FoundMyFitness - #053 COVID-19 Q&A #1 with Rhonda Patrick, Ph.D.

Episode Date: April 14, 2020

This episode features Dr. Rhonda Patrick answering some of the most popular questions related to COVID-19. Look for another COVID-19-focused Q&A, coming soon.  In this episode, you'll discover: (00:00) Introduction (02:37) Are children and infants susceptible to COVID-19? Are some more susceptible to a more severe form of the disease? Are they carriers of it and possibly spreading transmission? (11:00) Can you explain a little about hydroxychloroquine as possibly treating COVID-19? How does it work? Does it have to do with it being a zinc ionophore? (17:58) Can you talk about quercetin's role as a zinc ionophore? (20:51) Is there any indication blood type influences COVID-19 risk? (24:52) Would you shed light on the conversation regarding vitamin D upregulating ACE2 receptors and vitamin D's influence on susceptibility to COVID19 infection? (43:45) Can you discuss whether sauna use might help prevent COVID19? (52:55) Is it true that high dose intravenous vitamin C might help treat COVID-19? (01:04:35) What are your thoughts on melatonin being a potential factor for impacting the severity of the virus via its effects on inflammation and oxidative stress? If you're interested in learning more, you can read the full show notes here. Join over 300,000 people and get the latest information straight to your inbox weekly: https://www.foundmyfitness.com/newsletter Become a FoundMyFitness premium member to get access to exclusive episodes, emails, live Q+A's with Rhonda and more: https://www.foundmyfitness.com/crowdsponsor

Hello friends. Today's episode is a special discussion around COVID-19. During a time with a lot of noise and misinformation online, our team here at Found My Fitness wants to make sure that you're getting well-sighted, accurate, and trusted information. We recently asked you the listeners by way of my email newsletter to submit your questions about COVID-19, and today I will be answering a few publicly. While I'm only answering the top questions today, we plan to release another publicly available COVID-19 Q&A session similar to this one very soon. Some of the topics covered in this episode include COVID-19 in infants, children, and pregnant women, hydroxychloroquine as a potential therapeutic for COVID-19, the flavonoid quercetin as

a zinc ionophore, blood-type influences on COVID-19 risk, vitamin D, ACE2 receptors in COVID-19, the sauna immunity in COVID-19, intravenous vitamin C in COVID-19, and, finally, and, Finally, melatonin in COVID-19. If you find value in today's Q&A and you'd like to support us to deliver even more high-quality, well-researched information, please consider becoming a Found My Fitness premium member. We do Q&A sessions for Found My Fitness premium members each and every month. I host the sessions live on camera and members can contribute in the live chat.

We cover many popular topics such as sauna, fasting, and sulfurophane, although these days many topics have been focused on immunity. Premium members also get access to recordings of all previous Q&As, our exclusive private podcast feed, Lifetime Genetic Report updates, and members-only emails, and more. Above all, your support will also help us do more of the important work of Found My Fitness, informing, sometimes even rebutting, but more importantly, synthesizing cross-disciplinary science-focused content. Visit my website to become a premium member at FoundMyFitness.com and click the Become a Member button at the top of the homepage. You can find supporting information for topics discussed in this episode,

including a summary, timeline, and references on the episodes page of my website at foundmyfitness.com forward slash episodes. Before we get started, I want to emphasize that the content in this podcast is not meant to diagnose any disease and is not intended for medical treatment. I am not a medical doctor and the information I share does not constitute medical advice. users should not use this information to treat any medical condition. My background is in science and not medicine, guys. So just keep that in mind. All right, that disclaimer aside, let's jump in.

The first question we're going to discuss is, are children and infants susceptible to COVID-19? Are some more susceptible to a more severe form of the disease? Are they carriers of it and possibly spreading transmission? So let's discuss a study titled, diagnosis, treatment, and prevention of 2019 novel coronavirus infection in children. Experts Consensus Statement. It was published in February of 2020. It stated, most infected children have mild clinical manifestations. They often have no fever or symptoms of pneumonia

with good prognosis. Most of them recover within one to two weeks after disease onset. Few may progress to lower respiratory infections. Another study titled Epidemiological Care characteristics of 2,143 pediatric patients with 2019 coronavirus disease in China was published in March. This study reports that epidemiological characteristics and transmission patterns of these pediatric patients with COVID-19 in China. The study found that children of all ages were susceptible to COVID-19 with no significant gender differences observed. Clinical manifestations of pediatric patients were generally less severe than those of adult patients. However, However, young children, particularly infants, were more vulnerable to the SARS-CoV-2 infection.

Among symptomatic children, 5% had shortness of breath or low levels of oxygen in the blood, and 0.6% progressed to acute respiratory distress syndrome, or multi-organ system dysfunction. These levels are much lower than those seen in adults. Infants younger than one year were more likely to have severe illness compared to older children. has speculated that a few possible reasons could explain why children experience less severe disease than adults. SARS-CoV-2 virus exploits the angiotensin-converting enzyme 2, or ACE2 as it's called receptor, to gain entry into cells.

Perhaps the maturity and function or binding ability of the ACE-2 receptor in children may be lower than that in adults. Children's immune systems are still developing and may respond to pathogens very differently than adults. Children also often experience respiratory infections like RSV in winter and may have higher levels of antiviral antibodies compared to adults. So let's address the question about the role children play in COVID-19 transmission. Understanding how COVID-19 affects children is vital to slowing the pandemic. A study titled COVID-19 and children initial characterization of the pediatric disease press release published in March of 2020 summarizes, children are less likely to become

severely ill than older adults. Children may play a major role in community-based viral transmission. Children may have more upper respiratory track involvement than lower respiratory track involvement, but there is still much to learn about the impact of this virus on children, as well as the impact of children on viral spread. There are some subpopulations of children with an increased risk for more significant illness. Those seem to include infants and preschoolers, immunocompromise children, children with other pulmonary health problems. This has also been reported for non-COVID-19 coronavirus infections. A meta-analysis including 45 published studies on COVID-19 found, as of March 18, 2020, children have accounted for about 1 to 5% of diagnosed COVID-19

cases. They often have milder disease in adults, and deaths have been extremely rare. Diagnostic findings have been similar to adults with fever and respiratory. symptoms being prevalent, but fewer children seem to have developed severe pneumonia. Elevated inflammatory markers were less common in children, and lymphocytopenia, which are low levels of lymphocytes in the blood, was rare. The clinical spectrum of children with COVID-19 has often been similar to that of influenza. On the topic of persistent fecal shedding of the virus, out of 10 pediatric SARS-CoV-2 infection cases, eight children persistently tested positive on rectal swabs even after nasopharyngeal testing was negative, raising the possibility of fecal

