Beta-caryophyllene is a dietary cannabinoid

Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9099-104. doi: 10.1073/pnas.0803601105. Epub 2008 Jun 23.

Abstract

The psychoactive cannabinoids from Cannabis sativa L. and the arachidonic acid-derived endocannabinoids are nonselective natural ligands for cannabinoid receptor type 1 (CB(1)) and CB(2) receptors. Although the CB(1) receptor is responsible for the psychomodulatory effects, activation of the CB(2) receptor is a potential therapeutic strategy for the treatment of inflammation, pain, atherosclerosis, and osteoporosis. Here, we report that the widespread plant volatile (E)-beta-caryophyllene [(E)-BCP] selectively binds to the CB(2) receptor (K(i) = 155 +/- 4 nM) and that it is a functional CB(2) 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 CB(2) receptor, showing ligand pi-pi stacking interactions with residues F117 and W258. Upon binding to the CB(2) 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 CB(2) receptors, providing evidence that this natural product exerts cannabimimetic effects in vivo. These results identify (E)-BCP as a functional nonpsychoactive CB(2) receptor ligand in foodstuff and as a macrocyclic antiinflammatory cannabinoid in Cannabis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Binding Sites
  • Binding, Competitive / drug effects
  • Cannabinoids / administration & dosage
  • Cannabinoids / chemistry
  • Cannabinoids / metabolism*
  • Cannabinoids / pharmacology
  • Cannabis / chemistry
  • Carrageenan
  • Cells, Cultured
  • Computational Biology
  • Diet*
  • Edema / chemically induced
  • Edema / metabolism
  • Enzyme Activation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • Humans
  • Interleukin-1beta / blood
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Ligands
  • Lipopolysaccharides / pharmacology
  • Mice
  • Monocytes / enzymology
  • Oils, Volatile / chemistry
  • Polycyclic Sesquiterpenes
  • Receptor, Cannabinoid, CB2 / agonists
  • Receptor, Cannabinoid, CB2 / metabolism
  • Sesquiterpenes / administration & dosage
  • Sesquiterpenes / chemistry
  • Sesquiterpenes / metabolism*
  • Sesquiterpenes / pharmacology
  • Signal Transduction / drug effects
  • Tumor Necrosis Factor-alpha / blood

Substances

  • Cannabinoids
  • Interleukin-1beta
  • Ligands
  • Lipopolysaccharides
  • Oils, Volatile
  • Polycyclic Sesquiterpenes
  • Receptor, Cannabinoid, CB2
  • Sesquiterpenes
  • Tumor Necrosis Factor-alpha
  • Carrageenan
  • caryophyllene
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • GTP-Binding Protein alpha Subunits, Gi-Go