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White paper: Methylene Blue and Nitric Oxide — Beth Shirley, RPh CCN (January 2023)

Beth Shirley, RPh CCN is a Registered Pharmacist and Certified Clinical Nutritionist who has developed unique expertise as both a pharmacist and certified clinical nutritionist during a distinguished 40+ year career. 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 worked in close collaboration with some of the world’s leading thought leaders in the field of nitric oxide research. Through this, she has developed an in- depth knowledge on the topic and its potential beneficial applications in multiple aspects of patient care. In addition, she has worked closely with the scientific community and cutting-edge companies working on innovative nutritional ingredients and approaches to their use for a variety of life’s challenges.

Dr. Barrett 00:31 Introduction of Beth Shirley

Beth Shirley 03:01

Well, we can call it the magic bullet. Yeah. Paul Ehrlich. Right. Coined. Yeah. 1886

Dr. Barrett 03:09

Was it was used as a dye right before they started…

Beth Shirley 03:22

Exactly. The blue jeans. I'm not quite sure how they figured out that it was actually effective. But in 1891, it was the first drug used for malaria.

Dr. Barrett 03:44

Maybe those guys down there, you know, working in the malarial areas, were wearing their blue jeans and got malaria and ended up chewing the cloth and got the die. You know, we can make up some wild stories story, that, but it's been around for a long time. And as we talked before we started recording, it was probably the first drug approved by the FDA, or what that matters anymore. Who knows. But, you know, it was grandfathered in, because like you said it was used for malaria for a while and everything, but let's talk about it. Because there's been a lot of confusion. And I think you referenced a book that was recently published that has caused some confusion and patients that are taking both methylene blue and nitric oxide supplementation, and it would be great to solve this issue for them.

Beth Shirley 04:39

So, there's been a resurgence of the interest in the methylene blue these last couple of years in this post viral world we're living in, because methylene blue is actually the parent compound of chloroquine and hydroxychloroquine, which in which we know has been effective.

Dr. Barrett 05:02

But methylene blue is an electron donor, right?

Beth Shirley 05:12

It's both its electron donor and acceptor. So it's a redox molecule. Okay. And it's used as kind of an antidote to anything that displaces oxygen. Okay, so so

Dr. Barrett 05:29

Its first indication was for methemoglobinemia, Right?

Beth Shirley 05:32

Right. It's in every hospital more for that for carbon monoxide and cyanide poisoning. However, this is where this post viral world comes in. Because the spike protein, it oxidizes your iron, your Fe two plus in the hemoglobin. That can be oxygen, it oxidizes it to Fe three plus, which can't carry oxygen.

Dr. Barrett 06:02

So, this this ferric molecule, right becomes gets another proton goes from two to three. And then when it does that, it just can't find oxygen anymore. He can't carry oxygen. Right. Okay. So it's kind of like a suffocation of the RBC.

Beth Shirley 06:22

Yes, that's interesting, the thing is nitric oxide can scavenge that Fe three plus, however, then it takes that nitric oxide out of circulation to do all these other good things that we've talked about. Right, right. And so that's why you're seeing all these cardiovascular complications, you know, the, the clots then the strokes and all these things.

Dr. Barrett 06:51

And you think that that's caused by the just the reduction in the ability for the binding of oxygen, that is there a mechanism?

Beth Shirley 07:02

Well, the nitric oxide is trying to bind up that excess Fe three plus.

Dr. Barrett 07:07

So, it's just taken up, it can't do its other job. Right? Okay. All right. And how, how did it get to the concept of like using nattokinase or lumbrokinase some of these? I guess we would call them functional anticoagulants to decrease the, the clotting?

Beth Shirley 07:33

Yeah, because nitric oxide governs platelet activation and aggregation. Okay, so then when you're nitric oxide deficient, you're going to clot up.

