DMT

# Research Output: DMT (N,N-Dimethyltryptamine)

**PSX ID:** PSX-0167 | **Slug:** dmt | **Date:** 2026-05-03
**Provenance ID:** 20fb5d09-b23a-465a-9a55-853a5d73e01d

---

## Chemical Identity

**Verified via PubChem CID 6089 [Ref — database_lookup]:**

| Property | Value | Source |
|---|---|---|
| PubChem CID | 6089 | PubChem (api_verified) |
| Molecular Formula | C₁₂H₁₆N₂ | PubChem CID 6089 |
| Molecular Weight | 188.27 g/mol | PubChem CID 6089 |
| IUPAC Name | 2-(1H-indol-3-yl)-N,N-dimethylethanamine | PubChem CID 6089 |
| InChIKey | DMULVCHRPCFFGV-UHFFFAOYSA-N | PubChem CID 6089 |
| CAS Number | 61-50-7 | Literature standard (unverifiable via API) |
| Chemical Class | Tryptamine / Indoleamine / Substituted tryptamine | Confirmed |

**SMILES:** The brief listed SMILES as missing. Standard confirmed SMILES: `CN(C)CCc1c[nH]c2ccccc12` (indolylethyl-dimethylamine structure). This should be added to the database.

**Notes on seed data discrepancies:**
- PubChem CID, molecular formula, molecular weight, SMILES, and InChIKey were all missing from the brief. All are now verified via PubChem CID 6089.
- The IUPAC name in the brief (`2-(1H-indol-3-yl)-N,N-dimethylethanamine`) matches PubChem exactly.
- No stereogenic centers; DMT is achiral. No active isomer complexity.

**Physical properties** (from literature; no primary source via API — flag as unverified):
- DMT freebase: white crystalline solid, mp ~40–44°C (widely cited; original analytical characterization unverifiable via PubMed)
- DMT fumarate salt (SPL026): water-soluble solid used in clinical trials (James et al. 2024 [Ref 26])
- Lipophilicity: Low (confirmed experimentally, Good et al. 2023 [Ref 25])
- Plasma protein binding: Low — consistent with rapid distribution (Good et al. 2023 [Ref 25])

---

## Pharmacology

### Primary Receptor Targets

**5-HT2A Receptor (primary psychedelic mechanism)**
DMT acts as a partial agonist at the serotonin 2A receptor (5-HT2AR), its primary mechanism for psychedelic effects. Binding affinity at the 5-HT2A receptor is lower than that of LSD but correlates with reported psychoactive doses in humans (Rickli et al. 2016 [Ref 5]). Carbonaro et al. (2015 [Ref 14]) confirmed in rodent models that 5-HT2A receptors are primary mediators of hallucinogenic behavioral effects (head twitch response), with mGluR2 modulation also contributing.

**Location Bias — Intracellular 5-HT2A:**
A critical 2023 *Science* paper (Vargas et al. [Ref 15]) 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 receptors. Serotonin itself cannot access these intracellular receptors. Barker (2025 [Ref 13]) proposes that DMT may be the endogenous ligand for intracellular 5-HT2ARs, which would explain both DMT's psychedelic effects and a natural neuroregulatory role. This represents a significant mechanistic advance that was not reflected in the seed data pharmacology.

**5-HT1A Receptor:**
DMT also binds 5-HT1A receptors. Li et al. (2025 [Ref in PubMed 41446874]) showed cryo-EM structures of related tryptamines at 5-HT1A, confirming conserved binding pocket engagement. 5-HT1A agonism is thought to dampen hallucinogenic effects mediated by 5-HT2A in some contexts (Glatfelter et al. 2024 [Ref — 39636099]).

**Sigma-1 Receptor:**
Fontanilla et al. (2009, *Science* [Ref 3]) demonstrated that DMT is an endogenous sigma-1 receptor agonist. DMT bound sigma-1 receptors, inhibited voltage-gated sodium channels, and induced hypermobility in wild-type but not sigma-1 knockout mice. This established sigma-1 as a pharmacologically relevant DMT target. Su et al. (2009, *Science Signaling* [Ref 4]) elaborated on the hypothetical signaling cascade. Szabó et al. (2021 [Ref 7]) confirmed sigma-1 receptor neuroprotective effects of DMT in a rat ischemia model.

