Did you know that a simple blue dye, once used to color fabrics, also has medical applications? This dye is called methylene blue.
While it was first made in the late 1800s for the textile industry, methylene blue has been FDA-approved for the treatment of methemoglobinemia and is studied for additional off-label medical applications.
From helping doctors during surgeries to treating specific blood and brain disorders, this dye has shown benefit in multiple areas and physical conditions.
This article will explore methylene blue’s history, how it works, the medical conditions it helps treat, and what scientists think it might do in the future.
We will also discuss its safety, side effects, and some of the most common questions people have about using it.
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Understanding Methylene Blue
Methylene blue (also known as methylthioninium chloride and sold under the brand name PROVAYBLUE) is a man-made dye and medicine with many uses in healthcare. It is best known for treating methemoglobinemia, a condition in which the blood can’t carry oxygen properly, by helping hemoglobin work correctly.
It is also used clinically to treat conditions like vasoplegic syndrome (a condition often following trauma when blood vessels fail to constrict, causing dangerously low blood pressure) and septic shock (when a severe infection causes low blood pressure and organ failure). Methylene blue does this by reducing blood vessel widening.
Doctors often use methylene blue as a dye during surgeries to locate lymph nodes or parathyroid glands. It has shown promise for other conditions, like malaria and certain types of nerve damage.
While it’s usually safe, higher doses can cause side effects like serotonin syndrome or blood problems in people with a deficiency in the enzyme glucose-6-phosphate dehydrogenase (G6PD).
In people with G6PD deficiency, red blood cells are more easily damaged by certain chemicals. Methylene blue can form byproducts that harm these cells, causing them to burst (hemolysis). As a result, it should be used carefully or avoided in these patients.
History and Discovery
The story of methylene blue begins in 1876 when a German chemist named Heinrich Caro first made it as a textile dye. Soon after, scientists noticed that methylene blue might have some medical uses. For example, early trials in the late 1800s found that it could kill certain parasites, which led to interest in its role as a treatment for malaria.
Over time, doctors discovered that it could also treat a blood disorder called methemoglobinemia and stain tissues during surgery.
Today, it is approved for several medical uses and is being researched for many more.
Mechanisms of Action
Methylene blue has a very interesting way of working in the body.
Methylene Blue and Redox Reactions
It works by facilitating redox reactions in the body. Redox reactions are chemical processes in which electrons are transferred between substances, involving one substance being oxidized (losing electrons) and another being reduced (gaining electrons).
By doing this, methylene blue can help cells use oxygen more efficiently: it restores hemoglobin’s ability to carry oxygen by converting its oxidized form (Fe³⁺) back to its functional form (Fe²⁺), which is why it is effective for treating methemoglobinemia.
People with methemoglobinemia have too much methemoglobin—the oxidized form of hemoglobin that cannot carry oxygen well—and methylene blue helps convert it back to normal hemoglobin.
Methylene Blue’s Effects on Blood Vessels
Methylene blue also inhibits enzymes like nitric oxide synthase and guanylate cyclase, reducing blood vessel widening and improving blood pressure in conditions like vasoplegic syndrome, septic shock, and malaria.
Methylene Blue’s Effects on Mitochondria
Methylene blue also seems to support normal activity in nerve cells by making it easier for mitochondria (the energy factories of our cells) to produce ATP, the molecule cells use for energy.
Methylene blue has been studied for its role in mitochondrial function, where it may help mitochondria work better by acting as a backup pathway for moving electrons in the energy-making process. It bypasses damaged parts of the mitochondria, helping them produce energy (ATP) more efficiently and reducing harmful molecules called reactive oxygen species (ROS).
By boosting energy production and lowering cell damage, methylene blue shows promise for protecting mitochondria and treating conditions linked to their dysfunction, like brain disorders.
Methylene Blue’s Antioxidant Properties
Methylene blue has antioxidant properties that help protect cells from damage caused by harmful ROS.
While methylene blue may help in some brain conditions, it may also slow skin aging and support longer-lasting, healthier cells.
