generation run 2026-04-24
95 min completedmodel pipeline-v5plan not recordedrun/3fa9f3bc…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
none raised on this run
Reproduce
- inputs
- 39 source keys (listed under Sources)
- plan
- not recorded — template version, prompt hash and git SHA are written from 2026-09 onward
- model
- pipeline-v5
- streams
- none — agent transcripts are persisted from 2026-09 onward
16 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubMed | 5-methoxy-N,N-dimethyltryptamine Bufo alvarius toad venom psychedelic | 3 | 2 | Key sources for use patterns and toad venom context |
| 2 | PubMed | 5-MeO-DMT GH001 treatment-resistant depression clinical trial | 1 | 1 | Key clinical trial publication |
| 3 | PubMed | 5-methoxy-N,N-dimethyltryptamine metabolism monoamine oxidase MAO cytochrome | 6 | 6 | Core metabolism and drug interaction data |
| 4 | PubMed | 5-MeO-DMT human study subjective effects pharmacokinetics clinical | 2 | 2 | Direct human PK/PD data |
| 5 | PubMed | 5-MeO-DMT 5-methoxy-N,N-dimethyltryptamine pharmacology receptor binding | 15 | 5 | Most directly relevant to receptor pharmacology and mechanism of action |
| 6 | OpenAlex | 5-MeO-DMT 5-methoxy-dimethyltryptamine psychedelic | 10 | 1 | Tyttarelli tryptamine review directly covers 5-MeO-DMT recreational use and toxicology |
| 7 | PubChem | 5-MeO-DMT | 1 | 1 | Core chemical identity verification |
| 8 | ClinicalTrials.gov | 5-MeO-DMT | 10 | 8 | All trials directly relevant to 5-MeO-DMT clinical development |
| 9 | PMC / WebFetch | PMC8902691 5-MeO-DMT narrative synthesis full text receptor binding PK | 1 | 1 | Comprehensive review; critical for pharmacology section |
| 10 | PubMed / Federal Register | 5-MeO-DMT DEA Schedule I final rule | 1 | 1 | Official US legal scheduling record |
| 11 | WebSearch / Erowid / Wikipedia | 5-MeO-DMT legal status UK Canada Australia Europe | 10 | 3 | International legal status coverage |
| 12 | WebSearch | 5-MeO-DMT first synthesis Hoshino Shimodaira 1936 history | 10 | 2 | Historical data not available in PubMed |
| 13 | IUPHAR/BPS Guide to Pharmacology | 5-MeO-DMT ligand ID 145 receptor binding | 1 | 1 | Primary source for verified receptor binding values; directly contradicts sigma-1 agonism in seed data |
| 14 | WebSearch / GH Research press release | GH001 NCT05800860 Phase 2b treatment resistant depression results | 1 | 1 | Clinical efficacy data for 5-MeO-DMT in TRD |
| 15 | IUPHAR/BPS GtoPdb vs PubMed receptor data | 5-MeO-DMT receptor binding affinity cross-reference sigma-1 SERT | 5 | 2 | Critical cross-reference for seed data flags: sigma-1 agonism NOT supported; SERT binding low micromolar |
| 16 | Verify key DOIs via Crossref | Ermakova 2022, Reckweg 2022, Reckweg 2023 DOIs | 3 | 1 | Verification of primary clinical pharmacology references |
88 claims by section — every cited sentence, checked against its source
safety27 · 16 ok
Animal LD₅₀ data reveal extreme species-specific variability:supported
LD50 data (sheep 1 mg/kg, mice 48-278 mg/kg) 02698811211050543
Claim in safety — inconclusiveinconclusiveworking →
Tryptamine intoxication can produce ataxia, tremor, convulsions, and respiratory failure at supratherapeutic exposures.supported
Covers 5-MeO-DMT adverse events and intoxication cases 1570159x13666141210222409
Claim in safety — inconclusiveinconclusiveworking →
5-MeO-DMT causes respiratory depression through 5-HT₁A-mediated inhibition of medullary respiratory neurons, as demonstrated in cat brainstem preparationssupported
5-MeO-DMT hyperpolarized respiratory neurons and reduced action potential discharges via 5-HT1A receptor activation; Documents respiratory depression mechanism pmid:7922531
Harmaline combination produces synergistic hyperthermia mediated through both 5-HT₁A and 5-HT₂A pathways — a serotonin toxicity mechanism that can be life-threatening.supported
Harmaline potentiates 5-MeO-DMT hyperthermia; both 5-HT1A and 5-HT2A involved; serotonin toxicity risk in combination use pmid:25446678
