Naturally Occurring Cannabinoids and their Role in Modulation of Cardiovascular Health

References

• Alfulaij N, Meiners F, Michalek J, Small‐Howard AL, Turner HC, Stokes AJ. 2018. Cannabinoids, the heart of the matter. J Am Heart Assoc. 7(14):e009099. doi:10.1161/JAHA.118.009099.
   PubMed Web of Science ®Google Scholar
• Amato G, Khan NS, Maitra R. 2019. A patent update on cannabinoid receptor 1 antagonists (2015–2018). Expert Opin Ther Pat. 29(4):261–269. doi:10.1080/13543776.2019.1597851.
   PubMed Web of Science ®Google Scholar
• Andre CM, Hausman JF, Guerriero G. 2016. Cannabis sativa: The plant of the thousand and one molecules. Front Plant Sci. 7:19.
   PubMed Web of Science ®Google Scholar
• Atalay S, Jarocka-Karpowicz I, Skrzydlewska E. 2019. Antioxidative and anti-inflammatory properties of cannabidiol. Antioxidants (Basel). 9(1):21. doi:10.3390/antiox9010021.
   PubMedGoogle Scholar
• Bairey Merz CN, Elboudwarej O, Mehta P. 2015. The autonomic nervous system and cardiovascular health and disease: a complex balancing act. JACC Heart Fail. 3(5):383–385. doi:10.1016/j.jchf.2015.01.008.
   PubMed Web of Science ®Google Scholar
• Baldissera M-D, Souza C-F, Grando T-H, Doleski P-H, Boligon A-A, Stefani L-M, Monteiro S-G. 2017. Hypolipidemic effect of β-caryophyllene to treat hyperlipidemic rats. Naunyn Schmiedebergs Arch Pharmacol. 390(2):215–223. doi:10.1007/s00210-016-1326-3.
   Google Scholar
• Baranowska-Kuczko M, Kozłowska H, Kloza M, Sadowska O, Kozłowski M, Kusaczuk M, Kasacka I, Malinowska B. 2020. Vasodilatory effects of cannabidiol in human pulmonary and rat small mesenteric arteries: modification by hypertension and the potential pharmacological opportunities. J Hypertens. 38(5):896–911. doi:10.1097/HJH.0000000000002333.
   PubMed Web of Science ®Google Scholar
• Batkai S, et al. 2004. Endocannabinoids acting at cannabinoid-1 receptors regulate cardiovascular function in hypertension. Circulation. 110(14):1996–2002.
   PubMed Web of Science ®Google Scholar
• Batkai S, et al. 2007. Decreased age-related cardiac dysfunction, myocardial nitrative stress, inflammatory gene expression, and apoptosis in mice lacking fatty acid amide hydrolase. Am J Physiol Heart Circ Physiol. 293(2):H909–H918.
   PubMed Web of Science ®Google Scholar
• Bergamaschi MM, Queiroz RHC, Zuardi AW, Crippa JAS. 2011. Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf. 6(4):237–249. doi:10.2174/157488611798280924.
   PubMedGoogle Scholar
• Bonz A, et al. 2003. Cannabinoids acting on CB1 receptors decrease contractile performance in human atrial muscle. J Cardiovasc Pharmacol. 41(4):657–664.
   PubMed Web of Science ®Google Scholar
• Bordicchia M, Battistoni I, Mancinelli L, Giannini E, Refi G, Minardi D, Muzzonigro G, Mazzucchelli R, Montironi R, Piscitelli F, et al. 2010. Cannabinoid CB1 receptor expression in relation to visceral adipose depots, endocannabinoid levels, microvascular damage, and the presence of the Cnr1 A3813G variant in humans. Metabolism. 59(5):734–741. doi:10.1016/j.metabol.2009.09.018.
   PubMed Web of Science ®Google Scholar
• Bouchard JF, Lepicier P, Lamontagne D. 2003. Contribution of endocannabinoids in the endothelial protection afforded by ischemic preconditioning in the isolated rat heart. Life Sci. 72(16):1859–1870. doi:10.1016/S0024-3205(02)02474-8.
   PubMed Web of Science ®Google Scholar
• Buckley NE, McCoy KL, Mezey E, Bonner T, Zimmer A, Felder CC, Glass M, Zimmer A. 2000. Immunomodulation by cannabinoids is absent in mice deficient for the cannabinoid CB(2) receptor. Eur J Pharmacol. 396(2–3):141–149. doi:10.1016/S0014-2999(00)00211-9.
   PubMed Web of Science ®Google Scholar
• Buckley NE. 2008. The peripheral cannabinoid receptor knockout mice: an update. Br J Pharmacol. 153(2):309–318. doi:10.1038/sj.bjp.0707527.
   PubMed Web of Science ®Google Scholar
• Chen D-J, Gao M, Gao F-F, Su Q-X, Wu J. 2017. Brain cannabinoid receptor 2: expression, function and modulation. Acta Pharmacol Sin. 38(3):312–316. doi:10.1038/aps.2016.149.
   PubMed Web of Science ®Google Scholar
• Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A. 2007. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet. 370(9600):1706–1713. doi:10.1016/S0140-6736(07)61721-8.
   PubMed Web of Science ®Google Scholar
• Cornicelli J-A, Gilman S-R, Krom B-A, Kottke B-A. 1981. Cannabinoids impair the formation of cholesteryl ester in cultured human cells. Arteriosclerosis. 1(6):449–454. doi:10.1161/01.atv.1.6.449.
   Google Scholar
• Defer N, Wan J, Souktani R, Escoubet B, Perier M, Caramelle P, Manin S, Deveaux V, Bourin M-C, Zimmer A, et al. 2009. The cannabinoid receptor type 2 promotes cardiac myocyte and fibroblast survival and protects against ischemia/reperfusion-induced cardiomyopathy. Faseb J. 23(7):2120–2130. doi:10.1096/fj.09-129478.
