The ECS Trifecta: Enzymes, Cannabinoids, and Receptors

Like a word stuck on the tip of your tongue, the endocannabinoid system (ECS) exists in the body—obscured and omnipresent—to impact a wide range of physiological mechanisms every minute of every day. The ECS is a system of the body just like the immune or digestive system, but instead of T cells and B cells or the stomach and gastrointestinal tract, it has a complex network of receptors, signaling molecules, and metabolic enzymes working together in tissues and organs all over the body.

Perhaps the core team associated with ECS activity includes the trifecta of cannabinoid receptors CB1 and CB2, metabolic enzymes, and cannabinoids, both endogenous (endocannabinoids) and exogenous (phytocannabinoids).¹ Of course, hemp and other cannabis species are known for producing the phytocannabinoids that, along with endocannabinoids, are responsible for activating CB1 and CB2, which then trigger a cascade of activities associated with the ECS.²

• CB1: Psychoactive, neuromodulatory, and analgesic activity

• CB2: Anti-inflammatory, immunomodulatory, and lymphatic activity

If the ECS is functioning optimally, cannabinoids bind CB1 and CB2 receptors, releasing various neurotransmitters destined to affect a particular mechanism in the body, such as:³

• Sleep
• Memory
• Gut health
• Metabolic function
• Stress response
• Inflammation

Cannabinoid Receptors

CB1 and CB2 are different in their chemical structure and, thus, their downstream targets. The two receptors also differ in the parts of the body where they are generally found. CB1 usually takes up residence in the brain, adipocytes, hepatocytes, and musculoskeletal tissues, while CB2 is typically found in immune-related cells and tissues and possibly the central nervous system.^4,5 Different phytocannabinoids from different plants may activate one receptor or the other. The phytocannabinoids found in hemp typically activate CB2, while the phytocannabinoids found in some other cannabis plants tend to activate CB1.

Hemp and Phytocannabinoids

According to the 2018 Farm Bill, hemp plants are legally defined as Cannabis sativa strains containing less than 0.3% tetrahydrocannabinol (THC), the phytocannabinoid infamous for its association with psychoactive effects in the body.⁶ A wide spectrum of other, different phytocannabinoids are found in hemp, depending on what part of the plant from which they are extracted— flower versus seeds versus leaves versus stalk. Hemp seeds are typically associated with seed oil, which contains saturated, monounsaturated, and polyunsaturated fats.⁷ The flower, leaves, and stalk of the hemp plant are linked to phytoactive compounds, including phytocannabinoids, terpenes, and stilbenes.⁸ Together, compounds from the different parts of the hemp plant may be extracted and combined to make hemp oil, which contains the full spectrum of phytocannabinoids available in hemp, such as:

• Cannabidiol (CBD)
• Cannabigerol (CBG)
• Cannabivarin (CBV)
• Cannabinol (CBN)

Endocannabinoids and Enzyme Catalysts

Omega-3 and omega-6 fatty acids serve as precursors of endocannabinoids in the body, eternally tying these polyunsaturated fatty acids (PUFAs) to nutritional support of the ECS. Omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) can be converted into endocannabinoids docosahexaenoyl ethanolamide (DHEA) and eicosapentaenoyl ethanolamide (EPEA), while omega-6 fatty acids are precursors to endocannabinoids N-arachidonoylethanolamine (anandamide/AEA) and sn-2-arachidonoylglycerol (2-AG).^9,10

Endocannabinoids AEA and 2-AG are broken down through enzymatic reactions controlled mostly by fatty acid amide hydrolase 1 (FAAH1) and monoacylglycerol lipase (MAGL), respectively.^10,11 FAAH1 has also been shown to metabolize EPEA and DHEA. Both sets of endocannabinoids activate both CB1 and CB2.⁹ Research has shown that all four of these endocannabinoids are at least partially responsible for the anticancer properties associated with supporting the ECS.^9,12

However, with a reliance on certain nutrients comes a vulnerability to falling out of balance. Deficiency in essential fatty acids inevitably leads to disruption of ECS balance, a flaw in human physiology that has a cascading effect on all the aspects of human health in which the ECS plays a homeostatic role. While omega-6 fatty acids are a common part of the Standard American Diet (SAD), studies show that adults in the United States do not consume enough omega-3 fatty-acid-rich foods.¹³

