Inclusion Criteria:
1. Adults, ages 22-65.
2. English language comprehension suitable to understand experimenter instructions and to communicate to study personnel/staff reasonably easily.
3. Current major depressive episode (without psychotic features), either as part of recurrent major depressive disorder (MDD) or single episode MDD with current episode present for at least the past 3 months (as determined by the Structured Clinical Interview for DSM-5; SCID-5).
4. Montgomery Asberg Depression Rating Scale (MADRS) score of 20 or greater at baseline assessment (at least moderate severity).
5. 1\. Treatment-resistant MDD, defined as either: a) failure to respond to an adequate dose and duration of two or more pharmacological treatments, with at least one failed medication trial occurring in the current major depressive episode; or b) failure to respond to an adequate dose and duration of 2 or more pharmacological treatments of different pharmacological classes in one or more past major depressive episodes. Adequate treatment dose and duration will be determined through the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ). Augmentation, where an add-on medication is used, will be counted as a second treatment, provided it is approved as an adjunctive treatment of MDD in the country where prescribed.
6. Willingness and ability to attend daily, full-day visits to the research site for a period of \~2 weeks and to participate in all study procedures (clinical assessments, treatments, and neurobiological assessments).
7. If currently taking an antidepressant medication (an SSRI, SNRI, or atypical antidepressant), antipsychotic, and/or other augmenting medication (e.g., lithium), willingness to discontinue medication(s) over a 2-8 week period with the assistance of study staff and maintain at least a 2-5 week period (5-week period for fluoxetine) off of medications prior to the baseline visit AND willingness to remain off medications for a period of 1 month following the end of the treatment course (approximately 6-8 weeks after the baseline visit).
Exclusion Criteria:
1. Prior history or current diagnosis of a psychotic disorder (including MDD with psychotic features), bipolar disorder, or personality disorder (based on medical history, clinician judgement, SCID-5 and/or SCID for Personality Disorders).
2. Current diagnosis of posttraumatic stress disorder, acute stress disorder, obsessive-compulsive disorder, anorexia nervosa, bulimia nervosa, or alcohol or substance-use disorder.
3. Having met criteria for an alcohol or substance-use disorder within the past year.
4. Use of electroconvulsive therapy, deep brain stimulation, or vagus nerve stimulation during the current major depressive episode.
5. Any prior rTMS treatment (10Hz, 5Hz, 1Hz, or conventional intermittent theta burst).
6. Current participation in an evidence-based psychotherapy for major depression (e.g., cognitive behavioral therapy, behavioral activation). Ongoing supportive psychotherapy is allowable if maintained at the same frequency throughout the duration of the short-term follow-up clinical endpoint (1 month after treatment cessation) of the study and if no recent change in therapy type or frequency for 1 month prior to enrollment.
7. Exhibiting significant suicide risk within the past 12 months, at screening, or at baseline, as evidenced by: a) suicidal ideation with some intent to act but no specific plan (item #4 from the Columbia Suicide Severity Rating Scale57; C-SSRS); b) suicidal ideation with intent to act and a specific plan (item #5 from the C-SSRS); c) suicide attempt or non-suicidal self-injury requiring medical attention in the past 12 months; or d) self-report of significant suicidal ideation with intent or significant non-suicidal self-injury during screening or baseline clinical interview.
8. Major depressive episode that is secondary to a medication or a general medical condition, as judged by investigators.
9. Any other factors, such as major medical conditions, unstable housing or threatening life circumstances, erratic behavior, etc. that are judged by the investigators to be a significant barrier to participation in the study protocol and/or to establishing therapeutic rapport necessary for safe administration of psilocybin.
10. Prior past-year ingestion of a serotonergic psychedelic, e.g., psilocybin, LSD, mescaline, dimethyltryptamine, etc. or more than 5 lifetime ingestions of a serotonergic psychedelic on separate occasions.
11. Participant unwillingness to not ingest or use additional serotonergic psychedelics outside the context of study procedures for the duration of the study follow-up period (12 months).
12. Ferrous metal, metallic implants, or implanted medical devices that would preclude administration of rTMS and/or participation in MRI procedures, including but not limited to: cochlear implants, implanted brain stimulators, aneurysm clips.
13. Past history of seizures or epilepsy (rTMS risk).
14. Neurological disorder, including epilepsy, stroke, or history of brain surgery.
15. Past penetrating brain injury or any head injury resulting in a loss of consciousness for 30 minutes or more or post-concussive symptoms for more than seven days following a head injury.
16. Head injury in the past two months, regardless of severity.
17. Currently pregnant and/or nursing or about to become pregnant. A positive urine pregnancy test at screening and/or baseline will lead to participant exclusion from the study.
18. Engagement in sexual intercourse which could result in pregnancy without use of a highly effective contraceptive method throughout participation in the study and for at least three months after COMP360 (psilocybin) administration.
19. Severe claustrophobia (prohibiting MRI acquisition).
20. Uncontrolled hypertension (resting blood pressure \> 140/90 mm hg).
21. Uncontrolled thyroid disease as indicated by unstable thyroid hormone dosage \< 3 months prior to screening, or abnormal and clinically significant thyroxine (FT4) levels (a free FT4 measurement will be conducted for all participants with an out-of-range thyroid-stimulating hormone \[TSH\] value irrespective of thyroid history).
22. Lifetime history of cardiomyopathy, stroke, heart disease, heart attack, tachycardia, elongated QT-interval corrected by Friderichia (\> 450ms for men and \> 470ms for women); clinically significant cardiac arrhythmia within 1 year of study entry; and/or abnormal electrocardiogram on study entry.
23. Type I diabetes mellitus or uncontrolled Type II diabetes mellitus (defined by hemoglobin A1c \> 8% at screening) or a history of diabetic ketoacidosis, hyperglycemic coma, or severe hypoglycemia with loss of consciousness (\< 3 months prior to signing of consent form).
24. Positive urine drug screening for drugs of abuse at screening and/or baseline will trigger a review with participant and assessment for eligibility based on pattern of use and willingness to abstain in conjunction with medical monitor and investigative team.
25. Clinically-significant results from physical examination, blood test, urine test, vital signs, or ECG at screening and/or baseline.
26. Current enrollment in another interventional study or participation within such a study within 6 months of screening.
27. Self-reported hypersensitivity to psilocybin or another serotonergic psychedelic.
