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Melatonin — A Standard of Treatment Adjunct for Acute Infections?

According to a June 2020 research paper, melatonin may be an important adjunct toCOVID-19 treatment. Incidentally, while not emphasized, melatonin is an optionaladdition to the highly effective MATH+ protocol promoted by the Front Line COVID-19Critical Care Working Group (FLCCC).

Melatonin — A Standard of Treatment Adjunct for Acute Infections?

President Trump's COVID-19 treatment was also said to include melatoninsupplementation. The authors note that melatonin attenuates several pathologicalfeatures of the illness, including excessive infiammation, oxidation and an exaggeratedimmune response resulting in a cytokine storm and acute lung injury (ALI), acuterespiratory distress syndrome (ARDS) and, potentially, death.

"Melatonin, a well-known anti-infiammatory and anti-oxidative molecule, isprotective against ALI/ARDS caused by viral and other pathogens,"

theresearchers state, adding:

"Melatonin is effective in critical care patients by reducing vessel permeability,anxiety, sedation use, and improving sleeping quality, which might also bebeneficial for better clinical outcomes for COVID-19 patients.Notably, melatonin has a high safety profile. There is significant data showingthat melatonin limits virus-related diseases and would also likely be beneficialin COVID-19 patients."

One of the things that makes melatonin so effective is that it doesn't just act as anantioxidant in and of itself; it also interacts with your body's innate antioxidant systemwhere it recharges glutathione.

High-Dose Melatonin to Combat COVID-19

A recent case series published in the journal Melatonin Research details how patientshospitalized with COVID-19 pneumonia who were given high-dose melatonin as anadjunct therapy to standard of care all improved within four to five days, and allsurvived.On average, those given melatonin were discharged from the hospital after 7.3 days,compared to 13 days for those who did not get melatonin. This is far better than theexpensive treatment remdesivir, which costs over $3,000 and doesn't produce anywherenear this improvement.

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However, the patients were given very large doses of melatonin, 36 mg to 72 mg per dayin four divided doses. When used for sleep, you'd typically start with a dose of 0.25 mgand work your way up as needed.Dr. Richard Neel and colleagues at Little Alsace and Uvalde Urgent Care clinics in Texasare also using high-dose melatonin in combination with vitamin C and vitamin D, andhad as of the last week of July 2020 successfully treated more than 400 patients.

Because of melatonin's potent antioxidant and anti-inflammatory activities, it would normally reduce thehighly proinflammatory cytokine storm and neutralizethe generated free radicals thereby preserving cellularintegrity and preventing lung damage. ~ Medical DrugDiscoveries June 2020

"I knew that nothing would work for everyone, but it is working for the majority. It isamazing what melatonin is doing for most patients," Neel told Kayleen Holder, editor ofDevine News.

Melatonin Inhibits COVID-19-Induced Cytokine Storm

Another paper, published in June 2020 in the journal Medical Drug Discoveries,describes the mechanics by which melatonin inhibits the cytokine storm associated withcritical SARS-CoV-2 infection. As explained by the authors:

"A causative factor related to the hyper-infiammatory state of immune cells istheir ability to dramatically change their metabolism. Similar to cancer cells …immune cells such as macrophages/monocytes under infiammatory conditionsabandon mitochondrial oxidative phosphorylation for ATP production in favor ofcytosolic aerobic glycolysis (also known as the Warburg effect) …
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The change to aerobic glycolysis allows immune cells to become highlyphagocytic, accelerate ATP production, intensify their oxidative burst and toprovide the abundant metabolic precursors required for enhanced cellularproliferation and increased synthesis and release of cytokines …Because of melatonin's potent antioxidant and anti-infiammatory activities, itwould normally reduce the highly proinfiammatory cytokine storm andneutralize the generated free radicals thereby preserving cellular integrity andpreventing lung damage."

