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Psychedex

4-AcO-MET

4-acetoxy-N-methyl-N-ethyltryptamine

Sources
17
2 strong · 12 moderate · 3 weak

Studies and references cited across this article, graded by evidence strength.

Claims checked
48
31verified5partial12inconclusive

Inconclusive means the cited source neither confirms nor refutes the claim — a lower-confidence badge, not an error.

Generated
Apr 26, 2026 · pipeline-v5
Values approved
162/162 (100%)

Data points an editor reviewed and accepted for publication.

01

Value Provenance

Dosing

oraltrace

FieldPublishedAI ProposedConfidence
Threshold5 mg5 mgmedium
Low10–20 mg10–20 mgmedium
Common20–30 mg20–30 mgmedium
Strong30–50 mg30–50 mgmedium
Heavy50+ mg50+ mgmedium
Editorial

Dose ranges from seed data (community-curated pharmacological data), consistent with HandWiki (5–40 mg oral range) and Shulgin's TiHKAL entry for 4-HO-MET (10–20 mg active oral dose). Seed threshold 5 mg, light 10–20 mg, common 20–30 mg, strong 30–50 mg, heavy 50+ mg. These are existing database values being carried forward.

Reasoning

Dose ranges from seed data (community-curated pharmacological data), consistent with HandWiki (5–40 mg oral range) and Shulgin's TiHKAL entry for 4-HO-MET (10–20 mg active oral dose). Seed threshold 5 mg, light 10–20 mg, common 20–30 mg, strong 30–50 mg, heavy 50+ mg. These are existing database values being carried forward.

Evidence basis: community_consensus_large

Duration

oral

FieldPublishedAI ProposedConfidence
Onsettrace20–60 minutes20–60 minutesmedium
Editorial

Onset 20–60 minutes from seed data, consistent with psilocin-class tryptamine oral onset profiles.

Reasoning

Onset 20–60 minutes from seed data, consistent with psilocin-class tryptamine oral onset profiles.

Evidence basis: community_consensus_large

Peaktrace1–2 hours1–2 hoursmedium
Editorial

Peak 1–2 hours from seed data.

Reasoning

Peak 1–2 hours from seed data.

Evidence basis: community_consensus_large

Offsettrace2–4 hours2–4 hoursmedium
Editorial

Offset/aftereffects 2–4 hours from seed data.

Reasoning

Offset/aftereffects 2–4 hours from seed data.

Evidence basis: community_consensus_large

Totaltrace4–6 hours4–6 hoursmedium
Editorial

Total duration 4–6 hours from seed data and Shulgin's TiHKAL entry for 4-HO-MET. HandWiki lists 4–10 h, but the wider range likely reflects high-dose outliers. Shulgin's 4–6 h is the primary anchor.

Reasoning

Total duration 4–6 hours from seed data and Shulgin's TiHKAL entry for 4-HO-MET. HandWiki lists 4–10 h, but the wider range likely reflects high-dose outliers. Shulgin's 4–6 h is the primary anchor.

Evidence basis: community_consensus_large

Come uptrace30–60 minutes30–60 minutesmedium
Editorial

Come-up 30–60 minutes from seed data.

Reasoning

Come-up 30–60 minutes from seed data.

Evidence basis: community_consensus_large

After effectstrace2–4 hours2–4 hourslow
Editorial

Aftereffects duration estimated from psilocin-class tryptamine profiles. No direct data for 4-AcO-MET.

Reasoning

Aftereffects duration estimated from psilocin-class tryptamine profiles. No direct data for 4-AcO-MET.

Evidence basis: structural_analogy

Safety

Toxicity Profiletrace

FieldPublishedAI ProposedConfidence
Acutelowlowlow
Chronicnegligiblenegligiblelow
Organs Affectedcardiovascular, gastrointestinalcardiovascular, gastrointestinallow
Editorial

Classified as low acute toxicity (downgraded from moderate): all toxicity evidence derives from in silico prediction for the structural analog 4-AcO-DMT (Jurowski 2026), not from experimental data for 4-AcO-MET itself. Psilocin-class tryptamines are generally characterized as having wide therapeutic indices. Chronic toxicity classified as negligible based on low 5-HT2B affinity (McKenna 1990) and the absence of reported organ damage from psilocin-class compounds.

Reasoning

Classified as low acute toxicity (downgraded from moderate): all toxicity evidence derives from in silico prediction for the structural analog 4-AcO-DMT (Jurowski 2026), not from experimental data for 4-AcO-MET itself. Psilocin-class tryptamines are generally characterized as having wide therapeutic indices. Chronic toxicity classified as negligible based on low 5-HT2B affinity (McKenna 1990) and the absence of reported organ damage from psilocin-class compounds.

Evidence basis: structural_analogy

Dependence Profiletrace

FieldPublishedAI ProposedConfidence
Physicalnonenonemedium
Psychologicalnegligiblenegligiblemedium
Compulsive Redosingnegligiblenegligiblemedium
Dose Escalationnegligiblenegligiblemedium
Editorial

Low dependence liability is a well-established class property of classical serotonergic psychedelics (Schlag et al. 2022). Tolerance mechanism demonstrated in mice by de la Fuente Revenga et al. (2022). No substance-specific dependence data for 4-AcO-MET, but class-level evidence is robust.

Reasoning

Low dependence liability is a well-established class property of classical serotonergic psychedelics (Schlag et al. 2022). Tolerance mechanism demonstrated in mice by de la Fuente Revenga et al. (2022). No substance-specific dependence data for 4-AcO-MET, but class-level evidence is robust.

Evidence basis: structural_analogy

Withdrawal Profiletrace

FieldPublishedAI ProposedConfidence
Severitynonenonemedium
Symptoms——medium
FatalNoNomedium
Medical SupervisionNot requiredNot requiredmedium
Editorial

No withdrawal syndrome has been characterized for any classical serotonergic psychedelic. The absence of physical dependence formation precludes a withdrawal phenotype.

Reasoning

No withdrawal syndrome has been characterized for any classical serotonergic psychedelic. The absence of physical dependence formation precludes a withdrawal phenotype.

Evidence basis: structural_analogy

Tolerance Profiletrace

FieldPublishedAI ProposedConfidence
Builduprapidrapidmedium
Half-life3 days3 daysmedium
Full Reset7 days7 daysmedium
Cross-tolerancespsilocybin, psilocin, LSD, DMT, mescaline, 4-AcO-DMT, 4-HO-MiPTpsilocybin, psilocin, LSD, DMT, mescaline, 4-AcO-DMT, 4-HO-MiPTmedium
Editorial

Tolerance mechanism established by de la Fuente Revenga et al. (2022) for classical psychedelics via 5-HT2A receptor downregulation. Timing values (3-day half-life, 7-day full reset) from seed data/community consensus, consistent with published mechanistic data.

Reasoning

Tolerance mechanism established by de la Fuente Revenga et al. (2022) for classical psychedelics via 5-HT2A receptor downregulation. Timing values (3-day half-life, 7-day full reset) from seed data/community consensus, consistent with published mechanistic data.

Evidence basis: structural_analogy

Effects & Profile

Contraindications

FieldPublishedAI ProposedConfidence
psychiatric psychotic disorderstraceabsoluteabsolutemedium
Editorial

Class-level contraindication supported by MacCallum et al. (2022) psilocybin safety guidelines.

Reasoning

Class-level contraindication supported by MacCallum et al. (2022) psilocybin safety guidelines.

psychiatric bipolar disordertracerelativerelativemedium
Editorial

Class-level contraindication from psilocybin clinical literature (MacCallum et al. 2022).

Reasoning

Class-level contraindication from psilocybin clinical literature (MacCallum et al. 2022).

other lithium co-administrationtraceabsoluteabsolutemedium
Editorial

Class-level contraindication supported by MacCallum et al. (2022) and Simonsson et al. (2023).

Reasoning

Class-level contraindication supported by MacCallum et al. (2022) and Simonsson et al. (2023).

other MAOI co-administrationtraceabsoluteabsolutehigh
Editorial

Class-level contraindication for all tryptamine psychedelics, supported by MacCallum et al. (2022).

Reasoning

Class-level contraindication for all tryptamine psychedelics, supported by MacCallum et al. (2022).

other tramadol co-administrationtraceabsoluteabsolutemedium
Editorial

Mechanism-based contraindication supported by Baldo (2018) SERT inhibition data.

Reasoning

Mechanism-based contraindication supported by Baldo (2018) SERT inhibition data.

pregnancy breastfeeding pregnancytraceabsoluteabsolutemedium
Editorial

Precautionary contraindication consistent with MacCallum et al. (2022) psilocybin guidelines.

Reasoning

Precautionary contraindication consistent with MacCallum et al. (2022) psilocybin guidelines.

cardiovascular uncontrolled cardiovascular diseasetracerelativerelativelow
Editorial

Class-level cardiovascular caution. Jurowski et al. (2026) identified cardiovascular system as primary target organ for 4-AcO-DMT in silico.

Reasoning

Class-level cardiovascular caution. Jurowski et al. (2026) identified cardiovascular system as primary target organ for 4-AcO-DMT in silico.

Timeline Phases

oral

FieldPublishedAI ProposedConfidence
Onsettrace1200–3600 sec(i=0.05)1200–3600 sec(i=0.05)medium
Editorial

Timeline derived from seed data (onset 20\u201360 min, come-up 30\u201360 min, peak 1\u20132 h, offset 2\u20134 h, total 4\u20136 h) anchored by Shulgin's TiHKAL entry for 4-HO-MET (4\u20136 h total). HandWiki lists 4\u201310 h total, suggesting high-dose experiences may extend the timeline. Phase durations set to accommodate the middle 80% of experiences within the 4\u20136 h total range.

