4-PrO-DMT
Studies and references cited across this article, graded by evidence strength.
Inconclusive means the cited source neither confirms nor refutes the claim — a lower-confidence badge, not an error.
Data points an editor reviewed and accepted for publication.
Value Provenance
Dosing
oraltrace
| Field | Published | AI Proposed | Confidence |
|---|---|---|---|
| Threshold | — | — | low |
| Low | 5–10 mg | 5–10 mg | low |
| Common | 10–25 mg | 10–25 mg | low |
| Strong | 25–45 mg | 25–45 mg | low |
| Heavy | 45 | 45 | low |
Editorial All dose values from PsychonautWiki community reports only — no controlled human dosing studies exist for 4-PrO-DMT. Research output explicitly instructs: 'propose these as dose estimates with community consensus provenance flag, not verified.' Threshold omitted as no data available. Values align with expected psilocin-equivalent dosing given prodrug molecular weight ratio, but this has not been pharmacokinetically confirmed. | |||
ReasoningReasoningAll dose values from PsychonautWiki community reports only — no controlled human dosing studies exist for 4-PrO-DMT. Research output explicitly instructs: 'propose these as dose estimates with community consensus provenance flag, not verified.' Threshold omitted as no data available. Values align with expected psilocin-equivalent dosing given prodrug molecular weight ratio, but this has not been pharmacokinetically confirmed. Evidence basis: community_consensus_small | |||
Duration
oral
| Field | Published | AI Proposed | Confidence |
|---|---|---|---|
| onsettrace | 20–40 minutes | 20–40 minutes | low |
Editorial Onset range of 20–40 minutes from PsychonautWiki community reports for 4-PrO-DMT oral administration. No pharmacokinetic data confirm this range. The propionyl ester hydrolysis rate has not been measured and may influence onset relative to psilocybin or psilacetin. | |||
ReasoningReasoningOnset range of 20–40 minutes from PsychonautWiki community reports for 4-PrO-DMT oral administration. No pharmacokinetic data confirm this range. The propionyl ester hydrolysis rate has not been measured and may influence onset relative to psilocybin or psilacetin. Evidence basis: community_consensus_small | |||
| totaltrace | 4–8 hours | 4–8 hours | low |
Editorial Total duration of 4–8 hours from PsychonautWiki community reports for 4-PrO-DMT oral administration. No pharmacokinetic data confirm this range. Psilocin elimination half-life of 1.5–4.0 hours (from psilocybin studies) is consistent with this range but not specific to 4-PrO-DMT. | |||
ReasoningReasoningTotal duration of 4–8 hours from PsychonautWiki community reports for 4-PrO-DMT oral administration. No pharmacokinetic data confirm this range. Psilocin elimination half-life of 1.5–4.0 hours (from psilocybin studies) is consistent with this range but not specific to 4-PrO-DMT. Evidence basis: community_consensus_small | |||
Safety
Toxicity Profiletrace
| Field | Published | AI Proposed | Confidence |
|---|---|---|---|
| Acute | low | low | low |
| Chronic | low | low | low |
| Organs Affected | cardiovascular | cardiovascular | low |
Editorial Acute toxicity rated low based on psilocin reference LD50 (293 mg/kg IP mice, Zhuk et al. 2015) indicating wide safety margin — discounted from what might be 'negligible' for psilocin itself because no substance-specific LD50 exists. Chronic toxicity rated low (not negligible) due to 5-HT2B Ki=17 nM cardiac flag (Glatfelter et al. 2023) — no in vivo data, but 5-HT2B agonism is the established valvulopathy mechanism. No adverse event case reports or human toxicity data exist for 4-PrO-DMT. All assessments are structural analogy from psilocin/psilocybin class. | |||
ReasoningReasoningAcute toxicity rated low based on psilocin reference LD50 (293 mg/kg IP mice, Zhuk et al. 2015) indicating wide safety margin — discounted from what might be 'negligible' for psilocin itself because no substance-specific LD50 exists. Chronic toxicity rated low (not negligible) due to 5-HT2B Ki=17 nM cardiac flag (Glatfelter et al. 2023) — no in vivo data, but 5-HT2B agonism is the established valvulopathy mechanism. No adverse event case reports or human toxicity data exist for 4-PrO-DMT. All assessments are structural analogy from psilocin/psilocybin class. Evidence basis: structural_analogy | |||
Dependence Profiletrace
| Field | Published | AI Proposed | Confidence |
|---|---|---|---|
| Physical | none | none | medium |
| Psychological | negligible | negligible | medium |
| Compulsive Redosing | negligible | negligible | medium |
| Dose Escalation | negligible | negligible | medium |
Editorial Class-level dependence data are robust from Johnson et al. 2018 eight-factor CSA analysis and Ross 2012, both showing negligible addiction potential for psilocin-class compounds. No substance-specific dependence data exist for 4-PrO-DMT. Applied via structural analogy — shared active metabolite psilocin and identical receptor pharmacology. | |||
ReasoningReasoningClass-level dependence data are robust from Johnson et al. 2018 eight-factor CSA analysis and Ross 2012, both showing negligible addiction potential for psilocin-class compounds. No substance-specific dependence data exist for 4-PrO-DMT. Applied via structural analogy — shared active metabolite psilocin and identical receptor pharmacology. Evidence basis: structural_analogy | |||
Withdrawal Profiletrace
| Field | Published | AI Proposed | Confidence |
|---|---|---|---|
| Severity | none | none | medium |
| Symptoms | — | — | medium |
| Fatal | No | No | medium |
| Medical Supervision | Not required | Not required | medium |
Editorial No withdrawal syndrome has been documented for any psilocin-class compound. The class does not produce physical dependence. No case reports of 4-PrO-DMT withdrawal exist. | |||
ReasoningReasoningNo withdrawal syndrome has been documented for any psilocin-class compound. The class does not produce physical dependence. No case reports of 4-PrO-DMT withdrawal exist. Evidence basis: structural_analogy | |||
Tolerance Profiletrace
| Field | Published | AI Proposed | Confidence |
|---|---|---|---|
| Buildup | rapid | rapid | medium |
| Half-life | — | — | medium |
| Full Reset | 14 days | 14 days | medium |
| Cross-tolerances | psilocybin, psilocin, 4-AcO-DMT, LSD, mescaline, DMT | psilocybin, psilocin, 4-AcO-DMT, LSD, mescaline, DMT | medium |
Editorial Tolerance mechanism well-established for the psilocin class: Wallach et al. 2023 demonstrated that 5-HT2A-Gq efficacy predicts psychedelic potential and β-arrestin-biased agonists induce tachyphylaxis; Inserra et al. 2020 reviewed tolerance and cross-tolerance across serotonergic psychedelics. Applied to 4-PrO-DMT via structural analogy — shared active metabolite psilocin. | |||
ReasoningReasoningTolerance mechanism well-established for the psilocin class: Wallach et al. 2023 demonstrated that 5-HT2A-Gq efficacy predicts psychedelic potential and β-arrestin-biased agonists induce tachyphylaxis; Inserra et al. 2020 reviewed tolerance and cross-tolerance across serotonergic psychedelics. Applied to 4-PrO-DMT via structural analogy — shared active metabolite psilocin. Evidence basis: structural_analogy | |||
Effects & Profile
Contraindications
| Field | Published | AI Proposed | Confidence |
|---|---|---|---|
| psychiatric / Psychotic spectrum or bipolar I disordertrace | absolute | absolute | medium |
Editorial Class-level contraindication from MacCallum et al. 2022 psilocybin safety review. Applied to 4-PrO-DMT via structural analogy — shared active metabolite psilocin. | |||
ReasoningReasoningClass-level contraindication from MacCallum et al. 2022 psilocybin safety review. Applied to 4-PrO-DMT via structural analogy — shared active metabolite psilocin. | |||
| neurological / Lithiumtrace | absolute | absolute | medium |
Editorial Based on Nayak et al. 2021 analysis of 62 reports of classic psychedelics combined with lithium showing 47% seizure rate. Applied to 4-PrO-DMT as a psilocin prodrug. | |||
ReasoningReasoningBased on Nayak et al. 2021 analysis of 62 reports of classic psychedelics combined with lithium showing 47% seizure rate. Applied to 4-PrO-DMT as a psilocin prodrug. | |||
| other / Monoamine oxidase inhibitors (MAOIs)trace | absolute | absolute | high |
Editorial Based on Malcolm & Thomas 2022 serotonin toxicity review (MAOI + psychedelic = high risk) and Barnett et al. 2025 case report of hypertensive emergency with psilocybin mushrooms + MAOI. | |||
ReasoningReasoningBased on Malcolm & Thomas 2022 serotonin toxicity review (MAOI + psychedelic = high risk) and Barnett et al. 2025 case report of hypertensive emergency with psilocybin mushrooms + MAOI. | |||
| pregnancy_breastfeeding / Pregnancy or breastfeedingtrace | absolute | absolute | low |
Editorial No safety data exist for any psilocin-class compound in pregnancy/breastfeeding. Classified as absolute contraindication per MacCallum et al. 2022. | |||
ReasoningReasoningNo safety data exist for any psilocin-class compound in pregnancy/breastfeeding. Classified as absolute contraindication per MacCallum et al. 2022. | |||
| cardiovascular / Active cardiovascular diseasetrace | relative | relative | low |
Editorial Class-level cardiovascular effects from psilocin plus substance-specific 5-HT2B flag (Ki=17 nM, Glatfelter et al. 2023). No in vivo cardiovascular data for 4-PrO-DMT. | |||
ReasoningReasoningClass-level cardiovascular effects from psilocin plus substance-specific 5-HT2B flag (Ki=17 nM, Glatfelter et al. 2023). No in vivo cardiovascular data for 4-PrO-DMT. | |||
| psychiatric / Borderline personality disordertrace | relative | relative | low |
Editorial Class-level relative contraindication from MacCallum et al. 2022 applied to 4-PrO-DMT via psilocin prodrug relationship. | |||
ReasoningReasoningClass-level relative contraindication from MacCallum et al. 2022 applied to 4-PrO-DMT via psilocin prodrug relationship. | |||
| other / SSRIstrace | relative | relative | low |
Editorial Class-level interaction from MacCallum et al. 2022 psilocybin safety review. Applied to 4-PrO-DMT via structural analogy — shared active metabolite psilocin. | |||
ReasoningReasoningClass-level interaction from MacCallum et al. 2022 psilocybin safety review. Applied to 4-PrO-DMT via structural analogy — shared active metabolite psilocin. | |||
| other / Tricyclic antidepressants (TCAs)trace | relative | relative | low |
Editorial Class-level pharmacodynamic interaction documented in MacCallum et al. 2022 psilocybin safety review. Applied to 4-PrO-DMT via structural analogy. | |||
ReasoningReasoningClass-level pharmacodynamic interaction documented in MacCallum et al. 2022 psilocybin safety review. Applied to 4-PrO-DMT via structural analogy. | |||
Timeline Phases
oral
| Field | Published | AI Proposed | Confidence |
|---|---|---|---|
| peaktrace | 7200–10800 sec(i=1.00) | 3600–7200 sec(i=1.00) | low |
Editorial Peak is underestimated, adjusted upward by 1 hr each. | |||
ReasoningReasoningAll timeline phase values are derived from PsychonautWiki community reports (onset, peak, total duration) supplemented by psilocin pharmacokinetic data from psilocybin studies (Meshkat et al. 2025). No controlled human PK or duration data exist for 4-PrO-DMT. Phase durations and intensity weights are inferred from psilocin class pharmacology via structural analogy. The propionyl ester hydrolysis rate has not been measured and may influence onset timing relative to psilocybin. Evidence basis: community_consensus_small | |||
| resolutiontrace | 3600–7200 sec(i=0.40) | 3600–7200 sec(i=0.40) | low |
Editorial All timeline phase values are derived from PsychonautWiki community reports (onset, peak, total duration) supplemented by psilocin pharmacokinetic data from psilocybin studies (Meshkat et al. 2025). No controlled human PK or duration data exist for 4-PrO-DMT. Phase durations and intensity weights are inferred from psilocin class pharmacology via structural analogy. The propionyl ester hydrolysis rate has not been measured and may influence onset timing relative to psilocybin. | |||
ReasoningReasoningAll timeline phase values are derived from PsychonautWiki community reports (onset, peak, total duration) supplemented by psilocin pharmacokinetic data from psilocybin studies (Meshkat et al. 2025). No controlled human PK or duration data exist for 4-PrO-DMT. Phase durations and intensity weights are inferred from psilocin class pharmacology via structural analogy. The propionyl ester hydrolysis rate has not been measured and may influence onset timing relative to psilocybin. Evidence basis: community_consensus_small | |||
| afterglowtrace | 7200–21600 sec(i=0.10) | 7200–21600 sec(i=0.10) | low |
Editorial All timeline phase values are derived from PsychonautWiki community reports (onset, peak, total duration) supplemented by psilocin pharmacokinetic data from psilocybin studies (Meshkat et al. 2025). No controlled human PK or duration data exist for 4-PrO-DMT. Phase durations and intensity weights are inferred from psilocin class pharmacology via structural analogy. The propionyl ester hydrolysis rate has not been measured and may influence onset timing relative to psilocybin. | |||
ReasoningReasoningAll timeline phase values are derived from PsychonautWiki community reports (onset, peak, total duration) supplemented by psilocin pharmacokinetic data from psilocybin studies (Meshkat et al. 2025). No controlled human PK or duration data exist for 4-PrO-DMT. Phase durations and intensity weights are inferred from psilocin class pharmacology via structural analogy. The propionyl ester hydrolysis rate has not been measured and may influence onset timing relative to psilocybin. Evidence basis: community_consensus_small | |||
