Psilocin

# Research Output: Psilocin

**PSX ID:** PSX-0314  
**Research Date:** 2026-05-03  
**Generation Provenance ID:** 380994a6-9e89-4583-8623-51c2266f2144

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## Chemical Identity

**Verified via PubChem CID 4980 (api_verified):**

| Property | Value | Source |
|---|---|---|
| PubChem CID | 4980 | PubChem API |
| Molecular Formula | C₁₂H₁₆N₂O | PubChem [Ref 4] |
| Molecular Weight | 204.27 g/mol | PubChem |
| SMILES (canonical) | `CN(C)CCC1=CNC2=C1C(=CC=C2)O` | PubChem API |
| InChIKey | SPCIYGNTAMCTRO-UHFFFAOYSA-N | PubChem |
| IUPAC Name | 3-[2-(dimethylamino)ethyl]-1H-indol-4-ol | PubChem |
| CAS Number | 520-53-6 | [Ref 34] |
| Melting Point | 173–176 °C | [Ref 34] |

**Seed Data Discrepancies:**
- The seed data was missing SMILES, molecular formula, molecular weight, InChIKey, PubChem CID, and CAS number — all now confirmed above.
- The seed data IUPAC name matches exactly.
- The seed data systematic name matches ("3-[2-(dimethylamino)ethyl]-1H-indol-4-ol").

**Stereochemistry:** Psilocin is not chiral — the molecule contains no stereocenters. It is a single, achiral entity. This contrasts with its prodrug psilocybin, which also lacks chirality at the indole ring but carries a phosphate group at position 4. No active vs. inactive isomer distinction applies to psilocin.

**Physical Properties:**
- Appearance: white to slightly yellowish crystalline solid
- Melting point: 173–176°C [Ref 34]
- Solubility: lipid-soluble; soluble in methanol and ethanol; poorly soluble in water [Ref 34]
- Stability: unstable on exposure to light and air (oxidizes); stable at low temperature in the dark [Ref 34]
- The indol-4-ol group undergoes rapid oxidation in solution, turning blue/green — this reaction (reminiscent of psilocybin mushroom bruising) is diagnostically significant

---

## Pharmacology

### Primary Mechanism of Action

Psilocin acts primarily as a **serotonin 5-HT₂A receptor agonist**, and this is the principal mechanism underlying its psychedelic effects. Activation of 5-HT₂A receptors has been demonstrated to be necessary and sufficient for hallucinogenic effects: pretreatment with the selective 5-HT₂A antagonist ketanserin completely blocks psilocybin-induced visual hallucinations, alpha-band oscillation changes, N170 visual-evoked potential suppression, and altered states of consciousness scores (Kometer et al. 2013 [Ref 25]; Pokorny et al. 2016 [Ref 43]).

### Receptor Binding Affinities

The following Ki values for psilocin at human and mouse brain receptors were determined by competition binding studies (Erkizia-Santamaría et al. 2022 [Ref 1]):

| Receptor | Ki (human brain) | Ki (mouse brain) | Functional Effect |
|---|---|---|---|
| 5-HT₂A | 120–173 nM | 173 nM | Full/partial agonist |
| 5-HT₂C | 79–311 nM | 79 nM | Agonist |
| 5-HT₁A | 152–146 nM | 146 nM | Partial agonist |

Rickli et al. (2016 [Ref 3]) independently confirmed psilocin binding at 5-HT₂A as a partial/full agonist, and demonstrated binding affinity lower than LSD but correlating with reported psychoactive doses. Psilocin also interacts with the **serotonin transporter (5-HTT/SERT)**, unlike LSD and mescaline — predicting partial MDMA-like psychoactive properties in addition to hallucinogenic effects (Rickli et al. 2016 [Ref 3]).

**FLAG for human review:** Ki values from Erkizia-Santamaría 2022 are from competition binding in brain tissue. Different assay methods yield variable Ki estimates across the literature. These represent best available human tissue data.

