Psilocybin as a Novel Therapy for Residual Anhedonia

Inclusion criteria

• Age between 18 and 65 years
• Able to provide voluntary signed and dated informed consent.
• Females of childbearing potential (FOCBP) must agree to practice an effective means of birth control throughout the duration of the trial
• Males who have FOCBPs as partners must agree to practice an effective means of birth control throughout the duration of the trial
• State willingness to comply and be available for all study requirements, including psychological, cognitive, imaging and procedural evaluations for the duration of the study
• Meet DSM-5 criteria for major depressive disorder (MDD)
• Screening Dimensional Anhedonia Rating Scale (DARS) total score of \< 28.5 points
• Have an identified support person
• Agree to refrain from taking all non-prescription medications and supplements (nutritional and herbal) for at least 1 week prior to the IP administration session unless approved by the Investigator.

Exclusion criteria

• Inability to speak and understand English sufficiently to complete informed consent and study procedures.
• Inability to provide informed consent.
• Women who are pregnant or who intend to become pregnant or nurse during the study duration.
• Prior exposure to classic psychedelics (i.e., psilocybin, LSD, ayahuasca, and/or mescaline) within the past 1 year.
• Current or previous psychiatric conditions that meet DSM-5 criteria for psychotic disorders (i.e., schizophrenia, schizoaffective disorder, MDD with psychosis), bipolar 1 or 2 disorder, or current diagnosis of active substance use disorder.
• Have active suicidal ideation with intent, based on Columbia-Suicide Severity Rating Scale (C-SSRS assessment (severity score \> 3) at the Screening visit, confirmed by the Investigator.
• Have made a medically significant suicide attempt (i.e., one that had a significant possibility of causing death or permanent harm in the absence of intervention) within the past 12 months, based on Screening C-SSRS assessment and confirmation by the Investigator.
• Immediate family history (i.e., parents, full siblings, or half siblings) with known or suspected psychotic disorder.
• Presence of medical conditions that may confound results of imaging study or that are contraindications to or psilocybin exposure (i.e., neurological, renal, hypertension, metabolic or cardiovascular disease or pregnancy);
• Presence of contraindications to MRI scanning (implantable devices, bone hardware, various IUD).
• Participants who received electroconvulsive therapy (ECT), trans magnetic cranial stimulation (TMS), and/or ketamine in the past 90 days.
• Has any other physical or psychological symptom, medication, or other relevant finding prior to randomization that, based on the clinical judgment of trial personnel, would make a participant unsuitable for the trial.
• Are unable or unwilling to discontinue taking any protocol-prohibited medications and supplements.