Phase 1, placebo-controlled, single ascending dose trial to evaluate the safety, pharmacokinetics and effect on altered states of consciousness of intranasal BPL-003 (5-methoxy-N,N-dimethyltryptamine benzoate) in healthy participants

Classic serotonergic psychedelics produce characteristic altered states of consciousness through activity at serotonin (5-HT) receptors, notably partial agonism at 5-HT2A. 5‑Methoxy‑N,N‑dimethyltryptamine (5‑MeO‑DMT) is a short‑acting tryptamine with high affinity across several 5‑HT receptors but preferential binding to 5‑HT1A versus 5‑HT2A. Preclinical work shows rapid metabolism of 5‑MeO‑DMT to inactive metabolites and the active metabolite bufotenine via CYP2D6, and animal models suggest behavioural and electrophysiological effects that can be differentially modulated by 5‑HT1A and 5‑HT2A antagonists. Human data on 5‑MeO‑DMT are sparse, limited largely to small observational studies and naturalistic reports, but its rapid onset and short duration have led to interest in clinical development as a potentially efficient psychedelic therapeutic. Rucker and colleagues set out to characterise the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of a novel intranasal dry‑powder benzoate salt formulation of 5‑MeO‑DMT (BPL‑003) in psychedelic‑naïve healthy adults. The trial aimed to determine dose‑exposure relationships and to assess subjective altered‑consciousness outcomes (including the Mystical Experience Questionnaire and Ego Dissolution Inventory) across an ascending single‑dose range, to inform selection of doses for further clinical development.

This was a Phase I, double‑blind, randomised, placebo‑controlled single ascending dose study conducted at a clinical research unit in London. Forty‑four healthy adults aged 25–55 years with body mass index 18.0–30.9 kg/m2 and no prior psychedelic use were enrolled. Participants were allocated into seven cohorts (up to seven participants per cohort); doses of BPL‑003 covered a range from 1 mg up to 12 mg, with up to two participants per cohort receiving placebo. The extracted text does not clearly report the exact dose assigned to every cohort, but the overall dose range and cohort structure are described. Sentinel dosing was used (two participants per cohort, one active and one placebo dosed ~23 h before the remainder) and a Safety Review Committee evaluated safety, tolerability, PK and PD data before dose escalation. Participants underwent screening up to 56 days prior to dosing and received two preparatory visits with a trained psychedelic monitor. Dosing occurred in a furnished room with supportive monitoring: an indwelling intravenous catheter was inserted, one nurse and one psychedelic monitor remained present, guided breathing and music were used, and participants were semi‑supine for intranasal administration. BPL‑003 or matching placebo was administered as a single intranasal spray into one nostril using an Aptar Unidose dry powder device by a trained clinician. Participants stayed overnight and had an integration visit 2 days later and a follow‑up at about 7 days. Safety assessments included recording treatment‑emergent adverse events (TEAEs), clinical laboratory tests, vital signs (blood pressure, heart rate, temperature), ECGs, nasal examinations, the Columbia‑Suicide Severity Rating Scale (C‑SSRS) and screening for post‑traumatic stress disorder symptoms (PCL‑5) and hallucinogen‑persisting perception disorder (HPPD) at follow‑up. Pharmacokinetic sampling quantified plasma and urine 5‑MeO‑DMT and bufotenine by validated LC‑MS/MS (lower limit of quantification approx. 0.5 ng/mL); urine was collected for 0–6 h post‑dose. Reported PK parameters included Cmax (peak concentration), tmax (time to Cmax), AUC (area under concentration‑time curve), terminal half‑life (t½) and clearance metrics. Pharmacodynamic measures comprised repeated subjective drug intensity (SDI) ratings every 2 min for up to 90 min post‑dose (0–10 Likert), the Mystical Experience Questionnaire (MEQ‑30) with a defined threshold for a 'complete mystical experience' (⩾60% on each subdomain), the Ego Dissolution Inventory (EDI; visual analogue scales), the Challenging Experience Questionnaire (CEQ), and an optional micro‑phenomenology qualitative interview conducted immediately after the acute effects subsided. The trial was exploratory with no formal hypothesis testing or sample size calculation; summary statistics were used and missing data were not imputed.