### Novel Mechanism: TrkB Binding

Moliner et al. (2023 [Ref 2], *Nature Neuroscience*, 414 citations) demonstrated that psilocin directly binds **TrkB** (the BDNF receptor) with affinities approximately **1,000-fold higher** than other antidepressants (fluoxetine, ketamine). Psilocin binds within the transmembrane domain of TrkB dimers, at a site that is distinct from but partially overlapping with other antidepressants. Critically:
- Antidepressant and neuroplasticity effects in mice depend on TrkB binding and potentiation of endogenous BDNF signaling
- These effects are **independent** of 5-HT₂A activation
- Head-twitching behavior (the animal proxy for hallucinogenic effect) is **5-HT₂A-dependent and TrkB-independent**

This suggests psilocin may have two functionally separable mechanisms: TrkB-mediated neuroplasticity and antidepressant action, and 5-HT₂A-mediated perceptual/experiential effects.

### Intracellular 5-HT₂A Receptors and Neuroplasticity

Vargas et al. (2023 [Ref 10], *Science*, 437 citations) showed that **intracellular** 5-HT₂ARs (not plasma membrane 5-HT₂ARs) mediate the plasticity-promoting properties of psychedelics including psilocin. This explains why serotonin itself does not trigger similar plasticity — serotonin cannot reach intracellular receptor pools in the same manner as lipophilic psychedelics. Location bias in 5-HT₂AR signaling is now understood as critical.

### Receptor Occupancy and Dose-Response

Madsen et al. (2019 [Ref 7], *Neuropsychopharmacology*, 480 citations) used PET imaging to demonstrate that psilocybin (acting via psilocin) causes dose-related 5-HT₂A receptor occupancy up to **72%** at clinically relevant doses. Plasma psilocin levels and 5-HT₂AR occupancy were closely and linearly associated with subjective intensity ratings. The dose-response relationship was non-linear.

### Role of 5-HT₁A and 5-HT₂C Receptors

- **5-HT₁A**: Blockade of 5-HT₁A with WAY100635 reverses psilocybin-induced hypothermia to hyperthermia. The 5-HT₁A agonist buspirone reduces visionary restructuralization and oceanic boundlessness from psilocybin (Pokorny et al. 2016 [Ref 43]), suggesting 5-HT₁A partially dampens the visual intensity. 5-HT₁A is a partial agonist target with Ki ~150 nM.
- **5-HT₂C**: The 5-HT₂C antagonist SB242084 increased the head-twitch response magnitude at higher psilocybin doses, suggesting 5-HT₂C limits the ceiling effect of 5-HT₂A-mediated effects (Erkizia-Santamaría et al. 2022 [Ref 1]).

### Pharmacokinetics

**Based on systematic reviews (Meshkat et al. 2025 [Ref 4]; Otto et al. 2025 [Ref 5]; Thaoboonruang et al. 2025 [Ref 21]) and primary studies (Becker & Holze et al. 2022 [Ref 37]):**

| PK Parameter | Value | Notes |
|---|---|---|
| Prodrug conversion | Psilocybin → psilocin | Alkaline phosphatase dephosphorylation |
| Oral bioavailability (psilocin) | 52.7 ± 20% | Single study, inter-individual variability high |
| Tmax (plasma) | 1.8–4 hours | After oral psilocybin |
| Half-life (free psilocin) | 1.8 hours (range 1.1–2.2h) | Becker & Holze 2022 [Ref 37] |
| Half-life (range across studies) | 1.5–4 hours | Meshkat et al. 2025 [Ref 4] |
| Volume of distribution | 277 ± 92 to 1,016 L | Extensive tissue distribution |
| Cmax (plasma) | 8.2 ± 2.8 ng/mL (dose-dependent) | Dose-dependent increase |

**Metabolism — Phase I (Chen et al. 2025 [Ref 6]; Meshkat et al. 2025 [Ref 4]):**
1. **MAO-A** is the primary Phase I enzyme, accounting for **80.9%** of total hepatic psilocin metabolism
2. MAO-A converts psilocin → **4-hydroxyindole-3-acetaldehyde (4-HIA)** (intermediate, first identified by Chen et al. 2025)
3. 4-HIA is further metabolized by cytosolic aldehyde oxidase (AO) and aldehyde dehydrogenases (ALDHs) → **4-hydroxyindole-3-acetic acid (4-HIAA)** (terminal metabolite)
4. **CYP2D6** and **CYP3A4** contribute secondary Phase I metabolism
5. Extensive extrahepatic MAO-A clearance: total organ clearance 614.81 mL/min vs hepatic 158.74 mL/min — indicating significant gut, lung, and other tissue metabolism

**Metabolism — Phase II:**
- **Glucuronidation** produces psilocin-O-glucuronide (detected in plasma and urine)
- **4-hydroxytryptophol** is another metabolite

**Critical finding**: Williamson et al. (2026 [Ref 33]) confirmed via BRET-based binding assay at 7 serotonin receptor subtypes that **only psilocin** shows discernible receptor binding — psilocin-O-glucuronide and 4-HIAA are pharmacologically inert. This confirms psilocin as the sole active form.

