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

Apr 27, 2026Neuro-Signals

Melatonin’s protective role against methamphetamine-caused brain cell death through daily rhythm and iron-related pathways

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Melatonin inhibits all programmed cell death pathways activated by methamphetamine (METH) neurotoxicity.

METH abuse affects 34 million individuals globally and causes severe neurotoxicity.
METH activates distinct cell death pathways: apoptosis, pyroptosis, necroptosis, and ferroptosis.
Melatonin may protect against these pathways through antioxidant and anti-inflammatory effects.
A circadian-ferroptosis link suggests that disruptions in circadian rhythms could influence ferroptosis.

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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.

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

Abstract

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