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Chronic PainPhase 2NCT06544291

Combined THC and CBD for OUD and Chronic Pain

A Phase 2 study testing CBD 300mg and CBD 600mg in people with Chronic Pain and Opioid Use Disorder, run by Yale University at 1 site in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial summary

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… Read more about this study

Who is it for?
Ages 18 to 65 years
Conditions the study is for
Chronic Pain, Opioid Use Disorder
What is being tested?
CBD 300mg and CBD 600mg
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
147 participants
Where
1 siteUnited States
Study dates
22 Oct 2024to 28 Jan 2028
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 65 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Provision of signed and dated informed consent form.
  • Stated willingness to comply with all study procedures and availability for the duration of the study.
  • Male or female aged 18-65 years.
  • 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).
  • 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.
  • Adherence to their clinically prescribed methadone therapy, on a stable dose (30-150 mg/day ≥ 3 weeks).
  • 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.
  • For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner.

Who cannot join

  • 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.
  • 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).
  • 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.
  • Contraindications for exposure to nociceptive stimuli, such as untreated hypertension, verbally noted by participant or verified during screening procedures.
  • Abnormal screening EKG (QTc interval >450 ms), arrythmia, or vasospastic disease.
  • 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.
Show all 18Show fewer
  • Currently lactating.
  • Male participants who plan to donate sperm starting at screening and through 90 days after final study drug administration.
  • Females who plan to donate ova starting at screening through 28 days after final study drug administration.
  • History of primary psychotic disorders or mood disorders with psychotic features.
  • Current suicidal ideation or related behavior.
  • 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.
  • Current, regular use of benzodiazepines, other prescription opioids, or platelet inhibitors (e.g., clopidogrel, apixaban, ticagrelor).
  • Allergy or serious adverse reaction to cannabis or its constituent cannabinoid.
  • Allergy or serious adverse reaction to sesame oil or seeds.
  • Allergy or serious adverse reaction to Butylated Hydroxytoluene (BHT).
  • Unable to swallow or have difficulty swallowing capsules.
  • 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.

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Julia V. Meyerovich, M.S. contact

203-932-5711 ext. 14805

julia.meyerovich@yale.edu

Joao P. De Aquino, M.D. contact

203-623-7493 ext. 12916

joao.deaquinolima@yale.edu

United States1 site, 1 recruiting

  • Connecticut Mental Health Center

    New Haven, Connecticut, 06519

    Joao P. De Aquino, M.D., 203-623-7493 ext. 12916, joao.deaquinolima@yale.edu

    Recruiting

Other trials in United States

About this study

Official title: 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.

Read the 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.

Being tested
CBD 300mg, CBD 600mg, Placebo 0mg
Keywords
Delta-9-Tetrahydrocannabinol, Cannabidiol, Cannabinoid, Methadone, Opioid Addiction, Pain
Medical subject headings
Chronic Pain, Opioid-Related Disorders, Pain

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CBD 300mgDrug

    Also called Nantheia™ ATL5 (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.

  • CBD 600mgDrug

    Also called Nantheia™ ATL5 (600mg)

    6 Nantheia™ (100mg) softgel capsules will be administered to participants on one of the three test session days.

  • Placebo 0mgDrug

    Also called Nantheia™ ATL5 (0mg)

    6 placebo (0 mg) softgel capsules will be administered to participants on one of the three test session days.

Study groups in NCT06544291
Study groupRoleWhat they receive
Dronabinol 5mgActive comparatorParticipants 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
Receives: Drug: CBD 300mg; Drug: CBD 600mg; Drug: Placebo 0mg
Dronabinol 10mgActive comparatorParticipants 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
Receives: Drug: CBD 300mg; Drug: CBD 600mg; Drug: Placebo 0mg
Placebo 0mgPlacebo comparatorParticipants 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
Receives: Drug: CBD 300mg; Drug: CBD 600mg; Drug: Placebo 0mg

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Primary Outcome Variable #1: Pain Sensitivity

    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.

    Measured: Up to 8 hours

  2. Primary Outcome Variable #2: Opioid Craving

    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.

    Measured: Baseline and +180 minutes post dose

Secondary outcomes (6)

  1. Secondary Outcome Variable #1a: Cognitive/psychomotor effects (CPT)

    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).

    Measured: +180 minutes post dose

  2. Secondary Outcome Variable #1b: Cognitive/psychomotor effects (HVLT)

    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.

    Measured: +180 minutes post dose

  3. Secondary Outcome Variable #2a: Abuse potential of combined THC and CBD (MCP)

    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).

    Measured: +480 post dose

  4. Secondary Outcome Variable #2b: Abuse potential of combined THC and CBD (DEQ)

    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".

    Measured: Up to 8 hours

  5. Secondary Outcome Variable #3a: Monitor adverse events from the study medications (SAFTEE)

    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.

    Measured: Baseline ; +480 minutes post dose; One-week after last test session

  6. Secondary Outcome Variable #3b: Monitor adverse events from the study medications (Cardiovascular)

    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.

    Measured: Up to 8 hours and One-week after last test session

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted9 Aug 2024
  2. Study start22 Oct 2024
  3. Primary completion28 Jan 2028 (estimated)
  4. Study completion28 Jan 2028 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Other
Allocation
Randomised
Intervention model
Crossover
Model description
This phase 2 study will utilize a 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.
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
147 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06544291
Sponsor's protocol ID
2000038372
Other IDs
1R01DA060066-01
Status last verified
Jul 2026
First submitted
1 Aug 2024
Last updated
16 Jul 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Cooper ZD, Haney M. Sex-dependent effects of cannabis-induced analgesia. Drug Alcohol Depend. 2016 Oct 1;167:112-20. doi: 10.1016/j.drugalcdep.2016.08.001. Epub 2016 Aug 5.

