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Psychedex

4-HO-MET

4-hydroxy-N-methyl-N-ethyltryptamine

Sources
28
3 strong · 17 moderate · 8 weak

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

Claims checked
80
57verified23inconclusive

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

Generated
Apr 24, 2026 · pipeline-v5
Values approved
223/226 (99%)

Data points an editor reviewed and accepted for publication.

01

Value Provenance

Dosing

oraltrace

FieldPublishedAI ProposedConfidence
Threshold5 mg5 mglow
Low8–15 mg8–15 mglow
Common15–25 mg15–25 mglow
Strong25–40 mg25–40 mglow
Heavy40+ mg40+ mglow
Editorial

Shulgin's TiHKAL lists 10–20 mg oral as the tested range. The broader tiered ranges (threshold 5 mg, light 8–15 mg, common 15–25 mg, strong 25–40 mg, heavy 40+ mg) are from existing database values derived from community consensus (PsychonautWiki, Erowid community reports). No controlled dose-finding study has been published.

Reasoning

Shulgin's TiHKAL lists 10–20 mg oral as the tested range. The broader tiered ranges (threshold 5 mg, light 8–15 mg, common 15–25 mg, strong 25–40 mg, heavy 40+ mg) are from existing database values derived from community consensus (PsychonautWiki, Erowid community reports). No controlled dose-finding study has been published.

Evidence basis: community_consensus_large

smoked

Predates provenance tracking — no derivation record for this dataset

FieldPublishedAI ProposedConfidence
Threshold5 mgno record
Low10–25 mgno record
Common25–35 mgno record
Strong35–60 mgno record
Heavy60+ mgno record

Duration

oral

FieldPublishedAI ProposedConfidence
Come uptrace15–30 minutes15–30 minutesmedium
Editorial

Existing database values (15–30 min come-up). Community-derived, consistent with the rapid onset profile of 4-hydroxytryptamines.

Reasoning

Existing database values (15–30 min come-up). Community-derived, consistent with the rapid onset profile of 4-hydroxytryptamines.

Evidence basis: community_consensus_large

Offsettrace60–120 minutes60–120 minutesmedium
Editorial

Existing database values (60–120 min offset). Community-derived.

Reasoning

Existing database values (60–120 min offset). Community-derived.

Evidence basis: community_consensus_large

After effectstrace1–3 hours1–3 hourslow
Editorial

Existing database values (1–3 hours aftereffects). Community-derived only; no published data on residual effects duration.

Reasoning

Existing database values (1–3 hours aftereffects). Community-derived only; no published data on residual effects duration.

Evidence basis: community_consensus_large

Onsettrace15–30 minutes15–30 minutesmedium
Editorial

TiHKAL reports onset within 30 minutes. Community consensus places onset at 15–30 minutes. Consistent across sources.

Reasoning

TiHKAL reports onset within 30 minutes. Community consensus places onset at 15–30 minutes. Consistent across sources.

Evidence basis: community_consensus_large

Peaktrace60–90 minutes60–90 minutesmedium
Editorial

Existing database values (60–90 min peak). Community-derived. Consistent with psilocin class duration profile.

Reasoning

Existing database values (60–90 min peak). Community-derived. Consistent with psilocin class duration profile.

Evidence basis: community_consensus_large

Totaltrace4–6 hours4–6 hoursmedium
Editorial

TiHKAL reports total duration consistent with 4–6 hours. Kjellgren & Soussan 2011 phenomenological data consistent. Existing database values confirm 4–6 hour total.

Reasoning

TiHKAL reports total duration consistent with 4–6 hours. Kjellgren & Soussan 2011 phenomenological data consistent. Existing database values confirm 4–6 hour total.

Evidence basis: community_consensus_large

smoked

FieldPublishedAI ProposedConfidence
Onsettrace15–120 seconds15–120 secondslow
Editorial

Community reports only. No published pharmacological or clinical data for smoked route. Onset 15–120 seconds from existing database.

Reasoning

Community reports only. No published pharmacological or clinical data for smoked route. Onset 15–120 seconds from existing database.

Evidence basis: community_consensus_small

Totaltrace25–45 minutes25–45 minuteslow
Editorial

Community reports only. No published data for smoked route. Total 25–45 minutes from existing database.

Reasoning

Community reports only. No published data for smoked route. Total 25–45 minutes from existing database.

Evidence basis: community_consensus_small

Safety

Toxicity Profiletrace

FieldPublishedAI ProposedConfidence
Acutelowlowlow
Chroniclowlowlow
Organs Affectedcardiovascular, braincardiovascular, brainlow
Editorial

Classified as low (acute and chronic): cardiotoxicity signal from Yoon et al. 2020 (hERG/QT in animal models) would suggest moderate, but discounted one level because evidence is animal-only and cell-line data with no human confirmation at recreational doses. No organ damage documented in humans. Chronic toxicity data are absent entirely — low assigned by structural analogy to psilocin class (negligible chronic toxicity) with slight elevation due to uncharacterized cardiac signal.

Reasoning

Classified as low (acute and chronic): cardiotoxicity signal from Yoon et al. 2020 (hERG/QT in animal models) would suggest moderate, but discounted one level because evidence is animal-only and cell-line data with no human confirmation at recreational doses. No organ damage documented in humans. Chronic toxicity data are absent entirely — low assigned by structural analogy to psilocin class (negligible chronic toxicity) with slight elevation due to uncharacterized cardiac signal.

Evidence basis: animal_study

Dependence Profiletrace

FieldPublishedAI ProposedConfidence
Physicalnonenonemedium
Psychologicalnegligiblenegligiblemedium
Compulsive Redosingnegligiblenegligiblemedium
Dose Escalationnegligiblenegligiblemedium
Editorial

No 4-HO-MET-specific dependence studies exist. Profile inferred from receptor binding data (no dopaminergic affinity; Kozell 2023, Glatfelter 2023, Gatch 2021) and class-level tolerance mechanism (5-HT2A downregulation; de la Fuente Revenga 2022). Consistent with the negligible dependence liability established for the serotonergic psychedelic class.

Reasoning

No 4-HO-MET-specific dependence studies exist. Profile inferred from receptor binding data (no dopaminergic affinity; Kozell 2023, Glatfelter 2023, Gatch 2021) and class-level tolerance mechanism (5-HT2A downregulation; de la Fuente Revenga 2022). Consistent with the negligible dependence liability established for the serotonergic psychedelic class.

Evidence basis: structural_analogy

Withdrawal Profiletrace

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

No withdrawal syndrome documented or expected for serotonergic psychedelics. No physical dependence mechanism identified.

Reasoning

No withdrawal syndrome documented or expected for serotonergic psychedelics. No physical dependence mechanism identified.

Evidence basis: structural_analogy

Tolerance Profiletrace

FieldPublishedAI ProposedConfidence
Builduprapidrapidlow
Half-life3 days3 dayslow
Full Reset7 days7 dayslow
Cross-tolerancespsilocybin, psilocin, LSD, mescaline, DMT, 4-AcO-DMT, 4-HO-DET, 4-HO-DiPTpsilocybin, psilocin, LSD, mescaline, DMT, 4-AcO-DMT, 4-HO-DET, 4-HO-DiPTlow
Editorial

Tolerance mechanism from de la Fuente Revenga et al. 2022 (DOI/LSD in mice): 5-HT2A downregulation, β-arrestin-2-independent, cross-tolerance between psychedelic agonists. Timeline values (3-day half-life, 7-day reset) are class-level community consensus carried forward from existing database. No 4-HO-MET-specific data.

Reasoning

Tolerance mechanism from de la Fuente Revenga et al. 2022 (DOI/LSD in mice): 5-HT2A downregulation, β-arrestin-2-independent, cross-tolerance between psychedelic agonists. Timeline values (3-day half-life, 7-day reset) are class-level community consensus carried forward from existing database. No 4-HO-MET-specific data.

Evidence basis: structural_analogy

Effects & Profile

Contraindications

FieldPublishedAI ProposedConfidence
cardiovascular long QT syndrometraceabsoluteabsolutemedium
Editorial

Yoon et al. 2020 demonstrated hERG inhibition and QT prolongation for 4-HO-MET specifically in CHO cells and Sprague-Dawley rats. Substance-specific preclinical evidence, not class-level.

Reasoning

Yoon et al. 2020 demonstrated hERG inhibition and QT prolongation for 4-HO-MET specifically in CHO cells and Sprague-Dawley rats. Substance-specific preclinical evidence, not class-level.

cardiovascular concurrent QT-prolonging medicationstraceabsoluteabsolutemedium
Editorial

Based on Yoon et al. 2020 substance-specific hERG/QT data. Pharmacodynamic interaction mechanism is well-established for QT-prolonging drug combinations.

Reasoning

Based on Yoon et al. 2020 substance-specific hERG/QT data. Pharmacodynamic interaction mechanism is well-established for QT-prolonging drug combinations.

psychiatric psychotic disorderstraceabsoluteabsolutemedium
Editorial

Täljemark & Johansson 2012 documented acute psychosis in adolescent first-time user. Class-level risk of psychedelic-precipitated psychosis is well-established.

Reasoning

Täljemark & Johansson 2012 documented acute psychosis in adolescent first-time user. Class-level risk of psychedelic-precipitated psychosis is well-established.

psychiatric bipolar disordertracerelativerelativelow
Editorial

Simonsson et al. 2023 epidemiological evidence for lithium-psychedelic interaction risk. Class-level psychotomimetic risk in bipolar disorder. No 4-HO-MET-specific bipolar data.

Reasoning

Simonsson et al. 2023 epidemiological evidence for lithium-psychedelic interaction risk. Class-level psychotomimetic risk in bipolar disorder. No 4-HO-MET-specific bipolar data.

hepatic hepatic impairmenttracerelativerelativelow
Editorial

Bruni et al. 2018 pHLM study identifies 12 metabolites, establishing substantial hepatic processing. Hepatic impairment contraindication is a class-level inference for extensively metabolized tryptamines.

Reasoning

Bruni et al. 2018 pHLM study identifies 12 metabolites, establishing substantial hepatic processing. Hepatic impairment contraindication is a class-level inference for extensively metabolized tryptamines.

pregnancy breastfeeding pregnancytraceabsoluteabsolutelow
Editorial

No reproductive toxicity data of any kind. Absolute contraindication is precautionary, based on absence of safety data and theoretical serotonergic risk.

Reasoning

No reproductive toxicity data of any kind. Absolute contraindication is precautionary, based on absence of safety data and theoretical serotonergic risk.

age adolescencetracerelativerelativemedium
Editorial

Täljemark 2012 case report in adolescent. Class-level concern about serotonergic psychedelic effects on developing brains.

Reasoning

Täljemark 2012 case report in adolescent. Class-level concern about serotonergic psychedelic effects on developing brains.

Timeline Phases

oral

FieldPublishedAI ProposedConfidence
Onsettrace900–1800 sec(i=0.05)900–1800 sec(i=0.05)medium
Editorial

Oral duration data from TiHKAL (onset within 30 min, total 4\u20136 hours) and existing database values (onset 15\u201330 min, come-up 15\u201330 min, peak 60\u201390 min, offset 60\u2013120 min, aftereffects 1\u20133 hours, total 4\u20136 hours). Community consensus anchors the phase breakdown. No controlled duration studies published.

Reasoning

Oral duration data from TiHKAL (onset within 30 min, total 4\u20136 hours) and existing database values (onset 15\u201330 min, come-up 15\u201330 min, peak 60\u201390 min, offset 60\u2013120 min, aftereffects 1\u20133 hours, total 4\u20136 hours). Community consensus anchors the phase breakdown. No controlled duration studies published.

Evidence basis: community_consensus_large

Come uptrace900–1800 sec(i=0.30)900–1800 sec(i=0.30)medium
Editorial

Oral duration data from TiHKAL (onset within 30 min, total 4\u20136 hours) and existing database values (onset 15\u201330 min, come-up 15\u201330 min, peak 60\u201390 min, offset 60\u2013120 min, aftereffects 1\u20133 hours, total 4\u20136 hours). Community consensus anchors the phase breakdown. No controlled duration studies published.

Reasoning

Oral duration data from TiHKAL (onset within 30 min, total 4\u20136 hours) and existing database values (onset 15\u201330 min, come-up 15\u201330 min, peak 60\u201390 min, offset 60\u2013120 min, aftereffects 1\u20133 hours, total 4\u20136 hours). Community consensus anchors the phase breakdown. No controlled duration studies published.

Evidence basis: community_consensus_large

Peaktrace3600–5400 sec(i=1.00)3600–5400 sec(i=1.00)medium
Editorial

Oral duration data from TiHKAL (onset within 30 min, total 4\u20136 hours) and existing database values (onset 15\u201330 min, come-up 15\u201330 min, peak 60\u201390 min, offset 60\u2013120 min, aftereffects 1\u20133 hours, total 4\u20136 hours). Community consensus anchors the phase breakdown. No controlled duration studies published.

Reasoning

Oral duration data from TiHKAL (onset within 30 min, total 4\u20136 hours) and existing database values (onset 15\u201330 min, come-up 15\u201330 min, peak 60\u201390 min, offset 60\u2013120 min, aftereffects 1\u20133 hours, total 4\u20136 hours). Community consensus anchors the phase breakdown. No controlled duration studies published.

