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.
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.
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.
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.
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.
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.