generation run 2026-05-03
95 min completedmodel pipeline-v5plan not recordedrun/e5a4c943…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
none raised on this run
Reproduce
- inputs
- 40 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
20 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubMed | N,N-dimethyltryptamine sigma-1 receptor binding endogenous | 7 | 3 | Primary sigma-1 receptor evidence |
| 2 | PubMed | DMT N,N-dimethyltryptamine pharmacokinetics human plasma | 10 | 9 | All directly relevant to DMT PK in humans or animal models |
| 3 | OpenAlex | N,N-dimethyltryptamine psychedelic pharmacology | 10 | 3 | High-citation landmark papers for DMT/psychedelics |
| 4 | PubChem | N,N-Dimethyltryptamine | 1 | 1 | Primary chemical identity verification |
| 5 | PubMed | DMT N,N-dimethyltryptamine intravenous human study Strassman subjective effects | 3 | 3 | Foundational human IV DMT studies |
| 6 | PubMed | DMT N,N-dimethyltryptamine pharmacology receptor binding serotonin | 15 | 5 | — |
| 7 | PubMed | DMT N,N-dimethyltryptamine near-death experience consciousness Timmermann | 4 | 4 | Key DMT phenomenology and consciousness papers |
| 8 | PubMed | ayahuasca DMT monoamine oxidase inhibitor metabolism oral bioavailability | 4 | 4 | Core ayahuasca oral DMT pharmacology |
| 9 | WebSearch | DMT synthesis discovery Manske 1931 Szara 1956 first synthesis history | 10 | 1 | Discovery history not in modern PubMed |
| 10 | OpenAlex | Strassman DMT tolerance sequential bolus 1996 | 4 | 3 | Clinical PK data and tolerance characterization |
| 11 | WebSearch | DMT N,N-dimethyltryptamine legal status Schedule I US UK international law | 10 | 1 | Legal status not available in academic databases |
| 12 | PubMed | PMID 30127713 | 1 | 1 | Comprehensive endogenous DMT review with biosynthesis and metabolism data |
| 13 | OpenAlex | DMT entity encounter survey psychedelic beings alien | 5 | 2 | Best evidence for entity encounter phenomenology |
| 14 | PubMed | Riba ayahuasca DMT oral pharmacokinetics humans plasma concentration | 2 | 2 | Human oral DMT PK data via ayahuasca |
| 15 | ClinicalTrials.gov | intravenous DMT fumarate SPL026 depression | 2 | 2 | Active/completed Phase 1 DMT trials |
| 16 | OpenAlex | ayahuasca regular users cognitive safety neuropsychological long-term | 5 | 1 | Key longitudinal safety data for regular DMT/ayahuasca users |
| 17 | PubMed | PMID 23881860 - Barker 2013 pineal gland DMT | 1 | 1 | Evidence for endogenous DMT in pineal gland |
| 18 | ClinicalTrials.gov | DMT dimethyltryptamine depression anxiety phase 2 | 5 | 3 | Ongoing and upcoming DMT clinical trials |
| 19 | PubMed | PMID 39568756 - Chaves 2024 DMT unique features | 1 | 1 | Recent DMT-specific review |
| 20 | Multiple | Tolerance seed data discrepancy - Erne et al. 2026 vs published content | 2 | 1 | Critical safety flag: seed data attribution to Erne may be misattributed |
96 claims by section — every cited sentence, checked against its source
pharmacology24 · 23 ok
Binding affinity at 5-HT2AR is lower than that of lsd but correlates with psychoactive doses in humanssupported
DMT: lower 5-HT2A affinity than LSD... Receptor profiles predict hallucinogenic effects similar to classic serotonergic hallucinogens. j.euroneuro.2016.05.001
In rodent models, 5-HT2A receptor activation is the primary mediator of hallucinogenic behavioral responses (head twitch response), with metabotropic glutamate receptor 2 (mGluR2) contributing a modulatory role.supported
5-HT2A and 5-HT2C as primary mechanisms for hallucinogenic drugs including DMT. mGluR2 contribution investigated. s00213-014-3658-3
A mechanistic advance published in 2023 demonstrated that psychedelics, including DMT, promote cortical neuroplasticity specifically through activation of intracellular 5-HT2ARs located on the Golgi apparatus of cortical neurons — not cell-surface receptorssupported