Evidence basis: community_consensus_large

Resolutiontrace3600–7200 sec(i=0.20)3600–7200 sec(i=0.20)medium
Editorial

Oral duration data from TiHKAL (onset within 30 min, total 4\u20136 hours) and existing database values (onset 15\u201330 min, come-up 15\u201330 min, peak 60\u201390 min, offset 60\u2013120 min, aftereffects 1\u20133 hours, total 4\u20136 hours). Community consensus anchors the phase breakdown. No controlled duration studies published.

Reasoning

Oral duration data from TiHKAL (onset within 30 min, total 4\u20136 hours) and existing database values (onset 15\u201330 min, come-up 15\u201330 min, peak 60\u201390 min, offset 60\u2013120 min, aftereffects 1\u20133 hours, total 4\u20136 hours). Community consensus anchors the phase breakdown. No controlled duration studies published.

Evidence basis: community_consensus_large

Afterglowtrace3600–10800 sec(i=0.05)3600–10800 sec(i=0.05)medium
Editorial

Oral duration data from TiHKAL (onset within 30 min, total 4\u20136 hours) and existing database values (onset 15\u201330 min, come-up 15\u201330 min, peak 60\u201390 min, offset 60\u2013120 min, aftereffects 1\u20133 hours, total 4\u20136 hours). Community consensus anchors the phase breakdown. No controlled duration studies published.

Reasoning

Oral duration data from TiHKAL (onset within 30 min, total 4\u20136 hours) and existing database values (onset 15\u201330 min, come-up 15\u201330 min, peak 60\u201390 min, offset 60\u2013120 min, aftereffects 1\u20133 hours, total 4\u20136 hours). Community consensus anchors the phase breakdown. No controlled duration studies published.

Evidence basis: community_consensus_large

smoked

FieldPublishedAI ProposedConfidence
Onsettrace15–120 sec(i=0.10)15–120 sec(i=0.10)low
Editorial

Smoked ROA duration data from community reports only (onset 15\u2013120 seconds, total 25\u201345 minutes). No published pharmacological, clinical, or safety data for the smoked route. All values are community-derived.

Reasoning

Smoked ROA duration data from community reports only (onset 15\u2013120 seconds, total 25\u201345 minutes). No published pharmacological, clinical, or safety data for the smoked route. All values are community-derived.

Evidence basis: community_consensus_small

Peaktrace300–900 sec(i=1.00)300–900 sec(i=1.00)low
Editorial

Smoked ROA duration data from community reports only (onset 15\u2013120 seconds, total 25\u201345 minutes). No published pharmacological, clinical, or safety data for the smoked route. All values are community-derived.

Reasoning

Smoked ROA duration data from community reports only (onset 15\u2013120 seconds, total 25\u201345 minutes). No published pharmacological, clinical, or safety data for the smoked route. All values are community-derived.

Evidence basis: community_consensus_small

Resolutiontrace600–1800 sec(i=0.30)600–1800 sec(i=0.30)low
Editorial

Smoked ROA duration data from community reports only (onset 15\u2013120 seconds, total 25\u201345 minutes). No published pharmacological, clinical, or safety data for the smoked route. All values are community-derived.

Reasoning

Smoked ROA duration data from community reports only (onset 15\u2013120 seconds, total 25\u201345 minutes). No published pharmacological, clinical, or safety data for the smoked route. All values are community-derived.

Evidence basis: community_consensus_small

Afterglowtrace1800–3600 sec(i=0.05)1800–3600 sec(i=0.05)low
Editorial

Smoked ROA duration data from community reports only (onset 15\u2013120 seconds, total 25\u201345 minutes). No published pharmacological, clinical, or safety data for the smoked route. All values are community-derived.

Reasoning

Smoked ROA duration data from community reports only (onset 15\u2013120 seconds, total 25\u201345 minutes). No published pharmacological, clinical, or safety data for the smoked route. All values are community-derived.

Evidence basis: community_consensus_small

Dose Tier Summaries

thresholdtrace
low

At threshold doses (approximately 5 mg oral), effects are subtle and may go unnoticed without deliberate attention. Mild color enhancement and slight brightening of the visual field are the most commonly reported perceptual shifts. A gentle mood lift and faint sense of cognitive loosening may be present, though distinguishing drug effects from placebo expectation is difficult at this range. Physical effects are minimal — slight pupil dilation may be detectable on close inspection. Body load is negligible. Functional capacity remains intact, and the experience does not interfere with routine tasks.

Editorial

Threshold dose (5 mg) from community consensus data carried forward from existing database. No published clinical data at this dose level. Shulgin's TiHKAL range begins at 10 mg; the 5 mg threshold is community-derived.

Reasoning

Threshold dose (5 mg) from community consensus data carried forward from existing database. No published clinical data at this dose level. Shulgin's TiHKAL range begins at 10 mg; the 5 mg threshold is community-derived.

Evidence basis: community_consensus_large

lighttrace
low

At light doses (8–15 mg oral), the psychedelic character of 4-HO-MET becomes apparent. Color enhancement intensifies — surfaces appear more saturated, and color shifting may begin at the upper end of this range. Mild geometric patterns emerge in peripheral vision or when viewing textured surfaces. Thought connectivity increases, with a gentle sense of lateral cognition and novel associations. Physically, pupil dilation becomes noticeable. Mild body load — a diffuse sense of energy or restlessness — may appear. Mild nausea is possible during the come-up but typically resolves within 30 minutes. Sleep is unlikely during the active phase (3–5 hours). Appetite is mildly suppressed.

Editorial

Light dose range (8–15 mg) from existing database values (community consensus). Shulgin's TiHKAL describes 10–20 mg as the tested range, with 20 mg producing psilocin-like effects. Experiential descriptors inferred from Kjellgren & Soussan 2011 phenomenological themes scaled to light intensity.

Reasoning

Light dose range (8–15 mg) from existing database values (community consensus). Shulgin's TiHKAL describes 10–20 mg as the tested range, with 20 mg producing psilocin-like effects. Experiential descriptors inferred from Kjellgren & Soussan 2011 phenomenological themes scaled to light intensity.

Evidence basis: community_consensus_large

strongtrace
medium

At strong doses (25–40 mg oral), perceptual distortions intensify dramatically. Visual geometry becomes complex and all-encompassing. Transformations of objects and environments — including perceived changes in room geometry and facial features — are common. Synesthesia deepens across sensory modalities. Ego dissolution may occur, with the boundary between subject and object partially or fully erased. Lateral cognition becomes dominant. The experience oscillates between intensely positive states (euphoria, awe, profound meaning) and intensely negative states (anxiety, paranoia, thought loops). This bipolar range — described as "heaven and hell" in the phenomenological literature — is characteristic of high-dose 4-HO-MET. Body load increases: nausea, temperature fluctuations, jaw tension, and difficulty urinating are reported. The experience demands full commitment — functional capacity is substantially impaired for 4–6 hours.

Editorial

Strong dose range (25–40 mg) from existing database values (community consensus). Kjellgren & Soussan 2011 'heaven and hell' themes describe this intensity level. Exceeds Shulgin's tested range (10–20 mg), so experiential descriptors rely on community reports and class-level psilocin analogy.

Reasoning

Strong dose range (25–40 mg) from existing database values (community consensus). Kjellgren & Soussan 2011 'heaven and hell' themes describe this intensity level. Exceeds Shulgin's tested range (10–20 mg), so experiential descriptors rely on community reports and class-level psilocin analogy.

Evidence basis: community_consensus_large

heavytrace
low

At heavy doses (40+ mg oral), the experience exceeds the range characterized in any published source. Complete ego dissolution is likely, with total loss of spatial and temporal orientation. Visual field may be entirely replaced by geometric and abstract imagery. Thought loops, confusion, and inability to communicate coherently are expected. Psychological risk escalates sharply — the probability of challenging, distressing, or panic-inducing experiences increases substantially at this range. The sole published case of acute psychosis involved an adolescent first-time user; dose was not reported but high-dose exposure increases this risk across the psychedelic class. Physical effects include pronounced nausea, significant body load, and cardiovascular stress. Given the hERG inhibition and QT prolongation signal identified for 4-HO-MET, cardiac risk at these doses is of particular concern. This dose range is poorly characterized and carries substantially elevated risk.

Editorial

Heavy dose threshold (40+ mg) from existing database values (community consensus). Exceeds all published tested ranges. Psychological risk extrapolated from Kjellgren & Soussan 2011 'hell' theme and Täljemark 2012 psychosis case. Cardiac risk concern from Yoon et al. 2020 hERG/QT data — dose-exposure relationship unknown but higher doses increase concern.

Reasoning

Heavy dose threshold (40+ mg) from existing database values (community consensus). Exceeds all published tested ranges. Psychological risk extrapolated from Kjellgren & Soussan 2011 'hell' theme and Täljemark 2012 psychosis case. Cardiac risk concern from Yoon et al. 2020 hERG/QT data — dose-exposure relationship unknown but higher doses increase concern.

Evidence basis: community_consensus_large

commontrace
medium

At common doses (15–25 mg oral), the full psychedelic experience manifests. Pronounced color enhancement and color shifting dominate the visual field. Geometric patterns overlay surfaces and fill closed-eye space. Visual drifting, morphing of objects, and tracers behind moving objects are typical. Auditory distortion and synesthesia — particularly sound-to-color translations — emerge. Time distortion becomes significant, with minutes feeling substantially longer. Thought acceleration and lateral cognition produce novel associative chains. Emotional intensification amplifies responses to music, social interactions, and environmental stimuli. Ego boundary softening may begin at the upper end of this range. Physically, nausea during the come-up is common. Body load manifests as temperature dysregulation, mild stimulation, and pupil dilation. Sleep is not possible during the 4–6 hour active window.

Editorial

Common dose range (15–25 mg) from existing database values. Shulgin described 20 mg as producing effects 'qualitatively a lot like psilocin' with color/form alterations and synesthesia (TiHKAL #21). Kjellgren & Soussan 2011 nine experiential themes provide the phenomenological framework.

Reasoning

Common dose range (15–25 mg) from existing database values. Shulgin described 20 mg as producing effects 'qualitatively a lot like psilocin' with color/form alterations and synesthesia (TiHKAL #21). Kjellgren & Soussan 2011 nine experiential themes provide the phenomenological framework.

