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

Background: Chronic 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. Aims: The purpose of this study was to investigate the relationships between neurocognition, the aforementioned biomarkers, and psychotic symptoms. Methods: We 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. Results: We 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. Conclusions: The 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement There was no specific funding for this specific study. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Following the International Guideline for Human Research Protection of the Declaration of Helsinki, the study was approved by the institutional review board (IRB) of the College of Science, University of Kufa, Iraq (89/2022), Karbala Health Directorate-Training and Human Development Center (Document No.18378/2021). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The dataset generated and/or analyzed during the current research period will be provided upon reasonable request from the corresponding author (MM) and after the author fully utilizes the dataset.