475. Psilocin pharmacokinetics and exposure-response relationships in Japanese patients with treatment-resistant depression receiving psilocybin therapy: an open-label study

Abstract Background Psilocybin, a prodrug metabolized to psilocin, a serotonin 2A receptor agonist, has reemerged as a promising therapeutic option for treatment-resistant depression (TRD). Clinical trials conducted mainly in North America and Europe have demonstrated that psilocybin administered with psychological support can produce rapid and sustained antidepressant effects with favorable tolerability. Previous pharmacokinetic (PK) studies have reported approximately dose-proportional psilocin exposure across clinically relevant oral doses. However, the pharmacokinetics of psilocin and its exposure-response relationships with clinical and subjective outcomes remain unknown in Asian populations, as no clinical trials of psilocybin have been conducted in Asia. Aims & Objectives The primary objective is to characterize plasma psilocin concentration-time profiles and key PK parameters following oral psilocybin administration in Japanese adults with TRD. Secondary objectives are to explore exposure-response relationships between psilocin exposure and (i) changes in depressive symptoms and (ii) the intensity of acute subjective psychedelic experiences.

Method: This is an open-label feasibility trial (jRCTs031230351) conducted at Keio University Hospital, Tokyo, Japan. Twelve Japanese adults with MDD diagnosed according to the DSM-5, who showed inadequate response to two or more antidepressant regimens, were enrolled. Participants received two courses of psilocybin therapy with psychological support, each consisting of one preparatory session, one dosing session, and two integration sessions delivered by psychiatrists and clinical psychologists. Psilocybin was administered orally in capsule form in an inpatient setting under continuous monitoring. The first six participants received 10 mg, and the subsequent six received 25 mg of psilocybin at both dosing sessions, separated by approximately 2-3 weeks. For PK assessment, serial blood samples were collected at 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after psilocybin administration at the second dosing session. Plasma psilocin concentrations were quantified using validated LC–MS/MS (lower limit of quantification: 0.03 ng/mL), and PK parameters (Cmax, Tmax, AUC0–∞, t1/2) were estimated. Exploratory analyses examined exposure-response relationships with changes in depressive symptoms and acute subjective experiences. Depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale, the 24-item Hamilton Depression Rating Scale, and the Quick Inventory of Depressive Symptomatology Self-Report from baseline to after the second dosing session, and followed up to 8 weeks. Acute subjective experiences were assessed using the 30-item Mystical Experience Questionnaire, the Challenging Experience Questionnaire, the Ego-Dissolution Inventory, and a Subjective Drug Intensity rating.

Results: Enrollment began in November 2024, and the trial is ongoing. As of December 14, 2025, 12 participants have been enrolled: 10 have completed all study procedures, 1 withdrew, and 1 is currently undergoing treatment. Study completion is scheduled in February 2026. Psilocin PK profiles, derived PK parameters, and exposure–response analyses with clinical and subjective outcomes will be presented at the congress. Discussion & Conclusions As the first clinical trial of psilocybin therapy for TRD conducted in Japanese patients, this study will provide novel data on psilocin pharmacokinetics and PK/PD relationships in Asian population. These findings may inform dose optimization, efficacy evaluation, and risk management strategies, and contribute to the development of ethnicity-informed clinical use of psilocybin.