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

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

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.

Study Overview

• Status: Completed
• Conditions: Opiate Addiction
• Intervention / Treatment: Drug: Control (placebo); Drug: CBD 400 mg; Drug: CBD 800 mg

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10003
      • Mount Sinai Beth Israel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Control; Subjects will receive a solution that resemble the Cannabidiol solution but do not have have its properties	Drug: Control (placebo); Subjects will receive a harmless, inactive solution to compare and validate the results of the other arms of the study; Other Names: CBD
EXPERIMENTAL: CBD 400mg; Subjects will receive 400mg of cannabidiol	Drug: CBD 400 mg; Subjects in Arm CBD 400 mg will receive 400mg of Cannabidiol in each of the three test sessions; Other Names: CBD
EXPERIMENTAL: CBD 800mg; Subjects will receive 800 mg of cannabidiol	Drug: CBD 800 mg; Subjects in Arm CBD 800 mg will receive 800mg of Cannabidiol in each of the three test sessions; Other Names: CBD

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
CBD Effects on Cognitive Behavior	Digit Span Backwards (DSB) is a memory task consisting of a span of digits recalled in reverse order. Participants are read a series of digits (e.g., 4,7,1) and must immediately repeat them back in reverse order (e.g., 1,7,4). Mean correct response times (hits) are reported below in milliseconds. Shorter response times indicate better participant outcomes. Digit Symbol Substitution Task (DSST) is a neuropsychological test consisting of digit-symbol pairs.The goal is to complete as many correct patterns as possible in 3 mins. Mean response times reported below in ms, with shorter times indicating better outcomes.	2 times: once at pre-screening and once at test day 4, within 2 weeks of each other.
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). VASA scale ranges from 0 for "Not Anxious at All" to 10 for "Extremely Anxious." Note, cue sessions occur consecutively in the same test day.	Test day I, II and IV: on arrival, baseline for cue sessions 1 and 2, post-cue sessions I and 2 (30 min from baseline), prior to discharge (approximately 2.5 hours from test day start on average); Test day III: on arrival and prior to discharge.
The Positive and Negative Affect Schedule(PANAS)	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. Note, cue sessions occur consecutively in the same test day. Positive affect scores range from 10 - 50. Higher scores represent higher levels of positive affect. Negative affect scores range from 10 - 50. Higher scores represent high levels of negative affect.	Baseline for cue sessions 1 and 2, post-cue sessions I and 2 (30 min from baseline) during test days I, II and IV.
Physiological Response to Stress - Salivary Cortisol Measures	Subjects will be asked to chew on a cotton swab, each time providing us with a saliva sample from which we can detect free cortisol levels and extrapolate serum levels of the stress indicator affected by the video cues. Note, cue sessions occur consecutively in the same test day. Thus, the physiological stress of craving will be monitored and measured across the multiple time points to observe any changes from baseline. Results reported below are mean percent change from baseline following exposure to neutral and heroin-associated cues in Session 1 in subjects with CBD or placebo administration.	Test day I: 15 min and 35 min post drug and neutral cue
Adverse Effects - SAFTEE	Before being sent home, subjects will be asked to complete the Systematic Assessment for Treatment of Emergent Events (SAFTEE) to ensure that they are not experiencing any negative effects of the treatment. There will also be a debriefing period at the end of each session aimed to minimize any potential increase in craving beyond the clinical laboratory session. At the end of the last study, subjects will be assessed and offered appropriate resources and guidance for seeking help for substance abuse or cravings should they need it after participation in the study has concluded.	Test day I, II, III and IV: at the end of day prior to discharge. Average time point: approximately 150 minutes into the test day.
CBD Effects on Cognitive Behavior	Continuous Performance Test is a computerized assessment of attention. The outcome measures include correct responses (hits), missed responses (misses), incorrect responses (false hits), correct misses, and reaction time of both hits and misses. Mean correct response times (hits) are reported below. Shorter response times indicate better participant outcomes.	2 times: once at pre-screening and once at test day 4, within 2 weeks of each other.

Collaborators and Investigators

• Sponsor: Hurd,Yasmin, Ph.D.
• Collaborators: Jazz Pharmaceuticals
• Investigators: Principal Investigator: Yasmin Hurd, PhD, Mount Sinai Health System

Publications and helpful links

General Publications

• Hurd YL, Spriggs S, Alishayev J, Winkel G, Gurgov K, Kudrich C, Oprescu AM, Salsitz E. Cannabidiol for the Reduction of Cue-Induced Craving and Anxiety in Drug-Abstinent Individuals With Heroin Use Disorder: A Double-Blind Randomized Placebo-Controlled Trial. Am J Psychiatry. 2019 Nov 1;176(11):911-922. doi: 10.1176/appi.ajp.2019.18101191. Epub 2019 May 21. Erratum In: Am J Psychiatry. 2020 Jul 1;177(7):641.

Study record dates

Study Major Dates

• Study Start: September 1, 2015
• Primary Completion (ACTUAL): May 24, 2017
• Study Completion (ACTUAL): May 24, 2017

Study Registration Dates

• First Submitted: August 25, 2015
• First Submitted That Met QC Criteria: September 2, 2015
• First Posted (ESTIMATE): September 3, 2015

Study Record Updates

• Last Update Posted (ACTUAL): September 1, 2022
• Last Update Submitted That Met QC Criteria: August 11, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Narcotic-Related Disorders; Opioid-Related Disorders
• Other Study ID Numbers: MSBI HSM# 087-14