Therapeutic Algorithm for Use of Melatonin in Patients With COVID-19
Russel J Reiter, Pedro Abreu-Gonzalez, Paul E Marik, Alberto Dominguez-Rodriguez
Frontiers in Medicine, doi:10.3389/fmed.2020.00226
The coronavirus, COVID-19, has infected hundreds of thousands and killed tens of thousands of individuals worldwide. This highly infectious condition continues to ravage the world population and has yet to reach it peak infective rate in some countries. Many conventional drugs including hydroxychloroquine/chloroquine, lopinavir, remdesivir, etc., have been repurposed as treatments for this often deadly disease, but there is no specifically-designed effective drug available; also, the drugs mentioned have significant side effects and their efficacy is unknown. New drugs and vaccines are being designed as COVID-19 treatment, but their development and testing will require months to years. Time is not a luxury that this crisis has. Thus, there is a serious unmet need for the identification of currently-available and safe molecules which can be used to slow or treat COVID-19 disease. Here, we suggest melatonin be given consideration for prophylactic use or treatment alone or in combination with other drugs. Melatonin's multiple actions as an anti-inflammatory, anti-oxidant, and anti-viral (against other viruses) make it a reasonable choice for use. Melatonin is readily available, can be easily synthesized in large quantities, is inexpensive, has a very high safety profile and can be easily self-administered. Melatonin is endogenously-produced molecule in small amounts with its production diminishing with increased age. Under the current critical conditions, large doses of melatonin alone or in combination with currently-recommended drugs, e.g., hydroxychloroquine/chloroquine, to resist COVID-19 infection would seem judicious.
AUTHOR CONTRIBUTIONS RR: conceptualization, writing-review, and editing. PA-G and PM: writing-review and editing. AD-R: resources, writing original draft, review, and editing. All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.
Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
Alhazzani, Møller, Arabi, Loeb, Gong, Surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19), Intensive Care Med,
doi:10.1007/s00134-020-06022-5Anderson, Maes, Markus, Rodriguez, Ebola virus: melatonin as a readily available treatment option, J Med Virol,
doi:10.1002/jmv.24130Anderson, Reiter, Melatonin: roles in influenza, Covid-19, and other viral infections, Rev Med Virol,
doi:10.1002/rmv.2109Biancatelli, Berrill, Mohammed, Marik, Melatonin for the treatment of sepsis: the scientific rationale, J Thorac Dis,
doi:10.21037/jtd.2019.12.85Boga, Caballero, Potes, Perez-Martinez, Reiter et al., Therapeutic potential of melatonin related to its role as an autophagy regulator: a review, J Pineal Res,
doi:10.1111/jpi.12534Borghi, Cicero, Nutraceuticals with a clinically detectable blood pressure-lowering effect: a review of available randomized clinical trials and their meta-analyses, Br J Clin Pharmacol,
doi:10.1111/bcp.12902Chafekar, Fielding, MERS-CoV: understanding the latest human coronavirus threat, Viruses,
doi:10.3390/v10020093Channappanavar, Fehr, Vijay, Mack, Zhao et al., Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice, Cell Host Microbe,
doi:10.1016/j.chom.2016.01.007Chen, Wu, Guo, Cao, Huang et al., Clinical and immunologic features in severe and moderate coronavirus disease 2019, J Clin Invest,
doi:10.1172/JCI137244Cipolla-Neto, Amaral, Afeche, Tan, Reiter, Melatonin, energy metabolism, and obesity: a review, J Pineal Res,
doi:10.1111/jpi.12137Crespo, Miguel, Laliena, Alvarez, Culebras et al., Melatonin prevents the decreased activity of antioxidant enzymes and activates nuclear erythroid 2-related factor 2 signaling in an animal model of fulminant hepatic failure of viral origin, J Pineal Res,
doi:10.1111/j.1600-079X.2010.00787.xDavey Rt, Dodd, Proschan, Neaton, Nordwall et al., A randomized, controlled trial of ZMapp for Ebola Virus infection, N Engl J Med,
doi:10.1056/NEJMoa1604330Diao, Wang, Tan, Chen, Liu et al., Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19), Front. Immunol,
