generation run 2026-04-26
66 min completedmodel pipeline-v5plan not recordedrun/c9a428ea…Selection
Verification
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- seen / partial
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The model's own caveats
6 further caveats recorded as free text — readable on the working page
Reproduce
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- 42 source keys (listed under Sources)
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- not recorded — template version, prompt hash and git SHA are written from 2026-09 onward
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- none — agent transcripts are persisted from 2026-09 onward
15 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | WebSearch | ayahuasca LD50 lethal dose toxicity harmine DMT animal study | 10 | 2 | — |
| 2 | WebSearch | ayahuasca legal status UK Australia Canada Brazil Peru Europe | 10 | 4 | — |
| 3 | OpenAlex | ayahuasca pharmacology psychedelic | 10 | 1 | — |
| 4 | WebSearch | ayahuasca legal status DMT Schedule I DEA ruling churches | 10 | 2 | — |
| 5 | PubMed | ayahuasca adverse events safety tolerability clinical study | 4 | 4 | — |
| 6 | PubMed | ayahuasca toxicity safety White Kennedy Ruffell systematic review 2024 | 1 | 1 | — |
| 7 | ClinicalTrials.gov | ayahuasca | 13 | 5 | — |
| 8 | PubChem | DMT, harmine, harmaline, tetrahydroharmine | 4 | 4 | — |
| 9 | PubMed | ayahuasca pharmacology DMT harmine beta-carboline mechanism | 6 | 5 | — |
| 10 | PubMed | ayahuasca depression anxiety mental health observational study | 6 | 4 | — |
| 11 | PubMed | ayahuasca pharmacokinetics DMT harmine human plasma | 7 | 5 | — |
| 12 | PubMed | ayahuasca BDNF neuroplasticity | 6 | 3 | — |
| 13 | PubMed | ayahuasca serotonin syndrome interaction medication SSRI | 1 | 1 | — |
| 14 | WebSearch | ayahuasca history discovery Richard Spruce Richard Evans Schultes 1851 | 10 | 2 | — |
| 15 | PubMed | ayahuasca brain imaging neuroimaging default mode | 9 | 4 | — |
83 claims by section — every cited sentence, checked against its source
safety28 · 19 ok
The principal acute danger is serotonin syndrome when combined with serotonergic medications — SSRIs, SNRIs, MAOIs, and tramadol are contraindicatedpartially supported
Interaction between MAOI harmala alkaloids in ayahuasca and SSRIs may induce serotonin syndrome with potentially grave outcome. pmid:9924842
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
No published fatalities have been directly attributed to ayahuasca pharmacology alonesupported
Generally safe; some adverse events reported... Acceptable safety profile in controlled settings. 10915818241230916
Riba et al. recorded a 9 mmHg increase in diastolic blood pressure at the high dose (0.85 mg/kg DMT) at 75 minutessupported
Diastolic BP increased 9 mmHg at high dose. pmid:12660312
No serious adverse cardiovascular events occurred in Phase 1 trials of inhaled DMT.supported
Mild transient blood pressure/heart rate increase. No serious adverse events. j.euroneuro.2023.12.006
Claim in safety — inconclusiveinconclusiveworking →
Abortifacient and teratogenic effects have been observed in animal models at higher dosessupported
Animal models at high doses show abortifacient/teratogenic effects. 10915818241230916
No changes in safety blood biomarkers (liver, kidney, or metabolic function) were observed in the Phase 1 inhaled DMT trialsupported
No changes in safety blood biomarkers. j.euroneuro.2023.12.006
Harmaline showed the most safety issues among the ayahuasca alkaloids in preclinical models.supported
Harmaline most problematic in preclinical models. 10915818241230916
The Global Ayahuasca Survey documented a high rate of challenging psychological effects, though these were generally not severe — most participants continued attending ceremonies, perceiving benefits as outweighing adverse effectssupported
High rate of adverse physical effects and challenging psychological effects, generally not severe. Most attendees continue ceremonies, perceiving benefits outweighing adverse effects. journal.pgph.0000438
