Neuroinflammation and Oxidative Stress in Methamphetamine-Induced Psychosis: Mechanisms and the Therapeutic Potential of Melatonin as a Neuroprotective Agent

<p>Methamphetamine-induced psychosis (MAP) is a prevalent and severe complication among methamphetamine (MA) users. Although current treatment follows antipsychotic-based strategies mirroring schizophrenia (SCZ) management, a substantial proportion of patients experience treatment failure, disease progression, or adverse effects, highlighting the need for novel treatment options. Emerging evidence suggests that MAP pathophysiology extends beyond neurotransmitter dysregulation to encompass immune disturbances and oxidant/antioxidant imbalance. MAP is characterized by a significant decrease across all immunological profiles, with the compensatory immune-regulatory reflex system (CIRS) being particularly depleted, thereby contributing to a selective upregulation of pro-inflammatory cytokines including IL-1α, CCL5, and IL-12p70, reflecting an aberrant immune-inflammatory response system (IRS)/CIRS imbalance that is distinct from patterns observed in SCZ, major depressive disorder, and bipolar disorder. MAP development is also associated with reduced antioxidant defense, increased advanced glycation end products (AGEs) and its soluble receptor sRAGE, circadian and mitochondrial dysregulation, and an increased oxidant/antioxidant ratio that correlates with psychosis severity. This narrative review is among the first to synthesize these two complementary pathways – IRS/CIRS imbalance and AGE/RAGE axis stress – within a unified neuroimmune-oxidative-circadian-mitochondrial framework of MAP pathophysiology. Building on this framework, melatonin, given its anti-inflammatory, antioxidant, circadian and mitochondria-optimizing properties, emerges as a promising adjunctive neuroprotective candidate. However, there is a lack of clinical evidence to establish the efficacy of melatonin in MAP patients. Future research priorities include randomized controlled trials of melatonin in MAP, investigation of mirtazapine and other adjunctive candidates, and exploration of metabolic disturbances as an additional etiological pathway in MAP.</p>