Safety and tolerability of multiple sublingual microdoses of 5-MeO-DMT in adults with moderate symptoms of depression and/or anxiety: a randomized, double-blind, placebo-controlled study.
Maria Beatriz Bistue Millón, Laura Noguera, Diana Bruno, Luciana Vita, Mariana Zanino, Diego E Kassuha, Javier E Ortiz, Gabriela E Feresin, Paola Díaz-Dellavalle, Lorena Orosco, M Agustina Garcés, Pablo Diez, Sergio G Albarracín, Martin A Bruno
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology July 15, 2025 DOI: 10.1038/s41386-025-02167-3 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Placebo-controlled Double-blind Peer reviewed |
|---|---|
| Population | Adults with moderate to high levels of anxiety and/or depression, without formal psychiatric diagnosis or ongoing treatment |
| Intervention | 5-MeO-DMT |
| Dose | 6 mg, 9 mg, or 12 mg |
| Duration | Four weeks |
| Topics | 5-MeO-DMT Anxiety Depression DMT |
| Keywords | Mental health therapy Clinical trials Drug safety |
| Citations | 4 |
| Registration | NCT06816667 |
| Key findings | Sub-psychedelic doses of sublingual 5-MeO-DMT were safe and well tolerated, with rapid absorption, no drug accumulation, and dose-dependent brain modulation without full psychedelic effects. |
Abstract
This Phase I clinical trial is the first to rigorously evaluate the safety, tolerability, and pharmacokinetics of a novel sublingual formulation of 5-MeO-DMT, administered at sub-psychedelic doses to adults with moderate to high levels of anxiety and/or depression, without formal psychiatric diagnosis or ongoing treatment. Using a double-blind, placebo-controlled design, participants received a single weekly sublingual dose of 5-MeO-DMT (6 mg, 9 mg, or 12 mg) or placebo over four weeks. The compound was well tolerated across all groups, with no significant adverse events or signs of organ toxicity; mild side effects such as nausea and headache were transient and self-resolving. Pharmacokinetic analyses showed rapid absorption, with peak plasma concentrations occurring within a median of 20 min and no evidence of drug accumulation. Neurophysiological assessments revealed dose-dependent modulation of brain activity without eliciting full psychedelic effects, supporting the feasibility of repeated sub-psychedelic dosing. Participants remained cognitively and behaviorally stable, maintaining their usual daily activities and social interactions. This study marks a pivotal advancement in the clinical exploration of psychedelic compounds, highlighting the potential of 5-MeO-DMT as a safe, fast-acting compound with favorable tolerability and emerging as a promising candidate for future therapeutic applications. These findings provide critical groundwork for future trials targeting psychiatric populations, positioning 5-MeO-DMT as a novel, fast-acting therapeutic strategy with broad clinical relevance. TRIAL REGISTRATION: ClinicalTrials.gov: NCT06816667.
In the evidence
This study is part of the evidence base for a synthesis in the library. Here is how each one recorded it.
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Sub-psychedelic sublingual doses of 5-MeO-DMT were safe and well tolerated with dose-dependent brain modulation, but the study assessed safety and tolerability rather than antidepressant efficacy.
Synthesized
Comparable studies
Other randomized controlled trials on DMT for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Phase 1, placebo-controlled, single ascending dose trial to evaluate the safety, pharmacokinetics and effect on altered states of consciousness of intranasal BPL-003 (5-methoxy-N,N-dimethyltryptamine benzoate) in healthy participants. Healthy psychedelic-naïve participants | 2024 | Double-blind, placebo-controlled single ascending dose study | n = 44 |
| Safety, tolerability, pharmacodynamic and wellbeing effects of SPL026 (dimethyltryptamine fumarate) in healthy participants: a randomized, placebo-controlled phase 1 trial. Psychedelic-naïve healthy participants | 2023 | Randomized, double-blind, placebo-controlled, parallel-group, single dose-escalation trial | n = 32 |