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

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.

This Phase I trial used a randomised, double-blind, placebo-controlled parallel-arm design. Recruitment occurred October–December 2024 and primary outcome assessments were completed by February 2025. Eligible volunteers were adults aged 40–80 years who provided written informed consent and met cut-offs for moderate to high anxiety and/or depression on standardized scales (STAI-S and STAI-T ≥ 20; Beck Depression Inventory ≥ 21), but they did not have a confirmed psychiatric diagnosis or ongoing psychiatric treatment. Key exclusions included recent use (within 90 days) of benzodiazepines, tricyclic antidepressants, stimulants, monoamine oxidase inhibitors or other agents affecting serotonin. Recruitment channels included social media and personal invitations. The extracted text reports that 114 individuals were screened, 72 were excluded, 42 met initial eligibility, two were disqualified after further evaluation and 40 were enrolled; four participants dropped out, resulting in a final analysed sample of 36 participants (n = 9 per arm). Note: the extracted text contains slightly inconsistent statements about enrolment (see Results), so the final analysed sample is reported as 36 (9 per group) in several sections. Participants were randomised to receive weekly sublingual administrations of BMND08 (5-MeO-DMT) at 6 mg, 9 mg, 12 mg or placebo for four consecutive weeks. The investigational product is a GMP-certified sublingual formulation intended for rapid absorption; product specifications were referenced to supplementary material. Safety monitoring included vital signs (blood pressure, heart rate, oxygen saturation, respiratory rate, temperature), 12-lead ECGs, and serial biochemical tests assessing hematological, renal, hepatic, cardiac and inflammatory markers. Adverse events (AEs) were captured at each visit and by phone and coded using MedDRA v27.0. Cognitive assessments (verbal fluency FAS, PASAT, Digit Span Sequencing) were administered to evaluate potential cognitive effects. Neurophysiological assessment comprised resting-state EEG recorded with eyes closed and open: 5 min baseline (eyes closed), 38 min post-administration (eyes closed) and 2 min eyes open, sampled at 256 Hz and filtered to 0.5–42 Hz. Power spectral density was estimated with Welch's periodogram using 4-s Hann-windowed segments with 50% overlap. Pharmacokinetic analysis was performed only for the 12 mg group using EDTA plasma samples drawn pre-dose and at 5, 10, 20, 30, 40, 50, 60 and 120 min post-dose. Quantification used UHPLC–HRMS and non-compartmental analysis to derive Cmax, Tmax, AUC, t1/2, clearance and apparent volume of distribution. Acute subjective effects were assessed retrospectively 1 h after dosing using the Peak Experience Scale (PES), Ego Dissolution Inventory (EDI) and the Mystical Experiences Questionnaire (MEQ-30). Statistical analyses used GraphPad Prism and R: distribution tests (D'Agostino or Pearson K2), t tests or non-parametric equivalents for group comparisons, ANOVA or Kruskal-Wallis for multi-group comparisons, and linear mixed-effects models (dose as fixed effect, week as repeated measure, subject ID random intercept) for repeated subjective measures. Pharmacokinetic parameters were computed with non-compartmental methods in R. Statistical significance threshold was p < 0.05.

