Safety and tolerability of NN-dimethyltryptamine (DMT) in healthy volunteers and Major Depressive Disorder (MDD) patients: A systematic review of early-phase clinical trials.
Progress in neuro-psychopharmacology & biological psychiatry – June 07, 2025
Source: PubMed
Summary
A naturally-occurring psychedelic, DMT shows promise as a safe treatment option for depression. Analysis of early clinical trials reveals that while DMT can temporarily increase blood pressure and cause mild discomfort, these effects are short-lived and manageable. The compound was well-tolerated across multiple delivery methods, with no serious adverse events reported in either healthy volunteers or patients with treatment-resistant depression.
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.