What's the deal with methylene blue?

21:42And that electron is donated to the electron transport chain in the mitochondria. And the best way I can explain the electron transport chain is like, imagine you have a reservoir, okay, and a dam that's holding back water. And then you can open a valve on that dam and water flows to a lower level and generates electricity. And then imagine below that level, you have a lower level that you can open a valve and the water drains down and generates more electricity and so on and so forth. That's the electron transport chain. There are four complexes in it and it takes that high energy electron. And every time that electron gets passed from one complex to another, it gets to a lower and lower energy state.

22:26And that energy is used to pump protons into the mitochondria. And at the very end, all those protons are stuck in the mitochondria. They're really eager to get out. They flow through this protein, which is like a turbine, which is called the proton ATP synthase. And that protein makes ATP. So you've got this really complicated process to take energy from electrons and stepwise get it into something that can make ATP. That's a mitochondria. And the ATP can do its thing. If one of those proteins doesn't work, okay, like the valve in the dam is stuck, you can't open the valve, okay? Those are typically genetic conditions that we call the mitochondrial diseases.

23:14So these are typically inherited from the mother because you get virtually all your mitochondrial DNA from your mom because the egg has all the mitochondria. So your mitochondrial DNA is maternal. And kids who have these particular mutations in the electron transport chain are severely disabled. I mean, sometimes fatally so because they can't generate ATP in adequate amounts. But of course, that's not what people are using methylene blue for.

23:42Perry Wilson:Okay. So we're in a back... No methylene blue yet, Perry. We're not ready for it. So the electron transport chain inside the mitochondria takes the electrons, they're high energy state, it turns them into ATP. In a person where that process is generally working fine, there is no meaning to the phrase, my mitochondria are tired. They aren't tired. You could be tired. And that is the thing. People get tired. People get fatigued. It's an experience people have. It's not because your mitochondria are like only sort of slowly. They're not like, ah, too many f***ing electrons today. Like I just, I want to take a nap and not move so many.

24:24Perry Wilson:Like that's not how this works. They're not tired. That's it. It's not a person. It's a chemical reaction cell. But when you hear people talk about mitochondria in the wellness space, that's often what it is. It's like, it's like, we're going to unleash your mitochondria. We're going to, you know, we're, we're, it's, it's as if you've got like a governor on the motor and you were going to, you know, whatever the supplement is, people are hawking. It's going to, you know, turn off that, um, that governor and things are going to go rip roaring and you'll feel like you're 19 again. And, you know.

24:55Perry Wilson:And I, I think the idea, I see the idea, the link there, which is like the mitochondria is making the ATP. The ATP is what's providing you energy. And it is true that there are things you can do that would lower your ability to do that. For example, if you don't have enough glucose, these like, you know, you don't have enough glycogen, this can't work because you need that to stick in to get the thing with the high energy to make the ATP on the other end. So it is true if you didn't have enough glucose, your mitochondria wouldn't be doing enough and then you'll be tired. Do you know what else you need to make that electron transport chain work?

25:28Is you need something to accept the low energy electron at the end to get it out of the mitochondria? It's called oxygen. That's oxygen. Turns out, if you do not breathe, your mitochondria suffer quite dramatically.

25:43Perry Wilson:And you'll feel tired and also dead. But the mitochondria are, they're not tired. They're just, okay. So - I have to say, as I was doing the reading again into the ETC and stuff, and now that I'm paying more attention to the wellness space, I was making a list of the number of supplements that like appear somewhere in the electron transport chain. So here's my list of things that are actually in the electron transport chain. Not saying that supplements make any difference here, by the way. I'm just saying like, here they are. Coenzyme Q10, NADH, riboflavin, vitamin B2, succinate, vitamin K2, magnesium.

26:24These are all things that like biologically speaking, facilitate the work of the electron transport chain. And all of those things will get marketed to you using the same exact logic as Bethelene blue, which we'll get to, which is like, don't you want your mitochondria to work better? And I think if there's one thing that people need to sort of understand, we've said this a lot, like maybe there's biologic plausibility here, but just because something is necessary in some amount to make a biological process work doesn't mean that getting more of that makes it work better. Like that's just not typically how the body works.

