Identification of a Safe and Non-Psychedelic Dose of Psilocybin

Overview

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 psychoactive effects. The TD will be the dose immediately before the dose at which escalation stops because of neuropsychiatric adverse events and/or a pharmacodynamic response pattern indicating a dose above the nonpsychoactive level. The study will end when a TD is identified or the 5 mg maximum dose is reached.

This study in healthy volunteers will evaluate the safety, pharmacodynamic effects, and pharmacokinetics of psilocybin and its primary active metabolite, psilocin, as a potential therapy for anxiety and depressive disorders after single ascending oral doses. The study is intended to support dose selection by identifying a threshold dose (TD) of psilocybin that does not produce psychoactive effects that would preclude outpatient or potential repeated dosing. The study will use a randomized, double-blind, placebo-controlled, single ascending dose design in healthy adult male and female subjects. Each subject will complete an outpatient Screening Visit (Visit 1), a 3-day/2-night inpatient Treatment Phase (Visit 2), and an outpatient Follow-Up Visit (Visit 3). The Treatment Phase begins the day before dosing (Day -1) and ends on Day 2. Screening Visit (Visit 1) Subjects will provide written informed consent before protocol-specified procedures. To reduce expectancy effects common in psychedelic studies, subjects will be told verbally and in the informed consent form that they may receive placebo or one of five drug classes/substances-niacin, alprazolam, ibuprofen, psilocybin, or methylphenidate-although they will actually receive only placebo or psilocybin. The informed consent form will describe safety risks associated with the listed substances, with no added risk from substances not administered. Screening will be completed within 28 days before admission for the Treatment Phase. Treatment Phase (Visit 2) Up to 80 subjects will be enrolled in a maximum of 10 cohorts. Each cohort will include 8 subjects randomized so that 6 receive a single oral dose of psilocybin and 2 receive matching placebo. The first cohort will receive 0.5 mg psilocybin or placebo. Subsequent dose levels will be determined by the Drug Safety Review Committee (DSRC) after review of each completed dosing level. Proposed psilocybin doses are 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, and up to 5 mg. Depending on emerging safety, tolerability, pharmacodynamic, or other relevant data, lower-than-planned doses may be tested, dose levels repeated, or smaller increments used (e.g., 0.25 mg). Proposed dose levels include 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, up to a maximum dose of 5 mg. Within the planned dose range, a dose lower than the planned dose may be tested, a dose level may be repeated, or smaller dosing increments may be applied (e.g., 0.25 mg), depending on emerging safety, tolerability, and/or other relevant data, such as pharmacodynamic data. Within each cohort, safety and pharmacodynamic data will be collected through 24 hours post dose. Safety monitoring will include adverse events (AEs), vital signs, electrocardiograms, clinical laboratory tests, physical examinations, concomitant medications, and Columbia-Suicide Severity Rating Scale results. Blood samples for pharmacokinetic assessments will be collected before and after dosing, and whole blood for possible retrospective pharmacogenetic analysis will be collected on Day -1. Pharmacodynamic assessments will include Alertness/Drowsiness, Agitation/Relaxation, Hallucinations, Any Effects, Bowdle internal/external perceptions, Bond-Lader, 5D-ASC, and State-Trait Anxiety Inventory measures. Cognitive and psychomotor assessments will include the 5-choice reaction time task, rapid visual information processing task, and spatial working memory task. Pupil diameter will serve as an objective physiological pharmacodynamic measure. Subjects will also be encouraged to report effects not captured by scales; such effects may be recorded as AEs at the investigator's discretion. To assess expectancy, subjects will be asked on Day 1 what treatment they believe they received and again before discharge on Day 2. Subjects will be discharged on Day 2 after completion of study procedures if no medical reason requires a longer stay. They will receive a 24-hour/7-day emergency clinic contact number. After each cohort, available blinded safety and pharmacodynamic data through 24 hours post dose will be reviewed by the DSRC before the next cohort begins. Escalation and any decision to stop the study will follow prespecified stopping rules. Because the goal is to identify a safe nonpsychoactive dose, the TD will be the dose immediately before the dose at which escalation stops because of neuropsychiatric AEs and/or the collective pharmacodynamic response pattern. Once a TD is identified, or the maximum dose of 5 mg is reached, the study will conclude. Follow-Up Visit (Visit 3) A Follow-Up Visit will occur 7±2 days after final study drug administration and will include end-of-study procedures. Dose Selection Rationale The planned starting dose is 0.5 mg, consistent with the objective of identifying a TD without perceptible psychoactive effects that would preclude outpatient or repeated dosing. Perceptible effects have been reported at plasma psilocin concentrations of 4 to 6 ng/mL. In a PET study of healthy subjects receiving single oral psilocybin doses of 3 to 30 mg (n=8), subject-rated effect intensity correlated with plasma psilocin concentration, with an EC50 of 4.5 ng/mL (95% CI: 2.1, 9.8). Dose-related neocortical 5-HT2A receptor occupancy ranged from 1.8% at 3 mg to 72% at 18 mg, with an EC50 of 1.95 ng/mL (95% CI: 1.17, 