Acute and Short-term Effects of Cannabidiol Admin 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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Opioid abuse is a significant global public health problem. 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. It is the goal of this second exploratory phase of the project to 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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Cannabidiol as Treatment Intervention for Opioid Relapse

Conditions
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Opiate Addiction

Intervention / Treatment
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* Drug: Cannabidiol 400
* Drug: Cannabidiol 800
* Drug: Control


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 DSM-IV(SCID-IV) 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-IV 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-IV (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 pills that resemble the Cannabidiol capsule but do not have have its properties. | Drug: Control<br>* Subjects will receive a harmless, inactive pill to compare and validate the results of the other arms of the study<br>* Other names: CBD;|
| Experimental: Cannabidiol 400<br>Subjects in Arm Cannabidiol 400 will receive 400 mg of cannabidiol | Drug: Cannabidiol 400<br>* Subjects in Arm CBD 400 will receive 400mg of Cannabidiol in each of the three test sessions<br>* Other names: CBD;|
| Experimental: Cannabidiol 800<br>Subjects in Arm Cannabidiol 800 will receive 800mg of cannabidiol | Drug: Cannabidiol 800<br>* Subjects in Arm CBD 800 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 or Post-neutral - 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 and neutral cue sessions in the clinic will be measured. In this way, changes in craving from baseline (pre-cue to post-cue and pre-neutral cue to post-neutral cue) within each test visit) will be measured and compared. Scale range: 0 (no craving) - 10 (extreme craving). **For test visits I, II and IV, there will be two cue sessions at each test visit: a neutral cue video (PN) and a drug-related cue video (PC) will be shown in random order at each visit. Before the beginning of each cue session (PN or PC), baseline measures will be taken. The same questionnaires will be administered immediately following the neutral cue video and the drug-related cue video. Thus there will be two sets of baselines and two sets of post cue measurements per test visit for test | VASC: test visits I, II and IV - baseline 1, post cue (PC), baseline 2, post neutral cue (PN) | 
| Changes in Out-of-Clinic Craving (From Pre-Dose to Approximately 6 Hours Post-Dose for Test Visits I and II; and From Pre-Dose Test Visit I to Pre-Cue Test Visit IV) - 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 visit 1 through test visit 4. Scale: 1 (strongly disagree) - 7 (strongly agree). Total Score Range: 14 (less cravings) - 98 (more cravings). ** The baseline measure for this outcome will be measured at the beginning of test session I prior to the administration of CBD/Placebo. Test measures will be taken approximately 6 hours following each dose for test sessions I, II and III. The final measure will be taken at test session IV, at the beginning of the session. | Test I and II: Change from pre-dose to approx. 6 hours post-dose; Change from pre-dose test visit I to pre-cue test visit IV | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vital Signs - Blood Pressure | Blood pressure (mmHg) will be monitored throughout the time course of the study and changes from baseline will be studied across the various time points. **For test visits I, II and IV, there will be two cue sessions at each test visit: a neutral cue video (PN) and a drug-related cue video (PC) will be shown in random order at each visit. Before the beginning of each cue session (PN or PC), baseline measures will be taken. Blood pressure will be measured again following the neutral cue video and the drug-related cue video. Thus there will be two sets of baselines and two sets of post cue measurements per test visit for test visits I, II and IV. | Test sessions 1,2,and 4: baseline 1, post cue (PC), baseline 2, post neutral cue (PN) | 
| Visual Analog Scale for Anxiety (VASA) | Questionnaires will be used to measure subjective responses. Anxiety will be assessed using a visual analog scale for anxiety (VASA). Scale: 0 (not at all anxious) - 10 (extremely anxious). **For test visits I, II and IV, there will be two cue sessions at each test visit: a neutral cue video (PN) and a drug-related cue video (PC) will be shown in random order at each visit. Before the beginning of each cue session (PN or PC), baseline measures will be taken for each variable. The same variables will be measured following the neutral cue video and the drug-related cue video. Thus there will be two sets of baselines and two sets of post cue measurements per test visit for test visits I, II and IV. | Test visit I, II and IV: baseline 1, post cue (PC), baseline 2, post neutral cue (PN) | 