   PubMed Web of Science ®Google Scholar
• Deng L, Guindon J, Cornett BL, Makriyannis A, Mackie K, Hohmann AG. 2015. Chronic cannabinoid receptor 2 activation reverses paclitaxel neuropathy without tolerance or cannabinoid receptor 1-dependent withdrawal. Biol Psychiatry. 77(5):475–487. doi:10.1016/j.biopsych.2014.04.009.
   PubMed Web of Science ®Google Scholar
• Despres JP, et al. 2005. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 353(20):2121–2134.
   PubMed Web of Science ®Google Scholar
• Devinsky O, Patel AD, Cross JH, Villanueva V, Wirrell EC, Privitera M, Greenwood SM, Roberts C, Checketts D, VanLandingham KE, et al. 2018. Effect of cannabidiol on drop seizures in the lennox-gastaut syndrome. N Engl J Med. 378(20):1888–1897. doi:10.1056/NEJMoa1714631.
   PubMed Web of Science ®Google Scholar
• Di Marzo V, Bifulco M, De Petrocellis L. 2004. The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov. 3(9):771–784. doi:10.1038/nrd1495.
   PubMed Web of Science ®Google Scholar
• Di Marzo V, Petrosino S. 2007. Endocannabinoids and the regulation of their levels in health and disease. Curr Opin Lipidol. 18(2):129–140. doi:10.1097/MOL.0b013e32803dbdec.
   PubMed Web of Science ®Google Scholar
• Di Marzo V, Piscitelli F. 2015. The Endocannabinoid system and its modulation by phytocannabinoids. Neurotherapeutics. 12(4):692–698. doi:10.1007/s13311-015-0374-6.
   PubMed Web of Science ®Google Scholar
• Di Marzo V. 2008. Targeting the endocannabinoid system: to enhance or reduce? Nat Rev Drug Discov. 7(5):438–455. doi:10.1038/nrd2553.
   PubMed Web of Science ®Google Scholar
• Di Paola R, Cordaro M, Crupi R, Siracusa R, Campolo M, Bruschetta G, Fusco R, Pugliatti P, Esposito E, Cuzzocrea S, et al. 2016. Protective effects of ultramicronized palmitoylethanolamide (PEA-um) in myocardial ischaemia and reperfusion injury in VIVO. Shock. 46(2):202–213. doi:10.1097/SHK.0000000000000578.
   PubMed Web of Science ®Google Scholar
• Duerr GD, Heinemann JC, Suchan G, Kolobara E, Wenzel D, Geisen C, Matthey M, Passe-Tietjen K, Mahmud W, Ghanem A, et al. 2014. The endocannabinoid-CB2 receptor axis protects the ischemic heart at the early stage of cardiomyopathy. Basic Res Cardiol. 109(4):425, doi:10.1007/s00395-014-0425-x.
   PubMed Web of Science ®Google Scholar
• El-Remessy AB, Rajesh M, Mukhopadhyay P, Horváth B, Patel V, Al-Gayyar MMH, Pillai BA, Pacher P. 2011. Cannabinoid 1 receptor activation contributes to vascular inflammation and cell death in a mouse model of diabetic retinopathy and a human retinal cell line. Diabetologia. 54(6):1567–1578. doi:10.1007/s00125-011-2061-4.
   PubMed Web of Science ®Google Scholar
• Esposito G, Izzo AA, Di Rosa M, Iuvone T. 2001. Selective cannabinoid CB1 receptor-mediated inhibition of inducible nitric oxide synthase protein expression in C6 rat glioma cells. J Neurochem. 78(4):835–841. doi:10.1046/j.1471-4159.2001.00465.x.
   PubMed Web of Science ®Google Scholar
• Formukong EA, Evans AT, Evans FJ. 1989. The inhibitory effects of cannabinoids, the active constituents of Cannabis sativa L. on human and rabbit platelet aggregation. J Pharm Pharmacol. 41(10):705–709. doi:10.1111/j.2042-7158.1989.tb06345.x.
   PubMed Web of Science ®Google Scholar
• Fulmer ML, Thewke DP. 2018. The endocannabinoid system and heart disease: The role of cannabinoid receptor type 2. Cardiovasc Hematol Disord Drug Targets. 18(1):34–51. doi:10.2174/1871529X18666180206161457.
   PubMedGoogle Scholar
• Gertsch J, Leonti M, Raduner S, Racz I, Chen J-Z, Xie X-Q, Altmann K-H, Karsak M, Zimmer A. 2008. Beta-caryophyllene is a dietary cannabinoid. Proc Natl Acad Sci USA. 105(26):9099–9104. doi:10.1073/pnas.0803601105.
   PubMed Web of Science ®Google Scholar
• Godlewski G, Alapafuja SO, Bátkai S, Nikas SP, Cinar R, Offertáler L, Osei-Hyiaman D, Liu J, Mukhopadhyay B, Harvey-White J, et al. 2010. Inhibitor of fatty acid amide hydrolase normalizes cardiovascular function in hypertension without adverse metabolic effects. Chem Biol. 17(11):1256–1266. doi:10.1016/j.chembiol.2010.08.013.
   PubMed Web of Science ®Google Scholar
• Gorelick DA, et al. 2006. The cannabinoid CB1 receptor antagonist rimonabant attenuates the hypotensive effect of smoked marijuana in male smokers. Am Heart J. 151(3):754 e1–754 e5.
   PubMed Web of Science ®Google Scholar
• Graham JD, Li DM. 1973. Cardiovascular and respiratory effects of cannabis in cat and rat. Br J Pharmacol. 49(1):1–10. doi:10.1111/j.1476-5381.1973.tb08262.x.
   PubMed Web of Science ®Google Scholar
• Grambow E, Strüder D, Klar E, Hinz B, Vollmar B. 2016. Differential effects of endogenous, phyto and synthetic cannabinoids on thrombogenesis and platelet activity. Biofactors. 42(6):581–590. doi:10.1002/biof.1294.