**PBPK modeling** (Thaoboonruang et al. 2025 [Ref 22]) demonstrated complete or near-complete psilocybin-to-psilocin conversion before systemic circulation, supporting psilocybin's role as a pure prodrug.

**Seed Data Comparison:**
- Seed data lists tolerance half-life as "3 days" — this appears to refer to cross-tolerance resolution rate, NOT pharmacokinetic half-life. Psilocin elimination half-life is 1.5–4 hours. The "3 day" figure likely reflects the receptor downregulation recovery timeline. **FLAG: generation agent should present these as distinct concepts.**

---

## History

### Discovery (1958–1959)

Psilocin was first identified by **Albert Hofmann** and **Franz Troxler** at **Sandoz Laboratories, Basel, Switzerland**, as part of the team that characterized the psychoactive principles of Mexican "magic mushrooms." The full discovery timeline:

- **1957–1958**: R. Gordon Wasson's ethnomycological accounts of *Psilocybe* mushrooms in *Life* magazine sparked Hofmann's interest. Hofmann obtained samples of *Psilocybe mexicana* and began isolation work.
- **1958**: Hofmann, Heim, Brack, Kobel, and colleagues reported the isolation of **psilocybin** as the primary psychoactive alkaloid from *Psilocybe mexicana*, published in *Helvetica Chimica Acta* (Hofmann et al. 1959 [Ref 18]). Psilocin was present in trace amounts only in mushrooms; psilocybin predominates (0.2–0.4% dry weight).
- **1959**: Hofmann and Troxler published "Identifizierung von Psilocin" (*Experientia*, Vol. 15, No. 3) [Ref 19], definitively identifying psilocin's structure as **4-hydroxy-N,N-dimethyltryptamine** — the dephosphorylated active form of psilocybin.
- **1963**: Hofmann and Troxler filed a patent covering the synthesis of both compounds.

### Key Structural Insight

The structural relationship between psilocin and serotonin (5-hydroxytryptamine) is immediately apparent: psilocin is a 4-hydroxy, N,N-dimethyl substituted tryptamine, differing from serotonin by the hydroxyl position (C4 vs. C5), dimethylation of the amino group, and absence of the primary amine. The tertiary amine confers higher 5-HT₂A binding affinity than serotonin's primary amine (Hakami Zanjani et al. 2023 [Ref not separately indexed]).

### Regulatory History

- **1966 (US)**: Drug Abuse Control Amendments effectively restricted hallucinogen research
- **October 27, 1970**: Psilocin and psilocybin simultaneously listed as **Schedule I** controlled substances under the US Comprehensive Drug Abuse Prevention and Control Act (Controlled Substances Act). Classified as "hallucinogens" with no accepted medical use and high abuse potential.
- **1971**: UN Convention on Psychotropic Substances placed psilocin in Schedule I, triggering equivalent controls across signatory nations.
- **2006**: Griffiths et al. landmark Psychopharmacology paper [Ref 24] reignited clinical interest with the first modern controlled trial showing psilocybin occasions mystical experiences with lasting personal meaning.
- **2016**: Carhart-Harris et al. Lancet Psychiatry trial [Ref 16] — first modern clinical trial for treatment-resistant depression.
- **2018**: FDA granted psilocybin **Breakthrough Therapy Designation** (twice: for TRD by COMPASS Pathfinder, and for MDD by Usona Institute).
- **2020**: Oregon Measure 109 passed by voters.
- **January 2023**: Oregon Psilocybin Services Act operational — first US state to permit supervised therapeutic psilocybin access [Ref 41].
- **July 1, 2023**: Australia reschedules psilocybin from Schedule 9 (prohibited) to **Schedule 8** (controlled) for medical treatment of TRD and PTSD — the first Western country to approve its therapeutic use [Ref 42].

