Cannabidiol as Adjunctive Treatment for Opioid Use Disorder
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|ClinicalTrials.gov Identifier: NCT03787628|
Recruitment Status : Not yet recruiting
First Posted : December 25, 2018
Last Update Posted : March 29, 2019
This research aims to determine the effects and safety of cannabidiol (CBD) oral solution as an adjunctive therapy for patients, who have Opioid Use Disorder and are taking buprenorphine + naloxone. Buprenorphine + naloxone 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.
Investigators will recruit participants from the Domiciliary treatment center at the West Los Angeles VA Medical Center (DOM). They will be receiving buprenorphine + naloxone 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.
Sixty 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 in each of two cohorts, corresponding to two dose groups of 20 participants per cohort (CBD 700 , 1400 mg/day). Within each cohort, 20 participants will receive CBD and 10 will receive placebo. The cohorts will be studied in ascending dose order to ensure safety.
After the baseline measurements, participants will travel to UCLA by taxi, accompanied by a research associate, every morning for 4 weeks (28 sessions). Each morning, he or she will take the study medication under supervision (CBD 700, 1400 mg or placebo). Questionnaires on opioid craving, withdrawal, and mood symptoms will be administered daily during the treatment period.
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 in residential treatment at the DOM), a treatment period (4 weeks when study CBD or placebo is administered at UCLA), and a follow-up period (4 weeks after termination of the test intervention).
|Condition or disease||Intervention/treatment||Phase|
|Opioid-use Disorder||Drug: Cannabidiol Oral Solution Drug: Placebo||Phase 2|
This will be a randomized, double-blind, placebo controlled, sequential, dose-ranging study of Cannabidiol Oral Solution (CBD) (700, 1400 mg/day) as an adjunctive therapy to buprenorphine + naloxone in patients who have Opioid Use Disorder and are receiving residential behavioral therapy, including cognitive behavioral therapy. The primary dependent variable will be cue-induced craving. Secondary measures will be reductions in spontaneous craving, opioid withdrawal, negative affective states, and relapse, as well as retention in treatment with buprenorphine + naloxone.
The study will be conducted at the Semel Institute in the David Geffen School of Medicine at the University of California Los Angeles (UCLA). Administration of the study compounds and all test procedures, and analyses will be conducted at UCLA.
Participants will be recruited from the Domiciliary Residential Rehabilitation Treatment Program of the Veterans Administration of Greater Los Angeles Health Center (the Dom).
This 300-bed program serves veterans with a wide range of psychiatric and medical conditions. More than 90% of those admitted to the program have been diagnosed with a substance use disorder. The Dom is staffed with psychiatrists, psychologists, social workers, recreation therapists, primary care physicians, and vocational rehabilitation specialists. It provides a therapeutic community that utilizes peer and professional support services in a structured, residential environment with 24-h and 7-days-a-week monitoring by on-site nurses and health technicians, who serve the needs of the patients and maintain communication. At the Dom, treatment as usual (TAU) for patients with Substance Use Disorder is 4 hours of group programming. Groups consist of various modalities, including cognitive behavioral therapy (CBT) for relapse prevention, Seeking Safety for Posttraumatic Stress Disorder,process groups, and Dialectical Behavioral Therapy. Matrix Model CBT, incorporating relapse prevention, is one of the core groups.
Sixty participants who meet all eligibility criteria will be randomized to receive CBD or placebo in each of two dose cohorts (30 participants per cohort): CBD 700 mg/day and 1400 mg/day. The cohorts will be studied sequentially according to ascending dose order to ensure safety. Within each cohort, participants will be randomized by baseline buprenorphine plasma level (either below or ≥ 2 ng/ml) so that 20 participants will receive active study medication and 10 will receive placebo. Thus, there will be 3 groups of 20 participants per treatment, including a group with 20 participants who receive placebo.
The study will comprise three periods: a 2-week 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. Laboratory 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),14 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, laboratory assessments of safety. Retention in treatment (this trial plus buprenorphine +naloxone) 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).
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||60 participants|
|Intervention Model:||Sequential Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Official Title:||Cannabidiol as Adjunctive Treatment for Opioid Use Disorder|
|Estimated Study Start Date :||June 1, 2019|
|Estimated Primary Completion Date :||March 31, 2021|
|Estimated Study Completion Date :||June 30, 2021|
Experimental: Cannabidiol Oral Solution (CBD)
Sixty participants who meet all eligibility criteria will be randomized to receive CBD or placebo in each of three dose cohorts (30 participants per cohort): CBD 700 and 1400 mg/day. The cohorts will be studied sequentially according to ascending dose order to ensure safety.
Drug: Cannabidiol Oral Solution
CBD Oral Solution (700 and 1400 mg/day) or matching placebo will be administered orally once daily in the morning. The concentration of the CBD Oral Solution is 100 mg/ml.