Reasoning

Timeline derived from seed data (onset 20\u201360 min, come-up 30\u201360 min, peak 1\u20132 h, offset 2\u20134 h, total 4\u20136 h) anchored by Shulgin's TiHKAL entry for 4-HO-MET (4\u20136 h total). HandWiki lists 4\u201310 h total, suggesting high-dose experiences may extend the timeline. Phase durations set to accommodate the middle 80% of experiences within the 4\u20136 h total range.

Come uptrace1800–3600 sec(i=0.35)1800–3600 sec(i=0.35)medium
Editorial

Timeline derived from seed data (onset 20\u201360 min, come-up 30\u201360 min, peak 1\u20132 h, offset 2\u20134 h, total 4\u20136 h) anchored by Shulgin's TiHKAL entry for 4-HO-MET (4\u20136 h total). HandWiki lists 4\u201310 h total, suggesting high-dose experiences may extend the timeline. Phase durations set to accommodate the middle 80% of experiences within the 4\u20136 h total range.

Reasoning

Timeline derived from seed data (onset 20\u201360 min, come-up 30\u201360 min, peak 1\u20132 h, offset 2\u20134 h, total 4\u20136 h) anchored by Shulgin's TiHKAL entry for 4-HO-MET (4\u20136 h total). HandWiki lists 4\u201310 h total, suggesting high-dose experiences may extend the timeline. Phase durations set to accommodate the middle 80% of experiences within the 4\u20136 h total range.

Peaktrace3600–7200 sec(i=1.00)3600–7200 sec(i=1.00)medium
Editorial

Timeline derived from seed data (onset 20\u201360 min, come-up 30\u201360 min, peak 1\u20132 h, offset 2\u20134 h, total 4\u20136 h) anchored by Shulgin's TiHKAL entry for 4-HO-MET (4\u20136 h total). HandWiki lists 4\u201310 h total, suggesting high-dose experiences may extend the timeline. Phase durations set to accommodate the middle 80% of experiences within the 4\u20136 h total range.

Reasoning

Timeline derived from seed data (onset 20\u201360 min, come-up 30\u201360 min, peak 1\u20132 h, offset 2\u20134 h, total 4\u20136 h) anchored by Shulgin's TiHKAL entry for 4-HO-MET (4\u20136 h total). HandWiki lists 4\u201310 h total, suggesting high-dose experiences may extend the timeline. Phase durations set to accommodate the middle 80% of experiences within the 4\u20136 h total range.

Plateautrace3600–5400 sec(i=0.50)3600–5400 sec(i=0.50)medium
Editorial

Timeline derived from seed data (onset 20\u201360 min, come-up 30\u201360 min, peak 1\u20132 h, offset 2\u20134 h, total 4\u20136 h) anchored by Shulgin's TiHKAL entry for 4-HO-MET (4\u20136 h total). HandWiki lists 4\u201310 h total, suggesting high-dose experiences may extend the timeline. Phase durations set to accommodate the middle 80% of experiences within the 4\u20136 h total range.

Reasoning

Timeline derived from seed data (onset 20\u201360 min, come-up 30\u201360 min, peak 1\u20132 h, offset 2\u20134 h, total 4\u20136 h) anchored by Shulgin's TiHKAL entry for 4-HO-MET (4\u20136 h total). HandWiki lists 4\u201310 h total, suggesting high-dose experiences may extend the timeline. Phase durations set to accommodate the middle 80% of experiences within the 4\u20136 h total range.

Resolutiontrace1800–3600 sec(i=0.20)1800–3600 sec(i=0.20)medium
Editorial

Timeline derived from seed data (onset 20\u201360 min, come-up 30\u201360 min, peak 1\u20132 h, offset 2\u20134 h, total 4\u20136 h) anchored by Shulgin's TiHKAL entry for 4-HO-MET (4\u20136 h total). HandWiki lists 4\u201310 h total, suggesting high-dose experiences may extend the timeline. Phase durations set to accommodate the middle 80% of experiences within the 4\u20136 h total range.

Reasoning

Timeline derived from seed data (onset 20\u201360 min, come-up 30\u201360 min, peak 1\u20132 h, offset 2\u20134 h, total 4\u20136 h) anchored by Shulgin's TiHKAL entry for 4-HO-MET (4\u20136 h total). HandWiki lists 4\u201310 h total, suggesting high-dose experiences may extend the timeline. Phase durations set to accommodate the middle 80% of experiences within the 4\u20136 h total range.

Afterglowtrace7200–14400 sec(i=0.05)7200–14400 sec(i=0.05)medium
Editorial

Timeline derived from seed data (onset 20\u201360 min, come-up 30\u201360 min, peak 1\u20132 h, offset 2\u20134 h, total 4\u20136 h) anchored by Shulgin's TiHKAL entry for 4-HO-MET (4\u20136 h total). HandWiki lists 4\u201310 h total, suggesting high-dose experiences may extend the timeline. Phase durations set to accommodate the middle 80% of experiences within the 4\u20136 h total range.

Reasoning

Timeline derived from seed data (onset 20\u201360 min, come-up 30\u201360 min, peak 1\u20132 h, offset 2\u20134 h, total 4\u20136 h) anchored by Shulgin's TiHKAL entry for 4-HO-MET (4\u20136 h total). HandWiki lists 4\u201310 h total, suggesting high-dose experiences may extend the timeline. Phase durations set to accommodate the middle 80% of experiences within the 4\u20136 h total range.

Dose Tier Summaries

thresholdtrace
medium

At threshold doses (approximately 5 mg oral), effects are subtle and easily overlooked. A mild brightening of colours, slight enhancement of ambient sounds, and gentle mood elevation may be perceptible. Some users report a light body awareness or mild tingling in the extremities. Cognitive effects are minimal — a faint sense of novelty or shifted attention without meaningful disruption of normal thought patterns. Physically, mild pupil dilation may be noticeable to an observer. Appetite and sleep are generally unaffected at this dose level. Functional impairment is negligible, though subtle perceptual shifts may persist for 2–3 hours.

Editorial

Threshold dose of 5 mg oral is consistent across seed data and community reports. Effects described by analogy with psilocin-class threshold experiences and Shulgin's characterization of 4-HO-MET as closely resembling psilocin.

Reasoning

Threshold dose of 5 mg oral is consistent across seed data and community reports. Effects described by analogy with psilocin-class threshold experiences and Shulgin's characterization of 4-HO-MET as closely resembling psilocin.

Evidence basis: community_consensus_large

lighttrace
medium

At light doses (10–20 mg oral), recognizable psychedelic effects emerge: colour saturation increases, surfaces may show faint visual drifting or breathing, and music gains emotional depth and textural richness. Thought connectivity begins to shift — associations feel looser and more creative. Emotional sensitivity increases, with both positive and challenging feelings amplified. Time distortion is mild but noticeable. Physically, pupil dilation becomes more apparent. Mild nausea during onset is possible, particularly on a full stomach. A light body load — described variably as warmth, heaviness, or gentle stimulation — is common. Functional capacity is reduced but not eliminated. This range corresponds to Shulgin's reported active dose for 4-HO-MET (10–20 mg oral). Duration at this level is typically 4–5 hours.

Editorial

Dose range aligns with Shulgin's TiHKAL entry for 4-HO-MET (10–20 mg). Effects profile inferred from psilocin-class pharmacology and Shulgin's qualitative description.

Reasoning

Dose range aligns with Shulgin's TiHKAL entry for 4-HO-MET (10–20 mg). Effects profile inferred from psilocin-class pharmacology and Shulgin's qualitative description.

Evidence basis: community_consensus_large

commontrace
medium

At common doses (20–30 mg oral), the full psychedelic experience develops. Visual effects become pronounced: geometric patterning overlays surfaces, colour enhancement intensifies, environmental objects may drift, morph, or breathe rhythmically. Closed-eye visuals feature complex geometric imagery. Time distortion is significant — minutes may feel expanded or compressed unpredictably. Thought acceleration and conceptual thinking increase substantially. Emotional responses to stimuli — music, nature, interpersonal interaction — can feel profoundly meaningful. Ego softening may begin, with the boundary between self and environment becoming less distinct. Thought loops are possible. Body load is moderate: nausea during come-up, jaw tension, temperature fluctuation, and difficulty with fine motor tasks are common. Sleep is not possible during the active phase. Total commitment is 5–6 hours including afterglow.

Editorial

20–30 mg common range from seed data, consistent with community reports. Effects profile based on psilocin-class 5-HT2A agonism and Shulgin's characterization of 4-HO-MET.

Reasoning

20–30 mg common range from seed data, consistent with community reports. Effects profile based on psilocin-class 5-HT2A agonism and Shulgin's characterization of 4-HO-MET.

Evidence basis: community_consensus_large

strongtrace
low

At strong doses (30–50 mg oral), psychedelic effects become intense and potentially overwhelming. Visual distortions are pervasive — environmental patterning, colour shifting, object morphing, and complex fractal geometry dominate the visual field. Ego dissolution may occur, with loss of normal self-referential processing. Thought patterns become highly non-linear, with profound conceptual insights interspersed with confusion or thought loops. Emotional intensity reaches a peak. Experiences range from mystical-type states of unity and meaning to acute anxiety and paranoia, heavily influenced by set and setting. Entity contact and transformative experiences are reported at this range. Physically, significant body load is expected: pronounced nausea, temperature dysregulation, jaw clenching, and complete loss of fine motor coordination. Sleep is impossible for 6+ hours. This dose range demands a safe, supported environment and an experienced sitter.

Editorial

30–50 mg strong range from seed data. Effects extrapolated from psilocin-class high-dose phenomenology. No controlled data at this dose level for 4-AcO-MET.

Reasoning

30–50 mg strong range from seed data. Effects extrapolated from psilocin-class high-dose phenomenology. No controlled data at this dose level for 4-AcO-MET.

