Project Summary of Parent Grant: A Novel Human Laboratory Model for Screening Medications for Alcohol Use Disorder (R21AA027180) While developing novel medications to treat AUD remains a high research priority area, there are major opportunities to refine the process of screening novel compounds. To that end, a key question in clinical studies of novel compounds for AUD, is how to efficiently determine whether a novel medication has sufficient evidence of initial efficacy to warrant the conduct of subsequent clinical trials. The process of screening novel compounds for initial efficacy, known as the early phase 2 of medications development, often consists of human laboratory studies assessing constructs of putative clinical relevance, such as alcohol craving, subjective response to alcohol, and alcohol self-administration under laboratory conditions. Nevertheless, these controlled human laboratory models lack the ecological validity of clinical trials in which medication effects are established via clinically meaningful endpoints in individuals motivated to change their drinking. The scientific premise of the proposal is that screening novel AUD medications can be efficient and clinically meaningful if early phase 2 studies combine the internal validity of experimental laboratory testing with the external validity of clinical trials. To that end, we propose to conduct a novel early efficacy detection paradigm informed by the smoking cessation medication development literature, to screen both an established (naltrexone) and a promising (varenicline) AUD medication. Specifically, this novel human laboratory protocol involves a randomized, double-blind, placebo-controlled, 3-arm parallel group design, in which individuals with current AUD reporting intrinsic motivation to change their drinking complete a week-long “practice quit attempt” and cue-reactivity paradigm. The primary outcome is the number of abstinent days during the practice quit week under active medication compared to placebo. The proposed laboratory protocol has been developed and validated for screening smoking cessation pharmacotherapies. The objective of this protocol is to adapt and validate this novel approach to screen pharmacotherapies for AUD.