Dr. Seheult: So we're looking at 25-hydroxyvitamin D. That's the storage form of vitamin D.

And what they found was as your levels started to drop below 50 nanograms per milliliter, we started to see an increase in SARS-CoV-2 positivity rate. And it didn't matter based on race, gender, geography, or age, all groups saw an increase in SARS COVID 2 infections associated with a lower level of 25-hydroxyvitamin D. The lower these levels went, the higher the positivity rate.

And that was just the beginning. I mean, this went on and on and on. No matter how you slice it or dice it, there was this very strong association of vitamin D deficiency with higher rates of COVID. Higher SARS-CoV-2 positivity rates and higher admissions. We see people being admitted to the hospital who had lower rates than those that had similar symptoms but we're not SARS-CoV-2 positive.

And, you know, as you know, just because you have an association doesn't tell you that you have causation. The only way you could really find that out is by doing randomized controlled trials that we've talked about.

Rhonda: And so you mentioned admissions, but also mortality. Weren't there some studies also showing that patients that were more vitamin D deficient were more likely to have a severe case and even die, versus ones that had higher vitamin D levels?

Dr. Seheult: Absolutely. Yeah. So they showed that there was a difference in mortality, that there was a difference in which ones went on to need ventilators. And so all of this. So the question wasn't, was the vitamin D involved in this somehow? The question was vitamin D, the causative role, or vitamin D deficiency the causative role?

Rhonda: Right. And as you mentioned, because these are observational studies one could argue, well, maybe low vitamin D is just biomarking unhealthy, in general, right. And this is where, as you mentioned, randomized control trials are really key. But there's another type of study that I love to cite and talk about, because as you had mentioned, previously, randomized controlled trials are very, very expensive to do, they're very difficult, you know, they take a long time. It's a challenge.

So another way of measuring more of a causative role, you know, of certain factors, and particularly, in this case, lifestyle factors or something that, you know, I call vitamin D lifestyle, because you're making it you know, from the sun, they're called Mendelian randomization studies. And essentially what they do is they measure, so everyone has, you know, different variations in their sequence of DNA in their genes. And these variations often are just a change in one DNA nucleotide, which is called the single-nucleotide polymorphism, or SNP for short, as you know. But for people listening and watching, there are many different variations in genes that convert, for example, 25-hydroxyvitamin D, the major circulating metabolite of vitamin D, into 1,25-hydroxyvitamin D, which is the active steroid hormone. And these changes in just one nucleotide of DNA in these genes are associated with lower circulating levels of 25-hydroxyvitamin D, because, you know, it's just, you know, different genes are doing different things. And sometimes genes get less active. And sometimes they're more active based on this, you know, sequence change.

So it's well known that these certain SNPs are associated with lower circulating 25-hydroxyvitamin D levels. And so there have been meta-analyses looking at people that have the SNP, didn't measure vitamin D levels at all, it's already known, they have lower circulating levels. So you can't say, Oh, you know, you're just measuring their low vitamin D. That's bio marketing and other health status. This is just genetics. We're just looking at a gene that's known to cause that. And these people have a much higher mortality from respiratory tract infections. They have a higher all-cause mortality, they have a higher cancer mortality. Cardiovascular-related mortalities is unchanged. But respiratory tract infections are much higher.

And so, that Mendelian randomization study, I love to cite that because it really is establishing causation because, you know, you're not just measuring vitamin D levels and then saying, well, maybe they're low in vitamin D because they don't go out and exercise or maybe they're low in vitamin D because they're, you know, obese and, you know, vitamin D is less bioavailable, which it is in obese individuals, as you mentioned.

So, the Medallia randomization studies, in addition to the randomized controlled trials, I think another piece of evidence that hints towards possible causation of vitamin D being important for preventing respiratory tract mortality as well.

Dr. Seheult: Oh, that's amazing. I wasn't even aware of that. That's a great way of showing causation. And of course, they are working on some pilot studies that are trying to show randomization, but how big of a study was that?