The Michaelis-Menten pharmacokinetics documented in mice mean that plasma exposure escalates non-proportionally with dosesupported
Nonlinear (Michaelis-Menten) PK in mice at high doses; AUC increased nonproportionally dmd.111.039107
The most common challenging effects include intense fear, anxiety, panic, confusion, and overwhelming ego dissolutionsupported
subjective effects, benefits, and consequences associated with 5-MeO-DMT use 0269881118769063
The most common challenging effects include intense fear, anxiety, panic, confusion, and overwhelming ego dissolutionsupported
adverse effects 02698811211050543
Claim in safety — inconclusiveinconclusiveworking →
Persistent after-effects reported by a minority of users include flashbacks, insomnia, and persisting anxietysupported
consequences associated with 5-MeO-DMT use from synthetic, toad, and plant sources 0269881118769063
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
The mechanism involves 5-HT₂A receptor down-regulation through receptor internalization and desensitizationpartially supported
5-HT2AR down-regulation in frontal cortex; beta-arrestin-2 independent acschemneuro.2c00170
In rodent models, tolerance to 5-HT₂A-mediated behavioral effects occurs within 24 hours of a single administration and is beta-arrestin-2-independentsupported
DOI induces rapid tolerance (24h) and cross-tolerance with LSD via 5-HT2A; beta-arrestin-2 independent acschemneuro.2c00170
Claim in safety — inconclusiveinconclusiveworking →
Harmaline 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 instabilitypartially supported
harmaline pretreatment raised 5-MeO-DMT exposure 3.6–4.4× and bufotenine 6–10× j.bcp.2010.02.020
Claim in safety — inconclusiveinconclusiveworking →
Harmaline 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 instabilitypartially supported
Harmaline potentiates 5-MeO-DMT hyperthermia; both 5-HT1A and 5-HT2A involved; serotonin toxicity risk in combination use pmid:25446678
Claim in safety — inconclusiveinconclusiveworking →
A systematic review identified limited data on 5-MeO-DMT interactions with SSRIssupported
identified 2 studies on 5-MeO-DMT interactions; no serious adverse drug events except a few case reports 02698811231211219
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
The quantified pharmacokinetic interaction (3.6–4.4× exposure increase) and documented serotonin toxicity risk place this combination in the highest-risk category.supported
harmaline pretreatment raised 5-MeO-DMT exposure 3.6–4.4× and bufotenine 6–10× j.bcp.2010.02.020
The quantified pharmacokinetic interaction (3.6–4.4× exposure increase) and documented serotonin toxicity risk place this combination in the highest-risk category.partially supported
serotonin toxicity risk in combination use pmid:25446678
Claim in safety — inconclusiveinconclusiveworking →
Respiratory compromise is a theoretical contraindication based on the demonstrated 5-HT₁A-mediated respiratory depression in animal models.supported
5-MeO-DMT hyperpolarized respiratory neurons and reduced action potential discharges via 5-HT1A receptor activation pmid:7922531
pharmacology18 · 11 ok
Psychedelic effects — indexed by head twitch response in rodent models, a behavioral correlate of hallucinogenic activity — are mediated primarily through 5-HT₂A receptor activationsupported
ED50 data for head twitch response (0.2–1.8 mg/kg); 5-HT1A agonism dampens 5-HT2A psychedelic-like effects acschemneuro.4c00513
Claim in pharmacology — inconclusiveinconclusiveworking →
Concurrent 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 effectssupported
5-HT1A agonism dampens 5-HT2A psychedelic-like effects acschemneuro.4c00513
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
The 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.supported
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 research.0987
5-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 bindingsupported
MD simulations: 5-MeO-DMT and DMT cross membranes spontaneously in neutral form; lipid bilayer partitioning may modulate receptor conformational equilibrium j.chemphyslip.2023.105279
