“Cannabidiol (CBD), a non-psychoactive cannabinoid, shows great promise in treating methamphetamine (METH) addiction. Nonetheless, the molecular target and the mechanism through which CBD treats METH addiction remain unexplored.

Herein, CBD was shown to counteract METH-induced locomotor sensitization and conditioned place preference. Additionally, CBD mitigated the adverse effects of METH, such as cristae loss, a decline in ATP content, and a reduction in membrane potential. Employing an activity-based protein profiling approach, a target fishing strategy was used to uncover CBD’s direct target.

ATP5A1, a subunit of ATP synthase, was identified and validated as a CBD target. Moreover, CBD demonstrated the ability to ameliorate METH-induced ubiquitination of ATP5A1 via the D376 residue, thereby reversing the METH-induced reduction of ATP5A1 and promoting the assembly of ATP synthase. Pharmacological inhibition of the ATP efflux channel pannexin 1, blockade of ATP hydrolysis by a CD39 inhibitor, and blocking the adenosine A1 receptor (A1R) all attenuated the therapeutic benefits of CBD in mitigating METH-induced behavioral sensitization and CPP. Moreover, the RNA interference of ATP5A1 in the ventral tegmental area resulted in the reversal of CBD’s therapeutic efficacy against METH addiction.

Collectively, these data show that ATP5A1 is a target for CBD to inhibit METH-induced addiction behaviors through the ADO-A1R signaling pathway.”

https://pubmed.ncbi.nlm.nih.gov/41132843/

“This study verifies that ATP5A1 directly binds with CBD both in vitro and in vivo, counteracting METH-triggered ATP5A1 ubiquitination and enhancing the assembly of ATP synthase, thereby preventing METH-induced mitochondrial damage. Additionally, CBD inhibits METH-induced addictive behaviors through the ADO–A1R signaling pathway. The results indicate that CBD alleviates methamphetamine addiction by targeting ATP5A1. Besides METH, CBD has shown potential therapeutic effects on addiction to opioids¹⁸ and THC⁶⁶. This implies that CBD has therapeutic potential for various forms of substance abuse. Consequently, ATP5A1 may serve as a target in the treatment of polysubstance use disorders, which warrants further exploration.”

https://www.sciencedirect.com/science/article/pii/S221138352500560X?via%3Dihub