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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
DOUBLE
Enrollment
147
3 Nantheia™ (100mg) softgel capsules and 3 placebo (0mg) softgel capsules will be administered to participants on one of the three test session days.
6 Nantheia™ (100mg) softgel capsules will be administered to participants on one of the three test session days.
6 placebo (0 mg) softgel capsules will be administered to participants on one of the three test session days.
Connecticut Mental Health Center
New Haven, Connecticut, United States
RECRUITINGPrimary 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.
Time frame: 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.
Time frame: Baseline and +180 minutes post dose
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).
Time frame: +180 minutes post dose
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.
Time frame: +180 minutes post dose
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).
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Time frame: +480 post dose
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".
Time frame: Up to 8 hours
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.
Time frame: Baseline ; +480 minutes post dose; One-week after last test session
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.
Time frame: Up to 8 hours and One-week after last test session