Why You Should Listen
In this episode, you will learn about the vast role that nitric oxide plays in supporting health and strategies to increase nitric oxide.
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About My Guest
My guest for this episode is Beth Shirley. Beth Shirley, RPh, CCN, developed an expertise as a compounding pharmacist and board-certified clinical nutritionist during a career spanning over 40 years. She has been a pioneer at the cutting edge of the evolution of what has now come to be known as “Integrative Pharmacy”, the junction between traditional pharmacy and the clinical use of nutritional supplementation. Since 2009, Beth has spent time working with some of the leading thought leaders in the world of nitric oxide research and through this has developed an in-depth knowledge of the topic and its potential applications in patient care. In addition, she has worked closely with the scientific community and cutting-edge companies working on innovative nutritional ingredients and approaches for their use in a variety of life’s challenges. In fact, Beth has formulated a product that was awarded the first patent on a supplement to “increase sexual desire and pleasure”. She currently is the Director of Education and Research for Approved Medical Solutions, the distributor of her oxalate-free nitrate product and her Libby line of women’s wellness products.
Key Takeaways
- What is nitric oxide (NO)?
- What functions does NO play in the body?
- What causes NO to be low?
- How can NO be supported with diet?
- Does NO level play a role in COVID?
- What is the connection between NO and methylation?
- Does NO have a role in the management of infections?
- What are the two pathways through which NO is created in the body?
- What is the connection between glyphosate and NO?
- How can any potential downsides of increasing NO be minimized?
- What is the role of NO in systemic inflammation?
- How does NO impact glucose, insulin, HbA1c, metabolic syndrome, and diabetes?
- What role does NO play in cardiovascular disease?
- Does NO impact MCAS and histamine?
- Can NO have a beneficial effect on intestinal hyperpermeability or on the microbiome?
- Does NO impact detoxification?
- Can methylene blue be used with NO?
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Interview Date
October 30, 2025
Transcript
Transcript Disclaimer: Transcripts are intended to provide optimized access to information contained in the podcast. They are not a full replacement for the discussion. Timestamps are provided to facilitate finding portions of the conversation. Errors and omissions may be present as the transcript is not created by someone familiar with the topics being discussed. Please Contact Me with any corrections.
[INTRODUCTION]
[0:00:02] ANNOUNCER: Welcome to BetterHealthGuy Blogcasts, empowering your better health. And now, here's Scott, your BetterHealthGuy.
The content of this show is for informational purposes only and is not intended to diagnose, treat, or cure any illness or medical condition. Nothing in today's discussion is meant to serve as medical advice or as information to facilitate self-treatment. As always, please discuss any potential health-related decisions with your own personal medical authority.
[0:00:35] SCOTT: Hello, everyone, and welcome to episode 224 of the BetterHealthGuy Blogcasts series. Today's guest is Beth Shirley, and the topic of the show is Nitric Oxide. Beth Shirley developed an expertise as a compounding pharmacist and board-certified clinical nutritionist during a career spanning over 40 years. She has been a pioneer at the cutting edge of the evolution of what has now come to be known as integrative pharmacy, the junction between traditional pharmacy and the clinical use of nutritional supplementation.
Since 2009, Beth has spent time working with some of the leading thought leaders in the world of nitric oxide research. And through this, has developed an in-depth knowledge of the topic and its potential applications in patient care. In addition, she's worked closely with the scientific community and cutting-edge companies working on innovative nutritional ingredients and approaches for their use in a variety of life's challenges. In fact, Beth has formulated a product that was awarded the first patent on a supplement to increase sexual desire and pleasure. She currently is the Director of Education and Research for Approved Medical Solutions, the distributor of her oxalate-free nitrate product, and her Libby line of women's wellness products.
And now, my interview with Beth Shirley.
[INTERVIEW]
[0:02:00] SCOTT: I'm excited today to have an expert in the field of nitric oxide here with us. This is really a topic that I'm looking forward to learning more about. To be very honest, I've historically avoided nitric oxide-focused supplements. I had some concerns that they could potentially lead to more oxidative stress, maybe had other downsides. So, I'm really happy today to have Beth Shirley here with us to really get into the nitty-gritty of nitric oxide. Thanks so much for being here, Beth.
[0:02:28] BETH: Thanks for having me. We'll have some fun.
[0:02:31] SCOTT: So, what was your life path that led you to becoming such an expert in nitric oxide? I know it's become a big focus and passion for you. Was there some health challenge that fueled your own exploration into nitric oxide?
[0:02:46] BETH: Well, it all kind of started. I became a pharmacist because I thought I was going to help people. And after 20 years of seeing them come back sicker and sicker, on more and more drugs, in 1997, I became a certified clinical nutritionist. So, I became the pharmacist to go to if you wanted to get off drugs or not go down that road to begin with.
The integrative pharmacy that I was running at the time was actually really close to where one of the first nitric oxide companies was based, the Neo40 people. And so, before Neo40 even came out, they were my clients. And we started talking about this in 2009. So, then I helped develop that lozenge, and that came out in 2010. So, they were one of the first people to actually have a specific nitric oxide product.
[0:03:50] SCOTT: That is the one that I remember from back in the early days, and I felt very conflicted about is this something I should do? Is this something I should hold off on?
So, talk to us a little bit about what nitric oxide is, what functions? And I know they're very wide and broad, but what are the functions that nitric oxide serves in the body? How long does it last in the body? And then building on that, what are some of the symptoms or conditions that we might want to then think, "Hmm. Maybe nitric oxide needs to be supported?"
[0:04:25] BETH: Well, nitric oxide governs circulation and microcirculation. So, it touches every single physiological process. Cardiovascular system, like high blood pressure, clotting, which is especially important in this post-vax, post-viral world. Because spike protein is decimating our nitric oxide. Learning and memory, nitric oxide-mediated. Kidney health, like chronic kidney disease is rampant these days. Our vision, our eyesight, all those little blood vessels need to be open to feed the things going on in our eyes. Our hormone balance starts with nitric oxide in the hypothalamus. Our immune system. Nitric oxide is our first defense against pathogens. Our lungs. Sex in both men and women, nitric oxide is the essential part of reproduction. It governs every facet of male and female fertility.
[0:05:40] SCOTT: And my understanding is that when we have nitric oxide in the body that it has a very, very short half-life, like maybe less than a second. And then when we get into here in a bit talking more about nitrate, then that is several hours. But nitric oxide itself is kind of blip, and it's gone. Right?
[0:06:01] BETH: Right. Right. Less than a second. You're right.
[0:06:04] SCOTT: So what are some of the things then that cause nitric oxide to be low? Is it entirely age-related? Are certain populations more likely to have low nitric oxide? Do our genetics play some role? And can we end up with lower nitric oxide because infection, environmental toxicity, other things increase the demand on nitric oxide, which then reduces the levels that we have in the body. So, the supply really cannot keep up with the demand. Or are we all low after a certain age?
[0:06:41] BETH: Well, yes to everything you said. Most of us are low after a certain age. Because by the time we're 40, our ability to make nitric oxide through that eNOS, the endothelial nitric oxide synthase enzyme, decreases to about 50%. And by the time we're 60, that enzyme is only functioning about 15%. So that's why it's so critical to support the nitrate to nitrite to nitric oxide pathway because cardiovascular disease is still the number one killer across the whole wide world.
But also, the standard American diet, which is devoid of nitrate-rich veggies influences that, the lack of exercise. Some medications, some drugs like antibiotics, the azole antifungals, SSRIs, birth control pills, NSAIDs like our ibuprofen. All of these interfere with – the PPIs, the proton pump inhibitors. When they were first put on the market, they were only supposed to be taken for 6 weeks. And now they've been on the market for decades. They're over the counter. The PPIs interfere with the production of nitric oxide through both pathways.
Pollution, glyphosate, EMF. When we're swimming in this sea of EMF, it's everywhere. Genetic SNPs like you were talking about. You can have some NOS SNPs. But it's just not NOS. MTHFR SNPs interfere with the methylation cycle, which interferes with your production of BH4, tetrahydrobiopterin. And tetrahydrobiopterin is what keeps that NOS coupled and functioning. Because when NOS is uncoupled, it doesn't produce nitric oxide, it actually produces superoxide. Stress. Stress uncouples that NOS enzyme. Stress increases oxidative stress. And the big one these days, this post-viral, post-vax world. That spike protein is interfering with our nitric oxide. That's why we're seeing the clots, the heart attacks, the sudden dying. And people just aren't thinking like they should be, because I don't think they're getting enough circulation in their brain. And the black population have a lot more NOS SNPs. So, it makes them more predisposed to cardiovascular disease, strokes, heart attacks.
[0:09:36] SCOTT: So it's not just age. Age certainly plays a role, but it does sound like the more of these stressors that we have that you just really articulated for us, the more demand there is for nitric oxide, thus we have less supply essentially. And so, we need to work both on supporting nitric oxide, but also working on what are some of these triggers, or stressors, or factors that are causing us to be more depleted in it.
[0:10:05] BETH: Right.
[0:10:06] SCOTT: What are some of the things that we can do for supporting nitric oxide production without immediately reaching for a supplement that maybe then we have to take for the rest of our lives? Are there specific foods, specific biohacks that can support the increase of nitric oxide? You mentioned exercise can be important as well. Where do we get some of these other raw materials for producing nitric oxide before we reach for an exogenous supplement?
