Cannabis Plant Flower

How The Endocannabinoid System Works

The human body and its organs require certain internal conditions for optimal function. The endocannabinoid system is one biological system keeping our body in a balanced state, also known as homeostasis. This is also the system through which THC, CBD, and other cannabinoids affect our bodies.

What does the endocannabinoid system do?

The endocannabinoid system’s primary function is maintaining homeostasis throughout the body. Bodily homeostasis is described as its ability to maintain optimal internal physiological conditions, even as the conditions around and within it change. These changes can be caused by several things, including pathogens, infections, or inflammation 1 Laurentiis, A., Araujo, H., & Rettori, V. (2014). Role of the Endocannabinoid System in the Neuroendocrine Responses to Inflammation. Current Pharmaceutical Design, 20(29), 4697–4706. https://doi.org/10.2174/1381612820666140130212957 .

Research continues into the full scope of the endocannabinoid system’s functions, but so far it has been found to help regulate several processes within the body, including:

The destabilization of the endocannabinoid system has been related to a few illnesses and ailments, such as

As research into the endocannabinoid system continues, researchers are finding cannabinoid receptors in new locations throughout the body. To date, scientists have found cannabinoid receptors present in adipocytes (fat cells), the liver, the pancreas, and even in skeletal muscles. The localization of these receptors (the area in which they are found), may be an important clue in determining the functions of the endocannabinoid system and how they are performed 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 .

How does the endocannabinoid system work?

To understand how the endocannabinoid system works within the body, it is first important to understand its different components. This complex system is comprised of cannabinoids, cannabinoid receptors, and a few cannabinoid-metabolizing enzymes.

What Are Cannabinoids?

Cannabinoids are naturally occurring organic chemical compounds that are capable of binding to cannabinoid receptors inside the body 4 Shevyrin, V. A., & Morzherin, Y. Y. (2015). Cannabinoids: structures, effects, and classification. Russian Chemical Bulletin, 64(6), 1249–1266. https://doi.org/10.1007/s11172-015-1008-1 . There are two main types of cannabinoids:

  1. Endocannabinoids. The prefix “endo-“comes from the word endogenous, which means a substance or an organ that grows or originates from within the organism. This the group of cannabinoids that are naturally produced within the body, and the first endocannabinoid discovered was Anandamide (AEA) in 1992 5 Devane, W., Hanus, L., Breuer, A., Pertwee, R., Stevenson, L., Griffin, G., Gibson, D., Mandelbaum, A., Etinger, A., & Mechoulam, R. (1992). Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science, 258(5090), 1946–1949. https://doi.org/10.1126/science.1470919 .
  2. Phytocannabinoids. The prefix “Phyto-” means something derived from plants. This is a group of cannabinoids that are found within cannabis plants. What makes these chemicals remarkable is that they bind to the same receptors as the endocannabinoids, activating the receptors in the process and causing them to send signals for similar functions 6 Folium Biosciences. (n.d.). What Is a Phytocannabinoid? Retrieved July 27, 2020, from https://foliumbiosciences.com/what-is-a-phytocannabinoid/ . Phytocannabinoids include the two most widely known cannabinoids; tetrahydrocannabinol (THC) and cannabidiol (CBD).

Cannabinoid Receptors

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.

Cannabinoid Receptor Breakdown

CB1

CB1 was the first cannabinoid receptor characterized. It has been detected in high concentration in the brain as well as in axons – also known as nerve fiber. The receptor’s localization in the brain, particularly in the hippocampus (region of the brain that helps regulate the memory function) has led to the belief that it is a mediator for the psychoactive effects of cannabinoids such as THC. CB1 receptors were also found in fat cells, the liver, pancreas, and skeletal muscles 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 . In addition to THC, CB1 receptors can be activated by endocannabinoids like 2-AG, as well as by other phytocannabinoids like cannabinol (CBN).

CB2

CB2 was discovered soon after that and was found to have a similar cellular structure as CB1. One of the main differences between the two receptors is their localization. CB2 has been detected in the brain but at a lesser density and is instead primarily present in immune cells. CB2 can be activated by the two main endocannabinoids 2-AG and AEA, and this activation is believed to be how CB2 mediates its anti-inflammatory effect – through the regulation of white blood cells’ function and response to infection or inflammation.

GPR55

GPR55 is a receptor also activated by both endocannabinoids and phytocannabinoids. Its discovery was recent, so information about it is limited. GPR55 was detected in the brain, and while THC and AEA activate it, it did not show any activity in response to CBD or 2-AG. When GPR55 is activated, it signals to IP3-gated receptors in the cell to increase intercellular calcium – IP3-gated receptors act like roadblocks in the cell, and this activation allows calcium ions to pass through the cellular wall from the endoplasmic reticulum (cellular storage) into the cytosol. The increase in calcium is accompanied by an increase in RhoA protein – a protein that is a key regulator of the cellular cycle and cell growth. Optimal RhoA function is believed to be a key defense mechanism against certain cancers, leading researches to further study cannabinoid activation of GPR55 as a way to reduce cancer cell reproduction and migration.