Intracellular 5-HT2ARs mediate plasticity-promoting properties of psychedelics... Location bias in 5-HT2AR signaling identified. science.adf0435
Barker (2025) has proposed that DMT may serve as the endogenous ligand for these intracellular 5-HT2ARs, providing both a psychedelic mechanism and a natural neuroregulatory function.supported
DMT proposed as endogenous ligand for intracellular 5-HT2A in Golgi. Neuroplastogen role. j.pnpbp.2025.111259
It functions as an endogenous agonist at sigma-1 receptors, where it inhibits voltage-gated sodium channels and produces behavioral effects absent in sigma-1 knockout micesupported
DMT bound to sigma-1 receptors and inhibited voltage-gated sodium ion channels... DMT induced hypermobility in wild-type mice but not sigma-1 knockout mice. science.1166127
Sigma-1 receptor activation by DMT confers neuroprotective effects in ischemic modelssupported
DMT mitigated spreading depolarizations via sigma-1R in rat ischemia model. Reduced apoptotic/ferroptotic cells. j.neuropharm.2021.108612
DMT also agonizes 5-HT1A receptors, which may attenuate some 5-HT2A-mediated hallucinogenic effects, and 5-HT2C receptorspartially supported
5-HT2A and 5-HT2C as primary mechanisms for hallucinogenic drugs including DMT. s00213-014-3658-3
At monoamine transporters, DMT behaves as a substrate (not an inhibitor) at both the serotonin transporter (SERT; K_I = 4.00 ± 0.70 µM) and the vesicular monoamine transporter 2 (VMAT2; K_I = 93 ± 6.8 µM), a mechanism that may facilitate intracellular accumulation at its receptor targetssupported
DMT inhibits [3H]5-HT uptake via SERT with KI of 4.00 ± 0.70 µM. High binding-to-uptake ratios support DMT is a transporter substrate not blocker at both SERT and VMAT2. s00702-009-0308-8
DMT produces a robust agonist response at the human trace amine-associated receptor (TAAR), though the functional significance of TAAR activation remains uncertainsupported
DMT: 5-HT1A/2A/2C partial agonism + sigma-1 + TAAR. s00018-024-05353-6
Claim in pharmacology — inconclusiveinconclusiveworking →
The first detailed human IV pharmacokinetic study (SPL026/DMT fumarate, 10-minute infusion, 24 healthy subjects, doses 9–21.5 mg freebase equivalent) yielded a mean elimination half-life of 9–12 minutes with dose-proportional pharmacokineticssupported
24 healthy subjects received escalating IV DMT (9-21.5 mg freebase as 10-min infusion). Mean elimination half-life 9-12 min. s13318-023-00822-y
Psychological effects begin within seconds of IV bolus administration, peak at 90–120 seconds, and resolve nearly completely within 30 minutessupported
Psychological effects began almost immediately after IV administration, peaked at 90-120 seconds, almost resolved by 30 minutes. archpsyc.1994.03950020022002
Continuous IV infusions (0.6–2.4 mg/min over 120 minutes) in 22 healthy participants confirmed dose-proportional PK, with subjective effects plateauing within 30 minutes and moderate acute tolerance developing during sustained infusion.supported
22 healthy participants received placebo and DMT (0.6-2.4 mg/min) over 120 min infusion. Dose-proportional PK, dose-dependent subjective effects plateau at 30 min. Moderate acute tolerance observed. s41386-024-02041-8
Urinary metabolite profiling reveals a shift from MAO-dependent to CYP-dependent metabolism: unmetabolized DMT accounts for 10% of urinary recovery, DMT-N-oxide for 28%, and indole-3-acetic acid (3-IAA) for 63%supported
Smoked route: fully psychoactive, IAA 63%, DMT-N-oxide 28%, unmetabolized DMT 10%. dta.1685
In a large naturalistic survey (n = 3,778), the median smoked dose was 40 mg with a median experience duration of approximately 10 minutes.supported
Qualitative analysis of 3778 Reddit DMT experiences 2009-2018. Median dose 40mg, median duration 10min. s41598-022-11999-8
Without MAO-A inhibition, oral DMT is essentially inactive: 97% of urinary recovery consists of the MAO-A metabolite 3-IAA, and no psychotropic effects occur at 25 mg oralsupported
