Psilocybin for Treatment of OCD-2

Inclusion Criteria: * Aged 18 years old, and older * Have OCD (DSM-5) based on diagnostic interview using the Structured Clinical Interview for DSM-5 Research Version (SCID). * At least moderate severity: Yale-Brown Obsessive-Compulsive Scale (YBOCS) score ≥16. * Failed at least one adequate trial of guideline concordant treatment. * Considered safe for independent living * Subjects must discontinue use of any of the following prescription or over the counter (OTC) products or nutritional supplements at least two weeks prior to initiating double-blind treatment: * Monoamine oxidase (MAOI), UGT1A10, and UGT1A9 inhibitors * Other active OCD treatments (cognitive behavioral therapy \[CBT\] or other psychotherapy; electrical or magnetic device treatments; pharmacological treatments such as antidepressant medications (e.g., SSRIs, SNRIs, MAOIs, TCAs, 5HT2 blockers, NERIs, etc.), lithium, antipsychotic drugs, 5-HT2 antagonists such as pimavanserin, and glutamatergic acting medications) * Note that fluoxetine must be discontinued at least 6 weeks prior to initiating double-blind treatment. * 5HT2 agonists (e.g., efavirenz, lorcaserin), which may alter the response to psilocybin * Serotonin-acting dietary supplements (e.g., 5-hydroxy-tryptophan, St. John's wort) due to potential for interaction with psilocybin and increased safety risks Exclusion Criteria: * Concurrent active substance use disorder, or a personal history of psychosis. * History of psychosis among first degree relatives as determined by the Family Interview for Genetic Studies (FIGS) 32 * Medical illness based on physical examination and routine blood testing that may complicate cardiovascular safety or drug metabolism or excretion, such as uncontrolled hypertension, severe cardiac disease, or kidney or liver failure. * Unstable Chronic Obstructive Pulmonary Disease (COPD) or severe sleep apnea * Clinically significant renal or hepatic impairment, per clinical judgment of a study physician * EKG QTc ≥ 450 msec * Psychiatric comorbidity that may represent an acute risk to their own or other's safety. * Subjects cannot require any sedative, narcotic, or neuroleptic medications on a regular basis. Any of these medications they have taken should have been stopped long enough in the past to allow for their elimination and safe withdrawal prior to starting administration of the study drug. The specific time required will be dependent on the medication the patient was previously receiving. * Women who are pregnant, breastfeeding, or unwilling/unable to practice medically acceptable highly effective birth control (double barrier, oral and injectable pharmacological contraceptives) during the study. * Suicidal behavior within the 12 months prior to enrollment, or significant risk of suicide as determined by the CSSRS items 4 (suicidal ideation with intent) and 5 (suicidal ideation with intent and plan) during screening or baseline assessment. * Any condition for which MRI is contraindicated, at the discretion of a study investigator or the MRI technician, including: Pacemakers and defibrillators; artificial heart valves which are not MRI safe; any metal in head, spinal cord, eyes or chest; any electrical devices such as cochlear implants, nerve stimulators, deep brain stimulators, gastric pacemaker, or insulin or pain pumps; aneurysm clips; ferrous (i.e. non titanium alloy) implants in any part of the body. * Use within the week prior to screening of drugs of abuse as listed in the current US DOJ DEA Drugs of Abuse Resource Guide, including: * Cannabinoids (marijuana, synthetic cannabinoids) * Simulants (amphetamine, cocaine, methamphetamine, methylphenidate, modafinil) * Opioids (natural and synthetic), * Sedatives (benzodiazepines, barbiturates, GHB, zolpidem, zaleplon, zopiclone) * Hallucinogens (DMT, ibogaine, LSD, MDMA, psilocybin, psilocin, PSP)