Enzymes

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:

How does THC interact with the endocannabinoid system?

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. 

How does CBD interact with the endocannabinoid system?

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 .

FAQs

What is the role of the endocannabinoid system?

The endocannabinoid system is responsible for regulating homeostasis in the body. It ensures that different physiological parameters like temperature, stress, and inflammation stay at levels that are optimal for bodily function, and it does so when we are healthy as well as when our body is fighting a pathogen or dealing with illness.

How does CBD affect the endocannabinoid system?

CBD affects the cannabinoid system through binding to and activating cannabinoid receptors. This interference can trigger certain chemical pathways, regulating the presence and concentration of hormones and other endocannabinoids. It can also suspend or slow down other pathways, suppressing the production of certain molecules like TNF which can bring up inflammation symptoms.

How can I strengthen my endocannabinoid system?

You can support your endocannabinoid system through lifestyle changes. Dietary changes such as the increase in consumption of Omega-3 fatty acids can assist in the formation of new cannabinoid receptors. Reducing stress factors in your day-to-day life can also lead to a healthier endocannabinoid system since cortisol, the stress hormone, can impair the function of certain cannabinoid receptors. Finally, you may wish to consider supplementing your endocannabinoids with phytocannabinoids such as THC or CBD which can be consumed in a variety of methods. 

How was the endocannabinoid system discovered?

The first cannabinoid discovered was cannabinol in 1940, with CBD and THC being discovered in 1963 and 1964, respectively. Learning more about how cannabinoids were processed within the body gave us the discovery of the endocannabinoid system in 1988 through a study at the St. Louis University that was funded by the U.S government. Finally, it was two years later in 1990 that molecular biologist, Lisa Matsuda, announced the characterization of the underlying DNA sequence of cannabinoid receptors – which allowed us to see the endocannabinoid system as a complex set of functions in the body 14 Lee, M. A. (2012). The Discovery of the Endocannabinoid System. BeyondTHC.Com. https://www.beyondthc.com/wp-content/uploads/2012/07/eCBSystemLee.pdf .

Sources
  1. Laurentiis, A., Araujo, H., & Rettori, V. (2014). Role of the Endocannabinoid System in the Neuroendocrine Responses to Inflammation. Current Pharmaceutical Design, 20(29), 4697–4706. https://doi.org/10.2174/1381612820666140130212957
  2. 2. Hillard, C. J., Weinlander, K. M., & Stuhr, K. L. (2012). Contributions of endocannabinoid signaling to psychiatric disorders in humans: genetic and biochemical evidence. Neuroscience, 204, 207–229. https://doi.org/10.1016/j.neuroscience.2011.11.020
  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
  4. Shevyrin, V. A., & Morzherin, Y. Y. (2015). Cannabinoids: structures, effects, and classification. Russian Chemical Bulletin, 64(6), 1249–1266. https://doi.org/10.1007/s11172-015-1008-1
  5. Devane, W., Hanus, L., Breuer, A., Pertwee, R., Stevenson, L., Griffin, G., Gibson, D., Mandelbaum, A., Etinger, A., & Mechoulam, R. (1992). Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science, 258(5090), 1946–1949. https://doi.org/10.1126/science.1470919
  6. Folium Biosciences. (n.d.). What Is a Phytocannabinoid? Retrieved July 27, 2020, from https://foliumbiosciences.com/what-is-a-phytocannabinoid/
  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.
  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
  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
  10. Sharma, P., Murthy, P., & Bharath, M. M. (2012). Chemistry, metabolism, and toxicology of cannabis: clinical implications. Iranian journal of psychiatry, 7(4), 149–156.
  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
  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
  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
  14. Lee, M. A. (2012). The Discovery of the Endocannabinoid System. BeyondTHC.Com. https://www.beyondthc.com/wp-content/uploads/2012/07/eCBSystemLee.pdf
  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
  16. Basavarajappa, B. (2007). Critical Enzymes Involved in Endocannabinoid Metabolism. Protein & Peptide Letters, 14
  17. Lauckner, J. E., Jensen, J. B., Chen, H.-Y., Lu, H.-C., Hille, B., & Mackie, K. (2008). GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current. Proceedings of the National Academy of Sciences, 105(7), 2699–2704. https://doi.org/10.1073/pnas.0711278105

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