Opioid Use Disorder (OUD)
Conditions
Brief summary
The long-term goal of the project is to determine whether cannabidiol (CBD) can reduce craving and relapse in individuals with opioid use disorder (OUD). The first phase of this project was an open cross-over design study in healthy individuals to confirm the safety and pharmacokinetic (PK) effects of CBD (BSPG CBD; Brains Bioceutical). The second phase was a double-blinded randomized controlled trial to determine whether CBD reduces craving and anxiety in individuals with OUD maintained on opioid agonist therapy. This phase 3 trial will determine whether CBD can serve as a potential adjunct treatment to reduce illicit opioid use in individuals with OUD maintained on opioid agonist therapy.
Detailed description
Responding to the urgent calls for developing non-opioid therapeutics to address the opioid addiction epidemic, we have been investigating the therapeutic potential of cannabidiol (CBD), a non-intoxicating cannabinoid as a possible strategy. Our preclinical animal studies demonstrated that CBD decreases cue-induced heroin seeking behavior during drug abstinence, associated with the incubation of craving. Moreover, the effects of CBD to reduce heroin-seeking behavior was still evident even in animals that were maintained on methadone. We also showed in randomized, double-blind placebo- controlled design human clinical trials that acute CBD (Epidiolex) administration (400 mg and 800mg) decreased craving and anxiety associated with heroin cues in abstinent individuals with heroin use disorder, an effect that persisted even a week after the last CBD dose (given daily for 3 days). Moreover, another of our human studies showed that CBD was safe even in combination with a potent opioid agonist (fentanyl) to address a potential relapse condition suggesting negligible negative interaction with opioids. Building on those studies, we next set out to investigate the potential for CBD as an adjunctive treatment to methadone or buprenorphine in opioid use disorder (OUD). To that end, we first conducted Phase 1 pharmacokinetic studies with a CBD formulation in oral capsules (BSPG CBD; Brains Bioceutical) in healthy participants that showed that oral administration of BSPG CBD (400 mg) led to comparable pharmacokinetic parameters of the CBD plasma levels and its active metabolite as Epidiolex (400 mg), an FDA-approved comparator CBD product that previously reduced craving. In the Phase 2 clinical trial, we evaluated the effect of 200mg CBD (vs placebo) twice daily for 4 weeks and an additional 4 weeks of 400 mg CBD, twice daily, on cue-induced craving and anxiety in individuals with OUD who are maintained on methadone or buprenorphine. In the next phase of this IND application, we will extend the Phase 2 study to evaluate the effects of 200mg CBD, 400 mg CBD and placebo, taken twice daily, over a 24-week period in the OUD individuals maintained on methadone or buprenorphine. Our goals in this double-blinded randomized controlled clinical trial (RCT) are to investigate the potential of CBD to 1) decrease illicit opioid use and 2) reduce craving.
Interventions
DRUGCannabidiol
1 capsule CBD 200mg
DRUGPlacebo
Bovine Gel Placebo capsule
Sponsors
National Institute on Drug Abuse (NIDA)
International Center for Health Outcomes and Innovation Research
Brains Bioceutical
Icahn School of Medicine at Mount Sinai
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Investigators and participants will be blinded to treatment assignment. The staff involved in primary outcome assessment and laboratory tests in local laboratories will also be blinded to treatment assignment. Randomization will be generated centrally and performed through a Web-based data collection system that automates the delivery of the randomization codes. The treatment assignment will be sent to the unblinded pharmacist or unblinded study team electronically, in a secure fashion, and electronic verification of the treatment assignment will be required before proceeding with the treatment intervention. Active drug and placebo will be identical to maintain study blinding.
Intervention model description
Randomization will be carried out within each site using stratification factors. Using stratified block randomization with randomly varying block sizes, participants who meet the eligibility requirements and provide informed consent will be randomly allocated to one of the study arms (1 capsule CBD (200 mg), 2 capsules CBD (400 mg), 1 capsule placebo and 2 capsules placebo) with a 1:1:0.5:0.5 allocation ratio. The placebo groups will be combined for statistical analysis purposes. Random permuted blocks sizes within stratification groups will be used to minimize the chance of selection bias.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Individuals between 18 and 65 years old. * Ability to understand and give informed consent. * Current opioid use disorder (OUD) or OUD in remission while on maintenance therapy with OAT, as determined by DSM-5 with the M.I.N.I. interview (Mini-International Neuropsychiatric Interview). * Current opioid agonist maintenance treatment with methadone or buprenorphine for at least 14 days prior to consent. With the following more specific criteria for each of these two medications: * Current methadone maintenance treatment with a dose of ≥ 10mg/day, (maximum: 250mg/day), AND urinary toxicology positive for methadone and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). * Current buprenorphine maintenance treatment with a dose of ≥ 2mg/day (maximum: 32mg/day), AND urinary toxicology positive for buprenorphine.
