Psilocybin vs Escitalopram for Major Depressive Disorder: Comparative Mechanisms

Inclusion Criteria: 1. Major depressive disorder (DSM-IV) 2. Depression of moderate to severe degree (17+ on the 17-item Hamilton Depression Scale (HAM-D)). 3. No Magnetic Resonance Imaging (MRI) contraindications 4. No SSRI contraindications 5. Has a general practitioner (GP) or other mental healthcare professional who can confirm diagnosis 6. 18-80 years of age 7. Males and females 8. Sufficiently competent with English language Key exclusion criteria: 1. Current or previously diagnosed psychotic disorder 2. Immediate family member with a diagnosed psychotic disorder 3. Medically significant condition rendering unsuitability for the study (e.g., diabetes, epilepsy, severe cardiovascular disease, hepatic or renal failure e.g. creatine clearance:renal clearance (CLRC) \< 30 ml/min etc.) 4. History of serious suicide attempts requiring hospitalisation. 5. Significant history of mania (determined by study psychiatrist and medical records) 6. Psychiatric condition judged to be incompatible with establishment of rapport with therapy team and/or safe exposure to psilocybin, e.g. borderline personality disorder 7. Blood or needle phobia 8. Positive pregnancy test at screening or during the study, women who are planning a pregnancy and/or women who are nursing/breastfeeding. 9. Participants who do not agree to use an acceptable contraceptive method throughout their participation in study. 10. Current drug or alcohol dependence 11. No email access 12. Use of contraindicated medication 13. Patients presenting with abnormal QT interval prolongation at screening or with a history of this (QTc at screening above 440ms for men and above 470ms for women)