Melatonin and COVID-19

A new use for an over-the-counter sleep aid?

Posted Nov 24, 2020

Researchers at the Cleveland Clinic recently reported that patients who were taking melatonin had a nearly 30 percent lower likelihood of testing positive for SARS-CoV-2, the virus producing COVID-19, and this reduction was even greater (30-52 percent) in those who were African American (1). 

These findings seem robust, allowing for variables such as presence of other diseases, age, and smoking history. It is a good example of ‘network medicine’, using large databases of electronic health records and biological data, and also of exploring the repurposing of substances which are already available. Although randomized, placebo-controlled studies will need to be done before we can speak with any certainty, it raises the possibility that an easily available substance might potentially lower the risk of infection. It seems like a good time, then, to look over what we know about melatonin, how it is currently used, and its possible benefits and risks.

 'Understanding Sleeping Pills' (reference 2), with permission from the author/copyright holder.
Interaction of the pineal gland and the SCN in the release of melatonin.
Source: From W.B. Mendelson: 'Understanding Sleeping Pills' (reference 2), with permission from the author/copyright holder.

Melatonin is a hormone, secreted by the pineal gland at the back of the brain when the body’s master timekeeper in the hypothalamus (the ‘SCN’) senses that it is dark outside and that it is nighttime (2). Melatonin circulates throughout the body, giving a signal that it is nighttime; one of the places it affects is the SCN itself, where it binds to specialized receptors and reduces its drive to wakefulness (2). For some decades, researchers have explored whether melatonin might be useful in treating various disorders related to sleep. It is not an FDA-approved medicine, but it is sold over-the-counter as a food additive, and is often purchased as a sleep aid. The global market for melatonin in 2016 was in the area of $851 million, and it has been estimated that it will rise to about $1.5 billion by 2021 (3).  

Melatonin has been used successfully in some sleep conditions involving disorders of the body clock, including delayed sleep phase syndrome and non-24-hour sleep wake cycle. In contrast, its benefits in insomnia, which is not due to body clock disorders, are much less clear. Though some individuals express enthusiasm based on their personal experience, its effects have mostly been very modest in systematic placebo-controlled studies (2). Large reviews of all studies meeting basic scientific criteria have tended to find that in insomnia, the time it takes to fall asleep is shortened on average by about seven minutes, while total sleep time may be increased by about eight minutes (4,5). It is not included in the recommended medicines for insomnia in the guidelines of the American Academy of Sleep Medicine. It continues to be studied for other disorders, however, for instance possibly treating delirium or potentially reducing the damage to nerve cells caused by stroke.

There are a number of concerns about self-administering melatonin. Since it is sold over-the-counter, there is much less oversight of the manufacturing process compared to FDA-approved medicines. One study of 31 Canadian products (before it was prohibited there for over-the-counter use) found that the amount of melatonin was actually anywhere from -83% to 478% of what the label showed, and other unlabeled substances have often been found (6). Even when the dosage is known, it can have a wide range of side effects. Up to 20 percent of persons taking it describe drowsiness, and some have headaches or dizziness. Research studies suggest that taking melatonin near mealtimes in either morning or evening impairs the body’s ability to process glucose, leading to higher glucose levels, suggesting to the researchers that melatonin should only be taken at least two hours after a meal (7). A recent case history paper described melatonin-induced facial swelling in an oncology patient, and reviewed reports of the rare occurrence of difficulty swallowing and breathing, and peripheral swelling and flushes, in persons taking it for jet lag (8). Melatonin also affects the reproductive organs and reduces fertility in a variety of animals, although whether this is true in humans continues to be studied. Melatonin also can interact with a variety of medicines including some for birth control, blood thinning, and diabetes.

In summary, one intriguing study has found an association between taking melatonin and a lower rate of positive tests for coronavirus. It is important to remember that this is a statistical association, and does not show that one thing causes the other; randomized placebo-controlled studies will be needed before we could have any confidence that melatonin helps prevent COVID-19. There is also much we do not know, for instance the dosage, formulation, or duration of administration. Melatonin is available without prescription as a food additive; for this reason it is manufactured without the scrutiny for quantity and purity which would be required of an FDA-approved drug. It can have a variety of side effects and can interact with other medicines. Until we learn more about these issues, it is prudent to consult a physician about the decision of whether to take it.

Portions of this article are adapted from Understanding Sleeping Pills.

References

1. Zhou, Y. et al.: A network medicine approach to investigation and population-based validation of disease manifestations and drug repurposing for COVID-19 PLoS Biology, November 6, 2020.   https://doi.org/10.1371/journal.pbio.3000970   See also: Cleveland Clinic Consult QD, 11/13/20: Melatonin a Promising Candidate for Prevention and Treatment of COVID-19. https://consultqd.clevelandclinic.org/melatonin-a-promising-candidate-for-prevention-and-treatment-of-covid-19/

3. Mikulic, M.: Total global melatonin supplements market size 2016 and 2021. Statista, Feb. 7, 2019.

https://www.statista.com/statistics/967361/total-melatonin-supplements-market-size-globally/

4. Ferracioli-Oda, E; Qawasmi, G; Bloch, M.H.: Meta-analysis: melatonin for the treatment of primary sleep disorders. PLoS One. May 17, 2013: e63773  DOI: 10.1371/journal.pone.0063773

5. Buscemi, N. et al.: The efficacy and safety of exogenous melatonin for primary sleep disorders: a meta-analysis. J. Gen. Intern. Med. 20: 1151-1158, 2005. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1490287/

6. Erland LA, Saxena PKMelatonin natural health products and supplements: presence of serotonin and significant variability of melatonin content. J Clin Sleep Med; 2017;132:275-281.

7. Rubio-Sastre, P. et al.: Acute melatonin administration in humans impairs glucose tolerance in both the morning and evening. Sleep 37: 1715-1719, 2014.

8. Patel, R.C. et al.: Melatonin-Associated Facial Swelling in an Oncology Patient: Case Report and Review of Swelling of the Face in Individuals With Head and Neck Cancer. Cureus. 2020 Oct; 12(10): e10866. Published online 2020 Oct 9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652014/