Methylene Blue

Ah, supplements.

Some of them are pure hokum (see my post on ashwagandha).

Some of them can genuinely improve your health. Vitamin supplements provide essential nutrients, though only 13 of them are essential, you only need them if you're deficient (you're probably not), and higher-than-recommended doses are only beneficial in special cases (e.g., folic acid for pregnant women).

Somewhere between these extremes are supplements that aren't essential but might be good for you in limited ways. For example, turmeric has anti-inflammatory properties, but it may not do much because curcumin, the active ingredient, is poorly absorbed by the body.

It's not surprising that you can buy turmeric supplements, given that the spice has been used for medicinal purposes for thousands of years.

But what about methylene blue?

This cobalt-blue compound was created in 1876 as a textile dye. Aquarium owners use it to kill fungus on fish eggs. How did something like that become a dietary supplement? Why are manufacturers and social media influencers claiming that it boosts brain health and mental clarity? Are they right?

Before I wrote this newsletter I thought they were full of...hokum.

McGill University's Science and Society page, for instance, claims there's no evidence that methylene blue (MB) has cognitive benefits.

After RFK Jr. was videotaped this February adding what appears to be MB to his water, some media sources also dismissed the practice as cognitively useless.

Turns out I was wrong. So were McGill and those media reports. Studies do suggest that MB boosts cognitive functioning. I find the evidence moderately persuasive, though I'll be advising against taking the supplement.

A short (and selective) history

TikTok is a poster child for bad health advice.

Case in point: The "methylene blue craze" featuring lots of blue tongues and burbling about mental clarity, but not so much acknowledgment of the risks.

Those blue tongues offer a hint as to how MB became a dietary supplement.

Consider for instance this Tik Tokker who takes MB in part because it's "antimicrobial – great to keep parasites at bay."

She's not wrong. In 1891, MB became the first synthetic drug for treating malaria, because it does destroy the parasites (similar to the way it kills fungus on fish eggs).

MB fell out of favor as an antimalarial because of the staining – it turns urine as blue as those tongues – though there's been a resurgence of use for drug-resistant strains.

Paul Ehrlich, the German scientist who developed MB as an antimalarial, also noticed that it crosses the blood-brain barrier and stains neurons blue.

Based on that observation, as well as MB's redox-cycling properties, Ehrlich and colleagues used the compound to treat pain, anxiety, and psychotic disorders. This marks the transition of MB from industrial dye and anti-malarial to potential supporter of cognitive health.

Now, more than a century later, scientists continue to use MB to treat bipolar disorder as well as neurodegenerative conditions like Alzheimer's and Parkinson's disease. But this is still early-stage research rather than clinical practice.

Currently MB is FDA-approved for treating methemoglobinemia, a rare blood disorder that prevents hemoglobin from delivering oxygen (and a word that I'll bet you can't say three times fast).

In short, MB is not an FDA-approved or otherwise "mainstream" means of supporting cognitive health. For that purpose, it's just a supplement.

(In Appendix A, I explain what "just a supplement" means. In Appendix B, I discuss some of the medical uses of MB, including a new study suggesting that it can aid in the treatment of breast cancer.)

Cognitive benefits

Dozens of studies suggest that short-term use of MB can improve cognitive functioning.

Unfortunately, these studies don't represent a concerted effort. Rather, they're scattered across different literatures that rely on a mix of populations, including rodents, people with healthy brains, and people with neurodegenerative conditions.

It's hard to make generalizations based on apples and oranges.

To give you a sense of what the data are like, I'll briefly describe one of the better studie, published in 2016 by researchers at the University of Texas (Austin and San Antonio).

In this double-blind experiment, 26 healthy adults were tested on reaction time and working memory. Then, 60 minutes after receiving a 280 mg dose of MB or a placebo, they repeated the tests.

(During the 60 minute interval, participants weren't allowed to pee. This kept the MB group from noticing the startlingly blue color of their urine and learning which substance they'd ingested.)

Below is an example of the working memory test. First participants are shown the square on the left for 4 seconds. Then, after a 6-second blank screen, they see the two squares on the right and press a key as quickly as possible to indicate which one corresponds to the original.

Setting aside some fMRI data, which I found ambiguous, the main findings were:

• No effects of MB on reaction time for either task.

• 7% improvement in accuracy on the working memory task after taking MB (versus a nonsignificant 1% decline after taking the placebo).

It's a small study, but the methods were strong, and the results are consistent with other small studies I alluded to earlier.

So, yes, I'm persuaded. Even a single dose of MB may improve mental clarity, enhance attention and memory, etc.

Two reasons why methylene blue might support cognitive functioning

1. Increase in cellular energy.

This is the hypothesis that most researchers favor.

