Inclusion Criteria:  Over the age of 18 years and under the age of 65; Diagnosed with major depressive disorder or bipolar II disorder by a healthcare provider; Experiencing a major depressive episode (MDE) without psychotic features as defined and operationalized in the DSM-5, where the duration of the current episode is at least 3 months; Have failed to respond to an adequate dose and duration of at least two guideline-concordant pharmacological treatments for the current MDE, as determined by the Massachusetts General Hospital-Antidepressant Treatment History Questionnaire; and Able to complete all protocol required assessment tools without any assistance or alteration to the copyrighted assessments, and to comply with all study visits.  Individuals meeting one or more of the following DSM-5-defined criteria will be excluded:  Current or past history of bipolar I disorder, schizophrenia, psychotic disorder, delusional disorder, paranoid personality disorder, or schizoaffective disorder, as assessed by a structured clinical interview (MINI) and International Personality Disorder Examination (IPDE); First degree history of schizophrenia or any psychotic disorders, including bipolar disorder with psychotic features; Currently experiencing symptoms of hypomania or mania as measured by the Young Mania Rating Scale (YMRS) total score > 12; History of a hypomanic or manic episode in the past 3 months; History of substance use and/or alcohol use disorder, of moderate severity or greater, in the past 3 months; Lifetime history of substance use disorder with a hallucinogen; Lifetime history of substance-induced psychosis; Currently experiencing psychotic symptoms as part of an MDE (mood congruent/mood incongruent).  Individuals meeting one or more of the following criteria will also be excluded:  Exposure to psilocybin or any other psychedelic in the past 12 months prior to screening and/or during the current MDE; Uncontrolled or insulin-dependent diabetes; Seizure disorder; Other personal circumstances or behaviour 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; Refusal to use an effective contraceptive method by the participant or participant's partner (i.e., combined estrogen- and progestogen-containing hormonal contraception or progestogen-only hormonal contraception with inhibition of ovulation; intrauterine device; intrauterine hormone-releasing system; bilateral tubal occlusion; vasectomized partner; sexual abstinence) throughout their participation in the study; Recent stroke (< 1 year from signing of ICF), 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; 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); Current enrolment in any investigational drug or device study or participation in such within 30 days of screening; Current enrolment in an interventional study for depression or participation in such within 30 days of screening; Abnormal and clinically significant results on the physical examination, vital signs, ECG, or laboratory tests at screening; 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.