**Serotonin Transporter (SERT):**
Cozzi et al. (2009 [Ref 6]) showed DMT acts as a transporter substrate (not a reuptake blocker) at SERT, with KI of 4.00 ± 0.70 µM for uptake inhibition. The high binding-to-uptake ratio confirms substrate behavior, meaning DMT can enter neurons via SERT. Similarly acts as VMAT2 substrate (KI 93 ± 6.8 µM). This transport mechanism may allow accumulation at intracellular receptor targets.

**Trace Amine-Associated Receptor (TAAR):**
DMT produces a robust agonist response at the human trace amine receptor (Jacob & Presti 2005 [Ref — 15780487]). Egger et al. (2024 [Ref 31]) confirm TAAR activity as a contributing target. The role of TAAR in DMT's psychedelic versus non-psychedelic effects remains uncertain.

**Summary of receptor profile:**
- 5-HT2A: Partial agonist — primary psychedelic mechanism; intracellular > cell-surface
- 5-HT1A: Agonist — may dampen 5-HT2A-mediated effects
- 5-HT2C: Agonist activity confirmed (Carbonaro et al. 2015 [Ref 14])
- Sigma-1: Endogenous agonist (Fontanilla et al. 2009 [Ref 3])
- SERT: Substrate (Cozzi et al. 2009 [Ref 6])
- VMAT2: Substrate (Cozzi et al. 2009 [Ref 6])
- TAAR: Agonist (Jacob & Presti 2005; Egger et al. 2024 [Ref 31])
- No significant dopaminergic or adrenergic activity (Rickli et al. 2016 [Ref 5])

### Pharmacokinetics

**Intravenous (IV) — Human Data:**
Good et al. (2023 [Ref 25]) published the first detailed human IV DMT PK study via 10-min infusion (SPL026/DMT fumarate, NCT04673383), 24 healthy subjects, doses 9–21.5 mg freebase:
- Mean elimination half-life: **9–12 minutes**
- Rapid attainment of peak plasma concentrations with rapid clearance
- Dose-proportional PK across the dose range

Strassman & Qualls (1994 [Refs 1, 2]) showed psychological effects onset essentially immediately after IV injection, peak at 90–120 seconds, nearly fully resolved by 30 minutes.

Erne et al. (2025 [Ref 8]) studied continuous IV infusions (0.6–2.4 mg/min over 120 min) in 22 healthy participants: dose-proportional PK, subjective effects plateau reached within 30 min, moderate acute tolerance to subjective effects observed (see Tolerance section).

**Oral (via Ayahuasca — with MAOI):**
Without MAO-A inhibition, oral DMT is essentially inactive: 97% of urinary recovery after oral ingestion is the MAO-A metabolite indole-3-acetic acid (3-IAA), with no psychotropic effect at 25 mg (Riba et al. 2015 [Ref 34]).

Riba et al. (2003 [Ref 29]) conducted an oral PK study with ayahuasca (harmine + DMT):
- Cmax: 12.14 ng/mL (0.6 mg/kg DMT) and 17.44 ng/mL (0.85 mg/kg)
- Tmax: 1.5 h (median) for both doses
- Peak subjective effects at 1.5–2 h
- Half-life notably longer than IV due to sustained absorption

PBPK models (Wittayakarn et al. 2025 [Ref 20]; Äbelö et al. 2025 [Ref 12]) confirm harmine markedly enhances DMT bioavailability and prolongs absorption via MAO-A inhibition in liver and lungs. Plasma Cmax ~33 ng/mL achievable with 120 mg buccal DMT + 180 mg harmine (Egger et al. 2025 [Ref 10]).

**Smoked:**
Riba et al. (2015 [Ref 34]) showed smoked DMT is fully psychoactive, with shift from MAO-dependent to CYP-dependent metabolism: unmetabolized DMT 10%, DMT-N-oxide 28%, IAA 63% in urine. Lawrence et al. (2022 [Ref 24]) analyzed 3,778 naturalistic smoked experiences: median dose 40 mg, median duration 10 min.

Witowski et al. (2024 [Ref 21]) reported IV half-life extended 20-fold with transdermal delivery, achieving consistent sub-hallucinogenic plasma levels (≤60 ng/mL).

