Cannabidiol as a Novel Candidate Alcohol Use Disorder Pharmacotherapy : A Systematic Review
Jasmine Turna, Sabrina K. Syan, Benicio N. Frey, Brian Rush, Mary Jean Costello, Mark Weiss, and James MacKillop
ALCOHOLISM: CLINICAL AND EXPERIMENTAL RESEARCH, 2019, 1-14
There is substantial interest in the therapeutic potential of cannabidiol (CBD), a nonpsychoactive cannabinoid found in plants of the genus Cannabis. The goal of the current systematic review was to characterize the existing literature on this topic and to evaluate the credibility of CBD as a candidate pharmacotherapy for alcohol use disorder (AUD). Using a comprehensive search strategy, 303 unique potential articles were identified and 12 ultimately met criteria for inclusion (8 using rodent models, 3 using healthy adult volunteers, and 1 using cell culture). In both rodent and cell culture models, CBD was found to exert a neuroprotective effect against adverse alcohol consequences on the hippocampus. In rodent models, CBD was found to attenuate alcohol-induced hepatotoxicity, specifically, alcoholinduced steatosis. Finally, findings from preclinical rodent models also indicate that CBD attenuates cue-elicited and stress-elicited alcohol seeking, alcohol self-administration, withdrawal-induced convulsions, and impulsive discounting of delayed rewards. In human studies, CBD was well tolerated and did not interact with the subjective effects of alcohol. Collectively, given its favorable effects on alcoholrelated harms and addiction phenotypes in preclinical models, CBD appears to have promise as a candidate AUD pharmacotherapy. This is further bolstered by the absence of abuse liability and its general tolerability. A clear limitation to the literature is the paucity of human investigations. Human preclinical and clinical studies are needed to determine whether these positive effects in model systems substantively translate into clinically relevant outcomes.
Key Words : Cannabidiol, Alcohol Use Disorder, CBD, Alcohol, Pharmacotherapy.
THERE IS BURGEONING interest in the therapeutic potential of compounds found in plants of the genus Cannabis. The cannabis plant contains more than 500 constituents and over 100 phytocannabinoids that actively interact with the body’s endocannabinoid system (eCB), of which delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most commonly studied. The eCB is an important physiological system with broad activity impacting various functions of the human body, including brain plasticity, inflammation, appetite regulation, and learning and memory among others (Aizpurua-Olaizola et al., 2017). It is comprised of at least 2 G protein–coupled receptors, the cannabinoid type 1 (CB1) and type 2 (CB2) receptors (Boggs et al., 2018). THC is a partial agonist of CB1 and CB2 receptors (Boggs et al., 2018), and studies using CB1 receptor antagonists attenuate the effects of THC suggesting responsibility for its psychoactive effects (e.g., Englund et al., 2016; Justinova et al., 2008; Klumpers et al., 2013). Unlike THC, CBD is nonpsychoactive which may be attributed to its function as a negative allosteric modulator of CB1 and CB2 receptors (Laprairie et al., 2015; Mechoulam et al., 2007). Further impact of CBD on the eCB involves blocking anandamide uptake and inhibiting its enzymatic hydrolysis (Pertwee, 2008; Thomas et al., 2007). There are also numerous non-endocannabinoid signaling systems that CBD may interact with, explaining its diverse biologic effects (Boggs et al., 2018). For instance, CBD can modulate 5-HT1A receptors (Russo et al., 2005), GPR55 (Ryberg et al., 2007), TRPV1 cation channels (Bisogno et al. 2001), and l- and d-opioid receptors (Kathmann et al., 2006).
