DESCRIPTION (provided by applicant): Zonisamide is an extremely promising anticonvulsant medication for the treatment of alcohol use disorder (AUD). Zonisamide reduces drinking, craving for alcohol, and anxiety in subjects with AUDs. We completed a randomized, placebo-controlled trial of zonisamide for treating alcohol dependence, which showed reductions in heavy drinking, overall drinking, and alcohol craving with the medication. Zonisamide was very well tolerated in the pilot study. Recently, another small placebo-controlled trial of zonisamide showed advantages of the medication over placebo in reducing drinking. However, no definitive study of ZNS treatment for alcoholism has been performed, and there is no such study currently underway in civilians. We have received notice of funding through a Merit Award from the VA Clinical Studies Research and Development (CSR&D) service to conduct a 5-year clinical trial evaluating the efficacy of zonisamide in 160 U.S. Military Veterans with alcoholism. In this R01 application, we propose to add a civilian arm to the study consisting of 160 civilians with Alcohol Use Disorder. Studying the medication's effects in civilians (as well as veterans) will allow us to fully evaluate its efficacy and will make the results more generalizable to the population at large We also propose to add mechanistic and translational components to the combined 320 subject (veteran plus civilian) sample that will allow us to understand better the mechanism of action of zonisamide and other anticonvulsants used to treat alcoholism, as well as help identify observable traits that predict better treatment response. We also propose a novel pharmacogenomic component that adds to the innovation and complements the state-of- the-art trial methods proposed.