Last updated: October 1, 2020
Commonly known as marijuana, Cannabis sativa has been used both medicinally and recreationally for millennia. More recently, the legal status of the plant prevented studying its pharmacologically active compounds, known as phytocannabinoids. (6) Eventually, the study of certain cannabis plant varieties and their actions led to the discovery of the endocannabinoid system in mammals. (3)(10) It is now known that the endocannabinoid system is involved in many physiological functions, including modulation of immune function, pain, inflammation, hunger, and metabolism. (7)
Continue reading to learn about the endocannabinoid system and its role in health.
What is the endocannabinoid system?
The endocannabinoid system (ECS) is a signaling system in the body that consists of cannabinoid receptors, endogenous ligands (endocannabinoids) that bind to cannabinoid receptors, and ligand metabolic enzymes involved in the metabolism of endocannabinoids. (1)(3)(7) The ECS is found in mammals in many cells throughout the body, including neurons (nerve cells) and immune cells. Di Marzo et al. have summarized the roles of the ECS briefly as “relax, eat, sleep, forget, and protect”. (2) The ECS may also contribute to health conditions when malfunctioning. (8) The components of the ECS are explained in detail below.
Cannabinoid receptors are G protein-coupled receptors found throughout the body. Once activated, the receptors are involved in signaling functions between various cells in the body. (12) The two primary receptors are known as cannabinoid receptor type-1 (CB1R) and cannabinoid receptor type-2 (CB2R). (3) While CB1Rs are found primarily in regions of the central nervous system, including the striatum, neocortex, and hippocampus, (1) they are also present in other cells throughout the body. CB1Rs regulate the release of various inhibitory and excitatory neurotransmitters. (10) CB2Rs are primarily located within cells governing immune function, such as microglia, splenocytes, monocytes, macrophages, and B- and T-cells, (8) but are also found in neurons. When activated, CB2Rs can modulate immune cell release and migration. (10)
Endogenous ligands, also known as “endocannabinoids”, include anandamide (AEA) and 2-arachidonoylglycerol (2-AG). (3) Endocannabinoids are synthesized in the body from dietary polyunsaturated fatty acids (PUFAs), omega-3 and omega-6 fatty acids. (12) AEA and 2-AG are released from precursors found in cell membranes, the outer layer of cells. They activate CB1 or CB2 receptors and are then broken down by enzymes to prevent further action and maintain homeostasis (physiological balance). (7)
In addition to endocannabinoids, phytocannabinoids and synthetic cannabinoids may interact with receptors within the ECS. These three types of cannabinoids are primarily distinguished based on their source, specifically:
- Endocannabinoids are produced endogenously, meaning they are synthesized internally by the body and are considered a part of the ECS. (7)
- Phytocannabinoids are cannabinoids that occur naturally in various strains of the Cannabis plant. Research has identified over 100 different phytocannabinoids in the cannabis plant, the most well-known and researched being cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC). (8)(13)
- Synthetic cannabinoids, also known as synthocannabinoids, are synthetically-produced compounds designed to mimic the effects of THC or CBD and are considered to be much more potent. Synthetic cannabinoids exist as pharmaceuticals (e.g., dronabinol) and as illegal street drugs. (5)(8)
Ligand metabolic enzymes
Ligand metabolic enzymes are involved in the biosynthesis (production) and catabolism (breakdown) of the endocannabinoids. These enzymes include:
- Diacylglycerol lipase, involved in the biosynthesis of 2-AG
- Fatty acid amide hydrolase (FAAH), involved in the catabolism of AEA
- Monoacylglycerol lipase (MAGL), involved in the catabolism of 2-AG
- N-acyl-phosphatidylethanolamine phospholipase D (NAPE-PLD), an enzyme involved in the biosynthesis of AEA (7)
Role of the endocannabinoid system in health
The ECS is involved in maintaining homeostasis. (3) Due to the wide distribution of C1BRs in the body, these receptors can influence mood, appetite, memory, cognition, and sensory responses. By binding to CB1Rs, endocannabinoids modulate the release of neurotransmitters, including dopamine and gamma-aminobutyric-acid (GABA). (1) CB2Rs are involved in immune cell function and may be up-regulated under certain pathological conditions. (8)
The ECS modulates several functions in the body, including:
- Apoptosis (the regular process of cellular destruction)
- Appetite and food intake
- Macronutrient metabolism
- Memory and mood
- Neural plasticity
- Sensory functions (1)(7)(12)
