Dronabinol and Epidiolex to Manage Uncontrolled Residual Symptoms of Buprenorphine Initiation Trial

Not Applicable

Not yet recruiting

• Conditions: Opioid Use Disorder
• Interventions: Drug: Dronabinol Capsules; Other: Placebo Dronabinol; Drug: Epidiolex 100 mg/mL Oral Solution; Other: Placebo Epidiolex

• Registration Number: NCT07148206
• Lead Sponsor: Montefiore Medical Center

Brief Summary

The goal of this pilot study is to test novel, adjunctive pharmacotherapy for patients with opioid use disorder (POUD) who may be at risk for overdose and other poor opioid use disorder (OUD) outcomes even after initiating buprenorphine. The investigator team proposes to test the effectiveness of combined dronabinol (synthetic delta-9-tetrahydrocannabinol \[THC\]) and Epidiolex (cannabidiol \[CBD\]) - two FDA-approved cannabinoids - to improve retention in buprenorphine treatment and reduce opioid use among POUD who are early in treatment. POUD who are early in treatment are at a critical juncture-a moment of opportunity and motivation, but also of high risk of return to opioid use and loss to follow up.

Detailed Description

OUD and opioid overdose death rates remain shockingly high in the United States fueled by high potency opioids like fentanyl. Buprenorphine is an evidence-based therapy for OUD that reduces mortality, improves OUD outcomes, and is increasingly available. Three-month buprenorphine retention halves all-cause mortality; however, only 40-60% of POUD are retained in buprenorphine treatment for 3 or more months. Further, POUD who use fentanyl report protracted opioid withdrawal symptoms including anxiety, pain, insomnia, and opioid cravings, even months after reaching maximum doses of buprenorphine. Nearly 50% of POUD who use fentanyl return to use within 3 months.12 To improve success of buprenorphine treatment, new strategies for starting buprenorphine have emerged, such as low-dose initiation with ongoing opioid agonists, however, few interventions exist to improve treatment after starting buprenorphine, and those that exist are non-pharmacologic. Alpha-2-agonists (e.g., clonidine) reduce some withdrawal symptoms but can only be given for a short time without cardiac side effects. Pharmacologic adjuncts to buprenorphine are desperately needed to improve OUD outcomes in the fentanyl era.

Cannabis, the two key ingredients of which are THC and CBD, reduces opioid withdrawal in observational studies and thus has biologic plausibility for improving buprenorphine treatment retention. In two randomized trials, THC improved acute opioid withdrawal symptoms (e.g., muscle aches, muscle tension, and flu-like prodrome) a common driver of ongoing opioid use. THC is also effective in reducing acute and chronic pain in POUD another driver of ongoing use; however, patients receiving THC alone may experience adverse effects, such as panic, anxiety, and poor cognition. Co-administration with CBD may counteract these effects and maximize THC's benefits. In pre-clinical and clinical trials CBD reduces anxiety, pain, cue-induced opioid cravings, and attentional bias to drug-induced cues. When THC and CBD are co-administered, patients experience improved analgesic effects and reduced adverse effects. The overarching hypothesis of this study is that adjunctive dronabinol + Epidiolex improves buprenorphine retention and opioid use in POUD through reducing opioid withdrawal (including cravings, and pain).

The investigator team has developed an innovative 12-week pilot randomized trial of dronabinol + Epidiolex (versus placebo) as an adjunct to buprenorphine for OUD outcomes. 40 POUD participants within 21 days of buprenorphine initiation who are continuing either to use illicit opioids or to experience opioid withdrawal symptoms will be enrolled. Participants will be randomized to one of two arms as described in this registration. Study visits will occur at enrollment, and weeks 1, 2, 4, 8, and 12.

There are two overarching Aims in this study.

Aim 1: To determine the effectiveness and safety of 8- weeks of dronabinol + Epidiolex (vs. placebo) as an adjunct to buprenorphine in improving retention in OUD treatment and reducing opioid use. Hypothesis 1a: The dronabinol + Epidiolex (vs. placebo) group will have better 12-week retention in OUD treatment. Hypothesis 1b: The dronabinol + Epidiolex (vs. placebo) group will report less illicit opioid use. Hypothesis 2: The dronabinol + Epidiolex (vs. placebo) group will have no difference in significant adverse events or treatment limiting adverse events.

