Written by: Dr. Jonny Lisano, Ph.D.
Everything you need to know about CBD and the role of the endocannabinoid system
You might have overheard or had conversations with friends and family about CBD, seen posts on social media or even currently use CBD yourself. But what is it really, and what does it do? The compound CBD, also known as cannabidiol, is one of over 100 identified cannabinoids that naturally occur within the cannabis plant. Cannabinoids like CBD work through our endocannabinoid system. This system, while relatively new in terms of its discovery, has receptors in tissues throughout the body and is implicated in tissue to tissue communication. The two most common sources of cannabinoids are marijauna and hemp. Both these plants belong to the family known as Cannabaceae. These two plants, while genetically similar, were selectively bred to express varying levels of cannabinoids, like CBD and THC. Marijuana is typically defined as having a high THC content and moderate CBD content, while hemp is classified as having less than 0.3% THC and a variable amount of CBD. While the legal status of marijuana varies from state to state the 2018 Farm Bill allows for cultivation, production and distribution of hemp derived products in all 50 states.
Cannabinoids, like THC and CBD, exert effects on tissues throughout the body through the endocannabinoid system; with receptors for this system dispersed to varying degrees within almost every tissue in the body (Joshi & Onaivi 2019). The endocannabinoid system was first discovered in the late 1980’s when compounds within cannabis, later to be identified as cannabinoids, were observed to interact with receptors within the brain (Devane et al. 1988 ). Thus, these receptors were termed: cannabinoid receptors. Research in this area quickly progressed and identified two cannabinoid receptors that make up the majority of the endocannabinoid system: the cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors. The CB1 receptor is primarily found within the brain and spinal cord (central nervous system) while the CB2 receptor is primarily found in tissues that are not part of the central nervous system (periphery) like muscle (Zhang et al. 2019), fat (O’Sullivan 2012; Zhang et al. 2014), skin (Wang et al. 2016) and other organs. THC is considered an activator of both the CB1 and CB2 receptors (Tham et al. 2019). The actions of THC on the CB1 receptor, which as we previously discussed is primarily located in the central nervous system, are believed to be the main reason individuals experience intoxication, or a “high” feeling, when using products containing large amounts of THC.
CBD, while extremely similar in structure to THC, has one key structural difference that does not allow CBD to activate the CB1 receptor or produce intoxicating effects. Until recently, CBD was believed to activate the CB2 receptor, but new literature from the scientific community suggests this might not be the case. Instead, some new research suggests that CBD is rather known as an allosteric inhibitor of the CB1 and CB2 receptors (Chung et al. 2019, Martinez-Panilla et al. 2017). This means that while CBD can bind to both receptors it inhibits them rather than activating them. This prevents other molecules like THC from activating the CB1 and CB2 receptors. However, this is a point of spirited debate within the scientific community as there are studies supporting the claims that CBD does indeed activate the CB2 receptor (Tham et al. 2019). Now you’re probably thinking, “Well if CBD doesn’t activate the CB2 receptor like everyone says, why am I taking it?”. Worry not… because it does a lot more than that. To make things more complicated, it turns out that phytocannabinoids also activate a number of receptors outside the traditional CB1 and CB2 receptors, including (but certainly not limited to) GPR55 (Irving et al. 2017), 5HT-1A (Sonego et al. 2016), PPARa (O’Sullivan 2012; Zhang et al. 2014), PPARg (O’sullivan 2012), and many many more, making the “endocannabinoid system” much more complex than previously thought. It’s possible that CBD primarily works through one or more of these other receptors, possibly activating CB2 through action upon a different system. Time, and much, much more science, will tell.
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Chung, H., Fierro, A., Pessoa-Mahana, C.D. 2019. Cannabidiol binding and negative allosteric modulation at the cannabinoid type 1 receptor in the presence of delta-9-tetrahydrocannabinol: An In Silico study. PLoS One, 14(7).
Joshi, N., Onaivi, E.S. 2019. Endocannabinoid System Components: Overview and Tissue Distribution. In: Bukiya A. (eds) Recent Advances in Cannabinoid Physiology and Pathology. Advances in Experimental Medicine and Biology, vol 1162. Springer, Cham
Martinez-Pinilla, E., Varani, K., Reye-Resina, I., Angelats, E., Vincenzi, F., Ferreiro-Vera, C., et. al. 2017. Binding and Signaling Studies Disclose a Potential Allosteric Site for Cannabidiol in Cannabinoid CB2 Receptors. Front Pharmacol.
Sonego, A.B., Gomes, F.V., Del Bel, E.A., Guimaraes, F.S. 2016. Cannabidiol attenuates haloperidol-induced catalepsy and c-Fos protein expression in the dorsolateral striatum via 5-HT1A receptors in mice. Behav. Brain Res. 309: 22-28.
Tham, M., Yilmaz, O., Alaverdashvili, M., Kelly, M.E.M., Denovan-Wright, E.M., Laprairie, R.B. 2019. Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors. Br. J. Pharmacol, 176(10): 1455-1469.
Wang, L.L., Zhao, R., Li, J.Y., Li, S.S., Liu, M., Wang, M., et al. 2016 Pharmacological activation of cannabinoid 2 receptor attenuates inflammation, fibrogenesis, and promotes re-epithelialization during skin wound healing. Eur. J. Pharmacol., 786: 128-136.
Zhang, M., Zhang, M., Wang, L., Yu, T., Jiang, S., Jiang, P., et al. 2019 Activation of cannabinoid type 2 receptor protects skeletal muscle from ischemia-reperfusion injury partly via Nrf2 signaling. Life Sci., 230: 55-67.
Zhang, Y.F., Yuan, Z.Q., Song, D.G., Zhou, X.H., Wang, Y.Z. 2014. Effects of cannabinoid receptor 1 (brain) on lipid accumulation by transcriptional control of CPT1A and CPT1B. Anim. Genet., 45(1): 38-47.