generation run 2026-09-05
142 min completedmodel pipeline-v5plan v5@3042d1d · aa4a2f8ca809run/b52b637d…draft
articleDraftworkingsimplify
articleSimplifiedworkingother
articleFullworkingSelection
Verification
- record
- seen / partial
- working
The model's own caveats
- safety_data_unverified
- sparse_evidence
- structural_inference
2 further caveats recorded as free text — readable on the working page
Reproduce
- inputs
- 29 source keys (listed under Sources)
- plan
- v5@3042d1d · aa4a2f8ca809
- model
- pipeline-v5
- streams
- none — agent transcripts are persisted from 2026-09 onward
20 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubMed | psilocin 4-hydroxy-DMT serotonin 5-HT2A receptor binding pharmacology | 9 | 8 | Background pharmacology for psilocin relevant to understanding 4-PrO-DMT as a prodrug; 5-HT2A structural biology informs binding mechanism |
| 2 | ClinicalTrials.gov · absence | 4-PrO-DMT psilocin analog | 0 | — | No trials found — consistent with emerging/research chemical status |
| 3 | PubMed · absence | psilocin ester analogs pharmacology serotonin receptor | 0 | — | Query too narrow; will reformulate |
| 4 | PubChem | CID 155907598 | 1 | 1 | Core chemical identity verification |
| 5 | PubMed | 4-PrO-DMT O-propionylpsilocin | 2 | 2 | Both directly relevant — 37082754 is the primary pharmacology study for 4-PrO-DMT; 40418247 provides plasma detection method and prodrug metabolic context |
| 6 | PubMed | Raithatha psilocin prodrug novel psilocybin pharmacological properties 2023 | 1 | 1 | — |
| 7 | Wikipedia | 4-PrO-DMT | 1 | 1 | — |
| 8 | Web search | 4-PrO-DMT legal status UK Misuse of Drugs Act psilocin ester | 5 | 2 | — |
| 9 | Crossref DOI verification | DOI verification for key papers | 4 | 1 | — |
| 10 | PsychonautWiki | 4-PrO-DMT dosage effects | 1 | 1 | — |
| 11 | PubChem | CID 155907598 - chemical identity verification | 1 | 1 | — |
| 12 | Cayman Chemical | 4-propanoyloxy-DMT product 29951 physical properties | 1 | 1 | — |
| 13 | OpenAlex | psilocybin lithium seizure psychedelic contraindication interaction | 8 | 4 | — |
| 14 | PubMed | psilocybin pharmacokinetics oral bioavailability systematic review | 1 | 1 | — |
| 15 | Web search/Wikipedia | 4-PrO-DMT legal status UK Germany Australia Canada | 8 | 1 | — |
| 16 | PubMed | psilocin CYP2D6 CYP3A4 MAO metabolism drug interaction | 2 | 1 | — |
| 17 | ClinicalTrials.gov · absence | psilocin prodrug 4-propionyloxy tryptamine psychedelic | 0 | — | Confirms no human clinical trials |
| 18 | PubMed | psilocin LD50 acute toxicity psilocybin mushrooms mice | 1 | 1 | — |
| 19 | PMC/PubMed | psilocin Ki 5-HT2A 5-HT1A 5-HT2C receptor comparison | 1 | 1 | — |
| 20 | PMC open access | Glatfelter 2023 4-PrO-DMT receptor binding Ki values ED50 HTR mice | 1 | 3 | — |
88 claims by section — every cited sentence, checked against its source
safety33 · 28 ok
The reference acute toxicity value for the pharmacologically active metabolite psilocin is an LD₅₀ of 293 mg/kg (intraperitoneal, mice)supported
Psilocin LD50: 293.07 mg/kg (IP, mice). toxins7041018
Claim in safety — inconclusiveinconclusiveworking →
Dependence: Serotonergic psychedelics as a class do not produce physical or psychological dependence syndromessupported
8-factor CSA analysis of psilocybin abuse potential. Limited reinforcing effects, low self-administration. j.neuropharm.2018.05.012
In mice, 4-PrO-DMT produces psychedelic-like effects (head-twitch response) at 0.3–3 mg/kg s.c., while 5-HT₁A-mediated sedation and hypothermia emerge at 3–30 mg/kg s.c. — consistent with the general safety margin observed across the psilocin class.supported
5-HT2A-mediated HTR (0.3-3 mg/kg s.c.) and 5-HT1A-mediated hypothermia and hypolocomotion (3-30 mg/kg s.c.) acsptsci.2c00222
Transient physiological effects expected at psychoactive doses include dose-dependent increases in systolic blood pressure and heart rate, pupil dilation (mydriasis), and nauseasupported
Practical guidance for psilocybin therapy including pharmacology, pharmacokinetics, dosing, contraindications, adverse events, drug interactions. fpsyt.2022.1040217
Claim in safety — inconclusiveinconclusiveworking →