Oral route: no psychotropic effects, 97% IAA in urine. dta.1685
In a controlled oral PK study, ayahuasca at DMT doses of 0.6 and 0.85 mg/kg produced Cmax values of 12.14 and 17.44 ng/mL respectively, with median Tmax of 1.5 hours and peak subjective effects at 1.5–2 hourssupported
Cmax for DMT: 12.14 ng/mL (low dose) and 17.44 ng/mL (high dose). Tmax median 1.5h both doses. Peak subjective effects 1.5-2h. pmid:12660312
PBPK models confirm that harmine markedly enhances DMT bioavailability through MAO-A inhibition in liver and lungs.supported
Harmine inhibits DMT metabolism via MAO-A in liver and lungs. kfaf118
PBPK models confirm that harmine markedly enhances DMT bioavailability through MAO-A inhibition in liver and lungs.supported
Harmine markedly enhanced DMT bioavailability and prolonged absorption. j.biopha.2025.118329
The primary metabolic pathway is MAO-A-mediated oxidative deamination to indole-3-acetic acid (3-IAA)supported
DMT metabolized to 3-indole-acetic acid (3-IAA) by MAO... MAO-A inhibition by harmala alkaloids prevents first-pass degradation to 3-IAA. ph13110334
The primary metabolic pathway is MAO-A-mediated oxidative deamination to indole-3-acetic acid (3-IAA)supported
Oral route: no psychotropic effects, 97% IAA in urine. dta.1685
A secondary CYP-mediated pathway produces DMT-N-oxide, with CYP2D6 as the primary enzyme and CYP2C19 contributing. In vitro clearance of DMT is reduced by MAO-A inhibition, CYP2D6 inhibition, and to a lesser extent CYP2C19 inhibitionsupported
In vitro: MAO-A primary clearance, CYP2D6 and CYP2C19 also involved. s13318-023-00822-y
A secondary CYP-mediated pathway produces DMT-N-oxide, with CYP2D6 as the primary enzyme and CYP2C19 contributing. In vitro clearance of DMT is reduced by MAO-A inhibition, CYP2D6 inhibition, and to a lesser extent CYP2C19 inhibitionsupported
In vitro: MAO-A primary clearance, CYP2D6 and CYP2C19 also involved. s13318-023-00822-y
The strong CYP2D6 inhibitors fluoxetine and paroxetine are predicted by PBPK modeling to increase DMT systemic exposure when co-administered with ayahuasca, compounding pharmacodynamic serotonin syndrome risk.supported
PBPK models to predict SSRI (fluoxetine, paroxetine as CYP2D6 inhibitors) coadministration impact on DMT and harmine systemic exposure. Relevant to serotonin syndrome risk. fmolb.2026.1768402
safety23 · 16 ok
Claim in safety — inconclusiveinconclusiveworking →
No human fatalities attributed to DMT alone have been documented in the published literaturesupported
Mildly to rarely severe adverse effects; no dependence. ph13110334
Claim in safety — inconclusiveinconclusiveworking →
SPL026 trial: 24 psychedelic-naive healthy subjects received IV DMT fumarate (9–21.5 mg, 10-minute infusion). No serious adverse events at any dose level.supported
Phase 1 SPL026 trial (NCT04673383). No serious adverse events... Psychedelic-naive healthy participants. fpsyt.2023.1305796
Claim in safety — inconclusiveinconclusiveworking →
Extended state protocol: 11 healthy volunteers received bolus plus 30-minute continuous infusion. Anxiety ratings remained low; heart rate habituated within 15 minutes.supported
Bolus + constant-rate infusion to extend DMT experience for 30 min. Eleven healthy volunteers. Anxiety remained low, HR habituated within 15 min. 02698811231196877
Strassman (1994) documented dose-dependent increases in heart rate, systolic and diastolic blood pressure, rectal temperature, and pupillary diameter following IV administrationsupported
Dose-response data for IV DMT fumarate neuroendocrine, cardiovascular, autonomic, and subjective effects. archpsyc.1994.03950020021001
Oral ayahuasca produces moderate sympathomimetic effects: diastolic blood pressure increased by 9 mmHg at the higher dose, with moderate increases in systolic blood pressure and heart ratesupported
Diastolic BP increased 9 mmHg at high dose; systolic BP and HR moderately increased. pmid:12660312
