Mechanisms and clinical evidence to support melatonin's use in severe COVID-19 patients to lower mortality
Dun-Xian Tan, Russel J Reiter
Life Sciences, doi:10.1016/j.lfs.2022.120368
The fear of SARS-CoV-2 infection is due to its high mortality related to seasonal flu. To date, few medicines have been developed to significantly reduce the mortality of the severe COVID-19 patients, especially those requiring tracheal intubation. The severity and mortality of SARS-CoV-2 infection not only depend on the viral virulence, but are primarily determined by the cytokine storm and the destructive inflammation driven by the host immune reaction. Thus, to target the host immune response might be a better strategy to combat this pandemic. Melatonin is a molecule with multiple activities on a virus infection. These include that it downregulates the overreaction of innate immune response to suppress inflammation, promotes the adaptive immune reaction to enhance antibody formation, inhibits the entrance of the virus into the cell as well as limits its replication. These render it a potentially excellent candidate for treatment of the severe COVID-19 cases. Several clinical trials have confirmed that melatonin when added to the conventional therapy significantly reduces the mortality of the severe COVID-19 patients. The cost of melatonin is a small fraction of those medications approved by FDA for emergency use to treat COVID-19. Because of its self-administered, low cost and high safety margin, melatonin could be made available to every country in the world at an affordable cost. We recommend melatonin be used to treat severe COVID-19 patients with the intent of reducing mortality. If successful, it would make the SARS-CoV-2 pandemic less fearful and help to return life back to normalcy.
References
Alizadeh, Keyhanian, Ghaderkhani, Dashti-Khavidaki, Shoormasti et al., A pilot study on controlling coronavirus disease 2019 (COVID-19) inflammation using melatonin supplement, Iran, J. Allergy. Asthma. Immunol,
doi:10.18502/ijaai.v20i4.6959Anand, Ziebuhr, Wadhwani, Mesters, Hilgenfeld, Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs, Science,
doi:10.1126/SCIENCE.1085658Ashrafizadeh, Najafi, Kavyiani, Mohammadinejad, Farkhondeh et al., Anti-inflammatory activity of melatonin: a focus on the role of NLRP3 inflammasome, Inflammation,
doi:10.1007/S10753-021-01428-9Aslan, Gül, Tektemur, Sahna, Ischemic postconditioning reduced myocardial ischemia-reperfusion injury: the roles of melatonin and uncoupling protein 3, anatol, J. Cardiol,
doi:10.14744/ANATOLJCARDIOL.2019.72609Authorizes, Pfizer oral COVID-19 treatment, first for at-home use
Behl, Kaur, Aleya, Sehgal, Singh et al., CD147-spike protein interaction in COVID-19: get the ball rolling with a novel receptor and therapeutic target, Sci. Total Environ,
doi:10.1016/J.SCITOTENV.2021.152072Boga, Coto-Montes, Rosales-Corral, Tan, Reiter et al., Beneficial actions of melatonin in the management of viral infections: a new use for this "molecular handyman, Rev. Med. Virol,
doi:10.3389/FIMMU.2020.576745Bologna, Madonna, Pone, Efficacy of prolonged-release melatonin 2 mg (PRM 2 mg) prescribed for insomnia in hospitalized patients for COVID-19: a retrospective observational study, J. Clin. Med,
doi:10.3390/JCM10245857Cao, Shrestha, Li, Yu, Chen et al., Melatonin-mediated mitophagy protects against early brain injury after subarachnoid hemorrhage through inhibition of NLRP3 inflammasome activation, Sci. Rep,
doi:10.1038/S41598-017-02679-ZCardinali, Brown, Pandi-Perumal, An urgent proposal for the immediate use of melatonin as an adjuvant to anti-SARS-CoV-2 vaccination, Melatonin Res,
doi:10.32794/MR11250091Cardinali, Brown, Reiter, Pandi-Perumal, Elderly as a high-risk group during COVID-19 pandemic: effect of circadian misalignmentSleep Dysregulation and Melatonin Administration, Sleep Vigil,
