Opportunities, Challenges and Pitfalls of Using Cannabidiol as an Adjuvant Drug in COVID-19
Barbara Malinowska, Marta Baranowska-Kuczko, Aleksandra Kicman, Eberhard Schlicker
International Journal of Molecular Sciences, doi:10.3390/ijms22041986
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to coronavirus disease 2019 (COVID-19) which, in turn, may be associated with multiple organ dysfunction. In this review, we present advantages and disadvantages of cannabidiol (CBD), a non-intoxicating phytocannabinoid from the cannabis plant, as a potential agent for the treatment of COVID-19. CBD has been shown to downregulate proteins responsible for viral entry and to inhibit SARS-CoV-2 replication. Preclinical studies have demonstrated its effectiveness against diseases of the respiratory system as well as its cardioprotective, nephroprotective, hepatoprotective, neuroprotective and anti-convulsant properties, that is, effects that may be beneficial for COVID-19. Only the latter two properties have been demonstrated in clinical studies, which also revealed anxiolytic and antinociceptive effects of CBD (given alone or together with ∆ 9 -tetrahydrocannabinol), which may be important for an adjuvant treatment to improve the quality of life in patients with COVID-19 and to limit post-traumatic stress symptoms. However, one should be aware of side effects of CBD (which are rarely serious), drug interactions (also extending to drugs acting against COVID-19) and the proper route of its administration (vaping may be dangerous). Clearly, further clinical studies are necessary to prove the suitability of CBD for the treatment of COVID-19.
References
Abdallah, Smith, Ware, Moore, Li et al., Effect of vaporized cannabis on exertional breathlessness and exercise endurance in advanced chronic obstructive pulmonary disease. A Randomized Controlled Trial, Ann. Am. Thorac. Soc,
doi:10.1513/AnnalsATS.201803-198OC
Adapa, Gayam, Konala, Annangi, Raju et al., Cannabis vaping-induced acute pulmonary toxicity: Case series and review of literature, J. Investig. Med. High. Impact Case Rep,
doi:10.1177/2324709620947267
Alenina, Bader, ACE2 in brain physiology and pathophysiology: Evidence from transgenic animal models, Neurochem. Res,
doi:10.1007/s11064-018-2679-4
Allsop, Copeland, Lintzeris, Dunlop, Montebello et al., Nabiximols as an agonist replacement therapy during cannabis withdrawal: A randomized clinical trial, JAMA Psychiatry,
doi:10.1001/jamapsychiatry.2013.3947
Appiah-Kusi, Petros, Wilson, Colizzi, Bossong et al., Effects of short-term cannabidiol treatment on response to social stress in subjects at clinical high risk of developing psychosis, Psychopharmacology,
doi:10.1007/s00213-019-05442-6
Arendse, Danser, Poglitsch, Touyz, Burnett et al., Novel therapeutic approaches targeting the renin-angiotensin system and associated peptides in hypertension and heart failure, Pharmacol. Rev,
doi:10.1124/pr.118.017129
Arkell, Lintzeris, Kevin, Ramaekers, Vandrey et al., Cannabidiol (CBD) content in vaporized cannabis does not prevent tetrahydrocannabinol (THC)-induced impairment of driving and cognition, Psychopharmacology,
doi:10.1007/s00213-019-05246-8
Arruza, Pazos, Mohammed, Escribano, Lafuente et al., Cannabidiol reduces lung injury induced by hypoxic-ischemic brain damage in newborn piglets, Pediatr. Res,
doi:10.1038/pr.2017.104
Asai, Konno, Ozaki, Otsuka, Vecchione et al., COVID-19 drug discovery using intensive approaches, Int. J. Mol. Sci,
doi:10.3390/ijms21082839
Atalay, Gęgotek, Wro Ński, Domigues, Skrzydlewska, Therapeutic application of cannabidiol on UVA and UVB irradiated rat skin. A proteomic study, J. Pharm. Biomed. Anal,
doi:10.1016/j.jpba.2020.113656
Atalay, Jarocka-Karpowicz, Skrzydlewska, Antioxidative and anti-inflammatory properties of cannabidiol, Antioxidants,
doi:10.3390/antiox9010021
Avraham, Grigoriadis, Poutahidis, Vorobiev, Magen et al., Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice, Br. J. Pharmacol,
doi:10.1111/j.1476-5381.2010.01179.x
Baban, Khodadadi, Vaibhav, Marchetti, Riccardi et al., Regulation of innate lymphoid cells in acute kidney injury: Crosstalk between cannabidiol and GILZ, J. Immunol. Res,
doi:10.1155/2020/6056373
Baj, Karakuła-Juchnowicz, Teresi Ński, Buszewicz, Ciesielka et al., Specific and non-specific clinical manifestations and symptoms: The current state of knowledge, J. Clin. Med,
doi:10.3390/jcm9061753
Baranowska-Kuczko, Kozłowska, Kloza, Sadowska, Kozłowski et al., Vasodilatory effects of cannabidiol in human pulmonary and rat small mesenteric arteries: Modification by hypertension and the potential pharmacological opportunities, J. Hypertens,
doi:10.1097/HJH.0000000000002333
Beigel, Tomashek, Dodd, Mehta, Zingman et al., ACTT-1 study group members. Remdesivir for the treatment of Covid-19-final report, N. Engl. J. Med,
doi:10.1056/NEJMoa2007764
Bergamaschi, Queiroz, Chagas, De Oliveira, De Martinis et al., Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients, Neuropsychopharmacology,
doi:10.1038/npp.2011.6
Bharadwaj, Strawn, Groban, Yamaleyeva, Chappell et al., Angiotensin-converting enzyme 2 deficiency is associated with impaired gestational weight gain and fetal growth restriction, Hypertension,
doi:10.1161/HYPERTENSIONAHA.111.179358
Biali, Broers, Besson, Demeules, Cannabinoids and COVID-19, Med. Cannabis Cannabinoids
Bielawiec, Harasim-Symbor, Konstantynowicz-Nowicka, Sztolsztener, Chabowski, Chronic cannabidiol administration attenuates skeletal muscle de novo ceramide synthesis pathway and related metabolic effects in a rat model of high-fat diet-induced obesity, Biomolecules,
doi:10.3390/biom10091241
Boggs, Surti, Gupta, Gupta, Niciu et al., The effects of cannabidiol (CBD) on cognition and symptoms in outpatients with chronic schizophrenia a randomized placebo controlled trial, Psychopharmacology,
doi:10.1007/s00213-018-4885-9
Bonow, Fonarow, O'gara, Yancy, Association of coronavirus disease 2019 (COVID-19) with myocardial injury and mortality, JAMA Cardiol,
doi:10.1001/jamacardio.2020.1105
Bourgonje, Abdulle, Timens, Hillebrands, Navis et al., Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19), J. Pathol,
doi:10.1002/path.5471
Britch, Babalonis, Walsh, Cannabidiol: Pharmacology and therapeutic targets, Psychopharmacology