Oral ayahuasca produces moderate sympathomimetic effects: diastolic blood pressure increased by 9 mmHg at the higher dose, with moderate increases in systolic blood pressure and heart ratepartially supported
Mild sympathomimetic effects... Milder effects on pupil than amphetamine. jcp.0b013e31823607f6
Anxiety and loss-of-control sensations are common at hallucinogenic doses, particularly with IV or smoked administration where onset is measured in secondssupported
Psychological effects began almost immediately after IV administration... loss of control and dissociated state. archpsyc.1994.03950020022002
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
A longitudinal study of 127 regular ayahuasca users (twice monthly or more) versus 115 controls found no evidence of psychological maladjustment, mental health deterioration, or cognitive impairment over one yearsupported
Longitudinal study of 127 regular ayahuasca users vs 115 controls... No evidence of psychological maladjustment, mental health deterioration or cognitive impairment. journal.pone.0042421
During continuous IV infusion, moderate acute tolerance to subjective effects develops despite rising plasma DMT concentrations, consistent with 5-HT2A receptor desensitization during sustained agonist exposuresupported
Plasma DMT increased consistently starting 10 min; psychological effects plateaued suggesting acute psychological tolerance during continuous infusion. 02698811231196877
During continuous IV infusion, moderate acute tolerance to subjective effects develops despite rising plasma DMT concentrations, consistent with 5-HT2A receptor desensitization during sustained agonist exposuresupported
Moderate acute tolerance observed. s41386-024-02041-8
The absence of tolerance with sequential bolus dosing has been reported in Strassman's original research program, a finding consistent with DMT's very short receptor occupancy time (half-life 9–12 minutes) — likely insufficient to trigger receptor internalization between dosessupported
Mean elimination half-life 9-12 min... Rapid peak and clearance. s13318-023-00822-y
Claim in safety — inconclusiveinconclusiveworking →
No physical or psychological dependence has been documented in clinical trials, survey literature, or longitudinal studies of regular ayahuasca userssupported
Mildly to rarely severe adverse effects; no dependence. ph13110334
SSRIs present a dual-mechanism risk with ayahuasca: (1) pharmacokinetic — strong CYP2D6 inhibitors (fluoxetine, paroxetine) increase DMT plasma concentrations; (2) pharmacodynamic — combined serotonin reuptake inhibition and MAO-A inhibition produce dangerous 5-HT accumulationsupported
PBPK models to predict SSRI (fluoxetine, paroxetine as CYP2D6 inhibitors) coadministration impact on DMT and harmine systemic exposure. Relevant to serotonin syndrome risk. fmolb.2026.1768402
Claim in safety — inconclusiveinconclusiveworking →
Concurrent MAOI + serotonergic medications: When DMT is administered via ayahuasca (with beta-carboline MAO inhibitors), any concurrent serotonergic medication — SSRIs, SNRIs, tramadol, St. John's wort — creates potentially fatal serotonin syndrome risk. This interaction is well-characterized mechanistically and confirmed by PBPK modeling.supported
PBPK models to predict SSRI (fluoxetine, paroxetine as CYP2D6 inhibitors) coadministration impact on DMT and harmine systemic exposure. Relevant to serotonin syndrome risk. fmolb.2026.1768402
Cardiovascular disease: Transient but meaningful increases in heart rate and blood pressure are documented in healthy volunteers at both IV and oral doses. Uncontrolled hypertension, unstable angina, recent myocardial infarction, and severe heart failure constitute relative contraindications, though DMT has not been studied in these populations.supported
Dose-response data for IV DMT fumarate neuroendocrine, cardiovascular, autonomic, and subjective effects. archpsyc.1994.03950020021001