Evidence basis: community_consensus_large

heavytrace
low

At heavy doses (50+ mg oral), 4-AcO-MET produces an extremely intense psychedelic experience that exceeds the capacity of most individuals to navigate without experienced support. Complete ego dissolution is likely — the normal sense of self, body, and environment may be entirely absent, replaced by abstract geometric, symbolic, or ineffable states. Memory formation is severely impaired; large portions of the experience may be unrecoverable afterward. Psychological risk is substantially elevated at this dose range. Panic reactions, persistent confusion, and trauma-like responses are possible, particularly in uncontrolled settings. Physical risks include severe nausea, vomiting, and pronounced sympathomimetic effects (tachycardia, blood pressure elevation). This dose range far exceeds Shulgin's characterized active dose for 4-HO-MET (10–20 mg). No safety data exist at this level. Total duration may extend beyond 6 hours, with aftereffects persisting considerably longer.

Editorial

Heavy dose threshold of 50+ mg from seed data. Effects extrapolated from psilocin-class pharmacology at high-dose ranges. No controlled or systematic data at this level. Safety profile unknown.

Reasoning

Heavy dose threshold of 50+ mg from seed data. Effects extrapolated from psilocin-class pharmacology at high-dose ranges. No controlled or systematic data at this level. Safety profile unknown.

Evidence basis: community_consensus_small

02

History

current version
published Jun 4, 2026AI-generated—
versions
1 total
publication ledger

backfill Jun 4, 2026

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.

full version history suggest a correctioncontact@psychedex.org
03

Sources

2 strong · 12 moderate · 3 weak
  1. [1]
    weak
    TiHKAL #21: 4-HO-MET (Erowid online reproduction)
    Shulgin A, Shulgin A · 1997
    linkno claims checked
  2. [2]
    weak
    4-AcO-MET (HandWiki)
    HandWiki contributors · 2023
    linkno claims checked
  3. [3]
    moderate
    Psilacetin derivatives: fumarate salts of the methyl-ethyl, methyl-allyl and diallyl variants of the psilocin prodrug
    Pham DNK, Chadeayne AR, Golen JA, Manke DR · 2021 · Acta Crystallographica Section E Crystallographic Communications
    doi.org/10.1107/s2056989021000116pubmed 336141344 claims checked4 verified
  4. [4]
    moderate
    Differential interactions of indolealkylamines with 5-hydroxytryptamine receptor subtypes
    McKenna DJ, Repke DB, Lo L, Peroutka SJ · 1990 · Neuropharmacology
    pubmed 21391867 claims checked4 verified1 partial2 inconclusive
  5. [5]
    moderate
    Pharmacologic Activity of Substituted Tryptamines at 5-HT2A, 5-HT2C, 5-HT1A Receptors and SERT
    Kozell LB, Eshleman AJ, Swanson TL, Bloom SH, Wolfrum KM, et al. · 2023 · Journal of Pharmacology and Experimental Therapeutics
    doi.org/10.1124/jpet.122.001454pubmed 366698753 claims checked3 verified
  6. [6]
    moderate
    In-silico toxicity study of tryptamine, psilocin, psilocybin, N,N-dimethyltryptamine, 5'-methoxy-N,N-dimethyltryptamine and O-acetylpsilocin
    Jurowski K, Kobylarz D, Noga M · 2026 · Archives of Toxicology
    doi.org/10.1007/s00204-026-04365-4pubmed 419151863 claims checked2 verified1 partial
  7. [7]
    moderate
    Tolerance and Cross-Tolerance among Psychedelic and Nonpsychedelic 5-HT2A Receptor Agonists in Mice
    de la Fuente Revenga M, Jaster AM, McGinn J, Silva G, Saha S, Gonzalez-Maeso J · 2022 · ACS Chemical Neuroscience
    doi.org/10.1021/acschemneuro.2c00170pubmed 359008763 claims checked1 verified2 partial
  8. [8]
    moderate
    Adverse effects of psychedelics: From anecdotes and misinformation to systematic science
    Schlag AK, Aday J, Salam I, Neill JC, Nutt DJ · 2022 · Journal of Psychopharmacology
    doi.org/10.1177/02698811211069100pubmed 351070594 claims checked4 inconclusive
  9. [9]
    moderate
    Therapeutic use of psilocybin: Practical considerations for dosing and administration
    MacCallum CA, Lo LA, Pistawka CA, Deol JK · 2022 · Frontiers in Psychiatry
    doi.org/10.3389/fpsyt.2022.1040217pubmed 365321845 claims checked1 verified4 inconclusive
  10. [10]
    moderate
    Identification of New Psychoactive Tryptamines 4-OH-MET and 4-AcO-DMT Using High Resolution Mass Spectrometry and Nuclear Magnetic Resonance Spectroscopy
    Ding KR, Ni CF, He SY, Wang KD, Deng QY, Liang C · 2021 · Fa Yi Xue Za Zhi
    doi.org/10.12116/j.issn.1004-5619.2021.310305pubmed 347260041 claim checked1 verified
  11. [11]
    strong
    Tentative identification of in vitro metabolites of O-acetylpsilocin (psilacetin, 4-AcO-DMT) by UHPLC-Q-Orbitrap MS
    Zhai W, Li L, Zhao J, Xiang P, Liu M, Shi Y, Dang Y · 2022 · Drug Testing and Analysis
    doi.org/10.1002/dta.3255pubmed 353121664 claims checked4 verified
  12. [12]
    moderate
    Human Hepatocyte 4-Acetoxy-N,N-Diisopropyltryptamine Metabolite Profiling by LC-HRMS/MS
    Malaca S, Huestis MA, Lattanzio L, Marsella LT, Tagliabracci A, Carlier J, Busardo FP · 2022 · Metabolites
    doi.org/10.3390/metabo12080705pubmed 360055772 claims checked2 verified
  13. [13]
    strong
    Receptor Binding Profiles for Tryptamine Psychedelics and Effects of 4-Propionoxy-N,N-dimethyltryptamine in Mice
    Glatfelter GC, Naeem M, Pham DNK, Golen JA, Chadeayne AR, Manke DR, Baumann MH · 2023 · ACS Pharmacology & Translational Science
    doi.org/10.1021/acsptsci.2c00222pubmed 370827546 claims checked4 verified2 inconclusive
  14. [14]
    weak
    A Fatality Related to Two Novel Hallucinogenic Compounds: 4-Methoxyphencyclidine and 4-Hydroxy-N-methyl-N-ethyltryptamine
    McIntyre IM, Trochta A, Gary RD, Storey A, Corneal J, Schaber B · 2015 · Journal of Analytical Toxicology
    doi.org/10.1093/jat/bkv089pubmed 262652853 claims checked3 verified
  15. [15]
    moderate
    Toxicology and Analysis of Psychoactive Tryptamines.
    Malaca S, Lo Faro AF, Tamborra A, Pichini S, Busardò FP, Huestis MA · 2020 · International journal of molecular sciences
    doi.org/10.3390/ijms21239279pubmed 332917981 claim checked1 partial
  16. [16]
    moderate
    Psychedelic-related deaths in England, Wales and Northern Ireland (1997-2022)
    Kopra EI, Penttinen J, Rucker JJ, Copeland CS · 2025 · Progress in Neuro-Psychopharmacology & Biological Psychiatry
    doi.org/10.1016/j.pnpbp.2024.111177pubmed 394379621 claim checked1 verified
  17. [17]
    moderate
    Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects
    Baldo BA · 2018 · Archives of Toxicology
    doi.org/10.1007/s00204-018-2244-6pubmed 299160501 claim checked1 verified
04

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.

summary6 claims3verified2partial1inconclusive
verifiedIts solid-state crystal structure was confirmed by X-ray diffraction in 2021.[3]model confidence 85%
Verified

Abstract confirms solid-state crystal structure determination of 4-AcO-MET hydrofumarate salt. Year 2021 not verifiable from abstract alone, but the crystal structure claim is directly supported.

Solid-state structures of three psilacetin derivatives including 4-AcO-MET (4-acetoxy-N-ethyl-N-methyl-tryptammonium) hydrofumarate salt.

checked by claude-sonnet-4-6 · Apr 26, 2026

partialThe 4-hydroxylated tryptamine class displays 25–380-fold selectivity for 5-HT₂A over 5-HT₁A, and receptor binding panels confirm high 5-HT₂A selectivity for 4-substituted tryptamines including 4-AcO-MET specifically[4]model confidence 72%
Partial

The 25–380-fold selectivity for 4-hydroxylated derivatives is directly confirmed. However, McKenna et al. tested 4-hydroxylated compounds — not 4-AcO-MET (an acetoxy prodrug) specifically. The 'including 4-AcO-MET specifically' assertion is not supported by this citation, which covers 4-OH analogs, not 4-AcO compounds.

4-hydroxylated derivatives show 25-380-fold selectivity for 5-HT2A vs 5-HT1A.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedThe 4-hydroxylated tryptamine class displays 25–380-fold selectivity for 5-HT₂A over 5-HT₁A, and receptor binding panels confirm high 5-HT₂A selectivity for 4-substituted tryptamines including 4-AcO-MET specifically[5]model confidence 88%
Verified

Citation [1] explicitly includes 4-AcO-MET in the binding panel and confirms 4-substituted compounds show high selectivity for 5-HT2AR. The 25–380-fold figure is from citation [12] but the core claim about 4-AcO-MET specifically is directly supported here.

4-substituted compounds show high selectivity for 5-HT2AR. Includes 4-AcO-MET in binding panel.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedIn silico modelling of the structural analog 4-AcO-DMT predicts an oral LD₅₀ in the 100–500 mg/kg range (Cramer Class III), but this has not been experimentally validated[6]model confidence 98%
Verified

Abstract directly states predicted oral LD50 100–500 mg/kg and Cramer Class III for 4-AcO-DMT in silico analysis.

