Using psilocybin to enhance buprenorphine treatment 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.