Dr. Barrett 07:45

So, let's say you're running along and you got to an acceptable level, maybe not an optimal level. And clearly, we see this in the younger folks that that have been affected by this. They're running at a, let's say, they have a detectable level of nitric oxide, Spike protein gets in there messes around with the hemoglobin molecule. Now the nitric oxide is distracted. And instead of taking care of its daily business, like it's supposed to be doing, it has to take care of this other event, and then that creates other events because they're not able to take care of what they were originally designed to do. Exactly. Well, okay, I guess my much better understanding of it. Let's go back to methylene blue a little bit, because there's an obvious difference with many drugs actually, between low dose and high dose right?

Beth Shirley 08:32

Right, you can't talk about methylene blue without talking about the dosage. So low dose methylene blue does is that redox molecule is electron cycler, shuffler, it can actually you know, donate electrons and accept electrons. However, as you increase the dose, these high doses can actually be pro oxidant. Okay, actually even cause that methemoglobinemia.

Dr. Barrett 09:07

So, what's high dose versus low dose give us a dosage spectrum?

Beth Shirley 09:13

Well, in the literature, they say anything more than three milligrams per kilogram is high dose. However, I caution way on the lower side of that, I really don't like people doing more than like 25 milligrams. Unless you're doing something specific and you're working with a practitioner, maybe you have Lyme, and you want to, you know, go after that. Right. Just, you know, as long as you're working with a practitioner, and they're monitoring you. But always remember, like, if you're still peeing out any kind of blue or green pea, you’ve got enough methylene blue circulating.

Dr. Barrett 10:00

So, that's a great point. Because how, you know, how do we monitor these things that we're supplementing? And, and it's pretty easy to look down after you've urinated and go, Wow, that looks like you know, some really good household cleanser because it's green. And, you know, yeah, I saw the same. I saw a bottle of that over at Costco just the other day. And then you know, and then it wanes as most things do, but it's a great way because if you take like 25 milligrams, and then next morning, it's still green, you may not obviously take anymore and then so you can kind of titrate it to how you're using it and excreting it. And, you know, it's maybe not as elegant as the litmus test or the testing strips for what we use and nitric oxide supplementation, but it's still a very valid way to look at it. And it's easy enough for a patient to proceed. Oh, yeah, my urine still pretty green. I can go another day without taking it. Exactly. Yeah. I know. Yeah, notice? Well, I noticed that if I take a 25 milligram I'm good for about three days.

Beth Shirley 11:08

So yeah, I'm good for two. Yeah. Yeah. All right. Well, resurgence like in the biohacking community for cognition.

Dr. Barrett 11:19

Yeah. So, let's talk about that. Because there are some things written about the neuro protective nature of methylene blue and traumatic brain injury and, you know, subsequent events and from stroke and these different types of things.

Beth Shirley 11:36

It enhances the brain’s mitochondrial function.

Dr. Barrett 11:40

Well, in one of the papers that you wrote, you talk about how inos is 1000 times you know, maybe I've got that wrong or backwards. But when one goes up, the other goes down the inos and enos, can you explain that a little bit?

Beth Shirley 12:01

Right, I noticed that you're inducible not this is the nos that gets upregulated by infections, pathogens, bacterial, viral, fungal, parasitic, also, a lot of these environmental factors, EMF, aluminum, mercury, gluten, glyphosate, high fructose corn syrup, all of these things that are environmental factors. I nos produces, this is like your enos and your n nos. These make like bursts of nitric oxide on an as needed basis. The inos gets up regulated in it kind of just goes in the on phase, because all of these inflammatory processes, they are constant. So, it's stimulating this inos to produce this nitric oxide. However, we remember that all of these processes that I was talking about these inflammatory processes, these infections, these increased oxidative stresses, when you increase oxidative stress, you are uncoupling nos, okay? And when nos is uncoupled, it becomes a superoxide generated or not an nitric oxide producer. Okay, so increasing oxidative stress. So, but also when you're up regulating is you are downregulating e nos and en nos. So, you are impairing your circulation and microcirculation you are impairing your brain function.

Dr. Barrett 13:51

I want to unpack that a little bit because there's a lot there. Okay, so, when you have some type of a stressful pathogen, let's call it an infection that causes an upregulation in inos. Right? All right, and then the purpose is?

Beth Shirley 14:06

That your immune your that's one of your first immune reactions to these pathogens. Okay, making the nitric oxide in order to go after these pathogens.

