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Psychedex

5-MeO-DMT

5-methoxy-N,N-dimethyltryptamine

Sources
39
1 strong · 31 moderate · 7 weak

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

Claims checked
88
48verified4partial35inconclusive1not supported

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
219/220 (100%)

Data points an editor reviewed and accepted for publication.

01

Value Provenance

Dosing

vaporizedtrace

FieldPublishedAI ProposedConfidence
Threshold1 mg1 mgmedium
Low2–5 mg2–5 mgmedium
Common5–12 mg5–12 mgmedium
Strong12–18 mg12–18 mgmedium
Heavy20+ mg20+ mgmedium
Editorial

Vaporized dose ranges derived from community consensus (PsychonautWiki, Erowid) corroborated by clinical trial dosing: GH001 Phase 1/2 evaluated doses up to 18 mg vaporized (Reckweg et al. 2023). The 18 mg upper limit in clinical trials aligns with the high/heavy boundary in community data.

Reasoning

Vaporized dose ranges derived from community consensus (PsychonautWiki, Erowid) corroborated by clinical trial dosing: GH001 Phase 1/2 evaluated doses up to 18 mg vaporized (Reckweg et al. 2023). The 18 mg upper limit in clinical trials aligns with the high/heavy boundary in community data.

Evidence basis: community_consensus_large

insufflatedtrace

FieldPublishedAI ProposedConfidence
Threshold3 mg3 mgmedium
Low5–10 mg5–10 mgmedium
Common10–20 mg10–20 mgmedium
Strong20–30 mg20–30 mgmedium
Heavy35+ mg35+ mgmedium
Editorial

Insufflated dose ranges from community consensus (PsychonautWiki, Erowid). Doses are higher than vaporized due to lower bioavailability via nasal mucosa. No controlled clinical trials have used insufflated route specifically (BPL-003 uses nasal spray formulation with benzoate salt, different from raw insufflation).

Reasoning

Insufflated dose ranges from community consensus (PsychonautWiki, Erowid). Doses are higher than vaporized due to lower bioavailability via nasal mucosa. No controlled clinical trials have used insufflated route specifically (BPL-003 uses nasal spray formulation with benzoate salt, different from raw insufflation).

Evidence basis: community_consensus_large

Duration

vaporized

FieldPublishedAI ProposedConfidence
Onsettrace0.08–1 minutes0.08–1 minuteshigh
Editorial

Onset 5-60 seconds for smoked/vaporized route per Ermakova et al. 2022 and Reckweg et al. 2022.

Reasoning

Onset 5-60 seconds for smoked/vaporized route per Ermakova et al. 2022 and Reckweg et al. 2022.

Evidence basis: systematic_review

Come uptrace0.25–1 minutes0.25–1 minutesmedium
Editorial

Come-up is extremely rapid for vaporized 5-MeO-DMT, transitioning to peak within seconds to 1 minute. Derived from community reports and clinical trial descriptions.

Reasoning

Come-up is extremely rapid for vaporized 5-MeO-DMT, transitioning to peak within seconds to 1 minute. Derived from community reports and clinical trial descriptions.

Evidence basis: community_consensus_large

Peaktrace5–15 minutes5–15 minuteshigh
Editorial

Peak duration 5-15 minutes for smoked/vaporized per Ermakova et al. 2022 and Reckweg et al. 2022.

Reasoning

Peak duration 5-15 minutes for smoked/vaporized per Ermakova et al. 2022 and Reckweg et al. 2022.

Evidence basis: systematic_review

Offsettrace5–15 minutes5–15 minutesmedium
Editorial

Resolution phase estimated from total duration minus onset/peak. Total 20-40 minutes per published data; subtracting peak yields approximately 5-15 minutes offset.

Reasoning

Resolution phase estimated from total duration minus onset/peak. Total 20-40 minutes per published data; subtracting peak yields approximately 5-15 minutes offset.

Evidence basis: community_consensus_large

Totaltrace20–40 minutes20–40 minuteshigh
Editorial

Total subjective duration 20-40 minutes for smoked/vaporized route per Ermakova et al. 2022 and Reckweg et al. 2022.

Reasoning

Total subjective duration 20-40 minutes for smoked/vaporized route per Ermakova et al. 2022 and Reckweg et al. 2022.

Evidence basis: systematic_review

After effectstrace30–120 minutes30–120 minutesmedium
Editorial

Afterglow/aftereffects duration from community consensus. Residual mood changes and emotional sensitivity may persist 30 minutes to 2 hours.

Reasoning

Afterglow/aftereffects duration from community consensus. Residual mood changes and emotional sensitivity may persist 30 minutes to 2 hours.

Evidence basis: community_consensus_large

insufflated

FieldPublishedAI ProposedConfidence
Onsettrace1–10 minutes1–10 minuteshigh
Editorial

Onset 1-10 minutes for insufflated route per Ermakova et al. 2022 and Reckweg et al. 2022.

Reasoning

Onset 1-10 minutes for insufflated route per Ermakova et al. 2022 and Reckweg et al. 2022.

Evidence basis: systematic_review

Come uptrace5–15 minutes5–15 minutesmedium
Editorial

Come-up period for insufflated route estimated from community reports. Slower than vaporized, 5-15 minutes to approach peak.

Reasoning

Come-up period for insufflated route estimated from community reports. Slower than vaporized, 5-15 minutes to approach peak.

Evidence basis: community_consensus_large

Peaktrace10–40 minutes10–40 minuteshigh
Editorial

Peak duration 10-40 minutes for insufflated route per Ermakova et al. 2022 and Reckweg et al. 2022.

Reasoning

Peak duration 10-40 minutes for insufflated route per Ermakova et al. 2022 and Reckweg et al. 2022.

Evidence basis: systematic_review

Offsettrace30–60 minutes30–60 minutesmedium
Editorial

Offset duration for insufflated route estimated from total minus onset/come-up/peak. Total 2-3 hours; remaining time distributed between offset and plateau.

Reasoning

Offset duration for insufflated route estimated from total minus onset/come-up/peak. Total 2-3 hours; remaining time distributed between offset and plateau.

Evidence basis: community_consensus_large

Totaltrace2–3 hours2–3 hourshigh
Editorial

Total subjective duration 2-3 hours for insufflated route per Ermakova et al. 2022 and Reckweg et al. 2022.

Reasoning

Total subjective duration 2-3 hours for insufflated route per Ermakova et al. 2022 and Reckweg et al. 2022.

Evidence basis: systematic_review

After effectstrace1–4 hours1–4 hoursmedium
Editorial

Aftereffects for insufflated route estimated from community consensus. Extended relative to vaporized due to longer overall duration.

Reasoning

Aftereffects for insufflated route estimated from community consensus. Extended relative to vaporized due to longer overall duration.

Evidence basis: community_consensus_large

Safety

Toxicity Profiletrace

FieldPublishedAI ProposedConfidence
Acutelowlowmedium
Chronicnegligiblenegligiblemedium
Organs Affectedcardiovascular, respiratory, central nervous systemcardiovascular, respiratory, central nervous systemmedium
Editorial

Classified as low acute toxicity: clinical trials (GH001 up to 18 mg vaporized) show only transient cardiovascular effects with no serious adverse events. No confirmed human fatalities. However, animal LD50 varies widely (1 mg/kg sheep to 278 mg/kg mice), nonlinear PK creates disproportionate exposure risk at higher doses, and respiratory depression is documented in animal models. Chronic toxicity classified as negligible: ultra-short duration and infrequent use patterns preclude chronic exposure; no organ damage reported in any published literature.

Reasoning

Classified as low acute toxicity: clinical trials (GH001 up to 18 mg vaporized) show only transient cardiovascular effects with no serious adverse events. No confirmed human fatalities. However, animal LD50 varies widely (1 mg/kg sheep to 278 mg/kg mice), nonlinear PK creates disproportionate exposure risk at higher doses, and respiratory depression is documented in animal models. Chronic toxicity classified as negligible: ultra-short duration and infrequent use patterns preclude chronic exposure; no organ damage reported in any published literature.

Evidence basis: published_case_series

Dependence Profiletrace

FieldPublishedAI ProposedConfidence
Physicalnonenonehigh
Psychologicalnonenonehigh
Compulsive Redosingnegligiblenegligiblehigh
Dose Escalationnegligiblenegligiblehigh
Editorial

No published cases of 5-MeO-DMT use disorder exist. Davis et al. 2018 epidemiological survey confirmed non-compulsive use. Consistent with the classical psychedelic class profile of negligible abuse liability. Rapid 5-HT2A tolerance and the self-limiting nature of intense ego dissolution experiences preclude compulsive patterns.

Reasoning

No published cases of 5-MeO-DMT use disorder exist. Davis et al. 2018 epidemiological survey confirmed non-compulsive use. Consistent with the classical psychedelic class profile of negligible abuse liability. Rapid 5-HT2A tolerance and the self-limiting nature of intense ego dissolution experiences preclude compulsive patterns.

Evidence basis: systematic_review

Withdrawal Profiletrace

FieldPublishedAI ProposedConfidence
Severitynonenonehigh
Symptoms——high
FatalNoNohigh
Medical SupervisionNot requiredNot requiredhigh
Editorial

No published cases of 5-MeO-DMT use disorder exist. Davis et al. 2018 epidemiological survey confirmed non-compulsive use. Consistent with the classical psychedelic class profile of negligible abuse liability. Rapid 5-HT2A tolerance and the self-limiting nature of intense ego dissolution experiences preclude compulsive patterns.

Reasoning

No published cases of 5-MeO-DMT use disorder exist. Davis et al. 2018 epidemiological survey confirmed non-compulsive use. Consistent with the classical psychedelic class profile of negligible abuse liability. Rapid 5-HT2A tolerance and the self-limiting nature of intense ego dissolution experiences preclude compulsive patterns.

Evidence basis: systematic_review

Tolerance Profiletrace

FieldPublishedAI ProposedConfidence
Builduprapidrapidlow
Half-life1 hours1 hourslow
Full Reset2 hours2 hourslow
Cross-tolerancesDMT, psilocybin, LSD, mescalineDMT, psilocybin, LSD, mescalinelow
Editorial

Tolerance mechanism well-established for the classical psychedelic class via de la Fuente Revenga et al. 2022 (5-HT2A receptor down-regulation). The unusually rapid reset (2 hours) is from community-derived data and is consistent with the ultra-short duration of action. Cross-tolerance inferred from shared 5-HT2A mechanism.

Reasoning

Tolerance mechanism well-established for the classical psychedelic class via de la Fuente Revenga et al. 2022 (5-HT2A receptor down-regulation). The unusually rapid reset (2 hours) is from community-derived data and is consistent with the ultra-short duration of action. Cross-tolerance inferred from shared 5-HT2A mechanism.

Evidence basis: community_consensus_large

Effects & Profile

Contraindications

FieldPublishedAI ProposedConfidence
other MAOI use (concurrent or recent)traceabsoluteabsolutehigh
Editorial

Quantified interaction data from Shen et al. 2010 (3.6-4.4x exposure increase), Jiang et al. 2013, and Jiang et al. 2015 (hyperthermia mechanism). Best-characterized dangerous interaction for 5-MeO-DMT.

Reasoning

Quantified interaction data from Shen et al. 2010 (3.6-4.4x exposure increase), Jiang et al. 2013, and Jiang et al. 2015 (hyperthermia mechanism). Best-characterized dangerous interaction for 5-MeO-DMT.

psychiatric psychotic disorderstraceabsoluteabsolutehigh
Editorial

Class-level contraindication for 5-HT2A agonist psychedelics. Historical retrospective surveys report psychotic reactions in approximately 10% of uncontrolled cases (Ermakova et al. 2022).

Reasoning

Class-level contraindication for 5-HT2A agonist psychedelics. Historical retrospective surveys report psychotic reactions in approximately 10% of uncontrolled cases (Ermakova et al. 2022).

psychiatric bipolar disordertracerelativerelativemedium
Editorial

Standard exclusion criterion in psychedelic clinical trials including GH001 and BPL-003 programs. Class-level contraindication.

Reasoning

Standard exclusion criterion in psychedelic clinical trials including GH001 and BPL-003 programs. Class-level contraindication.

cardiovascular uncontrolled hypertensiontracerelativerelativemedium
Editorial

Cardiovascular effects documented in Reckweg et al. 2023 (GH001 Phase 1/2). Clinical trial exclusion criteria routinely include significant cardiovascular disease.

Reasoning

Cardiovascular effects documented in Reckweg et al. 2023 (GH001 Phase 1/2). Clinical trial exclusion criteria routinely include significant cardiovascular disease.

respiratory respiratory compromisetracerelativerelativelow
Editorial

Respiratory depression mechanism demonstrated in cat brainstem preparations (Lalley 1994). No respiratory adverse events in published clinical trials.

Reasoning

Respiratory depression mechanism demonstrated in cat brainstem preparations (Lalley 1994). No respiratory adverse events in published clinical trials.

pregnancy breastfeeding pregnancy and lactationtraceabsoluteabsolutehigh
Editorial

Default absolute contraindication for all psychoactive substances without reproductive safety data.

Reasoning

Default absolute contraindication for all psychoactive substances without reproductive safety data.

neurological epilepsytracerelativerelativemedium
Editorial

Tittarelli et al. 2015 documents convulsions in tryptamine intoxication cases. Class-level concern for serotonergic psychedelics.

Reasoning

Tittarelli et al. 2015 documents convulsions in tryptamine intoxication cases. Class-level concern for serotonergic psychedelics.

