Melatonin and COVID-19: More Studies Emerging That Melatonin Is Useful As An Adjuvant Treatment For COVID-19 Due to Its Anti-Inflammatory Properties.

Melatonin and COVID-19: Another study by researchers from Peking Union Medical College in China and the University of Texas- San Antonio in America have in a new peer-reviewed finding that is published in the journal: Life Sciences By Science Direct, propose that Melatonin should be incorporated as an adjuvant treatment for COVID-19 as it has proven mechanisms to target Inflammasomes that triggers cytokine storms and ARDS (Acute Respiratory Disease Syndrome) caused by the SARS-CoV-2 coronavirus. https://www.sciencedirect.com/science/article/pii/S0024320520303313#!

Thailand Medical News had already covered about the potential usage of Melatonin supplements for COVID-19 in an article dated May 10 from materials gathered from an independent researcher Messrs Doris Loh. https://www.thailandmedical.news/news/breaking-covid-19-supplements-melatonin-helps-lessen-severity-risk-in-covid-19-patients-by-preventing-cytokine-storms
 
Melatonin (N-acetyl-5-methoxytryptamine) is a bioactive molecule with an array of health-promoting properties; melatonin has been successfully used to treat sleep disorders, delirium, atherosclerosis, respiratory disease and viral infections https://www.melatonin-research.net/index.php/MR/article/view/71
 
Past research has documented the positive effects of melatonin in alleviating acute respiratory stress induced by virus, bacteria, radiation, etc. https://www.hindawi.com/journals/omcl/2019/4087298/ and https://onlinelibrary.wiley.com/doi/abs/10.1111/jpi.12020 and https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-079X.2009.00733.x
 
In this new study, the researchers focused on finding evidence indicating that melatonin will have supportive adjuvant utility in treating COVID-19 induced pneumonia, acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).
 
Melatonin is not viricidal but it has indirect anti-viral action due to its anti-inflammation, anti-oxidation and immune enhancing features.  https://www.cell.com/iscience/pdf/S2589-0042(19)30510-3.pdf?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2589004219305103%3Fshowall%3Dtrue  and https://onlinelibrary.wiley.com/doi/full/10.1002/rmv.1714 and https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.24130  and https://jou rnals.physiology.org/doi/abs/10.1152/physiol.00034.2019
 
Melatonin exerts anti-inflammatory effects through various pathways. Sirtuin-1 (SIRT1) may mediate the anti-inflammatory actions of melatonin by inhibiting high mobility group boxechromosomal protein 1 (HMGB1), and thus down-regulating the polarization of macrophages towards the pro-inflammatory type.
 
In sepsis-induced ALI, the proper regulation of SIRT1 attenuates lung injury and inflammation, in which the application of melatonin might be beneficial. Nuclear factor kappa-B (NF-κB) is closely associated with pro-inflammatory and pro-oxidative responses while being an inflammatory mediator in ALI. The anti-inflammatory effect of melatonin involves the suppression of NF-κB activation in ARDS. Melatonin reportedly down-regulate NF-κB activation in T cells and lung tissue. The stimulation of NF-E2-related factor 2 (Nrf2) is crucial in protecting lung from injury. In related studies, melatonin induces the up-regulation of Nrf2 with therapeutic effects in hepatoprotection, cardioprotection,etc
 
The anti-oxidative effect of melatonin cooperates with its anti-inflammatory actions by up-regulating anti-oxidative enzymes (e.g. superoxide dismutase), down-regulating pro-oxidative enzymes (e.g. nitric oxide synthase), and it may also interact directly with free radicals, functioning as free radical scavenger. Viral infections and their replication constantly generate oxidized products. In a SARS-induced ALI model, the production of oxidized low density lipoprotein activates innate immune response by the overproduction of IL-6 alveolar macrophages via Toll-like receptor 4 (TLR4)/NF-kB signaling, thereby leading to ALI. TLR4 is a receptor for the innate immune system, and it is also a therapeutic target for melatonin. In brain ischemia, gastritis and periodontitis disease models, melatonin has documented anti-inflammation actions via TLR4 signaling. The anti-oxidative effect of melatonin has also been confirmed in ALI caused by radiation, sepsis and ischemia-reperfusion. In ALI/ARDS patients, especially when the disease is advanced and in patients treated in intense care units (ICUs), severe inflammation, hypoxemia and mechanical ventilation with high oxygen concentrations inevitably increases oxidant generation locally and systematically.
 