27:03Perry Wilson:It is not. Okay. So with that background, I hope people enjoyed this AP bio lesson. Let's talk about methylene blue. So methylene blue is a dye. It was first prepared in the late 1800s by a guy named Heinrich, Heinrich, presumably Caro, as a dye for fabrics. It makes things blue like fabric or your poop or pee. And it has the property that it can stain cells and bacteria without necessarily killing them. That turns out to be a very valuable property because it generates some uses where you can basically color cells and bacteria. Yeah. Which is helpful for various diagnostic things we can talk about.

27:55Perry Wilson:And it was originally used in a variety of medical settings, like for UTIs. It may have some efficacy as an anti-malarial, although we have much better versions of that now. But I will say the thing I did not dig up, although perhaps you know, is like, how on earth did people have this fabric dye? And then they were like, let's try drinking it. Where's the link there? It is really hard. I mean, I don't have a one-to-one link, but I think I can tell a story here, which is that you get this fabric dye in the late 1800s. This is the heyday of microscopy and germ theory. We're starting to categorize bacterias and amoebas.

28:37And so people are really excited about what are called vital dyes, dyes that don't kill the thing you're trying to study under the microscope. They're just like most dyes kill the thing and then they don't move anymore. And so this was really cool. And they also saw that it had some anti-malarial effects. So people started taking it for things like malaria. So at least then you've got, okay, there's human data that it doesn't kill humans when you take it. And then it's really not until I think the year here is almost like 2008, like the early 2000s, when people started experimenting with methylene blue in cell culture to see what its effects would be specifically on oxidative stress in cells.

29:27So one of the things that makes methylene blue sort of special is that it can accept electrons and give electrons to things. We've talked about electrons in the electron transport chain, and this is going to be why it's important. And chemists knew that property of it. They were actually using methylene blue as an indicator dye in chemical reactions. So you could, if you remember, like in chemistry where you would, you know, you'd titrate things and like it would turn like red and then you'd add acid and it would turn blue. Like those were so fun. So methylene blue does that too. because it's an electron acceptor and an electron donor, depending on the conditions.

30:01And so it made sense that like, oh, if it can do that, maybe it will do something with mitochondria. And so people started experimenting with that in vitro, in cell culture, with some promising results. And we can talk about those. And I think like all wellness things, you get like one tiny study in a Petri dish full of cells. And then especially if that thing is cheap and already available and you can just like market it without needing approval from the FDA, like you are off to the races, man.

30:34Perry Wilson:And I think here it is like worth stepping one step back into the discussion of the electron transport chain and thinking about why this might matter. So if you think about methylene blue as like a bus that can pick up some electrons and drop them somewhere else, it is possible if there's like a problem in the electron transport chain where one of those pieces of the dam doesn't open. In principle, this could take some of those electrons and deliver them to a later part of the transport chain and kind of bypass something that is stuck. Exactly. If that valve is stuck between complex one and complex two, methylene blue can take an electron from complex one and give it straight to complex three.

31:21And I should say, medically speaking, this has been used for cyanide poisoning. So second time cyanide has come up on this podcast for longtime listeners. Cyanide blocks the very end of the electron transport chain, that step where oxygen is there to pick up the low powered electron and get rid of it so that things can keep moving. So it blocks that very end point. And because of that, ATP synthesis stops and you die. Cyanide is quite poisonous. And so again, this might be a recurring theme. We have better treatments for cyanide toxicity now, but before we did, methylene blue was used for this basically to like pick up that last electron to kind of keep things moving a little bit, even in the presence of cyanide while you tried to wait.

32:09Does it work? It does work. I mean, it doesn't work. I mean, still people died a lot, but like it does work better than nothing and not as good as, you know, the current treatments for cyanide toxicity.

