Human Cardiovascular System
The cardiovascular system is an order of organs that carry blood through vessels to and from all parts of the body, transport nutrients and oxygen to tissues and removing carbon dioxide and other waste. The blood is propelled in this closed tubular system by the heart. The cardiovascular system consists of two circuits, pulmonary and systemic, composed of arterial, capillary and venous components.
The endocannabinoid system and the cardiovascular system are interlinked mainly through CB1 receptors. The endocannabinoid system influences several elements; these include the cardiac output (amount of blood pumped by the heart), blood pressure, vessel patency and perfusion. Irregularities that develop within the cardiovascular system such as cardiac arrhythmias, atherosclerosis, and myocardial ischemia are due to a clinical endocannabinoid deficiency. 1, 5, 9, 15, 25, 32, 39
Role of CBD in Cardiovascular Diseases
An increasing number of studies are proposing the beneficial part of CBD for overall cardiovascular health. Cannabidiol has a direct effect on isolated arteries; it reduces tension in blood vessel walls in both acute and time-dependent scenarios. Hence, improving vessel patency, perfusion, and reperfusion especially after an injury or blockage. In animals with impaired endothelium-dependent vasorelaxation, in vitro immunization with CBD has shown improvement in vasodilatory responses. Research has also shown that CBD administration can reduce ischemic tissue damage from a coronary attack. Moreover, cannabidiol can protect against vascular damage caused by an elevated glucose environment and inflammation. In animal models, CBD has shown to reduce vascular hyperpermeability from cases such as type 2 diabetes. This reduction is due to the anti-inflammatory and antioxidant properties of CBD. 34, 39
Arteries are vessels that transport oxygen-rich blood from the heart to different parts of the body. Atherosclerosis is a disease that results in plaque buildup within the arteries, hardening over time and narrowing the arteries. The plague is made up of different substances found in the blood and fat, cholesterol and calcium. Narrow or blocked arteries increase the risk of stroke, myocardial infarction, and hypertension. Monocytes and macrophages are critical to the formation and progression of atherosclerotic plaque. Oxidative stress and inflammation result directly in distributed blood flow and dysfunction of endothelial cells (cells that overlay the interior surface of blood and lymphatic vessels).
Atherosclerosis relates to an acquired and genetic clinical endocannabinoid deficiency and a dysfunctional immune response to the presence of endothelial adhesion molecules. CB2 receptors within the circulatory system regulate immune responses. Administration of phytocannabinoids can reduce inflammation responses to abnormal endothelial molecules and reactive oxidative species that play a role in plaque formation and death of cells. Research suggests that CBD can be used in the prevention and treatment of atherosclerosis. 5, 6, 7, 10, 11, 14, 15, 18, 20, 25,27, 33, 34
Cardiomyopathy represents diseases that affect the heart making it harder for it to pump blood. The disease is associated with increased oxidative stress and adhesion molecules and decreased diastolic and systolic myocardial performance. The increase in vascular adhesion molecules results in the rapid growth of fibrosis and connective tissue eventually ending in cell death.
Numerous causes can result in cardiomyopathies such as infection, drugs, myocardial ischemia and as repercussions associated with diabetes mellitus and metabolic syndrome. Cardiomyopathy is an acquired clinical endocannabinoid deficiency. Research already supports the positive effect of cannabidiol through CB1 and CB2 receptors, this is also true for cardiomyopathy. CBD administration improves cardiac dysfunction, reduces oxidative stress and correlated cell death. Improving CB2 receptivity by increasing anandamide levels will decrease the inflammatory response. Fibrotic scarring is diminished by cannabidiol, stressing the significance of an augmented cellular glucose usage especially in conditions such as diabetes and hyperinsulinemia. CBD is beneficial in both primary cardiomyopathy and ones associated with metabolic syndromes, as a therapeutic and protective treatment.8, 9, 11, 16, 31, 34, 35
The abnormal increase in circulating blood pressure leads to medical complications like stroke, dementia, myocardial infarction, and peripheral vascular disease. Hypertension is an acquired and genetic clinical endocannabinoid deficiency influenced by the decrease in circulating cannabinoids. Increasing anandamide levels, the lipid neurotransmitter that directly binds to CB1 and CB2 receptors correlate with relaxing the blood vessels. When blood vessels relax, the systemic blood pressure reduces. Therefore, cannabidiol administration is recommended to protect against the risk of malignant hypertension and for treatment after diagnosis.2-4, 6, 7, 10, 11, 12, 13, 16, 17, 23, 24, 25, 28, 29, 31, 34
Myocardial ischemia takes place when blood flow to the heart is restricted, preventing it from receiving enough oxygen, and reducing glucose both of which are necessary for cell viability and function. Damage to myocardial tissue can result from this partial or complete blocked of the coronary arteries; damage can be verified using an electrocardiogram (EKG) or echocardiogram test.