Chronic 5-HT₂B agonism is the established mechanism underlying cardiac valvulopathy associated with ergotamine derivatives and the weight-loss drug fenfluraminesupported
5-HT2A/2B/4 receptor concerns. Clinical trials show relative cardiovascular safety in healthy volunteers. s43440-023-00539-4
Three factors mitigate the relevance of this finding: 4-PrO-DMT is a prodrug that converts to psilocin (which has lower 5-HT₂B affinity); psychedelic use is typically intermittent rather than chronic; and clinical psychedelic studies in healthy volunteers have demonstrated relative cardiovascular safetysupported
Clinical trials show relative cardiovascular safety in healthy volunteers. s43440-023-00539-4
Acute psychological distress — including anxiety, confusion, paranoia, and transient psychotic-like symptoms — can occur at high doses or in unprepared individualssupported
Practical guidance for psilocybin therapy including pharmacology, pharmacokinetics, dosing, contraindications, adverse events, drug interactions. fpsyt.2022.1040217
Hallucinogen persisting perception disorder (HPPD) — characterized by enduring perceptual disturbances (visual snow, halos, trailing phenomena, geometric afterimages) persisting weeks to months after drug use — has been documented across the serotonergic hallucinogen class including psilocybinsupported
HPPD is a rare disorder with enduring perceptual symptoms after psychedelic use. s41598-024-82216-x
Persons with personal or family history of schizophrenia, schizoaffective disorder, or bipolar I disorder are at elevated risk for prolonged or severe psychotic episodes and should not use 4-PrO-DMT.supported
Practical guidance for psilocybin therapy including pharmacology, pharmacokinetics, dosing, contraindications, adverse events, drug interactions. fpsyt.2022.1040217
At the class level, repeated 5-HT₂A agonism causes receptor downregulation and functional desensitization, generating rapid tolerance (tachyphylaxis) within days of consecutive usepartially supported
Beta-arrestin-biased 5-HT2A agonists block psychedelic effects and induce receptor downregulation and tachyphylaxis (tolerance). s41467-023-44016-1
At the class level, repeated 5-HT₂A agonism causes receptor downregulation and functional desensitization, generating rapid tolerance (tachyphylaxis) within days of consecutive usesupported
Covers tolerance, cross-tolerance, and therapeutic mechanisms. pharmrev.120.000056
Dependence: Serotonergic psychedelics as a class do not produce physical or psychological dependence syndromessupported
Serotonergic hallucinogens do not produce dependence syndromes and appear to have low risk of misuse. j.psc.2012.04.002
The addiction potential of the psilocin class is assessed as low based on the eight-factor Controlled Substances Act analysis.supported
8-factor CSA analysis of psilocybin abuse potential. Limited reinforcing effects, low self-administration. Schedule IV may be appropriate if approved as medicine. j.neuropharm.2018.05.012
Serotonergic psychedelics without concurrent MAOI use are classified as low risk for serotonin toxicity; the addition of a proserotoninergic drug — especially an irreversible MAOI — transforms the risk profilesupported
True serotonin toxicity requires MAOI combination. Psychedelics alone are low-risk. s00213-021-05876-x
A case report documented hypertensive emergency and myocardial infarction in a patient taking tranylcypromine (MAOI) and dextroamphetamine who consumed psilocybin mushroomssupported
Case report: severe hypertension and MI following combination of psilocybin mushrooms, dextroamphetamine, and tranylcypromine (MAOI). 02791072.2024.2368617
Lithium: Analysis of 62 reports of classic psychedelics combined with lithium found that 47% involved seizures and 39% required medical attentionsupported
47% of 62 lithium+psychedelic reports involved seizures; 39% required medical attention. a-1524-2794
By contrast, zero of 34 lamotrigine + psychedelic reports involved seizuressupported
None of 34 lamotrigine reports involved seizures. a-1524-2794
Tricyclic antidepressants may enhance intensity through serotonin and norepinephrine reuptake inhibition.supported