Aim 2: To explore the mechanism by which cannabinoids may improve OUD outcomes after buprenorphine initiation in POUD. The investigator team will explore how dronabinol + Epidiolex use are associated with change in opioid withdrawal symptoms, opioid cravings, and pain and whether these changes are associated with OUD outcomes. Hypothesis 3: The dronabinol + Epidiolex (vs. placebo) group will have fewer withdrawal symptoms, opioid cravings and pain, which will mediate the impact of cannabinoids on OUD outcomes.

Study Timeline

• Status Verified: 2025-08
• Study First Submitted: 2025-08-21
• Study First Submitted QC: 2025-08-21
• Last Update Submitted: 2025-08-21
• Study First Posted: 2025-08-29
• Last Update Posted: 2025-08-29
• Study Start: 2025-09-01
• Primary Completion: 2027-04
• Study Completion: 2027-04-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

• Fluency in English and Spanish
• DSM-V diagnosis of OUD
• Newly initiated on buprenorphine within 21 days
• Positive urine toxicology for opioids other than buprenorphine in the past week OR opioid withdrawal symptoms in the past week based on the Clinical Opioid Withdrawal Scale (COWS) >=5
• Any cannabis use in the past at or after the age of 18 years based on self-report

Exclusion Criteria

• Urine toxicology positive for cannabinoids
• Inability to provide informed consent
• Liver tests (AST or ALT) >3 times the upper limit of normal, or a history of liver disease
• Pregnancy or breast/chest feeding
• Unstable cardiac disease, history of hypotension or syncope
• Psychotic disorder, or history of suicidal behavior and/or ideation
• Progressive neurological conditions, frequent falls, or history of epileptic seizures
• Severe alcohol use disorder, benzodiazepine use disorder or stimulant use disorder
• Other serious medical conditions that would be a contraindication to THC or CBD use

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dronabinol + Epidiolex Arm	Dronabinol Capsules	Dronabinol (THC) will be dosed every 12 hours. To limit potential adverse effects, the dose of dronabinol will be titrated up gradually over 15 days to a final daily dose of 20 mg (10 mg every 12 hours). This final dosage will be administered twice daily from Day 16 to Week 8. Epidiolex (CBD) will also be dosed every 12 hours. To limit potential adverse effects, the dose of Epidiolex will be titrated up gradually over 15 days to a final dose of 400 mg every 12 hours. Participants will start off taking 200 mg daily (100 mg every 12 hours) for 5 days, then uptitrate to 400 mg (200 mg every 12 hours) for 5 days, then uptitrate to 600 mg for 5 days (300 mg every 12 hours), and finally 800 mg from day 16 through week 8 (400 mg every 12 hours).
Dronabinol + Epidiolex Arm	Epidiolex 100 mg/mL Oral Solution	Dronabinol (THC) will be dosed every 12 hours. To limit potential adverse effects, the dose of dronabinol will be titrated up gradually over 15 days to a final daily dose of 20 mg (10 mg every 12 hours). This final dosage will be administered twice daily from Day 16 to Week 8. Epidiolex (CBD) will also be dosed every 12 hours. To limit potential adverse effects, the dose of Epidiolex will be titrated up gradually over 15 days to a final dose of 400 mg every 12 hours. Participants will start off taking 200 mg daily (100 mg every 12 hours) for 5 days, then uptitrate to 400 mg (200 mg every 12 hours) for 5 days, then uptitrate to 600 mg for 5 days (300 mg every 12 hours), and finally 800 mg from day 16 through week 8 (400 mg every 12 hours).
Placebo Arm	Placebo Dronabinol	Placebo Dronabinol capsules will be labeled and identical in appearance to dronabinol capsules. They will be made of pearl capsules filled with lactose by Montefiore's Investigational Drug Pharmacy team. Placebo Epidiolex oral solution will be made up of ethanol (79.0 mg/mL), sucralose (0.5 mg/mL), strawberry flavor (0.2 mg/mL), and refined sesame oil (to a volume of 1 mL). This mixture will be identical in appearance, taste, and composition of Epidiolex, except for the active ingredient of pure CBD.
Placebo Arm	Placebo Epidiolex	Placebo Dronabinol capsules will be labeled and identical in appearance to dronabinol capsules. They will be made of pearl capsules filled with lactose by Montefiore's Investigational Drug Pharmacy team. Placebo Epidiolex oral solution will be made up of ethanol (79.0 mg/mL), sucralose (0.5 mg/mL), strawberry flavor (0.2 mg/mL), and refined sesame oil (to a volume of 1 mL). This mixture will be identical in appearance, taste, and composition of Epidiolex, except for the active ingredient of pure CBD.

