Controlled clinical trials suggest that fast-acting psychedelic approaches may reduce symptoms of depression, but researchers emphasize the need for cautious interpretation and large-scale long-term studies.

study: Short-acting psychedelic intervention for major depressive disorder: a phase IIa randomized placebo-controlled trial.. Image credit: BLACKDAY / Shutterstock

In a recent study published in the journal natural medicineresearchers evaluated safety and efficacy of The short-acting psychedelic dimethyltryptamine (DMT), adults with major depressive disorder (MDD).

MDD is a leading cause of disability worldwide, affecting quality of life and posing a significant public health burden. Many patients experience inadequate responses or unacceptable side effects with commonly used first-line treatments, such as selective serotonin reuptake inhibitors, highlighting the need for more effective treatments.

Psychedelics have recently shown promise in treating mood disorders. DMT is a naturally occurring tryptamine that acts as a serotonin 5-hydroxytryptamine receptor 2A agonist. Unlike other hallucinogens, DMT has a short half-life and short psychoactive duration, allowing for shorter treatment sessions. Rather than demonstrating direct cost savings, this feature may improve feasibility and scalability.

Phase IIa study design and psychotherapy support

In this study, researchers evaluated the safety and efficacy of intravenous DMT in patients with MDD. This was a two-stage, randomized, placebo-controlled, Phase IIa study, with the first stage being double-blind and the second stage being open-label. Participants were 18 years of age or older, diagnosed with moderate to severe MDD, and had at least two previous treatment failures.

Individuals with a positive pregnancy test, history of severe suicide attempts, use of serotonergic hallucinogens, pre-existing mental illness, or personal or family history of psychosis were excluded. Participants received up to two intravenous doses of DMT or placebo, along with psychotherapeutic support including a structured preparation session, a therapist-supervised dosing session, and a post-session psychological integration visit.

In stage 1, participants were assigned to blind treatment, placebo or DMT. Because DMT causes significant subjective effects, the researchers noted that functional blinding may have occurred. Two weeks later, in stage 2, a placebo-active DMT was administered as the first dose to patients who received a placebo in stage 1.P.A.) group, or as a second dose to patients who received DMT in stage 1, active-active (A.A.) Group. A dose of 21.5 mg of DMT fumarate was infused intravenously over 10 minutes in two steps, an initial small infusion followed by the remaining dose.

The primary outcome was change in the Montgomery-Asberg Depression Rating Scale (MADRS) Scores from baseline 2 weeks after first dose. Secondary efficacy measures included MADRS scores at week 1 after the first dose and at weeks 1, 2, 4, and 12 after the second dose. Adverse events were recorded and categorized by severity. Safety monitoring includes heart rate, blood pressure, and electrocardiogram (ECG), and laboratory tests. Ratings of depression severity were performed by an independent rater who was not present during the administration session to reduce bias.

Tolerability was assessed by asking participants after administration whether they regretted the experience. The primary endpoint was analyzed using a t-test. Secondary endpoints were assessed using repeated measures mixed models. Logistic regression was used to analyze response rates (defined as ≥50% reduction in MADRS score) and remission rates (defined as MADRS score ≤10).

Antidepressant efficacy, response rates, and safety results

In this study, 34 participants were randomly assigned to PA or AA groups. Four participants in the AA group did not receive the second dose but participated in the study. Participants had a mean age of 32.8 years and most identified as Caucasian (88%), which may limit generalizability to more diverse populations. Depression severity was similar across groups at baseline.

The mean change in MADRS scores from baseline to 2 weeks after the first dose was significantly greater in DMT recipients than in placebo recipients. The reduction was significant even 1 week after administration. MADRS scores were not significantly different between those who received one dose of DMT and those who received two doses at any time point of follow-up, but this comparison was exploratory as there was no blinding and no placebo control in stage 2.

Most clinical improvement in patients who received two doses of DMT occurred within 2 weeks of the first dose. After 1 week, MADRS responses were observed in 6% of the PA group and 44% of the AA group, with remission occurring in 13% and 44%, respectively. After 2 weeks, response rates were 12% for PA and 35% for AA, and remission rates were 12% and 29%, respectively. Given the small sample size and the exploratory nature of the later stage analyses, these estimates should be interpreted with caution.

Exploratory analyzes suggested that the effects of antidepressants were partially related to the intensity of the acute psychedelic experience, indicating the possibility of psychological mediation rather than a purely pharmacological effect.

Treatment was generally well tolerated. Adverse events that occurred during treatment (TEAE) occurred in most participants, with approximately three-quarters reporting potentially treatment-related events. TEAEs were mild in 15 participants and moderate in 10. Injection site pain, anxiety, insomnia, headache, and restlessness were most frequently reported.

No serious adverse events or deaths occurred. Clinical evaluation, including ECG and laboratory tests, did not reveal any significant abnormalities during the study. A transient increase in heart rate and blood pressure was observed immediately after DMT injection. No significant changes in suicidal ideation were observed.

Clinical implications and future research needs

A single 21.5 mg dose of DMT administered with psychological support rapidly and significantly reduced depressive symptoms lasting up to 3 months in adults with MDD within the constraints of a small, carefully screened phase IIa study population. Treatment was safe and well tolerated during short follow-up. Larger, longer-term studies, including comparisons with current treatments, are needed to further evaluate the safety, efficacy, durability of response, and cost-effectiveness of DMT in treating MDD.