Myocardial ischemia is an acquired clinical endocannabinoid deficiency; it manifests due to a decrease in the density of available cannabinoids to CB1 and CB2 receptors in the cardiac muscle. Studies suggest the therapeutic administration of cannabidiol to improve myocardial ischemia outcome. CBD has vasodilatory effects that restore blood flow to the heart and reducing residual damage. The risk of myocardial ischemia increases in individuals with metabolic diseases. CBD can, therefore, reduce or prevent the risk of myocardial ischemia in diabetes, hypertension, and atherosclerosis.5, 8, 11, 14, 15, 16, 19, 20, 22, 25, 32, 32, 36-38, 39
When blood flow to the heart lessens or stops, it causes myocardial infarction (MI) or more commonly a heart attack. MI results in damage to the heart muscle in the form of cell death. A common cause of MI is atherosclerotic blockage of a coronary artery that may ultimately lead to a full cardiac arrest and possibly death. The risk of myocardial infarction increases with blood cell and cholesterol accumulation within the arteries.
MI is influenced by a clinical endocannabinoid deficiency, through affected CB1 and CB2 receptors throughout the myocardial tissue. CBD can, therefore, play a therapeutic role, by reducing inflammation, immunological responses and ultimately endothelial wall plaque formation within the coronary arteries. Research has also shown that CBD administration can improve reperfusion and avoid abnormal heart rhythms after a heart attack. Increasing cannabinoid engagement with CB receptors would limit damage to heart tissue.4, 7, 8, 11, 21, 25, 26, 30, 31, 34, 36-38, 39
- Endocannabinoids: a new class of vasoactive substances, Randall, M.D. et al., Trends in Pharmacological Sciences , Volume 19 , Issue 2 , 55 – 58 (1998) available at https://www.ncbi.nlm.nih.gov/pubmed/9550942
- Cannabinoid receptors and their ligands, Pertwee, R.G. et al. Prostaglandins, Leukotrienes and Essential Fatty Acids , Volume 66 , Issue 2 , 101 – 121 available at https://www.ncbi.nlm.nih.gov/pubmed/12052030
- Vincenzo Di Marzo, ‘Endocannabinoids’ and other fatty acid derivatives with cannabimimetic properties: biochemistry and possible physiopathological relevance, Biochimica et Biophysica Acta (BBA) – Lipids and Lipid Metabolism, Volume 1392, Issues 2–3, 1998, Pages 153-175, available at https://www.sciencedirect.com/science/article/pii/S0005276098000423?via%3Dihub
- Grotenhermen, F. Clin Pharmacokinet (2003) 42: 327. https://doi.org/10.2165/00003088-200342040-00003
- Russo E. B, Neuro Endocrinol Lett. 2004 Feb-Apr;25(1-2):31-9. Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Available at https://www.ncbi.nlm.nih.gov/pubmed/15159679
- O’Neill, S. and O’Driscoll, L. (2015), Metabolic syndrome. Obes Rev, 16: 1-12. Available at https://onlinelibrary.wiley.com/doi/abs/10.1111/obr.12229
- Gertsch, J. (2017) Cannabimimetic phytochemicals in the diet – an evolutionary link to food selection and metabolic stress adaptation?. British Journal of Pharmacology, 174: 1464–1483, available at https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.13676
- Lipina, C., & Hundal, H. S. (2017). The endocannabinoid system: no longer anonymous in the control of nitrergic signalling? Journal of Molecular Cell Biology, 9(2), 91-103, available at https://discovery.dundee.ac.uk/en/publications/the-endocannabinoid-system-no-longer-anonymous-in-the-control-of-
- Scarabino, T., Salvolini, U. Atlas of Morphology and Functional Anatomy of the Brain. Springer-Verlag Berlin Heidelberg, (2006).
