Effect of dulaglutide on functional and structural MRI changes during cigarette smoking cessation

Abstract Glucagon-like peptide-1 (GLP-1) receptor agonists are investigated for treating addiction. However, it remains unclear whether these agents modulate addiction-related neural circuitry. To address this question, we conducted a predefined neuroimaging subtrial of a larger randomized placebo-controlled trial. While the parent trial enrolled 255 participants with at least moderate nicotine dependence, this mechanistic study included a subset of 71 participants. Participants were randomized to receive either 1.5 mg dulaglutide (N = 35) or placebo (N = 36) for 12 weeks, both administered alongside a standard-of-care regimen of varenicline and behavioral counseling. Structural and functional MRI assessments were performed at baseline and after 12 weeks. Main outcome measures included abstinence rates, changes in craving for cigarette smoking, working memory performance, whole-brain functional activation when exposed to smoking and neutral videos, resting state functional connectivity, and grey matter volume changes from baseline to 12 weeks. We found that 12 weeks of intervention (59 participants completed the 12-week visit (N = 57 usable functional, N = 58 usable structural data)), abstinence rates were comparable between the dulaglutide (54%) and placebo (68%) groups (p = 0.27). Across the entire cohort, craving for cigarette smoking significantly decreased (p < 0.001) and was consistently higher during smoking-cue versus neutral-cue videos (p < 0.001). Working memory improved significantly among participants who achieved smoking abstinence (p = 0.02). While we observed small-to-medium reductions in addiction- and reward-related brain activation from baseline to week 12 across the entire cohort, no significant differences were found between dulaglutide and placebo for any clinical, functional, or structural outcomes. Our findings demonstrate that dulaglutide conferred no incremental benefit over a potent standard-of-care regimen of varenicline and behavioral counseling. These findings are critical for the field, as they suggest a potential ceiling effect of current first-line therapies and define the boundaries of GLP-1 receptor agonists in addiction. While dulaglutide did not modulate cue-induced neural activation in this adjunctive context, this study establishes the feasibility of using longitudinal mechanistic neuroimaging to guide the development of future incretin-based interventions.