Cytotoxic Effects of the Synthetic Cannabinoid, 5F-MDMB-PICA on Human Glioblastoma U87-MG Cells

Synthetic cannabinoids, particularly 5F-MDMB-PICA, have emerged as potent psychoactive substances, exhibiting a binding affinity to the CB1 receptor approximately 380 times greater than that of Δ9-THC, the principal psychoactive compound in cannabis. Their widespread abuse has been associated with severe intoxication and fatalities globally. This study aimed to investigate the cytotoxic effects and mechanisms of 5F-MDMB-PICA in U87-MG astrocyte-like cells, a common model in neurobiological research. U87-MG cells (passages 7-15) were treated with increasing concentrations of 5F-MDMB-PICA (1-200 μM) for 24 hours. We employed several assays to evaluate cytotoxicity (MTT assay), oxidative stress, mitochondrial membrane potential, cellular migration (wound healing), and cell death (flow cytometry). Additionally, gene expression analysis via qRT-PCR focused on apoptotic and inflammatory markers. A receptor docking study was performed to verify similarities in binding sites between 5F-MDMB-PICA and Δ9-THC. Our results showed that exposure to 5F-MDMB-PICA led to a concentration-dependent increase in cytotoxicity and oxidative stress, alongside a significant decrease in mitochondrial membrane potential. There was a marked elevation in apoptosis and necrosis, coupled with impaired cellular migration. Gene expression analysis revealed significant upregulation of pro-apoptotic and inflammatory genes, such as P53, Bax, TNF-α, and COX-2, indicating a robust pro-apoptotic and pro-inflammatory response. Notably, key residues (Phe200 and Ser383) in the CB1 binding pocket were identified as crucial for the interaction of both compounds, which might provide insight into the shared patterns of cytotoxic effects. These findings highlight the neurotoxic effects of 5F-MDMB-PICA, underscoring the serious public health risks associated with synthetic cannabinoids.