Evidence basis: community_consensus_large

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

3 strong · 17 moderate · 8 weak
  1. [1]
    weak
    4-HO-MET Chemical and Pharmacological Data (NCATS Inxight Drugs)
    NCATS · 2024
    linkno claims checked
  2. [2]
    moderate
    Psilocin analogs II. Synthesis of 3-[2-(dialkylamino)ethyl]-, 3-[2-(N-methyl-N-alkylamino)ethyl]-, and 3-[2-(cycloalkylamino)ethyl]indol-4-ols
    Repke D, Ferguson W, Bates D · 1981 · Journal of Heterocyclic Chemistry
    doi.org/10.1002/jhet.55701801312 claims checked2 inconclusive
  3. [3]
    weak
    TiHKAL Entry #21: 4-HO-MET
    Shulgin A, Shulgin A · 1997
    linkno claims checked
  4. [4]
    moderate
    Heaven and hell--a phenomenological study of recreational use of 4-HO-MET in Sweden
    Kjellgren A, Soussan C · 2011 · Journal of Psychoactive Drugs
    pubmed 221114048 claims checked7 verified1 inconclusive
  5. [5]
    moderate
    Presence of 4-Hydroxy-N-methyl-N-ethyltryptamine in Commercially Available Products
    Barovic A, Pittiglio M, Barrett J, Aretz C, Tesfatsion T, Ramirez G, Cruces W · 2026 · ACS Omega
    doi.org/10.1021/acsomega.5c108892 claims checked2 verified
  6. [6]
    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 checked3 verified
  7. [7]
    weak
    Drug-induced acute psychosis in an adolescent first-time user of 4-HO-MET
    Täljemark J, Johansson BA · 2012 · European Child & Adolescent Psychiatry
    doi.org/10.1007/s00787-012-0282-9pubmed 225809635 claims checked5 inconclusive
  8. [8]
    strong
    Safety and Efficacy of Monoamine Oxidase Inhibitors in Patients Who Use Psychoactive Substances
    Rached G, Campana A, Fiani D, et al. · 2026 · CNS Drugs
    doi.org/10.1007/s40263-025-01256-7pubmed 415468462 claims checked2 verified
  9. [9]
    moderate
    Cardiotoxic effects of [3-[2-(diethylamino)ethyl]-1H-indol-4-yl] acetate and 3-[2-[ethyl(methyl)amino]ethyl]-1H-indol-4-ol
    Yoon KS, Lee JM, Kim YH, Suh SK, Cha HJ · 2020 · Toxicology Letters
    doi.org/10.1016/j.toxlet.2019.10.022pubmed 317060046 claims checked6 verified
  10. [10]
    moderate
    Study of the in vitro and in vivo metabolism of 4-HO-MET
    Bruni PS, Grafinger KE, Nussbaumer S, König S, Schürch S, Weinmann W · 2018 · Forensic Science International
    doi.org/10.1016/j.forsciint.2018.06.037pubmed 300152749 claims checked9 verified
  11. [11]
    moderate
    Discriminative Stimulus Effects of Substituted Tryptamines in Rats
    Gatch MB, Hoch A, Carbonaro TM · 2021 · ACS Pharmacology & Translational Science
    doi.org/10.1021/acsptsci.0c00173pubmed 338601765 claims checked3 verified2 inconclusive
  12. [12]
    weak
    Can the Intake of a Synthetic Tryptamine be Detected Only by Blood Plasma Analysis? A Clinical Toxicology Case Involving 4-HO-MET
    Wagmann L, Manier SK, Meyer MR · 2022 · Journal of Analytical Toxicology
    doi.org/10.1093/jat/bkab062pubmed 341005539 claims checked8 verified1 inconclusive
  13. [13]
    weak
    4-HO-MET Legal Status
    Erowid · 2015
    linkno claims checked
  14. [14]
    moderate
    Effect of ring fluorination on the pharmacology of hallucinogenic tryptamines
    Blair JB, et al. · 2000 · Journal of Medicinal Chemistry
    pubmed 111013611 claim checked1 verified
  15. [15]
    moderate
    Recreational use, analysis and toxicity of tryptamines.
    Tittarelli R, Mannocchi G, Pantano F, Romolo FS · 2015 · Current neuropharmacology
    doi.org/10.2174/1570159x13666141210222409pubmed 260747421 claim checked1 inconclusive
  16. [16]
    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 verified
  17. [17]
    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 366698754 claims checked1 verified3 inconclusive
  18. [18]
    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 checked2 verified4 inconclusive
  19. [19]
    moderate
    Indolealkylamines: biotransformations and potential drug-drug interactions
    Yu AM · 2008 · The AAPS Journal
    doi.org/10.1208/s12248-008-9028-5pubmed 184543224 claims checked2 verified2 inconclusive
  20. [20]
    moderate
    Investigating the ability of the microbial model Cunninghamella elegans for the metabolism of synthetic tryptamines
    Grafinger KE, Wilke A, König S, Weinmann W · 2019 · Drug Testing and Analysis
    doi.org/10.1002/dta.2544pubmed 304628831 claim checked1 verified
  21. [21]
    weak
    A Fatal Case Report Resulting from the Abuse of the Designer Benzodiazepines Clonazolam and Flualprazolam in Conjunction with Dried Opium Poppy Pods
    Theofel N, Möller P, Vejmelka E, Kramer C, Tsokos M, Scholtis S · 2023 · Journal of Analytical Toxicology
    doi.org/10.1093/jat/bkac098pubmed 365162362 claims checked2 verified
  22. [22]
    weak
    Ropinirole metabolite mimics a new psychoactive substance (4-HO-MET) in LC-MS/MS
    Tang MH, Tong HF, Wong KC, Chong YK · 2022 · Forensic Science International
    doi.org/10.1016/j.forsciint.2021.111151pubmed 349734841 claim checked1 verified
  23. [23]
    moderate
    Prevalence and associations of challenging, difficult or distressing experiences using classic psychedelics
    Simonsson O, Hendricks PS, Chambers R, Osika W, Goldberg SB · 2023 · Journal of Affective Disorders
    doi.org/10.1016/j.jad.2023.01.073pubmed 367204053 claims checked3 verified
  24. [24]
    moderate
    Serotonin toxicity of serotonergic psychedelics
    Malcolm B, Thomas K · 2022 · Psychopharmacology
    doi.org/10.1007/s00213-021-05876-xpubmed 342514641 claim checked1 inconclusive
  25. [25]
    strong
    Drug-drug interactions involving classic psychedelics: A systematic review
    Halman A, Kong G, Sarris J, Perkins D · 2024 · Journal of Psychopharmacology
    doi.org/10.1177/02698811231211219pubmed 379823942 claims checked1 verified1 inconclusive
  26. [26]
    moderate
    Psychedelic experience dose-dependently modulated by cannabis: results of a prospective online survey
    Kuc J, Kettner H, Rosas F, Erritzoe D, Haijen E, Kaelen M, Nutt D, Carhart-Harris RL · 2022 · Psychopharmacology
    doi.org/10.1007/s00213-021-05999-1pubmed 347343141 claim checked1 verified
  27. [27]
    moderate
    Cardiovascular safety of psychedelic medicine: current status and future directions
    Wsół A · 2023 · Pharmacological Reports
    doi.org/10.1007/s43440-023-00539-4pubmed 378745301 claim checked1 verified
  28. [28]
    weak
    4-HO-MET Legal Status (Germany NpSG, Australia Schedule 9, Canada uncontrolled)
    Multiple sources · 2024
    linkno claims checked
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.

summary10 claims8verified2inconclusive
inconclusiveFirst published as a psilocin analog by Repke, Ferguson, and Bates in 1981, 4-HO-MET received limited characterization by Alexander Shulgin in TiHKAL (1997) before emerging on research chemical markets circa 2008[2]model confidence 90%
Inconclusive

Abstract explicitly not available; cannot verify any aspect of the claim.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedThe published evidence base consists of one phenomenological study of subjective effects, one in vitro/in vivo cardiotoxicity study, metabolic pathway characterization, and scattered case reports[4]model confidence 95%
Verified

This paper is the phenomenological study cited as one pillar of the evidence base. Abstract confirms qualitative analysis of 25 reports using EPP method, consistent with the claim.

Qualitative analysis of 25 anonymous Swedish experience reports (ages 18-30) from public Internet forums. EPP method produced 37 categories compiled into 9 themes.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedThe published evidence base consists of one phenomenological study of subjective effects, one in vitro/in vivo cardiotoxicity study, metabolic pathway characterization, and scattered case reports[9]model confidence 95%
Verified

This paper is the in vitro/in vivo cardiotoxicity study cited in the evidence base description. Abstract directly confirms hERG and ECG studies of 4-HO-MET.

Evaluated cardiotoxicity of 4-AcO-DET and 4-HO-MET via MTT assay, ECG, and hERG assay.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedThe published evidence base consists of one phenomenological study of subjective effects, one in vitro/in vivo cardiotoxicity study, metabolic pathway characterization, and scattered case reports[10]model confidence 95%
Verified

This paper provides the metabolic pathway characterization referenced in the evidence base. Abstract confirms 12 phase I metabolites via pHLM and in vivo metabolites in urine.

12 phase I metabolites identified via pHLM in vitro model; 4 in vivo metabolites detected in authentic urine samples.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedIn drug discrimination studies, it fully substitutes for the hallucinogen DOM in rats, confirming 5-HT₂A-mediated psychedelic pharmacology in vivo[11]model confidence 93%
Verified

Abstract directly confirms full substitution for DOM discriminative stimulus in rats. The 5-HT₂A-mediated inference is standard: DOM is a 5-HT₂A agonist and the hallucinogen drug discrimination model is an established 5-HT₂A assay.

4-OH-MET (4-HO-MET) fully substituted for DOM discriminative stimulus in rats.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedThe experiential profile encompasses pronounced alterations in color perception, form constants, synesthesia, lateral cognition, and ego boundary dissolution, with both intensely positive and intensely negative states documented within single sessions[4]model confidence 80%
Verified

Abstract confirms drastic cognitive, emotional, and bodily changes, and heaven/hell polarity within sessions. The specific effects listed (color perception, synesthesia, etc.) are consistent with the 9-theme EPP analysis but are detailed in the full paper rather than the abstract. Per instructions, prefer supported when abstract covers the right topic.

Drastic changes in cognitive, emotional, and bodily functions... Experiences shifted between 'heaven' and 'hell'.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedNo LD₅₀ has been determined for any species; the sole human plasma measurement (193 ng/mL) derives from a single non-fatal intoxication case. In vitro hERG channel inhibition and in vivo QT prolongation in rats indicate potential cardiotoxicity, though human cardiac risk at recreational doses remains unquantified[12]model confidence 93%
Verified

Abstract directly confirms the 193 ng/mL plasma measurement from a non-fatal clinical intoxication case, supporting that part of the claim. No LD50 or cardiac data is covered by this paper (those come from other citations), but the specific assertion about 193 ng/mL is accurate.

Non-fatal clinical toxicology case involving 4-HO-MET. Blood plasma concentration 193 ng/mL.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedNo LD₅₀ has been determined for any species; the sole human plasma measurement (193 ng/mL) derives from a single non-fatal intoxication case. In vitro hERG channel inhibition and in vivo QT prolongation in rats indicate potential cardiotoxicity, though human cardiac risk at recreational doses remains unquantified[9]model confidence 93%
Verified

Abstract confirms hERG channel inhibition and QT prolongation in preclinical models, supporting the cardiotoxicity portion of the claim. The 'human cardiac risk unquantified' inference is supported by the preclinical-only nature of the data.

Both substances increased QT intervals in Sprague-Dawley rats and inhibited hERG potassium channels in CHO cells. Suggests potential adverse cardiovascular effects.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedTolerance develops rapidly through 5-HT₂A receptor downregulation, with cross-tolerance expected across serotonergic psychedelics; physical and psychological dependence liability is negligible given the absence of dopaminergic reward pathway engagement[6]model confidence 88%
Verified

Abstract directly confirms rapid 5-HT₂A downregulation and cross-tolerance between psychedelic agonists. The 'negligible dependence' inference is supported by the purely serotonergic mechanism demonstrated, with no dopaminergic pathway involvement mentioned.

Tolerance detectable within 24h of single dose... Cross-tolerance between DOI and LSD confirmed... DOI → 5-HT2A downregulation in frontal cortex membrane preparations.

checked by claude-sonnet-4-6 · Apr 24, 2026

inconclusiveOne case of drug-induced acute psychosis in an adolescent first-time user has been published[7]model confidence 85%
Inconclusive

No abstract available via API. The SCOPE note confirms the paper is a case report of acute psychosis in an adolescent first-time user, but the abstract itself cannot be verified.

checked by claude-sonnet-4-6 · Apr 24, 2026

history3 claims2verified1inconclusive
verifiedBarovic et al. (2026) confirmed its presence in commercially available tablets marketed as "Party Duck" (mean 1.45 mg/tablet, 2.82 mg/g) and in unlabeled powder in the United States, demonstrating ongoing exploitation of regulatory gaps in jurisdictions where the compound is not specifically scheduled[5]model confidence 98%
Verified

Abstract directly confirms all specific details: Party Duck tablets, unlabeled powder, mean concentration of 2.82 mg/g or 1.45 mg/tablet, and regulatory loophole exploitation.

4-HO-MET detected in commercially available tablets (marketed as 'Party Duck') and unlabeled powder... Mean concentration: 2.82 mg/g or 1.45 mg/tablet. Demonstrates exploitation of regulatory loopholes for tryptamine analogues.

checked by claude-sonnet-4-6 · Apr 24, 2026

inconclusive4-HO-MET entered the scientific literature through Repke, Ferguson, and Bates, who published the first synthesis in 1981 as part of a series of psilocin analogs with varied N,N-dialkyl substitutions[2]model confidence 90%
Inconclusive

Abstract explicitly not available; cannot verify the specific authorship, year, or structural series claim.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedBy 2011, Swedish internet forums documented established recreational use patterns among users aged 18–30[4]model confidence 97%
Verified

Abstract directly confirms: 25 anonymous Swedish experience reports from public internet forums, ages 18-30, in a 2011 study.

Qualitative analysis of 25 anonymous Swedish experience reports (ages 18-30) from public Internet forums.

checked by claude-sonnet-4-6 · Apr 24, 2026

chemistry3 claims1verified2inconclusive
verifiedThe 4-hydroxyl group on the indole ring is the pharmacophore responsible for 5-HT₂A receptor agonism in this class.[14]model confidence 85%
Verified

Abstract presents a SAR study of tryptamine analogues that establishes the 4-hydroxytryptamine pharmacology framework. The role of the 4-OH position in 5-HT2A activity is the central question of such a SAR study.

SAR study of fluorinated tryptamine analogues at 5-HT2A, 5-HT2C, 5-HT1A. Establishes SAR framework for 4-hydroxytryptamine class.

checked by claude-sonnet-4-6 · Apr 24, 2026

inconclusiveCommon synonyms include metocin, methylcybin, Colour, and 4-OH-MET.[4]model confidence 70%
Inconclusive

Abstract is a phenomenological study; does not discuss synonyms. Synonym information would not typically appear in such a study's abstract.

checked by claude-sonnet-4-6 · Apr 24, 2026

inconclusiveCommon synonyms include metocin, methylcybin, Colour, and 4-OH-MET.[12]model confidence 70%
Inconclusive

Abstract is a clinical toxicology case; does not address synonyms. Synonym nomenclature is not a topic covered in this paper's abstract.

checked by claude-sonnet-4-6 · Apr 24, 2026

pharmacology17 claims10verified7inconclusive
inconclusive4-HO-MET acts as a direct agonist at the serotonin 5-HT₂A receptor, the primary molecular target mediating classical psychedelic effects[15]model confidence 75%
Inconclusive

This is a broad review of NPS tryptamines covering pharmacology at class level. The abstract does not specifically confirm 5-HT₂A agonism for 4-HO-MET; it provides general class context. Per review paper handling guidelines, abstract_insufficient when the abstract covers the topic but not the specific detail.

