Combined THC and CBD for OUD and Chronic Pain

January 12, 2026 updated by: Joao De Aquino, Yale University

Combination of THC and CBD as Novel Treatment for Co-Occurring Opioid Use Disorder and Chronic Pain

The primary objective of this phase 2 study is to investigate the therapeutic potential of orally administered combined delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in relieving both pain and cue-induced opioid craving in people with co-occurring opioid use disorder (OUD) and chronic pain who are undergoing methadone therapy.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

This phase 2 study will utilize a rigorous double-blind, placebo-controlled, crossover experimental design. We will enroll 147 participants with co-occurring OUD and chronic pain who are receiving methadone maintenance treatment and randomize them into three groups (n=49). Across three test sessions, each group will receive single doses of THC (5 mg, 10 mg, or placebo) and CBD (300 mg, 600 mg, or placebo) in a 3x3 design, with THC dose as a between-subject (parallel-group) factor and CBD dose as within-subject (crossover) factor. All three groups will undergo otherwise identical procedures to ensure internal validity.

Our central hypothesis posits that, combined, THC and CBD will be more effective in alleviating pain and cue-induced opioid craving than either drug alone. While THC's analgesic effects may benefit those with co-occurring OUD and chronic pain, its abuse potential and cognitive/psychomotor deficits require careful dose consideration. Combining THC with non-hedonic and neuroprotective CBD could offer a compelling two-pronged approach to alleviate both pain and opioid craving. This study will also explore if sex influences the responses to THC and CBD, given the growing evidence indicating sex-specific effects of cannabinoids and pain responses. If our hypothesis is confirmed, selected THC/CBD doses may serve as a novel, dual-action therapy to alleviate both pain and opioid craving in co-occurring OUD and chronic pain.

Study Type

Interventional

Enrollment (Estimated)

147

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Connecticut
      • New Haven, Connecticut, United States, 06519
        • Recruiting
        • Connecticut Mental Health Center
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Provision of signed and dated informed consent form.
  2. Stated willingness to comply with all study procedures and availability for the duration of the study.
  3. Male or female aged 18-65 years.
  4. Co-occurring OUD (meeting DSM-5 criteria) and chronic pain (uniformly operationalized as high-impact [occurring most days, limiting life or work activities] non-cancer low back pain for ≥ 3 months).
  5. Prior exposure to cannabis or its constituent cannabinoids at least once in the last 10 years, 1-10 times in the last 20 years, or more than 20 times in lifetime.
  6. Adherence to their clinically prescribed methadone therapy, on a stable dose (30-150 mg/day ≥ 3 weeks).
  7. For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation and for an additional 2 weeks after the last test session.
  8. For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner.

Exclusion Criteria:

  1. Meeting DSM-5 criteria for cannabis use disorder and/or substance use disorders (SUDs) within the last 3 months. Participants meeting DSM-5 criteria for OUD and/or tobacco use disorder, either currently or within the last 3 months, will not be excluded per this criterion.
  2. Clinically significant medical disorders as noted by the participant or through study screening procedures (e.g. liver dysfunction, as indicated by ALT and/or AST > 1.5 times the normal limit).
  3. Neurological conditions that may change the response to nociceptive stimuli (e.g., stroke, neuropathy), or that lead to loss of balance, evidenced by a neuro-sensory exam during screening.
  4. Contraindications for exposure to nociceptive stimuli, such as untreated hypertension, verbally noted by participant or verified during screening procedures.
  5. Abnormal screening EKG (QTc interval >450 ms), arrythmia, or vasospastic disease.
  6. Positive urine pregnancy test, or lack of birth control measures in women of childbearing potential. For males of reproductive potential refusal to use condoms or other methods to ensure effective contraception with partner.
  7. Currently lactating.
  8. Male participants who plan to donate sperm starting at screening and through 90 days after final study drug administration.
  9. Females who plan to donate ova starting at screening through 28 days after final study drug administration.
  10. History of primary psychotic disorders or mood disorders with psychotic features.
  11. Current suicidal ideation or related behavior.
  12. 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 the sponsor-investigator. If possible, the morning dose will be administered after the study visit.
  13. Current, regular use of benzodiazepines, other prescription opioids, or platelet inhibitors (e.g., clopidogrel, apixaban, ticagrelor).
  14. Allergy or serious adverse reaction to cannabis or its constituent cannabinoid.
  15. Allergy or serious adverse reaction to sesame oil or seeds.
  16. Allergy or serious adverse reaction to Butylated Hydroxytoluene (BHT).
  17. Unable to swallow or have difficulty swallowing capsules.
  18. 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 ≤ 150 mg/mL. If a participant tests greater than ≤ 150 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Dronabinol 5mg
Participants will be randomized to which dronabinol (or placebo) dose they receive. The fixed dose they receive will be administered across all three test sessions. Therefore, participants may receive a single capsule of 5 mg Dronabinol across all three test sessions
Drug: CBD 300mg
3 Nantheia™ (100mg) softgel capsules and 3 placebo (0mg) softgel capsules will be administered to participants on one of the three test session days.
Other Names:
  • Nantheia™ ATL5 (300mg)
Drug: CBD 600mg
6 Nantheia™ (100mg) softgel capsules will be administered to participants on one of the three test session days.
Other Names:
  • Nantheia™ ATL5 (600mg)
Drug: Placebo 0mg
6 placebo (0 mg) softgel capsules will be administered to participants on one of the three test session days.
Other Names:
  • Nantheia™ ATL5 (0mg)
Active Comparator: Dronabinol 10mg
Participants will be randomized to which dronabinol (or placebo) dose they receive. The fixed dose they receive will be administered across all three test sessions. Therefore, participants may receive a single capsule of 10 mg Dronabinol across all three test sessions
Drug: CBD 300mg
3 Nantheia™ (100mg) softgel capsules and 3 placebo (0mg) softgel capsules will be administered to participants on one of the three test session days.
Other Names:
  • Nantheia™ ATL5 (300mg)
Drug: CBD 600mg
6 Nantheia™ (100mg) softgel capsules will be administered to participants on one of the three test session days.
Other Names:
  • Nantheia™ ATL5 (600mg)
Drug: Placebo 0mg
6 placebo (0 mg) softgel capsules will be administered to participants on one of the three test session days.
Other Names:
  • Nantheia™ ATL5 (0mg)
Placebo Comparator: Placebo 0mg
Participants will be randomized to which dronabinol (or placebo) dose they receive. The fixed dose they receive will be administered across all three test sessions. Therefore, participants may receive a single capsule of 0 mg Dronabinol across all three test sessions
Drug: CBD 300mg
3 Nantheia™ (100mg) softgel capsules and 3 placebo (0mg) softgel capsules will be administered to participants on one of the three test session days.
Other Names:
  • Nantheia™ ATL5 (300mg)
Drug: CBD 600mg
6 Nantheia™ (100mg) softgel capsules will be administered to participants on one of the three test session days.
Other Names:
  • Nantheia™ ATL5 (600mg)
Drug: Placebo 0mg
6 placebo (0 mg) softgel capsules will be administered to participants on one of the three test session days.
Other Names:
  • Nantheia™ ATL5 (0mg)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Primary Outcome Variable #1: Pain Sensitivity
Time Frame: Up to 8 hours
We will measure pain sensitivity using a comprehensive QST battery at baseline and approximately hourly for 8 hours. The battery includes several nociceptive modalities such as pressure, mechanical, heat, and cold stimuli. The main outcome will be a composite pain sensitivity measure, integrating data from the QST battery.
Up to 8 hours
Primary Outcome Variable #2: Opioid Craving
Time Frame: Baseline and +180 minutes post dose
We will measure opioid craving using the short form Heroin Craving Questionnaire (HCQ-14) given to participants before and after a watching a visual probe task used to induce craving.
Baseline and +180 minutes post dose