doi:10.1007/S41782-020-00111-7Castillo, Quizon, Juco, Roman, De Leon et al., Melatonin as adjuvant treatment for coronavirus disease 2019 pneumonia patients requiring hospitalization (MAC-19 PRO): a case series, Melatonin Res,
doi:10.32794/MR11250063Castrillón, Esquifino, Varas, Zapata, Cutrera et al., Effect of melatonin treatment on 24-h variations in responses to mitogens and lymphocyte subset populations in rat submaxillary lymph nodes, J. Neuroendocrinol,
doi:10.1046/J.1365-2826.2000.00519.XCecon, Fernandois, Renault, Coelho, Wenzel et al., into the brain and virus-induced damage of cerebral small vessels,
doi:10.1101/2021.12.30.474561Cecon, Izabelle, Le Poder, Real, Zhu et al., Therapeutic potential of melatonin and melatonergic drugs on K18-hACE2 mice infected with SARS-CoV-2, J. Pineal Res,
doi:10.1111/JPI.12772Costantino, Cuzzocrea, Mazzon, Caputi, Protective effects of melatonin in zymosan-activated plasma-induced paw inflammation, Eur. J. Pharmacol,
doi:10.1016/s0014-2999(98)00673-6Crespo, Fernández-Palanca, San-Miguel, Álvarez, González-Gallego et al., Melatonin modulates mitophagy, innate immunity and circadian clocks in a model of viral-induced fulminant hepatic failure, J. Cell. Mol. Med,
doi:10.1111/JCMM.15398Cuesta, Cerezuela, Esteban, Meseguer, In vivo actions of melatonin on the innate immune parameters in the teleost fish gilthead seabream, J. Pineal Res,
doi:10.1111/J.1600-079X.2008.00557.XCuzzocrea, Zingarelli, Gilad, Hake, Salzman et al., Protective effect of melatonin in carrageenan-induced models of local inflammation: relationship to its inhibitory effect on nitric oxide production and its peroxynitrite scavenging activity, J. Pineal Res,
doi:10.1111/j.1600-079x.1997.tb00342.xDavies, Adlimoghaddam, Albensi, The effect of COVID-19 on NF-κB and neurological manifestations of disease, Mol. Neurobiol,
doi:10.1007/S12035-021-02438-2Ding, Fu, Wang, Liu, Wang et al., The complex interplay between autophagy and NLRP3 inflammasome in renal diseases, Int. J. Mol. Sci,
doi:10.3390/IJMS222312766Duan, Guo, Yang, Han, Thakur et al., Modeling COVID-19 with human pluripotent stem cell-derived cells reveals synergistic effects of antiinflammatory macrophages with ACE2 inhibition against SARS-CoV-2, Res. Sq,
doi:10.21203/RS.3.RS-62758/V1El-Sokkary, Omar, Hassanein, Cuzzocrea, Reiter, Melatonin reduces oxidative damage and increases survival of mice infected with Schistosoma mansoni, Free Radic, Biol. Med
Fakhriravari, Jin, Kachouei, Le, Lopez, Systemic corticosteroids for management of COVID-19: saving lives or causing harm?, Int. J. Immunopathol. Pharmacol,
doi:10.1177/20587384211063976Feitosa, Júnior, Neto, Matos, Moura et al., COVID-19: rational discovery of the therapeutic potential of melatonin as a SARS-CoV-2 main protease inhibitor, Int. J. Med. Sci,
doi:10.7150/IJMS.48053Feng, Adeniran, Huang, Li, Ma et al., The ameliorative effect of melatonin on LPS-induced sertoli cells inflammatory and tight junctions damage via suppression of the TLR4/MyD88/NF-κB signaling pathway in newborn calf, Theriogenology,
doi:10.1016/J.THERIOGENOLOGY.2021.11.020Gurunathan, Kang, Choi, Reiter, Kim, Melatonin: a potential therapeutic agent against COVID-19, Melatonin Res,
doi:10.32794/MR11250081Hasan, Atrakji, Mehuaiden, The effect of melatonin on thrombosis, sepsis and mortality rate in COVID-19 patients, Int. J. Infect. Dis,
doi:10.1016/J.IJID.2021.10.012Hasan, Islam, Matsumoto, Kawai, Meta-analysis of single-cell RNAseq data reveals phenotypic switching of immune cells in severe COVID-19 patients, Comput. Biol. Med,
doi:10.1016/J.COMPBIOMED.2021.104792Hazra, Chaudhuri, Tiwary, Chakrabarti, Matrix metallopeptidase 9 as a host protein target of chloroquine and melatonin for immunoregulation in COVID-19: a network-based meta-analysis, Life Sci,
doi:10.1016/J.LFS.2020.118096Heskin, Pallett, Mughal, Davies, Moore et al., Caution required with use of ritonavir-boosted PF-07321332 in COVID-19 management, Lancet,