---

## Subjective Effects

### Published Descriptions from Controlled Studies

Clinical studies using psilocybin (whose effects are mediated entirely by psilocin) have characterized a reproducible cluster of effects:

**Onset and Duration** (Carhart-Harris et al. 2016 [Ref 16]):
- Psychedelic effects detectable 30–60 minutes after oral dosing
- Peak effects at 2–3 hours
- Subsided to negligible by 6 hours
- This is consistent with the seed data (onset 20–45 min, peak 2–3h, total 4–6h) — well-supported by published data

**Experiential Domains** (Griffiths et al. 2006 [Ref 24]; Vollenweider et al. 2007 [Ref 31]; Studerus et al. 2010 [Ref not in registry]):

1. **Visionary Restructuralization** — geometric visual phenomena, hallucinations (internal and external), visual drifting and distortions, afterimages, altered color perception. All blocked by 5-HT₂A antagonism (Kometer et al. 2013 [Ref 25]).

2. **Oceanic Boundlessness** — unity/interconnectedness, ego dissolution, emotional enhancement, bliss, derealization/depersonalization. Partially modulated by 5-HT₁A.

3. **Dread of Ego Dissolution** — anxiety, paranoia, confusion, thought disorder — reported in a minority of participants; dose-dependent (Carhart-Harris et al. 2016 [Ref 16]: transient anxiety in all 12 patients at onset, confusion in 9/12).

4. **Mystical Experience** — sense of profound personal meaning, spiritual significance, unity — documented by Griffiths et al. (2006 [Ref 24]) persisting at 2-month follow-up, with community observers confirming positive behavioral changes.

**Dose-Dependent Effects** (Vollenweider et al. 2007 [Ref 31]):
- 115, 215, and 315 µg/kg psilocybin all produced dose-dependent 5D-ASC scale increases
- Sustained attention impaired dose-dependently
- Prepulse inhibition: complex dose- and ISI-dependent changes

**Duration Data Assessment:**
- Seed data total duration 4–6 hours, onset 20–45 min, peak 2–3h are consistent with Carhart-Harris et al. (2016 [Ref 16])
- Aftereffects lasting 4–24 hours: consistent with psychological integration period post-acute; supported by Griffiths (2006 [Ref 24]) noting effects lasting into the following day
- Come-up of 1.5–3 hours appears somewhat long vs Carhart-Harris 2016 report of peak at 2–3h with onset at 30–60 min — **FLAG: come_up duration may be conflated with onset-to-peak duration. The 20–45 min onset appears correct; come_up of 1.5-3h is plausible as full effect escalation timeline.**

---

## Safety & Toxicity

### Acute Toxicity

**LD50 Data (Zhuk et al. 2015 [Ref 36]):**
- Psilocin LD50: **293.07 ± 1.02 mg/kg** (intraperitoneal, mice)
- For comparison, a human psychoactive dose of psilocin-equivalent is approximately 6–25 mg orally (10–40 mg psilocybin × ~0.6 bioavailability factor), corresponding to <0.3–0.35 mg/kg for a 70 kg person
- This yields a **therapeutic index (LD50/ED)** in the order of 1,000:1 — consistent with the characterization of "negligible acute toxicity" in the seed data

**Psilocybin LD50 comparators** (from published pharmacological literature):
- Psilocybin: 285 mg/kg IV in mice, 280 mg/kg oral in rats
- Rabbits are notably more sensitive (12.5 mg/kg IV) — species differences significant

The seed data values of "acute: negligible" and "chronic: negligible" are supported by published evidence. No human fatalities attributable solely to psilocin/psilocybin overdose have been reported in the peer-reviewed literature.

### Controlled Clinical Safety Data

**Romeo et al. (2024) meta-analysis [Ref 15] — 30 studies, >1,000 psychedelic administrations:**
- 9 serious adverse events total (1 acute, 8 post-acute) — very low rate
- No suicide attempts during acute phase
- 3 cases of self-harm post-acute phase
- Increased risk: elevated heart rate, systolic and diastolic blood pressure at all dose ranges
- Common: nausea, headaches, anxiety, decreased concentration/appetite
- Well-tolerated in controlled settings with appropriate inclusion criteria

**Cardiovascular effects (Yu et al. 2022 [Ref 40]):**
- Systolic BP increase: ~+19 mmHg (pooled)
- Diastolic BP increase: ~+8.66 mmHg (pooled)
- Heart rate: comparable to placebo — no significant increase in pooled analysis
- **FLAG: Cardiovascular effects represent a clinically relevant contraindication for patients with uncontrolled hypertension or significant cardiovascular disease.**