[0:10:37] BETH: Well, there's only two ways we make nitric oxide, and one is through the NOS pathway, the nitric oxide synthase pathway. And the other is through the nitrate to nitrite to nitric oxide pathway. So even if we do all of these things, like the breathing, the PEMF, all of these devices, these biohacking devices that we use to increase nitric oxide, we have to have functioning NOS enzyme or a good nitrate, nitrite stores.
So, we get the nitrate from high nitrate vegetables, from arugula, spinach, beets, celery, bok choy. All of these have high nitrates, all of them, except for arugula have the possibility of increasing oxalates. And if anybody's got leaky gut or any kind of chronic issue, they may have an issue with absorbing too much oxalate and not being able to clear it. So, there is a caveat with the high nitrate veggies, except for the arugula.
[0:11:52] SCOTT: Things like breathing, humming, mouth taping, I think, is one that can actually help support the production of nitric oxide, is something that I have done daily for many years. Before we jump away from kind of the dietary conversation, I'm glad that you highlighted the oxalate piece. And I know later we're going to talk about some of the products that you've helped formulate that do not contain oxalates. But we see so many foods that are advertised as nitrate-free, as though that is beneficial. And it seems to me that nitrates have maybe been framed as a toxic poison. So, is it better to be getting our nitrates from vegetables? Can we still get them from cured or processed meats? And if we do get some of these nitrates from meats, should we potentially also be thinking about some antioxidants like vitamin C or vitamin E?
[0:12:52] BETH: Yes. The "study" that came out that maligned nitrate in the early 70s was never peer-reviewed. And by the time it got peer reviewed, it was discounted. And in fact, in 1972, they had the nitrates that were added to these be incorporated with either vitamin C or erythorbate, which is a vitamin C. It's in the vitamin C family to offset any potential nitrosamine production. All it takes is a little vitamin C, a little antioxidant, and you won't be forming the nitrosamines.
So, we get most of our nitrates from the vegetables, tremendously more than what we would ever get from these processed meats. And I'm not saying these processed meats are healthy because there's probably other things in them and especially if they're smoked. I mean, there's other things in them that might not be healthy. But it's not the nitrates or the nitrites in them that are detrimental.
And in fact, there's lots of studies that show that even too much nitrate or nitrate – well, look at the DASH diet, the dietary approaches to stop hypertension. This is a diet that is used as therapy for hypertension, and it has about 1200 to 1500 milligrams of nitrate per day. So that's a lot. That's a lot. Because 5 ounces of spinach has about 325, between 300 and 400, or 7 ounces of beets. To get that much nitrate is a lot, and it's used as therapy.
[0:14:54] SCOTT: Let's talk a little bit about celery. Where does celery or celery seed come into the nitrate, nitric oxide discussion? Is celery seed high in nitrate? I've read some people say that it is, others say that it's not. Do the celery stalks themselves also have high levels of nitrate? Is this a different type of celery than what many people are often with good results juicing daily? There was the celery juice craze that some people still find beneficial, others, maybe not. And is it possible that that is because of – is it possible that the benefits of celery juice could be from the impact on nitric oxide?
And then I want to extend on that just a little bit. I'm seeing more and more supplements coming out that have celery seed. They talk about blood pressure, and vascular health, and inflammation, oxidation or antioxidant properties, kidneys, antimicrobial. A lot of the things that you mentioned also being related to nitric oxide. So, does taking supplemental celery or celery seed have benefits in the nitric oxide realm, or are some of those benefits for other reasons?
[0:16:18] BETH: Celery and celery seed, they are high in nitrates. And in fact, long time ago, when I was first getting into it, I figured here's where the benefit of juicing this celery came from. In the foods that you see where it says no nitrates, nitrites added, what they have added is celery seed. Okay? So, they've added additional nitrates. Only it doesn't say that.
[0:16:54] SCOTT: You mean they're not telling us the truth?
[0:16:56] BETH: Imagine that. Imagine that. But it's high nitrate.
[0:17:03] SCOTT: How much of a role then does nitric oxide play - you alluded to this - during the pandemic. Did we observe that people that had higher nitric oxide had better outcomes if they did have COVID? I know I've seen nasal sprays that were nitrite sprays that were said to be helpful for COVID to increase nitric oxide. Wondering if nasal delivery of some of these materials can potentially be enough to support systemic nitric oxide levels.
And then given that COVID, we know some of the biggest issues are the hypercoagulation, the clotting, the microclotting, where does nitric oxide fit in from a blood vessel health and blood flow optimization perspective? And I understand that during COVID, you had created some recommendations for people to do better if they did have COVID.
[0:18:02] BETH: Right. Nitric oxide played a pivotal role in whether you got COVID, how quickly you recovered from COVID, and then how detrimental maybe the vax might have been to you. So those nasal sprays was the nitrite. And then also, you had spoke about the N101. Dr. Brian had a study going on with COVID patients with his nitrite lozenges. But nasal delivery won't effectively raise systemic NO levels. However, it is effective for killing off the pathogen as you breathe it in.
And like I said, that spike protein is decimating our nitric oxide. And so that's why you see the clotting. Nitric oxide governs platelet activation and aggregation, which is clotting. When you're nitric oxide deficient, you are going to clot. Cells can't be more than two cells away from functioning microcapillary. So, when you've got these little microclots in those tiny, tiny capillaries, your tissues aren't being fed oxygen, glucose, nutrients. And just as importantly, cellular debris isn't being carried away. So, cells and tissues can die.
And yes, I had some recommendations that I used for a lot of patients. High-dose melatonin, doing a nitrate supplement. And if you had the virus or you just had the vax, I would recommend doing the supplement actually twice a day. If you were nitric oxide deficient prior to, if you had any chronic issue, because any chronic issue will make you nitric oxide deficient, because chronic issues increase oxidative stress. Oxidative stress uncouples that NOS enzyme. So that NOS enzyme isn't producing nitric oxide. It's actually producing superoxide, which is increasing your oxidative stress even more.
[0:20:39] SCOTT: Let's talk a little bit about the connection between nitric oxide and methylation. Wondering if it's true that those with MTHFR genetic SNPs are by definition deficient in nitric oxide? Wondering a little bit about the mechanism there and why some people seem to suggest that nitric oxide supplementation may not be good for people with MTHFR mutations, which, from my perspective, would mean there wouldn't be much of a market for them. Because I think if we look, about half of us have a single mutation in 677, another half in at least one mutation or one SNP in 1298. 10% to 15% of people are compound heterozygous, having at least one mutation in both 677 and 1298, which is me personally.
And I tend to think that the whole MTHFR discussion is a little bit overblown. I tend to see people kind of immediately jump to, "Well, I have MTHFR, and I can't detoxify. And there's no hope for me," and that kind of thing. And I don't really think the body is that simplistic. But help us understand the connection between MTHFR or methylation and nitric oxide.
[0:22:00] BETH: Well, the MTHFR genetic SNPs interfere with what's called the methylation cycle. But this methylation cycle is intricately involved in the production of BH4, tetrahydrobiopterin. So, if you've got genetic SNPs in that methylation cycle, you are not making your BH4 optimally. That BH4 is what keeps that NOS coupled. If you're not making your BH4, and you're BH4 deficient, you're nitric oxide deficient. You can't keep that NOS coupled.
[0:22:45] SCOTT: We'll get in a little bit later into BH4 a little more. I know historically I have had issues with BH4. We used to be able to get BH4 as a tablet from Europe. I don't think it's quite as easily accessible anymore. So, we're going to get into some conversation about how we can also support BH4 as part of this whole conversation. But I want to talk a little bit about the role of nitric oxide in the management of chronic infections.
Most of our listeners are dealing with Lyme, and co-infections, and chronic viruses, fungal colonization potentially from their external environment, so many different chronic pathogens. So, does low nitric oxide give the microbes a stronger foothold? Does it open the door for them to take up residence? I have read that nitric oxide could be helpful against Borrelia and other microbes. So, how does nitric oxide affect both the immune function, the inflammation? And would you consider nitric oxide to be immune-modulating? Meaning, can it be safely increased in people with autoimmunity, or is it boosting the immune system in ways that could have potential problems?
[0:24:05] BETH: Okay, nitric oxide, our first defense against these pathogens, any pathogens, viral, bacterial, fungal. When you're nitric oxide-deficient, it makes it easier for these pathogens to grow. For example, stress uncouples that NOS enzyme. When we're stressed, we get sick easier, because that iNOS isn't functioning.
Supporting the nitrate to nitrite to nitric oxide is totally okay in autoimmune conditions. In fact, a lot of the autoimmune conditions have oxidative stress and inflammation at their base. Remember what I said about oxidative stress? It uncouples that NOS enzyme. So, you're actually making more oxidative stress.
A couple of years ago, I did a talk at A4M on autoimmune and supporting the nitrate to nitrite to nitric oxide pathway. A lot of studies were actually saying the atherosclerosis was an autoimmune issue. But just know, with autoimmunity, you've got a lot of oxidative stress. So, you've uncoupled that NOS. So, you're walking around nitric oxide-deficient. Look at Raynaud's, autoimmune. Your circulation and microcirculation is impaired.
[0:25:36] SCOTT: Is Raynaud's a condition where supporting nitric oxide has led to notable improvement or resolution?
