Discovery of a novel cannabinoid in food

Abstract

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.