Alcohol use disorder (AUD) is a highly prevalent, highly comorbid, chronic condition that affects over 100 million people globally (Burnette et al., 2022). Within the United States alone, AUD contributes to approximately 88,000 deaths annually (Mason and Heyser, 2021), and produces an economic burden of $250 billion dollars across the USA (Ray et al., 2019). The hallmark characteristics of AUD include an impaired ability to stop or control alcohol intake despite adverse consequences (Mason and Heyser, 2021). AUD is associated with comorbid mood disorders (anxiety, depression), as well as alcohol-associated conditions such as acute and chronic inflammation, and neuropathy (Castillo-Carniglia et al., 2019, Rehm, 2011, Julian et al., 2019). Despite the high prevalence of AUD, the limited available treatments are only modestly effective and are severely under-utilized (Burnette et al., 2022), indicating a need for novel strategies and pharmacotherapies.

Cannabidiol (CBD) is one of the main constituents of Cannabis sativa L.; certain strains of Cannabis sativa L. are cultivated to contain high amounts of CBD (e.g., CBD-dominant) and CBD is also extracted from hemp and sold in a variety of formulations (e.g., edibles, tinctures, oils). An oral formulation of CBD has demonstrated efficacy as an anticonvulsant (Food and Drug Administration, 2018) and has advanced to clinical trials to evaluate therapeutic potential to alleviate pain, anxiety, inflammation, and depression (Devinsky et al., 2014, Kogan et al., 2007 Blessing et al., 2015). The exact mechanism of action of CBD is unclear, but it has been proposed to act in part via the endogenous cannabinoid system as a partial agonist at and a neuroimmune modulator of the cannabinoid type-2 receptor (CB2) and possibly via a negative allosteric mechanism at cannabinoid type-1 receptors (CB1) (Laprairie et al., 2015). CBD also has pharmacodynamic effects on nicotinic acetylcholine receptors (nAChR), serotoninergic 1A receptors (5-HT1A), and mu-opioid receptors (Gonzalez-Cuevas et al., 2018). CBD has been considered a pharmacotherapeutic candidate for AUD treatment due to its anxiolytic, anti-convulsant, anti-inflammatory and neuroprotective effects (Campos et al., 2016). Furthermore, CBD has no detectable abuse liability (Haney et al., 2016; Babalonis et al., 2017) and an oral CBD formulation is already FDA-approved for human use to treat epileptic seizures.

To date, several preclinical studies conducted in rodents have seen promising results for CBD effects on alcohol intake and alcohol-associated behaviors. In mice, chronic administration of CBD (30–120 mg/kg, ascending dose order) decreased voluntary alcohol intake and preference in a two-bottle choice paradigm (Viudez-Martinez et al., 2018). Further, chronic CBD (30 mg/kg/day) reduced the reinforcing and motivational properties of alcohol in an operant paradigm (Viudez-Martinez et al., 2018). In this same study, CBD given during a test of reinstatement to alcohol-seeking behavior reduced responding after treatment with 60 mg/kg then 120 mg/kg CBD (Viudez-Martinez et al., 2018). A separate study with rats also demonstrated effectiveness of CBD to reduce stress-induced and cue-induced reinstatement (Gonzalez-Cuevas et al., 2018). Rodent studies of CBD have also shown promise in affecting behaviors comorbid with AUD in humans. In rats, CBD reduced anxiety-like behaviors in alcohol naive and alcohol experienced animals (Gonzalez-Cuevas et al., 2018). Further, several studies in rodents have indicated neuroprotective effects of CBD on alcohol-induced neurodegeneration (Liput et al., 2013, Hamelink et al., 2005), as well as reduced hepatic inflammation, metabolic dysregulation and liver steatosis induced by chronic and binge alcohol feeding (Liput et al., 2013, Hamelink et al., 2005; Wang et al., 2017; Yang et al., 2014). To date, the effects of CBD on alcohol seeking and self-administration have not yet been tested in nonhuman primate models.

Our laboratory employs a baboon model where alcohol is self-administered under a chained-schedule of reinforcement (CSR) that was designed to evaluate seeking and consumption within the same session (Weerts et al., 2006). The CSR procedure reliably produces alcohol self-administration at high levels (∼1.0 g/kg per day). Blood alcohol levels (BALs) in excess of 0.08% after comparable alcohol intake has been demonstrated in multiple prior studies in using this procedure in our baboons (Kaminski et al., 2008; Kaminski et al., 2014; Holtyn et al., 2014; Holtyn et al., 2017a). Further, alcohol metabolism and pharmacokinetic parameters in baboons are more similar to humans than rodents (Fridman and Popova, 1988, Jolivette and Ward, 2005), which may yield information on potential drug interactions with alcohol that may not be apparent in rodent models. Other AUD pharmacotherapies we have assessed include naltrexone, varenicline, baclofen, mifepristone, and novel benzodiazepine-GABA receptor modulators (Duke et al., 2014; Holtyn et al., 2017a; Holtyn et al., 2017b; Holtyn et al., 2019; Kaminski et al., 2012; Kaminski et al., 2013; Kaminski et al., 2014). Thus, the CSR procedure in baboons provides insightful information and can improve prediction of efficacy of potential therapeutics in humans.

Therefore, the aim of the current study was to determine if acute and chronic administration of CBD could reduce alcohol seeking and self-administration in baboons with an extensive history of daily alcohol self-administration. Additionally, daily behavioral observations were assessed to verify any potential disruptions to species-typical behaviors associated with administration of CBD following alcohol administration.