️ no reports yetRate×
• Personal bias suppression👤 no reports yet⚕️ no reports yetRate×
• Ego replacement👤 no reports yet⚕️ no reports yetRate×
• Personality regression👤 no reports yet⚕️ no reports yetRate×
• Catharsis👤 no reports yet⚕️ no reports yetRate×
• Rejuvenation👤 no reports yet⚕️ no reports yetRate×
• Addiction suppression👤 no reports yet⚕️ no reports yetRate×
• Time distortion👤 no reports yet⚕️ no reports yetRate×

Auditory

• Auditory acuity enhancement👤 no reports yet⚕️ no reports yetRate×
• Auditory distortion👤 no reports yet⚕️ no reports yetRate×
• Auditory hallucination👤 no reports yet⚕️ no reports yetRate×

Multi-sensory

• Synaesthesia👤 no reports yet⚕️ no reports yetRate×
• Dosage independent intensity👤 no reports yet⚕️ no reports yetRate×

Transpersonal

• Spirituality intensification👤 no reports yet⚕️ no reports yetRate×
• Existential self-realization👤 no reports yet⚕️ no reports yetRate×
• Unity and interconnectedness👤 no reports yet⚕️ no reports yetRate×

Subjective-effect profile adapted from PsychonautWiki, CC BY-SA 4.0.

+ Add an effect

Pharmacokinetics

Absorption

Psilocybin is absorbed from the gastrointestinal tract after oral administration. Dephosphorylation to psilocin by intestinal and hepatic alkaline phosphatase begins immediately on absorption; psilocybin itself is not detected at meaningful concentrations in systemic plasma. Peak psilocin plasma concentration occurs approximately 80 to 120 minutes after oral dosing, with subjective onset typically detectable at 20 to 45 minutes (the lag between absorption and subjective onset reflects the time required to achieve threshold central nervous system concentrations). Food in the stomach delays absorption substantially and may reduce peak plasma psilocin concentration; the standard pre-session fast in clinical and ceremonial settings (typically 4 to 8 hours) reflects this. Oral bioavailability of psilocin from administered psilocybin is approximately 50 percent.

Distribution

Psilocin is moderately lipid-soluble and crosses the blood-brain barrier readily; brain concentrations rise rapidly during the absorption phase. Plasma protein binding of psilocin is modest. Volume of distribution is not extensively characterized in modern publications; older data suggest distribution into total body water with some fat partitioning.[citation needed]

Metabolism

Psilocin is metabolized predominantly by glucuronidation, with UGT1A10 and UGT1A9 the principal enzymes; the resulting psilocin-O-glucuronide is the major plasma and urinary metabolite. A minor metabolic pathway is oxidation by MAO-A to 4-hydroxyindole-3-acetaldehyde, which is further oxidized to 4-hydroxyindole-3-acetic acid. Cytochrome P450 isoenzymes are not the principal metabolic route, distinguishing psilocin from most other classical psychedelics; the implication is that clinically relevant pharmacokinetic interactions with CYP3A4 and CYP2D6 inhibitors and inducers are limited compared to the corresponding interactions for, for example, LSD. MAO inhibitors potentiate psilocin and prolong its action; this is the basis of the historical Mesoamerican practice of co-administering psilocybin mushrooms with Banisteriopsis caapi or other MAO-inhibitor-containing material in some lineages, though the practice is not universal.[citation needed]

Elimination

Psilocin elimination half-life is approximately 2 to 3 hours; the active subjective duration of 4 to 6 hours reflects this half-life and the time required for plasma concentrations to fall below threshold. Elimination is renal, with psilocin-O-glucuronide as the principal urinary metabolite; minor amounts of unchanged psilocin appear in urine. Clearance is unaffected by mild to moderate renal impairment in the limited published data.[citation needed]

Pharmacodynamics

Psilocybin is a prodrug. Within minutes of oral absorption, gastric and intestinal alkaline phosphatases dephosphorylate psilocybin to psilocin (4-hydroxy-N,N-dimethyltryptamine), which is the active compound at central serotonin receptors. Psilocin is a partial agonist at the 5-HT2A receptor, the action that defines the classical-psychedelic mechanism and that all of the major psychedelics (LSD, mescaline, DMT, 2C-B, the 4-substituted tryptamines) share in common. Psilocin has additional substantial activity at 5-HT2C, 5-HT1A, and 5-HT2B receptors. The 5-HT2A action is the principal driver of the psychedelic experience: selective 5-HT2A antagonists such as ketanserin abolish the subjective effects of psilocin in human studies. The cortical 5-HT2A receptor is expressed densely on layer V pyramidal neurons; 5-HT2A agonism by psilocin produces increased glutamate release in cortical circuits, which is one of the proposed substrate-level mechanisms for the psychedelic state.