oral transmission. However, we do not have evidence of replication-competent virus in fecal swabs, which is required to confirm the potential for fecal-to-oral transmission. On the topic of mother-to-child transmission of COVID-19, mother-to-child transmission of diseases, also known as vertical transmission, can occur during pregnancy. Several viruses, including hepatitis B, herpes very cell exhauster, which is chickenpox, and human immunodeficiency virus or HIV can be passed via vertical transmission. A recent report indicates that Sargecove-2, the virus that causes COVID-19, is not transmissible from pregnant mothers to their infants at birth. The report describes the clinical course of four live-born full-term infants born to pregnant women who tested positive for COVID-19

in Wuhan, China. Three of the four infants did not test positive for the virus. virus. The mother of the fourth infant did not provide consent for testing. None of the infants manifested clinical signs of COVID-19, such as respiratory or gastrointestinal problems, but two had mild rashes at birth. One of the infants developed breathing problems but responded to non-invasive mechanical ventilation. Although three of the four infants described in the report were born by a cesarean section, one was born vaginally and did not test positive for the virus. all the infants were isolated after birth and were formula fed. The authors of a report collected placenta, amniotic fluid, neonatal blood, gastric fluid,

and anal swab samples from the infants for further study. Another study titled Clinical Characteristics and Interuterine Vertical Transmission Potential of COVID-19 Infection in nine pregnant women also found that there was no evidence of Sarge COVID-2 viral transmission from mother to child in nine births from COVID-19. infected women. All nine births were done by Cesarian section in the third trimester. Amionic fluid, cord blood, neonatal throat swab, and breast milk samples from six patients were tested for SARS COVE 2, and all samples tested negative for the virus. The clinical characteristics of COVID-19 pneumonia and pregnant women were similar to those reported for non-pregnant adult patients who

developed COVID-19 pneumonia. And yet another study titled, an analysis of 38 pregnant women with COVID-19, their newborn infants and maternal fetal transmission of SARS-CoV-2 actually described 38 pregnant women with COVID-19 and their newborns in China. The report found there was no evidence of SARS-CoV-2 undergoing any type of inter-uterine or transplacental transmission from infected pregnant women to the fetuses. Since all of the published data seems to indicate that infants born to mothers with COVID-19 do not actively have the SARS-Cove-2 virus, the question is, what about antibodies from this virus? So a publication found that among six mothers with confirmed COVID-19, SARS-CoV-2 was not detected in the serum or throat swab in any of the newborns.

However, virus-specific antibodies were detected in neonatal blood serum samples. IGG concentrations were elevated in five infants, and IGG normally crosses the placenta, and IGM concentrations were elevated in two infants. So IGM is a larger, molecule and it's not thought to usually cross the placenta. So this either indicates that maybe the placenta could possibly be damaged in COVID-19, allowing the IGM to cross the placenta, or the SARS-Co2 may cross the placenta and could result in the infant in producing the IGM. That's two possibilities. We're not sure exactly what's causing the infants to have the elevated IGM concentrations. So the CDC has recommendations for the CDC has recommendations for the

the care of pregnant women and breastfeeding. They recommend that a mother with COVID-19 still continues to breastfeed since the virus does not seem to be present in breast milk, but they should wash their hands before touching the infant and wear a face mask if possible while feeding at the breast. Okay, let's move on to the next question, which is, can you explain a little bit about hydroxychloroquine as a possible treatment for COVID-19? How does it work? does it have to do with it being a zinc ionophore? Hydroxychloroquine is an old off-patent drug that is inexpensive with a known safety profile drug interactions and side effects.

It is an anti-malarial therapeutic that is also used to treat rheumatoid arthritis and lupus. It's pretty well tolerated. However, there are safety concerns. Antimalarial drugs can cause ventricular arrhythmias, QTC prolongation, which can lead to fatal ventricular arrhyth and sudden cardiac death and other cardiac toxicity, which may pose particular risk to critically ill persons. This is not something people should be taking at home without a physician's guidance. However, there are currently no published double-blinded

randomized controlled trials for its use in the treatment of COVID-19. It is possible that it may be used to treat symptomatic patients and may decrease the length of time the virus remains and the respiratory tract, thus limiting community spread. However, more data is needed and this is based off of the very limited data that has been published, which is not super high quality data. But let's discuss that data. A small open label study titled hydroxychloroquine and azithromycin as a treatment of COVID-19, results of an open-label non-randomized clinical trial. This study was published in March.

The study involved 32 confirmed COVID-19 patients who were administered 600 milligrams of hydroxychloroquine daily for six days. Some patients also receive the antibiotic. azithromycin. Nasofaryngial samples were taken on day six of the treatment and it indicated that 70% of the hydroxychloroquine treated patients had cleared the virus compared to 12.5% in the group receiving standard of care. All of the patients who receive both the antibiotic isythromycin and the hydroxychloroquine cleared the virus from their nasofaryngial samples. Iszithromycin is an antibiotic that has been shown to have antiviral activity against some viruses like Ebola,

in animal studies. The safety profile of taking both hydroxychloroquine and azithromycin still needs to be determined. In a follow-up observational study including 80 patients receiving a combination of hydroxychloroquine and azithromycin, a clinical improvement was found in all but one of the one patient who was an 86-year-old patient who died and one 74-year-old patient that was still in intensive care. In addition to clinical improvements, reduction of the the viral carriage from patients' respiratory samples was seen with hydroxychloriclin plus the azithromycin treatment. In addition, randomized control trials need to confirm whether these therapeutics are

effective for the treatment of COVID-19. Large randomized controlled trials are underway in China and in the U.S. Another very small pilot study out of China found that patients with mild to moderate COVID-19 didn't have much difference at all in their recovery rates when they were given hydroxychloroquine. And yet another very, very small observational study, including 11 people, found no clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. So this was a very small observational study.

So since there was no control, it's hard to know how these patients would have responded without the treatment. possible side effects, the most common side effects of hydroxychloroquine include gastrointestral infections like nausea, vomiting, diarrhea, and abdominal discomfort. The most severe complication is a development of retinopathy with prolonged use. To talk about possible mechanisms, let's take a quick step back and talk a little bit about the Sarge-Cove 2 virus. Sarge-Cove 2 is an RNA virus.

It binds and docks to the ACE-2 receptor on. a cell and injects its genetic material, which is RNA, into the cytosol of a cell. Inside of the cell, viral RNA molecules are translated to produce RNA-dependent RNA polymerase, also known as replicase. This is a key enzyme involved in the reproduction of RNA viruses. RNA-dependent RNA polymerase drives replication of the viral RNA to produce more viral genomes. Hence, you get viral reproduction. Viral RNA is packaged into infective virion particles, which are released from the cell and able to infect neighboring cells.