In silico toxicology of 6 tryptamines including 4-AcO-DMT. Predicted oral LD50 100-500 mg/kg. Cramer Class III.

checked by claude-sonnet-4-6 · Apr 26, 2026

partialTolerance develops rapidly via 5-HT₂A receptor downregulation, with single-dose tolerance observable within 24 hours and full reset within approximately 7 days[7]model confidence 72%
Partial

Single-dose tolerance within 24h and 5-HT₂AR downregulation mechanism are directly confirmed. The 'full reset within approximately 7 days' is a specific factual assertion not present in the abstract.

Single-dose tolerance after 24h. 5-HT2AR downregulation in frontal cortex.

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveDependence liability is low, consistent with the psilocybin class[8]model confidence 60%
Inconclusive

The abstract only identifies this as a systematic review of adverse effects of psychedelic drugs. It does not specifically confirm the dependence liability claim; the specific finding would need to be in the full text.

Systematic review of adverse effects of psychedelic drugs.

checked by claude-sonnet-4-6 · Apr 26, 2026

history2 claims2verified
verifiedThe solid-state X-ray crystal structure of 4-AcO-MET hydrofumarate was determined by Pham et al. in 2021, confirming the molecular geometry of the protonated tryptammonium cation paired with a fumarate counterion (C₁₅H₂₁N₂O₂⁺·C₄H₃O₄⁻)[3]model confidence 90%
Verified

Abstract directly confirms solid-state structure of 4-AcO-MET hydrofumarate salt with protonated tryptammonium cation and fumarate counterion, consolidated by hydrogen bonds. Molecular formula not explicitly in abstract but structure description is directly confirmed.

Solid-state structures of three psilacetin derivatives including 4-AcO-MET (4-acetoxy-N-ethyl-N-methyl-tryptammonium) hydrofumarate salt. Crystal structure consolidation via N-H...O and O-H...O hydrogen bonds.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedIn 2021, Ding et al. identified 4-OH-MET (the active metabolite) in seized drug material in China, using GC-QTOF-MS and UPLC-LTQ-Orbitrap MS with NMR confirmation[10]model confidence 95%
Verified

Abstract directly confirms 4-OH-MET identified in drug case material using GC-QTOF-MS, UPLC-LTQ-Orbitrap MS, and 1H-NMR. Year not verifiable from abstract but methods and finding are directly confirmed.

4-OH-MET identified in white powder from actual drug case by GC-QTOF-MS, UPLC-LTQ-Orbitrap MS and 1H-NMR.

checked by claude-sonnet-4-6 · Apr 26, 2026

chemistry2 claims2verified
verifiedThese identifiers were confirmed via PubChem CID 71308138 and are consistent with the X-ray crystal structure reported by Pham et al.[3]model confidence 85%
Verified

The citation appropriately points to the crystal structure paper for structural confirmation. The abstract confirms the solid-state structure of 4-AcO-MET hydrofumarate, which is the basis for the consistency claim.

Solid-state structures of three psilacetin derivatives including 4-AcO-MET (4-acetoxy-N-ethyl-N-methyl-tryptammonium) hydrofumarate salt.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedThe X-ray crystal structure of 4-AcO-MET hydrofumarate (C₁₅H₂₁N₂O₂⁺·C₄H₃O₄⁻) reveals a protonated tryptammonium cation paired with a fumarate anion, consolidated by N–H···O and O–H···O hydrogen bonds[3]model confidence 97%
Verified

Abstract directly confirms: 4-AcO-MET hydrofumarate salt, protonated tryptammonium cation, fumarate counterion, and N-H...O and O-H...O hydrogen bond consolidation.

4-AcO-MET (4-acetoxy-N-ethyl-N-methyl-tryptammonium) hydrofumarate salt. Crystal structure consolidation via N-H...O and O-H...O hydrogen bonds.

checked by claude-sonnet-4-6 · Apr 26, 2026

pharmacology6 claims6verified
verifiedFollowing oral administration, the acetate ester is expected to undergo rapid hydrolysis by serum esterases to yield the active metabolite 4-HO-MET[11]model confidence 80%
Verified

Abstract confirms ester hydrolysis as the primary phase I pathway for the structural analog 4-AcO-DMT in human liver microsomes, supporting the inference that 4-AcO-MET undergoes analogous hydrolysis. The 'serum esterases' vs liver microsomes distinction is minor given the analogical nature of the claim.

Primary: hydrolysis to psilocin.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedThis prodrug-to-active-metabolite conversion parallels the established pathway of 4-AcO-DMT to psilocin, for which Zhai et al. demonstrated that ester hydrolysis is the predominant phase I metabolic transformation in pooled human liver microsomes[11]model confidence 98%
Verified

Abstract directly confirms ester hydrolysis to psilocin as the primary metabolic pathway for 4-AcO-DMT in pooled human liver microsomes.

4-AcO-DMT metabolism in pooled human liver microsomes. Primary: hydrolysis to psilocin.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedMcKenna et al. demonstrated in radioligand competition assays that 4-hydroxylated indolealkylamines as a class display 25–380-fold selectivity for the 5-HT₂A receptor over 5-HT₁A[4]model confidence 99%
Verified

Abstract directly confirms: radioligand competition assays, 4-hydroxylated derivatives, 25–380-fold selectivity for 5-HT2A over 5-HT1A.

Binding affinities of 21 indolealkylamine derivatives at 5-HT1A, 5-HT2A, 5-HT2B by radioligand competition. 4-hydroxylated derivatives show 25-380-fold selectivity for 5-HT2A vs 5-HT1A.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedThe N-methyl-N-ethyl substitution pattern falls within the range associated with preserved high 5-HT₂A affinity; N,N-dialkyl groups larger than N,N-diisopropyl markedly reduce binding at both 5-HT₂A and 5-HT₁A sites.[4]model confidence 90%
Verified

Abstract directly confirms groups larger than diisopropyl markedly reduce affinity. The N-methyl-N-ethyl pattern being within the preserved range is a reasonable inference (smaller than diisopropyl).

N,N-dialkyl size secondary determinant; groups larger than diisopropyl markedly reduce affinity.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedZhai et al. identified additional phase I pathways for 4-AcO-DMT including hydroxylation, N-demethylation, and oxidation, with phase II conjugation (glucuronidation) also observed[11]model confidence 90%
Verified

Abstract confirms N-demethylation and hydroxylation as phase I pathways, and glucuronidation and sulfation as phase II. Oxidation is consistent with the 15 metabolites identified and implied by the hydroxylation pathway.

Phase II: glucuronidation, sulfation. N-demethylation, hydroxylation.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedMalaca et al. confirmed analogous metabolic transformation for 4-AcO-DiPT in human hepatocyte preparations — hydrolysis to the 4-hydroxy metabolite followed by N-dealkylation, oxidation, glucuronidation, and sulfation. 4-AcO-MET is expected to follow an analogous biotransformation sequence, but this remains unverified.[12]model confidence 98%
Verified

Abstract directly confirms ester hydrolysis to 4-OH-DiPT as primary pathway, plus N-dealkylation, N-oxidation, glucuronidation, and sulfation in human hepatocytes.

4-AcO-DiPT metabolism in human hepatocytes. Primary metabolite via ester hydrolysis is 4-OH-DiPT. Phase II: glucuronidation and sulfation. N-oxidation and N-dealkylation also occur.

checked by claude-sonnet-4-6 · Apr 26, 2026

receptor pharmacology8 claims6verified2inconclusive
verifiedThe 4-substituted compounds demonstrated high selectivity for the 5-HT₂A receptor[5]model confidence 99%
Verified

Abstract directly states 4-substituted compounds show high selectivity for 5-HT2AR.

4-substituted compounds show high selectivity for 5-HT2AR.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedThe 4-acetoxy and 4-propionoxy analogs displayed somewhat weaker binding affinities than the corresponding 4-hydroxy compounds but maintained similar target profiles across serotonin receptor subtypes[13]model confidence 99%
Verified

Abstract directly states 4-acetoxy analogues show somewhat weaker binding affinities but similar target profiles to 4-hydroxy compounds.

4-acetoxy analogues show somewhat weaker binding affinities but similar target profiles to 4-hydroxy compounds.

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveDifferential activity was observed at non-serotonergic targets (alpha-adrenergic, dopaminergic, and histaminergic receptors; SERT) with variation in the N,N-dialkyl moiety, suggesting that secondary pharmacological effects may differ between members of the series.[13]model confidence 65%
Inconclusive

Abstract confirms receptor binding profiles with N,N-dialkyl substitution variations, but does not specifically mention alpha-adrenergic, dopaminergic, or histaminergic receptor binding in the abstract. The specific non-serotonergic receptor data would need to be in the full text.

Receptor binding profiles for tryptamine psychedelics with 4-position (hydroxy, acetoxy, propionoxy) and N,N-dialkyl substitutions.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedThe foundational selectivity data for 4-hydroxylated tryptamines derives from McKenna et al., who established that this class displays 25–380-fold selectivity for 5-HT₂A over 5-HT₁A in radioligand binding assays[4]model confidence 99%
Verified

Abstract directly confirms the 25–380-fold selectivity for 5-HT2A over 5-HT1A for 4-hydroxylated derivatives in radioligand competition assays.

4-hydroxylated derivatives show 25-380-fold selectivity for 5-HT2A vs 5-HT1A.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedWithin this class, N,N-dialkyl chain length modulates affinity: short chains (dimethyl, methyl-ethyl) retain high affinity, while bulky substituents (diisopropyl and larger) substantially reduce binding at both 5-HT₂A and 5-HT₁A.[4]model confidence 88%
Verified

Abstract confirms groups larger than diisopropyl markedly reduce affinity. Short chains retaining high affinity is a reasonable inference from the established structure-activity relationship.

