Welcome back, team, to the Building Lifelong Athletes Podcast. Thanks so much for stopping by. I really appreciate it. If we haven't had the chance to meet yet, my name is Jordan Reynke. I'm a dual board certified physician in family and sports medicine. And the goal of this podcast is to keep you active and healthy for life through actual Edmonton's form education. Today, we're talking all about methylene blue. It's a topic that's been out there. So, let's dive in. This is an interesting one. So it's a unique conversion point, right? So this is something that has been around for years and years and years, right? This is going back 100 plus years. And compound initially made in the textile and dye industry, is what it came down to. But it turns out this was the first ever fully synthetic therapeutic agent, meaning this was the first ever Product that was completely made in the lab and then used on patients. So that's what it is. And it's interesting because it's understanding where it comes from and how it's paradoxical and how it kind of we can use it. And so We'll kind of go through the history of it and how it was made into the uses of it, you know, today, modern use cases for it, you know, the actually like FDA approved uses for it, and then actually what people are talking about on the internet. Because we're talking about it today, because a lot of people on the biohacking community or in social media are talking about this a lot. So that's why I want to dive into it. So, first, let's go back to its roots. So, it was first synthesized. In 1876, by a German chemist, and he's at a chemical company. So, essentially, the official chemical name is methylthionium chloride. So, that is a long name, organomethylene blue, is what we're going to say today. But it holds a special distinction, right? It was, as I mentioned before, the very first fully synthetic drug to be used in medicine. And so there also is a caveat as well. So methylene blue is distinct and often confused with other dyes like methyl blue. Or new methylene blue, which apparently are very different. So, methylene blue is different from those things. Initially, this was made, it was purely industrial, right? So, this company was awarded Uh, a patent for this for dying things is what it kind of came down to. It was a very blue thing. You've ever seen a picture of it, like it's a very, very blue, like vibrant blue. Its widespread uses for were because of the blue color. So it was used in textiles, wool, silk, cotton, as well as paper. So that's like what's the main thing it was used for. So essentially, this thing that we're talking about today was used as a dye. But it's kind of interesting because there was a leap, right, from this industrial dye to a therapeutic agent. How did that happen? Well, it was actually like kind of a cool story. So it was definitely a result of a deliberate scientific hypothesis from a German physician. And Nobel laureate, actually, Paul Ehrlich is his name, and he had a guiding principle. He believed drugs and dyes work similar fashion because they selectively bind into things. So he kind of had a core theory. If a dye could preferentially stain a pathogen, it might also be able to selectively harm or kill it without affecting the host tissues, right? So, in medicine, in pathology specifically, a lot of times, You use stains to then stain certain things on the microscope you're looking for. So, the slide you're looking at, you're looking at a certain membrane or organelle or a You know, pathogens, something like that, it goes to them. And so he's saying, Hey, if they can do that, can we actually go in the body and attack something specifically? So it's kind of interesting. What happened was late in the 19th century, that physician observed that methylene blue selectively stained the malaria parasite Plasmodium. Within human blood samples. So it was able to stay in plasmodium. And then this observation was a catalyst for Sam's kind of magic bullet concept: a chemical design to seek and destroy a specific pathogen. He's saying, hey, why does it go just to this plasmodium? Can I use it in other ways as well? And so that's kind of where it came from. And then putting his theory to test in 1891, Ehrlich and his colleagues administered methylene blue to two patients suffering from malaria and reportedly successfully cured them. Obviously, this is going a long time back, and there's lots of other confounding factors, but. That's kind of where this started. And, you know, this was hailed as kind of a big event because this is the first time ever in history a fully synthetic lab-created chemical was used to treat an infectious disease in humans. And so this event kind of gave birth to the field of What we know now in terms of current pharmacologics, in terms of creating entirely synthetic things, also time a lot of chemotherapies as well. So, we kind of started saying, hey, this is an origin story of that. I thought it was kind of interesting. To at least understand that backstory, where it came from, not that it's like the most important thing, but this is a podcast, it's