Forty‑four participants were enrolled: 31 received a single dose of BPL‑003 and 13 received placebo. All 31 active participants were included in PK and PD analyses. The sample was predominantly male (73%) and white (59%), according to supplemental tables referenced in the text. Safety and tolerability: Overall, 21 participants (47.7%) experienced one or more TEAEs: 19 of 31 (61.3%) in the BPL‑003 group and 2 of 13 (15.4%) in the placebo group. There were no serious adverse events and no TEAEs leading to withdrawal. Most TEAEs were mild (89.5% of events, 34/38) and 10.5% were moderate; the most frequent events were nasal discomfort, nausea, headache and vomiting. Transient increases in heart rate and blood pressure were observed after dosing but returned to baseline within the 90‑minute observation window without intervention. Seven BPL‑003 participants (22.6%) had two or more post‑dose heart rate readings >100 bpm (range 101–166 bpm). Post‑dose systolic blood pressure above the reference range occurred in 15 BPL‑003 participants (48.4%; range 141–181 mmHg) and diastolic elevations in 17 participants (54.8%; range 91–113 mmHg); five participants had transient systolic BP >160 mmHg. No increases in suicidal ideation were recorded and no HPPD or PTSD symptoms were identified at the 1‑week follow‑up. Pharmacokinetics: 5‑MeO‑DMT was rapidly absorbed after intranasal dosing, with median tmax across dose levels of approximately 4–15 min and arithmetic mean terminal half‑life (t½) of about 15–27 min. Plasma concentrations fell below the limit of detection by 4 h post‑dose. Systemic exposure generally increased with dose: the geometric mean Cmax was reported as 5.7 ng/mL after 1 mg and 28.2 ng/mL after 12 mg. Apparent clearance (CL/F) ranged widely (522–953 L/h) and there was no dose that exceeded pre‑defined toxicokinetic thresholds derived from animal data (Cmax threshold 421 ng/mL; AUC threshold ~213 h·ng/mL). Plasma bufotenine concentrations were below quantification limits (<0.5 ng/mL) except for one sample in one participant. Urinary excretion of unchanged 5‑MeO‑DMT was negligible, with mean fraction excreted up to 6 h ranging from 0.06% to 0.38%; urine bufotenine was also below quantification. Pharmacodynamics and subjective effects: SDI ratings from both participants and monitors rose with increasing dose, with rapid onset typically within 2–10 min and effects generally resolving within 45–90 min. Peak SDI coincided approximately with plasma tmax and declined as plasma concentrations fell, indicating a temporal association between PK and acute subjective intensity. MEQ‑30 total and subdomain scores increased with dose: mean total score reached 3.7 at 12 mg versus 0.6 for placebo. A 'complete mystical experience' (⩾60% on all four MEQ‑30 subdomains) was reported in 3 of 5 participants (60%) at both 10 mg and 12 mg doses; lower doses yielded at most one complete mystical experience per cohort (⩽25%). EDI scores also rose with dose: mean total EDI was 7.2 for placebo, 45.0 for 8 mg (n=5), 41.1 for 10 mg (n=5) and 74.3 for 12 mg (n=5). Challenging experiences as measured by CEQ were moderate: subdomain scores were generally <40% and total CEQ scores ranged 20%–35% for BPL‑003 doses of 4–12 mg. On acceptability at follow‑up, 27 of 31 (87%) BPL‑003 recipients said they would accept the same or a higher dose in future; four participants indicated they would not, citing unpleasantness or re‑experiencing painful memories. Qualitative micro‑phenomenology interviews (reported descriptively) described a consistent temporal progression: rapid onset, inward focus, altered time perception, intense emotion and sometimes fear early on, with the possibility of 'letting go' leading to sensations of floating, calmness or bliss and later reflective insight. Higher doses (10–12 mg) more commonly produced full mystical experiences and ego dissolution.

Rucker and colleagues interpret these Phase I findings as indicating that single intranasal doses of BPL‑003 up to 12 mg are generally safe and well tolerated in healthy, psychedelic‑naïve adults, with predictable, dose‑proportional pharmacokinetics and a short duration of action. The investigators highlight a rapid absorption (tmax ≈10 min) and short terminal half‑life (≈20 min) that matched the acute subjective experience duration (approximately 45–90 min). Most adverse events were mild and transient, and no serious adverse events occurred; transient increases in heart rate and blood pressure were observed but resolved without intervention. The authors position the PD results in the context of prior 5‑MeO‑DMT reports, noting that BPL‑003 elicited profound consciousness‑altering effects including mystical experiences and ego dissolution that increased with dose. A dose range of 10–12 mg produced a 'complete mystical experience' in 60% of participants, and 8–12 mg is suggested as a potential range for further clinical development. The investigators underline a clear temporal relationship between plasma 5‑MeO‑DMT concentrations and subjective drug intensity, supporting close PK–PD coupling for this intranasal formulation. Limitations acknowledged by the study team include the controlled hospital‑like setting and enrolment of healthy volunteers, which may limit generalisability to patients or to other environments. Functional unblinding is noted as inevitable in psychedelic trials and may have influenced subjectively rated outcomes. The authors also point out the short follow‑up (1 week) for assessments such as PTSD or HPPD and note that longer surveillance would be required to detect rarer or delayed adverse psychiatric events. They advise cautious progression into patient trials with careful eligibility criteria and monitoring, given reports of serious psychiatric adverse events with other serotonergic hallucinogens in the literature. Finally, the investigators observe interindividual variability in dose‑response: some participants had strong effects at 8 mg while others did not reach a full mystical experience at 12 mg, mirroring variability reported in other 5‑MeO‑DMT studies. They suggest this variability and the favourable acute safety and PK profile support further investigation of BPL‑003 in neuropsychiatric conditions, while emphasising the need for controlled patient studies and appropriate safety precautions.

This Phase I single ascending dose trial found that intranasal BPL‑003 (5‑MeO‑DMT benzoate) up to 12 mg was safe and well tolerated in healthy psychedelic‑naïve adults and produced rapid, short‑lasting profound psychedelic effects. Pharmacokinetic profiles were predictable and dose‑related, and higher doses (8–12 mg) increased measures of mystical experience and ego dissolution. The authors conclude that doses between 8 and 12 mg warrant further clinical development for neuropsychiatric indications with high unmet need.