MB seems to get brain cells to expend more energy by transporting electrons into the mitochondria that stimulate production of ATP. You might think of it as mitochondrial caffeine.

(I know, it's a terrible metaphor. I'm not sure I like the "powerhouse of the cell" image any better.)

2. Better mood.

MB is a monoamine oxidase inhibitor (MAOI), which means that it blocks the action of enzymes that break down neurotransmitters. MB ultimately allows more serotonin to be available to the neurons in your brain.

This is important, because increasing serotonin levels can improve mood. (MAOIs were once widely used as antidepressants, and they remain a treatment of last resort in some cases).

Some studies have shown that taking MB temporarily improves mood. A independent line of studies shows that better mood can lead to improvement on tests of attention and memory.

So – this is me speculating – MB may enhance cognitive functioning by improving a person's mood. Feel better, test better.

Either or both of these explanations (increased cellular energy, better mood) could explain why MB supports cognition.

Still, I have no plans for selling MB on TikTok.

Two reasons not to take methylene blue supplements

Though I've talked up the data, I haven't shared as much detail as I usually do in these newsletters.

The reason is that even if we trust the data, MB supplements don't seem advisable.

1. The benefits aren't dramatic.

Whenever MB is shown to boost cognitive performance, the effect sizes are small.

MB can make you more alert, improve your memory, and so on. But so can a little caffeine. Or a nap. Or moderate exercise. Or just standing up and stretching.

Studies have shown that each of these activities can temporarily improve cognitive functioning. Why use MB when you can achieve comparable effects through these other means?

2. The health impacts of long-term use are unknown.

Studies also show that when pursued sensibly, activities like caffeine consumption, naps, and exercise are not only safe but can improve your health in specific ways over time.

Why use MB when the long-term safety record is unknown?

Still...

If, after reading this, you've decided you really want to try methylene blue, know at least that even one dose is dangerous if you're pregnant and/or taking any other serotonergic drugs (e.g., SSRIs). A number of minor discomforts are sometimes reported as well.

A safe dose would max out at around 2 to 4 mg per kg body weight, depending on which source you trust (and keeping in mind that very little is known about long-term safety).

As for me, I prefer coffee in the mornings, long runs, and naps. Not at the same time.

Thanks for reading!

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Appendix A: Supplements vs. medicines

Legally speaking, over-the-counter methylene blue is a dietary supplement. Here, lightly revised from an earlier post, is some context on what that means:

In the U.S., medicines are FDA-approved, meaning, among other things, that they've undergone rigorous testing for effectiveness and safety.

Supplements are not approved by the FDA for the prevention or treatment of any disease. Rather, as the FDA itself notes, once a supplement comes to market, the agency simply monitors its safety (in the limited sense of inspecting manufacturing facilities, investigating complaints of harm, etc.) and ensures that companies aren't making unwarranted health claims.

Are supplements less trustworthy than medicines? I think this is a fair generalization. Although FDA approval doesn't guarantee that a product is safe and effective, it does tell you at least that the product has undergone rigorous testing, and expert panels have probably agreed (more or less) on the findings.

The fact that a supplement isn't FDA-approved doesn't mean that benefits haven't been scientifically demonstrated, as in the case of folic acid supplements needed during pregnancy.

The problem with supplements is that manufacturers aren't required to demonstrate safety and effectiveness via rigorous research. Roughly speaking, anything that's not already proven to be harmful can be sold as a supplement and described as good for you, so long as the wording is careful not to overpromise (by the FDA's arguably lax standards).

The result is that many supplements have no clear health benefits. The science behind them is weak at best.

In the case of methylene blue, the cognitive benefits are evident (to me) from findings scattered across a variety of literatures, but there hasn't been a unified, systematic study of the topic, and statements about these benefits haven't been FDA-approved.

Thus, what we're left with are products that make vague claims ("improves brain performance") and occasional misinformation by unscrupulous people (e.g., Joe Rogan and Mel Gibson, jointly implying in a January interview that methylene blue cures cancer).

Appendix B: Some medical applications of methylene blue

MB has been endlessly repurposed as a lab tool (for dyeing or staining tissue), as a medical treatment (for malaria, cyanide poisoning, urinary tract infections, vasoplegic syndrome, etc.), and in agricultural settings (as a test for contaminants in milk, an antimicrobial in fish tanks, etc).

One of the most useful characteristics of MB is that it's a photosensitizer, meaning that it can absorb light and transfer the energy to nearby molecules.

This can be desirable if the goal of the energy transfer is to damage nearby tissue. For instance, a study published in January showed that MB aids in the treatment of warts when applied in combination with sunlight.

Three weeks ago, a study published in Journal of Medicinal Chemistry showed that adding MB to an estrogen receptor modulator creates a compound that can disrupt the growth of breast tumors. The biochemistry is beyond me, but the data seems promising.