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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

Neuropsychopharmacology volume 50, pages 1715–1723 (2025)Cite this article

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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.

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ClinicalTrials.gov: NCT06816667

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Fig. 1: CONSORT diagram depicting participant flow and schematic timeline of Phase I trial procedures.
Fig. 2: Plasma concentration–time curve following sublingual administration of 12 mg 5-MeO-DMT.
Fig. 3: Acute psychedelics experience.
Fig. 4: EEG power spectrum analysis illustrating the effects of 5-MeO-DMT on Delta (1–4 Hz), Theta (4–8 Hz), and Alpha (8–12 Hz) frequencies across different dosage groups.

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Data availability

Data will be made available upon request.

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Acknowledgements

This work was supported by Biomind Labs Inc.

Author information

Author notes

  1. These authors contributed equally: Maria Beatriz Bistue Millón, Laura Noguera.

Authors and Affiliations

  1. Instituto de Ciencias Biomédicas (ICBM), Facultad de Ciencias Médicas, Universidad Católica de Cuyo, San Juan, Argentina

    Maria Beatriz Bistue Millón, Laura Noguera & Martin A. Bruno

  2. Ministerio de Salud Pública (MSP), Gobierno de la Provincia de San Juan, San Juan, Argentina

    Maria Beatriz Bistue Millón

  3. Consejo Nacional de Investigaciones Científicas y Técnica (CONICET), Buenos Aires, Argentina

    Maria Beatriz Bistue Millón, Mariana Zanino, Diego E. Kassuha, Pablo Diez & Martin A. Bruno

  4. Instituto de Investigaciones en Psicología Básica y Aplicada (IIPBA), Facultad de Filosofía y Humanidades, Universidad Católica de Cuyo, San Juan, Argentina

    Laura Noguera, Diana Bruno, Luciana Vita & Mariana Zanino

  5. Instituto de Investigaciones en Ciencias Químicas (ICQ), Facultad de Ciencias Químicas y Tecnológicas, Universidad Católica de Cuyo, San Juan, Argentina

    Diego E. Kassuha

  6. Hospital Público Descentralizado Dr. Guillermo Rawson. Ministerio de Salud Pública (MSP), Gobierno de la Provincia de San Juan, San Juan, Argentina

    Diego E. Kassuha

  7. Instituto de Biotecnología, Facultad de Ingeniería, Universidad Nacional de San Juan, CCT CONICET San Juan, San Juan, Argentina

    Javier E. Ortiz & Gabriela E. Feresin

  8. Biomind Labs, Brookfield Place, Toronto, ON, Canada

    Paola Díaz-Dellavalle

  9. Instituto de Bioingeniería (INBIO), Universidad Nacional de San Juan, San Juan, Argentina

    Lorena Orosco, M. Agustina Garcés & Pablo Diez

  10. Facultad de Ciencias Médicas, Universidad Católica de Cuyo, San Juan, Argentina

    Sergio G. Albarracín

  11. Hospital Público Dr. Marcial V. Quiroga, San Juan, Argentina

    Sergio G. Albarracín

Authors
  1. Maria Beatriz Bistue Millón
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Contributions

MBBM and LN contributed equally to the work. Designed and performed the research; analyzed the data and wrote the manuscript. BD, VL, and MZ. Conducted the neuropsychological and psychiatric tests KD, OJ, and FG performed PK studies; OL, GMA, and DP. Analyzed EEG data; PDD served as the Chief Scientific Officer of Biomind Labs Inc. during the study; SGA was the Medical Director of the clinical trial and MAB. Designed the research; Contributed to data analysis, and reviewed the final version of the manuscript. All authors gave final approval to the manuscript.

Corresponding author

Correspondence to Martin A. Bruno.

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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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Bistue Millón, M.B., Noguera, L., Bruno, D. et al. 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. Neuropsychopharmacol. 50, 1715–1723 (2025). https://doi.org/10.1038/s41386-025-02167-3

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