Cannabidiol attenuates methamphetamine-induced psychosis via anti-oxidative stress: σ1R-mediated mitochondrial dysfunction as a critical pathway.

BACKGROUND

Methamphetamine-induced psychosis (MIP) occurs in 26-46% of chronic METH users, yet its pathogenesis and effective treatments remain unclear. Cannabidiol (CBD), a neuroprotective phytocannabinoid, exhibits antioxidant effects and has shown therapeutic potential in neuropsychiatric disorders.

PURPOSE: This study aimed to elucidate CBD's therapeutic mechanisms against MIP, focusing on Sigma-1 receptor (σ1R)-mediated mitochondrial dysfunction.

METHODS

We employed in vitro and in vivo METH-exposure models. MIP-related behaviors were assessed using the open field, elevated plus maze, novel object recognition, Y-maze, and Morris water maze tests. Network pharmacology was used to identify CBD targets associated with MIP. Molecular analyses included assessments of neuronal morphology, oxidative stress markers, mitochondrial superoxide, and Ca²⁺ levels in the mouse hippocampus and HT22 cells. To modulate σ1R function, genetic knockout or overexpression strategies were employed. The interaction between CBD and σ1R was investigated using molecular dynamics simulations and surface plasmon resonance (SPR).

RESULTS

We found that CBD (40 mg/kg) alleviated METH-induced anxiety-like behaviors and cognitive deficits in mice. Network pharmacology revealed that CBD alleviated MIP through anti-oxidative stress. CBD also reduced neuronal damage, mitochondrial superoxide production, membrane potential loss, and Ca²⁺ dysregulation in the mouse hippocampus and HT22 cells. Mechanistically, the neuroprotective effects of CBD were recapitulated by σ1R knockout or inhibition and diminished by its overexpression; this functional link was supported by molecular dynamics simulations and SPR assays, which confirmed stable CBD-σ1R binding.

CONCLUSION

CBD alleviates METH-induced anxiety-like behaviors, cognitive impairments, and hippocampal neuronal damage in mice by attenuating σ1R-mediated mitochondrial oxidative stress and Ca²⁺ overload.