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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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Finding Rare Cannabinoids in Non-Cannabis Plants

Special glands protruding from cannabis flowers express a series of unique molecules. Cannabinoids, as they are known, exist in cannabis. But it turns out that identical molecules are present in non-cannabis plants, as well. Researchers from Israel’s Weizmann Institute recently reported that they found cannabigerolic acid (CBGA) and other rare cannabinoids in Helichrysum umbraculigerum, a perennial shrub informally known as the woolly umbrella.1

A South African Botanical

Ferdinand Bohlmann and Evelyn Hoffman first discussed the chemical irregularity of Helichrysum. In a 1979 paper published in Phytochemistry2, they analyzed the South African species H. umbraculigerum, native to the eastern part of the country, where it was used in traditional medicine and fumigation rituals.

Bohlmann and Hoffman asserted that the plant’s tops — both leaves and flowers — produce cannabis-specific compounds. But a follow-up study conducted by Italian researchers in 2017 failed to find CBG or its acidic precursor in H. umbraculigerum flowers. They did, however, identify an analog of CBG known as Heli-CBG (also present in some fiber hemp varietals), which binds to the CB2 cannabinoid receptor.3,4

In a May 2023 article in Nature Plants, Weissman Institute scientists confirmed that woolly umbrella produces CBGA in trichomes on its leaves, but hardly any CBGA was present on its flowers. That’s different from cannabis, where CBGA and other cannabinoids are concentrated in trichomes on flower tops.1

Trichomes found on cannabis inflorescence (flowers) have a special cellular build, according to a 2022 study by University of British Columbia researchers in Current Biology. The gland’s bulbous head holds large porous cells that let acidic cannabinoids (CBGA, CBDA, THCA, etc.) move through the trichome.5 The Weizmann Institute team reported that H. umbraculigerum produces a similar cannabinoid transport network on its leaves.1

Sourcing Rare Cannabinoids in Non-Cannabis Shrubs

How did the Israeli scientists figure this out? They fed woolly umbrella precursor compounds responsible for making cannabinoids in cannabis. When given two precursors (hexanoic acid and phenylalanine), the shrub produced more cannabinoids compared to plants fed regular nutrients. This means that the same biosynthetic pathway exists in both cannabis flowers and woolly umbrella leaves.

The woolly umbrella shrub naturally produces on its leaves over 4% cannabigerolic acid alongside other rare cannabinoids. The shrub also contains water-soluble cannabinoids, which are not found in cannabis.

The woolly umbrella shrub produces CBGA in trichomes on its leaves, but not on its flowers.

Essentially, two different plant species have developed the same machinery to produce CBGA. Yet, woolly umbrella is evolutionarily distinct from cannabis. And unlike the shrub, cannabis makes two unique enzymes that flip CBGA into either THCA and/or CBDA.

Exploring a New Phytocannabinoid Toolkit

Thus, there are two toolboxes for cannabinoid phyto-synthesis in the phylogenetic tree. Terpenes and a few flavonoids accompany lipophilic cannabis flowers, whereas a complex array of flavones and water-soluble cannabinoids develop in H. umbraculigerum. By understanding their similarities and differences, we can better assess the therapeutic potential of each plant.

Cannabinoid compounds found in woolly umbrella dissolve more easily in water and can target specific areas of the body, such as the deeper bowel. But greater bioavailability, an argument for water-soluble cannabinoids, is not necessarily equivalent to greater potency. That which is absorbed quickly and easily also leaves the body and loses efficacy faster. And cannabinoid receptors have more affinity for fat-loving compounds compared to water-soluble agonists.6,7

Travis Cesarone is a freelance writer and communicator focusing on medical cannabis sciences. © Copyright, Project CBD. May not be reprinted without permission.

