Dexamethasone to target stress and immune system changes during early abstinence in individuals with Alcohol Use Disorder (AUD)

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PROJECT SUMMARY Approximately one third of Americans consume enough alcohol to be considered at risk for dependence and between 50 to 90% of alcoholics who attempt abstinence experience relapse, highlighting the need for better developed medications and medication targets. Our program of research has shown that early abstinence from alcohol is characterized by a dysphoric state where five minutes of psychological stress exposure can elicit exaggerated levels of anxiety, negative mood and craving that can persist for up to one hour. The link between this sensitized response to stress and relapse factors also suggests that the stress-induced craving state may be an optimal, yet under explored, target for medications development. In view of this, attempts to characterize the biological adaptations underlying provoked alcohol craving have elucidated discrete changes to tonic stress and immune system function, including elevated adrenal sensitivity (cortisol and cortisol / ACTH ratios), and suppressed anti-inflammatory cytokines. We therefore postulate that dexamethasone (an anti-inflammatory glucocorticoid), may be able to attenuate provoked alcohol craving by manipulating combined stress and immune system tone. We present compelling preliminary data to support this. We propose a proof of concept, double-blind, cross-over laboratory study to recruit N=50 one month abstinent men and women with alcohol use disorder (AUD). We will examine whether 1.5mgs dexamethasone (DEX) versus placebo (PBO) can decrease alcohol craving during stress by decreasing adrenal sensitivity, increasing anti-inflammatory cytokine levels and potentially normalizing the immune response to stress. Our primary aims are therefore to determine whether DEX Vs PBO can attenuate alcohol craving, negative mood and anxiety during stress (H1), as well as assess the effects of DEX Vs PBO on stress and immune system tone and following stress exposure (H2). We also examine whether DEX-related changes predict decreases in alcohol craving (H3). All participants will take part in two, laboratory sessions after being randomized to either DEX or PBO, with a 7-day washout period in between. During each laboratory session participants will be randomly exposed to two, 5-minute personalized imagery conditions (stress and relaxing) with a 30-minute break in between. Subjective anxiety, negative mood and alcohol craving as well as plasma pro-inflammatory cytokines (TNFα, TNFR1, IL-6,) anti- inflammatory cytokines (IL-10, IL-1a), and hypothalamic-pituitary-adrenal (HPA) axis markers (cortisol , ACTH) will be collected at baseline, immediately following exposure to imagery and at various recovery time-points until 1-hour post imagery. If hypotheses are confirmed, the use of DEX to engage key stress and immune system markers will serve to identify a clear pharmacological target underpinning provoked alcohol craving. Findings may also help develop a conceptually unique treatment paradigm which encourages the use of a cheap, well-tolerated and widely available medication for use on a pro re nata (PRN) basis, during periods of self-identified vulnerability.