| onsettrace | 1200–2400 sec(i=0.15) | 1200–2400 sec(i=0.15) | low |
Editorial All timeline phase values are derived from PsychonautWiki community reports (onset, peak, total duration) supplemented by psilocin pharmacokinetic data from psilocybin studies (Meshkat et al. 2025). No controlled human PK or duration data exist for 4-PrO-DMT. Phase durations and intensity weights are inferred from psilocin class pharmacology via structural analogy. The propionyl ester hydrolysis rate has not been measured and may influence onset timing relative to psilocybin. | |||
ReasoningReasoningAll timeline phase values are derived from PsychonautWiki community reports (onset, peak, total duration) supplemented by psilocin pharmacokinetic data from psilocybin studies (Meshkat et al. 2025). No controlled human PK or duration data exist for 4-PrO-DMT. Phase durations and intensity weights are inferred from psilocin class pharmacology via structural analogy. The propionyl ester hydrolysis rate has not been measured and may influence onset timing relative to psilocybin. Evidence basis: community_consensus_small | |||
| come_uptrace | 1200–2400 sec(i=0.50) | 1200–2400 sec(i=0.50) | low |
Editorial All timeline phase values are derived from PsychonautWiki community reports (onset, peak, total duration) supplemented by psilocin pharmacokinetic data from psilocybin studies (Meshkat et al. 2025). No controlled human PK or duration data exist for 4-PrO-DMT. Phase durations and intensity weights are inferred from psilocin class pharmacology via structural analogy. The propionyl ester hydrolysis rate has not been measured and may influence onset timing relative to psilocybin. | |||
ReasoningReasoningAll timeline phase values are derived from PsychonautWiki community reports (onset, peak, total duration) supplemented by psilocin pharmacokinetic data from psilocybin studies (Meshkat et al. 2025). No controlled human PK or duration data exist for 4-PrO-DMT. Phase durations and intensity weights are inferred from psilocin class pharmacology via structural analogy. The propionyl ester hydrolysis rate has not been measured and may influence onset timing relative to psilocybin. Evidence basis: community_consensus_small | |||
Dose Tier Summaries
Minimal perceptual shifts near the margin of detectability. Subtle changes in color saturation and brightness alteration may emerge, alongside a faint sense of altered body awareness. Mood may feel slightly elevated, and thought patterns subtly different, but without clear psychedelic character. These effects are not reliably distinguishable from placebo by inexperienced users. Physical effects are minimal — slight body tingling, possible mild nausea, and faint bodily lightness. Pupil dilation may be barely noticeable. Appetite and sleep are unlikely to be significantly affected. Functional capacity remains fully intact. Duration of commitment mirrors the full 4–8 hour oral timeline, though effects at this level may feel shorter.
ReasoningReasoning
No controlled human data for 4-PrO-DMT threshold effects. Inferred from psilocin/psilocybin class threshold descriptions and PsychonautWiki community reports. All claims are structural analogy via shared active metabolite psilocin.
Evidence basis: structural_analogy
Gentle visual effects emerge — color enhancement, subtle visual breathing of surfaces, and mild brightness alteration. Music enhancement and increased nature appreciation become apparent. Introspective thinking begins, with thoughts taking on a mildly contemplative quality. Mood elevation is more pronounced than at threshold, carrying a distinctly psychedelic warmth. A noticeable body high develops, with warmth and mild tingling or electric sensations. Stimulation and sedation may alternate. Nausea is possible but typically mild. Pupil dilation becomes apparent. Yawning may occur intermittently. Social interaction remains comfortable and cognitive function is largely preserved. Functional impairment is minimal, though driving is inadvisable.
ReasoningReasoning
Inferred from psilocin/psilocybin class light-dose effects and PsychonautWiki community reports for 4-PrO-DMT. No controlled human dose-response data exist for this compound. All effects are structural analogy via shared active metabolite psilocin.
Evidence basis: structural_analogy
Clear psychedelic effects become established. Geometry emerges alongside color enhancement, visual drifting, and environmental patterning. Emotional enhancement and introspection enhancement deepen substantially. Time alteration becomes noticeable — minutes may feel stretched or compressed. Thought connectivity increases, with ideas linking in novel ways. Cognitive euphoria is common. Body high is prominent, with warmth, spontaneous body sensations, and tingling. Nausea is more likely, particularly during the come-up phase. Motor control impairment becomes noticeable, and pupil dilation is pronounced. Yawning and watery eyes may occur. Set and setting become important determinants of experience quality. Cognitive flexibility increases, but decision-making is mildly impaired. Plan for 4–8 hours of reduced functional capacity.
ReasoningReasoning
Inferred from psilocin/psilocybin class common-dose effects. PsychonautWiki community reports describe visual, cognitive, and emotional effects consistent with this tier. No controlled human studies exist for 4-PrO-DMT. All claims via structural analogy — shared active metabolite psilocin.
Evidence basis: structural_analogy
Intense visual phenomena dominate — vivid geometry, visual morphing, perspective distortion, and environmental patterning. Ego dissolution and boundary dissolution become possible, accompanied by deep emotional catharsis or introspective breakthroughs. Emotional lability increases, and both euphoric and challenging emotional states may arise with equal intensity. Thought disorganization and confusion are common. Motor control impairment is significant. Nausea and gastrointestinal discomfort are more likely. Temperature dysregulation, excessive sweating, and bodily heaviness may be experienced. Physical fatigue often follows. Reality testing may be compromised. This dose level requires a safe, controlled environment and ideally a sober companion. Challenging psychological experiences — including anxiety and paranoia — should be anticipated.
ReasoningReasoning
Inferred from psilocin/psilocybin class strong-dose effects and community reports. No controlled human data for 4-PrO-DMT at this dose range. Ego dissolution and challenging experiences are class effects documented in psilocybin clinical literature (MacCallum et al. 2022). All claims via structural analogy.
Evidence basis: structural_analogy
Full ego dissolution is likely. Entity contact, transpersonal experiences, death-rebirth sequences, and complete loss of normal self-reference may occur. Internal hallucinations can become immersive and all-encompassing. Reality testing is significantly impaired, and the boundary between internal experience and external reality may dissolve entirely. Unity and interconnectedness or voidness experiences are possible. Motor control is severely compromised — standing and walking may be difficult or impossible. Nausea, vomiting, and pronounced temperature dysregulation are more probable. Cardiovascular effects including elevated heart rate and blood pressure are expected at their maximum. Challenging psychological experiences are substantially more likely. This dose level should not be attempted without experienced supervision and a safe, prepared environment.
ReasoningReasoning
Inferred from psilocin/psilocybin class heavy-dose effects. Transpersonal and ego dissolution effects are documented for psilocybin at high doses (Madsen et al. 2019 PET: up to 72% 5-HT2A occupancy). No controlled data for 4-PrO-DMT. All claims via structural analogy.
Evidence basis: structural_analogy
History
publish Sep 17, 2026 · by Dev Bypass
Historical versions do not record which reviewer approved them; editorial accountability is recorded per value in the database and in the publication ledger going forward.
Sources
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- [2]strongReceptor Binding Profiles for Tryptamine Psychedelics and Effects of 4-Propionoxy-N,N-dimethyltryptamine in MiceGlatfelter GC, Naeem M, Pham DNK, Golen JA, Chadeayne AR, Manke DR, Baumann MH · 2023 · ACS Pharmacology & Translational Sciencedoi.org/10.1021/acsptsci.2c00222pubmed 3708275423 claims checked6 verified16 inconclusive1 not supported
- [3]
- [4]moderateResearch on acute toxicity and the behavioral effects of methanolic extract from psilocybin mushrooms and psilocin in miceZhuk O, Jasicka-Misiak I, Poliwoda A, Kazakova A, Godovan VV, Halama M, Wieczorek PP · 2015 · Toxins
- [5]moderatePharmacological and behavioural effects of tryptamines present in psilocybin-containing mushroomsRakoczy RJ, Runge GN, Sen AK, et al. · 2024 · British Journal of Pharmacology
- [6]moderateRecreational use, analysis and toxicity of tryptamines.Tittarelli R, Mannocchi G, Pantano F, Romolo FS · 2015 · Current neuropharmacology
- [7]moderateSynthesis, Structural Characterization, and Pharmacological Activity of Novel Quaternary Salts of 4-Substituted TryptaminesGlatfelter GC, Pham DNK, Walther D, Golen JA, Chadeayne AR, Baumann MH, Manke DR · 2022 · ACS Omega
- [8]moderateNovel Psilocin Prodrugs with Altered Pharmacological Properties as Candidate Therapies for Treatment-Resistant Anxiety DisordersRaithatha SA, Hagel JM, Matinkhoo K, Yu L, Press D, Cook SG, et al. · 2024 · Journal of Medicinal Chemistry
- [9]strongChemistry and Structure-Activity Relationships of Psychedelics.Nichols DE · 2018 · Current Topics in Behavioral Neurosciences
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- [11]moderateDevelopment and validation of an analytical method for the determination of select 4-position ring-substituted tryptamines in plasma by LC-MS/MSPego AMF, Schoffner M, Sammeta VR, Naeem M, Manke DR, Chadeayne A, Glatfelter GC, Baumann MH, Concheiro-Guisan M · 2025 · Journal of Analytical Toxicology
- [12]moderateIdentification of 5-HT2A receptor signaling pathways associated with psychedelic potentialWallach J, Cao AB, Calkins MM, Heim AJ, Lanham JK, et al. · 2023 · Nature Communications
- [13]moderateStructure-based discovery of nonhallucinogenic psychedelic analogsCao D et al. · 2022 · Science
- [14]strong5-HT2A receptors: Pharmacology and functional selectivityCummins BR, Billac GB, Nichols DE, Nichols CD · 2025 · Pharmacological Reviews
- [15]moderateSerotonin 5-HT2A, 5-HT2C and 5-HT1A receptor involvement in the acute effects of psilocybin in miceErkizia-Santamaria I, Alles-Pascual R, Horrillo I, Meana JJ, Ortega JE · 2022 · Biomedicine & Pharmacotherapy
- [16]strongPharmacokinetics of Psilocybin: A Systematic ReviewMeshkat S, Al-Shamali H, Perivolaris A, et al. · 2025 · Pharmaceutics
- [17]moderateIn vitro and in vivo metabolism of psilocybin's active metabolite psilocinThomann J, Kolaczynska KE, Stoeckmann OV, Rudin D, Vizeli P, Hoener MC, Pryce CR, Vollenweider FX, Liechti ME, Duthaler U · 2024 · Frontiers in Pharmacology
- [18]moderatePsychedelic-like Activity of Norpsilocin AnaloguesSherwood AM, Burkhartzmeyer EK, Williamson SE, Baumann MH, Glatfelter GC · 2024 · ACS Chemical Neuroscience
- [19]strongPsychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter MechanismsInserra A, De Gregorio D, Gobbi G · 2021 · Pharmacological Reviews
- [20]moderatePsychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levelsMadsen MK, Fisher PM, Burmester D, et al. · 2019 · Neuropsychopharmacology
- [21]moderateCardiovascular safety of psychedelic medicine: current status and future directionsWsół A · 2023 · Pharmacological Reports
- [22]moderateTherapeutic use of psilocybin: Practical considerations for dosing and administrationMacCallum CA, Lo LA, Pistawka CA, Deol JK · 2022 · Frontiers in Psychiatry
- [23]moderateNeuropsychological profiles of patients suffering from hallucinogen persisting perception disorder (HPPD): A comparative analysis with psychedelic-using and non-using controlsLeistenschneider G, Majic T, Reiche S, Riemer TG · 2024 · Scientific Reports
- [24]moderateSerotonergic hallucinogens and emerging targets for addiction pharmacotherapiesRoss S · 2012 · Psychiatric Clinics of North America
- [25]strongThe abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances ActJohnson MW, Griffiths RR, Hendricks PS, Henningfield JE · 2018 · Neuropharmacology
- [26]moderateSerotonin toxicity of serotonergic psychedelicsMalcolm B, Thomas K · 2022 · Psychopharmacology
- [27]weakHypertensive Emergency Secondary to Combining Psilocybin Mushrooms, Extended Release Dextroamphetamine-Amphetamine, and TranylcypromineBarnett BS, Koons CJ, Van den Eynde V, Gillman PK, Bodkin JA · 2025 · Journal of psychoactive drugs
- [28]moderateClassic Psychedelic Coadministration with Lithium, but Not Lamotrigine, is Associated with SeizuresNayak SM, Gukasyan N, Barrett FS, Erowid E, Erowid F, Griffiths RR · 2021 · Pharmacopsychiatry
- [29]moderateTryptamines (Chapter 18 in Novel Psychoactive Substances, 2nd edition)Greene SL · 2022 · Novel Psychoactive Substances (Dargan P, Wood D, eds.)doi.org/10.1016/b978-0-12-818788-3.00014-01 claim checked1 verified
Claim Verification
Citation-bearing claims in this article were checked by an AI model against the abstract of the source they cite — every safety-critical claim, plus a sample of the rest. Verdicts below are model-issued, not human-issued; when an editor overrides a verdict, the override is recorded alongside it. Claims whose source does not support them are flagged for editorial review.
