The Endocannabinoid System and Cannabidiol's Promise for the Treatment of Substance Use Disorder

Abstract

Substance use disorder is characterized by repeated use of a substance, leading to clinically significant distress, making it a serious public health concern. The endocannabinoid system plays an important role in common neurobiological processes underlying substance use disorder, in particular by mediating the rewarding and motivational effects of substances and substance-related cues. In turn, a number of cannabinoid drugs (e.g., rimonabant, nabiximols) have been suggested for potential pharmacological treatment for substance dependence. Recently, cannabidiol (CBD), a non-psychoactive phytocannabinoid found in the cannabis plant, has also been proposed as a potentially effective treatment for the management of substance use disorder. Animal and human studies suggest that these cannabinoids have the potential to reduce craving and relapse in abstinent substance users, by impairing reconsolidation of drug-reward memory, salience of drug cues, and inhibiting the reward-facilitating effect of drugs. Such functions likely arise through the targeting of the endocannabinoid and serotonergic systems, although the exact mechanism is yet to be elucidated. This article seeks to review the role of the endocannabinoid system in substance use disorder and the proposed pharmacological action supporting cannabinoid drugs' therapeutic potential in addictions, with a focus on CBD. Subsequently, this article will evaluate the underlying evidence for CBD as a potential treatment for substance use disorder, across a range of substances including nicotine, alcohol, psychostimulants, opioids, and cannabis. While early research supports CBD's promise, further investigation and validation of CBD's efficacy, across preclinical and clinical trials will be necessary.

2-Linoleoylglycerol Is a Partial Agonist of the Human Cannabinoid Type 1 Receptor that Can Suppress 2-Arachidonolyglycerol and Anandamide Activity

“…42,43 However, pharmacological intervention is not without risk as has been demonstrated by the adverse psychiatric side effects of Rimonabant, a synthetic CB1 antagonist that was developed to treat obesity, 44,45 and the very serious adverse psychotic effects of the highly potent synthetic cannabinoid agonists colloquially termed ''Spice''. 46 It is perhaps worth noting that some of the most promising medicines targeting eCB signaling are based on using the natural cannabinoids from plants, including D9tetrahydrocannabinol and/or CBD, 47,48 or based on small molecule drugs that increase the levels of AEA 49,50 2-LG IS A PARTIAL AGONIST OF THE CB1 RECEPTOR or 2-AG. 51,52 In this context, strategies that increase 2-LG levels could have therapeutic potential as in some instances, they could introduce or maintain a moderate tone and/or mitigate against overactivation of the system.…”

Clinical uses of cannabis and cannabinoids in the United States

“…Notably, studies examining the abuse potential of CBD have not identified any evidence of tolerance or physical dependence [15]. Indeed, some have even suggested that CBD's ability to therapeutically modulate dopaminergic neurotransmission in the mesolimbic pathway supports its role as a treatment for other substance use disorders [70]. Due to these findings, a World Health Organization report recommended that CBD not be labeled as a scheduled substance [15].…”

Distinct functions of endogenous cannabinoid system in alcohol abuse disorders

“…Within the eCB system, CBD is a non‐competitive antagonist of CB 1 receptors. CBD acts through negative allosteric modulation and has a low affinity for the primary ligand site of CB 1 receptors (for a recent review, see Chye, Christensen, Solowij, & Yucel, ). The administration of CBD decreases alcohol intake, alcohol‐induced hypothermia, and handling‐induced convulsions without altering blood alcohol concentrations in C57BL/6J mice.…”