Probenecid for Alcohol Use Disorder

SUMMARY The premise prompting this 12-week clinical trial paired to a human laboratory study is based on the direct evidence from our preliminary work with probenecid, first conducted in a preclinical model of alcohol use disorder (AUD) (R01AA028982, Alcohol Alcohol 2019) and then, in a human laboratory study testing probenecid when co-administered with alcohol (R21AA027614, ACER 2024). The scientific rationale for testing probenecid in AUD was derived by the well-known mechanism of action of probenecid as a pannexin 1 channel inhibitor, its role in alcohol-induced extracellular adenosine release, and that this process is promoted by a history of exposure to excessive alcohol. The preclinical work demonstrated that probenecid is able to reduce alcohol consumption in alcohol-dependent rats. The human alcohol-drug interaction study demonstrated that probenecid did not altered the pharmacokinetics parameters and the neuropsychopharmacological responses of alcohol. We also demonstrated that probenecid was able to reduce acute alcohol craving. The goal of this application is to replicate findings previously conducted in our rodent and human studies and to understand mechanistically the role of the pannexin 1 channels for reducing the inflammation process in AUD. To achieve this goal, this study proposes a 12 week, between-subject, double-blind, randomized controlled trial (RCT) with probenecid (2g/day) compared to placebo in 120 individuals with AUD. There are three aims in this study that test the hypothesis that probenecid compared to placebo, decreases: acute alcohol craving in an alcohol cue reactivity procedure (Aim 1), alcohol craving (Aim 2) and alcohol consumption (Aim 3) during the overall 12-week trial. We also included an Exploratory Aim to further shed light on potential mechanism of probenecid effect in reducing alcohol craving and consumption, that evaluates pro- and anti-inflammatory markers (cytokines, hormones and factors) pre- and post-treatment. The proposed research is significant because, holds the potential to evaluate the role of a novel pharmacological target (pannexin 1 channels) in a full-powered RCT and provide the possibility to discover a novel AUD therapeutic opportunity. This study also will be the first to assess the efficacy of probenecid for AUD in an integrated behavioral and clinical setting.