32:19Perry Wilson:Okay. I think that's a good segue into the fact that this actually is something with some small number of real medical uses. And so one obviously is cyanide poisoning in the past. The other usage that is still the one FDA approved indication for use of methylene blue is for something called acquired

32:47methamoglobinemia. Maybe you could say it.

32:50Perry Wilson:Methamoglobinemia. Methamoglobinemia. Methamoglobinemia. That's it. Methamoglobinemia, which is a hemoglobin disorder, effectively. Yeah, but can be acquired and is really bad. So this is the FDA approved indication. Methamoglobinemia is like your hemoglobin has an iron atom in the middle to pick up oxygen. And that under certain states and like certain drugs do this, like benzocaine toxicity can do this, but I guess maybe more relevant is poppers. Like those are the recreational drugs, like the inhalants, alkyl nitrates. So that can reduce the iron in hemoglobin to a state that cannot bind oxygen.

33:38It kind of, imagine it like rusts the iron in the hemoglobin. So like the iron doesn't work anymore. And this is really bad. And like the blood turns this chocolate brown color. If you've seen hemoglobinemia, it is very strange and disturbing. It's like, it's not dark blue, like Venus blood. It's not bright red. It's brown, like hot chocolate. Very weird. And you need to give an electron back to that iron to get it back into its ordinary hemoglobin state. And methylene blue, as we've said, can like donate electrons under the proper circumstances, can receive electrons under other circumstances.

34:11That's its main indication. I actually see it as a nephrologist, not infrequently when I'm rounding in the cardiothoracic intensive care unit, you see the Foley bag, that's the urine bag, you know, next to the bed. And every once in a while, One is blue, sometimes green if the person is a little bit more dehydrated because yellow and blue makes green. And these are people who get methylene blue after heart surgery. So if you're on cardiopulmonary bypass, when you put the patient back, when you switch their heart back on and now they're supporting themselves, they often will have this phenomenon called vasoplegia where just like their blood vessels don't, they kind of like are like floppy and their blood pressure just drops extremely.

34:53And methylene blue, the data is not great for this, but it is common practice to use methylene blue to sort of reverse that post-cardiac surgery vasoplesia probably reduces nitric oxide synthase for the biologists who are listening. And the practical upshot is that I see a lot of blue urine when I walk through the cardiothoracic ICU. So obviously you should take this to make yourself like have more energy from daily life, right?

35:19Perry Wilson:But here is where I think I can see why this compound is so like compelling in the wellness space, because there are a lot of processes in our body for which electrons need to be moved around. not just the yes, including the mitochondria function, but also all these other things. And now you're sort of listing like, oh, well, here are some ways that, you know, someone who has had a serious surgery or has like overdosed on poppers or in some other way has some kind of diffuse problem that involves electrons. And this is the thing that fixes it. You can see why you would get to like, well, I'm feeling tired and like I'm, you know, maybe I need more electrons moving around.

36:07Perry Wilson:Like that sounds fun. And maybe it is going to fix my problem because we don't really understand that much about exactly how this is working. So it seems plausible. I mean, I think that's the, that's the kind of interesting thing about all these spaces, but this one in particular for me. Yeah. One of the things I liked about this particular topic is because it's not just nonsense. It's not total snake oil. It's not, you know, it's something that someone made up or like homeopathic remedies that have nothing actually in them. Like it does do things. But let me give you a counterpoint for someone who's worried about their sleepy mitochondria, which is based on what I just told you.

36:43Let's say your mitochondria are working okay. Like there isn't a blockage. And by the way, I don't know why people are like, oh, your mitochondria are blocked up. Like I don't know why we think that's happening, but let's say you have normally functioning mitochondria, you know, so you take high energy electrons and they go down the chain and drive a gradient to make ATP. If I skip a step in that chain artificially, like that gives me less energy per unit, right? Like, like why would, if, if I need to skip a step because something's blocked up, that's one thing. But if not, like, why would you think this is better?

37:19This is, you know, short circuiting a system that is supposed to work the way it's supposed to work.