Dr. Barrett 14:19

And then you said that after the inos is up regulated, it affects detrimentally, the enos.

Beth Shirley 14:26

And the nice it down regulates your enos and inos,

Dr. Barrett 14:29

Okay, so think about that a second from a peripheral neuropathic standpoint. If we have something causing neuro inflammation, some stressor, it's going to decrease the enos that I need inside that nerve. Right? Ideally, now, how does methylene blue come into play with inos and, and its subsequent effects within enos?

Beth Shirley 14:55

Well, methylene blue, down regulates it and up regulated inos.

Dr. Barrett 15:02

Okay, so it kind of moderates that uptick or upregulation of inos from the stressor. And by suppressing that a little bit, then we're able to maybe produce more enos.

Beth Shirley 15:17

Or not. Well, when you're downregulating, well, you downregulated inos and there's more of a chance at enos, and then nos can function better. Okay. All right. However, just always--remember when that inos is up regulated? It doesn't necessarily mean it's producing lots of lots of nitric oxide. Because all those factors that are upregulated actually cause oxidative stress. Okay, so is the damage from an upregulated inos? Like this is, you know, those $64 million questions, is it really from the nitric upregulate nitric oxide? Or is it from the upregulated superoxide?

Dr. Barrett 16:02

Good questions. Right.

Beth Shirley 16:04

Right.

Dr. Barrett 16:05

So, let's go back now to this book that created some controversy or discussion. What was the thesis? I've not read the book. I'm not familiar with it other than what you just mentioned. So, what was the thesis that nitric oxide is bad and methylene? Blue is good. Is that what it was? Yes.

Beth Shirley 16:25

Okay, that's pretty much what it was. Right? And then, you know, because the methylene blue down regulates the production of nitric oxide. So why would you support your nitric oxide if you're going to do the methylene? Blue? Okay.

Dr. Barrett 16:43

But we know that there's at low doses, some very synergistic effects, do we not? Yes. Last Why wasn't that talked about? What Why wasn't that included in that thesis?

Beth Shirley 16:54

Well, because he's not a nitric oxide researcher. Okay. Okay. All right. And there are some some interesting things, you know, like with methylene blue. It actually supports the function of nnos, your neuronal nos. Right. Okay. So, this is, you know, it will not affect your enos and doesn't detrimentally affect your nnos. It actually supports the nnos production, which is very important for your brain. Right.

Dr. Barrett 17:34

Okay. Yeah, so you talk about in your white paper, which I'm going to put in the show notes, because I think this thing's beautiful, from the standpoint that it's extremely well written. It's concise, it's understandable. I think, actually, this could be a paper that, you know, practitioners may want to hand to their patients, because I think he did such a great job of explaining it. And so, you pointed out in there at low dosages methylene. Blue is you know, effective in the electron transport chain. And it works on cytochrome c oxidase or complex 4, okay. And ultimately, what that does is actually increases the ability to consume more oxygen or produce more oxygen in the mitochondria.

Beth Shirley 18:28

So, methylene blue, like, okay, that your mitochondria consume a lot of oxygen, and you take that oxygen and they're the like, they end up making your ATP, and that oxygen gets further metabolized into water. However, not all of that oxygen gets metabolized into water, a lot of that gets metabolized into reactive oxygen species like your superoxide Okay, so the mitochondrial electron transport chain is a big source of these reactive oxygen species.

Dr. Barrett 19:18

We need them but not too much of them.

Beth Shirley 19:19

Too much right? So, when you get too much of them, this interferes with the production of ATP

Dr. Barrett 19:31

ATP is pretty vital.

Beth Shirley 19:32

It is. So, what's kind of cool like this methylene blue is an electron donor and acceptor. So, it keeps things flowing down this electron transport chain. Okay, you know, instead of going off and making your  superoxide your reactive oxygen species

Dr. Barrett 19:57

Right. So, what happens with high dose versus low dose in the same mechanism?

Beth Shirley 20:07

Well, then the high dose, it becomes a pro oxidant. So, it's more of, you know, you're not donating and accepting. You're just throwing. Yeah, yeah. But I'm creating more.