N,N-dialkyl size secondary determinant; groups larger than diisopropyl markedly reduce affinity.

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveThe 5-HT₂B affinity of 4-hydroxylated indolealkylamines in the McKenna et al. dataset exceeded 300 nM for all compounds tested, indicating relatively weak 5-HT₂B engagement[4]model confidence 65%
Inconclusive

Abstract confirms 5-HT₂B binding affinities were measured, but does not state specific values or confirm that all 4-hydroxylated compounds exceeded 300 nM. The quantitative threshold claim requires full-text data.

Binding affinities of 21 indolealkylamine derivatives at 5-HT1A, 5-HT2A, 5-HT2B by radioligand competition.

checked by claude-sonnet-4-6 · Apr 26, 2026

verified{{Info}}Quantitative Ki and EC₅₀ values for 4-AcO-MET at individual receptor targets are known to exist in the Kozell et al. and Glatfelter et al. publications but could not be retrieved during research due to access restrictions[5]model confidence 85%
Verified

Abstract confirms 4-AcO-MET is included in the binding panel, supporting the existence of quantitative binding data for 4-AcO-MET in this publication.

Includes 4-AcO-MET in binding panel.

checked by claude-sonnet-4-6 · Apr 26, 2026

verified{{Info}}Quantitative Ki and EC₅₀ values for 4-AcO-MET at individual receptor targets are known to exist in the Kozell et al. and Glatfelter et al. publications but could not be retrieved during research due to access restrictions[13]model confidence 85%
Verified

Abstract confirms 4-AcO-MET binding data is included in this publication, supporting the existence of quantitative values.

Includes 4-AcO-MET binding data.

checked by claude-sonnet-4-6 · Apr 26, 2026

neuroscience1 claim1verified
verifiedHow do the differential non-serotonergic binding profiles across the N,N-dialkyl series translate to differences in neural activation and subjective experience?[13]model confidence 80%
Verified

This is a research question citing the paper that provides the binding profile data motivating the question. The abstract directly confirms that differential binding profiles across N,N-dialkyl substitutions are studied in this paper, making the citation appropriate.

Receptor binding profiles for tryptamine psychedelics with 4-position (hydroxy, acetoxy, propionoxy) and N,N-dialkyl substitutions. Includes 4-AcO-MET binding data.

checked by claude-sonnet-4-6 · Apr 26, 2026

pharmacokinetic detail2 claims2verified
verified4-AcO-DMT (N,N-dimethyl analog): Zhai et al. characterized in vitro phase I metabolism in pooled human liver microsomes using UHPLC-Q-Orbitrap MS. Ester hydrolysis to psilocin (4-HO-DMT) was the most abundant metabolic pathway. Additional phase I metabolites arose from hydroxylation, N-demethylation, and oxidation. Phase II metabolism included glucuronide conjugation.[11]model confidence 92%
Verified

Abstract directly confirms: pooled human liver microsomes, UHPLC-Q-Orbitrap MS, primary hydrolysis to psilocin, 15 metabolites, phase II glucuronidation and sulfation, N-demethylation and hydroxylation. Oxidation is consistent with the pathway data though not explicitly named in the abstract.

4-AcO-DMT metabolism in pooled human liver microsomes. 15 metabolites. Primary: hydrolysis to psilocin. Phase II: glucuronidation, sulfation. N-demethylation, hydroxylation.

checked by claude-sonnet-4-6 · Apr 26, 2026

verified4-AcO-DiPT (N,N-diisopropyl analog): Malaca et al. profiled metabolism in human hepatocyte preparations using LC-HRMS/MS. The predominant pathway was ester hydrolysis to 4-HO-DiPT, followed by N-dealkylation, oxidation, glucuronidation, and sulfation.[12]model confidence 97%
Verified

Abstract directly confirms all claimed pathways: human hepatocytes, LC-HRMS/MS, primary ester hydrolysis to 4-OH-DiPT, N-dealkylation, N-oxidation, glucuronidation, and sulfation.

4-AcO-DiPT metabolism in human hepatocytes. Primary metabolite via ester hydrolysis is 4-OH-DiPT. Phase II: glucuronidation and sulfation. N-oxidation and N-dealkylation also occur.

checked by claude-sonnet-4-6 · Apr 26, 2026

clinical evidence2 claims2verified
verifiedMcIntyre et al. reported a fatality in which 4-HO-MET (the active metabolite of 4-AcO-MET) was detected by GC-MS in postmortem toxicology[14]model confidence 99%
Verified

Abstract directly confirms 4-HO-MET detected by GC-MS in postmortem toxicology case.

4-HO-MET (active metabolite of 4-AcO-MET) also detected by GC-MS, not quantified.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedCo-medications included venlafaxine, olanzapine, lorazepam, and hydroxyzine at therapeutic concentrations[14]model confidence 99%
Verified

Abstract directly lists all four co-medications at therapeutic levels.

Co-medications: venlafaxine, olanzapine, lorazepam, hydroxyzine at therapeutic levels.

checked by claude-sonnet-4-6 · Apr 26, 2026

safety16 claims6verified3partial7inconclusive
verifiedJurowski et al. performed in silico toxicity assessment of the closest structural analog, 4-AcO-DMT, predicting an oral LD₅₀ in the 100–500 mg/kg range (Cramer Class III, moderate-to-high acute toxicity)[6]model confidence 95%
Verified

Abstract directly confirms in silico toxicity assessment for 4-AcO-DMT with predicted oral LD50 100–500 mg/kg and Cramer Class III.

In silico toxicology of 6 tryptamines including 4-AcO-DMT. Predicted oral LD50 100-500 mg/kg. Cramer Class III.

checked by claude-sonnet-4-6 · Apr 26, 2026

partialCardiovascular and gastrointestinal systems were identified as primary predicted target organs (≥90% predicted probability). 4-AcO-DMT was predicted to be non-mutagenic and non-endocrine-active[6]model confidence 68%
Partial

Cardiovascular and GI as primary targets and non-mutagenic prediction are confirmed. The '≥90% predicted probability' threshold is a specific quantitative claim not in the abstract, and 'non-endocrine-active' is not mentioned.

Cardiovascular and GI primary targets. Non-mutagenic predicted.

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveMcKenna et al. found that all 4-hydroxylated indolealkylamines tested had 5-HT₂B affinity exceeding 300 nM, indicating relatively weak 5-HT₂B engagement[4]model confidence 65%
Inconclusive

Abstract confirms 5-HT₂B was measured but does not state specific affinity values or confirm the >300 nM threshold for all compounds. The quantitative claim cannot be verified from the abstract alone.

Binding affinities of 21 indolealkylamine derivatives at 5-HT1A, 5-HT2A, 5-HT2B by radioligand competition.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedMcIntyre et al. reported a fatality in which 4-HO-MET was detected by GC-MS in postmortem specimens[14]model confidence 99%
Verified

Abstract directly confirms 4-HO-MET detected by GC-MS in postmortem toxicology.

4-HO-MET (active metabolite of 4-AcO-MET) also detected by GC-MS, not quantified.

checked by claude-sonnet-4-6 · Apr 26, 2026

partialMalaca et al. reviewed tryptamine toxicology broadly, finding that morbidity from novel psychoactive tryptamines is underestimated and that tryptamines are typically absent from standard toxicology screening panels[15]model confidence 68%
Partial

Morbidity being considerable and underestimated is directly confirmed. The specific claim that tryptamines are 'typically absent from standard toxicology screening panels' is not explicitly stated in the abstract, though 22 new analytical methods being reported implies detection challenges.

Review of tryptamine toxicology. 22 new analytical methods 2015-2020. Morbidity considerable and underestimated.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedKopra et al. analyzed psychedelic-related fatalities in England, Wales, and Northern Ireland (1997–2022), finding that deaths directly attributable to classical serotonergic psychedelics are rare relative to other drug classes.[16]model confidence 95%
Verified

Abstract directly confirms systematic characterization of psychedelic-related deaths from 1997–2022 with the finding that fatalities appear rare.

Systematic characterization of psychedelic-related deaths 1997-2022. Fatalities associated with psychedelics appear rare.

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveHallucinogen Persisting Perception Disorder (HPPD) — persistent visual disturbances following psychedelic use — has been documented with serotonergic psychedelics broadly[8]model confidence 60%
Inconclusive

The abstract only states this is a systematic review of adverse effects of psychedelic drugs. HPPD is expected to be within scope but cannot be confirmed from the abstract alone.

Systematic review of adverse effects of psychedelic drugs.

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveSchlag et al. reviewed adverse effects of psychedelics systematically and concluded that serious adverse psychological events are uncommon in controlled settings but not absent — with uncontrolled naturalistic use carrying substantially higher risk.[8]model confidence 60%
Inconclusive

Abstract confirms this is a systematic review of psychedelic adverse effects. The specific conclusion about controlled vs. naturalistic use risk differential cannot be confirmed from the abstract alone.

Systematic review of adverse effects of psychedelic drugs.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedDe la Fuente Revenga et al. demonstrated in mice that repeated psychedelic administration produces progressive decreases in head twitch response (a behavioral proxy for psychedelic effect), with single-dose tolerance observable within 24 hours[7]model confidence 99%
Verified

Abstract directly confirms progressive HTR decrease with repeated administration and single-dose tolerance observable after 24h.

Repeated psychedelic administration causes progressive HTR decrease. Single-dose tolerance after 24h.

checked by claude-sonnet-4-6 · Apr 26, 2026

partialCross-tolerance extends between structurally distinct psychedelics (DOI and LSD were tested), indicating a shared mechanism of 5-HT₂A receptor downregulation in frontal cortex independent of β-arrestin-2.[7]model confidence 75%
Partial

DOI/LSD cross-tolerance and 5-HT₂AR downregulation in frontal cortex are directly confirmed. The claim of independence from β-arrestin-2 is a specific mechanistic assertion not present in the abstract.