37:25Perry Wilson:Yeah, I was explaining this to my husband the other night before we met, and he was like, you know, I just don't think you should be messing with your mitochondria. I just feel like they're just, I feel that they should just do their thing. And I was like, I can see that perspective. Let the mitochondria be the mitochondria. I'm a big proponent of the mitochondrial rights movement. All right. So let's talk about what the data, what some of the data says, because this is a place where we've had a little bit of people trying treatment with this for various things and mostly with pretty limited success, I would say.

38:04Yeah. It's, again, one of those things where if you do it in a small test tube with cells and everything's very carefully done, you can generate some interesting results. And then if we scale up to full-size humans.

38:15Perry Wilson:Or even to mice. Even to mice. We can go through the mice. But let me, maybe can I, I want to touch on one of the studies that really got this going, which was a study of lung fibroblasts among some other types of cells. So these are just, these are lung cells in a Petri dish. And they were looking at the rate at which the cells would double, which is like a measure of lifespan. Like how many times can they double before they like give up and die, right? Like how many kids can they have, I guess, is one way to think about it. And the study shows that cells exposed to methylene blue compared to, you know, treated with a vehicle that doesn't contain methylene blue had a significantly longer lifespan.

39:00So, okay, long fiber breasts in a Petri dish. Okay. But they live longer. That's cool. But if you read this study, and sorry, this is in the FaceApp Journal 2008. If you read the study, the cells were all treated with either hydrogen peroxide or cadmium. So they were given a poison and particularly poisons that are redox agents. So poisons that like messing with electrons would be the appropriate treatment for. And then they showed that, okay, treatment with methylene blue like makes the cells live longer. And I just want to point that out that like the devil's in the details here. It's not like, oh, these were healthy, happy cells that they showed live longer.

39:43These were cells that were actively being killed by hydrogen peroxide. And then you add some ethylene blue and they don't get killed as much. So I'm level setting again that like there's a difference between you just had cardiac surgery and are in cardiogenic shock versus like you feel a little sleepy. Yeah.

39:59Perry Wilson:And then, you know, we, when they've sort of moved this into, say, mice, they've tried to evaluate like lifespan effects in mice, and they do not find lifespan effects in mice, maybe. So this is a study in with an incredibly difficult to pronounce title called Archibos-7-alpha-estridol and Nordi-hydroguanuretic acid extend my lifespan, preferentially in males. But what they find here - A classic. Did I not say that right? No, no, no. It's great. I just think it's hilarious. I can guarantee this is the only time this study has ever been mentioned by full title anywhere in the universe. And I think that's very special for us.

40:50Perry Wilson:Yeah. Congratulations to the 23 authors of this study. I have successfully said the title of your paper, but unfortunately, they do not find treatment with methylene blue improved lifespan in even in mice. And this is, you know, again, when we think about some of these biological, some of these sort of like there's a biologically plausible argument, then maybe you go into cells, maybe you see something, then maybe you go into mice. And there's oftentimes, even if we see something in mice, then we don't see it in people. And here we kind of couldn't quite get to mice. And again, that may be a result of, you know, maybe the mice were fine.

41:26Perry Wilson:I don't think these were unhealthy mice. It was like regular mice. And the mice maybe didn't need their electrons to be moved around quite much. Yeah. I did Google earlier just to see like, is Brian Johnson taking methylene blue? Brian Johnson is that like influencer that, you know, is like experimenting on himself. Let's face our lives on him. Yes, of course he takes it. He takes everything. Of course he is. He has some posts with like, you know, the blue tongue. The influencers will post their blue tongue because it stains living tissue. You can also get that from cupcakes, actually, as most parents will know.

42:02Perry Wilson:You can get a blue tongue from eating too many frosted cupcakes. I mean, equally disturbing to me in some sense. That also will make your poop blue, by the way. How did the wellness – there is something about like, okay, wait, we like dyes now. Like what about – don't we hate food dyes? Only some of the dyes. Yeah, we like some dyes. Not Red Dye 40, my friend. This is the – yeah. Anyway, Brian Johnson is, yes. And I was reading an article about like some of the changes in biomarkers from before and after he took methylene blue and it had the greatest caveat ever, which was that unfortunately during this period of treatment, he was also taking a hundred other vitamins and supplements.

