Ten years ago, most cannabis users could not distinguish a terpene from a cannabinoid. But today things are different. The cannabis flower is classified according to the terpene profile. Product manufacturers add terp blends to edibles and concentrates. Limonene is pretty much a household name.
And for good reason. Terpenes impart desirable flavors and aromas. And they also seem to be good for the body.1 Now it turns out that some terpenes can also contribute to a cannabis high.
A 2021 study2 University of Arizona scientists have concluded that some terpenes are \”cannabimimetic\” (in a mouse model of cannabis intoxication) and can selectively increase cannabinoid activity.
And this month comes a brand new article in the magazine Biochemical pharmacology3 by Israeli researchers who report that three cannabis terpenes – at concentrations similar to those found in real cannabis plants – significantly increase THC signaling at the CB1 receptor.
CB1 activation
Using a in vitro cell model, the Israeli team compared the activation of the CB1 receptor by 16 different cannabis terpenes with that of THC alone and with THC-terpene blends at a botanically relevant ratio of 10:1.
When tested individually, all 16 terpenes activated CB1, at around 10-50% the activation of THC alone. This is remarkable in and of itself, although it\’s not a huge surprise. Although their chemical structures differ widely, terpenes and cannabinoids share key characteristics; both belong to a larger group of plant compounds called terpenoids. Indeed, cannabinoids are technically classified as terpeno-phenolic substances.
Different answers
Next, the researchers tested terpenes and THC together. What they found runs the gamut. In the case of beta-pinene and geraniol, the blends actually produced less of an effect than the sum of the individual parts, as if these terpenes nullified some of the activity of the THC.
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.
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 terpene separately. In other words, if the terpene was a 3 and the 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 last point to be their most significant finding. It represents the first demonstration of THC-terpene synergy in a in vitro controlled environment, and gives the title to the article: selected cannabis terpenes synergize with THC to produce greater activation of the CB1 receptor.
Is this evidence of the legendary entourage effect of cannabis? Strictly speaking, no, according to the authors of the article. They note that the term entourage effect, as originally coined in a 1998 paper in the European Journal of Pharmacology,4 refers to cases where compounds that do not bind directly to CB1 or CB2 still increase the activity of the endocannabinoid system.
Since terpenes activate CB1, this does not fit the original concept of the entourage effect. Given that cannabis terpenes demonstrate direct agonism at the CB1 receptor,\” the authors argue, \”the effects of the THC terpene go beyond the classic definition of entourage.
Therapeutic applications?
Semantics aside, the paper\’s key findings on THC-terpene interactions, at similar ratios to the cannabis plant and at very low terpene concentrations, could have significant implications for both future research and real-world cannabis use .
The mere fact that different terpenes can modify THC activity in different ways seems worthy of attention on its own, but the authors placed 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 even rarer. Consequently, they suggest that these terpenes could be intentionally added to cannabis extracts to maximize the efficacy of their THC content.
The use of selected terpenes may allow the THC dose to be reduced in some treatments and, as a result, potentially minimize THC-related adverse effects, they conclude. This would also help tailor the treatment to more sensitive populations such as children and the elderly.
The authors continue: Enrichment with selected terpenes can allow adaptation of the composition to personal needs and changes during chronic use, for example for daytime versus sleep.
Of course, these claims are speculative and not necessarily supported by clinical research. They also have some marketing, which isn\’t surprising given that four of the authors are employees of the Bazelet Group, a medical cannabis producer in Israel that prides itself on using groundbreaking technology to formulate specific wishes [cannabinoid-terpene formulations] to provide greater therapeutic effect in various medical conditions.
As always in cannabis science and medicine, the real world is much more complex than the laboratory, and preclinical discoveries don\’t always translate into lived experience. But at least, the study provides more evidence of interactions between terpenes, cannabinoids, and the endocannabinoid system, something Project CBD will further explore in a subsequent article on beta-caryophyllene, the super terpene.
Project CBD contributing writer Nate Seltenrich is the author of the Bridging the Gap column. An independent science journalist based in the San Francisco Bay Area, he covers a wide range of topics, including environmental health, neuroscience and pharmacology. Copyright, CBD Project. May not be reprinted without permission.
Footnotes
- Cox-Georgian, Destinney et al. Therapeutic and medicinal uses of terpenes. Medicinal plants: from the farm to the pharmacy 333359. 12 November 2019, doi:10.1007/978-3-030-31269-5_15
- LaVigne, Justin E et al. Cannabis sativa terpenes are cannabimimetic and selectively enhance cannabinoid activity. Scientific reports vol. 11.1 8232. 15 April 2021, doi:10.1038/s41598-021-87740-8
- 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
- Ben-Shabat, S et al. An entourage effect: Glycerol esters of inactive endogenous fatty acids enhance the activity of the cannabinoid 2-arachidonoyl-glycerol. European Journal of Pharmacology vol. 353.1 (1998): 23-31. doi:10.1016/s0014-2999(98)00392-6
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