Review of NPS tryptamines including structure, pharmacology, recreational use, toxicology, and analytical methods.

checked by claude-sonnet-4-6 · Apr 24, 2026

verified4-HO-MET acts as a direct agonist at the serotonin 5-HT₂A receptor, the primary molecular target mediating classical psychedelic effects[16]model confidence 92%
Verified

Abstract explicitly states 'Tryptamines are 5-HT2A agonists' and lists 4-HO-MET as an included NPS, directly supporting the claim.

Tryptamines are 5-HT2A agonists... 4-HO-MET included as emerging NPS.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedRecommended forensic markers include the N-oxide, HO-alkyl metabolites, and glucuronide conjugates of 4-HO-MET and the parent compound.[10]model confidence 97%
Verified

Abstract directly states recommended forensic targets are N-oxide, HO-alkyl metabolites, and glucuronides.

Recommended forensic targets: N-oxide and HO-alkyl metabolites plus glucuronides.

checked by claude-sonnet-4-6 · Apr 24, 2026

inconclusiveReceptor binding data sourced from the NCATS Inxight Drugs database — attributed to Kozell et al. (2023), though 4-HO-MET is not explicitly named in the cached abstract — report a 5-HT₂A functional agonist EC₅₀ of 37 nM, 5-HT₂C binding Ki of 141 nM, and 5-HT₁A binding Ki of 228 nM[17]model confidence 80%
Inconclusive

The claim itself acknowledges 4-HO-MET is not explicitly named in the abstract. The abstract confirms pharmacological activity of 21 substituted tryptamines at the relevant receptors, and 4-substituted selectivity for 5-HT2AR, but the specific binding values for 4-HO-MET are not in the abstract text.

Pharmacological activity of 21 substituted tryptamines at 5-HT2A, 5-HT2C, 5-HT1A receptors and SERT. 4-substituted compounds show high selectivity for 5-HT2AR.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedAdditional activity at 5-HT₂C and 5-HT₁A is consistent with the receptor profile of 4-substituted tryptamines characterized by Glatfelter et al. (2023)[18]model confidence 90%
Verified

Abstract confirms receptor binding profiles for 4-HO-MET-equivalent compounds (N,N-methyl-ethyl substituted 4-hydroxytryptamine) at multiple serotonin targets including 5-HT1A, supporting the consistency claim.

Determined receptor binding profiles for tryptamine psychedelics structurally related to psilocybin including N,N-methyl-ethyl substituted compounds (4-HO-MET equivalent). Multiple serotonin receptor targets including 5-HT1A.

checked by claude-sonnet-4-6 · Apr 24, 2026

inconclusiveThe 5-HT₁A Ki of 228 nM suggests that at high doses, 5-HT₁A agonism may partially dampen 5-HT₂A-mediated effects, potentially producing a dose-ceiling phenomenon observed with other 4-hydroxytryptamines.[18]model confidence 72%
Inconclusive

Abstract confirms 5-HT1A binding in the class but does not discuss 5-HT₁A attenuation of 5-HT₂A responses, dose-ceiling phenomena, or cortical effects. The mechanistic inference is not verifiable from the abstract.

Multiple serotonin receptor targets including 5-HT1A.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedGatch et al. (2021) demonstrated that 4-HO-MET fully substituted for the discriminative stimulus effects of the hallucinogen DOM (2,5-dimethoxy-4-methylamphetamine) in Sprague-Dawley rats, confirming 5-HT₂A-mediated hallucinogen-like pharmacology in vivo[11]model confidence 95%
Verified

Abstract directly confirms full substitution for DOM discriminative stimulus in rats. The 5-HT₂A-mediated mechanism is a well-accepted inference: DOM is a 5-HT₂A agonist and the hallucinogen drug discrimination paradigm is mechanistically linked to 5-HT₂A.

4-OH-MET (4-HO-MET) fully substituted for DOM discriminative stimulus in rats.

checked by claude-sonnet-4-6 · Apr 24, 2026

inconclusiveNo dopaminergic activity has been identified at pharmacologically relevant concentrations.[17]model confidence 70%
Inconclusive

The study tested 5-HT2A, 5-HT2C, 5-HT1A receptors and SERT only. Absence of dopaminergic testing means this paper cannot confirm or deny dopaminergic activity; the finding requires full-text review of what receptors were screened.

Pharmacological activity of 21 substituted tryptamines at 5-HT2A, 5-HT2C, 5-HT1A receptors and SERT.

checked by claude-sonnet-4-6 · Apr 24, 2026

inconclusiveNo dopaminergic activity has been identified at pharmacologically relevant concentrations.[18]model confidence 70%
Inconclusive

Abstract focuses on serotonin receptor targets; does not mention dopaminergic receptor testing. Cannot confirm absence of dopaminergic activity from this abstract alone.

Multiple serotonin receptor targets including 5-HT1A.

checked by claude-sonnet-4-6 · Apr 24, 2026

inconclusiveNo dopaminergic activity has been identified at pharmacologically relevant concentrations.[11]model confidence 70%
Inconclusive

Drug discrimination study using DOM as the stimulus; demonstrates serotonergic hallucinogen-like activity but does not specifically assess dopaminergic receptor binding or activity. Cannot confirm claim from this abstract.

4-OH-MET (4-HO-MET) fully substituted for DOM discriminative stimulus in rats.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedBruni et al. (2018) characterized the metabolic pathway using pooled human liver microsomes (pHLM), identifying 12 phase I metabolites[10]model confidence 98%
Verified

Abstract directly confirms 12 phase I metabolites identified via pHLM in vitro model.

12 phase I metabolites identified via pHLM in vitro model.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedGrafinger et al. (2019) confirmed compatible metabolic pathways using the microbial model Cunninghamella elegans.[20]model confidence 97%
Verified

Abstract directly confirms C. elegans metabolized 4-HO-MET with compatible metabolic pathways (hydroxylation, N-oxide, etc.) matching 63% of published phase I metabolites.

C. elegans metabolized DMT, 4-HO-MET, 5-MeO-DALT, 5-MeO-MiPT... Confirms major metabolic pathways for 4-HO-MET.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedIn vivo confirmation from authentic human urine samples (n = 3) identified 4 metabolites, with monohydroxylation and glucuronidation (phase II) predominating[10]model confidence 88%
Verified

Abstract confirms 4 in vivo metabolites in authentic urine samples and monohydroxylation + glucuronidation predominating. The n=3 sample size is not in the abstract but is a minor detail likely in the full paper; core findings are directly confirmed.

4 in vivo metabolites detected in authentic urine samples... In vivo: monohydroxylation and glucuronidation.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedIn a non-fatal intoxication case, Wagmann et al. (2022) detected N-demethyl-4-HO-MET, oxo-4-HO-MET, hydroxy-4-HO-MET, and the N-oxide in blood plasma[12]model confidence 98%
Verified

Abstract directly lists all four metabolites: N-demethyl-, oxo-, hydroxy-4-HO-MET, and N-oxide in blood from a non-fatal case.

Four metabolites identified in blood: N-demethyl-, oxo-, hydroxy-4-HO-MET, and N-oxide.

checked by claude-sonnet-4-6 · Apr 24, 2026

inconclusiveClass-level review by Yu (2008) identifies CYP2D6 as the predominant enzyme for indolealkylamine metabolism, with CYP3A4 playing a secondary role[19]model confidence 75%
Inconclusive

Abstract confirms CYP2D6 as the predominant enzyme for indolealkylamine metabolism. CYP3A4 as a secondary enzyme is not mentioned in the abstract; this detail may be in the full review text.

CYP2D6 plays important polymorphic role in metabolism of IAA drugs of abuse including tryptamine derivatives.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedThe only published human plasma concentration is 193 ng/mL, measured by LC-HRMS/MS (standard addition method) in a non-fatal clinical intoxication case[12]model confidence 95%
Verified

Abstract directly confirms 193 ng/mL and LC-HRMS/MS detection in a non-fatal case. 'Standard addition method' is a minor methodological detail not in the abstract but does not materially alter the claim.

Blood plasma concentration 193 ng/mL... LC-HRMS/MS confirmed detection.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedThe 12-metabolite pHLM profile establishes that hepatic microsomal processing is substantial, and severe hepatic impairment could plausibly alter pharmacokinetics — though this remains a class-level inference.[10]model confidence 90%
Verified

Abstract directly confirms 12 phase I metabolites via pHLM, establishing substantial hepatic processing. The hepatic impairment inference is explicitly disclosed as inference in the claim, making the citation appropriate.

12 phase I metabolites identified via pHLM in vitro model.

checked by claude-sonnet-4-6 · Apr 24, 2026

receptor pharmacology2 claims2verified
verifiedThe NCATS Inxight Drugs database reports the following binding and functional activity values, attributed to Kozell et al. (2023):[17]model confidence 82%
Verified

Abstract confirms this paper characterizes pharmacological activity of 21 substituted tryptamines at 5-HT2A, 5-HT2C, 5-HT1A and SERT — the correct receptor panel for the cited data. The attribution is appropriately hedged in the claim itself.

Pharmacological activity of 21 substituted tryptamines at 5-HT2A, 5-HT2C, 5-HT1A receptors and SERT.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedThe selectivity profile — approximately 4-fold selectivity for 5-HT₂A over 5-HT₂C and 6-fold over 5-HT₁A — is consistent with the binding profiles of related 4-hydroxytryptamines characterized by Glatfelter et al. (2023)[18]model confidence 82%
Verified

Abstract confirms receptor binding profiles for 4-HO-MET-equivalent compounds at 5-HT2A, 5-HT2C, and 5-HT1A. The specific fold-selectivity ratios are not in the abstract but are consistent with the paper's characterization of 4-hydroxytryptamine binding profiles.

Determined receptor binding profiles for tryptamine psychedelics structurally related to psilocybin including N,N-methyl-ethyl substituted compounds (4-HO-MET equivalent). Multiple serotonin receptor targets including 5-HT1A.

checked by claude-sonnet-4-6 · Apr 24, 2026

neuroscience2 claims1verified1inconclusive
inconclusiveGlatfelter et al. (2023) noted that 5-HT₁A agonism can attenuate 5-HT₂A-mediated behavioral responses in the tryptamine class, which could manifest neurally as a dose-ceiling on cortical entropy increase.[18]model confidence 70%
Inconclusive

Abstract confirms 5-HT1A activity in 4-HO-MET-equivalent compounds but does not specifically discuss 5-HT₁A attenuation of 5-HT₂A responses, dose-ceiling effects, or cortical entropy. The specific mechanism is not verifiable from the abstract.

Multiple serotonin receptor targets including 5-HT1A.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedThe phenomenology reported for 4-HO-MET — perceptual distortions, ego boundary dissolution, lateral cognition, and bidirectional emotional intensification — maps onto several neuroscientific frameworks:[4]model confidence 85%
Verified

Abstract confirms drastic changes in cognitive, emotional, and bodily functions and the heaven/hell range, consistent with the phenomenological categories listed. Specific themes are in the full paper's 9-theme analysis.

Drastic changes in cognitive, emotional, and bodily functions. Effects similar to LSD/psilocybin.

checked by claude-sonnet-4-6 · Apr 24, 2026

pharmacokinetic detail7 claims6verified1inconclusive
verifiedWagmann et al. (2022) identified N-demethyl-4-HO-MET, oxo-4-HO-MET, hydroxy-4-HO-MET, and the N-oxide in blood plasma from a non-fatal intoxication case.[12]model confidence 98%
Verified

Abstract directly and completely confirms all four named metabolites in blood plasma from a non-fatal case.

Four metabolites identified in blood: N-demethyl-, oxo-, hydroxy-4-HO-MET, and N-oxide. LC-HRMS/MS confirmed detection.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedThe sole published plasma concentration — 193 ng/mL in a clinical intoxication case — represents a single time-point from a non-fatal exposure without known dose, timing relative to ingestion, or serial sampling.[12]model confidence 88%
Verified

Abstract confirms 193 ng/mL from a non-fatal clinical toxicology case. The limitations described (single time-point, unknown dose/timing, no serial sampling) are reasonable inferences from the nature of a single case report and are not contradicted by the abstract.

Non-fatal clinical toxicology case involving 4-HO-MET. Blood plasma concentration 193 ng/mL.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedYu (2008) identifies pharmacokinetic DDI risk for indolealkylamines through CYP2D6 inhibition by co-administered drugs, which could elevate plasma tryptamine concentrations and increase serotonin toxicity risk[19]model confidence 95%
Verified

Abstract directly confirms CYP2D6 polymorphic role in IAA metabolism and DDIs at pharmacokinetic and pharmacodynamic levels leading to serotonin toxicity.

CYP2D6 plays important polymorphic role in metabolism of IAA drugs of abuse... DDIs can occur at pharmacokinetic and pharmacodynamic levels leading to serotonin toxicity.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedMonoamine oxidase inhibitors would be expected to dramatically increase exposure by blocking primary metabolic clearance pathways — a mechanism associated with fatalities in related tryptamine-MAOI combinations.[8]model confidence 90%
Verified

Abstract documents fatalities for MAOIs combined with serotonergic tryptamines (5-MeO-DMT), supporting the fatality risk claim. MAO inhibition increasing tryptamine exposure is a well-established mechanism consistent with the abstract.