So let's talk a little bit about the involvement of zinc. Zinc inhibits the action of RNA-dependent RNA polymerase. That means it stops the replication of viruses. However, zinc is a positively charged ion and cannot get insufferate. cells without a transporter. Zinc requires an ionophore, which is a compound that transports ions across a lipid membrane. So how do you get zinc into cells? A zinc ionophore in combination with zinc is a potent inhibitor of the replication of SARS-CoV-1, the original SARS virus. Zinc mediated inhibition could be reversed through the addition of a zinc keelator, which binds up the zinc

and prevents it from getting into the cell. Chloroquine diphosphate was shown to be a zinc ionophore in a cancer model. The conclusion was that zinc chloroquine is a zinc ionophore based on the detection of significantly elevated intracellular zinc levels when both zinc and chloroquine were added to cell culture medium. Adding even a small amount of chloroquine increased the amount of intracellular zinc, meaning zinc inside of the cell. There may also be some other mechanisms that play as well, as chloroquine has been shown to impair early stage replication of the virus by interfering with pH-dependent endosome-mediated viral entry into the cell. So let's talk a little bit about hydroxychloroquine versus chloroquine phosphate.

Hydroxychloroquine is a less toxic version of chloroquine that has been used to treat autoimmune diseases such as lupus. It has anti-inflammatory properties, so it can decrease the production of pro-inflammatory cytokines. It may also play a role in counteracting the cytokine storm seen in critically ill COVID-19 patients. However, this still needs to be confirmed. Hydroxychloroquine was found to be three times more potent at killing the Sarge-CoV-2 virus than chloroquine phosphate in cells in culture. Again, larger randomized controlled trials are needed to confirm whether or not hydroxychloroquine

is in effective treatment for COVID-19. So let's move on to the next question, which is about quercetin. The question is, can you talk about quercetin's role as a zinc ionophore? So quercetin is a flavonoid. It's found in onions, green tea, apples, berries. It's found in other plants like Ginklpiloba, St. John's War buckwheat tea. Quercetin has been reported to block the entry of Sarge Cove 1, the virus that caused the original SARS outbreak in host cells. And so this was in cells in a petri dish. The cytotoxicity,

of course, it is very low. It's already an FDA-approved drug ingredient. People can take it as a supplement. It has not been clinically tested in SARS-cove-2. Clinical trials, or at least one clinical trial, is beginning in a collaborative effort between Canada and China with outcomes expected in around four months. So there was a possible. publication that involved the screening of old drugs to sort of repurpose them against COVID-19. And based on that publication, there was a genome similarity. SARS is the closest virus to the SARS-CoV-2 and followed by mares and other human coronavirus diseases.

Data mining identified 34 COVID-2019-related genes and 24 disease-related pathways. Using drug prioritization algorithms, researchers identified 78 drug. to repurpose. There was manual filtering based on clinical knowledge and a variety of other screening methods, but quercetin was included in this group. In another virtual screening of Chinese herbal medicines, quercetin was also predicted as a potentially useful drug to repurpose against the SARS-CoV-2 virus. The literature is pretty supportive of quercetin having antiviral capacities when it's cultured with targeted cells and a broad spectrum of pathogens, including rhinoviruses, edinoviruses, and coronaviruses.

Another in vitro study with cultured cells found that quercetin does seem to have zinc ionophore activity. So polyphenols such as quercetin as well as EGCG can transport zinc cations across the plasma membrane independently of plasma membrane zinc transporters. Zinc inhibits the action of RNA-dependent RNA polymerase, as mentioned earlier, a key enzyme in the reproduction of RNA viruses. So that's pretty much what the current literature says on quercetin as a zinc ionophore and the limited amount of literature showing it does have antiviral activity, particularly

has been shown to have antiviral activity against the SARS-Co-1 virus. So let's move on to the next question, which is, is there any indication blood type influences COVID-19 risk? So based on some very small studies, just very limited evidence, there is some indication that people with blood group A may have a higher risk of acquiring COVID-19 compared to non-A blood groups, whereas individuals with blood type O may have a lower risk of the infection compared to. to non-O blood groups. So A-B-O blood groups have been involved in the susceptibility to other viral infections. In the related SARS-CoV-1 virus, type A antibodies, as found in people with type O or type B blood types, can provide protection by inhibiting the interaction of the virus with the ACE-2 receptor. So first, blood type is a classification of blood based on the presence or absence

of antibodies, as well as inherited antigenic substances on the surface of red blood cells. One of the most important blood type systems is the ABO system, and it's important to understand that the ABO, so type A, type A, type A, type A, is the most dominant antigen. So this is the signal that evokes an immune response that is present in blood cells. This antigen type is essentially just a modified sugar. So people with type A blood have a type A antigen on the surface of their cells, which means they make antibodies against antigens that are type B because this is recognized as not self. This is why a person with type A blood will reject a blood transfusion with a type B blood type

due to immune response. So the body makes type B antibodies to attack that antigen and vice versa. A person with type O blood, which is, I think it's the most common. does not express either A or B antigen, therefore they make antibodies against both A and B antigens since they are both considered foreign. This means that people with type O blood can donate blood to a person with any blood type since their blood cells do not express either A or B antigen. It will not elicit an immune response. But they can only receive blood from a person with type O since they make antibodies against A and B antigens. So again, again,

Again, this very preliminary data suggests that people with type O blood may be less susceptible to COVID-19 because they produce the type A antibodies, which are possibly inhibiting the interaction between SARS-CoV-2 and the ACE2 receptor. Now, that has been shown to be the case for SARS-CoV-1. In one study investigating the relationship between ABO blood group and the COVID-19 susceptibility, it was found that people with blood group A have a higher risk for acquiring COVID-19 compared to non-A blood groups, whereas blood groups O have a significantly lower risk for the infection compared to non-O blood groups. Another study, a retrospective analysis from clinical features in 101 death cases with COVID-19,

the ABO blood group distribution of deaths differed pretty remarkably between that from the Han population in Wuhan. Although not analyzed statistically, type O was comparatively low while type A was high. It's possible that some of the protection for type O blood groups and some of the increased risk for the type A blood groups may be similar to the mechanisms that have been seen with SARS-Cove 1, namely the fact that type A and antibodies have been shown to provide protection by inhibiting the interaction between the Sarge Cove 1 virus and the ACE2 receptor, which is how the virus gets entry into the cell. Let's move on to the next question, which has to do with vitamin D. The question is, would you shed light on the conversation regarding vitamin D upregulating ACE2 receptors and its influence

on susceptibility to COVID-19 infection? This is such an important question, and I'm so glad to get a chance to talk about vitamin D. I think it is a very important topic and I think there's been some confusion around vitamin D. The first thing to know about vitamin D is that it is not just a vitamin. It's a steroid hormone. Underscoring its importance for health, it actually regulates more than 5% of the protein encoding human genome. Our biology needs this hormonal signal to know how to function optimally, period. Immune function is just one important aspect of what is actually a larger conversation around the incredibly broad role of vitamin D. It wouldn't make sense to try to talk about everything there is to know about vitamin D here today. However, some background is useful, so let's dig in.

