Using Melatonin to Fight COVID-19

Coronaviruses are RNA viruses that infect both humans and animals with their main focus of damage on the respiratory, gastrointestinal, and central nervous systems (Cui et al., 2019). They cause the common cold and the novel SARS-CoV-2 or “COVID-19” infection.

You may have also learned that we’ve faced adversity before during multiple coronavirus epidemics: Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) which have caused thousands of deaths in their own right.

The outbreak in Wuhan, China certainly rocked our world in 2020, and although antiviral therapy, corticosteroid therapy, and mechanical respiratory support have been applied to treat those infected, there is a lack of targeted treatments for COVID-19 (Huang et al., 2020) which actually works. Hence, there is a TON of interest in finding resources already available to us which can both prevent the infection and accelerate its recovery process. And one of those is the Anti-inflammatory Melatonin, the hormone released by the pineal gland inside of the brain which regulates our sleep–wake cycle.

Melatonin (scientific name N-acetyl-5-methoxytryptamine) is a bioactive molecule with a wide variety of health-promoting properties. There is unquestionable evidence today which indicates that melatonin is critical for both supporting optimal human physiology, for preventing and fighting infections, like COVID-19.

What’s the Rationale for Melatonin Use?

Based on genetic homology and pathologic features of the infected lung, most scientists agree that the cytokine storm likely rages on in patients infected with COVID-19. Read more about that in a previous post.

What I see all the time in practice is now being confirmed in the scientific literature. Recent studies highlight that in some COVID-19 patients (although being negative for the viral nucleic acid test), can still present with marked inflammation. This is why we see that clinical trials which use certolizumab pegol (a powerful tumor necrosis factor (TNF) cytokine blocker), along with other anti-virus therapies, have beneficial effects in COVID-19 patients.

Thus, excessive inflammation, depressed immune system function, and an activated cytokine storm all substantially contribute to the pathogenesis of COVID-19 and serious consequences from infection.

In the beginning stages of coronavirus infections, dendritic cells and epithelial cells are altered of the encroaching infection and pump out a cluster of pro-inflammatory cytokines and chemokines including IL-1β, IL-2, IL-6, IL-8, both IFN-α/β, TNF, CeC motif chemokine 3 (CCL3), CCL5, CCL2, and IP-10, etc.

Once more, these are under complete control of the immune system, and overproduction of these cytokines and chemokines contributes to the development of disease (Cheung et al., 2005; Law et al., 2005; Chu et al., 2016). Our body is doing the damage with the molecules produced above.

Note, IL-10, produced by T-helper-2 (Th2), is actually a helpful cytokine we want because it is antiviral, but it appears that an infection of coronaviruses leads to a decrease in this cytokine (Chien et al., 2006; Fehr et al., 2016). Interestingly, COVID-19 patients can have a rise in the level of IL-10 floating around (Huang et al., 2020); whether this is a hallmark of COVID-19 infection or the result of medical treatment is to be determined.

In theory, the amplification of the inflammatory response would drive cellular apoptosis or necrosis of the affected cells, which would further intensify inflammation, followed by increasing permeability of blood vessels and the aberrant accumulation of inflammatory monocytes, macrophages, and neutrophils in the lung alveoli (Channappanavar et al., 2016).

Bottom line: The vicious cycle intensifies the situation as the regulation and balance of immune response is lost and the cytokine storm is further activated. This results in dire consequences.

The cytokine storm pathology associated with coronaviruses is well supported by experimental SARS-CoV models. In fact, one research team found that the severity of ALI was accompanied with an increased expression of inflammation-related genes rather than increased viral titers (Channappanavar et al., 2016).

This means that the virus was less damaging than the cytokines made by immune cells. Talk about some power we possess! And in another report, the elimination of IFN-α/β receptors or the depletion of inflammatory monocytes/macrophages lead to a significant rise in the survival rate of coronaviruses host without a change in viral load (Smits et al., 2010).

Both of the aforementioned situations point to a potential amplifying mechanism involved in CoV-induced ALI/ARDS, regardless of the viral load. If a similar pathology also exists in COVID-19, which it likely does, then the attenuation of the cytokine storm by targeting several key steps in the process could bring about improved outcomes. This is where melatonin comes in.

How Melatonin Works

Melatonin possesses anti-inflammatory action through various pathways. Let’s start with Sirtuin-1, which is a member of a protein family that functions in the cellular response to inflammatory, metabolic, and oxidative stressors. If your body senses danger, Sirtuin-1 (or SIRT1) is activated and goes in to assess the chemical damage.

SIRT1 is one of the hallmark proteins in the body; it engages with your mitochondria and regulates the expression of genes key for ATP generation and proliferation. SIRT1 also increases mitochondrial biogenesis—the process by which cells increase mitochondrial mass—, thereby contributing to increased healthy life-span and reducing aging-related diseases (Yuan et al., 2016). It’s a protein you want hanging around, especially if you have increased inflammation!

This protein appears to mediate the anti-inflammatory effect of melatonin by inhibiting a protein called HMG-1 (or high-mobility group box 1 protein), which is secreted by immune cells like macrophages, monocytes, and dendritic cells. HMG-1 is a nuclear protein that organizes the DNA and regulates transcription (Klune et al., 2008). Thus, SIRT1, with the help of melatonin, downregulates the polarization of macrophages towards the pro-inflammatory type (Hardeland, 2018).