**Goodwin et al. (2022 NEJM [Ref 9]) — Phase 2 RCT, 233 participants:**
- Adverse events in 77% (179/233): headache, nausea, dizziness (all dose groups)
- Suicidal ideation or behavior or self-injury occurred in **all dose groups** including the 1 mg control
- This finding complicates causal attribution to psilocybin itself — likely reflects baseline TRD population risk

**Carhart-Harris et al. (2016 [Ref 16]) — open-label, 12 patients:**
- All patients: transient anxiety at onset
- 9/12: transient confusion or thought disorder
- 4/12: mild, transient nausea
- 4/12: transient headache
- No serious or unexpected adverse events

### Headaches

Johnson, Sewell & Griffiths (2012 [Ref 30]) documented that psilocybin **dose-dependently causes delayed, transient headaches** in healthy volunteers. Onset is typically the day after administration. This is notable given psilocybin's structural relationship to triptan migraine medications. The mechanism is uncertain.

### Psychological Risks

**Hallucinogen Persisting Perception Disorder (HPPD):**
- HPPD is associated with psilocybin/psilocin use (along with LSD, mescaline, MDMA, cannabis) (Orsolini et al. 2017 [Ref 26])
- Characterized by prolonged or recurrent perceptual symptoms reminiscent of acute effects: geometric pseudo-hallucinations, halos, afterimages, visual snow, altered motion perception
- First described 1954; established as DSM syndrome in 2000
- Prevalence in the context of controlled clinical trials appears very low (not quantified separately for psilocin)

**Psychosis exacerbation:**
- Contraindicated in individuals with personal or family history of psychotic disorders (Johnson et al. 2018 [Ref 23])
- Johnson et al. (2018) 8-factor CSA analysis: exacerbation of psychosis in predisposed individuals is a primary harm concern, though scope of harm remains low compared to other abused substances

**Challenging experiences:**
- Simonsson et al. (2023 [Ref 38]): 8.9% of lifetime users reported functional impairment >1 day; 2.6% sought medical/psychiatric help
- Challenging experiences associated with: negative mindset, no preparation, no psychological support, disagreeable setting, excessive dose, major life event

---

## Harm Reduction

### Published Risk Reduction Strategies

**Johnson et al. (2018 [Ref 23]) — safety framework from 8-factor analysis:**
- Use only in medical/research settings with dose control
- Thorough patient screening (exclude psychosis risk, mania, unstable medical conditions)
- Psychological preparation sessions before administration
- Supervised setting with trained monitors/guides
- Post-session integration support
- These measures are reported to render adverse effects of medical psilocybin manageable

**Contraindications (from clinical trial exclusion criteria and safety data):**
- Personal or family history of schizophrenia, bipolar disorder type I, or any psychotic disorder
- Current use of lithium or mood stabilizers (strong contraindication — see Interactions)
- Uncontrolled hypertension or significant cardiovascular disease (BP elevations documented)
- Current pregnancy or breastfeeding (insufficient data)
- History of severe trauma without psychological support available

**Set and Setting:**
- Simonsson et al. (2023 [Ref 38]) identified six modifiable set/setting factors predicting harm: no preparation, disagreeable environment, negative mindset, no psychological support, dose too large, major life event prior
- Controlled clinical environments eliminate most of these risks

**Testing:**
- Psilocin/psilocybin react with Ehrlich's reagent (4-dimethylaminobenzaldehyde) to produce a distinctive **purple color** — reliable field test for indole-containing compounds
- Oxidizes and discolors with heat, light, or moisture — authenticity may be assessed by appearance (fresh material should be white; blue/green coloration indicates oxidation)

**Emergency Response:**
- No specific antidote exists
- Reassurance ("talking down") is the primary intervention for acute anxiety or difficult experiences
- 5-HT₂A antagonists (antipsychotics, particularly those with 5-HT₂A inverse agonist properties — e.g., risperidone, olanzapine) can rapidly terminate psychedelic effects
- Benzodiazepines can reduce anxiety without fully aborting the experience
- Avoid restraint unless immediate danger — physical restraint can escalate fear and worsen outcomes

---

## Tolerance & Dependence

### Tolerance

**Mechanism:** Repeated administration of serotonergic hallucinogens leads to **downregulation of 5-HT₂ receptors**. Buckholtz et al. (1990 [Ref 14]) demonstrated that psilocybin (1.0 mg/kg, 8 days) produced a significant decrease in 5-HT₂ receptor binding in rat brain cortex. The decrease:
- Appeared within 3 days of initiation
- Still present 48h after last administration
- Not demonstrable at 96h after last dose
- **Paralleled behavioral tolerance development**

**Cross-tolerance:** Serotonergic hallucinogens show **complete cross-tolerance** to each other (LSD, psilocin/psilocybin, mescaline), mediated by the shared 5-HT₂A receptor downregulation mechanism (Halberstadt 2015 [Ref 12]; Halberstadt & Geyer 2011 [Ref 13]). This explains the seed data notation of cross-tolerance with "psychedelic" class.