deep dive, it's what we do. But yeah, that's interesting. So, now though, we know where it came from. Let's talk about like How it might actually work. So, the mechanism of it, and how it actually is something called pleiotropic. Pleotropic, meaning many effects. So, there's multiple different things that's going on, it can have different things. It isn't just a single target drug, right? It's pleiotropic, meaning it works through multiple distinct mechanisms, potentially. Its pharmacologic kind of properties, it's kind of like a chameleon, kind of depending on the context. It can change. So, whether it's the cell type or the concentration, it can act as different things. So, specifically, it can act as a mitochondrial enhancer, a neuromodulator, a vasopressor, or potentially an antidote as well. So, there's kind of multiple things that it can do. The key to understanding its varied effects, though, is the concept of hormesis or hermetic response curve. So, meaning there's a biphasic response curve, meaning if you go low concentration, they're typically considered therapeutic and bioenergetic, working from the mitochondria. Whereas when they're higher concentrations, they can become inhibitory or even toxic potentially and could potentially produce the complete opposite effect of the low doses. So when we talk about this hormetic or biphasic response curve, meaning, hey, at one dose, a lower dose, we have a different Outcome then, if we do at a higher dose. That's essentially what we're looking for. So let's dive into these mechanisms one by one. The first mechanism is going through talking about the mitochondria and electron transport train. This is kind of the big one that everyone talks about, and the reason there's so much bust about this today in social media for neurogeneric diseases, neurotropics, anti-aging, all that stuff. Here's the problem. I'm sorry, in states of metabolic stress. So, the problem meaning when you are metabolically stressed or aging or have disease, your mitochondria can have. Inefficiencies in getting energy. So, essentially, specifically the electron transport chain, it's essentially the production line of energy. It can get bogged down, meaning that, hey, they don't function as well. One of the hallmarks of aging is that we don't add Aren't as efficient as we usually were, or when we were younger, with our electron transport chain with our mitochondria in general. And so, the idea is: hey, in some sort of issue, if the mitochondria is not functioning at full capacity, that can be an issue. And can methylene blue work in that capacity? And so. There are multiple complexes of the electron transport chain. We're not going to go through this. This is like a biochemistry class, and I'm not here to do that. Nobody wants to hear biochemistry, but. There are multiple complexes in the that are associated one to two to three to four that kind of move down along the line, transferring electrons to then produce electricity, electricity and energy is what we're going for. So it's all electricity, right? It's just electrons. But energy is specifically, I was trying to say. And there are multiple common points of failures usually that complexes one and three are the big ones. And a lot of times, these electron flow can potentially stall out. And then this can have major consequences, meaning impaired ATP production, as I talked about, less energy. And potentially a leak of electrons that creates different things called the reactive oxygen species. So we have these electrons that are charged and they escape out, and they can create these reactive oxygen species, which drive oxidative stress, which is not good. So these are different. Reactive oxygen molecules that lead to bad things, typically bad outcomes. And so, how does methane blue fit into this? Well, at lower doses, it acts as an electron cycler. Or essentially an alternate electron carrier. You can take on these electrons and kind of bypass the electron transport chain and continue to move the energy through the cell. So it's almost like creating a bypass or detour around a potential traffic jam in the electron transport chain. And step by step, what we can go through this in talks about accepting electrons directly from NAD, then completely bypassing it or whatever. It's not really that important. Just know that it can shuttle electrons back and forth. It can kind of skip there and kind of go as well. One thing that is worth mentioning, though, is that when The oxidized methylene blue gets converted to its reduced colorless form. That is one of the properties as well. So, it can be a blue blue when it's oxidized, and then when it's reduced down, it can be kind of this clear thing called leukomethylene blue. And that's interesting in dimension. And that. That leukomethylene blue diffuses across the mitochondria and donates these electrons. So essentially, that can happen. And so the big thing is it can kind of go in between these two different forms, which is kind of interesting, the reduced and oxidized form, but it can kind of shuttle back and forth. And yeah, it works out