Terpenes and terpenoids are all around us and represent a class of molecules that number in the tens of thousands. Terpenes are molecules that have only carbon and hydrogen present in their chemical structure, whereas terpenoids consist of additional functional groups such as alcohols, aldehydes, carboxylic acids, esters, thiols, and more. Terpenes and terpenoids are some of the key constituents that plants use to interact with their environment. From communicating with their own species about their location and use of local resources, to warding off predators and attracting insect recruits to fight off annoying and harmful pests, terpenes and terpenoids have a myriad of functions for plants.
Chemically speaking, terpenes and terpenoids are constructed from the primary building block of isoprene. Isoprene is a small molecule consisting of only 5 carbons. Plants use this molecular foundation in a series of orchestrated and elegant biosynthetic steps to construct additional molecules that range from the relatively simple to the exceptionally complex. Terpenes and terpenoids are often referred to as secondary metabolites of plants since they are not directly involved in the normal growth, development, or reproduction of the plant. That said, we should not take the word secondary to mean less important. In fact, secondary metabolites are exceptionally important to both the plant and those seeking to use the plant in various fashions. From medicines, to perfumes, to sustainable chemical resources and more, terpenes and terpenoids represent a vast treasure trove of utility that is only beginning to be tapped by mankind.
Cannabis sativa L. is known to produce over 100 different terpenes and terpenoids in various ratios and combinations. Almost all of the terpenes and terpenoids that have been found in cannabis thus far are also present in other plants. Limonene is the primary component of orange essential oil, representing over 90% of that essence. Linalool is a major component of lavender oil. Both limonene and linalool are present in almost every cannabis cultivar, along with other terpenes and terpenoids such as beta-caryophyllene, myrcene, and pinene. What’s special about cannabis-based terpenes and terpenoids is their pairing with cannabinoids, and specifically how the combination of these components can present unique and complex physiological interactions that are often called the entourage effect or ensemble effects. Cannabis truly is an example of the sum being greater than the parts.
While it is not yet fully understood how these complex interactions and mechanisms of action work, science (LaVigne, 2020) is now beginning to unravel some of the foundational biochemical pieces to support what millions of cannabis consumers have long touted: the benefits of complex cannabis compositional benefits to patients and consumers. If single molecule cannabinoid compositions were wildly effective there would be no need for medical cannabis or other ‘whole plant’ type cannabis products. Yet, it is well-documented and exceptionally apparent that patients demand these complex products to assuage what ails them. Recent scientific work further supports improved therapeutic windows from the use of more than just a single cannabinoid. (Galilly, 2015)
Cannabis sativa L. is one plant species that has been categorized as two legal forms–marijuana and hemp–in the United States solely based upon delta-9-tetrahydrocannabinol (THC) content. While these forms have been distinguished for legal reasons, they both produce very similar sets of molecules. Hemp is legally defined as cannabis cultivars that produce less than 0.3% THC on a dry weight basis, whereas marijuana has no limitation on the amount of THC produced. Therefore, hemp often consists of cannabidiol (CBD) or cannabigerol (CBG) as the major cannabinoid.
Both hemp and marijuana generally produce the same terpenes and terpenoids. But they sometimes do so in varying amounts or in different ratios. Much how various marijuana cultivars produce a similar amount of THC, say 15%, yet come in an almost endless array of smells, tastes, and effects due to the various terpenes and terpenoids they produce; the same goes for hemp cultivars, which can produce similar amounts of CBD yet differ wildly in their terpene and terpenoid profiles produced. The key to effectively using a cannabis product for a specific physiological need is that the composition is consistent time and again. That each and every batch contains the same amounts and ratios of cannabinoids, terpenes, and terpenoids in the formulation is the key to an effective product.
While there has been much focus on the biological function of cannabinoids, and there is undoubtedly much more to learn, it is only relatively recently that much attention has been given to the terpenes and terpenoids. That isn’t because they lack activity, but perhaps more so because there are just so many more of them and their effects are more subtle than for cannabinoids, such as THC and CBD. Most of the research to date has explored isolated and purified compounds in an effort to reduce research complexity, but this trend is beginning to change as we are now understanding some things behave differently within a mixture.
