Podcast

INCREASE Nitric Oxide in the Body, Kill VIRUSES & Benefits of NASAL BREATHING w/ Dr. Louis Ignarro

https://www.youtube.com/watch/jQavl5HxM9k

The following is an Operation Podcast production. I was awarded the Nobel Prize in Medicine for the work. Every male patient who was on the drug, although they got a decrease in their blood pressure, developed an erection. The nurses were very aware of that in the clinic. One of the most important factors that lead to diabetes is a deficiency in nitric oxide. Viagra stops working after a while. People get too casual with it. There are serious side effects, one of which is hearing loss. Is there any truth to this? First of all, have you heard of the carnivore diet? Yeah, they only ever eat meat, usually red meat, which is a deadly diet. Can we say Mediterranean food is the best way to live? There's no question about it. In serious respiratory distress situations, the inhalation of nitric oxide gas can work. If I inhaled a little bit of nitric oxide, would I get a breathing enhancement? Would it optimize my lung capacity? Because NO is antiviral, not just a vasodilator. We make NO to kill viruses in our body to sustain our lives. Why have we, why have I not heard, why has no one heard about this? Hi, my name is Lou Naro. I am a professor of Pharmacology and Physiology, and I am here to talk about nitric oxide. I want to welcome everyone to Ever Forward Radio. Hey everybody, welcome back to Ever Forward Radio. I have a repeat guest here today. I'm so excited to invite back on the show, and we're doing this really for you, especially on YouTube. This video over the last year has just been popping off. We are about a year old, over 234,000 views as of April here, 2024, and nearly 5,000 likes. One of the most popular videos I put out on YouTube for the podcast. Dr. Lou, welcome back to the show.

"Well, thanks, Chas. It's great to be back here, and I'm so happy to learn that so many people are interested in nitric oxide. Not me necessarily, but nitric oxide."

"Well, if my audience is unaware of who you are, can you give us a brief recap of your expertise and professional history?"

"Of course. Yes, I went to medical school and graduate school, but focused on graduate school. So, I have a doctorate degree, a PhD, in biology and pharmacology. My research has always been in the cardiovascular system, and right from the get-go, I started trying to figure out what causes high blood pressure, what causes diabetes, what causes coronary artery disease, and so on. By just working hard and pursuing my dreams of trying to unravel all this, I was able to discover that our bodies produce a very magical molecule, if I may call it that, called nitric oxide, or NO. This is a molecule we produce that works to protect us against all kinds of cardiovascular disease."

"Quite the humble man heard in that story. He left out a very interesting detail: Nobel Prize recipient for the discovery of nitric oxide in the human body, right?"

"Yes, I was. I was awarded the Nobel Prize in Medicine for the work, and the two criteria for the Nobel Prize, which most people don't know, are: one, you have to have made an original first-time discovery. So, my discovery was that the body makes nitric oxide. But that's not enough. The second requirement to be considered for the Nobel Prize is that your discovery has to be of obvious benefit to humankind. And, of course, we know that nitric oxide can save your life, can extend your life. Many drugs now work through a nitric oxide mechanism, and that's why I was awarded the Nobel Prize."

"Congratulations again. I mean, that's quite the feat. For anybody that is unfamiliar about nitric oxide, I'm sure we'll get into this a little bit more. The format of this episode is going to kind of bring our attention back to nitric oxide: what it is, why it's important, but really we're going to be answering quite a few questions from that first video that people are still curious about in terms of why it is important, how can I create it, how can I get it, and a few other things. So, just to kind of set the tone, I pulled a definition from Google. Nitric oxide is a gas formed by combining nitrogen and oxygen. It occurs naturally both outside and inside the body. Outside the body, nitric oxide is a colorless, sweet-smelling gas that is toxic at high levels. Inside the body, it acts as an important chemical messenger involved in many bodily functions. Did Google get it right? Would you add or subtract anything?"

"Google's getting better and better over the years, so they got it right with nitric oxide."

"So, my first question, or our first question, is: how can NO affect pre-diabetics?"

"Oh, in a very favorable way. The thing to remember is that there are certain factors in the body that lead up to diabetes or pre-diabetes, and one of the most important factors that leads to diabetes is a deficiency in nitric oxide when your nitric oxide levels are low. So, if one were to maintain, if one could maintain at least normal levels of nitric oxide, then the likelihood of one developing diabetes, especially type 2 diabetes, is quite low. The thing is this, that if people adapt an unhealthy lifestyle, meaning poor diet, no physical activity, mostly a sedentary lifestyle, these are the factors that lead to a decrease in nitric oxide. Well known for the last 25 years. And when you lower your nitric oxide levels, you lower the protection that the nitric oxide has to prevent the development of diabetes. So, if your NO is normal, you probably won't get diabetes."

I mean, there are always exceptions to these rules, sure, but in general, what you want to do is have a normal nitric oxide level. So, the question was, what can NO do in pre-diabetics? Yeah, how can nitric oxide affect pre-diabetics? Yeah, it can improve their condition, no question about it. It can certainly slow down and delay the development of full-blown diabetes. So, if someone is a pre-diabetic, then the key thing the physician should tell them is, you must immediately embark on a healthy balanced diet. We can talk about that later: healthy balanced diet and please put some physical activity in your life. Even if it's just walking three or four days a week, that will do it. 

And correct me if I'm wrong, I haven't looked at the charts in a little while, but I believe pre-diabetes is considered an A1C of 5.7 to 6.1?

Yes, in that range. Yes, around six.

Right, so is it safe to say that if someone is pre-diabetic, meaning they have an A1C within that range, is it safe to say then that most likely they have low NO levels as well?

Yes, right. Where it's been examined clinically, everyone with a high level of hemoglobin A1C, or just call it A1C, those patients have lower levels of nitric oxide in certain areas of the cardiovascular system. Looking at it another way, where it's been examined, those people with normal levels of hemoglobin A1C have normal production and action of nitric oxide. So that's why this is a very strong association. Other research has shown that there's no question about it: when the nitric oxide level is low, the protection is lost. There are a variety of metabolic changes, which I won't get into, that cause problems, which cause a rise in hemoglobin A1C. We're going to get into this a little bit later on in terms of ways to naturally, i.e., internally boost or create more NO, or even foods and supplementation. But aside from that, it should make sense that we increase nitric oxide production and therefore can reduce or get out of that pre-diabetic range by means of the best way to create more NO, which is through what you're talking about: physical activity, strength training, exercise. That's really how the body creates more of it naturally. So, naturally, yes, increase healthier lifestyle through activity and exercise boosts NO and therefore gets you out of that pre-diabetic range.

It's a simple answer, that's what I tell people, and most of them don't believe me because they say, "Well, it can't be that simple." And I say, "Well, why can't it be that simple?" People are looking for a magic drug, a magic bullet. They want to be able to eat their hamburgers and not get up and take a pill. Yeah, and take a pill, and that's going to cure them. The OIC? Yes, that drug will aid one in losing weight, that's for sure.

Losing weight, GP1 agonist, yeah, exactly. But just losing weight, I'm afraid, is not going to do it because you're going to still develop diabetes if you don't do anything to boost your nitric oxide. While you're losing weight, you will lose weight, but years down the line, you're going to still develop cardiovascular disease. Now, OIC has been out a short time. We have to wait 20, 30 years to see the results of OIC in decreasing the incidence of cardiovascular disease. We're not going to see that for a long time. You can't do a study in two or three years and say, "Oh, OIC prevents cardiovascular disease." No, you have to. I mean, what does it do? It does a number of things: it allows you to lose body weight. But the smart patient and the smart physician will tell the patient, take advantage of the OIC. While you take the drug and lose weight, increase your physical activity, switch your diet over to a healthy balanced diet, and between the OIC and those two other more natural phenomena, you're going to be very healthy.

It's a great start.

Absolutely, yes.

Yeah, amazing. Okay, so number two, the second question: Viagra stops working after a while. People get too casual with it. There are serious side effects, one of which is hearing loss. Is there any truth to this?

