“Mitochondrial autophagy has been regarded as a new signaling pathway for the action of antidepressant drugs.

The neuroprotective properties of the non-psychoactive cannabinoid cannabidiol (CBD) have been demonstrated in different animal models of neurological disorders. However, the therapeutic effect of cannabidiol on neuroinflammation-induced depression and its underlying molecular mechanisms involved has not been comprehensively studied.

In this study, depressive-like behaviors were induced in male C57BL/6 mice by LPS injection, with intragastric administration of CBD (70 or 140 mg/kg/day) for 6 days.

Our results demonstrated that CBD treatment significantly attenuated lipopolysaccharide (LPS)-induced depressive-like behaviors, accompanied by a marked amelioration of synaptic healthiness in the hippocampal region.

CBD effectively inhibited reactive oxygen species production, normalized the levels of oxidative stress markers, and restored superoxide dismutase activity, involving a mechanism that promotes mitochondrial biogenesis and mitophagy. In addition, LPS-induced neuroinflammation was reduced by CBD, as evidenced by a marked decrease in neuroinflammatory activation markers. CBD also inhibited LPS-activated inflammasome activation by targeting NLRP3/IL-1β/Caspase-1 signaling pathway.

These findings suggest that CBD may be a potential therapeutic drug for managing major depressive disorder.”

https://pubmed.ncbi.nlm.nih.gov/41484536

https://link.springer.com/article/10.1007/s12035-025-05614-w