doi:10.3389/fimmu.2020.00827Dominguez-Rodriguez, Abreu-Gonzalez, De La Torre-Hernandez, Consuegra-Sanchez, Piccolo et al., Usefulness of early treatment with melatonin to reduce infarct size in patients with ST-segment elevation myocardial infarction receiving percutaneous coronary intervention (from the melatonin adjunct in the acute myocardial infarction treated with angioplasty trial), Am J Cardiol,
doi:10.1016/S0735-1097(17)34668-5Dominguez-Rodriguez, Abreu-Gonzalez, De La Torre-Hernandez, Gonzalez-Gonzalez, Garcia-Camarero et al., Effect of intravenous and intracoronary melatonin as an adjunct to primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: results of the melatonin adjunct in the acute myocardial infarction treated with angioplasty trial, J Pineal Res,
doi:10.1111/jpi.12374Dominguez-Rodriguez, Abreu-Gonzalez, Piccolo, Galasso, Reiter, Melatonin is associated with reverse remodeling after cardiac resynchronization therapy in patients with heart failure and ventricular dyssynchrony, Int J Cardiol,
doi:10.1016/j.ijcard.2016.07.056Foley, Steel, Adverse events associated with oral administration of melatonin: a critical systematic review of clinical evidence, Complement Ther Med,
doi:10.1016/j.ctim.2018.11.003Grunewald, Shaban, Mackin, Fehr, Perlman, Murine coronavirus infection activates the aryl hydrocarbon receptor in an indoleamine 2,3-dioxygenase-independent manner, contributing to cytokine modulation and proviral TCDD-inducible-PARP expression, J Virol,
doi:10.1128/JVI.01743-19Guan, Ni, Hu, Liang, Ou et al., Clinical characteristics of coronavirus disease 2019 in China, N Engl J Med,
doi:10.1056/NEJMoa2002032Hardeland, Melatonin and the theories of aging: a critical appraisal of melatonin's role in antiaging mechanisms, J Pineal Res,
doi:10.1111/jpi.12090Huang, Liu, Chen, Lu, Li et al., Melatonin prevents endothelial dysfunction in SLE by activating the nuclear receptor retinoic acid-related orphan receptor-α, Int Immunopharmacol,
doi:10.1016/j.intimp.2020.106365Huo, Jin, Zou, Qi, Xiao et al., Lethal influenza A virus preferentially activates TLR3 and triggers a severe inflammatory response, Virus Res,
doi:10.1016/j.virusres.2018.09.012Imenshahidi, Karimi, Hosseinzadeh, Effects of melatonin on cardiovascular risk factors and metabolic syndrome: a comprehensive review, Naunyn Schmiedebergs Arch Pharmacol,
doi:10.1007/s00210-020-01822-4Liao, Yang, Yuan, Wen, Xu et al., The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing, medRxiv,
doi:10.1101/2020.02.23.20026690Maclaren, Fisher, Brodie, Preparing for the most critically Ill patients with COVID-19: the potential role of extracorporeal membrane oxygenation, JAMA,
doi:10.1001/jama.2020.2342Madjid, Safavi-Naeini, Solomon, Vardeny, Potential effects of coronaviruses on the cardiovascular system: a review, JAMA Cardiol,
doi:10.1001/jamacardio.2020.1286Majidinia, Reiter, Shakouri, Mohebbi, Rastegar et al., The multiple functions of melatonin in regenerative medicine, Ageing Res Rev,
doi:10.1016/j.arr.2018.04.003Nogueira, Sampson, Chu, Yu, Andriole et al., Individual variations in serum melatonin levels through time: implications for epidemiologic studies, PLoS ONE,
doi:10.1371/journal.pone.0083208Nordlund, Lerner, The effects of oral melatonin on skin color and on the release of pituitary hormones, J Clin Endocrinol Metab,
doi:10.1210/jcem-45-4-768Obayashi, Saeki, Tone, Kurumatani, Relationship between melatonin secretion and nighttime blood pressure in elderly individuals with and without antihypertensive treatment: a cross-sectional study of the HEIJO-KYO cohort, Hypertens Res,
doi:10.1038/hr.2014.99Paemanee, Hitakarun, Roytrakul, Smith, Screening of melatonin, α-tocopherol, folic acid, acetyl-L-carnitine and resveratrol for anti-dengue 2 virus activity, BMC Res Notes,
doi:10.1186/s13104-018-3417-3Pandi-Perumal, Bahammam, Brown, Spence, Bharti et al., Melatonin antioxidative defense: therapeutical implications for aging and neurodegenerative processes, Neurotox Res,
doi:10.1007/s12640-012-9337-4Prado, Ferder, Manucha, Diez, Anti-inflammatory effects of melatonin in obesity and hypertension, Curr Hypertens Rep,
doi:10.1007/s11906-018-0842-6Ramos, Farré-Alins, Egea, López-Muñoz, Reiter et al., Melatonin's efficacy in stroke patients; a matter of dose? A systematic review, Toxicol Appl Pharmacol,
doi:10.1016/j.taap.2020.114933Reutrakul, Sumritsopak, Saetung, Chanprasertyothin, Chailurkit et al., Lower nocturnal urinary 6-sulfatoxymelatonin is associated with more severe insulin resistance in patients with prediabetes, Neurobiol Sleep Circadian Rhythms,
