A short-acting psychedelic intervention for major depressive disorder: a phase IIa randomized placebo-controlled trial

Dimethyltryptamine (DMT) is tested as a short-acting psychedelic intervention for adults with moderate-to-severe major depressive disorder (MDD) in a phase IIa randomized, double-blind, placebo-controlled trial. Participants received a single intravenous DMT fumarate dose (21.5 mg) infused over 10 minutes or placebo, alongside supportive psychotherapeutic support, with the primary outcome measured at 2 weeks using the Montgomery-Åsberg Depression Rating Scale (MADRS). The DMT group showed a significantly greater reduction in MADRS scores than placebo at 2 weeks (mean difference -7.35; P = 0.023). An open-label phase allowed a second DMT dose for those assigned to the active arm, with antidepressant effects persisting up to 3 months. Adverse events were mostly mild to moderate (notably infusion site pain, nausea, and transient anxiety), and no serious adverse events were reported. Overall, the study reports rapid symptom improvement with a well-tolerated, short-duration IV DMT dosing approach.