Brown, Cannabidiol as prophylaxis for SARS-CoV-2 and COVID-19? Unfounded claims versus potential risks of medications during the pandemic, Res. Soc. Adm. Pharm,
doi:10.1016/j.sapharm.2020.03.020
Burrell, Risvanis, Kubota, Dean, Macdonald et al., Myocardial infarction increases ACE2 expression in rat and humans, Eur. Heart. J,
doi:10.1093/eurheartj/ehi114
Cannalire, Stefanelli, Cerchia, Beccari, Pelliccia et al., Entry inhibitors: Small molecules and peptides targeting virus or host cells, Int. J. Mol. Sci,
doi:10.3390/ijms21165707
Cao, Lu, Tuo, Liu, Zhang et al., Angiotensin-converting enzyme 2 regulates endoplasmic reticulum stress and mitochondrial function to preserve skeletal muscle lipid metabolism, Lipids. Health. Dis,
doi:10.1186/s12944-019-1145-x
Capano, Weaver, Burkman, Evaluation of the effects of CBD hemp extract on opioid use and quality of life indicators in chronic pain patients: A prospective cohort study, Postgrad. Med,
doi:10.1080/00325481.2019.1685298
Capasso, Borrelli, Aviello, Romano, Scalisi et al., Cannabidiol, extracted from Cannabis sativa, selectively inhibits inflammatory hypermotility in mice, Br. J. Pharmacol,
doi:10.1038/bjp.2008.177
Cassol, Comim, Silva, Hermani, Constantino et al., Treatment with cannabidiol reverses oxidative stress parameters, cognitive impairment and mortality in rats submitted to sepsis by cecal ligation and puncture, Brain Res,
doi:10.1016/j.brainres.2010.06.023
Chai, Hu, Zhang, Han, Lu et al., Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection, medRxiv
Cheng, Luo, Wang, Zhang, Wang et al., Kidney disease is associated with in-hospital death of patients with COVID-19, Kidney Int,
doi:10.1016/j.kint.2020.03.005
Chesney, Mcguire, Freeman, Strang, Englund, Lack of evidence for the effectiveness or safety of over-the-counter cannabidiol products, Ther. Adv. Psychopharmacol,
doi:10.1177/2045125320954992
Chueh, Zheng, Hou, Lu, Novel evidence of acute kidney injury in COVID-19, J. Clin. Med,
doi:10.3390/jcm9113547
Contin, Mancinelli, Perrone, Sabattini, Mohamed et al., Tetrahydrocannabinol/cannabidiol oromucosal spray in patients with multiple sclerosis: A pilot study on the plasma concentration-effect relationship, Clin. Neuropharmacol,
doi:10.1097/WNF.0000000000000294
Coperchini, Chiovato, Croce, Magri, Rotondi, The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system, Cytokine Growth Factor Rev,
doi:10.1016/j.cytogfr.2020.05.003
Cortopassi, Warfarin dose adjustment required after cannabidiol initiation and titration, Am. J. Health Syst. Pharm,
doi:10.1093/ajhp/zxaa268
Costiniuk, Jenabian, Acute inflammation and pathogenesis of SARS-CoV-2 infection: Cannabidiol as a potential anti-inflammatory treatment?, Cytokine Growth Factor Rev,
doi:10.1016/j.cytogfr.2020.05.008
Couch, Cook, Ortori, Barrett, Lund et al., Palmitoylethanolamide and cannabidiol prevent inflammation-induced hyperpermeability of the human gut in vitro and in vivo-A randomized, placebo-controlled, doubleblind controlled trial, Inflamm. Bowel Dis,
doi:10.1093/ibd/izz017
Crippa, Derenusson, Ferrari, Wichert-Ana, Duran et al., Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: A preliminary report, J. Psychopharmacol,
doi:10.1177/0269881110379283
Crippa, Zuardi, Garrido, Wichert-Ana, Guarnieri et al., Effects of cannabidiol (CBD) on regional cerebral blood flow, Neuropsychopharmacology,
doi:10.1038/sj.npp.1300340
Cruces, Díaz, Puga, Erranz, Donoso et al., Angiotensin-converting enzyme insertion/deletion polymorphism is associated with severe hypoxemia in pediatric ARDS, Intensive Care. Med,
doi:10.1007/s00134-011-2381-3
Devinsky, Cilio, Cross, Fernandez-Ruiz, French et al., Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders, Epilepsia,
doi:10.1111/epi.12631
Devinsky, Cross, Laux, Marsh, Miller et al., Cannabidiol in Dravet Syndrome Study Group. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome, N. Engl. J. Med,
doi:10.1056/NEJMoa1611618
Devinsky, Patel, Cross, Villanueva, Wirrell et al., Effect of Cannabidiol on drop seizures in the Lennox-Gastaut syndrome, N. Engl. J. Med,
doi:10.1056/NEJMoa1714631
Dhaundiyal, Kumari, Jawalekar, Chauhan, Kalra et al., Is highly expressed ACE 2 in pregnant women "a curse" in times of COVID-19 pandemic?, Life Sci,
doi:10.1016/j.lfs.2020.118676
Domi Ńska, Involvement of ACE2/Ang-(1-7)/MAS1 axis in the regulation of ovarian function in mammals, Int. J. Mol. Sci,
doi:10.3390/ijms21134572
Donoghue, Wakimoto, Maguire, Acton, Hales et al., Heart block, ventricular tachycardia, and sudden death in ACE2 transgenic mice with downregulated connexins, J. Mol. Cell. Cardiol,
doi:10.1016/S0022-2828(03)00177-9
Duan, Beli, Li Calzi, Quigley, Miller et al., Loss of angiotensin-converting enzyme 2 exacerbates diabetic retinopathy by promoting bone marrow dysfunction, Stem. Cells,
doi:10.1002/stem.2848
Dudášová, Keir, Parsons, Molleman, Page, The effects of cannabidiol on the antigen-induced contraction of airways smooth muscle in the guinea-pig, Pulm. Pharmacol. Ther,
doi:10.1016/j.pupt.2013.02.002
Duran, Pérez, Abanades, Vidal, Saura et al., Preliminary efficacy and safety of an oromucosal standardized cannabis extract in chemotherapy-induced nausea and vomiting, Br. J. Clin. Pharmacol,
doi:10.1111/j.1365-2125.2010.03743.x
Durst, Danenberg, Gallily, Mechoulam, Meir et al., Cannabidiol, a nonpsychoactive Cannabis constituent, protects against myocardial ischemic reperfusion injury, Am. J. Physiol. Heart Circ. Physiol,
doi:10.1152/ajpheart.00098.2007
Elms, Shannon, Hughes, Lewis, Cannabidiol in the treatment of post-traumatic stress disorder: A case series, J. Altern. Complement. Med,
doi:10.1089/acm.2018.0437
Epelman, Shrestha, Troughton, Francis, Sen et al., Soluble angiotensin-converting enzyme 2 in human heart failure: Relation with myocardial function and clinical outcomes, J. Card. Fail,
doi:10.1016/j.cardfail.2009.01.014
Esposito, Pesce, Seguella, Sanseverino, Lu et al., The potential of cannabidiol in the COVID-19 pandemic, Br. J. Pharmacol,
doi:10.1111/bph.15157
Evans, Rainger, Mason, Guzik, Osto et al., Endothelial dysfunction in COVID-19: A position paper of the ESC Working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science, Cardiovasc. Res,
doi:10.1093/cvr/cvaa230
