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You may have heard of the term “entourage effect” when discussing the effects of cannabis. But what does this mean? Essentially, the entourage effect refers to the potential for different types of cannabis molecules to work together in your body, enhancing or creating additional therapeutic benefits. When cannabis is consumed, our bodies integrate hundreds of different compounds from the plant including phytocannabinoids, terpenes, and flavonoids. Understanding each type of molecule can help clarify the entourage effect concept.  

Phytocannabinoids are cannabinoids produced in the glandular trichome of female flowers and interact with the endocannabinoid system (ECS) in the human body, composed of G-protein-coupled receptors cannabinoid receptors 1 and 2 (CB1R and CB2R).1,2 While more than 100 are known, cannabidiol (CBD) and D-9 tetrahydrocannabinol (THC) are the most studied for their therapeutic benefits.   

Similar to phytocannabinoids, terpenes are also produced in the trichomes but contribute to the fragrance of cannabis flowers and products.3 In total, more than 100 terpenes have been identified in the cannabis plant, each contributing to different therapeutic effects. These may include relaxation, stress-relief, focus, acuity as well as anti-inflammatory properties depending on the type. Some of the most common terpenes found in cannabis include: myrcene (found in mangos and lemongrass), which is reported to have analgesic and sedative properties, pinene (basil and rosemary), caryophyllene (clove and cinnamon) useful for pain as anti-inflammatory agents, and limonene (orange and lemon), which has been shown to be an anxiety and stress reliever.4-8 

Finally, flavonoids are phytonutrients found in nearly all fruits and vegetables, produced by trichomes in the cannabis plant, and are primarily responsible for giving its pigmentation and contributing to aroma and flavor. They may have medicinal effects including anti-inflammatory, antioxidant, and neuroprotective properties, but are the most understudied compounds in the cannabis plant. There are about 20 flavonoids identified in the cannabis plant, but the most common include: quercetin, which may improve mental/physical performance and reduce inflammation (grapes and apples), cannflavins A, B, C (Cannabis Sativa), which also have anti-inflammatory properties, and kaempferol (spinach and broccoli), which acts as an antioxidant, anticancer and anti-inflammatory agent. 9-11 

The term “entourage effect” was first coined in 1998 by Dr. Ben-Shabat in the laboratory of Dr. Raphael Mechoulam, as a way to explain how two compounds 2-linoleoylglycerol and 2-palmitoylglycerol improved the ability of the endocannabinoid, 2-Arachidonoylglycerol (2-AG), to bind to CB1R and CB2R.12 This concept was further elaborated in 2011 by Dr. Ethan Russo who provided evidence on the positive therapeutic outcome from the addition of various types of phytocannabinoids, terpenes, and flavonoids present in the cannabis plant for the treatment of pain, inflammation, and depression to name a few.13 In other words, this research suggests that a combination of cannabis compounds can be more effective than a single molecule working alone, and that together they can harmonize as a symphony to create a fuller and potentially more beneficial effect.  

In conclusion, the term “entourage effect” refers to the suggested contribution of phytocannabinoids, terpenes, and flavonoids to activate multiple signaling pathways that have the potential to increase the therapeutic benefits of cannabis, as compared to administration of a single molecule (e.g., CBD or THC). Understanding how each of these interactions work synchronously may shine new light on the potential applications of cannabis in various disease settings, potentially replacing existing therapies with adverse side effects. 

  1. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990;346(6284):561-4. DOI: 10.1038/346561a0.
  2. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993;365(6441):61-5. DOI: 10.1038/365061a0.
  3. Booth JK, Page JE, Bohlmann J. Terpene synthases from Cannabis sativa. PLoS One 2017;12(3):e0173911. DOI: 10.1371/journal.pone.0173911.
  4. Rao VS, Menezes AM, Viana GS. Effect of myrcene on nociception in mice. J Pharm Pharmacol 1990;42(12):877-8. DOI: 10.1111/j.2042-7158.1990.tb07046.x.
  5. do Vale TG, Furtado EC, Santos JG, Jr., Viana GS. Central effects of citral, myrcene and limonene, constituents of essential oil chemotypes from Lippia alba (Mill.) n.e. Brown. Phytomedicine 2002;9(8):709-14. DOI: 10.1078/094471102321621304.
  6. Kim DS, Lee HJ, Jeon YD, et al. Alpha-Pinene Exhibits Anti-Inflammatory Activity Through the Suppression of MAPKs and the NF-kappaB Pathway in Mouse Peritoneal Macrophages. Am J Chin Med 2015;43(4):731-42. DOI: 10.1142/S0192415X15500457.
  7. Brito LF, Oliveira HBM, das Neves Selis N, et al. Anti-inflammatory activity of beta-caryophyllene combined with docosahexaenoic acid in a model of sepsis induced by Staphylococcus aureus in mice. J Sci Food Agric 2019;99(13):5870-5880. DOI: 10.1002/jsfa.9861.
  8. Song Y, Seo S, Lamichhane S, et al. Limonene has anti-anxiety activity via adenosine A2A receptor-mediated regulation of dopaminergic and GABAergic neuronal function in the striatum. Phytomedicine 2021;83:153474. DOI: 10.1016/j.phymed.2021.153474.
  9. Davis JM, Murphy EA, Carmichael MD. Effects of the dietary flavonoid quercetin upon performance and health. Curr Sports Med Rep 2009;8(4):206-13. DOI: 10.1249/JSR.0b013e3181ae8959.
  10. Erridge S, Mangal N, Salazar O, Pacchetti B, Sodergren MH. Cannflavins – From plant to patient: A scoping review. Fitoterapia 2020;146:104712. DOI: 10.1016/j.fitote.2020.104712.
  11. Imran M, Rauf A, Shah ZA, et al. Chemo-preventive and therapeutic effect of the dietary flavonoid kaempferol: A comprehensive review. Phytother Res 2019;33(2):263-275. DOI: 10.1002/ptr.6227.
  12. Ben-Shabat S, Fride E, Sheskin T, et al. An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur J Pharmacol 1998;353(1):23-31. DOI: 10.1016/s0014-2999(98)00392-6.
  13. Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol 2011;163(7):1344-64. DOI: 10.1111/j.1476-5381.2011.01238.x.

 

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Author Yoel H. Sitbon

Yoel is a Medical Writer in the Medical Content division at Csequence. His scientific expertise is in Neuroscience (neural mechanisms behind drug addiction) and Molecular & Cellular Pharmacology (molecular mechanisms behind mutations induced cardiovascular diseases). Yoel has over five years of scientific writing experience as evidenced by 8 peer-reviewed publications in scientific journals. He is an effective oral communicator having presented his PhD thesis work at many biomedical conferences nationally. He also has strong mentorship and leadership experience. Yoel has a B.S in Neuroscience at the University of California, Los Angeles and a Ph.D. in Molecular & Cellular Pharmacology at the University of Miami, Miller School of Medicine.

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