Cannabimimetic Plants Throughout Earth’s Flora
This piece was co-authored with Dr. Melanie Bone and was initially published in the 25th Issue of Terpenes and Testing Magazine published in 2021 and is being shared for educational purposes on this blog. Please cite as Bone, CB and Bone, Melanie M.D. FACOG “Cannabinoids Beyond Cannabis: Exploring Cannabimimetic Plants” Terpenes & Testing Magazine. March/April 2021, Volume 4: Issue 26.
The green rush is in full swing with the federal government taking up the issue of rescheduling cannabis and the US Department of Agriculture and Food and Drug Administration beginning to acquiesce to industry concerns in their rule-making. All signs point toward a positive future for Cannabis sativa L. It’s worth understanding the broader role of cannabinoids in plant life. As cannabinoids become increasingly accessible and their therapeutic potential is further explored, the nature of endocannabinoid modulation requires further scrutiny. Indeed, the rise of entourages and spectrums as gold standards as well as general focus on endocannabinoid system (ECS) tone [1] are indicators that future cannabinoid product development may lie in plants beyond cannabis.
Cannabimimetic plants are a novel assortment of flowers, herbs, and vegetables that either has some degree of cannabinoid expression or produce moieties that modulate the body’s ECS. [2,3] Indeed, cannabinoids and ECS modulators are surprisingly abundant, with historical applications as traditional medicines and even contemporary applications as superfoods. Cannabinoids as a class of compounds ubiquitous to the cannabis plant and the proliferation of exotic compounds like delta-8- tetrahydrocannabinol are evidence that there’s still more room for exploration and discovery in this realm. Moreover, non-cannabis-derived cannabinoids and cannabimimetics may provide pathways for clinical testing, increased understanding of the ECS, and generally improved consumer experiences.
The ECS is composed of a series of receptors in the brain and the peripheral nervous system, which are acted upon by endogenous endocannabinoids and exogenous cannabinoids to aid in the body’s homeostatic processes. Endocannabinoids include anandamide (Sanskrit for “bliss”) and 2-arachidonoylglycerol, or 2-AG. Exogenous cannabinoids that are best known are delta-9-tetrahydrocannabinol (THC), the analogue for anandamide, and cannabidiol (CBD), the analog for 2-AG. [4]
Nerve endings in our body have multiple receptors for cannabinoids, but the best studied are the CB1 and CB2 receptors. Essentially, THC work by affecting CB1 receptors, and CBD works, mostly, by affecting CB2 receptors, but these receptors impact each other. [5] In fact, there are hundreds of cannabinoids in cannabis and there is a multitude of related receptors on which they act. Different chemicals act on these receptors to elicit a cascading series of effects that produce the effects of cannabis. This process involves the body’s own systems responding to external stimuli to produce a response and this is why endocannabinoid modulation beyond cannabis has so much potential.
Take for instance the novelty of bioidentical or synthetic CBD, a product that was largely ahead of its time but whose methodology is certainly an inspiration to produce compounds like cannabinol (CBN) and delta8-tetrahydrocannabinol (delta-8-THC). Techniques and technologies to obtain CBD from materials like allegedly orange peels [6] and algae [7] are similar to the infrastructure that manufacturers use to produce compounds like delta-8-THC and even CBN as these processes require a laboratory setting beyond what is typically found in an extraction facility. As the industry focuses on cannabinoids not abundantly available in nature, the nonplant endocannabinoid modulator of today may become the bioidentical treatment of tomorrow.
Endocannabinoid modulation is the core of cannabinoid care. [8] Whether it’s recreational or medical use, CBD or THC (or another cannabinoid), the pharmacology of these substances is interrelated. Understanding the role of the ECS, and, by extension, how it can be modulated, requires the input of medical cannabis professionals. Qualified medical cannabis professionals are already intimately familiar with the ECS as well as exogenous cannabinoids and will continue to push the charge for broader social acceptance of these products. To support them, it’s up to the industry—manufacturers and consumers alike—to popularize and advocate for the exploration of cannabinoid and cannabimimetic treatments, to normalize endocannabinoid care, and to help identify the diversity of ways endocannabinoid deficiencies may present and be treated.