Some. First of all, there's very, very little evidence that taking Viagra leads to the development of tolerance to the drug. Tolerance means you're responding less and less to the drug. If you look at the clinical literature, the evidence for the development of tolerance to Viagra at the normal recommended dose, which is 50 milligrams for a man to take, there's very little evidence. What most urologists believe is that the tolerance to the drug, I mean, it's not the tolerance to the drug that's developing, but it's the worsening over time of the erectile dysfunction.

Oh, interesting. Really?

They're happening together, so you can't blame the Viagra for the tolerance. Instead, the ED, the erectile dysfunction, is getting worse. Remember now, folks, Viagra does not cure ED. It does not reverse ED. It has nothing to do with the disease. What Viagra does is allow the man to get an erection when he can't really get one because he has erectile dysfunction. So it increases the ability to get the erection, but it has nothing to do with treatment of the disease.

Can you maybe, Dr. Lou, walk us through a high-level understanding of what is happening with erectile dysfunction? Now, again, we did touch on this quite a bit in the first episode, but just so people are clear.

Well, people forget. Erectile dysfunction, most forms—there are many different forms—but let's focus on the most common form of erectile dysfunction. It is brought about by the failure of the nerves. The nerves that attach to the erectile tissue in the penis are not releasing, they're not functioning normally, and they're not releasing their neurotransmitter. All nerves release a chemical called the neurotransmitter, and that neurotransmitter then produces a function on the organ that the nerves are attached to. In the case of the erectile tissue, the nerves are releasing, as we first found, nitric oxide. And nitric oxide is a vasodilator, right? It expands the blood vessels.

Blood vessels, so what happens when you expand blood vessels?

They fill up with blood. I don't have to explain how that relates to erectile function, okay? I mean, that's how Viagra works. So in patients with ED, for some reason that's now becoming clear, the nerves are not releasing enough nitric oxide, so a normal erection cannot be obtained in order to perform sexual intercourse or anything else for that matter. And so what we understand now are the factors that can lead to this decrease in nitric oxide release from the nerves. Once again, what is it? It is a poor diet and a lack of physical activity. The poor diet and the lack of physical activity is very strongly associated with erectile dysfunction.

How would you define poor diet? What do you mean by that?

A poor diet is not eating enough fruits and vegetables, which naturally boost your nitric oxide tremendously. And it's eating the wrong kinds of carbohydrates. Carbs are good—the fruits and vegetables are carbs—but so is refined sugar. So it's sugar, potatoes, potato chips, and all the packaged carbs.

Mostly processed foods?

Mostly processed foods, you know, that's a big problem. And also, it's important to eat protein, but it's important to eat healthy protein.

How do you define healthy protein?

Well, let me tell you what healthy protein is not, okay? A nice fatty wagyu beef or steak.

You're saying saturated fat?

Saturated fat is a big, big problem, and we can get into that later.

There's a lot of controversy about that. A lot of people feel like it's not as big of a demon as a lot of people make it out to be.

It depends. Well, it depends who a lot of people are. They're not cardiologists, I assure you. Ask a handful of cardiologists. Now, it just depends how you look at that. Some saturated fats may be worse than others. And there's also—saturated fat in your body, when you eat it, leads to the formation of something called free radicals. I don't know how many viewers know that. You can look that up. You can Google that or if you use ChatGPT—that is an amazing tool to learn something. I use it all the time. Really, I've tested it. I tested it asking it questions about myself and my work. It got it right every time, so that's good. But no, what saturated fats, the fat in certain cuts of beef, for example, any fat that is solid at room temperature—any fat that is solid at room temperature in the body is oxidized. It undergoes oxidation metabolism to free radicals. So if you're healthy, admittedly, if you're healthy and you have your saturated fats but you also have a fairly well-balanced diet and you're of normal weight and you don't have cardiovascular disease, you could probably handle that load of saturated fat and all those free radicals formed are not going to destroy your cells and decrease your NO production.

I would love to, while we're here kind of talking about it, I would love to get your take on—you said the carnivore diet is a deadly diet. That's a pretty big claim. I'd be curious to hear your definition.

Well, you know, you have to understand where I'm coming from. I understand nutrition. I'm an expert in the cardiovascular system, and I'm a hell of a biochemist.

Okay.

I absolutely, I will say that. So I understand how the body handles saturated fat, you know, and the body handles saturated fat in only one way: whenever you consume something, your digestive system breaks it down, right? So it breaks it down into the smaller components, like fatty acids or amino acids, because those tiny molecules are the ones that can get through the membranes in your gastrointestinal tract and wind up in the blood. If you can't digest something, it just comes out in the feces. So the way your body metabolizes saturated fat is the fat goes to the liver and other organs and gets broken down into small fatty acids. In those reactions—and all of those reactions are well known—in all those reactions, free radicals are produced. So if you're healthy, if you're—admittedly, if you're healthy and you have your saturated fats but you also have a fairly well-balanced diet and you're of normal weight and you don't have cardiovascular disease, you could probably handle that load of saturated fat and all those free radicals formed are not going to destroy your cells and decrease your NO production.

Podcast

Elevate Your Nitric Oxide Levels: 7 Science-Backed Strategies

https://www.youtube.com/watch/9P7LkwIRkP8

Aloha everyone, and welcome to Out of the Doldrums. I’m Irminne Van         

Dyken MD. Today we're diving deep into the biochemistry and physiology of nitric oxide,     

a molecule imperative to our vascular health, cognitive function, and so much more.       

Stick with me as we uncover seven science-backed ways to boost nitric oxide levels in our body. 

1 Nasal Breathing:Our nose is not just an organ for smelling; it’s a       

sophisticated piece of biological machinery. Deep within the paranasal sinuses, specialized cells         

produce nitric oxide. When we breathe through our noses, we actively channel this nitric oxide into     

our lungs. As you take in a deep, nasal breath, the nitric oxide travels from your sinuses to   

the lungs. Here, it increases the lungs' oxygen uptake by improving blood flow. It does this by   

expanding tiny air sacs in the lungs (called alveoli) and dilating the surrounding blood       

vessels. This allows for a more efficient exchange of oxygen and carbon dioxide, enriching our bodies     

with life-sustaining oxygen. Nitric oxide also acts as a bronchodilator and an antimicrobial       

agent. Lastly, by dilating blood vessels, nitric oxide helps regulate blood pressure. Remember,       

the nose isn’t just an ornament; it’s a pathway to improved vascular health!     

You might be wondering: 'What happens when we mouth breathe? Well, mouth breathing bypasses       

the nitric oxide-rich environment of our nasal passages. As a result, you miss out       

on the added oxygenation and other benefits that come from the NO produced in the sinuses.     

Simply put, while we can obtain oxygen via mouth breathing,           

it’s not as efficient or beneficial as nasal breathing. So - just say NO to mouth breathing. 

2 Humming:I did a whole video on this - it's linked below.      

Like we just discussed - our paranasal sinuses are nitric oxide factories. This region produces NO     

continually, and when we breathe through our nose, we transport this beneficial molecule       

straight to our lungs. Researchers have discovered that the act of humming amplifies the production     

and release of nitric oxide. How, you ask? Well, humming creates a resonating sound wave.     

This vibration increases airflow oscillation in the sinuses, leading to a surge in nitric       

oxide release. In fact, a 2002 study published in the American Journal of Respiratory and Critical     

Care Medicine found that the airflow oscillations caused by humming resulted in a 15-fold increase     

in nitric oxide release. More fascinatingly, not all hums are equal. Optimal frequencies lie       

between 100 to 200 Hz, with around 130 Hz seeming to be the sweet spot for maximizing NO release.  

For context, this frequency is somewhat akin to the pitch of a low male voice.     

How long and how frequently do we need to hum to get the NO release?    

While specific durations haven’t been universally recommended,             

a practical approach is to incorporate periods of humming into daily routines. Dedicate, say,       

five minutes daily to focused humming, ensuring you’re in the optimal frequency range. This will     

not only be a meditative exercise but also one rich in physiological rewards     

3 Exercise:Onto exercise, a tried and TRUE method. Every           

time we exercise, our muscles require more oxygen. To meet this demand,         

blood flow must increase. The inner lining of our blood vessels, known as the endothelium,     

becomes activated during exercise. These endothelial cells produce nitric oxide         

in response to the mechanical forces exerted by the increased blood flow.       