**Tolerance timeline (seed data):**
- "Almost immediately after ingestion" — supported by 5-HT₂A downregulation beginning acutely
- "Half-life 3 days" — consistent with Buckholtz (1990) showing presence at 48h, resolution by 96h; this refers to **receptor re-sensitization rate**, not PK half-life
- "Full reset 7 days" — consistent with the receptor biology; clinically validated by study designs using 2-week intervals between psilocybin doses

These tolerance parameters appear well-supported by published evidence. **FLAG: Distinguish pharmacokinetic half-life (~1.8h) from tolerance-related half-life (~3 days) in article prose.**

### Dependence and Abuse Potential

Johnson et al. (2018 [Ref 23]) — comprehensive 8-factor analysis:
- **Limited reinforcing effects**: psilocybin supports marginal, transient self-administration in non-human primates; not reliably self-administered
- **No physical dependence**: No withdrawal syndrome documented
- **Low compulsive use**: Normative pattern is a few lifetime use occasions
- Overall: abuse potential substantially lower than prototypical Schedule I drugs (opioids, stimulants)
- Proposed appropriate schedule if medicalized: **Schedule IV**

Seed data "not habit-forming" is well-supported.

---

## Interactions

### Lithium and Mood Stabilizers (HIGH RISK)

**Simonsson et al. (2023 [Ref 38]) — US nationally representative survey (N=613 psychedelic users):**
- Co-use of **lithium** was significantly associated with **both** degree of difficulty during the experience AND overall risk of harm in multivariate regression models
- Co-use of **other mood stabilizers** showed the same associations
- Lithium was the strongest pharmacological predictor of challenging/harmful outcomes among all variables tested

**Mechanism:** Lithium lowers seizure threshold. Psilocin's serotonergic activity at 5-HT₂A and other receptors may interact synergistically with lithium's effect on second messenger systems (inositol, PKC). Case reports of seizures after psychedelic + lithium combinations exist in the literature (not retrieved as primary papers in this search — **FLAG: case reports not independently verified in this research pass**).

**Clinical implication:** Lithium co-administration is a widely recognized contraindication to psilocin/psilocybin use.

### SSRI and Serotonin Transporter Inhibitors

**Becker, Holze et al. (2022 [Ref 37]) — double-blind RCT, escitalopram + 25 mg psilocybin:**
- Escitalopram pretreatment (10–20 mg/day for 14 days) did **not** alter psilocin pharmacokinetics
- Escitalopram **did** significantly reduce: bad drug effects, anxiety, adverse cardiovascular effects of psilocybin
- Positive mood effects of psilocybin were **not** reduced
- This contradicts older clinical anecdote suggesting SSRIs "blunt" the experience — at least for escitalopram at therapeutic doses

**Goodwin et al. (2023 [Ref 17]) — Phase II exploratory study, psilocybin + ongoing SSRI:**
- 19 participants, 25 mg psilocybin with concurrent SSRI
- 63.2% had treatment-emergent adverse events (mild, resolved same day)
- No serious TEAEs, no increased suicidal ideation
- Mean MADRS improvement: -14.9 (good antidepressant response)
- Conclusion: Therapeutic effect preserved; safety maintained with concurrent SSRI

**Kleditzsch et al. (2025)** confirmed escitalopram (at low doses) did not alter psilocybin-induced head-twitch response or locomotion in mice, suggesting 5-HTT blockade alone does not mediate psilocybin's acute behavioral effects.

### 5-HT₂A Antagonists (Antipsychotics)

Ketanserin completely blocks all psychedelic effects of psilocybin in humans (Kometer et al. 2013 [Ref 25]; Pokorny et al. 2016 [Ref 43]). Atypical antipsychotics with 5-HT₂A inverse agonist activity (risperidone, olanzapine, quetiapine) can terminate or substantially blunt the experience. This is both a safety intervention option and a significant interaction contraindication for patients on these medications.