   Google Scholar
• Gugliandolo A, et al. 2018. In vitro model of neuroinflammation: Efficacy of cannabigerol, a non-psychoactive cannabinoid. Int J Mol Sci. 19(7):1992.
   Web of Science ®Google Scholar
• Hamblin M, Chang L, Fan Y, Zhang J, Chen YE. 2009. PPARs and the cardiovascular system. Antioxid Redox Signal. 11(6):1415–1452. doi:10.1089/ars.2008.2280.
   PubMed Web of Science ®Google Scholar
• Haney M, Malcolm RJ, Babalonis S, Nuzzo PA, Cooper ZD, Bedi G, Gray KM, McRae-Clark A, Lofwall MR, Sparenborg S, et al. 2016. Oral cannabidiol does not alter the subjective, reinforcing or cardiovascular effects of smoked cannabis. Neuropsychopharmacology. 41(8):1974–1982. doi:10.1038/npp.2015.367.
   PubMed Web of Science ®Google Scholar
• Hao E, Mukhopadhyay P, Cao Z, Erdélyi K, Holovac E, Liaudet L, Lee W-S, Haskó G, Mechoulam R, Pacher P, et al. 2015. Cannabidiol protects against doxorubicin-induced cardiomyopathy by modulating mitochondrial function and biogenesis. Mol Med. 21:38–45. doi:10.2119/molmed.2014.00261.
   PubMed Web of Science ®Google Scholar
• Harb H-A, Bustanji Y-k, Abdalla S-S. 2018. Hypocholesterolemic effect of β-caryophyllene in rats fed cholesterol and fat enriched diet. J Clin Biochem Nutr. 62(3):230–237. doi:10.3164/jcbn.17-3.
   Google Scholar
• Hiley CR. 2009. Endocannabinoids and the heart. J Cardiovasc Pharmacol. 53(4):267–276. doi:10.1097/FJC.0b013e318192671d.
   PubMed Web of Science ®Google Scholar
• Ho WS, Barrett DA, Randall MD. 2008. ‘Entourage’ effects of N-palmitoylethanolamide and N-oleoylethanolamide on vasorelaxation to anandamide occur through TRPV1 receptors. Br J Pharmacol. 155(6):837–846. doi:10.1038/bjp.2008.324.
   PubMed Web of Science ®Google Scholar
• Huang Y, Wan T, Pang N, Zhou Y, Jiang X, Li B, Gu Y, Huang Y, Ye X, Lian H, et al. 2019. Cannabidiol protects livers against nonalcoholic steatohepatitis induced by high-fat high cholesterol diet via regulating NF-κB and NLRP3 inflammasome pathway. J Cell Physiol. 234(11):21224–21234. doi:10.1002/jcp.28728.
   PubMed Web of Science ®Google Scholar
• Huestis MA, Boyd SJ, Heishman SJ, Preston KL, Bonnet D, Le Fur G, Gorelick DA. 2007. Single and multiple doses of rimonabant antagonize acute effects of smoked cannabis in male cannabis users. Psychopharmacology (Berl). 194(4):505–515. doi:10.1007/s00213-007-0861-5.
   PubMed Web of Science ®Google Scholar
• Iannotti FA, Marzo VD, Petrosino S. 2016. Endocannabinoids and endocannabinoid-related mediators: Targets, metabolism and role in neurological disorders. Prog Lipid Res. 62:107–128. doi:10.1016/j.plipres.2016.02.002.
   PubMed Web of Science ®Google Scholar
• Iffland K, Grotenhermen F. 2017. An update on safety and side effects of cannabidiol: A review of clinical data and relevant animal studies. Cannabis Cannabinoid Res. 2(1):139–154. doi:10.1089/can.2016.0034.
   PubMedGoogle Scholar
• Jadoon KA, Tan GD, O’Sullivan SE. 2017. A single dose of cannabidiol reduces blood pressure in healthy volunteers in a randomized crossover study. JCI Insight. 2(12):e93760. doi:10.1172/jci.insight.93760.
   PubMed Web of Science ®Google Scholar
• Jagannathan R, Patel SA, Ali MK, Narayan KMV. 2019. Global updates on cardiovascular disease mortality trends and attribution of traditional risk factors. Curr Diab Rep. 19(7):44. doi:10.1007/s11892-019-1161-2.
   PubMed Web of Science ®Google Scholar
• Jarai Z, Wagner JA, Varga K, Lake KD, Compton DR, Martin BR, Zimmer AM, Bonner TI, Buckley NE, Mezey E, et al. 1999. Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc Natl Acad Sci USA. 96(24):14136–14141. doi:10.1073/pnas.96.24.14136.
   PubMed Web of Science ®Google Scholar
• Kapellos TS, Taylor L, Feuerborn A, Valaris S, Hussain MT, Rainger GE, Greaves DR, Iqbal AJ. 2019. Cannabinoid receptor 2 deficiency exacerbates inflammation and neutrophil recruitment. Faseb J. 33(5):6154–6167. doi:10.1096/fj.201802524R.
   PubMed Web of Science ®Google Scholar
• Karniol IG, Shirakawa I, Takahashi RN, Knobel E, Musty RE. 1975. Effects of delta9-tetrahydrocannabinol and cannabinol in man. Pharmacology. 13(6):502–512. doi:10.1159/000136944.
   PubMed Web of Science ®Google Scholar
• Kones R. 2013. Molecular sources of residual cardiovascular risk, clinical signals, and innovative solutions: relationship with subclinical disease, undertreatment, and poor adherence: implications of new evidence upon optimizing cardiovascular patient outcomes. Vasc Health Risk Manag. 9:617–670. doi:10.2147/VHRM.S37119.
   PubMedGoogle Scholar
• Kunos G, Tam J. 2011. The case for peripheral CB₁ receptor blockade in the treatment of visceral obesity and its cardiometabolic complications. Br J Pharmacol. 163(7):1423–1431. doi:10.1111/j.1476-5381.2011.01352.x.