Now, let’s get a little bit more technical. When you exercise,         

the shear stress – that’s the frictional force of blood – activates an enzyme called     

endothelial nitric oxide synthase (or eNOS for short). eNOS facilitates the conversion of an       

amino acid called L-arginine into our star molecule, nitric oxide."         

So what happens when we produce nitric oxide while exercising?          

First, we get vasodilation: NO signals the smooth muscles in our arteries to relax,       

leading to widening of the blood vessels. This is called vasodilation, which allows       

more blood to flow and cater to the oxygen demands of our working muscles.      

Second, we get enhanced Oxygen Delivery: With vasodilation, more oxygen-rich           

blood reaches the muscles, ensuring they work efficiently and recover faster post-exercise.        

Third, we get increased nutrient delivery: It's not just about oxygen! Increased blood flow means     

faster delivery of essential nutrients to the muscles, aiding in repair and growth."     

Another thing to note is that these benefits are long term.         

Consistent exercise does more than provide an immediate boost in nitric oxide. Over time,       

it enhances the endothelium's capacity to produce nitric oxide, even when you’re at rest. This can     

contribute to improved vascular health and lower risks of cardiovascular diseases."       

Lastly, when it comes to nitric oxide production, Not All Exercises Are Equal:      

While almost all forms of exercise stimulate nitric oxide production,           

aerobic exercises like jogging, swimming, and cycling tend to have a more pronounced effect       

on NO release due to the sustained increase in blood flow. Resistance         

training also generates nitric oxide, especially during high-intensity sets.         

4 Eating Nitrate-Rich Foods:Our diet plays a pivotal role in         

nitric oxide production. Consuming Nitrate-Rich Foods helps boost nitric oxide. When we consume       

vegetables like beetroot or spinach, our body converts their nitrates to nitrites,       

thanks to the oral bacteria. Once in our stomach, nitrites can be further converted to nitric oxide.   

This pathway highlights the importance of dietary nitrates in cardiovascular health.        

The journey of dietary nitrates to nitric oxide is a fascinating one. Foods like spinach, arugula,     

beets, and celery are teeming with nitrates. But here's the kicker – our bodies don't     

directly convert these nitrates to nitric oxide. Instead, it's a multi-step process involving       

bacteria and multiple organs."Let’s take a quick moment to           

review the Nitrate-Nitrite-NO Pathway:Here's are the main four steps of the pathway:     

1 Dietary Intake: When you consume nitrate-rich foods,             

these nitrates are absorbed into the bloodstream through the small intestine.        

2 Salivary Concentration: A significant portion of these nitrates gets concentrated in the       

salivary glands and then secreted into the mouth.3. The Oral Microbiome: The oral cavity houses   

specific bacteria that reduce these nitrates to another compound called nitrites.        

4 Swallowing and Conversion: Once swallowed, these nitrites, under certain conditions,         

especially in conditions of low oxygen (like during intense exercise), can be reduced to       

form nitric oxide. Moreover, the stomach's acidic environment can also convert nitrites to NO."     

Top food sources of nitrates are Beets, Spinach, Arugula, Celery, and Lettuce       

With dietary nitrates, it's essential to maintain balance. Excess nitrate intake,         

especially from sources like processed meats, can have health risks. These nitrates often       

come with other compounds, such as amines, which can form nitrosamines, some of which     

are carcinogenic. Thus, it's always recommended to get nitrates from natural, vegetable sources.     

5 Photobiomodulation:Ever heard of Photobiomodulation - or             

PBM for short? At its core, photobiomodulation, often referred to as low-level laser therapy or     

red light therapy, involves using specific wavelengths of light to trigger biological       

reactions within cells. This isn't your everyday light – PBM specifically uses       

red and near-infrared light, which have unique penetration properties and physiological effects.       

So, how does shining light on our skin or tissues influence this tiny       

molecule? The science revolves around cellular structures called cytochromes,           

present in our mitochondria – the powerhouse of the cell.           

Cytochromes, especially cytochrome c oxidase, play a pivotal role in cellular energy production.       

Nitric oxide, under certain conditions, can bind to these cytochromes, inhibiting their function       

and thus reducing cellular energy production. Then you get a sad, powerless mitochondria. PBM,       

particularly at wavelengths around 660 nm (red) and 850 nm (near-infrared),         

can displace the nitric oxide from these cytochromes, restoring mitochondrial function.        

With NO released from the cytochromes, it causes vasodilation, or the widening of blood vessels.     

This effect improves blood flow, bringing more oxygen and nutrients to the treated area.     

6 Supplementing with L-arginine and Citrulline:            

L-arginine is an amino acid, the building blocks of proteins. It         

plays a crucial role in the synthesis of nitric oxide. Here is the exact mechanism:   

1 Endothelial Cells' Role: Our blood vessels' lining, known as the endothelium, contains cells       

that produce an enzyme called endothelial nitric oxide synthase (eNOS for short).        

2 eNOS catalyzes the conversion of L-arginine to NO and L-citrulline.        

3 L-citrulline, initially produced as a by-product in the L-arginine to NO conversion,       

doesn't just sit idle. The kidneys transform L-citrulline into L-arginine,           

which can then re-enter the NO production cycle.         

Here's a cool fact – supplementing with citrulline can sometimes be more effective       

at increasing L-arginine levels in the body than supplementing with L-arginine itself!         

This is because L-arginine can be metabolized in the liver before reaching the bloodstream,       

whereas citrulline bypasses this metabolism and is converted to L-arginine in the kidneys,       

ensuring a more significant boost to circulating L-arginine.           

7 Optimizing the Oral Microbiome:Our mouths are teeming with a diverse community       

of bacteria, fungi, and viruses, collectively termed the 'oral microbiome'. While some of these       

microbes can cause disease (hello, cavities!) many are crucial for maintaining oral health.       

Beneficial bacteria in our mouths play a pivotal role in converting dietary nitrates to nitrites,     

the precursor to nitric oxide. In essence, our oral microbiome acts as a bio-reactor,       

aiding in the production of a molecule crucial for our well-being.         

Overusing antiseptic mouthwash can disrupt this bacterial balance,             

hindering nitric oxide production. To optimize the enterosalivary circuit, we need these         

bacteria intact. Check out the video I made all about this process, it’s linked down below.   

And there we have it — seven ways, grounded in science, to elevate       

your nitric oxide levels. For a molecule so small, its impact on our health is profound.   

If you appreciated this deep dive into the science of nitric oxide, please give this video     

a thumbs up. If you want to show us some real support, subscribe. We love hearing from you,   

so please share your thoughts on the video and suggestions for future videos below.       

Thank you for joining us. Until next time, stay safe, cherish your health, and as always, Aloha.

Podcast

Nitric Oxide: The Holy Grail Of Inflammation & Disease - Fix This For Longevity | Dr. Nathan Bryan