Claim in safety — inconclusiveinconclusiveworking →
The first biomedical study of long-term ayahuasca users (the Hoasca Project) found remission of psychopathology in long-term UDV members, high functional status, and no personality or cognitive deterioration.supported
Salient findings: remission of psychopathology following initiation of hoasca use; no evidence of personality or cognitive deterioration. High functional status. pmid:8596116
Both a comprehensive toxicodynamics review and a systematic thematic review of adverse events confirm the absence of tolerancesupported
Abuse does not lead to dependence or tolerance. ph13110334
Both a comprehensive toxicodynamics review and a systematic thematic review of adverse events confirm the absence of tolerancesupported
No evidence of dependence or tolerance. 10915818241230916
Multiple studies document reduced alcohol and substance use following ayahuasca exposure, suggesting a negative relationship between ayahuasca use and drug-seeking behavior.supported
4/5 human studies reported significant reductions in dependence symptoms. 02791072.2016.1188225
Claim in safety — inconclusiveinconclusiveworking →
Long-term neuropsychological assessment reveals no detectable cognitive impairments in chronic ayahuasca users when evaluated after abstinencesupported
No significant neuropsychological differences. j.euroneuro.2026.112782
Experienced users with more than 20 years of ritual use showed improved working memory compared to beginners.supported
Experienced group showed higher working verbal and visuospatial memory scores than beginners. s00406-024-01817-9
The primary danger is serotonin syndrome — a potentially life-threatening hyperserotoninergic state — when ayahuasca is combined with medications that increase central serotonin levels.supported
Interaction between MAOI harmala alkaloids in ayahuasca and SSRIs may induce serotonin syndrome with potentially grave outcome. pmid:9924842
SSRIs (fluoxetine, sertraline, paroxetine), SNRIs (venlafaxine, duloxetine), and pharmaceutical MAOIs (phenelzine, tranylcypromine) are contraindicated due to serotonin syndrome risk when combined with MAO-A inhibitionpartially supported
Interaction between MAOI harmala alkaloids in ayahuasca and SSRIs may induce serotonin syndrome with potentially grave outcome. pmid:9924842
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
The interaction profile above is derived from MAOI-class pharmacology and the foundational warning by Callaway and Grob rather than ayahuasca-specific controlled data.supported
Interaction between MAOI harmala alkaloids in ayahuasca and SSRIs may induce serotonin syndrome with potentially grave outcome. Caution advised. pmid:9924842
Based on published literature:supported
Systematic thematic review of 78 articles. 10915818241230916
Based on published literature:supported
Comprehensive review of toxicokinetics and toxicodynamics of all four main ayahuasca alkaloids. ph13110334
pharmacology13 · 9 ok
Ayahuasca's pharmacology rests on a drug-drug interaction between the brew's own constituentssupported
B. caapi contains harmine, harmaline, and tetrahydroharmine while admixtures contain DMT. Beta-carbolines are reversible MAO inhibitors. pmid:6587171
Ayahuasca's pharmacology rests on a drug-drug interaction between the brew's own constituentssupported
Primary mechanism is MAO-A inhibition by beta-carbolines protecting oral DMT from deamination. 1516-4446-2020-0884
Once in systemic circulation, DMT crosses the blood-brain barrier and acts primarily as a 5-HT₂A receptor agonist on cortical neurons, producing the characteristic psychedelic effectssupported
5-HT2A as primary target. ph13110334
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
A systematic review found the existing literature insufficient to distinguish between these modelssupported
Synergistic vs additive interactions remain unclear. 1516-4446-2020-0884
McKenna et al. demonstrated that the beta-carboline MAOI effects in combination are additive, not synergistic.supported
