COVID-19 Supplements: Melatonin Helps Lessen Severity Risk by Preventing Cytokine Storms
While there has been many over blown claims by the unscrupulous, there are also many medical benefits that are often not extolled because of intense lobbying by the big pharmaceutical companies that have government and health authorities in their pockets along with greedy and unethical doctors who will come out to dispute any benefits of supplement despite supporting studies as they prefer to peddle the overpriced drugs for their hefty commissions and benefits.
In drug repurposing studies for COVID-19 studies, many suitable cheaper drugs and supplements have emerged from various studies as suitable candidates either as antivirals or to treat the cytokines storms associated with the disease or even other symptoms such as clotting issues. However many of these suitable candidates are often left on the shelves as the patents have expired or there are no patents on them hence the pharmaceutical giants are not motivated to have these further explored as they are unable to profit from them.
In the case of preventing cytokine storms in COVID-19 patients, there have been many cheaper drug options as suitable candidates for further study such as colchicine, melatonin, and many more. In this article which is part of a series of articles that Thailand Medical News will be presenting to readers, we will be focusing on Melatonin as a suitable drug candidate to prevent Cytokine Storms in those infected with COVID-19.The big pharmaceuticals prefer to push expensive drugs like Tocilizumab that currently costs around $1,030 per injection and a patient might be needing like 2 to 3 injections whereas a bottle of decent 600mg of melatonin tablets might only cost about $20.
Already there were past studies that demonstrated that Melatonin acts as a anti-inflammatory agent. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001216/ and https://www.nature.com/articles/s41419-019-1556-7 and https://www.researchgate.net/publication/325772786_Antiinflammatory_effects_of_Melatonin_A_mechanistic_review and https://www.spandidos-publications.com/mmr/17/4/6122/abstract
A percentage of COVID-19 patients often develop acute respiratory distress syndrome and acute lung injury (ARDS/ALI). The uncontrolled progressive inflammation in the lungs causes acute diffuse alveolar damage recognized as areas with ground-glass opacities, and other areas with increased density but without any recognizable vessels.
As ARDS progress to the acute phase, alveolar flooding (edema), interstitial inflammation and compression atelectasis, as well as increase in lung tissue and reduction in lung gas volume are observed .COVID-19 patients suffering from ARDS/ALI often require intubation and invasive mechanical ventilation to assist difficulty in breathing because the increasing hypoxemic respiratory failure results in acute diffuse alveolar damage.
ARDS or Acute respiratory distress syndrome and ALI or acute lung injury are often characterized by the accumulation of neutrophils in the lungs and the increased production of inflammatory cytokines, chemokines, proteases and oxidants. The initiation and development of ARDS/ALI is dependent upon the activation of inflammasomes.
Inflammasomes are an integral part of our innate immune system. Inflammasomes sense pathogens, danger associated molecular patterns (DAMPs) as well as biological crystals including urate and cholesterol. The activation of inflammasomes releases proinflammatory cytokines interleukin (IL)‑1β and IL‑18. Recently, the NLRP3 inflammasome has been identified as key to the induction of ADRS/ALI . Interleukin 1 beta (IL-1β) is a potent proinflammatory cytokine that is implicated in the pathogenesis of acute respiratory distress syndrome because the initiation of hypoxemia (low oxygen levels in blood) is induced by IL-1β signaling. The production of IL-1β is tightly controlled and is dependent upon NLRP3 inflammasome activation. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172370/#b15-mmr-18-05-4399 and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4061751/ and https://link.springer.com/article/10.1186/s12974-017-1051-y and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930947/
Melatonin is well known for its chronobiotic effects, regulating biological functions tied to circadian rhythms. Numerous studies have revealed that melatonin exerts effects beyond the control of circadian oscillators. The NLRP3 inflammasome is now recognized as a target for melatonin!
The fact that the pro-inflammatory cytokine storm effects are induced by the activation of NLRP3 inflammasomes, the ability of melatonin to INHIBIT NLRP3 inflammasome elevates this powerful molecule to a truly unique position in the fight against COVID-19. This also means that if a patient, regardless of age, has adequate melatonin, the infectiousness of COVID-19 will be greatly reduced, and the chances of developing ARDS/ALI significantly diminished.