**Metabolism:**
Primary pathway: MAO-A oxidative deamination → indole-3-acetic acid (3-IAA) [Ref 33, 34]
Secondary CYP-mediated: CYP2D6 (primary), CYP2C19 (secondary) → DMT-N-oxide [Ref 25]
In vitro clearance of DMT reduced by MAO-A inhibition, CYP2D6 inhibition, and to lesser extent CYP2C19 inhibition (Good et al. 2023 [Ref 25]).

**CYP interactions:** SSRIs fluoxetine and paroxetine are strong CYP2D6 inhibitors that would increase DMT systemic exposure when co-administered with ayahuasca. Ribeiro et al. (2026 [Ref 45]) developed PBPK models predicting these pharmacokinetic interactions; this also raises pharmacodynamic serotonin syndrome risk.

---

## History

**First Synthesis (1931):**
DMT was first synthesized by Canadian chemist Richard Manske in 1931. The compound was not assessed for human pharmacological effects at that time [Ref 47 — web_retrieved].

**Natural Product Isolation (1946):**
Brazilian chemist and microbiologist Oswaldo Gonçalves de Lima isolated an alkaloid from the root bark of *Mimosa tenuiflora* in 1946. It was not until 1959 that this compound was unequivocally identified as DMT [Ref 47].

**First Human Administration (1956):**
Hungarian chemist and psychiatrist Stephen Szára conducted the first human DMT study in 1956, administering synthetic DMT by intramuscular injection to 20 volunteers (0.7 mg/kg). He reportedly sought LSD from Sandoz but was refused; DMT was his alternative research target. Effects at medium doses were described as similar to mescaline and LSD, including visual illusions and hallucinations, distortion of body image, speech disturbances, and mood changes [Ref 47 — web_retrieved; unverified primary source].

**Discovery of Endogenous Occurrence:**
DMT was detected in human urine in the 1960s–1970s, prompting speculation about a role in schizophrenia and endogenous psychosis (reviewed in Barker 2018 [Ref 28]). Much early research proved inconclusive. In 2009, Fontanilla et al. (*Science* [Ref 3]) identified DMT as an endogenous sigma-1 receptor regulator — the most impactful mechanistic finding in decades. In 2013, Barker et al. [Ref 41] detected DMT in rat pineal gland microdialysate for the first time.

**Strassman's University of New Mexico Program (1990–1995):**
Rick Strassman conducted the first authorized human DMT research in decades at UNM, administering IV DMT to approximately 60 volunteers. The resulting Hallucinogen Rating Scale (HRS) remains a primary psychometric instrument. Strassman's findings were published in *Archives of General Psychiatry* (1994 [Refs 1, 2]) and later summarized in the 2001 book *DMT: The Spirit Molecule* [Ref 48], which coined the popular name.

**Prohibition and Scheduling:**
- 1971: DMT placed in Schedule I of the US Controlled Substances Act at the law's passage.
- 1971: UN Convention on Psychotropic Substances lists DMT as Schedule I internationally.
- Recent: Decriminalization in Oregon (2020) and Colorado (2022) for personal use [Ref 39].

**Modern Research Renaissance (2018–present):**
Timmermann and Carhart-Harris at Imperial College London published landmark EEG (2019 [Ref 36]) and EEG-fMRI (2023 [Ref 35]) studies of IV DMT. Small Pharma's SPL026 program (NCT04673383) completed Phase 1 in 2023. As of 2026, multiple Phase 2 trials are active or planned.

---

## Subjective Effects

All controlled human IV data are from Strassman et al. (1994 [Refs 1, 2]), Timmermann et al. (2018 [Ref 23], 2019 [Ref 36], 2023 [Ref 35]), Luan et al. (2024 [Ref 9]), and Erne et al. (2025 [Ref 8]).

Naturalistic inhaled DMT phenomenology is documented in Lawrence et al. (2022 [Ref 24], n=3,778 reports) and Michael et al. (2021 [Ref 40]).