[0:25:45] BETH: Yes. Yeah. I've seen quite a few cases myself. Yes.
[0:25:50] SCOTT: So, let's dig in a little bit to these two different pathways. And this is where Beth is so much smarter than I am with the biochemistry and physiology. So, I'm going to try to keep up with her.
But the first pathway is that NOS pathway that you've talked about. It's also sometimes called the L-arginine pathway. The second is the nitrate-nitrite-nitric oxide pathway. So, should we be working to support the NOS pathway to create nitric oxide? Are we better to put our focus on the nitrate-nitrite-nitric oxide or second pathway? Does one of those come with greater risk, potentially? One with fewer risks in terms of the best way to support nitric oxide? And then kind of just give us the high level of each of these pathways, and then we'll dig a little deeper as we continue the conversation.
[0:26:49] BETH: I do not recommend arginine to support the NOS pathway. See, that NOS enzyme is very sensitive, and it has a lot of cofactors. It needs oxygen. It needs NADPH. It needs FAD. It needs the BH4. It has a lot of sensitives. It's sensitive to pH. So, this pathway has a lot of factors to make sure that it's making nitric oxide. But if it is not coupled and we're supplementing with arginine, arginine, it cannot go down that pathway. NOS, it's a dimer, and BH4 is what keeps it together.
If we're supplementing with arginine, it's not a dimer if there's oxidative stress, if it's uncoupled. And so, arginine has other pathways it can go down instead of the NOS pathway. It can increase ammonia, increase urea, increase ADMA. And we don't want that, because ADMA is connected to all-cause mortality.
[0:28:11] SCOTT: Activation of herpetic viruses as well with arginine.
[0:28:13] BETH: Exactly. Yeah. Oxidative stress activates that pathway. Yes. By supporting the nitrate to nitrite to nitric oxide pathway, you're not only increasing the nitric oxide directly. Nitrate actually helps support that NOS pathway. Nitrate increases production of BH through the cyclohydrolase enzyme. So that keeps NOS coupled.
Nitrate downregulates the three main ways that we make superoxide and increase oxidative stress. Nitrate downregulates NADPH oxidase, whose only purpose is to make superoxide. Nitrate helps recouple that NOS enzyme. Because, remember, when NOS is uncoupled, it makes superoxide. And nitrate helps recouple that electron transport chain that, when it gets uncoupled, makes a lot of reactive oxygen species. So, supporting that nitrate to nitrite to nitric oxide pathway actually supports both pathways without detrimental effects.
[0:29:37] SCOTT: So, we talked a little bit about some of the factors that could negatively impact NOS or nitric oxide synthase. Some people would refer to those as NOS knockouts. Many of us are on antibiotics or azole antifungals. You mentioned that those could have a negative effect on NOS and resulting nitric oxide levels.
So, first, I just want to go back through and kind of review some of the things that you mentioned that impact NOS. You talked about stress, lack of exercise, the standard American diet, a number of medications, anti-depressants, potentially, birth control pills, NSAIDs, PPIs, you mentioned. Some of the genetics as well. If someone were taking antibiotics or antifungals, given that those are common in the population of our listeners, would you then suggest that they also are doing something in parallel to support their nitric oxide?
[0:30:40] BETH: Definitely, for sure. Either with vegetables or with a standard dose of nitrate. Yes.
[0:30:50] SCOTT: And we're going to get more into the secondary pathway, the nitrate, nitrite, nitric oxide pathway. But since you mentioned BH4 relative to NOS, does BH4 play a role in the secondary pathway as well, or is that only relevant in the NOS pathway?
[0:31:11] BETH: Just the NOS pathway.
[0:31:12] SCOTT: You can be low in BH4 and still do well taking nitrate and working on increasing nitric oxide from the secondary pathway.
[0:31:22] BETH: Right. And remember, you also need BH4 to make your neurotransmitters. It's the essential cofactor in making your serotonin, dopamine, norepinephrine, epinephrine, melatonin. Even by supporting the nitrate pathway, you're actually supporting BH4 production to help you make your neurotransmitters.
[0:31:43] SCOTT: So that's a key piece of information. I know historically, like I mentioned, we could sometimes get BH4. There's a supplement, a little different, but Pteridin-4 also can help support BH4. Sounds like working on this nitrate pathway can also support BH4. Are there other things that you think about that we should be doing to support BH4?
[0:32:10] BETH: Well, make sure that I'm a big believer in the activated B vitamins to help with the methylation, but also make sure you're getting enough vitamin C. BH4 is oxidized to BH3. And if we don't have sufficient vitamin C, because vitamin C is the only molecule that can reduce that BH3 back to BH4. If we're vitamin C deficient, that BH3 oxidizes to BH2, which then uncouples that NOS.
[0:32:48] SCOTT: Are there readily accessible ways today to test someone's BH4 level?
[0:32:55] BETH: Not that I know of. They can do it in the lab. But as far as us being able to test, I don't know of any.
[0:33:02] SCOTT: Let's talk a little bit about the role of hormones on the optimal functioning of NOS. And thus, nitric oxide production. We're talking still about that NOS pathway, the L-arginine pathway. Do women have more problems with the creation of nitric oxide after menopause? And what about fluctuations in male hormones that shift with age?
[0:33:27] BETH: Right. Us women have a little better production of nitric oxide through that NOS pathway until we reach menopause, and then it kind of evens out because estrogen actually supports NOS function and supports cardiovascular health. But the hypothalamus requires adequate nitric oxide in order to make gonadotropin-releasing hormone, which then goes to the pituitary to make your LH and your FSH, which then travels down to your ovaries and testes to make your estrogen, progesterone, testosterone. And these hormones actually stimulate NOS production of nitric oxide as long as NOS is coupled.
There's only a couple of hormones that actually interfere with that NOS pathway, like prolactin. So, we see high prolactin in like PCOS or other infertility. And PCOS is a nitric oxide-deficient state. Fertility is nitric oxide mediated through every single facet, and cortisol, or stress hormone, helps uncouple that NOS enzyme. But most of the other hormones actually stimulate nitric oxide production through that NOS pathway. That's why hormones help keep us young and healthy.
[0:34:54] SCOTT: Let's talk a little bit about the ubiquitous environmental exposure we all have to glyphosate. Even people these days eating organic diets are surprised to see that they have high glyphosate levels when they test. Dr. Neil Nathan has shared that recently with his own experience. We know that glyphosate could impact NOS and thus our nitric oxide production. And then we're told to eat organically to reduce glyphosate exposure. But isn't it also true that organic vegetables are lower in nitrates than conventionally grown vegetables? And is that because of the fertilizer? What's the reason? And then what are your thoughts on if we're really trying to increase nitric oxide or nitrate, are we doing ourselves a disservice by eating organically?
[0:35:49] BETH: Well, I don't think we're doing a disservice by eating organically. However, you are correct. The organic vegetables do have less nitrate in them. And vegetables grown in different areas of the country will have different nitrate concentrations. Glyphosate does interfere with that NOS enzyme. So, it does interfere with our nitric oxide production. It's pretty toxic, and it's everywhere. Even if you are eating totally organic, you are still getting glyphosate. It's in the air. It's everywhere. It's in our water. The water that they may be watering these vegetables with, even if they're organic, might be loaded with glyphosate. Glyphosate's bad news.
[0:36:40] SCOTT: And is the reason that conventionally grown vegetables have more nitrate related to nitrate that's used in the fertilizer that then is taken up into the vegetables?
[0:36:52] BETH: Yes, because potassium nitrate is one of the ingredients to the fertilizers.
[0:36:59] SCOTT: All right. So, this next question is lengthy and complex, and I'm going to just throw it out there and then let you go where you go. But this really gets at kind of the crux of my confusion around nitric oxide. So, if we talk about the nitric oxide synthase or the NOS enzyme that helps to make nitric oxide, what are eNOS, which is endothelial NOS, iNOS, which is inducible, nNOS, which is neuronal NOS? And then I want to understand, do we want all three of those to be upregulated? I know that we do benefit from upregulation of eNOS, that endothelial, that vascular support. However, I thought that the induction of iNOS could lead to negative things, tissue damage, oxidative stress. And at the same time, impaired iNOS could lead to less infection control. Coming back to what you talked about with the infection. To me, it seems like iNOS is a double-edged sword. Potentially good, potentially bad. So, when are the good versus bad, and how do we selectively support only those eNOS, nNOS that are going to be health-promoting?
[0:38:27] BETH: Okay. So it's not necessarily that we want eNOS upregulated. We just want eNOS to be functioning well. Okay? We do want iNOS to be upregulated when there is an infection, when there is a pathogen. Remember that when there's inflammation and oxidative stress that NOS becomes uncoupled on all NOS. Even though iNOS can potentially upregulate it hundreds of times more and make hundreds of times more nitric oxide than eNOS, it gets upregulated during infection.
However, the longer the infection goes on, the inflammation goes on, the longer the oxidative stress is around. So, then the iNOS becomes uncoupled. So, it's not making nitric oxide necessarily. It's making superoxide. So, when you've got like a chronic infection, you don't want that iNOS upregulated so much, making that superoxide.
[0:39:47] SCOTT: At least not long term, right?