Cardiovascular disease: Transient but meaningful increases in heart rate and blood pressure are documented in healthy volunteers at both IV and oral doses. Uncontrolled hypertension, unstable angina, recent myocardial infarction, and severe heart failure constitute relative contraindications, though DMT has not been studied in these populations.supported
Diastolic BP increased 9 mmHg at high dose; systolic BP and HR moderately increased. pmid:12660312
summary10 · 10 ok
Smoked or intravenously administered, DMT produces a complete psychedelic state lasting 5–20 minutes — the shortest of any classical serotonergic psychedelic — with an elimination half-life of 9–12 minutessupported
Mean elimination half-life 9-12 min... Rapid peak and clearance. s13318-023-00822-y
The compound occupies a singular position in psychedelic pharmacology as a putative endogenous neuroregulator: it is biosynthesized in mammalian brain tissue, functions as an endogenous sigma-1 receptor agonist, and may serve as the natural ligand for intracellular 5-HT2A receptorssupported
First report of DMT in rat pineal gland microdialysate using LC/MS/MS. bmc.2981
The compound occupies a singular position in psychedelic pharmacology as a putative endogenous neuroregulator: it is biosynthesized in mammalian brain tissue, functions as an endogenous sigma-1 receptor agonist, and may serve as the natural ligand for intracellular 5-HT2A receptorssupported
Indicates DMT is an endogenous sigma-1 receptor agonist. science.1166127
The compound occupies a singular position in psychedelic pharmacology as a putative endogenous neuroregulator: it is biosynthesized in mammalian brain tissue, functions as an endogenous sigma-1 receptor agonist, and may serve as the natural ligand for intracellular 5-HT2A receptorssupported
DMT proposed as possible endogenous ligand. science.adf0435
DMT acts as a partial agonist at the serotonin 5-HT2A receptor — its primary psychedelic mechanism — with lower binding affinity than lsd but sufficient to produce full hallucinogenic effects at doses ≥0.2 mg/kg IVsupported
DMT: lower 5-HT2A affinity than LSD, interacted with SERT, partial/full 5-HT2A agonist. j.euroneuro.2016.05.001
Critically, neuroplasticity is promoted through activation of intracellular 5-HT2ARs on the Golgi apparatus rather than cell-surface receptorssupported
Intracellular 5-HT2ARs mediate plasticity-promoting properties of psychedelics... Location bias in 5-HT2AR signaling identified. science.adf0435
Secondary targets include sigma-1 receptors and serotonin/vesicular monoamine transporters, where DMT behaves as a substrate rather than an inhibitor.supported
High binding-to-uptake ratios support DMT is a transporter substrate not blocker at both SERT and VMAT2. s00702-009-0308-8
The experience at hallucinogenic doses is characterized by vivid geometric visuals, entity encounters (reported in 45.5% of inhaled experiences), ego dissolution, and features phenomenologically overlapping with near-death experiencessupported
Entity encounters 45.5%. Fractals/patterns dominant visual... Features of mystical experience and ego dissolution common. s41598-022-11999-8
No human fatalities have been attributed to DMT alone, and Phase 1 trials at doses up to 21.5 mg IV report no serious adverse eventssupported
No serious adverse events. 21.5 mg dose most likely to provide intense, tolerated experience. fpsyt.2023.1305796
During continuous IV infusion, moderate acute tolerance develops consistent with 5-HT2A receptor desensitization, though sequential bolus dosing may not produce tolerance due to insufficient receptor occupancy timesupported
Moderate acute tolerance observed. s41386-024-02041-8
pharmacokinetic-detail8 · 8 ok
Good et al. (2023) published the first comprehensive human IV DMT PK characterization using SPL026 (DMT fumarate) administered as a 10-minute infusion to 24 healthy, psychedelic-naive subjects at doses of 9, 12, 14, 18, and 21.5 mg freebase equivalent.supported