Sample and protocol adherence: The extracted text reports that 36 adults (21 females, 15 males) aged 41–76 were randomised and analysed in four parallel arms (placebo, 6 mg, 9 mg, 12 mg) with n = 9 per group. Earlier extraction lines indicate 40 enrolled with four dropouts leaving 36; the manuscript consistently reports a final analysed sample of 36 participants. Body mass index did not change significantly between baseline and week 5 in any group (dependent t test, p > 0.05). Safety, tolerability and cognition: Across the trial there were no serious adverse events or discontinuations attributable to the study drug. A total of 19 treatment-emergent adverse events were recorded, all graded as mild (Grade 1); commonly reported events included nausea, headache, muscle discomfort, transient increased heart rate and dizziness. The 12 mg group accounted for the largest share of events (12 events, 63% of AEs). All AEs resolved spontaneously without medical intervention. No clinically meaningful changes were observed in vital signs, ECG parameters, hematology or biochemical markers of liver, kidney, metabolic or cardiac function. Neurocognitive tests administered 90 min after dosing (FAS, PASAT, Digit Span Sequencing) showed no adverse effects on semantic or phonological verbal fluency, processing speed, working memory or attentional control at any dose compared with placebo. Pharmacokinetics (12 mg group): Non-compartmental analysis of the 12 mg cohort showed rapid absorption with a median Tmax of 20 min post-dose and a mean elimination half-life (t1/2) of 28.15 min. Mean peak plasma concentration (Cmax) was 2.23 µg/L and the area under the concentration–time curve (AUC) was 105.36 µg•min/L. Clearance (CL) was 0.11 L/min and apparent volume of distribution (Vd) 4.63 L. The investigators report no evidence of drug accumulation over the repeated weekly dosing schedule. Subjective acute effects: Retrospective ratings at 1 h indicated that overall PES, MEQ-30 and EDI scores remained below commonly used cut-offs for profound psychedelic experiences (average PES < 75, MEQ < 60), consistent with a sub-psychedelic classification. Within-group comparisons across weeks showed no statistically significant cumulative increases (Kruskal-Wallis, p > 0.05). Between-group comparisons revealed that the 12 mg group had significantly higher PES, MEQ and EDI scores versus placebo during weeks 1 and 2 (Kruskal-Wallis with Dunn's post-hoc, p < 0.05). The 9 mg group showed higher PES in week 1 and higher MEQ in weeks 1 and 2 versus placebo (p < 0.05). The 6 mg group did not differ from placebo across the four weeks. Linear mixed-effects modelling identified significant dose-by-week interactions for PES, EDI and MEQ-30, with the 12 mg group showing the largest effects (PES β = 30.64, p < 0.001; MEQ β = 23.56, p < 0.01; EDI β = 25.34, p < 0.01). The investigators also observed a progressive attenuation of subjective effects across repeated weekly dosing, particularly in higher dose groups. EEG findings: Baseline EEG spectra were comparable across groups. At 15 min post-dose, all 5-MeO-DMT dose groups showed a suppression of alpha (8–12 Hz) power relative to baseline, contrary to the placebo group where alpha power increased in the eyes-closed rest condition. Dose-dependent attenuation was also observed in theta (4–8 Hz) and delta (1–4 Hz) bands, with more pronounced suppression at 9 mg and 12 mg than at 6 mg. These spectral changes indicate rapid, dose-responsive modulation of resting-state neural oscillations 15 min post-administration. Blinding: Participants completed a post-study questionnaire about perceived assignment; a generalised linear mixed model found no significant effects of dose, week or their interaction on guess accuracy (all p > 0.05). There was a non-significant trend toward higher correct guessing in the 9 mg and 12 mg groups, suggesting that stronger subjective effects at higher doses may have partially reduced blinding effectiveness, but overall blinding was judged to be preserved.

Beatriz and colleagues interpret the findings as evidence that sublingual 5-MeO-DMT administered weekly at 6 mg, 9 mg or 12 mg is well tolerated in adults with moderate symptoms of anxiety and/or depression and produces rapid, short-lived pharmacokinetic exposure with minimal accumulation. The study team emphasises that all adverse events were mild and self-limited, that there were no clinically meaningful changes in vital signs, ECGs or laboratory safety parameters, and that cognitive performance was preserved. The 12 mg arm showed the highest incidence of mild AEs but no psychotic or severe adverse reactions were observed, and participants maintained normal daily activities throughout the trial. The investigators link the rapid Tmax (median 20 min) and short elimination half-life (mean t1/2 ~28 min for the 12 mg group) to the profile of brief subjective effects and to the EEG changes observed 15 min post-dose. They note a dose-dependent suppression of alpha, theta and delta power relative to eyes-closed resting state in placebo, suggesting that 5-MeO-DMT disrupts intrinsic resting-state rhythms even at sub-psychedelic doses. Subjective ratings remained below thresholds typically associated with profound psychedelic states, supporting the sub-psychedelic classification; nevertheless, the 12 mg dose produced measurable increases in PES, MEQ and EDI scores relative to placebo during the early weeks. The authors acknowledge several limitations. The extracted text notes that the study did not measure the primary metabolite bufotenine and therefore cannot comment on its presence or potential effects. The sample size is modest and the trial is a Phase I safety/tolerability study rather than an efficacy trial; efficacy-related outcomes are said to be under analysis and will be reported separately. The investigators also raise uncertainty about the progressive attenuation of subjective effects with repeated dosing, suggesting this could reflect psychological accommodation (reduced novelty or expectancy shifts) rather than pharmacodynamic tolerance, and they call for larger studies to distinguish these possibilities. In conclusion, the study team frames this trial as a pioneering safety and pharmacokinetic characterisation of a sublingual 5-MeO-DMT formulation, providing foundational data to justify further clinical research. They highlight preserved blinding, the favourable safety profile across tested doses, and objective neurophysiological effects as supporting the feasibility of repeated sub-psychedelic dosing in future trials targeting clinical populations. Efficacy and longer-term safety remain to be established in subsequent studies.