With cases skyrocketing across the United States, scientists are hard at work exploring all possible options for COVID-19 prevention and treatment.
In April 2020, we published our first article on the promising research surrounding melatonin. Three months later, we wanted to share an update on what the scientific world has learned since then.
In July 2020, researchers from Cleveland Clinic published their results from an observational study. Looking at 18,118 patients from a COVID-19 registry, researchers found that taking melatonin was associated with a 64% reduced likelihood of having a positive test result for SARS-CoV-2 (the virus that causes COVID-19). This was after the researchers had adjusted for age, sex, race, and underlying illnesses (1).
These results are observational only; they do not prove that taking melatonin supplements can reduce the likelihood of getting COVID-19. Furthermore, since this study is still in pre-print, it has not yet been peer-reviewed.
Still, the results are compelling, especially given the growing number of scientific articles advocating for melatonin use in prevention and treatment.
When we published our initial article on melatonin research and COVID-19 in April, there were only 4 related scientific articles listed on PubMed®. At the time of publishing this article, there are 26, with more articles coming out weekly.
Here are some of the main reasons why scientists think melatonin may be advantageous for COVID-19 prevention and treatment:
One of the key things that makes SARS-CoV-2 so dangerous is its ability to attach to a special receptor called Angiotensin Converting Enzyme 2 (ACE2). Because the ACE2 receptors are present in many of our cells, it provides SARS-CoV-2 the possibility of attacking multiple organs and different types of cells throughout our bodies.
Melatonin isn’t a ‘virucidal’ (meaning that it doesn’t kill viruses or stop them from replicating directly), but it does indirectly influence ACE2 expression (2, 3). Excitingly, it may have the ability to help block viral attachment to the ACE2 receptors — although researchers caution that these findings have to be reproduced and validated in clinical trials (4).
The dreaded ‘cytokine storm’ has gotten a lot of publicity regarding COVID-19 complications. During a cytokine storm, the body mounts a massive inflammatory response in an effort to fight the virus. Unfortunately, this excessive inflammatory response can do more harm than good, leading the immune cells to attack healthy tissue and cells and creating free radical damage. In severe cases, it can lead to organ failure and death.
Produced in the mitochondria of every cell (as well as in the pineal gland), melatonin is one of the body’s foremost tools for fighting free radical damage. In addition, melatonin has strong anti-inflammatory properties, helping lower cytokines levels in the body. For these reasons, it’s thought that melatonin supplementation could help reduce the severity of a cytokine storm and mitigate its free radical damage (5).
Some researchers suggest that melatonin supplementation could be helpful for elderly individuals who do not produce enough melatonin on their own.
Many physiological functions are regulated by the circadian rhythm. This includes our immune system (which explains why so many people get sick when they sleep poorly). Research indicates that the disruption of the circadian rhythm can increase viral replication and worsen inflammation in patients with viral infections (6, 7).
One of melatonin’s key roles is to regulate our circadian rhythm. In clinical trials, melatonin supplementation has been successful in re-establishing circadian rhythm (e.g. jet lag)(8). This feature could make melatonin supplementation especially effective in hospital settings, where light at night, noise, and periodic waking to administer medications and food can further disrupt a patient’s circadian rhythm (7).
Studies have already linked melatonin supplementation with shortened ICU stay and improved sleep quality, so it’s possible that these benefits could extend to COVID-19 patients as well (9).
While no one is immune from catching SARS-CoV-2, certain populations are clearly at higher risk than others. COVID-19 disproportionately affects the elderly and those with pre-existing health issues like high blood pressure, diabetes, and obesity.
As we’ve discussed in previous articles, melatonin levels significantly decrease with age (10). Reduced melatonin levels are also strongly associated with aging and other age-related diseases. For these reasons, some researchers believe that melatonin supplementation could be particularly useful for those who are unable to produce enough melatonin.
Melatonin supplementation could also be a helpful adjunct for some underlying health issues. For instance, a 2011 meta‐analysis of double‐blind, placebo‐controlled randomized trials (RCTs) found that patients who took 2-5 mg of melatonin per night experienced a significant reduction in blood pressure (11).
