Inpatient Buprenorphine Induction With Psilocybin for Opioid Use Disorder (BIPOD-In)

Inclusion Criteria: Age 21-70 years Have given written informed consent Meet diagnostic criteria for OUD No antidepressant medications for approximately 5 half-lives prior to enrollment Not currently taking methadone, buprenorphine or naltrexone 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 electrocardiogram abnormality (e.g., atrial fibrillation), Transient Ischemic Attack or Stroke in the last 6 months, 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 inhibitors. o For individuals who have intermittent or as needed 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 medicines such as phenytoin, regorafenib, eltrombopag. Currently taking buprenorphine, methadone, or naltrexone. 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, nervous system tumor, movement disorders or any neurodegenerative condition. Morbidly obese (>100 pounds above ideal body weight, or Body Mass Index (BMI) >=40, or BMI >=35 with high blood pressure or diabetes) Body weight < 45 kilograms Be judged by a study team clinician to be at risk for moderate or severe alcohol or benzodiazepine withdrawal. Allergic to buprenorphine or hydromorphone 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. Psychiatric Exclusion Criteria: Current or past history of meeting diagnostic 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.