[0:39:49] BETH: Not chronically. No. Right. Because it's not making nitric oxide. So, it's increasing the oxidative stress. It's increasing the superoxide. So, it's increasing the oxidative stress, which increases the inflammation.
[0:40:07] SCOTT: But is it still helping to control the chronic infection?
[0:40:13] BETH: No. No. It gets upreg. I don't think so. So, because when it's uncoupled, it's not making the nitric oxide.
[0:40:23] SCOTT: And are the factors that lead to uncoupling of iNOS, are they the same in terms of eNOS and nNOS, or are they different factors that lead to uncoupling of each of the different types of NOS?
[0:40:39] BETH: They the same, oxidative stress. Because BH4 keep – NOS is a dimer. It means it's two kind of molecules of the same thing and it's held together by BH4. Oxidative stress oxidizes that BH4, and the NOS becomes uncoupled. And so, it's not making nitric oxide.
[0:41:07] SCOTT: When we think about taking an exogenous nitric oxide supplement, we are potentially then supporting eNOS, iNOS, and nNOS, the neuronal NOS. So, is that potentially problematic? And is my thought process reasonable that the one we're more concerned about upregulating is the inducible NOS or the iNOS? And then building on that, could dysregulation of NOS even be a contributor to excitotoxicity or neurodegenerative conditions?
[0:41:45] BETH: Well, nitrate will actually downregulate an upregulated iNOS.
[0:41:53] SCOTT: The second pathway.
[0:41:55] BETH: Right. So, you can actually even help modulate your NOS enzymes with the nitrate. When you've got a chronic issue and you've got lots of oxidative stress, so that NOS is uncoupled. However, infection and inflammation will upregulate it even if it's not making nitric oxide. If you're upregulating an uncoupled iNOS, you are upregulating superoxide production.
[0:42:28] SCOTT: What I'm hearing you say then is people who already have chronic health challenges, chronic infections, high levels of oxidative stress, that it may be detrimental to attempt to increase nitric oxide via the L-arginine pathway, unwise. And that our focus should be on what we're going to talk about in more detail, which is the nitrate pathway, which has less or no potential for causing these problems with specifically iNOS, creating more superoxide. Is that reasonable?
[0:43:05] BETH: It's reasonable. Yes. Yes.
[0:43:09] SCOTT: Okay. Trying to keep up with this smart lady….
[0:43:10] BETH: I know. It's complicated. It is complicated. See, you've really got to look into some of these studies and see exactly what they say. Because if you just read the abstract or something, it might not be really what that study says.
[0:43:34] SCOTT: And is it true that the majority of the foods we would be consuming, the high nitrate foods, would be supporting that secondary pathway? Or do we need to also be concerned about high arginine foods working through the NOS pathway that could then lead to a detrimental outcome?
[0:43:58] BETH: Exactly. Just like if you've got a herpes virus, but it's not active. If you eat a bunch of peanuts, which are high arginine, you could potentially reactivate it.
[0:44:16] SCOTT: And we see lots of people using, myself included, protein powders, collagen powders, we need to stop and think about what amount of arginine are we consuming, potentially, that could be then working in this NOS pathway that may not be all beneficial.
[0:44:36] BETH: Right. And one thing you could do is even you can check your ADMA levels.
[0:44:44] SCOTT: Tell us more.
[0:44:46] BETH: Well, asymmetric dimethylarginine, okay? If arginine is not going down that NOS pathway, it has other pathways that can go down, like urea, ammonia, ADMA. And ADMA is something easy that we can check.
[0:45:04] SCOTT: And then if there is an elevation of ADMA, is that largely concluding that we need to be reducing arginine? Or are there other things that that potentially might lead us to consider?
[0:45:18] BETH: Well, it means that your NOS is uncoupled. I would reduce the arginine, but I would also make sure it means you're under a lot of oxidative stress.
[0:45:27] SCOTT: And potentially low BH4, and potentially not enough nitrate.
[0:45:34] BETH: Right. Right.
[0:45:35] SCOTT: You're so good at connecting the dots. I'm learning a lot. I thought I had done a lot of research, which I did, but I'm definitely still learning a lot.
I think we've covered some of this, but I want to put it out there. Make sure that we're connecting all the dots. Building on NOS, we have the eNOS, iNOS, and nNOS. We need BH4 or tetrahydrobiopterin to generate nitric oxide. If we're low in BH4, which many of us are, historically, I have been as well, you have more of a risk for generating superoxide free radical oxidant. So, you're potentially causing more problems.
The way that we minimize the potential for taking a supplement or eating a food that may be supporting nitric oxide production and doing exactly the opposite is by focusing more on the nitrate pathway rather than the L-arginine or NOS pathway. Also, potentially doing some of the things that you talked about related to BH4 just in case we're supporting with our diet, that NOS pathway. We want to make sure that we have enough BH4.
And then I want to talk a little bit about Marty Paul, Dr. Martin Paul's NO/ONOO-cycle. And he's been a deep researcher in this realm. He talks about how excess nitric oxide creates peroxynitrite, damages cells and drives perpetual inflammation.
[0:47:11] BETH: Oh, this is my favorite.
[0:47:13] SCOTT: Yeah. So, talk to us a little about that and then some of the strategies, which I think we largely elucidated, but some of the strategies that we implement to make sure that if we're doing more dietary support or supplement support for nitric oxide, I want to minimize the chance that this backfires. I don't want more superoxide. I don't want more peroxynitrite. What do we do?
[0:47:38] BETH: Okay. Martin Paul is not a nitric oxide researcher as such. And peroxynitrite has gotten a really bad rap. However, when you go to read these studies, like what I was telling you, they do not measure peroxynitrite. Peroxynitrite is formed when nitric oxide reacts with superoxide. And EMF causes the influx of calcium into the cell. And he theorized that the increase of calcium increases the calcium/calmodulin-dependent enzyme, the NOS, which is the NOS enzyme, increase of NO. He says the increased NO from that influx of calcium reacts with superoxide to increase peroxynitrite.
And then he suggests that the peroxynitrite injures cells and tissues. However, the data on that is really severely limited. Nitric oxide may be present. However, that doesn't mean it's causing the pathology because they don't measure peroxynitrite. They're actually measuring nitrotyrosine and they're just assuming that peroxynitrite was formed. Because the peroxynitrite actually hangs around even less than nitric oxide. However, there's the new paradigm that's emerging that best peroxynitrite, which is ONOO.
[0:49:22] SCOTT: The ONOO part of the NO/ONOO-cycle.
[0:49:26] BETH: Right. It isomerases the NO3, which is nitrate and inert. There's other nitro-saving species that can form nitrotyrosine, not just the peroxynitrite. So, you read these studies and you will see that they're talking about nitrotyrosine. They're not talking about peroxynitrite. And they're assuming that the peroxynitrite was there, and that's what's causing damage.
However, EMF causes oxidative stress. EMF increases the NADPH oxidase enzyme, making superoxide. So, remember what I said, oxidative stress uncouples that NOS. So, I think EMF is actually increasing the superoxide production, not necessarily the nitric oxide production. Because with EMF, they've known since the 60s that it causes cardiovascular disease, that it causes diabetes. Those are nitric oxide-deficient states.
[0:50:44] SCOTT: Is there some benefit in incorporating antioxidants while we're also working to upregulate nitric oxide to minimize the potential for superoxide production? Let's say hydrogen water, for example, or breathing hydrogen gas. Is there any reason to even think about pairing some support for oxidative stress with our approach to increasing nitric oxide?
[0:51:14] BETH: Beautiful. Beautiful. Decrease that oxidative stress. Yeah.
[0:51:20] SCOTT: If we think then about iNOS, and the stimulation of iNOS and what that does to NOS and nitric oxide, that stimulation of iNOS uncouples the NOS enzyme, leads to lower levels of nitric oxide. It can increase that superoxide free radical, can negatively impact BH4. And so, I want to touch on some of the other things we can do to keep iNOS from creating more oxidative stress. We know it sounds like the primary one is working through the nitrate pathway. But if we reduce inflammation, I read that LPS or endotoxin plays a role in stimulating or driving iNOS. So maybe looking at our gut dysbiosis and working on removing endotoxin, maybe bovine immunoglobulins, for example, reducing that oxidative stress. Is it worth doing a lot of these other things as well to try and keep iNOS behaving?
[0:52:27] BETH: Yes, it is. But the beautiful thing about nitrate though, is nitrate supports healthy guts. Nitrate supports the good bacteria in your gut, increases the population of your good bacteria. Nitrate supports your tight junctions in your gut, in your brain, your tight junctions everywhere. That's a beautiful thing. And nitrate actually downregulates LPS production. It's just beautiful how many processes nitrate supports.
[0:53:09] SCOTT: You mentioned NADPH oxidase, or NOX, and that its real only purpose is in the production of the superoxide. So, how do we calm or minimize NADPH oxidase's potential for creating superoxide? Is there anything that we want to do around that enzyme? And then talk to us a little more about what superoxide dismutase, superoxide, what they do in terms of pathogens, in terms of apoptosis, iron dysregulation. And then, obviously, we know oxidative stress increases. But what about the apoptosis, iron dysregulation piece of the discussion?