Melatonin exerts regulatory actions on the immune system and directly enhances the immune response by improving proliferation and maturation of natural killing cells, T and B lymphocytes, granulocytes and monocytes in both bone marrow and other tissues. In macrophages, antigen presentation is also augmented after the application of melatonin, where the up-regulation of complement receptor 3, MHC class I and class II, and CD4 antigens were detected.
 
NOD-like receptor 3 (NLRP3) inflammasome is part of the innate immune response during lung infection. The pathogen, including a virus (CoVs has not yet been tested), triggers NLRP3 activation to amplify the inflammation. There is probably a balance of the protective and damaging actions of NLRP3 in the lung. Thus, in a mouse experiment, inhibition of NLRP3 in the early phase of infection increased mortality, whereas suppression of NLRP3 at the peak of infection allowed for a protective effect. This supports the use of melatonin in ALI/ARDS when inflammation is most severe. Inflammasome NLRP3 is correlated to lung diseases caused by infection, including influenza A virus, syncytial virus, and bacteria.

The efficacy of melatonin in regulating NLRP3 has been proven in radiation-induced lung injury, allergic airway inflammation and oxygen-induced ALI and LPS-induced ALI models, in which melatonin reduced the infiltration of macrophages and neutrophils into the lung in ALI due to the inhibition of NLRP3 inflammasome.
 
Melatonin ability to reduce cytokine levels has been demonstrated in many situations. In a randomized controlled trial, 8-week oral intake of 6 mg/d melatonin caused a significant decrease in serum levels of IL-6, TNF-α and hs-C-reactive protein (hs-CRP) in patients with diabetes mellitus and periodontitis  https://link.springer.com/article/10.1007/s10787-018-0539-0
 
In another trial of patients suffering with severe multiple sclerosis, orally 25 mg/d of melatonin for 6 months also promoted a significant reduction in serum concentrations of TNF-α, IL-6, IL-1β and lipoperoxides https://www.sciencedirect.com/science/article/abs/pii/S0188440918305514?via%3Dihub
 
In the acute phase of inflammation, including during surgical stress, brain reperfusion, and coronary artery reperfusion, melatonin intake of 10 mg/d, 6 mg/d and 5 mg/d of melatonin for less than 5 days induced a reduced level of pro-inflammatory cytokines. A recent meta-analysis of a total of 22 randomized controlled trials suggested that a supplementary use of melatonin is associated with a significant reduction of TNF-α and IL-6 level https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-079X.2007.00545.x
https://onlinelibrary.wiley.com/doi/abs/10.1111/jpi.12521
https://journals.lww.com/md-journal/Fulltext/2018/07270/Effects_of_N_acetyl_cysteine_and_melatonin_on.12.aspx
https://link.springer.com/article/10.1007%2Fs00394-019-02123-0
 
All this clinical evidence suggests that the use of melatonin as a supplement may effectively reduce the levels of circulating cytokines, and may potentially also lower pro-inflammatory cytokine levels in COVID-19 patients.
 
The new study showed that Melatonin had beneficial effects such as anti-inflammation, anti-oxidation, immune response regulation to prevent the cytokine storms that could result in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) and could also ameliorate septic shock via the NLRP3 pathway.
 
Compared to the more expensive drugs being touted by the pharma giants to prevent cytokine storms in COVID-19, melatonin which is a not-patented supplement is a much more cheaper and cost-effective drug.
 
For more on Melatonin and COVID-19, keep on logging to Thailand Medical News.
 
Note: Readers are not to start taking melatonin supplements without consulting a licensed doctor. If you think you have COVID-19, immediately report to the nearest health authorities or hospitals to have a test done and for a doctor to evaluate your health condition and to start necessary treatments. Merely taking melatonin by yourself can be fatal as certain individuals with underlying health conditions should not take melatonin. Also never self-treat, always consult a doctor

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