Eating disorders (ED) affect 5 % of youth, are associated with reward system alterations, and lead to substantial morbidity. Naltrexone, an opioid antagonist, is used to treat ED behaviors such as binge eating and purging. However, not all patients respond, and the optimal dose is unknown. Neuroimaging may serve as a tool to detect drug response in the brain, acting as a pharmacodynamic biomarker to support therapeutic optimization. Currently, no pharmacodynamic biomarkers for psychopharmacology exist. Building on pilot work, we present the protocol for a randomized controlled trial to validate neuroimaging as a pharmacodynamic biomarker of opioid antagonism in adolescents with ED. Youth aged 13-21 years with binge/purge ED are randomized to receive a single dose of oral naltrexone and placebo in a double-blind using a crossover design with an interdose interval ≥ 2 weeks. Task-based functional neuroimaging detects reward pathway modulation 2 h post-dose. Blood and urine are collected over a model-informed time course. Response (primary outcome) is defined as naltrexone-related blood oxygenation-level dependent signal change (Δ%BOLD) in a priori reward regions of interest and secondary exposure outcomes are naltrexone C