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 used fMRI paradigm for studying substance use disorders (SUDs), yet its link to behaviour remains inconsistent due to methodological and clinical heterogeneity.In this systematic review and activation likelihood estimation (ALE) meta-analysis of 92 fMRI studies, we examined how design-related factors (fMRI design, control condition valence, stimulus matching for action/tool-related content) and clinical factors (treatment compliance, drug use severity) influence neural DCR. In addition to identifying the main DCR effect and meta-analytic connectivity, we conducted contrast analyses and fitted penalised logistic regression models to assess whether specific factor levels and their interactions predicted regional DCR replicability.Results revealed that bilateral temporo-occipital regions and fusiform gyri were more commonly engaged when drug and control stimuli were not well matched for action/tool content. The superior parietal lobule was more frequently involved in treatment-compliant samples. Higher drug use severity was linked to greater involvement of the left amygdala and decreased engagement of medial prefrontal and anterior cingulate cortices – key anterior default mode network (DMN) nodes. Notably, the decline in anterior DMN activity was amplified by both treatment compliance and control condition valence, indicating a progressive reduction in the motivational value of drug cues as drug use severity increases.We conclude that DCR is remarkably interspersed by visual confounds and, clinically, may be sensitive to individual differences in drug “liking” and drug devaluation. These findings have implications for understanding the neural mechanisms of SUD and for improving the translational utility of DCR in predicting patient-relevant outcomes.