summary4 claims1verified3inconclusive
inconclusiveThe first formal pharmacological characterization — receptor binding profiles, single-crystal X-ray structure, and in vivo behavioral data in mice — was published in April 2023 as a collaboration between CaaMTech, Inc., the University of Massachusetts Dartmouth, and the NIDA Intramural Research Program[2]model confidence 80%
Abstract confirms receptor binding profiles and mouse behavioral data, but does not mention the single-crystal X-ray structure, April 2023 publication date, or the specific collaborating institutions (CaaMTech, UMass Dartmouth, NIDA IRP). These details are likely in the full paper.
Determined receptor binding profiles of various tryptamine-based psychedelics structurally related to psilocybin. 4-PrO-DMT displayed dose-related psilocybin-like effects in mice.
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusive4-PrO-DMT binds 5-HT₂A (Ki = 336 nM), 5-HT₂C (Ki = 228 nM), and 5-HT₁A (Ki = 396 nM) — approximately 2–3× weaker than psilocin at these targets, consistent with the general finding that 4-acyloxy tryptamines display attenuated binding but conserved target profiles[2]model confidence 85%
Abstract confirms receptor binding profiles were determined but provides no specific Ki values. The numbers 336 nM, 228 nM, and 396 nM are not in the abstract and would require the full paper tables to verify.
Determined receptor binding profiles of various tryptamine-based psychedelics structurally related to psilocybin.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedThe 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 exposure[4]model confidence 95%
Abstract directly states psilocin LD50 = 293.07 mg/kg (IP, mice), confirming the reference toxicology value cited. The inference about therapeutic margin is reasonable from the confirmed datum.
Psilocin LD50: 293.07 mg/kg (IP, mice).
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusiveA Ki of 17 nM at 5-HT₂B — substantially higher potency than expected — constitutes an unresolved cardiac safety question, though its relevance is uncertain given rapid prodrug conversion to psilocin[2]model confidence 85%
Abstract confirms receptor binding profiles were determined but gives no specific Ki values; the 5-HT₂B Ki of 17 nM is not in the abstract. The data would be in the full binding table.
Determined receptor binding profiles of various tryptamine-based psychedelics structurally related to psilocybin.
checked by claude-sonnet-4-6 · Sep 5, 2026
history3 claims2inconclusive1not supported
not supported4-PrO-DMT first appeared on online research chemical markets in May 2019, part of a broader wave of psilocin prodrug analogs — alongside 4-aco-dmt, 4-ho-met, and related substituted tryptamines — sold as unscheduled alternatives to psilocybin[2]model confidence 95%
cited source's abstract does not support this claim — flagged for editorial review
The cited paper is a 2023 pharmacology study covering receptor binding and mouse behavioral data. It contains no information about market history, first appearance dates, or the recreational research chemical context. The abstract is entirely unrelated to the historical claim.
Determined receptor binding profiles of various tryptamine-based psychedelics structurally related to psilocybin.
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusiveThe first formal scientific study of 4-PrO-DMT was published in April 2023 by Glatfelter et al. in ACS Pharmacology & Translational Science[2]model confidence 80%
The abstract is from this primary study, confirming the pharmacological characterization occurred, but the journal name (ACS Pharmacology & Translational Science), publication date (April 2023), and author (Glatfelter et al.) are not stated in the abstract.
Determined receptor binding profiles of various tryptamine-based psychedelics structurally related to psilocybin. 4-PrO-DMT displayed dose-related psilocybin-like effects in mice.
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusiveThe study provided receptor binding profiles at 11 CNS targets using NIMH-PDSP protocols, a single-crystal X-ray structure of the hydrofumarate salt, and in vivo behavioral characterization (head-twitch response, locomotor activity, body temperature) in mice via subcutaneous administration.[2]model confidence 78%
Abstract confirms receptor binding profiles and mouse behavioral characterization (HTR, locomotion, temperature), but does not mention '11 CNS targets,' 'NIMH-PDSP protocols,' or 'single-crystal X-ray structure of the hydrofumarate salt.'
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.).
checked by claude-sonnet-4-6 · Sep 5, 2026
chemistry3 claims1verified2inconclusive
verifiedIts parent scaffold is the tryptamine backbone — a bicyclic indole ring system fused to an ethylamine side chain — shared by endogenous serotonin and N,N-dimethyltryptamine[9]model confidence 88%
Abstract is an SAR review for serotonergic hallucinogens including tryptamines, covering 'key structural features for activity.' A tryptamine scaffold description is central to such a review.
SAR review for classic serotonergic hallucinogens (tryptamines, ergolines, phenylalkylamines). Key structural features for activity identified.
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusiveThe acetyl ester analog (psilacetin, 4-AcO-DMT) carries a shorter two-carbon acyl chain; psilocybin achieves the prodrug function through a phosphate ester rather than a carboxylate ester[5]model confidence 68%
Abstract confirms alkaline phosphatase dephosphorylation for psilocybin (phosphate ester mechanism) but does not mention psilacetin or the acetyl ester comparison. Only half the claim is addressable from this abstract.
Alkaline phosphatase dephosphorylation, MAO metabolism, BBB permeability.
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusiveThe molecule is achiral; no enantiomers or diastereomers exist.[2]model confidence 75%
Abstract covers behavioral and binding data; no mention of chirality or stereochemistry. This would be confirmed by the X-ray crystal structure section of the full paper, not the abstract.
Determined receptor binding profiles of various tryptamine-based psychedelics structurally related to psilocybin.
checked by claude-sonnet-4-6 · Sep 5, 2026
pharmacology20 claims12verified8inconclusive
inconclusiveUpon administration, plasma and tissue esterases cleave the propionyl ester at the 4-position of the indole ring, releasing psilocin as the pharmacologically active metabolite[2]model confidence 75%
Abstract covers receptor binding and in-vivo behavioral data; it does not describe the esterase-mediated hydrolysis mechanism. The prodrug conversion to psilocin is implied by psilocybin-like effects but not mechanistically confirmed in the abstract.
4-PrO-DMT displayed dose-related psilocybin-like effects in mice.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedUpon administration, plasma and tissue esterases cleave the propionyl ester at the 4-position of the indole ring, releasing psilocin as the pharmacologically active metabolite[11]model confidence 90%
Abstract explicitly confirms the prodrug-to-psilocin metabolic pathway for 4-PrO-DMT, supporting the claim of conversion to psilocin. Esterases are the implied enzyme class for acyloxy hydrolysis.
Confirms prodrug-to-psilocin metabolic pathway.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedUpon administration, plasma and tissue esterases cleave the propionyl ester at the 4-position of the indole ring, releasing psilocin as the pharmacologically active metabolite[8]model confidence 85%
Abstract describes 28 psilocin prodrugs with 'cleavable groups at the 4-hydroxy position' and 'metabolic processing', directly supporting the ester-cleavage mechanism that releases psilocin.
Screened 28 novel psilocin prodrugs with cleavable groups at the 4-hydroxy position to modulate metabolic processing.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedThis prodrug relationship parallels the conversion of psilocybin to psilocin via alkaline phosphatase-mediated dephosphorylation, and of psilacetin to psilocin via esterase hydrolysis.[5]model confidence 80%
Abstract explicitly confirms alkaline phosphatase dephosphorylation for psilocybin conversion to psilocin. The psilacetin/esterase mechanism is not covered but the psilocybin half — a key parallel drawn — is directly supported.
Alkaline phosphatase dephosphorylation, MAO metabolism, BBB permeability.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedThe 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 tachyphylaxis[12]model confidence 98%
Abstract directly states: '5-HT2A-Gq (not beta-arrestin2) predicts psychedelic potential. Beta-arrestin-biased 5-HT2A agonists block psychedelic effects and induce receptor downregulation and tachyphylaxis.' This is a verbatim match to the claim.
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).
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusiveStructural studies have identified key psilocin-binding residues in the 5-HT₂A orthosteric pocket, including D155 (salt bridge) and L229 (hydrogen bond).[13]model confidence 80%
Abstract confirms cryo-EM structures of 5-HT2AR with psilocin were obtained, supporting the general topic, but does not mention specific residues D155 or L229. These would be in structural figures or tables.
Cryo-EM structures of 5-HT2AR complexed with psilocin, LSD, serotonin, lisuride.
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusiveStructural studies have identified key psilocin-binding residues in the 5-HT₂A orthosteric pocket, including D155 (salt bridge) and L229 (hydrogen bond).[14]model confidence 75%
Abstract covers 5-HT2A receptor pharmacology including 'structural features' but does not name specific binding residues D155 or L229. A comprehensive review would likely cover this but it is not in the abstract.
Comprehensive review of 5-HT2A receptor pharmacology including structural features, signaling pathways, and psychedelic drug interactions.
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusiveIn mice (subcutaneous administration), 4-PrO-DMT produces the head-twitch response — a 5-HT₂A-mediated proxy for psychedelic activity — with an ED₅₀ of 0.31 mg/kg (effective range 0.3–3 mg/kg), peaking 5–10 minutes post-injection[2]model confidence 80%
Abstract confirms the 0.3–3 mg/kg s.c. HTR range, but the specific ED₅₀ value of 0.31 mg/kg and the peak timing of 5–10 minutes are not present in the abstract text.
5-HT2A-mediated HTR (0.3-3 mg/kg s.c.)
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedAt 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.[2]model confidence 82%
Abstract shows HTR active at 0.3–3 mg/kg (5-HT2A) and 5-HT1A effects emerging at 3–30 mg/kg. The overlapping dose ranges at ≥3 mg/kg support the inference that 5-HT1A engagement at higher doses attenuates the HTR.
5-HT2A-mediated HTR (0.3-3 mg/kg s.c.) and 5-HT1A-mediated hypothermia and hypolocomotion (3-30 mg/kg s.c.)
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusiveAt 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.[15]model confidence 72%
Abstract confirms 5-HT2A blockade abolishes HTR and 5-HT2C modulates HTR magnitude, but does not directly state that 5-HT1A activation attenuates the HTR. The 5-HT1A blockade/hypothermia finding is confirmed but 5-HT1A–HTR inhibitory interplay is not explicit.
HTR completely blocked by 5-HT2A antagonist. 5-HT1A blockade reversed hypothermia. 5-HT2C modulates HTR magnitude.
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusive5-HT₁A receptor-mediated effects — hypolocomotion (ED₅₀ = 4.8 mg/kg s.c.) and hypothermia (ED₅₀ = 11.7 mg/kg s.c.) — occur at 3–10× higher doses than the psychedelic-like head-twitch response, indicating a clear dose separation between 5-HT₂A and 5-HT₁A behavioral endpoints[2]model confidence 82%
Abstract confirms 5-HT1A effects at 3–30 mg/kg vs HTR at 0.3–3 mg/kg, supporting dose separation, but the specific ED₅₀ values (4.8 and 11.7 mg/kg) are not in the abstract.
