Phytoterpenes

Phytoterpenes are commonly found throughout the botanical world as most plants have evolved to produce them for various defense, reproduction and communication mechanisms. The aroma of plants is primarily due to their phytoterpenes, volatile compounds known as the essential oil of plants when extracted. Phytoterpenes play an important role in plant therapies harnessed for millennia by traditional and classical medicine systems, and are the primary force in aromatherapy. Modern science reveals phytoterpenes have significant pharmacological activity being lipophilic, interacting with cell membranes, various ion channels, neurotransmitter receptors and G-protein coupled receptors. [1-4]

1. Phytoterpene Basics
2. Phytoterpene Biosynthesis
3. Phytoterpenes in Hemp
4. Structure/Function Effects of Key Phytoterpenes

Also known as “isoprenoids”, terpenes are hydrocarbons based upon repeating 5-carbon “isoprene” building blocks of C₅H₈:

Some terpenes include extra hydrogen atoms to the above in their unique structures. “Terpenoids” are a modified class of terpenes with additional functional groups, usually oxygen. One common terpenoid is the monoterpene alcohol Linalool (C₁₀H₁₈O) that powers lavender. Following conventional language, our use of the term “terpene” encompasses terpenes and terpenoids.

Phytoterpenes are formed by similar biosynthetic pathways in all plants. The methylerythritol phosphate (MEP) pathway in the plastid and the mevalonate (MVA) pathway in the cytosol both generate 5-carbon isopentenyl pyrophosphate (IPP) and its isomer dimethylallyl pyrophosphate (DMAPP). IPP and DMAPP then condense together in the following ways to produce:

1 IPP + 1 DMAPP = 1 Geranyl Pyrophosphate (GPP) (10 carbons)
2 IPP + 1 DMAPP = 1 Farnesyl Pyrophosphate (FPP) (15 carbons)
3 IPP + 1 DMAPP = 1 Geranylgeranyl Pyrophosphate (GGPP) (20 carbons)

(GPP is also a fundamental precursor in phytocannabinoid biosynthesis)

Finally, a wide variety of terpene synthases catalyze the formation of diverse 10-carbon monoterpenes from GPP, 15-carbon sesquiterpenes from FPP, and 20-carbon diterpenes from GGPP. Triterpenes are formed by cyclizing 30-carbon squalene produced from the condensation of two FPP molecules. [1, 2, 5]

Close-up of Cannabis leaflet showing collections of glandular trichomes where phytoterpenes and phytocannabinoids get produced.

Cannabis phytoterpenes are produced alongside phytocannabinoids in the glandular trichomes found across aerial parts of the plant. Cannabis sativa is able to synthesize approximately 200 terpenes, primarily of the monoterpene and sesquiterpene types, while essential oils of single cannabis varieties can contain more than 100 terpenes above 0.01% (w/w). [4, 6]

Cannabis terpenes were first detected by Wood, Spivey and Easterfield in 1896 together with their pioneering discovery of cannabinoids (Cannabinol, CBN), alongside which they isolated one monoterpene and one sesquiterpene [7, 8]. Interestingly, it appears volatile monoterpenes are more highly expressed in cannabis floral trichomes for repelling insects, while bitter sesquiterpenes are more highly expressed in cannabis leaves for repelling grazing animals [9]. Different varieties of cannabis produce widely varying phytoterpene levels and profiles that significantly influence a variety’s unique effects. Modern cannabis selective breeding is producing varieties with high terpene content, some containing over 4% terpenes by dried weight. [3, 4, 6, 10]

 
Relative phytoterpene levels in one of CANNACEA's select organic hemp varieties - 42 detected and 39 quantified out of 56 phytoterpenes analyzed (~0.01% detection limit).

β-Caryophyllene (C₁₅H₂₄), a bicyclic sesquiterpene alkene, is the most common sesquiterpene in cannabis and often the most prevalent terpene in CANNACEA Hemp Oils. β-Caryophyllene is the primary sesquiterpene contributor to the spiciness of black pepper, and is also found in cloves, hops, rosemary, and copaiba. β-Caryophyllene is prevalent in the essential oils of black pepper (9.4% - 30.9%), melissa (up to 19.1%), and fenugreek (14.6%). [3, 4, 11]

