Efficacy of Psilocybin in OCD: a Double-Blind, Placebo-Controlled Study.

Aim 1: To investigate the effects of psilocybin on OCD symptomatology. OCD symptom severity
will be assessed before treatment and 24 and 48 hours after treatment, one week after
treatment, two weeks, one month, three months, and six months after treatment. Hypothesis: We
hypothesize that 0.25mg/kg of psilocybin will lead to greater symptom improvement than niacin
(as the active-placebo-control agent) at all assessment points.

Aim 2: To explore the relationship between the psilocybin-induced brain connectivity changes
and neuronal activation following symptom provocation in OCD. Resting-state brain
connectivity will be assessed before and 48 hours after treatment. Neuronal activation
induced by OCD-relevant provocative stimuli will be assessed 48 hours after the treatment.
Hypothesis: We hypothesize that (i) psilocybin will normalize abnormal fronto-striatal
functional connectivity in patients with OCD; (ii) psilocybin will decrease activation of
anterior cingulate cortices, amygdala, and putamen in response to symptom-provoking stimuli,
and normalization of one or more of these abnormalities will correlate with improvement in
symptomatology after psilocybin treatment.

This study will pilot a single-center, randomized, active-placebo-controlled, double-blind
design to examine the clinical and neural effects on OCD, of either 0.25mg/kg of psilocybin
or active placebo-control agent (niacin 250mg), given along with non-drug preparatory and
follow-up support appointments to 30 study participants.The duration of the randomized study
phase is from consent until two weeks after drug administration. Participants will be
followed for 24 weeks (3 months) post-study drug administration.

Eligible participants will be admitted as an inpatient for at least 3 nights / 4 days
surrounding the initial drug administration (or more, at the option of the subject and the
investigator). Participants will be randomized into active medication and
active-placebo-control groups, and will be blinded as to their study condition. This
admission 2 nights prior to the drug administration will allow the participant to adjust to
sleeping on the unit and allow them to settle in to the research unit routine. A return for
an fmri scan (48 hours after the administration session) will be scheduled. The participants
who received active-placebo-control will be offered the option to receive open-label
psilocybin.

Inclusion Criteria:

1. DSM-5 diagnosis of OCD established by a trained clinician interview and confirmed by
Mini International Neuropsychiatric Interview MINI (edition 7).

2. YBOCS score of 18 or greater at evaluation.

3. Patients must have failed at least one medication and/or therapy trial of standard
care treatment for OCD.

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 sign a medical release for the investigators to communicate directly with their
therapist and doctors to confirm a medication and/or medical history.

6. Are willing to be driven home the morning after the experimental sessions, after the
48-hour post session assessments either by a driver arranged by the subject or by the
site personnel or taxi.

7. Has been off selective serotonin inhibitors for five half-lives of the drug plus 2
weeks.

8. Must avoid 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.

9. 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.

10. Are willing to refrain from taking any psychiatric medications during the study
period.

11. Must have a negative pregnancy test at study entry and prior to each experimental
session if able to bear children, and must agree to use adequate birth control.

12. Are willing to commit to medication dosing, experimental sessions, follow-up 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. Active suicidal intent

3. Unremitted Tourette syndrome

4. Pervasive developmental disability

5. Current substance abuse disorder

6. Anxiolytic, neuroleptic, and SRI medications

7. Unstable neurological or medical condition; history of seizure, chronic/severe
headaches.

8. Any contraindications to undergoing an MRI scan, including having metal implants or
metal fragments in the body. With participants who may have been exposed to metal
fragments and who wish to participate in the MRS scans, a plain film X-ray may be
order to clarify their eligibility status. Women of childbearing potential who elected
not to have the pregnancy test, will be excluded from MRI.

9. Any history of head injury with loss of consciousness for more than 30 minutes.

10. Positive urine pregnancy test at the time of screening

11. Any unstable medical condition that my render study procedures unsafe.