Investigating Oleoylethanolamide (OEA) as a Novel Multi-System Based Therapeutic for Young Adults with Alcohol Use Disorder - PROJECT SUMMARY Alcohol use disorder (AUD) reaches peak prevalence during young adulthood, a period of ongoing neurodevelopment and heightened vulnerability to the long-term consequences of heavy alcohol use. Emerging evidence suggests that alcohol disrupts multiple interrelated systems, including neural, immune, and microbial networks, which may collectively contribute to the development and persistence of AUD. Despite the high prevalence of AUD in this age group, few treatment options are developmentally tailored or informed by these complex multisystem disruptions. Oleoylethanolamide (OEA), a naturally occurring lipid in the extended endocannabinoid system, is a promising candidate for targeting these disruptions. Preclinical studies indicate that OEA reduces alcohol-related behaviors and neuroinflammation, modulates the microbiome, and dampens immune responses. Although human research on OEA and alcohol use is still emerging, clinical trials in other populations have shown that OEA supplementation improves inflammatory profiles, cognitive performance, and gut health. However, no studies to date have tested OEA as a therapeutic agent for AUD in young adults. This K01 project will use a randomized, double-blind, placebo-controlled design to evaluate the effects of six weeks of OEA supplementation (125 mg per day) on peripheral inflammation (IL-6, TNF-α, IL-1β, LPS), oral microbiome composition, neurocognitive function related to reward and impulsivity, and alcohol use outcomes assessed by self-report and biomarkers, in young adults (N = 42, ages 18 to 25) with AUD. By targeting multiple biological and behavioral mechanisms simultaneously, this project will generate novel and translatable insights into the systems that underlie alcohol use and may help identify objective indicators of treatment response. The proposed research builds on Dr. Browning’s expertise in the microbiome, inflammation, and neuroimaging, while providing targeted training in key areas needed to support her transition to independence. The training plan will provide advanced instruction in (1) clinical trial design and implementation, (2) a mechanistic understanding of the extended endocannabinoid system with a focus on OEA and its interactions with immune, microbial, and neural systems, (3) proficiency in cognitive assessment methods in youth, (4) continued training in responsible conduct of research, and (5) refinement of scientific writing, grant development, and science communication skills. These integrated research and training activities will position Dr. Browning to lead a productive, independent research program focused on developing innovative, multisystem-informed interventions for adolescent substance use.