Practical guidance for psilocybin therapy including pharmacology, pharmacokinetics, dosing, contraindications, adverse events, drug interactions. fpsyt.2022.1040217
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
CYP2D6 genotype alone does not significantly influence psilocin levels, suggesting these interactions are of low-to-moderate clinical significance.supported
CYP2D6 genotype did not influence psilocin plasma concentrations in humans. fphar.2024.1391689
Personal or family history of schizophrenia, psychosis, or bipolar I disorder — risk of prolonged psychotic episodes or maniasupported
Practical guidance for psilocybin therapy including pharmacology, pharmacokinetics, dosing, contraindications, adverse events, drug interactions. fpsyt.2022.1040217
Current lithium use — 47% seizure rate in case reports involving classic psychedelics combined with lithium; no mechanism identifiedsupported
47% of 62 lithium+psychedelic reports involved seizures; 39% required medical attention. Mechanism unknown. a-1524-2794
Current MAOI use — serotonin toxicity and hypertensive emergency; case-report-documented myocardial infarctionsupported
True serotonin toxicity requires MAOI combination. Psychedelics alone are low-risk. s00213-021-05876-x
Current MAOI use — serotonin toxicity and hypertensive emergency; case-report-documented myocardial infarctionsupported
Case report: severe hypertension and MI following combination of psilocybin mushrooms, dextroamphetamine, and tranylcypromine (MAOI). 02791072.2024.2368617
Pregnancy or breastfeeding — no safety data existsupported
Practical guidance for psilocybin therapy including pharmacology, pharmacokinetics, dosing, contraindications, adverse events, drug interactions. fpsyt.2022.1040217
Claim in safety — inconclusiveinconclusiveworking →
Active cardiovascular disease — transient hypertension and tachycardia are class effects of psilocin; the unresolved 5-HT₂B affinity of 4-PrO-DMT (Ki = 17 nM) adds additional uncertainty for cardiac patientssupported
5-HT2A/2B/4 receptor concerns. Clinical trials show relative cardiovascular safety in healthy volunteers. s43440-023-00539-4
Borderline personality disorder — emotional lability may be intensifiedsupported
Practical guidance for psilocybin therapy including pharmacology, pharmacokinetics, dosing, contraindications, adverse events, drug interactions. fpsyt.2022.1040217
Current TCA use — potential enhancement of psychedelic intensitysupported
Practical guidance for psilocybin therapy including pharmacology, pharmacokinetics, dosing, contraindications, adverse events, drug interactions. fpsyt.2022.1040217
Current SSRI use — blunted effects may lead to compensatory dose escalationsupported
Practical guidance for psilocybin therapy including pharmacology, pharmacokinetics, dosing, contraindications, adverse events, drug interactions. fpsyt.2022.1040217
pharmacology20 · 12 ok
Claim in pharmacology — inconclusiveinconclusiveworking →
Upon administration, plasma and tissue esterases cleave the propionyl ester at the 4-position of the indole ring, releasing psilocin as the pharmacologically active metabolitesupported
Confirms prodrug-to-psilocin metabolic pathway. bkaf045
Upon administration, plasma and tissue esterases cleave the propionyl ester at the 4-position of the indole ring, releasing psilocin as the pharmacologically active metabolitesupported
Screened 28 novel psilocin prodrugs with cleavable groups at the 4-hydroxy position to modulate metabolic processing. acs.jmedchem.3c01225
This prodrug relationship parallels the conversion of psilocybin to psilocin via alkaline phosphatase-mediated dephosphorylation, and of psilacetin to psilocin via esterase hydrolysis.supported
Alkaline phosphatase dephosphorylation, MAO metabolism, BBB permeability. bph.16466
The psychedelic effect of psilocin at the 5-HT₂A receptor is mediated by Gq/11 protein-coupled signaling rather than β-arrestin2 recruitment. 5-HT₂A-Gq efficacy — not β-arrestin2 recruitment — predicts psychedelic potential in the head-twitch response model; β-arrestin-biased agonists suppress the psychedelic response and induce tachyphylaxissupported
