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

Study Overview
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Brief Summary
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This study will investigate whether psilocybin administered under supportive conditions can reduce illicit opioid use and improve quality of life in individuals with Opioid Use Disorder (OUD) in Methadone Maintenance Treatment (MMT) who are concurrently using other opioids illicitly.

Detailed Description
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This randomized double-blind placebo-controlled trial will investigate whether 2 doses of psilocybin administered under supportive conditions can reduce illicit opioid use (assessed by self-report and urine toxicology) and improve quality of life as measured by World Health Organization Quality of Life (WHOQOL-BREF) in individuals with OUD in MMT who are concurrently using other opioids illicitly. In addition, the investigators will investigate secondary outcomes including whether psilocybin under supportive conditions improves mood, reduces use of tobacco and other non-opioid drugs, improves chronic pain and sleep. Ninety-two participants aged 21-70 who meet Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for OUD, are enrolled in a MMT program for at least 3 months, and have urine toxicology positive for methadone and another opioid will be recruited from the community and complete all study procedures. Participants will be randomized to an active group or control group (46 per group). Participants will undergo a total of 2 dosing sessions (whether psilocybin or placebo). The active group will receive 40mg psilocybin first. All participants will receive a second dosing session at three months. The active group will be further randomized, with half receiving 40mg psilocybin, and half receiving placebo at three months to test a secondary hypothesis that two doses of psilocybin are more effective in treating OUD than a single dose.

Official Title
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A Randomized, Double-Blind Study of Psilocybin for Opioid Use Disorder in Patients on Methadone Maintenance With Ongoing Opioid Use

Conditions
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Opioid Use Disorder

Intervention / Treatment
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* Drug: Placebo
* Drug: Psilocybin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Participants will be randomized to an active group or control group (46 per group). Participants will undergo a total of 2 dosing sessions (whether psilocybin or placebo). The active group will receive 40mg psilocybin first. All participants will receive a second dosing session at three months. The active group will be further randomized, with half receiving 40mg psilocybin, and half receiving placebo at three months.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Psilocybin<br>Participants will be administered 40mg of psilocybin in a clinical setting. Psilocybin is administered orally as a capsule and taken with water. At 3 months, half will be randomized to receive a blinded dose of psilocybin 40mg and half a blinded dose of placebo. | Drug: Placebo<br>* Participants will receive placebo in a clinical setting.<br>Drug: Psilocybin<br>* Participants will receive 40mg psilocybin in a clinical setting.<br>|
| Placebo Comparator: Placebo<br>Participants will be administered placebo in a clinical setting. Placebo is administered orally as a capsule taken with water. At 3 months, participants will receive a blinded dose of psilocybin 40mg. | Drug: Placebo<br>* Participants will receive placebo in a clinical setting.<br>Drug: Psilocybin<br>* Participants will receive 40mg psilocybin in a clinical setting.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in non-methadone opioid use as assessed by urine toxicology | The primary outcome variable will be change in non-methadone opioid use as verified by urine toxicology at each visit. | Baseline and 3-months after first experimental drug administration session | 
| Change in non-methadone opioid use as assessed by the Timeline Follow Back self report | The primary outcome variable will be change in non-methadone opioid use as verified by Timeline Follow Back (TLFB) of mean number of days of non-methadone opioid use. The TLFB is a widely used, standardized, calendar-based retrospective self-report assessment to quantify daily opioid use. | Baseline and 3-months after first experimental drug administration session |