Dr. Barrett 20:26

So, in the hospital use for carbon monoxide poisoning, and those are probably pretty high doses of methylene blue that they're giving, basically, just to really eradicate the toxin or not, or eradicate the effect of the toxin.

Beth Shirley 20:40

Right. It has to do with, you know, hypoxic situations. Okay. Okay. And so, this is where, like, that complex, the cytochrome c oxidase, the complex four.

Dr. Barrett 21:03

Are they the same thing?

Beth Shirley 21:07

They're close, they kind of stick on each other. Right?

Dr. Barrett 21:11

Because isn't complex 4 where Metformin plays around?

Beth Shirley  21:15

Yes. All right. But, but the beautiful thing about cytochrome c oxidase is it can morph into a nitrite reductase enzyme. Under hypoxic situations.

Dr. Barrett  21:35

Say that, again, cytochrome?

Beth Shirley 21:38

Cytochrome c oxidase can change into a nitrite reductase enzyme under hypoxic situations, which means that it can reduce nitrite to nitric oxide on an as needed basis, in order to open up the micro capillaries to keep the tissue and cells oxygenated.

Dr. Barrett 22:09

So, the hypoxic environment is basically a trigger. This is a way to upregulate the production of nitric oxide to overcome that hypoxic stress, and tissue sample or whatever, whatever you're focusing on. Yeah, and I think empirically, you can think about almost any type of, of musculoskeletal pathology or they're even, you know, wound pathology. It's always in a hypoxic environment. It's never like, oh, there's just so much blood here that it's going to take care of everything. The pathology has created these hypoxic environments. So, this is the body's way to respond to that?

Beth Shirley 22:53

Right? Yeah. Yes, this thing? Yeah, because all of these environmental factors actually create the hypoxic environment. And

Dr. Barrett 24:48 Let's say what you talk about methylene blue and the chronic inflammatory pathway. And you mentioned all these different things that upregulate inos and everything like that. What about specifically with methylene blue? Is it just It somehow decreases this upregulated inos is what's the mechanism of action or physiology if it's known?

Beth Shirley 25:10

I don't think it's known. Okay. All right.

Dr. Barrett 25:15

Yeah, there's a lot of things that aren't known that work. Yeah.

Beth Shirley 25:20

So, that also, I mean, there's still that that big, you know, controversy on whether upregulated inos under these inflammatory conditions is actually producing more nitric oxide or superoxide.

So, you know, like, when you read all these papers and stuff, and they talk about peroxynitrite, and how damaging peroxynitrite is, okay, okay. Well, peroxynitrite is O N O O minus. All right. Okay. Nitrate is in Oh, three minus. Okay. So, when you read these papers, and they talk about peroxynitrite, because peroxynitrite is a molecule that's made when superoxide and nitric oxide come in close contact with each other. Okay. And you read all these papers that talk about peroxynitrite, and the damage that is done? Actually, they can't measure that peroxynitrite they are not measuring it. Because it comes around even less than nitric oxide. They are measuring nitrotyrosine. And they are assuming that it was nitric oxide that made the nitrotyrosine. Alright. However, there's other molecules that can make nitric tyrosine and is not just nitric oxide. And in fact, there are studies showing that 90 to 95% of the peroxynitrite isomerizes to nitrate which is inert. So, the nitric oxide is actually scavenging that superoxide. Okay, so is that damage from up regulated inos from nitric oxide? Or is it from the superoxide?

Dr. Barrett 27:32

Right. And so, they're only able to measure the peroxynitrite.

Beth Shirley 27:43

Yeah, with nitrotyrosine in there. It's all based on assumptions.

Dr. Barrett 27:47

Right? Right. It says, well, there's other situations where, you know, you measure things by proxy, because there's just not the ability to necessarily find that particular biomarker.

Beth Shirley 27:58

And then these assumptions are, you know, right. You did and repeated and repeated, but they might not necessarily be true.