References

  1. Berman, P., de Haro, L.A., Jozwiak, A. et al. Parallel evolution of cannabinoid biosynthesis. Nat. Plants (2023).
  2. Cannabigerol-ähnliche verbindungen aus Helichrysum umbraculigerum. Phytochemistry. 1979;18(8):1371-1374.
  3. Pollastro, F., De Petrocellis, L., Schiano-Moriello, A., Chianese, G., Heyman, H., Appendino, G., & Taglialatela-Scafati, O. (2017). Amorfrutin-type phytocannabinoids from Helichrysum umbraculigerum. Fitoterapia, 123, 13–17.
  4. Pollastro F, Taglialatela-Scafati O, Allarà M, Muñoz E, Di Marzo V, De Petrocellis L, Appendino G. Bioactive prenylogous cannabinoid from fiber hemp (Cannabis sativa). J Nat Prod. 2011 Sep 23;74(9):2019-22. doi: 10.1021/np200500p. Epub 2011 Sep 8. PMID: 21902175.
  5. Livingston, S. J., Rensing, K. H., Page, J. E., & Samuels, A. L. (2022). A polarized supercell produces specialized metabolites in cannabis trichomes. Current biology : CB, 32(18), 4040–4047.e4. https://doi.org/10.1016/j.cub.2022.07.014
  6. Li, X., Chang, H., Bouma, J. et al. Structural basis of selective cannabinoid CB2 receptor activation. Nat Commun 14, 1447 (2023).
  7. Stadel, R., Ahn, K. H., & Kendall, D. A. (2011). The cannabinoid type-1 receptor carboxyl-terminus, more than just a tail. Journal of neurochemistry, 117(1), 1–18. https://doi.org/10.1111/j.1471-4159.2011.07186.x

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The Plant, the Whole Plant & Nothing But the Plant

It has long been known that resinous cannabis flower tops are infused with robust therapeutic properties. But there are also pharmacologically active components in other parts of the plant that shouldn’t be ignored when assessing the health benefits of cannabis.

The earliest reference to the therapeutic use of cannabis dates back to 2700 BC in ancient China, “the land of hemp and mulberry.” Cannabis (“Ma”) was subsequently included in the Shennong Ben Cao Jing, humankind’s first pharmacopeia, which had been assembled by Emperor Shen Nung, the legendary father of traditional Chinese medicine, who is credited with introducing the custom of drinking tea. Ma was recommended for more than a hundred ailments, including gout, rheumatism, malaria, constipation, beri-beri, and absent-mindedness.

The Shennong Ben Cao Jing called Ma one of the “Supreme Elixirs of Immortality.” It was said to confer longevity and good health. If consumed over a long period of time, Ma could “enable one to communicate with the spirit light and make the body light. It mainly supplements the center and boosts the qi [chi]. Protracted taking may make one fat, strong, and never senile.”1

When consumed in excess, however, “it may make one behold ghosts and frenetically run about.”

Seeds of Health

In traditional Chinese medicine, protein-rich cannabis seeds figured prominently both as a food source and a remedy — apparently more so than resinous cannabis flower tops. The seeds don’t contain CBD, THC, or any other cannabinoids. But modern science confirms that cannabis seeds are an excellent source of omega 3 fatty acids, which are indispensable biochemical building blocks for a healthy endocannabinoid system.

A 2011 study published in Nature Neuroscience states: “Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions.”2 Low levels of omega-3 fatty acids have been linked to neuropsychiatric diseases and impaired emotional behavior.

“Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions.”

Our endocannabinoids — the “marijuana-like” compounds that bind to the cannabinoid receptors CB1 and CB2, as well as other receptors in the brain and body — are actually derivatives or byproducts of omega 3 and omega 6 omega fatty acids. These are referred to as “essential” fatty acids because they can’t be produced by the body in adequate amounts and therefore must be ingested.

But the typical Western diet skews heavily toward corn, wheat, and other cereal grains, which are high in omega 6, whereas today we eat much less food — fish, nuts, leafy greens — that is rich in omega 3. This dietary imbalance is a major factor that contributes to many chronic diseases. It turns out that cannabis seeds (commercially available as hempseed oil, hemp hearts or hempseed protein powder) are gifted with an excellent balance of omega 3 and omega 6 fatty acids.

The Root of the Matter

Practitioners of traditional Chinese medicine also used an extract from raw cannabis roots to treat infections and to help women during childbirth. A decoction made by boiling the roots could be consumed orally as a tincture or juice or applied topically as a poultice.

Herbalists and healers have employed cannabis root preparations to treat a wide range of maladies not only in China but in other parts of the world. The first reference to the therapeutic properties of cannabis roots in Western medicine is found in the Natural Histories (77 AD) by Pliny the Elder. The Latin naturalist wrote that “the roots [of the cannabis plant] boiled in water ease cramped joints, gout too, and similar violent pain.”

Cannabis roots are endowed with medicinal compounds that have anti-inflammatory and analgesic properties.

As is the case with cannabis seeds, the roots don’t contain THC or CBD or any of the so-called minor cannabinoids. Nor are aromatic essential oils (which give cannabis flower its lively fragrance) present in the roots. Instead, the roots are endowed with other medicinal components that have analgesic and anti-inflammatory properties. Various alkaloids and sterols unique to cannabis roots are noteworthy antioxidants. Friedelin, a triterpenoid compound found in algae and lichen, as well as in cannabis roots, is known to reduce fevers.

