The primary objective is to evaluate whether a single dose of psilocybin (25 mg), compared to placebo, can restore fronto-striatal reward circuit function and thereby improve anhedonia and emotional blunting in individuals with residual symptoms despite ongoing SSRI or SNRI treatment. This will be assessed using precision functional mapping (PFM), task-based fMRI, and clinical rating scales (DARS).

Inclusion Criteria:

• Age between 18 and 65 years
• Able to provide voluntary signed and dated informed consent.
• Females of childbearing potential (FOCBP) must agree to practice an effective means of birth control throughout the duration of the trial
• Males who have FOCBPs as partners must agree to practice an effective means of birth control throughout the duration of the trial
• State willingness to comply and be available for all study requirements, including psychological, cognitive, imaging and procedural evaluations for the duration of the study
• Meet DSM-5 criteria for major depressive disorder (MDD)
• Screening Dimensional Anhedonia Rating Scale (DARS) total score of < 28.5 points
• Have an identified support person
• Agree to refrain from taking all non-prescription medications and supplements (nutritional and herbal) for at least 1 week prior to the IP administration session unless approved by the Investigator.

Exclusion Criteria:

• Inability to speak and understand English sufficiently to complete informed consent and study procedures.
• Inability to provide informed consent.
• Women who are pregnant or who intend to become pregnant or nurse during the study duration.
• Prior exposure to classic psychedelics (i.e., psilocybin, LSD, ayahuasca, and/or mescaline) within the past 1 year.
• Current or previous psychiatric conditions that meet DSM-5 criteria for psychotic disorders (i.e., schizophrenia, schizoaffective disorder, MDD with psychosis), bipolar 1 or 2 disorder, or current diagnosis of active substance use disorder.
• Have active suicidal ideation with intent, based on Columbia-Suicide Severity Rating Scale (C-SSRS assessment (severity score > 3) at the Screening visit, confirmed by the Investigator.
• Have made a medically significant suicide attempt (i.e., one that had a significant possibility of causing death or permanent harm in the absence of intervention) within the past 12 months, based on Screening C-SSRS assessment and confirmation by the Investigator.
• Immediate family history (i.e., parents, full siblings, or half siblings) with known or suspected psychotic disorder.
• Presence of medical conditions that may confound results of imaging study or that are contraindications to or psilocybin exposure (i.e., neurological, renal, hypertension, metabolic or cardiovascular disease or pregnancy);
• Presence of contraindications to MRI scanning (implantable devices, bone hardware, various IUD).
• Participants who received electroconvulsive therapy (ECT), trans magnetic cranial stimulation (TMS), and/or ketamine in the past 90 days.
• Has any other physical or psychological symptom, medication, or other relevant finding prior to randomization that, based on the clinical judgment of trial personnel, would make a participant unsuitable for the trial.
• Are unable or unwilling to discontinue taking any protocol-prohibited medications and supplements.

The de-identified participant data from the final research dataset will be shared with researchers who provide a methodologically sound proposal, or investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose, beginning 9 to 36 months after publication or as required by a condition of awards or supporting agreements, provided the requesting investigator executes a data use agreement with NYU Langone Health. This instance of data sharing will also require separate IRB review as well as review from NYU Langone's Data Sharing Strategy Board (DSSB). Requests should be directed to: Joshua Siegel, MD, PhD, Joshua.Siegel@nyulangone.org. The protocol and statistical analysis plan will be posted on Clinicaltrials.gov only as required by federal regulation or supporting awards and agreements.

Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.

Researchers who provide a methodologically sound proposal, or investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose, will be granted access upon reasonable request, including to achieve aims in the approved proposal and for individual participant data meta-analysis. Requests should be directed to Joshua.Siegel@nyulangone.org. To gain access, data requestors will need to sign a data access agreement. This instance of data sharing will also require separate IRB review as well as review from NYU Langone's DSSB.