Overview
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.
Description
Major depressive disorder (MDD) is a common and disabling condition associated with high functional burden, incomplete response to standard antidepressant treatments, and persistent suicide risk. Current pharmacological treatments often require weeks to months to achieve meaningful benefit and are limited by delayed onset, side effects, and non-response in a substantial proportion of patients. Other interventions, including esketamine and electroconvulsive therapy, may provide benefit in selected cases but present limitations related to durability, logistics, invasiveness, or tolerability.
N,N-dimethyltryptamine (DMT) is a classic serotonergic psychedelic with rapid onset and short duration of action when administered by inhalation, with acute effects typically lasting about 10 to 20 minutes. Prior studies conducted by the study group suggested that inhaled DMT has a favorable safety and tolerability profile and may produce rapid antidepressant and antisuicidal effects.
This study is a multicenter Phase 2b clinical trial designed in 2 stages. In Stage 1, participants are randomized 1:1 in a double-blind parallel-group design to receive either a higher-dose inhaled DMT regimen (15 mg followed 1 hour later by 60 mg) or a lower-dose inhaled DMT regimen used as an active comparator (1 mg followed 1 hour later by 4 mg). The total planned sample size is 140 randomized participants.
Participants who do not achieve remission at Day 7, defined in the protocol as MADRS \>10, enter Stage 2, an open-label extension in which all non-remitters receive the higher-dose DMT regimen on Day 14 (±3 days). The study will also explore the clinical effects of re-dosing among non-remitters from both initial treatment groups.
The trial recruits adults with DSM-5 MDD and a current moderate-to-severe depressive episode, with baseline MADRS score ≥20, stable treatment regimen for at least 4 weeks, and ability to provide informed consent. Participants are followed for up to 12 months after treatment. Recruitment is multicenter and includes psychiatric clinical sites at Brazilian universities.
The primary efficacy objectives are to compare the two treatment groups with respect to change in total MADRS score from baseline to Day 7 and change in the suicidal ideation item of the MADRS (MADRS-SI, item 10) from baseline to Day 1. Secondary outcomes include additional depression, suicidality, safety, functioning, quality-of-life, subjective experience, and psychological measures assessed across follow-up visits through Month 12.
The primary analysis follows the intention-to-treat principle. The primary endpoint is analyzed using a generalized linear mixed model / mixed model for repeated measures framework with fixed effects for treatment group, time, and treatment-by-time interaction, with participant-level random intercepts. Missing data are handled by restricted maximum likelihood estimation. Additional analyses include response and remission comparisons, effect size estimation, and exploratory associations between acute subjective effects, biomarkers, and clinical outcomes.
Eligibility
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