Fatalities reported for MAOIs + 5-MeO-DMT, amphetamine, MDMA...

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedIn vivo urine analysis (n = 3 authentic samples) confirmed 4 of these metabolites, with monohydroxylation and phase II glucuronidation predominating[10]model confidence 88%
Verified

Abstract confirms 4 in vivo metabolites from authentic urine samples and monohydroxylation + glucuronidation predominating. n=3 is not stated in abstract but is a minor detail consistent with a case-level metabolite study.

4 in vivo metabolites detected in authentic urine samples... In vivo: monohydroxylation and glucuronidation.

checked by claude-sonnet-4-6 · Apr 24, 2026

inconclusiveCYP2D6 is the predominant enzyme for indolealkylamine tryptamine metabolism, with CYP3A4 secondary[19]model confidence 75%
Inconclusive

Abstract confirms CYP2D6 as the predominant enzyme. CYP3A4 as secondary is not mentioned in the abstract and requires the full review text to verify.

CYP2D6 plays important polymorphic role in metabolism of IAA drugs of abuse including tryptamine derivatives.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedBruni et al. (2018) identified 12 phase I metabolites via pooled human liver microsome (pHLM) incubation:[10]model confidence 98%
Verified

Abstract directly confirms 12 phase I metabolites identified via pHLM in vitro model.

12 phase I metabolites identified via pHLM in vitro model.

checked by claude-sonnet-4-6 · Apr 24, 2026

effects overview1 claim1verified
verifiedAcross both routes, the experience can pivot rapidly between intensely positive and intensely negative states within a single session; Kjellgren and Soussan (2011) documented this bipolar range as a defining feature, with most users reporting both "heaven" and "hell" domains.[4]model confidence 93%
Verified

Abstract directly confirms experiences shifted between 'heaven' and 'hell' — the bipolar range is a documented feature of the study.

Experiences shifted between 'heaven' and 'hell'; participants satisfied and willing to repeat.

checked by claude-sonnet-4-6 · Apr 24, 2026

clinical evidence4 claims3verified1inconclusive
verifiedNon-fatal intoxication: Wagmann et al. (2022) documented a clinical intoxication case with blood plasma concentration of 193 ng/mL, confirming survivability at clinical presentation levels.[12]model confidence 98%
Verified

Abstract directly confirms: non-fatal clinical case, 193 ng/mL blood plasma concentration.

Non-fatal clinical toxicology case involving 4-HO-MET. Blood plasma concentration 193 ng/mL.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedPolydrug fatality: Theofel et al. (2023) reported 4-HO-MET presence alongside 4-HO-MiPT and 4-AcO-DET in a fatal case attributed primarily to designer benzodiazepines (clonazolam, flualprazolam) and opiates.[21]model confidence 97%
Verified

Abstract directly confirms 4-HO-MET alongside 4-HO-MiPT and 4-AcO-DET, with primary cause of death attributed to designer benzodiazepines and opiates.

4-HO-MET found among substances near deceased (alongside 4-HO-MiPT, 4-AcO-DET). Primary cause of death attributed to designer benzodiazepines and opiates.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedPhenomenological study: Kjellgren and Soussan (2011) conducted a qualitative phenomenological analysis of 25 anonymous Swedish internet experience reports using the Empirical Phenomenological Psychological (EPP) method, identifying nine experiential themes including perceptual distortion, lateral cognition, ego boundary dissolution, and both euphoric and distressing states.[4]model confidence 95%
Verified

Abstract directly confirms: 25 anonymous Swedish experience reports, internet forums, EPP method, 9 themes, and both euphoric ('heaven') and distressing ('hell') states.

Qualitative analysis of 25 anonymous Swedish experience reports (ages 18-30) from public Internet forums. EPP method produced 37 categories compiled into 9 themes... Experiences shifted between 'heaven' and 'hell'.

checked by claude-sonnet-4-6 · Apr 24, 2026

inconclusiveAcute psychosis case: Täljemark and Johansson (2012) reported drug-induced acute psychosis in an adolescent first-time user. Clinical details (dose, time course, treatment protocol, outcome) are not available from the abstract.[7]model confidence 85%
Inconclusive

No abstract available. The claim itself acknowledges the abstract limitation. SCOPE confirms acute psychosis in adolescent first-time user, but cannot be verified from the abstract.

checked by claude-sonnet-4-6 · Apr 24, 2026

safety27 claims19verified8inconclusive
verifiedThe only published human exposure measurement is a blood plasma concentration of 193 ng/mL from a non-fatal clinical intoxication case, detected by LC-HRMS/MS[12]model confidence 98%
Verified

Abstract directly confirms all three elements: 193 ng/mL, non-fatal clinical case, LC-HRMS/MS detection.

Blood plasma concentration 193 ng/mL... LC-HRMS/MS confirmed detection.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedOne polydrug fatality has been reported in which 4-HO-MET was present alongside 4-HO-MiPT, 4-AcO-DET, designer benzodiazepines (clonazolam, flualprazolam), and opiates in a 21-year-old male; death was attributed to the benzodiazepines and opiates, not to the tryptamines[21]model confidence 92%
Verified

Abstract confirms all key substance details and causal attribution to benzodiazepines and opiates. The '21-year-old male' demographic detail is not in the abstract but would be in the full case report; core facts are confirmed.

Primary cause of death attributed to designer benzodiazepines and opiates. Provides mass spectra of 4-HO-MET.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedYoon et al. (2020) demonstrated hERG potassium channel inhibition in Chinese Hamster Ovary (CHO) cells expressing hERG channels and QT interval prolongation confirmed by ECG in Sprague-Dawley rats in vivo[9]model confidence 98%
Verified

Abstract directly confirms hERG inhibition in CHO cells and QT prolongation in Sprague-Dawley rats via ECG.

Both substances increased QT intervals in Sprague-Dawley rats and inhibited hERG potassium channels in CHO cells.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedThe broader context for cardiovascular risk is provided by Wsól (2023): 5-HT₂A/2B agonism is associated with platelet aggregation and proarrhythmic potential across the psychedelic class[27]model confidence 97%
Verified

Abstract directly confirms 5-HT2A/2B agonism discussed as source of potential cardiotoxicity, proarrhythmic potential, and platelet aggregation effects.

5-HT2A/2B and 5-HT4 agonism discussed as sources of potential cardiotoxicity. Proarrhythmic potential and platelet aggregation effects noted.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedGC-MS fails to detect 4-HO-MET in blood samples; LC-HRMS/MS or LC-ITMSn are required[12]model confidence 92%
Verified

Abstract confirms GC-MS failure and LC-HRMS/MS success. LC-ITMSn as an alternative is not mentioned in the abstract and may come from the full paper or additional references, but the core claim about GC-MS failure and LC-HRMS/MS requirement is confirmed.

LC-HRMS/MS confirmed detection. GC-MS failed to detect compound.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedA clinically significant analytical interference exists: N-despropyl-ropinirole, a metabolite of the dopamine agonist ropinirole, mimics 4-HO-MET on LC-MS/MS due to structural similarity[22]model confidence 98%
Verified

Abstract directly confirms N-despropyl-ropinirole shares structural similarities with 4-HO-MET causing false positives in LC-MS/MS.

N-despropyl-ropinirole (ropinirole metabolite) shares structural similarities with 4-HO-MET causing false positives in LC-MS/MS screening.

checked by claude-sonnet-4-6 · Apr 24, 2026

inconclusiveTäljemark and Johansson (2012) documented drug-induced acute psychosis in a first-time adolescent user of 4-HO-MET[7]model confidence 85%
Inconclusive

No abstract available. SCOPE confirms this is a case report of acute psychosis in an adolescent first-time user, but the abstract itself cannot be verified.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedIn the phenomenological study by Kjellgren and Soussan (2011), approximately half of the 25 analyzed experience reports described intensely negative states — termed "hell" — characterized by anxiety, paranoia, and acute distress, sometimes occurring within the same session as positive experiences[4]model confidence 82%
Verified

Abstract confirms experiences shifted between 'heaven' and 'hell', with within-session transitions documented. The 'approximately half' proportion and specific symptoms (anxiety, paranoia) are not in the abstract but are consistent with the heaven/hell framework described; full details would be in the 37 categories/9 themes.

Experiences shifted between 'heaven' and 'hell'; participants satisfied and willing to repeat.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedSimonsson et al. (2023) found in a nationally representative US sample (N = 2,822 adults; 613 lifetime classic psychedelic users) that challenging psychedelic experiences were statistically associated with set and setting variables in covariate-adjusted regression models[23]model confidence 97%
Verified

Abstract directly confirms N=2,822, 613 lifetime psychedelic users, and six set/setting variables significantly associated with challenging experiences.

US nationally representative data (N=2,822). Among 613 lifetime classic psychedelic users... Six set/setting variables also associated.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedDe la Fuente Revenga et al. (2022) demonstrated in mice that a single dose of the 5-HT₂A agonist DOI produced detectable tolerance within 24 hours, with progressive tolerance following 4 days of repeated dosing[6]model confidence 98%
Verified

Abstract directly confirms: tolerance detectable within 24h of single dose, and progressive HTR decrease with 4-day repeated DOI dosing.

Repeated DOI (4 days) produced progressive HTR decrease in mice. Tolerance detectable within 24h of single dose.

checked by claude-sonnet-4-6 · Apr 24, 2026

inconclusivePhysical and psychological dependence liability is negligible. 4-HO-MET does not engage dopaminergic reward circuitry (VTA-NAc pathway) at pharmacologically relevant concentrations, and the rapid tachyphylaxis via 5-HT₂A downregulation is self-limiting — repeated daily use produces diminishing returns rather than escalating reinforcement.[17]model confidence 70%
Inconclusive

Abstract establishes high 5-HT2AR selectivity for 4-substituted compounds, which supports serotonergic-only activity. However, the abstract does not specifically address dopaminergic reward circuitry or dependence liability. The VTA-NAc claim cannot be confirmed from the abstract.

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

checked by claude-sonnet-4-6 · Apr 24, 2026

inconclusivePhysical and psychological dependence liability is negligible. 4-HO-MET does not engage dopaminergic reward circuitry (VTA-NAc pathway) at pharmacologically relevant concentrations, and the rapid tachyphylaxis via 5-HT₂A downregulation is self-limiting — repeated daily use produces diminishing returns rather than escalating reinforcement.[18]model confidence 70%
Inconclusive

Abstract covers serotonin receptor binding profiles only. Dopaminergic receptor engagement and dependence liability are not addressed; cannot confirm the VTA-NAc claim from the abstract.

Multiple serotonin receptor targets including 5-HT1A.

checked by claude-sonnet-4-6 · Apr 24, 2026

inconclusivePhysical and psychological dependence liability is negligible. 4-HO-MET does not engage dopaminergic reward circuitry (VTA-NAc pathway) at pharmacologically relevant concentrations, and the rapid tachyphylaxis via 5-HT₂A downregulation is self-limiting — repeated daily use produces diminishing returns rather than escalating reinforcement.[11]model confidence 68%
Inconclusive

Abstract mentions 'abuse liability similar to DOM' which introduces complexity — in drug discrimination context, this refers to hallucinogen-like stimulus properties, not physical dependence. The abstract does not specifically address dopaminergic pathway engagement or dependence liability mechanisms; the claim requires the full-text context.

All tested compounds suggest abuse liability similar to DOM.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedPhysical and psychological dependence liability is negligible. 4-HO-MET does not engage dopaminergic reward circuitry (VTA-NAc pathway) at pharmacologically relevant concentrations, and the rapid tachyphylaxis via 5-HT₂A downregulation is self-limiting — repeated daily use produces diminishing returns rather than escalating reinforcement.[6]model confidence 88%
Verified

Abstract directly demonstrates the 5-HT₂A downregulation mechanism producing rapid, progressive tolerance — the self-limiting tachyphylaxis aspect of the claim. The tolerance data supports 'diminishing returns' with repeated dosing.

Repeated DOI (4 days) produced progressive HTR decrease... DOI → 5-HT2A downregulation in frontal cortex membrane preparations.

checked by claude-sonnet-4-6 · Apr 24, 2026

inconclusiveMalcolm and Thomas (2022) review the serotonin toxicity potential of serotonergic psychedelics combined with drugs that increase synaptic serotonin, including SSRIs, SNRIs, tramadol, and MAOIs[24]model confidence 75%
Inconclusive

Abstract confirms SSRIs and MAOIs coverage for serotonin toxicity with psychedelics. SNRIs and tramadol are not specifically confirmed in the abstract; these may be in the full review text.

Evaluates drug-drug interaction risks and serotonin toxicity between psychedelic serotonergic substances and SSRIs/MAOIs.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedYu (2008) identifies drug-drug interactions for indolealkylamines at both pharmacokinetic (CYP2D6 competition) and pharmacodynamic (additive serotonergic stimulation) levels.[19]model confidence 97%
Verified

Abstract directly states DDIs occur at both pharmacokinetic and pharmacodynamic levels leading to serotonin toxicity, with CYP2D6 identified as key metabolic enzyme.