The many signaling activities in which the ECS is involved holds promise for potential therapeutic targets, including phytocannabinoids. Potential therapeutic applications include substance use disorder, (1) migraines, irritable bowel syndrome (IBS), (11) pain and inflammation, obesity and metabolic changes, neurodegenerative diseases, anxiety, mood disorders, and neuronal injury (e.g., stroke, traumatic brain injury). (9)
Factors that impact the endocannabinoid system
Research demonstrates that several factors may either increase or decrease ECS function. Factors that alter normal ECS function include chronic stress, pesticides, and chronic alcohol consumption. Interventions that upregulate the ECS include certain pharmaceuticals (e.g., antidepressants, anxiolytics, antipsychotics, analgesics), certain dietary supplements (e.g., omega-3 fatty acids, certain probiotics), and medium- to high-intensity exercise. Interestingly, the effect of certain factors on the ECS may be determined by the duration of exposure. For example, acute treatment with opiates and glucocorticoids has been shown to enhance the activity of endocannabinoids, while chronic treatment may downregulate or have a negative effect on the ECS. (7)
Clinical endocannabinoid deficiency
It’s been suggested that ECS dysregulation may be associated with various health conditions. E.B. Russo, an author and researcher in the field of cannabis, was the first to categorize deficiencies in the ECS as “clinical endocannabinoid deficiency” (CECD). (11) Research shows that an underlying endocannabinoid deficiency may be involved in the pathophysiology of multiple sclerosis (MS), Huntington’s disease, uncompensated anorexia, (7) migraines, IBS, and fibromyalgia. (11) Similarly, a dysfunctional CB1 receptor system in infants may be associated with failure to thrive. (4)
The bottom line
Our current understanding of the endocannabinoid system is largely based on animal models and is still evolving. (7)(8) While there are many possible therapeutic applications, researchers warn that further clinical trials are warranted to improve our understanding of specific interventions targeting the ECS. (7) Existing research has shown that the ECS participates in numerous bodily functions, including immune system function, inflammation, and metabolism. Certain interventions may help upregulate the ECS, including exercise and supplementation of omega-3 fatty acids and some probiotics. If you’re a patient, speak to your integrative healthcare practitioner for specific recommendations.
- Chye, Y., Christensen, E., Solowij, N., & Yücel, M. (2019). The endocannabinoid system and cannabidiols promise for the treatment of substance use disorder. Frontiers in Psychiatry, 10.
- Di Marzo, V., Melck, D., Bisogno, T., & Petrocellis, L. D. (1998). Endocannabinoids: Endogenous cannabinoid receptor ligands with neuromodulatory action. Trends in Neurosciences, 21(12), 521–528.
- Di Marzo, V., & Piscitelli, F. (2015). The endocannabinoid system and its modulation by phytocannabinoids. Neurotherapeutics, 12(4), 692–698.
- Fride, E. (2004). The endocannabinoid-CB receptor system: Importance for development and in pediatric disease. Neuroendocrinology Letters, 25(1-2), 24-30.
- Higgins, K, O’Neill, N., O’Hara, L, Jordan, J. A., McCann, M., O’Neill, T., … Campbell, A. (2019). Chapter 7, Synthetic cannabinoids. Evidence for public health on novel psychoactive substance use: A mixed-methods study. Retrieved from: https://www.ncbi.nlm.nih.gov/books/NBK544991/
- Kaur, R., Ambwani, S. R., & Singh, S. (2016). Endocannabinoid system: A multi-facet therapeutic target. Current Clinical Pharmacology, 11(2), 110–117.
- McPartland, J. M., Guy, G. W., & Marzo, V. D. (2014). Care and feeding of the endocannabinoid system: A systematic review of potential clinical interventions that upregulate the endocannabinoid system. PLoS ONE, 9(3).
- McPartland, J. M., Duncan, M., Di Marzo, V., & Pertwee, R. G. (2015). Are cannabidiol and Δ(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. British journal of pharmacology, 172(3), 737–753.
- Pacher, P., Bátkai, S., & Kunos, G. (2006). The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacological Reviews, 58(3), 389-462.
- Pertwee, R. G., Howlett, A. C., Abood, M. E., Alexander, S. P., Di Marzo, V., Elphick, M. R., … Ross, R. A. (2010). International union of basic and clinical pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB₁ and CB₂. Pharmacological Reviews, 62(4), 588–631.
- Russo, E. B. (2008). Clinical endocannabinoid deficiency (CECD): Can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuroendocrinology Letters, 29, 192-200.
- Watkins, B. A., & Kim, J. (2015). The endocannabinoid system: Directing eating behavior and macronutrient metabolism. Frontiers in psychology, 5, 1506.
- Zou, S., & Kumar, U. (2018). Cannabinoid receptors and the endocannabinoid system: Signaling and function in the central nervous system. International journal of molecular sciences, 19(3), 833.