Methylene blue

• 1. Introduction

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  Methylene blue is a dark green powder that turns water a deep, unmistakable blue. During World War II, soldiers who were given it disliked the experience and left behind a rhyme: "Even at the loo, we see, we pee, navy blue." The joke points to the compound's most visible habit. It colors whatever it touches, including the body's own waste. That one trait has made it useful in strange and surprising places. Doctors inject it into veins to rescue people whose blood has stopped carrying oxygen. Surgeons use it to trace hidden tissue. Chemistry teachers use it to make a bottle of liquid flicker between blue and clear. Fish hobbyists use it in their tanks, and dairy inspectors use it on milk. How did a dye become a medicine? Why does a blue chemical save people from certain poisons? And why, a century and a half after it was first made, are doctors warning the public to be careful with it?

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• 2. A Dye Becomes a Drug

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  In 1876, the German chemist Heinrich Caro first prepared methylene blue. The compound has since been described as the first fully synthetic drug used in medicine.

  In 1891, Paul Guttmann and Paul Ehrlich pioneered its use against malaria. In those years before World War I, researchers such as Ehrlich held a bold idea. They believed that drugs and dyes worked in the same way, by selectively staining disease-causing organisms and possibly harming them. The theory was only partly correct. Many drugs do act by changing the cell membrane of a pathogen, but the full picture is far more complicated.

  Even so, the idea bore fruit. Methylene blue became the original prototype, or lead compound, for a whole family of later medicines. These include the antimalarial chloroquine, a range of antihistamines, and antipsychotics such as chlorpromazine.

  Today the compound appears on the World Health Organization's List of Essential Medicines. Its most dramatic job there involves rescuing blood that can no longer do its work.

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• 3. Rescuing Blood

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  Broad beans can poison some people. So can certain pharmaceuticals and toxins, and the result can be methemoglobinemia, a condition in which hemoglobin loses its ability to carry oxygen. The iron in hemoglobin has been pushed into its ferric form. Normally, enzymes called methemoglobin reductases, which depend on NADH or NADPH, turn it back. When a large amount of methemoglobin appears after a poisoning, those enzymes are overwhelmed.

  Methylene blue steps in as an antidote. Given by injection into a vein, it is first reduced to leucomethylene blue. That form then restores the heme group in methemoglobin to ordinary hemoglobin. The effect on timing is striking. Methylene blue can shorten the half-life of methemoglobin from hours to minutes. Doctors turn to it when methemoglobin levels climb above 30 percent, or when symptoms persist despite oxygen therapy. The chemistry has a catch. At high doses, methylene blue actually causes methemoglobinemia, running the same pathway in reverse.

  Sodium nitrite overdose is one indication, particularly when the nitrite was taken in a suicide attempt. Isobutyl nitrite is another culprit. It is one of the compounds sold as poppers, an inhalant that produces a brief euphoria. Severe methemoglobinemia from it may be treated with methylene blue.

  Cyanide poisoning offers a second rescue. Methylene blue has a reduction potential close to that of oxygen, and parts of the electron transport chain can reduce it. For that reason, large doses are sometimes used as a cyanide antidote. Bo Sahlin of Lund University first demonstrated the effect in 1926. In San Francisco in 1933, Matilda Moldenhauer Brooks successfully tested it, and she is credited with discovering that the dye also counters carbon monoxide poisoning.

  Shock is a murkier story. In vasoplegic syndrome, a form of redistributive shock, methylene blue raises blood pressure. It does not, however, improve the delivery of oxygen to tissues, and it does not lower mortality. For shock caused by calcium channel blocker toxicity that resists first-line drugs, it has been tried as a rescue therapy. A 2024 review of case reports found only low-quality evidence that it might shorten hospital stays, reduce the time on vasopressors, and lower short-term mortality.

