ß-caryophyllene introduction

ß-caryophyllene is a terpene that makes up about 35% of Cannabis sativa L essential oils. This compound is also found in These authors reminded the readers that is found in black pepper, oregano, and cinnamon. ß-caryophyllene is a full agonist of CB2 ands binds to the THC site of CB2. The (E) enantomer of ß-caryophyllene binds with and affinity of Ki = 155 ± 4 nM. Like the endocannabinoid 2-AG, ß-caryophyllene acts via the Go pathway that results in an increase in intracellular Ca2+. The (E) enantomer is anti-inflammatory in nature. It reduces monocyte activation by lipopolysaccharide and edema induced when carrageenan is injected into wild type mice.[1]

PPAR-γ, or peroxisome proliferator-activated receptor gamma receptors are proteins in the nucleus that bind fatty acids, hypolipidemic drugs, and many lipid like substances in foods. PPAR-γ and its binding partner the retinoid X receptor regulate the transcription of various genes.

PGC1α is how many signaling pathways impact gene transcription. Normal physiological adaptation to dyslimidemia depend on the coorination of two transcriptional regulators: PPAR-γ and its coactivator PPAR-γ PPAR gamma coactivator 1α (PGC1α ). [2]. Lipid-induced insulin resistance occurs when β-oxidation genes are up regulated without a commensurate up regulation of TCA cycle genes.

In 2007 exercise was shown to restore this coupling by activating PGC1α, [2] , Suppression of this coupling by overfeeding may contribute to diet-induced mitochondrial dysfunction. [2] Could exercise release of endocannabinoids be the missing link to preventing insulin resistance and mitochondrial dysfunction?

PGC1α is also expressed in another tissue of high energy metabolism: the brain. [3] It is important in the transcription of various genes controlling glucose transport, proteins like the superoxide dismutases, and mitochondrial biogenesis and respiration, [3] These authors mentioned that PGC1α can be regulated by phosphorylation [3], but did not say if the kinases were those activated by G protein coupled receptor pathways. PPARγ interaction is mediated by PPARγ ligands such as fatty acids and eicosanoids. [3] Endocannabinoids and eicosanoids are both derivatives of arachidonic acid. This will come into a play in the use of a PPARγ antagonist in the featured ß-caryophyllene study.

Featured ß-Caryophyllene Study

The featured study came out of Egypt. [4] The authors were particularly concerned about the effects of the high fructose, high fat Western diet on the prefrontal cortex. [1] Male Wistar rats were fed a high fructose corn syrup and high fat for 12 weeks to develop insulin resistance. [4] Rats were assigned to these groups [4]

  1. Regular rat chow (21% crude protein, 3,48% crude fat, 3.74% crude fiber) and tap water to drink, 8 rats
  2. High fat/fructose diet HFFD (21% crude protein, 36.52% palm oil + 3.48% soybean oil”, 3.74% crude fiber) plus 10% fructose in drinking water, 8 rats
  3. HFFD plus 30 mg/kg ß-caryophyllene in olive oil. 8 rats
  4. HFFD/ß-caryophyllene + CB2 antagonist AM630 (1 mg/kg, I.P) 8 rats
  5. HFFD/ß-caryophyllene + PPARγ antagonist BADGE (15 mg/kg, I.P). 8 rats

Behavior Tests

  1. The elevated water maze measures anxiety.
  2. The open field test measures exploratory locomotor activity and anxiety.
  3. The light/dark box measures anxiety.
  4. The two trial Y-maze test evaluates the ability of a rat to recognize familiar places and desire to explore a new place.
  5. The forced swimming test (FST) is considered a test for depression in rats. Rats are able to swim around or just float if they are depressed.

In general terms, the HFFD compromised the rats’ performance in the first three tests that measure anxiety. ß-caryophyllene restored the scores to about those of the rats on the normal diet. The CB2 and PPARγ antagonists resulted in scores more consistent with the HFFD without ß-caryophyllene. [4]

In the two trial Y-maze test that measures memory, ß-caryophyllene improved the HFFD score to a level indistinguishable from rats on the normal chow. The PPARγ antagonist abrogated most but not all of this improvement. [4]

in the forced swim test that measures depression, rats whose HFFD was supplemented with ß-caryophyllene were improved but still showed signs of depression. The CB2 antagonist abrogated this improvement. [4]

