Tag: Terpenes

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Beta-Caryophyllene: Terpene Powerhouse

Project CBD recently reported on studies indicating that cannabis terpenes — the compounds that give the plant its robust and distinctive smell — activate the CB1 cannabinoid receptor. What’s more, in the presence of THC (also a CB1 agonist), terpenes appear to modulate cannabinoid activity in varied and interesting ways.1,2 Today we focus on spicy-peppery beta-caryophyllene (BCP), one of the most common cannabis terpenes, which acts on several targets that impact the endocannabinoid system, not just CB1.

BCP is also a component of black pepper, basil, oregano, cinnamon, hops, rosemary, cloves, and citrus, as well as many leafy greens. Approved by the United States Food and Drug Administration for use as a flavoring and fragrance agent in food, this powerhouse sesquiterpene has been the subject of considerable medical-science research. Recent papers explore the potential role of BCP in treating a wide range of conditions including non-alcoholic fatty liver disease, chronic pain, and substance abuse.

A “Dietary Cannabinoid”

Beta-caryophyllene, a weak CB1 agonist, is what scientists refer to as a “full agonist” at the CB2 cannabinoid receptor, which plays an important role in regulation of immune function and inflammation. Its presence in many foods and spices and its strong affinity for CB2 has earned BCP recognition as the first known “dietary cannabinoid.”

Multiple studies have shown that beta-caryophyllene also interacts with peroxisome proliferator-activated receptors (PPARs, pronounced pee-parrs) located on the surface of the cell’s nucleus. CBD also activates these receptors, which regulate metabolism and energy homeostasis.

Given the role of PPARs and the endocannabinoid system in modulating metabolic processes, a group of researchers based in Turin, Italy, wanted to see if BCP was effective in a cellular model of non-alcoholic fatty liver disease, the most common chronic liver disorder worldwide with a global prevalence of more than 30%.3

Because of its presence in many foods and spices and its strong affinity for the CB2 receptor, beta-caryophyllene is known as a “dietary cannabinoid.”

Writing in the International Journal of Molecular Sciences in March 2023,4 the researchers note that not only did they observe improvements in diseased liver cells, but they also confirmed through the use of specific receptor antagonists that these changes were indeed mediated by CB2 and two PPAR receptor types: PPAR-alpha and PPAR-gamma.

(Interestingly, multiple large epidemiological studies5 — including one published in May 2023 in the journal PLoS One6 — have linked cannabis use with reduced risk of fatty liver disease. This new evidence out of Italy suggests that activation of CB2 and PPAR receptors may be at least partly responsible.)

Alzheimer’s & Substance Abuse

Other studies in recent years have added to our understanding of beta-caryophyllene’s myriad potential health benefits and multiple methods of action. In 2014, for example, Chinese researchers at Chongqing Medical University reported that BCP prevented cognitive impairment in a mouse model of Alzheimer’s. This positive cognitive outcome “was associated with reduced beta-amyloid burden in both the hippocampus and the cerebral cortex,” according to their paper in the journal Pharmacology,7 which identified CB2 receptor activation and the PPAR-gamma pathway as mediators of BCP’s neuroprotective effects.

More recently, a July 2022 paper in BioFactors8 by Iranian scientists reviewed the antioxidant and immunomodulatory effects of beta-caryophyllene, which was shown to reduce relevant proinflammatory cytokines while increasing anti-inflammatory cytokines. CB2 and PPAR-gamma, among other cellular pathways, were cited as key mechanisms of action.

And a December 2022 article in Current Neuropharmacology,9by researchers in Brazil, investigated BCP’s potential “as a new drug for the treatment of substance use disorders.” The authors reviewed previous preclinical studies using animal models of addiction to cocaine, nicotine, alcohol, and methamphetamine. “Remarkably,” they concluded, the terpene “prevented or reversed behavioral changes resulting from drug exposure,” with evidence again pointing to the involvement of both CB2 and PPAR-gamma.

Painkiller

Finally, a paper by scientists with an Indian company called Vidya Herbs, which produces a black-pepper-seed extract called Viphyllin, suggests that beta-caryophyllene can reduce pain in mice primarily via activation of CB2, PPAR-alpha, and a third pathway also shared with cannabidiol: the TRPV1 (pronounced trip-vee-one) ion channel.

Published in the Journal of Pain Research10 in February 2022, the study involved administration of both 90% pure beta-caryophyllene and the black-pepper extract Viphyllin, which contains at least 30% beta-caryophyllene alongside lesser quantities of limonene, beta-pinene, and sabinene (three terpenes that can also be found in various cannabis strains).

Medical scientists are studying beta-caryophyllene as a treatment for non-alcoholic fatty liver disease, chronic pain, and substance abuse.

When Viphyllin was given at about three times the dose of pure BCP, the two treatments proved to be similarly effective at reducing pain in all four behavioral models employed.

