Effects of substance use disorder on oxidative and antioxidative stress markers: A systematic review and meta-analysis

Abstract

Recently, it has been suggested that central and peripheral toxicities identified in persons with substance use disorder (SUD) could be partially associated with an imbalance in reactive oxygen species and antioxidant defenses. We conducted a systematic review and meta-analysis to investigate whether SUD is associated with oxidative stress and to identify biomarkers possibly more affected by this condition. We have included studies that analysed oxidant and antioxidant markers in individuals with SUD caused by stimulants, alcohol, nicotine, opioids, and others (cannabis, inhalants, and polysubstance use). Our analysis showed that persons with SUD show higher oxidant markers and lower antioxidant markers than healthy controls. SUD was associated specifically with higher levels of oxidant markers malondialdehyde, thiobarbituric acid reactive substances and lipid peroxidation. Conversely, the antioxidant superoxide dismutase and the total antioxidant capacity/status were lowered in the SUD group. A meta-regression analysis revealed that persons with alcohol use disorder had higher oxidative stress estimates than those with stimulant use disorder. Moreover, individuals evaluated during abstinence showed smaller antioxidant effect sizes than non-abstinent ones. Our findings suggest a clear oxidative imbalance in persons with SUD, which could lead to cell damage and result in multiple associated comorbidities, particularly accelerated aging.

Keywords: aging; antioxidants; illicit drugs; meta-analysis; oxidative stress; substance-related disorders.

FIGURE 1

Flowchart of the systematic review. SUD, substance use disorder

FIGURE 2

Forest plots. A: Grouped meta‐analysis of substance use disorder (SUD) effects on oxidant/antioxidant markers; B: malondialdehyde (MDA) meta‐analysis; C: superoxide dismutase (SOD) meta‐analysis; D: thiobarbituric acid reactive substance (TBARS) meta‐analysis; E: total antioxidant capacity status (TACS) meta‐analysis; F: lipid peroxidation (LP) meta‐analysis. Negative values indicate a significant reduction whereas positive values indicate a significant increase; red indicates oxidant markers; blue indicates antioxidant markers. CI, confidence interval; RE, random‐effects; SMD, standardized mean difference

FIGURE 3

Oxidative stress and substance use disorders. The lifestyle and adverse environmental exposure related to substance use disorders (SUD) are characterized by chronic stress, use of multiple drugs, increased exposure to infections, financial problems, sleep disturbances, insufficient exercise and poor nutrition. All those factors are associated with the activation of the immune system and oxidative stress. NADPH oxidases, xanthine oxidase and the mitochondrial electron‐transport chain can act as active sources of reactive oxygen species (ROS), mainly producing the radical superoxide. SUD can increase reactive oxygen species (ROS) production and negatively affect enzymatic and non‐enzymatic antioxidant capacity. As an effect of this imbalance, biomolecules such as lipids, proteins and DNA can be modified by ROS, having their function disrupted and even ending up in cell death. Participants with SUD, particularly alcohol use disorder, presented elevated levels of lipid damage biomarkers (malondialdehyde [MDA], thiobarbituric acid reactive substances [TBARSs] and lipid peroxidation), reduced superoxide dismutase (SOD) activity and a reduction of total antioxidant capacity (TAC). These results can help to explain the cellular mechanisms and metabolic changes associated with SUD, particularly outcomes related with accelerated ageing. CAT, catalase; Fe, iron; GPx, glutathione peroxidase; H, hydrogen; H₂O, water; H₂O₂, hydrogen peroxide; NADPH, reduced nicotinamide adenine dinucleotide phosphate; O₂, oxygen; ${\mathrm{O}}_2^{•-}$, radical superoxide; ^•OH, radical hydroxyl; ROS, reactive oxygen species. Created with BioRender.com