Modern neuroimaging studies, particularly the Carhart-Harris group's work at Imperial College London, have proposed that the subjective and clinical effects of psilocybin are correlated with desynchronization of the default mode network and with increased entropy of cortical activity (the "entropic brain" hypothesis). Functional MRI studies during active psilocybin sessions have shown decreased connectivity within the default mode network and increased connectivity between networks that are typically segregated. The relationship between these network-level findings and the lasting antidepressant effects observed in clinical trials is the subject of active investigation.

The neuroplasticity hypothesis, advanced by several modern psilocybin research groups, proposes that 5-HT2A agonism produces upregulation of brain-derived neurotrophic factor (BDNF) and a period of enhanced synaptic plasticity that opens a window for psychotherapeutic restructuring; the window is hypothesized to extend for days to weeks after a single high dose and to underlie the durability of the antidepressant effect. The hypothesis is supported by animal model evidence and by some human biomarker data; the precise relationship between psychedelic-occasioned neuroplasticity and clinical outcome remains under investigation.

Interactions

No interactions reported yet.

+ Add an interaction

The clinically important interaction concerns for psilocybin:

• Serotonergic medicines: serotonin syndrome risk. Concurrent use of SSRIs, SNRIs, MAOIs, tramadol, or dextromethorphan carries serotonin syndrome risk and should be avoided. MAOI co-administration is particularly dangerous, with both serotonin syndrome risk and substantial potentiation of psilocin effect.
• Lithium: seizure and severe-reaction risk. Lithium combined with psilocybin and other classical psychedelics is associated with markedly elevated risk of seizures and severe adverse reactions, distinct from serotonin syndrome. The combination is documented in multiple case reports and should be avoided.[citation needed]
• Psychostimulants: additive cardiovascular load. Psilocin produces modest sympathomimetic activation (heart rate and blood pressure elevation in the order of 10 to 20 percent above baseline at clinical doses); concurrent psychostimulants compound the cardiovascular burden.
• Neuroleptic medicines and other strong 5-HT2A antagonists: psilocybin effect is abolished. Ketanserin, risperidone, olanzapine, quetiapine, and other agents with substantial 5-HT2A antagonism block or substantially attenuate the subjective and clinical effects of psilocybin; this is the predicted consequence of the receptor mechanism and is the clinical basis for the use of 5-HT2A antagonists to terminate intolerable psilocybin experiences in some clinical-trial protocols.[citation needed]
• Benzodiazepines and other GABA-A modulators: psilocybin effect is attenuated but not abolished. Modest doses of benzodiazepines reduce the intensity of psilocybin experiences without fully terminating them; they are used in some clinical and harm-reduction protocols to manage acute anxiety during sessions.
• Tolerance and cross-tolerance. Tolerance to psilocybin develops rapidly and dissipates within several days; daily dosing produces near-complete tolerance within four days. Cross-tolerance exists with LSD, mescaline, DMT, and other 5-HT2A agonists, consistent with the shared receptor mechanism.
• CYP-mediated interactions: minimal, as psilocin metabolism is predominantly UGT-mediated.

  Pregnancy and lactation

Psilocybin has not been studied in human pregnancy. The Schedule I status of the medicine, the absence of any approved clinical use in any population, and the absence of pregnancy registries for psilocybin-using cohorts mean that the human pregnancy data are essentially limited to anecdotal reports.

The cross-placental transfer of psilocin would be predicted on pharmacokinetic grounds (small molecule, modest protein binding, lipid solubility) but has not been directly characterized in humans. Animal reproductive toxicology studies have not been conducted to modern regulatory standards. The 5-HT2A receptor is expressed in developing neural tissue from early gestation, and 5-HT2A agonism has effects on neuronal migration and synaptogenesis in animal models; the implication for human fetal exposure is unclear.[citation needed]

Lactation data are similarly limited. Psilocin would be predicted to enter breast milk in modest amounts on pharmacokinetic grounds; the clinical implication of acute psilocin exposure to a breast-fed infant is not characterized. The relatively short half-life of psilocin (2 to 3 hours) and the typical clinical-session schedule (a single dose with a clear pre-dose and post-dose interval) make pump-and-discard strategies straightforward where lactation must continue.

