196 - Cellular Recharge: Can Nicotinamide Riboside help in Long Covid Recovery?

I'm joined today by Edmarie Guzman-Velez & Rudy Tanzi as we dig into a clinical trial of nicotinamide riboside for Long Covid, why NAD matters for cellular energy, and where the results show promise for fatigue, sleep, mood, and executive function. We share what worked, what did not, and the next steps.

• Overview of NAD, mitochondria, and energy in brain and immune cells
• Why Covid may deplete NAD and how NR restores it
• Trial design using intra-individual crossover with placebo run-in
• Dosing at 2,000 mg NR daily under IRB oversight
• Serial NAD blood measurements confirming a threefold rise
• Outcomes on fatigue, sleep quality, depressive symptoms, executive function
• Limits of small samples and reinfection attrition
• Safety, label guidance, and medical supervision for supplements
• Plans for biomarkers of inflammation and activity data from wearables
• Future research on symptom clusters, sex differences, and combinations

Links:

Full paper available HERE

More about Niagen Bioscience 

Dr. Tanzi is paid consultant for, and equity holder in Niagen Biosciences.

For more information about Long Covid Breathing courses & workshops, please check out LongCovidBreathing.com

(music credit - Brock Hewitt, Rule of Life)

Chapters

• 1:51 Meet The Guests And Study Aim
• 4:08 Why NAD Matters For Energy And Brain
• 10:11 How COVID May Deplete NAD
• 11:55 Why Nicotinamide Riboside Instead Of NMN
• 17:19 Trial Design And Dosing Choices
• 23:50 Measuring Outcomes And Biomarkers
• 26:27 Results: NAD Up, Symptoms Shift
• 31:18 Executive Function, Fatigue, Sleep, Mood
• 36:11 Safety, Dosage, And Practical Use
• 41:36 Ageing, Inflammation, And Microglia
• 47:46 Next Studies And Biomarker Plans
• 53:48 Reflections, Teamwork, And What’s Next

Transcript

Jackie Baxter: 0:56

Hello and welcome to this episode of the Long COVID podcast. I'm delighted to be joined today by two guests, and we're going to be talking about a recent research study, and we're going to get into what all that is in just a moment. But my wonderful guests today are Dr. Rudy Tanzi and Dr. Ed marie -Guzman Velez. So before we get any further into this, would you guys just like to say a few words about who you are and what do you do?

Edmarie Guzman-Velez: 1:26

Well, thank you so much for uh inviting us to the podcast. Um I am an assistant until a month ago, I was an assistant professor at Harvard Medical School, Mass General Hospital. Um currently I'm an assistant professor in the Department of Neurology at the Rutgers Robert Wood-Johnson Medical School and Center for Healthy Aging Research. Um and um my I recently led the study that we're going to be talking about in collaboration with several colleagues, including Dr. Tanzi, with long COVID and neurological symptoms associated with it.

Rudolph E. Tanzi: 2:05

And I'm Rudy Tanzi. I'm a professor of neurology at Harvard Medical School. And at Mass General Hospital, I direct the Genetics and Aging Research Unit, which is 11 labs carrying out preclinical Alzheimer's research. I also serve as director of the McCann Center, which uh funded um most of this study that we're hearing about today, um, and uh where we study um the role of supplements, natural products in uh treating neurological um diseases, and we're we're very uh proud to be part of the study that uh Dr. Guzman uh uh uh led.

Jackie Baxter: 2:46

Perfect. Thanks so much, guys. Um, so maybe the first thing to do is just to take a little sort of snapshot of what is this study um that we're talking about. And then I'd love to talk a little bit more about like the hypothesis and why. Why did we actually think that this might work in the first place? Um so do you want to give us like a little bit of an overview?

Edmarie Guzman-Velez: 3:11

Yes, of course. So, you know, obviously this was inspired by uh the alarming number of individuals who had COVID-19 and haven't fully recovered. Um, and this was a clinical trial. So we were looking at whether an nicotinamin rebocide it's a form of vitamin B3, um, could help improve or elevate levels of NAD, which we can talk more about later. Um, and if this in turn could help reduce or improve some of the symptoms that are most common in people with lung COVID, particularly this cognitive difficulty. So a lot of people talk about it as brain fog, um, and also other symptoms such as fatigue, sleep difficulties, and others that um people experience and that can interfere with their daily activities. Um, and yeah, that's kind of a very short summary. So, yeah, clinical trial trying to figure out whether this could be helpful for people with lung COVID.

Rudolph E. Tanzi: 4:15

And I would just add that you know, NAD plus has been shown to play a key role in cellular resistance resilience of cells and the energy in cells. And in um COVID patients, NAD plus levels drop. And these this NAD deficiency leads to all types of issues that could uh likely contribute to long COVID symptoms. And so nicotinamide ribicide is probably the uh the easiest and best way to uh increase your NAD plus uh level. So it just seemed that this was an obvious trial um to to initiate and see if we could help long COVID uh patients by increasing NAD plus levels using nicotinamide ribicide, in this case through the uh uh NIA gen uh from NIAGEN Biosciences. I also just want to state for uh conflict of interest, I am a longtime consultant to NIAGEN Biosciences and uh and whole equity in the company as well. And so for that reason, I was not directly involved in the trial execution, but involved with the early conception and design and then later the interpretation of results to follow conflict of interest rules at Mass General Hospital.