doi:10.1016/j.nbscr.2017.06.001Sedova, Bernikova, Cuprova, Ivanova, Kutaeva et al., Association between antiarrhythmic, electrophysiological, and antioxidative effects of melatonin in ischemia/reperfusion, Int J Mol Sci,
doi:10.3390/ijms20246331Tong, Tang, Li, Li, Wang et al., Potential presymptomatic transmission of SARS-CoV-2, Zhejiang Province, China, Emerg Infect Dis,
doi:10.3201/eid2605.200198Valero, Mosquera, Alcocer, Bonilla, Salazar et al., Melatonin, minocycline and ascorbic acid reduce oxidative stress and viral titers and increase survival rate in experimental Venezuelan equine encephalitis, Brain Res,
doi:10.1016/j.brainres.2015.06.034Vural, Van Munster, De Rooij, Optimal dosages for melatonin supplementation therapy in older adults: a systematic review of current literature, Drugs Aging,
doi:10.1007/s40266-014-0178-0Wu, Li, Shi, Chen, Jiang et al., Early antiviral treatment contributes to alleviate the severity and improve the prognosis of patients with novel coronavirus disease (COVID-19), J Intern Med,
doi:10.1111/joim.13063Zhou, Hou, Shen, Huang, Martin et al., Network-based drug repurposing for novel coronavirus 2019-nCov/SARS-CoV-2, Cell Discov,
doi:10.1038/s41421-020-0153-3Zou, Ruan, Huang, Liang, Huang et al., SARS-CoV-2 viral load in upper respiratory specimens of infected patients, N Engl J Med,
doi:10.1056/NEJMc2001737{ 'indexed': {'date-parts': [[2024, 4, 30]], 'date-time': '2024-04-30T17:51:23Z', 'timestamp': 1714499483683},
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'responses cause lethal pneumonia in SARS-CoV-infected mice',
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'model of fulminant hepatic failure of viral origin',
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'doi-asserted-by': 'publisher',
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'(COVID-19)',
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{ 'key': 'B26',
'doi-asserted-by': 'publisher',
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'in elderly individuals with and without antihypertensive treatment: a '
'cross-sectional study of the HEIJO-KYO cohort',
'volume': '37',
'author': 'Obayashi',
'year': '2014',
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'doi-asserted-by': 'publisher',
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'volume': '393',
'author': 'Imenshahidi',
'year': '2020',
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'severe insulin resistance in patients with prediabetes',
'volume': '4',
'author': 'Reutrakul',
'year': '2017',
'journal-title': 'Neurobiol Sleep Circadian Rhythms'},
{ 'key': 'B35',
'doi-asserted-by': 'publisher',
'first-page': '359',
'DOI': '10.1016/j.ijcard.2016.07.056',
'article-title': 'Melatonin is associated with reverse remodeling after cardiac '
'resynchronization therapy in patients with heart failure and '
'ventricular dyssynchrony',
'volume': '221',
'author': 'Dominguez-Rodriguez',
'year': '2016',
'journal-title': 'Int J Cardiol.'},
{ 'key': 'B36',
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'DOI': '10.1016/S0735-1097(17)34668-5',
'article-title': 'Usefulness of early treatment with melatonin to reduce infarct size in '
'patients with ST-segment elevation myocardial infarction receiving '
'percutaneous coronary intervention (from the melatonin adjunct in the '
'acute myocardial infarction treated with angioplasty trial)',
'volume': '120',
'author': 'Dominguez-Rodriguez',
'year': '2017',
'journal-title': 'Am J Cardiol'},
{ 'key': 'B37',
'doi-asserted-by': 'publisher',
'DOI': '10.1111/jpi.12374',
'article-title': 'Effect of intravenous and intracoronary melatonin as an adjunct to '
'primary percutaneous coronary intervention for acute ST-elevation '
'myocardial infarction: results of the melatonin adjunct in the acute '
'myocardial infarction treated with angioplasty trial',
'volume': '62',
'author': 'Dominguez-Rodriguez',
'year': '2017',
'journal-title': 'J Pineal Res'},
{ 'key': 'B38',
'doi-asserted-by': 'publisher',
'DOI': '10.1001/jama.2020.2342.',
'article-title': 'Preparing for the most critically Ill patients with COVID-19: the '
'potential role of extracorporeal membrane oxygenation',
'author': 'MacLaren',
'year': '2020',
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