doi:10.1016/S0140-6736(21)02657-XHosseini, Esmaeili Gouvarchin, Ghaleh, Aghamollaei, Fasihi Ramandi et al., Evaluation of Th1 and Th2 mediated cellular and humoral immunity in patients with COVID-19 following the use of melatonin as an adjunctive treatment, Eur. J. Pharmacol,
doi:10.1016/J.EJPHAR.2021.174193Hu, Li, Wang, Guo, Li et al., Melatonin inhibits endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation in lipopolysaccharide-induced endometritis in mice, Int. Immunopharmacol,
doi:10.1016/j.intimp.2018.08.028Hu, Zhang, Wen, Liu, Cai et al., Melatonin decreases M1 polarization via attenuating mitochondrial oxidative damage depending on UCP2 pathway in prorenin-treated microglia, PLoS One,
doi:10.1371/JOURNAL.PONE.0212138Jauhari, Baranov, Suofu, Kim, Singh et al., Melatonin inhibits cytosolic mitochondrial DNA-induced neuroinflammatory signaling in accelerated aging and neurodegeneration, J. Clin. Invest,
doi:10.1172/JCI135026Khalili, Karamouzian, Nasiri, Javadi, Mirzazadeh et al., Epidemiological characteristics of COVID-19: a systematic review and metaanalysis, Epidemiol. Infect,
doi:10.1017/S0950268820001430Klann, Bojkova, Tascher, Ciesek, Münch et al., Growth factor receptor signaling inhibition prevents SARS-CoV-2 replication, Mol. Cell,
doi:10.1016/J.MOLCEL.2020.08.006Kong, Zhang, Liu, Li, Liu et al., Melatonin attenuates angiotensin II-induced abdominal aortic aneurysm through the down-regulation of matrix metalloproteinases, Oncotarget,
doi:10.18632/oncotarget.15093Kucia, Ratajczak, Bujko, Adamiak, Ciechanowicz et al., An evidence that SARS-Cov-2/COVID-19 spike protein (SP) damages hematopoietic stem/progenitor cells in the mechanism of pyroptosis in Nlrp3 inflammasome-dependent manner, Leukemia,
doi:10.1038/S41375-021-01332-ZLei, Hou, Yu, Zhang, Ndzouboukou et al., Kinetics of neutralizing antibody response underscores clinical COVID-19 progression, J. Immunol. Res,
doi:10.1155/2021/9822706Li, Ying, Cai, Yang, Wu, Exogenous melatonin alleviates hemorrhagic shock-induced hepatic ischemic injury in rats by inhibiting the NF-κB/IκBα signaling pathway, Mol. Med. Rep,
doi:10.3892/MMR.2021.11980Loh, The potential of melatonin in the prevention and attenuation of oxidative hemolysis and myocardial injury from cd147 SARS-CoV-2 spike protein receptor binding, Melatonin Res,
doi:10.32794/mr11250069Luo, Song, Zhang, Zhang, Liu et al., Melatonin mediated Foxp3-downregulation decreases cytokines production via the TLR2 and TLR4 pathways in H. Pylori infected mice, Int. Immunopharmacol,
doi:10.1016/J.INTIMP.2018.08.034Mahase, Covid-19: UK becomes first country to authorise antiviral molnupiravir, BMJ,
doi:10.1136/BMJ.N2697Maldonado, García-Moreno, González-Yanes, Calvo, Possible involvement of the inhibition of NF-κB factor in anti-inflammatory actions that melatonin exerts on mast cells, J. Cell. Biochem,
doi:10.1002/JCB.25491Maldonado, Mora-Santos, Naji, Carrascosa-Salmoral, Naranjo et al., Evidence of melatonin synthesis and release by mast cells. Possible modulatory role on inflammation, Pharmacol. Res,
doi:10.1016/j.phrs.2009.11.014Manik, Singh, Role of toll-like receptors in modulation of cytokine storm signaling in SARS-CoV-2-induced COVID-19, J. Med. Virol,
doi:10.1002/JMV.27405Marqueze, Nogueira, Vetter, Skene, Cipolla-Neto et al., Exogenous melatonin decreases circadian misalignment and body weight among early types, J. Pineal Res,
doi:10.1111/JPI.12750Mayo, Sainz, Antolín, Herrera, Martin et al., Melatonin regulation of antioxidant enzyme gene expression, Cell. Mol. Life Sci,
doi:10.1007/PL00012498Mayo, Sainz, Tan, Hardeland, Leon et al., Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), in macrophages, J. Neuroimmunol,
doi:10.1016/j.jneuroim.2005.05.002Mohapatra, Sarangi, Kandi, Azam, Tiwari et al., Omicron (B.1.1.529 variant of SARS-CoV-2); an emerging threat: current global scenario, J. Med. Virol,