Basic research into the efficacy, safety, and toxicity of cannabimimetics is inconsistent and largely separate from medical cannabis literature. This translates into disparities in product formulations, recommendations, and consumption that impedes the adoption of these treatments and, subsequently, further research. [9] Standardized, double-blinded, randomized clinical studies of all cannabinoids from C. sativa and cannabimimetic plants are long overdue and would be a tremendous boon to an industry trying to prioritize between a multitude of development trajectories. Most importantly, the information gleaned from these studies is vital to preventing unintended harm that may come from compassionate care initiatives.
And while cannabis advocates may be quick to point out the general safety and lack of toxicity associated with these products, no cannabinoid has been declared Generally Recognized as Safe (GRAS) by the FDA and we can’t take for granted that they will be. A recent fatality associated with a lyophilized cannabinoid formula [10] as well as the tremendous controversy surrounding the endocannabinoid-modulating drug Rimonabant is only a few examples of the potential fallout that can arise without proper research and precautionary measures.
Since the biosynthesis of cannabinoids from novel materials like algae and apparently the production of cannabinoids in oranges, the need to create a better understanding of the ECS and the myriad moieties that modulate it has never been clearer. Indeed, a quick survey of successful brands and products points to the recognition of broader phytonutrients as evidenced by the integration of ingredients like melatonin, elderberry, etc. While the growing availability of novel cannabinoids is great and entourage-informed products are becoming the norm, products that take advantage of the diverse array of cannabimimetic plants are not. This means there is a clear need for the industry to get up to speed and establish research priorities and standards for care that consider the role of various kinds of ECS modulators, not just Cannabis. The opportunities to embrace broader paradigms of nutritional wellness that emphasize the role of micronutrients like cannabinoids—such as cannabinoid tea [11]—and the ability to take interdisciplinary approaches to understand the ECS are exciting directions that should be pursued aggressively. [12]
This article provides a summary of existing cannabimimetic plants to guide industry stakeholders in assessing research priorities for future cannabinoid development. The industry used to rely on an outdated idea of the lock-and-key mechanism to explain the ECS; however, understanding the endocannabinoid system and the array of natural modulators may be the keys to the future for our industry.
References
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[3] Gertsch J. Cannabimimetic phytochemicals in the diet - an evolutionary link to food selection and metabolic stress adaptation?. Br J Pharmacol. 2017;174(11):1464-1483.
[4] Justinova Z, Solinas M, Tanda G, Redhi GH, Goldberg SR. The endogenous cannabinoid anandamide and its synthetic analog R(+)-methanandamide are intravenously self-administered by squirrel monkeys. J Neurosci. 2005;25(23):5645-5650.
[5] Hryhorowicz S, Kaczmarek-Rys M, Andrzejewska A, et al. Allosteric modulation of cannabinoid receptor 1-current challenges and future opportunities. Int J Mol Sci. 2019;20(23):5874.
[6] Lauckner JE, Jensen JB, Chen HY, Lu HC, Hille B, Mackie K. GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current. Proc Natl Acad Sci U S A. 2008;105(7):2699-2704.
[7] CBD Wire. Japanese company starts extracting CBD from orange peels. CBD Wire website. Uploaded February 20, 2020; Accessed February 23, 2021.
[8] Dolgin E. The bioengineering of cannabis. Nature website. Uploaded August 29, 2019; Accessed February 23, 2021.
[9] Johnson SA, Rodriguez D, Allred K. A systematic review of essential oils and the endocannabinoid system: A connection worthy of further exploration. Evid Based Complement Alternat Med. 2020;2020:8035301.
[10] Ladha KS, Ajrawat P, Yang Y, Clarke H. Understanding the medical chemistry of the cannabis plant is critical to guiding real world clinical evidence. Molecules. 2020;25(18):4042.
[11] Yin HY, Hadjokas N, Mirchia K, Swan R, Alpert S. Commercial cannabinoid oil-induced StevensJohnson syndrome. Case Rep Ophthalmol Med. 2020;2020:6760272.
[12] Bone C. Terpenes and teas: Exploring the relationship between cannabinoids and catechins. Extraction Magazine. Jan.-Feb. 2019, pg 44–45. [13] Gertsch J, Pertwee RG, Di Marzo V. Phytocannabinoids beyond the Cannabis plant - do they exist?. Br J Pharmacol. 2010;160(3):523-529.
