Combined THC and CBD for OUD 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.

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.

Eligibility Criteria:
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) other than OUD or tobacco use disorder, within the last 12 months.
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 ≤ 50 mg/mL. If a participant tests greater than ≤ 50 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.