Safety and Tolerability of Cannabidiol Among Persons With Opioid Use Disorder Receiving Methadone or Buprenorphine

Study Overview
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Brief Summary
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The overarching goal of this study is to evaluate the potential of Cannabidiol (CBD) as an adjunctive treatment for comorbid opioid use disorder (OUD) and chronic pain. This is a randomized, placebo-controlled, crossover human laboratory study investigating the dose-dependent safety and acute effects of CBD on measures of pain and opioid craving in outpatients with OUD receiving medication-assisted treatment (MAT) with methadone or buprenorphine.

Detailed Description
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An initial safety pilot phase will recruit six participants: three receiving treatment with methadone and three receiving treatment with buprenorphine. If the results of the pilot study support the safety of CBD administration in this clinical sample, the general study will recruit 48 participants with comorbid OUD and chronic pain, for a total of 24 completers - 12 subjects (6 men and 6 women) receiving methadone and 12 subjects (6 men and 6 women) receiving buprenorphine. Both sub-studies will enroll participants who do not currently require an inpatient hospitalization.

Official Title
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Cannabidiol Pharmacotherapy for Comorbid Opioid Addiction and Chronic Pain

Conditions
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Addiction

Intervention / Treatment
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* Drug: CBD Day 1
* Drug: CBD Day 2
* Drug: CBD Day 3


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females, Veterans and non-Veterans, aged between 18 and 70 years old. Diagnosed with OUD and currently enrolled in methadone or buprenorphine maintenance treatment. Having chronic pain, uniformly operationalized as grade II (high-intensity) non- cancer pain for ≥ 6 months 49. Capable of providing informed consent in English. Compliant in opioid maintenance treatment and on a stable dose for four weeks or longer. Not meeting DSM-5 criteria for substance use disorders other than OUD or tobacco use disorder within the last 12 months. No current medical problems deemed contraindicated for participation by principal investigator. For women, not pregnant as determined by pregnancy screening; not breast-feeding; using acceptable birth control methods. Acceptable contraception for females includes oral contraceptives, contraceptive depot injections, contraceptive subdermal implants, intrauterine devices, or surgical contraception methods. Acceptable contraception for males includes condoms or surgical contraception methods. Exclusion Criteria: Other current major psychiatric disorders deemed clinically unstable by the principal investigator, such as severe depression and/or active suicidal ideation. Having experienced major psychosocial stressors recently (≤ 6 weeks before enrollment), at the discretion of the principal investigator. Methadone dose under 60mg or over 100mg Buprenorphine over 24mg. Having received inpatient psychiatric treatment recently (≤ 60 days before enrollment). Candidates receiving products containing either THC or CBD will be excluded. Current use regular use other prescription opioids, gabapentinoids (pregabalin, gabapentin), antidepressants (SSRIs, SNRIs, TCAs), benzodiazepines, platelet inhibitors (e.g., clopidogrel, apixaban, ticagrelor), or NSAIDs. Current weight of less of 60 kg. Allergy to sesame seed oil, which is an ingredient of the CBD formulation used. Serious medical or neurological illness or treatment for a medical disorder that could interfere with study participation as determined by principal investigator. Participants who have elevation of liver enzymes (ALT and/or AST) 2x above the normal limit or higher.

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Initial safety pilot phase of 6 participants,(3 methadone and 3 on Buprenorphine) The general study is a randomized, placebo-controlled, crossover human laboratory study investigating the dose-dependent safety and acute effects of CBD on measures of pain and opioid craving in outpatients with OUD receiving medication-assisted treatment (MAT) with methadone or buprenorphine.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: CBD 400mg<br>CBD 400mg | Drug: CBD Day 1<br>* CBD 400mg<br>|
| Active Comparator: CBD 800mg<br>CBD 800mg | Drug: CBD Day 2<br>* CBD 800mg<br>|
| Active Comparator: CBD 1200mg<br>CBD 1200mg | Drug: CBD Day 3<br>* CBD 1200mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Agitation Calmness Evaluation Scale (ACES) | The ACES consists of a single item that rates overall agitation and sedation of the participant at the time of evaluation, where 1 indicates marked agitation; 2: moderate agitation; 3: mild agitation; 4: normal behavior; 5: mild calmness; 6: moderate calmness; 7: marked calmness; 8: deep sleep; and 9: unarousable. Clinically significant sedation was a priori defined as an ACES score of 7 (marked calmness) or higher at any point during the session. | 8 hours | 
| Mini Mental Status Examination (MMSE) | The MMSE is a 30-point scale that measures five areas of cognitive function: orientation, registration, attention and calculation, recall, and language. The MMSE is used extensively in clinical and research settings to measure cognitive impairment. A score of 23 or lower is indicative of cognitive impairment. | 8 hours | 
| Systematic Assessment of Side Effects (SAFTEE) | The SAFTEE is a multi-symptom checklist that has been used successfully in our previous studies to assess and monitor any adverse events and possible side effects of study medications. It includes information regarding the severity of any presenting symptoms (0= none, 1= mild, 2= moderate, and 3= severe), as well as the course of action taken by the study staff in response. The SAFTEE was administered before the administration of CBD at baseline, (timepoint -30 minutes) and 4.5 hours after the administration of CBD (timepoint +240 minutes) during each test session. We did not observe evidence of confusion, fatigue, inability to respond to things, slowed thinking, dizziness/lightheadedness, weakness, slowed movements, or lack of coordination. | 8 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quantitative Sensory Testing (QST) | Pain will be assessed using a comprehensive QST battery | 8 hours |