Basic Labs and Biochemistry

  • ß-caryophyllene did little to stop the HFFD weight gain.
  • ß-caryophyllene decreased the increase in visceral fat. The SB2 and PPARγ antagonists abrogated the improvement.
  • ß-caryophyllene brought the HFFD increases in fasting blood glucose and insulin back to control levels. Only the CB2 antagonist abrogated this improvement.
  • ß-caryophyllene dropped the close to doubling of HOMA insulin resistance induced by the HFFD to the level of the control. Only the CB2 antagonist abrogated this improvement.
  • Consistent with inducible nitric oxide synthase (iNOS) levels, ß-caryophyllene brought NO levels back to control levels. The CB2 and PPARγ antagonists partially abrogated the improvement.
  • The HFFD decreased reduced glutathione (GSH to 1/5th of the control. ß-caryophyllene brought the GSH up to close to the control. Less dramatic changes were seen in total antioxidant (TAC) levels [1]
  • Malondialdehyde MDA, a product of lipid metabolism, were increased 4x by the HFFD diet. MDA may form adducts with nucleic acids and proteins. ß-caryophyllene brought these levels down to close to the control. The CB2 and PPARγ antagonists partially abrogated the improvement.

Peptide/Protein Levels

The the end of the study, protein levels of inflammatory proteins iNOS, TNF-α, and NF-κB were measured in the prefrontal cortex. [1] ß-caryophyllene improved the levels of these markers to levels indistinguishable from rats on the control diet. The CB2 and PPARγ antagonists partially but not totally abrogated the improvement seen with ß-caryophyllene. [4]

Neuronal growth related factors PGC-1α, and PPAR-γ itself were also measured in these rats. The HFFD decreased the amount of these factor 4-5x. ß-caryophyllene increased the amounts of these factors but did not bring their levels to that of rats on the control diet. The PPAR-γ antagonist partially abrogated the improvement seen with ß-caryophyllene. The CB2 antagonist totally abrogated the improved levels of PGC-1α and BDNF but only partially abrogated the improvement in PPAR-γ.


A 100 kg male human is probably not going to be interested in consuming 300 mg ß-caryophyllene per day in order to make up for a bad Western diet. Assuming that he has 5 liters of blood, this is a concentration of about 60 mg/ L or about 294 µM. The concentration could be a lot less if ß-caryophyllene partitions into the tissue. Recall from the introduction that has a Ki = 155 ± 4 nM when it comes to dislodging THC from the CB2 receptor. [1] This is about 2000x less than 294 µM. We might be able to disregard binding to PPAR-γ with low affinity. What is really interesting about this study is the behavior influences of the HFFD that go along with biochemical changes. [4] Our 100 kg human male can ask himself if he feels inclined to just stand around in the pool rather than swimming some laps. Youssef and coauthors go into great detail of the rat behavior tests, [4] The reader can decide how much they correlate with their own behavior on the Western Diet. Could taking a ß-caryophyllene supplement with his health care provider’s guidance help him overcome the neuro inflammation that makes exploring new things (like a better diet) a source of “anxiety”? Does prefrontal cortex neuro inflammation cause a condition in humans that makes them too “depressed” to exercise? If so, could a ß-caryophyllene supplement help? In this case a health care provider’s assistance is definitely in order less our male seek the ß-caryophyllene supplement in a hops rich ale at the local pub.


  1. Gertsch, J., Leonti, M., Raduner, S., Racz, I., Chen, J. Z., Xie, X. Q., Altmann, K. H., Karsak, M., & Zimmer, A. (2008). Beta-caryophyllene is a dietary cannabinoid. Proceedings of the National Academy of Sciences of the United States of America, 105(26), 9099–9104. PMC free article
  2. Muoio DM, Koves TR. 92007) Skeletal muscle adaptation to fatty acid depends on coordinated actions of the PPARs and PGC1 alpha: implications for metabolic disease. Appl Physiol Nutr Metab. 2007 Oct;32(5):874-83.
  3. Katsouri L, Blondrath K, Sastre M. Peroxisome proliferator-activated receptor-γ cofactors in neurodegeneration. IUBMB Life. 2012 Dec;64(12):958-64. PMC free article
  4. Youssef DA, El-Fayoumi HM, Mahmoud MF. Beta-caryophyllene alleviates diet-induced neurobehavioral changes in rats: The role of CB2 and PPAR-γ receptors. Biomed Pharmacother. 2019 Feb;110:145-154. PMC free article

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