Efficacy, Safety, and Tolerability of COMP360 in Participants With TRD

Key Inclusion Criteria:

1. Aged ≥18 years at Screening

2. Major depression without psychotic features (single or recurrent episode as informedby the Diagnostic and Statistical Manual of Mental Disorders, 5th edition [DSM-5])

3. If the current major depressive episode is the participant's first lifetime episodeof depression, the length of the current episode must be ≥3 months and ≤2 years atScreening

4. MADRS total score ≥20 at Screening and Baseline to ensure at least moderate severityof depression

5. TRD, defined as failure to respond to an adequate dose and duration of two, three,or four different pharmacological treatments for the current episode as determinedthrough the Massachusetts General Hospital Antidepressant Treatment ResponseQuestionnaire (MGH-ATRQ) and using the supplementary advice on additionalantidepressants not included in MGH-ATRQ.

6. At Screening, agreement to discontinue all prohibited medications.

Key Exclusion Criteria:

Psychiatric Exclusion Criteria:

1. Prior or ongoing bipolar disorder, any psychotic disorder, including schizophrenia,schizophreniform disorder, schizoaffective disorder, brief psychotic disorder (unless substance induced or due to a medical condition), antisocial personalitydisorder as assessed by a structured clinical interview (MINI 7.0.2)

2. Lifetime paranoid, schizoid, schizotypal, histrionic, narcissistic personalitydisorder, or any ongoing serious psychiatric comorbidity based on medical historyand clinical judgement

3. Borderline personality disorder as demonstrated by medical history or the MiniInternational Neuropsychiatric Interview Plus (MINI plus) - borderline personalitydisorder module

4. Ongoing post-traumatic stress disorder, obsessive-compulsive disorder, or anorexianervosa as assessed by medical history and a structured clinical interview (MINI 7.0.2)

5. Psychiatric inpatient within the past 12 months prior to Screening

6. Use of electroconvulsive therapy, deep brain stimulation, or vagus nerve stimulationduring the current depressive episode

7. Transcranial magnetic stimulation within the past six months prior to Screening

8. Current enrolment in a psychological therapy programme that will not remain stablefor the duration of the study. Psychological therapies cannot have been initiatedwithin 30 days prior to Screening

9. Exposure to COMP360 psilocybin therapy prior to Screening