Rhonda: It was quite large. I don't recall off the top of my head, I do have it linked in my notes, I can get up and send you. But yeah, there's been other SNPs in, like, the vitamin D receptor, for example. So children that have a single nucleotide polymorphism in the vitamin D receptor, they also have a higher mortality from respiratory tract infections as well, you know. So vitamin D, as you mentioned, you know, it's a steroid hormone, it's going into the nucleus, you know, it binds to the vitamin D receptor, which then heterodimerizes with another receptor called the retinoid receptor. And that complex, you know, goes into the nucleus where your DNA is and it recognizes a very specific sequence of DNA called a vitamin D response element. And these are in more than 5% of the protein-encoding human genome. I mean, that's a lot of genes vitamin D is regulating in all sorts of tissues. You know, brain in the immune cells, you know, and other organs as well.

So, I do think like, you know, thinking about mechanism, and I know, you've talked about, you know, the role looking, you know, underlying mechanisms, how does vitamin D regulate the immune system? I mean, there's a variety of ways. And specifically, it's really interesting. And I'm getting off topic here. I want to get to the pilot randomized controlled trials, but are you aware of the role vitamin D plays in the ACE2 and renin-angiotensin system?

Dr. Seheult: I know there is a connection. I was actually reading that just briefly. I think you're the one that sent me the article. But I need to remind myself.

Rhonda: We covered it back in March or April. I did a short little Q&A podcast on it. And it's really interesting, you know much more about the renin-angiotensin system than I do as a medical practitioner, which, you know, it obviously plays an important role in regulating blood pressure and fluid homeostasis, and, you know, I think even in the lungs too. But what's interesting about the vitamin D renin-angiotensin system kind of it converges on the ACE2 receptor, which, as you know, and probably most of the world has heard by now is how the SARS-CoV-2 virus enters into ourselves, it binds that receptor. Well, what's been shown with SARS-CoV-1 is when the virus which also binds to the same receptor to get inside of the cell, it binds to the receptor and it internalizes the receptor and down-regulates ACE2, which is not good because that is really important for this renin-angiotensin regulation, as you know, Dr. Seheult. So that's been shown with SARS-CoV-1.

And what happens when the ACE2 gets down-regulated, acute lung injury gets really bad. And so there's been some animal studies that have found, for example, if you high-dose with the active form of vitamin D, the animals, and then you cause acute lung injury, ACE2 goes down, acute lung injury goes up in the placebo group, but the vitamin D group, it normalizes the ACE2 levels.

So if you think about it, you know, this is a hypothesis, of course, another potential way vitamin D could be playing an important role in this specific virus is through regulating ACE2 levels. And what's interesting is that there was just a very recent study that came out. ACE2, the gene, it's located on the X chromosome. And women have two X chromosomes most of the time. One of those X chromosomes, the gene is inactivated. But there are genes that escape that. And ACE2 is one of those. And so women have much higher levels of ACE2. And so researchers are thinking this is protecting them from a more severe COVID-19 outcome because they're getting that ACE2 levels, like, you know, higher in terms of, you'd think, Oh, well, more ACE2, that means the virus is getting in and, but actually, biology always tricks you. You know, you always think one thing, and then it's like this beautiful, you know, sort of complex scenario.

But I'm digressing. And I just, kind of, wanted to bounce it off you because you're such a scholar, and I thought you probably would find that interesting, and I certainly hope scientists are testing that hypothesis because it seems very relevant.

Dr. Seheult: Yeah, it does. Not only that, the human body is so complex as you say that there's so many connections. The other aspect of angiotensin or ACE2 I should say is that it gets rid of pro-oxidative products and it increases antioxidant products. So for instance, angiotensin II, and angiotensin (1-7), those are in balance and ACE2 tries to keep those in balance. But when ACE2 is knocked out by other SARS-CoV-2 or SARS 1, the amount of oxidative stress goes up dramatically. And what we see that that may play a role in terms of thrombosis. So you have oxidative stress in the ACE2 receptors at the endothelium of the vasculature that causes inflammatory stress, oxidative stress, that causes thrombosis. And that's where that happens as well. So all of these things, it seems as though we've got the dots, connecting them requires very good randomized controlled trials. But again, like you said, hypothesis driving type of studies that may answer that question.