### Time Course

**Intravenous (bolus):**
- Onset: essentially immediate (within seconds)
- Peak: 90–120 seconds after administration (Strassman et al. 1994 [Ref 1])
- Resolution: nearly complete by 30 minutes
- Duration of hallucinogenic state: 5–20 minutes total

**Smoked (inhaled):**
- Onset: 15–45 seconds
- Peak: 2–5 minutes
- Total duration: median ~10 minutes (Lawrence et al. 2022 [Ref 24])

**Oral (ayahuasca — with MAOI):**
- Onset: 20–45 minutes
- Peak: 1.5–2 hours (Riba et al. 2003 [Ref 29])
- Duration: 4–5 hours (Egger et al. 2025 [Ref 10])

### Dose-Dependent Subjective Effects

At **threshold/low doses** (≤0.1 mg/kg IV), primarily affective and somaesthetic effects; 0.1 mg/kg elicited the least desirable effects in Strassman's study (Strassman et al. 1994 [Ref 1]).

At **hallucinogenic doses** (≥0.2 mg/kg IV), full psychedelic effects emerge: "A rapidly moving, brightly colored visual display of images. Loss of control, associated with a brief but overwhelming rush, led to a dissociated state, where euphoria alternated or coexisted with anxiety. These effects completely replaced subjects' previously ongoing mental experience and were more vivid and compelling than dreams or waking awareness" (Strassman et al. 1994 [Ref 1]).

At **higher continuous infusion doses** (2.4 mg/min), greater anxious ego dissolution and significant anxiety compared to 1.8 mg/min (Erne et al. 2025 [Ref 8]). A ceiling effect for "good drug effect" was observed at 1.8 mg/min.

### Visual Effects
- Fractals, shapes, and patterns: most common visual content (32.6%) in naturalistic reports (Lawrence et al. 2022 [Ref 24])
- Vivid colors (25.2%)
- Alternate/higher dimensions described (25.2%)
- EEG: alpha and beta band power suppression, emergence of delta/theta correlating with peak visual experience (Timmermann et al. 2019 [Ref 36])

### Entity Encounters
Entity encounters were reported in 45.5% of 3,778 naturalistic inhaled experiences (Lawrence et al. 2022 [Ref 24]). Entity phenotypes: predominantly feminine (24.2%), deities (17.0%), aliens (16.3%), creature-based (9.2%, including reptilian/insectoid), mythological beings (8.4%), jesters (6.5%).

Entity interactions: predominantly positive and benevolent (34.9%), companion/pedagogical (32.4%). The DMT world's architectural features: alternate dimensions, rooms (including "waiting room"), tunnels.

Timmermann et al. (2018 [Ref 23]) demonstrated in a placebo-controlled study (n=13) that IV DMT significantly increased NDE (near-death experience) phenomenological features vs. placebo, with near-complete overlap with actual NDE experiencers. NDE scores correlated with ego dissolution and mystical-type experiences.

### Transpersonal Effects
Mystical and ego-dissolution experiences are common and documented in controlled studies. Timmermann et al. (2021 [Ref — 34815421]) showed psychedelics including DMT induce lasting shifts from physicalist to panpsychist metaphysical beliefs, persisting ≥6 months.

### Neural Correlates
Timmermann et al. (2023, PNAS [Ref 35]) in the most comprehensive neuroimaging study (n=20 healthy volunteers, EEG-fMRI):
- Robust increases in global functional connectivity (GFC)
- Network disintegration and desegregation
- Compression of the principal cortical gradient
- GFC × subjective intensity correlated with 5-HT2AR PET maps
- Predominant action on transmodal association cortex (species-specific psychological functions)

---

## Safety & Toxicity

### Acute Toxicity
No LD50 data in humans. No human fatalities attributed to DMT alone have been documented in the published literature (reviewed in Melani et al. 2026 [Ref 32]; Brito-da-Costa et al. 2020 [Ref 33]).

Phase 1 trials provide the best safety data:
- **SPL026 (Good et al. 2023 [Ref 25]; James et al. 2024 [Ref 26]):** 24 psychedelic-naive healthy subjects, doses 9–21.5 mg IV (10-min infusion). No serious adverse events. All doses safe and well tolerated.
- **Luan et al. (2024 [Ref 9]):** 11 healthy volunteers, bolus + continuous infusion (30-min extended state). Anxiety ratings remained low, HR habituated within 15 min, indicating psychological and physiological safety of extended DMT.
- **Erne et al. (2025 [Ref 8]):** 22 healthy participants, up to 2.4 mg/min continuous infusion for 120 min. No serious adverse events. Dose 2.4 mg/min induced greater anxious ego dissolution vs 1.8 mg/min; 1.8 mg/min identified as optimal for good effects without excess anxiety.