[0:53:58] BETH: Well, NADPH oxidase is upregulated by a lot of environmental factors, by EMF, by infections, inflammation, by an upregulated, like interleukins 6, the RAS cycle, iron, like you were talking about, upregulates NADPH. But guess what? Supporting the nitrate to nitrite to nitric oxide pathway modulates it. It downregulates. And this is important because when that NADPH oxidase enzyme gets upregulated, it will preferentially steal the raw material for that enzyme. So then you don't have that NADPH that you're needed for all these other factors that you need it for, like detoxification, or all of these other things that it's involved in. But supporting the nitrate to nitrite to nitric oxide pathway will actually downregulate that. Dr. Bob Miller and I, we've had some really good discussions around that.
[0:55:10] SCOTT: So then building a little bit on the Bob Miller reference, superoxide, which is an oxidant, increases oxidative stress, not going to be good for chronic infections, right? It's not going to be creating more containment of those infections. It's working in the wrong direction. It's not, as I understand, good for healthy apoptosis or removal of the cells that should be removed, right?
[0:55:43] BETH: Right. Well, with the oxidative stress, your microcirculation is cut down because you're not making the nitric oxide. So, your cells aren't going to be fed what they need to be fed. And if you're doing any kind of therapy, the therapy is not going to be able to get to where it needs to go. But just as importantly, your body can't clean up that cellular debris. It can't clear away what you want to get rid of either.
[0:56:19] SCOTT: I know Bob Miller talks about this. Is the presence of both superoxide, maybe peroxynitrite as well, but superoxide combined with elevated levels of iron, which we commonly see in people with chronic illness, with some HFE or other genetic SNPs, is that what leads us to the ferroptosis conversation?
[0:56:47] BETH: Yes. I do a weekly blog and stuff, and supporting the nitrate to nitrite to nitric oxide pathway downregulates ferroptosis. Nitric oxide plays a huge part in downregulating that.
[0:57:05] SCOTT: So I want to come back a little bit to the stress, the cortisol impact on NOS, on nitric oxide. Is it reasonable to say that stress and cortisol increase superoxide, decrease nitric oxide? What part of the pathway for producing nitric oxide is cortisol impacting? And then does that then also negatively impact our immune response? The whole inducible, the iNOS piece again. And what is the role of nitric oxide specific to the adrenals? Do the adrenals need nitric oxide? While at the same time, cortisol itself is impairing nitric oxide production? It sounds like it's a little of a chicken-or-egg kind of discussion.
[0:57:55] BETH: The adrenals need adequate nitrite, nitric oxide, in order to make the glucocorticoids. But then the glucocorticoids uncouple NOS. Glucocorticoids increase oxidative stress. Chronic glucocorticoid, okay? Which kind of what we're all living under now. There's a time and a place to run away or to fight, but it's this chronic production of glucocorticoids that increase oxidative stress, which then uncouples NOS. Then when you're uncoupling iNOS, when you're stressed chronically, you can't fight infections. Okay?
When you're chronically stressed, you have more cardiovascular disease, you have more strokes, you have more MIs. So that you're uncoupling that eNOS. So stress also interferes with the arginine uptake in the cell, too. But stress increases your blood glucose, which then increases oxidative stress. Because when you got glucose dysregulation, when you've got diabetes, what gets you is the cardiovascular complications.
[0:59:30] SCOTT: Are you saying then that mind-body, that that connection is real?
[0:59:38] BETH: For sure.
[0:59:42] SCOTT: I know it's an obvious question, but it's funny because a lot of times in the chronic illness realm, so much of the time were gas lit with practitioners that say, "Oh, it's all psychological. You need to just go and think happy thoughts or whatever." But there really is a connection between our –
[1:00:00] BETH: There's a physiological connection. Yes.
[1:00:05] SCOTT: All right. So then, just to kind of recap, pathway one is the NOS L-arginine pathway. We then have pathway two, which is nitrate-nitrite-nitric oxide. Tell us a little more about that. When we take in nitrate either in our diet or supplements, how is it then converted, or where is it converted to nitrite and then nitric oxide? My understanding then is we can inhibit with this pathway some of the free radicals. We can minimize the production of that superoxide. And that this pathway really is a better approach for supporting nitric oxide production. We don't have to worry as much about BH4 impacting it. We don't have to worry about that oxidative stress or free radical production like we do with the NOS or L-arginine pathway. So, give us a little bit into this second pathway and how the nitrate becomes nitrite and nitric oxide.
[1:01:08] BETH: Well, we consume the nitrate either with a supplement or with the foods, gets absorbed. And it's readily absorbed, circulates around. It gets concentrated in the salivary glands. Salivary glands release the nitrate. We've got good bacteria on the dorsal aspect of our tongue that will reduce the nitrate to nitrite. So, if you've ever used any of those saliva strips to check, you're checking the nitrite concentration of your saliva.
So, we swallow the nitrite in the acidic environment of the stomach. Some of that nitrite gets reduced further to nitric oxide. Here's your protection against E. coli, H. pylori. However, most of the nitrite gets absorbed, and we've got different tissues, different cells in our body that can reduce the nitrite to nitric oxide on an as-needed basis.
For example, when you're exercising and those muscles need more oxygen, glucose, nutrients, and the debris to be carried away, myoglobin can reduce nitrite to nitric oxide on an as-needed basis in the electron transport chain. When there's a lot of oxidative stress, cytochrome c oxidase can reduce nitrite to nitric oxide on an as needed basis to open up those blood vessels to open up the circulation to allow more oxygen to get to the cells and the tissues. We've got other tissues that can reduce nitrite to nitric oxide on an as-needed basis.
[1:02:56] SCOTT: So, I'm not going to go there yet, but based on what Beth just said, listen as we later talk about the potential impact of mouthwashes, the oral microbiome on this whole nitric oxide conversation. We're going to come back to that. And I think it's a really important piece of the discussion.
Let's talk a little more about inflammation. More and more people recognize that inflammation is at the core of chronic illness. Dr. Neil Nathan's been talking more about inflammation, doing more presentations about how chronic inflammation is central to chronic illness. Talk to us a little about the role of nitric oxide on inflammatory interleukins. We know that COVID itself activated the NLRP3 pathway, which leads to an increase in cytokines, increase in interleukins. Melatonin, which you mentioned earlier, is one tool for modulating that NLRP3-driven inflammation that can really be excellent. Can nitric oxide itself reduce systemic inflammation, reduce cytokines, reduce interleukins? And in some cases, could it increase them?
[1:04:14] BETH: Yes. And I've been talking about this since March of 2020 because of the virus and then the vax, how the virus increased all those inflammatory cytokines, the NLRP3, interleukin 6, your interleukin 8. The nitric oxide downregulates those inflammatory cytokines. So that's one of the reasons why optimizing your nitric oxide was so critical then and even now, because a lot of these chronic – there's oxidative stress and inflammatory component to every single chronic issue, which means you are nitric oxide deficient because you've got the oxidative stress.
[1:05:08] SCOTT: I wish there was a functional medicine panel that we could order before and after incorporation of either dietary nitrate or exogenous supplements aimed at increasing nitric oxide to see would we expect to see a reduction in CRP, for example? Are there certain cytokines or interleukins that we could measurably – or maybe someone has done research that shows before and after nitric oxide support how those things reduce?
[1:05:43] BETH: I have seen the hs-CRP come down on people, okay? And especially, when the virus was so rampant. I had a doctor friend who did his labs, and then he did his labs when he had the virus. And just his inflammatory markers, his hs-CRP went up from .4 to 4.3, you know? And then we got him on the supplement twice a day, and we brought it back down. We brought it back down.
[1:06:21] SCOTT: One of the most interesting parts of the discussion around nitric oxide for me is blood sugar, glucose regulation, insulin resistance, diabetes, metabolic syndrome. Talk to us about insulin resistance. Is that by definition a nitric oxide-deficient state? And then how does GLUT4, how does that come into the conversation? Have you seen reductions in fasting glucose, in insulin, in A1C when we're supporting and optimizing nitric oxide production? And what's the connection between A1C and nitric oxide?
[1:07:05] BETH: Right. Insulin resistance, diabetes, nitric oxide-deficient state. That GLUT4 receptor requires nitric oxide attached to it in order to translocate and bring glucose into the cell. So, when you're nitric oxide deficient, you're not bringing that glucose into the cell optimally.
[1:07:29] SCOTT: Thus, increasing your blood glucose level.
[1:07:33] BETH: Right. And we have seen fasting blood glucose come down with regular supplemental nitrate. The hemoglobin A1C goes up when your blood glucose has risen. It's an average of what the blood glucose has been doing for the last three months. Well, hemoglobin A1C binds tightly with nitric oxide, which then takes nitric oxide out of being bioavailable to do all these other things that we need it to do to keep that microcirculation open, to keep clotting down.
[1:08:21] SCOTT: So, when we have dysregulation in our glucose, insulin, metabolism, metabolic syndrome, we will be lower in nitric oxide, which then leads to a host of other systemic challenges, cardiovascular, and otherwise.
[1:08:38] BETH: Yes. Because like I said, with the diabetes, with glucose dysregulation, it's the cardiovascular complications that gets these people, the nitric oxide deficiency.
[1:08:50] SCOTT: You mentioned a few times the electron transport chain. I want to talk a little bit about the impact to the mitochondria, ATP production, energy currency when we have low versus normal or robust levels of nitric oxide. How does nitric oxide impact mitochondria or even mitochondrial biogenesis? The creation of new mitochondria?