Rhonda: That was very enlightening. I do remember reading about that. And, wow, I didn't realize it played the role in the thrombosis as well. So that's super interesting. But as you mentioned, yes. randomized controlled trials are key. And there have been, I've seen, you know, one stronger, but small trial that was published, was it back in September, that found... I think it was in, was it Spain, perhaps?

Dr. Seheult: Yes. Yep. It was October, I've got it pulled up here, October of 2020. And it was Marta Castillo who was the lead author on this one out of Spain. There was a little issues with the randomization. So probably the effect was overemphasized. But if you look at the effects, they were quite dramatic. In the calcifediol group. Lets us back up a little bit, what's calcifediol? That's the name that we give the 25-hydroxyvitamin D.

So in this study, they didn't give just vitamin D, they gave the product of the metabolism in the liver of vitamin D.

Rhonda: Now, do you think that's important for someone that is undergoing, let's say, I mean, if you're so sick, and maybe your liver's not working properly, your kidneys aren't working? I mean, how are you going to convert these vitamin D metabolites into this steroid hormone? Right? So, do you think it's important to give someone that, you know, more downstream, like an active form versus vitamin D3, for example?

Dr. Seheult: Exactly. And so that's the question is whether, because it takes some time for the vitamin D to be metabolized in the liver. I've seen some people say up to, you know, seven days. It probably is a little bit less than that. But when you're giving vitamin D in the acute situation, it doesn't really matter if you're just supplementing over a long period of time and you're hoping to prevent yourself from having bad outcome with COVID-19. But if you've already got COVID-19, what they may be saying here is that supplementing not with vitamin D, the product prior to liver metabolism, but in fact, calcifediol 25-hydroxyvitamin D, might be a more efficacious intervention. And that's what they did in this study.

Rhonda: And you know another thing this sort of brings to my mind, you'd mentioned the pre-pandemic randomized controlled trials looking at the role of vitamin D supplementation in preventing respiratory tract infections. I believe it was Martineau that was the senior author on that.

Dr. Seheult: Yes.

Rhonda: And what was so interesting about those meta-analyses was that they found weekly doses, daily doses, worked, but monthly doses did not in terms of protecting against key respiratory tract infections. And to me, it's like we can't learn from the past. Like, there's something wrong, you know. So when you're designing a clinical trial, you need to be familiar with literature and see, oh, there's these meta-analyses showing that monthly doses don't work. Maybe we shouldn't design the trial that way. Maybe we shouldn't just do one large dose which I think I've seen a preprint floating around for COVID-19 where there was one large dose and there was no effect.

Dr. Seheult: Yes. Yeah. You're referring to the Brazilian study where they gave 200,000 international units at the very beginning.

Rhonda: Yes, I don't believe it's peer-reviewed yet. Am I correct for saying that?

Dr. Seheult: You're correct. At least I haven't seen it yet.

Rhonda: Okay.

Dr. Seheult: This study though, this Spanish study where they gave something called calcifediol which is, again, 25-hydroxy. This is not an over the counter medication. This is a prescription-only. It's usually prescribed by nephrologists in patients with renal disease that have very high, you know, parathyroid hormone levels. And they gave it on day one, they gave it on day, I believe three, and then again at day seven. And what they found was in the calcifediol group, there was only 2% that went to the intensive care unit, whereas in the placebo group, 50% of those went to the intensive care units. That's a very, very marked number. Again, there was, I think, the British recently got together and looked at all of the data. And you may have known they made a recommendation that there still was not enough evidence to cause supplementation to prevent COVID-19. Interestingly, they discounted this Spanish study because they felt that the randomization was not good enough. But there's been some mathematicians that have looked at this study and said that it would be impossible for that randomization to fully describe what happened in this study. In other words, they believe that there was an effect of calcifediol in the study.