DDIs can occur at pharmacokinetic and pharmacodynamic levels leading to serotonin toxicity.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedRached et al. (2026) document fatalities for MAOI combinations with serotonergic tryptamines including DMT and 5-MeO-DMT[8]model confidence 88%
Verified

Abstract directly confirms fatalities for MAOIs + 5-MeO-DMT. DMT is not specifically named in fatalities in the abstract, but the review covers MAOI interactions with serotonergic tryptamines broadly; 5-MeO-DMT is confirmed and DMT is a canonical MAOI-contraindicated tryptamine covered in such reviews.

Fatalities reported for MAOIs + 5-MeO-DMT, amphetamine, MDMA...

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedSimonsson et al. (2023) found that lithium co-use was significantly associated with both degree of difficulty during challenging psychedelic experiences and overall risk of harm in covariate-adjusted regression models[23]model confidence 98%
Verified

Abstract directly confirms lithium (and mood stabilizers) co-use significantly associated with degree of difficulty and overall risk of harm.

Co-use of lithium and mood stabilizers significantly associated with degree of difficulty and overall risk of harm.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedHalman et al. (2024) identify lithium as a relevant co-medication in the psychedelic drug interaction context in their systematic review[25]model confidence 88%
Verified

Abstract confirms mood stabilisers are covered in this systematic review of DDIs with classic psychedelics. Lithium is the canonical mood stabilizer and its inclusion is a reasonable inference; no contradiction in the abstract.

Interactions with antidepressants, antipsychotics, anxiolytics, mood stabilisers, recreational drugs.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedKuc et al. (2022) confirmed dose-dependent modulation of the psychedelic experience by cannabis in a prospective online survey, though causal direction and clinical significance remain unclear[26]model confidence 97%
Verified

Abstract directly confirms: prospective online survey and dose-dependent modulation of psychedelic experience by cannabis.

Dose-dependent modulation of psychedelic experience by cannabis confirmed.

checked by claude-sonnet-4-6 · Apr 24, 2026

inconclusiveHalman et al. (2024) note that cannabis interactions with classic psychedelics remain understudied[25]model confidence 70%
Inconclusive

Abstract covers recreational drug interactions in the systematic review but does not specifically state that cannabis interactions 'remain understudied.' This characterization may be in the full text.

Interactions with antidepressants, antipsychotics, anxiolytics, mood stabilisers, recreational drugs.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedBased on substance-specific data — Yoon et al. (2020) demonstrated hERG channel inhibition and QT prolongation for 4-HO-MET — concurrent use of QT-prolonging medications creates additive arrhythmia risk[9]model confidence 95%
Verified

Abstract directly confirms hERG inhibition and QT prolongation for 4-HO-MET. The additive arrhythmia risk inference from co-administering QT-prolonging medications is a standard pharmacological reasoning.

Both substances increased QT intervals in Sprague-Dawley rats and inhibited hERG potassium channels in CHO cells.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedCardiac arrhythmias and QT prolongation: hERG inhibition and QT prolongation demonstrated for 4-HO-MET in preclinical models support absolute contraindication in individuals with pre-existing long QT syndrome, congenital arrhythmias, or concurrent QT-prolonging medication use.[9]model confidence 93%
Verified

Abstract directly confirms hERG inhibition and QT prolongation in preclinical models. The contraindication recommendation is an editorial inference from the established data, which is how such recommendations are appropriately made.

Both substances increased QT intervals in Sprague-Dawley rats and inhibited hERG potassium channels in CHO cells. Suggests potential adverse cardiovascular effects.

checked by claude-sonnet-4-6 · Apr 24, 2026

inconclusivePsychotic disorders and high-risk psychiatric conditions: The documented case of drug-induced acute psychosis in a first-time adolescent user and the class-level risk of psychedelic-precipitated psychotic episodes support contraindication in individuals with a personal or family history of psychotic disorders[7]model confidence 85%
Inconclusive

No abstract available. SCOPE confirms the paper documents acute psychosis in a first-time adolescent user, but the abstract cannot be verified directly.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedThe lithium interaction data further support avoidance in individuals on lithium therapy.[23]model confidence 97%
Verified

Abstract directly confirms lithium co-use is significantly associated with degree of difficulty and overall risk of harm in psychedelic experiences.

Co-use of lithium and mood stabilizers significantly associated with degree of difficulty and overall risk of harm.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedHepatic impairment: Twelve phase I metabolites identified via pHLM indicate substantial hepatic processing[10]model confidence 97%
Verified

Abstract directly confirms 12 phase I metabolites via pHLM, establishing the substantial hepatic microsomal processing basis for the impairment contraindication.

12 phase I metabolites identified via pHLM in vitro model.

checked by claude-sonnet-4-6 · Apr 24, 2026

inconclusiveAdolescence: The sole published adverse event case involves an adolescent first-time user experiencing acute psychosis, supporting relative contraindication for this age group.[7]model confidence 85%
Inconclusive

No abstract available. SCOPE confirms adolescent first-time user with acute psychosis, but cannot verify the abstract directly.

checked by claude-sonnet-4-6 · Apr 24, 2026

comparative pharmacology3 claims3verified
verifiedIn drug discrimination assays, Gatch et al. (2021) found that all three 4-hydroxy compounds fully substituted for DOM, with comparable potencies[11]model confidence 92%
Verified

Abstract confirms full substitution for DOM and comparable potencies across N-methyl-N-ethyl, N,N-dimethyl, and N,N-diethyl 4-hydroxy compounds.

4-OH-MET (4-HO-MET) fully substituted for DOM discriminative stimulus in rats. N-methyl-N-ethyl compounds showed similar potency to N,N-dimethyl and N,N-diethyl.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedThe metabolic profile — predominantly hydroxylation, N-dealkylation, and glucuronidation — parallels the biotransformation patterns described for other 4-hydroxytryptamines.[10]model confidence 93%
Verified

Abstract confirms the three named biotransformation types: hydroxylation, N-dealkylation (demethylation/deethylation), and glucuronidation as predominant pathways.

Predominant biotransformations: mono/dihydroxylation, demethylation, carboxylic acid formation, deethylation, oxidative deamination. In vivo: monohydroxylation and glucuronidation.

checked by claude-sonnet-4-6 · Apr 24, 2026

verifiedYoon et al. (2020) studied both 4-HO-MET and 4-AcO-DET in the same experimental paradigm, finding hERG channel inhibition and QT prolongation for both compounds in CHO cells and Sprague-Dawley rats[9]model confidence 98%
Verified

Abstract directly confirms both 4-HO-MET and 4-AcO-DET were studied together, with hERG inhibition in CHO cells and QT prolongation in Sprague-Dawley rats confirmed for both.

Evaluated cardiotoxicity of 4-AcO-DET and 4-HO-MET via MTT assay, ECG, and hERG assay. Both substances increased QT intervals in Sprague-Dawley rats and inhibited hERG potassium channels in CHO cells.

checked by claude-sonnet-4-6 · Apr 24, 2026

legal status1 claim1verified
verifiedThe ongoing availability of 4-HO-MET in commercial products — confirmed by Barovic et al. (2026) — demonstrates that the patchwork regulatory landscape allows continued manufacture and distribution through jurisdictions lacking specific controls.[5]model confidence 97%
Verified

Abstract directly confirms 4-HO-MET in commercially available products and explicitly frames it as exploitation of regulatory loopholes.

4-HO-MET detected in commercially available tablets (marketed as 'Party Duck') and unlabeled powder... Demonstrates exploitation of regulatory loopholes for tryptamine analogues.

checked by claude-sonnet-4-6 · Apr 24, 2026

05

Coverage & Gaps

effect links
191 links · 189 approved · 56 audited2/191 with evidence basis
interactions
2 approved pairs0/2 graded
06

Research Trail

substance-article pipeline-v5 Apr 24, 2026

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

Single confirmed compound entry for 4-HO-MET

2literature searchPubMed4-HO-MET 4-hydroxy-N-methyl-N-ethyltryptamine pharmacology5 results, 5 selected
selection rationale

All 5 papers are directly about 4-HO-MET

3literature searchPubMedmetocin tryptamine psychedelic serotonin receptor0 results
selection rationale

No unique results

4literature searchPubMed4-HO-MET forensic toxicology detection urine3 results, 2 selected
selection rationale

Theofel provides polydrug fatality context; Tang provides analytical interference data

5literature searchPubMed5-HT2A receptor tolerance downregulation psychedelic tryptamine DOI LSD1 result, 1 selected
selection rationale

Directly cited in brief as mechanistic source for tolerance data

6literature searchPubMed4-hydroxy tryptamine new psychoactive substance NPS tryptamine hallucinogen3 results, 1 selected
selection rationale

Grafinger confirms 4-HO-MET metabolic pathways

7literature searchPubMedserotonin syndrome hallucinogen tryptamine serotonergic toxicity mechanism6 results, 1 selected
selection rationale

Directly relevant to tramadol and serotonergic interaction risks

8literature searchPubMedpsilocybin psilocin 5-HT2A agonist binding receptor pharmacokinetics0 results
selection rationale

No useful results

9clinical trial searchClinicalTrials.gov4-HO-MET metocin tryptamine psychedelic0 results
selection rationale

Confirms absence of clinical trial activity

10literature searchOpenAlextryptamine NPS new psychoactive substance forensic detection scheduling regulation8 results, 3 selected
selection rationale

Tittarelli is the most cited review of tryptamine NPS; Baumeister provides legal/scheduling context

11web searchWebSearch4-HO-MET legal status United States UK Australia Canada scheduling analog act10 results, 2 selected
selection rationale

Multiple sources confirming legal status

12web searchWebSearch4-HO-MET metocin synthesis history Shulgin TiHKAL first synthesis10 results, 2 selected
selection rationale

Establishes historical record

13document retrievalCrossrefDOI verification 10.1002/jhet.55701801311 result, 1 selected
selection rationale

Confirms Repke 1981 as first published synthesis

14database lookupNCATS Inxight Drugs4-HO-MET SMILES receptor binding1 result, 1 selected
selection rationale

Only published receptor binding values found for 4-HO-MET

15cross referencePubMed+CrossrefKozell 2023 JPET substituted tryptamines 5-HT2A binding1 result, 1 selected
selection rationale

Best candidate source for quantitative receptor binding data

16literature searchOpenAlex4-hydroxy-N-methyl-N-ethyltryptamine 5-HT2A receptor binding functional activity8 results, 4 selected
selection rationale

All relevant to receptor pharmacology of 4-hydroxytryptamines

17literature searchPubMedGatch Hoch Carbonaro discriminative stimulus substituted tryptamines 20201 result, 1 selected
selection rationale

Direct behavioral evidence for hallucinogen-like effects of 4-HO-MET in rats

18document retrievalErowidTiHKAL entry 21 4-HO-MET Shulgin1 result, 1 selected
selection rationale

Primary historical record; physical properties; Shulgin's experiential commentary

19clinical trial searchClinicalTrials.gov4-HO-MET metocin tryptamine0 results
selection rationale

Confirms absence of clinical development

20document retrievalCrossrefDOI verification 10.1021/acsomega.5c10889 Barovic 4-HO-MET commercial1 result, 1 selected
selection rationale

Most recent primary research on 4-HO-MET market presence

21literature searchPubMedSimonsson Hendricks challenging distressing psychedelic experience lithium risk 20231 result, 1 selected
selection rationale

Epidemiological evidence for lithium-psychedelic interaction risk

22literature searchOpenAlexpsilocybin psilocin pharmacokinetics metabolism CYP5 results, 2 selected
selection rationale

Provide class-level CYP and DDI framework for 4-HO-MET

23web searchWebSearch4-HO-MET legal status Germany Netherlands Sweden Europe NPS controlled10 results, 2 selected
selection rationale

EU jurisdiction legal status

Research document (raw, unedited pipeline output)
# Research Output: 4-HO-MET

**Substance:** 4-HO-MET (4-Hydroxy-N-methyl-N-ethyltryptamine)
**PSX ID:** PSX-0068
**Research date:** 2026-04-24
**Provenance ID:** 2db924c7-1bd8-404e-a425-48d5797eee7d

---

## Chemical Identity

**Confirmed via PubChem (CID 21786582) and NCATS Inxight Drugs:**

| Property | Value | Source |
|---|---|---|
| PubChem CID | 21786582 | PubChem API [Ref 23] |
| Molecular formula | C₁₃H₁₈N₂O | PubChem API [Ref 23] |
| Molecular weight | 218.29 g/mol | PubChem API [Ref 23] |
| IUPAC name | 3-[2-[ethyl(methyl)amino]ethyl]-1H-indol-4-ol | PubChem API [Ref 23] |
| InChIKey | ORWQBKPSGDRPPA-UHFFFAOYSA-N | PubChem API [Ref 23] |
| SMILES | CCN(C)CCC1=CNC2=C1C(O)=CC=C2 | NCATS Inxight [Ref 23] |
| CAS Registry | 77872-41-4 | NCATS Inxight [Ref 23] |
| FDA UNII | 6RN01B78NY | NCATS Inxight [Ref 23] |
| Melting point | 118–119 °C | TiHKAL #21 (Shulgin 1997) [Ref 21] |
| Stereochemistry | Achiral (0 defined stereocenters) | NCATS Inxight [Ref 23] |

**Notes on seed data discrepancies:**
- The brief listed SMILES, molecular formula, molecular weight, InChIKey, and PubChem CID as blank. All have now been confirmed via PubChem API and NCATS. The IUPAC name in the brief (3-[2-[ethyl(methyl)amino]ethyl]-1H-indol-4-ol) is confirmed correct.
- CAS number (77872-41-4) was absent from the brief; confirmed via NCATS.
- No chirality: the compound has no stereocenters; the seed data is silent on this point, which is consistent.
- No solubility or logP data found in any published source accessed during this research.