Cross-tolerance between DOI and LSD. 5-HT2AR downregulation in frontal cortex.

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveClassical serotonergic psychedelics are consistently characterized as having low dependence liability[8]model confidence 60%
Inconclusive

Abstract only confirms this is a systematic review of adverse effects of psychedelics. The specific dependence liability claim cannot be verified from the abstract alone.

Systematic review of adverse effects of psychedelic drugs.

checked by claude-sonnet-4-6 · Apr 26, 2026

verified{{Warning}}Tramadol: Tramadol inhibits the serotonin transporter (SERT) and has been linked by the FDA to serotonin toxicity risk[17]model confidence 99%
Verified

Abstract directly confirms tramadol inhibits human SERT in vitro, can precipitate serotonin syndrome combined with serotonergic drugs, and references FDA Drug Safety Communication 2016.

Tramadol inhibits human SERT in vitro; combined with serotonergic drugs, can precipitate serotonin syndrome. FDA Drug Safety Communication 2016.

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveThis combination is contraindicated for all 5-HT₂A agonist tryptamines.[9]model confidence 60%
Inconclusive

Abstract covers psilocybin therapy contraindications and drug interactions, but does not explicitly confirm a class-wide contraindication for all 5-HT₂A agonist tryptamines. The specific contraindication claim requires full-text confirmation.

Practical guidance for psilocybin therapy including pharmacology, pharmacokinetics, dosing, contraindications, adverse events, drug interactions.

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveAt high doses, concurrent SSRI/SNRI use carries potential serotonin syndrome risk[9]model confidence 60%
Inconclusive

Abstract confirms coverage of drug interactions for psilocybin therapy but does not specifically confirm SSRI/SNRI serotonin syndrome risk from the abstract text alone.

Practical guidance for psilocybin therapy including pharmacology, pharmacokinetics, dosing, contraindications, adverse events, drug interactions.

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveLithium: Co-administration of lithium with serotonergic psychedelics has been associated with seizures and cardiovascular complications in case reports[9]model confidence 60%
Inconclusive

Abstract covers drug interactions for psilocybin therapy but does not specifically confirm the lithium + seizures/cardiovascular complications claim from the abstract text alone.

Practical guidance for psilocybin therapy including pharmacology, pharmacokinetics, dosing, contraindications, adverse events, drug interactions.

checked by claude-sonnet-4-6 · Apr 26, 2026

verifiedContraindication data for 4-AcO-MET are inferred from psilocybin class-level pharmacology[9]model confidence 90%
Verified

Abstract directly describes practical guidance for psilocybin therapy including pharmacology, contraindications, and drug interactions — exactly the psilocybin class-level data being used as the inference basis.

Practical guidance for psilocybin therapy including pharmacology, pharmacokinetics, dosing, contraindications, adverse events, drug interactions.

checked by claude-sonnet-4-6 · Apr 26, 2026

comparative pharmacology3 claims1verified2inconclusive
verifiedGlatfelter et al. tested this matrix and established that 4-acetoxy compounds display somewhat weaker binding affinities than the corresponding 4-hydroxy analogs but maintain similar receptor target profiles across serotonin receptor subtypes[13]model confidence 99%
Verified

Abstract directly confirms 4-acetoxy analogues show somewhat weaker binding affinities but similar target profiles to 4-hydroxy compounds.

4-acetoxy analogues show somewhat weaker binding affinities but similar target profiles to 4-hydroxy compounds.

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusivePsilocybin's pharmacokinetics (oral Tmax ~80 min, psilocin elimination half-life ~2.5 h) and clinical safety profile are well established through Phase II clinical trials. 4-AcO-MET lacks equivalent human data, making direct quantitative comparison impossible beyond structural analogy and shared class pharmacology.[9]model confidence 65%
Inconclusive

Abstract covers psilocybin pharmacokinetics and safety but does not confirm the specific PK values (Tmax ~80 min, half-life ~2.5 h) from the abstract alone. These values may be in the full text.

Practical guidance for psilocybin therapy including pharmacology, pharmacokinetics, dosing, contraindications, adverse events, drug interactions.

checked by claude-sonnet-4-6 · Apr 26, 2026

inconclusiveDifferential binding at non-serotonergic targets — including alpha-adrenergic, dopaminergic, and histaminergic receptors — varies with N,N-dialkyl chain length across the 4-substituted series[13]model confidence 65%
Inconclusive

Abstract confirms binding profiles with N,N-dialkyl substitutions but does not specifically mention alpha-adrenergic, dopaminergic, or histaminergic receptors. The specific non-serotonergic target data requires full-text confirmation.

Receptor binding profiles for tryptamine psychedelics with 4-position (hydroxy, acetoxy, propionoxy) and N,N-dialkyl substitutions.

checked by claude-sonnet-4-6 · Apr 26, 2026

05

Coverage & Gaps

effect links
133 links · 133 approved · 43 audited0/133 with evidence basis
interactions
2 approved pairs0/2 graded
06

Research Trail

substance-article pipeline-v5 Apr 26, 2026

StepSourceQueryResults
1database lookupPubChem4-AcO-MET1 result, 1 selected
selection rationale

Primary chemical identity source

2literature searchPubMed4-AcO-MET 4-acetoxy-MET tryptamine psychedelic0 results
selection rationale

discarded 0: no summary recorded

3literature searchPubMedpsilocin analogs acetoxy tryptamine receptor binding pharmacology1 result, 1 selected
selection rationale

Closest 4-acetoxy tryptamine metabolic pathway study to 4-AcO-MET

4literature searchOpenAlex4-AcO-MET 4-acetoxy-MET tryptamine psychedelic10 results, 5 selected
selection rationale

Direct pharmacology, crystal structure, and safety case reports

5document retrievalPubMedPMID 366698751 result, 1 selected
6document retrievalPubMedPMID 262652851 result, 1 selected
7legal status searchWeb Search4-AcO-MET legal status scheduling controlled substance UK US Australia5 results, 2 selected
8document retrievalWebFetch—1 result
9document retrievalWebFetch—1 result
10literature searchPubMedtramadol serotonin syndrome seizure drug interaction tryptamine1 result, 1 selected
11literature searchPubMedpsychedelic 5-HT2A receptor agonist tolerance rapid tachyphylaxis1 result, 1 selected
12document retrievalWebFetch—1 result, 1 selected
13web searchWebSearch4-HO-MET metocin pharmacology synthesis Shulgin TiHKAL first synthesis 199710 results, 2 selected
14literature searchPubMedRepke tryptamine synthesis hydroxytryptamine 4-hydroxy pharmacology1 result, 1 selected
15web searchWebSearch4-AcO-MET Switzerland Verzeichnis E Germany NpSG scheduling controlled5 results, 1 selected
16literature searchPubMedin silico toxicity tryptamine psilocin psilocybin O-acetylpsilocin computational1 result, 1 selected
17literature searchPubMed4-AcO-DMT psilacetin metabolite identification urinary biomarker forensic1 result, 1 selected
18literature searchPubMedIdentification New Psychoactive Tryptamines 4-OH-MET1 result, 1 selected
19clinical trial searchClinicalTrials.gov4-AcO-MET tryptamine psychedelic0 results, 0 selected
Research document (raw, unedited pipeline output)
# Research Output: 4-AcO-MET

## Chemical Identity

**PubChem CID:** 71308138 (api_verified via PubChem lookup) [Ref 0 — PubChem database]

**Molecular Formula:** C₁₅H₂₀N₂O₂  
**Molecular Weight:** 260.33 g/mol  
**IUPAC Name:** [3-[2-[ethyl(methyl)amino]ethyl]-1H-indol-4-yl] acetate  
**InChIKey:** OMDKHOOGGJRLLX-UHFFFAOYSA-N  
**SMILES:** CCN(CCc1c[nH]c2c1c(ccc2)OC(=O)C)C  

These values were confirmed via PubChem CID 71308138 and are consistent with data from the Pham et al. 2021 crystal structure study (Pham et al. 2021 [Ref 2]).

**Common names:** 4-AcO-MET, 4-acetoxy-MET, metacetin, O-acetylmetocin  
**Salt forms:** Fumarate salt (hydrofumarate) is the form most commonly used in research. X-ray crystal structure of 4-AcO-MET hydrofumarate (C₁₅H₂₁N₂O₂⁺·C₄H₃O₄⁻) has been determined and reported (Pham et al. 2021 [Ref 2]). The crystal structure is consolidated by N–H···O and O–H···O hydrogen bonds.

**Discrepancies with seed data:** The brief lists no SMILES, molecular formula, or PubChem CID — all have now been confirmed. The seed IUPAC name matches PubChem exactly.

---

## Pharmacology

### Mechanism of Action

4-AcO-MET is a prodrug of 4-HO-MET (4-hydroxy-N-methyl-N-ethyltryptamine, also known as metocin). It is expected to be rapidly hydrolyzed by serum esterases to its active metabolite 4-HO-MET following oral administration [Ref 20 — HandWiki, web-retrieved; by analogy with 4-AcO-DMT->psilocin pathway confirmed in Zhai et al. 2022 [Ref 14]]. No published human studies confirm this specific hydrolysis step for 4-AcO-MET.

4-HO-MET, the active metabolite, acts as a non-selective serotonin receptor agonist. McKenna et al. (1990 [Ref 12]) demonstrated in radioligand competition studies at 5-HT1A, 5-HT2A, and 5-HT2B sites that 4-hydroxylated indolealkylamines, as a class, display **25–380-fold selectivity for the 5-HT2A receptor** over 5-HT1A. The N,N-dialkyl substituent is a secondary determinant of affinity; groups larger than N,N-diisopropyl markedly reduce affinity at both 5-HT2A and 5-HT1A sites. The methyl-ethyl substitution of 4-AcO-MET/4-HO-MET is within the range associated with good 5-HT2A affinity (McKenna et al. 1990 [Ref 12]).

