Cannabidiol in Opioid Use Disorder and Chronic Pain

Cannabidiol Pharmacotherapy for Co-occurring Opioid Use Disorder and Chronic Pain

This is a randomized, placebo-controlled, crossover human laboratory study investigating the dose-dependent safety and acute effects of Cannabidiol (CBD) on measures of pain and opioid craving in outpatients with opioid use disorder (OUD) receiving medication-assisted treatment with methadone or buprenorphine. With a duration of approximately 4 weeks, participants will come to the testing site for a total of five times: one initial screening session, and four experimental sessions where study medication, CBD, will be administered, separated by at least 72 hours to limit carryover effects.

Study Overview

• Status: Recruiting
• Conditions: Chronic Pain; Opioid Use Disorder
• Intervention / Treatment: Drug: 400 mg Cannabidiol; Drug: 800 mg Cannabidiol; Drug: 1200 mg Cannabidiol; Drug: Beta carotene oral solution without CBD

Detailed Description

Thirty-four male and female (ages 18-70) participants with comorbid opioid use disorder (OUD) and non-cancer chronic pain for at least 6 months, currently receiving methadone (n= 22) or buprenorphine (n= 12), will be enrolled. Across four test sessions, prior to their daily methadone or buprenorphine dose, and thus at trough plasma levels of opioid, participants will receive oral CBD (400 mg, 800 mg, 1200 mg) or placebo. Subsequently, all participants will undergo laboratory testing of opioid-related outcomes.

Pain sensitivity will be measured using Quantitative Sensory Testing (QST), the Pain Catastrophizing Scale (PCS), and a pain Visual Analog Scale (VAS). Attentional bias and cue-induced opioid craving will be measured using a visual probe task and the Heroin Craving Scale (HCQ-14). Subjective opioid withdrawal symptoms will be assessed using the Subjective Opiate Withdrawal Scale (SOWS). Abuse potential will be measured using the Drug Effects Questionnaire (DEQ). Negative affect will be measured using the Positive and Negative Affect Schedule (PANAS). Cognitive performance will be measured by a comprehensive cognitive battery that includes the Continuous Performance Test (CPT) and the Hopkins Verbal Learning Test (HVLT). Safety will be thoroughly measured with the Systematic Assessment for Treatment Emergent Events (SAFTEE) for adverse effects.

The order of study medication administration will be counterbalanced order to minimize carryover effects. On the initial screening day and at the end of medication treatment, blood will be drawn to determine serum drug levels. Participants will be thoroughly evaluated by a physician prior to discharge on each experimental session. One week after the last study medication dose, participants will be conducted by phone for a follow-up session.

• Study Type: Interventional
• Enrollment (Estimated): 34
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Julia Meyerovich, M.S.; Phone Number: 14805 203-932-5711; Email: julia.meyerovich@yale.edu
• Study Contact Backup: Name: Joao De Aquino, M.D.; Phone Number: 12916 203-932-5711; Email: joao.deaquinolima@yale.edu

