generation run 2026-05-03
59 min completedmodel pipeline-v5plan not recordedrun/7e6e3e5c…Selection
Verification
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- seen / partial
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The model's own caveats
none raised on this run
Reproduce
- inputs
- 40 source keys (listed under Sources)
- plan
- not recorded — template version, prompt hash and git SHA are written from 2026-09 onward
- model
- pipeline-v5
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- none — agent transcripts are persisted from 2026-09 onward
18 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubMed | psilocybin safety tolerability adverse events systematic review | 5 | 2 | Meta-analyses with pooled adverse event data across controlled studies |
| 2 | OpenAlex | psilocin psilocybin serotonin receptor psychedelic mechanism | 10 | 6 | Selected most-cited foundational papers on mechanism, clinical effects, and brain imaging |
| 3 | PubMed | psilocin pharmacokinetics human metabolism | 10 | 5 | Systematic reviews and primary PK studies directly relevant to psilocin disposition |
| 4 | PubMed | psilocybin tolerance serotonin cross-tolerance hallucinogen | 4 | 3 | Key reviews on tolerance mechanisms and cross-tolerance among serotonergic hallucinogens |
| 5 | PubChem | psilocin | 1 | 1 | Primary chemical identity verification — confirms formula, weight, InChIKey absent from brief seed data |
| 6 | OpenAlex | psilocybin psilocin safety toxicity adverse events controlled study | 8 | 3 | Safety data in controlled clinical settings, including adverse event documentation |
| 7 | OpenAlex | psilocybin lithium SSRI drug interaction hallucinogen | 8 | 2 | Primary evidence for drug-drug interactions relevant to psilocin |
| 8 | PubMed | psilocin receptor binding affinity serotonin pharmacology | 11 | 5 | Selected primary receptor pharmacology papers with Ki/EC50 data and mechanism of action studies |
| 9 | WebSearch | psilocin physical properties melting point solubility | 10 | 2 | Physical property data not available via structured APIs |
| 10 | ClinicalTrials.gov | psilocybin psilocin treatment depression anxiety | 13 | 5 | Selected diverse trials across phases and conditions; CYB003 is deuterated psilocin analog in Phase 3 |
| 11 | PubMed | PMID 39812743, 40284409, 30685771, 39751877, 36049313 | 5 | 5 | All are primary sources for key PK and pharmacology data |
| 12 | WebSearch | psilocin LD50 lethal dose 50 mg/kg mouse rat | 10 | 1 | Primary source for LD50 data |
| 13 | WebSearch | psilocin discovery history Albert Hofmann Troxler 1959 isolation synthesis | 10 | 2 | Primary sources for discovery history |
| 14 | WebSearch | psilocin legal status Schedule I US UK DEA controlled substance | 10 | 2 | Legal status across major jurisdictions |
| 15 | PubMed | Becker Holze escitalopram psilocybin interaction pharmacokinetics | 1 | 1 | Key SSRI-psilocin interaction data with PK confirmation |
| 16 | WebSearch | Oregon Measure 109 psilocybin Australia Schedule 8 rescheduling 2023 | 10 | 2 | Recent landmark legal changes relevant to article |
| 17 | PubMed · absence | psilocybin psilocin LD50 lethal dose animal | 0 | — | Fell back to web search for LD50 data |
| 18 | PubChem API | CID 4980 SMILES InChIKey | 1 | 1 | Chemical identity verification for article |
83 claims by section — every cited sentence, checked against its source
safety24 · 19 ok
The LD₅₀ in mice is 293.07 ± 1.02 mg/kg by intraperitoneal injectionsupported
Psilocin LD50: 293.07 mg/kg (IP, mice). toxins7041018
Pooled data demonstrate clinically relevant blood pressure elevations: systolic BP increase of approximately +19 mmHg and diastolic BP increase of approximately +8.66 mmHg across dose rangessupported
Systolic BP +19 mmHg, diastolic +8.66 mmHg. jcm11040938