Insys Development Company, Inc. has successfully manufactured a pharmaceutical grade, synthetic CBD drug substance. It is manufactured in Insys' current Good Manufacturing Practices (cGMP) manufacturing facility. This facility is approved by the Drug Enforcement Administration (DEA) and has been inspected by the Food and Drug Administration (FDA). This active pharmaceutical ingredient is ≥ 99.5% pure and can be consistently produced without concern for contaminant.
Placebo Comparator: Placebo
Within each cohort, participants will be randomized by baseline buprenorphine plasma level (either below or ≥ 2 ng/ml) so that 20 participants will receive active study medication and 10 will receive placebo. Thus, there will be 3 groups of 20 participants per treatment, including a group with 20 participants who receive placebo.
The reference therapy will be placebo, consisting of an oral solution that matches the active test medication in appearance. Different volumes of placebo will be administered to match that of the active compound, daily in the morning for each of 28 days.
- Cue-induced opioid craving [ Time Frame: During the laboratory session before dosing on Day 0 (baseline without CBD) and on Days 7 and 28 after adjunctive treatment with CBD. ]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).
- spontaneous opioid craving using the Penn Alcohol-Craving Scale adapted for opioid [ Time Frame: at baseline before dosing(Day 0), daily during treatment period(28 days), and weekly during follow-up period (up to 4 weeks). ]A brief (5-item) unidimensional measure of craving. Items assess craving retrospectively during the week before testing. Responses can range from 0 to 6, and the scale is defined as the mean item score.Higher scores show higher levels of craving.
- Spielberger State-Trait Anxiety Inventory [ Time Frame: at baseline before dosing(Day 0), daily during treatment period(28 days), and weekly during follow-up period (up to 4 weeks). ]A 40-item self-report rating scale for assessing anxiety. It comprises two subscales (each 20 items): the State Anxiety subscale evaluates how respondents feel "right now" and the Trait Anxiety subscale measures a generalized propensity to be anxious. All items are rated on a 4-point scale (e.g., from "Almost Never" to "Almost Always"). Higher scores indicate greater anxiety.
- Positive and Negative Affect Schedule (PANAS) [ Time Frame: at baseline before dosing(Day 0), daily during treatment period(28 days), and weekly during follow-up period (up to 4 weeks). ]Affect is assessed using this 20-item questionnaire that measures both positive and negative affect. Each item is rated on a 5-point scale ranging from 1 (very slightly or not at all).
- Daily Opioid Craving [ Time Frame: at baseline before dosing(Day 0), daily during treatment period(28 days), and weekly during follow-up period (up to 4 weeks) ]Daily spontaneous opioid craving will be assessed using a 13-item questionnaire derived from the DDQ. Patients will be asked to rate their urge to use opioids ("How much do you want to use an opioid?") on a seven-step Likert-scale answer sheet based on what they feel or think at the moment. Patients indicate how much they agree or disagree with each of the statements on the questionnaire by placing a single checkmark along each line between STRONGLY DISAGREE and STRONGLY AGREE, so that the craving score may range from 7 to 49. Higher scores show higher levels of craving.
- plasma levels of buprenorphine and metabolites (norbuprenorphine and buprenorphine glucuronide) [ Time Frame: during the screening(2 weeks), at baseline (Day 0) and during the treatment period (28 days) and follow-up period (up to 2 weeks). ]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.
- plasma levels of anandamide and 2 AG [ Time Frame: At baseline(Day 0)and at the end of the treatment period(Day 28). ]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.
- treatment retention [ Time Frame: throughout the study period(10 weeks). ]treatment retention as indicated by number of days of continued participation
- days of rescue medications [ Time Frame: throughout the 28-day treatment period ]days of rescue medications (e.g., clonidine, lofexidine, loperamide) for withdrawal symptoms
- CBD plasma levels [ Time Frame: during the treatment (28 days) and follow up period( up to 2 weeks). ]Plasma concentrations of CBD will be used to determine the pharmacokinetic (PK) parameters using noncompartmental PK analysis.
- Blood pressure [ Time Frame: on screening ( Day -14), at baseline (Day 0) and during the treatment period ( 28 days). ]Systolic and diastolic blood pressure will be monitored throughout the study.
- Heart rate [ Time Frame: on screening ( Day -14), at baseline (Day 0) and during the treatment period ( 28 days). ]Heart rate will be monitored throughout the study.
- Respiratory rate [ Time Frame: on screening ( Day -14), at baseline (Day 0) and during the treatment period ( 28 days). ]Respiratory rate will be monitored throughout the study.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03787628
|Contact: Edythe London, PhD||3108250606||ELondon@mednet.ucla.edu|
|Contact: Anaheed Shirazi, MDfirstname.lastname@example.org|
|Principal Investigator:||Edythe London, PhD||University of California, Los Angeles|