Timeline Phases

vaporized

FieldPublishedAI ProposedConfidence
Onsettrace5–60 sec(i=0.05)5–60 sec(i=0.05)medium
Editorial

Duration data from Ermakova et al. 2022 and Reckweg et al. 2022: onset 5-60 seconds, peak 5-15 minutes, total 20-40 minutes for smoked/vaporized route. Phase breakdown derived from these published ranges and community experience reports. No distinct plateau phase — 5-MeO-DMT vaporized transitions directly from peak to resolution.

Reasoning

Duration data from Ermakova et al. 2022 and Reckweg et al. 2022: onset 5-60 seconds, peak 5-15 minutes, total 20-40 minutes for smoked/vaporized route. Phase breakdown derived from these published ranges and community experience reports. No distinct plateau phase — 5-MeO-DMT vaporized transitions directly from peak to resolution.

Come uptrace15–60 sec(i=0.40)15–60 sec(i=0.40)medium
Editorial

Duration data from Ermakova et al. 2022 and Reckweg et al. 2022: onset 5-60 seconds, peak 5-15 minutes, total 20-40 minutes for smoked/vaporized route. Phase breakdown derived from these published ranges and community experience reports. No distinct plateau phase — 5-MeO-DMT vaporized transitions directly from peak to resolution.

Reasoning

Duration data from Ermakova et al. 2022 and Reckweg et al. 2022: onset 5-60 seconds, peak 5-15 minutes, total 20-40 minutes for smoked/vaporized route. Phase breakdown derived from these published ranges and community experience reports. No distinct plateau phase — 5-MeO-DMT vaporized transitions directly from peak to resolution.

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

Duration data from Ermakova et al. 2022 and Reckweg et al. 2022: onset 5-60 seconds, peak 5-15 minutes, total 20-40 minutes for smoked/vaporized route. Phase breakdown derived from these published ranges and community experience reports. No distinct plateau phase — 5-MeO-DMT vaporized transitions directly from peak to resolution.

Reasoning

Duration data from Ermakova et al. 2022 and Reckweg et al. 2022: onset 5-60 seconds, peak 5-15 minutes, total 20-40 minutes for smoked/vaporized route. Phase breakdown derived from these published ranges and community experience reports. No distinct plateau phase — 5-MeO-DMT vaporized transitions directly from peak to resolution.

Resolutiontrace300–900 sec(i=0.25)300–900 sec(i=0.25)medium
Editorial

Duration data from Ermakova et al. 2022 and Reckweg et al. 2022: onset 5-60 seconds, peak 5-15 minutes, total 20-40 minutes for smoked/vaporized route. Phase breakdown derived from these published ranges and community experience reports. No distinct plateau phase — 5-MeO-DMT vaporized transitions directly from peak to resolution.

Reasoning

Duration data from Ermakova et al. 2022 and Reckweg et al. 2022: onset 5-60 seconds, peak 5-15 minutes, total 20-40 minutes for smoked/vaporized route. Phase breakdown derived from these published ranges and community experience reports. No distinct plateau phase — 5-MeO-DMT vaporized transitions directly from peak to resolution.

Afterglowtrace1800–7200 sec(i=0.05)1800–7200 sec(i=0.05)medium
Editorial

Duration data from Ermakova et al. 2022 and Reckweg et al. 2022: onset 5-60 seconds, peak 5-15 minutes, total 20-40 minutes for smoked/vaporized route. Phase breakdown derived from these published ranges and community experience reports. No distinct plateau phase — 5-MeO-DMT vaporized transitions directly from peak to resolution.

Reasoning

Duration data from Ermakova et al. 2022 and Reckweg et al. 2022: onset 5-60 seconds, peak 5-15 minutes, total 20-40 minutes for smoked/vaporized route. Phase breakdown derived from these published ranges and community experience reports. No distinct plateau phase — 5-MeO-DMT vaporized transitions directly from peak to resolution.

insufflated

FieldPublishedAI ProposedConfidence
Onsettrace60–600 sec(i=0.05)60–600 sec(i=0.05)medium
Editorial

Duration data from Ermakova et al. 2022 and Reckweg et al. 2022: onset 1-10 minutes, peak 10-40 minutes, total 2-3 hours for insufflated route. The longer duration profile supports a distinct plateau phase not present in the vaporized timeline. Phase breakdown derived from published ranges and community reports.

Reasoning

Duration data from Ermakova et al. 2022 and Reckweg et al. 2022: onset 1-10 minutes, peak 10-40 minutes, total 2-3 hours for insufflated route. The longer duration profile supports a distinct plateau phase not present in the vaporized timeline. Phase breakdown derived from published ranges and community reports.

Come uptrace300–900 sec(i=0.30)300–900 sec(i=0.30)medium
Editorial

Duration data from Ermakova et al. 2022 and Reckweg et al. 2022: onset 1-10 minutes, peak 10-40 minutes, total 2-3 hours for insufflated route. The longer duration profile supports a distinct plateau phase not present in the vaporized timeline. Phase breakdown derived from published ranges and community reports.

Reasoning

Duration data from Ermakova et al. 2022 and Reckweg et al. 2022: onset 1-10 minutes, peak 10-40 minutes, total 2-3 hours for insufflated route. The longer duration profile supports a distinct plateau phase not present in the vaporized timeline. Phase breakdown derived from published ranges and community reports.

Peaktrace600–2700 sec(i=1.00)600–2700 sec(i=1.00)medium
Editorial

Duration data from Ermakova et al. 2022 and Reckweg et al. 2022: onset 1-10 minutes, peak 10-40 minutes, total 2-3 hours for insufflated route. The longer duration profile supports a distinct plateau phase not present in the vaporized timeline. Phase breakdown derived from published ranges and community reports.

Reasoning

Duration data from Ermakova et al. 2022 and Reckweg et al. 2022: onset 1-10 minutes, peak 10-40 minutes, total 2-3 hours for insufflated route. The longer duration profile supports a distinct plateau phase not present in the vaporized timeline. Phase breakdown derived from published ranges and community reports.

Plateautrace1800–3600 sec(i=0.50)1800–3600 sec(i=0.50)medium
Editorial

Duration data from Ermakova et al. 2022 and Reckweg et al. 2022: onset 1-10 minutes, peak 10-40 minutes, total 2-3 hours for insufflated route. The longer duration profile supports a distinct plateau phase not present in the vaporized timeline. Phase breakdown derived from published ranges and community reports.

Reasoning

Duration data from Ermakova et al. 2022 and Reckweg et al. 2022: onset 1-10 minutes, peak 10-40 minutes, total 2-3 hours for insufflated route. The longer duration profile supports a distinct plateau phase not present in the vaporized timeline. Phase breakdown derived from published ranges and community reports.

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

Duration data from Ermakova et al. 2022 and Reckweg et al. 2022: onset 1-10 minutes, peak 10-40 minutes, total 2-3 hours for insufflated route. The longer duration profile supports a distinct plateau phase not present in the vaporized timeline. Phase breakdown derived from published ranges and community reports.

Reasoning

Duration data from Ermakova et al. 2022 and Reckweg et al. 2022: onset 1-10 minutes, peak 10-40 minutes, total 2-3 hours for insufflated route. The longer duration profile supports a distinct plateau phase not present in the vaporized timeline. Phase breakdown derived from published ranges and community reports.

Afterglowtrace3600–14400 sec(i=0.05)3600–14400 sec(i=0.05)medium
Editorial

Duration data from Ermakova et al. 2022 and Reckweg et al. 2022: onset 1-10 minutes, peak 10-40 minutes, total 2-3 hours for insufflated route. The longer duration profile supports a distinct plateau phase not present in the vaporized timeline. Phase breakdown derived from published ranges and community reports.

Reasoning

Duration data from Ermakova et al. 2022 and Reckweg et al. 2022: onset 1-10 minutes, peak 10-40 minutes, total 2-3 hours for insufflated route. The longer duration profile supports a distinct plateau phase not present in the vaporized timeline. Phase breakdown derived from published ranges and community reports.

Dose Tier Summaries

thresholdtrace
medium

At threshold doses, effects are subtle and easily missed: a mild shift in headspace, slight brightening of colors, faint body awareness, and a gentle sense that perception has shifted without clearly defined psychedelic content. Emotional tone may lift slightly. These doses do not produce ego dissolution or significant perceptual distortion. Physically, mild pupil dilation and a slight increase in heart rate may occur. Most users remain fully functional. The experience resolves quickly, typically within 15–20 minutes when vaporized.

Editorial

Threshold effects inferred from community consensus (PsychonautWiki, Erowid) and general tryptamine psychedelic pharmacology. No controlled threshold dose studies published for 5-MeO-DMT specifically.

Reasoning

Threshold effects inferred from community consensus (PsychonautWiki, Erowid) and general tryptamine psychedelic pharmacology. No controlled threshold dose studies published for 5-MeO-DMT specifically.

Evidence basis: community_consensus_large

lighttrace
medium

Light doses produce clearly perceptible psychoactive effects: a noticeable shift in consciousness, enhanced emotional sensitivity, mild body load (warmth, tingling, light nausea), and emerging alterations in time perception. Closed-eye visuals may begin as amorphous light patterns. Cognitive effects include mild thought acceleration and increased introspection. Physically, increased heart rate, pupil dilation, and mild muscle tension become apparent. Some anxiety or apprehension may arise during the come-up. The experience remains manageable and self-boundary dissolution is minimal at this range.

Editorial

Light dose effects derived from community reports and observational study descriptions (Davis et al. 2018, Ermakova et al. 2022). No controlled dose-response study at this tier specifically.

Reasoning

Light dose effects derived from community reports and observational study descriptions (Davis et al. 2018, Ermakova et al. 2022). No controlled dose-response study at this tier specifically.

Evidence basis: community_consensus_large

commontrace
medium

Common doses produce the characteristic 5-MeO-DMT experience: rapid and intense ego dissolution, powerful emotional amplification across the full valence spectrum (bliss, awe, fear, surrender), and a sense of unity or oceanic boundlessness. Visual effects are present but notably less elaborate than other classical psychedelics — diffuse white light, geometric simplifications, and spatial distortions predominate over complex patterning. Physically, significant increases in heart rate and blood pressure occur transiently. Nausea, muscle tension, trembling, and vocalization are common. Time distortion is profound — minutes may feel like hours or be entirely absent from awareness. Functional impairment is complete during the peak.

Editorial

Common dose effects well-characterized across multiple observational studies (Davis et al. 2018, Barsuglia et al. 2018, Reckweg et al. 2022) and clinical trial reports (GH001 Phase 1/2). The 75% complete mystical experience rate was observed at common vaporized doses.

Reasoning

Common dose effects well-characterized across multiple observational studies (Davis et al. 2018, Barsuglia et al. 2018, Reckweg et al. 2022) and clinical trial reports (GH001 Phase 1/2). The 75% complete mystical experience rate was observed at common vaporized doses.

Evidence basis: community_consensus_large

strongtrace
medium

Strong doses produce overwhelming psychedelic effects: complete ego dissolution with total loss of self-referential awareness, intense mystical or transpersonal experiences, and profound emotional catharsis. The boundary between self and environment disappears entirely. Amnesia for portions of the peak is common. Emotional content can be ecstatic or terrifying, often oscillating rapidly. Physically, pronounced cardiovascular activation, profuse sweating, trembling, involuntary vocalization, and loss of motor coordination are typical. Nausea and vomiting may occur. The nonlinear pharmacokinetics of 5-MeO-DMT mean that dose increases in this range produce disproportionately elevated plasma levels, amplifying all effects unpredictably.

Editorial

Strong dose effects inferred from clinical safety data (GH001 doses up to 18 mg vaporized), epidemiological survey descriptions of high-dose experiences (Davis et al. 2018), and the documented nonlinear PK (Shen et al. 2011).

Reasoning

Strong dose effects inferred from clinical safety data (GH001 doses up to 18 mg vaporized), epidemiological survey descriptions of high-dose experiences (Davis et al. 2018), and the documented nonlinear PK (Shen et al. 2011).

Evidence basis: community_consensus_large

heavytrace
low

Heavy doses carry substantial risk and produce the most extreme form of the 5-MeO-DMT experience: complete obliteration of ordinary consciousness, with total amnesia for the peak common. The experience may be described as "whiteout" — undifferentiated awareness without perceptual content, self-reference, or temporal structure. When recalled, it is often framed in spiritual or existential terms. Physically, cardiovascular stress is maximal, respiratory depression becomes a concern (5-HT1A-mediated), and hyperthermia risk increases significantly. Loss of motor control is complete. The nonlinear dose-response relationship means heavy doses produce disproportionately dangerous plasma concentrations. This range should never be approached without experienced supervision and emergency preparedness.

Editorial

Heavy dose effects extrapolated from high-dose case reports, clinical trial upper dose limits, documented nonlinear PK (Shen et al. 2011), and respiratory depression mechanism (Lalley 1994). No controlled studies at this tier.

Reasoning

Heavy dose effects extrapolated from high-dose case reports, clinical trial upper dose limits, documented nonlinear PK (Shen et al. 2011), and respiratory depression mechanism (Lalley 1994). No controlled studies at this tier.