Jackie Baxter: 5:28

Of course, yes. Um, so can we talk a little bit about NAD? Now it's it's alphabet soup, isn't it, in um in in sort of medical research world, I think. So uh I guess what would be a really good sort of good place to start would be what is NAD? Um, what does it actually mean? What is it? What does it do in the body and what do different levels of it mean or might what different levels of it might mean?

Rudolph E. Tanzi: 6:00

I can start. Um NAD stands for nicotinamide adenine dinucleotide. It's basically uh called a coenzyme. It it allows various activities to take place in the cell, especially given the cell energy to do what it needs to do. Um the uh the the batteries of our cells are mitochondria. And mitochondria tend to start getting defective in cells, especially in association with long COVID. So NAD plus is a way to supercharge up those mitochondria again. And and um it plays a role in what's called a mitochondrial respiratory chain. In other words, how mitochondria supply energy uh to cells. And so if you have a energy, if you have an NAD plus deficiency, everything your cells are supposed to do that's gonna do less well. And uh you see this manifest as problems with uh immune resistance, with uh fatigue, with uh just generally how much energy you have. Um even um psychiatric symptoms, so depression, anxiety, agitation, sleep. NAD plus is so important. And and so it's it's it's unfortunate that COVID particularly targets NAD plus levels, and this probably is a major, if not the major, contributor to symptoms of long COVID.

Jackie Baxter: 7:22

And do we know what the mechanism is in that COVID reduces the levels of NAD in the body? Do we know like what what it is that it does there, or do we just know that it does happen?

Rudolph E. Tanzi: 7:34

And maybe I don't know. Do you know? I don't I don't know if we know the mechanism.

Edmarie Guzman-Velez: 7:38

I I don't know. And I think this one of the limitations is that we need more research um on this. If you make a quick look, you're not gonna find much information out there, particularly specifically to COVID. But what is out there, I think it's very convincing that there's definitely an association between the virus and depletion of NAD.

Rudolph E. Tanzi: 8:04

I mean, without getting deep in the weeds, there are this there's these enzymes called PARP PARP enzymes, and they help maintain your genome and uh protect cells from dying. And so the virus, COVID virus, does by activating these genes, it it causes the NAD plus to be used up. So, in terms of you know, a precise molecular mechanism, that uh could be one possible way in which you know you're depleting NAD plus by activating uh and it may be that the cell's trying to protect itself from the virus, so it's activating these these PARP genes in order to maintain resilience, but that's energy consuming, and that means the NAD plus gets used up, like using up a battery. So that could be one way in which it happens, but we don't know exactly all the details.

Jackie Baxter: 8:55

Right, right. But what we do know is that the levels of NAD do get depleted in people with long COVID, and that is something that you can then uh look at in terms of their study. Uh, how do we increase those levels? Or is it how do we stop them from being depleted? Uh or maybe both.

Rudolph E. Tanzi: 9:15

Uh I should probably clarify that uh patients who are hospitalized with COVID, who are severe COVID, have NAD plus levels that are depleted. So we're assuming they were long COVID, this also happens, but I don't know if there's been a study that shows specifically this in long COVID. It's in severe COVID cases requiring hospitalization that you see this drop in NED plus levels.

Edmarie Guzman-Velez: 9:38

Yes, that's correct.

Jackie Baxter: 9:39

Yes. Right. So it's a sort of assumption that uh it does it in the body of anybody with COVID, or is it you're thinking, or is it more severe in people with who who have who go on to develop long COVID? Or is this is this something that's not not really been looked into?

Edmarie Guzman-Velez: 9:59

Oh well, that's part of what we wanted to answer um with the lung COVID study, um, is actually see if if we already know what happens in the acute stage, you know, may that be explaining um at least partially why these individuals group of people have not fully recovered. Um, and to kind of also go back to your first question, so in this case, it wouldn't be so much as preventing the depletion, but trying to, we are assuming that there's already a depletion we're trying to increase and get it back to normal levels for that person, right? Okay, cool.

Jackie Baxter: 10:40

Um so how does no, you're gonna have to remind me what the name of the the building block was, but it's the the niogin is is what you've used in the study, isn't it? Um what is that and why is that relevant to the NAD levels?

Rudolph E. Tanzi: 11:02

Yeah, niogen is nicotinamide ribicide, which if if you look at the pathway to making NAD plus, nicotinamide ribicide or NR gets turned into something that's abbreviated NMN, and then that turns into NAD plus. But if you want to s increase NAD plus levels, you would use nicotinamide ribicide and then in the blood that turns that that that would be taken into the cell and then turn into NMN and NAD plus. If you use NMN to do it, NMN would have to be turned back to nicotinamide ribicide in the blood before the cell could take it up. So it's a less direct way to increase NAD plus with NMN. NR will do it directly, but it's just one of it's just along the synthetic pathway to NAD plus NR is one of the steps along the way, and the easiest one to uh pharmacologically affect to get NAD plus levels higher, which it you know, which has been shown to do.

Edmarie Guzman-Velez: 12:04

Right. I wanted to exactly uh say that uh it's already been shown in animal models and even some smaller clinical trials, that this is an effective way to increase NAD plus levels. So, you know, that information was already available, um, which made us confident that in fact we were we would be able to increase NAD plus in this population.

Jackie Baxter: 12:27

Because that was kind of one of my thoughts that was just going through my head. Like, if you want to increase the NAD levels, can you not just give people NAD? But no, because it would have to break it down anyway.