In the COMPASS Phase 2 trial (N = 233), 77% of participants experienced treatment-emergent adverse events — predominantly headache, nausea, and dizzinesssupported
Adverse events in 77%: headache, nausea, dizziness. nejmoa2206443
In Carhart-Harris et al.'s open-label study (N = 12), all patients experienced transient anxiety at onset, 9/12 transient confusion, 4/12 nausea, 4/12 headache — no serious or unexpected adverse events occurredsupported
Transient anxiety at onset in all 12 patients. Transient confusion (9), nausea (4), headache (4). No serious adverse events. s2215-0366(16)30065-7
Johnson et al. documented dose-dependent delayed headaches occurring the day after administration in healthy volunteers.supported
Dose-dependent delayed transient headaches after psilocybin. j.drugalcdep.2011.10.029
Claim in safety — inconclusiveinconclusiveworking →
Johnson et al.'s 8-factor Controlled Substances Act analysis identified exacerbation of psychosis in predisposed individuals as a primary harm concern, though the overall scope of harm remains low compared to other scheduled substances.supported
Potential harms: dangerous behavior in unsupervised users; exacerbation of psychotic disorders. Scope of use and harms low vs prototypical drugs. j.neuropharm.2018.05.012
HPPD — characterized by prolonged or recurrent perceptual symptoms including geometric pseudo-hallucinations, halos, afterimages, visual snow, and altered motion perception — is associated with psilocin/psilocybin usesupported
HPPD associated with LSD, psilocybin, mescaline, cannabis, MDMA. Symptoms include geometric pseudo-hallucinations, halos, afterimages, flashes of color. fpsyt.2017.00240
Simonsson et al. surveyed 613 psychedelic users in a US nationally representative sample: 8.9% of lifetime users reported functional impairment lasting more than one day, and 2.6% sought medical or psychiatric assistancesupported
Of 613 lifetime classic psychedelic users: 8.9% functional impairment >1 day; 2.6% sought medical help. j.jad.2023.01.073
In the COMPASS Phase 2 trial, suicidal ideation or self-injury occurred across all dose groups including the 1 mg control, suggesting this finding reflects baseline treatment-resistant depression risk rather than a drug-specific effectsupported
Suicidal ideation occurred in all dose groups. nejmoa2206443
Claim in safety — inconclusiveinconclusiveworking →
Complete cross-tolerance exists between psilocin, lsd, and mescaline, mediated by the shared 5-HT₂A downregulation mechanismsupported
5-HT2A receptor is primary site of hallucinogen action. Cross-tolerance among serotonergic hallucinogens. j.bbr.2014.07.016
Complete cross-tolerance exists between psilocin, lsd, and mescaline, mediated by the shared 5-HT₂A downregulation mechanismsupported
5-HT2A is primary target but non-5-HT2 receptors also contribute to psilocin effects. Cross-tolerance among hallucinogens documented. j.neuropharm.2011.01.017
Johnson et al.'s comprehensive 8-factor analysis concluded:supported
Comprehensive 8-factor CSA analysis. j.neuropharm.2018.05.012
Claim in safety — inconclusiveinconclusiveworking →
Escitalopram pretreatment (10–20 mg/day for 14 days) did not alter psilocin pharmacokinetics but significantly reduced adverse effects (anxiety, cardiovascular stress, bad drug effects) without diminishing positive mood effectssupported
Escitalopram did not alter psilocin pharmacokinetics. Escitalopram reduced anxiety and adverse cardiovascular effects. cpt.2487
In a separate study, 25 mg psilocybin administered to 19 patients on concurrent SSRIs produced a mean MADRS improvement of −14.9 with no serious adverse events.supported
25 mg psilocybin with concurrent SSRI. 19 participants... No serious TEAEs or increased suicidal ideation. MADRS -14.9 at Week 3. s41386-023-01648-7