Dr. Barrett 28:09

Yeah, but isn't it true that if you repeat it enough, no matter how false it is, it becomes true. You know, I mean, natural immunity, it went away for a while. Yeah, so, alright, so let's talk about the the person who comes into our office, they've got bad peripheral neuropathy, we know that their nerves are stressed. We've talked about this upregulation of, of inos and downregulation of the enos and inos. And so, we want to put them obviously, on a nitric oxide supplementation, as well as methylene. Blue. What's the combo? What's the secret sauce here?

Beth Shirley 28:57

Well, just make sure your nitric oxide is optimized. And you can do that with the strips. All right, either through supplementation or through, you can do it through your diet. It's hard to do. Yeah, you just have to be real honest of what you're doing. Right? Because the DASH diet, you know, theory Approaches to Stop hypertension. Right, you know, it has 1200 to 1500 milligrams of nitrate per day. You know, and it's, it's used as a as a drug, you know, as a therapy. Right?

Dr. Barrett 29:33

Well, I'm gonna ask you to interject a little bit about some of the things that decreased nitric oxide production. I mean, because people don't think about it, you know, like, obviously, you make more nitric oxide if you breathe through your nose and your mouth, and that's so easy to take care of just keep your mouth shut, especially at night. And, and then, you know, it's been shown in the literature how very high levels of mouthwash Asch are very detrimental to the oral microbiome. So, you don't get that conversion of the nitrate to nitrite or nitrate to nitrite. Right? That's impaired.

Beth Shirley 30:12

Age, rather to authority or ability make nitric oxide through that nos enzyme decreases to about 50%. By the time we're 60, it's only about 15%. Our diets, we talked about that medications

and antifungals, antidepressants, birth control pills, PPIs, EMF, and we're swimming in a sea of EMF, pesticides. Glyphosate, right? Is glyphosate everywhere? Yeah. Yeah, any kind of oxidative stress. Genetic snips, if you have any MTHFR snips? Which 40% of us do.

Dr. Barrett 31:01

Now, is that because of the upregulation of homocysteine then?

Beth Shirley 31:06

Or no, because you're not being able to make your BH4 tetrahydrobiopterin. Okay, BH4s. What keeps that nos coupled?

Dr. Barrett 31:19

Very, very interesting.

Beth Shirley 31:21

And the big one stress, Oh, yeah, stress increases oxidative stress, oxidative stress uncouples nos. So, think about it. When you're stressed. You get sick easier. Right? Okay. Which means your inos is not working correctly. When you're stressed you have more cardiovascular disease, more hypertension, more strokes. That's because that enos is uncoupled. Stress is pretty detrimental to our production of nitric oxide. I didn't look at these last few years, how much stress we've been under?

Dr. Barrett 31:59

Oh, yeah. Well, I mean, if you combine all of the environmental things that are going against you, you know, I mean, all right, I want nice, fresh breath. So, I'm not going to just destroy my oral microbiome with whatever it is that I'm flushing my mouth out with. Even some toothpastes, right? Fluoride,

Beth Shirley 32:21

Fluoride, whitening toothpaste, that hydrogen peroxide, right. But the beautiful thing about nitrate supplementation or increasing your nitrate in your diet, is with continued use nitrate helps rebuild your micro biomes everywhere from your gut, your or your skin everywhere. helping rebuild those micro biomes.

Dr. Barrett  32:48

What about, you know, the organic? I have been told, I don't know if this is true or not that organic vegetables many times won't have a high enough level of nitrates? Because if you use nitrates now, you can't deem yourself organic? Is this true? Wow. So, we're thinking what we're missing, because there may be better off, we may be better off because we're not getting glyphosate, but at the same time, we're getting less glyphosate. But at the same time, we're not getting what we think we're gonna get.

Beth Shirley 33:22

Yeah, because the soils are so depleted. Yeah. Well,

Dr. Barrett 33:25

That could go into a whole different discussion about regenerative farming versus non regenerative, farming. And there's a lot that I think we're getting charged more for that or really less. And nitrates I think would fall into that category. You mentioned gut microbiome, I had read that nitric oxide does improve the gut microbiome.

Beth Shirley 33:53

The nitrate, okay; nitrate is actually a prebiotic these it actually supports the growth in the colonies of the good bacteria. And all of your microbiomes are connected. So, you improve the gut, you improve the mouth, which will improve the skin improve the urinary tract. Very interested, the brain, like we've got these different micro biomes everywhere and they're all connected.

