Cannabinoid Biochem
What’s going on inside your body when you consume THC/CBD (and why you should care)
By Jillian Jastrzembski, PhD
THC and CBD are just two out of over 100 cannabinoids found in cannabis. They are often consumed to achieve a recreational “high,” or in a medical context for therapeutic benefits.
Most people can accurately describe the effects of cannabinoids on the body. What isn’t necessarily public knowledge is the biochemical mechanism behind those effects. How is it that chemical compounds in a plant are able to enact such profound changes in the body?
There’s a general rule when it comes to drug-body interactions: if a chemical compound is biologically relevant, it means that there already exists in your body a receptor that is perfectly designed to bind that compound. In the case of cannabinoids found in plants, phytochemicals like THC and CBD interact with receptors in your body called CB1, CB2, and potentially many others [Lu].
The very fact that those cannabinoid receptors exist in your body means that your body can produce its own endogenous cannabinoids. We call these “endocannabinoids” to differentiate them from “phytocannabinoids” found in plants. Broadly defined, a cannabinoid is any molecule that can interact with the cannabinoid receptors in your body. The first endocannabinoids were characterized in the 1990s, decades after scientists had first elucidated the structures of THC and CBD [Duggan]. Given this fairly recent discovery, an intricate map of the endocannabinoid system is still in the works.
Surprisingly, phytocannabinoids don’t look anything like our bodies’ own endocannabinoids, at least in terms of their chemical components. The only reason they are able to act on the same receptors is because their 3D conformations are remarkably similar [Maccarrone].
The two best-characterized receptors of the endocannabinoid system are CB1 and CB2. CB1 receptors are found principally in the central nervous system and are implicated in memory and learning, anxiety, addiction, and psychosis. CB2 receptors are found mainly in immune tissue and are implicated in the body’s inflammatory response [Gülck].
The cannabinoid receptors are not like buttons!
It’s important not to take a reductionist approach to classifying these receptors. They aren’t buttons to be pressed to turn on/off inflammation or disease states. The actual biochemistry is much more nuanced, which can have profound implications for how cannabis can be optimally and safely utilized.
CB1 and CB2 are examples of G-protein coupled receptors, or GCPRs. When a molecule binds to a GCPR, it causes a conformational change in the structure which results in a downstream signaling pathway. The implication of this is that different binding molecules, whether it be an endocannabinoid like 2-arachidonoyl glycerol or a phytocannabinoid like THC, will result in different conformational changes. Hence, even though molecules may activate the same receptor they can result in vastly different biological effects [Lu]. This partially explains why you don’t experience a “high” from your own endogenous cannabinoids.
Furthermore, because phytocannabinoids compete for the same receptors, chronic cannabis use is established to down-regulate CB1 receptors [Maccarrone]. Whether or not that is a good thing is contextual, and the subject of on-going research.
THC and CBD go together like PB&J
The CB receptors are large enough that a molecule can bind on another site and effectively change the function of the receptor. CBD is one such molecule. Unlike THC, an agonist, which binds and “activates” the receptor, CBD is an antagonist of the receptor and thereby tempers the effects of THC [Gado]. Hence, consuming THC with higher amounts of CBD can reduce psychoactive effects, as well as some of the detrimental effects of THC consumption, such as anxiety and cognitive impairment [Lu].
This interaction is important, particularly as THC:CBD ratios continue to rise in retail marijuana [Madras]. Chronic cannabis use is associated with an increased incidence of psychosis, mood disorders, and cognitive alterations [Maccarrone]. The modulatory actions of CBD provide a tool to harness the power of cannabis for its therapeutic effects in ongoing research.
The take-away
Following relatively recent legalization, cannabis is a plant that is often caught between folklore and science. As one of the earliest cultivated plants, humans have sought the therapeutic and recreational effects of cannabis for thousands of years. The science behind those effects is only beginning to be elucidated. In the excitement and urgency to create new therapeutic agents and sell marijuana products, it is tempting to simplify the complicated biochemistry of the endocannabinoid system. In marketing and colloquial descriptions, the effects of THC are often distilled down to “psychoactivity,” and the effects of CBD are distilled down to “anti-inflammatory.” In reality, there is no such mechanism that exists in isolation from other biological effects. An in-depth understanding of the endocannabinoid system is still forthcoming.
Bio
Jillian holds a PhD in Food Chemistry from Cornell University and a B.S. in Chemistry from the University of Delaware. She has worked in the industry as a Senior Analytical Chemist, leading and collaborating on product development projects for food and beverages. Her research has focused primarily on chromatographic and mass spectrometric methods for the analysis of trace level compounds in complex matrices.
References
Duggan, Peter J. “The Chemistry of Cannabis and Cannabinoids.” Australian Journal of Chemistry, vol. 74, no. 6, 2021, pp. 369–387., https://doi.org/10.1071/ch21006.
Gado, Francesca, et al. “Allosteric Modulators Targeting Cannabinoid CB1 and CB2 Receptors: Implications for Drug Discovery.” Future Medicinal Chemistry, vol. 11, no. 15, 2019, pp. 2019–2037., https://doi.org/10.4155/fmc-2019-0005.
Gülck, Thies, and Birger Lindberg Møller. “Phytocannabinoids: Origins and Biosynthesis.” Trends in Plant Science, vol. 25, no. 10, 2020, pp. 985–1004., https://doi.org/10.1016/j.tplants.2020.05.005.
Lu, Hui-Chen, and Ken Mackie. “Review of the Endocannabinoid System.” Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, vol. 6, no. 6, 2021, pp. 607–615., https://doi.org/10.1016/j.bpsc.2020.07.016.
Maccarrone, Mauro. “Phytocannabinoids and Endocannabinoids: Different in Nature.” Rendiconti Lincei. Scienze Fisiche e Naturali, vol. 31, no. 4, 2020, pp. 931–938., https://doi.org/10.1007/s12210-020-00957-z.
Madras, Bertha K. “Tinkering with THC-to-CBD Ratios in Marijuana.” Neuropsychopharmacology, vol. 44, no. 1, 2018, pp. 215–216., https://doi.org/10.1038/s41386-018-0217-3.