Cannabidiol Effects on Craving and Relapse Prevention in Opioid Use Disorder

This research aims to determine the effects and safety of cannabidiol (CBD) (ATL5 softgel capsules) as an adjunctive therapy for patients who have Opioid Use Disorder and are taking buprenorphine + naloxone or methadone. Buprenorphine + naloxone and methadone is an approved treatment for Opioid Use Disorder, but relapse to opioid misuse is common among patients who receive this treatment. Finding an adjunctive treatment for these patients would be helpful.

We will recruit participants from the Tarzana Treatment Center (TTC) in the San Fernando Valley. They will be receiving buprenorphine + naloxone or methadone as part of residential therapy. Potential participants who pass initial screening and wish to continue in the study will provide written, informed consent and will complete a 2-day evaluation, including blood and urine tests, questionnaires about their mood, medical, psychiatric and drug use history and physical exam.

Up to 60 participants who meet all eligibility criteria will be invited to complete baseline assessments (blood and urine tests, questionnaires), and will be assigned randomly to receive CBD (600 mg/day) or placebo, corresponding to two groups of up to 30 participants each.

After the baseline measurements, participants will take part in a 28-day treatment phase for 4 weeks. They will take the study medication under supervision (CBD 300 mg twice daily or placebo). Questionnaires on opioid craving, withdrawal, and mood symptoms will be administered daily during the treatment period, excluding weekends. After the 28-day intervention, participants will complete the questionnaires and undergo urine drug tests in 4 weekly follow-up visits.

The study will last \~10 weeks, comprising three periods: a screening period (2-weeks when participants are stabilized on buprenorphine + naloxone or methadone in residential treatment at the Tarzana Treatment Center), a treatment period (4 weeks when study CBD or placebo is administered at Tarzana Treatment Center), and a follow-up period (4 weeks after termination of the test intervention).

This will be a randomized, double-blind, placebo controlled, study of cannabidiol (CBD) (600 mg/day) as an adjunctive therapy to buprenorphine + naloxone or methadone in patients who have Opioid Use Disorder and are receiving residential behavioral therapy, including cognitive behavioral therapy. The primary endpoint will be safety and tolerability of CBD in these patients, as indicated by the incidence of treatment-emergent adverse events (n/% per group). Participants will be evaluated via measurement of cardiovascular parameters (heart rate, blood pressure, and cardiac rhythm and conduction on EKG), other vital signs, liver enzymes, pulse oximetry, adverse events, and pharmacokinetics. Secondary measures will include cue-induced craving, reductions in spontaneous craving, opioid withdrawal, and negative affective states.

Patients will be recruited from the Tarzana Treatment Center (TTC) in the San Fernando Valley, where buprenorphine + naloxone or methadone (as part of their treatment) and CBD (as part of this protocol) will be administered. Tarzana Treatment Centers, Inc. is a community-based, private non-profit behavioral healthcare organization located in Southern California with several agency sites, including the one in the San Fernando Valley, where this protocol will be conducted. TTC delivers drug and alcohol use treatment, has been accredited by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) since 1987, and has a workforce that includes physicians, psychologists, and nurses. TTC's substance use treatment approach includes residential programs that are overseen by a Program Director and are staffed by a clinical supervisor, operations supervisor, counselors, interns, nursing staff and 24/7 technicians. Groups and services include an education group, process group, 12-step, family group, mental health services and recreation skills. Cognitive-behavioral treatment is used in both individual and group therapy to address craving and relapse issues and in the treatment of mental health problems.

Up to 75 participants who meet all eligibility criteria will be invited to complete baseline assessments (blood and urine tests, questionnaires), and will be assigned randomly to receive CBD or placebo, corresponding to two groups of up to 30 participants each. Within each group, participants will be randomized by baseline buprenorphine plasma level (either below or ≥ 2 ng/ml).

The study will comprise three periods: 1) a screening period (\~7-14-days) while participants are stabilized on buprenorphine + naloxone; 2) a 4-week treatment period when study medication will be administered; and 3) a 4-week follow-up period after termination of treatment with the study medication. Cue-induced craving sessions will be conducted at three times: Day 0 (baseline), Day 7 (when a steady state of CBD should have been reached; half-life of CBD after oral administration is 18-32 h), and Day 28 (end of treatment).

