The main aim of the study is to investigate the possible long-term therapeutic effects of psilocybin on the symptoms of severe depression, as well as the brain mechanisms underlying these changes. Depression severity is assessed before and after (i.e., 1 week, 3 months and 6 months after) a single dose of psilocybin and compared to respective scores of a group receiving an active placebo, ketamine. Brain activity (using functional magnetic resonance imaging) is measured before and one week after drug administration in order to determine whether changes in brain networks related to emotional and self-referential processing correlate with any observed changes in depression scores. Further, blood samples will be obtained from the participants and analyzed in order to reveal gene expression and molecular level correlates underlying rapid antidepressant effects, and to identify biomarkers that predict treatment outcome.

Inclusion Criteria:

1. Major depression of a moderate to severe degree (17+ on the 21-item HAM-D).
2. No health-related contraindications.

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 etc.).
4. History of suicide attempts.
5. History of mania.
6. Current 5-HT2A antagonist antidepressant medication.
7. Blood or needle phobia.
8. Positive pregnancy test.
9. Current drug or alcohol dependence.
10. Lack of appropriate use of contraception.
11. Breast-feeding.

Since the psilocybin is ingested orally in capsule form, whereas ketamine is administered intranasally, the participants will either receive a placebo capsule containing microcrystalline cellulose (if they belong to the group receiving ketamine), or intranasally administered saline solution (with added bitter flavoring which will mimic the taste of ketamine that is often detectable even when administered intranasally).