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

Cannabidiol Pharmacotherapy for Comorbid Opioid Addiction and Chronic Pain

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 methadone or buprenorphine.

Study Overview

• Status: Completed
• Conditions: Addiction
• Intervention / Treatment: Drug: CBD Day 1; Drug: CBD Day 2; Drug: CBD Day 3

Detailed Description

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 participants with comorbid OUD and chronic pain, with half the subjects receiving methadone and half receiving buprenorphine. Both sub-studies will enroll participants who do not currently require an inpatient hospitalization.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • West Haven, Connecticut, United States, 06516
      • Veteran Affairs Hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Men and women 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 women includes oral contraceptives, contraceptive depot injections, contraceptive subdermal implants, intrauterine devices, or surgical contraception methods. Acceptable contraception for men 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: CBD 800mg	Drug: CBD Day 2; CBD 800mg
Active Comparator: CBD 1200mg	Drug: CBD Day 3; CBD 1200mg
Active Comparator: CBD 400mg	Drug: CBD Day 1; CBD 400mg

What is the study measuring?

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. A score was averaged across all time intervals.	Baseline (30 minutes before the administration of CBD), hourly for 4 hours after the administration of methadone (administered +210 minutes after CBD) and 3 hours after the administration of buprenorphine (administered +210 minutes after CBD)
Mini Mental Status Examination (MMSE)	The MMSE is a 30-point scale ranging from 0 to 30 that measures five areas of cognitive function: orientation, registration, attention and calculation, recall, and language. Each scale is summed to compute a total score. The MMSE is used extensively in clinical and research settings to measure cognitive impairment. A score of 24 or higher is generally considered within the normal range, while lower scores suggest potential cognitive impairment. Scores are often interpreted as follows: 25-30 = normal cognition, 21-24 = mild impairment, 10-20 = moderate impairment, and below 10 = severe impairment.	Baseline (30 minutes before the administration of CBD), hourly for 4 hours after the administration of methadone (administered +210 after CBD) and 3 hours after the administration of buprenorphine (administered +210 minutes after CBD)
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. Data presented here is the number of participants that reported symptoms on SAFTEE.	baseline and 4.5 hours after the administration of CBD

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantitative Sensory Testing (QST)- 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), and when the participant can no longer tolerate the stimuli (Tolerance). The temperature ranges from 37 degrees celsius to 50 degrees celsius. A lower temperature represents a lower pain threshold and a higher temperature represents a higher pain threshold. A lower temperature represents a lower pain tolerance and a higher temperature represents a higher pain tolerance.	baseline, 2 hours and 4 hours after the administration of CBD.
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), 2 hours (+120 minutes), and 4 hours (+240 minutes) after the administration of CBD.
Quantitative Sensory Testing (QST) Temporal Summation of Pain (TSP)	Pain will be assessed using a comprehensive QST battery. QST measures are sensitive to the effects of cannabinoids, important biomarkers of chronic pain, and predictors of the pain treatment response. 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, 2 hours and 4 hours after the administration of CBD.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in The Heroin Craving Questionnaire - Short Form 14 (HCQ-SF-14)	The Heroin Craving Questionnaire - Short Form 14 (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)

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): December 8, 2021
• Primary Completion (Actual): June 28, 2024
• Study Completion (Actual): June 28, 2024

Study Registration Dates

• First Submitted: September 29, 2021
• First Submitted That Met QC Criteria: October 12, 2021
• First Posted (Actual): October 13, 2021

Study Record Updates

• Last Update Posted (Actual): November 26, 2025
• Last Update Submitted That Met QC Criteria: November 12, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Compulsive Behavior; Impulsive Behavior; Behavior; Behavior, Addictive
• Other Study ID Numbers: 2000029286 (Other Identifier: Yale HRPP); 1K23DA052682-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No