Various research has linked suboptimal ECS function with a variety of disease states, including:^14-25

• Migraine
• Fibromyalgia
• Irritable bowel syndrome
• Depression
• Schizophrenia
• Multiple sclerosis
• Huntington’s disease
• Parkinson’s disease
• Anorexia
• Chronic motion sickness

Nutrition and Lifestyle Support of the ECS

While such an extensive list of potential health problems associated with poor ECS function may be overwhelming, the volume represents the ubiquitous regulatory nature of this system and its ultimate foundational importance in human health. Supporting healthy ECS function may include promoting regular production of endocannabinoids AEA, 2-AG, DHEA, and EPEA by including essential fatty acids in the diet or through supplementation. Some studies have also shown that supporting the gut microbiome with probiotics and prebiotics may promote cannabinoid receptor activation.^26-28 Additional lifestyle interventions may support healthy ECS function, such as:^29-37

• Eating foods containing vitamin E
• Reducing exposure to toxins found in pesticides, such as chlorpyrifos and diazinon
• Herbal remedies including salvia, red clover, green tea, kava, and turmeric
• Stress management
• Acupuncture
• Diet and weight management

The wide range of health issues connected to suboptimal ECS function and the diverse profile of supportive plants, nutrients, and lifestyle choices that encourage healthy ECS function accentuate the extent to which this vital body system is intertwined with daily quality of life. The science illustrating the physiology of the ECS is only beginning to scratch the surface of just how important this system is for mechanisms all over the body. Supporting the ECS with nutrition and lifestyle habits is a top priority.

Kara Credle, MA, manages content development and strategy for WholisticMatters.com as the Clinical Nutrition Communication Specialist at Standard Process Inc. Her background is in scientific writing with a focus on biomedical sciences, nutrition, health, and wellness and a passion for translating scientific findings for different audiences.