Quantitative analysis confirmed MAOI activity is additive not synergistic. pmid:6587171
The dominant pharmacokinetic determinant is harmine's inhibition of MAO-A, which occurs predominantly at peripheral (gastrointestinal and hepatic) sites — harmine plasma levels are negligible after oral ayahuasca ingestion, confirming that its action is exerted before DMT reaches systemic circulation.supported
Predominantly peripheral site of action for harmine. pmid:12660312
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Peak DMT plasma concentrations (Tmax) occur at approximately 1.5–1.8 hours post-ingestion across studies, with subjective effects closely tracking plasma levelssupported
DMT Cmax 12.14 and 17.44 ng/mL respectively, Tmax ~1.5h. Subjective effects peaked 1.5-2h. pmid:12660312
Peak DMT plasma concentrations (Tmax) occur at approximately 1.5–1.8 hours post-ingestion across studies, with subjective effects closely tracking plasma levelssupported
DMT Tmax 107.5 ± 32.5 min. Peak psychoactivity correlated with high alkaloid concentrations. pmid:10404423
Total subjective effects duration is 4–5 hours with standardized single-dose preparations, extending to 4–8 hours in traditional ceremonial contexts where brew potency varies and re-dosing may occur.supported
Effects lasted 4-5h. j.biopha.2025.117908
summary9 · 7 ok
Western scientific characterization began with Richard Spruce's 1851 botanical observations and advanced decisively when McKenna, Towers, and Abbott established the MAOI-DMT mechanism in 1984supported
Beta-carbolines are reversible MAO inhibitors. Quantitative analysis confirmed MAOI activity is additive not synergistic. pmid:6587171
The first randomized controlled trial — in treatment-resistant depression — demonstrated rapid antidepressant effectssupported
First controlled trial of a psychedelic in treatment-resistant depression. Supports safety and therapeutic value of ayahuasca for depression. s0033291718001356
Claim in summary — inconclusiveinconclusiveworking →
Tetrahydroharmine contributes weak serotonin reuptake inhibition; harmine exhibits DYRK1A inhibition and dopamine transporter activity beyond its MAOI function.partially supported
Review of harmine pharmacology: MAOI, 5-HT2A effects, imidazoline receptor activity, DYRK1A inhibition, dopamine transporter inhibition. j.pnpbp.2012.06.001
Set, setting, and facilitator competence substantially modulate outcomes.supported
Both groups showed mental health improvements (placebo response). Highlights importance of placebo-controlled designs. s00213-021-05817-8
Claim in summary — inconclusiveinconclusiveworking →
No tolerance or dependence develops with repeated use; the 5-HT₂A agonist profile does not engage dopaminergic reward pathwayssupported
5-HT2A as primary target. Abuse does not lead to dependence or tolerance. ph13110334
Pregnancy is contraindicated based on animal teratogenicity datasupported
Animal models at high doses show abortifacient/teratogenic effects. 10915818241230916
Batch-to-batch alkaloid variability remains a significant practical safety concern: without laboratory analysis, the psychoactive content of any given brew cannot be reliably predicted.supported
Considerable variation in alkaloid profiles within and between sources. pmid:16149328
clinical-evidence7 · 7 ok
Preclinical evidence supports a BDNF-TrkB dependent mechanism in the infralimbic cortex underlying ayahuasca's effects on fear memory.supported
effects abolished by anti-BDNF antibody or TrkB antagonist ANA-12 in infralimbic cortex. j.euroneuro.2025.11.009
The first randomized, placebo-controlled trial of any psychedelic in treatment-resistant depression (TRD)supported
First controlled trial of a psychedelic in treatment-resistant depression. s0033291718001356
A 2026 systematic review examined ayahuasca's effects on suicidal ideation across treatment-resistant depression populations and proposed BDNF-mediated neuroplasticity as a mechanistic contributor.supported
Ayahuasca associated with rapid reductions in suicidal ideation. Neurobiologically: promotes neuroplasticity via BDNF upregulation. 02791072.2026.2661580