Feng, Chen, Yin, Xia, Liu et al., Effects of cannabidiol on acute reperfused myocardial infarction in rabbits: Evaluated with 3.0T Cardiac Magnetic Resonance Imaging and Histopathology, J. Cardiovasc. Pharmacol,
doi:10.1097/FJC.0000000000000287
Feng, Wan, Liu, Zhang, Ma et al., The angiotensin-converting enzyme 2 in tumor growth and tumor-associated angiogenesis in non-small cell lung cancer, Oncol. Rep,
doi:10.3892/or_00000718
Ferrandi, Alway, Mohamed, The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies, J. Appl. Physiol,
doi:10.1152/japplphysiol.00321.2020
Fiani, Sarhadi, Soula, Zafar, Quadri, Current application of cannabidiol (CBD) in the management and treatment of neurological disorders, Neurol. Sci,
doi:10.1007/s10072-020-04514-2
Galanopoulos, Gkeros, Doukatas, Karianakis, Pontas et al., COVID-19 pandemic: Pathophysiology and manifestations from the gastrointestinal tract, World J. Gastroenterol
Gan, Rosoman, Henshaw, Noble, Georgius et al., COVID-19 as a viral functional ACE2 deficiency disorder with ACE2 related multi-organ disease, Med. Hypotheses,
doi:10.1016/j.mehy.2020.110024
Garduño-Soto, Choreño-Parra, Cazarin-Barrientos, Dermatological aspects of SARS-CoV-2 infection: Mechanisms and manifestations, Arch. Dermatol. Res,
doi:10.1007/s00403-020-02156-0
Garg, Royce, Tikellis, Shallue, Batu et al., Imbalance of the renin-angiotensin system may contribute to inflammation and fibrosis in IBD: A novel therapeutic target?, Gut,
doi:10.1136/gutjnl-2019-318512
Gemmati, Bramanti, Serino, Secchiero, Zauli et al., COVID-19 and individual genetic susceptibility/receptivity: Role of ACE1/ACE2 genes, immunity, inflammation and coagulation. Might the double X-chromosome in females be protective against SARS-CoV-2 compared to the single X-Chromosome in males?, Int. J. Mol. Sci,
doi:10.3390/ijms21103474
Gheblawi, Wang, Viveiros, Nguyen, Zhong et al., Angiotensin-Converting Enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: Celebrating the 20th anniversary of the discovery of ACE2, Circ. Res,
doi:10.1161/CIRCRESAHA.120.317015
Gilbert, Lamarca, Granger, ACE2 and ANG-(1-7) in the gravid uterus: The new players on the block, Am. J. Physiol. Regul. Integr. Comp. Physiol,
doi:10.1152/ajpregu.00018.2008
Gonca, Darici, The effect of cannabidiol on ischemia/reperfusion-induced ventricular arrhythmias: The role of adenosine A1 receptors, J. Cardiovasc. Pharmacol. Ther,
doi:10.1177/1074248414532013
Gonzalez, Orozco-Aguilar, Achiardi, Simon, Cabello-Verrugio, SARS-CoV-2/renin-angiotensin system: Deciphering the clues for a couple with potentially harmful effects on skeletal muscle, Int. J. Mol. Sci,
doi:10.3390/ijms21217904
Grambow, Strüder, Klar, Hinz, Vollmar, Differential effects of endogenous, phyto and synthetic cannabinoids on thrombogenesis and platelet activity, BioFactors,
doi:10.1002/biof.1294
Greene, Wiley, Yu, Clowers, Craft, Cannabidiol modulation of antinociceptive tolerance to ∆9-Ktetrahydrocannabinol, Psychopharmacology,
doi:10.1007/s00213-018-5036-z
Guan, Ni, Hu, Liang, Ou et al., Clinical characteristics of coronavirus disease 2019 in China, N. Engl. J. Med,
doi:10.1056/NEJMoa2002032
Gupte, Thatcher, Boustany-Kari, Shoemaker, Yiannikouris et al., Angiotensin converting enzyme 2 contributes to sex differences in the development of obesity hypertension in C57BL/6 mice, Arterioscler. Thromb. Vasc. Biol,
doi:10.1161/ATVBAHA.112.248559
Guzik, Mohiddin, Dimarco, Patel, Savvatis et al., COVID-19 and the cardiovascular system: Implications for risk assessment, diagnosis, and treatment options, Cardiovasc. Res,
doi:10.1093/cvr/cvaa106
Gáll, Farkas, Albert, Ferencz, Vancea et al., Effects of chronic cannabidiol treatment in the rat chronic unpredictable mild stress model of depression, Biomolecules,
doi:10.3390/biom10050801
Hamming, Timens, Bulthuis, Lely, Navis et al., Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis, J. Pathol,
doi:10.1002/path.1570
Haney, Malcolm, Babalonis, Nuzzo, Cooper et al., Oral cannabidiol does not alter the subjective, reinforcing or cardiovascular effects of smoked Cannabis, Neuropsychopharmacology,
doi:10.1038/npp.2015.367
Hashimoto, Perlot, Rehman, Trichereau, Ishiguro et al., ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation, Nature,
doi:10.1038/nature11228
Haupts, Vila, Jonas, Witte, Álvarez-Ossorio, Influence of previous failed antispasticity therapy on the efficacy and tolerability of THC:CBD oromucosal spray for multiple sclerosis spasticity, Eur. Neurol,
doi:10.1159/000445943
Hayakawa, Mishima, Irie, Hazekawa, Mishima et al., Cannabidiol prevents a post-ischemic injury progressively induced by cerebral ischemia via a high-mobility group box1-inhibiting mechanism, Neuropharmacology,
doi:10.1016/j.neuropharm.2008.06.040
He, Liu, Chen, Liu, Cai et al., Mesenchymal stem cells overexpressing angiotensin-converting enzyme 2 rescue lipopolysaccharide-induced lung injury, Cell. Transplant,
doi:10.3727/096368914X685087
He, Zhou, Yu, Wang, Deng et al., Natural product derived phytochemicals in managing acute lung injury by multiple mechanisms, Pharmacol. Res,
doi:10.1016/j.phrs.2020.105224
Herbst, Musgrave, Respiratory depression following an accidental overdose of a CBD-labeled product: A pediatric case report, J. Am. Pharm. Assoc,
doi:10.1016/j.japh.2019.09.023
Hoggart, Ratcliffe, Ehler, Simpson, Hovorka et al., A multicentre, open-label, follow-on study to assess the long-term maintenance of effect, tolerance and safety of THC/CBD oromucosal spray in the management of neuropathic pain, J. Neurol,
doi:10.1007/s00415-014-7502-9
Holappa, Vapaatalo, Vaajanen, Local ocular renin-angiotensin-aldosterone system: Any connection with intraocular pressure? A comprehensive review, Ann. Med,
doi:10.1080/07853890.2020.1758341
Honorato-Sampaio, Andrade, Bader, Martins, Santos et al., Genetic deletion of the Angiotensin-(1-7) receptor Mas leads to a reduced ovulatory rate, Peptides,
doi:10.1016/j.peptides.2018.08.007
Horby, Lim, Emberson, Mafham, Bell et al., Dexamethasone in hospitalized patients with Covid-19-Preliminary report, N. Engl. J. Med,
doi:10.1056/NEJMoa2021436
Hsu, Painter, Probable interaction between warfarin and inhaled and oral administration of cannabis, J. Pharm. Pract,
doi:10.1177/0897190019854958
Hundal, Lister, Evans, Antley, Englund et al., The effects of cannabidiol on persecutory ideation and anxiety in a high trait paranoid group, J. Psychopharmacol,