β-Caryophyllene is a selective agonist at the CB2 cannabinoid receptor as confirmed in rodent models of nociception, pain, and inflammation, hence it may also be classed as a phytocannabinoid. β-Caryophyllene also interacts with peroxisome proliferator-activated receptors (PPARs), toll-like receptor complexes (i.e., CD14/TLR4/MD2), μ-opioid receptor pathways, and homomeric nicotinic acetylcholine receptors (7-nAChRs). β-Caryophyllene affects multiple biomolecular targets by altering their gene expression, signaling pathways, or via direct interaction. Various experiments evidence that β-Caryophyllene helps regulate various liver functions, cardiac functions, gastric functions, neurological functions, kidney functions, inflammatory functions, and immune functions, while also displaying antioxidant and antimicrobial functionality. [3, 4]

In one study, increased comfort was associated with the use of cannabis varieties having a Caryophyllene-dominant terpene profile. [10]

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Humulene (α-Caryophyllene, C₁₅H₂₄), a monocyclic sesquiterpene, is one of the more common sesquiterpenes in cannabis, after β-Caryophyllene. Humulene was the first sesquiterpene to be identified in cannabis, isolated in 1942 by Simonsen and Todd [8]. Humulene is most commonly found in hops (Humulus lupulus, after which it is named), and is also found in sage and ginseng. Humulene is prevalent in the essential oils of hops (36.7%), lantana (6.2%), and geranium (up to 6%). [11, 12].

Humulene has been shown to help regulate cellular functions and inflammatory functions, while also displaying analgesic functionality [4, 12].

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Limonene (D-Limonene, C₁₀H₁₆), a cyclic monoterpene, is common to citrus rinds and throughout Nature, though found more randomly in cannabis. Limonene is prevalent in the essential oils of sweet orange (83.9% - 95.9%), tangerine (87.4% - 91.7%) and celery seed (68% - 75%). [4, 11]

Limonene is highly bioavailable in humans with 70% absorption after inhalation and is rapidly metabolized. In mice, Limonene is confirmed to help regulate some psychological functions, comparably to diazepam but seemingly through nonbenzodiazepine mechanisms, while boosting serotonin and dopamine levels. One Japanese study showed citrus scents could significantly help in regulating some psychological functions in humans. Limonene has been shown to help regulate some inflammatory functions and immune functions, while displaying antioxidant functionality. Limonene has also been shown to possess antibiotic functionality, inhibiting oro-dental Streptococcus biofilms, suppressing acne Propionibacterium more potently than tricolsan, and suppressing some fungal dermatophytes. [3, 4, 12]

In one study, a panel of 30 subjects given cannabis having 1:5 CBD:THC ratio with varying terpene profiles consistently reported increased inspiration and focus when using Limonene-dominant varieties. [10]

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Linalool (C₁₀H₁₆O) is a noncyclic monoterpene alcohol (monoterpenoid) and can be found in some cannabis varieties, sometimes at significant levels. Linalool is most commonly known as the dominant terpene in various Lavender species and is also found in rose, basil and bitter orange blossom (neroli). Linalool is prevalent in the essential oils of rosewood (82.3% - 90.3%), coriander seed (59% - 87.5%), lavender (25% - 45%), and ylang-ylang (0.8% - 30%). [4, 11]

Linalool has established abilities to help regulate drowsiness, psychological functioning, and immune functioning. Linalool has also demonstrated the ability to help regulate involuntary muscular functioning and glutamatergic functions. Linalool has anesthetic effects equal to those of procaine and menthol. Linalool has shown antibiotic functionality against acne Propionibacterium and antiparasitic functionality against Leishmania. Linalool as part of inhaled lavender essential oil also decreased morphine opioid usage in surgical patients. [4]

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β-Myrcene (Myrcene, C₁₀H₁₆) is a very common monoterpene in Hemp and is the most prevalent terpene in modern-day cannabis varieties of the United States and Europe. One study found Myrcene comprised more than 30% of the terpene content in 13 of 16 cannabis varieties analyzed, with over 80% Myrcene detected in the terpene fraction of one variety [9]. Myrcene is also found in hops, lemongrass, basil, mangos, and Myrcia sphaerocarpa, the traditional Brazilian medicinal shrub after which it is named. Myrcene is prevalent in the essential oils of rosemary (up to 52.1%), hops (25%) and West Indian lemongrass (5.6% - 19.2%). [4, 11, 12]

Myrcene is recognized as a potent analgesic while also helping regulate inflammatory functions and psychological functioning. The duration of its analgesic effects in mice have exceeded that of morphine (4 hours). It has been proposed that Myrcene’s significant analgesic action comes via the alpha 2-adrenoceptor-stimulated release of endogenous opiates that act upon the μ-opioid receptor. At very high doses, Myrcene sedated mice comparably to phenobarbital. Myrcene also helped regulate the functioning of glucose tolerance in rats comparably to metformin, without affecting glucose levels in normal rats. [3, 4, 12]

