Acute and Short-term Effects of CBD on Cue-induced Craving in Drug-abstinent Heroin-dependent Humans

Study Overview
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Brief Summary
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Despite the current available therapies for opioid-dependent patients, most patients relapse. This research project focuses on the development of a novel compound, cannabidiol, to modulate opioid craving in humans based on animal models showing its selective effectiveness to inhibit drug-seeking behavior. The development of a targeted treatment for opioid relapse would be of tremendous medical and public health value.

Detailed Description
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There has been an epidemic rise in heroin abuse and overdose in recent years. Of the more than one million people suffering today from opiate dependency, less than a quarter of such individuals receive treatment. Pharmacotherapeutic approaches traditionally have targeted mu opioid receptors since heroin and its metabolites bind with highest affinity to this receptor subtype. Although such treatment strategies have improved substance abuse outcomes, they do not effectively block opiate craving and thus are still associated with high rates of relapse. Using a strategy of indirectly regulating neural systems to modulate opioid-related behavior, our preclinical rodent studies consistently demonstrated that cannabidiol (CBD), a nonpsychoactive component of cannabis, specifically inhibited cue-induced heroin-seeking behavior. CBD's selective effect on drug-seeking behavior was pronounced after 24 hrs and endured even two weeks after the last drug administration following short-term CBD exposure. The fact that drug craving is generally triggered by exposure to conditioned cues suggests that CBD might be an effective treatment for heroin craving, specially given its protracted impact on behavior. CBD has already been shown in Phase I of our study and in various clinical studies to be well tolerated with a wide safety margin in human subjects. CBD thus represents a strong candidate for the development as a potential therapeutic agent in humans for opioid craving and relapse prevention. Preliminary pilot study showed CBD decreased craving. It is the goal of the current study to more fully characterize the effects of CBD administration on cue-induced craving in drug-abstinent heroin-dependent subjects using a random double blind design during a post-acute (greater than 6 days since last use) heroin withdrawal period. Study participants will be administered CBD during 3 test sessions and studied for the effects on cue-induced craving during those sessions as well as one week after the final CBD administration on the final test day (session 4).

Official Title
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To Characterize the Acute and Short-term Effects of Cannabidiol (CBD) Administration on Cue-induced Craving in Drug-abstinent Heroin-dependent Humans

Conditions
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Opiate Addiction

Intervention / Treatment
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* Drug: CBD 400 mg
* Drug: CBD 800 mg
* Drug: Control (placebo)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be between 21 and 65 years old Must have an opiate dependence that meets criteria set in the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (DSM-V) Structured Clinical Interview for DSM (SCID-V) over the last three months No opioid use in the past 7 days (will be verified via urine drug screen and opiate metabolite test) Exclusion Criteria: Using any psychoactive drug (other than nicotine) any time up to test session 3 Having a diagnosis of drug dependence (except for heroin or nicotine) in the past 3 months, based on the SCID-V interview criteria Being maintained on methadone or buprenorphine, or taking opioid antagonists such as naltrexone Having a positive a drug screen Showing signs of acute heroin withdrawal symptoms Having medical conditions, including Axis I psychiatric conditions under DSM-V (examined using the Mini International Neuropsychiatric Interview [MINI]) Having a a history of cardiac disease, arrhythmias, head trauma, and seizures Having a history of hypersensitivity to cannabinoids Arriving to the study site visibly intoxicated as determined by a clinical evaluation for signs and symptoms of intoxication and as verified by a drug screen Participating in a another pharmacotherapeutic trial in the past 3 months Being pregnant of breastfeeding Not using or irregularly using appropriate methods of contraception such as hormonal contraceptives (e.g., Depo-Provera, Nuva-Ring), an intrauterine device (IUD), or double barrier method (combination of any two barrier methods used simultaneously, e.g., condoms, spermicide, diaphragms)

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control<br>Subjects will receive a solution that resemble the Cannabidiol solution but do not have have its properties | Drug: Control (placebo)<br>* Subjects will receive a harmless, inactive solution to compare and validate the results of the other arms of the study<br>* Other names: CBD;|
| Experimental: CBD 400mg<br>Subjects will receive 400mg of cannabidiol | Drug: CBD 400 mg<br>* Subjects in Arm CBD 400 mg will receive 400mg of Cannabidiol in each of the three test sessions<br>* Other names: CBD;|
| Experimental: CBD 800mg<br>Subjects will receive 800 mg of cannabidiol | Drug: CBD 800 mg<br>* Subjects in Arm CBD 800 mg will receive 800mg of Cannabidiol in each of the three test sessions<br>* Other names: CBD;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Cue-Induced In-Clinic Craving (From Baseline to Post-cue (30 Minutes), and From Test Day 1 Through Test Day 4 (1 Week)) - Via the Visual Analog Scale for Craving (VASC) | The VASC will be administered to assess potential variations in the subjective craving effects associated with heroin. Following the administration of the investigational drug, craving induced in response to the cue sessions in the clinic will be measured. Note, cue sessions occur consecutively in the same test day. In this way, changes in craving from baseline (pre-cue to post-cue within each test day), as well as changes in cue-induced craving over the short-term (test day 1 through test day 4 a week later) will be monitored and measured. VASC scale ranges from 0 for Not Craving at All to 10 for Extremely Craving. | VASC: test day I, II and IV - at arrival, baseline for cue 1 and 2, post-cue 1 and 2, before discharge (approximately 2.5 hours from session start on average); test day III: at arrival and discharge (approx. 2.5 hours from session start on average) | 
| Changes in Out-of-Clinic Craving (From Pre-dose to Approximately 4-6 Hours Post-dose; and From Test Day 1 to Test Day 4 or 1 Week) - Via the Heroin Craving Questionnaire (HCQ) | Subjects will be asked to complete the short version of the HCQ on their own time at home and bring it with them when they return for their next visit. Upon arrival to the clinic, subjects will also complete an HCQ with the coordinator to assess daily baseline cravings. This questionnaire will help us assess changes in craving generated outside of the clinical laboratory session from test day 1 through test day 4 (1 week later). Each item is scored on a scale ranging from 1 for Strongly Disagree to 7 for Strongly Agree. Sum of all 14 items are scored and added. Mean scores reported below. Total Score Range: 14 (less cravings) - 98 (more cravings). | HCQ: once in clinic pre-dose at each test day, and once at home after each test day. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vital Signs | Blood pressure (in mmHg), heart rate (in beats/min), temperature (in degrees Fahrenheit), respiratory rate (in breaths/min), and O2 saturation and pain will be monitored throughout the time course of the study and changes from baseline will be studied across the various time points. Note, cue sessions occur consecutively in the same test day. Results reported below are responses from baseline following exposure to neutral and heroin-associated cues in Session 1 in subjects with CBD or placebo administration. | Pre-placebo/drug, -60 min pre-cue, -40 min pre-cue, -20 min pre-cue, cue (time 0), 15 min post-cue, 35 min post-cue, 50 min post-cue, 65 min post-cue, 85 min post-cue |