doi:10.1002/JMV.27561Morchang, Malakar, Poonudom, Noisakran, Yenchitsomanus et al., Melatonin inhibits dengue virus infection via the sirtuin 1-mediated interferon pathway, Viruses,
doi:10.3390/V13040659Mousavi, Heydari, Mehravaran, Saeedi, Alizadeh-Navaei et al., Melatonin effects on sleep quality and outcomes of COVID-19 patients: an open-label, randomized, controlled trial, J. Med. Virol,
doi:10.1002/JMV.27312Muxel, Pires-Lapa, Monteiro, Cecon, Tamura et al., NF-κB drives the synthesis of melatonin in RAW 264.7 macrophages by inducing the transcription of the arylalkylamine-Nacetyltransferase (AA-NAT) gene, PLoS One,
doi:10.1371/JOURNAL.PONE.0052010Ouoba, Okimoto, Nagashima, Kitahara, Miwata et al., Sequential dynamics of virological and serological changes in the serum of SARS-CoV-2 infected patients, J. Med. Virol,
doi:10.1002/JMV.27518Pan, Zhang, Su, Wang, Liu, Melatonin balance the autophagy and apoptosis by regulating UCP2 in the LPS-induced cardiomyopathy, Molecules,
doi:10.3390/MOLECULES23030675Pavlovich, Lovett, Koroleva, Guito, Arnold et al., The egyptian rousette genome reveals unexpected features of bat antiviral immunity, Cell,
doi:10.1016/j.cell.2018.03.070Polidoro, Hagan, De Santis, Santiago, Schmidt, Overview: systemic inflammatory response derived from lung injury caused by SARS-CoV-2 infection explains severe outcomes in COVID-19, Front. Immunol,
doi:10.3389/FIMMU.2020.01626Qin, Liu, Sun, Li, Xu et al., Protective effects of melatonin on the white matter damage of neonatal rats by regulating NLRP3 inflammasome activity, Neuroreport,
doi:10.1097/WNR.0000000000001642Ramlall, Zucker, Tatonetti, Melatonin is significantly associated with survival of intubated COVID-19 patients, MedRxiv Prepr. Serv. Heal. Sci,
doi:10.1101/2020.10.15.20213546Ramos, Míguez, Morgado, Sanchez-Correa, Gordillo et al., Melatonin enhances responsiveness to dichelobacter nodosus vaccine in sheep and increases peripheral blood CD4 T lymphocytes and IgG-expressing B lymphocytes, Vet. Immunol. Immunopathol,
doi:10.1016/J.VETIMM.2018.11.006Regeneron, New, Government Agreement to Purchase Additional Doses of REGEN-COVTM (casirivimab and imdevimab) Antibody Cocktail
Reiter, Abreu-Gonzalez, Marik, Dominguez-Rodriguez, Therapeutic algorithm for use of melatonin in patients with COVID-19, Front. Med,
doi:10.3389/FMED.2020.00226Reiter, Sharma, Ma, Liu, Manucha et al., Plasticity of glucose metabolism in activated immune cells: advantages for melatonin inhibition of COVID-19 disease, Melatonin Res,
doi:10.32794/MR11250068Reiter, Tan, Rosales-Corral, Galano, Zhou et al., Mitochondria: central organelles for melatonin's antioxidant and anti-aging actions, Molecules,
doi:10.3390/molecules23020509Ren, Sun, Li, Chen, Ge et al., Exogenous melatonin inhibits neutrophil migration through suppression of ERK activation, J. Endocrinol,
doi:10.1530/JOE-15-0329Ryu, Park, Kim, Lee, Seo et al., SARS-CoV 3CLpro inhibitory effects of quinone-methide triterpenes from tripterygium regelii, Bioorg. Med. Chem. Lett,
doi:10.1016/J.BMCL.2010.01.152Sanchez-Barcelo, Rueda, Mediavilla, Rodriguez-Cue, Reiter, Clinical uses of melatonin in neurological diseases and mental and behavioural disorders, Curr. Med. Chem,
doi:10.2174/0929867324666170718105557Sen, Does serotonin deficiency lead to anosmia, ageusia, dysfunctional chemesthesis and increased severity of illness in COVID-19?, Med. Hypotheses,
doi:10.1016/j.mehy.2021.110627Shukla, Htoo, Wintachai, Hernandez, Dubois et al., Melatonin stimulates the nonamyloidogenic processing of βaPP through the positive transcriptional regulation of ADAM10 and ADAM17, J. Pineal Res,
doi:10.1111/jpi.12200Simpson, Oliver, ROS generation in microglia: understanding oxidative stress and inflammation in neurodegenerative disease, Antioxidants,