42:40So it's like -

42:41Perry Wilson:It's like a worst study design ever. This is the problem, dude. I changed literally everything. Yeah. So great. Anyway, all right. Moving on from trying to extend your life, I think people do tend to focus a little bit more on the energy cognition stuff. And I will mention a paper just because it comes out in a lot of influencers suggesting that the use of methylene blue can maybe improve memory a little bit. This is a paper in Radiology 2016, 26 Healthy Adults. This is from UT Health San Antonio. And they got just a single dose of methylene blue versus placebo. And it was randomized and double blind, everything you would want.

43:29And then an hour later, they got an fMRI and did some like short-term memory tasks. And after the methylene blue, they had like a 7 % increased correct response on the short-term memory task. And that's what people will lean on when they're like the data, the randomized clinical trial data shows that methylene blue improves your memory. What do you think, Em?

43:56Perry Wilson:What's the placebo? Some pill that did not contain methylene blue. Yeah. So it was - I think my first question would be here is like, did you know? Like, did you know that you were getting the methylene blue? Was the other pill blue? I think the other pill was blue and I think it was encapsulated so it wouldn't turn your tongue blue. Yeah. Okay. So 7%, an hour later. My read of this is like, first of all, 7 % is a very small effect. The P value on this is not aggressive. It's 0.01, which is a fine P value, but given the number of things that we test and my general feeling about fMRI machines, I'm not wildly impressed.

44:39Perry Wilson:And also like with many things here, you do a study on 26 people, you need to do another study. Maybe there are 50 studies of this, and this is the only one that found this, and it's the only one that got published. There's a publication bias issue. There are just a lot of reasons why pulling out a single study of a small number of people and saying, aha, there's a statistically significant result at a conventional level is actually different than saying we have hard quality evidence of this being true. And whenever you're talking about wellness stuff and you want to look at studies, You know, studies, appropriately so, are often controlled with placebo, but that's not really the question that you as, like, an individual need to ask.

45:22Like, let's say I want to improve my memory. The question isn't, should I take methylene blue or should I take a blue-colored sugar pill? That's not – my actual question is, like, should I take methylene blue or should I do the New York Times crossword every day or should I just, like, practice memory drills on flashcards?

45:39Perry Wilson:Or should I sleep more? Or should I sleep more? Sleep more. Yeah. So I think people are so quick to lean on placebo-controlled studies that they forget that the problem in this space is that there are almost too many choices. Brian Johnson's 100 supplements is a problem. That's not the right strategy. I'm sure at the very least it's incredibly expensive and none of us can afford it. He's not dead yet. And I think consistent with this view, there are some follow-up papers or at least later papers that have looked at this question of cerebral blood flow and oxygen consumption, other things which could be correlates of this, which haven't found that same kind of impact.

46:25Perry Wilson:So it isn't the case that there's this study and then there's a million follow-up studies with the same kind of thing. we see some, I would say, mixed evidence on the brain. And none of it is very big. Right. And I mean, there's even some evidence to the contrary. Did you see the study that actually maybe looked like the use of methylene blue decreases blood flow to the brain? But again, it's like, yeah, so there's a study that says it decreases blood flow. There's a study that says it increases blood flow. Again, maybe the studies that say nothing are just sitting in someone's drawer, not published because it's not very interesting to publish a paper that says, I did this with these people and nothing happened.

47:07Fair enough.

47:08Perry Wilson:Very hard to publish a null finding. That's something we can talk about. Oh, I've been there. Yeah, let's actually pause on that because I think this is something we can talk about more in other contexts. But when you are reading papers that are published, you want to remember that there are many studies that happen that do not get published. And we are more likely to see things published if the result is significant in one way or the other. If you think about what is the journal looking for, you're usually looking for something that's significant or surprising or... Yeah. Impactful. Yeah. And so there is a thing called publication bias, which is why we less frequently see null results, which means results where the effect was zero than we might expect to because many of those things get run and then just no one ever reports out on them.