Rhonda: And it seems very likely, if we have, as you mentioned, meta-analyses of many, many, many, you know, over 25, different randomized controlled trials, showing vitamin D supplementation prevents respiratory tract infections, you know, in people that are vitamin D deficient between 50% to 70%, and even still had an effect and people that had normal, sufficient levels of vitamin D, maybe we can talk about what those are. But what would make, I mean, of course, you know, viruses are different, but I mean, a respiratory tract infection, you know, to some degree, there's got to be some common denominators, right? I mean, so, to me, it would seem, you know, logical that something like vitamin D, where, in the United States, you know, 70% of the U.S. population is categorized as vitamin D insufficient, which defined by the endocrine society is less than 30 nanograms per milliliter. And 30% of the U.S. population is what is called vitamin D deficient, so they have less than 20 nanograms per milliliter of blood levels of 25-hydroxyvitamin D, which is the major, you know, circulating metabolite of vitamin D.

So, I mean, you know, the question becomes, and maybe we can talk a little bit about vitamin D supplementation and safety. But is it really, I mean, you don't have to make a bold statement that it's going to prevent COVID-19. I mean, absolutely, we should be following the CDC guidelines on social distancing, on wearing masks, on washing our hands. And also, you know, as soon as they become available vaccinations, but in addition to following the CDC guidelines, it might be prudent to say, it's probably important to become vitamin D sufficient. In other words, if we already have data that, you know, 70% of the U.S. population, you know, has insufficient levels of vitamin D, then clearly, people need to take a vitamin D supplement, and, you know, I think or maybe need to get their levels measured. I mean, the best way is to go to a doctor, get your vitamin D levels measured, you know, and then see what those are, and then take a supplement to bring them up.

And the reason I say that is because, as you mentioned, you know, we make vitamin D in our skin. But depending on where you live, you know, you said UVB radiation is how we make it in the skin, depending on where you live, many parts of the year, UVB radiation is not even hitting the atmosphere. Right? So.

Dr. Seheult: Exactly. And so if you live above the 35th parallel, which, if you're in the United States, that would be the southern border of Tennessee or just a few miles north of us here in Southern California. You know, most of the country lives above the 35th parallel, which means that you're not going to get enough UVB radiation in the winter months to supplement or to keep elevated your vitamin D levels sufficiently. And so you've got to take supplementation.

Rhonda: And sunscreen blocks UVB radiation and most people are wearing sunscreen. Most people are indoors now. You know, we're on our computers, we're not in agrarian society like we used to be. You know, people aren't out in the sun all the time. People are inside. I mean, if you look at, you know, enhanced data over the past couple of decades, you see vitamin D levels are steadily just going down, down, down, down. And I think that's because most people are now spending more time indoors. Also, as you mentioned, people like African Americans, people with darker skin have much lower levels of vitamin D. In fact, African Americans, the most recent enhanced data that was published, they're 30 times more likely to be vitamin D deficient than Caucasians.

And the reason for that is because melanin is a natural sunscreen, I mean, it protects you from the burning rays of the sun. So if you live in, you know, Australia or closer to the equator, you know, Somalia, for example. That's great because you're getting a lot of UVB exposure year round. But when you take a person and they migrate, say they move from Africa to New York City to Chicago, well, it becomes a problem because you're much further from the equator. And now you've got this natural sunscreen that helps you, you know, protect you from the burning rays of the sun. And now you're living in a place where you're not getting as much sun. And so there was a study that came out of the University of Chicago A few years ago that found African Americans in Chicago have to stay in the sun six times as long as a Caucasian to make the same amount of vitamin D in the skin.

Dr. Seheult: Yeah, I believe it. And you know, the other thing people say, Well, if that's the case, then how come people are getting COVID-19 in sunny places, in hot places? For instance, if you remember back in the early part of summer, there was a huge epidemic in Arizona, and also in Florida, in Texas. Well, I mean, if you think about it, yeah, there's a lot of sun. But if you're inside, you're not going to get exposed to the sun.

Rhonda: Right. You think people in Arizona are going out in the sun in the summer, dude, it's like living in winter in summer. I lived in Tennessee for six years, and I'm from Southern California. So summers, I was used to spending on the beach. When I went to graduate school summers became like winter because I did not want to be outside. It was like 95 degrees, humidity, hot. I mean, so I spent way more time inside in the summer in Tennessee than I did in the winter in [Southern California.

