Appetite effects of prefrontal stimulation depend on COMT Val158Met polymorphism: A randomized clinical trial

The regulation of appetite is supported by dopamine-modulated brain circuits. Recent studies have shown that transcranial direct current stimulation (tDCS) aimed at increasing the excitability of the dorsolateral prefrontal cortex can reduce appetite, but the underlying mechanisms remain unknown, and response variability is large. The aim of this study was to determine whether individual differences in Catechol-O-methyl transferase (COMT) Val158Met polymorphism can influence tDCS effects on appetite. Thirty-eight adult women with obesity, classified as carriers or non-carriers of the Met allele, underwent a randomized, double-blind, sham-controlled tDCS intervention involving three phases: Phase I, target engagement (immediate effects of tDCS on working memory performance), Phase II, tDCS only (10 sessions, two weeks), and Phase III, tDCS + hypocaloric diet: (6 sessions, two weeks, 30% energy intake reduction, inpatient). Data were analyzed using linear mixed-effects models and mixed ANCOVA. Appetite was evaluated using visual analogue scales. We found that Met-carriers receiving active tDCS were the only participants who experienced a significant reduction of appetite over time. Conversely, Met non-carriers maintained high levels of appetite during the intervention; this effect was driven by a delayed paradoxical rise in appetite after stimulation. Working memory task performance at phase I correlated with subsequent appetite change in a COMT-dependent manner: speed improvements during the task predicted appetite increase in Met carriers and appetite reduction in Met non-carriers. Our findings suggest that genotype differences impacting dopamine levels influence prefrontal tDCS effects on appetite. This source of variability should be considered in the design of future studies.