In sepsis-induced acute lung injury (ALI), the “proper” regulation of SIRT1 reduces lung injury and inflammation, and the application of melatonin adds to the therapeutic effect of SIRT1 (Wang et al., 2019). We know that SIRT1 plays a key role in chronic inflammation, and its expression and protein levels are reduced in several common (and chronic) inflammatory diseases in the U.S., including arterial inflammation, obesity, and Alzheimer’s disease (Hadar et al., 2017)

Nuclear factor kappa-B (NF-κB) is another essential pathway, and if there is anything you take away from this blog (besides the benefit of melatonin), it’s that we want to turn off NF-κB as much as we possibly can.

Granted, the influence that NF-κB has on cell survival is an ever-evolving story; it can be neuroprotective or proinflammatory, depending on cell type, developmental stage, and pathological state (Qin et al., 2007), but this is beyond the scope of this post. For this discussion, NF-κB is generally (and closely) associated with pro-inflammatory and pro-oxidative responses, while at the same time being an inflammatory mediator in ALI. The anti-inflammatory effect of melatonin involves the suppression of NF-κB activation in acute respiratory distress syndrome (ARDS) (Sun et al., 2015; Ling et al., 2018). Melatonin downregulates NF-κB activation in T cells and lung tissue (Shang et al., 2009; da Cunha Pedrosa et al., 2010). This halts the build up of inflammation.

And since NF-κB is involved in cell survival, which works to our advantage in the acute sense, it’s clear why we find it turned on indefinitely in cancer cells. Besides melatonin, though, calorie restriction (or fasting) is one of the most effective ways to shut down NF-κB, thereby shutting down the entire inflammatory system that drives the progression of chronic and acute diseases.

While some inflammation is actually good for us, we too often tip the scale and accumulate an excessive amount of reactive oxygen species (ROS) in our cellular environment. This is considered to give rise to an unfortunately unrecognized state plaguing our society: underlying oxidative stress (Sies, 1997).

Fortunately for us, each cell in our body has its own internal defense mechanism to fight against oxidative stress. Chiefly, this is mediated by the transcription factor NF-E2-related factor 2 (Nrf2). If NF-κB is the master regulator of pro-inflammatory cascades, Nrf2 is the master regulator of anti-inflammatory cascades; it offers a battery of defensive mechanisms and regulates detoxification genes. Indeed, Nrf2 is stabilized and activated when ROS and electrophiles rise (Shelton & Jaiswal, 2013).

Bottom line: Inflammation is associated with an elevated production of cytokines and chemokines, and melatonin is associated with a reduction in those pro-inflammatory cytokines , with a concomitant elevation in the level of the anti-inflammatory cytokine IL-10 (Habtemariam et al., 2017; Hardeland, 2019). While there are a few concerns about the potential pro-inflammatory actions of melatonin when used in very high doses or under suppressed immune conditions (where it may induce an increase production of pro-inflammatory cytokines, IL-1β, IL-2, IL-6, IL-12, TNF-α, and IFN-γ) (Carrascal et al., 2018), it’s important to remember that in ALI-infection models, melatonin consistently demonstrates anti-inflammatory and protective action (Huang et al., 2010).

The Antioxidative Effect of Melatonin

Viral infections (and their replication) constantly produce oxidized products. We know this from SARS-induced acute lung injury (ALI) models, where the production of oxidized low density lipoprotein (LDL) activate the innate immune response by the overproduction of IL-6 lung (alveolar) macrophages via Toll-like receptor 4 (TLR4)/NF-kB signaling, thereby leading to ALI (Imai et al., 2008).

TLR4 is a receptor for the innate immune system, and it is also a therapeutic target for melatonin. In cerebral ischemia (when an insufficient amount of blood flows to the brain), gastritis, and periodontitis disease models, melatonin has documented anti-inflammation actions via TLR4 signaling (Luo et al., 2018; Renn et al., 2018; Zhao et al., 2019).

The anti-oxidative effect of melatonin has also been identified in acute lung injury caused by radiation, sepsis, and ischemia-reperfusion (Chen et al., 2014; Wang et al., 2018; Wu et al., 2019). In ALI/ARDS patients, especially when this condition is advanced and in patients treated in ICUs, severe inflammation, hypoxemia, and mechanical ventilation with high oxygen concentrations increases oxidant generation locally and, inevitably, spills out to the rest of the body systematically (Sarma & Ward, 2011; Tamura et al., 2020). Melatonin could help clean a lot of this inflammatory damage up.

Melatonin’s use is not a novel idea.

Its use as a therapy has been known for well over a decade, thanks, in part, to the extensive studies conducted by Gitto and his colleagues in 2004 and 20055 (during the aftermath of the first SARS pandemic). It was this team that used melatonin to treat newborn infants with respiratory distress that found the antioxidant and anti-inflammatory actions of melatonin in the lung. Thus, the application of melatonin would likely be beneficial in controlling inflammation and oxidation in those infected with coronavirus.

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AUTHOR

Dr. Payal Bhandari M.D. is one of U.S.'s top leading integrative functional medical physicians and the founder of SF Advanced Health. She combines the best in Eastern and Western Medicine to understand the root causes of diseases and provide patients with personalized treatment plans that quickly deliver effective results. Dr. Bhandari specializes in cell function to understand how the whole body works. Dr. Bhandari received her Bachelor of Arts degree in biology in 1997 and Doctor of Medicine degree in 2001 from West Virginia University. She the completed her Family Medicine residency in 2004 from the University of Massachusetts and joined a family medicine practice in 2005 which was eventually nationally recognized as San Francisco’s 1st patient-centered medical home. To learn more, go to www.sfadvancedhealth.com.