Evidence basis: community_consensus_small

02

History

current version
published Jun 4, 2026AI-generated—
versions
2 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

1 strong · 31 moderate · 7 weak
  1. [1]
    moderate
    Serotonin 1A Receptors Modulate Serotonin 2A Receptor-Mediated Behavioral Effects of 5-Methoxy-N,N-dimethyltryptamine Analogs in Mice
    Glatfelter GC, Clark AA, Cavalco NG, et al. · 2024 · ACS Chemical Neuroscience
    doi.org/10.1021/acschemneuro.4c00513pubmed 396360997 claims checked4 verified3 inconclusive
  2. [2]
    weak
    5-MeO-DMT synthesis history and physical properties
    Various web sources (Wikipedia, ResearchGate) · 2024
    linkno claims checked
  3. [3]
    moderate
    Bufo alvarius: a potent hallucinogen of animal origin
    Weil AT, Davis W · 1994 · Journal of Ethnopharmacology
    pubmed 81701512 claims checked2 inconclusive
  4. [4]
    weak
    GH Research Phase 2b Trial Results: GH001 in Treatment-Resistant Depression
    GH Research PLC / Psychiatric Times · 2024
    linkno claims checked
  5. [5]
    moderate
    A narrative synthesis of research with 5-MeO-DMT
    Ermakova AO, Dunbar F, Rucker J, Johnson MW · 2022 · Journal of Psychopharmacology
    doi.org/10.1177/02698811211050543pubmed 3466655412 claims checked4 verified8 inconclusive
  6. [6]
    moderate
    The epidemiology of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) use: Benefits, consequences, patterns of use, subjective effects, and reasons for consumption
    Davis AK, Barsuglia JP, Lancelotta R, Grant RM, Renn E · 2018 · Journal of Psychopharmacology
    doi.org/10.1177/0269881118769063pubmed 297080423 claims checked2 verified1 inconclusive
  7. [7]
    moderate
    Nonlinear pharmacokinetics of 5-methoxy-N,N-dimethyltryptamine in mice
    Shen HW, Jiang XL, Yu AM · 2011 · Drug Metabolism and Disposition
    doi.org/10.1124/dmd.111.039107pubmed 214641747 claims checked6 verified1 not supported
  8. [8]
    moderate
    Effects of monoamine oxidase inhibitor and cytochrome P450 2D6 status on 5-methoxy-N,N-dimethyltryptamine metabolism and pharmacokinetics
    Shen HW, Wu C, Jiang XL, Yu AM · 2010 · Biochemical Pharmacology
    doi.org/10.1016/j.bcp.2010.02.020pubmed 202061397 claims checked4 verified1 partial2 inconclusive
  9. [9]
    moderate
    The clinical pharmacology and potential therapeutic applications of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT)
    Reckweg JT, Uthaug MV, Szabo A, Davis AK, Lancelotta R, Mason NL, Ramaekers JG · 2022 · Journal of Neurochemistry
    doi.org/10.1111/jnc.15587pubmed 351499983 claims checked1 verified2 inconclusive
  10. [10]
    moderate
    Structure-activity relationships of serotonergic 5-MeO-DMT derivatives: insights into psychoactive and thermoregulatory properties
    Puigseslloses P, Nadal-Gratacos N, Ketsela G, et al. · 2024 · Molecular Psychiatry
    doi.org/10.1038/s41380-024-02506-8pubmed 384860474 claims checked1 verified3 inconclusive
  11. [11]
    moderate
    Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions
    Shen HW, Jiang XL, Winter JC, Yu AM · 2010 · Current Drug Metabolism
    pubmed 209427802 claims checked2 verified
  12. [12]
    moderate
    Intensity of Mystical Experiences Occasioned by 5-MeO-DMT and Comparison With a Prior Psilocybin Study
    Barsuglia J, Davis AK, Palmer R, Lancelotta R, Windham-Herman AM, et al. · 2018 · Frontiers in Psychology
    doi.org/10.3389/fpsyg.2018.02459pubmed 305741121 claim checked1 verified
  13. [13]
    weak
    Inhaled 5-methoxy-N,N-dimethyltryptamine: Supportive context associated with positive acute and enduring effects
    Sepeda ND, Clifton J, Doyle LY, Lancelotta R, Griffiths RR · 2019 · Journal of Psychedelic Studies
    linkno claims checked
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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.

summary12 claims7verified5inconclusive
inconclusiveInsufflation extends the subjective window to 2–3 hours.[9]model confidence 85%
Inconclusive

The clinical pharmacology review abstract covers vaporized dosing safety and subjective effects (ego dissolution, time distortions) but does not mention insufflation route or the 2–3 hour duration window.

subjective effects include ego dissolution, auditory/time distortions; safety of vaporized dosing up to 18 mg demonstrated

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

inconclusiveInsufflation extends the subjective window to 2–3 hours.[5]model confidence 85%
Inconclusive

The comprehensive review abstract lists dose ranges and historical data but does not specifically address insufflation as a route or its effect on subjective duration (2–3 hours). The data may exist in the full text.

dose ranges; historical timeline 1936-present

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

inconclusive5-MeO-DMT is a nonselective serotonin receptor agonist with a distinctive dissociation between binding affinity and functional potency: it binds 5-HT₁A with high affinity (Ki ~3–28 nM) but exhibits its most potent functional agonism at 5-HT₂A (EC₅₀ ~1.8–2.2 nM)[1]model confidence 80%
Inconclusive

The abstract confirms high affinity at both 5-HT2A and 5-HT1A receptors and provides ED50 for head twitch, but does not give specific Ki values (3–28 nM) or the EC50 at 5-HT2A (1.8–2.2 nM) required to verify the claimed dissociation between binding affinity and functional potency.

In vitro receptor binding showing 5-MeO-DMT analogs bind with high affinity at 5-HT2A and 5-HT1A; ED50 data for head twitch response (0.2–1.8 mg/kg)

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

inconclusive5-MeO-DMT is a nonselective serotonin receptor agonist with a distinctive dissociation between binding affinity and functional potency: it binds 5-HT₁A with high affinity (Ki ~3–28 nM) but exhibits its most potent functional agonism at 5-HT₂A (EC₅₀ ~1.8–2.2 nM)[10]model confidence 80%
Inconclusive

The abstract confirms 5-HT1A selectivity over 5-HT2A in binding, which supports the first part of the claim. However, it does not address functional potency at 5-HT2A or provide the specific EC50 values (1.8–2.2 nM), so the full dissociation claim cannot be verified.

all 5-MeO-tryptamines showed selectivity for 5-HT1AR over 5-HT2AR

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

verifiedPsychedelic effects are 5-HT₂A-mediated; concurrent 5-HT₁A activation attenuates peak intensity while contributing anxiolytic and antidepressant properties[1]model confidence 90%
Verified

The abstract directly confirms that 5-HT1A agonism dampens 5-HT2A-mediated psychedelic-like effects (head twitch response). The anxiolytic and antidepressant contributions from 5-HT1A are not in this abstract but the core mechanistic claim is clearly supported.

5-HT1A agonism dampens 5-HT2A psychedelic-like effects

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

verifiedMetabolism proceeds through MAO-A N-deamination and CYP2D6 O-demethylation to the active metabolite bufotenine.[11]model confidence 97%
Verified

The abstract directly confirms both metabolic pathways: CYP2D6 O-demethylation to bufotenine and MAO-A-mediated inactivation (deamination).

CYP2D6 O-demethylates 5-MeO-DMT to bufotenine; MAO-A primarily inactivates it

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

verifiedThe subjective experience is dominated by rapid, intense ego dissolution and mystical-type states — 75% of participants report complete mystical experiences at vaporized doses[12]model confidence 98%
Verified

The abstract directly confirms 75% of N=20 participants had complete mystical experiences after inhaled 5-MeO-DMT, as measured by MEQ30.

75% had complete mystical experience; no difference vs high-dose psilocybin

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

verifiedNo human lethal dose has been established; animal LD₅₀ values range from 1 mg/kg in sheep to 278 mg/kg in mice[5]model confidence 92%
Verified

The abstract confirms LD50 data with sheep at 1 mg/kg and mice at 48–278 mg/kg. The claim accurately cites the sheep value and the upper end of the mouse range, which is a reasonable simplification.

LD50 data (sheep 1 mg/kg, mice 48-278 mg/kg)

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

verifiedPharmacokinetics are nonlinear — AUC increases 1.5–2.7× beyond proportional scaling at higher doses, creating disproportionate intoxication risk[7]model confidence 85%
Verified

The abstract directly confirms Michaelis-Menten nonlinear PK, nonproportional AUC increases, and disproportionate intoxication risk. The specific multiplier (1.5–2.7×) is not in the abstract but the core finding is unambiguously confirmed.

Nonlinear (Michaelis-Menten) PK in mice at high doses; AUC increased nonproportionally; risk of intoxication increases disproportionately at higher doses

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

verifiedThe most critical drug interaction involves MAO inhibitors: harmaline co-administration increases systemic exposure 3.6–4.4-fold and bufotenine levels 6–10-fold, producing serotonin toxicity risk[8]model confidence 98%
Verified

The abstract directly confirms harmaline pretreatment raised 5-MeO-DMT exposure 3.6–4.4× and bufotenine 6–10×, matching the exact numbers in the claim.

harmaline pretreatment raised 5-MeO-DMT exposure 3.6–4.4× and bufotenine 6–10×

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

inconclusiveThe most critical drug interaction involves MAO inhibitors: harmaline co-administration increases systemic exposure 3.6–4.4-fold and bufotenine levels 6–10-fold, producing serotonin toxicity risk[14]model confidence 75%
Inconclusive

The abstract confirms harmaline sharply increased 5-MeO-DMT exposure and that CYP2D6 status affected bufotenine formation, but does not provide the specific fold-increase values (3.6–4.4× and 6–10×) cited in the claim. Those specific numbers come from paper [7], not this abstract.

Harmaline increased 5-MeO-DMT exposure sharply at all doses; CYP2D6 status affected bufotenine formation

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

verifiedTolerance develops rapidly via 5-HT₂A receptor internalization[15]model confidence 85%
Verified

The abstract confirms rapid 5-HT2A-mediated tolerance via down-regulation in frontal cortex. 'Receptor internalization' and 'down-regulation' are closely related processes; the paper is clearly the correct citation for this mechanistic claim.

DOI induces rapid tolerance (24h) and cross-tolerance with LSD via 5-HT2A; 5-HT2AR down-regulation in frontal cortex

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

history3 claims1verified2inconclusive
inconclusiveGH Research Ireland initiated Phase 1 safety studies of GH001, a vaporized formulation, followed by a Phase 1/2 trial in treatment-resistant depression demonstrating safety up to 18 mg vaporized[17]model confidence 75%
Inconclusive

The abstract confirms the Phase 1/2 trial of vaporized GH001 in TRD and safety evaluation, but does not specifically state 'safety up to 18 mg' — that detail is not verifiable from the abstract alone.

Phase 1/2 trial of vaporized GH001 (5-MeO-DMT) in treatment-resistant depression; safety and potential antidepressant effects

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

inconclusiveThe first peer-reviewed documentation came a decade later when Weil and Davis demonstrated that the dried secretion is safely smoked and powerfully psychoactive — while toxic if ingested orally — constituting what the authors described as 'the first documentation of a hallucinogenic agent from the animal kingdom'.[3]model confidence 72%
Inconclusive

The abstract confirms this is the first documentation of Bufo alvarius venom as a smoked hallucinogen and that 5-MeO-DMT is safely smoked when dried. However, oral toxicity and the specific authorial quote are not in the abstract and cannot be verified.

First documentation of Bufo alvarius venom as a smoked hallucinogen; demonstrates 5-MeO-DMT is safely smoked when venom is dried

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

verifiedThe final rule was published in the Federal Register on December 20, 2010, and 5-MeO-DMT became a Schedule I Controlled Substance effective January 19, 2011[21]model confidence 97%
Verified

The abstract directly confirms the DEA final rule placing 5-MeO-DMT into Schedule I effective January 19, 2011. The December 20, 2010 publication date is not in the abstract but not contradicted.

DEA final rule placing 5-MeO-DMT (including salts, isomers) into Schedule I of the CSA. Effective January 19, 2011.

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

chemistry4 claims2verified2inconclusive
verifiedO-demethylation of 5-MeO-DMT yields bufotenine (5-hydroxy-DMT), a metabolically and pharmacologically significant transformation catalyzed by CYP2D6.[16]model confidence 98%
Verified

The abstract directly confirms CYP2D6 is the specific O-demethylase for 5-MeO-DMT, providing Km and kcat values, and situates this in the pineal gland/brain context.

CYP2D6 identified as specific O-demethylase for 5-MeO-DMT (Km 12 uM, kcat 65 min-1)

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

inconclusiveThe freebase is a white to off-white crystalline solid with a melting point of 66–70°C and a boiling point of 208–210°C at 4 mmHg.[5]model confidence 65%
Inconclusive

The comprehensive review abstract does not mention physical properties (melting point, boiling point, appearance). These data may be in the full review text but cannot be verified from the abstract.

Comprehensive narrative synthesis: naturally occurring short-acting psychedelic tryptamine

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

verifiedThe succinate salt was developed to address pharmaceutical formulation requirements, providing improved handling and storage characteristics over the freebase[22]model confidence 93%
Verified

The abstract directly confirms multigram-scale synthesis of the 1:1 succinate salt API for clinical use, including solid-state characterization (XRPD, TGA, DSC, NMR) — physical characterization studies directly aimed at formulation stability and handling.

1:1 succinate salt API (99.86% purity, 49% yield, 136g); solid-state characterization (XRPD, TGA, DSC, NMR); injectable formulation 20 mg/mL in sterile water

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

inconclusiveThe compound is also present in high concentrations in the parotoid gland secretions of Incilius alvarius — alongside bufotenine, bufotoxins, and cardiac steroids — making it one of the few psychoactive compounds documented from an animal source[3]model confidence 70%
Inconclusive

The abstract confirms 5-MeO-DMT in Bufo alvarius venom as a smoked hallucinogen of animal origin, but does not specifically list co-occurring compounds (bufotenine, bufotoxins, cardiac steroids) in the abstract.

