Psilocybin for Major Depressive Disorder (MDD)

Approximately 240 eligible adult participants (≥18 years old) who meet Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR) criteria for Major Depressive Disorder (MDD) will be enrolled. Participants will be randomly assigned to receive a single oral dose of Psilocybin 25 mg, Psilocybin 5 mg, or inactive placebo. The purpose of this study is to evaluate the efficacy, safety, and tolerability of Psilocybin 25 mg versus placebo in adults with MDD, as assessed by the difference between groups in change in depressive symptoms from Baseline to Day 43 post-dose, and to characterize the durability of initial treatment effect and subsequent response to optional Psilocybin 25 mg re-administration(s) during the 1-year Follow-up Period.

Inclusion Criteria: * Adults ≥18 years old. * Able to swallow capsules. * If of childbearing potential, agree to practice an effective means of birth control throughout the duration of the study. * Meet the DSM-5-TR criteria for a diagnosis of major depressive disorder and are currently experiencing a major depressive episode of at least a 60-day duration at the time of Screening. * Have at least moderate severity of depression symptoms at Screening and Trial Baseline. Exclusion Criteria: * Participants who are pregnant, who intend to become pregnant during the trial, or who are currently nursing. * Have any of the following cardiovascular conditions: coronary artery disease, congenital long QT syndrome, cardiac hypertrophy, cardiac ischemia, congestive heart failure, clinically-relevant valvular heart disease, pulmonary hypertension, myocardial infarction, a clinically significant ECG abnormality, or tachycardia. * Have elevated blood pressure. * Have neurological conditions such as stroke, including transient ischemic attack, epilepsy, neurodegenerative disease (e.g., dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, etc.), or brain tumor. * Have severe hepatic or renal impairment. * Have uncontrolled diabetes mellitus or unstable existing thyroid disorder. * Are hepatitis or HIV positive. * Have a positive urine drug test for illicit, non-prescribed, or prohibited substances. * Meet DSM-5-TR criteria for schizophrenia spectrum or other psychotic disorders, including major depressive disorder with psychotic features ,bipolar disorder (types 1 or 2), antisocial personality disorder, borderline personality disorder or moderate or severe alcohol or drug use disorder * Meet DSM-5-TR criteria for active post-traumatic stress disorder within 6 months prior to Screening. * Have a first-degree relative with schizophrenia spectrum or other psychotic disorders, or bipolar I disorder.