Each participant will begin with a screening visit (V1), during which eligibility will be determined through clinical and psychiatric assessments of the participant's physical and mental health. Following confirmation of eligibility, the study procedures will begin.
The participant will begin with a 2-4 week tapering period during which they will taper and discontinue any conventional antidepressants. Most conventional antidepressants will require a minimum 2-week tapering period, with the exception of fluoxetine, which will require a 4-week tapering period. Additional time may be added at the discretion of the study investigator. During the tapering period, there will be weekly check-ins with a study psychiatrist by in-person assessment or brief telephone calls to monitor for worsening depression and suicidality. Following the tapering period, participant eligibility will be re-assessed for the eligibility.
At Study Visit 2 (Baseline, V2), participants will complete a series of questionnaires and assessments (Table 2) and preparatory therapy with trained study therapists. The participant will also receive a brain MRI scan lasting for about 45 minutes.
At Study Visits 3 \& 4 (V3/V4), participants will receive oral doses of psilocybin (safety dose of 10 mg at V3, treatment dose of 25 mg at V4), to assess the tolerability and efficacy of psilocybin. These sessions will be held one week apart and will last 6 to 8 hours each. These sessions will take place in a pre-decorated treatment room at CAMH. Throughout the entire duration of the dosing sessions, participants will be monitored by a minimum of two trained therapists. At the end of each session, participants will be evaluated for safety by a study psychiatrist before being discharged. Participants will also rate the 11-Dimension Altered States of Consciousness (11D-ASC) at the end of each dosing day when the subjective effects of psilocybin have subsided to a negligible level. In addition, the participant will also receive a second brain MRI scan lasting for about 30 minutes (V3a) following V3 Safety dosing. To reduce participant burden, MRI scan can be completed on the following day or within 1-3 days following safety dosing (V3). The participants will also be required to complete the self-rated questionnaires at this additional MRI assessment.
Visit 5 (V5) will be held one day after administration of the treatment dose (V4). During V5 the participants will complete post-treatment clinical and cognitive assessments, alongside the third and final MRI scan (of the main clinical trial design). Participants will also undergo a 1-hour integration therapy session to debrief their experiences the day before. Visit 6 (V6) will be held one week following the treatment dose (V4). During V6 a second 1-hour integration therapy session takes place and all post-treatment clinical assessments will be repeated. Subsequent clinical progress will be evaluated virtually at V7, V8, V9, which will respectively be held 2, 4, and 12 weeks following the treatment session (V4).
10 participants out of 20 participants in the main clinical trial could opt to receive 7 additional brain MRI scans besides the MRI scans at V2, V3a and V5 required in the main clinical trial. These 7 additional scans will be assessed at V1, in the middle of medication washout/tapering period V6, V7, V8, 8 weeks following the treatment dose (V4), and V9, respectively. At each optional MRI visit, self-rated assessments will also be collected.
