How The Endocannabinoid System Works

A receptor is a protein-based structure found throughout cells in the body that initiates a physiological reaction when activated by specific molecules, and different receptors are activated by different mechanisms ^{7 Féger, J., Gil-Falgon, S., & Lamaze, C. (1994). Cell receptors: definition, mechanisms and regulation of receptor-mediated endocytosis. Cellular and molecular biology (Noisy-le-Grand, France), 40(8), 1039–1061.} . Cannabinoid receptors are a group of receptors that are activated by phytocannabinoids molecules such as THC, CBD, and CBG as well as by endocannabinoid molecules such as 2-AG and AEA. Cannabinoid receptors are classified as G protein-coupled receptors (GPCRs), which can be found on the cell surface and rely on G proteins to transmit signals from the outside to the inside of the cell ^{3 Mackie, K. (2008). Cannabinoid Receptors: Where They are and What They do. Journal of Neuroendocrinology, 20(s1), 10–14. https://doi.org/10.1111/j.1365-2826.2008.01671.x} .

There are various kinds of cannabinoid receptors in the body. They vary in structure, function, localization and in which cannabinoids activate them. The first two cannabinoid receptors discovered are named CB₁ and CB₂ ^{8 Pacher, P., & Mechoulam, R. (2011). Is lipid signaling through cannabinoid 2 receptors part of a protective system? Progress in Lipid Research, 50(2), 193–211. https://doi.org/10.1016/j.plipres.2011.01.001} . Researchers believe that while these two receptors deliver most of the effects of cannabinoids in the body, there are other active cannabinoid receptors present in the body.

Enzymes are molecules found within living organisms that act as a catalyst for various chemical reactions taking place inside the body. Enzymes are produced throughout the body and are critical to the body’s functions, such as metabolism and muscle contraction ^{9 9. Berg, J. S., Powell, B. C., & Cheney, R. E. (2001). A Millennial Myosin Census. Molecular Biology of the Cell, 12(4), 780–794. https://doi.org/10.1091/mbc.12.4.780} .

Within the endocannabinoid system, enzymes are mainly responsible for synthesizing cannabinoids, metabolizing them, as well as catabolizing them – breaking them down after they have served their purpose. It is difficult to pinpoint a single enzyme that is responsible for the system’s function, but some of the enzymes that are known to play a part include:

• NAPE-PLD is the enzyme that catalyzes the synthesis of anandamide (AEA), an endocannabinoid believed to help regulate appetite, motivation, with some speculation around it contributing to female fertility ^{16 Basavarajappa, B. (2007). Critical Enzymes Involved in Endocannabinoid Metabolism. Protein & Peptide Letters, 14} .
• FAAH (fatty acid amide hydrolase) is the catabolic enzyme responsible for breaking down AEA as well as 2-AG, another endocannabinoid. Current research is underway to help manage anxiety, pain, and depression through inhibiting FAAH ^{15 Panlilio, L. V., Justinova, Z., & Goldberg, S. R. (2013). Inhibition of FAAH and activation of PPAR: New approaches to the treatment of cognitive dysfunction and drug addiction. Pharmacology & Therapeutics, 138(1), 84–102. https://doi.org/10.1016/j.pharmthera.2013.01.003} .

Picture a cannabinoid receptor as being a seaport and cannabinoids in the bloodstream like ships at sea. Activating a receptor can occur when a molecule binds to it, like a ship docking and unloading its cargo, this molecule is described as an agonist. However, a docked ship can also block other ships from docking at the same spot at the same time, preventing the other ships from unloading their own cargo, or preventing molecules from exerting their intended effect, and when a molecule blocks others from binding, we refer to it as an antagonist.

Cannabinoids, both endogenous or of plant origin, can be receptor agonists or antagonists. Following the analogy above, it means that they can affect the body by triggering certain reactions, or by impeding other reactions – reducing their rate or completely halting them ^{11 Reggio P. H. (2010). Endocannabinoid binding to the cannabinoid receptors: what is known and what remains unknown. Current medicinal chemistry, 17(14), 1468–1486. https://doi.org/10.2174/092986710790980005} . 

Research has found that THC can be an agonist or an antagonist of cannabinoid receptors. THC can act as an agonist for CB₁, CB₂, GPR55, and other receptors. When acting as an agonist, THC has been found to suppress locomotor activity, reduce signs of nausea, and lead to increased appetite ^{12 Donvito, G., Nass, S. R., Wilkerson, J. L., Curry, Z. A., Schurman, L. D., Kinsey, S. G., & Lichtman, A. H. (2017). The Endogenous Cannabinoid System: A Budding Source of Targets for Treating Inflammatory and Neuropathic Pain. Neuropsychopharmacology, 43(1), 52–79. https://doi.org/10.1038/npp.2017.204} . When acting as an antagonist of the same receptors, THC has been reported to mimic the effects of other CB1 receptors. This can lead to the disruption of certain neurotransmission pathways and can cause increased excitedness and anxiety. 

Cannabidiol, the second major cannabinoid in cannabis, can also exhibit receptor agonist and antagonist behaviors within the body through CB1 and CB2 receptors. This means that it delivers effects through either binding to cannabinoid receptors or blocking other molecules from doing so. What determines how CBD behaves remains to be fully understood, but its concentration and the location of a group of receptors is believed to have a significant impact. In both cases, CBD has been found to produce its desirable effects, with no psycho-activity detected ^{12 Donvito, G., Nass, S. R., Wilkerson, J. L., Curry, Z. A., Schurman, L. D., Kinsey, S. G., & Lichtman, A. H. (2017). The Endogenous Cannabinoid System: A Budding Source of Targets for Treating Inflammatory and Neuropathic Pain. Neuropsychopharmacology, 43(1), 52–79. https://doi.org/10.1038/npp.2017.204} .

CBD contributes to numerous chemical pathways in the body, and each of these pathways has the potential to carry positive or adverse effects. One of the main CBD benefits users seek is its anti-inflammatory effect. CBD has been reported to help relieve inflammation through suppressing the production of TNF, one of the cellular proteins involved in producing inflammation and arthritis symptoms ^{13 Mechoulam, R., Sumariwalla, P. F., Feldmann, M., & Gallily, R. (2005). Cannabinoids in Models of Chronic Inflammatory Conditions. Phytochemistry Reviews, 4(1), 11–18. https://doi.org/10.1007/s11101-004-1534-1} .