Early Phase in the Development of Cannabidiol as a Treatment for Addiction: Opioid Relapse Takes Initial Center Stage

 

The Endocannabinoid System As A Treatment Target For Addiction

Among potential emerging neurobiological targets for treating craving and addiction, the endogenous cannabinoid receptors and ligands that constitute the endocannabinoid (eCB) system have been the subject of growing interest. The eCB has tight neurobiological interaction with other neurotransmission systems that have important implications for the neural adaptations induced by drug use. For example, type 1 cannabinoid receptors (CB1R) are co-localized with opioid μ opioid receptors (which mediate the actions of opioid drugs) in striatal output projection neurons of the nucleus accumbens and dorsal striatum that modulate reward, goal-directed behavior, and habit formation relevant to addiction []. Type 2 cannabinoid receptors (CB2R) have very low expression in the brain generally, but recently they have been shown to be expressed in dopamine neurons of the midbrain ventral tegmental area and modulate the functional excitability of dopamine neurons central to addiction related behaviors such as drug reinforcement []. Stimulation of CB2R in mice models has an inhibitory influence on cocaine and alcohol self-administration and related conditioned place preference, as well as nicotine place preference behavior [].

 

CBD And Human Translational Studies

Human studies regarding CBD’s potential impact on the abuse of other drugs are even more limited than preclinical animal investigations. Thus far, there has only been 1 report with cigarette-dependent participants, and CBD was observed to reduce the number of cigarettes consumed by active users[]. The same investigative team has also evaluated CBD in relation to cannabis abuse. In naturalistic studies conducted with cannabis users, the concentration of CBD in smoked cannabis did not attenuate psychomimetic symptoms in participants when they were acutely intoxicated []; however, CBD reduced “wanting” and “liking” of cannabis-related stimuli []. Additionally, a case report in 1 patient indicated that CBD might reduce withdrawal symptoms and the amount of cannabis smoked upon resumption of cannabis use, but no systematic study has been conducted in relation to CBD and cannabis relapse behavior.

Based on the animal data supporting the effect of CBD on opioid-seeking behavior, we initiated pilot human clinical laboratory studies to begin to explore the potential of this cannabinoid as a medication for opioid craving. A critical first step was to document that CBD, if combined with a potent opioid, would be safe as there was always the chance for a lapse in abstinent heroin abusers. Our double-blind, placebo-controlled cross-over phase I study in healthy subjects demonstrated that CBD (400 mg and 800 mg; approximately 10–15 mg/kg) co-administered with intravenous fentanyl is well tolerated and does not exacerbate adverse effects associated with intravenous fentanyl administration such as respiratory depression or cardiovascular complications []. Measurements of CBD plasma levels showed the time to peak CBD concentration occurred at 3 h (Cmax 181.2 ± 39.8 μg/l and 221.1 ± 35.6 μg/l, respectively, for the 400-and 800-mg doses; Fig. 5). Exploratory analysis of subjective measures scales [Positive and Negative Affect Schedule and Opioid Visual Analog Scale], as well as anxiety visual analog scale (VAS) scores suggested that CBD at the doses examined did not significantly alter their affective states, which was consistent with other reports [].

Time course of plasma concentrations of 400 mg and 800 mg cannabidiol and placebo in combination with a potent opioid fentanyl in healthy individuals. Modified from Manini et al. [

The effect of cannabidiol (CBD) on craving and anxiety in abstinent heroin-dependent subjects. (a) Cue-induced craving (visual analog scale; VAS) induced by heroin video cue was blunted by a single administration of CBD (400 mg or 800 mg 

An investigation with a larger number of participants is currently being conducted, but it is clear more studies are necessary to confirm these preliminary findings, as well as to evaluate different treatment schedules in order to fully evaluate the spectrum of CBD’s effects. Nevertheless, the current human data are consistent with results from the rat models, suggesting that CBD attenuates cue-induced and general craving in opioid-dependent individuals and that the effects are protracted even after the acute exposure to the cannabinoid []. Overall, the pilot human and preclinical animal laboratory studies provide a foundation for continued exploration of CBD in treating opioid dependence.