Vitamin D3 is a fat soluble vitamin that gets converted into a steroid hormone. It is made in the skin upon UVB exposure from the sun. This fact alone leaves many of us vulnerable to at least suboptimal levels. We wear clothes. We wear sunscreen. We may work inside all day. Many aspects of modern life are in a sense at odds with our natural production of vitamin D. Let's talk about deficiency and insufficiency, how widespread it is, who is likely to have it, and how it is defined. According to Enhan's data, approximately 70% of the U.S. has what is called vitamin D insufficiency, while a further 28.9% has low enough levels to be called deficient.

According to the Endocrine Society, blood levels of 25 hydroxy vitamin D, below 20 nanograms per milliliter is considered deficient, and less than 30 nanograms per milliliter is insufficient. The reason the endocrine society defines vitamin D deficiency as below 20 nanograms per milliliter, by the way, is because this is the cutoff point where parathyroid hormone levels, which are involved in calcium homeostasis, start to rise outside of healthy ranges. This point at which the balance of parathyroid hormone begins to shift is the physiological definition, for the beginning of vitamin D deficiency. When we look at the demographics, epidemiologists have long known where vitamin D deficiency tends to concentrate and what populations are the most affected.

It is the elderly, where efficiency of cutaneous biosynthesis of vitamin D declines with age. According to N. Haines data, older adults were 63% more likely to have vitamin D deficiency and 46% more likely to have vitamin D insufficiency than young adults, while other sources have have suggested a 70-year-old may produce four times less vitamin D than their former 20-year-old selves. It is also in the obese, where fat-soluble vitamin D has greater difficulty being released into the bloodstream. Obese individuals have greater than 50% less bioavailability of vitamin D compared to non-obese individuals. Obeses adults in the U.S. had three times higher prevalence of vitamin D deficiency and 1.9 times higher prevalence of vitamin D deficiency.

D insufficiency than non-obesce adults. It is also in those living in northern latitudes, where less UVB radiation reaching the atmosphere means less of it reaching our skin to facilitate the production of vitamin D. And it is in darker skin people, where synthesis of vitamin D is naturally reduced as a biological bargain made by melanin, a natural sunscreen, which protects us from the damaging effects of UV radiation. According to Enhain's data, non-Hispanic blacks have 24.6 times higher vitamin D deficiency and 3.7 times higher vitamin D insufficiency than non-Hispanic whites. A recent CDC study of about 1,500 hospitalized COVID-19 patients in 14 U.S. states found that 48% of people hospitalized for COVID-19 were obese. COVID-19 hospitalizations

were also much higher in people over the age of 65. According to the CDC, 33% of people hospitalized for COVID-19 were African-American, who only constitute 13% of the U.S. population. By contrast, this report found that 45% of hospitalizations were among white people who make up 76% of the population in the United States, suggesting that African-Americans may be at a much higher risk for severe COVID-19. But the epidemiological story doesn't end there. Another paper published in BMJ in March of 2020 reported Somali immigrants living in Stockholm, Sweden

make up 40% of the COVID-19 related deaths reported at that time in Sweden. Sweden is a country that is at a northern latitude, which increases the risk of vitamin D deficiency. This rate of hospitalization is really high, considering that Somalis only make up 0.84% of the Stockholm County population. Several studies have previously established that Somalis living within Sweden have extreme vitamin D deficiency due to overlapping factors of hereditary and geography. Whether these are just associations or whether vitamin D really does play a crucial role in COVID-19 defense, only time will tell. However, the authors of the study felt the connection strong enough to make the following statement, quote, in order to cope with the COVID-

COVID-19 epidemic, preventative measures could be administration of vitamin D to high-risk population. Example, dark-skinned adults with low sun exposure and or individuals with risk factors for respiratory tract infections. Although it may not always be helpful, it is unlikely to be harmful, end quote. There are mechanistic reasons why vitamin D may be an important part of this COVID-19 story. There is very strong evidence to suggest that vitamin D is protective against respiratory track infections. There is data from 25 different randomized controlled trials from around the world showing that daily or weekly supplementation of vitamin D reduced the risk of acute respiratory infection

by more than 50% in people with the lowest vitamin D levels at baseline. People that had higher baseline vitamin D levels also benefited. They had a 10% lower risk of acquiring an acute respiratory track infection. We know that vitamin D plays a very important role in the innate immune response, and people with low vitamin D may have a weaker innate immune defense. So let's talk a little bit about everything from how the ACE2 receptor is used by the SARS COV2 virus to gain entry into the cell, to how it is actually very important for protecting against acute lung injury and acute respiratory distress syndrome, which are sort of interchangeably

use terms that describe this lung dysfunction and that's a severe complication associated with COVID-19. So the angiotensin converting enzyme 2 or ACE2 acts alongside the angiotensin converting enzyme ACE to regulate blood pressure, inflammation, and body fluid homeostasis. It's important to keep these two arms, the ACE and the ACE2, of the renin angiotensin system in balance for it to perform its functions. ACE2 plays a crucial role in the rean-angiotensin system. In pre-clinical studies, a renean angiotensum system in balance with higher ACE and lower ACE2

results in atherosclerosis, hypertension, heart failure, chronic kidney disease, serious lung injury, conditions where ACE2 increases seem to be protective. So balance is critical in the lung where reigning angiotensin system activity and ACE2 expression levels are high. If rean-an angiotensin system activity is greatly imbalanced, more severe events may occur, and this happens when ACE2 levels decrease. So the loss of ACE2 function can lead to increased neutrophil infiltration, exaggerated inflammation, and lung injury. Once lung infection leads to hypoxia, reen is released and sets up this vicious cycle for decreasing ACE2 and causing more damage.

Acute respiratory distress syndrome, which is a complication of severe COVID-19 illness, and was also a complication of the original SARS, is the most severe form of a wide spectrum of pathological processes designated as acute lung injury. So acute respiratory distress syndrome is characterized by pulmonary edema due to increase vascular permeability, the accumulation of inflammatory cells and severe hypoxia. Acute lung injury results in a very strong downregulation of ACE2, which then causes more severe injury. So the SARS-Co2 virus enters human cells via the ACE-2 receptor.