doi:10.1177/0269881117737400
Hunt, East, Lanas, Malfertheiner, Satsangi et al., COVID-19 and gastrointestinal disease. Implications for the gastroenterologist, Dig. Dis,
doi:10.1159/000512152
Hurd, Spriggs, Alishayev, Winkel, Gurgov et al., Cannabidiol for the reduction of cue-induced craving and anxiety in drug-abstinent individuals with heroin use disorder: A double-blind randomized placebo-controlled trial, Am. J. Psychiatry,
doi:10.1176/appi.ajp.2019.18101191
Iannotti, Pagano, Moriello, Alvino, Sorrentino et al., Effects of non-euphoric plant cannabinoids on muscle quality and performance of dystrophic mdx mice, Br. J. Pharmacol,
doi:10.1111/bph.14460
Iffland, Grotenhermen, An update on safety and side effects of cannabidiol: A review of clinical data and relevant animal studies, Cannabis Cannabinoid Res,
doi:10.1089/can.2016.0034
Imai, Kuba, Rao, Huan, Guo et al., Angiotensin-converting enzyme 2 protects from severe acute lung failure, Nature,
doi:10.1038/nature03712
Ingraham, Barakat, Reilkoff, Bezdicek, Schacker et al., Understanding the renin-angiotensin-aldosterone-SARS-CoV axis: A comprehensive review, Eur. Respir. J
Irving, Iqbal, Nwokolo, Subramanian, Bloom et al., A randomized, double-blind, placebo-controlled, parallel-group, pilot study of cannabidiol-rich botanical extract in the symptomatic treatment of ulcerative colitis, Inflamm. Bowel Dis,
doi:10.1093/ibd/izy002
Iwasaki, Saito, Zhao, Sakamoto, Hirota et al., Inflammation triggered by SARS-CoV-2 and ACE2 augment drives multiple organ failure of severe COVID-19: Molecular mechanisms and implications, Inflammation
Janmohamed, Soale, Forastiere, Tang, Sha et al., Intersection of the web-based vaping narrative with COVID-19: Topic modeling study, J. Med. Internet Res,
doi:10.2196/21743
Jayarangaiah, Kariyanna, Chen, Jayarangaiah, Kumar, COVID-19-associated coagulopathy: An exacerbated immunothrombosis response, Clin. Appl. Thromb. Hemost,
doi:10.1177/1076029620943293
Jiang, Yang, Zhang, Dong, Wang et al., Angiotensin-converting enzyme 2 and angiotensin 1-7: Novel therapeutic targets, Nat. Rev. Cardiol,
doi:10.1038/nrcardio.2014.59
Jing, Run-Qian, Hao-Ran, Hao-Ran, Ya-Bin et al., Potential influence of COVID-19/ACE2 on the female reproductive system, Mol. Hum. Reprod,
doi:10.1093/molehr/gaaa030
Juan, Gil, Rong, Zhang, Yang et al., Effect of coronavirus disease 2019 (COVID-19) on maternal, perinatal and neonatal outcome: Systematic review, Ultrasound Obstet. Gynecol,
doi:10.1002/uog.22088
Kangussu, Marzano, Souza, Dantas, Miranda et al., The renin-angiotensin system and the cerebrovascular diseases: Experimental and clinical evidence, Protein Pept. Lett,
doi:10.2174/0929866527666191218091823
Karmaus, Wagner, Harkema, Kaminski, Kaplan, Cannabidiol (CBD) enhances lipopolysaccharide (LPS)-induced pulmonary inflammation in C57BL/6 mice, J. Immunotoxicol,
doi:10.3109/1547691X.2012.741628
Karschner, Darwin, Goodwin, Wright, Huestis, Plasma cannabinoid pharmacokinetics following controlled oral delta9-tetrahydrocannabinol and oromucosal cannabis extract administration, Clin. Chem,
doi:10.1373/clinchem.2010.152439
Kassiri, Zhong, Guo, Basu, Wang et al., Loss of angiotensinconverting enzyme 2 accelerates maladaptive left ventricular remodeling in response to myocardial infarction, Circ. Heart. Fail,
doi:10.1161/CIRCHEARTFAILURE.108.840124
Katsi, Maragkoudakis, Marketou, Tsioufis, Parthenakis et al., The role of angiotensin-(1-7)/Mas axis and angiotensin type 2 receptors in the central nervous system in cardiovascular disease and therapeutics: A riddle to be solved, Curr. Vasc. Pharmacol,
doi:10.2174/1570161117666181105154843
Khodadadi, Salles, Jarrahi, Chibane, Costigliola et al., Cannabidiol modulates cytokine storm in acute respiratory distress syndrome induced by simulated viral infection using synthetic RNA, Cannabis Cannabinoid Res,
doi:10.1089/can.2020.0043
Kicman, Toczek, The effects of cannabidiol, a non-intoxicating compound of cannabis, on the cardiovascular system in health and disease, Int. J. Mol. Sci,
doi:10.3390/ijms21186740
Kimura, Francisco, Conway, Martinez, Vercelli et al., Type 2 inflammation modulates ACE2 and TMPRSS2 in airway epithelial cells, J. Allergy. Clin. Immunol,
doi:10.1016/j.jaci.2020.05.004
Kochi, Tagliari, Forleo, Fassini, Tondo, Cardiac and arrhythmic complications in patients with COVID-19, J. Cardiovasc. Electrophysiol,
doi:10.1111/jce.14479
Konturek, Harsch, Neurath, Zopf, COVID-19 -more than respiratory disease: A gastroenterologist's perspective, J. Physiol. Pharmacol,
doi:10.26402/jpp.2020.2.02
Kossakowski, Schlicker, Toczek, Weresa, Malinowska, Cannabidiol affects the Bezold-Jarisch reflex via TRPV1 and 5-HT 3 receptors and has peripheral sympathomimetic effects in spontaneously hypertensive and normotensive rats, Front. Pharmacol,
doi:10.3389/fphar.2019.00500
Krueger, Murrell, Garcet, Navrazhina, Lee et al., Secukinumab lowers expression of ACE2 in affected skin of patients with psoriasis, J. Allergy Clin. Immunol,
doi:10.1016/j.jaci.2020.09.021
Kuba, Imai, Ohto-Nakanishi, Penninger, Trilogy of ACE2: A peptidase in the renin-angiotensin system, a SARS receptor, and a partner for amino acid transporters, Pharmacol. Ther,
doi:10.1016/j.pharmthera.2010.06.003
Lafuente, Pazos, Alvarez, Mohammed, Santos et al., Effects of cannabidiol and hypothermia on short-term brain damage in new-born piglets after acute hypoxia-ischemia, Front. Neurosci,
doi:10.3389/fnins.2016.00323
Lazartigues, Qadir, Mauvais-Jarvis, Endocrine significance of SARS-CoV-2's reliance on ACE2, Endocrinology,
doi:10.1210/endocr/bqaa108
Lee, Erdelyi, Matyas, Mukhopadhyay, Varga et al., Cannabidiol limits T cell-mediated chronic autoimmune myocarditis: Implications to autoimmune disorders and organ transplantation, Mol. Med,
doi:10.2119/molmed.2016.00007
Leweke, Piomelli, Pahlisch, Muhl, Gerth et al., Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia, Transl. Psychiatry,
doi:10.1038/tp.2012.15
Li, Feng, Li, Yuece, Lin et al., Anti-inflammatory role of cannabidiol and O-1602 in cerulein-induced acute pancreatitis in mice, Pancreas,
doi:10.1097/MPA.0b013e318259f6f0
Li, Wu, Yao, Guo, Liao et al., Caution on kidney dysfunctions of COVID-19 patients, medRxiv
