Cytotoxicity of synthetic cannabinoids found in "Spice" products: the role of cannabinoid receptors and the caspase cascade in the NG 108-15 cell line.

The worldwide distribution of "Spice" that contains synthetic cannabinoids with a pharmacological activity similar to Δ⁹-tetrahydrocannabinol has been reported. In the current study, we evaluated the cytotoxicity of the synthetic cannabinoids, CP-55,940, CP-47,497 and CP-47,497-C8 towards NG 108-15 cells and investigated their mechanism of cytotoxicity. CP-55,940, CP-47,497 and CP-47,497-C8 were all cytotoxic for NG 108-15 cells in a concentration-dependent manner. The cytotoxicity of these synthetic cannabinoids was suppressed by preincubation with the selective CB₁ receptor antagonist AM251, but not with the selective CB₂ receptor antagonist AM630. Preincubation with a caspase-3 inhibitor significantly suppressed the cytotoxicity of these synthetic cannabinoids for NG 108-15 cells. Induction of apoptosis by these cannabinoids was also confirmed by staining of the cells with annexin V. Our results indicate that the cytotoxicity of synthetic cannabinoids towards NG 108-15 cells is mediated by the CB₁ receptor, but not by the CB₂ receptor, and further suggest that caspase-cascades may play an important role in the apoptosis induced by these synthetic cannabinoids.