In three of these tests, the researchers also used blockers of CB1, CB2, TRPV1, and PPAR-alphato evaluate how Viphyllin worked on the molecular level. They found that CB2, PPAR-alpha, and TRPV1 were most responsible for conveying the black pepper extract’s analgesic effect, but that the common terpene target CB1 may have played a role, as well.

Nate Seltenrich, Project CBD contributing writer, is the author of the column Bridging the Gap. An independent science journalist based in the San Francisco Bay Area, he covers a wide range of subjects, including environmental health, neuroscience, and pharmacology. © Copyright, Project CBD. May not be reprinted without permission.

Footnotes

  1. Raz, Noa et al. “Selected cannabis terpenes synergize with THC to produce increased CB1 receptor activation.” Biochemical pharmacology vol. 212 (2023): 115548. doi:10.1016/j.bcp.2023.115548
  2. LaVigne, Justin E et al. “Cannabis sativa terpenes are cannabimimetic and selectively enhance cannabinoid activity.” Scientific reports vol. 11,1 8232. 15 Apr. 2021, doi:10.1038/s41598-021-87740-8
  3. Younossi, Zobair M et al. “The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review.” Hepatology (Baltimore, Md.) vol. 77,4 (2023): 1335-1347. doi:10.1097/HEP.0000000000000004
  4. Scandiffio, Rosaria et al. “Beta-Caryophyllene Modifies Intracellular Lipid Composition in a Cell Model of Hepatic Steatosis by Acting through CB2 and PPAR Receptors.” International journal of molecular sciences vol. 24,7 6060. 23 Mar. 2023, doi:10.3390/ijms24076060
  5. Kim, Donghee et al. “Inverse association of marijuana use with nonalcoholic fatty liver disease among adults in the United States.” PloS one vol. 12,10 e0186702. 19 Oct. 2017, doi:10.1371/journal.pone.0186702
  6. Du, Rui et al. “Marijuana use is inversely associated with liver steatosis detected by transient elastography in the general United States population in NHANES 2017-2018: A cross-sectional study.” PloS one vol. 18,5 e0284859. 18 May. 2023, doi:10.1371/journal.pone.0284859
  7. Cheng, Yujie et al. “β-Caryophyllene ameliorates the Alzheimer-like phenotype in APP/PS1 Mice through CB2 receptor activation and the PPARγ pathway.” Pharmacology vol. 94,1-2 (2014): 1-12. doi:10.1159/000362689
  8. Baradaran Rahimi, Vafa, and Vahid Reza Askari. “A mechanistic review on immunomodulatory effects of selective type two cannabinoid receptor β-caryophyllene.” BioFactors (Oxford, England) vol. 48,4 (2022): 857-882. doi:10.1002/biof.1869
  9. Asth, Laila et al. “Effects of β -caryophyllene, A Dietary Cannabinoid, in Animal Models of Drug Addiction.” Current neuropharmacology vol. 21,2 (2023): 213-218. doi:10.2174/1570159X20666220927115811
  10. Venkatakrishna, Karempudi et al. “ViphyllinTM, a Standardized Black Pepper Seed Extract Exerts Antinociceptive Effects in Murine Pain Models via Activation of Cannabinoid Receptor CB2, Peroxisome Proliferator-Activated Receptor-Alpha and TRPV1 Ion Channels.” Journal of pain research vol. 15 355-366. 5 Feb. 2022, doi:10.2147/JPR.S351513

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Which Terpenes Enhance the Cannabis High?

Ten years ago, most cannabis consumers couldn’t tell a terpene from a cannabinoid. But today things are different. Cannabis flower is categorized according to terpene profile. Product manufacturers add terp blends back into edibles and concentrates. Limonene is practically a household name.

And for good reason. Sure, terpenes impart desirable flavors and aromas. They appear to be good for the body, as well.1 Now it turns out that some terpenes also may contribute to the cannabis high.

A 2021 study2 by University of Arizona scientists concluded that certain terpenes are “cannabimimetic” (in a mouse model of cannabis intoxication) and can selectively enhance cannabinoid activity.

And this month comes a brand-new paper in the journal Biochemical Pharmacology3 by Israeli researchers who report that three cannabis terpenes — at concentrations similar to those found in actual cannabis plants — significantly boost THC signaling at the CB1 receptor.

CB1 Activation

Using an in vitro cellular model, the Israeli team compared CB1 receptor activation by 16 different cannabis terpenes to that of THC alone and to THC-terpene blends with a botanically relevant ratio of 10:1.

When tested individually, all 16 terpenes activated CB1, at about 10% to 50% of activation of THC alone. This is notable in and of itself, though not a huge surprise. While their chemical structures differ quite a bit, terpenes and cannabinoids share key features; both belong to a larger group of plant compounds called terpenoids. In fact, cannabinoids are technically classified as “terpeno-phenolic” substances.