Ketanserin completely blocks all psychedelic effects of psilocybin in humans — visual hallucinations, altered consciousness, alpha oscillation changes, and N170 suppressionsupported
All effects blocked by 5-HT2A antagonist ketanserin. 5-HT2A activation overwhelms stimulus-driven cortical excitation via alpha modulation. Key mechanism for visual hallucinations. jneurosci.3007-12.2013
Claim in safety — not_supportednot supportedworking →
{{Warning}}MAO-A accounts for 80.9% of hepatic psilocin clearancesupported
MAO-A mediates 80.9% of total hepatic psilocin metabolism. s00204-024-03952-7
Claim in safety — inconclusiveinconclusiveworking →
Concurrent lithium or mood stabilizer use is an absolute contraindication based on epidemiological evidence of significantly increased harmsupported
Lithium co-use and mood stabilizers significantly associated with difficulty and risk of harm. j.jad.2023.01.073
MAO inhibitor co-administration is a relative contraindication based on metabolic pathway inference.supported
MAO-A mediates 80.9% of total hepatic psilocin metabolism. Extensive extrahepatic MAO-A clearance. s00204-024-03952-7
Uncontrolled hypertension or significant cardiovascular disease represents a relative contraindication given documented systolic BP elevations of ~19 mmHg.supported
Systolic BP +19 mmHg, diastolic +8.66 mmHg. jcm11040938
pharmacology15 · 11 ok
This mechanism is both necessary and sufficient for the 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.supported
All effects blocked by 5-HT2A antagonist ketanserin. 5-HT2A activation overwhelms stimulus-driven cortical excitation via alpha modulation. Key mechanism for visual hallucinations. jneurosci.3007-12.2013
Claim in pharmacology — not_supportednot supportedworking →
Competition binding in human brain tissue yields Ki values of 120–173 nM at 5-HT₂A, 79–311 nM at 5-HT₂C, and 146–152 nM at 5-HT₁Asupported
Psilocin Ki at 5-HT2A 120-173 nM, 5-HT2C 79-311 nM, 5-HT1A 152-146 nM (human and mice brain). j.biopha.2022.113612
Psilocin functions as a full-to-partial agonist at 5-HT₂A, with binding affinity lower than LSD but correlating with reported psychoactive dosessupported
Psilocin and other tryptamines interact with 5-HT2A as partial/full agonists. Psilocin binding affinity at 5-HT2A lower than LSD. j.euroneuro.2016.05.001
Uniquely among classical psychedelics, psilocin also interacts with the serotonin transporter (SERT/5-HTT), predicting partial MDMA-like properties in addition to hallucinogenic effects.supported
Psilocin interacts with serotonin transporter (5-HTT). Tryptamine profile predicts hallucinogenic + MDMA-like properties. j.euroneuro.2016.05.001
PET imaging demonstrates that psilocybin (acting via psilocin) produces dose-related 5-HT₂A receptor occupancy up to 72% at clinically relevant doses, with plasma psilocin levels linearly associated with both receptor occupancy and subjective intensity.partially supported
PET imaging: psilocybin causes dose-related 5-HT2AR occupancy up to 72%. Plasma psilocin levels and 5-HT2AR occupancy closely correlated with subjective intensity ratings. Non-linear dose-response relationship. s41386-019-0324-9
Moliner et al. demonstrated that psilocin directly binds TrkB (the BDNF receptor) within the transmembrane domain of TrkB dimers at affinities approximately 1,000-fold higher than conventional antidepressants (fluoxetine, ketamine)supported
Psilocin directly binds TrkB with affinities 1000-fold higher than other antidepressants. s41593-023-01316-5
Vargas et al. showed that intracellular 5-HT₂A receptors — not plasma membrane receptors — mediate the plasticity-promoting properties of psychedelics including psilocinsupported
Intracellular 5-HT2ARs mediate plasticity-promoting properties of psychedelics including psilocin. Explains why serotonin does not engage similar plasticity mechanisms. science.adf0435