- Roger G. Pertwee, Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities, Phil. Trans. R. Soc. B 2012 367 3353-3363; available at http://rstb.royalsocietypublishing.org/content/367/1607/3353.long
- George W. Booz, Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress, Free Radical Biology and Medicine, Volume 51, Issue 5, 2011, Pages 1054-1061, ISSN 0891-5849, available at: http://www.sciencedirect.com/science/article/pii/S0891584911000116
- Crandall J, Matragoon S, Khalifa Y, M, Borlongan C, Tsai N, -T, Caldwell R, B, Liou G, I, Neuroprotective and Intraocular Pressure-Lowering Effects of (–)Δ<sup>9</sup>-Tetrahydrocannabinol in a Rat Model of Glaucoma. Ophthalmic Res 2007;39:69-75, available at https://www.karger.com/Article/Abstract/99240#
- Novack GD, Cannabinoids for treatment of glaucoma. Current Opinion in Ophthalmology 27:146–150, MAR 2016, available at https://insights.ovid.com/pubmed?pmid=26840343#
- Mia Levite, Nerve-Driven Immunity: Neurotransmitters and Neuropeptides in the Immune System, Springer, Vienna (2012), available at https://link.springer.com/book/10.1007%2F978-3-7091-0888-8#toc
- Smith SC, Wagner MS. Clinical endocannabinoid deficiency (CECD) revisited: can this concept explain the therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuro Endocrinol Lett. 2014; 35(3): 198 – 201. Available at https://www.ncbi.nlm.nih.gov/pubmed
- Tatiana Barichello, Renan A. Ceretta, Jaqueline S. Generoso, Ana Paula Moreira, Lutiana R. Simões, Clarissa M. Comim, João Quevedo, Márcia Carvalho Vilela, Antonio Waldo Zuardi, José A. Crippa, Antônio Lucio Teixeira, Cannabidiol reduces host immune response and prevents cognitive impairments in Wistar rats submitted to pneumococcal meningitis, European Journal of Pharmacology, Volume 697, Issues 1–3, 2012, Pages 158-164, ISSN 0014-2999, available at https://doi.org/10.1016/j.ejphar.2012.09.053.
- Chen, J., Simon, P. & Fliri, H. Abnormal Cannabidiols as Agents for Lowering Intraocular Pressure. 2, 1-13 (2013), available at https://patents.google.com/patent/US7618966B2/en
- Parray, H.A. & Yun, J.W. Cannabidiol promotes browning in 3T3-L1 adipocytes. Mol Cell Biochem (2016) 416: 131. https://doi.org/10.1007/s11010-016-2702-5
- Gregory I. Liou, John A. Auchampach, Cecilia J. Hillard, Gu Zhu, Bilal Yousufzai, Salman Mian, Sohail Khan, Yousuf Khalifa; Mediation of Cannabidiol Anti-inflammation in the Retina by Equilibrative Nucleoside Transporter and A2A Adenosine Receptor. Invest. Ophthalmol. Vis. Sci. 2008;49(12):5526-5531. Available at http://iovs.arvojournals.org/article.aspx?articleid=2164704
- Zuardi, Antonio Waldo. (2008). Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. Revista Brasileira de Psiquiatria, 30(3), 271-280. Available at https://dx.doi.org/10.1590/S1516-44462008000300015
- Paul Consroe, Joan Laguna, James Allender, Stuart Snider, Lawrence Stern, Reuven Sandyk, Kurt Kennedy, Karl Schram, Controlled clinical trial of cannabidiol in Huntington’s disease, Pharmacology Biochemistry and Behavior, Volume 40, Issue 3, 1991, Pages 701-708, ISSN 0091-3057, available at https://doi.org/10.1016/0091-3057(91)90386-G.
- Fernández-Ruiz, J., Sagredo, O., Pazos, M. R., García, C., Pertwee, R., Mechoulam, R., & Martínez-Orgado, J. (2013). Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid? British Journal of Clinical Pharmacology, 75(2), 323–333. Available at http://doi.org/10.1111/j.1365-2125.2012.04341.x
- Szaflarski, Jerzy P. et al. Cannabis, cannabidiol, and epilepsy — From receptors to clinical response, Epilepsy & Behavior , Volume 41 , 277 – 282 (2014), availble at https://doi.org/10.1016/j.yebeh.2014.08.135
- Tomida, I. et al. Effect of Sublingual Application of Cannabinoids on Intraocular Pressure: A Pilot Study. Journal of Glaucoma. 15(5):349-353, OCT 2006, available at https://insights.ovid.com/pubmed?pmid=16988594#
- Baron, E. P. (2015), Comprehensive Review of Medicinal Marijuana, Cannabinoids, and Therapeutic Implications in Medicine and Headache: What a Long Strange Trip It’s Been …. Headache: The Journal of Head and Face Pain, 55: 885-916. Available at https://doi.org/10.1111/head.12570
