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.

In this first-in-human Phase I clinical trial, a novel sublingual formulation of 5-MeO-DMT was tested at sub-psychedelic doses in adults with moderate to high anxiety and/or depression, but without a formal psychiatric diagnosis or ongoing treatment. The compound was well tolerated across all groups (6 mg, 9 mg, or 12 mg), with no significant adverse events or organ toxicity; mild side effects like nausea and headache were transient. Pharmacokinetics showed rapid absorption, peak plasma concentrations within a median of 20 minutes, and no drug accumulation. Dose-dependent modulation of brain activity occurred without full psychedelic effects, and participants maintained normal daily activities. These results support the safety and feasibility of repeated sub-psychedelic dosing and lay groundwork for future therapeutic trials.

Study at a glance

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.