References

1. De Petrocellis, L., & Di Marzo, V. (2010). Non-CB1, non-CB2 receptors for endocannabinoids, plant cannabinoids, and synthetic cannabimimetics: focus on G-protein-coupled receptors and transient receptor potential channels. Journal of Neuroimmune Pharmacology: The Official Journal of the Society on Neuroimmune Pharmacology, 5(1), 103–121. https://doi.org/10.1007/s11481-009-9177-z.
2. Russo E. B. (2016). Beyond Cannabis: Plants and the endocannabinoid system. Trends in Pharmacological Sciences, 37(7), 594–605. https://doi.org/10.1016/j.tips.2016.04.005.
3. Joshi, N., & Onaivi, E. S. (2019). Endocannabinoid system components: overview and tissue distribution. Advances in Experimental Medicine and Biology, 1162, 1–12. https://doi.org/10.1007/978-3-030-21737-2_1.
4. Glass, M., Dragunow, M., & Faull, R. L. (1997). Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience, 77(2), 299–318. https://doi.org/10.1016/s0306-4522(96)00428-9.
5. Atwood, B. K., & Mackie, K. (2010). CB2: a cannabinoid receptor with an identity crisis. British Journal of Pharmacology, 160(3), 467–479. https://doi.org/10.1111/j.1476-5381.2010.00729.x.
6. Hemp Farming Act of 2018, S.2667, 115th Congress. (2017-2018). https://www.congress.gov/bill/115th-congress/senate-bill/2667/text.
7. Kitamura, M., Kiba, Y., Suzuki, R., Tomida, N., Uwaya, A., Isami, F., & Deng, S. (2020). Cannabidiol content and in vitro biological activities of commercial cannabidiol oils and hemp seed oils. Medicines (Basel, Switzerland), 7(9), 57. https://doi.org/10.3390/medicines7090057.
8. ElSohly, M. A., Radwan, M. M., Gul, W., Chandra, S., & Galal, A. (2017). Phytochemistry of Cannabis sativa L. Progress in the Chemistry of Organic Natural Products, 103, 1–36. https://doi.org/10.1007/978-3-319-45541-9_1.
9. Brown, I., Cascio, M. G., Wahle, K. W., Smoum, R., Mechoulam, R., Ross, R. A., Pertwee, R. G., & Heys, S. D. (2010). Cannabinoid receptor-dependent and -independent anti-proliferative effects of omega-3 ethanolamides in androgen receptor-positive and -negative prostate cancer cell lines. Carcinogenesis, 31(9), 1584–1591. https://doi.org/10.1093/carcin/bgq151.
10. McPartland, J. M., Guy, G. W., & Di Marzo, V. (2014). Care and feeding of the endocannabinoid system: a systematic review of potential clinical interventions that upregulate the endocannabinoid system. PloS one, 9(3), e89566. https://doi.org/10.1371/journal.pone.0089566.
11. Howlett A. C. (2002). The cannabinoid receptors. Prostaglandins & Other Lipid Mediators, 68-69, 619–631. https://doi.org/10.1016/s0090-6980(02)00060-6.
12. Mimeault, M., Pommery, N., Wattez, N., Bailly, C., & Hénichart, J. P. (2003). Anti-proliferative and apoptotic effects of anandamide in human prostatic cancer cell lines: implication of epidermal growth factor receptor down-regulation and ceramide production. The Prostate, 56(1), 1–12. https://doi.org/10.1002/pros.10190.
13. Papanikolaou, Y., Brooks, J., Reider, C., & Fulgoni, V. L., 3rd (2014). U.S. Adults are not meeting recommended levels for fish and omega-3 fatty acid intake: results of an analysis using observational data from NHANES 2003-2008. Nutrition Journal, 13, 31. https://doi.org/10.1186/1475-2891-13-31.
14. Russo E. B. (2004). Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions?. Neuro Endocrinology Letters, 25(1-2), 31–39.
15. Fride E (2004) The endocannabinoid-CB receptor system: importance for development and in pediatric disease. Neuroendocrinology Letters, 25: 24–30.
16. Hill MN, Gorzalka BB (2005) Is there a role for the endocannabinoid system in the etiology and treatment of melancholic depression? Behav Pharmacol, 16: 333–352.
17. Giuffrida A, Leweke FM, Gerth CW, Schreiber D, Koethe D, et al. (2004) Cerebrospinal anandamide levels are elevated in acute schizophrenia and are inversely correlated with psychotic symptoms. Neuropsychopharmacolog, 29: 2108–2114.
18. Sarchielli P, Pini LA, Coppola F, Rossi C, Baldi A, et al. (2007) Endocannabinoids in chronic migraine: CSF findings suggest a system failure. Neuropsychopharmacology, 32: 1384–1390.
19. Di Filippo M, Pini LA, Pelliccioli GP, Calabresi P, Sarchielli P (2008) Abnormalities in the cerebrospinal fluid levels of endocannabinoids in multiple sclerosis. Journal of Neurology Neurosurgery and Psychiatry, 79: 1224–1229.
20. Allen KL, Waldvogel HJ, Glass M, Faull RLM (2009) Cannabinoid (CB1), GABAA and GABAB receptor subunit changes in the globus pallidus in Huntington’s disease. Journal of Chemical Neuroanatomy, 37: 266–281.