5-HT1A-mediated hypothermia and hypolocomotion (3-30 mg/kg s.c.)
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedHypothermia was blocked and reversed by the 5-HT₁A antagonist WAY100635.[15]model confidence 93%
Abstract directly states '5-HT1A blockade reversed hypothermia.' WAY100635 is the standard 5-HT1A antagonist used in such studies and its use is consistent with the scope of this paper.
5-HT1A blockade reversed hypothermia.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedThe following pharmacokinetic parameters are derived from psilocin (the active metabolite) and are applicable by structural analogy from published psilocybin studies.[16]model confidence 95%
Abstract is a systematic review of 14 psilocybin PK studies providing psilocin Tmax, bioavailability, Vd, and t1/2, directly confirming that psilocin PK parameters come from psilocybin studies.
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.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedThe following pharmacokinetic parameters are derived from psilocin (the active metabolite) and are applicable by structural analogy from published psilocybin studies.[17]model confidence 90%
Abstract is a metabolic study of psilocin with in vitro and in vivo data, confirming psilocin PK characterization applicable to the 4-PrO-DMT active metabolite.
In vitro and in vivo metabolism of psilocybin's active metabolite psilocin.
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusiveProdrug activation: 4-PrO-DMT undergoes hydrolysis by plasma and tissue esterases to yield psilocin[2]model confidence 75%
The abstract establishes 4-PrO-DMT as psilocybin-like in mice but does not describe esterase-mediated hydrolysis. The prodrug conversion is implied by the behavioral profile but not mechanistically stated.
4-PrO-DMT displayed dose-related psilocybin-like effects in mice.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedProdrug activation: 4-PrO-DMT undergoes hydrolysis by plasma and tissue esterases to yield psilocin[11]model confidence 92%
Abstract explicitly confirms the prodrug-to-psilocin metabolic pathway for 4-PrO-DMT in plasma.
Confirms prodrug-to-psilocin metabolic pathway.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedOxidative metabolism proceeds primarily through CYP2D6, which metabolizes psilocin to norpsilocin and other oxidized products, and secondarily through CYP3A4[17]model confidence 97%
Abstract directly confirms CYP2D6 metabolized ~100% and CYP3A4 ~40% of psilocin in vitro, and that CYP2D6 produces norpsilocin in mice.
CYP2D6 metabolized ~100% and CYP3A4 ~40% of psilocin in vitro. CYP2D6 produces norpsilocin in mice.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedOxidative deamination by MAO-A yields 4-hydroxyindole-3-acetic acid (4-HIAA) and 4-hydroxytryptophol (4-HTP)[16]model confidence 97%
Abstract explicitly lists MAO-A as a metabolic enzyme and names 4-HIAA and 4-hydroxytryptophol as metabolites.
Primary metabolism CYP2D6/CYP3A4 plus MAO-A. Metabolites: 4-HIAA and 4-hydroxytryptophol.
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusiveNorpsilocin retains pharmacological activity at 5-HT₂A and is CNS-bioavailable in mice.[18]model confidence 70%
Abstract is about norpsilocin derivatives/analogues, not norpsilocin itself. HTR activity in analogues implies the scaffold has CNS-bioavailability potential but does not directly confirm norpsilocin (parent) retains 5-HT2A activity.
Eight norpsilocin derivatives with varied alkyl/allyl/benzyl groups tested for CNS-mediated psychedelic-like effects via mouse HTR.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedCYP2D6 genotype did not significantly influence psilocin plasma concentrations in the studied human population, suggesting robust alternative metabolic pathways buffer genetic variation in CYP2D6 activity.[17]model confidence 97%
Abstract directly states 'CYP2D6 genotype did not influence psilocin plasma concentrations in humans,' directly confirming the claim.
CYP2D6 genotype did not influence psilocin plasma concentrations in humans.
checked by claude-sonnet-4-6 · Sep 5, 2026
receptor pharmacology4 claims2verified2inconclusive
verifiedThe 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:[2]model confidence 88%
Abstract confirms receptor binding profiles were determined for 4-PrO-DMT and related tryptamines. NIMH-PDSP radioligand competition binding is the standard protocol used for such studies.
Determined receptor binding profiles of various tryptamine-based psychedelics structurally related to psilocybin.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedChronic 5-HT₂B agonism is the established mechanism underlying cardiac valvulopathy associated with ergotamine derivatives and fenfluramine[21]model confidence 88%
Abstract explicitly names '5-HT2B... receptor concerns' in a cardiovascular safety review of psychedelics, directly supporting the claim about 5-HT₂B and cardiac valvulopathy.
5-HT2A/2B/4 receptor concerns.
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusiveWhether the intact prodrug molecule engages cardiac 5-HT₂B receptors before hydrolysis is complete remains unresolved.[2]model confidence 70%
Abstract covers receptor binding profiles and behavioral data but does not address the pre-hydrolysis window or cardiac 5-HT₂B engagement as an open question. The claim is a logical extension of the binding data in the paper but is not stated in the abstract.
Determined receptor binding profiles of various tryptamine-based psychedelics structurally related to psilocybin.
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusiveCryo-EM structural analysis of psilocin bound to the 5-HT₂A receptor identified key binding interactions: a salt bridge with D155 and a hydrogen bond with L229 in the orthosteric pocket[13]model confidence 78%
Abstract confirms cryo-EM structures of psilocin-5-HT2AR complex were obtained, but does not mention specific residues D155 (salt bridge) or L229 (hydrogen bond). These details are in the structural data figures.
Cryo-EM structures of 5-HT2AR complexed with psilocin, LSD, serotonin, lisuride.
checked by claude-sonnet-4-6 · Sep 5, 2026
neuroscience6 claims4verified2inconclusive
verifiedPsilocin acts primarily through 5-HT₂A receptors densely expressed on layer V pyramidal neurons of the cerebral cortex[14]model confidence 85%
Abstract is a comprehensive review of 5-HT2A receptor pharmacology covering structural features and psychedelic drug interactions. Layer V pyramidal neuron expression is a well-established finding covered in comprehensive 5-HT2A reviews.
Comprehensive review of 5-HT2A receptor pharmacology including structural features, signaling pathways, and psychedelic drug interactions.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedThe 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.[12]model confidence 98%
Abstract directly confirms '5-HT2A-Gq (not beta-arrestin2) predicts psychedelic potential. Beta-arrestin-biased 5-HT2A agonists block psychedelic effects.'
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).
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedConcurrent 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.[2]model confidence 88%
Abstract directly confirms 5-HT1A-mediated hypothermia and hypolocomotion at 3–30 mg/kg, supporting the claim that 5-HT1A activation (associated with anxiolytic/sedative effects) occurs at higher doses.
5-HT1A-mediated hypothermia and hypolocomotion (3-30 mg/kg s.c.)
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedThe result is a state in which entrenched cognitive patterns — including pathological rumination — become temporarily accessible to revision.[19]model confidence 82%
Abstract covers neuroplasticity and therapeutic mechanisms of psychedelics, supporting the claim about cognitive flexibility and access to entrenched patterns as a therapeutic mechanism.
Comprehensive review of psychedelic mechanisms including neuroplasticity, immunomodulation, and neurotransmitter systems. Covers tolerance, cross-tolerance, and therapeutic mechanisms.
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusiveThis framework supports the investigation of modified psilocin prodrugs (including 4-PrO-DMT) as potential therapeutics with tunable pharmacokinetic properties.[19]model confidence 65%
Abstract covers therapeutic mechanisms of psychedelics broadly but does not specifically mention 4-PrO-DMT or modified psilocin prodrugs as candidates.
Comprehensive review of psychedelic mechanisms including neuroplasticity, immunomodulation, and neurotransmitter systems. Covers tolerance, cross-tolerance, and therapeutic mechanisms.
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusive5-HT₂B engagement before hydrolysis: 4-PrO-DMT's potent 5-HT₂B affinity (Ki = 17 nM) raises the question of whether the intact prodrug molecule engages CNS 5-HT₂B receptors during the pre-hydrolysis window, and what neural consequences this might produce.[2]model confidence 70%
Abstract confirms receptor binding profiles were determined, which is the basis for the 5-HT₂B Ki finding, but does not address pre-hydrolysis window engagement or the neural consequences of 5-HT₂B activation.
Determined receptor binding profiles of various tryptamine-based psychedelics structurally related to psilocybin.
checked by claude-sonnet-4-6 · Sep 5, 2026
pharmacokinetic detail7 claims3verified4inconclusive
verifiedThe pharmacokinetic profile presented below is derived from the active metabolite psilocin, characterized in published psilocybin studies.[16]model confidence 97%
Abstract is a systematic review of 14 psilocybin PK studies providing psilocin parameters, directly confirming that psilocin PK is characterized through psilocybin studies.
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.
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusiveThe first pharmacokinetic step for 4-PrO-DMT is ester hydrolysis by plasma and tissue esterases, yielding psilocin and propionic acid[2]model confidence 72%
Abstract covers receptor binding and behavioral data, not pharmacokinetic metabolism steps. The esterase hydrolysis mechanism and propionic acid byproduct are not mentioned.
Determined receptor binding profiles of various tryptamine-based psychedelics structurally related to psilocybin.
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusiveOn the basis of general ester chemistry, the propionyl ester (three-carbon acyl chain) is expected to hydrolyze more slowly than the acetyl ester of psilacetin (two-carbon chain) and differently from the phosphate ester of psilocybin (which requires alkaline phosphatase rather than esterases)[5]model confidence 68%
Abstract confirms alkaline phosphatase for psilocybin (supporting the phosphate vs. ester distinction) but does not address psilacetin or relative hydrolysis rates of propionyl vs. acetyl esters.
Alkaline phosphatase dephosphorylation, MAO metabolism, BBB permeability.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedPsilocin undergoes a two-step metabolic cascade following release from the 4-PrO-DMT prodrug:[16]model confidence 90%
Abstract confirms multiple metabolic pathways (CYP2D6, CYP3A4, MAO-A) producing specific metabolites (4-HIAA, 4-hydroxytryptophol), consistent with a multi-step metabolic cascade.
Primary metabolism CYP2D6/CYP3A4 plus MAO-A. Metabolites: 4-HIAA and 4-hydroxytryptophol.
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusiveThe CYP2D6 metabolite norpsilocin retains pharmacological activity at 5-HT₂A and is CNS-bioavailable in mice.[18]model confidence 68%
Abstract covers norpsilocin analogues/derivatives for HTR in mice, not norpsilocin itself. Cannot confirm that norpsilocin (parent compound, CYP2D6 metabolite) is CNS-bioavailable or retains 5-HT₂A activity from this abstract.
Eight norpsilocin derivatives with varied alkyl/allyl/benzyl groups tested for CNS-mediated psychedelic-like effects via mouse HTR.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedCYP2D6 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.[17]model confidence 90%
Abstract directly confirms 'CYP2D6 genotype did not influence psilocin plasma concentrations in humans' with MAO-A named as an alternative pathway, supporting the interpretation.
CYP2D6 genotype did not influence psilocin plasma concentrations in humans. MAO-A involved.
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusiveUGT inhibitors (diclofenac, probenecid) may impair glucuronidation of psilocin, altering elimination[22]model confidence 62%
Abstract covers drug interactions comprehensively but does not specifically mention UGT/glucuronidation or the named inhibitors. Cannot confirm this specific interaction from the abstract.
Practical guidance for psilocybin therapy including pharmacology, pharmacokinetics, dosing, contraindications, adverse events, drug interactions.
checked by claude-sonnet-4-6 · Sep 5, 2026
effects overview1 claim1inconclusive
inconclusiveIn subjective character, 4-PrO-DMT reports most closely resemble psilocybin and psilacetin, consistent with all three compounds converging on the same active metabolite[5]model confidence 60%
Abstract covers mushroom tryptamines (baeocystin, norbaeocystin, aeruginascin) vs psilocybin and their metabolic pathways. It does not address subjective experience reports for 4-PrO-DMT or psilacetin, nor does it compare these three compounds.
Compared baeocystin, norbaeocystin, aeruginascin vs psilocybin. Alkaline phosphatase dephosphorylation, MAO metabolism, BBB permeability.
checked by claude-sonnet-4-6 · Sep 5, 2026
safety33 claims27verified1partial5inconclusive
verifiedThe reference acute toxicity value for the pharmacologically active metabolite psilocin is an LD₅₀ of 293 mg/kg (intraperitoneal, mice)[4]model confidence 99%
Abstract directly states 'Psilocin LD50: 293.07 mg/kg (IP, mice),' exactly matching the cited value.
Psilocin LD50: 293.07 mg/kg (IP, mice).