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Secondary Outcome Variable #1a: Cognitive/psychomotor effects (CPT)
Time Frame: +180 minutes post dose
The cognitive/psychomotor effects of THC and CBD will be assessed using the Continuous Performance Test (CPT). 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).
+180 minutes post dose
Secondary Outcome Variable #1b: Cognitive/psychomotor effects (HVLT)
Time Frame: +180 minutes post dose
The cognitive/psychomotor effects of THC and CBD will be assessed using the Hopkins Verbal Learning Test (HVLT). The primary outcome for the HVLT will be immediate and delayed recall, which index verbal memory.
+180 minutes post dose
Secondary Outcome Variable #2a: Abuse potential of combined THC and CBD (MCP)
Time Frame: +480 post dose
The abuse potential of combined THC and CBD will be assessed using a modified Multiple-Choice Procedure (MCP) at the end of each test session. The primary outcome for the MCP is the crossover point (i.e., the value at which participants choose money over the study medication).
+480 post dose
Secondary Outcome Variable #2b: Abuse potential of combined THC and CBD (DEQ)
Time Frame: Up to 8 hours
The abuse potential of combined THC and CBD will be assessed using the Drug Effects Questionnaire (DEQ) administered at baseline and every 30 minutes. The primary DEQ outcome is the Stimulatory Effects subscale, obtained by averaging participants responses to the items: "Feel High"; "Feel Stimulated"; and "Feel the Drug Strength".
Up to 8 hours
Secondary Outcome Variable #3a: Monitor adverse events from the study medications (SAFTEE)
Time Frame: Baseline ; +480 minutes post dose; One-week after last test session
To monitor adverse events from the study medications, the Systematic Assessment for Treatment Emergent Events (SAFTEE) will be administered before and after each experimental session and during the one-week follow-up. This is a symptom checklist that has been used successfully in our previous studies to assess possible side effects of study medications. It includes information regarding severity of any presenting side effects, as well as the course of action taken by study staff in response.
Baseline ; +480 minutes post dose; One-week after last test session
Secondary Outcome Variable #3b: Monitor adverse events from the study medications (Cardiovascular)
Time Frame: Up to 8 hours and One-week after last test session
To monitor cardiovascular effects from the study medications, heart rate and blood pressure will be measured at baseline and every 30 minutes during the experimental sessions, and at the one-week follow-up.
Up to 8 hours and One-week after last test session

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Central Sensitization
Time Frame: Up to 8 hours
A central sensitization score will be generated by averaging mechanical temporal summation (TSP), thermal TSP, and conditioned pain modulation (CPM), and after-sensation Z-scores. Negative values will denote antinociception, and positive values will denote pronociception (or central sensitization).
Up to 8 hours
THC and CBD plasma levels
Time Frame: Up to 8 hours
Whole blood methadone and THC/CBD levels will be obtained to examine potential drug interactions, using liquid chromatography-tandem mass spectrometry (LC-MS/MS). We will determine the peak concentration (Cmax) and time to attain Cmax concentration (Tmax) of each analyte.
Up to 8 hours
Influence of sex
Time Frame: Up to 8 hours
We will explore if sex moderates the relationships hypothesized in the primary and secondary objectives.
Up to 8 hours

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Yale University

Collaborators

National Institute on Drug Abuse (NIDA)
National Institutes of Health (NIH)

Investigators

  • Principal Investigator: Joao P. De Aquino, M.D., Yale University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 22, 2024

Primary Completion (Estimated)

January 28, 2028

Study Completion (Estimated)

January 28, 2028

Study Registration Dates

First Submitted

August 1, 2024

First Submitted That Met QC Criteria

August 5, 2024

First Posted (Actual)

August 9, 2024

Study Record Updates

Last Update Posted (Actual)

January 13, 2026

Last Update Submitted That Met QC Criteria

January 12, 2026

Last Verified

January 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2000038372
  • 1R01DA060066-01 (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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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