Randomized, Double-Blind, Placebo-Controlled Phase IIb Trial of Inhaled N,N-Dimethyltryptamine (DMT) for Major Depressive Disorder

Official Summary

This Phase 2b, randomized, double-blind, active-controlled clinical trial will evaluate the efficacy and safety of inhaled N,N-dimethyltryptamine (DMT) in adults with Major Depressive Disorder (MDD). The study will test whether inhaled DMT can rapidly reduce depressive symptoms and suicide risk compared with a low-dose active comparator. A total of 140 participants will be randomized 1:1 to receive either 15 mg followed 1 hour later by 60 mg of inhaled DMT, or 1 mg followed 1 hour later by 4 mg of inhaled DMT. Participants who do not achieve remission at Day 7 will enter an open-label extension and receive a high-dose DMT session on Day 14 (±3 days). All participants will be followed for up to 12 months to evaluate the durability of response, safety, functioning, and quality of life.

Eligibility Requirements

• Minimum Age: 18 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: QUADRUPLE
• Enrollment: 140 participants

Study Arms

• High-Dose DMT → Remitters (No Re-dosing) (EXPERIMENTAL)
  Participants randomized to the high-dose DMT group (15 mg followed by 60 mg on Day 0) who achieve remission at Day 7 (MADRS ≤10) receive no further dosing and enter long-term follow-up.
• High-Dose DMT → Non-Remitters (Open-Label Re-dosing) (EXPERIMENTAL)
  Participants randomized to the high-dose DMT group (15 mg followed by 60 mg on Day 0) who do not achieve remission at Day 7 (MADRS \>10) receive an additional open-label high-dose session (15 mg followed by 60 mg) on Day 14 (±3 days), followed by long-term follow-up.
• Low-Dose DMT → Remitters (No Re-dosing) (ACTIVE_COMPARATOR)
  Participants randomized to the low-dose DMT group (1 mg followed by 4 mg on Day 0) who achieve remission at Day 7 (MADRS ≤10) receive no further dosing and enter long-term follow-up.
• Low-Dose DMT → Non-Remitters (Open-Label Re-dosing) (ACTIVE_COMPARATOR)
  Participants randomized to the low-dose DMT group (1 mg followed by 4 mg on Day 0) who do not achieve remission at Day 7 (MADRS \>10) receive an open-label high-dose session (15 mg followed by 60 mg) on Day 14 (±3 days), followed by long-term follow-up.

Interventions

• DRUG: N,N-Dimethyltryptamine (15 mg + 60 mg) — Inhaled N,N-dimethyltryptamine (DMT) administered via a Volcano Medic 2 vaporizer in two inhalations 1 hour apart, using a high-dose regimen (15 mg + 60 mg).
• DRUG: N,N-Dimethyltryptamine (1 mg + 4 mg) — Inhaled N,N-dimethyltryptamine (DMT) administered via a Volcano Medic 2 vaporizer in two inhalations 1 hour apart, using a low-dose regimen (1 mg + 4 mg).

Primary Outcomes

• Change from Baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score (Antidepressant efficacy) (Baseline and Day 7 (D7) after the dosing session)
• Incidence of Suicidal Ideation and Behavior as Assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) (Day 1 post-intervention)

Secondary Outcomes

• Change from Baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score (Baseline (pre-DMT session), 150 minutes post-DMT session (Day 0), Day 1, Day 7, Day 14, 1 month, 3 months, and 12 months post-intervention)
• Number and proportion of adverse events (AEs) (Baseline (pre-DMT session), 150 minutes post-DMT session (Day 0), Day 1, Day 7, Day 14, 1 month, 3 months, and 12 months post-intervention)
• Incidence of Suicidal Ideation and Behavior as Assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) (Baseline (pre-DMT session), 150 minutes post-DMT session (Day 0), Day 1, Day 7, Day 14, 1 month, 3 months, and 12 months post-intervention)
• Change from Baseline in the Montgomery-Åsberg Depression Rating Scale - Suicidal Ideation (MADRS-SI, Item 10) Score (Antisuicidal efficacy) (Baseline (pre-DMT session), 150 minutes post-DMT session (Day 0), Day 1, Day 7, Day 14, 1 month, 3 months, and 12 months post-intervention)
• Change from Baseline in the Beck Scale for Suicide Ideation (BSI) Total Score (Baseline (pre-DMT session), 150 minutes post-DMT session (Day 0), Day 1, Day 7, Day 14, 1 month, 3 months, and 12 months post-intervention)

Eligibility Criteria

Inclusion Criteria:

* 18 years or older, capable of making decisions, and able to provide informed consent.
* Major Depressive Disorder (MDD) according to DSM-5 criteria
* Current depressive episode of moderate to severe intensity
* Episode duration of at least two weeks
* Baseline MADRS score ≥ 20
* No treatment changes (including antidepressants) in the 4 weeks prior to the study
* Abstain from psychedelics ≥14 days before dosing (D0) and during the 12-month follow-up

Exclusion criteria:

* Major cardiac, hepatic, or renal disease; unstable cardiovascular conditions
* Uncontrolled hypertension, QTc prolongation, arrhythmias, or valvular disease COPD or asthma
* Severe obesity, uncontrolled diabetes, coagulopathy, thyroid disease, or glaucoma
* Neurological risk (e.g., aneurysm, ↑ICP, epilepsy/seizures, severe disorders)
* MAO deficiency or history of serotonin syndrome
* Pregnant, breastfeeding, positive test, or no effective contraception
* Secondary depression
* Cluster B personality disorders (incl. borderline with ≥2 suicidal behaviors in past 12 months) or poor therapeutic rapport
* Psychotic disorders, MDD with psychotic features, or first-degree family history of psychosis/bipolar disorder
* Mania/hypomania (YMRS ≥8)
* OCD, dissociative disorders, active PTSD, or decompensated eating disorders
* Moderate-severe use disorder (past 6 months; except nicotine/caffeine)
* Lifetime ketamine, PCP, psychedelics, or MDMA use disorder
* Current use of MAO inhibitors, unless discontinued at least 14 days prior to dosing
* Psychedelic trial participation in past 12 months
* Cognitive impairment affecting valid assessment

Trial Locations

• Hospital de Saúde Mental Professor Frota Pinto, Fortaleza, Ceará, Brazil
• Complexo Hospitalar Universitário Professor Edgard Santos, Federal University of Bahia (HUPES-UFBA), Salvador, Estado de Bahia, Brazil
• Instituto de Psiquiatria da Universidade Federal do Rio de Janeiro (IPUB-UFRJ), Rio de Janeiro, Rio de Janeiro, Brazil
• Hospital Universitário Onofre Lopes - HUOL - UFRN, Natal, Rio Grande do Norte, Brazil
• Instituto de Psiquiatria - Hospital das Clínicas - IPq - HC - USP, São Paulo, São Paulo, Brazil

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