The general neurocognitive decline in patients with methamphetamine (MA) use and transient MA-induced psychosis is primarily determined by oxidative and AGE-RAGE stress.

BackgroundChronic methamphetamine (MA) usage is linked to oxidative stress (OS), AGE-RAGE stress, changes in magnesium, calcium, and copper, increased psychotic symptoms and neurocognitive deficits. Nevertheless, it is still unclear whether the latter impairments are mediated by these biological pathways. AimsThe purpose of this study was to investigate the relationships between neurocognition, the aforementioned biomarkers, and psychotic symptoms. MethodsWe recruited 67 participants, namely 40 patients diagnosed with MA-substance use and 27 healthy controls, and assessed the Brief Assessment of Cognition in Schizophrenia (BACS), symptoms of psychosis, excitation, and formal thought disorders, OS toxicity (computed as the sum of myeloperoxidase (MPO), oxidized high-density lipoprotein (HDL), oxidized low-DL, and malondialdehyde), antioxidant defenses (catalase, glutathione peroxidase, total antioxidant capacity, zinc, and HDL), increased advanced glycation end products (AGEs), and soluble AGE receptors. ResultsWe were able to extract one validated latent vector from the Mini Mental State Examination score and the BACS tests results (including executive functions, verbal fluency, attention), labeled general cognitive decline (G-CoDe). We found that 76.1% of the variance in the G-CoDe was explained by increased OS toxicity, lowered antioxidant defenses, number of psychotic episodes, and MA dose. In patients with MA use, MPO was significantly associated with the G-CoDe. ConclusionsThe use of MA induces mild cognitive impairments through MA-induced activation of detrimental outcome pathways, including oxidative and AGE-RAGE stress, and suppression of protective outcome pathways (antioxidants). Increased OS, MPO, and AGE-RAGE stress are new drug targets to prevent neurocognitive deficits and psychosis due to MA use.