Dr. Seheult: Right. And here's the other thing, too is that UVB barely gets through the atmosphere down to us, and it does hit us when we're outside. And the sun's got to be pretty high up in the sky. You go behind a piece of glass, there's almost no UVB at all, the only thing that's coming through is UVA, which is, you know, nasty ultraviolet radiation that makes your furniture, you know, fade, your carpet fade, and it gives you aging wrinkles on your skin. So if you think that you're sitting by the window is going to give you some nice vitamin D, think again.

Rhonda: And clothing, right? Clothing also blocks it, you know. So, you know, the question becomes why vitamin D insufficiency and deficiency is so prevalent in our country. And also, you know, in places like the UK where you said, you know, they're not finding enough evidence to recommend vitamin D to prevent COVID. Well, maybe that's a strong statement, and you need more randomized control trials to make an extraordinary claim like that. But you can still make a claim that it's probably in your best health interest to maintain good levels of vitamin D. And that because we know vitamin D deficiency is so prevalent that it's probably best to get a vitamin D test and measure your levels and take a vitamin D supplement.

Dr. Seheult: Exactly. And the thing that's a little confusing too, is that a lot of these levels that we've come up with are based on the endocrinological function of vitamin D with bone metabolism. We don't know if that's the value that we need for immunological functioning or COVID. But we do have some associative studies that seem to show at least in those studies that we talked about earlier where looked at 191,000 people that SARS-CoV-2 rates started to go up once levels dropped below 50. So that's an interesting number.

Rhonda: That's interesting. Back in 2013, there was a meta-analysis published, I don't know the author's name, but the studies dated back from the 1960s to the 2013. And it was looking at all-cause mortality in association with vitamin D blood levels. And it was found that you know, levels, somewhere between 40 to 60, or 70, like was the lowest all-cause mortality. Like, there was this sweet spot. You know, and of course, it's one of those things where, you know, associative studies, there's always the problems that people try to, you know, correct for confounding factors. But the idea is to look.

And this is what you've done such a fantastic job, you know, with your scholarly work at MedCram videos is looking at the whole body of evidence. The observational data, the mechanistic data, the case studies, and you know, if there are randomized controlled trials, the animal studies as well, you know, because that helps give us some insight on mechanism, and of course, you can't translate an animal study to humans, but if you take the whole body of data, right, everything together, then you can begin to tell a story as well. So, in terms of supplementation, though, you know, the upper tolerable intake that's been set by the Institute of Medicine has been 4000 IUs a day. And, you know, vitamin D is a fat-soluble vitamin, what about toxicity? [inaudible 00:50:30]

Dr. Seheult: Toxicity, there was a statement that I read that said that vitamin D is probably the least toxic fat-soluble vitamin. So there was a study where these Polish scientists looked at the Mayo Clinic's database, and they looked at 20,000 people. And we've talked about this in our in their video that we recently published, one person had hypercalcemia, out of those 20,000. And they had ranges, people supplementing anywhere from 0 to 55,000 units a day. And really just one person. And that person's vitamin D level, if I recall correctly, was up in the 200, 300 range. That's nanograms per milliliter. And that's [inaudible 00:51:14]

Rhonda: That's hard to do. Wow.

Dr. Seheult: Yeah, it's massive.

Rhonda: Yeah, I remember reading a study, and I'm sure you've seen this one where there was the long-term supplementation with 10,000 IUs a day and it was really no toxic effect. And that was, I forgot how long term it was. But...

Dr. Seheult: Yeah. The other thing that I've seen is that, you know, it's not a linear-response curve. So as you go up in supplementation, it's not like your nanograms per milliliter are going to go up linearly. What we notice actually, is that the first 1000 units that you supplement causes an increase of about 4.8 to 5 nanograms per milliliter. Whereas, when you get up to about 15,000, 20,000, 30,000 that each additional 1000 goes up by about a 10th of that. So it's a nonlinear relationship. It's exponential, but the reverse of exponential. As you go up higher and higher, the increment becomes less and less. It's almost like you're saturating receptors, if you will, it's probably not the case but that's what it seems to be like.