The Ayahuasca Treatment Outcome Project (ATOP) reported one-year outcomes from the Takiwasi Center, documenting sustained reductions in substance use following ayahuasca-assisted treatment in a real-world clinical setting.supported
1-year outcomes from Takiwasi Centre Peru, ayahuasca-assisted addiction rehabilitation program. Naturalistic evaluation. jsad.23-00005
A naturalistic longitudinal study documented improvements in mental health, wellbeing, and personality measures — including increased openness and reduced neuroticism — following ayahuasca use in retreat settings.partially supported
1-month post: significant reductions in depression, anxiety, stress. Increases in positive mood, self-efficacy, extraversion, spirituality. fphar.2022.884703
Uthaug et al. conducted a placebo-controlled study demonstrating that non-pharmacological factors (set and setting) contribute substantially to mental health improvements in ayahuasca retreats, independent of the pharmacological effectssupported
30 experienced participants, 14 ayahuasca / 16 placebo. Both groups showed mental health improvements (placebo response). s00213-021-05817-8
A Phase 1 clinical trial of inhaled DMT (BMND01 candidate) in healthy volunteers found no serious adverse cardiovascular events and no changes in safety blood biomarkers (liver, kidney, metabolic function).supported
Phase I trial, 27 healthy volunteers, inhaled DMT 5-60mg. Mild transient blood pressure/heart rate increase. No serious adverse events. No changes in safety blood biomarkers. j.euroneuro.2023.12.006
neuroscience7 · 6 ok
The first functional magnetic resonance imaging (fMRI) study of ayahuasca demonstrated that the psychedelic state modulates activity and connectivity within the default mode network (DMN) — the brain's primary self-referential and resting-state networksupported
fMRI study of 10 experienced subjects. Ayahuasca caused significant decrease in DMN activity including PCC/Precuneus and mPFC. Decreased functional connectivity within PCC/Precuneus. journal.pone.0118143
A systematic review of neuroimaging studies across classical hallucinogens confirmed that ayahuasca produces cortical activation patterns and DMN disruption consistent with other serotonergic psychedelics.supported
Acute effects: excitation of frontolateral/frontomedial cortex, medial temporal lobe, occipital cortex; inhibition of DMN. j.neubiorev.2016.10.026
Long-term ayahuasca users exhibit cortical thinning in the posterior cingulate cortex (PCC), inversely correlated with both duration and intensity of usesupported
PCC cortical thinning in users. CT inversely correlated with intensity/duration of use. j.euroneuro.2015.01.008
Preclinical evidence confirms that ayahuasca modulates fear memory extinction through BDNF-dependent mechanisms in the infralimbic cortex, providing a neurobiological substrate for the brew's PTSD-relevant therapeutic effectssupported
Oral ayahuasca (0.3 mg/kg DMT) enhanced extinction learning; effects abolished by anti-BDNF antibody or TrkB antagonist ANA-12 in infralimbic cortex. j.euroneuro.2025.11.009
Claim in neuroscience — inconclusiveinconclusiveworking →
Experienced users with more than 20 years of ritual use showed improved working memory compared to beginners.supported
Experienced group showed higher working verbal and visuospatial memory scores than beginners. s00406-024-01817-9
The sigma-1 receptor agonism of DMT is proposed as an additional neuroplastogenic mechanism, potentially mediating neuroprotective effectssupported
serotonergic and sigma-1 receptor effects, anti-inflammatory properties via Sig-1R, and therapeutic applications. fphar.2016.00035
pharmacokinetic-detail6 · 4 ok
A double-blind, placebo-controlled study in 18 healthy volunteers using freeze-dried encapsulated ayahuasca at two DMT doses (0.6 mg/kg and 0.85 mg/kg):supported
Double-blind placebo-controlled trial with 18 volunteers. Doses 0.6 and 0.85 mg DMT/kg. pmid:12660312
