Cannabidiol as Adjunctive Treatment for Opioid Use Disorder

• ClinicalTrials.gov Identifier: NCT03787628
• Recruitment Status: Recruiting
• First Posted: December 26, 2018
• Last Update Posted: May 24, 2022
• Sponsor: University of California, Los Angeles
• Information provided by (Responsible Party): Edythe London, University of California, Los Angeles

Study Description

Brief Summary:

This research aims to determine the effects and safety of cannabidiol (CBD) 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 does not have abuse liability and reduces relapse for these patients would be helpful.

Investigators will recruit participants from the Tarzana Treatment Center in Los Angeles. 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 screening evaluation, including blood and urine tests, questionnaires about their mood, medical, psychiatric and drug use history and a 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 three cohorts, corresponding to two dose groups of 20 participants per cohort (CBD 600, 1200mg/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.

Each day, participants will take the study medication twice daily under supervision. Questionnaires on opioid craving, withdrawal, and mood symptoms will be administered daily during the treatment period. Cue-induced craving will be assessed at 3 timepoints (days 0, 7 and 28). PK samples will be assessed at multiple time-points during the study.

After the 28-day intervention, participants will complete questionnaires and undergo urine drug tests in weekly follow-up visits (days 29-56). PK samples will be assessed at multiple time-points during the follow-up period.

The study will last ~9 weeks, comprising three periods: a screening period (~7 days during which participants are stabilized on buprenorphine + naloxone in residential treatment at Tarzana Treatment Center), 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 (CBD) 600 mg; Drug: CBD 1200 mg; Drug: Placebo	Phase 2

Detailed Description:

This will be a randomized, double-blind, placebo controlled, sequential, dose-ranging study of Cannabidiol (CBD) (600, 1200 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 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.

Patients will be recruited from the Tarzana Treatment Center (TTC) in the San Fernando Valley, where buprenorphine (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.

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 three cohorts, corresponding to two dose groups of 20 participants per cohort (CBD 600, 1200mg/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. 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)-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, 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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Cannabidiol as Adjunctive Treatment for Opioid Use Disorder
• Actual Study Start Date: May 19, 2022
• Estimated Primary Completion Date: August 13, 2023
• Estimated Study Completion Date: November 15, 2023

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Cannabidiol (CBD) 600 mg; Twenty participants who meet all eligibility criteria will be randomized to receive CBD (ATL5; Ananda Scientific) at a dose of 600 mg. The active comparator cohorts will be studied sequentially according to ascending dose in order to ensure safety.	Drug: Cannabidiol (CBD) 600 mg; 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.
Active Comparator: CBD 1200 mg; Twenty participants who meet all eligibility criteria will be randomized to receive CBD (ATL5; Ananda Scientific) at a dose of 1200 mg. The active comparator cohorts will be studied sequentially according to ascending dose in order to ensure safety.	Drug: CBD 1200 mg; CBD (600 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). ATL5 Softgel Capsules will be manufactured by Baxco Pharmaceutical Inc., (California, USA) under cGMP conditions.
Placebo Comparator: Placebo; Twenty participants who meet all eligibility criteria will be randomized to receive placebo.	Drug: Placebo; 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.

Outcome Measures

Primary Outcome Measures :

1. The primary endpoint will be safety and tolerability of CBD [ Time Frame: Days 1-56 ]
   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.
2. Safety will also be assessed via measurement of plasma levels of buprenorphine and metabolites (norbuprenorphine and buprenorphine glucuronide). [ Time Frame: 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). ]
   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.
3. Safety will also be assessed via measurement of plasma levels of anandamide and 2 AG. [ Time Frame: 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). ]
   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.
4. Safety will also be assessed via measurement of plasma levels of CBD as well as its metabolites 7-hydoxy-CBD and 7-carboxy-CBD. [ Time Frame: 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). ]
   Plasma concentrations of CBD and its metabolites will be used to determine the pharmacokinetic (PK) parameters using noncompartmental PK analysis.