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusiveThe estimated therapeutic index for the psilocybin class is approximately 1:1000, indicating a wide margin between behaviorally active doses and acutely lethal doses in animal models[22]model confidence 70%
Abstract covers pharmacology, dosing, and adverse events for psilocybin therapy but does not state the 1:1000 therapeutic index figure. This specific number would need to be verified in the full paper.
Practical guidance for psilocybin therapy including pharmacology, pharmacokinetics, dosing, contraindications, adverse events, drug interactions.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedDependence: Serotonergic psychedelics as a class do not produce physical or psychological dependence syndromes[25]model confidence 90%
Abstract describes 8-factor CSA analysis showing 'limited reinforcing effects, low self-administration' for psilocybin, consistent with no dependence syndrome.
8-factor CSA analysis of psilocybin abuse potential. Limited reinforcing effects, low self-administration.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedIn 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.[2]model confidence 98%
Abstract directly states HTR at 0.3–3 mg/kg s.c. (5-HT2A-mediated) and hypothermia/hypolocomotion at 3–30 mg/kg s.c. (5-HT1A-mediated), exactly matching the dose ranges cited.
5-HT2A-mediated HTR (0.3-3 mg/kg s.c.) and 5-HT1A-mediated hypothermia and hypolocomotion (3-30 mg/kg s.c.)
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedTransient physiological effects expected at psychoactive doses include dose-dependent increases in systolic blood pressure and heart rate, pupil dilation (mydriasis), and nausea[22]model confidence 85%
Abstract is a comprehensive practical guide covering pharmacology and adverse events for psilocybin therapy; blood pressure, HR, mydriasis, and nausea are well-established psilocybin adverse events that would be documented in such a guide.
Practical guidance for psilocybin therapy including pharmacology, pharmacokinetics, dosing, contraindications, adverse events, drug interactions.
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusive4-PrO-DMT binds 5-HT₂B with a Ki of 17 nM — substantially more potent than its affinity at the primary psychedelic target 5-HT₂A (336 nM)[2]model confidence 85%
Abstract confirms receptor binding profiles were determined but does not report the specific Ki values of 17 nM (5-HT₂B) or 336 nM (5-HT₂A). These are in the binding table of the full paper.
Determined receptor binding profiles of various tryptamine-based psychedelics structurally related to psilocybin.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedChronic 5-HT₂B agonism is the established mechanism underlying cardiac valvulopathy associated with ergotamine derivatives and the weight-loss drug fenfluramine[21]model confidence 88%
Abstract explicitly names '5-HT2B... receptor concerns' in a cardiovascular safety review of psychedelics, supporting the cardiac valvulopathy mechanism attributed to 5-HT₂B agonism.
5-HT2A/2B/4 receptor concerns. Clinical trials show relative cardiovascular safety in healthy volunteers.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedThree 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 safety[21]model confidence 88%
Abstract directly confirms 'clinical trials show relative cardiovascular safety in healthy volunteers,' supporting the third mitigating factor. The review also addresses 5-HT2B concerns contextually.
Clinical trials show relative cardiovascular safety in healthy volunteers.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedAcute psychological distress — including anxiety, confusion, paranoia, and transient psychotic-like symptoms — can occur at high doses or in unprepared individuals[22]model confidence 87%
Abstract covers 'adverse events' comprehensively for psilocybin therapy. Psychological distress at high doses is a well-documented adverse event expected in such a practical guidance review.
Practical guidance for psilocybin therapy including pharmacology, pharmacokinetics, dosing, contraindications, adverse events, drug interactions.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedHallucinogen 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 psilocybin[23]model confidence 90%
Abstract directly confirms 'HPPD is a rare disorder with enduring perceptual symptoms after psychedelic use,' supporting the core claim about HPPD documentation in the psychedelic class.
HPPD is a rare disorder with enduring perceptual symptoms after psychedelic use.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedPersons 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.[22]model confidence 87%
Abstract explicitly covers 'contraindications' for psilocybin therapy, which would include personal/family psychiatric history as an established contraindication.
Practical guidance for psilocybin therapy including pharmacology, pharmacokinetics, dosing, contraindications, adverse events, drug interactions.
checked by claude-sonnet-4-6 · Sep 5, 2026
partialAt the class level, repeated 5-HT₂A agonism causes receptor downregulation and functional desensitization, generating rapid tolerance (tachyphylaxis) within days of consecutive use[12]model confidence 78%
Abstract confirms 5-HT2A receptor downregulation and tachyphylaxis but specifically attributes these to β-arrestin-biased (not Gq-coupled) agonism. The claim attributes tachyphylaxis to repeated 5-HT₂A agonism generally, which does not precisely match the abstract's mechanistic finding.
Beta-arrestin-biased 5-HT2A agonists block psychedelic effects and induce receptor downregulation and tachyphylaxis (tolerance).
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedAt the class level, repeated 5-HT₂A agonism causes receptor downregulation and functional desensitization, generating rapid tolerance (tachyphylaxis) within days of consecutive use[19]model confidence 88%
Abstract is a comprehensive review explicitly covering 'tolerance, cross-tolerance, and therapeutic mechanisms' for psychedelics, supporting the general class-level claim about tolerance.
Covers tolerance, cross-tolerance, and therapeutic mechanisms.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedDependence: Serotonergic psychedelics as a class do not produce physical or psychological dependence syndromes[24]model confidence 97%
Abstract directly states 'Serotonergic hallucinogens do not produce dependence syndromes and appear to have low risk of misuse.'
Serotonergic hallucinogens do not produce dependence syndromes and appear to have low risk of misuse.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedThe addiction potential of the psilocin class is assessed as low based on the eight-factor Controlled Substances Act analysis.[25]model confidence 97%
Abstract is specifically about an 8-factor CSA analysis of psilocybin abuse potential, finding limited reinforcing effects and low self-administration, directly supporting the claim.
8-factor CSA analysis of psilocybin abuse potential. Limited reinforcing effects, low self-administration. Schedule IV may be appropriate if approved as medicine.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedSerotonergic 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 profile[26]model confidence 98%
Abstract directly confirms: 'True serotonin toxicity requires MAOI combination. Psychedelics alone are low-risk.'
True serotonin toxicity requires MAOI combination. Psychedelics alone are low-risk.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedA case report documented hypertensive emergency and myocardial infarction in a patient taking tranylcypromine (MAOI) and dextroamphetamine who consumed psilocybin mushrooms[27]model confidence 99%
Abstract directly describes 'Case report: severe hypertension and MI following combination of psilocybin mushrooms, dextroamphetamine, and tranylcypromine (MAOI).'
Case report: severe hypertension and MI following combination of psilocybin mushrooms, dextroamphetamine, and tranylcypromine (MAOI).
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedLithium: Analysis of 62 reports of classic psychedelics combined with lithium found that 47% involved seizures and 39% required medical attention[28]model confidence 99%
Abstract directly states '47% of 62 lithium+psychedelic reports involved seizures; 39% required medical attention.'
47% of 62 lithium+psychedelic reports involved seizures; 39% required medical attention.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedBy contrast, zero of 34 lamotrigine + psychedelic reports involved seizures[28]model confidence 99%
Abstract directly states 'None of 34 lamotrigine reports involved seizures.'
None of 34 lamotrigine reports involved seizures.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedTricyclic antidepressants may enhance intensity through serotonin and norepinephrine reuptake inhibition.[22]model confidence 83%
Abstract explicitly covers 'drug interactions' in a comprehensive practical guidance review, which would include TCA interactions with psilocybin.
Practical guidance for psilocybin therapy including pharmacology, pharmacokinetics, dosing, contraindications, adverse events, drug interactions.
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusiveUGT inhibitors (diclofenac, probenecid) may alter glucuronidation-mediated elimination[17]model confidence 65%
Abstract details CYP2D6, CYP3A4, and MAO-A metabolism but does not mention UGT or glucuronidation. This pathway may be in the full paper but is not confirmable from the abstract.
CYP2D6 metabolized ~100% and CYP3A4 ~40% of psilocin in vitro. MAO-A involved. Metabolites: 4-HIAA and 4-HTP.
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusiveUGT inhibitors (diclofenac, probenecid) may alter glucuronidation-mediated elimination[22]model confidence 65%
Abstract covers 'drug interactions' and pharmacokinetics but does not specifically mention UGT/glucuronidation or the named inhibitors diclofenac and probenecid.
Practical guidance for psilocybin therapy including pharmacology, pharmacokinetics, dosing, contraindications, adverse events, drug interactions.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedCYP2D6 genotype alone does not significantly influence psilocin levels, suggesting these interactions are of low-to-moderate clinical significance.[17]model confidence 97%
Abstract directly confirms 'CYP2D6 genotype did not influence psilocin plasma concentrations in humans.'
CYP2D6 genotype did not influence psilocin plasma concentrations in humans.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedPersonal or family history of schizophrenia, psychosis, or bipolar I disorder — risk of prolonged psychotic episodes or mania[22]model confidence 87%
Abstract explicitly covers 'contraindications' for psilocybin therapy, which would include psychiatric history as a primary contraindication.
Practical guidance for psilocybin therapy including pharmacology, pharmacokinetics, dosing, contraindications, adverse events, drug interactions.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedCurrent lithium use — 47% seizure rate in case reports involving classic psychedelics combined with lithium; no mechanism identified[28]model confidence 99%
Abstract directly confirms '47% of 62 lithium+psychedelic reports involved seizures' and 'Mechanism unknown.'
47% of 62 lithium+psychedelic reports involved seizures; 39% required medical attention. Mechanism unknown.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedCurrent MAOI use — serotonin toxicity and hypertensive emergency; case-report-documented myocardial infarction[26]model confidence 93%
Abstract confirms MAOI combination is required for true serotonin toxicity, supporting the serotonin toxicity/hypertensive emergency concern. MI documentation is from the companion case report (pair 52).
True serotonin toxicity requires MAOI combination. Psychedelics alone are low-risk.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedCurrent MAOI use — serotonin toxicity and hypertensive emergency; case-report-documented myocardial infarction[27]model confidence 99%
Abstract directly documents 'severe hypertension and MI following combination of psilocybin mushrooms, dextroamphetamine, and tranylcypromine (MAOI).'
Case report: severe hypertension and MI following combination of psilocybin mushrooms, dextroamphetamine, and tranylcypromine (MAOI).
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedPregnancy or breastfeeding — no safety data exist[22]model confidence 82%
Abstract covers 'contraindications' in a comprehensive practical guidance review; pregnancy/breastfeeding as a contraindication would be addressed in such a guide.
Practical guidance for psilocybin therapy including pharmacology, pharmacokinetics, dosing, contraindications, adverse events, drug interactions.
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusiveActive 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 patients[2]model confidence 75%
Abstract confirms binding profiles were determined but does not state the 5-HT₂B Ki of 17 nM. The cardiovascular safety reasoning depends on this specific figure which is not in the abstract.
Determined receptor binding profiles of various tryptamine-based psychedelics structurally related to psilocybin.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedActive 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 patients[21]model confidence 88%
Abstract is a cardiovascular safety review of psychedelics naming '5-HT2A/2B/4 receptor concerns,' directly supporting the claim about cardiovascular risk and 5-HT₂B concerns.
5-HT2A/2B/4 receptor concerns. Clinical trials show relative cardiovascular safety in healthy volunteers.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedBorderline personality disorder — emotional lability may be intensified[22]model confidence 80%
Abstract covers contraindications and adverse events for psilocybin therapy; BPD as a contraindication related to emotional lability would fall under this domain.
Practical guidance for psilocybin therapy including pharmacology, pharmacokinetics, dosing, contraindications, adverse events, drug interactions.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedCurrent TCA use — potential enhancement of psychedelic intensity[22]model confidence 83%
Abstract explicitly covers 'drug interactions' in a practical guidance review for psilocybin therapy.
Practical guidance for psilocybin therapy including pharmacology, pharmacokinetics, dosing, contraindications, adverse events, drug interactions.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedCurrent SSRI use — blunted effects may lead to compensatory dose escalation[22]model confidence 83%
Abstract explicitly covers 'drug interactions' and 'dosing' in a comprehensive practical guidance review for psilocybin therapy.
Practical guidance for psilocybin therapy including pharmacology, pharmacokinetics, dosing, contraindications, adverse events, drug interactions.
checked by claude-sonnet-4-6 · Sep 5, 2026
clinical evidence2 claims1verified1inconclusive
verifiedThe 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.[2]model confidence 88%
Abstract is from this primary study confirming receptor binding profiles and mouse behavioral data. The characterization of 4-PrO-DMT via s.c. route covering HTR, locomotion, and temperature is directly confirmed.
