Oral Cannabidiol for Opioid Withdrawal

Study Overview
=================
Brief Summary
-----------------
This pilot study will examine the safety of the cannabinoid cannabidiol (Epidiolex) in a human laboratory model of clinically relevant withdrawal. The study will be a residential within-subject comparison; all participants will receive placebo dosing and active cannabidiol. Results may be used to support an R01 grant application to more closely examine this hypothesis.

Detailed Description
-----------------
Based on preclinical research and emerging human research, cannabidiol (CBD; a major constituent of the cannabis plant) is a promising pharmacotherapy for the treatment of opioid withdrawal. Most recently, CBD decreased cue-induced craving and anxiety (two common withdrawal symptoms) among abstinent heroin-dependent individuals relative to placebo. As of June 2018, Epidiolex, an oral formulation of plant-derived pure CBD, has been approved by the U.S. Food and Drug Administration (FDA) for treating severe forms of epilepsy and can be prescribed for other off-label indications. Epidiolex has a low side effect and high safety profile. Given the recent FDA approval of Epidiolex, and a growing interest to develop existing pharmaceuticals to address issues related to Opioid Use Disorder (OUD) and its recovery, the investigators are proposing a pilot study to examine the safety of Epidiolex in a human laboratory model of clinically relevant withdrawal. The study will be a residential within-subject comparison; methadone-maintained participants will undergo spontaneous withdrawal and receive placebo dosing and active cannabidiol. Data collected for this study will establish: (1) the safety of administering two dosing regimens of Epidiolex within the investigators' withdrawal paradigm and (2) the feasibility of the investigators' withdrawal paradigm for demonstrating clinically meaningful increases in withdrawal. Results may be used to support an R01 grant application to more closely examine this hypothesis.

Official Title
-----------------
A Randomized Placebo-Controlled Evaluation of the Safety of Oral Cannabidiol in a Clinically Relevant Model of Opioid Withdrawal

Conditions
-----------------
Opioid Withdrawal, Opioid Craving, Opioid Use Disorder

Intervention / Treatment
-----------------
* Drug: Epidiolex
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Medically cleared to take study medication Are not pregnant or breast feeding Willing to comply with the study protocol Provides urine that tests positive for methadone Maintained on 80-120 mg of daily methadone with no dose changes in the past 2 weeks (verified through a medical release with the participant's provider) Exclusion Criteria: Meet Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 criteria for alcohol/substance use disorder other than opioid use disorder Previous adverse reaction to a cannabinoid product Self-report any illicit drug use or cannabinoid use in the past 7 days Presence of any clinically significant medical/psychiatric illness judged by the investigators to put subject at elevated risk for experiencing an adverse events Past year suicidal behavior as assessed via the Columbia Suicide Severity Rating Scale History of seizure disorder Past 14 day use of any of the following contraindicated medications: Clobazam, Valproate Moderate or strong inhibitors of CYP3A4 or CYPC19 (with the exception of methadone, as outlined in the Protection Against CBD Risks section). Strong CYP3A4 or CYP2C19 inducers UGT1A9, UGT2B7, CYP1A2, CYP2C8, CYP2C9 and CYP2C19 substrates (with the exclusion of caffeine). Central nervous system (CNS) depressants that are contraindicated with Epidiolex Breathalyzer that tests positive for alcohol prior to session admission Self-reported consumption of grapefruit juice within 24 hours of session admission Have a history of clinically significant cardiac arrhythmias or vasospastic disease Have circumstances that the study investigators believe are contraindicated with study participation and/or would interfere with study participation (e.g., impending jail). Moderate-severe hepatic impairment as indicated by ALT or AST levels > 3x ULN and/or Bilirubin levels >2x ULN as evidenced by a blood test.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Within subject comparison of Epidiolex to placebo. The order of study drug (active Epidiolex or placebo) is randomized across participants. Epidiolex is flavor masked with cherry syrup.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Epidiolex (CBD) Then Placebo<br>Participants first receive 8 mL of Epidiolex (800 mg of cannabidiol) + 16 mL of inactive cherry syrup delivered every 12 hours for 48 hours total (4 doses) during which prescribed methadone is withheld. After 1 week, they receive 20 mL of inactive cherry syrup delivered every 12 hours for 48hours total (4 doses) during which prescribed methadone is withheld. | Drug: Epidiolex<br>* Epidiolex 100 mg/mL Oral Solution<br>* Other names: Cannabidiol;Drug: Placebo<br>* Cherry syrup oral solution<br>|
| Placebo Comparator: Placebo Then Epidiolex<br>Participants first receive 20 mL of inactive cherry syrup delivered every 12 hours for 48hours total (4 doses) during which prescribed methadone is withheld. After 1 week washout, they receive 8 mL of Epidiolex (800 mg of cannabidiol) + 16 mL of inactive cherry syrup delivered every 12 hours for 48 hours total (4 doses) during which prescribed methadone is withheld. | Drug: Epidiolex<br>* Epidiolex 100 mg/mL Oral Solution<br>* Other names: Cannabidiol;Drug: Placebo<br>* Cherry syrup oral solution<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as Assessed by Number of Adverse Events | Number of Adverse Events reported across sessions with and without study drug. Adverse events were collected for the entire 57 hour session. | through completion of the two study sessions, an average of 17 days | 
| Number of Participants Whose Aspartate Aminotransferase (AST)/Alanine Aminotransferase (ALT) Levels >3x Upper Limit of Normal | Number of participants whose AST/ALT levels >3x upper limit of normal (ULN) at the end of a study session when they receive Epidiolex and Placebo. This will be used in the assessment of safety. | End of residential stay, prior to discharge | 
| Change in Withdrawal Scores From Baseline AfterReceiving Placebo | Change in withdrawal scores during laboratory evaluation of spontaneous withdrawal. Withdrawal is measured with the Subjective Opiate Withdrawal Scale (SOWS). That has a range of 0-64 where a mild score is represented by a score of 1-10, a moderate score is represented by a score of 11-20 and a severe score is considered anything greater than 21. | Baseline, during residential session up to 57 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Initial Efficacy of Study Drug as Assessed by Area Under the Curve for the Subjective Opiate Withdrawal Scale (SOWS) Scores | Withdrawal symptom suppression during active and placebo conditions. Area Under the Curve (AUC) analyses will be calculated to characterize withdrawal on the Subjective Opiate Withdrawal Scale (SOWS) scores across time. SOWS AUC will be compared between the two conditions. AUC will range from 0 to 3072 where 0 represents no withdrawal during study drug administration and 3072 represents the most severe withdrawal during study drug administration. | After first administration of study drug and up to 48 hours | 
| Acceptability Assessed by Number of Participants Who Would Recommend the Medication to a Family Member or Friend | Number of participants who would recommend the medication to a family member or friend trying to taper down from opioid medications. | at the end of the 57-hour residential session, prior to discharge | 
| Acceptability Assessed by Visual Analog Ratings | Visual analog ratings of the degree to which the medication suppressed opioid withdrawal symptoms. The visual analog ratings will be scored on a scale from 0-100 where 0 represents no suppression of withdrawal and 100 represents complete suppression of withdrawal. | at the end of the 57-hour residential session, prior to discharge | 
| Acceptability Assessed by Rating of Medication Acceptance on a 5-point Acceptance Rating Scale | Participant rating of medication acceptance on a 5-point acceptance rating scale. The acceptance rating scale will range from 0-4 where 0 represents no acceptance of the medication and 4 represents complete acceptance of the medication. | at the end of the 57-hour residential session, prior to discharge |