Claim in pharmacology — inconclusiveinconclusiveworking →
Metabolism proceeds through two primary pathways:supported
CYP2D6 O-demethylates 5-MeO-DMT to bufotenine; MAO-A primarily inactivates it pmid:20942780
Metabolism proceeds through two primary pathways:supported
CYP2D6 identified as specific O-demethylase for 5-MeO-DMT (Km 12 uM, kcat 65 min-1) pmid:12777961
Claim in pharmacology — not_supportednot supportedworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
CYP2D6 poor metabolizers consequently produce less bufotenine, potentially altering the qualitative character of the subjective experiencesupported
CYP2D6 metabolizer status may affect 5-MeO-DMT experiences especially with MAOIs cpt.3459
Animal data provide the primary pharmacokinetic characterization:supported
Nonlinear (Michaelis-Menten) PK in mice at high doses; AUC increased nonproportionally; brain concentrations also nonlinear dmd.111.039107
A 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)supported
Nonlinear (Michaelis-Menten) PK in mice at high doses; AUC increased nonproportionally; risk of intoxication increases disproportionately at higher doses dmd.111.039107
Co-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-foldsupported
harmaline pretreatment raised 5-MeO-DMT exposure 3.6–4.4× and bufotenine 6–10× j.bcp.2010.02.020
Claim in pharmacology — inconclusiveinconclusiveworking →
This pharmacokinetic potentiation produces dangerous hyperthermia mediated through both 5-HT₁A and 5-HT₂A activation — a serotonin toxicity mechanism.supported
Harmaline potentiates 5-MeO-DMT hyperthermia; both 5-HT1A and 5-HT2A involved; serotonin toxicity risk in combination use pmid:25446678
summary12 · 7 ok
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
Psychedelic effects are 5-HT₂A-mediated; concurrent 5-HT₁A activation attenuates peak intensity while contributing anxiolytic and antidepressant propertiessupported
5-HT1A agonism dampens 5-HT2A psychedelic-like effects acschemneuro.4c00513
Metabolism proceeds through MAO-A N-deamination and CYP2D6 O-demethylation to the active metabolite bufotenine.supported
CYP2D6 O-demethylates 5-MeO-DMT to bufotenine; MAO-A primarily inactivates it pmid:20942780
The subjective experience is dominated by rapid, intense ego dissolution and mystical-type states — 75% of participants report complete mystical experiences at vaporized dosessupported
75% had complete mystical experience; no difference vs high-dose psilocybin fpsyg.2018.02459
No human lethal dose has been established; animal LD₅₀ values range from 1 mg/kg in sheep to 278 mg/kg in micesupported
LD50 data (sheep 1 mg/kg, mice 48-278 mg/kg) 02698811211050543
Pharmacokinetics are nonlinear — AUC increases 1.5–2.7× beyond proportional scaling at higher doses, creating disproportionate intoxication risksupported
Nonlinear (Michaelis-Menten) PK in mice at high doses; AUC increased nonproportionally; risk of intoxication increases disproportionately at higher doses dmd.111.039107
The 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 risksupported
harmaline pretreatment raised 5-MeO-DMT exposure 3.6–4.4× and bufotenine 6–10× j.bcp.2010.02.020
Claim in summary — inconclusiveinconclusiveworking →
Tolerance develops rapidly via 5-HT₂A receptor internalizationsupported
DOI induces rapid tolerance (24h) and cross-tolerance with LSD via 5-HT2A; 5-HT2AR down-regulation in frontal cortex acschemneuro.2c00170
pharmacokinetic-detail6 · 3 ok
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
All animal PK data are from Shen et al. 2011supported
Nonlinear (Michaelis-Menten) PK in mice at high doses; AUC increased nonproportionally; brain concentrations also nonlinear dmd.111.039107
At higher doses, 5-MeO-DMT exhibits Michaelis-Menten (saturable) pharmacokinetics: AUC increases 1.5–2.7× more than predicted by dose-proportional scalingsupported
Nonlinear (Michaelis-Menten) PK in mice at high doses; AUC increased nonproportionally dmd.111.039107