Primary Outcome Measures

Name	Time	Method
Retention in OUD Treatment	~12 weeks following initiation of intervention	Retention in OUD Treatment will be assessed as a dichotomous measure and will be based on the number of participants maintaining both an active buprenorphine prescription AND urine toxicology positive for buprenorphine at 12 weeks. The number/percentage of participants will be summarized by study arm.

Secondary Outcome Measures

Name	Time	Method
Opioid Use - Urine Toxicology	Baseline and ~2-weeks, 4-weeks, 8-weeks, and 12 weeks following initiation of intervention	Opioid use will also be assessed using a urine toxicology immunoassay. Unobserved urine sample collection will be conducted at defined visits and samples will be analyzed to detect for the presence opioids and their metabolites. Results above the laboratory threshold for opiates will be reported as Either "Positive" or "Negative" and summarized by study arm at each timepoint.
Opioid Use Disorder Symptoms - Subjective Opiate Withdrawal Scale	Baseline and ~4-weeks, 8-weeks, and 12 weeks following initiation of intervention	Opioid Use Disorder Symptoms will be assessed using the Subjective Opiate Withdrawal Scale (SOWS). The SOWS is a 16-item clinician administered scale designed to reproducibly rate the severity of opiate withdrawal symptoms. Participants rate each symptom on a 5-point scale ranging from 0 ("Not at all") to 4 ("Extremely") based on the intensity they are experiencing at the moment, yielding an overall possible range from 0-64, wherein higher scores are associated with more severe withdrawal symptoms. Specific scoring guideline categories include 1-10 = mild withdrawal; 11-20 = moderate withdrawal; 21-30+ = severe withdrawal. Mean scores will be summarized by study arm at each timepoint using basic descriptive statistics.
Opioid Use Disorder Symptoms - Opiate Craving Scale	Baseline and ~4-weeks, 8-weeks, and 12 weeks following initiation of intervention	Opioid Use Disorder Symptoms will also be assessed using the 3-item Opiate Craving Scale. The Opiate Craving Scale is a clinician administered scale designed to evaluate opiate cravings over the prior week. Participants are asked to (1) "Please rate how strong your desire was to use in the past 24 hours." (2) "Please imagine yourself in the environment in which you previously used drugs or alcohol. If you were in this environment today, what is the likelihood you would use?" and (3) "Please rate how strong your urges are for drugs or alcohol when something in the environment reminds you of it." Each item is rated on a scale ranging from 0 to 9 and an average score from the 3 items is calculated. Higher scores are indicative of greater craving. Mean scores will be summarized by study arm using basic descriptive statistics.
Retention in OUD Treatment	Baseline and ~1-week, 2-weeks, 4-weeks, and 8-weeks following initiation of intervention	Retention in OUD Treatment will be assessed as a dichotomous measure and will be based on the number of participants maintaining both an active buprenorphine prescription AND urine toxicology positive for buprenorphine at 12 weeks. The number/percentage of participants will be summarized by study arm.
Pain Severity	Baseline and ~1-week, 2-weeks, 4-weeks, 8-weeks, and 12 weeks following initiation of intervention	Pain Severity will be assessed by administration of the Pain Severity questions within the Brief Pain Inventory-Short Form (BPI-SF). Pain severity over the prior 24 hours is calculated by averaging the ratings for worst, least, and average pain for the past week as well as current pain (four individual items on the BPI-SF). This results in a Pain Severity score ranging from 0-10, with higher scores being indicative of more severe pain. A score of 0 means "No pain" and a score of 10 means "Pain as bad as you can imagine." Scores will be summarized by study arm at each timepoint using basic descriptive statistics.
