Safety and tolerability of NN-dimethyltryptamine (DMT) in healthy volunteers and Major Depressive Disorder (MDD) patients: A systematic review of early-phase clinical trials.

Treatment-resistant depression (TRD) is difficult to treat because many patients do not respond to standard antidepressants. NN-dimethyltryptamine (DMT), a fast-acting psychedelic, may offer benefits due to its rapid onset and short duration. This systematic review of five clinical trials found that DMT was generally well-tolerated, with no serious adverse events. Intravenous DMT caused temporary increases in systolic blood pressure (up to 25.7%) and heart rate at higher doses. Inhalation led to mild throat discomfort, and oral or intranasal use caused mild nausea and dizziness, all short-lived. Psychotomimetic effects like ego dissolution were dose-dependent but manageable. Larger, well-controlled studies are needed to confirm safety and efficacy in TRD patients.

Study at a glance

Abstract

Treatment-resistant depression (TRD) remains a challenge, with many patients unresponsive to standard antidepressants. NN-dimethyltryptamine (DMT), a fast-acting psychedelic, offers potential benefits due to its rapid onset and short duration. This review, registered with the Open Science Framework (DOI: 10.17605/OSF.IO/6D9WC), summarizes the safety and tolerability of DMT in early-phase trials. A systematic review was conducted following PRISMA guidelines. Databases including PubMed, SCOPUS, Web of Science, and EMBASE were searched until October 2024. Eligibility criteria included clinical trials assessing safety and tolerability outcomes of DMT in healthy volunteers or patients with major depressive disorder (MDD). Risk of bias was assessed using RoB2 and ROBINS-I tools. Results were synthesized narratively. Out of 505 records, 5 trials were included in the review. Intravenous trials (NCT04711915, NCT04673383) showed increased systolic blood pressure (up to 25.7 %) and heart rate at higher doses, but these resolved quickly. The inhalation trial (NCT05573568) reported mild throat discomfort and respiratory irritation, while oral and intranasal trials (NCT04716335) noted mild nausea and dizziness, all of which were short-lived. No serious adverse events were reported, and DMT was generally well-tolerated. Psychotomimetic effects, including ego dissolution and mystical experiences, were dose-dependent but manageable. Randomized trials exhibited low to moderate risk of bias, whereas non-randomized trials showed serious risk. Limitations include the small number of trials and the predominance of healthy volunteer samples. Funded by the Medical University of Gdańsk; the funder had no role. Although promising, further large-scale, well-controlled studies are needed to establish DMT's safety and efficacy in TRD populations.