(85) Converging Evidence from Human Pharmacoepidemiology and Rodent Psychopharmacology Studies on the Role of Spironolactone as a Potential Pharmacotherapy for Alcohol Use Disorder

Publication Number: 759

Background: Recent evidence suggests that aldosterone and its main receptor, the mineralocorticoid receptor (MR), modulate alcohol seeking and consumption. Therefore, it has been suggested that spironolactone, an MR antagonist, may represent a novel pharmacotherapy for alcohol use disorder (AUD).

Objectives: The aim of this study was to test the effects of spironolactone on alcohol consumption via psychopharmacological experiments in mice and rats and a pharmacoepidemiological study in humans.

Methods: First, the effect of spironolactone injection (25 mg/kg, 50 mg/kg, 100 mg/kg, and 200 mg/kg) vs. vehicle was examined in male and female C57BL/6J mice in a validated model of alcohol binge drinking (drinking-in-the-dark). Next, the effect of spironolactone injection (25 mg/kg, 50 mg/kg, and 75 mg/kg) vs. vehicle was tested on operant alcohol self-administration in alcohol dependent (vapor exposure model) and nondependent male Wistar rats. Finally, the association between spironolactone receipt and change in self-reported alcohol consumption, using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), was investigated in a pharmacoepidemiological cohort study of patients exposed to spironolactone, compared to propensity score-matched unexposed controls, in the largest integrated healthcare system in the US.

Results: Spironolactone dose-dependently reduced the intake of sweetened or unsweetened alcohol solutions in male and female mice. No effects were observed on drinking of a non-alcoholic sweet solution, food or water intake, motor coordination, alcohol-induced ataxia, or blood alcohol levels. Furthermore, spironolactone dose-dependently reduced alcohol self-administration in dependent and nondependent male rats. In humans, a greater reduction in alcohol consumption was observed among those who received spironolactone, compared to propensity-score matched individuals who did not receive spironolactone. The largest effects were among those who reported hazardous/heavy episodic alcohol consumption at baseline (AUDIT-C ≥ 8) and those exposed to ≥ 50 mg/day of spironolactone.

Conclusions: Convergent findings across rodent and human studies suggest that spironolactone reduces alcohol use and support the hypothesis that this medication may be further studied in clinical trials as a novel pharmacotherapy for AUD.