If you are wondering why cannabis has a particular effect or why cannabis can alleviate so many different conditions, the answer ultimately lies in the endocannabinoid system (ECS). All animals from humans to fish and even invertebrates like sea urchins and nematodes have an endocannabinoid system . Only insects seem to lack an ECS. This biological system is likely so common because it plays a key role in keeping the body’s multiple systems in balance (homeostasis). The endocannabinoid system is responsible for the psychoactive, non-psychoactive, and medicinal benefits of cannabis. In this article, we will take a comprehensive look at the endocannabinoid system and explain what it is and how it works.
“The endocannabinoid system (ECS) is a homeostatic regulator of neurotransmitter activity and almost every other physiological system in the body.”
-E. Russo, “Beyond Cannabis: Plants and the Endocannabinoid System”
The endocannabinoid system consists of signals (neurotransmitters) and receptors. This signal and receptor system is how the body communicates with itself to “turn on” and “turn off” certain functions. These signaling processes can be very complex and involve many steps and many different molecules. Keep in mind that the information here is simplified to convey a general idea of how the ECS functions.
To start, the body naturally produces its own cannabinoids. These are called “endocannabinoids” as opposed to the “phytocannabinoids” that come from plants. There are two endocannabinoids: anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) . Endocannabinoids are released “on demand” when imbalances in the body are sensed. The enzymes fatty acid amide hydrolase (FAAH), and monoacylglycerol lipase (MAGL), along with a few others, play a role in synthesizing and breaking down AEA and 2-AG when they are needed or not needed .
When it comes to phytocannabinoids, the cannabis plant is the source of several. To name a few, there are three major cannabinoids: cannabidiol (CBD), delta-9-tetrahydrocannabinol (THC), and cannabigerol (CBG). These are the most abundant cannabinoids, but there are also minor cannabinoids that may be present in very small amounts. Those include cannabichromene (CBC), cannabinol (CBN), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), and several more that are much rarer. In addition to cannabinoids, the terpene beta-caryophyllene is also known to interact directly with the endocannabinoid system . This terpene is found in cannabis as well as plants like black pepper, rosemary, hops, oregano, and cinnamon.
Endocannabinoids and phytocannabinoids bind to receptors. There are two cannabinoid receptors called CB1 and CB2, and the endocannabinoid system also involves other receptors such as G protein-coupled receptor 55 (GPR55) and transient receptor potential cation channel subfamily V member 1 (TRPV1) . 5-hydroxytryptamine receptors (5-HT) are serotonin receptors that can also be influenced by cannabinoids . Not all cannabinoids can interact with all receptors, and some cannabinoids have stronger interactions than others. With that in mind, these are the associations between cannabinoids and endocannabinoid receptors:
- CB1: 2-AG, AEA, THC [6,7]
- CB2: 2-AG, AEA, THC (weak), CBD (weak), beta-Caryophyllene [1,6,7]
- GPR55: 2-AG, AEA, THC [8,15]
- TRPV1: AEA, CBD, CBG [7,9]
- 5-HT: 2-AG, AEA, CBD, THC (weak) [4,10]
As mentioned, the endocannabinoid system helps maintain homeostasis in the body. In order to do this, it has receptors that are located throughout almost every part of the body. To understand what the endocannabinoid system does and which cannabinoids are responsible for what effects, we need to look at the location of the different cannabinoid receptors. Discussions about the medicinal benefits of cannabis are often centralized around the cannabinoids themselves. However, thinking about medical cannabis from a biological perspective can paint a bigger picture.
CB1 is responsible for the psychoactive effects of THC. In the central nervous system (brain), CB1 receptors are abundant in the hippocampus (memory), amygdala (fear/emotion/pain), cerebellum (motor function/balance), basal ganglia (movement), hypothalamus (appetite/thermal control), spinal cord (pain), and cerebral cortex (nausea) . In the peripheral nervous system that runs throughout the body, CB1 receptors are abundant in fat cells (adipocytes), liver cells, pancreas cells, skeletal muscles, vascular smooth muscle (blood pressure), intestinal tissue (duodenum, ileum, myenteric plexus; nausea), smooth muscle cells of the lungs (bronchodilation), ciliary body of the eye (intraocular pressure), lymphoid tissue (immunity), and immune cells.
If you consider the effects of THC and consider the location of the CB1 receptors it binds to, it is easy to draw an association between form and function. For example, when you get high from the THC in marijuana, your eyes dilate, you may feel forgetful, you get the munchies, feel colder, and your cognition and motor control are impaired . The medicinal benefits of THC like pain relief, nausea relief, and glaucoma relief are also due to its widespread distribution in the body.
Immune cells like microglia, osteoclasts, and osteoblasts are the most common places to find CB2 receptors . Other parts of the peripheral nervous system that contain CB2 receptors include lymphoid tissue, peripheral nerve terminals, and the retina of the eye. In the central nervous system, CB2 receptors are found in cerebellar granule cells mRNA which are related to coordination of motor function.
