White matter signatures of addiction diverge across opioids, cannabis and nicotine and predict impulsive choice in cannabis dependence

Abstract White matter (WM) microstructure is implicated in the neurobiology of substance use disorders (SUDs), yet direct comparisons across substance-dependence syndromes remain scarce. It is also unclear whether WM abnormalities relate to impulsive decision-making and substance use severity. We performed a cross-sectional, dual-centre diffusion MRI study and quantified WM microstructure using diffusion tensor imaging and neurite orientation dispersion and density imaging in 87 individuals with SUDs (48 with cannabis dependence (CUD), 16 with opioid dependence (OUD), and 23 with nicotine dependence (NUD)) and 53 nonsmoking healthy controls. Whole-brain tract-based spatial statistics and tract-specific analyses of the middle longitudinal fasciculus (MLF), a temporo-parietal tract implicated in cognitive control and valuation, were performed. OUD and CUD exhibited convergent, widespread WM abnormalities characterised by reduced fractional anisotropy and increased mean diffusivity and orientation dispersion across fronto-temporo-parietal and limbic pathways, including the superior longitudinal fasciculus, arcuate fasciculus, cingulum, and MLF. In contrast, NUD showed more circumscribed alterations observed primarily in MD and localised mainly to anterior and callosal white matter regions. In CUD, higher MLF orientation dispersion was associated with steeper delay discounting (r = 0.41, p = 0.011). Moderated mediation analyses indicated that this association was indirectly driven by cannabis consumption, with asignificant conditional indirect effects observed only among daily users. No significant MLF-discounting associations were observed in OUD. Our findings reveal both shared and distinct WM alterations across SUDs and identify a link between MLF microstructure and impulsive choice in cannabis dependence.