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Methylene blue (or methylthioninium chloride) is a very old drug making a comeback, as it were.

A vibrantly blue dye, methylene blue was also the first drug used to treat malaria even back to the 19th century, and it was the primary drug used for that purpose during WWII. It’s the parent compound from which the common rheumatologic (and recently politicized) medication, hydroxychloroquine (HCQ) was derived.

It’s still the only known treatment for a condition called methemoglobinemia, which is when the hemoglobin in red blood cells become oxidized and and cannot therefore transport oxygen to tissues. This can occur with various types of poisoning, including carbon monoxide, formaldehyde, various pharmaceuticals and heavy metals, fluoride, and nitrates.

How does methylene blue accomplish all these feats, and what does that suggest about its ability to aid in other, more chronic conditions?

Methylene Blue and the Mitochondria

Methylene blue does its work in the mitochondria, where the body produces ATP, its energy currency. The possible consequences of mitochondrial dysfunction are many, varied, and potentially dire, depending upon the degree of dysfunction and the tissue involved.

Inside the mitochondria is the electron transport chain, in which electrons get passed to four different complexes until finally, ATP is produced at complex 5 (stick with me, this will matter later). This process is called oxidative phosphorylation, and it can make 38 ATP from one glucose molecule (or 129 ATP per fatty acid). Without oxygen (or if one or more of the complexes is dysfunctional), the mitochondria cannot perform oxidative phosphorylation, and they have to use an alternate pathway. This anaerobic pathway can make only 2 ATP per glucose molecule, and it also produces lactic acid.

Clearly, then, if tissues are damaged, it’s very useful to find a way to restore oxidative phosphorylation, so that the mitochondria can produce far more energy again.

Methylene blue manages to do this, still using glucose as the initial energy source. Like the original electron transport chain, methylene blue accepts an electron from NADH, or activated Vitamin B3—but then it bypasses the first four complexes in oxidative phosphorylation altogether, acting as an alternate electron carrier to complex 5. Yet it only does this when those original complexes are dysfunctional.

Did you get that? Most mitochondrial support merely gives building blocks that might be lacking, either at complexes 1-4, or the original electron donors, or support to shuttle fatty acids inside the mitochondria where they can hopefully be broken down into energy, if all is well. Beyond that, we’re mostly relegated to trying to identify and remove toxins that have caused mitochondrial dysfunction in the first place—which can work great, but can also be a slow, frustrating process, particularly if detoxification pathways are hampered by insufficient ATP to do their job. It becomes a catch-22.

Methylene blue essentially reroutes the electrons, bypassing poorly functioning mitochondrial complexes to deliver the needed energy for repair, even before the job is complete. Methylene blue significantly increases cellular glucose and oxygen utilization, and ATP production.

Even better: while it does this, methylene blue also helps to stimulate pathways for mitochondrial biogenesis: to make new, healthy mitochondria.

Methylene Blue’s Impact on Neurodegeneration

Methylene blue also crosses the blood brain barrier, which makes it useful for affecting metabolic disorders in the brain.

Neurodegenerative disorders such as Alzheimer’s Disease, Parkinson’s Disease, and ALS are increasingly found to have a metabolic cause—in other words, the problem is due to an energy deficit.

In Alzheimer’s, one of the main characteristics is a decline in the function of complex 4 in oxidative phosphorylation. Methylene blue can improve the function of complex 4 by 30%, according to this study.

Mitochondrial dysfunction is also a primary feature in Parkinson’s Disease, as is decreased glucose uptake in the brain. In this animal study, methylene blue was found to reduce the loss of dopamine-producing neurons in the brain, and thus improve symptoms of motor impairment as well.

Methylene Blue and Cancer

While cancer cells are well known to consume sugar voraciously, they do so via a less efficient mechanism than that of oxidative phosphorylation outside of the mitochondria, a process called the Warburg Effect. This mechanism involves fermentation of lactic acid. Lactic acid suppresses immune function, increases stress hormone release, and decreases blood flow.

