Single Dose of DMT Shows Rapid Antidepressant Effects in Phase II Trial

A single intravenous dose of the psychedelic drug dimethyltryptamine (DMT), given with psychological support, rapidly reduced depressive symptoms in 34 adults with major depressive disorder, according to a phase IIa clinical trial published in the journal Nature Medicine. The improvements, which continued over the ensuing two weeks, suggest that this short-acting treatment could be a more practical therapy compared with other longer-acting psychedelic therapies.

The study was a two-stage, randomized, placebo-controlled phase IIa trial, with stage 1 conducted double-blind and stage 2 conducted open-label. Participants were aged 18 years or older with a diagnosis of moderate-to-severe major depressive disorder and had a history of at least two previous unsuccessful treatment attempts. Participants had a mean age of 32.8 years, and most identified as White (88%).

Individuals with a positive pregnancy test, history of serious suicide attempts, use of serotonergic psychedelics, preexisting psychiatric conditions, or personal or family history of psychosis were excluded. Participants received up to two intravenous doses of DMT or placebo along with psychotherapeutic support that included structured preparatory sessions, therapist-monitored dosing sessions, and post-session psychological integration visits.

In stage 1, participants were randomly assigned to receive either DMT or a placebo. The dose, 21.5 mg DMT fumarate, was infused intravenously over 10 minutes in two phases, consisting of an initial lower infusion followed by the remaining dose. A therapist sat with each participant to ensure comfort and safety while the psychedelic effects were active, remaining silent throughout the treatment.

Two weeks later, in stage 2, DMT was administered either as a first dose to those who had received a placebo in stage 1, the placebo-active (PA) group, or as a second dose to those who had received DMT in stage 1, the active-active (AA) group. Four participants in the AA group did not receive their second dose but remained in the trial.

The primary outcome was the change in the Montgomery–Åsberg Depression Rating Scale (MADRS) score from baseline at two weeks after the first dose. The mean change in MADRS score from baseline to two weeks after the first dose was significantly greater in DMT recipients than in placebo recipients. Reductions were also significant at one week after dosing. Two weeks after the first dose, the participants who received DMT scored about seven points lower, on average, than those who received a placebo. On this commonly used clinical scale, a drop of that size is generally considered a meaningful reduction in symptom severity.

At one week, MADRS response was observed in 6% of the PA group and 44% of the AA group, while remission occurred in 13% and 44%, respectively. At two weeks, response rates were 12% in PA and 35% in AA. Response was defined as a greater than 50% decrease in MADRS score, and remission was defined as a MADRS score less than or equal to 10.

MADRS scores did not differ significantly between individuals who received a single DMT dose and those who received two doses at any follow-up time point, although this comparison was exploratory because stage 2 lacked blinding and a placebo control. Most clinical improvements among those receiving two DMT doses occurred within two weeks of the first dose. Antidepressant effects lasted for 12 weeks and some patients remained in remission for at least six months following the treatment.

Unlike psilocybin and lysergic acid diethylamide (LSD), whose effects can last for hours, intravenous DMT has a half-life of around five minutes. Its psychedelic effects are correspondingly brief, lasting minutes rather than hours, potentially making it more practical to administer in clinical settings. Traditional psychedelic-assisted therapy sessions can last most of a day and sometimes require multiple clinicians present throughout. The psychedelic effects of psilocybin persist for around two hours, which has made therapeutic sessions long and difficult to scale up. In contrast, DMT is a fast-acting psychedelic drug that, when administered intravenously, causes a brief period of subjective psychedelic effects of around 30 minutes.

The treatment was generally well tolerated. Most adverse events were mild or moderate, such as infusion-site pain, nausea or temporary anxiety, and no serious treatment-related adverse events were reported. Brief increases in heart rate and blood pressure were observed immediately after dosing. Safety monitoring included heart rate, blood pressure, electrocardiograms (ECGs), and laboratory tests. Depression severity assessments were conducted by independent raters not present during dosing sessions to reduce bias.

Tolerability was assessed post-dose by asking participants whether they regretted the experience. Because DMT produces pronounced subjective effects, investigators noted that functional unblinding may have occurred, and the study did not assess whether participants could guess which treatment they received.

Major depressive disorder is a leading global cause of disability, impacting quality of life and creating a significant public health burden. Many patients experience insufficient responses or unacceptable side effects with commonly used first-line treatments such as selective serotonin reuptake inhibitors, underscoring the need for more effective therapies. A substantial proportion either do not respond adequately or experience side effects that make long-term treatment difficult, including sexual dysfunction, weight gain, and sleep disturbance.

DMT is a naturally occurring tryptamine that acts as a serotonin 5-hydroxytryptamine receptor 2A agonist. Unlike other psychedelics, DMT has a short half-life and brief psychoactive duration, allowing shorter treatment sessions, a feature that may improve feasibility and scalability rather than demonstrating direct cost savings.

Larger studies are needed to confirm how effective DMT is for treating major depression, how long the benefits last, and how it compares with other existing therapies. 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 major depressive disorder.