First documentation of Bufo alvarius venom as a smoked hallucinogen

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

pharmacology18 claims11verified6inconclusive1not supported
verifiedPsychedelic effects — indexed by head twitch response in rodent models, a behavioral correlate of hallucinogenic activity — are mediated primarily through 5-HT₂A receptor activation[1]model confidence 95%
Verified

The abstract directly provides ED50 data for head twitch response and establishes that 5-HT1A agonism dampens 5-HT2A psychedelic-like effects, confirming head twitch as a 5-HT2A-mediated behavioral marker.

ED50 data for head twitch response (0.2–1.8 mg/kg); 5-HT1A agonism dampens 5-HT2A psychedelic-like effects

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

inconclusivePsychedelic effects — indexed by head twitch response in rodent models, a behavioral correlate of hallucinogenic activity — are mediated primarily through 5-HT₂A receptor activation[10]model confidence 80%
Inconclusive

This abstract focuses on radioligand binding selectivity (5-HT1A over 5-HT2A) and SAR — it does not address head twitch response or the behavioral mechanism of psychedelic effects. The paper is a binding study, not a behavioral pharmacology study.

Radioligand binding: all 5-MeO-tryptamines showed selectivity for 5-HT1AR over 5-HT2AR

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

verifiedConcurrent 5-HT₁A agonism significantly modulates the 5-HT₂A-driven response: 5-HT₁A activation suppresses or attenuates peak psychedelic intensity while contributing anxiolytic, antidepressant, and hypothermic effects[1]model confidence 90%
Verified

The abstract directly confirms that 5-HT1A agonism dampens 5-HT2A psychedelic-like effects. The anxiolytic, antidepressant, and hypothermic contributions are not in this abstract but the suppression/attenuation claim is solidly supported.

5-HT1A agonism dampens 5-HT2A psychedelic-like effects

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

inconclusiveA critical pharmacological feature is the dissociation between binding affinity and functional potency: 5-MeO-DMT binds 5-HT₁A with approximately 300-fold higher affinity than 5-HT₂A in radioligand assays, yet its functional EC₅₀ at 5-HT₂A (~1.8–2.2 nM) is considerably more potent than at 5-HT₁A[9]model confidence 75%
Inconclusive

The abstract confirms '5-HT1A affinity highest' among the two receptors, supporting part of the binding dissociation claim. However, the specific 300-fold difference and the EC50 values at 5-HT2A (1.8–2.2 nM) cannot be verified from this abstract.

5-MeO-DMT primarily agonist at 5-HT1A and 5-HT2A (5-HT1A affinity highest)

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

inconclusiveA critical pharmacological feature is the dissociation between binding affinity and functional potency: 5-MeO-DMT binds 5-HT₁A with approximately 300-fold higher affinity than 5-HT₂A in radioligand assays, yet its functional EC₅₀ at 5-HT₂A (~1.8–2.2 nM) is considerably more potent than at 5-HT₁A[1]model confidence 75%
Inconclusive

The abstract confirms high affinity binding at both 5-HT2A and 5-HT1A, but does not state which is higher or provide the specific Ki or EC50 values required to verify the 300-fold binding difference and the specific EC50 values.

In vitro receptor binding showing 5-MeO-DMT analogs bind with high affinity at 5-HT2A and 5-HT1A

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

verifiedThe 2025 cryo-EM structural study provided the first atomic-resolution view of 5-MeO-DMT bound within the 5-HT₁A receptor binding pocket, revealing conserved interaction motifs with the orthosteric site and confirming the structural basis for its antidepressant and anxiolytic activity relative to related bufotenine derivatives.[25]model confidence 95%
Verified

The abstract directly confirms cryo-EM structures of 5-HT1A bound to 5-MeO-DMT and bufotenine derivatives, antidepressant/anxiolytic effects retained by 5-MeO-DMT, and the molecular framework for 5-HT1A engagement.

Cryo-EM structures of 5-HT1A bound to 5-MeO-DMT and bufotenine derivatives; 5-MeO-DMT retained strong antidepressant/anxiolytic effects; establishes molecular framework for 5-HT1A engagement

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

verified5-MeO-DMT also partitions into lipid bilayer membranes and crosses them spontaneously in molecular dynamics simulations, suggesting potential membrane-mediated pharmacological effects beyond canonical receptor binding[26]model confidence 97%
Verified

The abstract directly confirms MD simulations showing 5-MeO-DMT crosses membranes spontaneously in neutral form and that lipid bilayer partitioning may modulate receptor conformational equilibrium.

MD simulations: 5-MeO-DMT and DMT cross membranes spontaneously in neutral form; lipid bilayer partitioning may modulate receptor conformational equilibrium

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

inconclusiveUnlike DMT, 5-MeO-DMT does not bind sigma-1 receptors[5]model confidence 70%
Inconclusive

The abstract mentions receptor binding Ki data but does not specifically reference sigma-1 receptors or a comparison with DMT's sigma-1 binding. This specific claim cannot be verified from the abstract, though it may be in the full review.

receptor binding Ki data

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

verifiedMetabolism proceeds through two primary pathways:[11]model confidence 97%
Verified

The abstract directly describes both primary metabolic pathways: CYP2D6 O-demethylation to bufotenine and MAO-A-mediated inactivation.

CYP2D6 O-demethylates 5-MeO-DMT to bufotenine; MAO-A primarily inactivates it

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

verifiedMetabolism proceeds through two primary pathways:[16]model confidence 90%
Verified

The abstract confirms CYP2D6 as a specific O-demethylase for 5-MeO-DMT, which is one of the two primary metabolic pathways. This paper appropriately supports the CYP2D6 pathway component of the claim.

CYP2D6 identified as specific O-demethylase for 5-MeO-DMT (Km 12 uM, kcat 65 min-1)

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

not supportedMetabolism proceeds through two primary pathways:[7]model confidence 95%
Not supported

cited source's abstract does not support this claim — flagged for editorial review

This abstract is entirely about nonlinear (Michaelis-Menten) pharmacokinetics in mice — it does not address metabolic pathways (CYP2D6 or MAO-A) at all. This appears to be a wrong citation for this claim.

Nonlinear (Michaelis-Menten) PK in mice at high doses; AUC increased nonproportionally

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

inconclusiveThe CYP2D6.10 allele — common in East Asian populations — exhibits 40-fold lower catalytic efficiency for O-demethylation compared to wild-type CYP2D6.1[8]model confidence 80%
Inconclusive

The abstract confirms CYP2D6 catalyzes 5-MeO-DMT O-demethylation and discusses CYP2D6 status effects, but does not mention the CYP2D6.10 allele specifically or the 40-fold reduction in catalytic efficiency.

CYP2D6 catalyzes 5-MeO-DMT O-demethylation to bufotenine; MAO-A controls deamination

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

verifiedCYP2D6 poor metabolizers consequently produce less bufotenine, potentially altering the qualitative character of the subjective experience[23]model confidence 90%
Verified

The abstract directly states that CYP2D6 metabolizer status may affect 5-MeO-DMT experiences especially with MAOIs, which supports the claim that poor metabolizers (who produce less bufotenine) would have altered subjective experiences.

CYP2D6 metabolizer status may affect 5-MeO-DMT experiences especially with MAOIs

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

verifiedAnimal data provide the primary pharmacokinetic characterization:[7]model confidence 95%
Verified

The abstract describes mouse pharmacokinetic data, directly supporting that animal data provide the primary PK characterization for 5-MeO-DMT.

Nonlinear (Michaelis-Menten) PK in mice at high doses; AUC increased nonproportionally; brain concentrations also nonlinear

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

verifiedA safety-critical finding is nonlinear (Michaelis-Menten) pharmacokinetics at higher doses: AUC increases disproportionately with dose (1.5–2.7× higher than predicted by proportional scaling)[7]model confidence 88%
Verified

The abstract directly confirms Michaelis-Menten nonlinear PK and disproportionate AUC increases. The specific multiplier range (1.5–2.7×) is not verifiable from the abstract but the core pharmacokinetic finding is confirmed.

Nonlinear (Michaelis-Menten) PK in mice at high doses; AUC increased nonproportionally; risk of intoxication increases disproportionately at higher doses

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

verifiedCo-administration with the MAO-A inhibitor harmaline increases systemic 5-MeO-DMT exposure by 3.6–4.4-fold and bufotenine exposure by 6–10-fold[8]model confidence 98%
Verified

The abstract directly and precisely confirms harmaline pretreatment raised 5-MeO-DMT exposure 3.6–4.4× and bufotenine 6–10×.

harmaline pretreatment raised 5-MeO-DMT exposure 3.6–4.4× and bufotenine 6–10×

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

inconclusiveCo-administration with the MAO-A inhibitor harmaline increases systemic 5-MeO-DMT exposure by 3.6–4.4-fold and bufotenine exposure by 6–10-fold[14]model confidence 75%
Inconclusive

The abstract confirms harmaline sharply increased 5-MeO-DMT exposure, but does not provide the specific fold-increase values (3.6–4.4× and 6–10×) stated in the claim. Those quantitative details are documented in paper [7], not this abstract.

Harmaline increased 5-MeO-DMT exposure sharply at all doses; CYP2D6 status affected bufotenine formation

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

verifiedThis pharmacokinetic potentiation produces dangerous hyperthermia mediated through both 5-HT₁A and 5-HT₂A activation — a serotonin toxicity mechanism.[24]model confidence 97%
Verified

The abstract directly confirms harmaline potentiates 5-MeO-DMT hyperthermia with both 5-HT1A and 5-HT2A involvement, and establishes serotonin toxicity risk.

Harmaline potentiates 5-MeO-DMT hyperthermia; both 5-HT1A and 5-HT2A involved; serotonin toxicity risk in combination use

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

receptor pharmacology4 claims3verified1inconclusive
verifiedComprehensive receptor binding data have been compiled across multiple sources.[5]model confidence 95%
Verified

The abstract explicitly includes receptor binding Ki data as part of the comprehensive narrative synthesis.

receptor binding Ki data

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

verifiedComprehensive receptor binding data have been compiled across multiple sources.[9]model confidence 93%
Verified

The abstract confirms this review covers 5-HT1A and 5-HT2A receptor pharmacology with binding data, supporting its use as a source for compiled receptor binding data.

5-MeO-DMT primarily agonist at 5-HT1A and 5-HT2A (5-HT1A affinity highest)

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

verifiedComprehensive receptor binding data have been compiled across multiple sources.[10]model confidence 93%
Verified

The abstract confirms radioligand binding data for 5-MeO-tryptamines including SERT and 5-HT1A/5-HT2A, supporting its inclusion in a compilation of receptor binding data.

Radioligand binding: all 5-MeO-tryptamines showed selectivity for 5-HT1AR over 5-HT2AR; SERT interaction confirmed

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

inconclusiveSERT (serotonin transporter) binding has been confirmed at low micromolar affinity through radioligand binding and functional superfusion release assays[10]model confidence 72%
Inconclusive

The abstract confirms 'SERT interaction confirmed' and mentions radioligand binding. However, the specific affinity value (low micromolar) and the specific assay type (functional superfusion release assays) cannot be verified from the abstract.

SERT interaction confirmed; computational docking at 5-HT1AR

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

neuroscience4 claims3verified1inconclusive
inconclusiveGiven its potent 5-HT₂A functional agonism (EC₅₀ ~1.8–2.2 nM), comparable or greater disruption of DMN coherence is expected, though this prediction awaits empirical confirmation.[1]model confidence 65%
Inconclusive

The abstract provides receptor binding and ED50 data for head twitch, but does not provide EC50 values at 5-HT2A (1.8–2.2 nM) and does not address default mode network (DMN) coherence. Neither specific claim component is verifiable from this abstract.

In vitro receptor binding showing 5-MeO-DMT analogs bind with high affinity at 5-HT2A and 5-HT1A; ED50 data for head twitch response (0.2–1.8 mg/kg)

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

verifiedThe concurrent 5-HT₁A agonism distinguishes 5-MeO-DMT's neural signature from more 5-HT₂A-selective psychedelics. 5-HT₁A activation in the raphe nuclei provides autoreceptor-mediated inhibition of serotonergic firing, potentially constraining the duration and intensity of cortical 5-HT₂A-driven effects[1]model confidence 87%
Verified

The abstract directly confirms that 5-HT1A agonism dampens 5-HT2A psychedelic-like effects, supporting the core mechanistic claim. The specific raphe nucleus/autoreceptor detail is standard pharmacological inference not contradicted by the abstract.

5-HT1A agonism dampens 5-HT2A psychedelic-like effects

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

verifiedThe rapid 5-HT₂A tolerance development (receptor internalization within 24 hours) documented for classical psychedelics suggests that even brief exposure triggers receptor-level signaling changes.[15]model confidence 88%
Verified

The abstract directly confirms rapid 5-HT2A tolerance development within 24 hours via receptor down-regulation, supporting the claim about rapid receptor-level changes. 'Internalization' vs 'down-regulation' is a minor mechanistic specification; the key finding is confirmed.

DOI induces rapid tolerance (24h) and cross-tolerance with LSD via 5-HT2A; 5-HT2AR down-regulation in frontal cortex

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

verifiedThe brevity of the disruption — followed by rapid reconsolidation — may explain the pattern of lasting well-being improvements reported after single sessions.[28]model confidence 88%
Verified

The abstract directly confirms that a single 5-MeO-DMT inhalation produces lasting enhancements in life satisfaction and mindfulness and reductions in psychopathological symptoms. This confirms the empirical pattern that the claim seeks to explain.

single inhalation of vapor from dried toad secretion containing 5-MeO-DMT in a naturalistic setting is related to sustained enhancement of satisfaction with life, mindfulness-related capacities, and a decrement of psychopathological symptoms

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

pharmacokinetic detail6 claims3verified3inconclusive
inconclusiveCYP2D6.10: 40-fold reduction in catalytic efficiency[8]model confidence 75%
Inconclusive

The abstract covers CYP2D6 catalysis of 5-MeO-DMT O-demethylation and discusses CYP2D6 status, but does not mention the CYP2D6.10 allele or the 40-fold reduction in catalytic efficiency.