### MAO Inhibitors (THEORETICAL)

Psilocin's primary Phase I metabolic pathway is via **MAO-A** (accounting for 80.9% of hepatic clearance — Chen et al. 2025 [Ref 6]). **MAO inhibitors (MAOIs)** would therefore be expected to significantly increase psilocin exposure and duration by inhibiting its primary clearance pathway. This interaction has not been directly studied for psilocin + MAOIs, but is well-established for other MAO-A substrates. **FLAG: This is a safety-critical interaction requiring empirical data — currently based on metabolic pathway inference only.**

---

## Legal Status

| Jurisdiction | Status | Scheduling | Date |
|---|---|---|---|
| United States (federal) | Schedule I | DEA Controlled Substances Act | October 27, 1970 |
| United Nations | Schedule I | 1971 Convention on Psychotropic Substances | 1971 |
| United Kingdom | Class A | Misuse of Drugs Act 1971 | 1971 |
| Canada | Schedule III | Controlled Drugs and Substances Act | 1996 |
| Australia | Schedule 8 (medical use only) | TGA Poisons Standard | July 1, 2023 |
| EU (most member states) | Prohibited (varies by country) | Based on UN 1971 Convention | Varies |
| Japan | Prohibited | Narcotics and Psychotropics Control Law | 2002 |
| Oregon (US state) | Supervised therapeutic use permitted | Measure 109, Oregon Psilocybin Services Act | January 2023 |

**Key recent developments:**
- **Australia (2023)**: First Western country to allow medical prescription. Psilocybin rescheduled from Schedule 9 (prohibited) to Schedule 8 (controlled, prescription-only) effective July 1, 2023, for treatment of treatment-resistant depression (TRD) and treatment-resistant PTSD [Ref 42].
- **Oregon (2023)**: Measure 109 (passed 2020) created supervised therapeutic psilocybin access for adults 21+ through licensed service centers. Possession or recreational use outside licensed centers remains illegal [Ref 41].
- **FDA Breakthrough Therapy Designations**: Psilocybin (the prodrug of psilocin) has received FDA Breakthrough Therapy status for both MDD and TRD; final approval pending. Carhart-Harris & Goodwin (2017 [Ref 32]) noted formidable regulatory hurdles.

---

## Clinical Trials

### Active and Recent Completed Trials (as of 2026-05-03)

| NCT ID | Title/Description | Phase | Status | Sponsor |
|---|---|---|---|---|
| NCT06793397 | CYB003 (deuterated psilocin analog) for MDD | Phase 3 | Recruiting | Cybin IRL |
| NCT06564818 | CYB003 for MDD (duplicate listing) | Phase 3 | Recruiting | Cybin IRL |
| NCT07479550 | Anesthesia-masked psilocybin for major depression | Phase 2 | Not yet recruiting | Stanford University |
| NCT07072728 | Psilocybin + psychotherapy for cancer + adjustment disorder | Phase 2 | Recruiting | Psyence Australia |
| NCT06796361 | Role of 5-HT₂A in psilocybin-induced altered states | Phase 1 | Recruiting | University Hospital Basel |
| NCT06341426 | 1 vs. 2 doses psilocybin for TRD | Phase 2 | Recruiting | University Health Network Toronto |
| NCT07490353 | Psilocybin anti-anhedonic effects | Phase 1 | Recruiting | Medical University Vienna |
| NCT06746441 | Psilocybin + CBT for MDD + metabolic markers | Phase 2 | Completed | Khyber Medical University |

**Notable:**
- **CYB003** (NCT06793397, NCT06564818) is a **deuterated analog of psilocin** developed by Cybin as a Phase 3 candidate — this is the most advanced clinical program currently active and specifically uses a psilocin-derived compound rather than psilocybin directly.
- Several trials continue to exclude SSRI co-administration; the Goodwin et al. 2023 [Ref 17] data suggests this may be unnecessarily restrictive.
- The landmark completed trials that anchored current research:
  - **Goodwin et al. 2022 NEJM [Ref 9]** (NCT03775200, COMPASS Pathfinder, Phase 2): 25 mg psilocybin significantly reduced MADRS vs 1 mg control
  - **Davis et al. 2021 JAMA Psychiatry [Ref 28]**: Johns Hopkins Phase 2 RCT; 71% response at week 4
  - **Carhart-Harris et al. 2016 Lancet Psychiatry [Ref 16]**: Open-label TRD study; 6-month follow-up data (Carhart-Harris et al. 2017 [Ref 29])

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## Gaps & Flags

### 1. SMILES in Seed Data
**Gap:** Seed data had no SMILES, molecular formula, molecular weight, InChIKey, or PubChem CID. All confirmed via PubChem API and flagged above.