   PubMed Web of Science ®Google Scholar
• Lee W-S, Erdelyi K, Matyas C, Mukhopadhyay P, Varga ZV, Liaudet L, Haskú G, Čiháková D, Mechoulam R, Pacher P, et al. 2016. Cannabidiol limits T cell-mediated chronic autoimmune myocarditis: Implications to autoimmune disorders and organ transplantation. Mol Med. 22:136–146. doi:10.2119/molmed.2016.00007.
   PubMed Web of Science ®Google Scholar
• Lepicier P, et al. 2003. Endocannabinoids protect the rat isolated heart against ischaemia. Br J Pharmacol. 139(4):805–815.
   PubMed Web of Science ®Google Scholar
• Li X, Hua T, Vemuri K, Ho J-H, Wu Y, Wu L, Popov P, Benchama O, Zvonok N, Locke K, et al. 2019. Crystal structure of the human cannabinoid receptor CB2. Cell. 176(3):459–467. doi:10.1016/j.cell.2018.12.011.
   PubMed Web of Science ®Google Scholar
• Lobato NS, Filgueira FP, Prakash R, Giachini FR, Ergul A, Carvalho MHC, Webb RC, Tostes RC, Fortes ZB. 2013. Reduced endothelium-dependent relaxation to anandamide in mesenteric arteries from young obese Zucker rats. PLoS One. 8(5):e63449. doi:10.1371/journal.pone.0063449.
   PubMed Web of Science ®Google Scholar
• MacLellan WR, Wang Y, Lusis AJ. 2012. Systems-based approaches to cardiovascular disease. Nat Rev Cardiol. 9(3):172–184. doi:10.1038/nrcardio.2011.208.
   PubMed Web of Science ®Google Scholar
• Malinowska B, Baranowska-Kuczko M, Schlicker E. 2012. Triphasic blood pressure responses to cannabinoids: do we understand the mechanism? Br J Pharmacol. 165(7):2073–2088. doi:10.1111/j.1476-5381.2011.01747.x.
   PubMed Web of Science ®Google Scholar
• Malinowska B, Kwolek G, Gothert M. 2001. Anandamide and methanandamide induce both vanilloid VR1- and cannabinoid CB1 receptor-mediated changes in heart rate and blood pressure in anaesthetized rats. Naunyn Schmiedebergs Arch Pharmacol. 364(6):562–569. doi:10.1007/s00210-001-0498-6.
   PubMed Web of Science ®Google Scholar
• Mallet C, Dubray C, Duale C. 2016. FAAH inhibitors in the limelight, but regrettably. Int J Clin Pharmacol Ther. 54(7):498–501. doi:10.5414/CP202687.
   PubMed Web of Science ®Google Scholar
• Marichal-Cancino BA, González-Hernández A, MaassenVanDenBrink A, Ramírez-San Juan E, Villalón CM. 2020. Potential mechanisms involved in palmitoylethanolamide-induced vasodepressor effects in rats. J Vasc Res. 57(3):112–152. doi:10.1159/000506158.
   Web of Science ®Google Scholar
• Martin Gimenez VM, et al. 2018. Anandamide and endocannabinoid system: an attractive therapeutic approach for cardiovascular disease. Ther Adv Cardiovasc Dis. 12(7):177–190.
   PubMedGoogle Scholar
• Matias I, Di Marzo V. 2006. Endocannabinoid synthesis and degradation, and their regulation in the framework of energy balance. J Endocrinol Invest. 29(3 Suppl):15–26.
   PubMedGoogle Scholar
• Matouk A, Taye A, El-Moselhy M, Heeba G-H, Abdel-Rahman A-A. 2018. Abnormal cannabidiol confers cardioprotection in diabetic rats independent of glycemic control. Eur J Pharmacol. 820:256–264. doi:10.1016/j.ejphar.2017.12.039.
   Google Scholar
• Mattace Raso G, Pirozzi C, d'Emmanuele di Villa Bianca R, Simeoli R, Santoro A, Lama A, Di Guida F, Russo R, De Caro C, Sorrentino R, et al. 2015. Palmitoylethanolamide treatment reduces blood pressure in spontaneously hypertensive rats: involvement of cytochrome p450-derived eicosanoids and renin angiotensin system. PLoS One. 10(5):e0123602. doi:10.1371/journal.pone.0123602.
   PubMed Web of Science ®Google Scholar
• Montecucco F, Lenglet S, Braunersreuther V, Burger F, Pelli G, Bertolotto M, Mach F, Steffens S. 2009. CB(2) cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/reperfusion. J Mol Cell Cardiol. 46(5):612–620. doi:10.1016/j.yjmcc.2008.12.014.
   PubMed Web of Science ®Google Scholar
• Montecucco F, Matias I, Lenglet S, Petrosino S, Burger F, Pelli G, Braunersreuther V, Mach F, Steffens S, Di Marzo V, et al. 2009. Regulation and possible role of endocannabinoids and related mediators in hypercholesterolemic mice with atherosclerosis. Atherosclerosis. 205(2):433–441. doi:10.1016/j.atherosclerosis.2008.12.040.
   PubMed Web of Science ®Google Scholar
• Mukhopadhyay P, Horváth B, Rajesh M, Matsumoto S, Saito K, Bátkai S, Patel V, Tanchian G, Gao RY, Cravatt BF, et al. 2011. Fatty acid amide hydrolase is a key regulator of endocannabinoid-induced myocardial tissue injury. Free Radic Biol Med. 50(1):179–195. doi:10.1016/j.freeradbiomed.2010.11.002.
   PubMed Web of Science ®Google Scholar
• Mukhopadhyay P, Rajesh M, Bátkai S, Patel V, Kashiwaya Y, Liaudet L, Evgenov OV, Mackie K, Haskó G, Pacher P, et al. 2010. CB1 cannabinoid receptors promote oxidative stress and cell death in murine models of doxorubicin-induced cardiomyopathy and in human cardiomyocytes. Cardiovasc Res. 85(4):773–784. doi:10.1093/cvr/cvp369.