Viral particles bind to the ACE-2 receptor, and together they are internalized into the cell. Numerous viral particles can then bind to ACE-2 molecules and sequester the ACE-2 molecules from the cell surface. This suggests that a loss of ACE2 function may occur during SARS-CoV-2 infection and can have serious health consequences because of the key role of ACE-2 in the Rhenian angiotensin system. This has been shown to occur in the original SARS-1 virus. So, SARS-CoV-1, which also enters the cell through the ACE-2 receptor, down-regulates or decreases cellular ACE2 expression levels, and this has been shown to cause worse disease severity

in the SARS-1 virus. SARS-CoV-1 also, like I said, binds to the ACE-2 receptors, and this results in the down-regulation of the receptors through binding of the SARS-Co-1 spike protein to the ACE-2. So ACE-2 is a key negative regulator for severity of lung edema and acute-livenous. lung failure. So SARS-CoV-1 spike protein mediated ACE-2-down-regulation then contributes to the severity of lung pathologies. So as the SARS-CoV-1 spike protein is binding to the ACE-2 receptor, it's resulting in down-regulation, and this then makes the lung pathologies more severe. So one might look at the isolated fact that SARS-Cove-2 docks on this ACE-2 receptor to enter the cell,

and conclude that it's best to have less ACE2 receptors. But as I just explained, the opposite is true. Ace 2 is really key for protection against acute lung injury and acute respiratory distress syndrome. And this has even been shown with the original SARS virus. This is really important because when you draw too broad of conclusions from a very isolated interaction that you kind of pull out from a biological system, it can lead to what seems to be a logically consistent conclusion, but it's actually the wrong

interpretation. It's very common and super easy to make that kind of mistake. There's always sort of, you know, lots of compensating factors, which is always the case in biology. So you always have to look at the whole context and the interaction of biological systems. So again, just as a quick summary, the SARS-CoV-1 and SARS-CoV-2 virus both gain entry to human cells by binding to the ACE2 receptor. It's been shown in the SARS Cove 1 that the binding of it to the ACE2 receptor results in a down regulation in ACE2 receptors. It results in decreased

levels of ACE2 and this exacerbates lung injury and leads to worse outcomes. So again, it's not as simple as more ACE2 receptor bad, less ACE2 receptor good. And in fact, it seems to be quite the opposite in terms of this SARS-CoV-1 virus, at least, when it's binding to the ACE-2 receptor. It's decreasing the ACE-2 receptor. It's also decreasing ACE-2 levels, and that is causing worse injury in the lungs because it's disregulating the reen andi-tutensin system. So let's talk a little bit about populations that are at risk for decreased ACE-2 levels.

People with chronic diseases. Age, ACE-2 levels decrease with age. And males also have a decrease levels of ACE2 compared to females. So the ACE2 gene is located on the X chromosome. And so women have two X chromosomes. And so they have more copies of the ACE2 gene and therefore higher levels. Interestingly, these seem to be the same populations of people that are at increased risk for COVID-19, people with chronic diseases, elderly people, and even in some cases,

some data suggests that males may be more susceptible to severe COVID-19. So let's talk a little bit about vitamin D and the renin angiotensin system. It's very important to reduce the SARS-Cope 2 unbalanced reanan angiotensin system. SARS-Cope 2 can unbalance the renin angiotensum system in the lung, and this may occur the same way that has been shown for SARS-1 via ACE-2 downregulation, which is followed by inflammation and hypoxia-induced reen release. During a cytokine storm, the renin angiotensin system is severely disturbed. The purpose of the reanan angiotensin system is to regulate blood pressure. It does so through a series of enzymes, including ACE2 that involve the kidneys,

adrenal glands, lungs, heart, and brain. Vitamin D deficiency leads to overexpression of renin and thus activation of the renin angiotensin system. causing renal and cardiovascular injuries. So vitamin D acts as an endocrine repressor of the renin angiotensin system by down-regulating the expression of reen, the rate-limiting enzyme in the renin angiotensin cascade. So in a pre-clinical model for acute lung injury, when the active form of vitamin D called calcitrile

was administered before lung injury in animals, it protected them from acute lung injury by helping to balance the reen andiotensin system. It did this by increasing ACE2 levels and down-regulating reen. The increased ACE-2 resulted in protection against acute lung injury. It is important to point out that the acute lung injury itself led to a decrease in ACE-2, which again I mentioned has been shown to occur with SARS-CoV-1 infection, and this resulted in worse disease outcome.

The vitamin D increased ACE2 receptor levels, only in conditions of acute lung injury where ACE2 levels decreased. When vitamin D was given to control animals that did not have an induced lung injury, it did not cause or increase ACE2 receptor levels. This means that vitamin D is normalizing the ACE2 receptor levels in situations where it is downregulated or dysregulated. In another preclinical study, it showed that vitamin D increased ACE2 levels in another situation where the reen and angiotensin system was again dysregulated in rats with diabetic kidney disease. Vitamin D increased ACE2 levels in diabetic rats and this improved kidney function.

It is worth noting that the increase in ACE2 levels in this study was actually soluble ACE2 in the bloodstream and not aase 2. ACE2 in the lungs. It's possible that ACE2 in the blood could actually be protective against COVID-19 infection because it could bind and sequester viral particles. In fact, a new study found that human recombinant soluble ACE2 reduce the SARS-CoV-2 infection in engineered human organoid tissues. This is because the soluble ACE-2 is thought to bind to the SARS-CoV-2. O2 virus and prevent it from infecting the cells. This recombinant soluble ACE2 is soon to be tested in clinical trials by European

biotech company Aperion Biologics. This data suggests that vitamin D may play a very important role in protecting against acute respiratory distress syndrome, acute lung injury, and it may do so by regulating the rean-angiotensin system. in cases where the ACE2 levels are decreased, which has been shown to happen in acute lung injury, it's been shown to happen with Sarge Cove 1, it may then help rebalance that ACE2 level by increasing the levels in that situation. Let's briefly talk about vitamin D supplementation.

Approximately 1,000 I use of vitamin D generally increases blood levels of 25 hydroxy vitamin D, which is the precursor to the active hormone, by around 1,000. five nanograms per mill. There are genetic factors that contribute to this and some people do it better than others. While the best way to determine how much vitamin D to supplement with is a blood test done at baseline and a month after supplementation, these are unprecedented times in going to a health care setting to try to get a vitamin D blood test can potentially put a person at risk for COVID-19 infection. I currently supplement with 4,000 I use per day and my levels are consistently 50 nanograms per milliliter.

I do not have any vitamin D related snips known to hamper the production of vitamin D steroid hormone. Vitamin D insufficiency is common and the more time people spend indoors, as during these times when many are sheltering in place, the more vitamin D insufficiency and deficiency may occur. But it is important to note that it is not good to take too much vitamin D. The food and nutrition board of the Institute of Medicine conservatively set the tolerable upper intake of vitamin D at 4,000 I use a day for all adults. And that is currently what I am taking.

The next question has to do with sonnas. And the question is, can you discuss whether sauna use may help prevent COVID-19? First of all, there's no data to suggest that using the sauna or other modalities of heat stress, such as steam showers or hot baths, will have any effect on COVID-19 illness. I can discuss other data that is published on pneumonia and the common cold and also the effect on just the immune system in general. But I can't speak directly to COVID-19 because there is no data to suggest whether or not the sauna will have any effect on COVID-19.