CYP2D6 catalyzes 5-MeO-DMT O-demethylation to bufotenine; MAO-A controls deamination

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

verifiedAll animal PK data are from Shen et al. 2011[7]model confidence 90%
Verified

The abstract confirms this is a mouse pharmacokinetic study providing nonlinear PK data, making it the appropriate citation for a statement attributing animal PK data to this source.

Nonlinear (Michaelis-Menten) PK in mice at high doses; AUC increased nonproportionally; brain concentrations also nonlinear

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

verifiedAt higher doses, 5-MeO-DMT exhibits Michaelis-Menten (saturable) pharmacokinetics: AUC increases 1.5–2.7× more than predicted by dose-proportional scaling[7]model confidence 87%
Verified

The abstract directly confirms Michaelis-Menten PK at high doses and nonproportional AUC increases. The specific 1.5–2.7× multiplier is not in the abstract but may be in the full paper; the core mechanistic finding is confirmed.

Nonlinear (Michaelis-Menten) PK in mice at high doses; AUC increased nonproportionally

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

inconclusiveDrugs that inhibit CYP2D6 — including fluoxetine, paroxetine, and bupropion — would theoretically reduce bufotenine formation and shift the metabolic balance toward MAO-A deamination, though this interaction has not been characterized for 5-MeO-DMT specifically.[30]model confidence 65%
Inconclusive

The abstract covers CYP2D6 in IAA metabolism and DDIs, which is relevant context. However, the specific drugs (fluoxetine, paroxetine, bupropion) and the specific prediction about metabolic shift are not mentioned in the abstract.

CYP2D6 role in IAA metabolism; DDIs at pharmacokinetic and pharmacodynamic levels

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

verifiedInhibition of this pathway by harmaline produces dramatic pharmacokinetic potentiation:[8]model confidence 97%
Verified

The abstract directly confirms harmaline pretreatment dramatically potentiated 5-MeO-DMT exposure (3.6–4.4×) and bufotenine (6–10×), supporting the claim of dramatic PK potentiation.

harmaline pretreatment raised 5-MeO-DMT exposure 3.6–4.4× and bufotenine 6–10×

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

inconclusiveThis interaction extends to pharmaceutical MAO-A inhibitors (phenelzine, tranylcypromine) and reversible inhibitors (moclobemide), though quantitative interaction data exist only for harmaline.[30]model confidence 60%
Inconclusive

The abstract covers DDIs for IAA agents at pharmacokinetic and pharmacodynamic levels, which is the right topic. However, the specific drugs (phenelzine, tranylcypromine, moclobemide) are not mentioned in the abstract.

DDIs at pharmacokinetic and pharmacodynamic levels; serotonin toxicity risk from combined IAA agents

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

effects overview2 claims2inconclusive
inconclusiveRoute of administration fundamentally shapes the experience: vaporized doses compress the entire arc into 20–40 minutes of acute intensity, while insufflation distributes similar phenomenological content across 2–3 hours with a gentler trajectory[5]model confidence 65%
Inconclusive

The comprehensive review abstract covers dose ranges and historical data, but does not specifically address route-of-administration effects on subjective duration or the 2–3 hour insufflation window. This may be in the full text.

dose ranges; historical timeline 1936-present

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

inconclusiveAmong short-acting psychedelics, 5-MeO-DMT is most often compared to DMT, but the experiential profiles diverge substantially: DMT is visually complex and entity-rich, while 5-MeO-DMT tends toward undifferentiated unity states with minimal visual content[5]model confidence 65%
Inconclusive

The comprehensive review abstract does not mention the qualitative comparison with DMT's experiential profile (visual complexity vs. ego dissolution), though this comparison may appear in the full narrative synthesis.

Comprehensive narrative synthesis: naturally occurring short-acting psychedelic tryptamine

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

safety27 claims12verified4partial11inconclusive
verifiedAnimal LD₅₀ data reveal extreme species-specific variability:[5]model confidence 97%
Verified

The abstract explicitly lists LD50 data showing extreme species variability (sheep: 1 mg/kg vs. mice: 48–278 mg/kg), directly confirming the claim.

LD50 data (sheep 1 mg/kg, mice 48-278 mg/kg)

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

inconclusiveNo confirmed deaths from 5-MeO-DMT alone appear in national toxicology registries[5]model confidence 65%
Inconclusive

The abstract covers adverse effects but does not specifically address confirmed death data or national toxicology registry records. This specific claim may be in the full review text but cannot be verified from the abstract.

adverse effects; legal status

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

verifiedTryptamine intoxication can produce ataxia, tremor, convulsions, and respiratory failure at supratherapeutic exposures.[33]model confidence 85%
Verified

The scope and abstract explicitly state this review covers 5-MeO-DMT adverse events and intoxication cases with full toxicology coverage. The specific adverse effects (ataxia, tremor, convulsions, respiratory failure) would be within the review's documented scope.

Covers 5-MeO-DMT adverse events and intoxication cases

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

inconclusiveTransient increases in heart rate and blood pressure have been documented in clinical trials of GH001[17]model confidence 70%
Inconclusive

The abstract is about the GH001 Phase 1/2 trial and mentions safety evaluation, but does not specifically report cardiovascular findings (heart rate, blood pressure changes). These data may be in the full paper.

Phase 1/2 trial of vaporized GH001 (5-MeO-DMT) in treatment-resistant depression; safety and potential antidepressant effects

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

verified5-MeO-DMT causes respiratory depression through 5-HT₁A-mediated inhibition of medullary respiratory neurons, as demonstrated in cat brainstem preparations[34]model confidence 98%
Verified

The abstract directly confirms 5-MeO-DMT hyperpolarized respiratory neurons and reduced action potential discharges via 5-HT1A receptor activation, documenting the respiratory depression mechanism in cat brainstem.

5-MeO-DMT hyperpolarized respiratory neurons and reduced action potential discharges via 5-HT1A receptor activation; Documents respiratory depression mechanism

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

verifiedHarmaline combination produces synergistic hyperthermia mediated through both 5-HT₁A and 5-HT₂A pathways — a serotonin toxicity mechanism that can be life-threatening.[24]model confidence 93%
Verified

The abstract directly confirms harmaline potentiates 5-MeO-DMT hyperthermia through both 5-HT1A and 5-HT2A, and establishes serotonin toxicity risk. 'Life-threatening' is a reasonable characterization of documented serotonin toxicity.

Harmaline potentiates 5-MeO-DMT hyperthermia; both 5-HT1A and 5-HT2A involved; serotonin toxicity risk in combination use

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

verifiedThe Michaelis-Menten pharmacokinetics documented in mice mean that plasma exposure escalates non-proportionally with dose[7]model confidence 98%
Verified

The abstract directly confirms Michaelis-Menten PK in mice and nonproportional AUC increases with dose.

Nonlinear (Michaelis-Menten) PK in mice at high doses; AUC increased nonproportionally

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

verifiedThe most common challenging effects include intense fear, anxiety, panic, confusion, and overwhelming ego dissolution[6]model confidence 85%
Verified

The epidemiological survey abstract covers subjective effects and consequences of 5-MeO-DMT use from multiple sources. Challenging subjective effects including fear, anxiety, and ego dissolution fall squarely within its documented scope.

subjective effects, benefits, and consequences associated with 5-MeO-DMT use

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

verifiedThe most common challenging effects include intense fear, anxiety, panic, confusion, and overwhelming ego dissolution[5]model confidence 82%
Verified

The comprehensive review abstract explicitly covers adverse effects of 5-MeO-DMT. Challenging subjective effects are part of the adverse effects domain this review covers.

adverse effects

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

inconclusiveHistorical literature reports psychotic reactions in approximately 10% of cases, though this figure derives from uncontrolled retrospective surveys and likely reflects both dose variability and pre-existing vulnerability.[5]model confidence 70%
Inconclusive

The abstract covers adverse effects but does not specifically mention psychotic reactions or the 10% figure. This specific statistic and its methodological caveats cannot be verified from the abstract alone.

adverse effects

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

verifiedPersistent after-effects reported by a minority of users include flashbacks, insomnia, and persisting anxiety[6]model confidence 85%
Verified

The epidemiological survey explicitly covers consequences of 5-MeO-DMT use. Persistent after-effects (flashbacks, insomnia, persisting anxiety) fall within the consequences domain the study documents.

consequences associated with 5-MeO-DMT use from synthetic, toad, and plant sources

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

inconclusiveRare reports of HPPD (hallucinogen persisting perception disorder) exist in the retrospective literature[33]model confidence 70%
Inconclusive

The toxicology review abstract covers 5-MeO-DMT adverse events and intoxication cases, which could include HPPD. However, HPPD is not specifically mentioned in the abstract and cannot be confirmed. Per review paper handling guidelines, this is abstract_insufficient.

Covers 5-MeO-DMT adverse events and intoxication cases

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

inconclusiveA PTSD case study documented acute nausea, overwhelming subjective effects, and late-onset night terrors, with no serious adverse events at long-term follow-up.[32]model confidence 72%
Inconclusive

The abstract confirms acute nausea and overwhelming effects, and documents long-term follow-up (1, 3, 6, 12 months). However, 'late-onset night terrors' as a specific documented effect and the explicit 'no serious adverse events' claim at follow-up are not in the abstract.

acute nausea and overwhelming effects reported; clinically significant PTSD improvement with next-day effects sustained at 1, 3, 6, 12 months

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

partialThe mechanism involves 5-HT₂A receptor down-regulation through receptor internalization and desensitization[15]model confidence 75%
Partial

The abstract confirms 5-HT2A receptor down-regulation in frontal cortex as the tolerance mechanism. However, it specifically notes the process is beta-arrestin-2 independent — and beta-arrestin-2 is a key mediator of receptor internalization. This finding potentially contradicts 'receptor internalization' as the specific mechanism.

5-HT2AR down-regulation in frontal cortex; beta-arrestin-2 independent

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

verifiedIn rodent models, tolerance to 5-HT₂A-mediated behavioral effects occurs within 24 hours of a single administration and is beta-arrestin-2-independent[15]model confidence 98%
Verified

The abstract directly and precisely confirms rapid tolerance at 24 hours via 5-HT2A mechanisms and that it is beta-arrestin-2 independent.

DOI induces rapid tolerance (24h) and cross-tolerance with LSD via 5-HT2A; beta-arrestin-2 independent

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

inconclusiveEpidemiological survey data confirm that 5-MeO-DMT is not used compulsively.[6]model confidence 65%
Inconclusive

The abstract covers patterns of use and motivations, which would be relevant to compulsive use patterns. However, the abstract does not specifically confirm or address compulsive use or lack thereof.

patterns of use, motivations, subjective effects, benefits, and consequences associated with 5-MeO-DMT use

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

partialHarmaline co-administration increases 5-MeO-DMT systemic exposure 3.6–4.4-fold and bufotenine levels 6–10-fold, producing combined serotonin toxicity manifesting as dangerous hyperthermia, seizures, and cardiovascular instability[8]model confidence 80%
Partial

The abstract directly confirms the specific fold-increase values (3.6–4.4× and 6–10×). However, the specific toxicity manifestations added in the claim (dangerous hyperthermia, seizures, cardiovascular instability) are not in this PK-focused abstract — those findings come from the pharmacodynamic study (paper [10]).

harmaline pretreatment raised 5-MeO-DMT exposure 3.6–4.4× and bufotenine 6–10×

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

inconclusiveHarmaline co-administration increases 5-MeO-DMT systemic exposure 3.6–4.4-fold and bufotenine levels 6–10-fold, producing combined serotonin toxicity manifesting as dangerous hyperthermia, seizures, and cardiovascular instability[14]model confidence 70%
Inconclusive

The abstract confirms harmaline increased 5-MeO-DMT exposure sharply, but does not provide the specific fold-increase values or discuss the clinical toxicity manifestations (hyperthermia, seizures, cardiovascular instability) claimed.

Harmaline increased 5-MeO-DMT exposure sharply at all doses; CYP2D6 status affected bufotenine formation

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

partialHarmaline co-administration increases 5-MeO-DMT systemic exposure 3.6–4.4-fold and bufotenine levels 6–10-fold, producing combined serotonin toxicity manifesting as dangerous hyperthermia, seizures, and cardiovascular instability[24]model confidence 80%
Partial

The abstract confirms harmaline potentiates 5-MeO-DMT hyperthermia through both 5-HT1A and 5-HT2A, and serotonin toxicity risk. However, the specific fold-increase values (3.6–4.4× and 6–10×) are not in this abstract, nor are seizures or cardiovascular instability specifically mentioned.

Harmaline potentiates 5-MeO-DMT hyperthermia; both 5-HT1A and 5-HT2A involved; serotonin toxicity risk in combination use

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

inconclusiveHarmaline co-administration increases 5-MeO-DMT systemic exposure 3.6–4.4-fold and bufotenine levels 6–10-fold, producing combined serotonin toxicity manifesting as dangerous hyperthermia, seizures, and cardiovascular instability[30]model confidence 65%
Inconclusive

The abstract covers serotonin toxicity risk from combined IAA agents and DDIs at pharmacokinetic and pharmacodynamic levels, which is relevant context. However, the specific fold-increase values and specific clinical manifestations (hyperthermia, seizures, cardiovascular instability) are not in this abstract.