Medical Applications of Methylene Blue
FDA-approved therapeutic uses of methylene blue include:
FDA-Approved Uses of Methylene Blue
Methemoglobinemia is the single FDA-approved use for methylene blue:
Treatment of Methemoglobinemia
- Description: Methemoglobinemia is a condition where hemoglobin (the molecule in red blood cells that carries oxygen) is turned into methemoglobin, which cannot carry oxygen. This can make a person’s skin look blue and lead to severe oxygen shortages.
- Use of Methylene Blue: when given intravenously, methylene blue helps return methemoglobin to normal hemoglobin, often reversing symptoms quickly.
- Dosing: Methylene blue is typically administered as an intravenous (IV) infusion at a dose of 1 mg/kg of a 1% solution, administered over 5 to 30 minutes.
- Mechanism: Methylene blue reduces oxidized hemoglobin (Fe³⁺) back to its functional form (Fe²⁺), allowing it to carry oxygen again.
Off-Label Uses of Methylene Blue
While the following are off-label uses for methylene blue, it has been used off-label in some clinical settings, though further studies are needed to confirm its effectiveness.
Vasoplegic Syndrome
- Description: vasoplegic syndrome is a serious condition where blood pressure drops to dangerously low levels during or after heart surgeries like coronary artery bypass grafting (CABG). This condition doesn't respond to standard treatments like typical blood pressure medications.
- Use of Methylene Blue: when other drugs, like epinephrine, fail to raise blood pressure, methylene blue can help by increasing the resistance in the blood vessels.
- Dosing: methylene blue is usually given through an IV at a dose of 2 mg per kilogram of body weight over 20 minutes. More doses can be given before or after surgery if necessary.
- Mechanism: methylene blue works by blocking certain enzymes (nitric oxide synthase and guanylate cyclase) that lower blood vessel tension. The overall effect causes the blood vessels to tighten and raises blood pressure.
Sentinel Lymph Node Mapping
- Description: sentinel lymph node mapping is commonly used during breast surgeries such as lumpectomies or mastectomies to identify lymph nodes most likely to contain cancer. Sentinel lymph nodes are the first few lymph nodes surrounding a tumor.
- Use of Methylene Blue: methylene blue is injected as a dye to make sentinel lymph nodes easier to locate and biopsy.
- Dosing: the typical dose is 2 mL or 5 mL of a 1% solution injected into the tissue near the tumor (an intraparenchymal injection).
Parathyroid Gland Identification
- Description: locating the parathyroid glands during parathyroidectomy surgery (which removes them) can be challenging, as they are small and can blend in with surrounding tissue.
- Use of Methylene Blue: administered intravenously, methylene blue stains the parathyroid glands, making them easier for surgeons to identify.
- Dosing: a dose of 5 mg/mL is given one hour before the procedure.
Ifosfamide-Induced Encephalopathy
- Description: ifosfamide is a chemotherapy drug that can sometimes cause harmful effects on the brain, leading to symptoms like confusion, agitation, and other signs of encephalopathy (a general term for brain dysfunction that can cause confusion, memory loss, personality changes, or difficulty thinking clearly).
- Use of Methylene Blue: methylene blue stops the production of toxic substances in the body that cause these symptoms, helping to reduce or eliminate them.
- Dosing: administered intravenously at a dose of 50 mg every 4 hours until symptoms resolve.
Malaria Treatment
- Description: Methylene blue has shown effectiveness against drug-resistant Plasmodium falciparum, particularly in areas where standard antimalarials like chloroquine are no longer effective.
- Methylene Blue acts as an antimalarial by inhibiting the parasite’s glutathione reductase, a key enzyme that helps the parasite survive.
- Dosing: for adults, the dose is 300–1000 mg per day, while children typically receive 20–300 mg per day, usually for three days.
Reducing Post-Injection Pain
- Description: propofol, a medicine often used for anesthesia, can cause pain when it’s injected.
- Use of Methylene Blue: giving a small dose of methylene blue right before propofol can help reduce this pain.
