Cannabis - an ancient resource with new therapeutic potential
Cannabis sativa L. is a widely-distributed herbaceous plant rich in textile fiber and unique phytochemicals1. Its fast-growing nature, versatility, and ability to produce these molecules have made it a rich source of food, fiber, and medicine. Humans have utilized Cannabis for millennia2, yet little is known about the full therapeutic potential of its complex repertoire of phytochemicals.
The ever-increasing list of pharmaceutical applications of Cannabis includes treatment of pain, glaucoma, nausea, multiple sclerosis, neuralgia (nerve pain) and depression3 – to name just a few. High-quality evidence is generally absent, however, and more research is urgently needed to establish the exact role medicinal cannabis has in the management of these disorders. More than 500 natural compounds have been identified and/or isolated from C. sativa L4. But which molecules are responsible for eliciting the potential therapeutic effects of the plant? Here, we provide a brief overview of the major chemical constituents in Cannabis and discuss their relevance to human health.
Glandular trichomes are the plant’s phytochemical factories
Many natural compounds in Cannabis are synthesized via pathways that are not absolutely required for growth and development, but aid in the plant’s survival; i.e., through secondary metabolism. Amongst these compounds are the terpenes (volatile organic compounds also found in the essential oils of many plants) and the cannabinoids (or phytocannabinoids) that have pharmaceutical effects in humans5. Cannabis terpenes and cannabinoids are manufactured in the secretory cavity of specialized structures on the surface of the plant, called glandular trichomes. These crystal-like outgrowths are densely concentrated on female flowers and in other aerial parts of Cannabis.16
While the exact biological function of terpenes and phytocannabinoids in Cannabis remains unclear, some hypothesize that increases in the production of these secondary metabolites might improve the plant’s chances of fertilization and bolster self-defenses against pests and microorganisms78. In humans, the majority of Cannabis pharmacological activity – including the well-known psychoactive effects – are thought to be caused by the phytocannabinoids.
The unique phytocannabinoids of Cannabis
Plant-derived cannabinoids (phytocannabinoids) are terpenophenolic compounds comprised of alkylresorcinol and monoterpene moieties9. Phytocannabinoids are found almost exclusively in Cannabis Sativa L., where they are biosynthesized as cannabinoid acids (or pre-cannabinoids) in the glandular trichomes. Over time, or with heat, these molecules are non-enzymatically decarboxylated to their neutral forms10. Figure 1 highlights these concepts.
Figure 1. Phytocannabinoids contain alkylresorcinol and monoterpene moieties and undergo non-enzymatic decarboxylation (indicated with an arrow). Pictured: Cannabigerolic acid.
Cannabis is known to produce over 120 different phytocannabinoids; unfortunately, many of these compounds have unknown or poorly defined pharmacological profiles11. The best-studied cannabinoids are the neutral derivatives of the most abundant cannabinoid acids produced in the plant and are shown in Figure 2. Studies show that these phytocannabinoids interact with various components of our endocannabinoid system (ECS). The ECS is believed to be a widespread homeostatic regulator for a number of physiological processes including pain, inflammation, metabolism, mood, and memory11213. To learn more about the ECS, we refer the reader to other reviews1314.
∆9-tetrahydrocannabinol (THC) was the first cannabinoid to be isolated from Cannabis15 and is highly concentrated (in its carboxylated form) in modern Cannabis drug chemotypes. In addition to its well-known psychoactive effects, THC potentially exerts a variety of therapeutic activities including analgesic (pain-relieving), anti-inflammatory, and possibly anticancer properties1614.
Cannabidiol (CBD) is another prevalent phytocannabinoid that has garnered attention because it is non-psychoactive and exhibits a complex pharmacology with numerous potential therapeutic activities. For instance, there is some evidence that CBD has analgesic, anti-inflammatory, anti-arthritic, anti-nausea and immunomodulatory activities in vitro (outside of living organisms, such as in test tubes) and in vivo (in living organisms)178. Furthermore, CBD may hold promise in the treatment of intractable pediatric epilepsy due to its anticonvulsant properties1830.
Cannabis produces relatively high levels of the cannabinoid acid form of cannabichromene (CBC)19. CBC has been shown to have anti-inflammatory and analgesic activities2021.
Figure 2. Common phytocannabinoids found in Cannabis
Another phytocannabinoid, cannabigerolic acid, was recently shown to be the primary precursor in the biosynthesis of the carboxylated forms of all the cannabinoids discussed above (THC, CBD, and CBC); therefore, it is often found at lower concentrations in Cannabis10. In its neutral form, cannabigerol (CBG) has been shown to exhibit analgesic and anti-erythemic (redness or irritation of the skin) effects2223.
Lastly, cannabinol (CBN) is an oxidative degradation product of THC, and therefore, is found in higher concentrations in aged Cannabis. CBN potentially exhibits anticonvulsant and anti-inflammatory activities2324.
Interestingly, the plant chemotype and environmental factors such as growing conditions can dramatically influence the phytocannabinoid concentrations in Cannabis12. Since the phytocannabinoid profile likely influences the pharmacological effects of the plant, knowing the relative proportion of each phytocannabinoid is important for medicinal users. Moreover, many believe that other Cannabis constituents, like terpenes, are relevant to the overall pharmacological effects in humans.
Terpenes may also influence the pharmacology of Cannabis
Terpenes are volatile chemicals that give Cannabis its unique aroma and flavor. These compounds are widespread in the plant kingdom - in fact, they’re the most abundant group of plant-produced chemicals with about 20,000 currently characterized25. Cannabis is known to produce over 140 terpenes, although, most are present in only trace amounts26. Some common terpenes found in Cannabis are presented in Figure 3. Many of these molecules are also found in the essential oils of familiar plants. For instance, α-pinene is the most prevalent terpene found in nature, and notably concentrated in conifers.
Figure 3. Terpenes produced in Cannabis are also present in other common plants (displayed to the right of the respective terpene).
The lipophilic nature of terpenes (i.e., their tendency to dissolve in lipids or fats) facilitates their passage across the blood-brain barrier27, yet few studies have focused on their pharmacology. It is possible Cannabis terpenes alone have biological activities, and/or that they work in combination with phytocannabinoids to exert pharmacological effects8. Indeed, some terpenes have been examined in clinical studies to inform on their therapeutic potential28. D-limonene for instance, a terpene found in high concentrations in lemon and other citrus essential oils, has shown promise in the treatment of depression and may stimulate the immune system29.
Looking beyond individual constituents
THC was long-thought to be the principal active agent in Cannabis. Research is only now beginning to probe the complex and wide-ranging pharmacological properties of the entire Cannabis constituent ensemble. Comprehensive analyses of all constituents in Cannabis samples, and testing in clinical trials, will undoubtedly help inform their potential therapeutic effects.