Pharmacokinetics and safety of a modified‐release psilocybin formulation: A SAD Phase I trial in normal‐weight and overweight/obese participants

Aims This study aimed to evaluate the safety, tolerability and pharmacokinetics of a novel oral modified‐release psilocybin formulation (REL‐P11) in normal‐weight and overweight/obese healthy adults and to assess its suitability for controlled, subperceptual exposure, in light of emerging evidence supporting serotonergic modulation in metabolic disorders. Methods Simulation‐based modelling compared predicted psilocin exposure with immediate‐release formulations. Then, a randomized, double‐blind, placebo‐controlled, single ascending dose Phase I study was conducted in eight normal‐weight and 32 overweight/obese adults. Single oral doses of 0.5, 1.0, 1.5 and 2.0 mg of REL‐P11 were administered. Plasma psilocin concentrations were measured using liquid chromatography–mass spectrometry, and pharmacokinetic parameters were derived using non‐compartmental analysis. Results Simulations indicated lower peak concentrations and prolonged absorption with the modified‐release formulation compared with immediate‐release psilocybin. No serious adverse events or adverse events of special interest (AESIs) occurred among REL‐P11‐treated participants, and no clinically meaningful treatment‐related changes were detected in the prespecified psychometric and safety assessments. Psilocin exposure increased proportionally with dose, with low interindividual variability. At the 2‐mg dose, pharmacokinetic parameters were broadly comparable between normal‐weight and overweight/obese participants, and median time to peak concentration was approximately 2 h. Conclusions Low‐dose modified‐release psilocybin provides predictable systemic exposure without measurable psychoactive effects across body weight categories. While these properties, together with preclinical evidence, are of potential interest in the context of metabolic regulation, the present findings remain preliminary. Further clinical studies are warranted to determine whether the favourable pharmacokinetic profile observed with controlled subperceptual psilocybin dosing translates into clinically relevant pharmacological and therapeutic effects in metabolic and liver‐related disorders.