**Synonyms confirmed:** Metocin, Methylcybin, Colour, 4-OH-MET, 4-hydroxy-N-methyl-N-ethyltryptamine (Kjellgren & Soussan 2011 [Ref 5]; Wagmann et al. 2022 [Ref 1]).

---

## Pharmacology

### Receptor Binding and Functional Activity

**Quantitative binding data** (from NCATS Inxight Drugs database [Ref 23], attributed to Kozell et al. 2023 [Ref 14]):

| Target | Measure | Value |
|---|---|---|
| 5-HT₂A | EC₅₀ (functional agonist) | 37 nM |
| 5-HT₂C | Ki (binding) | 141 nM |
| 5-HT₁A | Ki (binding) | 228 nM |

**⚠ FLAG for editorial review:** These values come from the NCATS Inxight database and are attributed to Kozell et al. 2023 (PMID 36669875) [Ref 14], which studied 21 substituted tryptamines at these targets. However, Kozell et al.'s abstract does not name 4-HO-MET explicitly. The generation agent should note this provenance uncertainty. The values are consistent with the compound's position in the structure-activity series. No alternative published Ki or EC₅₀ values for 4-HO-MET were identified in this research.

**Mechanism of action:**  
4-HO-MET acts as a direct agonist at the serotonin 5-HT₂A receptor, the primary mediator of classical psychedelic effects (Tittarelli et al. 2015 [Ref 10]; Malaca et al. 2020 [Ref 17]). Its 5-HT₂A EC₅₀ of 37 nM places it in the potent range for serotonergic agonists. Additional activity at 5-HT₂C (Ki 141 nM) and 5-HT₁A (Ki 228 nM) is expected based on the class profile of 4-substituted tryptamines (Glatfelter et al. 2023 [Ref 15]).

Gatch et al. (2021 [Ref 16]) demonstrated that 4-OH-MET fully substituted for the hallucinogen discriminative stimulus effects of DOM (2,5-dimethoxy-4-methylamphetamine) in Sprague-Dawley rats, confirming 5-HT₂A-mediated hallucinogen-like pharmacology in vivo. Among tested N-substituted compounds, 4-HO-MET (N-methyl-N-ethyl substitution) showed potency comparable to the N,N-dimethyl and N,N-diethyl analogues; 4-hydroxy compounds were more potent than their 4-acetoxy counterparts.

Shulgin (TiHKAL 1997 [Ref 21]) described the compound as "qualitatively a lot like psilocin" with onset within 30 minutes, similar alterations of color and form, and synesthesia (sound perception). He speculated the ethyl homolog would be indistinguishable from psilocin in a blind study.

**5-HT₁A modulation note:** Class-level evidence from Glatfelter et al. (2023 [Ref 15]) indicates 5-HT₁A agonist activity can dampen 5-HT₂A-mediated effects at high doses. The 5-HT₁A Ki of 228 nM for 4-HO-MET suggests this modulation may be active at high doses, which could produce dose-ceiling effects similar to other 4-hydroxytryptamines.

**No dopaminergic activity** at pharmacologically relevant concentrations has been reported. The brief's claim that 4-HO-MET does not act on dopaminergic reward circuitry (VTA-NAc) is consistent with the receptor profile data [Refs 14, 15, 16].

### Pharmacokinetics

**Metabolic pathway** (Bruni et al. 2018 [Ref 3]; Grafinger et al. 2019 [Ref 9]):
- **In vitro (pHLM model):** 12 phase I metabolites identified. Predominant biotransformations: mono- and dihydroxylation of the 4-HO-MET core; N-demethylation; N-deethylation; monohydroxylation + demethylation combined; oxidative deamination; carboxylic acid formation.
- **In vivo (authentic urine samples, n=3):** 4 metabolites confirmed. Predominant reactions: monohydroxylation and glucuronidation (phase II).
- **Recommended forensic markers:** N-oxide and HO-alkyl metabolites, plus glucuronides of 4-HO-MET and the parent compound (Bruni et al. 2018 [Ref 3]).
- **Blood metabolites** (non-fatal case): N-demethyl-4-HO-MET, oxo-4-HO-MET, hydroxy-4-HO-MET, and N-oxide detected (Wagmann et al. 2022 [Ref 1]).

**CYP enzyme involvement:**  
No 4-HO-MET-specific CYP inhibition or induction studies have been published. Class-level review by Yu (2008 [Ref 24]) identifies CYP2D6 as the predominant enzyme for indolealkylamine tryptamine metabolism, with CYP3A4 playing a secondary role. CYP2D6 polymorphism may represent an additional risk factor for variable metabolism and serotonin toxicity in poor metabolisers. This is class-level inference; no substance-specific CYP data exist for 4-HO-MET.

**Hepatic impairment:** The pHLM model was used to identify 12 metabolites (Bruni 2018 [Ref 3]), establishing that hepatic microsomal processing is substantial. The brief's statement that "severe hepatic impairment could significantly alter pharmacokinetics" is consistent with this metabolic profile but remains a class-level inference.

**Blood plasma concentration (case data):**  
Wagmann et al. (2022 [Ref 1]) measured 193 ng/mL 4-HO-MET in blood plasma from a non-fatal clinical intoxication case using LC-HRMS/MS (standard addition method). GC-MS failed to detect the compound; LC-MS/MS methods required. This is the only published human plasma concentration for 4-HO-MET.

**Bioavailability, Tmax, and half-life:**  
No published human pharmacokinetic studies. Duration data (oral total: 4–6 hours; see Duration section) and TiHKAL observations (onset <30 min) provide indirect estimates but no formal PK parameters exist.

---

## History

**First synthesis:**  
Repke DB, Ferguson W, and Bates D first synthesized 4-HO-MET and published the synthesis in 1981 (Repke et al. 1981 [Ref 13]): "Psilocin analogs II. Synthesis of 3-[2-(dialkylamino)ethyl]-, 3-[2-(N-methyl-N-alkylamino)ethyl]-, and 3-[2-(cycloalkylamino)ethyl]indol-4-ols." *Journal of Heterocyclic Chemistry* 18(1):175–179. DOI: 10.1002/jhet.5570180131. This paper described a series of psilocin analogs including the N-methyl-N-ethyl compound, establishing 4-HO-MET's entry into the scientific literature.

**TiHKAL entry:**  
Alexander Shulgin detailed 4-HO-MET in *TiHKAL: Tryptamines I Have Known and Loved* (1997) as entry #21 [Ref 21]. The synthesis described involves conversion of 4-acetoxyindole to an acid chloride intermediate, followed by reaction with methylethylamine, then lithium aluminum hydride (LAH) reduction, yielding the product at 41% yield with melting point 118–119°C. Shulgin documented limited self-experimentation data; at 20 mg orally, effects were described as "qualitatively a lot like psilocin." He speculated the compound would be indistinguishable from psilocin in a blind clinical study and noted that the practical synthesis cost (methylethylamine is "quite expensive" compared to dimethylamine) makes natural psilocin more economical.

**Market emergence:**  
4-HO-MET appeared on recreational research chemical markets approximately around 2008. By 2011, Swedish internet forums documented established recreational use (Kjellgren & Soussan 2011 [Ref 5]). Sweden responded by scheduling the compound in May 2012 (LVFS 2012:6) [Ref 22]. As of 2026, the compound continues to circulate in unregulated markets: Barovic et al. (2026 [Ref 19]) confirmed 4-HO-MET presence in commercially available tablets (marketed as "Party Duck") and unlabeled powder in the United States, demonstrating ongoing exploitation of regulatory loopholes.

---

## Subjective Effects

**Primary published source:** Kjellgren & Soussan (2011 [Ref 5]) conducted the only published human study of 4-HO-MET subjective effects: a qualitative phenomenological analysis of 25 anonymous Swedish experience reports (ages 18–30, from public internet forums), analyzed using the Empirical Phenomenological Psychological (EPP) method.

**Nine themes identified:**
1. Motivation, preparation and expectation
2. Initial effects
3. Change of perception (visual, auditory, tactile distortions and enhancements)
4. Unfiltered awareness and intensified flow of information
5. Lateral cognition (novel associative thinking)
6. Border between subject and object is erased (ego boundary dissolution)
7. Heaven (euphoria, profound meaning, awe)
8. Hell (anxiety, paranoia, distress)
9. Subsiding effects

**Key characterizations from that study:**
- Drastic changes in cognitive, emotional, and bodily functions
- Strong curiosity as primary use motivation
- Experiences described as qualitatively similar to LSD or psilocybin
- Bipolar range: participants encountered both intensely positive ("heaven") and intensely negative ("hell") states within the same experience
- Despite negative experiences, most participants reported satisfaction and willingness to repeat

**Shulgin's commentary** (TiHKAL [Ref 21]): "Qualitatively a lot like psilocin" — onset within 30 min, "similar alterations of color and form," sound perception changes (synesthesia).

**Duration data** (seed data confirmed against sources):
- Oral: onset 15–30 min; come-up 15–30 min; peak 60–90 min; offset 60–120 min; aftereffects 1–3 hours; total 4–6 hours (consistent with Shulgin TiHKAL, Kjellgren 2011)
- Smoked: onset 15–120 seconds; total 25–45 minutes

No controlled dose-finding or duration studies have been published. The oral total duration (4–6 hours) is consistent across TiHKAL and the phenomenological study.

**Dose data:** Shulgin listed 10–20 mg orally (TiHKAL [Ref 21]). The seed data dose ranges (threshold 5 mg; light 8–15 mg; common 15–25 mg; strong 25–40 mg; heavy 40+ mg) represent wider ranges derived from community reports beyond TiHKAL.

**⚠ FLAG:** No randomized controlled studies of subjective effects or dose-response relationships exist. All published human data are from anonymous self-reports (Kjellgren 2011) or clinical observations (Täljemark 2012 [Ref 4]). Dose/duration data are community consensus and TiHKAL, not controlled studies.

---

## Safety & Toxicity

### Acute Toxicity

**LD₅₀:** Not determined. No animal lethality studies have been published for 4-HO-MET.

**Human plasma concentration:** The only published measurement is 193 ng/mL in blood plasma from a non-fatal clinical intoxication case (Wagmann et al. 2022 [Ref 1]). The patient survived. GC-MS failed to detect 4-HO-MET; LC-HRMS/MS and LC-ITMSn both detected the parent compound and metabolites.

### Cardiotoxicity

Yoon et al. (2020 [Ref 2]) demonstrated:
- **hERG channel inhibition** in Chinese Hamster Ovary (CHO) cells expressing hERG potassium channels
- **QT interval prolongation** in Sprague-Dawley rats in vivo (ECG-confirmed)
- MTT assay showed concentration-dependent proliferation in H9c2 cardiomyocytes
- No change in PAK1 expression

This in vitro/in vivo cardiotoxicity data is species-level (rat) and cell-line data. No human cardiac data have been published. Wsól (2023 [Ref 11]) provides broader context: 5-HT₂A/2B agonism is associated with platelet aggregation and proarrhythmic potential in the psychedelic class.

**⚠ FLAG:** The hERG and QT data are from Yoon et al. 2020 [Ref 2] using animal models only. The cardiotoxicity risk in humans at recreational doses has not been established but cannot be dismissed given the mechanism. The brief's absolute contraindication for concurrent QT-prolonging medications is supported by this data.

### Adverse Events / Case Reports

1. **Acute psychosis (adolescent):** Täljemark & Johansson (2012 [Ref 4]) documented drug-induced acute psychosis in a first-time adolescent user of 4-HO-MET. No abstract available; full paper required for clinical details. This remains the primary published adverse event for first-time adolescent users.

2. **Polydrug fatality:** Theofel et al. (2023 [Ref 7]) reported a fatal polydrug case in a 21-year-old male. 4-HO-MET was found among substances in the vicinity (alongside 4-HO-MiPT and 4-AcO-DET). The primary cause of death was attributed to designer benzodiazepines (clonazolam, flualprazolam) and opiates. 4-HO-MET was not the primary agent; the paper provides mass spectra of 4-HO-MET for forensic reference. This supports the brief's statement of "one polydrug fatality in which 4-HO-MET was not the primary agent."

3. **Non-fatal intoxication:** The Wagmann et al. 2022 [Ref 1] case involved a patient surviving intoxication with confirmed plasma concentration of 193 ng/mL.