47:59Yeah, sadly. There is maybe one area, and I'm actually curious if you're going to agree with me on this, but there is one area that I think methylene blue might actually work, and that's for mood. All right. You're making skeptical face. Okay.

48:19Perry Wilson:Give me your pitch. Let's test this out. Okay. One of the things that methylene blue does is inhibits something called monoamine oxidase. It is an MAO inhibitor. And does that ring a bell to anyone? Does anyone remember what the MAO inhibitors were? Maybe not because these are pretty old drugs. MAO inhibitors were the first antidepressants. They were invented like in the 1950s, 1960s. Monoamine oxidase in the brain breaks down serotonin and dopamine and stuff like that. So if you inhibit that, the levels of serotonin and dopamine in your brain go up and it has an antidepressant effect and they do work.

49:06They're actually still used today for refractory depression. But there's a reason that we don't use MAO inhibitors anymore, and that's because the side effects are quite brutal. It has this effect where if you're on MAO inhibitors, you can't eat certain aged cheeses or other things that contain tyramine because you can get dramatic spikes in blood pressure due to a difficulty to metabolize tyramine that can be life-threatening. And so MAO inhibitors, once SSRIs came out and tricyclic antidepressants came out, MAO inhibitors just kind of like because of that side effect profile went to the wayside.

49:46But methylene blue is an MAO inhibitor. We have good in vitro documentation that it is an MAO inhibitor at doses that people take and with a potency that is similar to some of the pharmacologic MAO inhibitors. I've got a human study from 1987. Yeah, you do.

50:04Perry Wilson:Okay. Okay. 15 people. How many people? Very small number of people. 30 patients with severe depression who got daily methylene blue for three weeks in addition to their existing treatment versus matched placebo. And they had a significant reduction in depression scores. That's back in 1987 before the SSRIs were really up and going. But there's even a study in 2017, which took 37 patients with bipolar disorder and randomized them to methylene blue for three months and then crossed them over in a random order to a placebo for three months. And they had significant improvement in depression scores.

50:47And so I'm going to argue, Emily, that it's an MAO inhibitor. It's not a regulated MAO inhibitor. You're not getting it prescribed by a doctor. We have some randomized trial data that suggests it improves depression scores. People say it gives them some energy. Maybe they're just taking an MAO inhibitor. Okay.

51:09Perry Wilson:I will say, I'm going to say a few things. So first, I am generally skeptical of a literature that has 30 years between papers and each of which have like 30 people in them. You know, it's just like if this were a very effective version of this, I think we would have seen more of it. The second thing I will say is. Even if this is true, I don't think it's very important, because if someone is struggling with depression, we have much better treatments than this now. We have treatments that are stigmatized. We have treatments that are I are are the I mean, I feel like we've made progress on that.

51:53I think in particular, there's like in the wellness space, there's this like very, there's this undercurrent that's highly skeptical of things like SSRIs. I mean, even skeptical of psychiatry.

52:05Perry Wilson:I guess. But I think to say like we should have people, like we should encourage people to take this because they're skeptical of SSRIs. No, no, no. And obviously I'm not saying that. But I think what I would say is like, if you just sort of look at from a science, if somebody came to me and they said, I'm struggling with depression, should I take methylene blue? my answer would be no, you should go talk to a doctor and see if you can get on one of the many effective treatments for depression or think about non-pharmacological remedies like exercise and so on, depending on kind of where you are in this space.

52:36Perry Wilson:I think the other, the third thing I will say is that one of the risks associated with methylene blue is it interacts in a dangerous way with serotonin inhibitors. So the thing I would really worry about is people who are on an SSRI who decide to take this as like a boost up in their antiderabrassion. That is actually incredibly risky. Super risky. Black box warning on the FDA label for methylene blue because of this, because you can't mix MAO inhibitors and selective serotonin reuptake inhibitors together. You get something called serotonin syndrome, which is terrible, super high blood pressures, fevers out of control, muscle problems, can be life-threatening and fatal.

