Systemic Biomarker Alterations in Alcohol and Psychoactive Substance Users: A Cross-Sectional Study.

Substance use disorders (SUDs) are increasingly associated with systemic inflammatory, neuroendocrine, and cardiometabolic dysregulation; however, the biological signatures underlying distinct substance-use patterns remain incompletely characterized. This study compared biomarker profiles among healthy controls and clinical groups comprising alcohol-associated polysubstance users (A + PS), non-alcohol substance users (PS-A), and alcohol-associated polysubstance users with comorbid post-traumatic stress disorder (PTSD+). Plasma levels of interleukin-6 (IL-6), C-reactive protein (CRP), cortisol, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were evaluated through comparative, multivariate, dose-response, and receiver operating characteristic (ROC) curve analyses. All clinical groups exhibited significantly increased IL-6, CRP, cortisol, and NT-proBNP levels compared with controls, indicating systemic physiological dysregulation associated with substance exposure. Among the evaluated biomarkers, IL-6 demonstrated the most robust and consistent performance across all analytical approaches. Multivariate regression identified alcohol consumption as an independent predictor of IL-6 elevation (p = 0.0003), while dose-response analysis revealed progressive increases in IL-6 according to alcohol consumption severity. ROC analysis further demonstrated that IL-6 exhibited the highest discriminatory performance (AUC = 0.844), outperforming CRP, cortisol, and NT-proBNP in distinguishing substance-using individuals from controls. Collectively, these findings were able to identify IL-6 as a central biomarker associated with substance-related systemic inflammatory dysregulation and support its translational potential as a sensitive indicator of physiological burden associated with chronic alcohol and substance exposure.