Beta-caryophyllene is a dietary cannabinoid

doi:10.1073/pnas.0803601105

Beta-caryophyllene is a dietary cannabinoid

*Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Eidgenössische Technische Hochschule (ETH) Zurich, 8092 Zürich, Switzerland;
^‡Dipartimento Farmaco Chimico Tecnologico, University of Cagliari, 01924 Cagliari, Italy;
^¶Department of Molecular Psychiatry, University of Bonn, 53115 Bonn Germany; and
^‖Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15260

Edited by L. L. Iversen, University of Oxford, Oxford, United Kingdom, and approved May 6, 2008
↵ ^§M.L. and S.R. contributed equally to this work. (received for review April 14, 2008)

Abstract

The psychoactive cannabinoids from Cannabis sativa L. and the arachidonic acid-derived endocannabinoids are nonselective natural ligands for cannabinoid receptor type 1 (CB₁) and CB₂ receptors. Although 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 functional CB₂ agonist. Intriguingly, (E)-BCP is a common constituent of the essential oils of numerous spice and food plants and a major component in Cannabis. Molecular docking simulations have identified a 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 weakly activates the mitogen-activated kinases Erk1/2 and p38 in primary human monocytes. (E)-BCP (500 nM) inhibits lipopolysaccharide (LPS)-induced proinflammatory cytokine expression in peripheral blood and attenuates LPS-stimulated Erk1/2 and JNK1/2 phosphorylation in monocytes. Furthermore, peroral (E)-BCP at 5 mg/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 nonpsychoactive CB₂ receptor ligand in foodstuff and as a macrocyclic antiinflammatory cannabinoid in Cannabis.

Footnotes

^†To whom correspondence should be addressed. E-mail: juerg.gertsch{at}pharma.ethz.ch
Author contributions: J.G. and M.K. designed research; J.G., M.L., S.R., I.R., and J.-Z.C. performed research; A.Z. contributed new reagents/analytic tools; J.G., X.-Q.X., K.-H.A., M.K., and A.Z. analyzed data; and J.G. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0803601105/DCSupplemental.