53:17So you definitely can't mix those two things. I think I'm more sort of bringing this issue up as like, maybe people aren't like, oh, I'm clinically depressed. But I have a feeling that there are more people walking around with some depression than are diagnosed with depression. And maybe they don't recognize it themselves. And maybe it's not full-blown major depressive disorder. Maybe it's dysthymia, which is kind of like the medical term for like, you're just not great. And if a person who's in that state decides to take some methylene blue, maybe just for energy, and it kind of bumps their mood up a little bit, does that like reinforce the idea like, wow, this thing works, I feel different?

54:01Because I think it can make you feel different. I'm not saying you should take it, but it has potential neurologic effects.

54:09Perry Wilson:I feel like you're just making an argument for the placebo effect. I feel like you're just saying like if you know, there's a lot of people walking around with depression who would benefit from thinking that they're taking something that helps them. And like, yeah, sure. The placebo effect is, as I've said many times, it's one of our best effects. Yeah. And so I can see it working for that reason. But at the same time, it seems like there are many other things without any risks that don't turn your pee blue that also work as a placebo. And then some things like exercise, which aren't even like have treatment effects on this that aren't a placebo.

54:41Yeah. Couldn't agree more. Let's mention risks because now I feel bad that I've been like, hey, everybody, it's a free, cheap antidepressant. I don't know.

54:50Perry Wilson:It's like, and later we'll be, we'll be put, see the link in the show notes for pairing wellness actually branded. Dr. Wilson's special methylene blue preparation turns your pee glow-in-the-dark. You know what? There is glow-in-the-dark pee. Sidebar. Why does that happen? Okay. It's actually a little sad, but people who drink ethylene glycol, which is antifreeze, I don't even know if I should say this. It's sweet tasting and it does make you feel drunk. It's also highly, highly toxic. Some people drink it as a suicide attempt. Some people drink it it makes you feel drunk. But antifreeze has a chemical in it that glows in the dark so you can see spills with a UV light.

55:36So when we are suspicious that someone has consumed ethylene glycol, we can go to the ED and we can put a little UV light on their urine. And if it glows, that is a quick way to make the diagnosis. Wow. Cool, right?

55:51Perry Wilson:Your job is unusual.

55:56Perry Wilson:Okay, let's talk about the risks. So we talked about the serotonin risk. So if you're on an SSRI, absolutely counterindicated. Do not take this. It is very dangerous. You could die. Good. Another big risk is that it's, like so many things, unregulated, not tested by the FDA. If you Google methylene blue, you'll find that methylene blue is in aquarium tank treatments. It can, you know, help some parasites on your fish or something like that. Don't take that kind of methylene blue. Like that's even less tested than the stuff that you can buy that are actually marketed to humans. But just to say it out loud.

56:37And then the other thing is if you have G6PD deficiency, methylene blue can cause hemolysis. and you don't know if you have G6PD deficiency. About 2 % of the population does, and there's no reason you would particularly be aware of it unless you are about to be treated with a medication that interacts with G6PD, in which case we test you first before we give you that medication. Methylene blue is one of those medications. So yeah, unless you've already been rolled out for G6PD deficiency, something to think about.

57:09Perry Wilson:All right, Perry, are you a smash or pass on methylene blue? I'm a pass on methylene blue. Is that going to shock Polymarket? Sorry, everyone. I'm a pass. This at best is an MAO inhibitor, which is a pretty bad antidepressant that we gave up on long ago. And at worst, it's something that you're going to waste your money on and it's going to turn your pee fun colors. I mean, reasonable party trick, but not worth your your wellness dollar. Uh, Emily smash pass. I'm a pass. Uh, I think to say that this is something that is dangerous for 2 % of the population, plus anyone on an SSRI feels like already significant downsides on top of there being no real upsides.