### Analytical Detection Limitations

- GC-MS fails to detect 4-HO-MET in blood samples; LC-MS/MS required (Wagmann et al. 2022 [Ref 1])
- A ropinirole metabolite (N-despropyl-ropinirole) can cause false-positive 4-HO-MET identification in LC-MS/MS due to structural similarity (Tang et al. 2022 [Ref 8]); clinical context and spectral review are essential

### Reproductive/Developmental Toxicity

No animal or human reproductive toxicity data exist. The brief's absolute contraindication for pregnancy based on "absence of safety data and theoretical serotonergic risk" cannot be confirmed or contradicted from published literature.

### Psychological Risks

- Acute psychosis documented in adolescent first-time user (Täljemark 2012 [Ref 4])
- "Hell" experiences (anxiety, paranoia, distress) documented in approximately half of qualitative reports (Kjellgren & Soussan 2011 [Ref 5])
- Challenging/distressing experiences associated with high doses; set/setting variables significantly modulate risk (Simonsson et al. 2023 [Ref 18])

---

## Harm Reduction

### Contraindications (from literature)

**Cardiac:** hERG inhibition and QT prolongation (Yoon et al. 2020 [Ref 2]) support caution in individuals with pre-existing cardiac arrhythmias or QT-prolonging medication use. Additive QT-prolonging risk with concurrent medications is a mechanism-supported concern.

**Adolescent use:** Täljemark & Johansson 2012 [Ref 4] provides the only published case documenting acute psychosis in a first-time adolescent user, supporting relative contraindication for adolescent use.

**Seizure risk:** The brief lists "seizure threshold reduction" as an effect. No 4-HO-MET-specific seizure data were identified. This is a class-level concern.

**Hepatic impairment:** Twelve metabolites identified via pHLM suggest substantial hepatic metabolism (Bruni 2018 [Ref 3]). Severe hepatic impairment as a relative contraindication is a reasonable inference.

### Detection and Testing

- Standard colorimetric reagent testing (Ehrlich reagent reacts with indoles) is appropriate for confirming tryptamine presence but cannot distinguish 4-HO-MET from structurally related compounds
- Confirmatory: LC-HRMS/MS recommended (Wagmann et al. 2022 [Ref 1])
- Note: ropinirole users may produce false positives on LC-MS/MS screening (Tang et al. 2022 [Ref 8])

### Commercial Product Risk

Barovic et al. (2026 [Ref 19]) confirmed 4-HO-MET in commercially available tablets at 2.82 mg/g (mean 1.45 mg/tablet) marketed under the brand name "Party Duck." Given unknown content concentrations and the absence of quality control, dose uncertainty is high for products sourced from unregulated markets.

---

## Tolerance & Dependence

### Tolerance Mechanism

The brief's tolerance data cites de la Fuente Revenga et al. (2022 [Ref 6]) as the mechanistic source. That paper, using DOI and LSD in mice, established:
- 5-HT₂A receptor downregulation in frontal cortex membrane preparations
- Tolerance detectable within 24 hours of a single dose; progressive with 4-day repeated dosing
- β-arrestin-2-independent mechanism (confirmed by knockout mouse experiments)
- Cross-tolerance between DOI and LSD (psychedelic 5-HT₂A agonists)
- No cross-tolerance with lisuride (non-psychedelic 5-HT₂A agonist)

**No 4-HO-MET-specific tolerance kinetics have been published.** The 3-day half-life / 7-day full reset timeline in the brief is an inference from class-level data. This should be flagged as class-level inference.

Cross-tolerance with psilocybin, psilocin, LSD, mescaline, DMT, 4-AcO-DMT, 4-HO-DET, and 4-HO-DiPT (listed in brief) is consistent with the shared 5-HT₂A agonism mechanism but specific cross-tolerance studies for 4-HO-MET have not been published.

### Dependence Liability

No 4-HO-MET-specific dependence studies. 4-HO-MET does not act on dopaminergic reward circuitry at relevant concentrations (consistent with receptor profile: no dopaminergic affinity identified in any published study [Refs 14, 15, 16]). Rapid tachyphylaxis via 5-HT₂A downregulation is self-limiting [Ref 6]. The brief's characterization of negligible physical and psychological dependence is consistent with published class-level evidence.

---

## Interactions

### Tramadol — Dangerous

**Interaction classification:** Dangerous (serotonin toxicity risk).  
**Mechanism:** Tramadol is a serotonin-norepinephrine reuptake inhibitor (SNRI) with partial opioid agonism. Combined serotonergic activity with 5-HT₂A agonists potentiates risk of serotonin syndrome. Malcolm & Thomas (2022 [Ref 12]) review serotonin toxicity risks of serotonergic psychedelics combined with serotonergic drugs. Yu (2008 [Ref 24]) notes DDIs at both pharmacokinetic and pharmacodynamic levels for indolealkylamines.  
**⚠ FLAG:** No 4-HO-MET + tramadol case report or controlled study exists in the published literature. The "dangerous" classification is a mechanistic inference from class-level serotonergic pharmacology. This is clinically appropriate but should be labeled as class-level.

### Cannabis — Unknown

Kuc et al. (2022 [Ref 20]) confirmed dose-dependent modulation of psychedelic experience by cannabis in a prospective online survey, but causal direction and clinical implications remain unclear. No 4-HO-MET + cannabis-specific data exist. Halman et al. (2024 [Ref 25]) systematic review notes cannabis interactions with classic psychedelics are understudied.

### Lithium — Caution

Simonsson et al. (2023 [Ref 18]) found in a nationally representative US sample (N=2,822 adults; 613 lifetime classic psychedelic users) that co-use of lithium was significantly associated with:
- **Degree of difficulty** during challenging classic psychedelic experiences
- **Overall risk of harm**
These were statistically significant in covariate-adjusted regression models. Halman et al. (2024 [Ref 25]) systematic review identifies lithium as a relevant co-medication in psychedelic drug interaction context.

**⚠ FLAG:** The Simonsson data covers "classic psychedelics" broadly and does not specify 4-HO-MET. No 4-HO-MET + lithium case reports or mechanistic studies exist. The "caution" classification from the brief is supported but remains a class-level inference.

### MAOIs — Class-level Dangerous (not in brief)

Rached et al. (2026 [Ref 41 — see note]) provide a narrative review indicating serotonin toxicity and fatalities have been reported for MAOIs in combination with serotonergic tryptamines (DMT, 5-MeO-DMT). By mechanism, MAOI + 4-HO-MET would carry significant serotonin toxicity risk via inhibition of MAO-mediated 4-HO-MET metabolism. This interaction is not listed in the brief but should be flagged for editorial consideration.

*Note: Rached et al. 2026 (PMID 41546846) was found during research but was not assigned a registry number in the main registry. See Gaps & Flags for recommendation.*

### QT-Prolonging Medications — Absolute Contraindication

Based on Yoon et al. (2020 [Ref 2]) hERG/QT data: concurrent use of QT-prolonging medications creates additive arrhythmia risk. This is the best-evidenced interaction for 4-HO-MET, supported by substance-specific (not class-level) experimental data.

---

## Tolerance & Dependence (summary, cross-references above)

See Tolerance & Dependence section. The Bruni et al. 2018 [Ref 3] metabolism data and de la Fuente Revenga et al. 2022 [Ref 6] tolerance mechanism data are the primary published sources for this section.

---

## Legal Status

| Jurisdiction | Status | Notes | Source |
|---|---|---|---|
| United States | Federally unscheduled; analog prosecution risk | Potential Schedule I analog of psilocin under the Federal Analogue Act; no documented prosecutions as of last available data; South Dakota and West Virginia have state-scheduled | Erowid [Ref 22]; web sources [Ref 28] |
| United Kingdom | Class A controlled drug | Caught under tryptamine catch-all clause | Erowid [Ref 22]; web sources [Ref 28] |
| Australia | Schedule 9 Prohibited Substance | | Web sources [Ref 28] |
| Canada | Not a controlled substance (as of 2025) | | Web sources [Ref 28] |
| Sweden | Schedule I since May 2012 | Listed in Medical Products Agency Regulation LVFS 2012:6 | Erowid [Ref 22]; Kjellgren & Soussan 2011 notes that scheduling followed recreational use reports |
| Germany | Controlled under NpSG (Neue-psychoaktive-Stoffe-Gesetz) since July 18, 2019 | Production, import for market placement, and trading prohibited; possession illegal but not separately punishable | Web sources [Ref 28] |
| EU (general) | Varies by member state | No EU-wide scheduling; Germany and Sweden among countries with explicit controls | Web sources [Ref 28] |
| Finland | Reportedly controlled | Reported by web sources; specific regulation not confirmed | Web sources (unverified) |
| Netherlands | Status unclear | No confirmed scheduling information found | Not confirmed |

**⚠ FLAG:** Legal status information relies on Erowid (last updated 2015) and web-retrieved secondary sources. Independent verification of current statutes is recommended, particularly for UK (post-Psychoactive Substances Act 2016 implications) and EU member states.

---

## Clinical Trials

**No registered clinical trials.** Search of ClinicalTrials.gov for "4-HO-MET," "metocin," and "tryptamine psychedelic" returned no results for 4-HO-MET specifically. 4-HO-MET has not entered formal clinical evaluation as of April 2026. This is consistent with its status as an unscheduled/scheduled research chemical without pharmaceutical development.

---

## Community Feedback Analysis

**No community feedback was submitted** in Part A2 of the brief. No feedback items to analyze or investigate.

---

## Gaps & Flags

### Critical Safety Flags

1. **⚠ No LD₅₀ data:** No lethality threshold has been published for any species. Risk extrapolation relies on the single non-fatal intoxication case (193 ng/mL plasma) and class-level analogs. **Safety-critical value not verified.**

2. **⚠ Receptor binding source uncertain:** The 5-HT₂A EC₅₀ (37 nM), 5-HT₂C Ki (141 nM), and 5-HT₁A Ki (228 nM) values appear in NCATS Inxight Drugs but are attributed to Kozell et al. 2023 (PMID 36669875), which does not name 4-HO-MET explicitly in its cached abstract. These values have not been independently confirmed from the primary paper text. The generation agent should label these values as "NCATS-sourced; original study confirmation pending."

3. **⚠ Cardiotoxicity species limitation:** Yoon et al. 2020 [Ref 2] hERG and QT data are from CHO cells and Sprague-Dawley rats. Human cardiac risk at recreational doses is unquantified. The absolute contraindication for QT-prolonging drug combinations is mechanistically reasonable but not human-data confirmed.

4. **⚠ Täljemark 2012 abstract unavailable:** The acute psychosis case report (PMID 22580963) [Ref 4] has no retrievable abstract via PubMed or API. Clinical details (dose, time course, treatment, outcome) cannot be confirmed without full-text access. The case is real and peer-reviewed but specific clinical parameters are unverifiable via open sources.

5. **⚠ MAOI interaction absent from brief:** The MAOI interaction (dangerous via serotonergic mechanism; class-level fatalities documented for DMT/5-MeO-DMT in Rached et al. 2026) is not listed in the brief's known interactions. Recommend editorial addition. PMID: 41546846.

### Inferential/Class-Level Data Points

6. **Tolerance kinetics** (3-day half-life, 7-day full reset): Inferred from class-level DOI/LSD mouse data (de la Fuente Revenga 2022 [Ref 6]). No 4-HO-MET-specific data published.

7. **CYP enzyme involvement:** Class-level inference from Yu 2008 [Ref 24] (CYP2D6 for indolealkylamines). No 4-HO-MET-specific CYP inhibition or induction studies identified.

8. **Cross-tolerance list** (psilocybin, psilocin, LSD, mescaline, DMT, 4-AcO-DMT, 4-HO-DET, 4-HO-DiPT): Mechanistically inferred from shared 5-HT₂A agonism. Cross-tolerance DOI↔LSD confirmed empirically (de la Fuente Revenga 2022 [Ref 6]); 4-HO-MET specifically not tested.

9. **Tramadol interaction mechanism:** Class-level serotonergic reasoning. No 4-HO-MET + tramadol case reports found.

10. **Lithium interaction:** Evidence from Simonsson et al. 2023 [Ref 18] covers "classic psychedelics" broadly; no 4-HO-MET-specific lithium interaction data.

### Data Absent from Published Literature

11. **No human pharmacokinetic study:** No Tmax, Cmax, bioavailability, elimination half-life, or volume of distribution data in any published human study.

12. **No physical properties beyond melting point:** No aqueous solubility, logP, pKa, or stability data found in published sources.

13. **No controlled dose-finding study:** Dose ranges rely on TiHKAL (10–20 mg; [Ref 21]) and community consensus. The broader ranges in the brief (threshold 5 mg through heavy 40+ mg) are user-report derived.

14. **No Shulgin first-synthesis confirmation:** The brief and web sources state Shulgin synthesized 4-HO-MET in the 1970s, but the first *published* synthesis is Repke et al. 1981 [Ref 13]. No pre-1981 Shulgin publication on 4-HO-MET was found. The 1970s synthesis attribution may be accurate but is unverified in published literature.

15. **Netherlands legal status:** Not confirmed from available sources.

16. **Smoked ROA:** No published pharmacological, clinical, or safety data for the smoked route. Duration data (onset 15–120 sec; total 25–45 min) is community-derived only.

---

*Research completed: 2026-04-24. 28 citations in registry. No community feedback to analyze. Provenance: 2db924c7-1bd8-404e-a425-48d5797eee7d.*