Rudolph E. Tanzi: 12:43

NAD was doesn't really make it out of the gut. Just if you just orally took NAD plus itself, you would it would never make it into cells. Just like NMN, even though it's close one step closer to NAD, it it the cells won't take it up. So it has to be reverted back to nicotinam iribicide or NR before the cells can take it up, then turn it back into NMN and into NAD plus. So NR is the is the most direct route to do it.

Jackie Baxter: 13:10

So it's kind of like the smallest, well, probably not the smallest, but you know, the smallest building block that the body can sort of handle in order to then build that back up. Um I'm visualizing Lego here.

Rudolph E. Tanzi: 13:22

Yeah, no, you got it, you got it. Yeah.

Jackie Baxter: 13:26

You've got to get the little pieces in order to build up to the the bigger um your Lego castles and things. Um I'm showing that I'm still a total child. I do have Lego castles in my in my house, and I don't have children, they're mine.

Rudolph E. Tanzi: 13:40

I use Lego metaphors all the time just so you aren't they brilliant.

Jackie Baxter: 13:45

Aren't they brilliant? Because we all understand them. Um so NR. Can we just talk a little bit more about what what actually is it? You know, we've talked about how it's this small building block and it will build up into NMR, you said, and then up to NAD. But what actually is it?

Rudolph E. Tanzi: 14:07

It's a it's a form of vitamin B3. Um and so it's a chemical, it has a structure. Um, and you know, for most things in the body require synthetic pathways, right? You just you know, you have the building blocks, and then they are modified by enzymes to turn into A, turns into B, into C, and then finally get D, in this case NAD. So nicotin myrobicide can be found as you know, in small amounts in in some foods like milk and yeast, and even a good IPA has nicotin myrobicide in it, believe it or not. Although I'm not suggesting that's how you get it.

Edmarie Guzman-Velez: 14:44

Uh I actually didn't know that one.

Rudolph E. Tanzi: 14:46

Yeah, yeah, it's in beer. Uh, but but uh but you know it's it's it's basically a uh a a chemical building block and in and it's technically a vitamin, it's a form of vitamin B3, which is also related to niacin. Niacin is uh is is uh uh is B3, but this is a form an alternative form of B3 related to niacin.

Jackie Baxter: 15:53

Right. And that is one, I mean, you know, people with long COVID and MECFS have they've you know been through and tried all the supplements, and and niacin is is one of those ones that does get talked about. Um so I think people will probably be familiar with that one. Um so let's talk a little bit about the study itself. So we've kind of talked about, you know, what what is this stuff? Why do we want it, and what does it do? Um let's get into the study. So, how how did the study work? Um, what was your kind of procedure? Was there a certain dosage? Well, I mean, there must have been a certain dosage that you used. Um, and how did you kind of monitor it? Um, what what did that kind of all look like?

Edmarie Guzman-Velez: 16:37

Yes, um, I'm happy to share that. So the dosage was 2,000 milligrams of nicotinamide rebocyte um per day. And so what we did was that we invited to participate people with lung COVID who had been infected with COVID-19 at least two months prior to um starting in the clinical trial and who were experiencing brain fog or these difficulties with memory or language, and also at least two other symptoms. Um and then these individuals also, none of them were hospitalized during acute infection. Um, so they experienced mostly mild to moderate illness, they stayed home when they had COVID instead of having to be hospitalized during the ICU. Um, and and then um everyone started taking placebo um after you know, we screwed did all the screening to make sure that they comply with all eligibility criteria. And they took placebo for two weeks. Um, and and then in two weeks we did a lot of testing. So we collected their medical history, all the medications that they were taking, including other supplements. Um we did some objective cognitive testing. So these are neuropsychological tests that have been validated to measure different aspects of thinking. Um, but in addition to that, we also wanted to understand what was their perception of their cognition. And so we also gather data using validated questionnaires about their perception of their cognitive changes, their perception, perception of their sleep quality, of their fatigue levels, um, their symptoms of depression, anxiety, trauma. So we really, really tried to get a good picture of what it was that they were experiencing because of COVID. And so at that point, once they completed all of these tests, um, some people then switched to and started taking nicotinamide rebocide. Um and they took NR for 20 weeks. And then there was another group that continued on placebo. And then after 10 weeks, they switched and started taking um NR. And we did this for several reasons. But one, it allows us to see placebo versus NR, right? That's kind of the usual model that you you live hear about when you do clinical trials, but also um this would allow us to compare people with themselves, right? Because you have some people who were in placebo and then they switched. But also we would provide everyone the opportunity to receive the intervention in case you know they could benefit from it. Um, and so all of these tests that I spoke about that they did at baseline, they also did in the middle of the of the clinical trial when the placebo group then switched to uh taking NR and at the end. And so that way we could track for 20 weeks, you know, people who've been taking NR for 20 weeks, people who've been taking NR for 10 weeks, and placebo for 10 weeks, and we were able then to monitor right changes and all of these symptoms that I that I mentioned. And also they provided blood. And with that, we are able to measure NAD plus. So we can also track changes over time in NAD and see how these changes in NAD relate um to their experience of different symptoms.

Jackie Baxter: 20:39

Right. So you're able to actually measure those levels. Did you take the blood samples before, like right at the start as well as in the middle and at the end? Correct. So you could literally track it through.

