Major depressive disorder (MDD) is a leading global cause of disability. It significantly impacts people’s quality of life and poses a substantial burden on public health. Many patients do not respond adequately to first-line selective serotonin reuptake inhibitors (SSRIs). Psychedelics, specifically psilocybin, have demonstrated rapid moderate to large antidepressant effects, which promote the examination of other 5-HT2A agonists like dimethyltryptamine (DMT). DMT has a short half-life and a rapid onset, enabling brief therapeutic sessions. Previous evidence suggests that inhaled or intravenous (IV) DMT is well tolerated and safe, as well as correlated with a rapid reduction in depressive symptoms, particularly when combined with psychological therapy. Both infusion- and inhaled-based approaches show promising effects. Building on prior research phase I research, David Erritzoe et al. conducted a two-stage Phase IIa trial for evaluating the efficacy and safety of a 10-minute IV DMT infusion (SPL026, DMT fumarate) in adults with moderate-to-severe MDD.
This Phase IIa was a double-blinded, placebo-controlled, randomized clinical study (NCT04673383) conducted in the UK. A total of 34 participants (mean age = 32.8±9.05 years, female = 10, male = 24, mean duration of depression = 10.4±8.5 years) were included in this study. They were randomized into 1:1 either to placebo (stage 1, placebo-active [PA] group) or DMT (active-active [AA] group) and followed two weeks later by open-label DMT (Stage 2). DMT (21.5 mg over 10 minutes) was administered in closely monitored inpatient settings, supported by preparatory sessions and post-dose integration therapy. Participants were followed for up to 3 months after their first infusion dose. Measurements were performed for 1 week, 2 weeks, 4 weeks, and 12 weeks post-treatment. An additional exploratory follow-up was completed in 6 months to determine the long-term clinical outcomes. The primary endpoint was the change in the Montgomery-Asberg depression rating scale (MADRS) score at 2 weeks after the initial dose. Secondary endpoints were assessment of safety, mood, subjective psychedelic effects, anxiety, and tolerability over the 3 months follow-up period.
In this study, DMT produced significantly greater reductions in MADRS scores compared to placebo at 2 weeks, with a mean difference of -7.35 (95% confidence interval [CI]: -13.62 to -1.08), p = 0.023, and Cohen’s d = 0.82. After 1 week, effects were larger with a mean difference of -10.75, 95% CI: -16.95 to -4.55, p = 0.002, and d = 1.09. In the open-label phase, no statistically significant differences were observed between PA and AA groups at 3 (p = 0.42), 4 (p = 0.41), 6 (p = 0.96), or 14 weeks (p = 0.08). At 1 week, remission rates were found to be 44% AA vs 13% PA (difference = 31.3% points, 95% CI: 2.0 to 60.5), whereas response rates were 44% AA vs 6% PA (difference = 37.5%, 95% CI: 10.5 to 64.6). At 2 weeks, response rates were 29% AA vs 12% PA (difference = 17.7%, 95% CI: −8.9 to 44.2), whereas remission rates were 35% AA vs 12% PA (difference = 23.5%, 95% CI: −3.9 to 50.9). At 6 months (pooled participants), response and remission rates were reported as 44% and 40%, respectively.
DMT was generally well tolerated. Treatment-emergent adverse events (TEAEs) occurred in 73.5% of participants, mostly mild (n = 15) or moderate (n = 10). TEAEs were more frequent after the initial dose of DMT (Stage 1 = 64.7%, Stage 2 = 62.5%) compared to the placebo group (23.5%), with no serious adverse events. Transient increases in heart rate and blood pressure were observed after administration of DMT. Anti-depressant responses at 2 weeks were significantly associated with mystical type experiences, such as higher mystical experiences questionnaire (MEQ) scores, ego dissolution, unity, and overall intensity ratings. In contrast, factors like prior psychedelic use, intention, settings, and rapport did not significantly affect the clinical outcomes.
Limitations of this study included limited ethnic diversity, exclusion of high-risk suicidal patients, small subgroup sizes, lack of blinding integrity assessment, open-label second dosing, limited causal interpretation, and concurrent psychotherapy.
In conclusion, a 21.5 mg IV DMT infusion significantly reduced the depressive symptoms within 2 weeks compared to placebo with rapid and sustained effects. Larger and longer comparative clinical trials are required to confirm the safety and efficacy of DMT as a treatment for MDD.
Reference: Erritzoe D, Barba T, Benway T, et al. A short-acting psychedelic intervention for major depressive disorder: a phase IIa randomized placebo-controlled trial. Nat Med. 2026. doi:10.1038/s41591-025-04154-z