Let's start by discussing lung health. Sona use has been associated with a reduced risk of developing certain chronic or acute respiratory illnesses, including pneumonia. sauna use promotes mild hyperthermia, which in turn induces a wide array of physiological responses. These responses reduce oxidative stress and inflammation and activate cellular defense systems that provide protection against many diseases. So data from a 2017 study suggests that sauna use reduces the risk of developing certain chronic or acute respiratory illnesses, including pneumonia, which is an acute respiratory illness

characterized by cough, fever, chills, and difficulty breathing. It's a common complication of influenza and other viral illness infections, including COVID-19, as well as bacterial infections. Pneumonia affects people of all ages, but children, older adults, and people who are immunocompromised seem to be most vulnerable. So this study drew on data from a population-based perspective cohort study of more than 2,000 healthy, middle-aged men between the age of 42 and 65 years old. And it was conducted in Finland where most people have a home sauna. The average sauna exposure reported in the study

was approximately 20 minutes per session and the temperature was 174 degrees Fahrenheit or 79 degrees Celsius. The data was adjusted for a variety of potential confounding factors like body mass index, smoking status, education level, alcohol consumption, total energy intake, socioeconomic status, physical activity, inflammatory status, and a history of diabetes, heart disease, asthma, bronchitis, or tuberculosis. So the study revealed that the frequency of sauna use was inversely associated with the incidence of respiratory illness. Men who used the sauna two to three times weekly were 27% less likely to develop pneumonia than those who use the sauna once a week or not at all.

Men who used the sauna four to seven times a week were 41% less likely to develop pneumonia compared to the infrequent sonnet users. The sauna's protective effects on the lungs may be due to reduced oxidative. stress and inflammation associated with hyperthermia or the direct beneficial effects on lung tissue. Frequent sauna use may decrease pulmonary congestion and lead to other improvements in lung function, including vital capacity, tidal volume, minute ventilation, and forced expatory volume.

Sauna use has been shown to improve lung function in people with obstructive pulmonary disease. Typical finish saunas are not the only type of heat stress that have been shown to be beneficial for lung health. Wayon therapy, which uses far-infrared dry saunas, also has been shown to improve lung function in patients with chronic pulmonary disease, also known as COPD. The temperature of far-infrared saunas are significantly lower than typical finish sonnas, so they're typically around 140 degrees Fahrenheit. Since the temperature is lower, the duration in many studies is longer.

around 45 minutes, and the frequency in many studies is daily for a few weeks. One of the major differences between dry saunas or finished sonas and far-infrared saunas is that both dry and finish sonnas, the heat, the ambient air, and that heat is transferred from the air to the body. But in far-infrared saunas, the thermal radiation is directly used to increase body temperature. Sona bathing was shown to reduce the incidence of common colds in 25 participants that use the sauna one to two times per week for six months compared to 25 controls that did not. It took three months before the sauna had a protective effect.

The mechanism by which frequent sauna use reduces the incidence of colds is unknown, but it could have to do with the modulation of the immune system. White blood cells, lymphocytes, and neutrophil counts were all. all increased in both trained and non-trained athletes after sauna use. While these findings are interesting, they're still preliminary and larger studies are needed to confirm. One of the protective adaptive responses to heat stress is the production of heat shock proteins. Heat shock proteins are a conserved class of proteins with critical roles in maintaining cellular

homeostasis and in protecting the cells from stressful conditions. heat shock proteins have been shown to be increased by approximately 50% after 30 minutes in a 163 degree Fahrenheit sauna in healthy young men and women. Once activated, they can remain so for up to 48 hours. It's been shown that being acclimated to heat, such as from regular sauna use, results in the production of more heat shock proteins under normal conditions and even more so under stressful conditions such as cell and tissue injury. This is good because as we age, we make less heat shock proteins. So anything to boost them is beneficial.

Heat shock proteins like heat shock protein 70 are also readily induced by fever. And when released from cells, heatchalk protein 70 can can stimulate the innate immune response through toll-like receptors 2 and 4. The relationship between exposure, temperature, and maximum. heat chock protein, 70 protein levels was linear between normal body temperature of 98.6 degrees Fahrenheit and 105.8 degrees Fahrenheit. So increasing approximately 50% per degree Celsius in human lung epithelial cells. Increasing evidence suggests that certain heatchuk proteins play a role in both innate and adaptive immunity. Heatchuk proteins can directly stimulate the innate immune

responses such as the maturation and activation of dendritic cells and the activation of natural killer cells. This means that there may be a direct role for Heechuk proteins in regulating the innate immune response, which plays an important role in the body's ability to fight off a disease that it's never been exposed to before. Heechok protein 70, when given to mice, acts as an adjuvant and stimulates the innate immune system. It confers a protection against, for example, HSV when exposed. In addition to directly impacting the immune function, heatchalk proteins such as heatchalk protein 70 have also been shown to directly inhibit viral activity and replication of influenza virus A. While the effect of heatchalk proteins on viruses is a bit nuanced,

the more important thing is that heat shock proteins activate the innate immune system. And sauna use has been shown to increase white blood cell and other monocyte levels. I know many people don't have access to a home sauna and without gyms open, you know, gyms are closed at this time, so it's kind of impossible for a lot of people to use the sauna. So let's talk a little bit about hot baths since most people do have access to a bathtub. Hot baths have also been shown to increase heatchalk proteins, which is good news. One study found that participants that sat in a 140 degree Fahrenheit hot bath from their waist down for one hour were able to increase their heatchalk protein levels.

So just in summary, it appears as though sauna use is protective against some respiratory illnesses like pneumonia as well as COPD and has been shown to be protective against the common cold. been shown to increase the innate immune response in terms of increasing white blood cell numbers and other monocyte numbers, and it's also known to activate the innate immune response. Hot baths, which also is another modality of heat stress, have been shown to increase heat shock proteins, which are thought to be the main regulator by which, or the main mechanism by which the sauna is modulating the immune system. The next question has to do with vitamin C, and the question is, is it true that high dose intravenous

vitamin C may help treat COVID-19? So first of all, there's no published data looking at the effect of intravenous vitamin C on COVID-19. So I cannot speak specifically to whether or not intravenous vitamin C may help treat COVID-19. There is a randomized placebo-controlled trial that began in China on February 14th, investigating the effect of high-dose intravenous vitamin C on severe COVID-19 infected pneumonia. The study will treat severe COVID-19 patients with 12 grams of intravenous vitamin C twice a day for a total of 24 grams of intravenous vitamin C for seven days.

The trial is expected to be completed by September 30th of 2020. There is some anecdotal evidence from correspondence from physicians in China that have been using intravenous vitamin C to treat complications associated with COVID-19. These correspondences are not peer-reviewed. They're essentially anecdotes from physicians that have been posted on websites. For example, one physician in China was treating 50 cases of moderate to severe COVID-19 with high intravenous vitamin C. The dose ranging from 10 to 20 grams a day for 7 to 10 days, with 10 grams for moderate cases

and 20 grams for the more severe cases. The pulmonary status and coagulation status was the determining factor for the severity of COVID-19. All patients who received the intravenous vitamin C, according to the anecdote, improved, and there was no mortality compared to the average of a 30-day hospital stay for COVID-19 patients, those patients who received high-dose intravenous vitamin C had a hospital stay about three to five days shorter than the overall patients. Again, that is anecdotal data, so there's really no conclusions that can be made from that data.

