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

Nkrumah R.; Wetzel L.; Böhmer J.; Eidenmueller K.; Bach P.; De Santis S.; Walter H.; Sommer W.; Ende G. · Translational psychiatry · 2026

**Background & Methods** This cross-sectional, dual-centre diffusion MRI study compared white matter (WM) microstructure across substance use disorders in 87 individuals with cannabis dependence (CUD, n=48), opioid dependence (OUD, n=16), nicotine dependence (NUD, n=23), and 53 healthy controls. WM microstructure was quantified using diffusion tensor imaging and neurite orientation dispersion and density imaging with whole-brain tract-based spatial statistics and tract-specific analyses of the middle longitudinal fasciculus (MLF). **Key Findings** • OUD and CUD showed convergent, widespread WM abnormalities characterized 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. NUD demonstrated more circumscribed alterations localized primarily to anterior and callosal white matter regions, suggesting substance-specific WM signatures. • In CUD, higher MLF orientation dispersion was significantly associated with steeper delay discounting (r=0.41, p=0.011), indicating a relationship between WM microstructure and impulsive decision-making. Moderated mediation analyses revealed this association was indirectly driven by cannabis consumption frequency, with significant effects observed only among daily users. • No significant MLF-discounting associations were identified in OUD, highlighting that the WM-impulsivity link is specific to cannabis dependence rather than a universal feature across SUDs. **Dosage & Administration** Not reported. **Safety & Adverse Effects** Not reported. **Evidence Quality** Study limitations include the cross-sectional design preventing causal inference, relatively small sample sizes particularly for OUD (n=16), and lack of longitudinal follow-up to establish temporal relationships between WM changes and behavioral outcomes. The dual-centre design enhances generalizability but may introduce site-related variability. The specificity of MLF-discounting associations to daily cannabis users suggests consumption frequency is a critical moderator, though this limits applicability to less frequent users. Findings are strengthened by objective neuroimaging biomarkers and standardized diffusion MRI protocols; however, the lack of neuropsychological testing beyond delay discounting limits understanding of broader cognitive domains affected. This represents moderate-quality evidence (observational study) identifying novel WM signatures differentiating SUDs and their behavioral correlates, warranting validation in larger prospective cohorts.

More recent cannabis research