### Cardiovascular Effects
The primary acute physiological risk is transient cardiovascular activation:
- Strassman & Qualls (1994 [Ref 2]) documented dose-dependent increases in heart rate, blood pressure, and pupillary dilation.
- Riba et al. (2003 [Ref 29]): oral ayahuasca increased diastolic BP by 9 mmHg at high dose; systolic BP and HR moderately increased.
- Dos Santos et al. (2011 [Ref 30]): moderate sympathomimetic effects.
- Cardiovascular effects are transient, resolving with the drug effect.

⚠️ **Safety Flag:** Cardiovascular disease (uncontrolled hypertension, unstable angina, recent MI, severe heart failure) is a relative contraindication per the brief. These cardiovascular effects are well-documented but have not been studied in patient populations with pre-existing cardiac conditions.

### Psychological Risks
Anxiety and loss-of-control sensations are common at hallucinogenic doses, particularly with IV administration (Strassman et al. 1994 [Ref 1]). At very high continuous infusion doses, significant anxiety and ego dissolution were more prevalent (Erne et al. 2025 [Ref 8]).

⚠️ **Safety Flag:** DMT is known to activate 5-HT2A pathways, which may trigger or exacerbate mania in individuals with bipolar disorder. This is an absolute contraindication in the brief; no published clinical data specifically on bipolar I patients exist — flag as class-based inference.

### Long-term Safety (Ayahuasca Users)
Bouso et al. (2012 [Ref 43]) conducted a longitudinal study of 127 regular ayahuasca users (≥twice/month) vs. 115 controls over one year:
- No evidence of psychological maladjustment, mental health deterioration, or cognitive impairment
- Users scored better on Stroop, Wisconsin Card Sorting Test, and Letter-Number Sequencing
- Higher wellbeing and life attitude scores maintained at 1-year follow-up

### Organ Toxicity
The brief states cardiovascular as the only organ affected. This is consistent with published evidence — no hepatotoxicity, nephrotoxicity, or neurotoxicity documented. The seed data's toxicity characterization is adequately supported.

---

## Harm Reduction

### Route-Specific Risks
- **Smoked/inhaled:** Respiratory irritation from burning DMT; consider vaporization; no pulmonary toxicity data available. Onset within 30–45 seconds means the window for deciding not to proceed is extremely short once inhalation has begun.
- **Intravenous:** Reserved for clinical/research settings only. Infection risk, dosing precision required.
- **Oral (ayahuasca):** Requires MAO inhibition — all serotonergic medications contraindicated (absolute). Nausea and vomiting common.

### Contraindications (from seed data — published evidence support noted)
- **MAO inhibitors + serotonergic medications:** Potentially fatal serotonin syndrome. Well-established mechanism (Brito-da-Costa et al. 2020 [Ref 33]; Ribeiro et al. 2026 [Ref 45]). ABSOLUTE contraindication.
- **Cardiovascular disease:** Transient but meaningful HR and BP increases documented in controlled studies (Strassman 1994 [Ref 2]; Riba 2003 [Ref 29]). RELATIVE contraindication.
- **Bipolar I disorder:** 5-HT2A agonism may trigger mania. Based on class pharmacology, not DMT-specific data. ABSOLUTE per brief.
- **Seizure disorders:** Particularly when combined with lithium. DMT + lithium combination is listed as dangerous in the database. Mechanism: lithium lowers seizure threshold; DMT may further reduce it. No specific DMT+lithium human data found in literature.
- **Pregnancy/breastfeeding:** No data; precautionary absolute contraindication.

### Testing and Identification
DMT freebase can be identified with Ehrlich reagent (turns purple/violet — characteristic of indoles). Mecke and Simon's reagents provide additional confirmation. For harm reduction, reagent testing can verify presence of indole structures but cannot confirm dose or purity.

### Set and Setting
The intensity of DMT experiences and rapid onset (particularly smoked) makes psychological preparedness critical. The brief duration does not diminish the intensity — experiences can be profoundly overwhelming. Clinical trials use psychological support protocols throughout all phases (James et al. 2024 [Ref 26]).

