Therapeutic Prospects of Cannabidiol for Alcohol Use Disorder and Alcohol-Related Damages on
the Liver and the Brain
Julia De Ternay, Mickaël Naassila Mikail Nourredine, Alexandre Louvet, François Bailly, Guillaume Sescousse, Pierre Maurage, Olivier Cottencin, Patrizia Maria Carrieri and Benjamin Rolland
Frontiers in Pharmacology, 2019, Volume 10, Article 627
doi : 10.3389/fphar.2019.00627
Background : Cannabidiol (CBD) is a natural component of cannabis that possesses a widespread and complex immunomodulatory, antioxidant, anxiolytic, and antiepileptic properties. Much experimental data suggest that CBD could be used for various purposes in alcohol use disorder (AUD) and alcohol-related damage on the brain and the liver.
Aim : To provide a rationale for using CBD to treat human subjects with AUD, based on the findings of experimental studies.
Methods : Narrative review of studies pertaining to the assessment of CBD efficiency on drinking reduction, or on the improvement of any aspect of alcohol-related toxicity in AUD.
Results : Experimental studies find that CBD reduces the overall level of alcohol drinking in animal models of AUD by reducing ethanol intake, motivation for ethanol, relapse, anxiety, and impulsivity. Moreover, CBD reduces alcohol-related steatosis and fibrosis in the liver by reducing lipid accumulation, stimulating autophagy, modulating inflammation, reducing oxidative stress, and by inducing death of activated hepatic stellate cells. Finally, CBD reduces alcohol-related brain damage, preventing neuronal loss by its antioxidant and immunomodulatory properties.
Conclusions : CBD could directly reduce alcohol drinking in subjects with AUD. Any other applications warrant human trials in this population. By reducing alcohol-related steatosis processes in the liver, and alcohol-related brain damage, CBD could improve both hepatic and neurocognitive outcomes in subjects with AUD, regardless of the individual’s drinking trajectory. This might pave the way for testing new harm reduction approaches in AUD, in order to protect the organs of subjects with an ongoing AUD.
Keywords : alcohol use disorder, alcohol-related damage, cannabidiol, liver fibrosis and cirrhosis, neuroprotection, addiction
Alcohol use disorder (AUD) is an addictive disorder characterized by a progressive loss of control upon alcohol use. AUD consists of several clinical criteria that include alcohol tolerance, withdrawal symptoms, craving, as well as medical and psychosocial consequences. AUD is responsible for a severe burden of disease. Worldwide, AUD causes more than 3 million deaths every year, which represents 5% of all deaths (World Health Organization, 2018). More specifically, subjects with AUD may be affected by the consequences of recurrent alcohol abuse on the body, including alcohol-related liver disease (ARLD), and alcoholrelated brain injury (ARBI). ARLD is a progressive alcohol-induced liver injury, which starts with an increase in the amount of fat in the liver—a process called steatosis—and continues into a progressive cell loss, fibrosis, and hepatic insufficiency—a process called cirrhosis (O’Shea et al., 2010). ARLD may result in severe liver failure, and represents a major risk factor for liver cancer. Overall, alcoholattributable liver damage is responsible for 493,300 deaths every year, and 14,544,000 disability adjusted life years (DALYs), representing 0.9% of all global deaths and 0.6% of all global DALYs all over the world (Rehm et al., 2013). In subjects with ARLD, preventing the transition from steatosis to cirrhosis is a major treatment goal, and this usually requires to stop or to dramatically reduce the average amount of consumed alcohol in the long term (European Association for the Study of the Liver A et al., 2018). AUD also affects the brain, through ARBI. Subjects with AUD display reduced gray matter volumes and reduced cortical thickness, as well as increased ventricular volumes, when compared to matching healthy controls (Bühler and Mann, 2011). The most significant reductions in grey matter volumes are observed in the corticostriatal–limbic circuits, including the insula, superior temporal gyrus, dorso-lateral prefrontal cortex, anterior cingulate cortex, striatum, and thalamus (Bühler and Mann, 2011). Cognitive functions associated with these brain areas (e.g., executive functions, working memory, emotion recognition, or long-term memory) are impaired in subjects with AUD (Stavro et al., 2013). Generally, cognitive dysfunctions start to improve quickly after alcohol withdrawal, but patients substantially recover only within the first weeks to months of alcohol abstinence, and sometimes remain impaired (Stavro et al., 2013; Schulte et al., 2014). Similarly, the recovery of structural brain alterations can be highly variable depending on brain areas and individual features (Durazzo et al., 2015; Zou et al., 2018). Overall, both ARLD and ARBI involve alcoholrelated inflammatory processes (Mandrekar and Ambade, 2014; Neupane, 2016). Current medications for reducing alcohol drinking or supporting alcohol abstinence in AUD subjects are still insufficiently effective at a population level, and new therapeutic prospects are needed (Rolland et al., 2016; Soyka and Müller, 2017). Moreover, no drug for reducing alcohol-related harms, either on the brain or the liver, has ever been studied. Cannabidiol (CBD) is a natural constituent of Cannabis sativa. Unlike tetra-hydrocannabinol (THC), CBD has no psychotomimetic properties. However, CBD