3.15). Follow-up results indicated that 5-HT2A receptor occupancy up to approximately 15% produced no perceptual subjective effects. Therefore, 0.5 mg and doses up to 2 mg are expected to produce exposures below 2 ng/mL and no perceptible subjective effects, although intersubject variability in exposure and response is recognized. The planned maximum dose of 5 mg is based on a prior study in 18 healthy subjects showing perceptible effects at this dose, and earlier studies suggesting that 3 to 5 mg psilocybin may produce perceptible sympathomimetic, but not hallucinogenic, effects depending on intersubject differences. Low-dose psilocybin (≤5 mg) is associated with very few or no treatment-emergent AEs, and doses up to about 8 times the proposed maximum (6 to 42 mg/70 kg) have been considered safe and well tolerated; most reported events were mild or moderate, with no serious AEs reported. The planned maximum oral psilocybin dose of 5 mg is based on a prior study of 18 healthy subjects indicating that this dose level was associated with perceptible effects, as well as earlier studies suggesting that psilocybin 3 to 5 mg (range due to inter-subject differences) may have perceptible sympathomimetic, but not hallucinogenic, effects. In addition, low-dose psilocybin (≤5 mg) is associated with very few or no TEAEs, while doses up to approximately 8 times the proposed maximum dose of 5 mg (6 to 42 mg/70 kg) are considered to be safe and have been well tolerated; the majority of events for which severity has been reported are mild or moderate in severity, and no serious AEs have been reported. Dose Escalation Stopping Criteria Dose escalation between cohorts will be interrupted and may be discontinued if any drug-related serious adverse event occurs in 1 or more subjects; if drug-related neuropsychiatric AEs of moderate intensity occur in 2 or more subjects; or if the DSRC concludes, based on the pattern, number, and severity of AEs and/or the collective pharmacodynamic response pattern excluding pupillometry, that a dose exceeding a nonpsychoactive dose has been reached. Removal of Subjects from Therapy or Assessment Subjects may withdraw consent and discontinue participation at any time for any reason. Subjects may also be discontinued by the investigator and/or sponsor for protocol entry violation, safety reasons including AEs, unacceptable concomitant medication use, noncompliance or major protocol violation, pregnancy, positive urine drug screen or breath alcohol test, administrative reasons such as termination of enrollment or study, or because continuation is not in the subject's best interest. The investigator will maintain a record of all subjects who discontinue before completion and document the reason(s). If a subject withdraws, the investigator should make a reasonable attempt to obtain and record the reason, although the subject is not required to provide one. If discontinuation occurs while the subject is at the clinical site, early termination procedures should be completed before discharge. For any early discontinuation, whether or not the subject is on site, the investigator should ask the subject to return for Follow-Up Visit procedures unless consent for those procedures has been withdrawn. Refusal to complete early termination or Follow-Up Visit procedures will be recorded. In the event that a subject is discontinued while at the clinical site, the early termination procedures should be performed prior to discharge from the study site. For any case of early discontinuation (whether or not the subject is at the clinical site), the investigator should ask the subject to return for the Follow-Up Visit procedures, provided that the subject has not withdrawn consent for those procedures. If a subject refuses to complete early termination procedures and/or the Follow-Up Visit, this information will be recorded. Study Restrictions In addition to inclusion/exclusion criteria, subjects must abstain from alcohol for 48 hours before Screening and before Treatment Phase admission (Day -1), confirmed by breath alcohol test. They will be asked to avoid strenuous physical activity for 48 hours before Screening and admission and may not perform strenuous exercise during the inpatient stay. Subjects must abstain from recreational drug use from Screening until after the Treatment Phase, confirmed by urine drug screen. From 1 week before dosing until after the final pharmacokinetic draw, they must avoid grapefruit or grapefruit products, pomegranate, pomelo, star fruit juice/products, poppy seeds, Seville oranges, apple juice, orange juice, and mustard-family vegetables such as kale, broccoli, watercress, collard greens, kohlrabi, brussels sprouts, and mustard. Subjects must fast for at least 10 hours before dosing and 4 hours after dosing; water is allowed except for about 1 hour before and after dosing. Caffeine/methylxanthine products are prohibited for 48 hours before dosing and while housed at the site. Smoking is prohibited for the study duration. Electronic devices are prohibited for 1 hour before and at least 6 hours after dosing. Subjects should avoid driving, machinery, or hazardous activities until they and clinic staff confirm the study drug has not impaired judgment or skilled-task performance. Subjects must remain awake and seated upright for at least 4 hours after dosing, rising only briefly under supervision for study activities or washroom use; afterward, they may ambulate within the clinic. If an AE occurs, they may be placed in an appropriate position at any time. For at least 1 hour after dosing, washroom visits will be monitored and recorded, and subjects may not flush so staff can inspect contents. Subjects must abstain from blood donation during the study and for 30 days after Follow-Up.