Key Inclusion Criteria:

   1. Aged ≥18 years at Screening

   2. Major depression without psychotic features (single or recurrent episode as informed
   by 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 episode of
   depression, the length of the current episode must be ≥3 months and ≤2 years at
   Screening

   4. MADRS total score ≥20 at Screening and Baseline to ensure at least moderate severity
   of 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 determined
   through the Massachusetts General Hospital Antidepressant Treatment Response
   Questionnaire (MGH-ATRQ) and using the supplementary advice on additional
   antidepressants not included in MGH-ATRQ

   6. At Screening, agreement to discontinue all prohibited medications

Key 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 personality disorder as
   assessed by a structured clinical interview (MINI 7.0.2)

   2. Lifetime paranoid, schizoid, schizotypal, histrionic, narcissistic personality
   disorder, or any ongoing serious psychiatric comorbidity based on medical history and
   clinical judgement

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

   4. Ongoing post-traumatic stress disorder, obsessive-compulsive disorder, or anorexia
   nervosa 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 stimulation
   during 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 stable for
   the duration of the study. Psychological therapies cannot have been initiated within
   30 days prior to Screening

   9. Exposure to COMP360 psilocybin therapy prior to Screening