A recent review suggests that melatonin may play a role in combating COVID-19 as an adjuvant therapy; excessive inflammation, oxidation, and exaggerated immune responses during infection contributes to the cytokine storm that progresses into acute lung injury and acute respiratory distress syndrome and the antioxidant, anti-inflammatory, and immunomodulating effects of melatonin have been shown to be protective against viral induced ALI and ARDS. (1)

Research indicates nucleotide similarity between SARS-COVs, MERS-CoVs and SARS-CoV02 which suggests a high genetic homology. With infection severe inflammatory and immune response may activate a cytokine storm such as apoptosis of epithelial cells and endothelial cells leading to vascular leakage and abnormal T-cell and macrophage responses that could induce ALI/ARDS and even death. This storm appears to be prevalent in those with COVID-19 based on genetic homology and pathologic features of infected lungs, and in the blood there is a marked increase of inflammatory markers IL-1B, IFN-y, IP-10, MCp-1, IL-4 and Il-10. Those with COVID-19 also present with suppressed immune function that is marked by hypo-albuminemia, lymphopenia, neutropenia, and a decreased percentage of CD8+ T-cells. The excessive inflammation, depressed immunity, and cytokine storm appear to contribute to the pathogenesis of COVID-19. (1,2,3,6)

Due to the antiviral, antioxidant, and immune enhancing properties melatonin has been shown to help reduce viremia, paralysis, and death in mice infected with encephalitis and it has led to the downregulation of acute lung oxidative injury, proinflammatory cytokine release and inflammatory cell recruitment in respiratory syncytial virus models. Findings support possible use of melatonin in treatment of viral diseases, additionally the actions of melatonin support has potential attenuation for COVID-19 infection.(1,4,5)

The anti-inflammatory effects are exerted through various pathways such as suppressing NF-kB activation in ARDS and downregulating NF-kN activation in T-cells and lung tissues. It also stimulates NF-E3 related factor 2 which is important in protecting against lung, liver, and cardiovascular injury. Melatonin has been shown to help reduce production of the cytokines and chemokines TNF-a, IL-1B, IL-6, and IL-8 which are involved in inflammation. (1,9,10,11)

NLRP3 is part of the innate immune response during lung infection that is activated by viruses to amplify inflammation. It is correlated to lung disease caused by infection and melatonin has been shown to be efficacious at inhibiting NLRP3 mediated lung injury by reducing inflammation of macrophages and neutrophils in lung tissues. (1,7,8)

Melatonin enhances immune response by improving proliferation and maturation of natural killer cells, T and B lymphocytes, granulocytes and monocytes; in macrophages antigen presentation is augmented after the application of melatonin including the upregulation of complement receptor 3, MHC class I and class II, as well as CD4 antigens. (1,12)

Although there are no studies related to the use of melatonin in the treatment of COVID-19 its use has been shown to be promising in other diseases with increased levels of inflammation. Doses of 5 mg/d and 25 mg/d have been shown to decrease serum levels of IL-6, TBF-a, and hs-C reactive protein in those with diabetes mellitus and periodontitis, as well as promoting reductions in serum concentrations of TNF-a, IL-6, IL-1B and lipoproteins with MS. Melatonin intake of 5-10 mg/d has also been shown to decrease many of the same inflammatory cytokines that are being seen in COVID-19. (1,13,14,15)

Even at higher doses the short term use of melatonin has been deemed safe, but while their safety has been verified in human studies its effects when given to those with COVID-19 remains unknown and should be monitored closely.

Animal models and human studies have continuously documented the efficacy and safety of melatonin. Those with viral infection or those dealing with inflammation based chronic conditions possible may benefit from melatonin. Thus melatonin testing could reveal the baseline status of this anti-inflammatory and immune modulating hormone to provide a framework for its supplementation.