A focus on alpha-1 blockade as a novel pharmacological treatment for alcohol use disorder

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ABSTRACT While the role of stress in alcohol use disorder (AUD) is well established, none of the current FDA-approved medications in the U.S target the stress system. One potential pharmacological target for the stress component of AUD is norepinephrine. The goal of this application is to replicate findings previously conducted in a pilot trial and to understand, mechanistically, the role of stress in the development of AUD pharmacotherapies that target noradrenergic blockade. To achieve these goals, this study proposes a 12 week, between-subject, double-blind, randomized clinical trial (RCT) with doxazosin (16 mg, or maximum tolerated dose, MTD) compared to placebo in 184 treatment seeking individuals with AUD. We will: (1) examine alcohol drinking and clinical outcomes at baseline, throughout treatment, and at posttreatment; (2) conduct a stress-induced alcohol cue-reactivity in a bar- laboratory; and (3) test moderators of doxazosin response to inform a personalized treatment approach. There are three aims in this research plan. In Aim 1, we will test if doxazosin decreases alcohol consumption (primary outcome) and alcohol craving (secondary outcome) in naturalistic conditions throughout the study. Then in Aim 2, in the bar laboratory, we will measure acute craving after a single oral dose of 32.4 mg yohimbine (to initiate the neuroendocrine process associated with stress induction and to enhance exposure therapy), combined with an alcohol cue reactivity protocol (to selectively target alcohol cues). Finally, in the exploratory aims, to further shed light on potential personalized medicine approaches with noradrenergic pharmacotherapies for AUD, we will test the hypotheses that baseline family history density of alcoholism, blood pressure and rs1611115 polymorphism moderate doxazosin's effect on alcohol consumption in individuals with AUD.