The Italian magazine Evolutamente recently published a well-researched article exploring the link between melatonin and COVID-19, pneumonia and inflammation. It’s a compelling article so let’s take a look at the key argument and see why melatonin could be so important.

Melatonin and Health

Melatonin is a hormone produced by the pineal gland during the hours of darkness to usher the initiation of sleep, and peaks at around 2 a.m. Its production is reduced when we are exposed to light during the night, such as when watching TV or looking at other electronic screens late at night. Melatonin production is also compromised in jet lag, shift workers, and non-24 sleep-wake disorder.

The role of melatonin in our health is extensive. It is a potent free radical scavenger and antioxidant, protecting DNA and other molecules from injury. It therefore has a significant anti-cancer effect [1,2] and the ability to protect against premature aging and other diseases related to oxidative stress, such as cardiovascular disease and type 2 diabetes [3].

Not only is melatonin a powerful antioxidant, it is also anti-inflammatory through modulation of cytokines. In particular, it has been found to be protective against activation of inflammasomes – specifically, the NLRP3 inflammasome [4]. Inflammasomes are intracellular components that are responsible for inducing the secretion of proinflammatory cytokines, which are part of the body’s inflammatory response against infection and injury.

COVID-19 and Inflammasomes

While the release of proinflammatory cytokines is part of the body’s normal defense mechanism, in the case of viral infections it can also mediate and enhance the spread of the infection throughout the body. As the article in Evolutamente points out, cytokines are “dangerous double-edged swords exploited by coronaviruses”. The reason why COVID-19 is so deadly is because it can induce a very severe acute pneumonia, which is particularly dangerous in people least able to withstand such an infection because of weakened lungs or compromised immunity. And the activation of the NLRP3 inflammasome is a key mediator of the acute respiratory distress that is characteristic of COVID-19 infection. Melatonin’s ability to inhibit activation of this inflammasome could therefore be a key to its potential importance in the war against COVID-19.

Melatonin and Age

It has been widely observed that children are not as susceptible to the most severe aspects of COVID-19 as older people, although they can still become infected and transmit the virus. The risk of dying from COVID-19 seems to increase starting at age 40 and going up significantly over 70 (see https://www.worldometers.info/coronavirus/coronavirus-age-sex-demographics/). This somewhat mirrors, in reverse, the age-related decline in melatonin production. A 1988 study found that during the first 6 months of life serum night-time melatonin production was low (mean 27.3 pg/mL), but it increased to a peak value at 1-3 years old (mean 329.5 pg/mL) and then declined later in childhood, correlating negatively with body size increase (mean 62.5 pg/mL at age 15-20). It then showed a progressive, but moderate decline until age 70-90 (29.2 pg/mL) [5]. While this does not exactly track the rise in COVID-19 severity with age, it could be a big factor in the natural protection that very young children appear to have against the virus.

Assessing Melatonin and Supplementing

Regarding supplementing with melatonin, this can be a controversial issue. Excessive supplementation results in sleepiness during the following day. Clinical studies have shown promising results in lowering oxidative stress markers with doses ranging from 10-20 mg/day [6,7] and the evidence shows that it has few adverse effects [8]. A review of dosages ranging up to 50 mg/day used in older adults (age 55 and over) suggested avoiding excessive dosing that resulted in supraphysiological levels and instead to use the lowest dose possible to mimic normal production in people with disordered circadian rhythms [9]. A prolonged-release formulation giving 2 mg/day has been used successfully to treat primary insomnia and poor sleep quality [10]. A typical dose for an over-the-counter supplement to help with sleep is 1-3 mg/day, but your doctor may be able to help with appropriate dosing for protection against oxidative stress.

For those who want to check the adequacy of their melatonin production, ZRT Laboratory includes dried urinary diurnal testing of the melatonin metabolite MT6s in our Sleep Balance profile, our Advanced Metabolites Profile, and can be added on to our Neurotransmitter testing; and we also offer first morning saliva melatonin in our LCMS Saliva Steroid Profile. But we can all help ourselves to more melatonin naturally by getting adequate sleep, ensuring that we don’t expose ourselves to bright light late in the evening and keep our bedroom as dark as possible during the night, and try to be asleep during the hours of darkness (not good news for those “night owls”!)

References

1. Hill SM, et al. Melatonin: an inhibitor of breast cancer. Endocr Relat Cancer. 2015;22:R183-204.
2. Sigurdardottir LG, et al. Sleep disruption among older men and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev. 2013;22:872-9.
3. Ulhôa MA, et al. Shift work and endocrine disorders. Int J Endocrinol. 2015;2015:826249.
4. Favero G, et al. Melatonin as an Anti-Inflammatory Agent Modulating Inflammasome Activation. Int J Endocrinol. 2017;2017:1835195.
5. Waldhauser F, et al. Alterations in nocturnal serum melatonin levels in humans with growth and aging. J Clin Endocrinol Metab. 1988;66:648-52.
6. Raygan F, et al. Melatonin administration lowers biomarkers of oxidative stress and cardio-metabolic risk in type 2 diabetic patients with coronary heart disease: A randomized, double-blind, placebo-controlled trial. Clin Nutr. 2019;38:191-196.
7. El-Sharkawy H, et al. Is dietary melatonin supplementation a viable adjunctive therapy for chronic periodontitis?-A randomized controlled clinical trial. J Periodontal Res. 2019;54:190-197.
8. Foley HM, Steel AE. Adverse events associated with oral administration of melatonin: A critical systematic review of clinical evidence. Complement Ther Med. 2019;42:65-81.
9. Vural EM, et al. Optimal dosages for melatonin supplementation therapy in older adults: a systematic review of current literature. Drugs Aging. 2014;31:441-51.
10. Hajak G, et al. Lasting treatment effects in a postmarketing surveillance study of prolonged-release melatonin. Int Clin Psychopharmacol. 2015;30:36-42.