This study will test the feasibility, safety, and evidence for efficacy of psilocybin administration in participants with obsessive compulsive disorder (OCD). This will serve as a preliminary proof of concept study for future larger studies aimed to investigate the utility, cognitive mechanisms, and neural correlates of this intervention.

Participants in this study will receive two doses of psilocybin approximately two weeks apart. Assessments will be conducted during screening visits, psilocybin sessions, and at follow up visits up to 6 months after the final psilocybin session. Thirty participants will complete all study visits including follow-up visits.

Primary objectives:

1. Investigate the feasibility, safety, and acceptability of psilocybin for OCD.
2. Investigate the effect of psilocybin on OCD symptoms and concomitant depression and anxiety symptoms.
3. Investigate the effect of psilocybin on quality of life.

Secondary objectives:

1. Investigate the effect of psilocybin on metacognition of episodic memory and decision-making.
2. Investigate the effect of psilocybin on model-based learning.
3. Investigate the effect of psilocybin on the ERN.
4. Investigate the effect of psilocybin on affect and social connection.
5. Investigate the effect of psilocybin on movement and communications.

Inclusion Criteria:

• Have given written informed consent
• Currently meet criteria for a DSM-5 diagnosis of OCD and report a history of OCD for at least 1 year prior to screening
• Have a Y-BOCS score of 18 or more
• Have at least one prior attempt at treatment, either ERP or pharmacotherapy
• No antidepressant medications for approximately five half-lives prior to acceptance in treatment phase of study
• Women who are of childbearing potential and sexually active who are not practicing an effective means of birth control must agree to practice an effective means of birth control throughout the duration of the study
• Be judged by study team clinicians to be at low risk for suicidality
• Concurrent psychotherapy is allowed if the type and frequency of the therapy has been stable for at least two months prior to screening and is expected to remain stable during participation in the study
• Be otherwise medically stable as determined by screening for medical problems via a personal interview, a medical questionnaire, a physical examination, an electrocardiogram (ECG), and routine medical blood and urinalysis laboratory tests (CBC, CMP, urine beta-HCG, urine toxicology screen)
• 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 mornings of drug session days. If the participant does not routinely consume caffeinated beverages, he/she must agree not to do so on session days
• Agree to refrain from using any psychoactive drugs, including alcoholic beverages, within 24 hours of each drug administration. The exceptions are caffeine and nicotine
• Agree not to take any PRN medications on the mornings of drug sessions
• Agree not to take sildenafil (Viagra®), tadalafil, or similar medications within 72 hours of each drug administration
• Agree that for one week before each drug session, he/she will refrain from taking any nonprescription medication, nutritional supplement, or herbal supplement except when approved by the study investigators. Exceptions will be evaluated by the study investigators and will include acetaminophen, non-steroidal anti-inflammatory drugs, and common doses of vitamins and minerals.
• Have limited lifetime use of hallucinogens (the following criteria are preferred: no use in the past 5 years; total hallucinogen use less than 10 times)

Exclusion Criteria:

• Clinically significant transaminitis (AST or ALT greater than two times normal value)
• Women who are pregnant (as indicated by a positive urine pregnancy test assessed at intake and before each drug session) or nursing
• Women who are of childbearing potential and sexually active who are not practicing an effective means of birth control
• Cardiovascular conditions: coronary artery disease, stroke, angina, uncontrolled hypertension, a clinically significant ECG abnormality (e.g., atrial fibrillation), prolonged QTc interval (i.e., QTc > 450 msec), heart valve, or transient ischemic attack (TIA) in the past year
• Epilepsy with history of seizures
• Type 1 diabetes
• BMI < 18
• Currently taking on a regular (e.g., daily) basis any psychoactive prescription medication or any medications having a primary centrally-acting serotonergic effect, or MAOIs. For individuals who have intermittent or PRN use of such medications, psilocybin sessions will not be conducted until approximately five half-lives of the agent have elapsed after the last dose.
• Current (severe) migraine or other recurring severe headaches
• Current or past history of meeting DSM-5 criteria for schizophrenia spectrum or other psychotic disorders (except substance-/medication-induced or due to another medical condition), or bipolar I disorder
• Current or history within one year of meeting DSM-5 criteria for a moderate or severe alcohol, or other drug use disorder (excluding tobacco and caffeine)
• Nicotine dependence that would be incompatible with an individual to be nicotine free for 8-10 hours on a psilocybin session day
• Have a first degree relative with schizophrenia or other psychotic disorders (except substance/medication-induced or due to another medical condition), or bipolar I disorder