Psilocybin-Assisted Psychotherapy for Treatment-Resistant Depression: Comparing One Versus Two Doses of Psilocybin

Inclusion Criteria: 1. Adults 18 to 65 years old. 2. Must be deemed to have capacity to provide informed consent. 3. Must sign and date the informed consent form. 4. Stated willingness to comply with all study procedures. 5. Ability to read and communicate in English, such that their literacy and comprehension is sufficient for understanding the consent form and study questionnaires, as evaluated by study staff obtaining consent. 6. Meets DSM-5 criteria for MDD, currently experiencing a Major Depressive Episode (MDE) without psychotic features, as diagnosed by a mood disorder specialist. Diagnosis will be confirmed using the Mini-International Neuropsychiatric Interview (MINI). 7. Current MDE must be moderate to severe, as determined by a MADRS score greater than 21. 8. Have not responded to at least two trials of antidepressants at an adequate dosage and duration based on the Antidepressant Treatment History Form Short Form (ATHF-SF) with no upper limit on the number of treatment failures. 9. Ability to take oral medication. 10. Individuals who are capable of becoming pregnant: use of highly effective contraception for at least 1 months prior to screening and agreement to use such a method during study participation in addition to monthly check-ins by study staff to determine the first day of their last menstrual period; 11. Individuals who are capable of making their partner pregnant: use of condoms or other methods for the duration of study participation to ensure effective contraception with partner. 12. Individuals who are willing to taper off concomitant medications (antidepressants, antipsychotics, mood stabilizers, ketamine, esketamine, monoaminergic medicines, and stimulants) for a minimum of 1-month prior to Baseline (V2, Day 0) and whose physician confirms that it is safe for them to do so. 13. Individuals who are willing to not receive additional psychotherapy (outside of the therapy provided as part of the study) during the 8-week trial and whose physician confirms that it is safe for them to do so; however, they may continue seeing their therapist before and after this time period. 14. Individuals who have a caregiver that will be able to bring them home after treatment sessions and stay with them for a minimum of 24 hours after discharge; 15. Agreement to adhere to Lifestyle Considerations (section 4.5) throughout study duration. Exclusion Criteria: 1. Lifetime history of mania, hypomania or psychosis as determined by clinical psychiatric assessment and the MINI. 2. Current symptoms of mania, hypomania or mixed features, as determined by the Young Mania Rating Scale (YMRS) score greater than 12. 3. Substance, cannabis, or alcohol use disorder within the past 3 months or lifetime history of hallucinogen use disorder as determined by the MINI and urine drug screen. 4. Major neurocognitive disorder, as determined by clinical assessment, including administration of the Montreal Cognitive Assessment (MoCA). 5. Have active suicidal ideation as determined by the C-SSRS and/or clinical interview (significant suicide risk is defined by suicidal ideation as endorsed by items 4 or 5 of the C-SSRS) or active suicidality requiring involuntary inpatient treatment or recent suicide attempts within the past 3 months. 6. Presence of a relative or absolute contraindication to psilocybin (within the past 12 months),, including a drug allergy, recent stroke history, uncontrolled hypertension, low or labile blood pressure, recent myocardial infarction (within the past 12 months),, cardiac arrhythmic, severe coronary artery disease, or moderate to severe renal (Glomerular Filtration Rate (GFR) less than 45ml/min/1.73 m2) or hepatic impairment (Child-Pugh B: 7 to 9 points and Child-Pugh C: 10 to 15 points). 7. Pregnant as assessed by a urine pregnancy test at Screening (V1) or individual's that intend to become pregnant during the study or are breastfeeding. 8. Treatment with another investigational drug or other intervention within 30 days of Baseline (V2). 9. Participants who will receive any form of brain stimulation (e.g., rTMS, ECT) during the trial or have within 30 days before Baseline (V2). 10. Individuals who have had changes to psychiatric medications 30 days before entering the trial, outside of as needed (PRN) medications. 11. Any DSM-5 lifetime diagnosis of a schizophrenia-spectrum disorder; obsessive- compulsive disorder, psychotic disorder (unless substance induced or due to a medical condition), bipolar I or II disorder, paranoid personality disorder, or borderline personality disorder as determined by medical history, the M.I.N.I clinical interview, and the International Personality Disorder Examination (IPDE) administered at Screening (V1). 12. Any first-degree relative with a diagnosis of schizophrenia-spectrum disorder; psychotic disorder (unless substance-induced or due to a medical condition); or bipolar I or II disorder as determined by the family medical history form and discussions with the participant. 13. Uncontrolled seizure disorder or a seizure within the past 12 months 14. Presence of baseline prolonged QTc or Torsade de Pointes as measured by the ECG or a history of long QTc syndrome or related risk factors. 15. Use of classic psychedelic drugs within the previous 6 months, including but not limited to psilocybin, psilocin, DMT, LSD, ayahuasca, mescaline, peyote, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). 16. Any other clinically significant physical illness including chronic infectious diseases 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 they take part in the study.