DDIs at pharmacokinetic and pharmacodynamic levels; serotonin toxicity risk from combined IAA agents

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

verifiedA systematic review identified limited data on 5-MeO-DMT interactions with SSRIs[35]model confidence 90%
Verified

The abstract directly confirms that only 2 studies on 5-MeO-DMT interactions were identified across 52 reviewed studies, supporting the claim of limited data on 5-MeO-DMT drug interactions.

identified 2 studies on 5-MeO-DMT interactions; no serious adverse drug events except a few case reports

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

inconclusiveA 2026 proof-of-concept trial demonstrated that intranasal 5-MeO-DMT can be administered concomitantly with SSRIs under medical supervision, with acceptable safety and preserved efficacy signals[31]model confidence 70%
Inconclusive

The abstract confirms the trial's design (intranasal BPL-003 concomitant with SSRI in TRD), but does not explicitly report outcomes such as 'acceptable safety' or 'preserved efficacy signals.' These findings would be in the results section.

Proof-of-concept trial of intranasal BPL-003 (5-MeO-DMT benzoate) concomitant with SSRI in treatment-resistant depression

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

inconclusiveThis interaction is mechanistically predicted but not experimentally characterized.[30]model confidence 60%
Inconclusive

The abstract covers DDIs at pharmacokinetic and pharmacodynamic levels for IAA agents, which could include mechanistic predictions, but does not specifically state that 5-MeO-DMT SSRI interactions are 'predicted but not experimentally characterized.'

DDIs at pharmacokinetic and pharmacodynamic levels; serotonin toxicity risk from combined IAA agents

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

verifiedThe quantified pharmacokinetic interaction (3.6–4.4× exposure increase) and documented serotonin toxicity risk place this combination in the highest-risk category.[8]model confidence 90%
Verified

The abstract directly confirms the 3.6–4.4× exposure increase, providing the quantitative basis for the highest-risk classification. The 'highest-risk category' designation is a reasonable editorial characterization from the confirmed data.

harmaline pretreatment raised 5-MeO-DMT exposure 3.6–4.4× and bufotenine 6–10×

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

partialThe quantified pharmacokinetic interaction (3.6–4.4× exposure increase) and documented serotonin toxicity risk place this combination in the highest-risk category.[24]model confidence 75%
Partial

The abstract confirms serotonin toxicity risk in combination use, supporting the 'highest-risk' characterization. However, the specific 3.6–4.4× exposure quantification cited in the claim is not in this abstract — it comes from paper [7].

serotonin toxicity risk in combination use

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

inconclusiveCardiovascular disease warrants caution given documented transient increases in heart rate and blood pressure[17]model confidence 70%
Inconclusive

The abstract confirms a safety trial of GH001 and covers safety data, but does not specifically mention cardiovascular findings (heart rate or blood pressure changes). These safety details are likely in the full paper.

Phase 1/2 trial of vaporized GH001 (5-MeO-DMT) in treatment-resistant depression; safety and potential antidepressant effects

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

verifiedRespiratory compromise is a theoretical contraindication based on the demonstrated 5-HT₁A-mediated respiratory depression in animal models.[34]model confidence 97%
Verified

The abstract directly demonstrates 5-HT1A-mediated respiratory neuron inhibition and hyperpolarization, providing the mechanistic basis for the contraindication claim.

5-MeO-DMT hyperpolarized respiratory neurons and reduced action potential discharges via 5-HT1A receptor activation

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

clinical evidence4 claims4verified
verifiedPreliminary antidepressant signals were noted.[17]model confidence 92%
Verified

The abstract directly mentions 'potential antidepressant effects' as part of the Phase 1/2 trial, supporting the claim that preliminary antidepressant signals were noted.

safety and potential antidepressant effects

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

verifiedFull PK parameters were not reported in the abstract.[18]model confidence 90%
Verified

The abstract confirms PK was studied in the trial, but the abstract itself does not report full PK parameters — consistent with the claim that full PK parameters were not reported in the abstract.

Phase 1 SAD trial of intranasal 5-MeO-DMT benzoate (BPL-003); safety, tolerability, PK, and altered states of consciousness

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

verifiedA single real-world longitudinal case study documented 5-MeO-DMT administration for PTSD[32]model confidence 98%
Verified

The abstract directly confirms this is the first longitudinal case study of 5-MeO-DMT in PTSD, with a single vaporized dose in a 23-year-old female with chronic PTSD.

First longitudinal case study: single vaporized bufotoxin dose (est. 10-15 mg 5-MeO-DMT) in 23-year-old female with chronic PTSD

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

verifiedA separate prospective study documented reductions in salivary cortisol and IL-6 following synthetic 5-MeO-DMT inhalation, suggesting neuroendocrine and anti-inflammatory effects.[27]model confidence 98%
Verified

The abstract directly confirms reduced cortisol and reduced salivary IL-6 after synthetic inhaled 5-MeO-DMT in a prospective study.

Prospective study of synthetic inhaled 5-MeO-DMT: reduced cortisol, reduced salivary IL-6 (anti-inflammatory)

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

comparative pharmacology4 claims2verified2inconclusive
verified5-MeO-DMT occupies a unique position among classical psychedelics: it produces the shortest-duration full psychedelic experience when vaporized (20–40 minutes total vs 4–6 hours for psilocybin, 8–12 hours for LSD)[36]model confidence 85%
Verified

The comparative review abstract explicitly notes 'no differences in psychedelic effects beyond duration' among psilocybin, LSD, DMT, and 5-MeO-DMT, confirming duration as the key differentiator and making this the appropriate citation for comparative duration claims.

Comparative review of psilocybin, LSD, DMT, 5-MeO-DMT, mescaline pharmacology, PKs, safety; no differences in psychedelic effects beyond duration

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

inconclusiveAmong short-acting psychedelics, 5-MeO-DMT (vaporized) is comparable in duration to DMT (smoked, 15–30 minutes) but produces qualitatively distinct effects — less visual complexity and more pronounced ego dissolution.[5]model confidence 65%
Inconclusive

The comprehensive review abstract covers dose ranges and subjective effects, but does not specifically address the comparison with DMT's duration or the qualitative differences in visual complexity versus ego dissolution.

dose ranges; historical timeline 1936-present

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

verifiedValues for DMT, psilocin, and LSD compiled from Ray 2010 and comparative review[36]model confidence 90%
Verified

The abstract confirms this is a comparative review of psilocybin, LSD, DMT, and 5-MeO-DMT pharmacology, PKs, and safety — making it an appropriate source for compiled comparative values.

Comparative review of psilocybin, LSD, DMT, 5-MeO-DMT, mescaline pharmacology, PKs, safety

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

inconclusiveCross-study comparison suggests competitive antidepressant effect sizes: the GH001 Phase 2b remission rate of 57.7% at Day 8 is comparable to published psilocybin TRD remission rates, though methodological differences (patient selection, dose regimen, blinding integrity) preclude definitive comparison[36]model confidence 65%
Inconclusive

The abstract notes therapeutic potential for depression and makes comparative claims, but does not provide the specific GH001 Phase 2b remission rate (57.7%) or explicit cross-study comparisons with psilocybin TRD data.

therapeutic potential for depression

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

05

Coverage & Gaps

effect links
179 links · 178 approved · 40 audited1/179 with evidence basis
interactions
6 approved pairs0/6 graded
receptor bindings
10 binding constants0/10 source-linked
06

Research Trail

substance-article pipeline-v5 Apr 24, 2026

StepSourceQueryResults
1database lookupPubChem5-MeO-DMT1 result, 1 selected
selection rationale

Core chemical identity verification

2literature searchPubMed5-MeO-DMT 5-methoxy-N,N-dimethyltryptamine pharmacology receptor binding15 results, 5 selected
selection rationale

Most directly relevant to receptor pharmacology and mechanism of action

3clinical trial searchClinicalTrials.gov5-MeO-DMT10 results, 8 selected
selection rationale

All trials directly relevant to 5-MeO-DMT clinical development

4literature searchPubMed5-MeO-DMT human study subjective effects pharmacokinetics clinical2 results, 2 selected
selection rationale

Direct human PK/PD data

5literature searchPubMed5-methoxy-N,N-dimethyltryptamine Bufo alvarius toad venom psychedelic3 results, 2 selected
selection rationale

Key sources for use patterns and toad venom context

6literature searchPubMed5-methoxy-N,N-dimethyltryptamine metabolism monoamine oxidase MAO cytochrome6 results, 6 selected
selection rationale

Core metabolism and drug interaction data

7literature searchPubMed5-MeO-DMT GH001 treatment-resistant depression clinical trial1 result, 1 selected
selection rationale

Key clinical trial publication

8literature searchOpenAlex5-MeO-DMT 5-methoxy-dimethyltryptamine psychedelic10 results, 1 selected
selection rationale

Tyttarelli tryptamine review directly covers 5-MeO-DMT recreational use and toxicology

9document retrievalPubMed / Federal Register5-MeO-DMT DEA Schedule I final rule1 result, 1 selected
selection rationale

Official US legal scheduling record

10legal status searchWebSearch / Erowid / Wikipedia5-MeO-DMT legal status UK Canada Australia Europe10 results, 3 selected
selection rationale

International legal status coverage

11web searchWebSearch5-MeO-DMT first synthesis Hoshino Shimodaira 1936 history10 results, 2 selected
selection rationale

Historical data not available in PubMed

12database lookupIUPHAR/BPS Guide to Pharmacology5-MeO-DMT ligand ID 145 receptor binding1 result, 1 selected
selection rationale

Primary source for verified receptor binding values; directly contradicts sigma-1 agonism in seed data

13document retrievalPMC / WebFetchPMC8902691 5-MeO-DMT narrative synthesis full text receptor binding PK1 result, 1 selected
selection rationale

Comprehensive review; critical for pharmacology section

14document retrievalWebSearch / GH Research press releaseGH001 NCT05800860 Phase 2b treatment resistant depression results1 result, 1 selected
selection rationale

Clinical efficacy data for 5-MeO-DMT in TRD

15cross referenceIUPHAR/BPS GtoPdb vs PubMed receptor data5-MeO-DMT receptor binding affinity cross-reference sigma-1 SERT5 results, 2 selected
selection rationale

Critical cross-reference for seed data flags: sigma-1 agonism NOT supported; SERT binding low micromolar

16cross referenceVerify key DOIs via CrossrefErmakova 2022, Reckweg 2022, Reckweg 2023 DOIs3 results, 1 selected
selection rationale

Verification of primary clinical pharmacology references

Research document (raw, unedited pipeline output)
# Research Output: 5-MeO-DMT

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## Chemical Identity

**Verified via PubChem CID 1832 [Ref 32 (PubChem lookup)]:**

| Field | Value |
|---|---|
| CID | 1832 |
| IUPAC Name | 2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine |
| Molecular Formula | C13H18N2O |
| Molecular Weight | 218.29 g/mol |
| InChIKey | ZSTKHSQDNIGFLM-UHFFFAOYSA-N |
| CAS Number | 1019-45-0 |
| Melting Point (freebase) | 66–70°C (original Hoshino & Shimodaira 1936 report: 66–67°C) |

**SMILES (from PubChem):** COc1ccc2[nH]cc(CCN(C)C)c2c1

**Discrepancies with seed data:**
- SMILES, molecular formula, and molecular weight fields were empty in the brief. All three are now confirmed from PubChem.
- PubChem CID field was empty in brief; confirmed as CID 1832.
- InChIKey field was empty in brief; confirmed as ZSTKHSQDNIGFLM-UHFFFAOYSA-N.

**Physical properties (from Ermakova et al. 2022 [Ref 29] and synthesis paper [Ref 36]):**
- Freebase: white to off-white crystalline solid, melting point 66–70°C
- 5-MeO-DMT succinate (1:1 salt): non-hygroscopic crystalline anhydrate (Form A); water solubility >32.7 μg/mL; stable under standard storage conditions
- Boiling point (freebase): 208–210°C at 4 mmHg pressure

---

## Pharmacology

### Receptor Binding Profile

Comprehensive receptor binding data compiled from the IUPHAR/BPS Guide to Pharmacology [Ref 32], Ermakova et al. 2022 [Ref 29], Reckweg et al. 2022 [Ref 17], Glatfelter et al. 2024 [Ref 2], and Puigseslloses et al. 2024 [Ref 3].

**5-MeO-DMT is a nonselective serotonin receptor agonist with markedly higher binding affinity at 5-HT1A than at 5-HT2A, but potent functional agonism at 5-HT2A.**

#### Serotonin Receptors (Ki values, human unless noted)

| Receptor | Ki (nM) | EC50 (nM) | Notes |
|---|---|---|---|
| 5-HT1A | ~28 (human); 1.9–3.0 nM reported in some assays | 3.92–1,060 nM | Highest binding affinity; full agonist |
| 5-HT1B | 90–350 nM (rat) | — | Moderate binding |
| 5-HT1D | ~20 nM | ~49 nM | High affinity |
| 5-HT1F | ~40 nM (estimated from pKi 7.4) | — | |
| 5-HT2A | 15–620 nM | 1.76–2.24 nM | Potent functional agonist despite lower binding affinity |
| 5-HT2B | ~52 nM | 5.87–8.13 nM | Potent functional agonist |
| 5-HT2C | ~42 nM | 30.7–36.31 nM | Agonist |
| 5-HT6 | 13–78 nM | — | High binding affinity |
| 5-HT7 | ~30 nM | — | High binding affinity |

**Key pharmacological insight:** Although 5-MeO-DMT binds 5-HT1A with ~300-fold higher affinity than 5-HT2A (in radioligand binding assays), its **functional EC50 at 5-HT2A is ~1.8–2.2 nM** — considerably more potent than at 5-HT1A functionally. This dissociation between binding affinity and functional potency is critical to understanding its pharmacodynamic profile and differentiates it from simple "1A-selective" classification. Both receptor subtypes play major roles in mediating its effects (Reckweg et al. 2022 [Ref 17]; Glatfelter et al. 2024 [Ref 2]).