 


Cannabidiol as an Intervention for Addictive Behaviors: A Systematic Review of the Evidence

 

Effects Of CBD On Cannabis-Related Addictive Behaviors

Outcomes of CBD on all three phases of cannabis addiction were found. Crippa et al investigated the effects of CBD on cannabis addiction and its withdrawal syndrome. They conducted an experimental trial on a 19-year-old female with cannabis dependence, who experienced withdrawal syndrome when she tried to cease cannabis use. CBD was administered for 11 days (300 mg on day 1, 600 mg on days 2–10, and 300 mg on day 11). Daily assessments using the Withdrawal Discomfort Score, Marijuana Withdrawal Symptom Checklist, Beck Anxiety Inventory, and Beck Depression Inventory showed a rapid decrease in withdrawal symptoms, leading to a score of zero in all tests by day 6. A 6-month follow-up showed a relapse in cannabis use, but at a lower frequency (one or twice a week vs. 7 days a week). In a naturalistic crossover clinical study, Morgan et al evaluated the impact of varying levels of CBD and THC on the acute effects of cannabis intoxication. They studied 134 cannabis users on two different days, approximately 1 week apart: once sober and once intoxicated with their own chosen cannabis. Samples of the drug were analyzed and two groups were formed based on levels of CBD, low (<0.14%) versus high (>0.75%), each containing 22 participants. They found no difference in either group in their rating of feeling “stoned”. Morgan et al conducted another study and evaluated the impact of CBD on the reinforcing effects of THC on addictive behavior. They studied the implicit “wanting” and the explicit “liking” of cannabis on 94 cannabis users, by attentional bias to drug and food stimuli, pleasantness ratings, a marijuana-craving questionnaire, and a visual analog scale in a crossover design similar to that described above (drug-free day and intoxicated day with their own cannabis, two groups of 32 participants based on low or high CBD:THC ratios). Greater attentional bias to drug and food stimuli was found in the low CBD:THC ratio group on the short picture presentation interval of the dot-probe task on the intoxicated day (implicit “wanting”). However, a greater attentional bias to both stimuli was found in both groups on the longer picture presentation interval on the intoxicated day and on both short and long picture presentation intervals on the drug-free day. Moreover, a high CBD:THC ratio was associated with lower ratings of pleasantness for drug stimuli (explicit “liking”), while no group difference in craving or stoned ratings was noted.

Overall, preliminary data suggest a possible beneficial impact of CBD on the reinforcing effect of cannabis, while a case report has shown positive outcomes for one patient treated with CBD during the withdrawal and relapse phase of cannabis dependence.

 

Effects Of CBD On Tobacco-Related Addictive Behaviors

Only one study looked at the impact of CBD on tobacco addiction. Morgan et al studied the impact of CBD on nicotine addiction by conducting a randomized, double-blind, placebo-controlled study on 24 smokers who wished to stop smoking. Two groups received either a CBD inhaler (400 μg/inhalation) or a placebo inhaler. They were told to use the inhaler whenever they felt the urge to smoke, to assess daily cigarette and inhaler use, and to monitor their craving once daily for 1 week. Cravings were measured at baseline and at the end of the week. A 2-week follow-up was organized to assess cigarette use. The results showed a significant reduction in the number of cigarettes smoked (≈40%) in the CBD inhaler group during the week of treatment, with a trend indicating a reduction after follow-up. Both groups also showed a reduction in cravings between day 1 and day 7, though not between day 1 and follow-up.

 

Effects Of CBD On Alcohol-Addictive Behaviors

Only the impact of CBD on the intoxication phase of alcohol addiction was extracted from the review of literature. Consroe et al assessed the effects of CBD on acute consumption of alcohol in 10 healthy volunteers in a randomized, double-blind, crossover study, by testing subjective responding after administration of alcohol (1 g/kg) and CBD (200 mg) alone or in combination. They found that there was no difference in feelings of being “drunk”, “drugged”, or “bad” in alcohol-alone and alcohol plus CBD groups.

 

Conclusions

CBD is an exogenous cannabinoid that acts on several neurotransmission systems involved in addiction. Animal studies have shown the possible effects of CBD on opioid and psychostimulant addiction, while human studies presented some preliminary evidence of a beneficial impact of CBD on cannabis and tobacco dependence. CBD has several therapeutic properties on its own that could indirectly be useful in the treatment of addiction disorders, such as its protective effect on stress vulnerability and neurotoxicity. Overall, emerging data remain very limited and are far from being conclusive; well-designed, randomized, controlled trials are necessary at this point to determine whether these properties translate into significant improvements on clinical outcomes in human populations. The importance of this area of research is emphasized by an increasing number of studies that are currently being conducted in the United States (source: www.clinicaltrials.gov) regarding the effects of CBD on cannabis and opioid addiction and there is one ongoing Canadian study on cocaine addiction (source: www.cihr-irsc. gc.ca). The dreadful burden of substance-use disorder worldwide, combined with the clear need for new medication in the addiction field, justifies the requirement of further studies to evaluate the potential of CBD as a new intervention for addictive behaviors.