Lichtman, Lux, Mcquade, Rossetti, Sanchez et al., Results of a double-blind, randomized, placebo-controlled study of nabiximols oromucosal spray as an adjunctive therapy in advanced cancer patients with chronic uncontrolled pain, J. Pain Symptom Manag,
doi:10.1016/j.jpainsymman.2017.09.001
Ligresti, De Petrocellis, Di Marzo, Phytocannabinoids to cannabinoid receptors and endocannabinoids: Pleiotropic physiological and pathological roles through complex pharmacology, Physiol. Rev,
doi:10.1152/physrev.00002.2016
Liou, Auchampach, Hillard, Zhu, Yousufzai et al., Mediation of cannabidiol anti-inflammation in the retina by equilibrative nucleoside transporter and A2A adenosine receptor, Invest. Ophthalmol. Vis. Sci,
doi:10.1167/iovs.08-2196
Liou, El-Remessy, Ibrahim, Caldwell, Khalifa et al., Cannabidiol as a putative novel therapy for diabetic retinopathy: A postulated mechanism of action as an entry point for biomarker-guided clinical development, Curr. Pharmacogen. Person Med,
doi:10.2174/1875692110907030215
Liu, Long, Zhang, Zhang, Chen et al., ACE2 expression in pancreas may cause pancreatic damage after SARS-CoV-2 infection, Clin. Gastroenterol. Hepatol,
doi:10.1016/j.cgh.2020.04.040
Lovren, Pan, Quan, Teoh, Wang et al., Angiotensin converting enzyme-2 confers endothelial protection and attenuates atherosclerosis, Am. J. Physiol. Heart. Circ. Physiol,
doi:10.1152/ajpheart.00331.2008
Luftner, Possinger, Ernst, Ruhstaller, Meissner et al., Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: A multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group, J. Clin. Oncol,
doi:10.1200/JCO.2005.05.1847
Lumbers, Delforce, Pringle, Smith, The lung, the heart, the novel coronavirus, and the renin-angiotensin system; The need for clinical trials, Front. Med,
doi:10.3389/fmed.2020.00248
Lundholm, Poku, Emanuele, Emanuele, Lopez, SARS-CoV-2 (COVID-19) and the endocrine system, J. Endocr. Soc,
doi:10.1210/jendso/bvaa144
Luís, Hipólito-Fernandes, Mota, Maleita, Xavier et al., A review of neuro-ophthalmological manifestations of human coronavirus infection, Eye Brain,
doi:10.2147/EB.S268828
Machhi, Herskovitz, Senan, Dutta, Nath et al., The natural history, pathobiology, and clinical manifestations of SARS-CoV-2 infections, J. Neuroimmune Pharmacol,
doi:10.1007/s11481-020-09944-5
Makwana, Venkatasamy, Spina, Page, The effect of phytocannabinoids on airway hyper-responsiveness, airway inflammation, and cough, J. Pharmacol. Expl. Ther,
doi:10.1124/jpet.114.221283
Mamber, Krakowka, Osborn, Saberski, Rhodes et al., Can unconventional immunomodulatory agents help alleviate COVID-19 symptoms and severity?, MSphere,
doi:10.1128/mSphere.00288-20
Maor, Yu, Kuzontkoski, Dezube, Zhang et al., Cannabidiol inhibits growth and induces programmed cell death in kaposi sarcoma-associated herpesvirus-infected endothelium, Genes. Cancer,
doi:10.1177/1947601912466556
Marquez, Wysocki, Pandit, Batlle, An update on ACE2 amplification and its therapeutic potential, Acta. Physiol,
doi:10.1111/apha.13513
Marshall, Gohlke, Chambers, Howell, Bottoms et al., Angiotensin II and the fibroproliferative response to acute lung injury, Am. J. Physiol. Lung. Cell. Mol. Physiol,
doi:10.1152/ajplung.00313.2002
Marshall, Webb, Bellingan, Montgomery, Chaudhari et al., Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome, Am. J. Respir. Crit. Care. Med,
doi:10.1164/rccm.2108086
Mawhirt, Frankel, Diaz, Cutaneous manifestations in adult patients with COVID-19 and dermatologic conditions related to the COVID-19 pandemic in health care workers, Curr. Allergy Asthma Rep,
doi:10.1007/s11882-020-00974-w
Mcguire, Robson, Cubala, Vasile, Morrison et al., Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: A multicenter randomized controlled trial, Am. J. Psychiatry,
doi:10.1176/appi.ajp.2017.17030325
Mcnamara, Dang, Sturza, Ziobro, Fedak Romanowski et al., Thrombocytopenia in pediatric patients on concurrent cannabidiol and valproic acid, Epilepsia,
doi:10.1111/epi.16596
Mecha, Feliú, Iñigo, Mestre, Carrillo-Salinas et al., Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis: A role for A2A receptors, Neurobiol. Dis,
doi:10.1016/j.nbd.2013.06.016
Millar, Stone, Bellman, Yates, England et al., A systematic review of cannabidiol dosing in clinical populations, Br. J. Clin. Pharmacol,
doi:10.1111/bcp.14038
Miller, Scheffer, Gunning, Sanchez-Carpintero, Gil-Nagel et al., Dose-Ranging effect of adjunctive oral cannabidiol vs placebo on convulsive seizure frequency in Dravet syndrome: A randomized clinical trial, JAMA Neurol,
doi:10.1001/jamaneurol.2020.0073
Mishima, Hayakawa, Abe, Ikeda, Egashira et al., Cannabidiol prevents cerebral infarction via a serotonergic 5-hydroxytryptamine 1A receptor-dependent mechanism, Stroke,
doi:10.1161/01.STR.0000163083.59201.34
Mukhopadhyay, Rajesh, Horváth, Bátkai, Park et al., Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death, Free Radic. Biol. Med,
doi:10.1016/j.freeradbiomed.2011.02.021
Nadarajah, Milagres, Dilauro, Gutsol, Xiao et al., Podocyte-specific overexpression of human angiotensin-converting enzyme 2 attenuates diabetic nephropathy in mice, Kidney Int,
doi:10.1038/ki.2012.83
Naftali, Mechulam, Marii, Gabay, Stein et al., Lowdose cannabidiol is safe but not effective in the treatment for Crohn's disease, a randomized controlled trial, Dig. Dis. Sci,
doi:10.1007/s10620-017-4540-z
Najjar, Najjar, Chong, Pramanik, Kirsch et al., Central nervous system complications associated with SARS-CoV-2 infection: Integrative concepts of pathophysiology and case reports, J. Neuroinflamm,
doi:10.1186/s12974-020-01896-0
Niu, Yang, Lin, Ji, Guo, Loss of angiotensin-converting enzyme 2 leads to impaired glucose homeostasis in mice, Endocrine,
doi:10.1007/s12020-008-9110-x
Nozato, Yamamoto, Takeshita, Nozato, Imaizumi et al., Angiotensin 1-7 alleviates aging-associated muscle weakness and bone loss, but is not associated with accelerated aging in ACE2-knockout mice, Clin. Sci,
doi:10.1042/CS20190573
Oláh, Tóth, Borbíró, Sugawara, Szöllõsi et al., Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes, J. Clin. Invest,
doi:10.1172/JCI64628
Osterreicher, Taura, De Minicis, Seki, Penz-Osterreicher et al., Angiotensin-converting-enzyme 2 inhibits liver fibrosis in mice, Hepatology,
doi:10.1002/hep.23104