Edmarie Guzman-Velez: 20:52

Yes. So everyone has at a baseline when no one um actually everyone had been in placebo for two weeks, so there's no intervention. Um, and then in the middle, after 10 weeks of the baseline, and then at the end, which would be 20 weeks.

Jackie Baxter: 21:07

So I mean, I I love that you have done this in the way that all the participants get to experience taking NR because like a I don't know if it's normal, um, but most of the clinical trials that I've heard of have the placebo group and the intervention group. Um so one of the groups don't actually get to take the intervention, and you know, some trials then give them the opportunity to take it afterwards. Um, but for the benefit of the trial, it's two separate groups. So I don't know if that's the normal way of doing it, and you guys have done it differently, or if it's just one that I've not heard of before.

Rudolph E. Tanzi: 21:46

This is a more powerful that group to group placebo and treatment requires huge numbers and it's very expensive. And frankly, we wouldn't have been able to afford between the funding from Nigerian biosensors and the funding from McCann Center, we wouldn't have been able to afford a classic placebo versus treatment group um trial. This the the what we're doing at the McCann Center now is trials where you use a person as their own placebo, and you also have so you might have people who are on placebo and then they switch over to true niogen. You look at the difference. That was one group here. Or you have another one where you're looking at uh they're on nigg, they're on uh niogen the whole time, then they go back, you know, niogen in the beginning, and then continue on niogen. So there is a there is a small is an ability to do a small comparison of placebo versus niogen by having the group that's for 10 weeks on niogen and 10 weeks on niogen again versus the group that's 10 weeks on placebo, then switching to niogen. But the main power comes from what's called the intra-individual uh um and the crossover analysis going from placebo to niogen, comparing to the people on niogen the whole time. And that's where we saw the results. And it just shows that that's where the power is versus just a classical trial. Do you want to add to that, Emory?

Edmarie Guzman-Velez: 23:10

I think another key factor here is that we already knew that NR was safe too. Um, so we're not concerned with, you know, oh, we're we can give this to everyone because we are not sure if this we already knew uh based on other trials that this was safe, that you know, all of them could take it. We were not worried about any um, you know, significant or severe side effects. So I think that also helps with um feeling comfortable um on making on being able to offer this to everyone. And one of our collaborators, Dr. Stephen Arnold, this is what he does in develop clinical trials. And so I think between all of us, we agreed that this would be a powerful um design.

Jackie Baxter: 23:54

And it it makes a lot of sense as well. I mean, you know, with long COVID, for example, you know, you've met one person with long COVID and you've met one person with long COVID. You know, everyone, you know, there's so much variation in the condition that it actually seems to make more sense to compare like person A to person A and person B to person B. Um, particularly if you've not got like thousands of people in the trial itself. So it it does seem to make a lot of sense to me. I've just never heard of it happening before.

Rudolph E. Tanzi: 24:27

You know, all the trials we're doing at the McCann Center now are intra-individual. So you don't instead of a placebo group, you you look at them before you give them the treatment and you track maybe biomarkers in the blood, or you might track, in this case, A D plus levels, and you look at various symptoms, and then then you then you put them on the treatment and then you see how they do afterwards. So it's called an intra-individual. In fact, um our biostatistician at Mass General, uh Roko Dodge, uh just published a paper on Alzheimer's and dementia, calling it the SLIM. I forgot what the SLIM stands for, but it explains this novel trial design where you get much more power from fewer people by having to serve as their own placebo. And that way no one's denied the the drug either. So it's I mean, you know, it's always terrible when you have a trial and half the people or one-third of people, you know, and I d I I don't know it, but they're not getting the drug. I mean, everybody wants to be able to benefit too.

Jackie Baxter: 25:54

Yes, I always thought it sounded a little bit cruel that half of the people who signed up for the trial didn't actually get to potentially benefit from it. Um so it's a way of, as you say, avoiding that as well. Yeah. Um, so let's talk about kind of like the the results. What did you find um from your sort of yeah, your your data measurements, what before, during, and then after. And and as you said, you had a variety of measurements, some of which were, you know, blood and sort of more objective questionnaires, and then you know, things that are maybe a bit more subjective because they're self-reported. Um, and uh yeah, I'd love to hear a bit about how that all came together. And yeah, of course.

Edmarie Guzman-Velez: 26:45

Um, so the first question that we needed to answer was like, did we indeed increase NAD plus levels? Um, and we did actually quite significantly, by threefold in five weeks. Um, because actually I something I failed to mention is that um uh the blood is collected every five weeks during those 20 weeks, not the other measures, but those are. Um, and so we could see that over each even with just five weeks, um, the NAD plus levels at least doubled. So we were successful in um doing what we wanted to accomplish. Um, and then the next question is what does this mean clinically? Um and so when we compare uh the placebo group with the people taking NR, we actually didn't see any differences in terms of their cognitive performance, both in objective and subjectively, or any of the other measures um that um have to do with mood and sleep and so on. And even when we take that, the smaller group, actually, it was a a group of 18 people, 21 people, so not a huge group of people. Um when we compare the placebo to the NR phase, we also didn't see any significant differences. Now, one of the challenges it was that only 18 people completed the complete clinical trial at the end. And this was mainly related to things that were totally not out of uh totally out of our control, um, particularly COVID reinfection. So between 2021 and 2024, we had many waves of of COVID. Um, and so people were getting reinfected, and once they did, we would we needed to exclude them. Um, and also some people, you know, leaving the state and just kind of going on with their lives. Um, so but that what this means, and the reason why this is relevant is that because we had a small group of people in each group, um we decided to do some more exploratory analyses that we had not contemplated at the beginning. And so what we did was we knew that everyone, regardless of what group they had been in, everyone had taken NR at least for 10 weeks. So the NR group who started NR from the beginning took 20 weeks, and the other group took 10 weeks, right? So then we lumped them together. We lumped the people who had taken NR the first 10 weeks of NR, and then the placebo group the 10 weeks of NR. I don't know if that makes sense, but now instead of having 18 in each group, we had over 50, uh 40, um, 43, I think. So over or over 40. Um, this increases our power and this increases our ability to detect differences. Um, and this is where we saw changes. Um, so when we compared uh the these individuals, the 10 weeks of taking NR compared to their baseline, we saw that there were significant differences in their symptoms of depression, sleep quality, and fatigue. Um, specifically that they were reporting that they were experiencing less fatigue, better sleep quality, and less symptoms of depression after taking those 10 weeks of NR.