Exclusion criteria
* Participants who are non-English speaking. * Psychiatric conditions under DSM-5 (examined with the MINI) that would make study participation unsafe, or which would prevent adherence to study procedure; examples include: suicidal (i.e. high risk for suicide on the Columbia suicide severity rating scale (C-SSRS) screen version) or homicidal ideation requiring immediate attention, inadequately-treated mental health disorder (e.g., active psychosis, uncontrolled bipolar disorder). * Current diagnosis of a severe substance use disorder (except for opioid and nicotine/tobacco) in the past 3 months, based on the MINI interview, that would preclude safe participation in the study as determined by the study medical clinician. * Signs of acute drug intoxication when arriving at the study site as determined by clinician assessment. * Medical or psychiatric contraindications for CBD administration (e.g., history of hypersensitivity to cannabinoids); or any of the ingredients in the product (gelatin or sesame oil). * Showing signs of acute opioid withdrawal symptoms (as determined by the result of the Clinical Opiate Withdrawal Scale (COWS). A Score of ≥ 5 or as interpreted by the investigator will be considered a positive result for withdrawal symptoms). * Have a medical condition that would make study participation unsafe, which would make treatment compliance difficult, or would prevent adherence to study procedure. This includes but is not limited to the following criteria: • \< 30mL/min/1.73m2 eGFR. •QTc Fridericia \> 500ms at screening. •Elevated liver enzymes at screening. The exclusionary lab values are: \>4x the upper limit of normal (ULN) per laboratory criteria for AST or ALT or \>1.5x ULN for bilirubin. * Participating in another pharmacotherapeutic trial in the past 3 months. * Participants who have used (within 14 days prior to consent) or plan to use (during the 24-week treatment period) any medications, dietary supplements (and/or grapefruit juice), or combination of medications and supplements known to alter the metabolism of, or interact with CBD (buproprion, rifampin, barbiturates, phenothiazines, cimetidine, anticoagulants, antiplatelets, etc.). * For women: being pregnant (positive urine test for pregnancy) or breastfeeding. * Not using an appropriate method of contraception such as hormonal contraception (oral hormonal contraceptives, Depo-Provera, Nuva-Ring), intrauterine device (IUD), sterilization, or double barrier method (combination of any two barrier methods used simultaneously, i.e. condom, spermicide, diaphragm). * Participants who have been court mandated to attend treatment centers
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of study participants with negative urine toxicology for illicit opioid use | 24 weeks | Percentage of study participants with negative urine toxicology for illicit opioid use over the course of 24 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Weeks of abstinence | Duration of the trial, 24 weeks | Weeks of abstinence of illicit opioid use |
| Use of non-opioid illicit substances | Duration of the trial, 24 weeks | Number of weeks using other non-opioid illicit substances |
| Duration of first opioid abstinence | Duration of the trial, 24 weeks | Duration of first opioid abstinence, defined as the number of weeks from randomization to first opioid test positive or urine test missed. |
| Cue-induced Visual Analog Scale for craving (VASC) | At 12 and 24-week time points | Cue-induced Visual Analog Scale for craving (VASC) Cue-induced Visual Analog Scale for craving is used to measure subjective craving responses to a drug and neutral video cues evaluated in the clinic. Total scale ranges from 0-10, with higher scores indicating extreme cravings. |
| Cue-induced Visual Analog Scale for anxiety (VASA) | At 12 and 24-week time points | Cue-induced Visual Analog Scale for anxiety (VASA) Cue-induced Visual Analog Scale Anxiety is used to measure subjective anxiety responses to a drug and neutral video cue evaluated in the clinic. Total scale from 0-10, with higher score indicating extreme anxiety. |
| Change in illicit opioids in plasma toxicology | 24 weeks | Change in illicit opioids in plasma toxicology |
| Change in illicit opioids in urine toxicology | 24 weeks | Change in illicit opioids in urine toxicology |
| Concentration of illicit opioids | Duration of the trial, 24 weeks | Concentration of illicit opioids in quantitative plasma toxicology (plasma every four weeks) |
| Opioid Craving Questionnaire (OCQ) | Every 4 weeks up to 24 weeks | General craving self-report using Opioid Craving Questionnaire (OCQ) Total scale from 0-9, with higher score indicating more severe craving |
| Generalized Anxiety Disorder Scale (GAD7) | Every 4 weeks up to 24 weeks | General anxiety self-report using the Generalized Anxiety Disorder Scale (GAD7). The General Anxiety Disorder 7-item questionnaire (GAD-7) is a 7-item questionnaire that asks user to rank how often they have been bothered by seven problems over the past two weeks from 0 (not at all) to 3 (nearly every day). The items that users are asked to rank levels of nervousness, anxiousness, relaxing, restlessness, irritability and fearfulness. Full scale from 0-21, with higher score indicating more symptoms. |
| Substance use other than opioids | Duration of the trial, 24 weeks | Proportion of substance use other than opioids |
| Methadone plasma concentrations | Duration of the trial, 24 weeks | Methadone plasma concentrations |
| Buprenorphine and metabolite plasma concentrations | Duration of the trial, 24 weeks | Buprenorphine and metabolite plasma concentrations |
| Retention in opioid agonist therapy | Duration of the trial, 24 weeks | Proportion of participants who remained in treatment with opioid agonist therapy |
| Study Retention | 24 weeks | Number of participants remaining in the study |
Countries
United States
Contacts
Primary ContactZoe Spieler
Backup ContactJonathan Hupf
Outcome results
None listed