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Clinical Trial
. 2025 Oct;50(11):1715-1723.
doi: 10.1038/s41386-025-02167-3. Epub 2025 Jul 15.

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 #  1   2   3 , Laura Noguera #  1   4 , Diana Bruno  4 , Luciana Vita  4 , Mariana Zanino  3   4 , Diego E Kassuha  3   5   6 , Javier E Ortiz  7 , Gabriela E Feresin  7 , Paola Díaz-Dellavalle  8 , Lorena Orosco  9 , M Agustina Garcés  9 , Pablo Diez  3   9 , Sergio G Albarracín  10   11 , Martin A Bruno  12   13
Affiliations
Clinical Trial

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 et al. Neuropsychopharmacology. 2025 Oct.

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.

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Conflict of interest statement

Competing interests: During the study, PD-D was the Chief Scientific Officer of Biomind Labs Inc. MB was the Clinical Advisor of Biomind Labs Inc. during the study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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