24 healthy subjects received escalating IV DMT (9-21.5 mg freebase as 10-min infusion). s13318-023-00822-y
Erne et al. (2025) extended PK characterization to continuous IV infusions (0.6–2.4 mg/min over 120 minutes) in 22 healthy participantssupported
22 healthy participants received placebo and DMT (0.6-2.4 mg/min) over 120 min infusion. s41386-024-02041-8
A novel buccal DMT/harmine formulation (120 mg DMT + 180 mg harmine) achieved plasma Cmax of approximately 33 ng/mL.supported
16 healthy participants received 6 dose combinations of buccal DMT (0-120 mg) and harmine (0-180 mg). Peak DMT Cmax ~33 ng/mL. j.biopha.2025.117908
PBPK modeling by Ribeiro et al. (2026) predicts clinically significant pharmacokinetic interactions between ayahuasca and SSRIs that are strong CYP2D6 inhibitors (fluoxetine, paroxetine), raising both DMT plasma concentrations and serotonin syndrome risksupported
PBPK models to predict SSRI (fluoxetine, paroxetine as CYP2D6 inhibitors) coadministration impact on DMT and harmine systemic exposure. Relevant to serotonin syndrome risk. fmolb.2026.1768402
Riba et al. (2003) characterized oral DMT PK under MAO-A inhibition via ayahuasca:supported
Double-blind placebo-controlled RCT. 18 volunteers with prior psychedelic experience received oral ayahuasca... Cmax for DMT: 12.14 ng/mL (low dose) and 17.44 ng/mL (high dose). pmid:12660312
PBPK models by Wittayakarn et al. (2025) and Abelo et al. (2025) confirm that harmine dramatically enhances DMT bioavailability through MAO-A inhibition in both hepatic and pulmonary first-pass sitessupported
Harmine markedly enhanced DMT bioavailability and prolonged absorption. j.biopha.2025.118329
The dominant pathway is MAO-A-catalyzed oxidative deamination producing indole-3-acetic acid (3-IAA), which accounts for 97% of urinary metabolites after oral administration without MAO inhibitionsupported
DMT metabolized to 3-indole-acetic acid (3-IAA) by MAO... MAO-A inhibition by harmala alkaloids prevents first-pass degradation to 3-IAA. ph13110334
After oral administration (without MAO inhibition), 3-IAA accounts for 97% of recovery, indicating near-complete MAO-A-mediated presystemic clearance.supported
Oral route: no psychotropic effects, 97% IAA in urine. dta.1685
clinical-evidence7 · 6 ok
In 24 psychedelic-naive healthy subjects receiving DMT fumarate by 10-minute IV infusion at doses of 9–21.5 mg freebase equivalent, no serious adverse events occurredsupported
No serious adverse events... Psychedelic-naive healthy participants. fpsyt.2023.1305796
Erne et al. (2025) reported results from continuous IV infusions (0.6–2.4 mg/min over 120 minutes) in 22 healthy participantssupported
22 healthy participants received placebo and DMT (0.6-2.4 mg/min) over 120 min infusion. s41386-024-02041-8
NCT05780216 investigated a buccal formulation combining DMT (120 mg) with harmine (180 mg) in healthy volunteerssupported
16 healthy participants received 6 dose combinations of buccal DMT (0-120 mg) and harmine (0-180 mg). j.biopha.2025.117908
Claim in clinical-evidence — inconclusiveinconclusiveworking →
NCT05780216 investigated a buccal formulation combining DMT (120 mg) with harmine (180 mg) in healthy volunteerssupported
Ayahuasca-inspired DMT/harmine formulation via buccal microcarrier delivery. PK-PD interactions characterized. pyaf001
Pharmacokinetics were dose-proportional with a mean elimination half-life of 9–12 minutessupported
Mean elimination half-life 9-12 min. s13318-023-00822-y
Luan et al. (2024) assessed the psychological and physiological effects of extended DMT states (bolus plus 30-minute continuous infusion) in 11 healthy volunteerssupported
Bolus + constant-rate infusion to extend DMT experience for 30 min. Eleven healthy volunteers. 02698811231196877
history7 · 7 ok
Detection of DMT in human urine during the 1960s and 1970s generated early speculation about a possible role in schizophrenia and endogenous psychosissupported
