Aims GLP‐1 analogs have recently risen to the forefront as effective medications for lowering weight through actions in the central nervous system (CNS). However, their actions in the CNS have not yet been studied in the human brain after longer‐term administration at the highest dose approved for obesity (liraglutide 3.0 mg). Materials and Methods A total of 20 participants with obesity were treated with placebo and liraglutide (3.0 mg) in the context of a randomized, placebo‐controlled, double‐blind, cross‐over trial after 5 weeks of dose escalation. Neurocognitive and neuroimaging (fMRI) responses to food cues were examined at the clinical research center of Beth Israel Deaconess Medical Center. Results While using liraglutide, patients lost more weight (placebo‐subtracted −2.7%; P < .001), had decreased fasting glucose (P < .001) and showed improved cholesterol levels. In an uncontrolled analysis, brain activation in response to food images was not altered by liraglutide vs placebo. When controlled for BMI/weight, liraglutide increased activation of the right orbitofrontal cortex (OFC) in response to food cues (P < .016, corrected for multiple comparisons). Conclusions In contrast to prior studies, we demonstrate for the first time that liraglutide treatment, administered over a longer period at the highest doses approved for obesity, does not alter brain activation in response to food cues. A counter‐regulatory increase in reward‐related OFC activation in response to food cues can be observed when neuroimaging data are controlled for BMI changes, indicating changes in CNS that could lead to later plateaus of weight loss. These data point to a promising focus for additional interventions which, by contributing to the CNS reward system, could provide tangible benefits in reversing the plateauing phenomenon and promoting further weight loss.

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