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Image credit: Ionut Stefan
In recent months, a substance called methylene blue has once again made the rounds as a potential “everything” booster, a “wonder supplement” claimed to improve your memory, give you more energy, cure mood problems and so on and so forth. Naturally, that tripped our “too good to be true” alarm. So we’ve decided to sift through the scientific studies, see whether they live up to the hype, and find out if “there’s no harm in trying it out” (spoiler alert: not so harmless).
And because we really seem to love disclaimers here, there’s the one for today: the topic of methylene blue, like many similar ones dealing with health-related improvements, is nuanced and complex. Perhaps most importantly, the evidence needs to be interpreted in the context in which it was acquired. As you’ll see more concretely later on, that means distinguishing between in vitro = Petri dish vs in vivo = in live organisms, a distinction that’s often the difference between hype and hope.
What is methylene blue?
Methylene blue (or methylthioninium chloride, by its grown-up name) is, in fact, a surprisingly old drug (we’re talking 19th-century old), included on the WHO Model List of Essential Medicines. But not for what you might hope. In humans, it’s used primarily to treat something called methemoglobinemia, a condition in which some of the hemoglobin that normally carries oxygen to cells is converted to methemoglobin, i.e. a form that cannot transport oxygen. It was also used as treatment for malaria and cyanide poisoning, although that’s no longer recommended. Pet fish owners might also know it as a fish tank add-on, thanks to its microbial and antifungal properties. And of course, it works great as a dye, both in textiles and in live tissues.
The cellular effects of methylene blue
This is the part where we look at potential mechanisms of action for methylene blue at the cellular level. It’s also where we keep in mind that mechanistic explanations in isolated cells do not guarantee successful effects in living, breathing humans. That’s because living, breathing humans tend to be a slightly more complicated soup of cells full of knobs, dials, feedback loops, and circuit breakers that interact in very unpredictable ways to dash even the best of therapeutic promises.
Methylene blue is kind of a jack of all trades: it acts as a monoamine oxidase (MAO) inhibitor, it has several effects in the mitochondria, and it can interfere in the nitric oxide pathway. Still there? Good, let’s unpack these one by one.
MAO inhibitor
Monoamines are a group of neurotransmitters and neuromodulators, such as dopamine, norepinephrine, and serotonin. Monoamine oxidases, MAOs, are enzymes that break down the monoamines. It might ring a bell if I tell you that MAO inhibitors are used to treat disorders such as depression: too little serotonin, maybe because the MAOs are going wild and breaking down too much of it → administer medication that blocks the MAOs → more serotonin to go around → less depression. So when we say that methylene blue is a MAO inhibitor, we’re basically saying that it interferes with the breakdown of molecules such as dopamine and serotonin.
Mitochondrial helper
The mitochondria effects are a bit more complicated (mitochondria themselves are a lot more complicated than “powerhouses of the cell”). But to start simple, we know that’s where ATP, the energy molecule, is made through a process called respiration. The process of respiration functions a bit like a game of hot potato, where electrons are passed down a series of proteins embedded in the membrane. Whenever electrons are thrown from one protein in this series to the next, a proton is sent from the inside to the outside of the mitochondrion. That’s how a proton gradient is built. The proton gradient is what drives the ATP synthase, i.e. the enzyme that produces ATP.
But what happens with the electron that arrived at the end of the game? It cannot just freely float around the mitochondrion. Normally, there’s another enzyme at the end of the chain, called cytochrome C oxidase. This one takes electrons and safely combines them with oxygen and protons to form water. But if a protein upstream is broken, the electron cannot make it safely through the entire chain. Instead, it escapes early, without safely forming water. Since the electron doesn’t like to be alone, it still combines with oxygen.
Unfortunately, this is a toxic relationship, because what comes out are free radicals (which cause damage in the cell). Enter methylene blue, who can accept the lost electron, bypass the broken part of the hot potato game, and thus prevent the appearance of free radicals. What’s more, it appears that methylene blue can increase the activity of cytochrome C oxidase, and even increase the expression of the genes responsible for making it. This is a glimpse behind the “it boosts mitochondria” curtain.
