A single 10-minute intravenous infusion of the psychedelic dimethyltryptamine (DMT) with psychological support led to a statistically significant reduction in depressive symptoms.

Results of a randomized, double-blind, placebo-controlled phase 2a study of adults with moderate-to-severe major depressive disorder (MDD).

The antidepressant effects were observed as early as 1 week following the session and, in some cases, lasted for up to 3 months.

DMT is a rapid acting psychedelic with very short duration of psychedelic effects, making it a potentially practical alternative to other longer-acting psychedelic therapies such as psilocybin, the investigators led by David Erritzoe, MD, PhD, psychiatrist and neuroscientist with Imperial College London, London, England, noted.

The study was published online on February 16 in Nature Medicine.

More Time-Efficient Option?

MDD remains a leading cause of disability worldwide, and many patients fail to respond adequately to first-line antidepressants or experience limiting side effects.

Psychedelic-assisted therapy — particularly with psilocybin — has demonstrated strong antidepressant effects. However, the psychedelic effects of psilocybin typically last for about 2 hours, creating logistical and scalability challenges.

In contrast, DMT has a very short half-life (~5 minutes) with psychedelic effects lasting only about 30 minutes, raising the possibility of a more time-efficient therapeutic model.

The study included 34 adults (mean age, 32.8 years) with moderate-to-severe MDD for an average of over 10 years. Participants were randomized (1:1) to receive 21.5 mg DMT infused over 10 minutes or placebo in the double-blind phase. This was followed 2 weeks later by an open-label phase in which all participants could receive DMT with therapist support.

At baseline, Montgomery-Åsberg Depression Rating Scale (MADRS) scores were similar across groups.

The study met its primary endpoint, with DMT leading to a significantly greater mean change from baseline in MADRS scores at 2 weeks after the first dose than placebo (mean difference, -7.35 points; P = .023).

The between-group effect size for reduction in depressive symptoms with DMT at 2 weeks (d = 0.82) was comparable or greater than that seen in trials with psilocybin, the researchers noted.

The reduction in MADRS scores between the two groups was also significant at 1 week (mean difference, -10.75 points; P = .002; d = 1.09).

In the open-label phase, the antidepressant effects of DMT persisted for up to 3 months with no significant differences in MADRS scores among those who received one dose of DMT and those who received two doses at any follow-up timepoints.

In participants who received two doses of DMT, most clinical improvements in MADRS scores were observed within the initial 2 weeks after the first dose, with no significant additional effect observed after the second dose, “suggesting that one dose may suffice for sustained benefits,” the authors said.

Response (≥ 50% reduction in MADRS) and remission rates (MADRS ≤ 10) — two secondary outcomes — were also significantly better with DMT than with placebo.

At week 1, 44% in the DMT-first group vs 6% in the placebo-first group responded; remission occurred in 44% vs 13%. At 2 weeks, response rates were 35% vs 12%, and remission rates were 29% vs 12%.

Safety findings were consistent with prior psychedelic research in controlled settings. Most adverse events were mild or moderate, such as infusion-site pain, nausea or transient anxiety, and no serious treatment-related adverse events were reported.

‘Important’ Research…With Caveats

Limitations include the small sample size, a lack of ethnic diversity among participants, and exclusion of individuals with a history of serious suicide attempts. In addition, there was no assessment made of blinding integrity or participant expectancy, which may have influenced outcomes, particularly given the distinct subjective effects of DMT, the authors noted.

“Longer and larger trials, including comparisons with existing treatments, are needed to further evaluate the efficacy, safety, and cost-effectiveness of DMT in the treatment of MDD,” they concluded.

In a statement issued by the UK nonprofit Science Media Centre, independent experts commenting on the study also noted the need for further research.

James Stone, MBBS, PhD, professor of psychiatry, Brighton and Sussex Medical School in Brighton, England, characterized the research as an “exciting and well-designed proof-of-concept study from a respected research group that gives the first suggestion that DMT might be useful as an antidepressant agent.” However, it’s “too early to say with certainty that this approach is effective and safe.”

Ian Maidment, PhD, professor in clinical pharmacy, Aston University, in Birmingham, England, cautioned that this was a pilot study.

“Based on the number of people treated, the risk of a placebo effect, and because phase 2 studies aren’t designed to definitively test whether the drug works, it is premature to conclude that DMT is an effective treatment for depression. Therefore, overall DMT should not be taken outside of a controlled clinical trial for depression,” Maidment said.

Also commenting on the research, Draulio Barros de Araujo, PhD, with the Center for Advanced Medical Psychedelics, Brain Institute, Federal University of Rio Grande do Norte, Natal, Brazil, said the “key novelty is that it provides placebo-controlled evidence that a single, short-acting DMT intervention, combined with psychological support, can lead to rapid and clinically meaningful reductions in depressive symptoms.”

“That rigor is especially valuable in the psychedelic field, where controlled data are still relatively scarce,” de Araujo, who wasn’t involved in the study, told Medscape Medical News.

He and his colleagues recently published results of an open-label phase 2a trial using inhaled DMT in treatment-resistant depression (TRD), which also led to rapid and sustained antidepressant effects over 3 months.

“From the perspective of our own work with vaporized DMT in TRD, what stands out is the convergence of the clinical signal. Despite important differences in methodology and population — their study being placebo-controlled in MDD, ours open-label in TRD — both point to rapid antidepressant effects of a similar clinical order of magnitude,” said de Araujo.

He added that “reassuring” to see that the signal his team observed with inhaled DMT reproduced under more stringent experimental conditions. His group is currently moving toward a placebo-controlled trial using vaporized DMT.

With respect to route of administration, de Araujo noted that intravenous DMT offers precise pharmacokinetic control, which is ideal for early-phase trials.

“Vaporized DMT, on the other hand, is noninvasive and potentially more accessible, with very similar pharmacokinetics (rapid peak exposure within minutes) and highly comparable psychological and neurophysiological effects,” he said.

He agreed that DMT could potentially be a more convenient option than psilocybin. “The very short duration of action of DMT may allow for much briefer therapeutic sessions, which could reduce costs and logistical barriers. However, it is still too early to frame this as a replacement. Different psychedelics may ultimately serve different clinical niches,” he added.

Regarding clinical use, he noted that while the field has not yet reached that stage, progress is accelerating, and he anticipates that the first DMT-based treatment could be approved within the next 3-4 years.

The study had no specific funding. Erritzoe reported being served as a paid scientific advisor for Aya Biosciences, Lophora Aps, Clerkenwell Health, and Mindstate Design Lab. Stone, Maidment, and de Araujo had no relevant disclosures.