The modulatory effects of design-related and clinical factors in neural drug cue reactivity: An ALE meta-analysis

Drug cue reactivity (DCR) is the most widely applied fMRI task in addiction neuroscience, yet its translational potential remains limited by unresolved methodological and clinical heterogeneity. In this systematic review and activation likelihood estimation (ALE) meta-analysis of 92 fMRI studies comprising 3647 participants, we examined how design-related factors (fMRI design, control condition valence, stimulus matching) and clinical factors (treatment compliance, drug use severity, common substance classes) shape neural DCR. Beyond identifying the core DCR pattern and its meta-analytic connectivity profiles, we conducted contrast analyses and penalised logistic regression to test whether these factors predicted regional replicability. Our results revealed that both design-related and clinical factors exert systematic modulatory influences. Default-mode network (DMN) regions dominated the core DCR pattern, yet anterior DMN contributions declined with increasing drug use severity. Conversely, amygdala involvement was more frequently observed in severe drug use and in substance classes other than alcohol and nicotine. Treatment-compliant samples showed heightened DCR in superior parietal regions. Importantly, temporo-occipital and fusiform activations were consistently linked to insufficiently matched task designs, revealing that the literature is densely interspersed with visual confounds. Taken together, these findings demonstrate that heterogeneity in task design and clinical characteristics systematically shapes neural DCR. They also illustrate the promise of extending beyond prevailing conditioning accounts toward models that emphasise context, motivation, and value-based encoding. We propose that advancing the translational utility of DCR will depend on rigorous task validation and design, consistent reporting standards, and theoretical frameworks expansive enough to embrace the multifaceted processes reflected in DCR.