Transdermal Delivery of Cannabidiol Attenuates Binge Alcohol- Induced Neurodegeneration in a Rodent Model of an Alcohol Use Disorder
Daniel J. Liput, Dana C. Hammell, Audra L. Stinchcomb, and Kimberly Nixon
Pharmacology, Biochemistry and Behavior, 2013, 111, 120–127.
doi : 10.1016/j.pbb.2013.08.013
Excessive alcohol consumption, characteristic of alcohol use disorders, results in neurodegeneration and behavioral and cognitive impairments that are hypothesized to contribute to the chronic and relapsing nature of alcoholism. Therefore, the current study aimed to advance the preclinical development of transdermal delivery of cannabidiol (CBD) for the treatment of alcohol-induced neurodegeneration. In experiment 1, 1.0%, 2.5% and 5.0% CBD gels were evaluated for neuroprotection. The 5.0% CBD gel resulted in a 48.8% reduction in neurodegeneration in the entorhinal cortex assessed by Fluoro-Jade B (FJB), which trended to statistical significance (p = 0.069). Treatment with the 5.0% CBD gel resulted in day 3 CBD plasma concentrations of ~100.0 ng/mL so this level was used as a target concentration for development of an optimized gel formulation. Experiment 2 tested a next generation 2.5% CBD gel formulation, which was compared to CBD administration by intraperitoneal injection (IP; 40.0 mg/kg/d). This experiment found similar magnitudes of neuroprotection following both routes of administration; transdermal CBD decreased FJB+ cells in the entorhinal cortex by 56.1% (p < 0.05), while IP CBD resulted in a 50.6% (p < 0.05) reduction in FJB+ cells. These results demonstrate the feasibility of using CBD transdermal delivery systems for the treatment of alcohol-induced neurodegeneration.
Keywords : alcoholism; ethanol; cannabidiol; neuroprotection; neurotoxicity; transdermal
Approximately 8.5% of the U.S. population currently meets the diagnostic criteria for an alcohol use disorder (AUD; Hasin et al., 2007). Although four pharmacotherapy based interventions are approved in the U.S. for the treatment of AUDs, these drugs have had limited efficacy in the patient population (Litten et al., 2012). Additionally, these medications primarily target the motivational properties of alcohol, while the neurodegenerative effects of alcohol that are hypothesized to impair behavioral control and decision making, are not managed by these specific treatments. Therefore, identification of novel targets and development of new therapeutic agents is critical to improve pharmacotherapy based treatment strategies for AUDs.
Neuroprotective agents are hypothesized to have high therapeutic utility for the treatment of AUDs (Crews, 1999). Excessive alcohol intake, characteristic of AUDs, results in neurodegeneration and cognitive and behavioral impairment, effects which are hypothesized to influence the transition to addiction (Koob and Le Moal, 1997; Crews, 1999; Sullivan and Pfefferbaum, 2005). Imaging studies have identified gross anatomical abnormalities throughout the brains of human alcoholics including widespread disruption of white matter tracts, atrophied cortical gray matter and increased cerebral spinal fluid filled space (Pfefferbaum et al., 1992; Mechtcheriakov et al., 2007; Demirakca et al., 2011). These effects have also been observed in postmortem studies showing significant cortical neuronal loss in alcoholic brains (Harper and Kril, 1989; Kril et al., 1997), which is consistent with studies demonstrating long term or permanent deficits in function (Stavro et al., 2012). Some brain structures appear to be more susceptible to the neurodegenerative effects of alcohol, including the frontal lobe (Kril et al., 1997; Pfefferbaum et al., 1997; Qin and Crews, 2012), temporal lobe (Sullivan et al., 1995) and hippocampus (Sullivan et al., 1995). The aforementioned brain regions are involved in problem solving, attention, information processing, learning and memory and behavioral control, therefore it is not surprising that these functions are impaired in AUDs (Stavro et al., 2012). Importantly, a recent study described an association between reductions in cortical gray matter and risk for relapse (Rando et al., 2011), further substantiating the role of alcohol-induced neurodegeneration in AUDs. Therefore, elucidating the mechanism(s) underlying alcohol-induced neurodegeneration and developing neuroprotective pharmacotherapies could improve prevention and treatment strategies for AUDs.
Studies have suggested that chronic alcohol exposure is associated with induction of neuroinflammatory mediators and/or oxidative stress, which leads to neurodegeneration (Crews and Nixon, 2009; Qin and Crews, 2012). Consistent with this hypothesis, a variety of antioxidants, including α-tocopherol, butylated hydroxytoluene (BHT) and cannabidiol (CBD) have been effective in reducing binge alcohol induced neurodegeneration (Hamelink et al., 2005; Crews et al., 2006). Neuroprotection mediated by antioxidant treatment is associated with inhibition of NF-κB-DNA binding, reductions of COX-2 expression and microglial activation (Crews et al., 2006), all of which support the hypothesis that neuroinflammatory signaling and/or oxidative stress contribute to alcohol-induced neurodegeneration (Crews and Nixon, 2009). These studies have clearly demonstrated that antioxidants protect against alcohol-induced neurodegeneration, therefore further development of these agents for clinical use is warranted.
CBD is a main constituent of cannabis sativa. Unlike the more commonly recognized constituent, (-)-Δ9-tetrahydrocannabinol, CBD does not exhibit psychotropic effects as it is not an agonist at cannabinoid 1 receptors (Pertwee, 2008). In fact, CBD is very well tolerated in humans (Cunha et al., 1980). CBD has a plethora of actions, including anticonvulsive, anxiolytic, anti-relapse and neuroprotective properties (Hampson et al., 1998; Mechoulam et al., 2002; Ren et al., 2009), which make it an ideal candidate for treating multiple pathologies associated with AUDs. CBD was initially shown to be neuroprotective in an in vitro model of excitotoxicity by scavenging reactive oxygen species (Hampson et al., 1998). Indeed, comparison of CBD with well-known antioxidants including BHT and α-tocopherol, showed that CBD has a higher antioxidant capacity (Hampson et al., 1998). Extending these findings, another study demonstrated that CBD was neuroprotective in the modified Majchrowicz binge model of alcohol-induced neurodegeneration, presumably through its antioxidant activity (Hamelink et al., 2005).
Although CBD is efficacious in preclinical models and is safe for human use (Cunha et al., 1980), its clinical use has been minimal because of poor oral bioavailability and low aqueous solubility. Estimated oral bioavailability of CBD is roughly 6% (Agurell et al., 1981; Ohlsson et al., 1986); therefore, it is difficult and expensive to achieve suitable plasma levels for clinical efficacy. These drug delivery obstacles may be circumvented by alternative delivery routes, such as transdermal delivery (Paudel et al., 2010). Additionally, transdermal delivery is advantageous because it promotes patient compliance, as this route of administration is non-invasive and pain free compared to injectable formulations, which is especially important in the alcohol dependent population (Swift et al., 2011). Therefore, the current study investigated the utility of CBD transdermal systems for preventing alcoholinduced neurodegeneration using a well-established model of and AUD, the modified Majchrowicz binge model.