Probenecid as a pharmacotherapy for alcohol use disorder: A randomized placebo-controlled alcohol interaction trial.

Background: This study shows the first evidence for pannexin 1 channels as a new target to develop medications for alcohol use disorder (AUD). Due to its history of long-term safe clinical use and preclinical evidence of reducing excessive alcohol intake in rodents, probenecid has clinical potential for AUD.

Methods: We conducted a Phase I/IIa randomized, double-blind, placebo-controlled, crossover trial investigating the safety, tolerability, and efficacy of an oral dose of probenecid (2 g) when administered with alcohol (0.08 g/dL) in individuals who regularly consume alcohol to the 0.08 g/dL level (N = 35) and in individuals with mild to severe AUD. Alcohol pharmacokinetics and subjective responses were evaluated to assess potential interactions between probenecid and alcohol. Alcohol craving, inflammatory biomarkers, cognitive assessments, and hemodynamics were assessed as additional alcohol research domains. All outcomes were assessed both in the ascending and descending limb of alcohol intoxication using Generalized Estimating Equation.

Results: Probenecid did not exert any significant effect on alcohol pharmacokinetics and did not affect alcohol stimulation or sedation. Probenecid, compared to placebo, significantly decreased alcohol craving during the alcohol ascending limb. Inflammatory biomarkers, cognitive performance following alcohol ingestion, and hemodynamics were likewise not affected by probenecid administration. Analysis of sex as a biological variable revealed no differences of probenecid compared to placebo.

Conclusions: Taken together, our data support the potential of probenecid for treatment of AUD and suggest that pannexin 1 channels represent a novel emerging therapeutic target for the development of new pharmacotherapies for treating AUD.