The evolution of addiction neurobiology highlights the limitations of conventional acute-phase pharmacological treatments in preventing long-term relapse. Chronic substance abuse triggers severe metabolic breakdown, neuroinfl ammation, mitochondrial dysfunction, and oxidative stress within the central nervous system, impairing the homeostasis of the glutamatergic system. This neuroprogressive state compromises prefrontal executive control, exacerbating craving and vulnerability to stress-induced relapse. Addressing this underlying biological deficit requires innovative therapeutic strategies aimed at restoring cellular homeostasis and neural plasticity. In this context, the complementary nutraceutical approach using N-acetylcysteine (NAC) and alpha-lipoic acid (ALA) represents a promising adjuvant intervention. NAC acts by restoring astrocytic glutamate homeostasis via the xCT exchanger and enhancing intracellular glutathione synthesis, thereby attenuating cueinduced craving. Concurrently, ALA supports mitochondrial bioenergetics, activates the Nrf2 antioxidant response pathway, and recycles endogenous antioxidants. Together, NAC and ALA offer a synergistic mechanism to mitigate neurotoxicity, alleviate neuroinflammation, and preserve cognitive function, providing a rationale-driven framework for relapse prevention and long-term neurocognitive rehabilitation.
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