Most of us have heard of, or even occasionally used the supplement melatonin. It is the most popular over-the-counter sleep remedy in the US, resulting in sales in excess of US $400 million during 2017.
Melatonin is a hormone that is primarily released by the pineal gland in the brain and helps to regulate the body’s sleep–wake cycle. As a supplement, it is often used for the short-term treatment of sleep troubles that can result from jet lag or shift work. Notably, melatonin has a high safety profile. It appears to cause very few side effects as tested in the short term, up to three months, at low doses.
In addition to its role as a sleep cycle regulator, melatonin is a potent antioxidant and free radical scavenger. Melatonin also promotes the expression of several important antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase, glutathione reductase, and catalase. It is this role, as a super antioxidant, that brings melatonin into the discussion of how to manage Covid-19.
Excessive inflammation, oxidation, and an exaggerated immune response very likely contribute to Covid-19 pathology. This leads to a cytokine storm and subsequent progression to acute lung injury /acute respiratory distress syndrome (ARDS) and often death. Melatonin has been shown to be protective against ARDS caused by viral and other pathogens. This is likely due to melatonin’s effects on inflammasomes, a critical part of our innate immunity. As part of the innate immune system, inflammasomes play an important role in the induction of inflammatory cascades and coordination of host defenses, via the activation and secretion of pro-inflammatory cytokines (chemokines, interferons, interleukins, lymphokines, and tumor necrosis factors).The overproduction of these cytokines and chemokines contributes to the development of severe disease.
The evidence suggests that melatonin may exert two distinctly different types of effects in Covid-19, each depending on dose and disease severity.
The NOD-like receptor 3 (NLRP3) inflammasome is part of the innate immune response that occurs during lung infection, including influenza A virus, syncytial virus, and bacteria. The innate immune response is a very old (by evolutionary standards) set of tools that activates when the body comes into contact with foreign invaders. Unlike the more sophisticated cytotoxic (immune cells that kill) and humoral (antibodies that clump or tag) immunities, innate defenses rely on recognizing molecular patterns known to be associated with bad microbes. These patterns trigger toll-like receptors (TLRs) which then activate a variety of inflammatory cascades in response, including the NLRP3 inflammasome.
Viral pathogens trigger NLRP3 activation to amplify the inflammation. The efficacy of melatonin in regulating NLRP3 has been proven in radiation-induced lung injury, allergic airway inflammation and several forms of induced lung injury. In these, melatonin reduced the infiltration of macrophages and neutrophils into the injured lung due to its inhibition of NLRP3 inflammasome.
There is probably a balance of the protective and damaging actions of NLRP3 in the lung. In mouse experiments, inhibiting NLRP3 in the early phase of infection increased mortality, whereas suppression of NLRP3 at the peak of infection allowed for a protective effect. This may imply that the best use of high-dose melatonin is in the acute lung injury /ARDS stage, when inflammation is most severe.
In addition to being a potent antioxidant, melatonin may have direct antiviral effects against COVID-19. In healthy people, melatonin levels plummet after the age of 40 years. In addition to falling antioxidant levels, this may partly explain the increased risk of death in patients with COVID-19 who are over the age of 40.
Melatonin indirectly regulates ACE2 expression, a key entry receptor involved in viral infection of human coronaviruses, including 2019-nCoV/SARS-CoV-2.Specifically, melatonin was reported to inhibit a calcium-binding protein (calmodulin) which interacts with ACE2 by inhibiting shedding of its ectodomain (the part of a membrane protein that extends into the extracellular space), a key infectious process of SARS-CoV-2.
Melatonin may play an important role in both the prevention and adjunct treatment of Covid-19.
This may be a dose-dependent set of responses: Melatonin being beneficial in prevention /early stage treatment in low doses (3-6 mg /day) and helpful for the management of lung injury/ ARDS in higher doses (20-40mg day).
Melatonin can also have indirect benefits in the management of critical care patients by reducing vessel permeability, anxiety, sedation use, and improving sleeping quality, all of which might also be beneficial for better clinical outcomes for COVID-19 patients.
Melatonin is safe, and commercially available melatonin from reliable manufacturers will possess superior purity. In addition, it is a very reasonably priced dietary supplement that should be affordable by almost anybody. For active prevention, a very low dose (3mg taken nightly) should provide significant antioxidant benefits and may help insure a restful night’s sleep.
And who couldn’t use that?