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-

To investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of BPL-003, a novel intranasal benzoate salt formulation of 5-methoxy- In all, 44 psychedelic-naïve participants enrolled in the double-blind, placebo-controlled single ascending dose study (1-12 mg BPL-003). Concentrations of 5-MeO-DMT and its pharmacologically active metabolite, bufotenine, were determined in plasma and urine. PD endpoints included subjective drug intensity (SDI) rating, the Mystical Experience Questionnaire (MEQ-30) and the Ego Dissolution Inventory (EDI). BPL-003 was well tolerated at doses up to 12 mg. There were no serious adverse events (AEs), and most AEs were mild; the most common being nasal discomfort, nausea, headache and vomiting. 5-MeO-DMT was rapidly absorbed and eliminated; the median time to peak plasma concentration was approximately 8-10 min and the mean terminal elimination half-life was <27 min. 5-MeO-DMT systemic exposure increased approximately dose-proportionally, while plasma bufotenine concentrations and urinary excretion of 5-MeO-DMT and bufotenine were negligible. The intensity of the SDI ratings was associated with plasma 5-MeO-DMT concentrations. MEQ-30 and EDI scores generally increased with the BPL-003 dose; 60% of participants had a 'complete mystical experience' at 10 and 12 mg doses. Profound and highly emotional consciousness-altering effects were observed with BPL-003, with a rapid onset and short-lasting duration. The novel intranasal formulation of BPL-003 was well tolerated with dose-proportional increases in PK and PD effects. The short duration of action and induction of mystical experiences suggest clinical potential, warranting further trials. NCT05347849.

Déclaration de conflit d'intérêts

Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: C.R. is an employee of Beckley Psytech Ltd. M.S. is currently an employee of Beckley Psytech Ltd but was employed by King’s College London (until July 2022) and is currently completing a PhD with King’s College London. F.W. was an employee of Beckley Psytech Ltd when this study was undertaken. F.D. is a medical advisor to Beckley Psytech Ltd. A.O.E. is a consultant to Beckley Psytech Ltd. J.J.R. has received payments for advisory boards for Clerkenwell Health (Past), Beckley Psytech Ltd (Past), Delica Therapeutics (Past) and articles for Janssen. He has received financial assistance for attendance at conferences from Compass Pathways (past) and Janssen. He has been awarded grant funding (received and managed by King’s College London) from Compass Pathfinder, Beckley Psytech Ltd, Multidisciplinary Association for Psychedelic Studies, National Institute for Health Research, Wellcome Trust, Biomedical Research Centre at the South London and Maudsley NHS Foundation Trust. He has no shareholdings in pharmaceutical companies and no shareholdings in companies developing psychedelics. A.H.Y. is employed by King’s College London and he is an Honorary Consultant of South London and Maudsley NHS Foundation Trust (NHS UK). His independent research is funded by the National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre in South London and Maudsley NHS Foundation Trust and King’s College London. He has previously received funding from Beckley Psytech Ltd. He has received payments for lectures and advisory boards for Flow Neuroscience, Novartis, Roche, Janssen, Takeda, Noema Pharma, Compass, Astrazenaca, Boehringer Ingelheim, Eli Lilly, LivaNova, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, Sage and Neurocentrx. He has received grant funding from the following companies: NIMH (USA); CIHR (Canada); NARSAD (USA); Stanley Medical Research Institute (USA); MRC (UK); Wellcome Trust (UK); Royal College of Physicians (Edin); BMA (UK); UBC-VGH Foundation (Canada); WEDC (Canada); CCS Depression Research Fund (Canada); MSFHR (Canada); NIHR (UK). Janssen (UK) EU Horizon 2020. He is the Editor of the