Melatonin is the reason why children under the age of 9 seldom exhibit severe symptoms. In fact, children may exhibit mild or even no symptoms at all, even though they have been infected by SARS-CoV-2 https://www.cdc.gov/coronavirus/2019-ncov/faq.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-ncov%2Fprepare%2Fchildren-faq.html
Normally for most individuals peak melatonin production is between the hours of 2 am to 3 am. The maximum melatonin levels measured in healthy adults between the ages of 65 to 70 years appeared to be around 49.3 picograms/ml (pg/ml). Adults more than 75 years of age only have maximum production levels of 27.8 pg/ml . https://pubmed.ncbi.nlm.nih.gov/27302542-physiological-melatonin-levels-in-healthy-older-people-a-systematic-review/
However young children, on the other hand, have extremely high melatonin levels, compared to adults. The maximum levels recorded for children showed a decline as age increased. Children between the ages of 1 to 5 had peak melatonin at 325 pg/ml, while those between the ages of 5 to 11 already declined to 133 pg/ml . https://pubmed.ncbi.nlm.nih.gov/6141425-fall-in-nocturnal-serum-melatonin-during-prepuberty-and-pubescence/
When compared to healthy adult seniors, a young child can easily have TEN TIMES the amount of peak melatonin levels. But even then, the actual physiological concentration is extremely low. What is the amount of one picogram:
To give one some an idea, most melatonin supplements are around 3 to 5 mg per capsule or tablet. One milligram equals 1,000,000,000 picograms. That is why the physiological dosage generally recommended for melatonin supplementation is around 0.3 milligram https://pubmed.ncbi.nlm.nih.gov/15649738-melatonin-as-a-hypnotic-pro/
The significant fact that young children have such high melatonin levels explains why kids show very mild symptoms after COVID-19 infections.
Melatonin Inhibits NLRP3 Inflammasomes
Sometimes called the 'night hormone', the ability of melatonin to regulate both pro- as well as anti-inflammatory cytokines in different pathophysiological conditions has only been extensively studied in the recent years.
In hospitals, controlling cytokine storms is one of the major challenges in the treatment of sepsis. The NLRP3 inflammasome has an interesting nickname of “Pandora’s Box for Sepsis”. Yet nature provides all the solutions to difficult health challenges. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294171/
It has been found that NLRP3 inflammasomes is a direct target of melatonin. Animal models of sepsis showed melatonin’s ability to maintain mitochondrial homeostasis, reduce reactive oxygen species and lower production of proinflammatory cytokines. Melatonin was shown to inhibit NLRP3 inflammasomes in mice with myocardial septic conditions, transforming severe myocardial inflammation into milder symptoms, preventing cardiac failure, and significantly enhanced survival rates of septic rodents. https://onlinelibrary.wiley.com/doi/abs/10.1111/jpi.12410 and https://link.springer.com/article/10.1007%2Fs00395-015-0526-1
An excellent study by Volt et al (2016) showed that chronic low doses of melatonin in aged mice could prevent increase in inflammation, ROS and mitochondria impairments reflective of inflammaging. Volt et al. also showed that acute administration of melatonin could counteract severe inflammatory responses. https://link.springer.com/article/10.1007%2Fs11357-011-9267-8 and https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-079X.2006.00416.x
Hence it not surprising to find that melatonin is able to prevent ARDS/ALI through suppression of NLRP3 inflammasomes. In rodent acute lung injury (ALI) models, melatonin was found to markedly reduce pulmonary injury, lower infiltration of macrophages and neutrophils into lungs. Melatonin protected mice from acute lung injuries by inhibiting the activation of NLRP3 inflammasomes through the suppression of extracellular release of histones and blocking histone-induced NLRP3 inflammasome activation. In rodent models of acute respiratory distress syndrome (ARDS), combined treatment of melatonin and mitochondria significantly attenuated progression of ARDS. https://onlinelibrary.wiley.com/doi/10.1111/jpi.12199
Melatonin Also Protects Lung Injury From Mechanical Ventilation Interventions
COVID-19 patients with ARDS/ALI often require intubation with mechanical ventilation. Even though the intervention may help patients, in many instances, patients develop ventilator-induced lung injury as a result of mechanical ventilation. In particular, high ventilation pressures and high tidal volumes required to maintain proper oxygenation and CO2 elimination can cause lung damage and impair gas exchange. https://jamanetwork.com/journals/jama/fullarticle/2762996
A research finding released on March 6, 2020 by Geng-Chin Wu et al. demonstrated that by increasing melatonin with the use of a melatonin receptor agonist, damaging effects of ventilator-induced lung injury could be prevented in rodent models. https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-020-1325-2
The full therapeutic potential of melatonin in its ability to modulate the immune system, especially the critical function of suppressing cytokine storms to prevent progression of acute respiratory distress syndrome (ARDS) and respiratory failure in infected patients was clearly demonstrated in a study by Huan]g et al. (2019). Huang et al. infected rodents with the highly lethal and infectious H1N1 influenza A virus. Co-treatment of these infected rodents with melatonin and an antiviral drug significantly increased their survival rates compared to mice treated only with antivirals alone [88]!