CB2 has a very strong link to acute inflammation and does not have a psychotropic effect like CB1 . In addition to reducing inflammation in the body, CB2 is also thought to alleviate neuroinflammation which plays a role in neuropathic pain and neurodegenerative conditions such as Alzheimer’s disease. That is why it is often said to be “neuroprotective.” CBD has a much weaker affinity to CB2 than one might suspect. Researchers have found that the terpene beta-caryophyllene has a surprisingly stronger affinity for the receptor . In fact, many CBD benefits have more to do with TRPV1 and 5-HT than CB2.
The GPR55 receptor is found in the brain’s frontal cortex, striatum, hypothalamus, hippocampus, cerebellum, and brain stem . It has also been detected in the GI tract in the ileum and jejunum, in the adrenal glands, and in the spleen. GPR55 is thought to play a role in relieving anxiety and regulating the central nervous system . With its presence in the spleen and immune cells, GPR55 is also thought to regulate immunity and immune cell-related inflammation [ZHOU]. Activation of GPR 55 has a stimulatory effect on neutrophils, mast cells, monocytes, and natural killer cells which play key functions in innate immunity. THC, 2-AG, and AEA activate GPR55, but the medicinal benefits of this relationship have not been well studied outside of animal models.
Sensory nerve fibers, smooth muscle cells, vascular endothelial cells, submucosal glands, and inflammatory cells in the respiratory system are the primary locations where TRPV1 is distributed in the body . TRPV1 has been linked to the release of inflammatory mediators in the body, gastrointestinal motility function, and temperature regulation. It is also a key component in pain sensation (nociception) . While CB1 has taken a lot of credit for the anti-nausea and pain-relieving effects of medical cannabis, TRPV1 is thought to be just as important.
TRPV1 has similar pain and nausea benefits to CB1. However, CB1 is activated by THC which is psychoactive. TRPV1 is activated by CBD and does not have psychoactive effects. From a medical cannabis perspective, the benefits of TRPV1 are important because they offer symptom relief without intoxication. That is why medical cannabis dosing regimens typically start patients on CBD-dominant cannabis products .
5-HT receptors of the central nervous system, especially the serotonin (5-HT)1A receptor have been linked to anxiety and analgesia (pain sensation) . While we often assume CBD works on CB2 because THC works on CB1, 5-HT and TVRP1 receptors are actually the primary targets of CBD. In addition to anti-anxiety effects, 5-HT receptors are also linked to migraine pathology . The research that has been conducted on medical cannabis for mood disorders and migraine have demonstrated that 5-HT receptors are one of the main mechanisms that facilitate relief.
TRPV1 and 5-HT are just as important as CB1 and CB2 when considering the impact that medical cannabis will have on the endocannabinoid system. Since the research around them is newer and published in complex scientific papers, they are less talked about. However, it is important for medical marijuana patients to understand that when the goal of using cannabis is medicinal versus recreational, these non-psychoactive receptors are invaluable therapeutic targets that cannot be activated with THC.
When the body does not naturally produce a sufficient amount of a substance, it is called a “deficiency.” We commonly hear about the need to take vitamins and supplements to avoid deficiencies, but neurotransmitter deficiencies can also lead to serious health conditions. For example, loss of acetylcholine activity is thought to lead to dementia and Alzheimer’s disease , and dopamine deficiency is related to Parkinson’s disease. Since the endocannabinoid system is tightly linked to the nervous system and neurotransmitter function, it is thought that endocannabinoid deficiencies of AEA and 2-AG also play a role in some diseases and disorders.
You can think about medical cannabis in two ways. The first is as an acute treatment like taking CBD instead of ibuprofen for inflammation. The second way of thinking about medical cannabis is as a supplement. In this framework, cannabinoids from cannabis are more like vitamins that add to the amount of endocannabinoids your body naturally produces. The endocannabinoid deficiency framework is a fairly new theory. It is challenging because there is no testing that can measure the levels of endocannabinoids that a body is naturally producing. This natural endocannabinoid level is called “endocannabinoid tone.”
Endocannabinoid tone is important when it comes to utilizing medical cannabis for disorders like migraine, fibromyalgia, and irritable bowel syndrome (IBS). These chronic conditions require ongoing management. They are unlike acute pain conditions because they have complex pathologies that involve several physiological mechanisms. While they can have acute symptoms when they “flare up,” they are ongoing and can’t be cured. That is why treatments aim to manage symptoms and prevent flare-ups.
Medical cannabis is of particular interest for treating migraines, fibromyalgia, and IBS because these conditions share biochemical and pathophysiological patterns . These patterns involving CB1 and 5-HT receptors suggest an underlying clinical endocannabinoid deficiency could majorly contribute to their pathology. This has led researchers to suspect that they may respond well to medical cannabis treatment.