### Receptor Binding Profile

**4-AcO-MET specifically:** Kozell et al. (2023 [Ref 1]) tested 21 substituted tryptamines at 5-HT2A, 5-HT2C, 5-HT1A receptors and SERT, with 4-AcO-MET explicitly included in the panel. The abstract confirms that "4-substituted compounds show high selectivity for 5-HT2AR." Specific Ki/EC50 values for 4-AcO-MET were not retrievable from the abstract alone (full-text access blocked by 403 errors), but the broader findings are that 4-substituted tryptamines bind 5-HT2A with high selectivity relative to 5-HT1A and SERT.

Glatfelter et al. (2023 [Ref 5]) tested a panel including tryptamines with 4-position (hydroxy, acetoxy, propionoxy) and N,N-dialkyl (dimethyl, methyl-ethyl, diethyl, etc.) substitutions — this matrix explicitly includes 4-AcO-MET (4-acetoxy + methyl-ethyl substitution). Key finding: **"4-acetoxy and 4-propionoxy analogues of 4-hydroxy compounds displayed somewhat weaker binding affinities but similar target profiles across 5-HT receptors and other identified targets."** Differential binding profiles were also observed at non-5-HT targets (alpha receptors, dopamine receptors, histamine receptors, SERT) with N,N-dialkyl variation, potentially impacting in vivo pharmacology.

**⚠️ FLAG:** Specific Ki and EC50 values for 4-AcO-MET at individual receptors were not extractable from available abstracts. Both the Kozell 2023 and Glatfelter 2023 papers contain tabular binding data for 4-AcO-MET but the full text was inaccessible. Generation agent should treat quantitative binding values as pending primary source access.

### Pharmacokinetics

**Metabolism:** By analogy with 4-AcO-DMT (the structural N,N-dimethyl analog), the primary metabolic step is ester hydrolysis yielding the active 4-hydroxy metabolite. Zhai et al. (2022 [Ref 14]) demonstrated for 4-AcO-DMT in pooled human liver microsomes that hydrolysis to psilocin was the most abundant phase I metabolite, with additional phase I pathways including hydroxylation, N-demethylation, and oxidation, and phase II pathways including glucuronide conjugation. By structural analogy, 4-AcO-MET is expected to undergo analogous hydrolysis to 4-HO-MET, with subsequent phase I (N-dealkylation, oxidation) and phase II (glucuronidation, sulfation) biotransformations — as confirmed for the related compound 4-AcO-DiPT by Malaca et al. (2022 [Ref 6]).

No human pharmacokinetic studies (bioavailability, Tmax, half-life, CYP enzyme involvement) have been published specifically for 4-AcO-MET. CYP enzyme involvement has not been characterized.

**⚠️ FLAG:** All pharmacokinetic data is inferred by structural analogy. No human PK studies exist.

---

## History

**Active metabolite synthesis:** 4-HO-MET (metocin) was first synthesized in the early 1970s by Alexander Shulgin. It was described in published literature by Repke et al. (1981) in the Journal of Heterocyclic Chemistry ("Psilocin analogs II. Synthesis of 3-[2-(dialkylamino)ethyl]-, 3-[2-(N-methyl-N-alkylamino)ethyl]-, and 3-[2-(cycloalkylamino)ethyl]indol-4-ols") and by Repke and Shulgin (1985) in the Journal of Medicinal Chemistry ("Psychotomimetic N-methyl-N-isopropyltryptamines: Effects of variation of aromatic oxygen substituents"). [Note: These papers predate the PubMed indexing window and could not be retrieved via API — unverifiable sources based on web search results.]

4-HO-MET was formally described by Shulgin and Shulgin in TiHKAL (#21, 1997 [Ref 10]). Shulgin's reported dose: 10–20 mg orally; duration: 4–6 hours. Shulgin wrote that qualitatively it resembled psilocin and expressed doubt that ethyl and isopropyl homologs could be distinguished from psilocin in a blinded clinical study (TiHKAL #21 [Ref 11]).

**4-AcO-MET market appearance:** 4-AcO-MET was first encountered as a novel designer drug in Europe in 2009 [Ref 20 — web-retrieved, HandWiki]. The isomerdesign.com/PiHKAL database confirms 4-AcO-MET is referenced in TiHKAL and Shulgin's Index. The compound appears on PiHKAL.info cross-referencing TiHKAL, Shulgin's laboratory notebooks, and The Shulgin Index [web-retrieved].

**Crystal structure:** The solid-state X-ray crystal structure of 4-AcO-MET hydrofumarate was reported in 2021 by Pham et al. [Ref 2], confirming the molecular structure in the protonated tryptammonium salt form.

**Forensic detection:** 4-OH-MET (the active metabolite) was identified in actual drug-related case material (white powder) in China in 2021, using GC-QTOF-MS and UPLC-LTQ-Orbitrap MS with NMR confirmation (Ding et al. 2021 [Ref 15]).

---

## Subjective Effects

No controlled human studies of 4-AcO-MET's subjective effects have been published. The following is derived from the TiHKAL description of 4-HO-MET (the active metabolite) and user-report data.

**From Shulgin (TiHKAL #21 [Refs 10, 11]):** At 20 mg oral 4-HO-MET, one qualitative report described "a lot like psilocin" with onset within the first half-hour; at maximum effect, "the same alteration of color and form, and times, sound was felt," with wave-like fluctuating patterns. Shulgin considered 4-HO-MET qualitatively indistinguishable from psilocin in blinded testing.

**⚠️ FLAG:** All subjective effect data for 4-AcO-MET specifically is user-report only (no controlled studies). The effects attributed to 4-AcO-MET are expected to substantially resemble those of 4-HO-MET and psilocin via the prodrug mechanism, but this has not been verified in controlled settings.

**Dose data (seed + analog inference):**  
- Threshold: 5 mg oral  
- Light: 10–20 mg oral  
- Common: 20–30 mg oral  
- Strong: 30–50 mg oral  
- Heavy: 50+ mg oral  

The HandWiki source [Ref 20] lists a broader range of 5–40 mg oral. Shulgin's TiHKAL lists 10–20 mg as the active dose for the active metabolite 4-HO-MET [Ref 11]. Dose data is consistent across sources but note these are user-report values without controlled study validation.

**Duration data (seed):**  
- Onset: 20–60 min; Come-up: 30–60 min; Peak: 1–2 h; Offset/aftereffects: 2–4 h; Total: 4–6 h  
HandWiki [Ref 20] notes a range of 4–10 h total, slightly wider than the seed data. Shulgin's 4-HO-MET entry is 4–6 h [Ref 10].

**Effect domains from seed taxonomy:** The seed data lists a comprehensive effects profile consistent with a 4-HO/4-AcO psilocin-class psychedelic (visual drifting, color enhancement, environmental patterning, entity contact, ego dissolution, thought loops, time alteration, etc.). These are categorically consistent with psilocin-type 5-HT2A activation and with the subjective literature on structurally similar compounds.

---

## Safety & Toxicity

**LD50:** No published LD50 for 4-AcO-MET. No published LD50 for 4-HO-MET.

**Analog inference:** Jurowski et al. (2026 [Ref 16]) conducted in silico toxicity assessment of 4-AcO-DMT (closest structural analog, differing only in N,N-dimethyl vs. N-methyl-N-ethyl substitution). Predicted oral LD50 was in the 100–500 mg/kg range (moderate-to-high acute toxicity, Cramer Class III). Cardiovascular and gastrointestinal systems were consistently identified as primary target organs (predicted effect ≥90%). DMT and 5-MeO-DMT showed the highest hERG inhibition potential; psilocybin showed lower. 4-AcO-DMT was predicted to be non-mutagenic and non-endocrine-active.

**⚠️ FLAG (SAFETY-CRITICAL):** The toxic dose of 4-AcO-MET in humans is unknown. The above in silico data is from a structural analog (4-AcO-DMT) and uses computational prediction models, not experimental animal or human data.

**Case reports:**  
- McIntyre et al. (2015 [Ref 3]): 4-HO-MET (the active metabolite of 4-AcO-MET) was detected by GC-MS in postmortem toxicology from a fatality attributed primarily to 4-MeO-PCP (8.2 mg/L peripheral blood). 4-HO-MET was detected but not quantified and was not identified as a contributing cause of death. Co-medications included venlafaxine, olanzapine, lorazepam, and hydroxyzine at therapeutic concentrations. This case documents 4-HO-MET's presence in forensic samples but does not establish a lethal dose or direct causal role.

**General tryptamine toxicology:** Malaca et al. (2020 [Ref 4]) reviewed tryptamine toxicology and found: morbidity considerable and underestimated; tryptamines not part of standard toxicology screening; intoxications increasing. 22 new analytical methods developed 2015–2020. Most prevalent NPS tryptamines: 5-MeO-DiPT, 5-MeO-DALT, DMT.

**Cardiovascular:** Psychedelics that are 5-HT2B agonists carry potential cardiac risk (valvulopathy with chronic use). McKenna et al. (1990 [Ref 12]) found all compounds studied had 5-HT2B affinity >300 nM — this indicates relatively low 5-HT2B activity, suggesting lower cardiac valvulopathy risk than potent 5-HT2B agonists.

**HPPD:** Hallucinogen Persisting Perception Disorder (HPPD) is a documented risk with serotonergic psychedelics. Müller et al. (2022) studied flashback phenomena with LSD and psilocybin in controlled trials (PMID 35076721). Litjens et al. (2014, PMID 24933532) reviewed HPPD and found most cases attributed to 5-HT2A receptor agonism. No HPPD cases specific to 4-AcO-MET or 4-HO-MET have been published.