Secondary Outcome Measures :

1. The extent to which CBD reduces cue-induced craving for opioids [ 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).

Other Outcome Measures:

1. 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.
2. 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.
3. 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).
4. Percentage of patients who relapse during the trial [ Time Frame: Throughout the study period ]
   The percentage of individuals who relapse to opioid use during the trial will be determined via self-report and biochemical confirmation obtained by daily urine drug testing.
5. Treatment retention [ Time Frame: Throughout the study period ]
   Treatment retention as indicated by number of days of continued participation

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Ability to read and speak English and has provided written informed consent.

1. Age between 18 and 65 years (inclusive).
2. Have an opiate use disorder that meets criteria set in the Mini-International Neuropsychiatric Interview (MINI 7.0.2) for DSM-5 ≥ three months before screening.
3. On a stable dose of 12-16 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.
4. Self-report of opioid use in the 30 days before screening; verified by treatment center records.
5. 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.
6. Body Mass Index (BMI) between 17.5 and 35 kg/m2; total body weight > 110 lb (50 kg).
7. Currently in residential treatment at the Tarzana Treatment Center.

Exclusion Criteria:

1. History of sensitivity to a CBD product or any of the ingredients in the study drug, including glycerin or gelatin.
2. A condition that may affect drug absorption (e.g., gastrectomy).
3. Taking a medications that has clinically significant interactions with CBD or are contraindicated for the study (check with study physician).
4. Meeting criteria for a substance use disorder, moderate or severe, other than OUD or Tobacco Use Disorder in the 3 months prior to screening.
5. Positive urine test for THC at screening.
6. Self-report of using CBD at screening.
7. PK analysis at screening showing evidence of CBD use (any level > 0).
8. Physiological dependence on alcohol or a sedative-hypnotic benzodiazepine drug.
9. Current medication-assisted treatment with methadone or naltrexone.
10. Acute opioid withdrawal symptoms, as defined by a score on the COWS > 4.
11. Clinical laboratory finding of AST or ALT > 3 times the upper limit of normal (ULN) or bilirubin > 1.5 times ULN.
12. AIDS or HIV positive status (because treatment medications have potential interactions with CBD).
13. Pregnancy or lactation.
14. 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.
15. 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.
16. Clinically significant cardiovascular, hematologic, hepatic, renal, or endocrine abnormalities, as determined by the study physician.
17. 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.
18. On the cue-induced opiate craving task at screening, the participant does not have a score of at least 50 (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.

Contacts and Locations

Contacts

Contact: Edythe London, PhD; 3108250606; ELondon@mednet.ucla.edu

Contact: Richard De La Garza, II, PhD; 3108250606; rdelagarza@mednet.ucla.edu

Locations

United States, California

Tarzana Treatment Centers; Recruiting

Tarzana, California, United States, 91356

Contact: Kenneth Bachrach, Ph.D. kbachrach@tarzanatc.org

Contact: Stan Galperson, Psy.D. sgalperson@tarzanatc.org

Principal Investigator: Richard De La Garza, Ph.D.

Sponsors and Collaborators

University of California, Los Angeles

Investigators

• Principal Investigator: Edythe London, PhD; University of California, Los Angeles
• Principal Investigator: Richard De La Garza, II, PhD; University of California, Los Angeles

More Information

• Responsible Party: Edythe London, Distinguished Professor in Residence, University of California, Los Angeles
• ClinicalTrials.gov Identifier: NCT03787628
• Other Study ID Numbers: 18-001748
• First Posted: December 26, 2018
• Last Update Posted: May 24, 2022
• Last Verified: May 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Edythe London, University of California, Los Angeles:

Buprenorphine; Cannabidiol; Opioid Use disorder

Additional relevant MeSH terms:

Disease; Opioid-Related Disorders; Substance-Related Disorders; Pathologic Processes; Narcotic-Related Disorders; Chemically-Induced Disorders; Mental Disorders; Cannabidiol; Anticonvulsants