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

## TL;DR

A single dose of the psychedelic DMT, with psychological support, rapidly and safely reduces depression symptoms in adults.

## Contribution

This study provides clinical evidence that a single DMT dose can significantly and sustainably reduce depressive symptoms in MDD patients.

## Key findings

- DMT showed a significant reduction in MADRS scores compared to placebo at 2 weeks.
- Depressive effects of DMT persisted up to 3 months with no serious adverse events.
- Adverse events were mild to moderate, including infusion site pain and transient anxiety.

## Abstract

Major depressive disorder (MDD) is a leading cause of disability worldwide, yet many patients have inadequate responses to current treatments. Dimethyltryptamine (DMT), a serotonergic psychedelic with rapid onset and short duration, shows promise as a potential antidepressant (AD), although clinical evidence in MDD remains limited. We conducted a phase IIa, double-blind, placebo-controlled, randomized clinical trial to evaluate the efficacy and safety of intravenous DMT (SPL026; DMT fumarate) in adults with moderate-to-severe MDD. Participants received a single 21.5-mg dose of DMT or placebo infused over 10 min, along with supportive psychotherapeutic support, followed by a 2-week assessment. A subsequent open-label phase offered all participants a second DMT dose. The primary outcome was the change in Montgomery–Åsberg Depression Rating Scale (MADRS) at 2 weeks. Secondary outcomes included response (≥50% reduction in MADRS score) and remission (MADRS ≤ 10). A total of 34 participants were randomized, 17 to placebo–active and 17 to active–active. At 2 weeks, the DMT group showed a significantly greater reduction in MADRS score than placebo (mean difference = −7.35; 95% CI = −13.62 to −1.08; P = 0.023). In the open-label phase, AD effects persisted up to 3 months, with no significant differences between those who received one versus two doses. Adverse events were mostly mild to moderate, commonly infusion site pain, nausea and transient anxiety. No serious adverse events occurred. A single dose of DMT with psychotherapeutic support produced a rapid, significant reduction in depressive symptoms, sustained up to 3 months. The treatment was well-tolerated and safe. ClinicalTrials.gov registration: NCT04673383.

A single intravenous dose of the psychedelic dimethyltryptamine, combined with psychological support, produces rapid and lasting reductions in depressive symptoms in adults with major depressive disorder.