Oudit, Kassiri, Patel, Chappell, Butany et al., Angiotensin II-mediated oxidative stress and inflammation mediate the age-dependent cardiomyopathy in ACE2 null mice, Cardiovasc. Res,
doi:10.1016/j.cardiores.2007.04.007
Pagano, Capasso, Piscitelli, Romano, Parisi et al., An orally active cannabis extract with high content in cannabidiol attenuates chemically-induced intestinal inflammation and hypermotility in the mouse, Front. Pharmacol,
doi:10.3389/fphar.2016.00341
Palmieri, Laurino, Vadalà, A therapeutic effect of CBD-enriched ointment in inflammatory skin diseases and cutaneous scars, Clin. Ter,
doi:10.7417/CT.2019.2116
Palumbo, Ávila, Naftolin, The Ovarian Renin-Angiotensin System (OVRAS): A Major Factor in Ovarian Function and Disease, Reprod. Sci,
doi:10.1177/1933719116672588
Pan, Zhan, Le, Zheng, Jin, Angiotensin-converting enzymes play a dominant role in fertility, Int. J. Mol. Sci,
doi:10.3390/ijms141021071
Paoli, Gorini, Caprio, The dark side of the spoon-glucose, ketones and COVID-19: A possible role for ketogenic diet?, J. Transl. Med,
doi:10.1186/s12967-020-02600-9
Pascolo, Zito, Zupin, Luppi, Giolo et al., Renin angiotensin system, COVID-19 and male fertility: Any risk for conceiving?, Microorganisms,
doi:10.3390/microorganisms8101492
Patel, Bodiga, Fan, Das, Wang et al., Cardioprotective effects mediated by angiotensin II type 1 receptor blockade and enhancing angiotensin 1-7 in experimental heart failure in angiotensin-converting enzyme 2-null mice, Hypertension,
doi:10.1161/HYPERTENSIONAHA.112.191650
Patel, Wallis, Fujinami, Wilcox, Smith, Cannabidiol reduces seizures following CNS infection with Theiler's murine encephalomyelitis virus, Epilepsia Open,
doi:10.1002/epi4.12351
Patra, Barker-Haliski, White, Whalley, Glyn et al., Cannabidiol reduces seizures and associated behavioral comorbidities in a range of animal seizure and epilepsy models, Epilepsia,
doi:10.1111/epi.14629
Patsalos, Szaflarski, Gidal, Van Landingham, Critchley et al., Clinical implications of trials investigating drug-drug interactions between cannabidiol and enzyme inducers or inhibitors or common antiseizure drugs, Epilepsia,
doi:10.1111/epi.16674
Pazos, Mohammed, Lafuente, Santos, Martínez-Pinilla et al., Mechanisms of cannabidiol neuroprotection in hypoxic-ischemic newborn pigs: Role of 5HT 1A and CB2 receptors, Neuropharmacology,
doi:10.1016/j.neuropharm.2013.03.027
Penna, Mercurio, Tocchetti, Pagliaro, Sex-related differences in COVID-19 lethality, Br. J. Pharmacol,
doi:10.1111/bph.15207
Pennisi, Lanza, Falzone, Fisicaro, Ferri et al., SARS-CoV-2 and the nervous system: From clinical features to molecular mechanisms, Int. J. Mol. Sci,
doi:10.3390/ijms21155475
Petrosino, Verde, Vaia, Allarà, Iuvone et al., Anti-inflammatory properties of cannabidiol, a nonpsychotropic cannabinoid, in experimental allergic contact dermatitis, J. Pharmacol. Exp. Ther,
doi:10.1124/jpet.117.244368
Pickering, Semple, Nazir, Murphy, Snow et al., Cannabinoid effects on ventilation and breathlessness: A pilot study of efficacy and safety, Chron. Respir. Dis,
doi:10.1177/1479972310391283
Pisanti, Malfitano, Ciaglia, Lamberti, Ranieri et al., Cannabidiol: State of the art and new challenges for therapeutic applications, Pharmacol. Ther,
doi:10.1016/j.pharmthera.2017.02.041
Pędzi Ńska-Betiuk, Weresa, Schlicker, Harasim-Symbor, Toczek et al., Chronic cannabidiol treatment reduces the carbachol-induced coronary constriction and left ventricular cardiomyocyte width of the isolated hypertensive rat heart, Toxicol. Appl. Pharmacol,
doi:10.1016/j.taap.2020.115368
Rahimi, Tehranchinia, A comprehensive review of cutaneous manifestations associated with COVID-19, Biomed. Res. Int,
doi:10.1155/2020/1236520
Raj, Park, Cho, Choi, Kim et al., Assessment of antiviral potencies of cannabinoids against SARS-CoV-2 using computational and in vitro approaches, Int. J. Biol. Macromol,
doi:10.1016/j.ijbiomac.2020.12.020
Rajesh, Mukhopadhyay, Bátkai, Patel, Saito et al., Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy, J. Am. Coll. Cardiol,
doi:10.1016/j.jacc.2010.07.033
Reis, Reis, Angiotensin-converting enzyme 2 (ACE2), angiotensin-(1-7) and Mas receptor in gonadal and reproductive functions, Clin. Sci (Lond),
doi:10.1042/CS20200865
Remiszewski, Jarocka-Karpowicz, Biernacki, Jastrz Ąb, Schlicker et al., 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,
doi:10.3390/ijms21041295
Rey-Parra, Vadivel, Coltan, Hall, Eaton et al., Angiotensin converting enzyme 2 abrogates bleomycin-induced lung injury, J. Mol. Med,
doi:10.1007/s00109-012-0859-2
Ribeiro, Almeida, Costola De, Souza, Ferraz De Paula et al., Cannabidiol improves lung function and inflammation in mice submitted to LPS-induced acute lung injury, Immunopharmacol. Immunotoxicol,
doi:10.3109/08923973.2014.976794
Ribeiro, Ferraz-De-Paula, Pinheiro, Vitoretti, Mariano-Souza et al., Cannabidiol, a non-psychotropic plant-derived cannabinoid, decreases inflammation in a murine model of acute lung injury: Role for the adenosine A2A receptor, Eur. J. Pharmacol,
doi:10.1016/j.ejphar.2011.12.043
Rock, Sullivan, Collins, Goodman, Limebeer et al., Evaluation of repeated or acute treatment with cannabidiol (CBD), cannabidiolic acid (CBDA) or CBDA methyl ester (HU-580) on nausea and/or vomiting in rats and shrews, Psychopharmacology,
doi:10.1007/s00213-020-05559-z
Rossi, Tortora, Argenziano, Di Paola, Punzo, Cannabinoid receptor type 2: A possible target in SARS-CoV-2 (CoV-19) infection?, Int. J. Mol. Sci,
doi:10.3390/ijms21113809
Ruiz-Valdepeñas, Martínez-Orgado, Benito, Millán, Tolón et al., Cannabidiol reduces lipopolysaccharideinduced vascular changes and inflammation in the mouse brain: An intravital microscopy study, J. Neuroinflamm,
doi:10.1186/1742-2094-8-5
Russo, Naro, Leo, Sessa, D'aleo et al., Evaluating Sativex®in neuropathic pain management: A clinical and neurophysiological assessment in multiple sclerosis, Pain Med,
doi:10.1093/pm/pnv080
Sadowska, Baranowska-Kuczko, Gromotowicz-Popławska, Biernacki, Kicman et al., Cannabidiol ameliorates monocrotaline-induced pulmonary hypertension in rats, Int. J. Mol. Sci,
doi:10.3390/ijms21197077
Sahara, Ikutomi, Morita, Minami, Nakajima et al., Deletion of angiotensin-converting enzyme 2 promotes the development of atherosclerosis and arterial neointima formation, Cardiovasc. Res
