Understanding Music and Mindfulness Preferences in Psilocybin-Assisted Psychotherapy

Inclusion Criteria: * At least 21 years of age at screening. * Diagnosis of unipolar Major Depressive Disorder (MDD) according to diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR), confirmed by a study psychiatrist using the Mini International Neuropsychiatric Interview (MINI) version 7.0.2. * Failure to achieve remission from at least two trials of evidence-based oral antidepressants, in the current episode, of adequate dose and duration. * Moderate to severe symptoms according to the clinician-administered Montgomery-Åsberg Depression Rating Scale (MADRS): total score ≥ 25 on screening. * Active follow-up in psychiatry. * Able and willing to give informed consent to participate in the study, and for the study clinicians to communicate with their psychiatrist throughout the intervention phase of the study. * Available and willing to comply with all study assessments. * Stable psychotropic medications for at least eight weeks at the time of enrollment. * Able to read and understand French and/or English. * Has at least one identified support person, including a friend or family member, who agrees to accompany patient home (or to an otherwise safe destination) following the psilocybin treatment sessions. Exclusion Criteria: * Deemed to be greater than low risk of suicide on psychiatric interview. * Currently or previously diagnosed with any of the following, according to available information and psychiatric interview: major depression with psychotic features, schizophrenia spectrum or other psychotic disorders, and/or bipolar affective disorder I or related disorders. * Current or past diagnosis of personality disorder deemed to pose a significant risk for safety and/or trial compliance. * Family history (first-degree relative) of psychosis. * Current or recent (\< six months) substance use disorder, except for tobacco use disorder. * Deemed to be greater than low risk of future substance use disorder. * Currently receiving and deemed to be unsuitable, on psychiatric interview, to discontinue medications with significant serotonin 2A antagonism (e.g., trazodone) or known potential for serious interactions with psilocybin including serotonin syndrome (e.g., monoamine oxidase inhibitors), seizures (e.g., lithium), or which may affect psilocybin pharmacokinetics (e.g. UDG modulators, aldehyde dehydrogenase inhibitors). * Unwilling or unable to maintain current psychotropic medications throughout the treatment phase of the trial. * Currently undergoing psychotherapy that will not remain stable for the duration of the study or was initiated within 21 days of baseline. * Prior use of serotonergic psychedelics in the past year and/or more than five life-time uses. * Use of any serotonergic psychedelic or ketamine, or any other illicit substance during the active treatment period of the trial. * Medical contraindications: * Current or past history of seizure disorder with the exception of infantile febrile seizures. * Significant cardiovascular disease including uncontrolled blood pressure (\> 140/90mmHg), clinically significant arrhythmia, heart failure, coronary artery disease, history of ischemic or hemorrhagic stroke, or history of myocardial infarction. * Abnormal and clinically significant results on the physical examination, laboratory investigations, or ECG at screening. * Any other clinically significant illness deemed to pose significant health risks for participation in the study. * Pregnant or lactating. * For women of child-bearing potential, defined as all women physiologically capable of becoming pregnant: unwilling to utilize highly effective contraceptive during the 10-week active intervention (e.g., oral contraceptive). Acceptable forms of highly effective contraception methods include: a. Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception; b. Male/female sterilization defined as: 1) Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed and documented by follow up hormone level assessment; 2) Male sterilization of the sole partner (at least 6 months prior to screening) of a female patient on the study. c. A combination of any two of the following (i+ii or i+iii or ii+iii): i) Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository ii) Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate \<1%), for example hormone vaginal ring or transdermal hormone contraception iii) Placement of an intrauterine device (IUD) or intrauterine system (IUS). * Men unwilling to not attempt to father a child or not donate sperm, while participating the active treatment period of this study.