PROJECT SUMMARY/ ABSTRACT Only a small proportion of individuals with past-year AUD received treatment. As such, development of novel, efficacious pharmacotherapies for AUD is a high research priority that may lead to higher treatment utilization and success rates. Establishing moderators of treatment response and mechanisms of action is an imperative step towards identifying predictors of good clinical response and furthering precision medicine. Modulation of immune function is one promising treatment target for addiction. Through activation of immune cell receptors, sustained heavy alcohol use induces a proinflammatory state, which contributes of AUD symptomatology. Negative affect is multi-faceted construct and common feature of AUD that is consistently associated with poorer treatment outcomes and may be linked to inflammation induced by chronic alcohol use. Anti-inflammatory therapies are shown to reduce levels of negative affect among individuals with psychiatric disorders. As such, reductions in facets of negative affect may be a potential mechanism of action involved in neuroimmune modulation in AUD. In regard to candidate moderators, research across disciplines shows that a particularly pronounced inflammatory profile might be more amenable to neuroimmune treatment. Examination of sex differences in response to immune treatment is also supported by several fields of research and delineated by NIH as a priority consideration that can inform clinical interventions. This proposal is based on recent indications that ibudilast, a neuroimmune modulator, is a potentially efficacious pharmacotherapy for AUD. An initial screening of ibudilast in the Sponsor's laboratory showed that following stress exposure, ibudilast promoted a stronger recovery of positive affect and strengthened the influence of negative affect on craving. The objective of this NRSA application is to foster my development as a clinical scientist with a focus on medications development for AUD, psychoneuroimmunology, and quantitative methods. This proposal will draw from an ongoing and funded 12-week clinical trial of ibudilast recruiting a treatment-seeking sample of AUD. Given the limited knowledge about how this class of therapy operates in human samples of AUD and who is most treatment responsive, the proposed study will investigate potential moderators of clinical response and mechanisms of action by leveraging data from this clinical trial of ibudilast. Specifically, Aim #1 tests the hypothesis that facets of negative affect will significantly mediate the relationship between treatment and heavy drinking. Aim #2 tests the hypothesis that peripheral proinflammatory biomarkers and sex will serve as moderators of clinical response to ibudilast. These Aims will be tested using a sophisticated analytic approach including longitudinal multilevel moderation and mediation models. The present study represents an important step in further immune pharmacotherapies for AUD and, with...