Opioid Use - Self Reported	Baseline and ~1-week, 2-weeks, 4-weeks, 8-weeks, and 12 weeks following initiation of intervention	Self-reported opioid use will be assessed using the Timeline Follow-back (TLFB) calendar-based research tool. Using the TFLB methodology, participants will be provided with a calendar and asked to record, using a binary "Yes" or "No" response, whether opioid was used during each day over the prior 30-day period. Participants will be guided by a trained assessor during this process to help facilitate recall. If a participant's most recent study visit was within 30 days, then opioid use will be limited to the period of time since the last study visit. The number of days using opioids over the prior 30-day period will be summarized by study arm.
Pain Interference	Baseline and ~1-week, 2-weeks, 4-weeks, 8-weeks, and 12 weeks following initiation of intervention	Pain Interference will be assessed using the corresponding Pain Interference questions within the Brief Pain Inventory-Short Form (BPI-SF). Pain interference over the prior 24 hours is calculated by averaging the ratings of the corresponding 7 items on the questionnaire to determine how much pain interferes with general activity, mood, walking, work, relations, sleep, and enjoyment of life. This results in a Pain Interference score ranging from 0-10, with higher scores indicating that the pain is more significantly interfering with daily activities. A score of 0 means "No Interference" and a score of 10 means "Pain completely interferes with daily activities." Scores will be summarized by study arm at each timepoint using basic descriptive statistics.
Panic Symptoms	Baseline and ~1-week, 2-weeks, 4-weeks, 8-weeks, and 12 weeks following initiation of intervention	Panic symptoms will be assessed by administration of the Panic Disorder Severity Scale (PDSS). The PDSS is a seven-item self-report scale that measures the severity of panic attacks and panic disorder symptoms. Each of the 7 items is rated on a 5-point Likert scale ranging from 0 ("No/None/Not at all") to 4 ("Extreme/Extremely/Nearly constantly") yielding an overall possible scoring range of 0-28, such that higher scores are indicative of greater severity of panic disorder. Scores will be summarized by study arm at each timepoint using basic descriptive statistics.
Anxiety Symptoms	Baseline and ~4-weeks, 8-weeks, and 12 weeks following initiation of intervention	Anxiety will be assessed by administration of the Generalized Anxiety Disorder 7-item (GAD-7) questionnaire. The GAD-7 is a seven-item screening tool used to assess the severity of generalized anxiety disorder over the prior two-week period. Each item on the questionnaire is rated on a 4-point Likert scale ranging from 0 ("Not at all") to 3 ("Nearly every day") yielding an overall possible scoring range of 0-21, such that higher scores are indicative of greater anxiety. Scores will be summarized by study arm at each timepoint using basic descriptive statistics.
Cognitive Function	Baseline and ~1-week, 2-weeks, 4-weeks, 8-weeks, and 12 weeks following initiation of intervention	Cognitive Function will be assessed by administration of the Patient-Reported Outcomes Measurement Information System Cognitive Function (PROMIS-CF) questionnaire. The PROMIS-CF questionnaire is a 4-item patient-reported outcome measures that assesses self-perceived cognitive abilities in the domains of memory (2 items) and concentration (2 items). Responses are scored on a 5-point Likert scale ranging from 1-5, yielding a scoring range of 4-20. Using item-level calibrations, raw scores are then converted to T-scores. T-scores are standardized to a metric with a mean of 50 and a standard deviation of 10 for reference to a population. Higher scores on the PROMIS-CF indicate better perceived cognitive function. Scores will be summarized by study arm at each timepoint using basic descriptive statistics.

Trial Locations

Locations (1)

Montefiore Health System (Montefiore) Buprenorphine Treatment Network; 🇺🇸 The Bronx, New York, United States