Study Locations

• United States
  • Connecticut
    • West Haven, Connecticut, United States, 06516
      • Recruiting
      • Department of Veterans Affairs Hospital
      • Principal Investigator: Joao De Aquino, M.D.
      • Contact: Joao De Aquino, M.D.; Phone Number: 12916 203-932-5711; Email: joao.deaquinolima@yale.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.
• 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 30 mg or over 150 mg/day.
• Buprenorphine dose over 24 mg per day.
• Having received inpatient psychiatric treatment recently (≤ 60 days before enrollment).
• Candidates receiving products containing either THC or CBD will be excluded. All participants will be asked to abstain from cannabinoids. Prior to receiving the study medication on the first test session, participants' cannabinoid use will be assessed using a quantitative point-of-care urine 11-nor-9-carboxy-THC concentration test with a cut-off of ≤ 50 mg/mL. If a participant tests greater than ≤50 mg/mL, they will be asked to abstain for an additional 7 to 14 days. If 14 days after their initial THC concentration test the participant continues to test positive, they will not be allowed to participate in the study.
• A physician will carefully evaluate participants for use of over-the-counter or prescription psychoactive drugs known to affect pain threshold or pain tolerance (including NSAIDS, serotonin-norepinephrine reuptake inhibitors (SNRIs) (e.g. venlafaxine, duloxetine), gabapentinoids, tricyclic antidepressants (e.g., nortriptyline, amitriptyline), anticonvulsant medications (e.g., topiramate, carbamazepine)). Only participants who are on stable doses (i.e., consistent daily administration of the medication for at least three months at the same dose following the last dose change, either increase or decrease) of these medications, and whose dosing schedules allow participation in the study visits, thus excluding instances of single-dose or temporary dosing of the medication, will be eligible as determined by principal investigator. If possible, the morning dose will be administered after the study visit.
• Current, regular use of benzodiazepines, other prescription opioids, or platelet inhibitors (e.g., clopidogrel, apixaban, ticagrelor).
• 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.
• Contraindications for exposure to cold temperatures, such as Raynaud's phenomenon and hypertension.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: CBD 400 mg	Drug: 400 mg Cannabidiol; Participants will receive 400 mg CBD; Other Names: CBD; Epidiolex
Active Comparator: CBD 800 mg; CBD 800mg	Drug: 800 mg Cannabidiol; Participants will receive 800 mg CBD; Other Names: CBD; Epidiolex
Active Comparator: CBD 1200 mg	Drug: 1200 mg Cannabidiol; Participants will receive 1200 mg CBD; Other Names: CBD; Epidiolex
Placebo Comparator: Beta carotene oral solution; Beta carotene oral solution without CBD	Drug: Beta carotene oral solution without CBD; Participants will receive beta carotene oral solution without CBD (placebo); Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Abuse potential of CBD measured by the Drug Effects Questionnaire (DEQ)	The DEQ will be administered to assess the abuse potential of CBD. The DEQ is a 10-item questionnaire used to assess the subjective effects of psychoactive drugs. Each item is a visual analogue scale (VAS) ranging from 0-100. The questionnaire is used to measure whether a subject feels the drug "feels high", likes or dislikes the effects, and whether they want more of the drug. The primary DEQ outcome will be the Stimulatory Effects subscale, obtained by averaging participants responses to the items: "Feel High"; "Feel Stimulated"; and "Feel the Drug Strength".	Baseline (30 minutes before the administration of CBD), and every 30 minutes after the administration of CBD (up to +240 minutes)
Cognitive effects of CBD measured by the Hopkins Verbal Learning Test (HVLT)	The HVLT will be used to assess the cognitive effects of CBD. The primary outcomes will be immediate and delayed recall, which index verbal memory. The HVLT consists of a 12-item word list, composed of four words from each of the three semantic categories. The participant is instructed to listen carefully as the examiner reads the word list and attempt to memorize the words. The participants' free recall of the list is recorded. The same procedure is repeated for two more trials (immediate recall). After approximately 15 minutes the participant will be asked to recall as many words from the list as they can without the list being re-read to them (delayed recall).	+210 minutes after the administration of CBD
Cognitive/psychomotor effects of CBD measured by the Continuous Performance Test (CPT)	The cognitive/psychomotor effects of CBD will be assessed using the Continuous Performance Test (CPT). CPT is a computerized neuropsychological assessment that measures participants sustained and selective attention. For the CPT, the primary outcome will be the throughput score, which indexes attention/working memory accuracy (i.e. percent of correct responses) and speed (i.e. reaction time).	+210 minutes after the administration of CBD
Safety and tolerability of CBD measured by the Systematic Assessment for Treatment Emergent Effects (SAFTEE)	The SAFTEE is a multi-symptom checklist that has been used successfully in the investigators 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 is administered before the administration of CBD at baseline, (timepoint -30 minutes) and 4 hours after the administration of CBD (timepoint +240 minutes) during each test session. Data will be presented as the number of participants that reported symptoms on the SAFTEE.	Baseline (30 minutes before the administration of CBD) and +240 minutes after the administration of CBD