https://www.youtube.com/watch/qGVLqLxAl0I

You have to get rid of fluoride, bifluoride-free toothpaste, get rid of fluoride in your drinking water and your home health system or home water system. And then if you're using an acid, you have to stop. For people who are unfamiliar with nitric oxide, what is it and what role does it play in the body? Well, I think it's been maybe a couple years since we last spoke. Well, not last spoke since we're on the podcast. I've seen you at several conferences, yeah, but yeah, nitric oxide is one of these fascinating molecules. It's a gas, it's produced naturally in the human body. The older we get, the less we make, and that's what's responsible for age-related disease. But it's, and you call it, it's a signaling molecule. It tells cells in the body to communicate. Its most common or known function is in vasodilation. So it's produced by the lining of the blood vessels. It diffuses into the smooth muscle where it leads to smooth muscle relaxation, vasodilation. So it controls blood flow and circulation to every organ, tissue, and cell in the body. And when we lose the regulation of blood flow, bad things happen as the earliest event in chronic disease. Wow, and it plays a role in all kinds of chronic disease conditions, right? Like type 2 diabetes, hypertension, even, I mean, I'm guessing, dementia, Alzheimer's disease where vascular dysfunction plays a role. For sure. So if you look kind of broadly, and I've been in academic medicine now for 25 years, we understand, the scientific community understands, what causes human disease. We know how to diagnose it, we know how to fix it. So the fact that we don't have a treatment for Alzheimer's and cardiovascular disease to me is unacceptable. So the problem is not that we don't know the science, it's that we can't, we haven't been able to communicate the science to the healthcare practitioners, physicians, and then teach them how to teach their patients. So when we look at chronic disease, there's four hallmarks of every single chronic disease. It doesn't matter if it's Alzheimer's, cardiovascular disease, diabetes, autoimmune disease. What is that? There's decreased blood flow to the organ, there's inflammation, oxidative stress, and immune dysfunction. And nitric oxide is what controls and mitigates all four of those. It improves blood flow. Some of my patterns on methods of reducing inflammation, we know we shut down the fires of inflammation. It prevents oxidative stress, and it mitigates the immune dysfunction that's occurring in those disease tissues. So it's really the Holy Grail in terms of cardiovascular medicine. But when we look at kind of the first, so there's a hierarchy of symptoms, right? When you start to develop nitric oxide deficiency, the first sign and symptom is usually erectile dysfunction. And that makes sense because when you lose the ability to dilate blood vessels, which you need to dilate the sex organs to get engorgement, to get an erection in both men and women, when you lose the ability to produce nitric oxide, you fail to get vasodilation, you don't get engorgement. And it's the fundamental basis for erectile dysfunction. So if you have ED, that's not just a sexual dysfunction. It's what we call the canary in the coal mine. Wow. If you have vascular dysfunction in the sex organs, you have vascular dysfunction in the heart, the brain, the liver, the kidneys. It's a systemic disease. So if you don't recognize that as a really serious sign and symptom and take steps to correct it, you're now on a very slippery slope to cardiovascular disease, the number one killer of men and women, insulin resistance, vascular dementia, Alzheimer's. Every single age-related chronic disease can be traced back to lack of nitric oxide. Wow, so it is like erectile dysfunction is like the major red flag. Are there others? Yeah, typically then if you have ED, if your blood pressure starts to creep up, you know, nitric, one of nitric oxide's fundamental roles is in regulation of acetone, keeping your blood vessels soft and compliant and being able to dilate upon need. And so when you lose the ability to make nitric oxide, that's the primary vasodilator, so the vessels become chronically constricted. You're now pumping the same volume of blood through a thinner hose. Wow. So you develop high blood pressure and then that leads to damage of the blood vessels, which leads to plaque deposition, atherosclerosis, heart attack, and stroke. So then two out of three Americans have an unsafe elevation in blood pressure. So it's a huge problem. It's the number one risk factor for the number one killer of men and women worldwide, which is cardiac disease. And then you mentioned one that's near and dear to your heart is dementia and Alzheimer's. And we know fundamentally what causes dementia and Alzheimer's. It's lack of cerebral blood flow and it's insulin resistance. It's, in fact, by many referred to as type 3 diabetes. And so what does nitric oxide do? It dilates the blood vessels, we can perfuse the brain, and it improves insulin signaling, potentiates glucose uptake, and we reverse the entire metabolic phenotype of dementia and Alzheimer's. Wow. And in fact, we have a drug now going into clinical trials specifically for Alzheimer's. That's incredible. Erectile dysfunction is something that, just going back to that for a minute, it's something that is fairly obvious to observe if you're a male, right? But what about in women? Because heart disease is still the number one killer in women, and women are at twice the risk of developing Alzheimer's as compared to men. So what is one of those early red flags that women could look out for? Well, I think it's the same thing. When you look at sexual function in women, in order for women to become aroused and stimulated and have an orgasm, you have to have an increase in blood flow. And that leads to an increase in interlabial pressure, intercultural pressure, and that's what leads to orgasm. So all of that increase in pressure is due to vasodilation from nitric oxide. Wow. If you can't make nitric oxide, you don't get dilation, you don't get the increased pressure, women become anorgasmic, and they develop sexual dysfunction. But so those, and women, you know, men are somewhat simple creatures. It's typically just a vascular problem. In women, it's hormonal, it's psychological, it's vascular, it's physiological. There are a number of different contributing factors, but it's still the underlying problem is the vascular dysfunction. You can do hormone replacement therapy, but if you don't fix nitric oxide production in the lining of the blood vessels, then you're only correcting half the problem. Wow. So what are the primary causes, then, of this decline in nitric oxide? You know, one of the fundamental questions I've asked in my research lab for the past 25 years is how does the human body make nitric oxide? What goes wrong in people that can't make it? What are the clinical consequences? Then how do we fix it? So in order to answer the second question, what goes wrong in people that can't make it, we have to understand how the human body normally makes it. There are two primary pathways. There's an enzyme in the lining of the blood vessels that makes nitric oxide. They're very complex. It's called a five-electron oxidation of L-arginine, which is a semi-essential amino acid. So that enzyme becomes dysfunctional with age and time. There's some genetic predispositions that cause it to become dysfunctional, but a lot of it is due to diet and lifestyle. You know, poor diet, sedentary lifestyle render that enzyme dysfunctional. So we know how to correct that. We know how to recouple the enzyme and restore the function. What's the name of the enzyme? It's called nitric oxide synthase. So it's found in the lining of the blood vessels. It's found in our immune cells, and it's found in neurons. Wow. So it's part of the neuro signaling and the action potentials by neurons, and the cell signaling is called a presynaptic or a retrograde messenger. It's how these neurons talk to one another. We also have it in our sinuses, enriched with nitric oxide synthase. So there's a high concentration of this enzyme in our epithelial cells. In fact, it's the basis for blood pressure-lowering effects of deep breathing. Wow. So mouth breathers bypass this. That's one of the reasons why mouth breathing is so detrimental because you're bypassing a fundamental nitric oxide production cascade. Wow. But if you have a dysfunctional enzyme in the endothelial cells, then that enzyme is dysfunctional in the epithelial cells. So you can do nasal breathing or deep breathing exercises, but if we don't fix that enzyme and make it functional, you're not going to get any nitric oxide produced when you do breathing exercises. So that's what people have failed to recognize is what's the enzymopathy in that enzyme, and then how do you fix it? Because that's really the Holy Grail in cardiovascular medicine. And then, so that's one way we become nitric oxide deficient. The other is kind of the aha moment for most people because about 20 years ago we recognized that there's an enterocellular circuit, right? So the mechanism of action of certain dietary patterns, whether it's a plant-based diet or Japanese diet or Mediterranean diet, we're consuming a lot of inorganic nitrate. And then this molecule is inert in humans. So humans cannot process this molecule. We're 100 percent dependent upon the bacteria. So there's bacteria on the crypts of the tongue that metabolize nitrate into nitrite and nitric oxide. So if you don't have the right oral microbiome, you can consume these vegetables, but you don't get the nitric oxide benefits of it. And here's where the problem comes in: mouthwash. Two out of three Americans use mouthwash. Two out of three Americans have an unsafe elevation in blood pressure, and we published, I think in 2015, that this is causal for hypertension. So when you eradicate these essential commensal nitrate-reducing bacteria, it causes an increase in blood pressure. The other problem is fluoride. Fluoride is an antiseptic, kills the bacteria. Most people put fluoride in their toothpaste or are using fluorinated toothpaste. There's fluoride in municipal water. Fluoride is an antiseptic, it's a neurotoxin, and it kills your thyroid function. Yikes. So we have to get rid of fluoride. Yeah, I mean, it is a serious toxin. Dude, you are the one who turned me on to this whole mouthwash thing, and I had the privilege of getting to go on the Joe Rogan podcast and talk about it because, I mean, since you brought it up on my podcast, I mean, it's a rabbit hole that I was happy to go down because it's just so fascinating. So just make it, like, if you can, I mean, you've already made it so clear, but just walk us through this again. How can mouthwash, something as benign, right, it's sold over the counter, right? Can, does over-the-counter mouthwash have this effect? Absolutely. So here's what happens, and the advertisements are correct, it kills 99.99 percent of the bacteria when you use it, and that's the problem. That's the problem. I mean, the bacteria that live in and on the human body outnumber human cells ten to one, right? So this is an entire ecology. We call this symbiosis. These bacteria provide metabolic benefits to the human host that we can't do. One of those is the production of nitric oxide. So when you eradicate these bacteria, there's an entire ecology from the mouth all the way down to the anus, right? Then it's the microbiome. A lot of people focused on the gut microbiome years ago, we focused on the oral microbiome. And what we found was that the more diverse the microbiome, the better cardiovascular health and the better blood pressure management. So when you eradicate this with mouthwash, we saw, I think the first paper was in maybe 2009, 2010. You take normal tens of patients, you just put them on mouthwash twice a day for seven days, you see an increase in blood pressure. Damn. Now, this drove kind of cardiologists and vascular biologists crazy because they thought, we thought, we had a pretty good understanding of vascular biology and maintenance of systemic blood pressure. So how, by killing oral bacteria, we're affecting systemic blood pressure and vascular tone? And then we figured out, well, it's through the production of nitric oxide. So yeah, alcohol-based mouthwash does this. The chlorhexidine prescription mouthwash is very effective at killing it. The good news is, and we published this in 2019.

