Pharmacokinetics and pharmacodynamics of oral psilocybin administration in healthy participants

Psilocybin is being investigated as a potential treatment for psychiatric and neurological disorders. Only a few studies have evaluated the pharmacokinetics of psilocybin and have used body weight-adjusted dosing. Data on pharmacokinetics and the pharmacokinetic-pharmacodynamic relationship of fixed doses that are commonly used are unavailable. The present study characterized the pharmacokinetics and pharmacokinetic-pharmacodynamic relationship of 15, 25, and 30 mg of orally administered psilocybin in 28, 23, and 28 healthy subjects, respectively. Plasma levels of unconjugated psilocin (the psychoactive metabolite of psilocybin) and corresponding subjective effects were repeatedly assessed up to 24 h. Pharmacokinetic parameters were determined using compartmental modelling. Concentration-subjective effect relationships were described using pharmacokinetic-pharmacodynamic modelling. Mean (95% confidence interval) maximal psilocin concentrations were 11 ng/ml (10-13), 17 ng/ml (16-19), and 21 ng/ml (19-24) after the administration of 15, 25, and 30 mg psilocybin, respectively. Maximal concentrations were reached after an average of 2 h. Elimination half-lives were 1.8 h (1.7-2.0), 1.4 h (1.2-1.7), and 1.8 h (1.6-1.9) for 15, 25, and 30 mg psilocybin, respectively. Mean (± SD) durations of subjective effects were 5.6 ± 2.2 h, 5.5 ± 1.6 h, and 6.4 ± 2.2 h, and maximal effects (“any drug” effects) were 58% ± 25%, 73% ± 27%, and 80% ± 18% after 15, 25, and 30 mg psilocybin, respectively. Psilocin exhibited dose-proportional pharmacokinetics. The duration and intensity of subjective effects were dose-dependent. Body weight did not influence pharmacokinetics or the response to psilocybin. These data may serve as a reference for future clinical trials.