But what we can speak a little bit more about today is published data on the use of intravenous vitamin C for infections, acute respiratory distress syndrome and sepsis. Both acute respiratory distress syndrome and sepsis can be complications associated with severe COVID-19 illness. So let's start by talking about the difference between intravenous versus oral vitamin C bioavailability. intravenous vitamin C bypasses intestinal absorption and the saturatable transport mechanisms. So consequently, the bioavailability of vitamin C differs appreciably between oral and intravenous administration. So, for example, in healthy adults, intravenous administration of vitamin C might reach blood-level concentrations that are anywhere between 30 to 70 times higher than the same oral dose.

In one clinical study in which 12 adults, between the ages of 19 and 20, were administered 1.25 grams of vitamin C either orally or intravenously, peak plasma concentrations reached 135 micromoles per liter of blood and 885 micromoles per liter of blood, respectively. Furthermore, a high dose of 3 grams taken every 4 hours resulted in peak blood concentrations of 220 micromoles per liter compared to 1,770.770. 60 micromole per liter for a single 3 gram dose of intravenous vitamin C. Let's talk a little bit about the use of intravenous vitamin C for the treatment of sepsis and acute respiratory distress syndrome, which as I mentioned earlier are both complications of

severe COVID-19. Sepsis is a potentially life-threatening condition caused by the body's innate immune response to acute infection. Under some circumstances, aspects of this response that are typically associated with defense against infection can induce extensive cell and tissue damage, leading to multiple organ failure, the hallmark of sepsis. Acute respiratory distress syndrome, also known as acute lung injury, is a serious lung condition that causes low blood oxygen. It is a common sepsis associated injury, and it can lead to respiratory failure and death. People diagnosed with sepsis typically have

low vitamin C levels, which might be predictive of increased risk for organ failure. Evidence suggests intravenous vitamin C might be an effective treatment for sepsis. A 2019 phase two clinical trial found that intravenous vitamin C reduced mortality in patients with sepsis and acute respiratory distress syndrome. The randomized double-blind placebo-controlled multi-center trial took place in seven medical intensive care units in the United States over a period of three years. The study participants included 167 male and female participants with sepsis and acute respiratory distress syndrome. Every six hours for four days, the patients received either intravenous vitamin C,

50 milligrams per kilogram of body weight, or placebo. The authors of the study noted a substantial difference in the death rates for the two groups, whereas approximately 30 percent of patients who received the intravenous vitamin C died, more than 46% of patients who took the placebo died. Patients who received vitamin C had fewer ventilated days, spent less time in intensive care, seven days versus 10, and their hospital stays were approximately one week shorter than those who received the placebo. These findings suggest that intravenous vitamin C administration might be beneficial in critically

ill patients who have sepsis. A separate study treated 47 patients with six grams of intravenous vitamin C four times per day for four days along with a steroid medication and vitamin B1, thiamine. A control group of 47 patients identified as having similar baseline characteristics of sepsis when admitted to the intensive care unit received standard of care. The death rate in the treated group was only 8.5% compared to 40.4% in the control group. In addition, the treated group exhibited improved organ function compared to the control group. These studies suggest that intravenous vitamin C alone or in combination with other treatments like thiamine decrease the risk of organ failure and mortality in patients diagnosed with sepsis. There have been several other

studies that have successfully used intravenous vitamin C and thiamine for the treatment of for the past several decades intravenous vitamin C has been used as an effective antiviral agent for the treatment of multiple types of viral infections including myocarditis Epstein-Barr virus and others. Furthermore, some studies have observed that in critically ill patients such as those with viral infections, plasma levels of vitamin C might be less than 25% of those observed in healthy people. Intervenous vitamin C's effectiveness in treating viral infections is like, due to its ability to enhance the immune system and also due to its ability to directly produce hydrogen peroxide, which we'll discuss in a minute. Immune cells such as lymphocytes and

neutrophils actively participate in eliminating pathogens such as bacteria or viruses from the body. Vitamin C is highly concentrated in immune cells with neutrophils and leukocytes having between 50 to 100 times higher vitamin C concentrations than plasma. One of the early stages of the body's immune response to viral or bacterial infection involves neutrophil infiltration into affected tissue, where the cells engulf the pathogens and initiate their removal. Nutrophils also generate large quantities of reactive oxygen species. The high levels of vitamin C found in immune cells protect the neutrophils from reactive oxygen species-induced DNA damage, while also promoting Nutrophil Ross production. Studies,

In humans have shown that vitamin C can enhance neutrophil function in young men between the ages of 18 to 30, as well as in older women. In addition, studies in guinea pigs suggest that vitamin C plays an important role in facilitating neutrophil migration to sites of infection. Vitamin C also appears to boost the immune system by promoting the proliferation of T cells and preventing T cell death. T cells play a major role in driving an immune response against pathogens, such as bacteria or viruses. Multiple in vitro studies in both mouse and human cell lines have demonstrated that

growing T cells in culture with vitamin C might enhance T cell development. While vitamin C acts primarily as an antioxidant at physiological concentrations of approximately 50 micromoles per liter, pharmacologic doses of intravenous vitamin C greater than one gram generates hydrogen peroxide, a type of reactive oxygen species that can damage DNA, RNA, and proteins, leading to tissue, damage. Multiple in vitro and in vivo studies suggest that high dose intravenous vitamin C leads to the formation of hydrogen peroxide. But it is important to note that successive treatments with high dose intravenous vitamin C has not been shown to increase pro-oxidative markers in healthy individuals, suggesting that while the high dose intravenous vitamin C may produce hydrogen peroxide and this

hydrogen peroxide may be killing other pathogens such as viruses or other, you know, unhealthy cells such as cancer cells, normal cells are not damaged by the burst of hydrogen peroxide produced by the high dose of intravenous vitamin C. Vitamin C also interferes directly with the replication of viral particles. Let's briefly discuss intravenous vitamin C safety. Intervenous vitamin C is pretty well-tolerated and has low toxicity. The most commonly reported side effects include mild to moderate nausea, headache, and dry mouth, with less commonly reported side effects being fatigue, hypertension, loss of appetite, and hyperglycemia. Some serious side effects have been reported with high dose, intravenous vitamin C in patients with cancer. Additionally, people who have a deficiency

in the enzyme glucose-6-phosphate dehydrogenase could be at risk of hemolysis. the rupturing of red blood cells when given high doses of intravenous vitamin C. Although these studies suggest that vitamin C could be contraindicated in these conditions, the intravenous doses administered were 40 grams or higher, which is pretty high. Other case reports have indicated that when given a dose between 1 to 10 grams, intravenous vitamin C actually reduced haemolysis. So it's possible that at lower doses, intravenous vitamin C is safe in people with glucose 6-phosphate dehydrogenase deficiency, but patients should definitely exert caution

and be pre-screened for this deficiency before receiving a high dose of intravenous vitamin C. All right, so let's move on to the last question I will address in this episode, which has to do with melatonin. The question is, what are your thoughts on melatonin being a potential factor to impacting the severity of the virus via its effect on inflammation and oxygen? oxidative stress. Before we dive into this, I want to emphasize there is no data to suggest that melatonin may prevent or less than the severity of COVID-19 illness. There was an article published in March of 2020 discussing the potential role of melatonin as an adjuvant treatment for COVID-19.