Historical overview of endogenous DMT research: biosynthesis and metabolism in brain and peripheral tissues, detection in body fluids and brain, sites of action, physiological and therapeutic roles. fnins.2018.00536
In 2013, Barker et al. achieved the first direct detection of DMT in rat pineal gland microdialysate, providing physiological evidence for active endogenous productionsupported
First report of DMT in rat pineal gland microdialysate using LC/MS/MS. bmc.2981
The identification in 2023 of intracellular 5-HT2A receptors as the site of psychedelic-driven neuroplasticity prompted the proposal that DMT may function as the endogenous ligand for these receptorssupported
DMT proposed as endogenous ligand for intracellular 5-HT2A in Golgi. Neuroplastogen role. j.pnpbp.2025.111259
The resulting dose-response studies, published in Archives of General Psychiatry, established the Hallucinogen Rating Scale (HRS) and remain foundational references for DMT's subjective and physiological effectssupported
HRS scale presented. Psychological effects began almost immediately after IV administration, peaked at 90-120 seconds, almost resolved by 30 minutes. archpsyc.1994.03950020022002
Contemporary DMT research accelerated from 2018, led by Timmermann and Carhart-Harris at Imperial College London, who published landmark EEG and combined EEG-fMRI studies of intravenous DMTsupported
13 healthy participants (6F, 7M), IV DMT vs placebo. EEG: marked reduction in alpha/beta oscillations, robust increase in signal diversity. s41598-019-51974-4
Small Pharma's SPL026 program (NCT04673383) completed Phase 1 safety and pharmacokinetic studies in 2023supported
Phase 1 component of Phase I/IIa trial (NCT04673383). 24 healthy subjects received escalating IV DMT. s13318-023-00822-y
As of 2026, multiple Phase 2 trials are active or planned for major depressive disorder and treatment-resistant depression, and novel delivery systems — including buccal formulations combining DMT with harmine and transdermal preparations — are under clinical investigation.supported
Four Phase II studies with 5-MeO-DMT and one with DMT for TRD; two Phase II studies with DMT fumarate for MDD. biomedicines14030506
comparative-pharmacology5 · 5 ok
The 9–12 minute elimination half-life and 5–20 minute subjective experience (IV/smoked) contrast sharply with psilocybin (4–6 hours), lsd (8–12 hours), and mescaline (8–12 hours)supported
Mean elimination half-life 9-12 min... Rapid peak and clearance. s13318-023-00822-y
Ramaekers et al. (2025) have argued that DMT's ultra-short action may offer therapeutic advantages: shorter clinical sessions, reduced staffing requirements, and potentially lower psychological risk from prolonged altered states.supported
Short interventions (15-30 min) safe and tolerated, marked improvement within 24h... Benefits: flexible single-day dosing. appi.ajp.20230890
DMT's unique polypharmacological profile — combining 5-HT2A partial agonism, sigma-1 agonism, monoamine transporter substrate behavior, and TAAR activation — has no direct parallel among classical psychedelics.supported
Review of DMT's unique properties and therapeutic potential. fpsyt.2024.1485337
DMT stands alone among classical psychedelics as a confirmed endogenous compound in mammalian tissuesupported
Review of endogenous DMT brain concentrations in rodents. j.pnpbp.2025.111259
While endogenous production has been suggested for some other tryptamines, only DMT has documented sigma-1 agonism confirmed in knockout models and a plausible role as the natural ligand for intracellular 5-HT2A receptorssupported
Intracellular 5-HT2ARs as therapeutic target; DMT proposed as possible endogenous ligand. science.adf0435
neuroscience5 · 5 ok
Timmermann et al. (2023) conducted the most comprehensive neuroimaging study of DMT to date, combining simultaneous EEG and fMRI in 20 healthy volunteers receiving IV DMTsupported