A pharmacokinetic study in 15 volunteers in a ceremonial setting (2 mL/kg dose):supported
Pharmacokinetics of DMT, harmine, harmaline, THH in 15 volunteers after ceremonial hoasca use (2 ml/kg). pmid:10404423
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Population pharmacokinetic-pharmacodynamic modeling of the same dataset quantified the magnitude of harmine's effect on DMT exposure.supported
Harmine markedly enhanced DMT bioavailability and prolonged absorption. Sigmoidal Emax PK/PD model. j.biopha.2025.118329
Wittayakarn et al. developed integrated physiologically based pharmacokinetic (PBPK) models for DMT-harmine interactions in rats and humanssupported
PBPK models for DMT and harmine in rats and humans. kfaf118
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
receptor-pharmacology4 · 3 ok
DMT's primary psychedelic target is the 5-HT₂A receptor, where agonism at cortical neurons — particularly layer V pyramidal cells — mediates the hallucinogenic and antidepressant effectssupported
5-HT2A as primary target. ph13110334
Sigma-1 receptor (Sig-1R): DMT is proposed as an endogenous Sig-1R agonist; activity at this target may mediate anti-inflammatory, neuroprotective, and neuroplastic effectssupported
serotonergic and sigma-1 receptor effects, anti-inflammatory properties via Sig-1R, and therapeutic applications. fphar.2016.00035
Harmine possesses multiple pharmacological activities beyond its role as a RIMA, several of which are relevant to the brew's anti-addictive and antidepressant properties:supported
Review of harmine pharmacology: MAOI, 5-HT2A effects, imidazoline receptor activity, DYRK1A inhibition, dopamine transporter inhibition. Discusses anti-addictive properties. j.pnpbp.2012.06.001
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
chemistry3 · 2 ok
Its psychoactivity arises from the combined action of four primary alkaloids derived from two plant sources.supported
B. caapi contains harmine, harmaline, and tetrahydroharmine while admixtures contain DMT. pmid:6587171
Claim in chemistry — inconclusiveinconclusiveworking →
Alkaloid composition remains stable at room temperature for approximately 80 dayssupported
Alkaloid composition stable at room temperature for 80 days. pmid:16149328
comparative-pharmacology3 · 3 ok
Smoked or vaporized DMT produces an intense psychedelic experience lasting 10–20 minutes, whereas the harmala-mediated MAO-A inhibition in ayahuasca extends the subjective experience to 4–8 hours with a gradual onset (Tmax ~1.5–1.8 h).supported
Tmax ~1.5h. Predominantly peripheral site of action for harmine. pmid:12660312
Phase 2a data for vaporized DMT in treatment-resistant depression demonstrate rapid antidepressant effects from the isolated compound, but whether the extended duration and MAOI-augmented serotonergic milieu of ayahuasca confer additional or different therapeutic benefit remains unresolved.supported
Phase 2a open-label dose-escalation of inhaled DMT in 14 TRD patients. 85.71% response rate, 57.14% remission at day 7. s41386-025-02091-6
Pharmahuasca preparations allow precise dose titration (mg-level accuracy), enabling the controlled clinical research that traditional brew preparations cannot support due to variable alkaloid contentsupported
Considerable variation in alkaloid profiles within and between sources. pmid:16149328
history3 · 2 ok
Claim in history — inconclusiveinconclusiveworking →
Schultes is credited as the first scientist to systematically and taxonomically characterize ayahuasca's preparation and use, earning recognition as "the father of modern ethnobotany".partially supported
Documents Schultes' inability to distinguish vine varieties that Amazonian practitioners could identify. 0306312720920362
Key findings included remission of prior psychopathology following initiation of hoasca use, no personality or cognitive deterioration, and high functional status among long-term users.supported
Salient findings: remission of psychopathology following initiation of hoasca use; no evidence of personality or cognitive deterioration. High functional status. pmid:8596116