Nitric oxide blocker
Finally, nitric oxide is a biological messenger. One of the roles of nitric oxide is to tell smooth muscles to relax, which in turn makes blood vessels dilate and increases blood flow. However, nitric oxide doesn’t talk to the muscle directly, but to yet another enzyme (told you there’s lots of knobs and dials), called guanylyl cyclase. Methylene blue interferes with this process by making guanylyl cyclase temporarily unresponsive to nitric oxide’s messages, basically jamming the signal. This leads to vasoconstriction instead of vasodilation (a reverse Viagra, if you will).
New word alert
Having a substance with so many potential targets is great. It means it has the potential to be used for many different problems. It can also be quite problematic though, because instead of finely tuning a knob, you’re basically just mashing the buttons and hoping for the best. And the struggle doesn’t stop there. To make matters more fun, methylene blue has what’s called a hormetic effect. It means that low doses produce beneficial effects, whereas high doses are harmful. In other words, more isn’t always better and sometimes it’s a lot worse.
The in vivo effects of methylene blue
Still, it’s time to move on to in vivo studies. Now, before medication is tried on humans, it’s usually tested on animals, both to see if it has the desired therapeutic effect and to check whether it’s safe. Methylene blue is no exception. And so far, it’s been quite successful in treating a variety of conditions in the scientists’ best friends, the lab rats and mice. These include depression, anxiety, schizophrenia, traumatic brain injury, stroke, Parkinson’s disease, and Alzheimer’s disease, among others . But as we like to say around here, humans aren’t mice.
Ok, so what does the data say in humans? Well, it’s been tested for a few things, including bipolar disorder, major depressive disorder, and schizophrenia. Some of these studies report some improvements in symptoms, however, and this is crucial, the sample sizes are very small, usually including only 20-30 participants. That means some preliminary evidence is there, but it still needs to be validated in larger studies and there still is a large potential for failure.
Take the example of using methylene blue for treating mild to moderate Alzheimer’s disease. Phase II studies (with smaller sample sizes) were promising, but the phase III study including almost 900 participants failed to find a positive effect, which means it didn’t work.
And how about any data showing what methylene blue does when taken by healthy individuals? Much shorter answer: it’s not there.
Why you shouldn’t chug methylene blue yet
Maybe the above wasn’t convincing enough. After all, you might be thinking, what if it doesn’t work? It won’t hurt me, will it? Sadly, that’s where you’ll be gambling.
First of all, methylene blue will color your urine blue. That’s just a small nuisance, except it can also cause bladder irritation and a bunch of more annoying side effects, such as nausea, vomiting, or headaches, among others. More seriously, in people who have something called G6PD deficiency, methylene blue can trigger hemolytic anemia, a condition in which red blood cells get destroyed faster than they are replenished and which can be life-threatening. And that’s not all. People taking SSRIs who add methylene blue to their diets are at risk of developing serotonin syndrome, which can also be fatal.
Plus, remember that hormetic effect we mentioned above? Well, even if you’re healthy and not on any medications, if the dose is too high, methylene blue will have damaging effects. In particular with respect to mitochondria, high doses of methylene blue inhibit cytochrome C oxidase activity, thus contributing to the production of free radicals.
And here’s another kicker: because there is not enough scientific evidence available, we don’t really know what’s a safe or effective dose of methylene blue. To make it even messier, what you ingest vs. what reaches your brain are not the same thing. Couple that with the fact that most over-the-counter supplements are barely regulated, and you’re rolling a pretty dangerous die.
Game over for methylene blue?
Just because you shouldn’t stuff your face with it doesn’t mean methylene blue is completely useless. As we discussed above, it still has some fascinating properties, from its effects in mitochondria to those on neurotransmitters, and researchers are still exploring ways to harness this power in a safe and effective manner. Until then, better stay on the safe side!
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References
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