Jackie Baxter: 30:30

So it's a different way of looking at the same data. Right. So it gives you a sort of different outlook on it, does it? Is that is that a right way of putting it, maybe?

Edmarie Guzman-Velez: 30:41

Yeah, so you know, when when you are ready to start a clinical trial, you are ready to plan, oh, okay, this is the specific analyses that I'm going to do, right? In this case, we were combining, we were comparing placebo versus NR. Um, and you know, we didn't expect that we were going to end up with a lower number that we we anticipated. Um, and so after we saw the small number, like, oh, you know, there's this other way that we could look at the data that is also a very valid way, even though we didn't contemplate it at first, that could help us, given that we have more people, that we could help us see if there are any changes. The more people you have, then the better, right? You were you mentioned actually earlier that I don't remember, I'm gonna, I can't quote you um uh word by word, but you say when you meet one person with lung COVID, you meet one person with lung COVID or something like that. Um, and what that means, right? You there's so much variability, right? There's, you know, people are so different even when they have lung COVID. So the larger the number of people, then the better you're able to capture who is this working in, you know, on so what this is telling us that when you do put these people together, you have more people. Um, and we can see that there are improvements. That some people are improving, are feeling better. Right. The next question would be: who are these people? Right. Is there a specific type of symptoms? Or, I don't know, you know, that predicts, oh, this person is more likely to benefit or not. And those are things that we need to do in the future.

Jackie Baxter: 32:25

You know, I think, you know, what people who are ill want to know is, you know, what's going to help. And, you know, a question like, you know, are there certain people with certain symptoms or certain types of symptoms, you know, all sorts of different symptom clusters? Um, and, you know, is the sort of neurological symptom cluster or you know, whichever particular one that you maybe have more of, is this more likely or less likely to help you? And then, you know, you got to be kind of targeted, haven't you? You know, that the the scatter gun approach doesn't really work. Um, so it's kind of like, where am I gonna target? Um, is this something that's worth me looking into, or is it more likely to help other people with a different symptom cluster? And maybe I should look elsewhere. Um, so that sounds like it would be really useful information to have.

Speaker 1: 33:24

Right. Yeah.

Rudolph E. Tanzi: 33:25

You know, if you look at the data, for first it the the direct placebo to to treatment group, we didn't see an effect, right? But but the but with this unique intra-individual, we saw that. But it was, you know, for cognition, it wasn't all cognition, right? It was executive function, but most would argue that executive function, the ability to make decisions, you know, and the right choices is probably the most important part of cognition. Of course, you know, memory and recall is important too, but for everyday life, executive function is important. And that's the one, unless you correct me, Henry, that we that was improved. Um and and there was, you know, the improvement in fatigue and depression um and sleep quality. So um, you know, at least, you know, we you don't want to overextend and say, okay, it helps every symptom, but at least for those using this trial design, there was a promising um improvement.

Jackie Baxter: 34:21

Yeah. And again, it comes back to, you know, if you're not well, you know, that there isn't a silver bullet, there's not one thing that's going to cure you. Um, and I'm not sure there ever will be, but there are all sorts of things that can help. So if what you guys have worked out from doing this trial is that doing, you know, taking this supplement or indeed any other supplement that people find in any other trial, um, you know, is something that is going to help people even a bit, you know, with a certain amount of symptoms to a certain extent. And it's something that might be worth doing. Um, so that's still useful information, even if it's not gonna, you know, solve everyone's problems um and make everyone 100% better, because that's that's quite a toll order, isn't it?

Rudolph E. Tanzi: 35:10

You know, it's also so weird that an over-the-counter supplement has a clinical effect. And you know, that's not common. It's it's uh it's always great when it happens.

Jackie Baxter: 35:20

So is this a supplement that people can just go out and buy and follow this sort of similar protocol that that you guys did in the trial? And is that something that you know I could just wake up tomorrow morning and go and do? I mean, again, you're you're not giving medical advice here.

Rudolph E. Tanzi: 35:39

But maybe Emily can address this, but the dosage was higher than what's recommended on the bottle. Like if you buy true niogen, you know, it it it can c it can come as 500 milligram capsules and they recommend two a thousand milligrams. This was a 2,000 milligram dose. So I I'd be careful here about saying, you know, go beyond the recommended dosage on the bottle and take double that. But that was what was used here in this uh trial. So that would require further thought and discussion, I think.