If you use mouthwash, we certainly see an increase in blood pressure. In 2020, I was on "The Doctors" show. We came in and revealed that if you use mouthwash, you actually lose the protective benefits of exercise. So think about this: if you're trying to do all the right things, you're eating a good balanced diet, you're getting exercise, but if you're using mouthwash, you lose the entire cardiovascular benefits of everything you're doing. The good news is four days after we stop using it, blood pressure normalizes; the bacteria will completely repopulate. So this is a resilient community. Just let them do their job, leave them alone. You know, there's a reason we don't take an oral antibiotic every day for the rest of our lives. There's known systemic effects of this, right? So it doesn't make any sense to use an oral antiseptic every day for the rest of our lives. Yet, two-thirds of Americans wake up every morning and use mouthwash. Shocking. To me, it's no wonder why Americans are the sickest population on the planet. They sometimes market these mouthwashes for people with diabetes, right? But that seems to be misguided. It's counter-intuitive, yeah, and misguided, and yeah, making it worse. As you suggested, if nitric oxide plays a role in insulin signaling, right, we'll have to look back and think about historically what caused this, right? What caused medicine to do the things they're doing today? Most of the time, there was good reason, right? So 50-60 years ago, there was a recognition of an oral-systemic link, right? That patients who have periodontal disease, gingivitis, have a higher incidence of heart attack and stroke. So they immediately assumed that it was the pathogens in the gum that translocated, got systemic, caused vascular inflammation, plaque instability, plaque rupture, heart attack, and stroke. So then the thought was, well, if that's the case, then we need to kill these bugs, kill the pathogens. But that was long before we understood the entire microbiome. So when I ask dentists this all the time, and I speak a lot at dental events: why do you still use fluoride rinses, and why are you still prescribing chlorhexidine or mouthwash to your patients? They think, well, that's just the way we've always done it. Well, you know, in medicine, years ago, we used to use leeches for exsanguination, right? We don't do that anymore because we have better methods, and we know the science. The science advances, so we have to be able to apply the innovations in basic science and translate that into clinical medicine. The only way to do that is to take this new information, pivot, and realize that okay, maybe what we were doing wasn't working because people aren't getting better going to physicians and taking medicine. In fact, they're getting worse.

And from a scientific standpoint, we understand the mechanism of disease today that we can fix every single chronic disease. Medicine is known for taking this reductionist approach, where the different organ systems of the body are siloed off and studied unto themselves. But if there's anything that the microbiome has shown us, it's that everything is connected. Yeah, the knee bone's connected to the hip bone. Yeah, the heart's connected to the mouth, to the lungs, to the sex organs. I mean, we're all connected through the cardiovascular system. When that fails, then you get end-organ disease and the human body fails. So what happens then when we eat a meal or a dish, a bowl of dark leafy greens, for example, rich in these inorganic nitrates, like what? Kale. Oh my God, people always pick on me for that. Is that the only dark leafy green that I like? I like arugula; I like the mixed organic greens. Yeah, so what’s happening, you know, as we lift the forkful of kale, we'll say, to our mouths?

This pathway was first discovered in the 1970s. These were cancer biologists trying to understand the etiology of oral cancers. At that time, it was thought that nitrate would form nitrosamines, which would intercalate DNA, cause mutations, and cause cancer. Then they recognized that the human body actually concentrates nitrate intentionally in our salivary glands. Kidneys reabsorb it and concentrate it in our salivary glands. The body doesn't make mistakes, right? Why would we intentionally reabsorb a molecule and then concentrate it in our salivary glands? They thought, okay, that's contributing to certain oral cancers. Well, fast forward 30 years, and now we recognize that the salivary glands secrete nitrate so that the bacteria living in the crypts of the tongue can metabolize this. These are facultative anaerobes, so when there's no oxygen around, they respire on nitrogen in the form of nitrate. This two-electron reduction forms nitrite in our saliva. Now, when we swallow our own saliva, we get a burst of nitric oxide in the lumen of the stomach. We've evolved a pathway to feed the bacteria that's right in our own mouth. It's a prebiotic, an endogenous prebiotic, and it's made to recycle and reproduce nitric oxide on a continual basis.

So this pathway is dependent upon, number one, getting enough nitrate from the diet; number two, the presence of the right oral bacteria; and number three, the presence of stomach acid. When you use stomach antacids, you completely shut down nitric oxide production. Under normal conditions, if you're healthy, eating a good balanced diet in moderation, have the right bacteria, and have stomach acid production, when we consume that meal, it takes 90 minutes. If we eat a salad with spinach or any nitrate-containing food, 90 minutes after we consume that, we can start seeing the secretion of nitrate in our salivary glands. Now for the next six, eight, ten hours, each time we salivate and swallow our own saliva, we get a burst of nitric oxide in the lumen of the stomach. Whoa. That nitric oxide, produced in the stomach, kills things like H. pylori, the ulcer-causing bacteria. If you've got some E. coli or salmonella or some pathogen on your salad or greens, it'll kill that. It enhances gastric mucosal blood flow, enhances nutrient absorption, and prevents ulcers from chronic NSAID use. It’s a fundamental physiological process that we interrupt at our own demise.

Now we find that people who have been on antacids for three to five years have a 40% higher incidence of heart attack and stroke. That's not increased risk; that's actual events. Wow. A study published two weeks ago showed that people who have been on proton pump inhibitors for four years had a 40% increase in dementia. Wow. Rapid onset of Alzheimer's. These drugs really should have a black box warning on them. These drugs were never approved by the FDA for long-term use; they were only approved for acute use for gastroesophageal reflux. But now you can buy them over the counter, and people have been taking them every day for 5, 10, 15 years, and the consequences are deadly. These are very dangerous drugs that should not be used. Antacids also block B12 absorption. Without stomach acid, you can't absorb iron, B vitamins, magnesium, iodine, selenium, or chromium. We become nutrient deficient, interrupt cell signaling and insulin signaling, become insulin resistant, shut down nitric oxide production, and develop autoimmune disease. Without stomach acid, you can't break down proteins into amino acids. We get peptide fragments absorbed across the gut, develop antibodies against it, and develop autoimmunity. It's all caused by a lack of stomach acid production. Wow. How do we increase stomach acid production if we're not on an antacid regularly? Are there any ways to boost stomach acid production? Yes, quite a bit actually. 

As a biochemist, we had to look at reactions, right? What is the chemical reaction in the parietal cells that make hydrochloric acid? That chemical reaction is very well elucidated. We need iodine, betaine hydrochloride, zinc, B vitamins, and carbon dioxide. The parietal cells make hydrochloric acid. But if you're on antacids, you can't absorb iodine, zinc, or B vitamins, so there's no way that your body can make stomach acid if you're on an acid. Wow. Because you don't have the nutrients to fuel that reaction. What we have to do is supplement the body. The whole Paradigm I work on is called restorative physiology, whether it's drug development or product development. Give the body what it needs, get out of the way; the body is a lot smarter than we are, and the body heals itself. Until people can supplement with iodine, most people are deficient in zinc and B vitamins. Now the parietal cells have what they need to secrete hydrochloric acid, and you overcome all the problems of nutrient deficiencies and nitric oxide production. I had no idea that iodine's role in stomach acid production was so crucial. I was familiar with its role in thyroid function, but when you're deficient in iodine, you get thyroid dysfunction, develop autoimmunity, and develop achlorhydria in the stomach, and everything that occurs thereafter. 

