A short-acting psychedelic intervention for major depressive disorder: a phase IIa randomized placebo-controlled trial.
David Erritzøe, Tommaso Barba, Tiffanie Benway, Zelah Joel, Meghan Good, Marie Layzell, Michelle Baker-Jones, Graham Campbell, Ashleigh Murphy-Beiner, Peter Rands, Malcolm Boyce, Helen Topping, Brandon Weiss, Christopher Timmermann, David Nutt, Robin Carhart-Harris, Carol Routledge, Ellen James
Nat Med February 16, 2026 DOI: 10.1038/s41591-025-04154-z (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Placebo-controlled Double-blind Open-label Peer reviewed |
|---|---|
| Sample size | 34 |
| Population | Adults with moderate-to-severe major depressive disorder |
| Intervention | Intravenous DMT (SPL026; DMT fumarate) |
| Dose | 21.5 mg |
| Duration | Single 10-minute infusion, 2-week assessment, open-label follow-up up to 3 months |
| Topics | Depression |
| Citations | 4 |
| Registration | NCT04673383 |
| Key findings | A single dose of DMT with psychotherapeutic support produced a rapid, significant reduction in depressive symptoms sustained up to 3 months. |
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 .