Project Summary The development of novel medications for alcohol use disorder (AUD) is a NIAAA research priority. The Clinical Research Project is designed to translate the discoveries of preclinical TSRI-ARC investigators for potential therapeutic use using proof-of-concept human laboratory testing. This component has 2-way interactions with all the individual Research Projects of the ARC and the Animal Models Core. The animal work will validate the choices of a “next generation” selective glucocorticoid receptor antagonist drug and a drug that is hypothesized to restore microtubule homeostasis, and the Clinical Research Project will validate these targets as potential therapeutics treatment of AUD. Should either target ultimately prove to be untenable to pursue human studies, other systems under study by the TSRI-ARC may be viable, such as specific glutamate, serotonin, or hypocretin targets. Drugs identified for human study will either be FDA-approved or available under an IND and will be selected by Dr. Mason based on scientific prioritization by the TSRI-ARC Steering Committee, Program Advisory Committee, and safety considerations. Drugs will be tested in a highly standardized, reliable, and valid human laboratory model informing the 3 stages of the addiction cycle: withdrawal/negative affect, preoccupation/anticipation, and binge/intoxication. Human laboratory results will serve as an analogue for drinking outcomes of clinical treatment trials. Subjects for each study will be 50 non- treatment-seeking male and female paid volunteers who meet DSM-5 criteria for AUD of ≥ moderate severity (AUD-MS). Studies are randomized, double-blind, and placebo-controlled. The treatment duration is at least 1- week and guided by drug pharmacokinetics. The primary endpoint is craving scores in response to in vivo alcohol cues presented in the laboratory with confirmatory physiological outcomes and naturalistic measures of drinking, negative affect, craving, sleep and executive function. Specific Aim 1: To evaluate TSRI-ARC drug candidates in paid non-treatment-seeking volunteers with current AUD-MS using the human lab model of the addiction cycle. Specific Aim 2: To identify potential biomarkers of clinical outcomes (e.g., peripheral markers of stress, including hypothalamic-pituitary-adrenal axis, serotonin, hypocretin, and measures of microtubule homeostasis) and drug plasma concentration. Safety Aim 3: To evaluate the safety and tolerability of TSRI- ARC drug candidates in subjects with AUD-MS as assessed by significant changes from baseline in EKG, routine blood and urine biochemistry, vital signs, physical exam, and subjective complaints relative to placebo. Hypothesis: The overall hypothesis under test is that, relative to placebo, novel drug candidates identified by the TSRI-ARC will significantly attenuate responsivity to alcohol cues in the human lab model and reduce drinking, craving, negative affect, insomnia and executive function deficits during treatment and 1-month follow-up. Interpretation of Results: Positive findings will provide clinical validation of stress targets identified by the TSRI-ARC and provide a rational basis for later phase testing of candidate drugs for AUD-MS.