Due to negative results in similar trials using 11C-UCB-J

Participants with depression will be given a single dose of psilocybin and supportive psychotherapy before, during, and after drug administration. Participants will undergo positron emission tomography (PET) imaging before and one week after psilocybin using a marker of synaptic density. This design allows us to assess the relationship between neurotrophic, and antidepressant effects produced by psilocybin.

The investigators are studying the neurotrophic effects of psilocybin using 11C-UCB-J, a PET marker for synaptogenesis. Psilocybin is a naturally occurring psychedelic and exerts perceptual effects via 5-HT2A receptor agonism. Psilocybin has gained a great deal of attention as a tool for psychiatric treatment, with clinical trials demonstrating symptom relief after a single dose that is immediate and persists for months. Recognizing the therapeutic potential of psilocybin, the US Food and Drug Administration granted breakthrough therapy status to the Usona Institute for Phase 2 testing of psilocybin in depression. Animal models suggest that psychedelics exert antidepressant effects by producing a rapid and powerful neurotrophic response in the brain.

The investigators will enroll patients with major depressive disorder and anhedonia. Participants will be given a single dose of psilocybin and supportive psychotherapy before, during, and after drug administration. Participants will undergo PET imaging before and one week after drug using 11C-UCB-J, a radiotracer that binds to SV2A - a marker of synaptic density and synaptogenesis. This design allows the investigators to assess the relationship between neurotrophic, and antidepressant effects produced by psilocybin.

Inclusion Criteria:

1. Men and women between 18 and 65 years of age;
2. Able to provide informed consent
3. Women of childbearing age must agree to be on two forms of contraception and men are required to utilize at least one form of contraception
4. Willingness to comply and be available for all study requirements, including psychological, cognitive, and imaging for the duration of the study
5. Meeting DSM-5 criteria for major depressive disorder and current depressive episode
6. Snaith-Hamilton Anhedonia Pleasure Scale (SHAPS) ≥ 6 points
7. Willing and able to taper and/or discontinue current psychotropic medications

Exclusion Criteria:

1. Women who are pregnant or who intend to become pregnant or nurse during the study duration.
2. Presence of psychiatric conditions that are contraindications to psilocybin exposure (e.g., personal or first degree relative with history of schizophrenia spectrum or bipolar disorder);
3. Use of psychotropic medication that may interact with psilocybin (TCA, MAOi, antipsychotic/neuroleptics, anti-epileptic/mood stabilizer, lithium, SSRI, SNRI, Mirtazapine, Buproprion, Vortioxetine).
4. Recent use of psychedelics (psilocybin, LSD, ayahuasca, mescaline; past 5 years); or prior severe adverse reactions to psychedelics
5. Active suicidal ideation or history of a suicide attempt.
6. Presence of medical conditions that are contraindications to psilocybin exposure (e.g., neurological conditions or severe hypertension, severe and/or unstable metabolic or cardiovascular conditions);
7. Current medical conditions that are known to increase risk of severe coronavirus infection or deemed by a study physician to put an individual at high risk (i.e., cancer, COPD, obesity, immunosuppression, type 2 diabetes, serious heart conditions, sickle cell disease, asthma);
8. Presence of contraindications to PET or MRI scanning (renal disease, implantable devices, bone hardware, some IUDs);
9. Body mass index >30 (due to MRI confounds).