The cannabinoid receptor 2 agonist, β-caryophyllene, improves working memory and reduces circulating levels of specific proinflammatory cytokines in aged male mice

Behav Brain Res. 2019 Oct 17;372:112012. doi: 10.1016/j.bbr.2019.112012. Epub 2019 Jun 4.


Age-related cognitive decline has been associated with proinflammatory cytokines, yet the precise relationship between cognitive decline and cytokine load remains to be elucidated. β-caryophyllene (BCP) is a cannabinoid receptor 2 (CB2) agonist with established anti-inflammatory effects that is known to improve memory and increase lifespan. It is of interest to explore the potential of BCP to reduce age-related cognitive decline and proinflammatory cytokine load. In this study, we assessed changes in circulating cytokines across the lifespan, memory performance in young and aged mice, and the effects of BCP on memory function and cytokine load. The plasma levels of 12 cytokines were assessed in male Swiss-Webster mice at 3, 12, and 18 months of age using multiplexed flow cytometry. Working memory was compared in 3 and 12 month-old mice using spontaneous alternations. A dose-response function (100-300 mg/kg, subchronic administration) for BCP-induced memory restoration was determined in 3- and 12- month-old mice. Finally, the effects on cytokine levels of the peak memory enhancing dose of BCP were assessed in 18- month-old mice. Circulating levels of several cytokines significantly increased with age. Multilinear regression analysis showed that IL-23 levels were most strongly associated with age. Aged mice showed deficits in working memory and higher levels of IL-23, both of which were reversed by BCP treatment. BCP appears to reverse age-associated impairments in memory and modulates cytokine production. IL-23 may play a significant role in the aging process, and future research should determine whether it has utility as a biomarker for novel anti-aging therapeutics.

Keywords: CB2; IL-12; IL-23; aging; cytokine; neuroinflammation; working memory; β-caryophyllene.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Cannabinoids / pharmacology
  • Cognitive Dysfunction / drug therapy
  • Cytokines / metabolism*
  • Male
  • Memory, Short-Term / drug effects*
  • Mice
  • Neuroimmunomodulation / drug effects
  • Polycyclic Sesquiterpenes / metabolism
  • Polycyclic Sesquiterpenes / pharmacology*
  • Receptor, Cannabinoid, CB2 / agonists
  • Receptor, Cannabinoid, CB2 / metabolism


  • Cannabinoids
  • Cytokines
  • Polycyclic Sesquiterpenes
  • Receptor, Cannabinoid, CB2
  • caryophyllene