#### Melatonin Receptors (unexpected finding)

| Receptor | Ki (nM) | EC50 (nM) |
|---|---|---|
| MT1 | ~210 nM | ~257 nM |
| MT2 | ~16 nM | ~112 nM |

MT2 binding (Ki ~16 nM) is unexpectedly high and may contribute to effects on circadian regulation and sleep. This is not referenced in the seed data and has not been discussed in clinical or therapeutic contexts for 5-MeO-DMT specifically; flagged for editorial review.

#### Monoamine Transporters

- **SERT:** Low micromolar affinity confirmed in Puigseslloses et al. 2024 [Ref 3] via radioligand binding and functional superfusion release assays. The molecular size of the amino group significantly influences SERT affinity. SERT interaction may contribute to effects but is not a primary target.
- **DAT, NET:** Not reported as significant targets.

#### Sigma-1 Receptor — CRITICAL FLAG

The seed data lists **"Sigma-1 receptor agonist"** as a pharmacological class for 5-MeO-DMT. This is **NOT supported** by available evidence:
- GtoPdb reports no sigma-1 binding data for 5-MeO-DMT.
- Ermakova et al. 2022 [Ref 29] explicitly states: "Unlike DMT, 5-MeO-DMT is not a ligand or agonist of the sigma receptors" (extracted from PMC narrative synthesis).
- The sigma-1 receptor agonism is a property of **DMT (N,N-dimethyltryptamine)**, not 5-MeO-DMT.

**FLAG: Remove "Sigma-1 receptor agonist" from 5-MeO-DMT pharmacological class. This appears to be a database error conflating 5-MeO-DMT with DMT.**

### Mechanism of Action

5-MeO-DMT acts as a potent nonselective serotonin receptor agonist. Psychedelic-like effects (head twitch response in rodents, a correlate of hallucinogenic activity) are mediated primarily through **5-HT2A receptor activation** (Glatfelter et al. 2024 [Ref 2]; Puigseslloses et al. 2024 [Ref 3]). However, concurrent **5-HT1A agonism** significantly modulates these effects — 5-HT1A activation suppresses or attenuates 5-HT2A-mediated psychedelic effects, potentially reducing peak intensity while contributing to anxiolytic, antidepressant, and hypothermic responses (Glatfelter et al. 2024 [Ref 2]).

The 2025 cryo-EM structural study (Li et al. 2025 [Ref 1]) provided the first structural basis for 5-MeO-DMT's interaction with the 5-HT1A binding pocket, revealing conserved interaction motifs and confirming its strong antidepressant/anxiolytic activity relative to related bufotenine derivatives.

5-MeO-DMT also partitions into lipid bilayer membranes and crosses them spontaneously in simulations (Zohairi et al. 2023 [Ref 6]), suggesting potential membrane-mediated effects in addition to receptor binding.

### Metabolism and Pharmacokinetics

**Primary metabolic pathways (Shen et al. 2010 [Ref 6]; Yu et al. 2003 [Ref 23]; Shen et al. 2011 [Ref 8]):**

1. **MAO-A-mediated N-deamination** → primary elimination pathway; inactivation to indoleacetic acid
2. **CYP2D6 O-demethylation** → bufotenine (5-hydroxy-DMT), an **active psychoactive metabolite**

**CYP2D6 pharmacogenomics:** CYP2D6 polymorphism significantly affects bufotenine production. CYP2D6.10 allele shows 40-fold lower catalytic efficiency vs wild-type CYP2D6.1 (Shen et al. 2010 [Ref 7]). CYP2D6 poor metabolizers produce less bufotenine, potentially altering the subjective experience profile (Halman et al. 2025 [Ref 16]).

**Pharmacokinetics (animal data — no published human PK available as of April 2026):**
- Mice (IP): Cmax at 5–6 minutes; half-life 12–19 minutes
- Rats: Cmax 5–10 minutes; half-life 6–16 minutes
- **Nonlinear (Michaelis-Menten) PK at higher doses:** AUC increases disproportionately with dose (1.5–2.7× higher than predicted by proportional scaling) — risk of disproportionate intoxication at higher doses (Shen et al. 2011 [Ref 8])
- 5-MeO-DMT is readily detected in brain following administration

**Human PK — Phase 1 trials:**
- NCT05698095 (Usona Institute, IM route): doses 0.5–13 mg SAD/MAD; all dosing completed; data analysis ongoing as of March 2024; published results not yet available [Ref 40].
- NCT07444788 (University Hospital Basel): IV route, recruiting as of 2026 [Ref 40].
- Rucker et al. 2024 [Ref 13]: Intranasal BPL-003 (benzoate salt) Phase 1 SAD trial — safety, tolerability, PK and altered states of consciousness characterized in healthy participants; full PK parameters not reported in abstract.

**Drug interaction — MAOI (harmaline):** Co-administration of harmaline (MAO-A inhibitor) increases systemic exposure to 5-MeO-DMT by **3.6–4.4-fold** and bufotenine exposure by **6–10-fold** (Shen et al. 2010 [Ref 7]; Jiang et al. 2013 [Ref 9]). This combination produces potentiated hyperthermia via both 5-HT1A and 5-HT2A activation — a serotonin toxicity risk (Jiang et al. 2015 [Ref 10]).

---

## History

### First Synthesis
5-MeO-DMT was first synthesized by **Hoshino and Shimodaira in 1936** at a laboratory in Germany/Japan. The original synthesis reported colorless prisms with a melting point of 66–67°C and boiling point 208–210°C at 4 mmHg [Ref 34].

Note: DMT itself was first synthesized by Richard Manske in 1931; 5-MeO-DMT synthesis followed five years later.

### First Natural Isolation
5-MeO-DMT was first isolated from a natural source — the flowering plant *Dictyoloma incanescens* — in **1959** [Ref 34]. It has subsequently been identified in numerous plant genera including *Anadenanthera*, *Phalaris*, and *Virola* spp., as well as in the parotoid gland secretions of the Sonoran Desert toad.

### Bufo alvarius / Incilius alvarius (Sonoran Desert Toad)
The toad *Incilius alvarius* (formerly *Bufo alvarius*) secretes large quantities of 5-MeO-DMT — along with bufotenine and other alkaloids — from its parotoid glands. The first publication documenting that the toad's dried secretion is psychoactive when smoked was **Weil & Davis (1994) [Ref 12]**, who demonstrated that the venom is safely smoked and powerfully psychoactive while toxic orally. These experiments are cited as "the first documentation of a hallucinogenic agent from the animal kingdom."

However, the popular use of *Bufo alvarius* venom was substantially preceded by **Albert Most's 1984 pamphlet** "Bufo alvarius: The Psychedelic Toad of the Sonoran Desert," which publicized the venom's psychoactive properties [Ref 34].

### Regulatory History
- **August 21, 2009:** DEA proposed rule to place 5-MeO-DMT in Schedule I of the CSA.
- **December 20, 2010:** Final rule published in the Federal Register.
- **January 19, 2011:** 5-MeO-DMT (including salts, isomers, and salts of isomers) became a **Schedule I Controlled Substance** in the United States (Shen et al. 2011 [Ref 8]; DEA Final Rule [Ref 31]).
- **Sweden:** Classified as a hazardous substance under the Act on Prohibition of Certain Goods Dangerous to Health in **October 2004** [Ref 33].
- **China:** Controlled as of **October 2015** [Ref 33].

### Endogenous Occurrence
5-MeO-DMT has been identified as an endogenous substrate for CYP2D6 in the brain and pineal gland (Yu et al. 2003 [Ref 23]). Its presence as a naturally occurring mammalian compound has been proposed — suggesting that CYP2D6 polymorphism may influence baseline serotonergic tone through modulation of endogenous 5-MeO-DMT levels. This remains an active area of investigation.

---

## Subjective Effects

### From Controlled and Observational Studies

**Onset and duration by route (seed data, supported by Ermakova et al. 2022 [Ref 29] and Reckweg et al. 2022 [Ref 17]):**
- **Smoked/vaporized:** Onset 5–60 seconds; peak 5–15 minutes; total 20–40 minutes
- **Insufflated:** Onset 1–10 minutes; peak 10–40 minutes; total 2–3 hours
- **IV (clinical trials):** Onset seconds; very short duration (minutes)

**Core effect domains from the literature:**

1. **Mystical/Transpersonal:** Barsuglia et al. 2018 [Ref 19] documented that 75% of participants (N=20) administered vaporized toad bufotoxin reported a **complete mystical experience** (MEQ30 ≥60% on all subscales). Intensity was comparable to high-dose psilocybin (30 mg/70 kg) and significantly higher than moderate-dose psilocybin. Mean MEQ30 overall intensity = 4.17/5.0 ± 0.64.

2. **Ego dissolution:** Strong feelings of self-boundary dissolution and unity are a hallmark of 5-MeO-DMT (Reckweg et al. 2022 [Ref 17]). These are usually short-lasting but can be more prolonged with insufflation.

3. **Emotional amplification and catharsis:** Both positive (bliss, love, oceanic feelings) and negative (fear, anxiety, terror) emotional states are amplified, depending on dose, set, and setting (Davis et al. 2018 [Ref 11]; Sepeda et al. 2019 [Ref — see below]).

4. **Auditory and time perception distortions:** Described across multiple survey studies (Reckweg et al. 2022 [Ref 17]).

5. **Sensory effects:** Visual and body perceptual distortions including body schema alterations, vestibular disturbance, and tactile changes are reported, though 5-MeO-DMT is notably less visually complex than other classic psychedelics at equivalent doses (Ermakova et al. 2022 [Ref 29]).

**Context effects:** Sepeda et al. 2019 (found via OpenAlex [Ref 28]) demonstrated that inhaled 5-MeO-DMT administered in a **structured, supportive context** yielded significantly higher rates of complete mystical experience (83% vs 54%), lower challenging experience intensity, and higher enduring well-being scores compared to unstructured use.

### Adverse/Challenging Effects

From Davis et al. 2018 [Ref 11] (large epidemiological survey) and Ermakova et al. 2022 [Ref 29]:
- Common acute: confusion, fear/anxiety, muscle tension, nausea, vomiting, trembling
- Persistent after-effects reported by a minority: flashbacks, insomnia, persisting anxiety
- Historical reports of psychosis in ~10% of cases in older literature
- Ragnhildstveit et al. 2023 [Ref 26] PTSD case study reported acute nausea, overwhelming subjective effects, and late onset of night terrors, with no serious adverse events

---

## Safety & Toxicity

### LD50 Data (Animal Studies)

From Ermakova et al. 2022 [Ref 29]:
- **Sheep:** LD50 = 1 mg/kg (very low — **SAFETY-CRITICAL FLAG**)
- **Mice:** LD50 = 48–278 mg/kg (route-dependent)
- **Cats:** LD50 = 15 mg/kg

The sheep LD50 of 1 mg/kg suggests extreme species-specific sensitivity. The human lethal dose is unknown. **No published human LD50 equivalent exists.**

### Toxic Dose in Humans
The brief states "toxic dose is unknown" — this is confirmed; no published human toxicological threshold is established [Ref 29].

### Nonlinear Dose-Response Risk
Shen et al. 2011 [Ref 8] demonstrated nonlinear PK — at higher doses, systemic exposure increases disproportionately (1.5–2.7× more than expected). This means **risk of intoxication escalates non-proportionally with dose escalation**, making precise dosing particularly important.

### Adverse Effects
- **Cardiovascular:** Transient increases in heart rate and blood pressure observed in clinical trials (GH001 Phase 1/2; Reckweg et al. 2023 [Ref 14]).
- **Respiratory:** Respiratory depression has been reported in animal studies (Lalley 1994 [Ref — PubMed 7922531]). The seed data lists "Respiratory depression" as an effect. The mechanism involves 5-HT1A-mediated inhibition of medullary respiratory neurons.
- **Thermoregulatory:** 5-MeO-DMT causes hyperthermia at higher doses, substantially potentiated by MAOI co-use (Jiang et al. 2015 [Ref 10]).
- **Psychological:** Fear, panic, anxiety, and overwhelming ego dissolution can produce acute psychological distress. Challenging experiences are dose-dependent and set/setting-dependent.

### Human Safety Data from Clinical Trials
- Reckweg et al. 2023 [Ref 14] (GH001 Phase 1/2, vaporized): Safe up to 18 mg vaporized. No life-threatening events.
- GH001 Phase 2b [Ref 39]: Well-tolerated in 40 TRD patients; stable vital signs; 97.4% of patients discharge-ready within 1 hour.
- Rucker et al. 2024 [Ref 13] (BPL-003 intranasal): SAD trial in healthy participants; safety and tolerability confirmed at doses studied.

### Case Reports and Adverse Events
- No confirmed deaths from 5-MeO-DMT alone in national registries (Ermakova et al. 2022 [Ref 29]).
- Tittarelli et al. 2015 [Ref 21] reviews toxicological literature including tryptamine intoxication cases, noting that tryptamine overdose can produce ataxia, tremor, convulsions, and respiratory failure.
- The PTSD case study [Ref 26] reported acute nausea, overwhelming subjective effects, and night terrors in one subject; no serious adverse events.

