SUMMARY/ABSTRACT While there have been developments in treatments for alcohol use disorder (AUD), current pharmacotherapies face several limitations, including the presence of adverse events. Intranasal (IN) insulin has shown promise for use in targeting addictive disorders. The overarching hypothesis of this proposal is based on the premise that IN insulin by providing improvement of brain cell energy and glucose metabolism and stress hormone reduction, may be an ideal approach for treating multiple domains of AUD including memory and impulsivity. Furthermore, studies of IN insulin demonstrate that it is a safe and effective method for delivering insulin to the central nervous system, circumventing the blood brain barrier and reducing adverse events (hypoglycemia). The main goal of this proposed work is to tune up and test an integrated pharmacological, biobehavioral and clinical protocol to test the safety/tolerability of IN insulin as a potential therapeutic for AUD. This is a Phase I/IIa, within-subject, crossover, double-blind, placebo-controlled human laboratory study with an acute IN insulin (80IU) administration compared to placebo in 40 non-treatment-seeking individuals with AUD. In Aim 1, we assess the safety, tolerability and acceptability of IN insulin as pharmacological intervention for AUD. In Aim 2, we evaluate whether there is a difference in adverse events between IN insulin and the placebo condition when co-administered with alcohol. In Aim 3, we will evaluate whether IN insulin, compared to placebo, improves memory and reduce impulsivity after the alcohol challenge. Finally, in Exploratory Aim, we will assess preliminary data on the effect of IN insulin, compare to placebo on alcohol craving. The proposed research will generate: 1) the necessary safety data and 2) the characterization of AUD patient endophenotype who may respond to IN insulin treatment.