Melatonin Plays Important Roles in Mitochondrial Function

Importantly, the Medical Drug Discoveries paper points out that while melatonin wasinitially thought to be exclusively synthesized in the pineal gland, researchers have nowdemonstrated that it is actually synthesized in mitochondria, which means melatoninproduction occurs in most cells, including human lung monocytes and macrophages.For those of you who might be familiar with melatonin, this is quite surprising as it hasbeen commonly accepted for the past 50 years that the sole source of melatonin wasthe pineal gland. This is quite an amazing breakthrough to find out it is actuallyproduced in the mitochondria, which are in every cell in your body except your red bloodcells.In healthy cells, melatonin synthesis in mitochondria occurs when the glucosemetabolite pyruvate enters the mitochondria. Glucose is a six-carbon molecule and isdivided into two three-carbon molecules of pyruvate. Once the pyruvate is inside themitochondria, it is subsequently metabolized into acetyl-coenzyme A.Presumably, a low-carb, high-fat diet that produces large amounts of ketones shouldprovide similar benefits as the ketones are directly metabolized to acetyl-coenzyme A.As explained in the Medical Drug Discoveries paper:

"In the absence of acetyl-coenzyme A, mitochondrial melatonin is no longeravailable to combat the infiammatory response or to neutralize the generated
reactive oxygen species and the massive damage that occurs in the respiratorytree resulting in the primary signs of COVID-19 disease.Importantly, endogenous melatonin production diminishes markedly with ageespecially in frail older individuals. This is consistent with the more seriousnature of a COVID-19 infection in the elderly."

Other research, including a Frontiers of Bioscience paper published in 2007, haspointed out that melatonin helps prevent mitochondrial impairment, energy failure andapoptosis (programmed cell death) in mitochondria damaged by oxidation.Melatonin may even help regulate gene expression via certain enzymes, and helpsregulate autophagy in certain pathological conditions. According to the authors, "Mostof the beneficial consequences resulting from melatonin administration may depend onits effects on mitochondrial physiology."

Melatonin Helps Protect Against Sepsis

Sepsis (blood poisoning) is another common outcome of an unhealthy immuneresponse to infection, and melatonin may play an important role in preventing this aswell. Evidence for this can be found in a Journal of Critical Care paper published in2010. According to the authors:

"Melatonin is an effective anti-infiammatory agent in various animal models ofinfiammation and sepsis, and its anti-infiammatory action has been attributedto inhibition of nitric oxide synthase with consequent reduction of peroxynitriteformation, to the stimulation of various antioxidant enzymes thus contributingto enhance the antioxidant defense, and to protective effects on mitochondrialfunction and in preventing apoptosis.In a number of animal models of septic shock, as well as in patients with septicdisease, melatonin reportedly exerts beneficial effects to arrest cellular damageand multiorgan failure …
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Apart from action on the local sites of infiammation, melatonin also exerts itsbeneficial actions through a multifactorial pathway including its effects asimmunomodulatory, antioxidant and antiapoptotic agent."

In summary, melatonin appears to reverse septic shock symptoms by:Decreasing synthesis of proinfiammatory cytokinesPreventing lipopolysaccharide (LPS)-induced oxidative damage, endotoxemia andmetabolic alterationsSuppressing gene expression of the bad form of nitric oxide, inducible nitric oxidesynthase (iNOS)Preventing apoptosis (cell death)More recently, a 2019 animal study in the journal Frontiers in Immunology details howmelatonin can protect against polymicrobial sepsis, i.e., sepsis caused by more thanone microbial organism. A hallmark of polymicrobial sepsis is severe loss oflymphocytes through apoptosis, resulting in a twofold higher lethality than unimicrobialsepsis (sepsis caused by a single microbe).In this case, melatonin appears to offer protection by having an antibacterial effect onwhite blood cells called neutrophils. A high neutrophil count is an indicator for infection.According to the authors of the 2019 study:

"Melatonin treatment inhibited peripheral tissue infiammation and tissuedamage … consequently reducing the mortality of the mice. We found thatmacrophages and neutrophils expressed melatonin receptors.Upon depletion of neutrophils, melatonin-induced protection againstpolymicrobial infection failed in the mice, but melatonin treatment inmacrophage-depleted mice attenuated the mice mortality resulting frompolymicrobial sepsis …The data from this study support previously unexplained antiseptic effects ofmelatonin during a polymicrobial infection and could be potentially useful for 20 21 22 23  human patients with sepsis."

