Outpatient Buprenorphine Induction With Psilocybin for Opioid Use Disorder (BIPOD-Out)

Inclusion Criteria: Age 21-70 years Have given written informed consent Meet Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 criteria for OUD No antidepressant medications for approximately 5 half-lives prior to enrollment Willing to undergo buprenorphine induction or has undergone buprenorphine induction in the past 3 weeks Reports previous buprenorphine maintenance Urine toxicology positive for an opioid Has access to stable housing Can read, write, and speak English fluently Be judged by study team clinicians to be at low risk for suicidality Have limited recent use of classic psychedelics (no use in the past year). Expresses a desire for sustained recovery from disordered opioid use. Exclusion Criteria: General medical exclusion criteria: Women who are pregnant, nursing, or not practicing an effective means of birth control Cardiovascular conditions: hypertension with resting blood pressure systolic >139 or diastolic >89, angina, heart rate > 99, a clinically significant ECG abnormality (e.g., atrial fibrillation, QTc > 450), transient ischemic attack (TIA) in the last 6 months, stroke, peripheral or pulmonary vascular disease, cardiac valvulopathy Epilepsy Insulin-dependent diabetes; if taking oral hypoglycemic agent, then no history of hypoglycemia Currently taking on a daily basis any medications (including herbal substances and supplements) with a central nervous system effect on serotonin, including serotonin-reuptake inhibitors and monoamine oxidase (MAO) inhibitors. For individuals who have intermittent or as needed (PRN) use of such medications, psilocybin sessions will not be conducted until at least 5 half-lives of the agent have elapsed after the last dose. Currently taking efavirenz, Acetaldehyde dehydrogenase inhibitors such as disulfiram (Antabuse), Alcohol dehydrogenase inhibitors, or UDP-glucuronosyltransferase (UGT)1A9 inhibitors or UGT1A10 inhibitors such as phenytoin, regorafenib, eltrombopag. Currently taking methadone or naltrexone. Currently on longstanding buprenorphine maintenance (3+ weeks post-induction) Naïve to buprenorphine Reports of significant adverse events (severe withdrawal, medical complications, hospitalization) during previous buprenorphine induction(s). Unable or unwilling to discontinue acid-reducing agents or major metabolizing enzyme inhibitors for 5-half lives prior to the experimental dosing session. Have a seizure disorder, multiple sclerosis, history of significant head trauma, central nervous system (CNS) tumor, movement disorders or any neurodegenerative condition. Morbidly obese (>100 lbs above ideal body weight, or Body Mass Index (BMI) >=40, or BMI >=35 with high blood pressure or diabetes) Body weight < 45 kg Be judged by a study team clinician to be at risk for moderate or severe alcohol or benzodiazepine withdrawal. Allergic to buprenorphine For blood samples, the following lab values will be exclusionary: transaminases greater than x2 the upper limit of normal lab reference range, hemoglobin less than 11 g/d, and creatinine clearance < 40 ml/min using the Cockraft and Gault equation. Psychiatric Exclusion Criteria: Current or past history of meeting DSM-5 criteria for Schizophrenia, Psychotic Disorder (unless substance-induced or due to a medical condition), Bipolar I or II Disorder or Major Depression with psychotic features. Have a first or second degree relative with schizophrenia, psychotic disorder (unless substance induced or due to a medical condition), or bipolar I or II disorder.