Combined THC and CBD for OUD and Chronic Pain

NCT06544291 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 20000383721R01DA060066-01
• Study Type: interventional
• Target: 147
• Locations: 1 country
• Sites: 1

Brief 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 undergoing methadone therapy.

Conditions

Opioid Use Disorder; Chronic Pain

Keywords

Delta-9-Tetrahydrocannabinol; Cannabidiol; Cannabinoid; Methadone; Opioid Addiction; Pain

Outcome Measures

Primary Outcomes (2)

• 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.

  Up to 8 hours

• 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.

  Baseline and +180 minutes post dose

Secondary Outcomes (6)

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

  +180 minutes post dose

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

  +180 minutes post dose

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

  +480 post dose

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

  Up to 8 hours

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

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

Other Outcomes (3)

• Central Sensitization

  Up to 8 hours

• THC and CBD plasma levels

  Up to 8 hours

• Influence of sex

  Up to 8 hours

Study Arms (3)

Dronabinol 5mg

ACTIVE COMPARATOR

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; Drug: CBD 600mg; Drug: Placebo 0mg

Dronabinol 10mg

ACTIVE COMPARATOR

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; Drug: CBD 600mg; Drug: Placebo 0mg

Placebo 0mg

PLACEBO COMPARATOR

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; Drug: CBD 600mg; Drug: Placebo 0mg

Interventions

CBD 300mg DRUG

3 Nantheia™ (100mg) softgel capsules and 3 placebo (0mg) softgel capsules will be administered to participants on one of the three test session days.

Also known as: Nantheia™ ATL5 (300mg)

Dronabinol 10mg; Dronabinol 5mg; Placebo 0mg

CBD 600mg DRUG

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

Also known as: Nantheia™ ATL5 (600mg)

Dronabinol 10mg; Dronabinol 5mg; Placebo 0mg

Placebo 0mg DRUG

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

Also known as: Nantheia™ ATL5 (0mg)

Dronabinol 10mg; Dronabinol 5mg; Placebo 0mg

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Yale University: lead
• National Institutes of Health (NIH): collaborator
• National Institute on Drug Abuse (NIDA): collaborator

Study Sites (1)

Connecticut Mental Health Center

New Haven, Connecticut, 06519, United States

RECRUITING

Related Publications (18)

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  PMID: 27522535 BACKGROUND

• 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.

  PMID: 28811670 BACKGROUND

• 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.

  PMID: 24440051 BACKGROUND

• 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.

  PMID: 30371854 BACKGROUND

• 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.

  PMID: 29933552 BACKGROUND

• 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.

  PMID: 33879842 BACKGROUND

• 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.

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• 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.

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• 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.

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• 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.

  PMID: 23271193 BACKGROUND

• 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.

  PMID: 3774930 BACKGROUND

• 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.

  PMID: 31045746 BACKGROUND

• 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.

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

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• 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.

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• De Aquino JP, Bahji A, Gomez O, Sofuoglu M. Alleviation of opioid withdrawal by cannabis and delta-9-tetrahydrocannabinol: A systematic review of observational and experimental human studies. Drug Alcohol Depend. 2022 Dec 1;241:109702. doi: 10.1016/j.drugalcdep.2022.109702. Epub 2022 Nov 18.

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• Oliveira D, Fontenele R, Weleff J, Sofuoglu M, De Aquino JP. Developing non-opioid therapeutics to alleviate pain among persons with opioid use disorder: a review of the human evidence. Int Rev Psychiatry. 2023 Aug-Sep;35(5-6):377-396. doi: 10.1080/09540261.2023.2229430. Epub 2023 Jun 28.

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• Costa GPA, Nunes JC, Heringer DL, Anand A, De Aquino JP. The impact of cannabis on non-medical opioid use among individuals receiving pharmacotherapies for opioid use disorder: a systematic review and meta-analysis of longitudinal studies. Am J Drug Alcohol Abuse. 2024 Jan 2;50(1):12-26. doi: 10.1080/00952990.2023.2287406. Epub 2024 Jan 15.

  PMID: 38225727 BACKGROUND

MeSH Terms

Conditions

Chronic Pain; Opioid-Related Disorders; Pain

Condition Hierarchy (Ancestors)

Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Narcotic-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Study Officials

• Joao P. De Aquino, M.D.

  Yale University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Julia V. Meyerovich, M.S.

CONTACT

203-932-5711; julia.meyerovich@yale.edu

Joao P. De Aquino, M.D.

CONTACT

203-623-7493; joao.deaquinolima@yale.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: The study medication will be prepared by the CMHC research pharmacy using over-encapsulation.
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Psychiatry

Model Details: 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.

Study Record Dates

• First Submitted: August 1, 2024
• First Posted: August 9, 2024
• Study Start: October 22, 2024
• Primary Completion (Estimated): January 28, 2028
• Study Completion (Estimated): January 28, 2028
• Last Updated: January 13, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)