This Phase I clinical trial (n=36) of sublingual 5-MeO-DMT (6-12 mg weekly doses over four weeks) in adults with moderate to high anxiety/depression demonstrated good safety and tolerability with no significant adverse events, rapid absorption with peak plasma concentrations at 20 minutes, dose-dependent neurophysiological modulation without full psychedelic effects, and maintenance of normal cognitive and behavioral function.
Abstract of Safety and tolerability of multiple sublingual microdoses of 5-MeO-DMT in adults with moderate symptoms of depression and/or anxiety
“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.“
Authors: 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
Summary of Safety and tolerability of multiple sublingual microdoses of 5-MeO-DMT in adults with moderate symptoms of depression and/or anxiety
Classical serotonergic psychedelics such as psilocybin, DMT, and LSD are known for their ability to profoundly influence perception, mood, and consciousness, primarily through their interaction with serotonin receptors in the brain, especially the 5-HT2A receptor. Unlike many psychoactive drugs, these substances are not associated with compulsive use or significant withdrawal syndromes, and previous research suggests they may have therapeutic value for conditions like depression, anxiety, post-traumatic stress, and certain substance-use disorders.
Recent interest has grown around two distinct dosing strategies. “Macrodosing” refers to the administration of full psychedelic doses under carefully controlled and supported conditions, typically producing intense and sometimes transformative subjective experiences. In contrast, “microdosing” involves repeated administration of very small doses designed to be sub-perceptual or minimally perceptual. Microdosing aims to produce subtle improvements in mood, anxiety, or cognition while avoiding significant perceptual or functional disruption. This strategy may appeal to individuals unwilling or unable to undergo full psychedelic sessions.
5-MeO-DMT is a powerful, short-acting tryptamine psychedelic occurring naturally in some plants and toad secretions but also synthesised for research and therapeutic contexts. It is structurally related to DMT but generally considered more potent and pharmacologically distinct due to its relatively high affinity for 5-HT1A receptors, which are associated with anxiolytic and mood-regulating effects. Oral ingestion is ineffective because monoamine oxidase (MAO) enzymes rapidly degrade the drug, necessitating alternative delivery routes such as inhalation or sublingual administration. Its fast onset and brief duration may make it suitable for outpatient treatment models where shorter sessions are desirable compared to substances like psilocybin or LSD.
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https://doi.org/10.1038/s41386-025-02167-3
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Cite this paper (APA)
Bistue Millón, M. B., Noguera, L., Bruno, D., Vita, L., Zanino, M., Kassuha, D. E., ... & Bruno, M. A. (2025). 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, 1-9.
Study details
Compounds studied
5-MeO-DMT
Placebo
Topics studied
Depression
Anxiety
Microdosing
Safety
Study characteristics
Placebo-Controlled
Double-Blind
Randomized
Bio/Neuro
Participants
36
Humans
Compound Details
The psychedelics given at which dose and how many times
5-MeO-DMT 6 - 12mg | 4x
Linked Clinical Trial
Safety, Tolerability, and Efficacy of Sublingual Microdoses of 5-MeO-DMT for Depression and Anxiety (5-MeO-DMT)This Phase I/II randomised, triple-blind, placebo-controlled trial (n=40) will investigate the safety, tolerability, and potential therapeutic effects of sublingual 5-MeO-DMT (6 mg, 9 mg, or 12 mg) in individuals with elevated symptoms of anxiety and depression. Participants will receive one dose per week for four weeks, with monitoring throughout the trial.