20 healthy volunteers, within-subjects placebo-controlled. Simultaneous EEG-fMRI during IV 20 mg DMT. pnas.2218949120
Eckernas et al. (2023) developed EEG pharmacokinetic-pharmacodynamic models demonstrating concentration-dependent EEG changes, providing a potential biomarker for clinical dose optimization.supported
Concentration-dependent EEG effects. Relevant for biomarker selection in clinical DMT development. psp4.12933
The sigma-1 receptor provides a parallel neuroprotective pathway: Szabo et al. (2021) demonstrated that DMT attenuated spreading depolarization and neurodegeneration in ischemic rat brain specifically through sigma-1 activation.supported
DMT mitigated spreading depolarizations via sigma-1R in rat ischemia model. Reduced apoptotic/ferroptotic cells. j.neuropharm.2021.108612
Endogenous function: What is the physiological role of endogenous DMT? The discovery of intracellular 5-HT2A receptors inaccessible to serotonin but accessible to DMT suggests a specific neuroregulatory function, but no causal demonstration of endogenous DMT activating these receptors in vivo has been published.supported
Review of endogenous DMT brain concentrations in rodents. Discusses intracellular sigma-1 and 5-HT2A binding. DMT proposed as endogenous ligand for intracellular 5-HT2A in Golgi. j.pnpbp.2025.111259
Dissociability of psychedelic and neuroplastic effects: Can DMT's neuroplastic (therapeutic) effects be achieved at sub-psychedelic doses, or does the subjective experience mediate the therapeutic outcome? Transdermal formulations achieving sub-hallucinogenic plasma levels (60 ng/mL or below) are designed to test this question.supported
77% bioavailability vs IV at sub-hallucinogenic plasma concentrations not exceeding 60 ng/mL. j.ejps.2024.106803
chemistry3 · 3 ok
The freebase exhibits low lipophilicity by experimental determination, with low plasma protein binding consistent with rapid tissue distributionsupported
Low lipophilicity, low plasma protein binding. Rapid peak and clearance. s13318-023-00822-y
Barker et al. (2013) detected DMT in rat pineal gland microdialysate by LC/MS/MS, and Barker (2025) characterized DMT concentrations and distribution across rodent brain regionssupported
First report of DMT in rat pineal gland microdialysate using LC/MS/MS. bmc.2981
The biosynthetic pathway from tryptamine via indolethylamine N-methyltransferase (INMT) has been assumed, though INMT knockout studies suggest alternative enzymatic routes may exist.supported
Rat INMT insufficient for NMT or DMT biosynthesis. Suggests alternative enzymatic pathway for DMT biosynthesis. s41598-023-27538-y
receptor-pharmacology3 · 3 ok
The discovery that psychedelic-driven neuroplasticity occurs through intracellular rather than cell-surface 5-HT2A receptors represents a paradigm shift in understanding DMT's mechanismsupported
Intracellular 5-HT2ARs mediate plasticity-promoting properties of psychedelics. Serotonin does not engage similar plasticity mechanisms. Location bias in 5-HT2AR signaling identified. science.adf0435
Fontanilla et al. (2009) demonstrated DMT's endogenous sigma-1 receptor agonism in a study published in Sciencesupported
Indicates DMT is an endogenous sigma-1 receptor agonist. science.1166127
Szabo et al. (2021) confirmed sigma-1-mediated neuroprotection in a rat cerebral ischemia model, where DMT attenuated spreading depolarization and restrained neurodegeneration.supported
DMT mitigated spreading depolarizations via sigma-1R in rat ischemia model. Reduced apoptotic/ferroptotic cells. j.neuropharm.2021.108612
effects-overview1 · 1 ok
The phenomenological overlap with near-death experiences is unique among classical psychedelics and has been confirmed in placebo-controlled studies.supported
Within-subjects placebo-controlled study... Significant increases in NDE phenomenological features after DMT. Significant overlap with 'actual' NDE experiencers across nearly all features. fpsyg.2018.01424