For women using psilocybin outside clinical or regulated-services contexts, the practical guidance from the limited available data is to avoid use during pregnancy and during lactation if breastfeeding is to continue without interruption. Women undergoing investigational psilocybin therapy are required to use contraception during the trial period in most modern protocols.[citation needed]

Monitoring

Psilocybin sessions in the modern clinical paradigm involve substantial pre-session screening, in-session monitoring, and post-session integration; the medicine is not used as a chronic pharmacotherapy and the monitoring framework reflects the single-session, high-dose, psychotherapy-anchored model.

Pre-session screening:

• Cardiovascular assessment. Modest cardiovascular activation during psilocin's active phase (heart rate and blood pressure increases of approximately 10 to 20 percent above baseline) is well-tolerated by healthy adults but is a relative contraindication in patients with significant cardiovascular disease, uncontrolled hypertension, or arrhythmia history. Baseline blood pressure and pulse; ECG in patients with cardiovascular risk factors.
• Psychiatric history. Personal or family history of psychotic-spectrum illness (schizophrenia, schizoaffective disorder) or bipolar I disorder is a relative or absolute contraindication in most modern clinical research protocols; the historical concern that 5-HT2A agonism may precipitate psychotic decompensation in predisposed individuals is supported by case reports though not by population-level data. Current depressive or anxiety episodes are not contraindications and are typically the indication.
• Medicine review. SSRI, SNRI, MAOI, lithium, and neuroleptic medicines as detailed in the interactions field; modern clinical trials typically require a structured taper of these medicines before the psilocybin session (lithium held for at least one week, MAOIs for at least two weeks, fluoxetine for at least four weeks due to its long half-life, other SSRIs and SNRIs for one to two weeks). The clinical question of whether SSRI taper substantially affects psilocybin response is under investigation.[citation needed]
• Pregnancy testing for women of reproductive potential per current trial protocols.

In-session monitoring: the modern clinical paradigm uses a quiet, comfortable session room, eye mask, curated music, two facilitators present continuously, intermittent vital sign assessment, and minimal directive intervention from the facilitators except in response to clinical need. Sessions are typically 6 to 8 hours in length.

Post-session integration: psychotherapy-style integration sessions are conducted in the days and weeks following the psilocybin session; the integration framework is considered part of the active treatment in most modern trial protocols.

Adverse experience management: acute anxiety, panic, or transient ego-dissolution-related distress are managed in-session through facilitator presence, reassurance, and (uncommonly) pharmacological intervention. Benzodiazepines can be used to attenuate intensity if non-pharmacological measures are insufficient; neuroleptic pretreatment is not typical in clinical settings but neuroleptics have been used as a rescue medicine. Persistent psychological effects beyond the active session, including persistent perceptual changes (HPPD) and emergent psychiatric symptoms, are uncommon at clinical doses with adequate screening but are reported in larger naturalistic cohorts; rates appear to be substantially lower at clinical-trial doses with screening than at unscreened recreational doses.[citation needed]

Patient counseling

Patients enrolled in clinical psilocybin trials and patients accessing regulated psilocybin services in jurisdictions where these exist (Oregon, Colorado) receive structured pre-session preparation, including discussion of the range of possible experiences, the "set and setting" framework, the value of surrender over resistance during the acute session, and the integration framework that follows. The counseling that follows from the medicine's pharmacology and from the modern clinical experience:

Set and setting. The intentional preparation of the psychological state (set) and the physical and social environment (setting) is the single most consequential variable in determining the character of the experience. This is the framework that the Mazatec tradition transmits through ceremonial structure and that the modern clinical paradigm transmits through pre-session preparation, session-room design, music selection, and facilitator presence. The framework applies whether the use is clinical, regulated-services, or personal.