| The Positive and Negative Affect Schedule (PANAS) - Positive Affect Schedule (PAS) Data | Questionnaires will be used to measure subjective responses. The Positive and Negative Affect Schedule will allow us to obtain positive and negative affect measures and observe their changes from baseline over the course of the cue-induced craving session. Scale: 0 (only slightly or not at all) - 5 (extremely). Total Score Range for Positive Affect Assessment (PAS): 10 (minimum) - 50 (maximum). Higher score reflects stronger positive affect. **For test visits I, II and IV, there will be two cue sessions at each test visit: a neutral cue video (PN) and a drug-related cue video (PC) will be shown in random order at each visit. Before the beginning of each cue session (PN or PC), baseline measures will be taken for each variable. The same variables will be measured following the neutral cue video and the drug-related cue video. Thus there will be two sets of baselines and two sets of post cue measurements per test visit for test visits I, II and IV. | Test session 1, 2, and 4: baseline 1, post cue (PC), baseline 2, post neutral cue (PN) | 
| The Positive and Negative Affect Schedule (PANAS) - Negative Affect Schedule (NAS) Data | Questionnaires will be used to measure subjective responses. The Positive and Negative Affect Schedule will allow us to obtain positive and negative affect measures and observe their changes from baseline over the course of the cue-induced craving session. Scale: 0 (only slightly or not at all) - 5 (extremely). Total Score Range for Negative Affect Assessment (NAS): 10 (minimum) - 50 (maximum). Higher score reflects stronger negative affect. **For test visits I, II and IV, there will be two cue sessions at each test visit: a neutral cue video (PN) and a drug-related cue video (PC) will be shown in random order at each visit. Before the beginning of each cue session (PN or PC), baseline measures will be taken for each variable. The same variables will be measured following the neutral cue video and the drug-related cue video. Thus there will be two sets of baselines and two sets of post cue measurements per test visit for test visits I, II and IV. | Test session 1, 2, and 4: baseline 1, post cue (PC), baseline 2, post neutral cue (PN) | 
| Vital Signs - Heart Rate | Heart rate (in beats/min) will be monitored throughout the time course of the study and changes from baseline will be studied across the various time points. **For test visits I, II and IV, there will be two cue sessions at each test visit: a neutral cue video (PN) and a drug-related cue video (PC) will be shown in random order at each visit. Before the beginning of each cue session (PN or PC), baseline measures will be taken. Heart rate will be measured again following the neutral cue video and the drug-related cue video. Thus there will be two sets of baselines and two sets of post cue measurements per test visit for test visits I, II and IV. | Test sessions 1,2,and 4: baseline 1, post cue (PC), baseline 2, post neutral cue (PN) | 
| Vital Signs - Respiratory Rate | Respiratory rate (in breaths/min) will be monitored throughout the time course of the study and changes from baseline will be studied across the various time points. **For test visits I, II and IV, there will be two cue sessions at each test visit: a neutral cue video (PN) and a drug-related cue video (PC) will be shown in random order at each visit. Before the beginning of each cue session (PN or PC), baseline measures will be taken. Respiratory rate will be measured again following the neutral cue video and the drug-related cue video. Thus there will be two sets of baselines and two sets of post cue measurements per test visit for test visits I, II and IV. | Test sessions 1,2,and 4: baseline 1, post cue (PC), baseline 2, post neutral cue (PN) | 
| Vital Signs - Temperature | Temperature (in degrees Fahrenheit) will be monitored throughout the time course of the study and changes from baseline will be studied across the various time points. **For test visits I, II and IV, there will be two cue sessions at each test visit: a neutral cue video (PN) and a drug-related cue video (PC) will be shown in random order at each visit. Before the beginning of each cue session (PN or PC), baseline measures will be taken. Temperature will be measured again following the neutral cue video and the drug-related cue video. Thus there will be two sets of baselines and two sets of post cue measurements per test visit for test visits I, II and IV. | Test sessions 1,2,and 4: baseline 1, post cue (PC), baseline 2, post neutral cue (PN) |