[1:09:18] BETH: Well, it's dependent on nitric oxide, the mitochondrial biogenesis. It needs the nitric oxide in order to regenerate. So, the electron transport chain, it's coupled to send that electron down the chain to make your ATP and water. But not all of your oxygen gets changed into water. Some of that oxygen gets oxidized into superoxide. The mitochondria is a big source of reactive oxygen species. The nitrite and nitric oxide can help recoup that electron transport chain to help downregulate that production of superoxide and reactive oxygen species.
[1:10:17] SCOTT: Let's come back to the cardiovascular disease conversation. When we have impaired endothelial NOS, we can have an increase in hypertension or blood pressure. We can have more myocardial infarction or heart attack; we could have more stroke. So, talk to us a little about maybe the mechanisms where increasing nitric oxide could mitigate those factors. Is it common to see blood pressure normalization with nitric oxide optimization? Gosh, I'm writing riddles there. We know that high blood pressure can also precede cognitive decline. Wondering if nitric oxide has a role in terms of plaque formation in our vascular system.
And then talking more about cardiovascular, POTS, or postural orthostatic tachycardia syndrome, that overlaps with the nervous system and the vascular system. Is there any benefit to using nitric oxide in people with POTS dysautonomia?
[1:11:24] BETH: Cardiovascular disease is still the number one killer in the whole world. I do weekly blogs. And last week was a recent study showing that, still, the number one killer all over the world. And so, by optimizing that nitric oxide, we will not only form the nitric oxide to help govern the circulation and microcirculation, we are helping to recouple that eNOS, that endothelial NOS.
So yes, I have seen normalization with blood pressure with the DASH diet, dietary approaches to stop hypertension. And if somebody doesn't want to eat all those vegetables, I just so happened to have formulated a good nitrate product that we can get people's blood pressure down.
A lot of times, people with blood pressure issues, they'll put them on one blood pressure pill, and that doesn't seem to cut it. So, then they add another one. And now they're even promoting a triple drug, blood pressure med to even start people on. However, if one blood pressure med doesn't work, that means that they don't have enough nitric oxide on board to even begin with. That's why allopathic medicine is going, "Well, let's just give them three drugs.".
Well, if you just optimize their nitric oxide to even begin with, you might not have to go down that road for blood pressure meds. And you can actually even get off the blood pressure meds as long as you're addressing other things that may have caused that to begin with, too. I mean, it's not just about eating the vegetables or taking a pill. You got to pay attention to how you're living. Do the stress reduction, change your diet, get some exercise in, be cognizant.
[1:13:41] SCOTT: So, talking about heart attacks, people use nitroglycerin. Is that related to nitric oxide?
[1:13:50] BETH: It is. Nitroglycerin, it's what's called an organic nitrate. The nitrate in the supplement or the nitrate in vegetables, those are called inorganic nitrates. That's precisely how the nitroglycerin works. Increases the nitric oxide. However, these organic nitrates, the nitroglycerin, the isosorbide, these are metabolized a little differently than the inorganic nitrates, like what you get with vegetables or supplement. So, those drugs, you can actually even become resistant to. You have to keep doing more and more to get the same effect. But you don't get that effect with the inorganic nitrates. You do not become acclimated to them. You don't have to do more and more to get the same effect.
[1:14:57] SCOTT: So, before we wrap up then on the vasculature conversation, cardiovascular system, does nitric oxide help with plaque formation in our vasculature? And have you seen people with POTS or dysautonomia positively benefited by optimizing nitric oxide?
[1:15:18] BETH: Yes. Optimizing the nitric oxide will keep your blood vessels open. So, you are not laying down all of this stuff. It helps protect your blood vessels so your body doesn't have to lay down protection on it. You're decreasing the inflammatory molecules that damage the blood vessels.
I have given my supplement to probably three people that have told me they had POTS, and it really helped them. I think it's more like a modulating effect. And some of that actually, I think, has to do with some of this circulation in their brain. You get that going, and then things just go a lot better.
[1:16:16] SCOTT: Many of our listeners are dealing with mast cell activation syndrome with histamine issues. Is there a connection between mast cells histamine and nitric oxide? And have you seen optimization of nitric oxide lead to resolution or lessening of those histamine issues?
[1:16:35] BETH: Right. Nitric oxide downregulates the mast cell release of histamine, downregulates these inflammatory cytokines. So yes, I have seen some positive results doing nitrate regularly. Yes.
[1:16:53] SCOTT: So many people these days fear cognitive decline, dementia, Alzheimer's. Two of the more common complaints that we hear in chronic illness are brain fog and fatigue. So does increasing nitric oxide help with the microcirculation in the brain? Do you see it improving cognitive function? And does nitric oxide potentially also play some role in the realm of anxiety, or depression, or balancing mental state?
[1:17:27] BETH: It sure does. Yes to everything. Okay. You've got to have good circulation in the brain for those cells to be fed. Oxygen is critical in the brain. So, our brain is like maybe 2% of the body weight, but it consumes 20% of our total oxygen. Oxygen is so critical for brain function. And if those microcapillaries aren't open, those cells aren't getting fed. And just as importantly, the debris is not taken away.
So, the brain microcirculation, the brain circulation, wants to be making 25% of the total nitric oxide production of the whole body. Circulation is that critical. You got oxygen. Okay, the hemoglobin has to have nitric oxide attached to it in order to release oxygen. So, you could even be super saturated with oxygen. But if you're nitric oxide deficient, that hemoglobin is not going to even be releasing that. And all of that exchange takes place down on that microcapillary level, those really tiny, tiny vessels.
[1:18:53] SCOTT: It's interesting and somewhat obvious, I think, at this point, how coagulation and nitric oxide conversations overlap in that we get less delivery of nutrients, even the supplements and things we're taking into the body. We get less delivery of oxygen, and we get less waste removal. Meaning that if we don't have adequate circulation, we are also not optimally detoxifying.
[1:19:24] BETH: Right. Exactly.
[1:19:25] SCOTT: Let's talk a little bit about nitric oxide and its impact on neurogenesis. And many people, myself included, have dealt with high glutamate levels. We know that's excitotoxic. So, does nitric oxide have some role on GABA? Does that then have a beneficial role on reducing glutamate? And is glutamate toxicity related to low nitric oxide?
[1:19:53] BETH: Yes. And all above. Yes. Nitric oxide increases BDNF, brain-derived neurotrophic factor, which plays a huge part on neuroplasticity. And also, all the neurons have all these little microcapillaries to be fed. And they can't store the ATP. So, they need to be fed all the time to keep them healthy. And some of these neurons in the brain, they're long-lived. They don't regenerate easily. So that means you've got to keep them fed and cleaned up all the time. The nitric oxide, it inhibits GABA transaminase, which allows GABA to be circulating, to be there longer.
[1:20:55] SCOTT: The calming neurotransmitter.
[1:20:56] BETH: Right. So that will inhibit that glutamate toxicity.
[1:21:02] SCOTT: Building a little bit on the oxidative stress conversation, there's a lot of labs we can do today to look at different things that might suggest we have higher levels of oxidative stress. Do you think that increasing nitric oxide is enough to see a reduction on some of those oxidative stress tests? Or do we still need things like glutathione, melatonin, antioxidants to create redox balance?
[1:21:30] BETH: Well, like I say all the time, nitric oxide will never be the only thing you do, but it should be at the base of everything you do. So just with the nitric oxide, with the nitrate therapy, I did see a decrease in my friend's hs-CRP, because that was the only thing that he did. We wanted to see what would happen. I did see a decrease of his hs-CRP.
[1:22:01] SCOTT: We touched a little bit just a moment ago on the impact of nitric oxide on detoxification. I want to talk specifically about the kidneys and the role of nitric oxide on the kidneys, on filtration, maybe on the estimated GFR, the glomerular filtration rate, or eGFR. And then building on the kidney conversation, what does dialysis do to our nitrate and nitrite? Could dialysis reduce nitric oxide, increase cardiovascular disease, and even exact exacerbate the kidney disease? That's the reason we're there for dialysis in the first place.
[1:22:42] BETH: It certainly does. Dialysis, the first pass, I think, takes out 80% of the nitrate in the blood. Okay? And then by the time you've gone through a few hours of dialysis, you don't have any left. I think it does exacerbate.
[1:23:02] SCOTT: Have you seen increases in people's GFR with nitric oxide?
[1:23:08] BETH: I haven't really looked at that yet. However, I have a friend who's a kidney doctor, and she uses my product with everybody to begin with. And like I said, it's not the only thing you're going to do, but it's the base of everything. You've got to have that microcirculation open in the kidneys. Because look at all that stuff that's happening in those kidneys.
[1:23:34] SCOTT: There is a lot of discussion these days on stem cells, exosomes. Is nitric oxide playing a role in either increasing our own endogenous release of stem cells or in targeting where the body kind of directs the stem cells for repair? And would it be beneficial to optimize nitric oxide before introduction of exogenous stem cells or exosomes?
[1:24:02] BETH: It's essential to optimize the nitric oxide first. It's absolutely essential. And I think some of the reasons why some of the treatments don't work is because the nitric oxide was not optimized. Nitric oxide is needed for the stem cells release, for where they're going to go, for differentiation, for what they're going to do. I mean, one of the reasons how hyperbaric works for increasing stem cells is because of the increase in nitric oxide.