When methylene blue ramps up oxidative phosphorylation, it shuts this process down, thereby interfering with cancer metabolism. This is critical, because studies show that at least one of the hallmarks of cancer is the way in which it produces energy. Healthy cellular metabolism means healthy cells.

Methylene Blue’s Impact on Hormones

Probably because of its metabolic effects, methylene blue also increases thyroid hormone production, the primary metabolic hormone.

Prolactin and thyroid tend to move in opposite directions, so methylene blue tends to lower prolactin also.

Testosterone, which tends to increase Growth Hormone, rises under the influence of methylene blue, while its downstream product, estrogen, tends to fall.

Methylene Blue and Nitric Oxide

Nitric oxide (NO) is often considered a beneficial compound, due to its ability to increase blood flow–and of course, the healing is in the blood, so in general, driving blood flow is a good thing. However, the primary gas in the bloodstream that increases blood flow is actually CO2.

Doesn’t that make sense? CO2 and O2 provide feedback to one another. When there’s not enough oxygen, there’s more CO2, which increases vasodilation to deliver more blood, which delivers the oxygen the tissue is lacking.

NO, by contrast, is an alternative way to restore blood flow to damaged tissues. This is positive in its place, like inflammation—but there are down sides, too.

One of the down sides is that NO inhibits complex 4 in oxidative phosphorylation. This means that even while nitric oxide increases blood flow, it decreases the ability of those tissues to utilize the oxygen it delivers to produce ATP.

Another down side is that nitric oxide can combine with oxygen to form peroxynitrite, one of the most powerful known oxidative stressors.

Another is that increased blood flow can be painful, just due to volume constraints. In the case of migraines, increased nitric oxide delivering more blood certainly has this effect. Nitric oxide inhibitors are even considered as a potential treatment for migraines.

Probably because methylene blue provides alternative routes for oxidative phosphorylation, decreasing the “emergency” signals in acute tissue injury, it also decreases synthesis of NO as well. This makes sense, as it helps to restore the normal oxygen to CO2 balance, so that there is less need for acute NO release.

Synergistic Treatments With Methylene Blue

Red light therapy, or visible light from the red part of the spectrum, can help to release nitric oxide from complex 4, thus restoring normal oxidative phosphorylation. Because of this, red light therapy combines well with methylene blue.

Methylene blue also accepts an electron from activated Vitamin B3, or NADH. Thus, adequate levels of NADH are necessary for methylene blue to do its job.

Dosing, Cautions, and Contraindications

Methylene blue is a hormetic drug, which means that at low doses it can improve oxidative phosphorylation, enhance glucose uptake, oxygen utilization, ATP production, and decrease inflammation and oxidative stress. However, at higher doses, it can do the opposite of all of these things, converting from medicine to poison. Therefore, the dose matters greatly. I recommend making sure that you have a naturopathic or functional medicine provider’s help in the process.

Methylene blue also comes in other forms besides pharmaceutical grade. Products that do not have the pharmaceutical grade designation are used as dyes industrially or for lab research, and can contain substantial amounts of toxic impurities not suitable for human (or animal) consumption. Therefore only pharmaceutical grade should be used.

Methylene blue should not be used in babies, in pregnancy or in breast feeding.

Unique contraindications for methylene blue include G6PD deficiency—G6PD is an enzyme that helps to protect red blood cells from oxidative stress. Insufficient levels can lead to hemolytic anemia. This is less likely at very low doses, but it is best to err on the side of caution.

The same is true of those who are taking any medications that increase serotonin levels in the body, such as SSRIs or SNRIs. At higher doses, methylene blue can also increase serotonin levels, increasing the risk of serotonin syndrome. Talk to your functional medicine provider about these possible interactions, and ways to mitigate them.

Oral ingestion of methylene blue can cause GI upset including nausea, but usually at higher doses. It will lead to blue or green urine, and can briefly cause the teeth to appear stained as well. This should go away with brushing, eating a meal, oil pulling, or it can be avoided altogether by drinking the solution through a straw and bypassing the teeth.