What are some sources of iodine? Kelp, seaweed. You can't get enough iodine from iodized salt to fuel everything you need to convert T4 to T3, active thyroid hormone. There's not enough iodine, and really Americans are deficient in iodine. We found that the Japanese diet is probably the only population diet out there that's getting enough nitrate from their food supply. Hmm. That's why I supplement with iodine every day, 12.5 milligrams, because the American diet and the food we eat in America is basically devoid of any iodine. Unless you're eating a

 Japanese diet rich in seaweed, kelp, or shellfish, you're not getting enough iodine. Wow. Iodine and the other nutrients are required for stomach acid production, and if you don't have stomach acid, you can shut down nitric oxide production, you become nutrient deficient, and it becomes a vicious cycle. And that's just one arm of the pathway. We also have the nitric oxide synthase pathway, which is regulated by the diet. It's regulated by the presence of oxidative stress and many other things. So there's multiple ways to make nitric oxide, but the easiest way is to simply eat a diet rich in nitrates and avoid antiseptic mouthwash.

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I'm not a chemist, but like, isn't there some kind of reaction that converts these compounds to nitrosamines?

Yeah, here's the chemistry: you've got to have a certain set of conditions or reactants present for this to occur. And it's not nitrosamines in general; it's only secondary amines, right? This is a certain type of low molecular weight amine. Primary amines typically rearrange to alcohols—they're non-reactive. Tertiary and quaternary amines have too much steric hindrance for the nitrite to react, so we don't worry about those. The only thing we worry about are secondary amines because they're small, they're low molecular weight, and nitrite can react to form nitrosamines. There are only a handful of these that are known carcinogens and mutagens that can cause cancer. So, I don't dispute the fact that nitrosamines are bad. What we have to understand is, is there endogenous formation of nitrosamines in the food we eat?

Number one, you have to have nitrite. Number two, you have to have the presence of secondary amines, which there typically are none in meat products. I mean, you can add dimethylamine and form nitrosodimethylamine, which is a huge liver carcinogen, but that's not naturally present. The other thing they realized in this chemistry was that vitamin C, polyphenols, and vitamin E are potent inhibitors of nitrosative chemistry. So, even if you have a secondary amine around and you've got nitrite, if you've got a certain amount of ascorbic acid or vitamin E or polyphenols, it completely inhibits—100% inhibits—that reaction.

Wow.

So, you don't get any nitrosamine formation. And I believe it was in 1972 the Code of Federal Regulations changed to require that any nitrite-cured meat product had to have ascorbic acid added to prevent any potential nitrosative chemistry. So now they use erythorbate. You'll see erythorbate on bacon and hot dogs, and that's kind of what we call an accelerant because it accelerates the one-electron reduction of nitrate to nitrite to nitric oxide, which is the actual curing agent, and it prevents any nitrosative chemistry. So now there's no cause for concern whatsoever. You're getting efficient nitric oxide production, you're getting efficient curing, and there's hardly any residual nitrite left in a cured meat product. It's nitric oxide that's bound to the heme of myoglobin in the meat muscle itself—there's hardly any residual nitrate.

Wow. So sodium nitrite actually, you're saying, is a cure?

It's a cure.

Very interesting. So, do we see any of the benefits that we would see from an acute boost of nitric oxide after the consumption of processed meat, for example?

Not right now, no, because there's so little in there. It's all reacted in the form of nitric oxide bound to myoglobin. The other thing is that, you know, this is a complex matrix, right? You've got proteins, you've got fat, you've got a lot of extracellular material in meat muscle, so it's a complex food to digest. But you don't get enough nitrite or nitric oxide from eating processed meats to really provide any therapeutic benefit. And I think that's the reason that we should eat a balanced diet in moderation. Historically, I've written about this, you know, the societal norms: you eat your salad before you eat your steak.

Why is that?

Well, the salad's providing the nitrate. So, by the time we're digesting the protein from the steak, 90 minutes later, we've got nitric oxide being produced, protecting the vasculature from the postprandial inflammation and oxidative stress.

Hmm.

The French do it the opposite way.

Right, that explains the French. I don't know, but the French paradox, right?

Yeah, actually the French paradox is interesting. It's not as paradoxical, I think, as we once thought it was. They eat a lot of cheese, they eat a lot of saturated fats, but saturated fats that are bound to this, what's called the milk fat globule membrane, which we're seeing is actually benign from a cardiovascular standpoint. And so they have like pristine heart health.

And they smoke a lot.

Yeah, but they're active. Europeans exercise a lot, right? They walk everywhere.

Yes.

So, I think it's, you know, we have to move. We have to exercise. In America, we go to our restaurant, we engorge ourselves, we drive home, and we never walk. We go to bed full. So, it's a constant battle.

There are a lot of pre-workout supplements on the market that claim to boost nitric oxide. Is there any merit to those claims in your typical pre-workout product? And for people that do like to lift—your boy being one of them—what is a good way to boost nitric oxide pre-workout?

Well, again, let's go back to 1998 when the Nobel Prize was awarded. That's when nitric oxide really hit kind of Main Street. In 1992, it was recognized as Molecule of the Year by Science magazine, so it was gaining some momentum in terms of the scientific community but still very little public awareness around it. And then in 1998, a Nobel Prize was awarded, and people got excited about it. Then it was recognized that there's an enzyme called nitric oxide synthase that converts arginine to nitric oxide. So the market was flooded with arginine-based products they called nitric oxide boosters.

The problem with these products is arginine is a semi-essential amino acid, right? Meaning that it's produced within the human body through the urea cycle, and then we get arginine from our diet—from plant proteins, animal proteins. It's one of the amino acids that make up proteins. So when we eat a protein diet, we get arginine. When we have normal cycling and influx through the urea cycle, we make arginine. The body is never deficient in arginine, so it doesn't make sense to supplement arginine. In fact, now there's clinical data showing that if you supplement high-dose arginine to patients that had a previous heart attack or peripheral artery disease, they get worse.

Whoa.

In post-infarct patients, it killed more patients than the placebo—giving arginine.

Wow.

So, arginine should not be recommended for patients with endothelial dysfunction. If you don't have endothelial dysfunction, which well-trained athletes typically have good endothelial function, there's some evidence out there that if you give a certain dose of arginine, you can kind of push a little bit of nitric oxide and get some out. But again, arginine is never the rate-limiting step in nitric oxide production. The function of the enzyme that converts it to nitric oxide is.

So those products don't work. Those were big for probably 15 years. Then in 2012, in the London Olympic Games, it was recognized that people were drinking gallons of beetroot juice. In fact, the UK Olympic team won more gold medals and more medals than any time in the history of the Olympics, and they attributed it to drinking their beet juice.

Wow.

So then the market was flooded with beetroot products. Now there are hundreds of beetroot products out there that are sold as pre-workouts. I've tested probably all of them. Ninety-nine percent of them do nothing but turn your pee and your poop pink and cause a lot of anxiety.

Interesting. I wonder if it's because you're drinking it and it's just, like, you know, right down the gullet.

Those products aren't allowed. The companies that are marketing these don't understand the science. They just think beet juice—they go out and buy the cheapest dehydrated beetroot product they can and sell it for 10, 15, 20 bucks. You have to have sufficient nitrate in it. You have to have the right bacteria, and you have to have stomach acid. And as we've already elucidated, most people don't have the right bacteria, and most people are on antacids, so they're not going to get a nitric oxide benefit. In fact, most of these beet products don't have any detectable nitrate or nitrite in them.

Wow.

So there's no way they can work.

Wow, it's just creative marketing.