[1:24:34] SCOTT: You're connecting so many dots. It's amazing.
[1:24:37] BETH: Good.
[1:24:38] SCOTT: In the realm of nitric oxide, I think most people think of it for erectile dysfunction, right? If people knew one thing, it's erectile dysfunction. That's an endothelial dysfunction, a vascular dysfunction. People reach for things like Viagra or Cialis. Are those increasing nitric oxide? And if you already have low nitric oxide, will they work, or do you need a healthy nitric oxide level for these PDE5 inhibitors to work as we hope they would? And is it potentially risky to combine nitrates with these Viagra, Cialis, PDE5 inhibitors?
[1:25:20] BETH: Erectile dysfunction, ED is ED. Erectile dysfunction is endothelial dysfunction. It's usually one of the first signs of cardiovascular disease. These PD5 inhibitors only allow the nitric oxide that's there to hang around longer. If you're deficient in nitric oxide, they're not going to work as well. So sometimes, even by optimizing your nitric oxide, you might not even need that PDE5 inhibitor.
Using the PDE5 inhibitors with the organic nitrates, like your nitroglycerin or your isosorbide, is not recommended. Because remember, I said they're metabolized a little differently. But we have seen people use the nitrate with these PDE5 inhibitors. You don't need as high a dosage of the PDE5 inhibitor, and you will see much better results. But nitric oxide is required for women, too. We need nitric oxide in order to be able to feel, to be able to respond. And lubrication is nitric oxide-mediated. So as women, if we can't feel anything, we're not responding, and we're not lubricating, do you think we even think about sex? Probably not so much.
[1:26:47] SCOTT: So, let's start moving now into a little more around supporting nitric oxide production in the body. We talked about the two pathways, the NOS pathway, the nitrate- nitrite-nitric oxide pathway. Many people, it seems, with supplements are working on the NOS pathway and using arginine, using citrulline, those types of things. I've always been hesitant for reasons we've already discussed. But is there any value in approaching low nitric oxide from the NOS pathway perspective? What are the upsides and downsides of trying to make a dysfunctional NOS function less dysfunctionally?
[1:27:28] BETH: Well, most of the studies using arginine for cardiovascular health or for positive increase on nitric oxide were done on young, male, fit athletes. Okay? They weren't done on people with any chronic issue. They weren't done on people with diabetes. They weren't done on people with cardiovascular disease. I do not recommend arginine supplementation.
Citrulline might be a little better because citrulline won't go down all the same pathways that arginine goes down. However, you're still trying to kick this dysfunctional, uncoupled NOS, and it's just not going to work with those amino acids. Like the – what is it called? The coefficient. The amount of arginine to saturate a NOS enzyme is very small. There are really very few people that are truly arginine-deficient.
[1:28:43] SCOTT: We also hear a lot of conversation around beets relative to nitric oxide optimization. Which of the pathways are beets supporting?
[1:28:54] BETH: The nitrate to nitrite to nitric oxide. However, you have to eat a bunch, like seven ounces of beets, which is that's pretty much. That's over, almost a half a pound.
[1:29:08] SCOTT: So, we know now, building on that, that the path of least resistance essentially is the nitrate-nitrite-nitric oxide pathway. What are some of the ingredients in supplements that support nitric oxide production via that second pathway? And why are some products supplying nitrate and others, nitrite?
[] 1:29:33BETH: The lozenges are nitrite. So that's putting nitrite right there in your mouth. So, if you've got dysbiosis in your mouth and you don't have the good bacteria, that's putting nitrite right there. Unfortunately, nitrite has a half-life of just 20 minutes to an hour, where nitrate has a half-life of 6 to 8 hours. And the beautiful thing about nitrate supplementation is you are rebuilding those microbiomes. Not only in your gut, but also in your mouth, on your skin, in your vagina. You're rebuilding microbiomes everywhere.
[1:30:19] SCOTT: Potassium nitrate is one ingredient. It is one that we'll talk about in a product that you created as well. So, how much nitrate does one generally need to support that pathway? Where does potassium nitrate come from? How is it created? Is it best to divide it in multiple doses throughout the day? Should we be doing these things once a day, twice a day? And should people be relying on nitric oxide-supporting products? Or should we be combining diet, where maybe we're taking the supplements in the morning and at night, but then having more nitrate in our vegetables, in our arugula salads, things of that nature for lunch and dinner? What does kind of the optimization of nitric oxide per Beth Shirley look like?
[1:31:15] BETH: Okay, so the study shows that it takes 300 to 400 milligrams of nitrate as a dose to make the preferred physiological changes, like the changes in the blood pressure. But also, I've helped a lot of people that have low blood pressure, and they've been able to take my supplement, too. So, it's more like a modulating effect.
I like a combination of both. I like a combination of high-nitrate veggies and a nitrate supplement. The nitrate supplement that I did formulate has about 320 mg of nitrate, and that's a physiological dose.
[1:32:11] SCOTT: Is that per capsule?
[1:32:12] BETH: No, per two capsules.
[1:32:14] SCOTT: Okay.
[1:32:15] BETH: And a lot of people, I recommend taking two of those in the morning and then adding some high-nitrate veggies at lunch or dinner to keep that level steady. I tell people you can do it all with vegetables, but use those test strips to see whether you're at optimal levels with your vegetable intake.
[1:32:43] SCOTT: I want to touch a little bit more on the microbiome of the mouth, the toothpastes, the mouthwashes. So, if we don't have the optimized microbiome in the mouth, my understanding from what you've taught us today is that we have deficiencies in nitrate converting to nitrite. And I want to hear a little bit of your thoughts on what is the negative impact of daily mouthwash on our nitric oxide levels. Thus, our cardiovascular health. Thus, our systemic health. Is what we think of as health-promoting with a mouthwash potentially doing great harm?
And then some companies I've seen have toothpastes that are helpful in optimizing their nitric oxide production by supporting the microbiome. Wondering if you feel that's a necessary component of all of this. And then lastly, if we know that some people are not going to be converters of nitrate to nitrite at optimal levels, but we also know that nitrate is helping the microbiome, should some people initially start by using both nitrate and nitrite?
[1:34:08] BETH: The use of antibacterial mouthwashes, fluoride toothpaste, whitening toothpaste with the hydrogen peroxide, all of these can be antimicrobial. These do have the potential to interfere with your oral microbiome. So, I don't recommend them. But with continued use of the nitrite, you're actually rebuilding those microbiomes. And I think it's the dysbiosis that actually causes the smelly breath as part of it.
There are people now that do have a nitrate toothpaste. So, you're putting the nitrate right there in your mouth. So that's what some of those toothpastes that are for sensitive teeth actually have nitrate in there. I have yet not seen somebody that we have not been able to rebuild that microbiome with nitrate. I've had a couple of people that took a couple of weeks, but these were people with pretty severe cardiovascular disease, pretty severe chronic issues. And I'm sure they had totally messed up guts, too. Because the oral microbiome and the gut microbiome, they share about 50% of the same microbiome.
[1:35:41] SCOTT: So, you're saying even without the toothpastes that people can use the nitrate, even if they have a less than optimal oral microbiome, and that is not going to negate the nitrates potential for increasing their nitric oxide.
[1:35:58] BETH: Right. Because I do these shows and we test people. We'll test them and then give them a couple capsules, and they'll come back in about an hour. There's been very rarely somebody that we don't see an increase of nitrate in their saliva. Very rarely.
[1:36:19] SCOTT: So, it sounds then like we don't necessarily need the toothpastes, but that we still might be wise to minimize carpet bombing our oral microbiome if we want to optimize nitric oxide production over time.
[1:36:37] BETH: For sure. Besides, we know fluoride isn't very good anyway.
[1:36:42] SCOTT: Most of the companies that I've seen with products to increase nitric oxide have their test strips that you can use to check your levels. You just mentioned doing that at conferences. Talk to us a little about how long after taking an exogenous nitrate, nitric oxide increasing supplement we should then test. And is there a point? Because we know that nitrate is lasting in the body 6 to 8 hours, we know nitric oxide is in the realm of seconds, is there a point where we get replenished enough that then we have the building materials that can keep our nitric oxide in that optimal range throughout the day, versus having this short burst of consuming nitrate? We have a burst of nitric oxide potentially, but then there's kind of a decline. Do we get to a point where we should be able to use those test strips at any time of the day and see a reasonably solid level of nitric oxide?
[1:37:46] BETH: Our muscles do store nitrate and nitrite. We can rebuild some of those stores. However, we still need to replenish it every single day, whether you do it with vegetables or you do it with a supplement. I tell people I don't really care how you do it, but do it some way every single day.
[1:38:12] SCOTT: When I'm first starting out, you want to do the strips about an hour or so after the –
[1:38:17] BETH: Hour and a half. Yeah.
[1:38:20] SCOTT: Hour and a half?
[1:38:20] BETH: Well, that's what they recommend. However, a lot of people, I just say by about an hour, things are flowing.
[1:38:31] SCOTT: And as over time, we have repleted our nitrate, would I then expect that the benefit of the exogenous supplements would be more durable? Meaning, if I took them in the morning, but I didn't do the test strip until 4 or 6 hours later, the longer that I'm supporting nitrate, would I expect to see more stable nitric oxide levels throughout the day?
