Clinical TrialParallelMajor Depressive Disorder (MDD)DMTDMTDMTDMTDMTRecruiting

Inhaled DMT for Major Depressive Disorder

This Phase IIb, randomised, double-blind, active-controlled trial (n=140) will evaluate the efficacy and safety of inhaled DMT in adults with major depressive disorder (MDD). It will assess whether a higher-dose inhaled DMT regimen can more rapidly reduce depressive symptoms and suicide risk than a lower-dose active comparator, with primary outcomes focused on change in Montgomery-Åsberg Depression Rating Scale (MADRS) score and incidence of suicidal ideation and behaviour. Participants will be allocated 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, administered via a Volcano Medic 2 vaporiser in two inhalations. Those who do not achieve remission at Day 7 (MADRS >10) will enter an open-label extension and receive a high-dose session on Day 14 (±3 days), while remitters will not be re-dosed; all participants will then be followed for up to 12 months to examine durability of response, safety, functioning and quality of life.

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Target Enrollment
140 participants
Study Type
Phase II interventional
Design
Randomized, quadruple Blind

Detailed Description

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.

Study Arms & Interventions

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.

Interventions

  • DMT15 - 60 mg
    via Inhalation• two inhalations 1 hour apart• 2 doses total

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.

Interventions

  • DMT15 - 60 mg
    via Inhalation• two inhalations 1 hour apart• 2 doses total

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.

Interventions

  • DMT1 - 4 mg
    via Inhalation• two inhalations 1 hour apart• 2 doses total

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

  • DMT15 - 60 mg
    via Inhalation• two inhalations 1 hour apart• 2 doses total
  • DMT1 - 4 mg
    via Inhalation• two inhalations 1 hour apart• 2 doses total

Participants

Ages
18 – ?
Sexes
Male & Female

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

Study Details

Study Team

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