Edmarie Guzman-Velez: 36:13

Yes, no, I totally agree. Um and and that is another question is is a thousand enough. A thousand and five hundred, we don't know, but for this clinical trial, we did use two thousand milligrams a day.

Jackie Baxter: 36:29

And you guys thought that was safe because you were monitoring it and keeping an eye on these people and it was under sort of supervision.

Edmarie Guzman-Velez: 36:37

We were monitoring, but also we were not there had been another study or studies that had had used 2,000 milligrams, and they had not seen any significant side effects. So we felt comfortable using 2,000 milligrams, and that you know, our participants were going to be safe.

Rudolph E. Tanzi: 36:59

The RRB or Institutional Review Board at Mass General reviews this and they they go into all the empirical data of has this dose been used before, just like Emma Marie was saying, and was it is it safe? So the fact that they approved the study means that they felt this was a safe dose. It's just not the recommended dose, it's double that.

Jackie Baxter: 37:18

Yeah, and obviously anyone adding supplements into their routine should do so under medical um advice. Um what I'm curious about, and I don't know if this is something that you measured, you know, you said you measured your NAD levels at the beginning and the middle and the end of the study, and that they had significantly increased during the study, which is obviously awesome. It's what you thought was going to happen, and it did. Um that's always good, right? Um what I would be curious about is did those NAD levels that had risen up while you were doing it, did they remain up there or did they drop back off?

Edmarie Guzman-Velez: 37:57

That's a really good question. And for the most part, they remained high.

Rudolph E. Tanzi: 38:01

I guess eventually they would drop off and stop supplementing, right?

Edmarie Guzman-Velez: 38:05

So it's really interesting because um and once our our the article is actually available to everyone, it's open access. Um so when you look at the first uh the first graph, you see that the people in the NR group uh after baseline, there's it's like super, you know, it's it's skyrocketed. There's a significant increase, whereas the placebo stays pretty flat. And then when the placebo changes to NR, then you see a very similar increase, you know, as the other group. So, you know, we it's very clear that the the NAD plus levels are increasing, and then um they pretty they stay up pretty high throughout the trial. We also um were our participants were amazing and they were very uh good at taking NAD plus. Um we do measure whether they're skipping days or not. Um, and for the most part, everyone was taking uh NR every day as instructed.

Rudolph E. Tanzi: 39:13

I I think it's also worth mentioning on the cognitive test, going back to that, that you know, this trailmaking B test, right? So I don't know if you how it works is you have to you know connect numbers and letters in order. So one to A to two to B to three to C. And they're all over the place, right? And so it's it's so you measure how fast you can do it. And it requires you to be able to focus, right? So if you're like confused, agitated, um, even highly depressed, it's hard to focus and say, and you know, be able to say one to A and two, now where's the B? Okay, there's the B. Oh, and what's next? Oh, yeah, three. So you so it's it's how much time you take. And I was and I've done a lot of these, you know, trials on Alzheimer's disease, which is my specialty, and we use Trailmaking B. And I thought, you know, knocking eight was it eight point four seconds off of the test um for those who are on NR after 10 weeks versus placebo.

Edmarie Guzman-Velez: 40:11

Wow. Um uh or is it after uh it was when we put yeah, 10 weeks uh baseline versus 10 weeks of NR.

Rudolph E. Tanzi: 40:20

Right, right. So after 10 weeks to get 8.4 seconds off that test is pretty good. And and we'd be we'd be really happy about that in an Alzheimer's uh trial. And so I I thought that was that was one of the more impressive things about the study for me. I don't know about Emma R, but I think maybe I'm just biased.

Jackie Baxter: 40:41

Yeah, that that does sound impressive. Um I mean, what what I'd be curious about is um that's probably another trial, um, is uh, you know, are there people, you know, particularly maybe where we talk about repeat infections or where people are, you know, I mean, people get sick with all sorts of things all the time. Um, and you know, is it just COVID that reduces these levels of NAD or is it any infection? And, you know, is it the sort of thing that might be useful for people to supplement, you know, when they get sick as a sort of precautionary measure? Um, and I don't know if that's anything that you guys have looked into or or are thinking of, but uh again, it's it's maybe something that people could do if you thought it might work.

Rudolph E. Tanzi: 41:33

Yeah, increasing age. Um I'm the oldest one on this podcast. Um, but age decreases NAD plus levels. And so um I often will provide family and friends with a list of supplements that I found to be helpful in our research lab, right? And I give a disclaimer this is not clinical advice. We don't have clinical, you know, evidence yet. Here we have some clinical evidence for this one. Um, but this is what I do personally. But I usually have uh niogen on that list for that reason that it's usually older people who are concerned about their brain health and what's gonna happen. So I I include niagen on there along with other supplements and natural products that I've tested in our model systems that we feel can help stave off you know age-related brain pathologies. But um, but yes, NED plus is something that goes downhill with age. And and it's because cells get old. It's like think about cells like toys with batteries, and mitochondria are the batteries, and you know, you might have a cell with 10%, 20% of the mitochondria are like dead batteries, and you need to stupid, you know, you re need to recharge them. That's that's how I think about um NR.

Edmarie Guzman-Velez: 42:52

I like that way of explaining when that was really good. Um and yeah, COVID-19 is not the only thing that will reduce um NAD plus levels, as Rudy mentioned. Um, there there is another study where they took people who were infected with COVID-19, so it was in the acute stage, and they combined NR with two other supplements, and they did see that this group recovered faster. So there it may be that this can help with the acute stage. We don't, you know, we there's to my knowledge, no one has done this only with NR, but at least um it may, it may be, you know, based on those results.