- Selim R Benbadis, Juan Sanchez-Ramos, Ali Bozorg, Melissa Giarratano, Kavita Kalidas, Lara Katzin, Derrick Robertson, Tuan Vu, Amanda Smith & Theresa Zesiewicz (2014) Medical marijuana in neurology, Expert Review of Neurotherapeutics, 14:12, 1453-1465, available at https://doi.org/10.1586/14737175.2014.985209
- Daniela Parolaro, Natalia Realini, Daniela Vigano, Cinzia Guidali, Tiziana Rubino, The endocannabinoid system and psychiatric disorders, Experimental Neurology, Volume 224, Issue 1, 2010, Pages 3-14, ISSN 0014-4886, available at https://doi.org/10.1016/j.expneurol.2010.03.018
- Yu, Y., Chen, H., & Su, S. B. (2015). Neuroinflammatory responses in diabetic retinopathy. Journal of Neuroinflammation, 12, 141. Available at http://doi.org/10.1186/s12974-015-0368-7
- Tezel, G., Yang, X., Luo, C., Peng, Y., Sun, S. L., & Sun, D. (2007). Mechanisms of Immune System Activation in Glaucoma: Oxidative Stress-Stimulated Antigen Presentation by the Retina and Optic Nerve Head Glia. Investigative Ophthalmology & Visual Science, 48(2), 705–714. Available at http://doi.org/10.1167/iovs.06-0810
- Giulia Di Carlo & Angelo A Izzo (2005) Cannabinoids for gastrointestinal diseases: potential therapeutic applications, Expert Opinion on Investigational Drugs, 12:1, 39-49, available at https://doi.org/10.1517/135437126.96.36.199
- Tam, J., Liu, J., Mukhopadhyay, B., Cinar, R., Godlewski, G., & Kunos, G. (2011). Endocannabinoids in Liver Disease. Hepatology (Baltimore, Md.), 53(1), 346–355. Available at http://doi.org/10.1002/hep.24077
- Fitzcharles, MA., Baerwald, C., Ablin, J. et al. Schmerz (2016) 30: 47. Available at https://doi.org/10.1007/s00482-015-0084-3
- Valerio Chiurchiù, Mirko Lanuti, Marco De Bardi, Luca Battistini, Mauro Maccarrone; The differential characterization of GPR55 receptor in human peripheral blood reveals a distinctive expression in monocytes and NK cells and a proinflammatory role in these innate cells, International Immunology, Volume 27, Issue 3, 1 March 2015, Pages 153–160, available at https://doi.org/10.1093/intimm/dxu097
- Stanley, C. P., Hind, W. H., & O’Sullivan, S. E. (2013). Is the cardiovascular system a therapeutic target for cannabidiol? British Journal of Clinical Pharmacology, 75(2), 313–322. Available at http://doi.org/10.1111/j.1365-2125.2012.04351.x
- Rajesh, M., Mukhopadhyay, P., Bátkai, S., Patel, V., Saito, K., Matsumoto, S., … Pacher, P. (2010). Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, inflammatory and cell death signaling pathways in diabetic cardiomyopathy. Journal of the American College of Cardiology, 56(25), 2115–2125. Available at http://doi.org/10.1016/j.jacc.2010.07.033
- Ersöz Gonca, Faruk Darıcı, The Effect of Cannabidiol on Ischemia/Reperfusion-Induced Ventricular Arrhythmias: The Role of Adenosine A1 Receptors. Volume: 20 issue: 1, page(s): 76-83 (2014), available at https://doi.org/10.1177/1074248414532013
- Ronen Durst, Haim Danenberg, Ruth Gallily, Raphael Mechoulam, Keren Meir, Etty Grad, Ronen Beeri, Thea Pugatsch, Elizabet Tarsish, and Chaim Lotan, Cannabidiol, a nonpsychoactive Cannabis constituent, protects against myocardial ischemic reperfusion injury. American Journal of Physiology-Heart and Circulatory Physiology 2007 293:6, H3602-H3607 available at https://doi.org/10.1152/ajpheart.00098.2007
- Walsh, S. K., Hepburn, C. Y., Kane, K. A. and Wainwright, C. L. (2010), Acute administration of cannabidiol in vivo suppresses ischaemia‐induced cardiac arrhythmias and reduces infarct size when given at reperfusion. British Journal of Pharmacology, 160: 1234-1242. Available at https://doi.org/10.1111/j.1476-5381.2010.00755.x
Walsh, S. K., Hepburn, C. Y., Kane, K. A., & Wainwright, C. L. (2010). Acute administration of cannabidiol in vivo suppresses ischaemia-induced cardiac arrhythmias and reduces infarct size when given at reperfusion. British Journal of Pharmacology, 160(5), 1234–1242. Available at http://doi.org/10.1111/j.1476-5381.2010.00755.x