Hmm. Fascinating. So we understood the science, and back in 2012, I recognized this and I developed my own fermented beet powder. So what we do is we convert it—we don't rely on the human body to convert it because everybody would have a differential response. I'm not interested in bringing a product to market that only works in a third of the people. We have to maintain the integrity of the science and provide safe and effective products that everybody's going to get the same effect. So we pre-convert our beetroot product into bioactive nitric oxide. When you put it in water, we generate nitric oxide gas. When you consume it, we're liberating nitric oxide systemically.

Wow.

We're not dependent upon the bacteria. We're not dependent upon your ability to produce stomach acid. We generate nitric oxide for you.

Wow. And what's the product that you gave me that has—it's like literally sodium nitrite and vitamin C and all this stuff—and it's like, swallow your saliva after?

That's our lozenge.

Okay, cool.

So that was the first product that I brought to market, and that came from kind of my first Eureka moment in science. In 2007, we published the first paper showing that nitric oxide was a hormone. Right, so if you're deficient in other hormones like testosterone or estrogen, what do you do? We have to take it, right? Same thing with nitric oxide. If you're deficient in nitric oxide production, we have to give you nitric oxide and we have to fix your body's ability to make it on its own. So that was the whole basis for me developing a product technology that,

 number one, if your body can't make nitric oxide, we have to do it for you. As I mentioned earlier, we understand the enzymology and the biochemistry that we can fix the enzyme in the lining of the blood vessel. And now we know how to repopulate these bacteria. So I developed this orally disintegrating tablet that you put in your mouth. It dissolves over five minutes, you just move it around, and we're providing nitric oxide gas. So as it's dissolving, we're generating about 30 parts per million nitric oxide gas.

Whoa.

It's not giving you or hoping your body can convert it. We can detect it, we can quantify it, we can verify it. And then the other important thing is we recouple the NOS enzyme. So we see about a 15% improvement in your body's ability to make it four hours after the lozenge, and then we're repopulating the good bacteria in your mouth.

Wow.

So it's just the opposite. So theoretically, people would need less and less of my product over time because as we're fixing your body's ability to make it, the less you need supplemental.

Interesting. You said it takes about 90 minutes for a high nitrate meal to boost nitric oxide. Is that the same timeframe that it takes for one of these lozenges?

Lozenge is immediate.

Wow.

Yeah, because I've been taking it, like, literally as I walk into my gym.

So we can see if we use an ultrasound or carotid artery, when you put that lozenge in your mouth, within 12 seconds we can see your carotid artery dilate.

Whoa.

So it's immediate dissolution, it's immediate vasoactivity, and you get systemic effects.

Is nitric oxide the answer to hypertension? We're seeing such staggering rates of metabolic illness.

Yeah, one in two people—one in two adults today—have hypertension. Two out of three have either pre-hypertension or hypertension.

Wow.

So yeah, I think there's different causes for hypertension, right? And if you look at different classes of drugs for antihypertensive medication, the first kind of effective drugs on the market were affecting what's called the renin-angiotensin system. So there are ACE inhibitors, which inhibit angiotensin-converting enzyme, and that is part of a kidney-related problem with hypertension. If you inhibit the conversion of angiotensin-converting enzyme in the lungs, you can prevent the production of a vasoconstrictor. Hypertension is really just an imbalance in the vasodilatory versus vasoconstrictive molecules. Nitric oxide is the primary vasodilator. So ACE inhibitors, ARBs, calcium channel antagonists, and then diuretics to correct fluid imbalances.

Wow.

But there's something called resistant hypertension. Fifty percent of people that have high blood pressure and are put on prescription medication don't respond with better blood pressure.

So why is that?

Because the root or the cause of their hypertension isn't related to their kidneys, isn't related to angiotensin, isn't related to calcium flux imbalance, and isn't related to fluid imbalance. What we've published on is that hypertension in many cases is a sign of oral dysbiosis.

Oral dysbiosis?

Yeah, so if you're using mouthwash, stop. Your blood pressure normalizes when you restore the ecology of the oral microbiome, your blood pressure normalizes.

Hmm. What about just drinking alcohol? People who just, you know, enjoy imbibing every once in a while—does drinking alcohol, vodka, tequila, whatever, can that disrupt the oral microbiome?

No. I'm a scotch drinker.

You are?

A social scotch drinker. In fact, I love my scotch. Here's the issue: if you were to drink alcohol—vodka, scotch, or whatever—and hold it in your mouth for 60 or 90 seconds as you would an antiseptic, yeah, maybe. Because these are 40% alcohol, right? But I mix mine with water, so probably what I'm drinking is maybe 10% alcohol.

Well, if there's anything I remember from 2020 and the whole COVID hygiene theater, it's that the alcohol percentage has to be 60% or higher for it to be antiseptic or something. Did I just butcher that?

Yeah, no, I think that's probably right. So what we're drinking, even if we were to hold the alcohol in the mouth for 30 seconds like we would a mouthwash, it's probably not going to get effective killing.

Hmm.

But, you know, during COVID, everything they were telling us to do was basically making people more susceptible to COVID infection.

Crazy.

Like the antiseptic hand sanitizers and using—I mean, that basically kills the microbiome. There were people telling you to use mouthwash and antacids and all that. I mean, you're making the patient more susceptible to COVID infection.

Hmm.

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Wild! Yeah, that was a crazy time. There was just that review published in, um, it was like exercise physiology, one of these journals, where they said that exercise literally is like the ultimate, most ideal first-line defense, for sure. Look, when I feel like my body's getting weak and I feel like I've got an onset of an illness coming, the first thing I do – the last thing I want to do – is go to the gym, but the first thing I do is go to the gym. Wow! And I exercise. I do 30 minutes of cardio and then I'll go sit in a sauna for 30 minutes. 

I haven't been sick in more than 20 years. Sauna does boost nitric oxide, does it not? 

Yes, certain wavelengths of light will stimulate nitric oxide production. 

Red light? So I have a red light device. Is that boosting nitric oxide when I use that?

So what's happening is there's what we call – and we published on this, I believe, in 2001 – there are photolabile stores of nitric oxide that you can activate. When nitric oxide is produced, it has certain cellular targets. It can bind to metals; they can bind to cysteine thiols. Infrared light will actually liberate nitric oxide bound to metals. If you look at infrared or ultraviolet light, it'll cleave NO-bound assisting thiols on proteins. When you get exposure to sunlight, you're getting both UV and infrared, and you're releasing nitric oxide.

Wow! But the problem is, if you're deficient in nitric oxide, you're deficient in these photolabile stores of nitric oxide. So if you've got a sick patient who can't make nitric oxide, red light therapy doesn't help because there's no nitric oxide to release. So what we do is we try to titrate up the nitric oxide, so either take arginine or our beet powder, and then expose to red light therapy. Now we're going to potentiate the effects of red light therapy. You're going to potentiate the effects – the blood pressure-lowering effects – of sunlight or exposure to different light sources.

Wow! But if your oral microbiome is intact and healthy and you regularly eat dark leafy greens, then there is a synergistic effect that you get in terms of nitric oxide synthesis with red light exposure, sun exposure, etc. 

Yeah, you need nitrate, you need bacteria, and you need stomach acid.

Wow! Without either of the three, if one of those is missing, you don't get the effects.

Do you think the carnivore diet is a terrible idea?

No, I think different people respond to different diets. I'm not a big fan of extreme diets perpetually. I think you can make some changes in human physiology and metabolism by these drastic changes. So I'm not a big fan of a straight vegan diet. I'm not a big fan of a straight carnivore diet forever. So I think you can do intermittent changes in this and see the benefits, but from what I know about science and agronomy and nutrient assimilation in vegetables and nutrient assimilation in animal proteins, we get the many nutrients and minerals that we need from a balanced diet, from a diverse diet. I think that's how we as humans have evolved. We get our nutrients from many different dietary sources.

Well, it's like they're not getting these inorganic nitrates.

There's really not. I mean, I think we published on this in 2015: there's very little residual nitrate or nitrite in animal meats and meat products.

So the animals we eat are vegetarians, right?

Yeah, so they're assimilating the nitrate from the grass and the vegetables they're eating into their own tissue, muscle tissue. Even non-cured meat, non-processed meats, like a rib-eye steak or things that's unprocessed, have some nitrate and nitrite. It's very little, but it's there and it's detectable.

