Psilocybin for Opioid Use Disorder in Patients on Methadone Maintenance With Ongoing Opioid Use

Inclusion Criteria:

* Age 21-70 years
* Have OUD
* Enrolled in a methadone maintenance program for at least 3 months
* Urine toxicology positive for methadone
* Urine toxicology positive for an additional opioid
* Access to stable housing
* Read, write, and speak English
* Be judged by study team clinicians to be at low risk for suicidality
* Have limited lifetime use of classic psychedelics (no use in the past 5 years; total classic psychedelic use less than 20 times)
* Are local to the Baltimore area

Exclusion Criteria:

* Women who are pregnant, nursing, or not practicing an effective means of birth control
* Cardiovascular conditions: hypertension with resting blood pressure systolic \>140 or diastolic \>90, angina, a clinically significant ECG abnormality (e.g., atrial fibrillation, corrected QT interval \> 450), transient ischemic attack in the last 6 months stroke, peripheral or pulmonary vascular disease
* Epilepsy
* Insulin-dependent diabetes; if taking oral hypoglycemic agent, then no history of hypoglycemia
* Currently taking a prescribed psychoactive medication on a daily basis (except methadone)
* 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 Uridine 5'-diphospho-glucuronosyltransferase Family 1 Member A9 (UGT1A9) inhibitors or UGT1A10 inhibitors such as phenytoin, regorafenib, eltrombopag.
* Have a seizure disorder, multiple sclerosis, history of significant head trauma, central nervous system tumor, movement disorders or any neurodegenerative condition.
* Morbidly obese (\>100 lbs above idea body weight, or BMI \>=40, or BMI \>=35 with high blood pressure or diabetes)
* Body weight \< 45kg
* Recent (within past 12 months) or extensive history of classic psychedelic use (\>19 lifetime uses).
* Physiological dependence on benzodiazepines or alcohol
* Abnormal screening labs: values for hemoglobin, white blood count, creatinine, potassium, and bilirubin outside of the normal lab reference rage. Transaminases greater than x2 the upper limit of normal lab reference range.