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

Introduction

Psychedelic compounds act primarily at serotonin receptors and can produce marked effects on perception, emotion and cognition without promoting dependence or withdrawal. Earlier research has established therapeutic potential for several classical serotonergic psychedelics in conditions such as anxiety, depression and PTSD, and distinguishes between macrodoses that elicit full psychedelic experiences and microdoses that are intended to produce subtler, daily-compatible benefits. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a potent, short-acting tryptamine with higher affinity for 5-HT1A receptors than DMT; it is orally inactive because of MAO metabolism but can be delivered via inhalation, intranasal, intravenous, intramuscular, rectal or sublingual routes. Clinical evidence specifically for 5-MeO-DMT has been limited to a small number of trials, observational reports and anecdotal data, leaving gaps in knowledge about repeat dosing, tolerability and objective neurophysiological effects. This study aimed to characterise the safety, tolerability and pharmacokinetics of a proprietary sublingual 5-MeO-DMT formulation (BMND08) administered at sub-psychedelic doses in adults with moderate symptoms of anxiety and/or depression but without formal psychiatric diagnoses or current treatment. Using a randomised, double-blind, placebo-controlled Phase I design with four parallel arms (placebo, 6 mg, 9 mg, 12 mg), the investigators administered one sublingual dose per week for four weeks and assessed clinical safety, EEG changes, pharmacokinetics and acute subjective effects. The stated objective was to identify sub-psychedelic doses that produce neurophysiological and psychological changes while maintaining a favourable safety and tolerability profile, thereby informing future therapeutic studies.