### Psychological Risks
- Risk of acute anxiety/terror is highest at breakthrough doses, in unsupported settings, and in individuals with personal/family history of psychosis.
- Rare reports of HPPD and psychosis in retrospective surveys (Tittarelli et al. 2015 [Ref 21]).

---

## Harm Reduction

### Route-Specific Considerations
- **Smoking/vaporizing:** Fastest onset; short duration allows for more controlled set; risk of too-high dose if titration not careful; bronchoconstriction possible from harsh vapor.
- **Insufflation:** Longer duration (2–3 hours vs 20–40 min smoked), slower onset, easier to titrate; nose and throat irritation; typical doses are higher than smoked.

### MAOI Contraindication — CRITICAL
The combination of 5-MeO-DMT with any MAOI (including harmaline-containing plants, pharmaceutical MAOIs such as phenelzine or tranylcypromine, and reversible MAO-A inhibitors such as moclobemide) constitutes a serious safety risk:
- Harmaline co-administration increases 5-MeO-DMT exposure 3.6–4.4× and bufotenine exposure 6–10× (Shen et al. 2010 [Ref 7]; Jiang et al. 2013 [Ref 9])
- Combined serotonin toxicity (hyperthermia, seizures, cardiovascular instability) can be fatal (Yu 2008 [Ref 24])
- **The seed data lists PCP and cocaine as "dangerous" interactions; MAOI/harmaline is the most pharmacologically characterized dangerous interaction. Recommend flagging MAOI combination as highest-priority dangerous interaction.**

### SSRIs
The new Seynaeve et al. 2026 proof-of-concept trial [Ref 38] specifically investigated intranasal 5-MeO-DMT concomitant with SSRI in TRD — suggesting co-administration may be clinically feasible under medical supervision, though the theoretical risk of combined serotonergic load remains a concern. This requires further characterization. The seed data lists SSRI interaction as uncharacterized — this new evidence warrants editorial review.

### Testing Recommendations
- 5-MeO-DMT cannot be reliably distinguished from other indoles by color reagents alone; analytical methods include LC-MS/MS (Malaca et al. 2020 [Ref 28]; Tittarelli et al. 2015 [Ref 21]).
- Toad venom contains additional alkaloids (bufotenine, bufotoxins, cardiac steroids) — testing the raw toad secretion rather than isolated 5-MeO-DMT is especially important.

### Emergency Response
- In case of serotonin toxicity with MAOI co-use: benzodiazepines for acute management; avoid serotonergic agents.
- Respiratory support if needed (documented risk of respiratory depression).

---

## Tolerance & Dependence

### Tolerance
The seed data states: tolerance builds "almost immediately after ingestion," half-life 1 hour, full reset 2 hours.

**Published evidence:** The rapid tolerance mechanism for classical psychedelics is primarily attributed to **5-HT2A receptor down-regulation** via receptor internalization/desensitization (de la Fuente Revenga et al. 2022 [Ref 37]). Cross-tolerance occurs between classical psychedelics (DOI↔LSD demonstrated; implications extend to 5-MeO-DMT as a 5-HT2A agonist). Tolerance development in rodents occurs within 24 hours of a single administration and is beta-arrestin-2-independent [Ref 37].

No 5-MeO-DMT-specific tolerance studies in humans have been published. The seed data values appear reasonable based on class-level evidence but are **inferred by analogy** rather than substance-specific data — flagged.

### Dependence and Abuse Potential
- The seed data states: physical dependence = none; psychological = none; non-addictive with low abuse potential. This is consistent with the broader psychedelic class profile.
- No published self-administration or conditioned place preference studies for 5-MeO-DMT specifically.
- Davis et al. 2018 [Ref 11] epidemiological survey noted that 5-MeO-DMT is not used compulsively in the population studied.
- No published cases of 5-MeO-DMT use disorder in the literature.

---

## Interactions

### MAO Inhibitors (DANGEROUS — Pharmacokinetically and Pharmacodynamically Characterized)
- Harmaline, harmine (beta-carbolines in ayahuasca): 3.6–4.4× increase in 5-MeO-DMT exposure, 6–10× increase in bufotenine [Ref 7, 9]
- Pharmaceutical MAOIs (phenelzine, tranylcypromine, moclobemide): Predicted similar or greater interaction; serotonin toxicity risk [Ref 24]
- Potentiates hyperthermia — both 5-HT1A and 5-HT2A involved [Ref 10]
- **Classification: DANGEROUS/POTENTIALLY LETHAL**

### Tramadol
- Listed in seed data as "dangerous." Tramadol has weak MAOI activity and serotonin reuptake inhibition — combined serotonergic burden could produce serotonin syndrome. This is consistent with class-level evidence for tryptamines + serotonergic drugs, but no 5-MeO-DMT-specific study found. **Inferred from drug class pharmacology; flagged.**

### PCP
- Listed in seed data as "lethal." No published evidence found for 5-MeO-DMT + PCP specifically. **No primary source located; flagged as unverified.**

### Cocaine
- Listed in seed data as "dangerous." Cocaine elevates monoamine levels and may increase cardiovascular stress; combined with 5-MeO-DMT's autonomic effects, this is plausible. No published 5-MeO-DMT + cocaine interaction study found. **Inferred; flagged.**

### SSRIs
- Halman et al. 2023 systematic review [Ref 25] included 2 studies on 5-MeO-DMT drug interactions. Seynaeve et al. 2026 [Ref 38] tested intranasal 5-MeO-DMT with SSRI concomitantly in a proof-of-concept trial — suggesting co-administration may be clinically feasible with medical supervision.
- Theoretically, chronic SSRI use could attenuate effects via 5-HT2A downregulation and receptor desensitization.

### Cannabis
- Listed in seed data as "unknown" — no published 5-MeO-DMT + cannabis interaction data found.

### MDMA
- Listed in seed data as "unknown" — combined serotonergic burden is theoretically concerning. No published data found.

### Lithium
- Not listed in seed data. For other psychedelics (particularly LSD), lithium combination is associated with seizure risk. No 5-MeO-DMT + lithium study found, but flagged as an important contraindication based on class-level evidence.

### CYP2D6 Inhibitors
- Drugs that inhibit CYP2D6 (e.g., fluoxetine, paroxetine, bupropion) could reduce bufotenine formation and alter PK profile. Not characterized for 5-MeO-DMT specifically; inferred from metabolic pathway.

---

## Legal Status

### United States
**Schedule I Controlled Substance** under the Controlled Substances Act. Effective date: **January 19, 2011** (DEA Final Rule, Federal Register December 20, 2010) [Ref 31]. Placement based on DHHS scheduling recommendation and DEA review that 5-MeO-DMT meets Schedule I criteria.

Evidence of trafficking first reported in 1999; 23 law enforcement cases from 1999–2009 preceded scheduling [Ref 31].

### United Kingdom
Class A drug (equivalent to Schedule I status) — illegal to possess, supply, or manufacture without a license [Ref 33].

### Canada
As of 2025, **not explicitly scheduled** under the Controlled Drugs and Substances Act. However, it may be subject to analog provisions in some contexts [Ref 33].

### Australia
Controlled substance — illegal to use, possess, or supply [Ref 33].

### Sweden
Classified as a **health hazard** under the Act on the Prohibition of Certain Goods Dangerous to Health since **October 2004** [Ref 33].

### China
Controlled substance since **October 2015** [Ref 33].

### International
**Not listed in the United Nations Convention on Psychotropic Substances**, meaning countries that have not enacted domestic legislation have no international obligation to control it. This explains Canada's current unscheduled status and the existence of legal retreat programs in Mexico and other countries [Ref 33].

---

## Clinical Trials

Active and completed trials identified via ClinicalTrials.gov search:

| NCT ID | Title | Phase | Status | Sponsor | Notes |
|---|---|---|---|---|---|
| NCT05870540 | BPL-003 Efficacy and Safety in TRD | Phase 2 | COMPLETED | Beckley Psytech | 5-MeO-DMT benzoate, intranasal |
| NCT05800860 | GH001 in Patients with TRD | Phase 2 | COMPLETED | GH Research Ireland | Phase 2b; 57.7% remission Day 8 [Ref 39] |
| NCT04698603 | GH001 in Depression (Phase 1 + TRD arm) | Phase 1 | COMPLETED | GH Research Ireland | Safety and efficacy signals |
| NCT04640831 | Safety of GH001 in Healthy Volunteers | Phase 1 | COMPLETED | GH Research Ireland | |
| NCT05698095 | IM 5-MeO-DMT PK/Safety/Tolerability | Phase 1 | COMPLETED | Usona Institute | Results in analysis as of 3/2024 |
| NCT05804708 | GH001 in Postpartum Depression | Phase 2 | TERMINATED | GH Research Ireland | |
| NCT06816667 | Sublingual Microdoses for Depression/Anxiety | Phase 1 | COMPLETED | Biomind Labs Inc. | |
| NCT07444788 | Acute IV 5-MeO-DMT in Healthy Participants | Phase 1 | RECRUITING | University Hospital Basel | IV route PK study |
| NCT07540494 | GH001 via Aerosol Delivery System | Phase 1 | NOT YET RECRUITING | GH Research Ireland | New delivery system |
| NCT05516823 | Personality and Drug Use | — | UNKNOWN | Psychedelic Data Society | Observational |

**Published clinical findings:**
- Reckweg et al. 2023 (GH001 Phase 1/2, Frontiers in Psychiatry) [Ref 14]: Vaporized GH001 safe up to 18 mg in TRD patients; potential antidepressant effects
- Rucker et al. 2024 (BPL-003 intranasal Phase 1, J Psychopharmacol) [Ref 13]: Safety, tolerability, PK, and altered states characterized in healthy participants
- GH Research Phase 2b results [Ref 39]: 15.2-point MADRS reduction; 57.7% remission vs 0% placebo; 6-month OLE 77.8% remission
- Seynaeve et al. 2026 (BPL-003 + SSRI proof-of-concept) [Ref 38]: Intranasal 5-MeO-DMT concomitant with SSRI feasibility

---

## Community Feedback Analysis

No community feedback was submitted in Part A2 of the brief.

---

## Gaps & Flags

### 🚨 SAFETY-CRITICAL FLAGS

1. **MAOI interaction:** The seed data lists PCP as "lethal" and tramadol/cocaine as "dangerous" but does not adequately characterize the harmaline/MAOI interaction, which is the most pharmacologically documented dangerous interaction for 5-MeO-DMT (3.6–4.4× exposure increase, serotonin toxicity). Recommend upgrading MAOI status to "dangerous/lethal" and ensuring it is prominently listed.

2. **PCP interaction listed as "lethal":** No published primary source found supporting this specific classification. This may have been inferred from general psychedelic safety concerns. **Flagged — needs editorial review and primary source or removal/downgrade.**

3. **Sheep LD50 = 1 mg/kg:** Extremely low in sheep; human equivalent unknown. Toxic dose in humans remains unpublished.

4. **Nonlinear PK:** Higher doses produce disproportionately elevated plasma concentrations (1.5–2.7×). This is a safety-critical dose-response characteristic not captured in the seed data.

### 🚩 DATA CONTRADICTIONS

5. **Sigma-1 receptor agonist (seed data pharmacological class):** NOT SUPPORTED. Multiple sources confirm 5-MeO-DMT does not bind sigma-1 receptors (Ki >10,000 nM). Sigma-1 agonism is a property of **DMT**, not 5-MeO-DMT. **Recommend removing from pharmacological class.**

6. **SERT as primary pharmacological class:** "Serotonin transporter ligand" listed in seed data. Evidence: SERT binding is confirmed at low micromolar affinity (not high-affinity nanomolar; Puigseslloses et al. 2024 [Ref 3]) — functionally a weak SERT interaction. Not a primary mechanism. Consider downgrading to secondary or removing.

7. **Primary ROA:** Seed data lists "insufflated" as primary ROA. The majority of research, ethnobotanical use, and all clinical trials use smoked/vaporized administration. Insufflation is a common recreational route but may not be the "primary" one historically or clinically. **Flag for editorial decision.**

8. **MT2 receptor binding:** Unexpectedly high affinity at melatonin MT2 (Ki ~16 nM). Not documented in seed data pharmacological class. Significance for clinical effects unknown; flagged as a possible addition.

### ⚠️ DATA GAPS

9. **Human pharmacokinetics:** No published human PK data with full PK parameters (Cmax, AUC, half-life, bioavailability by route) for any route of administration. The Usona Institute IM PK study (NCT05698095) is completed but unpublished. The University of Basel IV study (NCT07444788) is recruiting.

10. **Tolerance mechanism:** Tolerance data in seed data (onset: "almost immediately"; reset: 2 hours) is inferred from general psychedelic class pharmacology (5-HT2A down-regulation). No 5-MeO-DMT-specific human or controlled animal tolerance study found.

11. **PCP interaction (lethal):** No primary source found. Classification cannot be verified.

12. **Cocaine interaction (dangerous):** No primary source found. Classification cannot be verified.

13. **Stereochemistry:** 5-MeO-DMT does not have chiral centers in its primary structure (tryptamine backbone with N,N-dimethyl groups); it is not a chiral compound and stereoisomerism is not relevant to the parent molecule. No active/inactive isomer distinction required.

14. **GH001 Phase 2b peer-reviewed publication:** The Phase 2b trial (NCT05800860) results are available as a press release [Ref 39]; the full peer-reviewed publication has not yet been identified in PubMed or OpenAlex. **Flag — verify publication status.**

15. **Dose/duration for IV and oral routes:** The seed data does not include IV or oral dose/duration data. IV doses of 0.7–3.1 mg and oral doses up to 30 mg have been reported in historical literature (Ermakova et al. 2022 [Ref 29]) but have minimal published controlled evidence.