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Inhibition of this pathway by harmaline produces dramatic pharmacokinetic potentiation:supported
harmaline pretreatment raised 5-MeO-DMT exposure 3.6–4.4× and bufotenine 6–10× j.bcp.2010.02.020
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
chemistry4 · 2 ok
O-demethylation of 5-MeO-DMT yields bufotenine (5-hydroxy-DMT), a metabolically and pharmacologically significant transformation catalyzed by CYP2D6.supported
CYP2D6 identified as specific O-demethylase for 5-MeO-DMT (Km 12 uM, kcat 65 min-1) pmid:12777961
Claim in chemistry — inconclusiveinconclusiveworking →
The succinate salt was developed to address pharmaceutical formulation requirements, providing improved handling and storage characteristics over the freebasesupported
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 acsomega.0c05099
Claim in chemistry — inconclusiveinconclusiveworking →
clinical-evidence4 · 4 ok
Preliminary antidepressant signals were noted.supported
safety and potential antidepressant effects fpsyt.2023.1133414
Full PK parameters were not reported in the abstract.supported
Phase 1 SAD trial of intranasal 5-MeO-DMT benzoate (BPL-003); safety, tolerability, PK, and altered states of consciousness 02698811241246857
A single real-world longitudinal case study documented 5-MeO-DMT administration for PTSDsupported
First longitudinal case study: single vaporized bufotoxin dose (est. 10-15 mg 5-MeO-DMT) in 23-year-old female with chronic PTSD fpsyt.2023.1271152
A separate prospective study documented reductions in salivary cortisol and IL-6 following synthetic 5-MeO-DMT inhalation, suggesting neuroendocrine and anti-inflammatory effects.supported
Prospective study of synthetic inhaled 5-MeO-DMT: reduced cortisol, reduced salivary IL-6 (anti-inflammatory) s00213-019-05414-w
comparative-pharmacology4 · 2 ok
5-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)supported
Comparative review of psilocybin, LSD, DMT, 5-MeO-DMT, mescaline pharmacology, PKs, safety; no differences in psychedelic effects beyond duration j.bpsc.2024.01.007
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Values for DMT, psilocin, and LSD compiled from Ray 2010 and comparative reviewsupported
Comparative review of psilocybin, LSD, DMT, 5-MeO-DMT, mescaline pharmacology, PKs, safety j.bpsc.2024.01.007
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
neuroscience4 · 3 ok
Claim in neuroscience — inconclusiveinconclusiveworking →
The 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 effectssupported
5-HT1A agonism dampens 5-HT2A psychedelic-like effects acschemneuro.4c00513
The rapid 5-HT₂A tolerance development (receptor internalization within 24 hours) documented for classical psychedelics suggests that even brief exposure triggers receptor-level signaling changes.supported
DOI induces rapid tolerance (24h) and cross-tolerance with LSD via 5-HT2A; 5-HT2AR down-regulation in frontal cortex acschemneuro.2c00170
The brevity of the disruption — followed by rapid reconsolidation — may explain the pattern of lasting well-being improvements reported after single sessions.supported
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 s00213-019-05236-w
receptor-pharmacology4 · 3 ok
Comprehensive receptor binding data have been compiled across multiple sources.supported
receptor binding Ki data 02698811211050543
Comprehensive receptor binding data have been compiled across multiple sources.supported
5-MeO-DMT primarily agonist at 5-HT1A and 5-HT2A (5-HT1A affinity highest) jnc.15587
Comprehensive receptor binding data have been compiled across multiple sources.supported
Radioligand binding: all 5-MeO-tryptamines showed selectivity for 5-HT1AR over 5-HT2AR; SERT interaction confirmed s41380-024-02506-8
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
history3 · 1 ok
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
The 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, 2011supported
DEA final rule placing 5-MeO-DMT (including salts, isomers) into Schedule I of the CSA. Effective January 19, 2011. pmid:21171485