Salles, Khodadadi, Jarrahi, Ahluwalia, Paffaro et al., Cannabidiol (CBD) modulation of apelin in acute respiratory distress syndrome, J. Cell. Mol. Med
Samidurai, Das, Cardiovascular Complications associated with COVID-19 and potential therapeutic strategies, Int. J. Mol. Sci,
doi:10.3390/ijms21186790
Sampaio, Nascimento, Santos, Systemic and regional hemodynamic effects of angiotensin-(1-7) in rats, Am. J. Physiol. Heart. Circ. Physiol,
doi:10.1152/ajpheart.01145.2002
Santos, Guimarães, Crippa, Hallak, Rossi et al., Serious adverse effects of cannabidiol (CBD): A review of randomized controlled trials, Expert Opin. Drug Metab. Toxicol,
doi:10.1080/17425255.2020.1754793
Santos, Sampaio, Alzamora, Motta-Santos, Alenina et al., The ACE2/Angiotensin-(1-7)/MAS axis of the renin-angiotensin system: Focus on Angiotensin-(1-7), Physiol. Rev,
doi:10.1152/physrev.00023.2016
Saponaro, Rutigliano, Sestito, Bandini, Storti et al., ACE2 in the era of SARS-CoV-2: Controversies and novel perspectives, Front. Mol. Biosci,
doi:10.3389/fmolb.2020.588618
Sawalha, Zhao, Coit, Lu, Epigenetic dysregulation of ACE2 and interferon-regulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients, medRxiv,
doi:10.1016/j.clim.2020.108410
Selvarajah, Gandhi, Emery, Tesfaye, Randomized placebo-controlled double-blind clinical trial of cannabisbased medicinal product (Sativex) in painful diabetic neuropathy: Depression is a major confounding factor, Diabetes Care,
doi:10.2337/dc09-1029
Sexton, Cannabis in the time of coronavirus disease 2019: The Yin and Yang of the endocannabinoid system in immunocompetence, J. Altern. Complement. Med,
doi:10.1089/acm.2020.0144
Shan, Shang, Zhang, Zhao, Chen et al., Effect of angiotensin-(1-7) and angiotensin II on the proliferation and activation of human endometrial stromal cells in vitro, Int. J. Clin. Exp. Pathol
Shannon, Lewis, Lee, Hughes, Cannabidiol in anxiety and sleep: A large case series, Perm. J,
doi:10.7812/TPP/18-041
Sharma, Stevens, Obukhov, Grant, Oudit et al., ACE2 (angiotensin-converting enzyme 2) in cardiopulmonary diseases: Ramifications for the control of SARS-CoV-2, Hypertension,
doi:10.1161/HYPERTENSIONAHA.120.15595
Shenoy, Kwon, Rathinasabapathy, Lin, Jin et al., Oral delivery of Angiotensin-converting enzyme 2 and Angiotensin-(1-7) bioencapsulated in plant cells attenuates pulmonary hypertension, Hypertension,
doi:10.1161/HYPERTENSIONAHA.114.03871
Shoemaker, Tannock, Su, Gong, Gurley et al., Adipocyte deficiency of ACE2 increases systolic blood pressures of obese female C57BL/6 mice, Biol. Sex. Differ,
doi:10.1186/s13293-019-0260-8
Shover, Humphreys, Debunking cannabidiol as a treatment for COVID-19: Time for the FDA to adopt a focused deterrence model?, Cureus,
doi:10.7759/cureus.8671
Soares, Vuolo, Dall'igna, Michels, Crippa et al., Evaluation of the role of the cannabidiol system in an animal model of ischemia/reperfusion kidney injury, Rev. Bras. Ter. Intensiva,
doi:10.5935/0103-507X.20150064
Solowij, Broyd, Beale, Prick, Greenwood et al., Therapeutic effects of prolonged cannabidiol treatment on psychological symptoms and cognitive function in regular cannabis users: A pragmatic open-label clinical trial, Cannabis Cannabinoid Res,
doi:10.1089/can.2017.0043
Solowij, Broyd, Greenwood, Van Hell, Martelozzo et al., A randomised controlled trial of vaporised ∆9-tetrahydrocannabinol and cannabidiol alone and in combination in frequent and infrequent cannabis users: Acute intoxication effects, Eur. Arch. Psychiatry Clin. Neurosci,
doi:10.1007/s00406-019-00978-2
Somasundaram, Ranathunga, Ratnasamy, Wijewickrama, Dissanayake et al., The impact of SARS-Cov-2 virus infection on the endocrine system, J. Endocr. Soc,
doi:10.1210/jendso/bvaa082
Tan, Liao, Zhou, Mei, Wong, Targeting the renin-angiotensin system as novel therapeutic strategy for pulmonary diseases, Curr. Opin. Pharmacol,
doi:10.1016/j.coph.2017.12.002
Tang, Li, Wang, Sun, Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia, J. Thromb. Haemost,
doi:10.1111/jth.14768
Thiele, Marsh, French, Mazurkiewicz-Beldzinska, Benbadis et al., Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): A randomised, double-blind, placebo-controlled phase 3 trial, Lancet,
doi:10.1016/S0140-6736(18)30136-3
Tikellis, Thomas, Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease, Int. J. Pept,
doi:10.1155/2012/256294
Tu, Chien, Yarmishyn, Lin, Luo et al., A review of SARS-CoV-2 and the ongoing clinical trials, Int. J. Mol. Sci,
doi:10.3390/ijms21072657
Van De Donk, Niesters, Kowal, Olofsen, Dahan et al., An experimental randomized study on the analgesic effects of pharmaceutical-grade cannabis in chronic pain patients with fibromyalgia, Pain,
doi:10.1097/j.pain.0000000000001464
Varatharaj, Thomas, Ellul, Davies, Pollak et al., Neurological and neuropsychiatric complications of COVID-19 in 153 patients: A UK-wide surveillance study, Lancet Psychiatry,
doi:10.1016/S2215-0366(20)30287-X
Verdecchia, Cavallini, Spanevello, Angeli, COVID-19: ACE2centric infective disease?, Hypertension
Verma, Shan, Lei, Yuan, Liu et al., ACE2 and Ang-(1-7) confer protection against development of diabetic retinopathy, Mol. Ther,
doi:10.1038/mt.2011.155
Verma, Xu, Du, Zhu, Liang et al., Expression of human ACE2 in Lactobacillus and beneficial effects in diabetic retinopathy in mice, Mol. Ther. Methods. Clin. Dev,
doi:10.1016/j.omtm.2019.06.007
Vilela, Gomides, David, Antunes, Diniz et al., Cannabidiol rescues acute hepatic toxicity and seizure induced by cocaine, Mediators Inflamm,
doi:10.1155/2015/523418
Vilela, Lima, Kunsch, Pinto, De Miranda et al., Anticonvulsant effect of cannabidiol in the pentylenetetrazole model: Pharmacological mechanisms, electroencephalographic profile, and brain cytokine levels, Epilepsy Behav,
doi:10.1016/j.yebeh.2017.07.014
Vuolo, Abreu, Michels, Xisto, Blanco et al., Cannabidiol reduces airway inflammation and fibrosis in experimental allergic asthma, Eur. J. Pharmacol
Vuolo, Petronilho, Sonai, Ritter, Hallak et al., Evaluation of serum cytokines levels and the role of cannabidiol treatment in animal model of asthma, Mediators Inflamm,
doi:10.1155/2015/538670
Wade, Makela, House, Bateman, Robson, Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis, Mult. Scler,
doi:10.1177/1352458505070618
Wade, Makela, Robson, House, Bateman, Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients, Mult. Scler,