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• 4. Seeing the Invisible

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  In 1887, Paul Ehrlich described a trick that made nerves visible in living tissue. A dilute methylene blue solution is injected into the tissue or applied to small, freshly removed pieces. The blue color develops only on exposure to air, and immersion in ammonium molybdate fixes it in place. For years, this vital staining was widely used to examine the nerve supply of muscle, skin and internal organs. Why the dye picks out nerve fibers so selectively is still incompletely understood. One clue is that ouabain, a drug that inhibits a pump in cell membranes, prevents the staining of nerves in skin.

  In the operating room, the same color serves as a guide. During endoscopic removal of a polyp, surgeons inject it into the tissue beneath the growth. Afterward, the blue marks the tissue plane, showing whether more tissue needs to be cut and whether perforation is a risk. Sprayed over the lining of the gut in chromoendoscopy, it reveals dysplasia, the pre-cancerous lesions. In sentinel lymph node surgery, it traces lymphatic drainage. During bowel resection or gastric bypass, it can test for leaks. Orthopedic surgeons add it to bone cement so that cement and native bone are easy to tell apart, and it also makes the cement harden faster. Because injected dye is readily released into the urine, it can also trace the body's plumbing.

  Under the microscope, the dye does subtler work. In the 1890s, D. L. Romanowsky noted in his thesis that methylene blue changes when it is oxidized in solution or "ripened" by fungal metabolism. It loses methyl groups step by step and forms Azure B, Azure A, Azure C and thionine. This process underlies the blue-staining half of the Romanowsky-Giemsa effect. Mixtures such as Wright-Giemsa and Diff-Quik rely on it in cytopathology, coloring both nuclei and cytoplasm. Without methylene blue, normal neutrophil granules tend to overstain and look toxic.

  Biologists use it, too. Living yeast cells reduce the dye and stay unstained, while dead cells turn blue. Researchers can also stain RNA on membranes in northern blotting with it. It is less sensitive than ethidium bromide, but it is less toxic and does not wedge itself into nucleic acid chains, so it does not disturb the experiment.

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• 5. Blue Bottle Chemistry

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  Shake a bottle holding glucose, methylene blue and sodium hydroxide, and the liquid turns blue. Leave it still, and it slowly fades to clear. This is the classic blue bottle experiment, a staple of chemical kinetics lessons. Oxygen oxidizes the dye when the bottle is shaken. The glucose then gradually reduces it back to its colorless form, called leucomethylene blue. The dye absorbs light most strongly near 670 nanometers, and its midpoint redox potential sits at +0.01 volts.

  That built-in color switch makes methylene blue a widely used redox indicator in analytical chemistry. It is blue in an oxidizing environment and goes colorless when a reducing agent arrives.

  The food industry borrows the trick for milk. A few drops in a sample should stay blue if enough dissolved oxygen remains. If the color vanishes, oxygen is scarce, which suggests the milk is not fresh or that bacteria are consuming its oxygen.

  Water testing uses the dye in several ways. How much methylene blue a granular activated carbon adsorbs indicates its filtering capacity, and it predicts how well the carbon removes pesticides. A color reaction with chloroform in an acidified solution detects anionic surfactants, in a test called the MBAS assay. It cannot tell one surfactant from another. A sulfide test works in reverse, because there the blue dye is the product of a reaction, not an added reagent. It measures sulfide from 0.020 to 1.50 milligrams per liter, and soil microbiologists use it to spot sulfate-reducing bacteria. In construction materials, the methylene blue value reflects how much clay is in fine aggregate.

  Aquarium keepers use the dye as well, most often to protect newly laid fish eggs from fungus. For sick fish, it is given as a medicated bath. Against the parasite that causes ich, a combination of malachite green and formaldehyde works far better. Nonprofessional sources claim it helps with ammonia poisoning, but the medical literature offers little support.

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• 6. Side Effects and the Placebo Problem

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  Blue urine made methylene blue a handy placebo. Physicians would tell patients to expect their urine to change color and treat it as a sign that their condition was improving. The same quirk ruins ordinary clinical trials, since patients on the real drug can tell. One workaround gives the control group a low dose, just enough to turn urine blue. A low dose is still not guaranteed to be inert.

  Headache, nausea and vomiting are the common side effects. Others include dizziness, mental confusion, fever, abdominal pain, bladder irritation and anemia. Skin can be stained, stools can be discolored, and injection beneath the skin can cause tissue death at the site.