With numerous and diverse pharmacological effects on a wide variety of body systems, CBD has gained attention for equally numerous health applications. It has demonstrated anti-inflammatory and anxiolytic effects and reports also suggest it may have antipsychotic, antiemetic, antioxidant, and anticonvulsant effects (Hampson et al., 1998; Parker et al., 2002; Zuardi et al., 2006). However, it is critical to note that this support is derived from a primarily preclinical literature. Despite the ubiquitous health claims of CBD, substantive support only exists in a small number of conditions. In Canada, Sativex (an oromucosal spray of THC and CBD) has been approved as an adjunctive treatment for neuropathic pain in multiple sclerosis (Health Canada, 2007). Similarly, randomized controlled trials of CBD only provide support for seizure disorders (Cunha et al., 1980; Devinsky et al., 2017, 2018a; Thiele et al., 2018). Reflecting these findings, earlier this year CBD (Epidiolex©) was approved by the Food and Drug Administration (FDA) for Lennox–Gastaut and Dravet syndrome, 2 rare and severe forms of pediatric epilepsy.
Given the salutary effects of CBD in preclinical studies, a variety of clinical applications have been considered, including alcohol use disorder (AUD) and other substance use disorders (SUDs). AUD is characterized by a problematic pattern of alcohol use, which leads to significant impairment and distress (American Psychiatric Association, 2013). It is a highly disabling condition and represents a serious public health concern. The FDA has approved 3 medications for treating AUD including naltrexone (both oral and intramuscular formulation), acamprosate, and disulfiram (Leggio and Lee, 2017); however, meta-analytic evidence only supports the use of acamprosate and naltrexone (Jonas et al., 2014). The European Medicines Agency has also approved nalmefene for AUD (Paille and Martini, 2014). These medications have distinct mechanisms of action and are effective for some patients, but predicting treatment response is difficult (Jonas et al., 2014). Despite existing pharmacological or psychological therapies, substantial proportions of patients do not have successful outcomes (e.g., naltrexone number needed to treat = 9; Aronson, 2015) and there is a clear need for additional treatments, particularly those targeting alternative novel mechanisms (Litten et al., 2012, 2016a,b), such as the eCB.
The rationale for CBD as an AUD pharmacotherapy comes from both oblique and direct evidence. First, there is evidence that AUD leads to dysfunction in a number of the biologic systems for which CBD has favorable effects. For example, alcohol is a potent modulator of the immune system, potentiating alcohol-induced liver inflammation and stimulating immune cells, like monocytes, macrophages, and T lymphocytes, which in turn cause the release of proinflammatory cytokines (reviewed in Neupane, 2016). To address these effects, CBD’s anti inflammatory effects may prove beneficial. Oxidative stress also plays a demonstrable role in potentiating alcohol-related harms (Hernandez et al., 2016; Li et al., 2015) which may be alleviated by CBD’s antioxidant properties. Further, based on the risk of seizures during alcohol withdrawal and persistent disturbances in glutamate neurotransmission (Jesse et al., 2017), CBD’s anticonvulsant effects may have therapeutic potential. Second, preclinical evidence suggests that the eCB plays important roles in motivational properties of alcohol as demonstrated by studies examining CB1 receptor modulation. More specifically, CB1 receptor antagonism has been shown to suppress rodent alcohol consumption (Arnone et al., 1997; Colombo et al., 1998; Femenıa et al., 2010; Wang et al., 2003) and can block the increased alcohol consumption noted with CB1 receptor agonist administration (Colombo et al., 2002). Given that CBD may decrease CB1 receptor activity (through negative allosteric modulation), and CB1 receptor antagonism has been shown to decrease alcohol consumption in animal models, this evidence further supports the notion that CBD may be a promising treatment for AUD.
The preceding lines of research obliquely suggest that CBD may be a viable AUD pharmacotherapy, but a number of studies have also directly examined the potential role of CBD. The goal of the current systematic review was to characterize the findings from those direct investigations of CBD’s effects on alcohol-related dysfunction or AUD. The broad goal was to appraise the extent to which CBD may be a credible AUD pharmacotherapy. Although a number of existing pharmacotherapies exist for AUD, suboptimal treatment outcomes remain common and the development of novel strategies remains a priority (Kranzler and Soyka, 2018; Litten et al., 2012, 2016a,b).