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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.