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain sensitivity measured by Quantitative Sensory Testing (QST) Pain threshold and tolerance	Pain threshold and tolerance will be assessed using a comprehensive QST battery. This is a reliable, dynamic, and computerized method of quantifying distinct mechanisms of the pain experience. QST measures are sensitive to the effects of cannabinoids, important biomarkers of chronic pain, and predictors of the pain treatment response. Threshold: the temperature the participant first begins to feel pain (average pain threshold). Tolerance: the temperature when the participant can no longer tolerate the stimuli. The temperature ranges from 37° Celsius to 50° Celsius. A lower temperature represents a lower pain threshold/tolerance and a higher temperature represents a higher pain threshold/tolerance.	Baseline (30 minutes before the administration of CBD), +120 minutes and +240 minutes after the administration of CBD.
Pain sensitivity measured by change in Quantitative Sensory Testing (QST) Conditioned Pain Modulation (CPM)	CPM indexes top-down pain inhibition, by leveraging the "pain inhibits pain phenomena". In CPM, a test stimulus is rated on a -100 to +100 Numeric Rating Scale (NRS) for pain both alone and during a concurrent conditioning stimulus applied elsewhere on the body. The CPM Score is the difference between these two ratings. CPM score is a Difference (Delta): Pain rating (test stimulus alone) - Pain rating (test stimulus with conditioning stimulus) Interpretation: Higher (more positive) values indicate greater pain inhibition.	Baseline (30 minutes before the administration of CBD), +120 minutes and +240 minutes after the administration of CBD.
Pain sensitivity measured by Quantitative Sensory Testing (QST) Temporal Summation of Pain (TSP)	TSP involves the repeated administration of noxious stimuli, indexing bottom-up pain facilitation. Therefore, TSP measures the increase in pain perception with repeated noxious stimuli, calculated as the area under the curve (AUC) of pain ratings over time during repeated stimulation. Higher TSP scores indicate worse outcomes (greater pain facilitation/central sensitization), while lower TSP scores indicate better outcomes (less pain facilitation/central sensitization). The TSP AUC values represent the cumulative pain experience during repeated stimulation (VAS units*seconds), where larger values reflect greater temporal summation of pain, which is associated with central nervous system sensitization and chronic pain conditions.	Baseline (30 minutes before the administration of CBD), +120 minutes and +240 minutes after the administration of CBD.
Response to Quantitative Sensory Testing (QST) battery measured by Pain Visual Analog Scale (VAS)	The pain VAS will be used by participants as a secondary rating scale for pain severity pain testing. This scale ranges from 0 to 100 and contains of a horizontal line, anchored by verbal descriptors of "no pain" and "pain as bad as it could be". Participants will place a vertical line at the point that best indicates their present pain.	Baseline (30 minutes before the administration of CBD), +120 minutes and +240 minutes after the administration of CBD.
Pain Catastrophizing measured by the Pain Catastrophizing Scale (PCS)	The PCS is a 13-item self-report scale designed to measure negative thoughts and feelings associated with pain. Each item is rated on a 5-point scale: 0 (Not at all) to 4 (all the time). Total scores range from 0 to 52, with higher scores indicating greater catastrophizing. The PCS contains three subscales: magnification (scores ranging from 0-12), rumination (scores ranging from 0-16), and helplessness (scores ranging from 0-24).	Baseline (30 minutes before the administration of CBD)
Opioid craving measured by change in the Heroin Craving Questionnaire - Short Form 14 (HCQ-SF-14)	The HCQ-SF-14 consists of 14 statements about the respondent's feelings and thoughts about using heroin as he or she is completing the questionnaire (i.e., right now). Each of the 14 items is scored on a scale from 1 (Strongly Disagree) to 7 (Strongly Agree). The HCQ-SF-14 score is obtained by adding the scores of all 14 statements and dividing the total by 14. Higher scores on the HCQ-SF-14 indicate a stronger craving for heroin. The HCQ-14 was administered before (+150 minutes) and after (+155 minutes) participants watched a cue-induced craving video. The difference of the two HCQ-14 scores (post - pre) will be used to index cue-elicited craving.	Average difference of scores from before cue-induced craving video (+150 minutes) and after cue-induced craving video (+155 minutes)
Opioid craving measured by the Subjective Opiate Withdrawal Scale (SOWS)	The SOWS is a 16-item, participant-administered questionnaire designed to rate the intensity of opioid withdrawal symptoms. It assesses symptoms on a 0-4 scale ("not at all" to "extremely"), with total scores of 1-10 indicating mild, 11-20 moderate, and 21-30 severe withdrawal.	Baseline (30 minutes before the administration of CBD), +30 minutes, +90 minutes, +150 minutes, +210 minutes, and +240 minutes after the administration of CBD
Negative affect measured by the Positive and Negative Affect Schedule (PANAS)	The PANAS is a 20-item self-report questionnaire listing adjectives relating to Positive Affect (PA) (e.g., excited, inspired) and Negative Affect (NA) (e.g., distressed, afraid). Items are rated on a Likert scale ranging from 1 "Very slightly or not at all" to 5 "extremely". The PANAS yields separate PA and NA scores, each ranging from 10 to 50. Higher PA scores indicate more positive feelings, while higher NA scores indicate more negative feelings. These scores are used to track emotional states over time. The PANAS will be used to measure the effects of CBD on mood.	Baseline (30 minutes before the administration of CBD), and every 30 minutes after the administration of CBD (up to +240 minutes)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Influence of sex	The investigator will explore if sex moderates the relationships hypothesized in the primary and secondary objectives.	Up to 6 hours

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute on Drug Abuse (NIDA); VA Connecticut Healthcare System
• Investigators: Principal Investigator: Joao De Aquino, M.D., Yale University

Study record dates

Study Major Dates

• Study Start (Actual): December 8, 2021
• Primary Completion (Estimated): August 31, 2026
• Study Completion (Estimated): August 31, 2026

Study Registration Dates

• First Submitted: October 2, 2020
• First Submitted That Met QC Criteria: October 13, 2020
• First Posted (Actual): October 14, 2020

Study Record Updates

• Last Update Posted (Actual): April 14, 2026
• Last Update Submitted That Met QC Criteria: April 9, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Pain; Methadone; Buprenorphine; Cannabidiol
• Additional Relevant MeSH Terms: Narcotic-Related Disorders; Neurologic Manifestations; Mental Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Pain; Opioid-Related Disorders; Chronic Pain; Organic Chemicals; Carotenoids; Polyenes; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Pigments, Biological; Biological Factors; Cannabinoids; Cannabidiol; beta Carotene
• Other Study ID Numbers: JD001; 2000029286 (Other Identifier: Yale HRPP); 1K23DA052682-01 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No