in dropping electrons off and. Doing that stuff and repeating the cycle and kind of helping with the mitochondria. So that's a way too simplified version of it. And I didn't feel like bogging down the details because, quite honestly, I wasn't super interested in learning all the biochemistry again. Obviously, you know, if you've gone through biochemistry, you're familiar with that stuff. But that's the general idea of what's going on. And so the idea is: hopefully, with this mechanism, what's happening? Well, one, we're producing more energy. Hopefully, You know, rescues cellular energy metabolism and restores the process of ATP synthesis to its full capacity. That's good. Hopefully, we also have two less damage, meaning by creating an alternate pathway, hopefully, we're preventing those electron jams, essentially traffic jams. And reduces the amount of reactive oxygen species and oxidative stress we have. And then the third is hopeful that we have kind of restart in the mitochondria as well. That some evidence may suggest that by improving the overall mitochondrial health, Methane blue may promote mitochondrial biogenesis, meaning actually the creation of more mitochondria. So that can be very helpful as well. And so, this triad of effects, enhancing ATP, reducing oxidative stress, and promoting mitochondrial renewal, this is hopefully like this is the reason why people say, hey, This is why it may work so well for so many different things. Like it's this mechanism, right? So that's the first one. Okay, and so that was mechanism one. And now moving on to mechanism two. So Completely separate from the mitochondrial effects, methylene blue can act as a neuromodulator as well, and it can be a powerful, reversible selective inhibitor of an enzyme called monomine oxidase A, so MAOA. If you prescribe medications, you've probably seen these monoamine oxidase inhibitors. So, what do these MAO inhibitors do or the enzymes? Well, they're responsible for breaking down key. Monomine neurotransmitters and these monomine transmitters. We'll talk about them. The big ones here: there's MAOA and MAOB. MAOB, not really that important for what we're looking at here. It breaks down, you know, phenylethylamine, but Monomine amoxase A breaks down serotonin, norepinephrine, apinephrine, and melatonin, so big ones. And also, both enzymes can metabolize dopamine and tyramine as well. But the big thing is, it can break down a lot of those things. And we talk about MAOA inhibitor, breaks down serotonin, norepinephrine, epinephrine, melatonin. That's pretty important stuff there. And so it is a very potent inhibitor of MAOA. It does also have a little bit of B as well, but it's more selective to A. So that's just something to mention as well. And so it means that at clinically relevant doses, it acts more as a selective MAOA inhibitor. And so, what happens when this happens? Well, by blocking MAOA, Methylene blue prevents the degradation of serotonin and norepinephrine, right? And this leads to an increased concentration and availability of these crucial neurotransmitters, which are heavily involved in regulating things like mood, anxiety, cognition, right? You think about SSRIs, we're trying to have more of these good chemicals. Anything like the anti-anxiety or depression, like pills, a lot of times what they're doing is they're trying to create more of these things, right? So we're trying to get more serotonin and more norepinephrine. That's what we're going for. And this mechanism is the mechanism behind its antidepressant and anti-enzolytic effects, so anti-anxiety effects as well. You can see it. It's done previously, they've done bipolar trials using this as well, so that's what it was. But this is a strong MAO inhibitor, right? And so it is, but it also is the source of probably the most dangerous interaction of the medication: the risk of life-threatening something called serotonin syndrome, which we'll talk more about. When you combine multiple medications, right? So, if you are on a SSRI and then you take methane blue, you could potentially precipitate this serotonin syndrome. So, something to think about. All right, and so that was our second mechanism. Now, let's talk about our third mechanism acting as a vasopressor. So, in critical care medicine, a methylene blue is known as a vasopressor, an agent that increases your blood pressure, right? This comes from, it kind of inhibits the nitric oxide pathway. So, in normal physiology, nitric oxide is the body's primary signal for rasodilation and relaxing those blood vessels. But in pathologic states, things like septic shock. This can lead to way too much NO and leading to way too much vasodilation. When we have way too much vasodilation, there's a dramatic drop in blood pressure. It can lead to lots of issues and doesn't respond necessarily to Pressors. So, pressers are like the medications you give to contract those blood vessels back down to increase that blood pressure. So, you usually give those when someone's sick and their blood pressure is too low or whatnot. And how Methylene Blue works, though, is they give