Discovery of a novel cannabinoid in food

The psychoactive cannabinoids from Cannabis sativa L. and the arachidonic acid-derived endocannabinoids are non-selective natural ligands for CB₁ and CB₂ receptors. While the CB₁ receptor is responsible for the psychomodulatory effects, activation of the CB₂ receptor is a potential therapeutic strategy for the treatment of inflammation, pain, atherosclerosis, and osteoporosis. Here we report that the widespread plant volatile (E)-β-caryophyllene ((E)-BCP) selectively binds to the CB₂ receptor (K _i=155±4 nM) and that it is a fully functional CB₂ agonist. Intriguingly, (E)-BCP is a common constituent of the essential oils of different food and spice plants, as well as a major component in Cannabis. Molecular docking simulations identify the putative binding site of (E)-BCP in the CB₂ receptor, showing ligand π-π stacking interactions with residues F117 and W258. Upon binding to the CB₂ receptor, (E)-BCP inhibits adenylate cylcase, leads to intracellular calcium transients and a weak activation of the mitogen-activated kinases Erk1/2 and p38 in primary human monocytes. (E)-BCP (500 nM) inhibits LPS-induced pro-inflammatory cytokine expression in peripheral blood and attenuates LPS-stimulated Erk1/2 and JNK1/2 phosphorylation in monocytes in an apparently CB₂ receptor-dependent manner. Furthermore, peroral (E)-BCP (5mg/Kg) strongly reduces the carrageenan-induced inflammatory response in wild type mice but not in mice lacking CB₂ receptors, providing evidence that this natural product exerts cannabimimetic effects in vivo. These results identify (E)-BCP as a functional non-psychoactive CB₂ receptor ligand in foodstuff and as a novel macrocyclic anti-inflammatory cannabinoid in Cannabis.

References: Gertsch et al. (2008) Proc. Natl. Acad. Sci. (PNAS), in press