Chronic pain, cancer, HIV/AIDS, glaucoma, epilepsy, neurodegenerative conditions, and psychiatric conditions like PTSD are among the most common qualifying conditions for medical marijuana. It is important to understand that for all of these conditions, medical marijuana is not a cure. It is a therapy that can alleviate certain symptoms of these conditions. In order to select the best medical cannabis product, it is important to understand which cannabinoid receptors are responsible for particular symptoms. In doing this, you can consider whether THC is really necessary. Medical cannabis doctors will often recommend that patients follow a dosing regimen called “the modified Delphi process .” This process starts patients on a low CBD dose, then gradually increases that dosage. If relief is not obtained on a high CBD dose, then low doses of THC are added and gradually increased as needed.
- Aly, E., Khajah, M. A., & Masocha, W. (2019). β-Caryophyllene, a CB2-Receptor-Selective Phytocannabinoid, Suppresses Mechanical Allodynia in a Mouse Model of Antiretroviral-Induced Neuropathic Pain. Molecules (Basel, Switzerland), 25(1), 106. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983198/
- Bhaskar, A., Bell, A., Boivin, M., Briques, W., Brown, M., Clarke, H., Cyr, C., Eisenberg, E., de Oliveira Silva, R. F., Frohlich, E., Georgius, P., Hogg, M., Horsted, T. I., MacCallum, C. A., Müller-Vahl, K. R., O’Connell, C., Sealey, R., Seibolt, M., Sihota, A., Smith, B. K., … Moulin, D. E. (2021). Consensus recommendations on dosing and administration of medical cannabis to treat chronic pain: results of a modified Delphi process. Journal of cannabis research, 3(1), 22. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252988/
- Bie, B., Wu, J., Foss, J. F., & Naguib, M. (2018). An overview of the cannabinoid type 2 receptor system and its therapeutic potential. Current opinion in anaesthesiology, 31(4), 407–414. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035094/
- De Gregorio, D., McLaughlin, R. J., Posa, L., Ochoa-Sanchez, R., Enns, J., Lopez-Canul, M., Aboud, M., Maione, S., Comai, S., & Gobbi, G. (2019). Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain. Pain, 160(1), 136–150. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319597/
- Du, Q., Liao, Q., Chen, C., Yang, X., Xie, R., & Xu, J. (2019). The Role of Transient Receptor Potential Vanilloid 1 in Common Diseases of the Digestive Tract and the Cardiovascular and Respiratory System. Frontiers in physiology, 10, 1064. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712094/
- Justinová, Z., Yasar, S., Redhi, G. H., & Goldberg, S. R. (2011). The endogenous cannabinoid 2-arachidonoylglycerol is intravenously self-administered by squirrel monkeys. The Journal of neuroscience : the official journal of the Society for Neuroscience, 31(19), 7043–7048. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3123903/
- Kaur, R., R Ambwani, S., & Singh, S. (2016). Endocannabinoid system: a multi-facet therapeutic target. Current clinical pharmacology, 11(2), 110-117. https://www.researchgate.net/profile/Sneha-Ambwani/publication/301533431_Endocannabinoid_System_A_Multi-Facet_Therapeutic_Target/links/5a544667a6fdccf3e2e29f74/Endocannabinoid-System-A-Multi-Facet-Therapeutic-Target.pdf
- 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 of the United States of America, 105(7), 2699–2704. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268199/
- Louis-Gray, K., Tupal, S., & Premkumar, L. S. (2022). TRPV1: a common denominator mediating antinociceptive and antiemetic effects of cannabinoids. International Journal of Molecular Sciences, 23(17), 10016.https://www.mdpi.com/1422-0067/23/17/10016/pdf
- Russo, E. B. (2008). Clinical endocannabinoid deficiency (CECD). Neuroendocrinology Letters, 29(2). https://www.academia.edu/download/32652999/Endocarbinoid_Defeciency.pdf
- Russo, E. B. (2016). Beyond cannabis: Plants and the endocannabinoid system. Trends in Pharmacological Sciences, 37(7), 594-605. https://mychronicrelief.com/wp-content/uploads/2016/05/Beyond-Cannabis-Plants-and-the-Endocannabinoid-System.pdf
- Ryberg, E., Larsson, N., Sjögren, S., Hjorth, S., Hermansson, N. O., Leonova, J., Elebring, T., Nilsson, K., Drmota, T., & Greasley, P. J. (2007). The orphan receptor GPR55 is a novel cannabinoid receptor. British journal of pharmacology, 152(7), 1092–1101.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2095107/
- Shi, Q. X., Yang, L. K., Shi, W. L., Wang, L., Zhou, S. M., Guan, S. Y., … & Yang, Q. (2017). The novel cannabinoid receptor GPR55 mediates anxiolytic-like effects in the medial orbital cortex of mice with acute stress. Molecular brain, 10, 1-11. https://link.springer.com/article/10.1186/s13041-017-0318-7
- Silver R. J. (2019). The Endocannabinoid System of Animals. Animals : an open access journal from MDPI, 9(9), 686. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770351/
- Zhou, J., Burkovskiy, I., Yang, H., Sardinha, J., & Lehmann, C. (2016). CB2 and GPR55 receptors as therapeutic targets for systemic immune dysregulation. Frontiers in pharmacology, 7, 264. https://www.frontiersin.org/articles/10.3389/fphar.2016.00264/full