A 12th century Persian medical text cited the antipyretic (fever-reducing) action of cannabis roots. And in 1542 the German physician Leonard Fuchs noted that a compress made with hemp root extract can soothe inflamed skin: “The raw root, pounded and wrapped, is good for the burn.” A hundred years later, English botanist John Parkinson recommended a decoction of hemp root “to cool inflammation of the head or any other part.” And Nicholas Culpepper’s Compleat Herbal, published in 1653, also mentions hemp roots as a remedy for inflammation.3

But keep in mind that cannabis is a bioaccumulator, meaning that its roots can draw heavy medals and other toxins from the soil. While that’s a great asset for cleaning up a contaminated ecosystem, it’s not what you want when growing an herb for human consumption. Where and how cannabis is cultivated are crucial factors that must be considered to avoid exposure to harmful material and to maximize the health benefits of the plant.

Flower Power

Cultivating high-quality cannabis isn’t rocket science, but it involves significant attention to detail. A hearty, adaptable plant that almost anyone can grow, cannabis lends itself to high-tech horticulture and sophisticated breeding methods designed to coax desired traits into prominence and fine-tune the quality of the high. The complexity of gourmet ganja — an adaptogen and euphoriant with an extraordinary range of smells and flavors and psychoactive subtleties — has reached a level of artistry comparable to today’s wine industry.

Growing the kindest bud ultimately depends on an ancient gardening ritual known as “sexing the plants,” a practice that entails separating male and female plants in their early stages to avoid pollination. Known as sinsemilla (Spanish for “without seeds”), the unfertilized female flower tops, oozing THC and CBD and a kaleidoscope of essential oils, are what cannabis is most famous for. The sexually frustrated females produce bigger buds with more sticky, aromatic resin in an unrequited attempt to catch pollen that never arrives.

Carl Linnaeus, the father of modern botany, wrote about this in his 1753 treatise Dissertation on the Sexes of Plants. The eminent Swedish scientist describes growing Cannabis sativa on his windowsill, an experience he greatly enjoyed:

“In the month of April, I sowed the seeds of hemp (Cannabis) in two different pots. The young plants came up plentifully . . . I placed each by the window, but in different and remote compartments. In one of them I permitted the male and female plants to remain together, to flower and bear fruit, which ripened in July . . . From the other, however, I removed all the male plants, as soon as they were old enough for me to distinguish them from the females. The remaining females grew very well, and presented their long pistilla in great abundance, these flowers continuing a very long time, as if in expectation of their mates . . . It was certainly a beautiful and truly admirable spectacle, to see the unimpregnated females preserve their pistilla so long green and flourishing, not permitting them to fade, till they had been for a very considerable time exploded, in vain, to access the male pollen . . .”4

Cannabis has been likened to a “pharmacological treasure trove.” CBD and THC are the crown jewels of this treasure trove. They are the power couple of cannabis therapeutics. But there are also dozens of secondary cannabinoids, terpenes, and flavonoids in the shimmering female inflorescence, each with specific healing attributes, which interact synergistically so that the therapeutic impact of whole plant cannabis is greater than the sum of its parts. From tap root to bud, whether seeded or seedless, the plant is the alpha and omega of cannabis medicine.

References

  1. Shou-zhong, Y. The Divine Farmer’s Materia Medica: A Translation of the Shen Nong Ben Cao Jing. Boulder, CO: Blue Poppy Press, 1997.
  2. Lafourcade M, Larrieu T, Mato S, Duffaud A, Sepers M, Matias I, De Smedt-Peyrusse V, Labrousse VF, Bretillon L, Matute C, Rodríguez-Puertas R, Layé S, Manzoni OJ. Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions. Nat Neurosci. 2011 Mar;14(3):345-50. doi: 10.1038/nn.2736. Epub 2011 Jan 30. PMID: 21278728.
  3. Ryz NR, Remillard DJ, Russo EB. Cannabis Roots: A Traditional Therapy with Future Potential for Treating Inflammation and Pain. Cannabis Cannabinoid Res. 2017 Aug 1;2(1):210-216. doi: 10.1089/can.2017.0028. PMID: 29082318; PMCID: PMC5628559.
  4. A Dissertation on the Sexes of Plants. Translated from the Latin of Linnaeus by James Edward Smith, F.R.S., into English and published 1786. Cited in Lee, Martin A. Smoke Signals. New York: Scribners: 2012, p. 22.

Martin A. Lee is the director of Project CBD. He’s authored and edited several books, including Smoke Signals, Acid Dreams, and The Essential Guide to CBD. © Copyright, Project CBD. May not be reprinted without permission.

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