Abstract <p>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.</p> Trial Registration <p>ClinicalTrials.gov: NCT06816667</p>