MAJOR depressive disorder (MDD) symptoms were significantly reduced after a single short-acting psychedelic intervention in a new phase IIa randomised controlled trial.
MDD remains one of the leading causes of disability worldwide, with many patients experiencing inadequate responses to conventional antidepressants and psychotherapy. The search for rapid-acting treatments has intensified in recent years, particularly for individuals with moderate-to-severe disease. Dimethyltryptamine (DMT), a serotonergic psychedelic with rapid onset and short duration of action, has emerged as a potential alternative.
DMT Therapy Shows Rapid Antidepressant Effects
In this double-blind, placebo-controlled study, 34 adults with moderate-to-severe MDD received either a single 21.5 mg intravenous dose of DMT (SPL026; DMT fumarate) infused over 10 minutes or placebo, alongside structured psychotherapeutic support. The primary endpoint was change in Montgomery–Åsberg Depression Rating Scale (MADRS) score at 2 weeks.
At 2 weeks, participants receiving DMT therapy showed a significantly greater reduction in MADRS score compared with placebo (mean difference: −7.35; 95% CI: −13.62–−1.08; p=0.023). Secondary outcomes were also measured, defined as ≥50% reduction in MADRS score, and remission, defined as MADRS≤10.
Following the blinded phase, all participants were offered an open-label DMT session. In this phase, antidepressant effects were sustained for up to 3 months, with no significant differences between those who received one versus two doses.
Adverse events were mostly mild-to-moderate and included infusion site pain, nausea, and transient anxiety. No serious adverse events were reported, suggesting that DMT therapy was well tolerated in this controlled clinical setting.
A New Frontier for MDD Treatment
MDD is characterised by persistent low mood, anhedonia, and cognitive and somatic symptoms that impair daily functioning. Unlike traditional antidepressants, which may take weeks to exert full effects, DMT’s rapid pharmacological action raises the possibility of faster symptom relief.
However, the sample size of this study was small and follow-up was limited. Larger, longer-term trials are needed to confirm durability, optimal dosing strategies, and safety in broader patient populations.
If replicated, these findings suggest that short-acting psychedelic interventions such as DMT therapy could represent a novel, rapid-acting treatment option for patients with major depressive disorder who have not responded adequately to existing therapies.
Reference
Erritzoe D et al. A short-acting psychedelic intervention for major depressive disorder: a phase IIa randomised placebo-controlled trial. Nat Med. 2026; DOI:10.1038/s41591-025-04154-z.
