ABSTRACT Compulsive overeating afflicts 30% of treatment-seeking individuals with obesity and correlates with cardiovascular disease (CVD) risk factors. Current obesity intervention approaches, however, do not specifically target mechanisms that underlie compulsive overeating. My research on obese women shows that compulsive overeating is associated with alterations in endogenous opioid activity as indexed by nausea (an opioidergic withdrawal symptom) following administration of the opioid antagonist naltrexone (NX). Data also show associations between compulsive overeating, highly palatable food intake, impulsivity, reward-sensitivity, and other factors, which, taken together, may characterize a compulsive overeating phenotype in obesity. This K23 Award will support the development of my independent research career focused on more effective interventions for compulsive overeating in obesity and its cardiovascular comorbidities. The proposed experimental medicine studies will advance this research program by investigating a compulsive overeating phenotype in obesity using: (1) a multimethod assessment battery (MAB) to assess behavioral, psychological, and nutritional correlates of obesity, (2) obesity-related indices of CVD risk (e.g., glycemic control, hypertension), and (3) my novel NX protocol to assess altered endogenous opioid activity (Aim 1). I will assess NX protocol test-retest reliability and, in a subset of participants who do not have a NX response (nausea) at initial testing, test whether NX response can be induced after administering our 2-week sugar-beverage consumption protocol, as sugar impacts endogenous opioid activity (Aim 2). With my mentors, I will identify intervention targets in compulsive overeating based on Study 1 results and a current review of the literature. I will then select intervention components that have produced change in these targets in prior research, and will develop, refine, and test these components in a pilot study of women with compulsive overeating and obesity (Aim 3). I will examine feasibility and acceptability of the intervention components and collect pilot data on pre- post change in the measures used in Study 1. Pilot data will inform the R34 Clinical Trial Pilot Study proposal I will submit to test an optimized intervention for compulsive overeating in obesity. The proposed training plan will provide me with the support and mentorship necessary to gain expertise in the identification of opioidergic, psychological, behavioral, and nutritional targets associated with compulsive overeating; to obtain the training needed to independently design and conduct laboratory research and to assess obesity-related CVD risk factors; and to obtain the training necessary to develop and test obesity interventions. These training experiences, coupled with the proposed research plan, will facilitate my career devoted to the development of interventions that act on mechanisms underlying compulsive overeating in ob...