Alcohol use Disorder (AUD) is common among Veterans and is associated with significant morbidity and mortality. In addition, the direct and indirect cost of AUD in Veterans is significant. Several FDA approved medications are available for the treatment of AUD and are thought to act through inhibitory and excitatory neuronal pathways including gamma-aminobutyric acid (GABA), glutamate and opioid pathways. However, effect sizes are generally small and they are used in a minority of patients. Thus, new medications with novel mechanisms of action are needed to improve outcomes. Pioglitazone is a peroxisome proliferator-activated receptor- gamma (PPAR) agonist that has been shown to reduce addictive behaviors in several pre- clinical studies and reduce cocaine and alcohol use in one small clinical study of cocaine dependent subjects. Pioglitazone is thought to modulate the inflammatory response related to repeated cycles of alcohol use, potentially reducing alcohol craving and improving behavioral flexibility. No clinical studies of pioglitazone focused on AUD are available. The proposed work would build on the pre-clinical data, one small study in cocaine users and a retrospective evaluation at the Minneapolis VA showing an association between pioglitazone and reduced alcohol use in Veterans. Therefore, we propose a randomized controlled double-blind trial of pioglitazone compared to placebo in Veterans with AUD of at least moderate severity and who are currently drinking. The primary outcome is drinking behavior (heavy drinking days in the last 8 weeks of the study, number of heavy drinking days per week and total drinks per week) and secondary outcomes include biological measures of alcohol use (ethyl glucuronide, ethyl sulfate and gamma-glutamyl transferase), craving and safety measures. Should this study provide evidence of efficacy and safety for pioglitazone in AUD, we would propose a larger clinical trial through the cooperative studies program. In addition, as pioglitazone is currently an FDA approved drug it could be used off-label in clinical practice to the immediate benefit of Veterans with AUD. Finally, as pioglitazone's mechanisms of action is unique, showing efficacy would potentially lead to a new avenue of medication discovery for AUD. Specifically, medications that address immune signaling such as other PPAR agonists might be pursued to address AUD and other substance use disorders.

Public Health Relevance

Alcohol use disorder (AUD) is common among Veterans but medication treatment is used infrequently and effect sizes are small to modest at best. Pioglitazone, a medication FDA approved for diabetes, has been shown in pre-clinical studies to reduce alcohol use. Our proposed study will test the efficacy of pioglitazone to reduce alcohol use in in a double-blind placebo controlled trial. If the results show that pioglitazone is effective in reducing alcohol use in Veterans and as pioglitazone is already FDA-approved, a novel, easily disseminated therapy to improve alcohol outcomes in Veterans with AUD could be made available immediately for use in VAHCS's across the country.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Special Emphasis Panel (ZRD1)
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Minneapolis VA Medical Center
United States
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