Safety and tolerability of inhaled N,N-Dimethyltryptamine (BMND01 candidate): A phase I clinical trial

The study used an open-label, single-ascending, fixed-order, dose-response design in healthy volunteers. The protocol was approved by the local ethics committee and registered on ClinicalTrials.gov (NCT05573568). Twenty-seven participants were recruited after medical and psychiatric screening and provided informed consent; candidates were required to abstain from psychedelics and related compounds for 14 days before dosing and 28 days afterwards. Two participants with unsatisfactory inhalation quality were excluded from analyses, and blood could not be collected for two other participants, who were excluded from biochemical analyses. BMND01 consisted of DMT free base (isolated from Mimosa tenuiflora root bark) dissolved in 99% ethanol and vapourised using a Volcano® Medic 2 vapouriser. Participants completed inhalation training (three runs inhaling air from a 2-l balloon) before each dosing. On dosing day (D0) each participant received two sessions in fixed order: a lower safety dose followed 120 minutes later by a higher "psychedelic" dose. Five paired dose schemes were used across participants: 5/20 mg, 7.5/30 mg, 10/40 mg, 12.5/50 mg, or 15/60 mg. During acute effects (+0 to +10 min) at least one psychiatrist, one psychologist and one nurse remained with the participant; music and a prepared physical setting were used as part of the supportive context. Participants completed short integration sessions after each dose and were followed up to day 28. Outcome measures included subjective perceptual ratings (Visual Analogue Scales for intensity [0–100] and valence [−50 to +50], and the Hallucinogen Rating Scale [HRS] with its factors), physiological monitoring (systolic and diastolic blood pressure, heart rate, respiratory rate, peripheral oxygen saturation, axillary temperature measured continuously around acute effects, and peak expiratory flow rate before and after), and biochemical safety markers (glucose, cholesterol profile, triglycerides, AST, ALT, estimated glomerular filtration rate using Cockcroft & Gault). EEG, saliva and acute blood sample analyses were collected but are reported elsewhere. Adverse events were coded using MedDRA terminology. For statistical analysis the investigators used General Linear Models for repeated measures (GLMrep): 'session' (1 vs 2) as a within-subject factor and 'dose' as a between-subject factor, with time point added for physiological and biochemical models where appropriate. BMI was included as a covariate for glucose and lipid measures. Pairwise comparisons and Pearson correlations were performed, with Bonferroni correction for multiple comparisons; significance was set at α = 0.05 (two-tailed). Analyses were conducted using IBM SPSS Statistics (v.22).

Sample flow and exclusions: 27 individuals were enrolled; all completed both sessions, but two subjects (both in the 10/40 mg group) were excluded from analyses for unsatisfactory inhalation quality. Two other subjects were excluded from blood analyses due to missing samples. Subjective effects: There was a robust main effect of session on subjective intensity (F(1,20) = 153.9, p < 0.001, partial η2 = 0.89), with higher intensity ratings in the second (higher-dose) session. A main effect of dose on intensity was observed (F(4,20) = 3.96, p = 0.016), driven by higher means for the 12.5/50 mg group compared with 10/40 mg (pairwise p = 0.012), although some dose comparisons did not survive correction. Valence also showed a main effect of session (F(1,20) = 5.17, p = 0.034, partial η2 = 0.21), with more positive ratings in session 2; there was no reliable main effect of dose on valence. Several HRS factors and selected single HRS items showed main effects of session: visual-related HRS factors increased in session 2, and non-factor items related to emotion ("excited"), control ("ease", "sanity"), and desire to repeat ("satisfaction", "regular") were higher after the second session. Some dose effects were detected for items such as breathing and sanity, but pairwise comparisons often did not survive correction, and small group sizes may limit interpretation. Correlational analyses showed positive associations of dose (5–60 mg range) with intensity (r = 0.584, p < 0.001, n = 54) and with HRS visual distortion (r = 0.437, p = 0.005), as well as with original HRS intensity and perception factors. Physiology: Acute cardiovascular responses were rapid and transient. Systolic blood pressure (SBP) showed a main effect of time point (F(20,400) = 57.5, p < 0.001), with SBP elevated versus baseline from +2 min to +26 min in both sessions. Diastolic blood pressure (DBP) also rose acutely (main effect of time point F(20,400) = 53.0, p < 0.001) and displayed a session-by-time interaction indicating longer elevations in session 2 (up to +24 min) than session 1. Heart rate (HR) increased (main effects of session and time point; interaction p < 0.001), with elevations versus baseline from +2 to +6 min in session 1 and from +2 to +10 min in session 2. Peripheral oxygen saturation (SpO2) transiently increased from +2 to +6 min. Axillary temperature rose in a delayed fashion, with higher means from +24 to +36 min. Peak expiratory flow rate (PEFR) and respiratory rate showed no clinically significant changes. Post-acute measurements at +60 and +120 min indicated return to baseline for physiological parameters. No participant reached hypertensive crisis levels. Biochemistry: No significant effects of time point, dose or interaction were found for glucose, total cholesterol, HDL, LDL, triglycerides, AST or ALT. Estimated GFR showed a small main effect of time point (F(2,36) = 3.78, p = 0.032) but pairwise comparisons did not survive correction; mean values at all time points remained within population norms. Adverse events: Across acute effects on D0, 54 distinct preferred terms were coded into ten system organ classes; all events were mild and 21 terms had incidence >10%. The most frequent events were respiratory, thoracic and mediastinal disorders (n = 56), largely reflecting coughing and throat irritation due to vapour inhalation, followed by general disorders/administration site conditions (n = 35) and nervous system disorders (n = 27). At day 14 only five participants reported mild (n = 4) or one moderate (n = 1) adverse events. No serious adverse events were reported. The investigators characterised most events as mild and likely adverse drug reactions related to inhalation or sympathomimetic physiology. Correlations: Dose showed positive correlations with subjective intensity and visual HRS measures but did not correlate with physiological or biochemical measures, suggesting a closer dose–response relationship for perceptual than for peripheral physiological or laboratory endpoints.

