This study aims to investigate the effects of a single dose of psilocybin, delivered in the contextof pre- and post-dose psychotherapy, on symptoms of depression and burnout suffered by healthcare clinicians as a result of frontline work in the COVID pandemic.

Aim 1:

To assess short- and longer-term effects of psilocybin-assisted psychotherapy (PAP) on symptoms of depression experienced by physicians and nurses with frontline work exposure in the COVID pandemic.

Hypothesis 1.1: Compared to active placebo, PAP will result in short term improvement in symptoms of depression 1 day and 1 week after the psilocybin dose session. Hypothesis 1.2: Compared to active placebo, PAP will result in longer term improvement of symptoms of depression 4 weeks after the medication dosing session. The primary outcome will be a comparison between the psilocybin 25 mg vs control groups of a combination of depression symptoms measured at 4 weeks post medication dose session. 1.1.2. Aim 2: To explore short- and longer-term effects of psilocybin-assisted psychotherapy (PAP) on symptoms of burnout experienced by physicians and nurses with frontline work exposure in the COVID pandemic. Hypothesis 2.1: Compared to active placebo, PAP will result in short term improvement in symptoms of burnout 1 day and 1 week after the psilocybin dose session.

Inclusion Criteria:

1. Participants must be physicians or nurses with at least 1 month of frontline clinical experience during the COVID pandemic who rate at least 2 of 4 items from the COVID Exposure index as 'more than half the days' during their peak 2 week period of exposure: i. Caring for someone critically ill with COVID-19, or who became critically ill while you were involved; ii. Working longer hours than usual in order to provide assistance or care to individuals with COVID-19; iii. Witnessing or responding to a death related to COVID-19, or losing a patient you had been caring for to COVID-19; iv. Caring for patients who have died without family physically present due to COVID-19 precautions
2. Have a Montgomery-Asberg Depression Rating Scale (MADRS) clinician-administered depression score >21, indicating moderately severe symptoms.
3. Have had persistent symptoms despite at least one medication and/or therapy trial of standard care treatment for depression.
4. English speaking - able to understand the process of consent and the risk and benefits associated with the study, and able to give written informed consent.
5. Must be willing to sign a medical release for the investigators to communicate directly with their therapist and doctors to confirm a medication and/or medical history. This is decided on a case-by-case basis upon the discretion of the PI.
6. Must be driven home after the medication dosing session by a driver (which could be a friend, family, rideshare or taxi).
7. Must provide at least one adult to have continuous contact with the participant, provide participant transportation, monitor changes in the participant's behavior, and notify research staff of behavior changes.
8. Has been off selective serotonin inhibitors (SSRIs) for at least five half-lives of the drug plus 2 weeks.
9. Must avoid taking any psychiatric medications or starting a new psychiatric medication during the study. Should participant's doctor recommend starting a new psychiatric medication, participant will be required to notify the study team and the subject would withdraw from the study
10. Must provide a contact (relative, spouse, close friend or other caregiver) who is willing and able to be reached by the Clinical Investigators in the event of a participant becoming suicidal.
11. If able to bear children, must have a negative pregnancy test at study entry.
12. Are willing to commit to preparation sessions, medication dosing sessions, integration sessions, to complete evaluation instruments and commit to be contacted for all necessary telephone contacts.

Exclusion Criteria:

1. Personal or immediate family history of schizophrenia, bipolar affective disorder, delusion disorder, paranoid disorder, or schizoaffective disorder.
2. Suicidal ideation with a Columbia Suicide Severity Rating Scale (C-SSRS) > 3
3. Current substance abuse disorder (except in the case of mild alcohol use )
4. Neuroleptic and SSRI medications that cannot be tapered and discontinued in conjunction with the participant's prescribing physician.
5. Unstable neurological or medical condition; history of seizure, chronic/severe headaches.
6. Positive urine pregnancy test at the time of screening
7. Any unstable medical condition that my render study procedures unsafe.
8. Any use of psychedelic drugs within the prior 12 months.
9. Use of tramadol, due to the potential for serotonin syndrome with concomitant use of psilocybin.

IPD that underlie results in a publication

We anticipate sharing these data starting with publication of study results and for at least 3 years.

To be determined.

To be eligible, clinicians had to have more than 1 month of direct frontline clinical care experience and had to endorse at least 2 of 4 items from a COVID-19 occupational exposure index as occurring more than half of the day during that time.

6 months after intervention was completed

Definitions are the same as clinicaltrials.gov

The investigators, study therapists, and outcomes assessors will all be blinded in the randomized phase of the study. Participants will be unblinded after the primary outcome, and those receiving placebo will be eligible to receive open label psilocybin.