Mazin Fadhil Altufaili

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.

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.

Background: a significant percentage of methamphetamine (MA) dependent patients develop psychosis. The associations between oxidative pathways and MA-induced psychosis (MIP) are not well delineated. Objective: the aim of this study is to delineate whether acute MA intoxication in MA dependent patients is accompanied by increased nitro-oxidative stress and whether the latter is associated with MIP. Method: we recruited 30 healthy younger males and 60 acutely intoxicated males with MA dependence and assessed severity of MA use and dependence and psychotic symptoms during intoxication, and serum oxidative toxicity (OSTOX) biomarkers including oxidized high (oxHDL) and low (oxLDL)-density lipoprotein, myeloperoxidase (MPO), malondialdehyde (MDA), and nitric oxide (NO), and antioxidant defenses (ANTIOX) including HDL-cholesterol, zinc, glutathione peroxidase (GPx), total antioxidant capacity (TAC), and catalase-1. Results: a large part (50%, n = 30) of patients with MA dependence could be allocated to a cluster characterized by high psychosis ratings including delusions, suspiciousness, conceptual disorganization and difficulties abstract thinking and an increased OSTOX/ANTIOX ratio. Partial Least Squares analysis showed that 29.9% of the variance in MIP severity (a first factor extracted from psychosis, hostility, excitation, mannerism, and formal thought disorder scores) was explained by HDL, TAC and zinc (all inversely) and oxLDL (positively). MA dependence and dosing explained together 44.7% of the variance in the OSTOX/ANTIOX ratio. Conclusions: MA dependence and intoxication are associated with increased oxidative stress and lowered antioxidant defenses, both of which increase risk of MIP during acute intoxication. MA dependence is accompanied by increased atherogenicity due to lowered HDL and increased oxLDL and oxHDL.

Background A significant percentage of methamphetamine (MA) dependent patients develop psychosis. However, the associations between oxidative pathways and MA-induced psychosis (MIP) are not well delineated. Objective The aim of this study is to delineate whether acute MA intoxication in MA dependent patients is accompanied by increased nitro-oxidative stress and whether the latter is associated with MIP. Method We recruited 30 healthy males and 60 acutely intoxicated MA males with MA dependence and assessed severity of MA use and dependence and psychotic symptoms during intoxication and measured serum oxidative toxicity (OSTOX) biomarkers including oxidized high (oxHDL) and low (oxLDL)-density lipoprotein, myeloperoxidase (MPO), malondialdehyde (MDA), and nitric oxide (NO), and antioxidant defenses (ANTIOX) including HDL-cholesterol, zinc, glutathione peroxidase (GPx), total antioxidant capacity (TAC), and catalase-1. Results A large part (50%, n=30) of patients with MA dependence could be allocated to a cluster characterized by high psychosis ratings including delusions, suspiciousness, conceptual disorganization and difficulties abstract thinking and an increased OSTOX/ANTIOX ratio. Partial Least Squares analysis showed that 29.9% of the variance in MIP severity (a first factor extracted from psychosis, hostility, excitation, mannerism, and formal thought disorder scores) was explained by HDL, TAC and zinc (all inversely) and oxLDL (positively). MA dependence and dosing explained together 44.7% of the variance in the OSTOX/ANTIOX ratio. Conclusion MA dependence and intoxication are associated with increased oxidative stress and lowered antioxidant defenses, which both increase risk of MIP during acute intoxication. MA dependence is accompanied by increased atherogenicity due to lowered HDL and increased oxLDL and oxHDL.