The Effects of Psilocybin on Self-Focus and Self-Related Processing in Major Depressive Disorder

Inclusion Criteria:

1. Must be able to sign the informed consent form (ICF). Participants will demonstratecapacity to provide informed consent by demonstrated understanding of the protocoland what their involvement in the study requires from them.

2. Be 18-55 years of age at screening.

3. At least moderate Major Depressive Disorder (MDD; single or recurrent episode asinformed by Diagnostic and Statistical Manual Version 5 (DSM-V); if single episode,duration of ≥ 3 months and ≤ 3 years) based on clinical assessment and a structuredclinical interview, the Mini International Neuropsychiatric Interview Version 7.02 (MINI).43

4. Structured Interview Guide for the Hamilton Depression Rating Scale with AtypicalDepression Supplement (SIGH-ADS)44 score ≥ 18 at Screening and at Baseline.

5. Failure to respond to an adequate dose and duration of 1, 2, 3, or 4 pharmacologicaltreatments for the current episode as determined through the Massachusetts GeneralHospital Antidepressant Treatment History Response Questionnaire (MGH-ATRQ)45 andusing the supplementary advice on additional antidepressants not included inMGH-ATRQ. Augmentation with an add-on treatment counts as a second treatment,provided it is approved for the adjunctive treatment of MDD.

6. McLean Screening Instrument for Borderline Personality Disorder (MSI-BPD) < 7 atScreening.

7. Participants will also have to successfully undergo a taper off of all psychotropicmedications under the supervision of a study psychiatrist and in coordination withtheir treatment team, which will be completed at least 2 weeks prior to BaselineScan. Please see below regarding details about discontinuation of antidepressants.

8. A score > 40 on the Wechsler Test of Adult Reading.46

9. Be right-handed as determined by the Edinburgh Handedness Inventory.48

10. Ability to complete all protocol required assessment tools without any assistance oralteration to the copyrighted assessments, and to comply with all study visits.

11. Have ongoing established mental health care.

Exclusion Criteria:

Patients meeting any of the following criteria are to be excluded from the study:

1. Current, past history, or family history, of schizophrenia, psychotic disorder (unless substance induced or due to a medical condition), bipolar disorder,delusional disorder, paranoid personality disorder, schizoaffective disorder,borderline personality disorder, or any serious psychiatric comorbidity as assessedby medical history and a structured clinical interview (version 7.0.2 MINI).

2. Positive Magnetic Resonance screen (e.g., metal implant, claustrophobia, etc).

3. Prior electroconvulsive therapy and/or ketamine for current episode.

4. Current cognitive behavioral therapy (CBT) that will not remain stable for theduration of the study. CBT cannot be initiated within 21 days of Baseline.

5. Current (within the last year) alcohol or substance abuse as informed by DSM-5 atScreening.

6. Significant suicide risk as defined by (1) suicidal ideation as endorsed on items 4or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS)49 within the past year,at Screening or at Baseline, or; (2) suicidal behaviors within the past year, or; (3) clinical assessment of significant suicidal risk during clinical interview.

7. Significant homicide risk as defined by clinical interview.

8. Depression secondary to other severe medical conditions.

9. Currently taking benzodiazepines daily.

10. Other personal circumstances and behavior judged to be incompatible withestablishment of rapport or safe exposure to psilocybin, as well as exposure topsilocybin or other psychedelics within one year of screening.

11. Women who are pregnant, nursing, or planning a pregnancy. Participants who aresexually active must agree to use a highly effective contraceptive method throughouttheir participation in the study. Women of childbearing potential must have anegative urine pregnancy test at Screening and Day Before Psilocybin.

12. Cardiovascular conditions: recent stroke (< 1 year from signing of consent), recentmyocardial infarction (< 1 year from signing of ICF), hypertension (blood pressure > 140/90 mmHg) or corrected QT interval > 450 msec) or clinically significantarrhythmia within 1 year of signing the ICF, current anticoagulant therapy,aneurysmal disease.

13. Uncontrolled insulin dependent diabetes.

14. Seizure disorder.

15. Positive urine drug screen for illicit drugs or drugs of abuse (to include but notlimited to opiates, phenylcyclohexyl piperidine(PCP), cocaine, amphetamines,methamphetamines, benzodiazepines, barbiturates, and cannabis) at Screening and DayBefore Psilocybin. Any positive urine drug test will be reviewed with participantsto determine the pattern of use and eligibility will be determined at theinvestigator's discretion.

16. Lifetime history of surgical procedures involving the brain or meninges,encephalitis, meningitis, degenerative central nervous system (CNS) disorder (e.g.,Alzheimer's or Parkinson's Disease), epilepsy, mental retardation, or any otherdisease/procedure/accident/intervention which, according to the screening clinician,is deemed associated with significant injury to or malfunction of the CNS, orhistory of significant head trauma within the past 2 years.

17. Any current or past history of any physical condition which in the investigator'sopinion might put the subject at risk or interfere with study resultsinterpretation.

18. Current enrollment in any investigational drug or device study or participation insuch within 6 months of Screening.

19. Current enrollment in an interventional study for depression or participation insuch within 6 months of Screening Visit.

20. Non-native speakers of English.