PROJECT SUMMARY This K99/R00 proposal examines a novel pharmacotherapy for alcohol use disorder (AUD) in older adults (aged ≥65). As the population is aging at an unprecedented rate and alcohol is the most commonly used drug among older adults, AUD in the older adult population is becoming an increasing area of importance in public health and clinical research. Chronic alcohol consumption leads to accelerated aging and exacerbation of age-related sequelae, including chronic inflammation and cognitive decline. Therefore, identifying a safe and effective treatment option for older adults with AUD is critical. As older adults tend to have co-morbid health conditions which necessitate being prescribed multiple medications, adding a medication with few drug-drug interactions is paramount. Metadoxine is a medication approved in Europe for the treatment of acute alcohol intoxication as it is able to induce urinary excretion of ethanol from the body. Metadoxine is formed by the salification of pyridoxal (vitamin B6) and pyrrolidone carboxylic acid and has an excellent safety profile. Moreover, metadoxine has been shown to be associated with reduced alcohol craving, improvement on cognitive tests, and decreased inflammation. Preliminary data also suggest that metadoxine may reduce alcohol consumption. However, no studies have evaluated metadoxine safety or efficacy in older adults nor used a cue reactivity paradigm to assess craving. During the K99 phase, we propose a within-subjects, crossover, double-blind, placebo-controlled human laboratory safety and tolerability study in older adults (aged ≥65) with AUD. For the R00, we propose a pilot double-blind, between-subjects, placebo-controlled randomized controlled trial (RCT) in older adults (aged ≥ 65) with AUD. For the pilot RCT we will assess acceptability and feasibility of metadoxine for older adults, evaluate the effect on alcohol craving using an established cue reactivity paradigm, and assess the effect on coginitive function relative to placebo. Additionally, we will obtain data on the efficacy of metadoxine for reducing alcohol consumption and inflammation. The research plan is complemented by an exceptional mentorship team and training plan at the Center for Alcohol and Addiction Studies, School of Public Health, Brown University. The application builds on the applicant’s extensive background in aging and neuroscience and clinical alcohol research by proposing new, focused mentorship in specific methods related to human laboratory studies, clinical trials, gerontological research, and biostatistics with clinical data. The combined research and training plans will prepare the applicant for a successful independent career in clinical alcohol research focused on identifying novel treatments for older adults. This research is aligned with NIAAA’s strategic goals to develop and improve treatments for AUD and alcohol-related consequences and to enhance the public health impact of NIAAA- supported rese...