DMT Shows Rapid Antidepressant Effects in Phase 2 Trial for Major Depression

Major depressive disorder symptoms were significantly reduced after a single short-acting psychedelic intervention in a new phase 2a randomised controlled trial. In the 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.

At 2 weeks, participants receiving DMT therapy showed a significantly greater reduction in Montgomery–Åsberg Depression Rating Scale (MADRS) score compared with placebo (mean difference: −7.35; 95% CI: −13.62–−1.08; p=0.023). Within one week of the first treatment, the DMT group had an average 10.8 point larger drop in MADRS scores than the placebo group.

The trial recruited 34 participants with a mean age of 32.8 years, who had experienced depression for, on average, 10.5 years. In the clinical trial, half of the patients received two doses of DMT, spaced two weeks apart, while the other half got one dose of placebo followed by the psychedelic. Patients and staff were blinded to the first dose, but all knew they were getting the active drug at the second visit.

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. The placebo group showed similar symptom improvement to that seen in the treatment group in the first stage, but there was no further improvement in the two-treatment group. The researchers suggest that a single dose may be sufficient to achieve the antidepressant effect.

Researchers followed participants at regular intervals for 3 months, with participants completing the MADRS at 1, 2, 3, 4, 6 and 14 weeks, and 6 months after the first treatment. The researchers said that DMT's efficacy seems to be dependent on the intensity of the acute psychedelic experience it generates, working better in those who saw the most vivid effects. Participants who reported a more intense psychedelic experience showed a greater improvement in symptoms.

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. No participants reported any serious adverse events.

MDD remains one of the leading causes of disability worldwide, with many patients experiencing inadequate responses to conventional antidepressants and psychotherapy. Unlike traditional antidepressants, which may take weeks to exert full effects, DMT's rapid pharmacological action raises the possibility of faster symptom relief. One possible advantage of DMT is that it is short-acting, with effects lasting only minutes, rather than hours, which could offer similar benefits at a reduced cost and with a comparable safety profile.

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. The researchers acknowledge that these are very early results, and that their study had some limitations, including a lack of ethnic diversity and the exclusion of anyone with a history of serious suicide attempts. They called for "longer and larger trials to further evaluate the efficacy, safety, and cost-effectiveness of DMT-assisted therapy compared with existing standard treatments."

The drug – called SPL026 – was originally developed by UK firm Small Pharma, which was acquired by Canadian firm Cybin in 2023. Cybin has since been renamed Helus Pharma and is developing novel serotonin agonist drugs based on both DMT and psilocybin, the psychoactive ingredient in magic mushrooms.

The study was published in Nature Medicine.