this, everything else isn't working, essentially. It's definitely not a first line. Like you're flipping through, you're going to be like, give me Methylene Blue. No, that's not going to be the case, but it may be helpful in that situation. What typically happens, how does it work? Well, it directly inhibits the enzymes that produce nitric oxide in the first place. And more importantly, it also inhibits an enzyme SCG. That nitric oxide talks to essentially preventing any nitric oxide that is produced from having its effects. So essentially, it's like shutting down the effects of nitric oxide. That's what it does. And so it shuts down this whole Pathologic vasodilation causing vasoconstriction and leading to an increase in blood pressure. That's the idea behind it. And a lot of times it's used for refractory septic shocks. Like I mentioned, this is not a first line, but it can be used there as well. Now, moving on to mechanism four can act as a redox agent, which is essentially a reducing agent, like we talked about with administering electrons and whatnot. So And this is the mechanism behind methane blue's only FDA-approved indication, treating acquired methemoglobinemia. And you're like, that's a big word. What is that? Well, met hemoglobinemia, this is a life-threatening condition where the iron in your hemoglobin is the wrong state. Meaning, normally the iron is iron 2. But in this situation, for whatever reason, it is iron 3. And this results in a molecule or methemoglobin which is incapable of transporting oxygen, leading to severe tissue hypoxia and potentially could have death. So, how does methane blue fix that? Well, it acts as a cofactor to dramatically speed up the body's natural but very slow pathway for fixing this problem. So, typically This is once again biochemistry boring. Inside the red blood cells, we have an enzyme in something called the pentose phosphate pathway that produces NADPH. And then this NADPH, another enzyme. Reduces the methylene blue. Remember, from methylene blue to leukomethylene blue, so the kind of neutral one. And then that leukomethylene blue Is a potent reducing agent And then donates an electron directly to methemoglobin and converting it back to its state, the oxygen-carrying state of iron2. So essentially, Methane blue helps donate electron to go from iron 3 plus to iron 2 plus, making it functional again and making you not die of hypoxia. That's what is going on. And yeah, it's very efficient, reduces the half-life of methemoglobin from hours to just minutes. And so that's kind of what happens. It's going to assist in there. But you have to be careful if you go way too high of a dose, like greater than seven milligrams per kilogram, it can overwhelm the system and start acting as an oxidizing agent, making the condition potential even worse. So, we got to go the right dosing there. They also have to consider that We have to think about something inside called G6PD. So the entire mechanism is absolutely dependent on NADPH from the pentose phosphate pathway in the red blood cells we talked about, but a key enzyme for that Is G6PD. And in patients with something called G6PD deficiency, there isn't enough NADPH to activate methylene blue into leukomethane blue. So the drug is completely ineffective. And so. Worse, this unmetabolized, oxidized methane blue puts on massive oxidative stress in already fragile red blood cells and could potentially cause even worse or make it worse or cause hemolysis, which is even worse as well. So, lots of things could happen. So, long story short, this is another thing where you have to know before you're giving this if someone has G6PD deficiency. So, this is screen for the military a lot of times. So, you have to understand that and do it. But this is an indication where, like, if you had this, like, straight contraindication, would not do it. And so we've talked about kind of the mechanism. It's a lot of nerdy stuff. And you're like, man, this is more than I signed up for. But hey, we're going to keep going. But what are the clinical applications, right? So, once again, there's kind of two roles that we're thinking about: the rescue agent versus the remodeling agent. When looking at the evidence, a clear pattern emerges, right? So, methane blue is at its best as a rescue agent in acute, life-threatening physiologic crises, right? Hemoluminemia, that's like the best thing we know it for. Where, in contrast, its utility is a long-term remodeling agent, meaning kind of working on the slow, chronic diseases. It's far less certain. We don't necessarily know. How it does that, or if it does any real benefits, but that's what everyone's talking about on the internet, right? So it's important to understand what the data actually shows versus like what people are saying online. And so we'll kind of go through that once again. The sole FDA-approved application is for that methemoglominemia. And this is like the one and only official job approved by the United States FDA treating methemoglominemia in both adults and children. You know, it's great that it's a proof of that because then we