Identification of a Safe and Non-Psychedelic Dose of Psilocybin

This randomized, double-blind, placebo-controlled, single ascending dose study will evaluate psilocybin in healthy adult subjects. Each subject will complete Screening within 28 days before admission, a 3-day/2-night inpatient Treatment Phase from Day -1 to Day 2, and Follow-Up 7±2 days after dosing. Up to 80 subjects will be enrolled in up to 10 cohorts of 8 subjects. In each cohort, 6 will receive a single oral dose of psilocybin and 2 matching placebo. The first cohort will receive 0.5 mg psilocybin or placebo. The DSRC will determine subsequent dose levels after each completed cohort. Proposed doses are 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, and up to 5 mg; lower doses, repeated levels, or smaller increments such as 0.25 mg may be used based on emerging data. Within each cohort, safety and pharmacodynamic data will be collected through 24 hours post dose. Safety monitoring will include adverse events, vital signs, ECGs, laboratory tests, physical examinations, concomitant medications, and C-SSRS results. Pharmacokinetic blood samples will be collected before and after dosing, and blood for possible retrospective pharmacogenetic analysis will be collected on Day -1. Pharmacodynamic assessments will include Alertness/Drowsiness, Agitation/Relaxation, Hallucinations, Any Effects, Bowdle, Bond-Lader, 5D-ASC, and STAI measures. Cognitive and psychomotor testing will include RTI, RVP, and SWM tasks. Pupil diameter will be measured as an objective marker. Other subject-reported effects may be recorded as adverse events at the investigator's discretion. Subjects will be discharged on Day 2 if medically appropriate and will receive a 24-hour/7-day emergency clinic contact number. After each cohort, the DSRC will review available blinded safety and pharmacodynamic data through 24 hours post dose before the next cohort begins. Escalation and any decision to stop will follow prespecified rules. The study aims to identify a safe threshold dose (TD) that does not elicit ps