---

## Tolerance & Dependence

### Tolerance — ⚠️ FLAG: Seed Data Discrepancy

The seed data states: *"Repeated IV bolus doses within a single session do not produce tolerance (Erne et al. 2026)"*

**Discrepancy found in research:**
PMID 39702577 (Erne et al., published 2025 in Neuropsychopharmacology) studied **continuous IV infusions** (not repeated bolus doses) and explicitly states: *"We observed moderate acute tolerance to acute effects of DMT."* This paper does NOT confirm absence of tolerance with bolus dosing.

The claim about no tolerance with sequential bolus doses originates from Strassman's original 1990–1995 UNM research program (referenced in [Ref 48], Strassman 2001), but no separate published primary paper on this specific tolerance finding was identified in the literature search. The attribution "Erne et al. 2026" in the seed data appears to be a misattribution or error.

**What is well-established from published literature:**
- Continuous IV infusion → moderate acute psychological tolerance, despite rising plasma concentrations (Luan et al. 2024 [Ref 9]; Erne et al. 2025 [Ref 8]). This is consistent with 5-HT2A receptor desensitization during sustained agonist exposure.
- The absence of tolerance with sequential bolus doses is consistent with DMT's very short receptor occupancy time (half-life 9–12 min per Good et al. 2023 [Ref 25]) — insufficient to trigger receptor internalization — but specific published evidence confirming this effect in a controlled sequential bolus study was not identified in this literature search.

**⚠️ Editorial action required:** Verify source for "repeated bolus dosing = no tolerance" claim. The tolerance half-life and full reset values in the seed data (1 hour) may be approximately correct given the 9–12 min half-life, but the specific Erne et al. citation is likely erroneous.

### Cross-Tolerance
Cross-tolerance with other 5-HT2A agonists (LSD, psilocybin, mescaline, 5-MeO-DMT) is expected via shared receptor mechanism. No direct DMT-specific cross-tolerance study was found; this is class-based inference. Flag this as unverified against a DMT-specific primary source.

### Dependence
No physical or psychological dependence documented in clinical trials, survey literature, or observational studies of regular ayahuasca users (Bouso et al. 2012 [Ref 43]; Brito-da-Costa et al. 2020 [Ref 33]). The seed data dependence characterization is well-supported. DMT does not produce significant dopaminergic reward pathway activation at psychedelic doses — consistent with absence of addiction potential.

---

## Interactions

### MAO Inhibitors (ABSOLUTE CONTRAINDICATION)
Concurrent MAO inhibitor use with DMT (or any serotonergic medication during ayahuasca-MAO inhibitor combination) constitutes a risk for potentially fatal serotonin syndrome. The mechanism:
- MAO-A inhibitors dramatically increase DMT plasma exposure (Wittayakarn et al. 2025 [Ref 20])
- Combined with other serotonergic agents, 5-HT accumulation can precipitate serotonin syndrome
- Ribeiro et al. (2026 [Ref 45]) PBPK models show SSRIs (especially fluoxetine, paroxetine as CYP2D6 inhibitors) also increase DMT exposure when co-administered

### SSRIs and SNRIs
- Pharmacokinetic interaction: Strong CYP2D6 inhibitors (fluoxetine, paroxetine) increase DMT plasma concentrations (Ribeiro et al. 2026 [Ref 45])
- Pharmacodynamic interaction: Reduced psychedelic effects expected due to 5-HT2A receptor downregulation/desensitization with chronic SSRI use
- Combined MAOI (from ayahuasca) + SSRI is the most dangerous scenario: serotonin syndrome risk

### Lithium
Listed as "dangerous" in the database. The proposed mechanism: lithium lowers seizure threshold; combination with DMT (which reduces seizure threshold per the brief's effects taxonomy) may precipitate seizures. No published primary data specific to DMT+lithium combination was found. This appears to be a class effect shared with all serotonergic psychedelics + lithium combinations, for which case reports exist (not specific to DMT). ⚠️ Flag: dangerous rating is class-based inference, not DMT-specific evidence.

### Tramadol
Listed as "dangerous" in the database. Mechanism: tramadol is a weak MAOI and serotonin/norepinephrine reuptake inhibitor; combination with DMT (particularly oral route with beta-carboline MAOIs) could precipitate serotonin syndrome. ⚠️ Flag: dangerous rating appears to be class-based inference; no DMT+tramadol-specific published data found.

### Cannabis / Synthetic Cannabinoids
Listed as "unknown" in the database. No published data on DMT + cannabis pharmacodynamic interactions found. Flag as data gap.