Melatonin's Antiviral Effects

The scientific review paper, "Melatonin Potentials Against Viral Infections IncludingCOVID-19: Current Evidence and New Findings," published October 2020 in the VirusResearch journal, also summarizes the many potential mechanisms by which melatonincan protect against and ameliorate viral infections.The authors review research looking at melatonin's beneficial effects against a variety ofviruses, including respiratory syncytial virus, Venezuelan equine encephalitis virus, viralhepatitis, viral myocarditis, Ebola, West Nile virus and dengue virus. Based on thesecollective findings, they believe melatonin may offer similar protection against SARS-CoV-2.One mechanistic basis for this relates to melatonin's effects on p21-activated kinases(PAKs), a family of serine and threonine kinases. They explain:

"In the last decade, PAKs have acquired great attention in medicine due to theircontribution to a diversity of cellular functions. Among them, PAK1 isconsidered as a pathogenic enzyme and its unusual activation could beresponsible for a broad range of pathologic conditions such as aging,infiammation, malaria, cancers immunopathology, viral infections, etc.In a recent study conducted by Oh (2016), 'Chloroquine' (CQ) (anantimalarial drug used as an experimental medication in COVID-19 treatmentprotocol) was found to increase the expression of p21 that was downregulatedby PAK1 in Th1 cells.Furthermore, Lu and colleagues have shown that phosphatase and tensinhomolog (PTEN), a tumor-suppressing phosphatase, may prevent thecoronavirus-induced Ag II-pathological vascular fibrosis through inactivation ofPAK1.
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Interestingly, melatonin exerts a spectrum of important anti-PAK1 properties insome abnormal conditions such as sleep disturbance, immune systemeffectiveness reduction, infectious disorders, infiammation, cancer, painfulconditions, etc.It has been proposed that coronaviruses could trigger CK2/RAS-PAK1-RAF-AP1signaling pathway via binding to ACE2 receptor. Although it is not scientificallyconfirmed as yet, PAK1-inhibitors could theoretically exert as potential agentsfor the management of a recent outbreak of COVID-19 infection.Indeed, Russel Reiter, a leading pioneer in melatonin research, has recentlyemphasized that melatonin may be incorporated into the treatment of COVID-19as an alternative or adjuvant."

Melatonin for Viral Infections Including COVID-19

In summary, "Melatonin Potentials Against Viral Infections Including COVID-19: CurrentEvidence and New Findings" and other research referenced in the list below suggestsmelatonin may play an important role in SARS-CoV-2 infection by:Regulating immune responses and preventing cytokine stormsQuelling infiammation and suppressing oxidative stressCombating viral and bacterial infectionsRegulating blood pressure (a risk factor for severe COVID-19)Improving metabolic defects associated with diabetes and insulin resistance (riskfactors for severe COVID-19) via inhibition of the renin-angiotensin system (RAS)Protecting mesenchymal stem cells (MSCs, which have been shown to amelioratesevere SARS-CoV-2 infection) against injuries and improving their biologicalactivities

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Promoting both cell-mediated and humoral immunityPromoting synthesis of progenitor cells for macrophages and granulocytes, naturalkiller (NK) cells and T-helper cells, specifically CD4+ cellsInhibiting NLRP3 infiammasomes

Melatonin — A Possible Vaccine Adjuvant?