The 5-HT₁A agonist buspirone reduces visionary restructuralization and oceanic boundlessness scores, suggesting 5-HT₁A partially dampens visual intensity of the psychedelic statesupported
Buspirone (5-HT1A agonist) reduced visionary restructuralization and oceanic boundlessness from psilocybin. j.euroneuro.2016.01.005
Claim in pharmacology — inconclusiveinconclusiveworking →
Psilocybin functions as a pure prodrug: PBPK modeling demonstrates complete or near-complete dephosphorylation to psilocin by alkaline phosphatase before systemic circulationsupported
Psilocybin assumes complete conversion to psilocin before systemic circulation. s41598-025-98202-w
Williamson et al. confirmed via BRET-based binding assay at 7 serotonin receptor subtypes that only psilocin shows discernible receptor binding — the metabolites psilocin-O-glucuronide and 4-hydroxyindole-3-acetic acid (4-HIAA) are pharmacologically inert.supported
BRET-based binding assay: only psilocin showed discernible binding at 7 serotonin receptor subtypes tested. Psilocin-O-glucuronide and 4-HIAA pharmacologically inert at receptors. acschemneuro.5c00879
MAO-A is the primary Phase I enzyme, accounting for 80.9% of total hepatic psilocin metabolismsupported
MAO-A mediates 80.9% of total hepatic psilocin metabolism. s00204-024-03952-7
Claim in pharmacology — not_supportednot supportedworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
neuroscience9 · 9 ok
Carhart-Harris et al. proposed this DMN dissolution as the neural correlate of ego-dissolutionsupported
DMN collapse and MTL decoupling characterize psychedelic state. fnhum.2014.00020
Siegel et al. provided the most detailed neuroimaging characterization to date, demonstrating persistent DMN desynchronization following psilocybin administration that correlated with therapeutic outcome measures.supported
Persistent hippocampal-DMN connectivity decrease for weeks. Individual FC changes linked to subjective experience. s41586-024-07624-5
The alpha-band suppression is specifically 5-HT₂A-dependent, as demonstrated by its complete blockade with ketanserin.supported
Psilocybin at 215 mcg/kg decreased parieto-occipital alpha power and N170 potentials. All effects blocked by 5-HT2A antagonist ketanserin. jneurosci.3007-12.2013
Tyls et al. confirmed psilocin-specific broadband EEG desynchronization in rats using direct psilocin administration, establishing the translational validity of the observation.supported
Psilocin directly administered; induces broadband EEG desynchronization in rats. fnins.2023.1152578
TrkB-BDNF axis: Direct allosteric potentiation of TrkB by psilocin enhances endogenous BDNF signaling, promoting dendritic spine growth and synaptogenesissupported
Psilocin directly binds TrkB with affinities 1000-fold higher than other antidepressants. Plasticity and antidepressant effects depend on TrkB binding independent of 5-HT2A activation. s41593-023-01316-5
Intracellular 5-HT₂A signaling: Activation of intracellular 5-HT₂A receptors triggers mTOR-dependent signaling cascades driving structural plasticitysupported
Intracellular 5-HT2ARs mediate plasticity-promoting properties of psychedelics including psilocin. science.adf0435
The entropic brain hypothesis positions the psychedelic state as an increase in neural entropy — measured as signal diversity, Lempel-Ziv complexity, or functional connectivity variance — from a constrained baseline toward a more disordered but potentially more flexible state.supported
Psilocybin neuroimaging data: elevated brain entropy. DMN collapse and MTL decoupling characterize psychedelic state. fnhum.2014.00020
The classification of psilocin as a psychoplastogen — a compound that rapidly promotes structural and functional neural plasticity — is supported by the dual TrkB and intracellular 5-HT₂A mechanisms described abovesupported