doi:10.1191/1352458504ms1082oa
Walsh, Hepburn, Kane, Wainwright, Acute administration of cannabidiol in vivo suppresses ischaemiainduced cardiac arrhythmias and reduces infarct size when given at reperfusion, Br. J. Pharmacol,
doi:10.1111/j.1476-5381.2010.00755.x
Wang, Kovalchuk, Li, Rodriguez-Juarez, Ilnytskyy et al., In search of preventive strategies: Novel high-CBD Cannabis sativa extracts modulate ACE2 expression in COVID-19 gateway tissues, Aging
Wang, Mukhopadhyay, Cao, Wang, Feng et al., Cannabidiol attenuates alcohol-induced liver steatosis, metabolic dysregulation, inflammation and neutrophil-mediated injury, Sci. Rep,
doi:10.1038/s41598-017-10924-8
Weisberg, Sattler, Yang, Parent, Gray et al., Current therapies under investigation for COVID-19: Potential COVID-19 treatments, Can. J. Physiol. Pharmacol,
doi:10.1139/cjpp-2020-0286
Wheal, Jadoon, Randall, O'sullivan, In Vivo cannabidiol treatment improves endothelium-dependent vasorelaxation in mesenteric arteries of zucker diabetic fatty rats, Front. Pharmacol,
doi:10.3389/fphar.2017.00248
Wilson, Bossong, Appiah-Kusi, Petros, Brammer et al., Cannabidiol attenuates insular dysfunction during motivational salience processing in subjects at clinical high risk for psychosis, Transl. Psychiatry,
doi:10.1038/s41398-019-0534-2
Wilson-Morkeh, Al-Abdulla, Sien, Mohamed, Youngstein, Important drug interactions exist between cannabidiol oil and commonly prescribed drugs in rheumatology practice, Rheumatology,
doi:10.1093/rheumatology/kez304
Xiao, Gao, Lazartigues, Zucker, Brain-selective overexpression of angiotensin-converting enzyme 2 attenuates sympathetic nerve activity and enhances baroreflex function in chronic heart failure, Hypertension,
doi:10.1161/HYPERTENSIONAHA.111.176636
Xue, Mi, Wang, Pang, Liu et al., High expression of ACE2 on keratinocytes reveals skin as a potential target for SARS-CoV-2, J. Invest. Dermatol,
doi:10.1016/j.jid.2020.05.087
Yamaleyeva, Pulgar, Lindsey, Yamane, Varagic et al., Uterine artery dysfunction in pregnant ACE2 knockout mice is associated with placental hypoxia and reduced umbilical blood flow velocity, Am. J. Physiol. Endocrinol. Metab,
doi:10.1152/ajpendo.00596.2014
Yamamoto, Ohishi, Katsuya, Ito, Ikushima et al., Deletion of angiotensin-converting enzyme 2 accelerates pressure overload-induced cardiac dysfunction by increasing local angiotensin II, Hypertension,
doi:10.1161/01.HYP.0000205833.89478.5b
Zheng, Feng, Liu, Targher, Byrne et al., Extrapulmonary complications of COVID-19: A multisystem disease?, J. Med. Virol,
doi:10.1002/jmv.26294
Zhong, Basu, Guo, Chow, Byrns et al., Angiotensin-converting enzyme 2 suppresses pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction, Circulation,
doi:10.1161/CIRCULATIONAHA.110.955369
Zhou, Kang, Li, Zhao, Understanding the neurotropic characteristics of SARS-CoV-2: From neurological manifestations of COVID-19 to potential neurotropic mechanisms, J. Neurol,
doi:10.1007/s00415-020-09929-7
Zhu, Verma, Prasad, Li, Expression and function of Mas-related G Protein-Coupled Receptor D and its ligand alamandine in retina, Mol. Neurobiol,
doi:10.1007/s12035-019-01716-4
Zorzenon, Santiago, Mori, Piovan, Jansen et al., Cannabidiol improves metabolic dysfunction in middle-aged diabetic rats submitted to a chronic cerebral hypoperfusion, Chem. Biol. Interact,
doi:10.1016/j.cbi.2019.108819
Zuardi, Cosme, Graeff, Guimarães, Effects of ipsapirone and cannabidiol on human experimental anxiety, J. Psychopharmacol,
doi:10.1177/026988119300700112
Zuardi, Rodrigues, Silva, Bernardo, Hallak et al., Inverted U-shaped dose-response curve of the anxiolytic effect of cannabidiol during public speaking in real life, Front. Pharmacol,
doi:10.3389/fphar.2017.00259
Ąsecka, Borovac, Guerreiro, Giustozzi, Parker et al., Thrombotic complications in patients with COVID-19: Pathophysiological mechanisms, diagnosis, and treatment, Cardiovasc. Drugs Ther,
doi:10.1007/s10557-020-07084-9
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'abstract': '<jats:p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to '
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'dysfunction. In this review, we present advantages and disadvantages of cannabidiol (CBD), a '
'non-intoxicating phytocannabinoid from the cannabis plant, as a potential agent for the '
'treatment of COVID-19. CBD has been shown to downregulate proteins responsible for viral '
'entry and to inhibit SARS-CoV-2 replication. Preclinical studies have demonstrated its '
'effectiveness against diseases of the respiratory system as well as its cardioprotective, '
'nephroprotective, hepatoprotective, neuroprotective and anti-convulsant properties, that is, '
'effects that may be beneficial for COVID-19. Only the latter two properties have been '
'demonstrated in clinical studies, which also revealed anxiolytic and antinociceptive effects '
'of CBD (given alone or together with Δ9-tetrahydrocannabinol), which may be important for an '
'adjuvant treatment to improve the quality of life in patients with COVID-19 and to limit '
'post-traumatic stress symptoms. However, one should be aware of side effects of CBD (which '
'are rarely serious), drug interactions (also extending to drugs acting against COVID-19) and '
'the proper route of its administration (vaping may be dangerous). Clearly, further clinical '
'studies are necessary to prove the suitability of CBD for the treatment of COVID-19.</jats:p>',
'DOI': '10.3390/ijms22041986',
'type': 'journal-article',
'created': {'date-parts': [[2021, 2, 18]], 'date-time': '2021-02-18T02:35:42Z', 'timestamp': 1613615742000},
'page': '1986',
'source': 'Crossref',
'is-referenced-by-count': 8,
'title': ['Opportunities, Challenges and Pitfalls of Using Cannabidiol as an Adjuvant Drug in COVID-19'],
'prefix': '10.3390',
'volume': '22',
'author': [ {'given': 'Barbara', 'family': 'Malinowska', 'sequence': 'first', 'affiliation': []},
{'given': 'Marta', 'family': 'Baranowska-Kuczko', 'sequence': 'additional', 'affiliation': []},
{'given': 'Aleksandra', 'family': 'Kicman', 'sequence': 'additional', 'affiliation': []},
{'given': 'Eberhard', 'family': 'Schlicker', 'sequence': 'additional', 'affiliation': []}],
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