Cannabidiol Effects on Craving and Relapse Prevention in Opioid Use Disorder

Study Overview
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Brief Summary
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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 that reduces relapse 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 (600mg/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).

Detailed Description
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This will be a randomized, double-blind, placebo controlled, study of Cannabidiol (CBD) (600mg/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, and it will be assessed 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, negative affective states, and relapse, as well as retention in treatment with buprenorphine + naloxone or methadone. 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 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 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 or placebo, corresponding of two cohorts of up to 30 participants each. Within each cohort, participants will be randomized by baseline buprenorphine plasma level (either below or ≥ 2 ng/ml). The study will comprise three periods: a multi ( 7-14)-day screening period while participants are stabilized on buprenorphine + naloxone), a 4-week treatment period when study medication will be administered, and a 4-week follow-up period after termination of treatment with 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 its metabolites as well as the endocannabinoids anandamide and 2-AG, which may contribute to the response to CBD, and laboratory assessments of safety. Retention in treatment (this trial plus buprenorphine +naloxone or methadone) will be assessed over the 28-day medication (CBD or placebo) period and weekly follow-up assessments for the subsequent month (28-day follow-up period).

Official Title
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Cannabidiol Effects on Craving and Relapse Prevention in Opioid Use Disorder

Conditions
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Opioid-use Disorder

Intervention / Treatment
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* Drug: Cannabidiol (CBD) 600 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cannabidiol (CBD) 600 mg<br>Thirty participants who meet all eligibility criteria will be randomized to receive CBD (ATL5; Ananda Scientific) at a dose of 600 mg. | Drug: Cannabidiol (CBD) 600 mg<br>* CBD (300 mg) will be administered orally twice daily in the morning and again in the afternoon. The active ingredient in the Ananda investigational new drug, ATL5, is cannabidiol (CBD), extracted from hemp, at a 10% strength (softgel capsules with 100 mg/ml od CBD per capsule). The novel formulation is based on the principle that a water-free mixture of some concentrated inactive ingredients (excipients) self-assemble spontaneously into liquid nanodomains that contain the active component CBD. ATL5 Softgel Capsules will be manufactured by Baxco Pharmaceutical Inc., (California, USA) under cGMP conditions.<br>|
| Placebo Comparator: Placebo<br>Thirty participants who meet all eligibility criteria will be randomized to receive placebo. | Drug: Placebo<br>* The placebo softgel capsule formulation will have a composition with the same relative proportions as the CBD ATL5 Softgel Capsules. This formulation will be manufactured by Baxco Pharmaceutical Inc under cGMP conditions. Different amounts (numbers of softgel capsules) of placebo will be administered to match that of the active compound, daily in the morning and afternoon for each of 28 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary endpoint will be safety and tolerability of CBD | Safety will be assessed via measurement of cardiovascular parameters (heart rate, blood pressure, and cardiac rhythm and conduction on EKG), other vital signs, liver enzymes, pulse oximetry, and adverse events. | Days 1-56 | 
| Safety will also be assessed via measurement of plasma levels of buprenorphine and metabolites (norbuprenorphine and buprenorphine glucuronide). | Investigators will evaluate whether CBD might pose potential safety concerns associated with buprenorphine treatment. This study will seek to understand the drug-drug interaction for safe and effective treatment of Opioid Use Disorder and to identify an optimal adjunctive dose of CBD for patients receiving buprenorphine + naloxone treatment. Investigators predict a drug-drug interaction between CBD and buprenorphine, in which CBD will dose-dependently inhibit buprenorphine metabolism and therefore increase the ratio of buprenorphine/norbuprenorphine concentrations. | Before dosing (day 0) and during the treatment (days 3,7,14,21 and 28) and during the follow-up period (days 35,42,49 and 56). | 
| Safety will also be assessed via measurement of plasma levels of anandamide and 2 AG. | Because CBD is an inhibitor of fatty acid amide hydrolase (FAAH), the principal enzyme catalyzing the catabolism of the major endocannabinoids (N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), administration of CBD may affect plasma concentrations of these endocannabinoids. Plasma levels of anandamide and 2-AG will be determined in order to obtain preliminary data on the extent to which CBD effects on the primary endpoints in the study reflect actions to increase anandamide and 2-AG concentrations. It is predicted that high baseline endocannabinoids will be associated with a smaller overall CBD effect and/or a maximum CBD effect at a lower dose. | Before dosing (day 0) and during the treatment (days 3,7,14,21 and 28) and during the follow-up period (days 35,42,49 and 56). | 
| Safety will also be assessed via measurement of plasma levels of CBD as well as its metabolites 7-hydoxy-CBD and 7-carboxy-CBD. | Plasma concentrations of CBD and its metabolites will be used to determine the pharmacokinetic (PK) parameters using noncompartmental PK analysis. | Before dosing (day 0) and during the treatment (days 3,7,14,21 and 28) and during the follow-up period (days 35,42,49 and 56). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The extent to which CBD reduces cue-induced craving for opioids | Patients will be presented with 90 images, which consist of 40 heroin-related, 40 prescription-opioid-related and 10 neutral pictures. After the presentation of each cue, patients will rate their opioid craving by responding to 7 items derived from the Desire for Drug Questionnaire (DDQ).Each item is measured on a 7-point Likert scale, so that the craving score may range from 7 to 49. The primary outcome will be quantified as the change in craving response in the context of opioid cue-induced craving from the laboratory session before dosing on Day 0 (baseline without CBD) to Days 7 and 28 (after adjunctive treatment with CBD). | During the laboratory session before dosing on Day 0 (baseline without CBD) and on Days 7 and 28 after adjunctive treatment with CBD. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Buprenorphine, Cannabidiol, Opioid Use disorder