   PubMed Web of Science ®Google Scholar
• Munro S, Thomas KL, Abu-Shaar M. 1993. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 365(6441):61–65. doi:10.1038/365061a0.
   PubMed Web of Science ®Google Scholar
• Murataeva N, Mackie K, Straiker A. 2012. The CB2-preferring agonist JWH015 also potently and efficaciously activates CB1 in autaptic hippocampal neurons. Pharmacol Res. 66(5):437–442. doi:10.1016/j.phrs.2012.08.002.
   PubMed Web of Science ®Google Scholar
• Naderi SH, Bestwick JP, Wald DS. 2012. Adherence to drugs that prevent cardiovascular disease: meta-analysis on 376,162 patients. Am J Med. 125(9):882–887. doi:10.1016/j.amjmed.2011.12.013.
   PubMed Web of Science ®Google Scholar
• Nadulski T, Pragst F, Weinberg G, Roser P, Schnelle M, Fronk E-M, Stadelmann AM. 2005. Randomized, double-blind, placebo-controlled study about the effects of cannabidiol (CBD) on the pharmacokinetics of Delta9-tetrahydrocannabinol (THC) after oral application of THC verses standardized cannabis extract. Ther Drug Monit. 27(6):799–810. doi:10.1097/01.ftd.0000177223.19294.5c.
   PubMed Web of Science ®Google Scholar
• Nahas G, Trouve R. 1985. Effects and interactions of natural cannabinoids on the isolated heart. Proc Soc Exp Biol Med. 180(2):312–316. doi:10.3181/00379727-180-42181.
   PubMed Web of Science ®Google Scholar
• Navarro G, Morales P, Rodríguez-Cueto C, Fernández-Ruiz J, Jagerovic N, Franco R. 2016. Targeting cannabinoid CB2 receptors in the central nervous system. Medicinal chemistry approaches with focus on neurodegenerative disorders. Front Neurosci. 10:406. doi:10.3389/fnins.2016.00406.
   PubMed Web of Science ®Google Scholar
• Navarro G, Varani K, Reyes-Resina I, Sánchez de Medina V, Rivas-Santisteban R, Sánchez-Carnerero Callado C, Vincenzi F, Casano S, Ferreiro-Vera C, Canela EI, et al. 2018. Cannabigerol action at cannabinoid CB1 and CB2 receptors and at CB1-CB2 heteroreceptor complexes. Front Pharmacol. 9:632. doi:10.3389/fphar.2018.00632.
   PubMed Web of Science ®Google Scholar
• Newmeyer MN, Swortwood MJ, Barnes AJ, Abulseoud OA, Scheidweiler KB, Huestis MA. 2016. Free and glucuronide whole blood cannabinoids' pharmacokinetics after controlled smoked, vaporized, and oral cannabis administration in frequent and occasional cannabis users: Identification of recent cannabis intake. Clin Chem. 62(12):1579–1592. doi:10.1373/clinchem.2016.263475.
   PubMed Web of Science ®Google Scholar
• Nichols JM, Kaplan BLF. 2020. Immune responses regulated by cannabidiol. Cannabis Cannabinoid Res. 5(1):12–31. doi:10.1089/can.2018.0073.
   PubMedGoogle Scholar
• Nissen SE, Nicholls SJ, Wolski K, Rodés-Cabau J, Cannon CP, Deanfield JE, Després J-P, Kastelein JJP, Steinhubl SR, Kapadia S, et al. 2008. Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: the STRADIVARIUS randomized controlled trial. JAMA. 299(13):1547–1560. doi:10.1001/jama.299.13.1547.
   PubMed Web of Science ®Google Scholar
• Okunrintemi V, Benson E-MA, Tibuakuu M, Zhao D, Ogunmoroti O, Valero-Elizondo J, Gulati M, Nasir K, Michos ED. 2019. Trends and Costs associated with suboptimal physical activity among US women with cardiovascular disease. JAMA Netw Open. 2(4):e191977. doi:10.1001/jamanetworkopen.2019.1977.
   PubMed Web of Science ®Google Scholar
• O'Leary DH, Reuwer AQ, Nissen SE, Després J-P, Deanfield JE, Brown MW, Zhou R, Zabbatino SM, Job B, Kastelein JJP, et al. 2011. Effect of rimonabant on carotid intima-media thickness (CIMT) progression in patients with abdominal obesity and metabolic syndrome: the AUDITOR Trial. Heart. 97(14):1143–1150. doi:10.1136/hrt.2011.223446.
   PubMed Web of Science ®Google Scholar
• O'Neil JD, Dalton WS, Forney RB. 1979. The effect of cannabichromene on mean blood pressure, heart rate, and respiration rate responses to tetrahydrocannabinol in the anesthetized rat. Toxicol Appl Pharmacol. 49(2):265–270. doi:10.1016/0041-008X(79)90250-3.
   PubMed Web of Science ®Google Scholar
• O'Sullivan SE, Sun Y, Bennett AJ, Randall MD, Kendall DA. 2009. Time-dependent vascular actions of cannabidiol in the rat aorta. Eur J Pharmacol. 612(1–3):61–68. doi:10.1016/j.ejphar.2009.03.010.
   PubMed Web of Science ®Google Scholar
• O'Sullivan SE. 2016. An update on PPAR activation by cannabinoids. Br J Pharmacol. 173(12):1899–1910. doi:10.1111/bph.13497.
   PubMed Web of Science ®Google Scholar
• Pacher P, Batkai S, Kunos G. 2004. Haemodynamic profile and responsiveness to anandamide of TRPV1 receptor knock-out mice. J Physiol (Lond). 558(Pt 2):647–657. doi:10.1113/jphysiol.2004.064824.
   Google Scholar
• Pacher P, Batkai S, Kunos G. 2006. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 58(3):389–462. doi:10.1124/pr.58.3.2.