Varying Responses

Next, the researchers tested terpenes and THC together. What they found runs the gamut. In the cases of beta-pinene and geraniol, the mixtures actually produced a smaller effect than the sum of the individual parts, as if these terpenes negated some of THC’s activity.

For eight of the THC-terpene blends, including some of the most common cannabis terpenes — alpha-pinene, beta-caryophyllene, bisabolol, eucalyptol, humulene, myrcene, nerolidol, and terpinolene — CB1 activation equaled that of THC alone. The presence of the terpene seemed to make no difference.

A 2021 study reports that some terpenes are “cannabimimetic” and can enhance cannabinoid activity.

But with three other terpene-THC blends — linalool, ocimene, and terpineol — the researchers observed an additive effect, meaning that CB1 activity equaled the sum observed with THC and the terpene separately. In other words, if the terpene was a 3 and THC was a 7, the blend was a 10.

Finally, three of the terpenes — limonene, borneol, and sabinene — produced a synergistic effect in combination with THC. In these cases, the whole was greater than the sum of its parts: an 11 or 12 rather than the expected 10.

THC-Terpene Synergies

The researchers consider this latter point their most significant finding. It represents the first demonstration of THC-terpene synergism in an in vitro controlled setting, and lends the paper its title: “Selected cannabis terpenes synergize with THC to produce increased CB1 receptor activation.”

Is this evidence of the fabled cannabis entourage effect? Strictly speaking, no, according to the paper’s authors. They note that the term “entourage effect,” as originally coined in a 1998 article in the European Journal of Pharmacology,4 refers to cases where compounds that don’t directly bind to CB1 or CB2 nonetheless boost the activity of the endocannabinoid system.

Since terpenes do activate CB1, this doesn’t fit with the original concept of the entourage effect. “Given that cannabis terpenes demonstrate direct agonism at CB1 receptor,” the authors contend, “THC-terpene effects are beyond the classical definition of entourage.”

Therapeutic Applications?

Semantics aside, the paper’s fundamental findings around THC-terpene interactions, at ratios similar to those in the cannabis plant and at very low terpene concentrations, could have significant implications for both future research and real-world cannabis use.

The simple fact that different terpenes can modify THC activity in different ways seems worthy of attention on its own, but the authors put particular emphasis on their discovery of a synergistic effect for limonene, borneol, and sabinene. While limonene is among the most common cannabis terpenes, borneol is less so, and sabinene is rarer still. As a result, they suggest that these terpenes could be intentionally added to cannabis extracts to maximize effectiveness of their THC content.

Terpenes could be added to cannabis extracts to maximize the effectiveness of their THC content.

“The use of selected terpenes may enable reducing the THC dose in some treatments, and as a result, potentially minimizing the THC-related adverse effects,” they conclude. “This would also help in adjusting the treatment to more sensitive populations such as children and elderly.”

The authors continue, “Enrichment with selected terpenes may allow for composition adjustment to personal needs and to changes during chronic use, such as for daytime versus for sleep.”

Of course, these statements are speculative and not necessarily supported by clinical research. They also smack a bit of marketing-speak, which is not surprising given that four of the authors are employees of the Bazelet Group, a medical cannabis manufacturer in Israel that boasts of using a “breakthrough technology” to “formulate specific desired [cannabinoid-terpene formulations] to supply enhanced therapeutic effect in various medical conditions.”

As always in cannabis science and medicine, the real world is far more complex than the lab, and preclinical findings don’t always translate into lived experience. But at the very least, the study provides further evidence of interactions between terpenes, cannabinoids, and the endocannabinoid system — something Project CBD will explore further in a subsequent article on beta-caryophyllene, the “super terpene.”

Nate Seltenrich, Project CBD contributing writer, is the author of the column Bridging the Gap. An independent science journalist based in the San Francisco Bay Area, he covers a wide range of subjects, including environmental health, neuroscience, and pharmacology. © Copyright, Project CBD. May not be reprinted without permission.

Footnotes

  1. Cox-Georgian, Destinney et al. “Therapeutic and Medicinal Uses of Terpenes.” Medicinal Plants: From Farm to Pharmacy 333–359. 12 Nov. 2019, doi:10.1007/978-3-030-31269-5_15
  2. LaVigne, Justin E et al. “Cannabis sativa terpenes are cannabimimetic and selectively enhance cannabinoid activity.” Scientific reports vol. 11,1 8232. 15 Apr. 2021, doi:10.1038/s41598-021-87740-8
  3. Raz, Noa et al. “Selected cannabis terpenes synergize with THC to produce increased CB1 receptor activation.” Biochemical pharmacology vol. 212 (2023): 115548. doi:10.1016/j.bcp.2023.115548
  4. Ben-Shabat, S et al. “An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity.” European journal of pharmacology vol. 353,1 (1998): 23-31. doi:10.1016/s0014-2999(98)00392-6

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Original Article