doi:10.3390/ANTIOX9080743Szewczyk-Golec, Rajewski, Gackowski, Mila-Kierzenkowska, Wesołowski et al., Melatonin supplementation lowers oxidative stress and regulates adipokines in obese patients on a calorie-restricted diet, Oxidative Med. Cell. Longev,
doi:10.1155/2017/8494107Sánchez-González, Mahíllo-Fernández, Villar-Álvarez, Llanos, What if melatonin could help COVID-19 severe patients?, J. Clin. Sleep Med,
doi:10.5664/JCSM.9554Tan, Chen, Poeggeler, Manchester, Reiter, Melatonin: a potent, endogenous hydroxyl radical scavenger, Endocr. J
Tan, Hardeland, Estimated doses of melatonin for treating deadly virus infections: focus on COVID-19, Melatonin Res,
doi:10.32794/mr11250062Tan, Hardeland, Manchester, Poeggeler, Lopez-Burillo et al., Mechanistic and comparative studies of melatonin and classic antioxidants in terms of their interactions with the ABTS cation radical, J. Pineal Res,
doi:10.1034/J.1600-079X.2003.00037.XTan, Hardeland, Potential utility of melatonin in deadly infectious diseases related to the overreaction of innate immune response and destructive inflammation: focus on COVID-19, Melatonin Res,
doi:10.32794/mr11250052Tan, Manchester, Fuentes-Broto, Paredes, Reiter, Significance and application of melatonin in the regulation of brown adipose tissue metabolism: relation to human obesity, Obes. Rev,
doi:10.1111/j.1467-789X.2010.00756.xTan, Manchester, Terron, Flores, Reiter, One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species?, J. Pineal Res,
doi:10.1111/j.1600-079X.2006.00407.xTan, Ruediger, Targeting host defense system and rescuing compromised mitochondria to increase tolerance against pathogens by melatonin may impact outcome of deadly virus infection pertinent to COVID-19, Molecules,
doi:10.3390/MOLECULES25194410Tan, Zanghi, Manchester, Reiter, Melatonin identified in meats and other food stuffs: potentially nutritional impact, J. Pineal Res,
doi:10.1111/jpi.12152Tan, Zheng, Kong, Manchester, Hardeland et al., Fundamental issues related to the origin of melatonin and melatonin isomers during evolution: relation to their biological functions, Int. J. Mol. Sci,
doi:10.3390/ijms150915858Tesarik, Melatonin attenuates growth factor receptor signaling required for SARS-CoV-2 replication, Melatonin Res,
doi:10.32794/MR11250077Venkatraja, Srilakshminarayana, Kumar, The dominance of severe acute respiratory syndrome coronavirus 2 B.1.617 and its sublineages and associations with mortality during the COVID-19 pandemic in India between 2020 and 2021, Am. J. Trop. Med. Hyg,
doi:10.4269/AJTMH.21-0812Wang, Chen, Zhang, Deng, Lian et al., CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells, Signal Transduct,
doi:10.1038/s41392-020-00426-xXu, Wang, Ai, Shi, Zhang et al., Melatonin suppresses TLR9-triggered proinflammatory cytokine production in macrophages by inhibiting ERK1/2 and AKT activation, Sci. Rep,
doi:10.1038/S41598-018-34011-8Zhai, Wang, Jiao, Zhang, Li et al., Melatonin and other indoles show antiviral activities against swine coronaviruses in vitro at pharmacological concentrations, J. Pineal Res,
doi:10.1111/JPI.12754Zhang, Karam, Glycemic profile of intravenous dexamethasone-induced hyperglycemia using continuous glucose monitoring, Am. J. Case Rep,
doi:10.12659/AJCR.930733Zhang, Li, Grailer, Wang, Wang et al., Melatonin alleviates acute lung injury through inhibiting the NLRP3 inflammasome, J. Pineal Res,
doi:10.1111/jpi.12322Zhou, Hou, Shen, Huang, Martin et al., Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2, Cell Discov,
doi:10.1038/s41421-020-0153-3Zhou, Hou, Shen, Mehra, Kallianpur et al., A network medicine approach to investigation and population-based validation of disease manifestations and drug repurposing for COVID-19, PLoS Biol,
doi:10.1371/JOURNAL.PBIO.3000970Zlacká, Stebelová, Zeman, Herichová, Interactions of renin-angiotensin system and COVID-19: the importance of daily rhythms in ACE2, ADAM17 and TMPRSS2 expression, Physiol. Res,
doi:10.33549/PHYSIOLRES.934754