5-HT2A-Gq (not beta-arrestin2) predicts psychedelic potential. Beta-arrestin-biased 5-HT2A agonists block psychedelic effects and induce receptor downregulation and tachyphylaxis (tolerance). s41467-023-44016-1
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
At higher doses (≥3 mg/kg), concurrent 5-HT₁A activation attenuates the head-twitch response — consistent with the inhibitory interplay between 5-HT₂A and 5-HT₁A observed across tryptamine psychedelics.supported
5-HT2A-mediated HTR (0.3-3 mg/kg s.c.) and 5-HT1A-mediated hypothermia and hypolocomotion (3-30 mg/kg s.c.) acsptsci.2c00222
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Hypothermia was blocked and reversed by the 5-HT₁A antagonist WAY100635.supported
5-HT1A blockade reversed hypothermia. j.biopha.2022.113612
The following pharmacokinetic parameters are derived from psilocin (the active metabolite) and are applicable by structural analogy from published psilocybin studies.supported
Systematic review of 14 psilocybin PK studies (112 healthy humans). Psilocin Tmax 1.8-4h, bioavailability 52.7±20%, Vd 277-1016 L, t1/2 1.5-4h. pharmaceutics17040411
The following pharmacokinetic parameters are derived from psilocin (the active metabolite) and are applicable by structural analogy from published psilocybin studies.supported
In vitro and in vivo metabolism of psilocybin's active metabolite psilocin. fphar.2024.1391689
Claim in pharmacology — inconclusiveinconclusiveworking →
Prodrug activation: 4-PrO-DMT undergoes hydrolysis by plasma and tissue esterases to yield psilocinsupported
Confirms prodrug-to-psilocin metabolic pathway. bkaf045
Oxidative metabolism proceeds primarily through CYP2D6, which metabolizes psilocin to norpsilocin and other oxidized products, and secondarily through CYP3A4supported
CYP2D6 metabolized ~100% and CYP3A4 ~40% of psilocin in vitro. CYP2D6 produces norpsilocin in mice. fphar.2024.1391689
Oxidative deamination by MAO-A yields 4-hydroxyindole-3-acetic acid (4-HIAA) and 4-hydroxytryptophol (4-HTP)supported
Primary metabolism CYP2D6/CYP3A4 plus MAO-A. Metabolites: 4-HIAA and 4-hydroxytryptophol. pharmaceutics17040411
Claim in pharmacology — inconclusiveinconclusiveworking →
CYP2D6 genotype did not significantly influence psilocin plasma concentrations in the studied human population, suggesting robust alternative metabolic pathways buffer genetic variation in CYP2D6 activity.supported
CYP2D6 genotype did not influence psilocin plasma concentrations in humans. fphar.2024.1391689
pharmacokinetic-detail7 · 3 ok
The pharmacokinetic profile presented below is derived from the active metabolite psilocin, characterized in published psilocybin studies.supported
Systematic review of 14 psilocybin PK studies (112 healthy humans). Psilocin Tmax 1.8-4h, bioavailability 52.7±20%, Vd 277-1016 L, t1/2 1.5-4h. pharmaceutics17040411
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Psilocin undergoes a two-step metabolic cascade following release from the 4-PrO-DMT prodrug:supported
Primary metabolism CYP2D6/CYP3A4 plus MAO-A. Metabolites: 4-HIAA and 4-hydroxytryptophol. pharmaceutics17040411
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
CYP2D6 genotype did not significantly influence psilocin plasma concentrations in the studied human population, suggesting that glucuronidation and MAO-A-mediated deamination provide sufficient alternative clearance to buffer CYP2D6 genetic polymorphism.supported
CYP2D6 genotype did not influence psilocin plasma concentrations in humans. MAO-A involved. fphar.2024.1391689
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
neuroscience6 · 4 ok
Psilocin acts primarily through 5-HT₂A receptors densely expressed on layer V pyramidal neurons of the cerebral cortexsupported
Comprehensive review of 5-HT2A receptor pharmacology including structural features, signaling pathways, and psychedelic drug interactions. j.pharmr.2025.100059
The 5-HT₂A-Gq signaling pathway — rather than β-arrestin2 recruitment — is the critical transduction mechanism for psychedelic effects, as demonstrated by the finding that β-arrestin-biased 5-HT₂A agonists fail to produce head-twitch responses in mice.supported