Falchi-Carvalho and colleagues interpret the findings as supporting the safety and tolerability of inhaled DMT (BMND01) in healthy volunteers when administered in a prepared setting with a lower safety dose followed by a higher dose. They emphasise that subjective effects were rapid (seconds to minutes), peaked around 1 minute and subsided within approximately 10–20 minutes, consistent with prior reports for parenteral DMT. The investigators note a dose-dependent increase in perceptual and visual experiences and stronger subjective comfort and control in the second session; however, they acknowledge that the fixed-order design means order effects and increased familiarity likely contributed to greater tolerability in session 2. In physiological terms, the authors highlight transient, self-limited increases in blood pressure and heart rate—up to about 30% above baseline—comparable to moderate-to-vigorous physical activity and without clinical sequelae in this healthy sample. Peripheral oxygen saturation increased briefly and axillary temperature showed delayed small rises; respiratory function measures remained stable, and no biochemical evidence of acute hepatic or renal injury was observed. The main adverse events were inhalation-related airway irritation and mild neuromuscular or autonomic complaints. Consequently, the principal risks identified are sympathomimetic cardiovascular effects and airway hyperresponsiveness from vapour inhalation, leading the investigators to recommend cardiovascular screening and real-time monitoring in future trials. The authors acknowledge key limitations that constrain interpretation and generalisability: the fixed-order (non-randomised) design precludes disentangling dose from order effects; the sample was small, socioeconomically and ethnically homogeneous and included participants with prior psychedelic experience; pharmacokinetic data were not collected so absorbed dose could not be quantified; inhalation technique varied between participants; and ECG morphology, including QT/QRS assessment, was not performed. They recommend future placebo-controlled, randomised designs with pharmacokinetic sampling, larger and more diverse samples, refined administration procedures, and cardiac monitoring to optimise dosing regimens and address possible tachyphylaxis. The investigators also suggest that, if Phase II trials demonstrate antidepressant efficacy, inhaled DMT could offer a non-invasive, shorter-duration, and potentially more scalable outpatient alternative to longer-acting oral psychedelics, while cautioning that clinical claims await such efficacy trials.

In this Phase I, in-lab study the investigators conclude that inhaled DMT (BMND01) was safe and well tolerated in healthy volunteers under the conditions tested, producing rapid, dose-related subjective psychedelic effects alongside mild, transient cardiovascular changes and mostly mild inhalation-related adverse events. They propose that inhaled administration may offer practical advantages over longer-acting oral psychedelics and a non-invasive alternative to intravenous routes, and that this approach warrants further testing in Phase II trials to establish antidepressant efficacy and broader clinical utility.