Plasticity and antidepressant effects depend on TrkB binding independent of 5-HT2A activation. s41593-023-01316-5
Optimal receptor occupancy for therapy: Madsen et al. demonstrated up to 72% 5-HT₂A occupancy — is this the therapeutic ceiling, or would higher occupancy improve outcomes?supported
PET imaging: psilocybin causes dose-related 5-HT2AR occupancy up to 72%. s41386-019-0324-9
summary9 · 7 ok
Claim in summary — inconclusiveinconclusiveworking →
Following decades of prohibition after US Schedule I placement in 1970, the compound re-entered clinical investigation with Griffiths et al.'s landmark 2006 trialsupported
Landmark double-blind RCT. 30 mg/70 kg psilocybin... Mystical-type experience confirmed. pmid:16826400
Psilocin acts as a full-to-partial agonist at 5-HT₂A receptors (Ki = 120–173 nM in human brain tissue) with secondary activity at 5-HT₂C (Ki = 79–311 nM) and 5-HT₁A (Ki = 146–152 nM)supported
Psilocin Ki at 5-HT2A 120-173 nM, 5-HT2C 79-311 nM, 5-HT1A 152-146 nM (human and mice brain). j.biopha.2022.113612
Pretreatment with the selective 5-HT₂A antagonist ketanserin completely abolishes all psychedelic effectssupported
All effects blocked by 5-HT2A antagonist ketanserin. jneurosci.3007-12.2013
A second, independent mechanism — direct high-affinity binding to TrkB (the BDNF receptor) at approximately 1,000-fold greater affinity than conventional antidepressants — mediates neuroplasticity effects separable from the hallucinogenic experience.supported
Psilocin directly binds TrkB with affinities 1000-fold higher than other antidepressants. Plasticity and antidepressant effects depend on TrkB binding independent of 5-HT2A activation. s41593-023-01316-5
Claim in summary — not_supportednot supportedworking →
Psilocin exhibits a therapeutic index on the order of 1,000:1 (LD₅₀ = 293 mg/kg IP in mice versus psychoactive doses <0.35 mg/kg in humans)partially supported
Psilocin LD50: 293.07 mg/kg (IP, mice). toxins7041018
Rapid tolerance develops via 5-HT₂ receptor downregulation, with near-complete resolution within 96 hours and full reset by 7 dayspartially supported
Psilocybin (1.0 mg/kg for 8 days) produced significant decrease in 5-HT2 binding. 5-HT2 downregulation parallels behavioral tolerance development. pmid:1969270
Oral bioavailability (52.7 ± 20%) and the contribution of extrahepatic MAO-A metabolism to total clearance remain incompletely characterized in diverse human populations.supported
bioavailability 52.7±20%... CYP2D6/CYP3A4 primary; MAO-A secondary. pharmaceutics17040411
clinical-evidence6 · 3 ok
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Goodwin et al. explored psilocybin 25 mg in 19 patients maintaining SSRI treatment:supported
25 mg psilocybin with concurrent SSRI. 19 participants. s41386-023-01648-7
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Randomized waitlist-controlled trial of psilocybin-assisted therapy for major depressive disorder.supported
RCT, 27 participants. Two psilocybin sessions (20 mg/70 kg then 30 mg/70 kg). Large effect sizes (Cohen d=2.5-2.6). jamapsychiatry.2020.3285
Romeo et al.'s meta-analysis pooling over 1,000 psychedelic administrations across 30 studies documented:supported
Meta-analysis of 30 studies (2000-2022). 9 serious adverse events in >1000 psychedelic administrations. j.psychres.2024.115880
pharmacokinetic-detail6 · 4 ok
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Escitalopram (10–20 mg/day, 14 days) does not alter psilocin pharmacokinetics, confirming that SERT inhibition alone does not affect psilocin clearance pathways.supported
Escitalopram did not alter psilocin pharmacokinetics. cpt.2487
PBPK modeling confirms complete or near-complete conversion to psilocin before reaching systemic circulation, establishing psilocybin as a pure prodrug with no independent pharmacological activitysupported
