This project is an open-label randomized study looking at an 8-week Mindfulness-Based Stress Reduction (MBSR) curriculum vs. an 8-week MBSR curriculum + a group psilocybin-assisted psychotherapy intervention for frontline healthcare providers struggling with symptoms of depression and burnout associated with the SARS-CoV-2 pandemic.

Following consenting and enrollment a total of 24 participants will be randomized to receive either an 8-week MBSR curriculum or the same 8-week MBSR curriculum + a group psilocybin-assisted psychotherapy intervention. The group psilocybin-assisted psychotherapy intervention will involve 3 group preparatory sessions (2 hours each), a single 8 hour group psilocybin administration session with a 1:1 therapist to participant ratio (25mg psilocybin dose), and 3 group integration sessions (2 hours each).

Inclusion Criteria:

___ Participants must be physicians or nurses with at least 1 month of frontline clinical experience during the COVID pandemic.

Yes/No Eligibility Questions (Response of "no" = subject ineligible)

• PHQ-9 score ≥ 10 and meet criteria for a DSM-5 depressive disorder (including adjustment disorder with depressed mood).
• Meet the study working definition of burnout which will involve a score on the emotional exhaustion subscale (≥ 27) and a 'high' score on one other subscale (either depersonalization ≥ 13 or personal accomplishment ≤ 21).
• Not taking regularly scheduled medications to treat depression and/or anxiety, including benzodiazepines, for at least 4 weeks prior to initiation of the study.
• Fluent in English.
• Reading literacy and comprehension sufficient for understanding the consent form and study questionnaires, as evaluated by study staff obtaining consent.
• Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines.
• ECOG Performance Status < or = 2.
• Have a support person that would be able to escort the subject home on the evening of the psilocybin dosing session. The use of ride services will not be permitted (e.g., Uber, Lift, taxi, etc.)
• Adequate liver function as defined as:
• Total Bilirubin < 1.5x institutional upper limit of normal (ULN) unless elevated bilirubin is related to Gilbert's Syndrome.
• AST(SGOT)/ALT(SGPT) <3 x institutional ULN
• For female subjects: Negative pregnancy test and agreement to use highly effective contraception or evidence of post-menopausal status. The post-menopausal status will be defined as having been amenorrheic for 12 months without an alternative medical cause.
• For male subjects: agree to condom use during intercourse for 24 hours post-psilocybin dose.
• Agree to refrain from using any psychoactive drugs, including alcoholic beverages, ondansetron, cannabis, and non-routine PRN medications within 24 hours of the psilocybin administration. Exceptions include daily use of caffeine, nicotine, and opioid pain medication.
• Agree that for one week preceding the psilocybin session, he/she will refrain from taking any nonprescription medication, nutritional supplement, or herbal supplement except when approved by the research team. Exceptions will be evaluated by the research team and will include acetaminophen, non-steroidal anti-inflammatory drugs, and common doses of vitamins and minerals.
• Agree not to use nicotine for at least 2 hours before the psilocybin administration and for the duration of the psilocybin session.
• Agree to consume approximately the same amount of caffeine-containing beverage (e.g., coffee, tea) that he/she consumes on a usual morning, before arriving at the research unit on the morning of the psilocybin session. If the subject does not routinely consume caffeinated beverages, he or she must agree not to do so on the day of psilocybin administration.
• Subjects requiring opioid use for pain are on a stable pain management regimen. Long-acting opioid medications (e.g., oxycodone sustained-release, morphine sustained release) will be allowed if the last dose occurred at least 6 hours before psilocybin administration; such medication will not be taken again until at least 6 hours after psilocybin administration.

Exclusion Criteria:

Yes/No Eligibility Questions (Response of "yes" = subject ineligible)

• Prior systemic antidepressants, antipsychotic, or anxiolytic medication within four weeks prior to study initiation.
• Personal history or first- or second-degree relatives with schizophrenia, bipolar affective disorder, delusional disorder, schizoaffective disorder, psychosis, or other psychotic spectrum illness as determined by patient report and chart review.
• Current or history within the last two years of meeting DSM-V criteria of substance use disorder (excluding caffeine and nicotine). Current substance use disorders may be identified through the drug urine screening test as determined by patient report and chart review.
• Currently meeting DSM-V criteria for Dissociative Disorder, or other psychiatric conditions judged to be incompatible with the establishment of rapport or safe exposure to psilocybin as determined by patient report and chart review.
• Currently meeting DSM-V criteria for Cluster B Personality Disorder as determined by patient report and chart review.
• Severe depression requiring immediate standard-of-care treatment (e.g., hospitalization).
• Suicidal ideation over the past month as assessed as a yes to question 3, 4, or 5 on the Columbia-Suicide Severity Rating Scale, Suicidal Ideation section
• Cancer with known CNS involvement, previously treated brain metastasis, or other major CNS disease.
• Employment as house staff/residents
• The subject has uncontrolled significant intercurrent or recent illness including, but not limited to, the following conditions:
• Cardiovascular disorders: Congestive heart failure, including all New York Heart Association Classes.
• Angina pectoris, cardiac hypertrophy, cardiac ischemia, myocardial infarction
• Uncontrolled hypertension at the time of enrollment (BP>140 systolic or 90 diastolic), coronary artery disease, artificial heart valve
• Prolonged or congenital long QT syndrome (>450 ms), serious cardiac arrhythmias, tachycardia, a clinically significant screening ECG abnormality
• Renal insufficiency as defined as creatinine clearance < 40 mL/min calculated by Cockcroft-Gault formula
• Hepatic disorders: Active infection including hepatitis B (known positive HBV surface antigen (HBsAg) result) or hepatitis C.
• Any other condition that would, in the investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, [patients may not receive the drug through a feeding tube], social/ psychological issues, etc.)
• Known prior severe hypersensitivity to investigational product or any component in its formulations (NCI CTCAE v5.0 Grade > 3).
• Subjects taking prohibited medications. A washout period of prohibited medications for a period of at least five half-lives should occur prior to study registration.