Increased AGE-RAGE axis stress in methamphetamine (MA) abuse and MA-induced psychosis: associations with oxidative stress and increased atherogenicity

Background and aims: Methamphetamine (MA)-induced psychosis (MIP) is associated with increased oxidative toxicity (especially lipid peroxidation) and lowered antioxidant defenses. Advanced glycation end products (AGEs) cause oxidative stress upon ligand binding to AGE receptors (RAGE). There are no data on whether MA use may cause AGE-RAGE stress, and whether the latter is associated with MIP. Methods: This case-control study recruited 60 patients with MA use disorder and 30 normal controls and measured serum levels of oxidative stress toxicity (OSTOX, lipid peroxidation), antioxidant defenses (ANTIOX), magnesium, copper, atherogenicity, and AGE, soluble RAGE (sRAGE), and computed a composite reflecting AGE-RAGE axis activity. Findings: MA dependence and use were accompanied by increased AGE, sRAGE, AGE-RAGE, OSTOX/ANTIOX, Castelli risk index 1 and atherogenic index of plasma, indicating that MA causes AGE-RAGE axis stress, oxidative damage, and atherogenicity. The severity of dependence and MA dose were strongly correlated with increased sRAGE concentrations. Increased AGE-RAGE stress was strongly associated with OSTOX, OSTOX/ANTIOX, and MA-induced intoxication symptoms, psychosis, hostility, excitation, and formal thought disorders. We found that 54.8% of the variance in MIP symptoms was explained by the regression on AGE-RAGE, the OSTOX/ANTIOX ratio, lowered magnesium, and increased copper, and that these biomarkers mediated the effects of increasing MA doses on MIP symptoms. We found that 36.0% of the variance in the atherogenicity indices was explained by OSTOX/ANTIOX, AGE-RAGE, and lowered magnesium. Conclusions: MA use causes intertwined increases in AGE-RAGE axis stress and oxidative damage, which together predict the severity of MIP symptoms and increased atherogenicity.