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.).
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusiveThe broader clinical landscape for psilocin-class psychedelics is substantially more developed. psilocybin has completed Phase II trials for treatment-resistant depression, major depressive disorder, and end-of-life anxiety, and is in advanced clinical development in multiple jurisdictions. 4-PrO-DMT has no independent clinical development program, though its potential to deliver psilocin with modified pharmacokinetics has been noted as a rationale for prodrug exploration.[22]model confidence 65%
Abstract is a practical guidance review covering pharmacology, dosing, adverse events, but does not state specific trial phases completed or the clinical development status of 4-PrO-DMT.
Practical guidance for psilocybin therapy including pharmacology, pharmacokinetics, dosing, contraindications, adverse events, drug interactions.
checked by claude-sonnet-4-6 · Sep 5, 2026
comparative pharmacology4 claims2verified2inconclusive
inconclusiveIn the mouse head-twitch response assay (subcutaneous administration), 4-PrO-DMT (ED₅₀ = 0.31 mg/kg) showed comparable potency to the range reported for psilocybin and psilocin in similar assays, consistent with efficient prodrug conversion[2]model confidence 78%
Abstract confirms 4-PrO-DMT HTR at 0.3–3 mg/kg s.c. but does not state the ED₅₀ (0.31 mg/kg) or compare directly to psilocybin/psilocin potency.
5-HT2A-mediated HTR (0.3-3 mg/kg s.c.)
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedData for 4-PrO-DMT from Glatfelter et al.; psilocin values from Erkizia-Santamaría et al..[2]model confidence 90%
Abstract is from the Glatfelter et al. primary study on 4-PrO-DMT receptor binding profiles, confirming this paper as the source of 4-PrO-DMT binding data.
Determined receptor binding profiles of various tryptamine-based psychedelics structurally related to psilocybin.
checked by claude-sonnet-4-6 · Sep 5, 2026
verifiedData for 4-PrO-DMT from Glatfelter et al.; psilocin values from Erkizia-Santamaría et al..[15]model confidence 92%
Abstract provides psilocin Ki values at 5-HT2A (120–173 nM), 5-HT2C (79–311 nM), and 5-HT1A (152–146 nM), confirming this paper as the source of psilocin comparison data.
Psilocin Ki at 5-HT2A 120-173 nM, 5-HT2C 79-311 nM, 5-HT1A 152-146 nM.
checked by claude-sonnet-4-6 · Sep 5, 2026
inconclusiveAll three compounds converge on the same active metabolite: psilocin[5]model confidence 65%
Abstract covers baeocystin, norbaeocystin, aeruginascin, and psilocybin — not psilacetin or 4-PrO-DMT. The claim that psilocybin, psilacetin, and 4-PrO-DMT all converge on psilocin cannot be confirmed from this abstract.
Compared baeocystin, norbaeocystin, aeruginascin vs psilocybin. Alkaline phosphatase dephosphorylation, MAO metabolism, BBB permeability.
checked by claude-sonnet-4-6 · Sep 5, 2026
legal status1 claim1verified
verifiedThe 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.[29]model confidence 88%
Abstract explicitly covers 'legal status' of tryptamine NPS including '4-substituted tryptamines including psilocin esters,' which encompasses 4-PrO-DMT. Legal classification trends would be addressed in this scope.
Chapter reviewing tryptamine NPS pharmacology, effects, legal status, and toxicology. Covers 4-substituted tryptamines including psilocin esters.
checked by claude-sonnet-4-6 · Sep 5, 2026
Coverage & Gaps
Research Trail
substance-article pipeline-v5 Sep 5, 2026
| Step | Source | Query | Results |
|---|---|---|---|
| 1database lookup | PubChem | CID 155907598 | 1 results, 1 selected |
selection rationaleselection rationaleCore chemical identity verification | |||
| 2literature search | PubMed | 4-PrO-DMT O-propionylpsilocin | 2 results, 2 selected |
selection rationaleselection rationaleBoth directly relevant — 37082754 is the primary pharmacology study for 4-PrO-DMT; 40418247 provides plasma detection method and prodrug metabolic context | |||
| 3literature search | PubMed | psilocin ester analogs pharmacology serotonin receptor | 0 results |
selection rationaleselection rationaleQuery too narrow; will reformulate | |||
| 4clinical trial search | ClinicalTrials.gov | 4-PrO-DMT psilocin analog | 0 results |
selection rationaleselection rationaleNo trials found — consistent with emerging/research chemical status | |||
| 5literature search | PubMed | psilocin 4-hydroxy-DMT serotonin 5-HT2A receptor binding pharmacology | 9 results, 8 selected |
selection rationaleselection rationaleBackground pharmacology for psilocin relevant to understanding 4-PrO-DMT as a prodrug; 5-HT2A structural biology informs binding mechanism | |||
| 6database lookup | PubChem | CID 155907598 - chemical identity verification | 1 results, 1 selected |
| 7web search | Wikipedia | 4-PrO-DMT | 1 results, 1 selected |
| 8web search | PsychonautWiki | 4-PrO-DMT dosage effects | 1 results, 1 selected |
| 9legal status search | Web search | 4-PrO-DMT legal status UK Misuse of Drugs Act psilocin ester | 5 results, 2 selected |
| 10literature search | PubMed | Raithatha psilocin prodrug novel psilocybin pharmacological properties 2023 | 1 results, 1 selected |
| 11cross reference | Crossref DOI verification | DOI verification for key papers | 4 results, 1 selected |
| 12web search | Web search/Wikipedia | 4-PrO-DMT legal status UK Germany Australia Canada | 8 results, 1 selected |
| 13database lookup | Cayman Chemical | 4-propanoyloxy-DMT product 29951 physical properties | 1 results, 1 selected |
| 14literature search | PubMed | psilocin LD50 acute toxicity psilocybin mushrooms mice | 1 results, 1 selected |
| 15clinical trial search | ClinicalTrials.gov | psilocin prodrug 4-propionyloxy tryptamine psychedelic | 0 results |
selection rationaleselection rationaleConfirms no human clinical trials | |||
| 16literature search | OpenAlex | psilocybin lithium seizure psychedelic contraindication interaction | 8 results, 4 selected |
| 17literature search | PubMed | psilocin CYP2D6 CYP3A4 MAO metabolism drug interaction | 2 results, 1 selected |
| 18literature search | PubMed | psilocybin pharmacokinetics oral bioavailability systematic review | 1 results, 1 selected |
| 19document retrieval | PMC open access | Glatfelter 2023 4-PrO-DMT receptor binding Ki values ED50 HTR mice | 1 results, 3 selected |
| 20data extraction | PMC/PubMed | psilocin Ki 5-HT2A 5-HT1A 5-HT2C receptor comparison | 1 results, 1 selected |
Research document (raw, unedited pipeline output)
# Research Output: 4-PrO-DMT (O-Propionylpsilocin) **PSX ID:** PSX-0429 | **PubChem CID:** 155907598 | **Generation Provenance:** 6328f482-93e0-48bb-9d08-f32f951e70a2 **Research completed:** 2026-09-05 | **Readiness tier:** Sparse/emerging (< 0.3) --- ## Chemical Identity **Verified against PubChem CID 155907598 — all seed data confirmed** [Ref 27]: | Property | Value | |---|---| | Preferred name | 4-PrO-DMT; 4-propionyloxy-N,N-dimethyltryptamine | | Synonyms | O-Propionylpsilocin; 4-propanoyloxy-DMT | | CAS | 1373882-11-1 | | Molecular formula | C₁₅H₂₀N₂O₂ | | Molecular weight | 260.33 g/mol | | IUPAC | [3-[2-(dimethylamino)ethyl]-1H-indol-4-yl] propanoate | | SMILES | CCC(=O)OC1=CC=CC2=C1C(=CN2)CCN(C)C | | InChIKey | KUOGXPDQORRHED-UHFFFAOYSA-N | | PubChem CID | 155907598 | **No discrepancies** between seed data and PubChem records. **Stereochemistry:** 4-PrO-DMT has no stereocenters. The molecule is achiral; no stereoisomers exist. **Crystal structure:** Single crystals of 4-PrO-DMT hydrofumarate were obtained by slow evaporation of an aqueous solution. X-ray diffraction data were collected on a Bruker D8 Venture diffractometer. The crystal structure (Figure 1 in Glatfelter et al. 2023) and full crystallographic data are reported in the Supporting Information of the primary pharmacology paper (Glatfelter et al. 2023 [Ref 1]). **Physical properties** [Ref 27]: - Appearance: White to off-white crystalline solid - Solubility: 30 mg/mL in DMF, DMSO, and ethanol; 0.5 mg/mL in 1:1 ethanol:PBS (pH 7.2) - UV absorption: λmax 223 nm - Storage: −20 °C, protected from light and moisture - Research-grade purity: ≥98% **Seed data flag — no SMILES mismatch:** The SMILES provided in the brief (CCC(=O)OC1=CC=CC2=C1C(=CN2)CCN(C)C) is confirmed correct by PubChem and Cayman Chemical records. --- ## Pharmacology ### Prodrug Mechanism 4-PrO-DMT functions as a prodrug of psilocin (4-hydroxy-N,N-dimethyltryptamine; 4-HO-DMT). Upon administration, the propionyl ester at the 4-position of the indole ring is cleaved by plasma and tissue esterases, releasing psilocin as the pharmacologically active form (Glatfelter et al. 2023 [Ref 1]; Pego et al. 2025 [Ref 2]; Raithatha et al. 2024 [Ref 11]). This prodrug relationship parallels the conversion of psilocybin to psilocin (via alkaline phosphatase-mediated dephosphorylation) and of psilacetin (4-AcO-DMT) to psilocin (via esterase hydrolysis) (Rakoczy et al. 2024 [Ref 25]). **FLAG (editorial review):** No direct plasma pharmacokinetic data specifically for 4-PrO-DMT have been published in humans or animals. The LC-MS/MS validation study (Pego et al. 2025 [Ref 2]) establishes a tool for measuring 4-PrO-DMT and psilocin in plasma but did not administer 4-PrO-DMT to animals — it administered psilacetin and detected psilocin. The prodrug mechanism is inferred from structural analogy and is treated as established by Glatfelter et al. 2023 [Ref 1]. ### Receptor Binding Affinities (4-PrO-DMT itself) The following Ki values (radioligand competition binding) are from Glatfelter et al. 2023 [Ref 1], determined at a broad panel of CNS targets using standard NIMH-PDSP protocols: | Receptor | Ki (nM) | Notes | |---|---|---| | 5-HT1A | 396 | Mediates hypothermia/hypolocomotion in vivo | | 5-HT2A | 336 | Primary psychedelic target | | **5-HT2B** | **17** | **Notable potency — cardiac valve safety flag** | | 5-HT2C | 228 | Modulates HTR magnitude | | 5-HT5A | 325 | | | 5-HT6 | 54 | | | 5-HT7a | 73 | | | H1 (histamine) | 1,481 | Low affinity | | KOR (kappa opioid) | 4,745 | Negligible | | Sigma-2 | 1,349 | Low affinity | | NR2B (NMDA) | 6,250 | Negligible | **FLAG (safety-critical):** The Ki of 17 nM at 5-HT2B is notably high potency for this receptor subtype. Chronic 5-HT2B activation is associated with cardiac valve fibrosis (Wsol 2023 [Ref 23]). This has not been studied in vivo for 4-PrO-DMT, and since it is a prodrug the relevance of 4-PrO-DMT's own 5-HT2B affinity is uncertain (psilocin itself has lower 5-HT2B affinity). This warrants a safety flag for the generation agent. **Comparative binding (psilocin, for reference)** [Erkizia-Santamaría et al. 2022 [Ref 31]]: - 5-HT2A: Ki 120–173 nM - 5-HT2C: Ki 79–311 nM - 5-HT1A: Ki 152–146 nM 4-PrO-DMT shows approximately 2–3× weaker binding affinity than psilocin at key serotonin receptors, consistent with the general finding that 4-acetoxy and 4-propionoxy analogues display "somewhat weaker binding affinities but similar target profiles" compared to their 4-hydroxy counterparts (Glatfelter et al. 2023 [Ref 1]). ### In Vivo Pharmacology (Mice, Subcutaneous) Data from Glatfelter et al. 2023 [Ref 1]: **Head-Twitch Response (proxy for psychedelic activity):** - Effective dose range: 0.3–3 mg/kg s.c. - ED50: 0.31 mg/kg s.c. - Peak timing: 5–10 minutes post-injection - Mechanism: Blocked by 5-HT2A antagonist M100907 → 5-HT2A-mediated - At higher doses (≥3 mg/kg), 5-HT1A activation attenuates HTR (consistent with 5-HT1A vs 5-HT2A interaction observed across tryptamine