   PubMed Web of Science ®Google Scholar
• Pacher P, Bátkai S, Osei-Hyiaman D, Offertáler L, Liu J, Harvey-White J, Brassai A, Járai Z, Cravatt BF, Kunos G, et al. 2005. Hemodynamic profile, responsiveness to anandamide, and baroreflex sensitivity of mice lacking fatty acid amide hydrolase. Am J Physiol Heart Circ Physiol. 289(2):H533–H541. doi:10.1152/ajpheart.00107.2005.
   PubMed Web of Science ®Google Scholar
• Pacher P, Mechoulam R. 2011. Is lipid signaling through cannabinoid 2 receptors part of a protective system? Prog Lipid Res. 50(2):193–211. doi:10.1016/j.plipres.2011.01.001.
   PubMed Web of Science ®Google Scholar
• Pacher P, Mukhopadhyay P, Mohanraj R, Godlewski G, Bátkai S, Kunos G. 2008. Modulation of the endocannabinoid system in cardiovascular disease: therapeutic potential and limitations. Hypertension. 52(4):601–607. doi:10.1161/HYPERTENSIONAHA.105.063651.
   PubMed Web of Science ®Google Scholar
• Pacher P, Steffens S. 2009. The emerging role of the endocannabinoid system in cardiovascular disease. Semin Immunopathol. 31(1):63–77. doi:10.1007/s00281-009-0145-8.
   PubMed Web of Science ®Google Scholar
• Pedzinska-Betiuk A, et al. 2017. Chronic inhibition of fatty acid amide hydrolase by URB597 produces differential effects on cardiac performance in normotensive and hypertensive rats. Br J Pharmacol. 174(13):2114–2129.
   PubMed Web of Science ®Google Scholar
• Pertwee RG. 2006. The pharmacology of cannabinoid receptors and their ligands: an overview. Int J Obes (Lond). 30 Suppl 1(Suppl 1):S13–S18. doi:10.1038/sj.ijo.0803272.
   PubMed Web of Science ®Google Scholar
• Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J, Rio-North America Study Group ft. 2006. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA. 295(7):761–775. doi:10.1001/jama.295.7.761.
   PubMed Web of Science ®Google Scholar
• Poirier B, Bidouard J-P, Cadrouvele C, Marniquet X, Staels B, O'Connor SE, Janiak P, Herbert J-M. 2005. The anti-obesity effect of rimonabant is associated with an improved serum lipid profile. Diabetes Obes Metab. 7(1):65–72. doi:10.1111/j.1463-1326.2004.00374.x.
   PubMed Web of Science ®Google Scholar
• Quercioli A, Pataky Z, Vincenti G, Makoundou V, Di Marzo V, Montecucco F, Carballo S, Thomas A, Staub C, Steffens S, et al. 2011. Elevated endocannabinoid plasma levels are associated with coronary circulatory dysfunction in obesity. Eur Heart J. 32(11):1369–1378. doi:10.1093/eurheartj/ehr029.
   PubMed Web of Science ®Google Scholar
• Rajesh M, Bátkai S, Kechrid M, Mukhopadhyay P, Lee W-S, Horváth B, Holovac E, Cinar R, Liaudet L, Mackie K, et al. 2012. Cannabinoid 1 receptor promotes cardiac dysfunction, oxidative stress, inflammation, and fibrosis in diabetic cardiomyopathy. Diabetes. 61(3):716–727. doi:10.2337/db11-0477.
   PubMed Web of Science ®Google Scholar
• Rajesh M, Mukhopadhyay P, Bátkai S, Haskó G, Liaudet L, Drel VR, Obrosova IG, Pacher P. 2007. Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption. Am J Physiol Heart Circ Physiol. 293(1):H610–H619. doi:10.1152/ajpheart.00236.2007.
   PubMed Web of Science ®Google Scholar
• Rajesh M, Mukhopadhyay P, Bátkai S, Haskó G, Liaudet L, Huffman JW, Csiszar A, Ungvari Z, Mackie K, Chatterjee S, et al. 2007. CB2-receptor stimulation attenuates TNF-alpha-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion. Am J Physiol Heart Circ Physiol. 293(4):H2210–H2218. doi:10.1152/ajpheart.00688.2007.
   PubMed Web of Science ®Google Scholar
• Rajesh M, Mukhopadhyay P, Bátkai S, Patel V, Saito K, Matsumoto S, Kashiwaya Y, Horváth B, Mukhopadhyay B, Becker L, et al. 2010. Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy. J Am Coll Cardiol. 56(25):2115–2125. doi:10.1016/j.jacc.2010.07.033.
   PubMed Web of Science ®Google Scholar
• Rajesh M, Mukhopadhyay P, Haskó G, Huffman JW, Mackie K, Pacher P. 2008. CB2 cannabinoid receptor agonists attenuate TNF-alpha-induced human vascular smooth muscle cell proliferation and migration. Br J Pharmacol. 153(2):347–357. doi:10.1038/sj.bjp.0707569.
   PubMed Web of Science ®Google Scholar
• Rajesh M, Mukhopadhyay P, Haskó G, Pacher P. 2008. Cannabinoid CB1 receptor inhibition decreases vascular smooth muscle migration and proliferation. Biochem Biophys Res Commun. 377(4):1248–1252. doi:10.1016/j.bbrc.2008.10.159.
   PubMed Web of Science ®Google Scholar
• Remiszewski P. 2020. Chronic cannabidiol administration fails to diminish blood pressure in rats with primary and secondary hypertension despite its effects on cardiac and plasma endocannabinoid system, oxidative stress and lipid metabolism. Int J Mol Sci. 21(4):1295.
   Web of Science ®Google Scholar
• Rinne P, Guillamat-Prats R, Rami M, Bindila L, Ring L, Lyytikäinen L-P, Raitoharju E, Oksala N, Lehtimäki T, Weber C, et al. 2018. Palmitoylethanolamide promotes a proresolving macrophage phenotype and attenuates atherosclerotic plaque formation. Arterioscler Thromb Vasc Biol. 38(11):2562–2575. doi:10.1161/ATVBAHA.118.311185.
