Cannabidiol alleviates methamphetamine-induced autophagy and oxidative stress by suppressing sigma 1 receptor...

Methamphetamine (METH) is currently considered one of the most notorious drugs globally. Chronic long-term METH abuse results in severe neurotoxicity, wherein oxidative stress and autophagy are key pathological phenomena and toxic phenotypes. However, the molecular mechanism by which METH induces oxidative stress and autophagy remains elusive. In this study, METH-induced autophagy and oxidative stress were replicated in both HT22 cells and C57BL/6 J mice. Notably, METH up-regulated the expression of chaperon protein sigma 1 receptor (S1R). However, METH-induced autophagy and oxidative stress were alleviated after targeted intervention with S1R using the chemical inhibitor, gene knockdown, or knockout techniques. More importantly, cannabidiol (CBD), a non-psychoactive natural cannabinoid derived from cannabis, exhibited therapeutic efficacy by down-regulating the high expression of S1R, autophagy, and oxidative stress following METH exposure both in vivo and in vitro. Overall, these results suggest that METH mediates autophagy and oxidative stress by up-regulating S1R expression, whereas CBD alleviates METH-induced autophagy and oxidative stress by suppressing S1R expression. This study expands our understanding of METH-induced neurotoxicity, identifying S1R as a potential therapeutic target against aberrant autophagy and oxidative stress, and further validates the medical value of CBD for the treatment of METH use disorder.