57:57Perry Wilson:So that we are aware of for healthy people. So I'm, uh, I'm a pass, but I did enjoy learning more about the electron transport chain. So yeah, that's a good biology episode. Good biology episode. Good bio. I'm going to have my kids listen to it, you know? Perfect. That's it for methylene blue, your mailbag question of the week after the break.

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1:00:22Hey, I'm Liam Perry. Here's one for you. I am a knuckle cracker. Am I going to give myself arthritis? Do you crack your knuckles?

1:00:32Perry Wilson:No, I don't. I think I used to, but I don't. And I don't think I could do it anymore. Maybe I'm just old. Do you? Try. I don't, but I think I could. Should we? Let's see if we can. Oh, our producer is like freaking out right now. Oh, yeah. My thumb. I can crack one of them. One of my thumb. That's good audio. Emily, is cracking knuckles bad for you? Do you get arthritis? Cracking knuckles is not bad. It doesn't give you arthritis. And I want to read you. This is a great opportunity for me because my favorite paper in the whole wide world of academic papers is about this topic. What? It is a 1998 letter to the editor in a journal called Arthritis and Rheumatism.

1:01:17Perry Wilson:Here is how it starts. During the author's childhood, various renowned authorities, his mother, several aunts, and later his mother-in-law, informed him that cracking his knuckles would lead to arthritis of the fingers. And then the author explains a study he performed. For 50 years, the author cracked the knuckles of his left hand at least twice a day, leaving those on the right as a control. Thus, the knuckles on the left were cracked at least 36 ,500 times, while those on the right were cracked barely. At the end of the 50 years, the hands were compared for the presence of arthritis. And he concludes he has no arthritis in either hand.

1:01:49Perry Wilson:And as a result, knuckle cracking doesn't matter. And I just love so very much this paper by Donald Unger, MD. Oh, my gosh. Dr. Unger, I salute you. That is great. Yes. Salute you. But we actually have some larger scale evidence. it also shows that there's no data here. We do. We do. Do you know what the sound comes from? Have you seen that? I don't. So it was always like people were like, oh, is it the bones kind of moving against each other? It's not. There was an MRI study that actually captured what was happening in the joint at the time the knuckles were cracked. And apparently it's what's called cavity formation, which happens when, I guess, when certain fluids are moved very rapidly.

1:02:37So if you've seen a propeller underwater of a boat, how bubbles will form behind it, even though it's not sucking bubbles down from the surface, like a submarine, that's cavitary bubble formation. And a tiny little version of that happens in your joint when you crack your knuckles, and that makes the sound.

1:02:57Perry Wilson:That is very interesting. People will sometimes also ask, once you do it, you have to keep doing it because when people do it, then they do keep doing it. But that's called habit formation. That's not a medical thing. So anyway, if you want to crack your knuckles, it's fine. But not in front of Tamar, our producer. Our producer doesn't like it. So if you're spending time with our producer Tamar, please do not crack your knuckles. She's about to crawl under the table.

1:03:26Perry Wilson:All right. That's it for us today. Okay, stick with us next week when we'll ask, what's the deal with red meat and the carnivore diet? Wellness Actually is produced in association with iHeart Media. Our senior producer is Tamar Avishai. Our executive producer at iHeart is Jennifer Bassett. Our theme music is by Eric Deutsch. And our content is for educational purposes only. If you like the show, help other people find us. Leave a rating and review on Apple Podcasts or your podcatcher of choice. and help us spread the word about the show, you can follow us on Instagram at wellnessactuallypod. And don't forget, we want to hear from you.

1:04:05Head over to wellnessactually.fm and leave us a question for our mailbag or suggest a topic for a future show.

1:04:11Perry Wilson:We'll let the influencers have the last word. The reason I argue with people so effectively is I'm absolutely out of my mind on methylene blue. You can get it. Go to tryreborn.com and get it in pill form if you don't like the avatar tongue or you can get it this one. Do it properly. If you're going to do it, do it right, innit? I still regret to this day not being an intravenous heroin addict, so there's no way I'm going to get by with just shoving methylene blue pills up my arse when I could be taking it straight down the gullet. Like a man.

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