Perhaps the most compelling case for melatonin is that, compared to many drugs, it has a very high safety profile over a large range of doses (from 1 to 1000 mg). Melatonin also is relatively inexpensive, easy to administer, and can be used as an adjuvant to other treatments and medications.
While researchers have made their case for why melatonin supplementation theoretically makes sense for COVID-19 patients, the clinical data is still quite limited. Here are the studies we’ve found so far:
One small-scale trial from the Manila Doctors Hospital in the Philippines gave high doses of melatonin to patients with COVID-19 symptoms (12). The study only included 10 patients, but it did find some promising results. All 10 of the patients given high doses of melatonin recovered, did not require mechanical ventilation, and were released from the hospital within an average of 8.6 days.
In comparison, of the COVID-19 patients who were admitted to the hospital during the same period of time (and did not receive melatonin supplementation), 35% died, 20% required ventilation, and the average release time for those who recovered was 13 days.
This small study wasn’t double-blinded and did not have an exact control group. Still, it is interesting to note that – other than sleepiness – the researchers did not find any side effects from using melatonin.
At the time of publishing this article, another study from Spain is also underway (13). This one focuses on providing melatonin to health care workers at risk for SARS-CoV-2 exposure (as a preventive measure). This particular study is utilizing 2 mg of melatonin per day before bedtime over a 12-week period. Given the doses suggested by other researchers, we wonder if this dose might be too low to provide significant results, but we will have to see.
As compelling as the research is to date, we still do not have sufficient clinical data on melatonin usage for COVID-19. Even so, some researchers have been passionately advocating for the administration of melatonin to COVID-19 patients already now. They argue that waiting until further research has been completed could be unethical, given the immediate need for treatment options and melatonin’s strong safety record.
Consider this quote from a review published in International Reviews of Immunology (14):
To date, there is no established optimal melatonin dose for older adults. However, one group of researchers (led by Russel Reiter, PhD, a melatonin pioneer) did provide some suggested numbers for certain groups of people:
For elderly adults with pre-existing conditions, Reiter et al suggested taking 3-10 mg of melatonin between 30 to 60 minutes before bedtime. Of course, taking melatonin was suggested in addition to following other scientifically-proven measures (such as covering one’s nose and mouth, washing hands frequently, social distancing, etc.)(10).
For healthcare workers at high risk of SARS-CoV-2 exposure, Reiter et al wrote that “40 mg or higher would not seem an inappropriate amount” (10). They recommended that healthcare workers take their melatonin 60 minutes before bedtime, along with employing safe work practices (e.g. handwashing, wearing PPE).
If a person is already ill, higher doses of melatonin may be necessary. In clinical contexts, Reiter et al suggested using between 100 to 400 mg of melatonin (10), although other doses have been proposed, too. For instance, one doctor in Texas reported seeing good results for his patients with 80 mg of melatonin, while the small-scale study in the Philippines used between 36 to 72 mg of melatonin.
In all of these instances, researchers are recommending melatonin as an adjunct to regular treatments, not by itself.
Bo and I have spent the last two decades specializing in the field of omega-3s. So why are we writing about melatonin? For those of you who have faithfully used our Omega Cure® oil for years, you may not be aware that we have another product called Omega Restore. Omega Restore uses Omega Cure as its base, and we infuse the oil with vitamin D3 and melatonin.
I point this out because I want to be transparent that we have an interest in melatonin, and I realize that this interest can influence our interpretation of the data. With that being said, it is hard to read these research articles and not want to share them.
We started adding melatonin to our Omega Cure oil because we saw a clear benefit for our customers, and we wanted to make those benefits available to more people at no extra cost. Over the years, we’ve observed that when melatonin is combined with vitamin D3 in our Omega Cure oil, it appears to have a more powerful effect than taking melatonin alone. Our belief is that the omega-3s seem to activate the melatonin and may be important for vitamin D metabolism, too. Both our own research and the studies we’ve read point to this synergy between omega-3s, melatonin and vitamin D.