---

## Legal Status

**United States:**
DMT is a Schedule I controlled substance under the Controlled Substances Act, placed in Schedule I at the law's enactment in 1971 [Ref 39]. Manufacture, distribution, possession, and purchase are federally illegal without DEA authorization. Exceptions exist for religious use (e.g., ayahuasca-using churches granted exemptions). Oregon (2020) and Colorado (2022) have removed criminal penalties for personal possession [Ref 39 — web_retrieved].

**United Kingdom:**
Class A controlled drug under the Misuse of Drugs Act 1971.

**Canada:**
Schedule III under the Controlled Drugs and Substances Act (CDSA). Religious exemptions exist.

**European Union:**
Controlled at the national level in most EU member states. Scheduling varies by country; generally illegal without authorization.

**Australia:**
Schedule 9 prohibited substance (Therapeutic Goods Administration).

**United Nations:**
Schedule I under the 1971 Convention on Psychotropic Substances. International trade requires strict controls; use restricted to scientific research.

**Brazil:**
Ayahuasca (which contains DMT) was legally sanctioned for religious use by Brazilian federal authorities in 2010. Isolated DMT is generally still controlled.

*Source: Web-retrieved [Ref 39]; not verifiable via academic API*

---

## Clinical Trials

### Completed Trials

| NCT | Title | Status | Phase | Sponsor | Notes |
|---|---|---|---|---|---|
| NCT04353024 | Effects of Dimethyltryptamine in Healthy Subjects | Completed | Phase 1 | University Hospital Basel | IV DMT PK/PD in healthy subjects |
| NCT04640831 | Safety of GH001 in Healthy Volunteers | Completed | Phase 1 | GH Research Ireland | Inhaled DMT formulation |
| NCT04673383 | SPL026 (DMT Fumarate) in Healthy Subjects and MDD Patients | Completed | Phase 1 | Small Pharma Ltd | Key PK study; Good et al. 2023 [Ref 25]; James et al. 2024 [Ref 26] |
| NCT05553691 | SPL026 With or Without SSRIs in Participants With MDD | Completed | Phase 1 | Small Pharma Ltd | CYP2D6 interaction assessment |
| NCT02914769 | Antidepressant Effects of Ayahuasca in Treatment Resistant Depression | Completed | Phase 1 | UFRN (Brazil) | Palhano-Fontes 2018 [Ref 19]; first RCT of DMT-containing preparation for TRD |
| NCT05780216 | Mindfulness and Psychedelics | Completed | Early Phase 1 | Milan Scheidegger | DMT + harmine buccal formulation; Egger et al. 2025 [Ref 10]; Äbelö et al. 2025 [Ref 12]; Mueller et al. 2024 [Ref 11] |

### Active / Recruiting / Planned Trials

| NCT | Title | Status | Phase | Sponsor | Notes |
|---|---|---|---|---|---|
| NCT04711915 | Fixed Order, Open-Label, Dose-Escalation Study of DMT in Humans | Active, Not Recruiting | Phase 1 | Yale University | Depression, Deepak D'Souza's group |
| NCT06671977 | Study of Safety, Tolerability, Electrophysiological Effects and Efficacy of DMT in Humans | Recruiting | Phase 1 | Deepak C. D'Souza | Electrophysiology + depression |
| NCT06258031 | PsilOCD: A Pharmacological-Challenge Feasibility Study | Completed | Phase 1 | Imperial College London | DMT as pharmacological probe for OCD |
| NCT05804708 | Phase 2 Clinical Trial of GH001 in Postpartum Depression | Terminated | Phase 2 | GH Research Ireland | Inhaled DMT for PPD; terminated |
| NCT07562191 | Inhaled DMT for Major Depressive Disorder | Not Yet Recruiting | Phase 2 | UFRN (Brazil) | First Phase 2 for DMT specifically in MDD |

**Key Pipeline Note (Melani et al. 2026 [Ref 32]):** As of early 2026, there are reportedly four Phase 2 studies of 5-MeO-DMT and one with DMT for TRD, plus two Phase 2 studies with DMT fumarate for MDD. These additional Phase 2 studies were not all captured in the ClinicalTrials.gov search and should be verified.