    PubMed 27522535

  • Cooper ZD, Craft RM. Sex-Dependent Effects of Cannabis and Cannabinoids: A Translational Perspective. Neuropsychopharmacology. 2018 Jan;43(1):34-51. doi: 10.1038/npp.2017.140. Epub 2017 Jul 17.

    PubMed 28811670

  • Cooper ZD, Haney M. Investigation of sex-dependent effects of cannabis in daily cannabis smokers. Drug Alcohol Depend. 2014 Mar 1;136:85-91. doi: 10.1016/j.drugalcdep.2013.12.013. Epub 2014 Jan 3.

    PubMed 24440051

  • Smith MT Jr, Remeniuk B, Finan PH, Speed TJ, Tompkins DA, Robinson M, Gonzalez K, Bjurstrom MF, Irwin MR. Sex differences in measures of central sensitization and pain sensitivity to experimental sleep disruption: implications for sex differences in chronic pain. Sleep. 2019 Feb 1;42(2):zsy209. doi: 10.1093/sleep/zsy209.

    PubMed 30371854

  • Turri M, Teatini F, Donato F, Zanette G, Tugnoli V, Deotto L, Bonetti B, Squintani G. Pain Modulation after Oromucosal Cannabinoid Spray (SATIVEX(R)) in Patients with Multiple Sclerosis: A Study with Quantitative Sensory Testing and Laser-Evoked Potentials. Medicines (Basel). 2018 Jun 21;5(3):59. doi: 10.3390/medicines5030059.

    PubMed 29933552

  • Dunn KE, Bergeria CL, Huhn AS, Speed TJ, Mun CJ, Vandrey R, Campbell CM. Within-subject, double-blinded, randomized, and placebo-controlled evaluation of the combined effects of the cannabinoid dronabinol and the opioid hydromorphone in a human laboratory pain model. Neuropsychopharmacology. 2021 Jul;46(8):1451-1459. doi: 10.1038/s41386-021-01007-4. Epub 2021 Apr 20.

    PubMed 33879842

  • Matheson J, Mann RE, Sproule B, Huestis MA, Wickens CM, Stoduto G, George TP, Rehm J, Le Foll B, Brands B. Acute and residual mood and cognitive performance of young adults following smoked cannabis. Pharmacol Biochem Behav. 2020 Jul;194:172937. doi: 10.1016/j.pbb.2020.172937. Epub 2020 May 1.

    PubMed 32360692

  • Leweke FM, Rohleder C, Gerth CW, Hellmich M, Pukrop R, Koethe D. Cannabidiol and Amisulpride Improve Cognition in Acute Schizophrenia in an Explorative, Double-Blind, Active-Controlled, Randomized Clinical Trial. Front Pharmacol. 2021 Apr 29;12:614811. doi: 10.3389/fphar.2021.614811. eCollection 2021.

    PubMed 33995015

  • Griffiths RR, Troisi JR, Silverman K, Mumford GK. Multiple-choice procedure: an efficient approach for investigating drug reinforcement in humans. Behav Pharmacol. 1993 Feb;4(1):3-13.

    PubMed 11224166

  • Morean ME, de Wit H, King AC, Sofuoglu M, Rueger SY, O'Malley SS. The drug effects questionnaire: psychometric support across three drug types. Psychopharmacology (Berl). 2013 May;227(1):177-92. doi: 10.1007/s00213-012-2954-z. Epub 2012 Dec 28.

    PubMed 23271193

  • Levine J, Schooler NR. SAFTEE: a technique for the systematic assessment of side effects in clinical trials. Psychopharmacol Bull. 1986;22(2):343-81. No abstract available.

    PubMed 3774930

  • Georgopoulos V, Akin-Akinyosoye K, Zhang W, McWilliams DF, Hendrick P, Walsh DA. Quantitative sensory testing and predicting outcomes for musculoskeletal pain, disability, and negative affect: a systematic review and meta-analysis. Pain. 2019 Sep;160(9):1920-1932. doi: 10.1097/j.pain.0000000000001590.

    PubMed 31045746

  • Yarnitsky D, Granot M, Nahman-Averbuch H, Khamaisi M, Granovsky Y. Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy. Pain. 2012 Jun;153(6):1193-1198. doi: 10.1016/j.pain.2012.02.021. Epub 2012 Apr 3.

    PubMed 22480803

  • Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers. 2007 Aug;4(8):1770-804. doi: 10.1002/cbdv.200790152. No abstract available.

    PubMed 17712819

  • De Aquino JP, Meyerovich J, Xie CZ, Ranganathan M, Compton P, Pittman B, Rogan M, Sofuoglu M. Delta-9-tetrahydrocannabinol modulates pain sensitivity among persons receiving opioid agonist therapy for opioid use disorder: A within-subject, randomized, placebo-controlled laboratory study. Addict Biol. 2023 Sep;28(9):e13317. doi: 10.1111/adb.13317.

    PubMed 37644897

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing CBD 300mg and CBD 600mg in people with Chronic Pain and Opioid Use Disorder, run by Yale University at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 16 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Julia V. Meyerovich, M.S. (203-932-5711 ext. 14805, julia.meyerovich@yale.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Primary Outcome Variable #1: Pain Sensitivity (time frame: Up to 8 hours). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06544291, which also lists 18 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Jul 2026.

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