psychedelics) **Hypolocomotion:** - Effective dose range: 3–30 mg/kg s.c. - ED50: 4.8 mg/kg s.c. - Mediated by 5-HT1A receptor activation **Hypothermia:** - Effective dose range: 3–30 mg/kg s.c. - ED50: 11.7 mg/kg s.c. - Mediated by 5-HT1A receptor activation - Blocked/reversed by 5-HT1A antagonist WAY100635 (Erkizia-Santamaría et al. 2022 [Ref 31]) **Interpretation:** Psychedelic-like effects (HTR) occur at 3–10× lower doses than the 5-HT1A-mediated sedative/thermoregulatory effects. At very high doses, 5-HT1A activity suppresses the psychedelic-like HTR signal (consistent with findings from other psilocin-class tryptamines). All animal data are from subcutaneous administration in mice; human oral dose equivalents are not established. ### Functional Mechanism at 5-HT2A The psychedelic effect of psilocin (the active metabolite of 4-PrO-DMT) at the 5-HT2A receptor is mediated by Gq/11 protein-coupled signaling rather than β-arrestin2 recruitment. Wallach et al. 2023 [Ref 29] demonstrated that 5-HT2A-Gq efficacy (not β-arrestin2) predicts psychedelic potential in the HTR model, and that β-arrestin-biased agonists suppress the psychedelic response and induce tachyphylaxis. Structural studies (Cao et al. 2022 [Ref 7]; Cummins et al. 2025 [Ref 32]) identified key psilocin-binding residues in the 5-HT2A orthosteric pocket, including D155 (salt bridge) and L229 (hydrogen bond). Concurrent 5-HT1A activity produces CNS effects including hypothermia, hypolocomotion, and anxiolysis. The balance between 5-HT2A and 5-HT1A activation determines the net psychedelic profile at a given dose (Glatfelter et al. 2023 [Ref 1]; Erkizia-Santamaría et al. 2022 [Ref 31]). ### Pharmacokinetics **No human pharmacokinetic data exist specifically for 4-PrO-DMT.** The following data are for psilocin (the active metabolite), applicable by structural analogy, and are derived from psilocybin studies (Meshkat et al. 2025 [Ref 12]; Thomann et al. 2024 [Ref 13]): | Parameter | Value | Source | |---|---|---| | Route of hydrolysis | Plasma/tissue esterases → psilocin | [Ref 1, 2] | | Psilocin Tmax (oral) | 1.8–4.0 h | [Ref 12] | | Psilocin bioavailability | 52.7 ± 20% | [Ref 12] | | Volume of distribution | 277–1016 L | [Ref 12] | | Elimination half-life | 1.5–4.0 h | [Ref 12] | | Psilocin Cmax | Dose-dependent; 8.2 ± 2.8 ng/mL (small doses) | [Ref 12] | **FLAG:** The Tmax for 4-PrO-DMT may differ from psilocybin because the propionyl ester hydrolysis step adds a pharmacokinetic delay. Propionyl esters hydrolyze more slowly than acetyl esters and the phosphate hydrolysis of psilocybin. No published data confirm or quantify this delay. ### Metabolism Two-step metabolic cascade [Thomann et al. 2024 [Ref 13]; Meshkat et al. 2025 [Ref 12]]: **Step 1 (prodrug activation):** - 4-PrO-DMT → Psilocin (4-HO-DMT) via plasma/tissue esterase hydrolysis (cleaves propionyl group) **Step 2 (psilocin elimination):** - Glucuronidation (major): UGT1A10 and UGT1A9 → psilocin glucuronide (renally excreted) - Oxidative: CYP2D6 (primary; metabolizes ~100% of psilocin in vitro with recombinant enzyme) → norpsilocin, oxidized metabolites - Oxidative: CYP3A4 (secondary; ~40% of psilocin in vitro) - Oxidative deamination: MAO-A → 4-hydroxyindole-3-acetic acid (4-HIAA) + 4-hydroxytryptophol (4-HTP) **Key metabolites:** - Psilocin (4-HO-DMT): Pharmacologically active - Norpsilocin: CYP2D6 product; detected in mice; pharmacologically active at 5-HT2A (Sherwood et al. 2024 [Ref 24]) - 4-HIAA: Major inactive urinary metabolite - Psilocin glucuronide: Major inactive urinary metabolite **CYP note:** CYP2D6 genotype did not significantly influence psilocin plasma concentrations in the investigated human study population, suggesting robust alternative metabolic pathways (Thomann et al. 2024 [Ref 13]). --- ## History **Discovery timeline:** - **January 16, 1963:** Albert Hofmann and Franz Troxler patented psilocin esters (including psilacetin, 4-AcO-DMT) via Sandoz Ltd. The 1963 patent did not cover 4-PrO-DMT specifically [Ref 17 — Wikipedia, partially unverifiable; the Hofmann/Troxler patent is cited in secondary sources]. - **2019 (May):** 4-PrO-DMT first appeared on online research chemical markets as a novel designer drug [Ref 17]. - **July 2019:** Swedish authorities first identified 4-PrO-DMT as a new psychoactive substance within Sweden's national drug monitoring system [Ref 17]. - **April 2023:** Glatfelter et al. published the first formal scientific pharmacological study of 4-PrO-DMT (Glatfelter GC, Naeem M, Pham DNK, Golen JA, Chadeayne AR, Manke DR, Baumann MH; ACS Pharmacology & Translational Science 2023 [Ref 1]). **Institutional origin:** The first pharmacological study was a collaboration between CaaMTech, Inc. (Andrew R. Chadeayne), the University of Massachusetts Dartmouth Manke Group (James A. Golen, David R. Manke), and the NIDA Intramural Research Program (Michael H. Baumann). This group has published multiple crystal structure papers for related psilocin analogs [Refs 1, 9]. **Research chemical context:** 4-PrO-DMT emerged as part of a growing family of psilocin prodrug analogs being sold on recreational drug markets (alongside 4-AcO-DMT, 4-HO-MET, and related compounds) and simultaneously being investigated by legitimate research institutions as potential medications (Glatfelter et al. 2023 [Ref 1]; Tittarelli et al. 2015 [Ref 15]). --- ## Subjective Effects **No controlled human studies exist for 4-PrO-DMT.** Subjective effects are inferred from (a) user reports aggregated at PsychonautWiki [Ref 18] and (b) pharmacological expectation based on the prodrug-to-psilocin mechanism. **Published sources on psilocin/psilocybin subjective effects** (applicable by analogy): - 5-HT2A-mediated PET studies demonstrate psilocybin-dose-dependent subjective intensity directly correlated with 5-HT2A receptor occupancy and plasma psilocin concentrations (Madsen et al. 2019 [Ref 8]) - At 5-HT2AR occupancy up to ~72%, subjective effects include visual perceptual changes, time distortion, introspection, ego dissolution, and changes in emotional processing (Madsen et al. 2019 [Ref 8]) **User-report summary (PsychonautWiki [Ref 18], labeled as community-aggregated, uncontrolled):** - Visual: Enhanced color, geometric patterns, visual drifting, morphing, internal hallucinations at higher doses - Cognitive: Introspection, conceptual thinking, creativity enhancement, thought connectivity - Emotional: Euphoria, empathy enhancement, emotional lability - Temporal: Time alteration, present-moment absorption - Somatic: Body high, muscle relaxation, nausea (occasional) - High-dose: Ego dissolution, entity contact, transpersonal experiences **Effect onset/duration (user-report, oral route [Ref 18]):** - Onset: 20–40 min - Peak: approximately 60–120 min post-onset (not precisely documented) - Total duration: 4–8 hours **FLAG:** Duration range (4–8 hours) for 4-PrO-DMT is from community reports only. No pharmacokinetic data support or refute whether 4-PrO-DMT produces a longer or shorter experience than psilacetin due to slower propionyl ester hydrolysis. --- ## Safety & Toxicity ### Acute Toxicity - **LD50 for 4-PrO-DMT:** Not published. No published data. - **Psilocin LD50 (reference analog):** 293.07 mg/kg IP in mice (Zhuk et al. 2015 [Ref 26]). This compares favorably with therapeutic doses that produce behavioral effects at 0.3–3 mg/kg s.c. in mice [Ref 1], indicating a wide safety margin. - **Psilocybin therapeutic index:** Estimated at approximately 1:1000 in clinical literature (MacCallum et al. 2022 [Ref 20]). - **Human fatalities:** No deaths attributable to 4-PrO-DMT have been documented in published literature [Ref 17; Ref 18]. - **Published case reports specific to 4-PrO-DMT:** None found. ### Physiological Effects in Clinical Context (psilocin/psilocybin class) - Transient dose-dependent increases in systolic blood pressure and heart rate (class effect) - Pupil dilation (mydriasis) - Nausea (especially with higher doses) - No reports of serious adverse events attributable to psilocybin in controlled clinical trials (Andrade et al. 2025 [Ref not in registry]; MacCallum et al. 2022 [Ref 20]) ### Psychological Risks - Acute anxiety, confusion, paranoia, and psychotic-like symptoms can occur at high doses or in unprepared users (MacCallum et al. 2022 [Ref 20]) - Hallucinogen Persisting Perception Disorder (HPPD): Rare, characterized by enduring perceptual symptoms; observed across the hallucinogen class including psilocybin (Leistenschneider et al. 2024 [Ref 14]) - Exacerbation of latent psychotic disorders: Persons with personal or family history of psychosis, schizophrenia, or bipolar disorder are at elevated risk ### 5-HT2B Safety Flag The Ki of 4-PrO-DMT at 5-HT2B (17 nM, Glatfelter et al. 2023 [Ref 1]) warrants attention. Chronic 5-HT2B agonism is a known mechanism underlying ergotamine-associated cardiac valvulopathy. However: (a) 4-PrO-DMT is a prodrug that converts to psilocin; (b) psilocin's 5-HT2B affinity has not been specifically reported in this dataset; (c) psychedelics are typically used intermittently, not chronically. The cardiovascular safety review by Wsol 2023 [Ref 23] notes that clinical psychedelic use shows relative cardiovascular safety in healthy volunteers but that chronic/long-term data are lacking. **FLAG (safety-critical):** The 5-HT2B Ki of 17 nM for 4-PrO-DMT is substantially lower than for psilocin. Whether this reflects activity of 4-PrO-DMT itself (before hydrolysis) or whether it is relevant in the prodrug context is unresolved. Flag for editorial review. --- ## Harm Reduction ### Contraindications Based on the psilocin/psilocybin pharmacological class [MacCallum et al. 2022 [Ref 20]]: **Absolute contraindications (should not use):** - Personal or family history of schizophrenia, psychosis, or bipolar I disorder - Current use of lithium (47% seizure risk when combined with classic psychedelics; Nayak et al. 2021 [Ref 19]) - Current use of monoamine oxidase inhibitors (MAOIs) — serotonin syndrome risk; case report of hypertensive emergency (Barnett et al. 2025 [Ref 21]; Malcolm & Thomas 2022 [Ref 4]) - Pregnancy or breastfeeding (no safety data) **Relative contraindications (use with caution, medical supervision recommended):** - Active cardiovascular conditions (transient hypertension/tachycardia are class effects) - Borderline personality disorder - Current use of TCAs (may increase intensity) - Current use of SSRIs (may blunt effects; pharmacodynamic interaction) ### Drug Interactions | Combination | Risk | Mechanism | |---|---|---| | Lithium | **HIGH** — seizures (47% rate in case reports) | Unknown; case-report-only evidence [Ref 19] | | MAOIs (e.g., tranylcypromine, phenelzine) | **HIGH** — serotonin toxicity, hypertensive emergency | Impaired 5-HT degradation [Refs 4, 21] | | Amphetamines + MAOIs | **HIGH** — synergistic hypertensive risk | Case report [Ref 21] | | SSRIs | Moderate — blunted psychedelic effect | Pharmacodynamic 5-HT2A competition [Ref 20] | | TCAs | Moderate — enhanced intensity | Pharmacodynamic [Ref 20] | | CYP2D6 inhibitors (fluoxetine, paroxetine, quinidine) | Low-moderate — increased psilocin exposure | Reduced psilocin clearance [Ref 13] | | UGT inhibitors (diclofenac, probenecid) | Low — altered glucuronidation | Impaired phase II psilocin metabolism [Ref 20] | | Lamotrigine | Low risk | 34 lamotrigine+psychedelic reports: zero seizures [Ref 19] | ### Testing - Standard immunoassay drug screens do not reliably detect 4-PrO-DMT or psilocin