What is CBD

August 14, 2019 by Jonny Lisano2

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. While synthetic cannabinoids are produced for research and of their function and potential therapeutic benefits, The two most common sources of naturally occurring 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 of the United States.

Cannabinoids, like THC and CBD, exert effects on tissues throughout the human body through the endocannabinoid system; with endocannabinoid receptors dispersed to varying degrees within almost every tissue in the body (Joshi & Onaivi 2019), including in the brain, organs, connective tissues, glands, and immune system. The endogenous cannabinoid system was first discovered in the late 1980’s when compounds within cannabis, later to be identified as endogenous 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. Cannabinoid binding sites exist throughout the central and peripheral nervous systems. 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 (Wright et al. 2008). Our bodies naturally produce many endocannabinoids that interact with these cannabinoid receptors, the most common of which are anandamide and 2-AG (2-arachidonoylglycerol). 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 psychoactive intoxication, or a “high” feeling, when using products containing large amounts of THC present in cannabis sativa.

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 the intoxicating effects of cannabis that’s used recreationally. 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.

References:

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).

Devane, W.A., Dysarz, F.A., Johnson, M.R., Melvin, L.S., Howlett, A.C. 1988 Determination and characterization of a cannabinoid receptor in rat brain. Mol. Pharmacol. 34: 605-613.

Irving, A., Abdulrazzag, G., Chan, S.L.F., Penman, J., Harvey, J., Alexander, S.P.H. 2017. Cannabinoid Receptor-Related Orphan G Protein-Coupled Receptors. Adv. Pharmacol, 80: 223-247.

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

Ligresti A, De petrocellis L, Di marzo V. From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology. Physiol Rev. 2016;96(4):1593-659.

Mackie K. Cannabinoid receptors: where they are and what they do. J Neuroendocrinol. 2008;20 Suppl 1:10-14. doi:10.1111/j.1365-2826.2008.01671.x.

Maccarrone M, Bab I, Bíró T, et al. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci. 2015;36(5):277-296.doi:10.1016/j.tips.2015.02.008

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.

O’Sullivan, S.E. 2012. Cannabinoid activation of peroxisome proliferator‐activated receptors: an update and review of the physiological relevance. Wiley Interdisciplinary Reviews.

Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153(2):199-215.

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.

Wright KL, Duncan M, Sharkey KA. Cannabinoid CB2 receptors in the gastrointestinal tract: a regulatory system in states of inflammation. Br J Pharmacol. 2008;148:191–199

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.

 

Jonny Lisano

2 comments

  • Jeremiah

    August 15, 2019 at 10:27 am

    Love it! Nice work Jonny!

    Reply

    • Jonny

      August 15, 2019 at 2:53 pm

      Thanks!

      Reply

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