Molecular mechanisms and treatment strategies for methamphetamine‑induced neurodegeneration, inflammation and neurotoxicity

Methamphetamine (METH) is a highly addictive psychostimulant known for its profound impact on the nervous system. Chronic METH use leads to neurotoxicity characterized by various molecular and structural alterations in the brain. This review article primarily aims to elucidate the mechanisms underlying METH‑induced neurotoxicity. METH’s mechanism of action involves the inhibition of dopamine, serotonin, and norepinephrine reuptake, resulting in altered synaptic function. Prolonged METH exposure triggers oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, impaired axonal transport, autophagy, and programmed cell death, ultimately contributing to neurotoxicity. These neurotoxic effects manifest as increased neuronal firing rate, disruptions in intracellular ion balance (Ca2+ and Na+), energy production imbalances, and excessive reactive oxygen species production. The blood‑brain barrier is compromised, leading to structural, functional, and neurochemical alterations, particularly in the fronto‑striatal circuit. While our comprehensive review addresses these intricate molecular and structural changes induced by METH, we also examined the latest therapeutic strategies designed to mitigate neurotoxicity. Our investigation sheds light on the critical need to comprehend the complex pathways underlying METH‑induced neurotoxicity and develop effective treatment approaches.