A Randomized Neuroimaging Trial of Psilocybin in Depression

Inclusion Criteria: * Able and voluntarily willing to provide written informed consent at the screening visit * Over 18 and under 65 years old * Able to complete all protocol required assessment tools without any assistance or alteration to the copyrighted assessments, and to comply with all study visits * Must have a responsible individual/caregiver who is able to monitor the participant at home for 24 hours after each treatment visit in the study * Must have a psychiatrist and/or general practitioner who is able to provide psychiatric follow-up care * Have a Mini-International Neuropsychiatric Interview (MINI) confirmed diagnosis of MDD, recurrent or single episode without psychotic features where the duration of the current episode is at least 3 months * Depression of at least moderate severity as defined by a Hamilton Depression Rating Scale (HAMD-17) score \>17 Exclusion Criteria: * Current or past history of bipolar I/II disorder, schizophrenia, schizoaffective disorder, psychotic disorder, or delusional disorder as assessed by a structured clinical interview (MINI) * A clinical diagnosis of antisocial personality disorder and/or paranoid personality disorder (defined as meeting DSM-5 criteria) based on clinical interview and the MINI 7.0. Positive diagnoses on the MINI will be subject to confirmation at a clinical interview by a psychiatrist. * An active clinical diagnosis of borderline personality disorder as confirmed by the MINI 7.0. * Depression secondary to other medical conditions or bipolar I and II disorder * Family history of a first degree relative with a diagnosis of schizophrenia or a primary psychotic disorder and/or bipolar disorder * Any symptoms consistent with psychosis * Any symptoms consistent with hypomania and/or mania as assessed by a psychiatrist * Personal history of ≥ 1 suicide attempt in the past year requiring hospitalization, defined using the Columbia Suicide Severity Rating Scale (CSSRS) (Q6 (past year) = "y") and clinical interview with a psychiatrist * Other personal circumstances or behavior judged to be incompatible with establishment of rapport or safe exposure to psilocybin * Women who are pregnant (self-report or via urine test), nursing, or planning a pregnancy * Lifetime history of substance use disorder with a hallucinogen * Lifetime history of substance-induced psychosis * Positive urine drug screen for illicit drugs or drugs of abuse at screening, a week prior to treatment, and during the trial (any positive urine drug test will be reviewed with participants to determine the pattern of use and eligibility will be determined at the investigator's discretion) * Abnormal and clinically significant results on a physical examination performed within one month of study participation by a general practitioner, vital signs, ECG, or laboratory test at screening * QTc prolongation on ECG * Uncontrolled or insulin-dependent diabetes * History of seizure disorder except for seizures from electroconvulsive therapy and/or febrile seizures in childhood * Diagnosis of any mild or major neurocognitive disorder meeting DSM-5 criteria and based on clinical interview/cognitive screening by a psychiatrist * History of stroke, recent myocardial infarction (\< 1 year from signing of ICF), uncontrolled hypertension (blood pressure \> 140/90 mmHg) or clinically significant arrhythmia within 1 year of signing the ICF * Any other clinically significant cardiovascular, pulmonary, gastrointestinal, hepatic, renal or any other major concurrent illness that, in the opinion of the investigator, may interfere with the interpretation of the study results or constitute a health risk for the participant if he/she takes part in the study * Exposure to psilocybin or any other psychedelic in the past 12 months prior to screening and/or during the current MDE and use of psychedelics, such as ayahuasca/LSD, during the current depressive episode * History of substance use and/or alcohol use disorder, of moderate severity or greater, in the past 12 months * Current enrolment in an interventional study for depression or participation in such within 30 days of screening * Serial blood counts to achieve a value to meet eligibility - abnormalities in screening/baseline blood work (complete blood counts, electrolyte panel, etc.) will be reviewed by MD, then repeated serially until abnormalities resolve.