Lastly, "Melatonin Potentials Against Viral Infections Including COVID-19: CurrentEvidence and New Findings" discusses the potential of using melatonin as a vaccineadjuvant, nothing that:

"Even if [a COVID-19] vaccine would be established, vaccine eficacy is probablyconsidered to be inferior for the elderly and other high-risk population groupscompared to people who are healthy and young. The immune responses tovaccines have been shown to be limited in the aforementioned groups becauseof a weakened immune system.Therefore, using immunomodulatory agents such as melatonin as an effectiveadjuvant besides vaccination may boost the vaccine's effectiveness in patientswith both compromised and healthy immune systems.As above-mentioned, melatonin is capable of enhancing the count of naturalkiller and CD4+ cells and amplifying the production of cytokines needed foreffective vaccine response. Furthermore, sleep deprivation weakens immuneresponse to viral infection, and melatonin has been proved to be a critical factorin improving sleep quality."

Melatonin Works Synergistically With Vitamin D

Interestingly, a paper published in the May 2020 issue of The Journal of SteroidBiochemistry and Molecular Biology stresses the synergistic effects between melatonin

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and vitamin D. Not only does melatonin enhance vitamin D signaling, the two moleculesact synergistically to optimize your mitochondrial function.I've written many articles detailing the importance of vitamin D optimization to preventSARS-CoV-2 infection and more serious COVID-19 illness. The evidence for this isfrankly overwhelming, and raising vitamin D levels among the general population may beone of the most important prevention strategies available to us. To learn more, pleasedownload my vitamin D report, available for free on According to theauthors of this May 2020 paper:

"A deficiency of these molecules has been associated with the pathogenesis ofcardiovascular diseases, including arterial hypertension, neurodegenerativediseases, sleep disorders, kidney diseases, cancer, psychiatric disorders, bonediseases, metabolic syndrome, and diabetes, among others.During aging, the intake and cutaneous synthesis of vitamin D, as well as theendogenous synthesis of melatonin are remarkably depleted, therefore,producing a state characterized by an increase of oxidative stress,infiammation, and mitochondrial dysfunction …Mitochondrial dysfunction has been related to the etiologies of many complexdiseases where overactivation of the renin-angiotensin-aldosterone system(RAAS), vitamin D deficiency and the reduction of melatonin synthesisconverge.In this sense, experimental and clinical evidence indicates that infiammation,oxidative stress, as in mitochondrial dysfunction, are consistent with low levelsof melatonin and vitamin D, and also represent risk factors connected with development and maintenance of prevalent acute and chronic pathologies."

Simple Ways to Optimize Your Melatonin and Vitamin D

While there are likely many benefits to supplementing with oral vitamin D3 andmelatonin, it makes no sense to do so unless you also optimize your body's own


production.The good news is it's relatively simple and inexpensive to increase your melatonin andvitamin D levels. To optimize your vitamin D, I recommend getting sensible sun exposureon large portions of your body on a regular basis, ideally daily.If for whatever reason you cannot get suficient amounts of sun exposure, considertaking a vitamin D3 supplement (along with a little extra vitamin K2 to maintain ahealthy ratio between these two nutrients, and magnesium to optimize vitamin Dconversion).I personally have not taken any oral vitamin D for well over 10 years and my levels aretypically over 70 ng/mL, even in the winter, but as I am now older than 65, I have startedtaking sublingual melatonin even though I sleep in pitch dark and get bright sunexposure around 85% of the time during the day.Optimizing your melatonin production starts with getting plenty of bright sunlight duringthe day, as this helps "set" your circadian clock. Then, as the evening wears on and thesun sets, you'll want to avoid bright lighting.Blue light from electronic screens and LED light bulbs is particularly problematic andinhibits melatonin the most. If you need lighting, opt for incandescent light bulbs,candles or salt lamps. The blue light from electronic screens can be counteracted byinstalling blue-blocking software such as Iris, or wearing blue-blocking glasses.My decision to personally use melatonin supplementation makes even more sense nowthat we understand that melatonin is not only produced in the pineal gland (which wouldbenefit from circadian optimization), but also in our mitochondria. So, it appears thatadditional melatonin could serve as a useful adjunct in modulating your immuneresponse.

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