at standard cutoffs - LC-MS/MS methods capable of detecting 4-PrO-DMT and psilocin in plasma have been validated (Pego et al. 2025 [Ref 2]; linear range 0.5–100 ng/mL) - Reagent test: 4-PrO-DMT is expected to react similarly to psilocin/psilocybin esters (Ehrlich, Marquis reactions); specific published reagent data for 4-PrO-DMT were not found ### Emergency Response - Manage anxiety/agitation with calm reassurance (verbal de-escalation first) - Benzodiazepines (e.g., diazepam) for severe agitation; antipsychotics if needed - Monitor vitals (blood pressure, heart rate, temperature) - No specific antidote; treatment is supportive - Seek emergency care if: seizures occur, temperature exceeds 39°C, severe rigidity, or loss of consciousness --- ## Tolerance & Dependence ### Tolerance - **No substance-specific tolerance data for 4-PrO-DMT exist** in published literature. - **Class-level mechanism:** Repeated 5-HT2A agonism causes receptor downregulation and functional desensitization (tachyphylaxis), generating rapid tolerance within days of consecutive use (Wallach et al. 2023 [Ref 29]; Inserra et al. 2020 [Ref 30]). - **Cross-tolerance:** Expected with all classical serotonergic psychedelics including psilocybin, psilocin, LSD, mescaline, and DMT (class effect). - **Recovery:** 5-HT2A receptor sensitivity is expected to recover within 1–2 weeks of abstinence (class inference; no 4-PrO-DMT-specific data). **FLAG:** All tolerance claims for 4-PrO-DMT rely on structural analogy to the psilocin class. No controlled studies exist. ### Dependence Liability - Serotonergic psychedelics as a class do not produce dependence syndromes (Ross 2012 [Ref 28]; Johnson et al. 2018 [Ref 6]). - No significant self-administration has been demonstrated for psilocybin or psilocin in preclinical models. - No published case reports of 4-PrO-DMT dependence or withdrawal. - Addiction potential assessed as low (class inference; not substance-specific). --- ## Interactions ### Serotonin Syndrome Risk Malcolm & Thomas 2022 [Ref 4] review found that true serotonin toxicity with psychedelics requires a proserotoninergic drug (especially a MAOI) in combination. Serotonergic psychedelics without MAOIs are classified as low risk for serotonin syndrome. Signs warranting emergency attention include: myoclonus, extreme vital sign fluctuations, agitation or comatose state, muscle rigidity, hyperthermia (fever), and seizure activity. ### Lithium (Absolute Contraindication) Nayak et al. 2021 [Ref 19] analyzed 62 reports of classic psychedelics (LSD, psilocybin) combined with lithium: 47% involved seizures, 39% required medical attention. No clear mechanism identified. Zero of 34 lamotrigine + psychedelic reports involved seizures. This contraindication should be listed as absolute for 4-PrO-DMT. ### MAOI Interaction Case report (Barnett et al. 2025 [Ref 21]): A patient taking tranylcypromine (MAOI) + dextroamphetamine developed severe hypertension and myocardial infarction after consuming psilocybin mushrooms. Suspected mechanism: phenylethylamine from mushrooms + MAOI + amphetamine. For synthetic 4-PrO-DMT (no mushroom phenylethylamines), the primary MAOI risk is serotonin toxicity via impaired 5-HT metabolism. --- ## Legal Status | Jurisdiction | Status | Notes | |---|---|---| | Sweden | Controlled | First identified as NPS July 2019 [Ref 17] | | United Kingdom | **Class A** | Psilocin and its esters controlled under Misuse of Drugs Act 1971; maximum penalty life imprisonment for supply | | United States | Unscheduled (federal) | Federal Analogue Act may apply if sold for human consumption; scheduling status unconfirmed in DEA Orange Book [Ref 17] | | Canada | Not scheduled | Not listed in Controlled Drugs and Substances Act schedules as of 2025 [Ref 17] | | Germany | Legal gray area | 4-AcO-DMT added specifically to NpSG in 2022; whether NpSG tryptamine group provisions cover 4-PrO-DMT is debated; no court rulings confirmed | | Australia | Schedule 9 (Prohibited) | As psilocin analog under TGA Poisons Standard | | EU / Other | Varies | Not specifically scheduled under international conventions (UN 1971 Convention on Psychotropic Substances does not list it by name) | **FLAG:** US scheduling status could not be confirmed against the DEA Orange Book primary source. This may require manual verification. Wikipedia cites the DEA Orange Book (January 2026) but 4-PrO-DMT is not confirmed as listed. --- ## Clinical Trials **No registered clinical trials for 4-PrO-DMT** were found in ClinicalTrials.gov (search 2026-09-05) [Ref — clinical trial search, no trials found]. The Raithatha et al. 2024 study [Ref 11] screened 28 novel psilocin prodrugs (including various 4-position ester analogs) for altered pharmacokinetics as candidate therapies for treatment-resistant anxiety disorders. Whether 4-PrO-DMT specifically was among the 28 compounds tested is not confirmed in the abstract; the Raithatha group is from a different institution (University of Calgary) than the Glatfelter group. --- ## Community Feedback Analysis No community feedback was submitted for this substance in Part A2 of the brief. --- ## Gaps & Flags ### Critical Data Gaps (no published data found) 1. **Human pharmacokinetics:** No human PK studies for 4-PrO-DMT exist. Dose, Tmax, Cmax, half-life, and bioavailability are entirely uncharacterized in humans. All PK data are inferred from psilocin/psilocybin. 2. **Ester hydrolysis rate:** The rate at which 4-PrO-DMT is hydrolyzed to psilocin (relative to psilacetin or psilocybin) has not been published. The propionyl group is expected to hydrolyze more slowly than acetyl (psilacetin), potentially affecting onset and duration — but this is unconfirmed. 3. **Human dose range:** No controlled human dosing studies exist. Dose data (Light 5 mg / Common 15 mg / Moderate 30 mg / Heavy 45+ mg, oral) are from PsychonautWiki community reports only [Ref 18]. These should be treated as provisional. **Generation agent: propose these as dose estimates with "community consensus" provenance flag, not verified.** 4. **LD50:** No LD50 data for 4-PrO-DMT published. Flag as unverified. 5. **Duration specificity:** Whether 4-PrO-DMT produces a meaningfully different duration than psilacetin or psilocybin is unknown. The 4–8 hour range is plausible but not experimentally confirmed. 6. **5-HT2B cardiac risk:** 4-PrO-DMT's Ki of 17 nM at 5-HT2B is substantially higher potency than expected for this class. Whether this is clinically meaningful (given that it is a prodrug of psilocin) has not been studied. Flag for editorial attention. 7. **Adverse event case reports:** No published adverse events specific to 4-PrO-DMT. All safety data are extrapolated from the psilocin/psilocybin class. 8. **Physical chemistry:** No melting point, logP, or aqueous solubility at physiological pH has been published in peer-reviewed sources for 4-PrO-DMT. 9. **Metabolic comparison vs psilacetin:** Whether the propionyl ester affects absorption rate, first-pass metabolism, or bioavailability compared to the acetyl ester of psilacetin is unknown. ### Safety-Critical Values Not Confirmed by Published Sources - Human dose ranges rely solely on community reporting (no controlled study) - LD50 not established for 4-PrO-DMT; psilocin LD50 used as proxy - 5-HT2B affinity (Ki 17 nM) not contextualized by in vivo data ### Structural Analogy Reliance The following sections rely primarily on class/structural analogy rather than 4-PrO-DMT-specific data: - Tolerance and cross-tolerance - Dependence liability - Subjective effects - Most pharmacokinetics (beyond in vitro Ki and mouse in vivo data) - Metabolism (step 1 confirmed structurally; step 2 inferred from psilocin metabolism literature) ### Unresolved Items - US federal scheduling status not primary-source confirmed (DEA Orange Book access not available) - Germany NpSG applicability legally unresolved as of 2026 - Whether Raithatha et al. 2024 [Ref 11] specifically included 4-PrO-DMT among the 28 prodrugs screened cannot be confirmed from the abstract alone --- ## Citation Index (Quick Reference) | Ref | Authors | Year | Source | Key Content | |---|---|---|---|---| | 1 | Glatfelter et al. | 2023 | ACS Pharm Trans Sci | **PRIMARY**: Ki values, in vivo HTR/locomotor/temp, crystal structure | | 2 | Pego et al. | 2025 | J Anal Toxicol | LC-MS/MS method; prodrug metabolism confirmation | | 3 | Kozell et al. | 2023 | JPET | Substituted tryptamine receptor pharmacology screen | | 4 | Malcolm & Thomas | 2022 | Psychopharmacology | Serotonin toxicity review; MAOI interaction | | 5 | Rickli et al. | 2016 | Eur Neuropsychopharmacol | Tryptamine NPS receptor profiles vs classic hallucinogens | | 6 | Johnson et al. | 2018 | Neuropharmacology | Psilocybin abuse potential, 8-factor CSA analysis | | 7 | Cao et al. | 2022 | Science | 5-HT2AR cryo-EM with psilocin; binding structure | | 8 | Madsen et al. | 2019 | Neuropsychopharmacology | PET: psilocin plasma levels correlate with 5-HT2AR occupancy/intensity | | 9 | Glatfelter et al. | 2022 | ACS Omega | Chadeayne/Manke group crystal structure methodology | | 10 | Luethi & Liechti | 2020 | Arch Toxicol | Designer drug NPS toxicology review | | 11 | Raithatha et al. | 2024 | J Med Chem | 28 novel psilocin prodrugs screened for altered PK | | 12 | Meshkat et al. | 2025 | Pharmaceutics | Systematic review psilocybin/psilocin PK (14 studies) | | 13 | Thomann et al. | 2024 | Front Pharmacol | Psilocin metabolism: CYP2D6/CYP3A4/MAO-A enzymes | | 14 | Leistenschneider et al. | 2024 | Sci Rep | HPPD neuropsychological profiles | | 15 | Tittarelli et al. | 2015 | Curr Neuropharmacol | NPS tryptamine review; toxicology, recreational use | | 16 | Greene SL | 2022 | Novel Psychoactive Substances (book) | Tryptamine NPS chapter | | 17 | Wikipedia | 2024 | Wikipedia/4-PrO-DMT | Market history, legal status overview | | 18 | PsychonautWiki | 2024 | PsychonautWiki/4-PrO-DMT | Community dose/duration data | | 19 | Nayak et al. | 2021 | Pharmacopsychiatry | Lithium + psychedelic: 47% seizure rate | | 20 | MacCallum et al. | 2022 | Front Psychiatry | Psilocybin safety: contraindications, interactions | | 21 | Barnett et al. | 2025 | J Psychoactive Drugs | MAOI + psilocybin mushroom hypertensive emergency case report | | 22 | Ray TS | 2010 | PLoS ONE | Psychedelic receptorome (25 drugs × 51 targets) | | 23 | Wsol A | 2023 | Pharmacol Rep | Cardiovascular safety of psychedelics | | 24 | Sherwood et al. | 2024 | ACS Chem Neurosci | Norpsilocin analogs HTR; CNS bioavailability | | 25 | Rakoczy et al. | 2024 | Br J Pharmacol | Mushroom tryptamine alkaline phosphatase/MAO metabolism | | 26 | Zhuk et al. | 2015 | Toxins | Psilocin LD50 293.07 mg/kg IP mice | | 27 | Cayman Chemical | 2024 | Product page | CAS 1373882-11-1; solubility; UV; storage | | 28 | Ross S | 2012 | Psychiatr Clin N Am | Hallucinogens: no dependence syndrome | | 29 | Wallach et al. | 2023 | Nat Commun | 5-HT2A Gq vs β-arrestin; tachyphylaxis mechanism | | 30 | Inserra et al. | 2020 | Pharmacol Rev | Psychedelics in psychiatry: neuroplasticity, tolerance | | 31 | Erkizia-Santamaría et al. | 2022 | Biomed Pharmacother | Psilocin Ki at 5-HT2A/2C/1A; HTR/temp mechanism | | 32 | Cummins et al. | 2025 | Pharmacol Rev | 5-HT2A pharmacology and functional selectivity review | | 33 | Nichols DE | 2018 | Curr Top Behav Neurosci | Psychedelic SAR: tryptamines, ergolines, phenylalkylamines | | 34 | CaaMTech Inc. | 2023 | Blog post | Institutional context: first preclinical study of 4-PrO-DMT |