   PubMed Web of Science ®Google Scholar
• Romano B, Borrelli F, Fasolino I, Capasso R, Piscitelli F, Cascio M, Pertwee R, Coppola D, Vassallo L, Orlando P, et al. 2013. The cannabinoid TRPA1 agonist cannabichromene inhibits nitric oxide production in macrophages and ameliorates murine colitis. Br J Pharmacol. 169(1):213–229. doi:10.1111/bph.12120.
   PubMed Web of Science ®Google Scholar
• Romano MR, Lograno MD. 2012. Involvement of the peroxisome proliferator-activated receptor (PPAR) alpha in vascular response of endocannabinoids in the bovine ophthalmic artery. Eur J Pharmacol. 683(1–3):197–203. doi:10.1016/j.ejphar.2012.02.049.
   PubMed Web of Science ®Google Scholar
• Romero-Zerbo S-Y, García-Fernández M, Espinosa-Jiménez V, Pozo-Morales M, Escamilla-Sánchez A, Sánchez-Salido L, Lara E, Cobo-Vuilleumier N, Rafacho A, Olveira G, et al. 2020. The atypical cannabinoid Abn-CBD reduces inflammation and protects liver, pancreas, and adipose tissue in a mouse model of prediabetes and non-alcoholic fatty liver disease. Front Endocrinol (Lausanne). 11:103. doi:10.3389/fendo.2020.00103.
   Google Scholar
• Russo EB. 2011. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 163(7):1344–1364. doi:10.1111/j.1476-5381.2011.01238.x.
   PubMed Web of Science ®Google Scholar
• Russo EB. 2016a. Beyond cannabis: Plants and the endocannabinoid system. Trends Pharmacol Sci. 37(7):594–605. doi:10.1016/j.tips.2016.04.005.
   PubMed Web of Science ®Google Scholar
• Russo EB. 2016b. Clinical endocannabinoid deficiency reconsidered: current research supports the theory in migraine, fibromyalgia, irritable bowel, and other treatment-resistant syndromes. Cannabis Cannabinoid Res. 1(1):154–165. doi:10.1089/can.2016.0009.
   PubMedGoogle Scholar
• Schwartz M, Bockmann S, Hinz B. 2018. Up-regulation of heme oxygenase-1 expression and inhibition of disease-associated features by cannabidiol in vascular smooth muscle cells. Oncotarget. 9(77):34595–34616. doi:10.18632/oncotarget.26191.
   PubMedGoogle Scholar
• Shmist YA, Goncharov I, Eichler M, Shneyvays V, Isaac A, Vogel Z, Shainberg A. 2006. Delta-9-tetrahydrocannabinol protects cardiac cells from hypoxia via CB2 receptor activation and nitric oxide production. Mol Cell Biochem. 283(1–2):75–83. doi:10.1007/s11010-006-2346-y.
   PubMed Web of Science ®Google Scholar
• Slavic S, Lauer D, Sommerfeld M, Kemnitz UR, Grzesiak A, Trappiel M, Thöne-Reineke C, Baulmann J, Paulis L, Kappert K, et al. 2013. Cannabinoid receptor 1 inhibition improves cardiac function and remodelling after myocardial infarction and in experimental metabolic syndrome. J Mol Med. 91(7):811–823. doi:10.1007/s00109-013-1034-0.
   PubMed Web of Science ®Google Scholar
• Smiley KA, Karler R, Turkanis SA. 1976. Effects of cannabinoids on the perfused rat heart. Res Commun Chem Pathol Pharmacol. 14(4):659–675.
   PubMedGoogle Scholar
• Stanley CP, Hind WH, Tufarelli C, O'Sullivan SE. 2016. The endocannabinoid anandamide causes endothelium-dependent vasorelaxation in human mesenteric arteries. Pharmacol Res. 113(Pt A):356–363. doi:10.1016/j.phrs.2016.08.028.
   PubMed Web of Science ®Google Scholar
• Steffens S, Pacher P. 2012. Targeting cannabinoid receptor CB(2) in cardiovascular disorders: promises and controversies. Br J Pharmacol. 167(2):313–323. doi:10.1111/j.1476-5381.2012.02042.x.
   PubMed Web of Science ®Google Scholar
• Steffens S, Veillard NR, Arnaud C, Pelli G, Burger F, Staub C, Karsak M, Zimmer A, Frossard J-L, Mach F, et al. 2005. Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature. 434(7034):782–786. doi:10.1038/nature03389.
   PubMed Web of Science ®Google Scholar
• Storozhuk MV, Zholos AV. 2018. TRP channels as novel targets for endogenous ligands: Focus on endocannabinoids and nociceptive signalling. Curr Neuropharmacol. 16(2):137–150. doi:10.2174/1570159X15666170424120802.
   PubMed Web of Science ®Google Scholar
• Strobbe E, Cellini M, Campos EC. 2013. Effectiveness of palmitoylethanolamide on endothelial dysfunction in ocular hypertensive patients: a randomized, placebo-controlled cross-over study. Invest Ophthalmol Vis Sci. 54(2):968–973. doi:10.1167/iovs.12-10899.
   PubMed Web of Science ®Google Scholar
• Sultan SR, et al. 2017. A systematic review and meta-analysis of the haemodynamic effects of cannabidiol. Front Pharmacol. 8:81.
   PubMed Web of Science ®Google Scholar
• Sultan SR, O'Sullivan SE, England TJ. 2020. The effects of acute and sustained cannabidiol dosing for seven days on the haemodynamics in healthy men: A randomised controlled trial. Br J Clin Pharmacol. 86(6):1125–1138. doi:10.1111/bcp.14225.