Adherence to medication in the trial will be assured as the participant will take the test medication (CBD or placebo) under supervision daily. Blood samples will be collected to determine plasma concentrations of CBD, buprenorphine, and laboratory assessments of safety. Cue-induced craving and other measures of craving and affect will be collected repeatedly during the study.

Eligibility Criteria:
Inclusion Criteria:

* Ability to read and speak English and has provided written informed consent.
* Age of 18-65 years (inclusive).
* Meeting criteria for an OUD according to the MINI for ≥ 3 months before screening.
* Self-report of opioid use in the 60 days before screening; verified by treatment center records.
* On a stable dose of ≥12 mg buprenorphine, either alone, or in combination with naloxone (buprenorphine/naloxone ratio of 4/1) for at least 7 days prior to starting and for the duration of the treatment phase of the study. OR, receiving methadone maintenance therapy for at least 7 days prior to starting and for the duration of the treatment phase of the study.
* If female, being surgically sterile or willing to use birth control (e.g., oral contraceptives, condoms, intrauterine device) or willingness to abstain from sex throughout the study.
* Body Mass Index (BMI) between 17.5 and 35 kg/m2; total body weight \> 110 lb (50 kg).
* Currently in residential treatment at the Tarzana Treatment Center.

Exclusion Criteria:

* History of sensitivity to a CBD product or any of the ingredients in the study drug, including glycerin or gelatin.
* A condition that may affect drug absorption (e.g., gastrectomy).
* Taking a medications that has clinically significant interactions with CBD or are contraindicated for the study (check with study physician).
* Positive urine test for THC at screening.
* Self-report of using CBD at screening.
* PK analysis at screening showing evidence of CBD use (a signal that is ≥ three times the background noise at the corresponding CBD retention time and MS2 transition).
* Physiological dependence on alcohol or a sedative-hypnotic benzodiazepine drug.
* Current medication-assisted treatment with naltrexone.
* Acute opioid withdrawal symptoms, as defined by a score on the COWS \> 4.
* Clinical laboratory finding of AST or ALT \> 3 times the upper limit of normal (ULN) or bilirubin \> 1.5 times ULN.
* AIDS or HIV positive status (because treatment medications have potential interactions with CBD).
* Pregnancy or lactation.
* Clinically significant EKG abnormalities, as determined by the study physician, including the following: QTc \>450 msec (men) or \>470 (women) or QRS interval \>120 msec (If QTc or QRS interval exceed these cutoff points, EKG will be repeated twice and the average of the three QTc values used to determine eligibility.), congenital long QT syndrome, history of prolonged QT in the 3 months before screening, corrected QT interval (Fridericia's - QTcF) \>450 msec (male) or \>470 msec (female) or history of risk factors for Torsades de Pointes.
* For women: any value outside reference ranges on a hormonal battery \[estradiol, follicle-stimulating hormone, free thyroxine index, luteinizing hormone, prolactin, T3 uptake, thyroid-stimulating hormone, and thyroxine\], followed by an abnormal ovarian ultrasound finding.
* Clinically significant cardiovascular, hematologic, hepatic, renal, or endocrine abnormalities, as determined by the study physician.
* Meeting criteria on the MINI for schizophrenia, Bipolar I disorder, psychotic disorder, having active suicidal ideation, or suicide attempt in the past 12 months. Or, answers "yes" to questions 4 or 5 on C-SSRS. NOTE: Participants with other psychiatric conditions, such as major depression, generalized anxiety, dysthymia, social phobia or specific phobia may be enrolled in the study if they are clinically stable.
* On the cue-induced opiate craving task at screening, the participant does not have a score of at least 25 (on a visual analogue scale with a maximum score of 100) for at least one image within one category. Note: Groups of images may be separated into smoking cues, pills and bottles, and injection paraphernalia. For example, for injection cues, a picture of a needle and syringe may elicit a craving response, though other images in the same group (i.e., picture of arm with vein bulging) do not elicit craving.