  A deeper hazard comes from its action as a monoamine oxidase inhibitor. If it is infused intravenously at doses above 5 milligrams per kilogram, it can cause serotonin syndrome in people taking SSRIs or other serotonergic drugs. Examples named include duloxetine, sibutramine, venlafaxine, clomipramine and imipramine.

  People with G6PD deficiency, also called favism, are said to risk hemolytic anemia. How real that danger is remains disputed, because the link was made from very few cases. In pregnancy, the drug may harm the fetus. Yet withholding it in methemoglobinemia is likely more dangerous.

  How the body handles the dye depends on the route. After intravenous dosing, early studies reported a terminal half-life of 5.25 hours, and the early drop in blood levels reflects the dye moving into organs. In rats, the brain, liver and bile held far more than the blood did. A dry gelatin capsule delivered only 6.5 percent of the exposure that an injection did. A later study, using an oral solution of 500 milligrams in 200 milliliters, found bioavailability of 72.3 percent.

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• 7. Research Frontiers

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  In 2009, researchers revived methylene blue as an antimalarial. It attacks the malaria parasite on many fronts at once, but the main mechanism appears to be a lethal amount of redox cycling. A 2018 meta-analysis found it effective against P. falciparum in Africa. It lowers levels of gametocytes, the transmission stage, and works in synergy with standard artemisinin-based combination therapy. The same analysis found no link between the dye and hemolysis in African patients with the moderate A minus type of G6PD deficiency. It did find a clinically insignificant dip in hemoglobin. How it performs against other malaria species, or in other regions, is unclear.

  In 1994, methylene blue was first reported as a treatment and preventive for ifosfamide neuropsychiatric toxicity. A toxic breakdown product of the chemotherapy drug, chloroacetaldehyde, disrupts the mitochondrial respiratory chain, and NADH accumulates. Methylene blue acts as an alternative electron acceptor. It also blocks the formation of chloroacetaldehyde. Reports describe improvement within 10 minutes to several days, with up to six doses a day. Some guidance recommends giving it the day before ifosfamide starts and three times daily during chemotherapy.

  Light changes the dye's behavior. Exposed to oxygen and light, methylene blue becomes a photosensitizer that produces singlet oxygen. In that state it can kill some viruses and some bacteria, even inside the human body in antimicrobial photodynamic therapy. It can also disinfect blood plasma. Using it to kill cancer cells locally remains at the preclinical stage, and its cell-killing ability may relate to inhibiting tubulin polymerization.

  The brain is the newest target. Methylene blue inhibits monoamine oxidase, dampens the glutamatergic system, modulates mitochondrial function and reduces activation of the NLRP3 and NLRC4 inflammasomes. People have tried it for bipolar disorder, especially depressive symptoms, followed in order of decreasing evidence by Alzheimer's disease, claustrophobia, ifosfamide encephalopathy and schizophrenia. Here the dose behaves oddly. A higher dose does not necessarily work better than a lower one.

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• 8. The Social Media Trend

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  In the late 2010s and early 2020s, a social media trend promoted methylene blue for anti-aging, metabolism, cognition, cancer and COVID-19. No scientific consensus supports these uses, and the U.S. Food and Drug Administration has not approved it for them. Medical experts warned that high doses can be toxic and that the dye may interact with other medications, weakening them or causing unforeseen effects. Their advice was to use it only on a doctor's prescription.

  The trend probably followed a handful of scientific papers on conditions such as progeria and skin aging. The dye was also explored in anticancer photodynamic therapy using lasers. Reviews of the literature split. One systematic review sounded optimistic while stressing the need for more extensive research. Another took a harder line, calling clinical use "a rather controversial problem" because the data are heterogeneous and preclinical data are lacking.

  In January 2025, Robert F. Kennedy Jr, then the nominee for U.S. health secretary, was filmed on a flight adding droplets of an unidentified blue liquid to his drink. Many people speculated that it was methylene blue. Kennedy has not addressed the claims.

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