5-HT2A-Gq (not beta-arrestin2) predicts psychedelic potential. Beta-arrestin-biased 5-HT2A agonists block psychedelic effects and induce receptor downregulation and tachyphylaxis (tolerance). s41467-023-44016-1
Concurrent 5-HT₁A agonism — evident in the hypothermic and hypolocomotive effects observed at higher 4-PrO-DMT doses in mice — likely contributes anxiolytic and sedative components to the psychedelic experience.supported
5-HT1A-mediated hypothermia and hypolocomotion (3-30 mg/kg s.c.) acsptsci.2c00222
The result is a state in which entrenched cognitive patterns — including pathological rumination — become temporarily accessible to revision.supported
Comprehensive review of psychedelic mechanisms including neuroplasticity, immunomodulation, and neurotransmitter systems. Covers tolerance, cross-tolerance, and therapeutic mechanisms. pharmrev.120.000056
Claim in neuroscience — inconclusiveinconclusiveworking →
Claim in neuroscience — inconclusiveinconclusiveworking →
comparative-pharmacology4 · 2 ok
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Data for 4-PrO-DMT from Glatfelter et al.; psilocin values from Erkizia-Santamaría et al..supported
Determined receptor binding profiles of various tryptamine-based psychedelics structurally related to psilocybin. acsptsci.2c00222
Data for 4-PrO-DMT from Glatfelter et al.; psilocin values from Erkizia-Santamaría et al..supported
Psilocin Ki at 5-HT2A 120-173 nM, 5-HT2C 79-311 nM, 5-HT1A 152-146 nM. j.biopha.2022.113612
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
receptor-pharmacology4 · 2 ok
The following binding affinities for 4-PrO-DMT were determined by radioligand competition binding at a broad panel of CNS targets using standard NIMH-PDSP protocols:supported
Determined receptor binding profiles of various tryptamine-based psychedelics structurally related to psilocybin. acsptsci.2c00222
Chronic 5-HT₂B agonism is the established mechanism underlying cardiac valvulopathy associated with ergotamine derivatives and fenfluraminesupported
5-HT2A/2B/4 receptor concerns. s43440-023-00539-4
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
summary4 · 1 ok
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
The psilocin reference LD₅₀ (293 mg/kg IP, mice) indicates a wide margin between behaviorally active doses (0.3–3 mg/kg s.c. in the head-twitch response assay) and acutely lethal exposuresupported
Psilocin LD50: 293.07 mg/kg (IP, mice). toxins7041018
Claim in summary — inconclusiveinconclusiveworking →
chemistry3 · 1 ok
Its parent scaffold is the tryptamine backbone — a bicyclic indole ring system fused to an ethylamine side chain — shared by endogenous serotonin and N,N-dimethyltryptaminesupported
SAR review for classic serotonergic hallucinogens (tryptamines, ergolines, phenylalkylamines). Key structural features for activity identified. 7854_2017_475
Claim in chemistry — inconclusiveinconclusiveworking →
Claim in chemistry — inconclusiveinconclusiveworking →
history3 · 0 ok
clinical-evidence2 · 1 ok
The preclinical evidence base consists of a single formal pharmacological study providing receptor binding profiles, crystal structure data, and mouse behavioral characterization (head-twitch response, locomotor activity, body temperature) via subcutaneous administration.supported
Determined receptor binding profiles of various tryptamine-based psychedelics structurally related to psilocybin. 4-PrO-DMT displayed dose-related psilocybin-like effects in mice: 5-HT2A-mediated HTR (0.3-3 mg/kg s.c.) and 5-HT1A-mediated hypothermia and hypolocomotion (3-30 mg/kg s.c.). acsptsci.2c00222
Claim in clinical-evidence — inconclusiveinconclusiveworking →
effects-overview1 · 0 ok
Claim in effects-overview — inconclusiveinconclusiveworking →
legal-status1 · 1 ok
The compound's classification as a novel psychoactive substance in Sweden and potentially under Germany's NpSG reflects the growing trend toward blanket legislation covering structural classes rather than individual compounds.supported
Chapter reviewing tryptamine NPS pharmacology, effects, legal status, and toxicology. Covers 4-substituted tryptamines including psilocin esters. b978-0-12-818788-3.00014-0