Summary: A Phase IIa randomized, placebo-controlled trial shows that a single, brief intravenous dose of dimethyltryptamine (DMT) — the main psychoactive compound in ayahuasca — can produce rapid and durable antidepressant effects in people with treatment-resistant major depressive disorder. Unlike psilocybin or LSD sessions that last many hours, the DMT experience in this trial was short (about 20–30 minutes) yet delivered clinically meaningful symptom reductions that, for some participants, lasted for months.
Because DMT’s effects arise and subside quickly, this approach could make psychedelic-assisted therapy more practical and scalable in standard clinical settings, reducing time and resource demands while maintaining safety and efficacy. The trial’s results, while preliminary, suggest a new pathway for fast-acting interventions for depression that warrant larger and longer follow-up studies.
Key Facts
- Short duration, rapid onset: The acute DMT experience typically lasted 20–30 minutes, compared with 6–8 hours for psilocybin or LSD sessions.
- Clinical improvement: One week after dosing, the DMT group showed an average 10.8-point greater reduction on the Montgomery–Åsberg Depression Rating Scale (MADRS) than placebo.
- Durable benefits: Antidepressant effects remained statistically significant at three months, and some participants maintained improvements for up to six months.
- Intensity linked to outcome: Treatment efficacy correlated with the intensity of the acute psychedelic or “peak” experience.
- Potential scalability: Shorter sessions could lower costs and simplify integration of psychedelic-assisted therapies into routine clinical practice.
Source: Imperial College London
Overview of the trial and main findings
Researchers from Imperial College London in collaboration with Cybin UK (now trading as Helus) ran a randomized, double-blind, placebo-controlled Phase IIa trial to test intravenous DMT fumarate (SPL026) in adults with moderate-to-severe major depressive disorder who had not responded to at least two prior treatments. The study randomized 34 participants: 17 initially to placebo then active, and 17 to active then active.
Participants received a single 21.5 mg intravenous infusion of DMT administered over 10 minutes, or a matched placebo infusion. All participants received standardized psychotherapeutic support that included pre-dose preparation, in-session support, and post-dose integration. Symptom severity was measured using the MADRS, which served as the primary outcome with assessment at two weeks post-dose.
At two weeks, the DMT group showed a statistically significant greater reduction in depression severity compared with placebo (mean difference in MADRS ≈ −7.35; 95% CI −13.62 to −1.08; P = 0.023). The DMT group already demonstrated strong improvement after one week, with an average 10.8-point larger drop in MADRS than placebo. In the open-label phase that followed, antidepressant effects persisted up to three months for the group as a whole and up to six months in some individuals. Secondary analyses found no clear advantage for a second dose over a single dose in this small sample.
Tolerability and safety
The treatment regimen was generally well tolerated. Adverse events were mostly mild to moderate and included infusion site pain, nausea and transient anxiety. No serious adverse events related to the treatment were reported, and there were no concerning increases in suicidal ideation or cardiovascular problems during the study.
Mechanistic and clinical considerations
DMT is a serotonergic psychedelic structurally related to psilocybin and serotonin and is the primary psychoactive component of ayahuasca. Unlike many classical psychedelics, DMT is metabolized rapidly, producing a brief but intense subjective experience. The investigators observed that greater therapeutic benefit was associated with more intense acute experiences, suggesting that the qualitative nature of the session may be an important mediator of clinical outcome.
Limitations and next steps
The authors emphasize that these are early-stage results from a small, relatively homogeneous sample. The trial excluded people with a history of serious suicide attempts, and participant diversity was limited. Larger, longer, and more diverse randomized trials are needed to replicate these findings, explore optimal dosing and therapeutic models, and compare DMT-assisted therapy directly with established treatments.
Funding and trial sites
The trial was designed, funded and sponsored by Cybin UK Ltd (now Helus), which provided the DMT fumarate (SPL026). Clinical work was conducted at Hammersmith Medicines Research Ltd (London) and MAC Clinical Research (Liverpool), with follow-up conducted by Imperial College London’s Hammersmith Campus. ClinicalTrials.gov identifier: NCT04673383.
Key Questions Answered:
A: While DMT and psilocybin are chemically related and both act on serotonergic systems, the subjective experience differs markedly. DMT typically produces a very rapid, intense onset and resolves within minutes, whereas psilocybin experiences unfold over several hours. This study indicates a short session can produce therapeutic changes similar to longer psychedelics.
A: No. This study used pharmaceutical-grade DMT administered intravenously in a controlled clinical environment, together with professional psychological support and integration therapy. Those elements are considered essential to the safety and durability of the therapeutic effect.
A: In this trial, DMT was generally well tolerated with no serious adverse cardiovascular events reported. Routine monitoring and clinical oversight are important when administering any psychoactive compound, especially in medically vulnerable individuals.
Editorial Notes:
- This piece was edited by a Neuroscience News editor.
- The underlying journal article was reviewed in full for accuracy.
- Additional contextual information was added by editorial staff.
About this research news
Author: Samantha Rey
Source: Imperial College London
Contact: Samantha Rey – Imperial College London
Image: Image credited to Neuroscience News
Original research: Open access. “A short-acting psychedelic intervention for major depressive disorder: a phase IIa randomized placebo-controlled trial” by David Erritzoe et al., published in Nature Medicine. DOI: 10.1038/s41591-025-04154-z.
Abstract
A short-acting psychedelic intervention for major depressive disorder: a phase IIa randomized placebo-controlled trial
Major depressive disorder is a leading cause of disability and many patients do not respond adequately to current treatments. Dimethyltryptamine (DMT) is a serotonergic psychedelic with rapid onset and brief duration that shows promise as an antidepressant. In this phase IIa, double-blind, placebo-controlled randomized trial, adults with moderate-to-severe major depressive disorder received a single 21.5 mg intravenous dose of DMT or placebo over 10 minutes alongside psychotherapeutic support. The primary outcome was change in MADRS at two weeks. Among 34 randomized participants, DMT produced a significantly greater reduction in MADRS at two weeks compared with placebo (mean difference −7.35; 95% CI −13.62 to −1.08; P = 0.023). Antidepressant effects were sustained up to three months in the open-label phase, and adverse events were generally mild to moderate with no serious drug-related events. A single dose of DMT with supportive therapy produced rapid, significant symptom reduction and was well tolerated, supporting further investigation in larger trials.