---

## Community Feedback Analysis

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

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## Gaps & Flags

### 🔴 Safety-Critical Flags

1. **Tolerance citation discrepancy (HIGH PRIORITY):** The seed data attributes "no tolerance with repeated IV bolus doses" to *Erne et al. 2026* (PMID 39702577). This paper actually studied continuous infusion and found *moderate* tolerance. The bolus tolerance claim originates from Strassman's 1990–1995 program, not Erne. The seed data contains an incorrect citation. **Recommend:** Correct the Erne citation; note tolerance mechanism language is accurate but citation is wrong.

2. **Lithium interaction mechanism:** The "dangerous" classification for DMT + lithium is a class-based inference (shared with LSD + lithium case reports); no DMT + lithium-specific published data found. Should be flagged as class inference in the article.

3. **Tramadol interaction:** "Dangerous" classification is based on tramadol's weak MAOI/serotonergic activity + theoretical serotonin syndrome risk; no DMT + tramadol primary data found.

4. **Cardiovascular safety in at-risk populations:** No published data on DMT administration in individuals with pre-existing cardiovascular disease. The relative contraindication is inferred from documented transient cardiovascular activation in healthy volunteers.

5. **Bipolar I contraindication:** No DMT-specific data; absolute contraindication is class-based inference from 5-HT2A agonism and clinical experience with other serotonergic psychedelics.

### 🟡 Data Gaps

6. **SMILES in database:** Missing from the brief — confirmed SMILES is `CN(C)CCc1c[nH]c2ccccc12`. Should be added to DB.

7. **PubChem CID in database:** Missing from the brief — confirmed as 6089. Should be added.

8. **Molecular formula and weight:** Missing from the brief — confirmed C₁₂H₁₆N₂, 188.27 g/mol.

9. **Strassman tolerance primary source:** No published primary paper was found specifically documenting the absence of tolerance with sequential bolus IV doses. Strassman's book [Ref 48] references this but is not peer-reviewed primary data. This is a gap for the tolerance section.

10. **Davis entity encounter survey:** The well-cited Davis et al. 2020 survey on entity encounter experiences (Journal of Psychopharmacology) was not locatable via PMID in the PubMed API during this search session. The entity encounter data is instead supported by Lawrence et al. (2022 [Ref 24], Scientific Reports, n=3,778).

11. **Cross-tolerance:** The claim that DMT shows cross-tolerance with LSD, psilocybin, mescaline, and 5-MeO-DMT is expected from shared 5-HT2A mechanism but was not found in a DMT-specific published study. Flag as class inference.

12. **Physical properties (melting point, solubility):** No primary source for DMT freebase mp ~40–44°C was located via API. Widely cited in literature but original characterization is pre-digital.

13. **CAS number 61-50-7:** Standard CAS for DMT freebase; not verifiable via the PubMed/Crossref APIs used.

14. **Endogenous DMT in humans:** Evidence in rodents is solid (Barker et al. 2013 [Ref 41]). The biosynthesis pathway via INMT is well-characterized mechanistically (Coutinho et al. 2023), but Glynos et al. (2023 [Ref 38]) showed INMT may not be the essential biosynthetic enzyme in rats — suggesting alternative pathways. The endogenous DMT hypothesis remains scientifically active but not fully resolved.

15. **Phase 2 clinical trials:** Melani et al. (2026 [Ref 32]) reference Phase 2 trials for DMT and 5-MeO-DMT in TRD/MDD, but not all trials were captured in ClinicalTrials.gov search. Generation agent should perform additional trial registry search before finalizing clinical section.

16. **Primary ROA in database:** Brief lists "Primary ROA" as blank. Based on current clinical research focus and historical use, smoked is the most common recreational ROA; IV is the research/clinical standard. The article should note both without designating a primary.

### 🟢 Seed Data Confirmed Accurate

- Chemical class: Indole, Indoleamine, Tryptamine — confirmed
- Pharmacological class: 5-HT2A/1A agonist, sigma-1 agonist — confirmed  
- Dose ranges (smoked, IV, oral) — broadly consistent with Strassman 1994 and Riba 2003
- Duration data — consistent with published PK and phenomenology studies
- Dependence data — confirmed: no physical or psychological dependence documented
- Toxicity data: negligible acute/chronic, cardiovascular primary — confirmed
- Contraindications — all biologically plausible; most confirmed by class pharmacology
- Known interactions with lithium and tramadol as "dangerous" — class-based but appropriate conservative rating