Study to Test the Safety and Efficacy of Cannabidiol as a Treatment Intervention for Opioid Relapse

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 over million opiate-dependent subjects today, only less than a quarter of such individuals receive treatment. Pharmacotherapeutic approaches traditionally have targeted 5 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 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 exploratory phase of the project to (1) determine the safety and basic pharmacokinetic characteristics of CBD when administered concomitantly with opiate in humans and (2) characterize the acute (24 hr) and short-term (3 days) effects of CBD administration on cue-induced craving in drug-abstinent heroin-dependent subjects using a random double blind design. This exploratory investigation together with ongoing complementary preclinical rodent studies has the potential to significantly impact the development of a novel agent for drug relapse prevention that is critical for ending the continued cycle of substance abuse. PUBLIC HEALTH RELEVANCE: 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.

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
* Drug: Fentanyl


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: being aged between 21 and 65 years old. having exposure at least once to an opioid (i.e. codeine, morphine, Fentanyl) in the past Exclusion Criteria: using any psychoactive drug or medication at any time during the study, or 24 hours before the test session having a past or current diagnosis of drug abuse or dependence (except for nicotine), based on the SCID-IV interview (Structured Clinical Interview for DSM-IV) being maintained on methadone or buprenorphine, or taking opioid antagonist such as naltrexone having taken any opioid in the last 14 days having medical conditions, including Axis I psychiatric conditions under DSM-IV (examined with the MINI International Neuropsychiatric Interview-MINI), history of cardiac disease, arrhythmias, head trauma, and seizures having a history of hypersensitivity to any opioid or cannabinoid being pregnant 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. spermicide, diaphragm) 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 for cocaine, cannabis, opiates, benzodiazepines, barbiturates, phencyclidine and amphetamines being actively treated and currently involved in an addiction treatment program being an anesthesiologist or a pharmacist

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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Accepts Healthy Volunteers

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: Placebo<br>Subjects will receive placebo | Drug: Fentanyl<br>* All subjects will receive 0.5 mcg/kg and 1mcg/kg of Fentanyl (test session 1 and test session 2)<br>* Other names: Fentanyl Citrate;|
| Experimental: CBD 400 mg<br>Subjects will receive 400 mg CBD | Drug: Cannabidiol<br>* Subjects in Arm CBD 400 mg will receive 400 mg of Cannabidiol in two test sessions along with 0.5 mcg/kg and 1mcg/kg of fentanyl. Subjects in Arm CBD 800 mg will receive 800 mg of Cannabidiol in two test sessions along with 0.5 mcg/kg and 1mcg/kg of fentanyl.<br>Drug: Fentanyl<br>* All subjects will receive 0.5 mcg/kg and 1mcg/kg of Fentanyl (test session 1 and test session 2)<br>* Other names: Fentanyl Citrate;|
| Experimental: CBD 800mg<br>Subjects will receive 800 mg CBD | Drug: Cannabidiol<br>* Subjects in Arm CBD 400 mg will receive 400 mg of Cannabidiol in two test sessions along with 0.5 mcg/kg and 1mcg/kg of fentanyl. Subjects in Arm CBD 800 mg will receive 800 mg of Cannabidiol in two test sessions along with 0.5 mcg/kg and 1mcg/kg of fentanyl.<br>Drug: Fentanyl<br>* All subjects will receive 0.5 mcg/kg and 1mcg/kg of Fentanyl (test session 1 and test session 2)<br>* Other names: Fentanyl Citrate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the safety of cannabidiol oral administration prior to fentanyl IV administration. | We will assess safety and adverse effects with the Systematic Assessment for Treatment Emergent Events (SAFTEE). Excessive sedation (GCS<10), cardiac dysrhythmia (on telematry monitor), hypotension (blood pressure < 90/60 mmHg), bradycardia (heart rate 50/minute),severe anxiety, or seizures (partial or generalized tonic-clonic) after the administration of either Fentanyl or Cannabidiol would result in discontinuation of the study for the subject and immediate medical attention. | 9 timepoints: -10 min, 30, 60, 90, 120, 180, 240, 360, 480 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| General cannabidiol pharmacokinetics | Blood will be taken at specified times to determine cannabidiol peak plasma concentration (Cmax), time to reach peak serum concentration (tmax) and serum elimination half-life (t1/2). | 9 timepoints: -10 min, 30, 60, 90, 120, 180, 240, 360, 480 | 
| Cortisol levels | Variation in plasma levels of cortisol will be measured at various time points. | -10 min, 30, 60, 90, 120, 180, 240, 360, 480 | 
| Cannabidiol clearance | Urine will be taken at specified times to estimate cannabidiol concentration in order to assess clearance and excretion functions. | 5 timepoints: -60 min, 45, 120, 240, 480 | 
| Vital signs-BP | Blood pressure (mmHg) will be monitored and change from baseline will be studied across the multiple time points. | -10, 30, 60, 75, 90, 120, 180, 240, 360, 480 min | 
| Vital signs-HR | Heart rate (beats/minute) will be monitored and change from baseline will be studied across the multiple time points. | -10, 30, 60, 75, 90, 120, 180, 240, 360, 480 min | 
| Vital signs - RR | respiratory rate (respirations/minute) will be monitored and change from baseline will be studied across the multiple time points. | -10, 30, 60, 75, 90, 120, 180, 240, 360, 480 min | 
| Vital signs - O2 | % oxygen saturation will be monitored and change from baseline will be studied across the multiple time points. | -10, 30, 60, 75, 90, 120, 180, 240, 360, 480 min | 
| Vital signs - temp | body temperature (degrees Fahrenheit) will be monitored and change from baseline will be studied across the multiple time points. | -10, 30, 60, 75, 90, 120, 180, 240, 360, 480 min | 
| Vital signs - EKG | EKG will be monitored and change from baseline will be studied across the multiple time points. | -10, 30, 60, 75, 90, 120, 180, 240, 360, 480 min | 
| Subjective measures-VAS | Questionnaires will be used to measure subjective responses. Anxiety will be assessed using a visual analog scale (VAS). | -1, 30, 65, 90, 120, 240, 360, 480 min. | 
| Subjective measures-PANAS | Questionnaires will be used to measure subjective responses. The PANAS (Positive and Negative Affect Schedule) will allow obtaining positive and negative affect measures. | -1, 30, 65, 90, 120, 240, 360, 480 min. | 
| Subjective measures-Opiate effect | Questionnaires will be used to measure subjective responses. Global Intoxication and Withdrawal Rating will be administered to assess potential variations in the subjective effects associated to fentanyl. | -1, 30, 65, 90, 120, 240, 360, 480 min. | 
| Subjective measures- OVAS | Questionnaires will be used to measure subjective responses. Opiate Visual Analog Scales (OVAS) will be administered to assess potential variations in the subjective effects associated to fentanyl. | -1, 30, 65, 90, 120, 240, 360, 480 min. |