exerts several important effects on the central nervous system, including anxiolytic, antipsychotic (Iseger and Bossong, 2015), analgesic, or antiepileptic effects (Campos et al., 2016; Lee et al., 2017). In this respect, an oromucosal spray with CBD and THC in a 1:1 ratio (SATIVEX®, GW Pharmaceuticals) has been approved in Canada as a treatment for multiple sclerosis spasticity (Keating, 2017) since 2005, and is now approved in 22 countries worldwide. More recently, CBD has been approved in the US for seizures prevention in Dravet and Lennox–Gastaut syndromes, and will therefore be available for clinical practice very soon (Food and Drugs Administration, 2018). Due to its action on cognitive processes and anxiety regulation, CBD is also increasingly considered as a potential treatment for other neuropsychiatric disorders, including anxiety, depression, and substance use disorders (Campos et al., 2016; Lee et al., 2017). In addition to its actions on the brain, CBD has systemic effects, through its complex immunomodulatory and antioxidant properties (Booz, 2011). This has raised increasing interest in CBD for various inflammatory or immunological diseases, such as cancer (Massi et al., 2013), neurodegenerative diseases (Fernández-Ruiz et al., 2013; Karl et al., 2017), colitis (Jamontt et al., 2010), cardiovascular diseases (Stanley et al., 2013), and diabetes (Gruden et al., 2016). CBD is a weak, noncompetitive, negative allosteric modulator of cannabinoid-1 (CB1) receptors (Pertwee, 2008; Laprairie et al., 2015; Tham et al., 2019), however, a large part of the pharmacological action of CBD seems to be based on mechanisms that do not involve cannabinoid receptors. For example, the molecular mechanisms through which CBD prevents seizures are currently debated on, but several potential molecular targets other than cannabinoid receptors have been identified. In particular, CBD is a partial antagonist of G protein-coupled receptor 55 (GRP55), identified as an endocannabinoid target (Ryberg et al., 2009), which could be involved in the decrease of neuronal excitability, through an action on gamma-aminobutyric acid-ergic (GABAergic) neurotransmission (Devinsky et al., 2014; Musella et al., 2017; Chen et al., 2018). CBD also régulâtes calcium (Ca2+) homeostasis by acting on mitochondria stores (Ryan et al., 2009), and blocks low voltage-activated (T-type) Ca2+ channels, modulating intracellular calcium levels (Ross et al., 2008). Other hypotheses include inhibition of anandamide hydrolysis via fatty acid amide hydrolase (FAAH) (Watanabe et al., 1998; Massi et al., 2008; Leweke et al., 2012), activation of peroxisome proliferator-activated receptor γ (PPAR-γ) (Devinsky et al., 2014), positive allosteric modulation of serotonin 1A receptors (5-HT1A receptors) (Rock et al., 2012), activation of transient receptor potential vanilloid type 1 (TRPV1), and reduction of adenosine reuptake increasing adenosine levels (Carrier et al., 2006; Zhornitsky and Potvin, 2012). The systemic immunomodulatory and antioxidant properties of CBD appear to be based on complex mechanisms. CBD acts on many cellular pathways of inflammation, such as the nuclear factor kappa-light-chain-enhancer of activated B cells (NF- κB) pathway (Rajesh et al., 2010; Juknat et al., 2012; Khaksar and Bigdeli, 2017), as well as the interferonβ/signal transducer and activator of transcription proteins (IFNβ/STAT) pathway (Juknat et al., 2012). Through activation of adenosine receptor A2a, and inhibition of adenosine reuptake (Carrier et al., 2006; Castillo et al., 2010), CBD can modulate the activity of multiple De Ternay et al. Cannabidiol in Alcohol Use Disorder inflammatory cells, including neutrophils, macrophages, or T-cells. CBD also decreases the production of inflammatory mediators such as interferon-c (IFN-c), interferon-γ (IFN-γ) (Lee and Erdelyi, 2016), tumor necrosis factor α (TNF-α) (Magen et al., 2009; Rajesh et al., 2010; Khaksar and Bigdeli, 2017; Wang et al., 2017), interleukin (IL)-1β (IL-1β) (Pazos et al., 2013; Wang et al., 2017), IL-6 (Lee and Erdelyi, 2016), and the expression of intercellular adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule 1 (VCAM1) (Rajesh et al., 2010). Furthermore, CBD decreases caspase 9 (Castillo et al., 2010) and caspase 3 activation (Iuvone et al., 2004; Rajesh et al., 2010; Da Silva et al., 2014; Santos et al., 2015), which are factors involved in apoptosis. CBD up-stimulates anti-inflammatory cytokines IL-10 (Kozela et al., 2017). Finally, CBD activates the PPAR-γ, a nuclear receptor that plays a central role in the regulation of metabolic and inflammatory cell processes, including those leading to apoptosis (O’Sullivan and Kendall, 2010). Because of its various effects on the brain and on systemic inflammation, CBD involves a large potential array of complementary therapeutic applications in AUD. First, CBD could help patients with AUD reduce their level of alcohol drinking. Second, by modulating the inflammatory processes in the liver, CBD could reduce alcohol-induced liver steatosis and fibrosis, thus constituting a novel harm reduction agent among subjects with AUD, particularly among those who still exhibit heavy drinking. Third, CBD could reduce ARBI. The aim of this narrative review is to offer a comprehensive overview of the current body of evidence about these three specific applications of CBD in subjects with AUD or animal models of AUD, and to discuss what should be the next steps of research on these topics.