PET Synaptogenesis After Psilocybin In DEpression Recovery (PET-SPIDER)

Inclusion Criteria: Men and women between 18 and 65 years of age; Able to provide informed consent 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 Willingness to comply and be available for all study requirements, including psychological, cognitive, and imaging for the duration of the study Meeting DSM-5 criteria for major depressive disorder and current depressive episode Snaith-Hamilton Anhedonia Pleasure Scale (SHAPS) ≥ 6 points Willing and able to taper and/or discontinue current psychotropic medications Exclusion Criteria: Women who are pregnant or who intend to become pregnant or nurse during the study duration. 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); Use of psychotropic medication that may interact with psilocybin (TCA, MAOi, antipsychotic/neuroleptics, anti-epileptic/mood stabilizer, lithium, SSRI, SNRI, Mirtazapine, Buproprion, Vortioxetine). Recent use of psychedelics (psilocybin, LSD, ayahuasca, mescaline; past 5 years); or prior severe adverse reactions to psychedelics Active suicidal ideation or history of a suicide attempt. 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); 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); Presence of contraindications to PET or MRI scanning (renal disease, implantable devices, bone hardware, some IUDs); Body mass index >30 (due to MRI confounds).