A Comprehensive Review of Melatonin as Multi-Pathway Neuroprotectant Against Methamphetamine-Induced Programmed Cell Death: Discovery of the Circadian-Ferroptosis Axis

INTRODUCTION: Methamphetamine (METH) abuse affects 34 million individuals globally, causing severe neurotoxicity through multiple programmed cell death (PCD) pathways. No approved pharmacotherapies exist. We comprehensively examined melatonin's neuroprotective mechanisms against METH-induced apoptosis, pyroptosis, necroptosis, and ferroptosis. METHODS: A comprehensive review of preclinical studies examining METH neurotoxicity mechanisms and melatonin's protective effects across all PCD pathways. RESULTS: METH activates apoptosis, pyroptosis, necroptosis, and ferroptosis via distinct molecular pathways. Melatonin inhibits all pathways through antioxidant, mitochondrial, anti-inflammatory, and direct signaling effects. A circadian-ferroptosis axis was identified, linking circadian disruption to ferroptosis. CONCLUSIONS: Melatonin exhibits strong multi-target neuroprotection and represents a promising candidate for clinical translation.