While their functions are vast, one particular terpene present in every cannabis cultivar, beta-caryophyllene, has been demonstrated to produce selective CB2 agonist activity around 100nM. (Gertsch, 2008) Beta-caryophyllene is known to produce anti-inflammatory, antibiotic, antioxidant, anticarcinogenic and local anaesthetic activities. (Legault, 2007) Humulene, also known as α-caryophyllene, is a ring-opened isomer of β-caryophyllene, which is notably lacking in CB2 activity. Nonetheless, it also possesses powerful anti-inflammatory activity equal to dexamethasone in an animal model (Fernandes, 2007). Humulene possesses both topical and systemic anti-inflammatory properties (Chaves, 2008) and is an effective analgesic when taken topically, orally, or by aerosol (Rogerio, 2009).
Limonene has found many uses as it is a major component of citrus oils. From use as a flavor and fragrance additive in cleaning and cosmetic products, food, beverages, and pharmaceuticals to also increasingly being used as a solvent. It is also used in the manufacturing of resins, as a wetting and dispersing agent, and in insect control. While its overall utility is vast, limonene has demonstrated numerous medicinal benefits in both human and animal studies as well as providing antioxidant and anticancer properties. Limonene has been suggested as an excellent dietary source for cancer prevention (Aggarwal, 2006). Limonene has shown anti-inflammatory effects in models of osteoarthritis (Rufino, 2015) and asthma (Hirota, 2012). Multiple modes of anticancer activity were observed, including chemoprevention (Crowell, 1994). Evidence from a phase I clinical trial shows a partial response in a patient with breast cancer and stable disease for more than 6 months in three patients with colorectal cancer (Vigushin, 1998).
α-Pinene, a bicyclic monoterpene, is the most widely distributed terpene in Nature (Asakawa, 2010) and possess a vast array of physiological effects. Most notable are anti-inflammatory via PGE-1 (Gil, 1989), as a bronchodilator in humans at low exposure levels (Falk, 1990), and as it possesses antioxidant properties it has been shown to inhibit prostaglandin E1 and NF-κB, thereby contributing to both anti-inflammatory and anti-carcinogenic effects (Miguel, 2010; Zhou, 2004).
p-Cymene is found in more than 100 plant species and has shown a variety of biological activities which include antioxidant, antinociceptive, anti-inflammatory, anxiolytic, anticancer and antimicrobial activities. Recent in vivo investigations performed on experimental animal model systems (adult male Swiss mice), showed that p-cymene increases the activity of antioxidant enzymes, reducing oxidative stress. (De Oliveira, 2015; Quintans-Júnior
2013) Additionally it shows anti-inflammatory activity through modulation of cytokine production (tumor necrosis factor-α-TNF-α, interleukin-1β-IL-1β, interleukin-6-IL-6) in vitro (murine macrophage-like cell line RW 264.7) and in vivo (Female C57BL/6) by inhibiting nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways involved in synthesis of pro-inflammatory cytokines. (Zhong, 2013) The anti-inflammatory activity of p-cymene at least partly justifies its antinociceptive activity, as recorded in several in vivo studies performed on murine model systems. (Bonjardim, 2012; De Santana, 2015)
Eucalyptol (1,8-cineole), a terpenoid oxide isolated from Eucalyptus species, is a promising compound for treating a number of conditions as it has been shown to have anti-inflammatory and antioxidant effects in various diseases, including respiratory disease, pancreatitis, colon damage, and cardiovascular and neurodegenerative diseases. Eucalyptol suppresses lipopolysaccharide (LPS)-induced proinflammatory cytokine production through the action of NF-κB, TNF-α, IL-1β, and IL-6 and the extracellular signal-regulated kinase (ERK) pathway and reduces oxidative stress through the regulation of signaling pathways and radical scavenging. The effects of eucalyptol have been studied in several cell and animal models as well as in patients with chronic diseases. Furthermore, eucalyptol can pass the blood-brain barrier and hence can be used as a carrier to deliver drugs to the brain via a microemulsion system (Seol, 2016).
As can be quickly demonstrated from the above, the complexity of cannabis, and moreover the terpenes and terpenoids present within their compositions, is nothing short of exceptional. The polypharmacy shown by cannabis compositions is undoubtedly partially impacted by the terpenes and terpenoids. Harnessing this potential will only come from the use of consistent complex formulations that are made through quality minded efforts. The future of cannabis-based products is very bright as they will undoubtedly provide medical practitioners with a considerable amount of useful tools in their toolbox.