### 2. Psilocin Half-Life vs. Tolerance Half-Life Conflation (FLAG — Safety-Critical)
The seed data lists tolerance "Half-life: 3 days" alongside PK data. Published PK data shows psilocin elimination half-life is **1.5–4 hours** (specifically ~1.8h for free psilocin). The "3 days" figure refers to the **receptor re-sensitization rate** (5-HT₂A downregulation recovery), not plasma half-life. These must be clearly distinguished in the article to avoid confusion.

### 3. Oral LD50 for Psilocin (FLAG — Safety-Critical)
The LD50 data confirmed (293 mg/kg IP, mice) is from **intraperitoneal administration** in mice (Zhuk et al. 2015 [Ref 36]). No published **oral** LD50 data for psilocin in humans was located. The toxicity characterization in the seed data ("negligible") is directionally correct but the specific values are animal-based (IP route), not human oral route.

### 4. Bioavailability Figure
The 52.7 ± 20% bioavailability figure comes from a single study (flagged in Meshkat et al. 2025 [Ref 4]). High inter-individual variability is expected. The generation agent should present this with appropriate uncertainty.

### 5. MAO-A Interaction (Safety-Critical, Unconfirmed by Direct Study)
Psilocin is primarily metabolized by MAO-A. MAO inhibitors would theoretically significantly increase psilocin exposure. No controlled human study of MAOI + psilocin interaction was found. This is a **safety-critical gap** — the interaction must be flagged as inferred from metabolic pathway data, not confirmed empirically.

### 6. Lithium Seizure Risk (Partially Verified)
Simonsson et al. (2023 [Ref 38]) provides strong epidemiological evidence that lithium co-use increases harm risk. Individual case reports of seizures with lithium + classic psychedelics exist in clinical lore but were not independently retrieved as peer-reviewed case reports in this research pass. **FLAG: Case report evidence for lithium-psilocin seizure interaction should be independently verified before citing specific mechanism.**

### 7. Dose Sensitivity Field (Seed Data Gap)
The seed data's "dose sensitivity" field is empty. Based on PK data (52.7% bioavailability, high Vd, extensive first-pass metabolism), dose-response varies considerably. **No published direct psilocin dose-sensitivity characterization was found** — dose sensitivity is typically characterized from psilocybin, not psilocin directly. The generation agent should note that dose sensitivity data is inferred from psilocybin literature.

### 8. Come-Up Duration (Minor Flag)
Seed data: come_up 1.5–3 hours. Carhart-Harris et al. (2016) reported effects detectable 30–60 min, peak 2–3h — suggesting come_up from onset to peak is ~1–2.5 hours, which is within the seed data range but on the shorter end. No contradiction, but worth noting in the article that come-up duration includes progressive escalation from initial onset to peak intensity.

### 9. Characterization Field ("emerging")
The seed data characterizes psilocin as "emerging" — this appears to be a legacy or data-entry artifact. Psilocin was isolated in 1959, has hundreds of published studies, and is a well-characterized classical psychedelic. The "emerging" classification likely reflects the Psychedex system's characterization of renewed clinical research interest, not chemical novelty. **FLAG for editorial review.**

### 10. Interactions Field (Empty in Seed Data)
The interactions field is empty in seed data. Key interactions identified in research:
- Lithium/mood stabilizers: significantly increased harm risk (strong contraindication)
- SSRI: no PK interaction; may attenuate adverse effects
- 5-HT₂A antagonists/atypical antipsychotics: blocks psychedelic effects
- MAO inhibitors: theoretically significant (unconfirmed)
The generation agent should propose these interactions for structured data entry.

### 11. Contraindications Field (Empty in Seed Data)
Empty in seed data. Well-supported contraindications from published literature:
- Personal/family history of psychosis, schizophrenia, mania
- Concurrent lithium or mood stabilizer use
- Uncontrolled cardiovascular disease or hypertension
- Current psychiatric crisis without professional support