   PubMed Web of Science ®Google Scholar
• Teo K, Lear S, Islam S, Mony P, Dehghan M, Li W, Rosengren A, Lopez-Jaramillo P, Diaz R, Oliveira G, et al. 2013. Prevalence of a healthy lifestyle among individuals with cardiovascular disease in high-, middle- and low-income countries: The Prospective Urban Rural Epidemiology (PURE) study. JAMA. 309(15):1613–1621. doi:10.1001/jama.2013.3519.
   PubMed Web of Science ®Google Scholar
• Thiele E, Marsh E, Mazurkiewicz-Beldzinska M, Halford JJ, Gunning B, Devinsky O, Checketts D, Roberts C. 2019. Cannabidiol in patients with Lennox-Gastaut syndrome: Interim analysis of an open-label extension study. Epilepsia. 60(3):419–428. doi:10.1111/epi.14670.
   PubMed Web of Science ®Google Scholar
• Topol EJ, Bousser M-G, Fox KAA, Creager MA, Despres J-P, Easton JD, Hamm CW, Montalescot G, Steg PG, Pearson TA, et al. 2010. Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial. Lancet. 376(9740):517–523. doi:10.1016/S0140-6736(10)60935-X.
   PubMed Web of Science ®Google Scholar
• Turcotte C, Blanchet M-R, Laviolette M, Flamand N. 2016. The CB2 receptor and its role as a regulator of inflammation. Cell Mol Life Sci. 73(23):4449–4470. doi:10.1007/s00018-016-2300-4.
   PubMed Web of Science ®Google Scholar
• Udoh M, Santiago M, Devenish S, McGregor IS, Connor M. 2019. Cannabichromene is a cannabinoid CB2 receptor agonist. Br J Pharmacol. 176(23):4537–4547. doi:10.1111/bph.14815.
   PubMed Web of Science ®Google Scholar
• Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rössner S. 2005. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet. 365(9468):1389–1397. doi:10.1016/S0140-6736(05)66374-X.
   PubMed Web of Science ®Google Scholar
• Varga K, Lake KD, Huangfu D, Guyenet PG, Kunos G. 1996. Mechanism of the hypotensive action of anandamide in anesthetized rats. Hypertension. 28(4):682–686. doi:10.1161/01.hyp.28.4.682.
   PubMed Web of Science ®Google Scholar
• Volpe M, Chin D, Paneni F. 2010. The challenge of polypharmacy in cardiovascular medicine. Fundam Clin Pharmacol. 24(1):9–17. doi:10.1111/j.1472-8206.2009.00757.x.
   PubMed Web of Science ®Google Scholar
• Wang Y, Mukhopadhyay P, Cao Z, Wang H, Feng D, Haskó G, Mechoulam R, Gao B, Pacher P. 2017. Cannabidiol attenuates alcohol-induced liver steatosis, metabolic dysregulation, inflammation and neutrophil-mediated injury. Sci Rep. 7(1):12064. doi:10.1038/s41598-017-10924-8.
   Google Scholar
• Weis F, Beiras-Fernandez A, Sodian R, Kaczmarek I, Reichart B, Beiras A, Schelling G, Kreth S. 2010. Substantially altered expression pattern of cannabinoid receptor 2 and activated endocannabinoid system in patients with severe heart failure. J Mol Cell Cardiol. 48(6):1187–1193. doi:10.1016/j.yjmcc.2009.10.025.
   PubMed Web of Science ®Google Scholar
• Wheal AJ, Alexander SP, Randall MD. 2010. Vasorelaxation to N-oleoylethanolamine in rat isolated arteries: mechanisms of action and modulation via cyclooxygenase activity. Br J Pharmacol. 160(3):701–711. doi:10.1111/j.1476-5381.2010.00770.x.
   PubMed Web of Science ®Google Scholar
• Wheal AJ, Cipriano M, Fowler CJ, Randall MD, O’Sullivan SE. 2014. Cannabidiol improves vasorelaxation in Zucker diabetic fatty rats through cyclooxygenase activation. J Pharmacol Exp Ther. 351(2):457–466. doi:10.1124/jpet.114.217125.
   PubMed Web of Science ®Google Scholar
• White R, Ho WS, Bottrill FE, Ford WR, Hiley CR. 2001. Mechanisms of anandamide-induced vasorelaxation in rat isolated coronary arteries. Br J Pharmacol. 134(4):921–929. doi:10.1038/sj.bjp.0704333.
   PubMed Web of Science ®Google Scholar
• Wong H, Cairns BE. 2019. Cannabidiol, cannabinol and their combinations act as peripheral analgesics in a rat model of myofascial pain. Arch Oral Biol. 104:33–39. doi:10.1016/j.archoralbio.2019.05.028.
   PubMed Web of Science ®Google Scholar
• Working Group on the Summit on Combination Therapy for CVD. 2014. Combination pharmacotherapy to prevent cardiovascular disease: present status and challenges. Eur Heart J. 35(6):353–364.
   PubMed Web of Science ®Google Scholar
• Youssef DA, El-Fayoumi HM, Mahmoud MF. 2019. Beta-caryophyllene protects against diet-induced dyslipidemia and vascular inflammation in rats: Involvement of CB2 and PPAR-γ receptors. Chem Biol Interact. 297:16–24. doi:10.1016/j.cbi.2018.10.010.
   PubMed Web of Science ®Google Scholar
• Younis N, Mohamed M-E. 2019. β-Caryophyllene as a potential protective agent against myocardial injury: the role of toll-like receptors. Molecules. 24(10):1929. doi:10.3390/molecules24101929
   Google Scholar
• Zolese G, Bacchetti T, Ambrosini A, Wozniak M, Bertoli E, Ferretti G. 2005. Increased plasma concentrations of palmitoylethanolamide, an endogenous fatty acid amide, affect oxidative damage of human low-density lipoproteins: an in vitro study. Atherosclerosis. 182(1):47–55. doi:10.1016/j.atherosclerosis.2005.01.043.
   PubMed Web of Science ®Google Scholar