say, hey, cool, it's uh, it's you know, it's it's safe. And when we give it in appropriate doses, that's great, and we love that. And so, a lot of times we're trying to figure out today: are there other ways we can use this? Not necessarily. Through just at this dosing, just for mental hemoglaminia, but how can we use it in other ways off-label is kind of what we say. But yeah, overall, that's kind of the first thing, right? It's the first line life-saving antidote for that and used for You know, pretty standard of care there. So it can be helpful. But most people aren't doing that, and that's necessarily the whole thing. This is usually a higher dose intravenously as well, worth mentioning. And now, I want to mention the off-label rescue uses, right? So, we talk about potential refractory shock, as I mentioned, can be a rescue agent for having refractory shock not responding to that. Can be helpful. Also, can be used for something called vasoplegic syndrome, a severe form of shock with profound low blood pressure that's refractory to, once again, conventional vasopressors. Most people listening to this, if you're in shock, someone else is taking care of you, you're not doing that. So we'll keep we'll keep moving on as well. So I'm not too worried about those big things. But also, of note, has been used in the past for cyanide poisoning, which I thought was interesting. We've kind of had it's no longer recommended as first line if we have different things that we can do, but it's used for that. Also, it can be used as a die in medical things, so a surgical diagnostic die. So, a lot of times, what happens is Can be used in sentinel lymph node, where essentially you can inject them near a tumor in breast cancer or melanoma surgeries, and it stains the first adrenal lymph node blue, allowing the surgeon to easily identify and remove them. So, just remove things we need to do can also be used for your logic and GI procedures, meaning, hey, it stains things saying, Hey, take these out. That's gonna be helpful as well. So, those are some indications as well. But now I want to move on to kind of like the next frontier, why people are talking about this on social media, right? And so First things first, they said, hey, all these things with the electrons and all these things with mitochondria, can this be helpful for neuro diseases? I mean, like Alzheimer's or dementia, anything like that. And so. There's lots of excitement come from preclinical studies showing it could inhibit the aggregation of tau protein, one of the pathologies, core pathologies of Alzheimer's, right? And there was a large-scale phase III trial. They were conducted using a stabilized form of the molecule called LMTM, designed for better oral absorption. And unfortunately, there was a kind of disappointing result. The trials failed their primary endpoints. The LMTM did not show a statistically significant benefit O of placebo in the overall study population. And subsequent research actually found an interesting explanation. They're saying, hey, while methane blue did inhibit the formation of large insoluble tau fibrils, so these tau fibrils are one of the hallmarks of dementia and Alzheimer's. It may also simultaneously stabilize small soluble tau olgomers. I mean, like growing body evidence supports that these big ones aren't actually a big problem. It's more the smaller ones that are the most neurotoxic. So they might have said, hey, actually. It didn't inhibit these big ones, which we don't necessarily need to do. We need to work on these smaller ones. And so it may not have been effective for that reason. And so the trial may have failed not because the drug was inactive, but because it was active on the wrong target. Potentially shifting the equilibrium towards a more toxic form of the protein. So that's just something to think about. There's also been talks about using it for things like Parkinson's disease and traumatic brain injury. And preclinical studies and animal models have shown methane blue can protect the vulnerable dopaminergic neurons, likely by improving mitochondrial function. Can be helpful. It's also the LMTM form was shown to reduce the aggregation of alpha-synuclein, which is another key pathologic protein in Parkinson's disease, in a mouse model. Once again, mouse models. And then also for traumatic brain injury, animal models. People have been treated, or these animals have been treated with methane blue and been shown to reduce neuronal apoptosis, improve blood-brain barrier integrity, and lead to better cognitive motor outcomes. And these benefits are. Directly attributed to its ability to restore mitochondrial respiration and reduce oxidative stress. Born again, this is just mouse, so we're not necessarily how to extrapolate that to humans. Other applications in psychiatry actually has been tried to use for bipolar disorder, and this is where the most prominent evidence probably is for psychiatry. In a randomized double bond control crossover study, found that methane blue used as an add-on therapy significantly improved residual symptoms of depression and