Though we still have much to learn about COVID-19 and melatonin, we feel hopeful about the results that have come out so far. Keep safe, keep well, and we encourage everyone to take a deeper dive into the references below.
1. Zhou, Y., Hou, Y., Shen, J., Kallianpur, A., Zein, et al. (2020). A Network Medicine Approach to Investigation and Population-based Validation of Disease Manifestations and Drug Repurposing for COVID-19. ChemRxiv: The Preprint Server for Chemistry, 10.26434/chemrxiv.12579137.v1.
2. Zhang, R., Wang, X., Ni, L., Di, X., Ma, B., Niu, S., Liu, C., & Reiter, R. J. (2020). COVID-19: Melatonin as a Potential Adjuvant Treatment. Life Sciences, 250, 117583.
3. Zhou, Y., Hou, Y., Shen, J. et al. (2020). Network-Based Drug Repurposing for Novel Coronavirus 2019-nCoV/SARS-CoV-2. Cell Discovery, 6, 14.
4. Jehi, L., Ji, X., Milinovich, A., Erzurum, S., Rubin, B., Gordon, S., Young, J., & Kattan, M. W. (2020). Individualizing Risk Prediction for Positive COVID-19 Testing: Results from 11,672 Patients. Chest, S0012-3692(20): 31654-8.
5. Reiter, R. J., Sharma, R., Ma, Q., Dominquez-Rodriguez, A., Marik, P. E., & Abreu-Gonzalez, P. (2020). Melatonin Inhibits COVID-19-induced Cytokine Storm by Reversing Aerobic Glycolysis in Immune Cells: A Mechanistic Analysis. Medicine in Drug Discovery, 6, 100044.
6. Anderson, G. & Reiter, R. J. (2020). Melatonin: Roles in influenza, Covid‐19, and Other Viral Infections. Reviews in Medical Virology, 30:e2109.
7. Sengupta, S., Tang, S. Y., Devine, J. C., Anderson, S. T., et al. (2019). Circadian Control of Lung Inflammation in Influenza Infection. Nature Communications, 10(1), 4107.
8. Arendt, J. (2019). Melatonin: Countering Chaotic Time Cues. Frontiers in Endocrinology, 10: 391.
9. Zambrelli, E., Canevini, M., Gambini, O., & D’Agostino, A. (2020). Delirium and Sleep Disturbances in COVID-19: A Possible Role for Melatonin in Hospitalized Patients? Sleep Medicine, 70, 111.
10. Reiter, R. J., Abreu-Gonzalez, P., Marik, P. E., & Dominguez-Rodriguez, A. (2020). Therapeutic Algorithm for Use of Melatonin in Patients With COVID-19. Frontiers in Medicine, 7, 226.
11. Borghi, C., & Cicero, A. F. (2017). Nutraceuticals with a Clinically Detectable Blood Pressure-Lowering Effect: A Review of Available Randomized Clinical Trials and Their Meta-Analyses. British Journal of Clinical Pharmacology, 83(1), 163–171.
12. Castillo, R.R., Quizon, G.R.A., Juco, M.J.M., Roman, A.D.E., de Leon, D.G., et al. (2020). Melatonin as Adjuvant Treatment for Coronavirus Disease 2019 Pneumonia Patients Requiring Hospitalization (MAC-19 PRO): A Case Series. Melatonin Research, 3(3), 297-310.
13. García, I. G., Rodriguez-Rubio, M., Mariblanca, A. R., de Soto, L. M., García, L. D. et al. (2020). A Randomized Multicenter Clinical Trial to Evaluate the Efficacy of Melatonin in the Prophylaxis of SARS-CoV-2 infection in High-Risk Contacts (MeCOVID Trial): A Structured Summary of a Study Protocol for a Randomised Controlled Trial. Trials, 21(1), 466.
14. Shneider, A., Kudriavtsev, A., & Vakhrusheva, A. (2020). Can Melatonin Reduce the Severity of COVID-19 Pandemic? International Reviews of Immunology, 39:4, 153-162.