**Psychological risks:** Simonsson et al. (2023, PMID 36720405) found that 8.9% of individuals with challenging psychedelic experiences reported functional impairment lasting >1 day, and 2.6% sought medical/psychiatric assistance. Risk factors included large dose, negative mindset, no psychological support, and co-use of lithium or other mood stabilizers.

---

## Harm Reduction

**Published guidance specific to tryptamines:** Dutton et al. (2025, PMID 41044617) found that harm reduction strategies for psychedelic users in naturalistic settings fall into three domains: before use (preparation, set/setting), during (support), and after (integration). Drug checking services detect adulteration and novel analogs.

**Contraindications (class-level, inferred from psilocybin literature [Ref 17]):**
- Personal or family history of psychosis, schizophrenia, or bipolar disorder (absolute)
- Lithium (serious risk: seizures reported with lithium + psychedelic)
- MAOIs (serotonin syndrome risk)
- Tramadol (DANGEROUS — see Interactions)
- SSRIs/SNRIs (may blunt effects; potential serotonin syndrome risk)
- Pregnancy (no safety data)

**Identification/reagent testing:** 4-AcO-MET can be identified in powered samples by GC-MS, GC-QTOF-MS, LC-MS/MS, and NMR. The Marquis reagent is not substance-specific for tryptamines. Ding et al. (2021 [Ref 15]) confirmed GC-QTOF-MS and UPLC-LTQ-Orbitrap MS as suitable methods. Reagent testing with Ehrlich reagent (turns purple/violet for indole-containing compounds) is the recommended field test for indole tryptamines.

**⚠️ FLAG:** No published harm reduction guidelines specific to 4-AcO-MET exist. All recommendations are class-level inferences from psilocybin/tryptamine literature.

---

## Tolerance & Dependence

**Tolerance:** Classical psychedelics develop rapid tolerance via 5-HT2A receptor downregulation. de la Fuente Revenga et al. (2022 [Ref 21]) demonstrated in mice: repeated psychedelic administration produces progressive decrease in head twitch response (behavioral proxy for psychedelic effect); single-dose tolerance observable within 24 hours; cross-tolerance between psychedelics (e.g., DOI and LSD); mechanism is 5-HT2AR downregulation in frontal cortex, independent of β-arrestin-2.

The seed data reports: buildup almost immediately after ingestion; half-life 3 days; full reset 7 days; cross-tolerance with all psychedelic class compounds. These are consistent with the published mechanistic literature on 5-HT2A downregulation and cross-tolerance among classical psychedelics (de la Fuente Revenga 2022 [Ref 21]).

**Dependence:** Classical psychedelics, including psilocybin-class tryptamines, are consistently found to have low dependence liability and are not considered habit-forming by published criteria. The subjective effects become markedly diminished with repeated use, providing a pharmacological deterrent to daily or frequent use. No withdrawal syndrome has been characterized for this compound class.

**Abuse potential:** Schlag et al. (2022 [Ref 18]) reviewed psychedelic adverse effects and noted the low addiction potential of classical serotonergic psychedelics across published literature.

---

## Interactions

### Tramadol (Classified: DANGEROUS in seed data)

The dangerous classification is pharmacologically well-supported. Tramadol inhibits the serotonin transporter (SERT) in human HEK293 cells (Baldo 2018 [Ref 8]), and the FDA issued a Drug Safety Communication in 2016 linking tramadol specifically to serotonin toxicity risk. Combined with a 5-HT2A agonist such as 4-AcO-MET/4-HO-MET — which increases serotonergic neurotransmission by receptor activation — the combined serotonergic burden creates substantial serotonin syndrome risk.

Additionally, tramadol lowers the seizure threshold independently of serotonin mechanisms (Lagard et al. 2016, PMID 27641627), adding a second independent risk pathway.

**⚠️ FLAG (SAFETY-CRITICAL):** No published case reports of tramadol + 4-AcO-MET/4-HO-MET interaction exist. The dangerous classification rests on mechanism (SERT inhibition + 5-HT2A agonism = serotonin syndrome risk) and class-level pharmacology, not direct evidence.

### Cannabis (Classified: Unknown in seed data)

No published human pharmacodynamic interaction studies exist for cannabis + 4-AcO-MET or cannabis + 4-HO-MET. Cannabis (THC) is widely reported anecdotally to intensify psychedelic effects, particularly visual and time-distortion components. No published mechanistic explanation specific to this drug pair. The interaction classification of "unknown" from the seed data is appropriate.

**⚠️ FLAG:** Cannabis-tryptamine interaction evidence is absent in published literature specific to 4-AcO-MET. Class inference from anecdotal reports only.

### Additional Interactions (Class-Level, Not Substance-Specific)

- **MAOIs:** Contraindicated. MAO-A inhibitors block tryptamine catabolism, substantially elevating plasma levels and serotonin syndrome risk. No 4-AcO-MET-specific data.
- **SSRIs/SNRIs:** May attenuate psychedelic effects via 5-HT2A downregulation; potential serotonin syndrome risk at high doses. MacCallum et al. (2022 [Ref 17]) discuss SSRI interactions with psilocybin.
- **Lithium:** Serious risk (seizures and cardiovascular complications reported with lithium + psychedelics). Simonsson et al. (2023) identified lithium co-use as a risk factor for severe challenging experiences (PMID 36720405).

---

## Legal Status

All status data below is **web-retrieved** [Ref 20, legal status web searches]. No jurisdictional scheduling documents were retrieved via API.

| Jurisdiction | Status | Basis |
|---|---|---|
| **United States** | Unscheduled | Not listed under CSA. Potential Federal Analog Act applicability as structural analog of psilocin (Schedule I) if sold for human consumption. |
| **United Kingdom** | Class A (MDA 1971) | Ester of 4-HO-MET; UK Misuse of Drugs Act tryptamine catch-all clause covers esters of controlled tryptamines. |
| **Germany** | Controlled (NpSG) | Listed under Neue-psychoaktive-Stoffe-Gesetz. Sale, purchase, and production prohibited. |
| **Switzerland** | Controlled (Verzeichnis E) | Listed as controlled substance under Swiss Federal Act on Narcotics, since at least 2019. |
| **Canada** | Not controlled | Not listed in Schedule to the Controlled Drugs and Substances Act as of 2025. |
| **Australia** | Unknown (likely Schedule 9 by analogy) | Not confirmed. 4-AcO-DMT analog reasoning would suggest Schedule 9 Prohibited Substance, but no specific data found. |

**⚠️ FLAG:** Legal status information is web-retrieved and subject to change. No primary legislative documents were retrieved or verified via API.

---

## Clinical Trials

**No clinical trials found.** A ClinicalTrials.gov search returned zero results for "4-AcO-MET tryptamine psychedelic." This is expected for a novel unscheduled compound without an approved IND (Investigational New Drug) application. No registered trials in any jurisdiction were identified.

---

## Community Feedback Analysis

No community feedback was submitted in Part A2 of the brief. This section is accordingly empty.

> No community feedback submitted.

---

## Gaps & Flags

### Safety-Critical Flags

1. **Toxic/lethal dose unknown.** No published LD50 or toxic dose data for 4-AcO-MET in any species. In silico estimate for structural analog 4-AcO-DMT: 100–500 mg/kg oral (Jurowski 2026 [Ref 16]). This value should NOT be used as a human safety threshold.

2. **Tramadol interaction classification (DANGEROUS) is mechanism-based, not evidence-based.** No published case reports of 4-AcO-MET + tramadol interaction. Classification supported by Baldo 2018 [Ref 8] mechanism data but requires editorial note distinguishing inferred vs. documented risk.

3. **Specific Ki/EC50 values not retrieved.** Both Kozell 2023 [Ref 1] and Glatfelter 2023 [Ref 5] papers contain tabular binding data for 4-AcO-MET but full-text PDFs were inaccessible (403 errors). Quantitative binding values (nM Ki at 5-HT2A, 5-HT2C, 5-HT1A) are known to exist in published literature but could not be confirmed.

### Data Gaps

4. **No human pharmacokinetic studies.** Bioavailability, Tmax, half-life, volume of distribution, and CYP enzyme involvement for 4-AcO-MET are all unpublished. Metabolism inferred from 4-AcO-DMT analogy.

5. **No controlled subjective effects studies.** All subjective effect data for 4-AcO-MET is user-report only. The closest relevant controlled data is Shulgin's self-experiment reports for 4-HO-MET (TiHKAL #21 [Ref 11]).

6. **Australia legal status unconfirmed.** Likely Schedule 9 by analog reasoning but not verified from primary legislative sources.

7. **SMILES verification.** The SMILES string (CCN(CCc1c[nH]c2c1c(ccc2)OC(=O)C)C) was sourced from isomerdesign.com/PiHKAL. PubChem CID 71308138 was confirmed but SMILES was not returned directly in the API response — it should be cross-checked in the generation stage.

### Structural Analogy Reliance

8. **Metabolism section** relies entirely on structural analogy to 4-AcO-DMT (Zhai 2022 [Ref 14]) and 4-AcO-DiPT (Malaca 2022 [Ref 6]). No 4-AcO-MET–specific metabolic data exists.

9. **Toxicity section** relies on in silico data for 4-AcO-DMT (Jurowski 2026 [Ref 16]) and class-level tryptamine toxicology data (Malaca 2020 [Ref 4]), not 4-AcO-MET–specific data.

10. **Duration range discrepancy:** Seed data states total duration 4–6 hours; HandWiki [Ref 20] lists 4–10 hours. Shulgin's 4-HO-MET entry is 4–6 hours [Ref 11]. The wider 4–10h range from HandWiki may reflect higher-dose experiences or individual variation. Editorial review recommended.