Outpatient Buprenorphine Induction With Psilocybin for Opioid Use Disorder

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, has undergone buprenorphine induction in the past 3 weeks, or are in buprenorphine treatment with ongoing use of other opioids (evidenced by positive urine toxicology for buprenorphine and another opioid at time of screen) * 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.