It is because of Melatonin that none of the pregnant mothers infected by COVID-19 admitted to Zhongnan Hospital of Wuhan University, Wuhan, China, developed severe pneumonia or died; nor were their babies infected by COVID-19 as Melatonin secretion in the third trimester of pregnancy is more than doubled compared to the first trimester. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30360-3/fulltext
A Simple Guide For Supplementing With Melatonin For COVID-19
Kindly note that the following is NOT MEDICAL ADVICE. Please consult a licensed doctor regarding COVID-19 treatment, especially if one has medical conditions like Cardiovascular Disease, High Blood Pressure,Diabetes, Respiratory diseases, Autoimmune disease and Cancer.
Melatonin Maintenance Dosages During COVID-19 Crisis
Exogenous intake during COVID-19 is recommended only because normal endogenous production for adults may not be adequate for protection against COVID-19. Children under nine are protected from COVID-19 because they have up to TEN TIMES the ‘normal’ amount of adults. Our high tech environment, light pollution at night have already vastly diminished the normally low level of melatonin in adults. Supplementing with a minimum physiological dose during COVID-19 pandemic can provide additional protection against infections.
Typically, adults without major health challenges should take no more than the physiological dosage recommended below.
The suggested dosage is a range. The higher end of the range applies to people who are older or have slightly weaker health. So if you are a young healthy adult, you may require no more than the lowest physiological dose of 0.2 mg.
Physiological dose: 0.2 milligram to 0.5 milligram per day
Only take melatonin at night, about 1 to 2 hours before sleep and 2 to 3 hours after your last meal. You should ideally finish eating before it is dark.
It is also extremely helpful if you can lower your ambient lighting at night, as the lowest amount of light will disrupt melatonin production. Melatonin is produced in all cells, including mitochondria, not just in pineal glands. https://www.mdpi.com/2071-1050/11/22/6400/htm
Dosage Upon COVID-19 Infection
If you suspect infection, notify health authorities in charge and your doctor or hospital immediately. If you are self-quarantined at home, the following dosage applies.
Melatonin COVID-19 Infection Dosage: 5 milligrams to 50 milligrams
The lower range is for individuals with mild or no symptoms. The higher range is for older individuals or those with more severe symptoms.
Those taking ACE inhibitors, or have cardiac conditions or hypertension need to consult your doctor before taking high doses of melatonin. Note that melatonin may lower blood pressure and cause hypotension at higher dosages.
The correct infection dose should ideally be divided into daytime and nighttime doses.
Daytime – 40% of total daily dose, divided into small equal portions to be taken every TWO HOURS.
Nighttime – 60% of total daily dose, divided into two portions taken 2-3 hours after dinner.
The final dose at night should be completed by 10 pm the latest. If one is diabetic, or have insulin resistance, DO NOT TAKE MELATONIN before 3 pm. Melatonin is able to suppress insulin. Please note that the oral dosage higher than physiological concentration is applicable during infections only. Supplementation of high dose melatonin MUST BE SUPPORTED by ascorbic acid. You may not experience full benefits of melatonin in the absence of ascorbic acid.