anxiety in patients with bipolar disorder. It's not a big study, but it is important because also. It's important to mention that this occurred without an increased switch or risk of increasing mania, right? So when we have a patient, we're given a medication, if they have bipolar and you give them like a traditional SSRI or something like that, you worry about flipping them to mania, which is this kind of hyperactive state of everything. This didn't seem to do that. There's also been some studies for depression. Early small studies from several decades ago suggested that maybe methane blue had a potent antidepressant effect in patients with severe depressive illness. And the evidence base for this is not very robust as for bipolar disorder, but it also has been tried for antidepressant, anti-angolytic as well. And it probably warrants further investigation, but is kind of looking at. Also, for malaria, it has been used. We talked about plasmodium back in the day, used to treat those people for malaria. It has been used previously, although a lot of times. We have other anti-malayers, although there's increased resistance going on in the world in those, so they're thinking about going, you know, kind of looking for other options as well. But it's definitely not their first line anymore, but it's something that has been used and been worthwhile. Other properties they talk about potentially having antiviral properties or antibacterial properties. They say it exhibits broad spectrum antiviral activity in vitro against a range of different viruses like Zika, dengue, HIV, and hepatitis C, which is kind of interesting, which is why they mentioned that. And then also, it's also been known to have antibacterial properties and was historically used for urinary tract infections. And yeah, so it's not a first line for any of those things, but that's kind of where we've been and things we've tried. And I do want to move into next, though, the modern phenomena, right? So methylene blue as a biohack. That's the big thing everyone talks about. Do we need to take it? And a recent phenomenon has been going on. It's been moved beyond the hospital and lab become a major trend online. You know, and the wellness influencers, the biohacking, anti-aging community is saying, you know, you need to take this. And this trend has been fueled by social media influencers and podcasters. Dang it. Just not me, not me, but no, it is. You look online and you look on YouTube, and there's just everywhere people are talking about it. And so that's why I was like, whoa, what the heck is this thing? But it's being promoted as a powerful nootropic, right? So a smart drug for enhancing memory, focus, and mental clarity, as well as a revolutionary anti-aging supplement. And it's important to remember upfront that these claims represent a significant extrapolation from the available human evidence, creating a major disconnect between preclinical promise and proven clinical deficit, right? Let's break down the narrative here, right? So, the central claim made by these biohackers and its proponents is that low doses, so low oral doses, can provide a tangible cognitive boost and slow the biological aging processes. And it's compelling, right? So, this is a compelling narrative because it's built upon scientifically valid foundation, right? Methylene blue has a well-documented ability to enhance mitochondrial respiration, potentially increase ATP. And reduce oxidative stress. And so the logic presented is definitely seductive, right? Since the brain is an extremely energy-intensive organ and mitochondrial decline is a hallmark of aging, a substance that improves mitochondrial efficiency should. In theory, improve brain function and promote longevity, right? That's what it is. But here's the big omission: right, this marketing narrative focuses on exclusively the mitochondrial effects, which leads to the complete omission of anything else it may be doing, and it's equally potent, MAO inhibiting effects as well. And so. The selective presentation of information creates a definitely a public health risk, saying, hey, just take it. It's fine. It's fine. It's at a low dose. But not mentioning that if you combine these things. With a traditional medication like SSRIS-SNRI, it could lead to this kind of serotonic serotonergic syndrome, so serotonin syndrome, which is not good. So, life-threatening could be bad. But people are saying, Hey, we've seen these studies, these little studies. If you take a low dose, it can do X, Y, and Z. So, therefore, we'll do that. That's a huge leap to make. And once again, I'm not the person who's going to be the most cutting edge. I won't say even cutting edge. Like, this isn't cutting edge. This is just like extrapolation, like, literally, just like saying, oh, it could do that. Cutting edge is like, hey, we have good data that, like, this could do that. We've tried these things. It's had a good response from here and there and everywhere along the cycle. And then like, this is the newest thing that's very evidence-based, whereas this is just like, oh, like, it could do the