We can discuss some of the rationale behind that publication. So as we've previously discussed, you know, some of the COVID-19 disease pathology includes excessive inflammatory and immune responses that may activate a cytokine storm. And this could result in cell death of epithelial cells and endothelial cells, disrupting the vascular endothelial barrier and leading to vascular leakage leakage, abnormal T-cell, and macrophage responses. And these can induce acute lung injury, acute respiratory distress syndrome. A common clinical feature, in COVID-19 patients is low albumin levels, low lymphocyte numbers, low neutrophil numbers, and decreased percentage of CD8 positive T cells.

So let's talk a little bit about melatonin. Melatonin is actually a hormone. It controls the activity of over 500 genes, many of them involved in circadian rhythm, inflammation, immune function, antioxidant activity, and more. In mammals, melatonin is synthesized in the pineal gland. with a rhythm regulated by an adogenous circadian clock, the most important factor for regulating its metabolism, being the light, dark cycle. So melatonin is inhibited with blue light, and melatonin production starts in the evening hours as the light goes away. Melatonin production

in the pineal gland declines with age starting around 40 years old. Besides being produced in the Pinio gland, melatonin is also synthesized in many other organs like the gastrointestinal tract, retina, and also leukocytes, both in the peripheral blood and in the bone marrow. For example, human lymphoid cells are an important physiological source of melatonin, since resting and activated human lymphocytes synthesize and release large amounts of melatonin, with melatonin concentration in medium increasing up to five times the nocturnal physiological levels in human serum. T lymphocytes, natural killer cells, and mass cells, possess melatonin receptors. Melatonin has the capability to regulate leukocyte function and contributes

to the control of inflammation in tissues acting as both an activator of the immune system and an inhibitor of the inflammatory and immune responses depending on the biological context. So melatonin seems to play a homeostatic role in regulating the immune system. activating it when it's needed or reducing inflammation when levels are too high. So let's go into a little more detail on the immune system. Melatonin administration increases the prolificive response of rat lymphocytes, increases the number of natural killer cells, stimulates to release of pro-inflammatory cytokines, tumor necrosis factor, it enhances vagocytosis and it modulates apoptosis.

So it can have immune activating functions. But on the other hand, in other experimental systems, melatonin can inhibit the translocation of nuclear factor Kappa B, NF Kappa B, as it's called to the nucleus, which then blunts the production of many different pro-inflammatory cytokines, which are regulated by that NF Kappa B. Melatonin's immune-stimulating versus immune dampening effect really depends on the biological context. So the immune dampening effect occurs in circumstances where inflammation is elevated. So melatonin has anti-inflammatory and antioxidant properties in the lungs. It has been shown to be protective against acute lung injury and acute respiratory distress

syndrome caused by other viral pathogens in preclinical animal studies. Melatonin ameliorates RSV-induced lung inflammatory injury in mice via inhibition of oxidative stress and pro-inflammatory cytokine production. RSV is a very contagious and common virus that infects the respiratory track of most children by two years of age. Two clinical studies have shown that melatonin has antioxidant and anti-inflammatory actions in the lungs, in newborns, born with respiratory distress syndrome. Melatonin treatment reduced pro-inflammatory cytokines and improved the clinical outcome.

So melatonin can decrease pro-inflammatory cytokines, as we've been discussing. Several clinical studies have found that melatonin, can reduce circulating levels of pro-inflammatory cytokine levels in people with higher circulating levels. A meta-analysis of randomized controlled trials suggested that the use of melatonin is associated with a reduction of TNF alpha and IL-6 levels. In chronic inflammatory conditions, like in an eight-week randomized controlled trial with patients with diabetes and also periodontitis, supplementation with 6 milligrams of melatonin per day decreased

serum levels of IL-6, TNF alpha, and highest sensitivity CET reactive protein, which are all biomarkers of inflammation. And another trial in patients with multiple sclerosis, supplementation with 25 milligrams of melatonin per day for six months promoted the reduction of serum concentrations of a variety of different pro-inflammatory cytokines, as well as biomarkers of oxidative stress. Also, during the acute phase of inflammation, for example, during surgical stress, brain reprofusion and coronary artery refusion, melatonin intake for less than five days, reduce the level of pro-inframatory cytokines.

Some evidence suggests that melatonin modulates the NLRP3 inflammatory lymphomomombsomes. Inflamosomes are large intracellular complexes that detect and respond to internal and external threats. Activation of inflammasomes have been implicated in a host of inflammatory disorders. Sarge Cove-1, the virus responsible for the original SARS outbreak, activates the NLRP-3 inflammatory hormone, triggering NF-CAPA-B and a cytokine storm in the lungs. During a cytokine storm, the excessive immune response ravages healthy lung tissue and drives acute respiratory failure.

Melatonin has been shown to reduce the infiltration of macrophage. and neutrophils into the lung in acute lung injury animal models due to the inhibition of the NLRP3 inflammation. Melatonin is commonly taken to improve sleep. Sleep is very important for regulating the immune system and lack of sleep can significantly dampen immunity. A meta-analysis of 19 randomized controlled trials demonstrates that melatonin decreases sleep, onset latency, increases total sleep time and improves overall sleep quality. Trials with longer duration and using higher doses of melatonin demonstrated greater effects on decreasing sleep latency and increasing total sleep time.

Melatonin has a pretty high safety profile. Short-term use of melatonin is safe even at high doses. There's no adverse effects that have been seen at doses even as high as one gram per day for a month. In patients in the ICU, doses of 3, 6, or 10 milligrams were shown to be safe compared to placebo. Also in animal models for acute lung injury, acute respiratory distress syndrome, there's been no adverse effects of melatonin supplementation. But even though melatonin has been considered safe in many, many human studies, there are currently no studies with melatonin supplementation in COVID-19 patients.

So that needs to be carefully monitored. In summary, melatonin seems to be beneficial for a variety of respiratory and inflammatory disease models. It's been shown in clinical studies to dampen inflammation. It regulates the immune system, lowers oxidative stress as well, and it does dampen the cytokine storm. It's also been shown to improve sleep. and that is associated with a decrease in anxiety.

While there's no direct evidence that melatonin use could prevent or treat COVID-19, it's plausible that melatonin may possibly have some beneficial role. Thank you so much for listening. I hope you enjoyed this special Q&A episode. If you would like to submit a question for the next round in this COVID-19 Q&A series, you can sign up for my email newsletter on my website at foundmyfitness.com. I will send out an email summarizing this Q&A episode along with the link to submit new questions. Better still if you'd like to become a member of my monthly member's Q&A where we have an even more robust long-term Q&A series,

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