[1:39:00] BETH: You should, because you will have some stores rebuilt. However, from experience of dealing with a lot of people, you still need to replenish it.
[1:39:14] SCOTT: Another controversy, since you seem to be very comfortable talking about controversies, is the methylene blue conversation. Many people are using in our community methylene blue for Bartonella infections, for mitochondrial support. There are some voices out there that suggest that methylene blue and nitric oxide supplements may not work well together. That methylene blue could inhibit nitric oxide-mediated damage. Are methylene blue and nitric oxide contraindicated together? Does methylene blue downregulate or reduce nitric oxide in the body?
[1:39:58] BETH: Methylene blue only downregulates an upregulated iNOS.
[1:40:05] SCOTT: Sounds like another good reason to take methylene blue to me.
[1:40:09] BETH: Yeah, it does. It does. So, they work really well together. And a couple years ago, I actually wrote a paper and I did a webinar on this because we had so many people saying, "Well, I read that book, and he said that methylene blue downregulates nitric oxide." So, we had all these people saying that they weren't going to optimize their nitric oxide.
However, they work really good together. So, this methylene blue, it supports your electron transport chain production, its consumption of the oxygen. It supports that electron transport down the electron transport chain. But it also helps make somewhat of a hypoxic condition in the mitochondria. So then in the mitochondria, if we've got good nitrite stores, that cytochrome C oxidase can reduce that nitrite to nitric oxide to increase the vasodilation and increase the cerebral blood flow, increase the glucose uptake. So, the way they work together is very synergistic.
[1:41:40] SCOTT: So, as we get to our last couple of questions, we should talk about potential contraindications to either eating or taking things that increase nitric oxide. If someone already has, for some reason, high levels, should we then not be attempting to increase it further? Are there any contraindications, condition, scenarios where increasing it could be a bad idea? Any side effects even if we're working with this secondary pathway of getting nitric oxide levels that are too high? And then what about those people with elevated iron? Do we need to be more cautious? Particularly if we're working with the NOS pathway and maybe increasing ferroptosis and the detrimental effects of iron, when should we be cautious?
[1:42:28] BETH: So, I have yet to see anybody with too much nitric oxide. Because even in septic shock where they can give people with septic shock nitrite to keep the perfusion going. Okay? That's one of the treatments of septic shock. Septic shock, they use methylene blue, too. They can use both methylene blue and nitrite to keep the profusion going. I've yet to see anybody with too much nitric oxide.
As far as too much nitrate, like the DASH diet, 1200 to 1500 milligrams of nitrate per day, that's like taking two capsules four to five times a day. Or eating 7 ounces of beets four to five times a day, five ounces of spinach four to five times a day. Not going to happen, right? I don't see people with too much nitric oxide. Once again, we're back to that peroxynitrite issue, which is a non-issue.
[1:43:44] SCOTT: So, no known contraindications then. I mean, I'm assuming maybe in pregnancy, not a great idea to do some of these things. But what are your thoughts?
[1:43:53] BETH: Well, only like the last month or so would I not recommend it. But every single facet of fertility is nitric oxide-mediated. Every single facet.
[1:44:08] SCOTT: I think listeners, when they hear something that sounds like a fix-it-all, which nitric oxide sounds the implications are very far-reaching, it increases our skepticism. So what do you say to those people who are skeptical about nitric oxide having as many potential benefits as we have discussed?
[1:44:34] BETH: Well, this is one of the reasons why I'm still researching nitric oxide since 2009 is because every single thing I research, nitric oxide is connected to it. It touches every single physiological process. It's not going to fix everything. Like I said, it's not the only thing you're going to do, but it should be at the base of every single thing you're going to do. You've got to optimize that circulation, microcirculation.
If you're taking any kind of supplement, if you're doing any kind of IV, if you're doing any kind of therapy, PEMF or any of these things, by optimizing that circulation, it will allow whatever else you're doing to work better. Things can get to where they need to go. So, it won't ever be the only thing, but it should be the base.
[1:45:38] SCOTT: Before we get to our final question, I want to talk a little bit about the nitric oxide supplements that you've created. There's one that's more targeted for women with Libby. There is the nitric oxide product through approved medical solutions as well. Tell us about the products that you formulated. What's in them? I know we talked about the benefit with the approved medical solutions product that it has third-party validation for not having any oxalates. And then I'd love for people to hear from your perspective why there are some methyl donors in these products. I historically have been very cautious about using products with methyl donors, whether it's methyl B12 or methyl folate, because people in this community tend to have strong responses to trying to move that methylation machinery, and ideally do it kind of on its own.
And then when we're looking at multivitamins and other things that are adding more methyl donors, sometimes too much is too much. So, why do we see some of those nutrients in these products? And then I'm also curious about how we get around the oral microbiome nitrate to nitrite conversion. We talked about that primarily happening in the mouth with the oral microbiome if what we're taking is a capsule of nitrate.
[1:47:09] BETH: Well, I put the methylfolate and the methyl B12 in there to support the methylation cycle, to support BH4 production, to support the coupling of the NOS enzyme.
[1:47:25] SCOTT: Ah, so you're working on both pathways.
[1:47:27] BETH: On both pathways, right. The vitamin C in there for an antioxidant-plus to be able to reduce that BH3 back to BH4, because vitamin C is the only molecule that can do that. And then there is some potassium nitrate and some hesperidin. There's lots of studies showing hesperidin supports cardiovascular health. And the arugula. So, most nitrate supplements have beets or spinach in it, which have oxalates. And I used arugula, which is high nitrate without oxalates.
[1:48:07] SCOTT: Which is great, because that stuff tastes awful. So, I'm happy to get it in a capsule.
[1:48:14] BETH: But like I said, the beautiful thing about nitrate supplementation is you're rebuilding those microbiomes. So, like I said, I've only had a couple of people that we couldn't get the strip to change right away. But after a couple weeks of continuous supplementation, we got the strip to change. But these were pretty sick people.
[1:48:36] SCOTT: So, the nitrate to nitrite conversion is happening in other places in the body outside of just the oral microbiome.
[1:48:44] BETH: Right.
[1:48:45] SCOTT: How much of this would the average person, if a serving size is two capsules, is that usually two capsules twice a day? What's the normal place?
[1:48:54] BETH: Usually, two capsules just once a day.
[1:48:56] SCOTT: All at the same time.
[1:48:57] BETH: Yeah, at the same time. Because that's the physiological dose. However, I do like them to add some veggies later on in the day. If we're doing something specific, like you don't want to go on blood pressure medications or you want to get off of them, then I would add two capsules twice a day. Or if you're having a little bit of sexual dysfunction, add another two capsules an hour prior to activity.
[1:49:23] SCOTT: All right. We'll put a link for people that are interested to Beth's product through Approved Medical Solutions. She also has a product that's a little more targeted for women, but as I understand could be used by men as well through Libby products for people that are interested in looking at some of the tools that Beth has formulated.
My last question is the same for every guest, and that is what are some of the key things that you do on a daily basis in support of your own health?
[1:49:51] BETH: Well, I do stress reduction activities. I walk. I eat pretty good. Lot of vegetables, a lot of proteins, not as many carbs. I turn off the Wi-Fi at night. Okay?
[1:50:11] SCOTT: Same here.
[1:50:13] BETH: Yeah. After I've been working on the computer, at least every hour, I'll get up and walk around. Don't stay there like staring at it for hours and hours.
[1:50:30] SCOTT: Don't forget to tell them that you support your nitric oxide.
[1:50:33] BETH: Oh, of course I do. And I've got a lot of oxidative stress right now, but I do it twice a day. I do it twice a day.
[1:50:44] SCOTT: Excellent. Excellent. This has been such a great conversation. And I will tell you, my brain feels a little like I've been to the gym and overexercised, because keeping up with you is a feat of nature, I think. But so wonderful to hear all of the potential things that people can improve by looking into this nitric oxide arena. You're super generous with your time. I know you're very, very respected in these practitioner circles. So, thank you so much for all that you do, Beth. And I just really want to honor you for not only educating us, but also for helping to create solutions to optimize our nitric oxide.
[1:51:27] BETH: Thank you very much. My pleasure.
[1:51:31] SCOTT: To learn more about today's guest, check out the links in the show notes.
Thanks so much for listening to today's episode. If you're enjoying the podcast, please leave a positive rating or review, as doing so will help the show reach a broader audience. To support the show, visit BetterHealthGuy.com/donate. To get my newsletter, visit BetterHealthGuy.com/newsletters. To follow me on Facebook, Instagram, X, or TikTok, you can find me there as BetterHealthGuy. This and other episodes can be found on Apple Podcasts, Spotify, Amazon Music, YouTube, and Odysee.
[1:52:10] ANNOUNCER: Thanks for listening to this Better HealthGuyBlogcast with Scott, your BetterHealthGuy. To check out additional shows and learn more about Scott's personal journey to better health, please visit BetterHealthGuy.com.
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Disclosure
BetterHealthGuy.com is an affiliate of Approved Medical Solutions.
Disclaimer
The content of this show is for informational purposes only and is not intended to diagnose, treat, or cure any illness or medical condition. Nothing in today's discussion is meant to serve as medical advice or as information to facilitate self-treatment. As always, please discuss any potential health-related decisions with your own personal medical authority.