In one study, a panel of 30 subjects given cannabis having 1:5 CBD:THC ratio with varying terpene profiles consistently reported relaxation and sedation when using Myrcene-dominant varieties. [10]

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β-Ocimene (Ocimene, C₁₀H₁₆) is a common monoterpene in cannabis. Ocimene is also one of the more common monoterpenes in Nature and is named after the Ocimum plant genus that includes sweet basil and holy basil (tulsi). Ocimene is prevalent in the essential oils of sweet basil (20.6%), tarragon (up to 9.5%), and tulsi/holy basil (3.4% - 6.2%). [4, 11]

Ocimene is a volatile pheromone important for the regulation of honeybee colonies, hence Ocimene-dominant cannabis varieties have been successfully used to produce “cannabis honey” [4]. Ocimene possesses potent antifungal functionality, killing 99.9% of Candida albicans inoculum within 20 minutes in one in vitro study [13].

In one study, a panel of 30 subjects given cannabis having 1:5 CBD:THC ratio with varying terpene profiles consistently reported increased calm when using Ocimene-dominant varieties. [10]

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α-Pinene (C₁₀H₁₆) is a bicyclic monoterpene and is the most widely distributed terpene in Nature. While not always detectable in cannabis, α-Pinene is the primary terpene in some cannabis varieties. α-Pinene is commonly found in conifer trees, particularly pine trees, after which it is named. α-Pinene is prevalent in the essential oils of various species of frankincense (up to 80%), St. John’s wort (31.4%) and black pepper (1.1% - 16.2%). [4, 10, 11]

α-Pinene is known to help regulate various inflammatory functions, while also displaying bronchodilating functionality. α-Pinene antibiotic functionality was noted against methicillin-resistant Staphylococcus aureus (MRSA), as well as Cryptococcus neoformans and Candida albicans yeasts, while significantly increasing the functionality of various pharmaceutical antibiotics against the gastroenteric pathogen Campylobacter jejuni. α-Pinene also demonstrated larvicidal functionality against mosquito vectors of malaria, dengue and Japanese encephalitis. After inhalation by mice, α-Pinene increased motility and helped regulate psychological functioning. The ability of α-Pinene inhalation to help regulate psychological functioning could be one source of the wellness benefit ascribed to walking through forests, as in Japan’s “Shinrin-yoku” or “forest bathing”. α-Pinene has also been shown to be an acetylcholinesterase inhibitor, which may aid with memory function. [3, 4]

β-Pinene is commonly found in cannabis together with α-Pinene, its isomer, though β-Pinene is normally present at lower levels than α-Pinene (CANNACEA Hemp Oils normally contain both α- and β-Pinene at detectable levels). While less studied than its more prevalent counterpart, β-Pinene shares some of the abilities of α-Pinene to help regulate various cellular functions, as well as its antibiotic functionality. [4]

In one study, a panel of 30 subjects given cannabis having 1:5 CBD:THC ratio with varying terpene profiles consistently reported increased focus when using Pinene-dominant varieties. [10]

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α-Terpinolene (Terpinolene, C₁₀H₁₆) is a cyclic monoterpene found in some cannabis varieties. When Terpinolene is primary in the terpene profile of cannabis varieties, they are often characterized as energizing “sativa” types. Terpinolene is also common to pine trees and is prevalent in the essential oils of parsnip (40.3% - 69%), turmeric leaf (11.5%) and parsley leaf (2.8% - 6.6%). [4, 11]

While Terpinolene seems to have energizing effects in humans, it showed sedative effects in one mouse study. Terpinolene also demonstrated antioxidative functionality for LDL cholesterol and in human lymphocytes. Terpinolene demonstrated various abilities to help regulate cellular homeostatic functions, as well as possessing antifungal and larvicidal functionality. Terpinolene at sub-active dosages also showed synergism with diclofenac's ability to help regulate nociception and inflammatory functions, including reduced hyperalgesia in a manner suggesting mediation via 5-HT_2A serotonin receptors. [4]

In one study, a panel of 30 subjects given cannabis having 1:5 CBD:THC ratio with varying terpene profiles consistently reported increased subjective energy when using Terpinolene-dominant varieties [10], supporting its association with energizing “sativa” cannabis varieties in humans [4].

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