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.