Rudolph E. Tanzi: 43:43

Um you know, just anecdotally, when February 2020 I had the first COVID strain, and I was so sick. I mean, and so I I treated myself with um with supplements that are meant to reduce inflammation, and and I I used true niogen. I was taking a thousand milligrams of that. And then I and then I wrote to an Ayurvedic doctor, I know, and he told me a concoction, I can an Ayurvedic concoction I can make at home to help with my lungs and my breathing. And it's amazing how how it helped. It was, you know, I mean that that's all I did, and I got through it. But I I don't know if it was just a diagram, but you know, it was one of the few few things I took just to help me do it because I said, okay, I'm getting attacked. I didn't know anything about NAD plus and COVID at that term. Nobody did. But I just knew that I I needed more energy. I needed to refuel my cells.

Edmarie Guzman-Velez: 44:38

In fact, one of the things um Rudy mentioned inflammation. Um, and we know from other studies that there is an association between increasing NAD plus and reduced inflammation, which can be really bad for the body, including the brain. Um, and so one of the things that we would love to do is also see, and we hypothesize that those people with higher NAD also have lower inflammation, and that may be contributing right to those who are feeling better over time.

Rudolph E. Tanzi: 45:10

Yeah, especially the the immune cells in the brain, the might what called microglia, um, they are normally housekeeping and cleaning up debris, including the amyloid plaque and Alzheimer's. But if they lose energy and start to become what's called senescent, they're more likely to turn into inflammatory cells. They convert from housekeepers to killers and they become neuroinflammatory. And so the way you stop that is you give them more energy. Well, energy you know comes from things like ATP and NAD plus. So uh, and luckily niagen and nicotine ribicide gets in affects the brain and and energy there. So um, yeah, we think I think that may have played help played a role here too, with as Emory was saying, is is is we didn't directly look at indicators of neuroinflammation, but if we looked for biomarkers of that, we might have seen something there too.

Jackie Baxter: 46:05

And that makes total sense because you know it's one of those things that's talked about a lot in in long COVID. And you know, it is that you know, reducing inflammation, which is healthy in the body anyway, isn't it? Um, but you know, particularly in in long COVID, if those levels of inflammation are are higher, um, then you know, more important to find a way to reduce that. So if if this is something that can be done that might help that, then that's an added bonus, isn't it? So you just mentioned about you know potentially looking at inflammation and and stuff like that. Um and you know, the results from this trial are really interesting, especially with the use of the different analysis that you talked about. Um so do you have plans to sort of continue in this kind of research with more long COVID and expanding the study that you've done into something else? And you know, what are your kind of plans around that?

Edmarie Guzman-Velez: 47:08

I would love to. Um, with the data that we have now, some of our plans are to look at some of these biomarkers of inflammation. Um, everyone also wore a Fitbit during those 20 weeks. So we may be able to look at um whether they were engaging in more physical activity, which is what we want. Um, and if you know sleep was improving as measured with the Fitbit. Um, but we definitely need to do more, um, more, collect more data, do new trials. Um, actually, someone, I think it was yesterday, was asking me, did you know, lung COVID tends to be uh more common in females? Um, and so uh she asked, Oh, is there a difference between uh the results for females and males? I'm like, I don't know. Um we need we need to we need more research and more trials, larger trials, so that we can address some of these questions that are important. Um and that may help us understand this better.

Rudolph E. Tanzi: 48:14

And also the McCann Center, working together with the Alzheimer's Clinical Trial Center at MassGen will did a uh niogen trial and Alzheimer's disease small trial. And while it was too small and not properly powered to see changes in cognition and memory, um we were able to look at biomarkers of the pathology in the brain, looking at blood plasma biomarkers. And there we did see an effect on one of one of the pathologies in Alzheimer's is tangles, the tangle formation, tau tangles. And we did see an effect on that, on that biomarker. Um, so I would like to, I I at the McCann Center, I we're now we're doing a uh a whole slew of Alzheimer's trials uh with natural products and supplements. And so I do plan on adding doing a trial where we get niggen added to other supplements aimed at lowering neuroinflammation and clearing out the plaque and tango pathology. Um, of course, with a supplement, you can never make any claims about a disease because it's just the rules, right? But we can still test them to see if it helps and put those papers up there, you know, about what it what it does in disease. Although, you know, I think there are rules about not being able to put that on the bottle, but you know, we can at least generate the data.

Jackie Baxter: 49:29

Yeah. And like you kind of mentioned earlier, you know, that there have been other studies done with Nyigen. Um, and you know, okay, they weren't specifically long COVID, but you know that it might reduce inflammation, you know that it has stuff to do with the brain, you know, you know, so it's it's not like you're coming in with with no information beforehand, I guess. You know, you already know that it does certain things. So you can use that to build another study in a certain group on that kind of going back to Lego analogies, aren't they? You know, the kind of the building blocks of studies that have been done previously.

Edmarie Guzman-Velez: 50:06

Absolutely. And I think uh clinical trials like these, um, in addition to helping us understand if a symptom can improve or not, it also allows us to understand the mechanism a little bit. Um, so you know, what are what is going on in the brain and the body that may be explaining this? And we spoke about inflammation, so on. So this is also telling us something about the role of NAD, um, which is also important for developing future potential interventions. Yeah.