21. Van Laere K, Casteels C, Dhollander I, Goffin K, Grachev I, et al. (2010) Widespread decrease of type 1 cannabinoid receptor availability in Huntington disease in vivo. Journal of Nuclear Medicine, 51: 1413–1417.
22. Pisani V, Moschella V, Bari M, Fezza F, Galati S, et al. (2010) Dynamic changes of anandamide in the cerebrospinal fluid of Parkinson’s disease patients. Movement Disorders, 25: 920–924.
23. Wong BS, Camilleri M, Eckert D, Carlson P, Ryks M, et al. (2012) Randomized pharmacodynamic and pharmacogenetic trial of dronabinol effects on colon transit in irritable bowel syndrome-diarrhea. Neurogastroenterology and Motility, 24.
24. Gerard N, Pieters G, Goffin K, Bormans G, Van Laere K (2011) Brain type 1 cannabinoid receptor availability in patients with anorexia and bulimia nervosa. Biological Psychiatry, 70: 777–784.
25. Chouker A, Kaufmann I, Kreth S, Hauer D, Feuerecker M, et al. (2010) Motion sickness, stress and the endocannabinoid system. PLoS ONE 5.
26. Rousseaux, C., Thuru, X., Gelot, A., Barnich, N., Neut, C., Dubuquoy, L., Dubuquoy, C., Merour, E., Geboes, K., Chamaillard, M., Ouwehand, A., Leyer, G., Carcano, D., Colombel, J. F., Ardid, D., & Desreumaux, P. (2007). Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nature Medicine, 13(1), 35–37. https://doi.org/10.1038/nm1521
27. Palermo, F. A., Mosconi, G., Avella, M. A., Carnevali, O., Verdenelli, M. C., Cecchini, C., & Polzonetti-Magni, A. M. (2011). Modulation of cortisol levels, endocannabinoid receptor 1A, proopiomelanocortin and thyroid hormone receptor alpha mRNA expressions by probiotics during sole (Solea solea) larval development. General and Comparative Endocrinology, 171(3), 293–300. https://doi.org/10.1016/j.ygcen.2011.02.009.
28. Muccioli, G. G., Naslain, D., Bäckhed, F., Reigstad, C. S., Lambert, D. M., Delzenne, N. M., & Cani, P. D. (2010). The endocannabinoid system links gut microbiota to adipogenesis. Molecular Systems Biology, 6, 392. https://doi.org/10.1038/msb.2010.46.
29. Crouzin, N., de Jesus Ferreira, M. C., Cohen-Solal, C., M’Kadmi, C., Bernad, N., Martinez, J., Barbanel, G., Vignes, M., & Guiramand, J. (2011). α-tocopherol and α-tocopheryl phosphate interact with the cannabinoid system in the rodent hippocampus. Free Radical Biology & Medicine, 51(9), 1643–1655. https://doi.org/10.1016/j.freeradbiomed.2011.07.012.
30. Quistad, G. B., Sparks, S. E., & Casida, J. E. (2001). Fatty acid amide hydrolase inhibition by neurotoxic organophosphorus pesticides. Toxicology and Applied Pharmacology, 173(1), 48–55. https://doi.org/10.1006/taap.2001.9175.
31. Capasso, R., Borrelli, F., Cascio, M. G., Aviello, G., Huben, K., Zjawiony, J. K., Marini, P., Romano, B., Di Marzo, V., Capasso, F., & Izzo, A. A. (2008). Inhibitory effect of salvinorin A, from Salvia divinorum, on ileitis-induced hypermotility: cross-talk between kappa-opioid and cannabinoid CB(1) receptors. British Journal of Pharmacology, 155(5), 681–689. https://doi.org/10.1038/bjp.2008.294.
32. Thors, L., Burston, J. J., Alter, B. J., McKinney, M. K., Cravatt, B. F., Ross, R. A., Pertwee, R. G., Gereau, R. W., 4th, Wiley, J. L., & Fowler, C. J. (2010). Biochanin A, a naturally occurring inhibitor of fatty acid amide hydrolase. British Journal of Pharmacology, 160(3), 549–560. https://doi.org/10.1111/j.1476-5381.2010.00716.x.
33. Ligresti, A., Villano, R., Allarà, M., Ujváry, I., & Di Marzo, V. (2012). Kavalactones and the endocannabinoid system: the plant-derived yangonin is a novel CB1 receptor ligand. Pharmacological Research, 66(2), 163–169. https://doi.org/10.1016/j.phrs.2012.04.003.
34. Hassanzadeh, P., & Hassanzadeh, A. (2012). The CB1 receptor-mediated endocannabinoid signaling and NGF: the novel targets of curcumin. Neurochemical Research, 37(5), 1112–1120. https://doi.org/10.1007/s11064-012-0716-2.
35. Hill, M. N., McLaughlin, R. J., Bingham, B., Shrestha, L., Lee, T. T., Gray, J. M., Hillard, C. J., Gorzalka, B. B., & Viau, V. (2010). Endogenous cannabinoid signaling is essential for stress adaptation. Proceedings of the National Academy of Sciences of the United States of America, 107(20), 9406–9411. https://doi.org/10.1073/pnas.0914661107.
36. Zhang, J., Chen, L., Su, T., Cao, F., Meng, X., Pei, L., Shi, J., Pan, H. L., & Li, M. (2010). Electroacupuncture increases CB2 receptor expression on keratinocytes and infiltrating inflammatory cells in inflamed skin tissues of rats. The Journal of Pain, 11(12), 1250–1258. https://doi.org/10.1016/j.jpain.2010.02.013.
37. Di Marzo, V., & Matias, I. (2005). Endocannabinoid control of food intake and energy balance. Nature Neuroscience, 8(5), 585–589. https://doi.org/10.1038/nn1457.