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

NCT05076370 | Completed Early Phase 1 Results DMC FDA Drug

• 2 other identifiers: 20000292861K23DA052682-01
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Addiction

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (3)

• Quantitative Sensory Testing (QST)- Threshold and Tolerance

  baseline, 2 hours and 4 hours after the administration of CBD.

• Change in Quantitative Sensory Testing (QST) Conditioned Pain Modulation (CPM)

  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)

  Baseline, 2 hours and 4 hours after the administration of CBD.

Other Outcomes (1)

• Change in The Heroin Craving Questionnaire - Short Form 14 (HCQ-SF-14)

  Average difference of scores from before cue-induced craving video (+150 minutes) and after cue-induced craving video (+155 minutes)

Study Arms (3)

CBD 400mg

ACTIVE COMPARATOR

CBD 400mg

Drug: CBD Day 1

CBD 800mg

ACTIVE COMPARATOR

CBD 800mg

Drug: CBD Day 2

CBD 1200mg

ACTIVE COMPARATOR

CBD 1200mg

Drug: CBD Day 3

Interventions

CBD Day 1 DRUG

CBD 400mg

CBD 400mg

CBD Day 2 DRUG

CBD 800mg

CBD 800mg

CBD Day 3 DRUG

CBD 1200mg

CBD 1200mg

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Yale University: lead
• National Institute on Drug Abuse (NIDA): collaborator

Study Sites (1)

Veteran Affairs Hospital

West Haven, Connecticut, 06516, United States

Location

MeSH Terms

Conditions

Behavior, Addictive

Condition Hierarchy (Ancestors)

Compulsive Behavior; Impulsive Behavior; Behavior

Results Point of Contact

• Title: Joao De Aquino, M.D.
• Organization: Yale University, Department of Psychiatry

joao.deaquinolima@yale.edu

203-932-5711

Study Officials

• Joao De Aquino, M.D.

  Yale University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: 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 methadone or buprenorphine.

Study Record Dates

• First Submitted: September 29, 2021
• First Posted: October 13, 2021
• Study Start: December 8, 2021
• Primary Completion: June 28, 2024
• Study Completion: June 28, 2024
• Last Updated: November 26, 2025
• Results First Posted: November 26, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)