João Antônio Valadão Leal, Thiago Wendt Viola, Rodrigo Grassi-Oliveira
Substance-use disorders are increasingly linked to structural and functional brain alterations consistent with neuroaxonal injury. Neurofilament light chain (NfL) is a sensitive blood-based marker of axonal damage, but evidence in substance-using populations remains fragmented. We systematically reviewed and meta-analyzed blood NfL levels in individuals who use psychoactive substances compared with controls. This PRISMA-guided systematic review and meta-analysis was registered in PROSPERO (CRD420251270728). MEDLINE, PubMed, Embase, and Scopus were searched from inception through August 23, 2026, without language or publication-date restrictions. Eligible observational studies measured blood NfL in plasma, serum, or whole blood among individuals with psychoactive substance use and controls. Effect sizes were calculated as geometric mean ratios (GMRs). Multilevel random-effects models accounted for correlated comparisons within studies, and meta-regression explored demographic, clinical, and methodological moderators. Eleven studies comprising 16 comparisons were included. Overall, individuals who use substances had significantly higher blood NfL levels than controls (GMR = 1.81, 95% CI: 1.49-2.20). Alcohol-specific analyses showed a larger pooled effect (GMR = 2.09, 95% CI: 1.62-2.70). In studies restricted to SIMOA assays, the association remained significant, although attenuated (GMR = 1.64, 95% CI: 1.41-1.91). Meta-regression indicated that higher male representation was associated with larger effect sizes, while most clinical and methodological moderators were nonsignificant. Graphical diagnostics did not suggest marked publication bias. Overall, substance use was associated with higher circulating NfL, a non-specific signal consistent with increased neurobiological burden but not sufficient on its own to establish the presence, anatomical source, or cause of neuroaxonal injury.