Rib-eyes are my love language.

Yeah, mine too. Love them.

There's also, correct me if I'm wrong, a role for some of these carna nutrients, like CoQ10, in terms of recycling nitric oxide so it can make a little go a longer way, hypothetically?

Well, there are a number of – the human body is redundant by nature, right? So there's enormous redundancy in the human body. In fact, if there was only one way to make nitric oxide, then probably humans would become extinct. So there have to be numerous ways to make this critical molecule, and there are different ways to recycle it and extend its biological half-life. That's kind of what we've harnessed in our therapeutic program, in our product development. Once nitric oxide is produced, it's gone in less than a second. In fact, the half-life of nitric oxide in the human body is two milliseconds.

Whoa!

But we can extend the biological half-life of this by understanding the metabolic hierarchy of nitric oxide: where does it go, what does it become, and what does it do? If we can capture that in the form of a product technology or therapeutic, then we can extend the biological half-life from two milliseconds out to tens of minutes and hours. We can do this through giving sulfur compounds, like glutathione, polyphenols. You mentioned CoQ10. CoQ10 is extremely important for mitochondrial function. Nitric oxide is what controls and regulates mitochondrial ATP production. It maintains the electrical potential across the mitochondria, so it can generate ATP and produce less superoxide and oxidative stress. Nitric oxide is what controls mitochondrial biogenesis. We can induce all these pathways, but if you don't have enough CoQ10 and all these mitochondrial cofactors, then the mitochondria are going to be dysfunctional. So in that case, it's not a nitric oxide deficiency, it's a mitochondrial issue. We have to give the body what it needs; the body incorporates what it needs and does its job.

Beyond cardiovascular health, are there other areas of well-being that nitric oxide influences, like immune function, for example, inflammation?

We learned a lot. There's a rich literature on nitric oxide and immune function. In fact, one of the first discoveries of nitric oxide was in macrophages, in this whole reaction of arginine to nitric oxide to nitrate. This is back in probably the mid-'80s. Our immune cells make nitric oxide. The whole purpose of this is when we're exposed to a pathogen, whether it's a virus or bacteria, our immune cells recognize that, the cardiovascular system mobilizes an immune response. We get the immune cells to the site of attachment, infection, and then these immune cells surround that and generate a ton of nitric oxide. This nitric oxide binds to the iron-sulfur centers of bacteria, shuts down the respiration, kills the bacteria, and it prevents the virus from replicating. So even if we're exposed to a virus, if our immune system is strong, it generates nitric oxide; we don't get sick from the virus.

Wow.

This is what we recognized in probably March of 2020 in COVID, that the people that were getting sick and dying from COVID were the people who couldn't make nitric oxide.

Wow.

So who was this? The elderly, people with a prior heart attack, diabetes, African-Americans, people with pulmonary hypertension or who smoked. These were the people that, if they got exposed to COVID, there was a very predictable sequence of events. Within three days, they were sick. Within four to five days, they were hospitalized from low blood oxygen saturation. Five to six days later, they were put on a mechanical vent. Ten days later, they were dead. This was very predictable. That's what initiated us to start our drug trial for COVID. We had a nitric oxide drug in phase three clinical trials for COVID. We filed our investigational new drug application in June, FDA approved it in July, we started enrolling patients in December of 2020. We were making people better, but at that time COVID had changed. The hospitals weren't overrun with patients, these new strains that evolved were less virulent, and people weren't going to the hospital. Our trial design was to reduce hospitalization by 20%, so we were enrolling high-risk patients and seeing if we could create an early treatment to keep them out of the hospital, keep their blood oxygen saturation up, prevent virus replicating, and we did this. But the problem was, in the patients that we were enrolling, no one was going to the hospital, even the ones on the placebo, because they were getting the milder form of the disease. Here's what we've learned, and I'm probably the best example. Since March of 2020, I've been on an airplane probably every week for the past four years. At one time, we had 26 COVID clinics around the U.S. We would go in, enroll patients. I didn't wear a mask. I was almost thrown off airplanes for not wearing a mask. I didn't get the jab. I've never had COVID.

Wow.

In fact, I haven't been sick from any infection or sickness since 2001, when I got the flu vaccine when I was at Boston Medical Center.

Damn.

So it's not that I'm not exposed to these pathogens. I'm exposed every day, but my immune system is robust. I make a lot of nitric oxide, and if I'm exposed, we shut it down at the source of infection. We prevent it from replicating and propagating and making people sick.

Wow. Fascinating.

What about just for, I mean, a lot of people today struggle from generalized low-grade chronic inflammation.

So mechanistically, in terms of inflammation, it's very well-defined in science. Most people just think, "Well, you're inflamed." They see it as the silent killer, which has been known for many decades. There are different markers of inflammation. One is high-sensitivity C-reactive protein that you can measure in the blood. In fact, one of my patents in nitric oxide is a method of reducing C-reactive protein. Nitric oxide reduces the inflammatory response, reduces C-reactive protein. Inflammatory cytokines like interleukin-6, interleukin-1 beta, and even TNF alpha, those are the main cytokines that mediate this inflammatory response. There are a number of different what we call nuclear transcription factors that get turned on with an inflammatory response, that drive this inflammatory gene response and this whole cascade of inflammation. Nitric oxide has a role in shutting those down. It's called NF-kappa B. So if you make enough nitric oxide, you reduce these inflammatory transcriptional factors, you shut down inflammation, and therefore nitric oxide is a very potent anti-inflammatory. The challenge is, "Why are people inflamed?" Number one, they're not making nitric oxide. Number two, it could be a diet or environmental toxins. We know that. It could be the bug in their mouth. Seventy percent of Americans have gum disease, and so you're getting low-grade bacterial infections that drive the systemic inflammatory response. So if you have gum disease, you've got leaky gums, you've got leaky gut, you've got a systemic inflammatory response. Nitric oxide can control that, but again, the best way to do this is prevention, right? Get your oral hygiene intact. Don't get periodontal disease. Get your gut microbiome intact, and don't have leaky gut and metabolic disease and inflammation.

Right. Well, it's fascinating. I mean, I know that, you know, for example, you mentioned oral hygiene. Like, people will go and get their annual teeth cleaning or biannual teeth cleaning, and they'll get a blood draw shortly thereafter, and they'll see elevations in their C-reactive protein. And it's almost like people could be walking around with chronic gum disease, which could be chronically elevating their levels of C-reactive protein, an indicator of systemic inflammation. So if you have chronic low-grade oral health issues, then you could just be chronically inflamed from the inside out.

Well, a lot of people don't realize that you can trace the blood flow from the oral cavity directly to the heart. There are two pathways. One is a circulatory pathway, the other is the lymphatic pathway. So in either case, the bacteria in your mouth are migrating throughout the body. So this was always fascinating to me, you know, back in the mid-2000s when we were doing a lot of this. The original work of Nobel laureates was done in endothelial cells, right? So it's known that endothelial cells make nitric oxide. It’s what regulates blood pressure, cardiovascular disease. But if you take a healthy individual who makes nitric oxide normally, you create endothelial dysfunction by making them brush their teeth with an antiseptic mouthwash. In three days, they become nitric oxide-deficient and hypertensive.

Oh my God. So people who are using antiseptic mouthwashes every day, thinking they're doing their mouths a service, could actually be hurting themselves by reducing nitric oxide production?

Absolutely. So let me just say: it’s not the oral bacteria that are bad. In fact, you need these oral bacteria to metabolize nitrate into nitrite and nitric oxide. But you don't want to kill the bacteria in your mouth. You want to prevent the bad bacteria from taking over. You have to allow the good bacteria to flourish. So you can do this by not using antiseptic mouthwash, don't use fluoride toothpaste, get rid of fluoride, don't use mouthwash that has alcohol. You want to support your oral microbiome. And there are many ways to do this: you can take probiotics, you can chew gum with xylitol, there are a number of things that can support your oral microbiome. But the key is to allow your oral microbiome to flourish and do its job, which is to metabolize nitrate into nitrite and then into nitric oxide. So don't kill the bacteria.