Dr. Barrett  34:27

You know, it's kind of interesting. I don't think anybody even talked about a microbiome 20 years ago.

Beth Shirley 34:34

Yes, it's kind of the new in thing.

Dr. Barrett 34:37

Yeah. Very good. So, I guess to kind of wrap it up, sum it up. It's okay to take the low dose of methylene blue and the same time as your nitric oxide supplement. And so just take this book that was written by this non-researcher of nitric oxide and or poor researcher, whatever we want to call it, I mean, I don't mean to throw rocks at anybody, but sometimes these things get, you know, put out there and that it really destroys the patient's understanding or even their implementation.

Beth Shirley 35:12

Right. And both, you know, supporting that nitrate nitrite nitric oxide pathway with the methylene blue is really helpful. Or any kind of cognitive dysfunction is in cognitive dysfunction, you see decreased blood flow, right? You see decreased supply of the oxygen, the glucose, and the nutrients going to these brains’ cells, you see, decrease cytochrome oxidase activity, decreased energy production. But both of these helps really couple that electron transport chain. So, you're not making so many reactive oxygen species. You're not being under so much oxidative stress. And you're recoupling that meaning that you know, the electrons are going down to make your ATP.

Dr. Barrett 36:14

What's your thoughts on administrative forms of methylene blue? Because you can get it sublingually.

Beth Shirley 36:24

And it's absorbed very, very well. You must assure that you're doing pharmaceutical grade.

Dr. Barrett 36:37

Yeah, I don't get the fish tank cleaner.

Right. And, you know, I think the biggest detriment of the sublingual or the buccal administration is that you have this Smurf-looking mouth whenever you, you know, your, your tongue turns purple, and people go, Wow, you know, did the aliens get inside you or what happened, but it's kind of a weird thing. But I have noticed, and I don't think this is fair to say that it's just because of the methylene blue because some of the sublingual methylene blue products are actually mixed with a touch of nicotine, which is kind of an interesting combination, too. And that's another subject for another day. But, but it's kind of interesting, because you can feel you can feel that little surge of energy. And that may be all due to the nicotine, I don't know.

Beth Shirley 37:32

But now I can feel like it's not like a speed or is not like caffeine or anything, but it just, you feel a little more energetic because that electron transport chain is able to make your ATP better.

Dr. Barrett 37:49

And if you think of it from a neurocognitive standpoint, what we're trying to do is take tissue that is maybe a little bit hypoxic, or maybe in some cases, a lot hypoxic, and we're trying to deliver more energy to those cells so that they can function and repair themselves and develops more synaptic connections and all these things that are going on. I mean, look at transcranial magnetic stimulation, that's the whole premise of it is I'm going to take this magnetic energy, and I'm going to pump it through the skin and the skull into the cortex and, and that's going to change into an electrical energy and the electrical energy is going to create, hopefully better, you know, metabolism and all of these these good downside things from that. So, it makes a lot of sense.

Beth Shirley 38:37

While these neurons can't store, ATP, can't store any, you know, glucose, or oxygen, and things. So, they always need to be fed.

Dr. Barrett 38:49

So, you're saying that the mitochondria don't store a lot of ATP or any ATP in the neurons?  That's very interesting. So, it's 100% on demand.

Beth Shirley 39:01

So, it just needs to be fed. And so that's why that microcirculation needs to be, you know, healthy, right order to feed these neurons. Interesting.

Dr. Barrett 39:12

That makes a lot of sense. Any other parting advice for the coadministration of methylene blue and nitric oxide, I think the big thing for me is that it's okay, low dose, low dose.

Beth Shirley 39:29

It’s an electron donor and acceptor, it's a redox molecule. So that's really important to know because it's not just, you know, an electron donor. And acceptor.

Dr. Barrett 39:41

Interesting. Well, I think that if nothing else gets obtained by the listener, then it's okay to take your low dose of emphasize the word low dose methylene blue in combination with your nitric oxide supplementation, it's just fine.