Inhaled DMT for Major Depressive Disorder

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

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

Conditions6

Interventions2

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