Rudolph E. Tanzi: 50:36

Right. We were also very fortunate to be able to work with um Charlie Brenner. And you know, Charlie Brenner was the guy who discovered uh nicotin byribicide linked to cellular energy. So uh it was under his supervision that the NAD plus levels were were measured, and uh we couldn't have had a better person do that.

Edmarie Guzman-Velez: 50:57

Yeah, we had a really, a really great team of investigators uh working on this.

Jackie Baxter: 51:03

And I guess that's the thing with the research project, isn't it? You know, it's like it is it is a team, and I guess that team includes your you know your participants as well, because you can't do it without them. And um, you know, it it's a a big joint effort, I suppose, isn't it, to make it a success. And um I can't remember who it was that that said to me, but um it was someone who worked in research and they said actually, whether you get a positive result or a negative result in your research, it doesn't matter because it still gives you information. Um so it either tells you, okay, this does work or this doesn't work, but it's still, you know, it's still solid information. Um and actually you guys seem to have had a positive result, certainly, um, with with some people. So that's that's really cool.

Rudolph E. Tanzi: 51:51

And you know, in 10 weeks isn't that long a time to get a result. Absolutely. Um even before this study, I was telling folks who had long COVID to try, to try this, you know, say, look, there's no clinical evidence yet, there's a trial going, but you know, there are preclinical lab studies that can predict whether things would work. And with that caveat and disclaimer, you don't have clinical evidence yet. You know, as soon as as long as it's safe and and and and available, you know, you can ask people to try it. And and so I got lots of anecdotal data back from people. And I emphasize anecdotal, not clinical, um, who just said, yeah, this really helped me uh feel better. And um, but it's nothing like real clinical data. And so Ed Marie ran an amazing trial.

Jackie Baxter: 52:41

Amazing. Um and just just finally, you you mentioned something there that made me think, ooh, um, you know, you said 10 weeks isn't very long. And it it's not. Um, so is something else that you could look into is okay, what would happen if they were to take it for longer? Um, would they get more benefits for taking it for a longer period of time?

Rudolph E. Tanzi: 53:04

I mean, keeping the NAD plus levels up, right? I mean, even after five weeks, the NAD plus levels are already up, right?

Edmarie Guzman-Velez: 53:12

Yeah.

Rudolph E. Tanzi: 53:12

And like threefold. And so that's pretty darn good. Absolutely. If if if if that's going to be the thing you need to do to feel better and to alleviate the symptoms.

Jackie Baxter: 53:24

Yeah. And is there like an upper level of how much NAD is kind of okay in the body? Like if you were to keep taking it when actually your levels were already high, would that potentially be dangerous? Or is that not something that you'd need to worry about?

Rudolph E. Tanzi: 53:44

I would say take the recommended dose of niogen again, you know, not what was used here. And, you know, if if you're using niogen or nicotine aerobicide every day at the recommended dose, then you're going to keep those NAD plus levels higher. There are lots of studies suggesting that it can help with resilience to cancer and other diseases. Um But you don't want to take too much. I think it's different to be is a difference between taking too high a dose versus just having it on a daily basis to maintain your NAD plus levels, especially if you're older when they naturally start the NAD levels naturally start to decline.

Edmarie Guzman-Velez: 54:26

And something that I think is relevant too is that um when our participants started the trial, we asked them to stop taking anything that had an R or niacin or anything like that, because then we had no control over you know how much uh NRN they were uh consuming. Therefore, that could definitely potentially change our results. Um, so these individuals were taking those 2,000 milligrams of NR and not anything else that could that like nice. And I think it's pre-workouts. I have a lot of niacin. So, you know, they couldn't, they had to stop.

Rudolph E. Tanzi: 55:08

This was the most successful trial I we've had for the McCann Center with Edmarie, and the Alzheimer's one was at least a good beginning for a trial, needs a bigger one. But you know, I do I would love to see more trials, and in fact, hopefully in collaboration with Edmund Marie at Rutgers now, you know, where we um add true NIAGEN, add it to other um supplements that can work synergistically with it.

Edmarie Guzman-Velez: 55:33

Yes, and you know, as you mentioned at the beginning and Jackie, some of a lot of these individuals are taking other supplements. I think this is very relevant to this population, too, um, who is not only taking an art, they're already combining this with other supplements. So I think that's definitely a really important question. And actually, uh that's one of the reasons why I love working with participants because you learn so much from them, right? You you think you know reading articles and whatnot, but it's not really until you interact with them that you really get to see, okay, this is what's really impairing or interfering with their daily activities. Or, you know, a lot of people have a lot of insight on what's happening. And so you get a lot of ideas by just talking to them.

unknown: 56:21

Yeah.

Jackie Baxter: 56:22

Yeah. And it's that sort of true collaboration, isn't it? Which is just really beautiful. Guys, I'm really excited to see what comes next. And, you know, one of the things I've learned from speaking to doctors and researchers like yourselves is that one research study is the launch pad for the next one. So it'll be really exciting to see where you launch next. Um, so thank you so much for being here, for giving up your time, for coming and chatting to me. I'll make sure that links to the paper and anything else you've mentioned go into the show notes. So if anyone wants to follow up with that, please do that. And yeah, thank you so much for being here. It's been awesome.

Edmarie Guzman-Velez: 57:02

Thank you. And thank you for joining this podcast.

Rudolph E. Tanzi: 57:05

Yeah, thank you very much. Thanks, Jessie.