Surrender, not resistance. The experiences that produce the most difficult acute distress in psilocybin sessions are typically those in which the participant attempts to resist or control the unfolding experience. The modern clinical guidance, developed empirically across hundreds of trial sessions, is to encourage non-resistance: to allow what arises to arise, to attend to it rather than push it away, and to trust that the experience will move through its phases. The advice is descriptively accurate but is itself easier to follow with preparation.

Challenging experiences. Difficult sessions are not failures and frequently produce the most durable clinical benefit. The framing "challenging experience" has substantially replaced the older "bad trip" terminology in the modern literature; the older term presupposes a binary the phenomenology does not actually present.

Integration. The work of integrating insights or shifts from a psilocybin session into ongoing life is the period in which most of the clinical effect appears to consolidate. Modern protocols include structured integration sessions in the days and weeks following the dose; outside formal protocols, journaling, conversation with a trusted friend or therapist, and intentional pacing of return to ordinary obligations are the basic elements.

Driving and safety-sensitive activities: do not drive, operate machinery, or engage in safety-sensitive activities during the session day. The acute experience lasts 4 to 6 hours; residual subjective effects can persist for some hours afterward. The standard clinical-trial discharge criterion is overnight observation or a trusted adult contact to assume responsibility for the participant.

Lasting perceptual changes: a minority of users report persistent visual phenomena (after-images, geometric patterns at the periphery of vision, sensitivity to certain visual stimuli) at low intensity for days to months after a session. Frank hallucinogen persisting perception disorder, in which the perceptual phenomena are clinically significant, is uncommon at clinical doses with adequate screening but is described in the literature.

Pregnancy and breastfeeding: as detailed in pregnancy_details, the data are limited and the practical guidance is to avoid use during pregnancy and during continuous breastfeeding.

Psilocybin and ongoing psychiatric medicines: if a participant is on SSRI, SNRI, MAOI, lithium, or neuroleptic medicine, the appropriate management is to discuss the medicine list with the prescribing clinician before any psilocybin session; the interaction profile, particularly for MAOIs and for lithium, is sufficiently consequential that ad hoc discontinuation is not advisable.

Relevant anecdote

No anecdotes yet. Share a relevant one.

+ Add an anecdote

Relevant Literature

No literature entries yet.

Log in to submit relevant literature.

See also

LSD, Mescaline, DMT, 2C-B, MDMA

References

Summary

Classes

Psychedelic, Serotonergic psychedelic, Tryptamine

Common uses

• Alcohol Use Disorder★★★★★★★★★★★★★★★—×
• Cancer-Related Distress★★★★★★★★★★★★★★★—×
• Cluster headache★★★★★★★★★★★★★★★—×
• Major Depressive Disorder★★★★★★★★★★★★★★★—×
• Obsessive-Compulsive Disorder★★★★★★★★★★★★★★★—×

+ 2 more uses →

Pharmacy

Starting dose

Modern clinical-trial standard: 25 mg synthesized psilocybin, single oral dose with psychological support

Preparations

Synthesized psilocybin capsules (COMP360 and other investigational formulations); dried whole Psilocybe mushrooms (variable potency, no legal supply chain in most jurisdictions); psilocybin truffles (Psilocybe sclerotia, legal in the Netherlands)

US FDA Max

Not FDA-approved; clinical-trial protocols use up to 30 mg in adult investigational dosing

Pill ID

Investigational only; not commercially available outside clinical trials and regulated services programs

Pharmacology

Routes

Oral

Onset

20-45 min subjective onset; psilocin formation from psilocybin requires intestinal and hepatic alkaline phosphatase

Duration

4-6 hours

Half-life

Psilocin: ~2-3 h; psilocybin itself is a prodrug, dephosphorylated within minutes of absorption

Bioavailability

Oral bioavailability of psilocin from administered psilocybin approximately 50%

Pregnancy

Not studied in human pregnancy; no approved clinical use in any population

Legal status

Schedule I (United States Controlled Substances Act 1970); Schedule I (United Nations Convention on Psychotropic Substances 1971); decriminalized possession or regulated-services-legal in a growing list of US jurisdictions (Oregon 2020, Colorado 2022, Denver May 2019, Oakland June 2019, others); legal sclerotium-product market in the Netherlands

Purported mechanism

Prodrug to psilocin (4-hydroxy-N,N-dimethyltryptamine), a partial agonist at the 5-HT2A serotonin receptor; the action that defines the classical-psychedelic mechanism