Psilocybin assumes complete conversion to psilocin before systemic circulation. s41598-025-98202-w
Oral bioavailability of the active metabolite psilocin is 52.7 ± 20%, though this figure derives from a single study with high inter-individual variability.supported
bioavailability 52.7±20% pharmaceutics17040411
Chen et al. elucidated the complete Phase I metabolic pathway:supported
MAO-A mediates 80.9% of total hepatic psilocin metabolism. Intermediate metabolite 4-HIA identified for first time. s00204-024-03952-7
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
receptor-pharmacology5 · 5 ok
The following Ki values derive from competition binding studies in human and mouse brain tissue homogenates:supported
Psilocin Ki at 5-HT2A 120-173 nM, 5-HT2C 79-311 nM, 5-HT1A 152-146 nM (human and mice brain). j.biopha.2022.113612
Rickli et al. independently confirmed 5-HT₂A agonism and characterized psilocin's interaction with SERT — a property not shared by lsd or mescaline, and one that predicts partial empathogenic properties alongside the hallucinogenic signature.supported
Psilocin interacts with serotonin transporter (5-HTT). Tryptamine profile predicts hallucinogenic + MDMA-like properties. j.euroneuro.2016.05.001
Psilocin binds the transmembrane domain of TrkB receptor dimers as a positive allosteric modulator of BDNF signalingsupported
Psilocin directly binds TrkB with affinities 1000-fold higher than other antidepressants. Plasticity and antidepressant effects depend on TrkB binding independent of 5-HT2A activation. s41593-023-01316-5
Vargas et al. demonstrated that psilocin's plasticity-promoting effects require activation of intracellular 5-HT₂A receptors, not surface-expressed receptorssupported
Intracellular 5-HT2ARs mediate plasticity-promoting properties of psychedelics including psilocin. Explains why serotonin does not engage similar plasticity mechanisms. science.adf0435
The 5-HT₁A agonist buspirone attenuates visionary restructuralization and oceanic boundlessness without eliminating the psychedelic state, suggesting a modulatory rather than permissive role.supported
Buspirone (5-HT1A agonist) reduced visionary restructuralization and oceanic boundlessness from psilocybin. 5-HT1A modulates intensity of psilocin effects. j.euroneuro.2016.01.005
comparative-pharmacology4 · 3 ok
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Psilocybin is a pure prodrug with no independent receptor activitysupported
BRET-based binding assay: only psilocin showed discernible binding at 7 serotonin receptor subtypes tested. acschemneuro.5c00879
Psilocin's TrkB binding affinity is approximately 1,000-fold higher than fluoxetine or ketaminesupported
Psilocin directly binds TrkB with affinities 1000-fold higher than other antidepressants. s41593-023-01316-5
Psilocin shows complete cross-tolerance with LSD and mescaline, mediated by shared 5-HT₂A receptor downregulationsupported
5-HT2A receptor is primary site of hallucinogen action. Cross-tolerance among serotonergic hallucinogens. j.bbr.2014.07.016
history4 · 2 ok
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
This was followed by Carhart-Harris et al.'s 2016 open-label feasibility study demonstrating rapid antidepressant effects in treatment-resistant depression, and the COMPASS Pathways Phase 2 RCT published in the New England Journal of Medicine in 2022.supported
Marked depression reduction at 1 week and 3 months. s2215-0366(16)30065-7
This was followed by Carhart-Harris et al.'s 2016 open-label feasibility study demonstrating rapid antidepressant effects in treatment-resistant depression, and the COMPASS Pathways Phase 2 RCT published in the New England Journal of Medicine in 2022.supported
Phase 2 RCT. 25 mg psilocybin significantly reduced MADRS at 3 weeks vs 1 mg control. nejmoa2206443
chemistry1 · 0 ok
Claim in chemistry — inconclusiveinconclusiveworking →