- Dosing: the typical dose is 50 mg (2 mL), administered 45 seconds before the propofol injection.
Other Potential Uses
Methylene blue is being explored for conditions involving cognitive impairment and as an anti-aging remedy.
Safety and Side Effects
When used at appropriate doses and under medical supervision, methylene blue is considered safe for FDA-approved indications and when used at or below about 2 mg/kg of body weight.
However, it may cause serious side effects in certain populations, including those with G6PD deficiency and serotonin-related conditions.
It can be given orally, intravenously, or even topically for certain skin conditions. The safest and most common route for serious conditions like methemoglobinemia is usually an IV infusion in a hospital setting.
Proper dosing is essential. At doses above 2 m/kg, taking too much methylene blue can do more harm than good, with severe reactions often occurring around 5 mg/kg.
Before prescribing it, doctors must consider a patient’s overall health, existing conditions, and any other medications they take.
Side Effects and Adverse Reactions
Commonly reported adverse reactions (>10%) include:
- Pain in arms or legs
- Chromaturia (blue discoloration of urine)
- Dysgeusia (altered taste)
- Feeling hot
- Dizziness
- Hyperhidrosis (excessive sweating)
- Nausea
- Skin discoloration
- Headache
Less common adverse reactions (2%-10%) include:
- Syncope (fainting)
- Back pain
- Musculoskeletal pain
- Paresthesia (tingling sensation)
- Pain at the IV administration site
- Feeling cold
- Pallor (pale skin)
- Contact dermatitis (increased risk of an allergic skin reaction)
- Pruritus (itching)
- Decreased appetite
- Chest discomfort
- Vomiting
- Chills
- Diarrhea
- Dyspnea (difficulty breathing)
Overdose Symptoms
While a relatively safe medication, overdose of methylene blue can occur. Symptoms of overdose include:
- Nausea and vomiting
- Chest pain
- Fast heartbeat (tachycardia)
- Dizziness
- Tremors
- Confusion
- Severe red blood cell destruction (hemolysis) with very high doses
Warnings and Precautions
It's important to be aware of the following concerns regarding methylene blue:
- Serotonin Syndrome: risk increases with other serotonin-related drugs (e.g., SSRIs, SNRIs, MAO inhibitors). Symptoms include confusion, unstable blood pressure, muscle problems, and nausea.
- Allergic Reactions: severe reactions like anaphylaxis (a medical emergency), swelling (angioedema), hives (urticaria), and difficulty breathing (bronchospasm) may occur.
- Hemolytic Anemia: higher risk in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency.
- Monitoring Interference: methylene blue can cause inaccurate readings on pulse oximeters and certain laboratory tests, potentially leading to misdiagnosis. Healthcare providers should be aware of this effect when interpreting oxygen saturation levels.
- Driving and Machinery Use: may cause confusion, dizziness, or vision problems that make it unsafe to operate machinery or drive.
- Light Sensitivity: increased risk of sunburn or skin damage due to light exposure (phototoxicity).
Who Requires Close Monitoring with Methylene Blue Use (Or Should Avoid It)?
Certain groups should only use methylene blue cautiously and under close observation, or should avoid it.
Kidney Problems (Renal Impairment)
Methylene blue is partly removed from the body through the kidneys. Patients with kidney issues may have a higher risk of side effects and need closer monitoring.
Liver Problems (Hepatic Impairment)
Since methylene blue is processed in the liver, people with liver disease may take longer to clear the drug and have a higher chance of side effects.
Pregnant Women
Methylene blue can harm an unborn baby. Risks include intestinal blockages, fetal death, or a type of anemia. It should only be used if the benefits are greater than the risks.
Breastfeeding Mothers
Methylene blue could cause serious side effects in babies. Mothers should stop breastfeeding for up to 8 days after treatment.
Elderly Adults
Older people often have reduced kidney function, which may require a lower dose or more frequent monitoring.
Children and Infants
Methylene blue is approved for use in children, but its possible side effects, like blood cell damage (hemolysis) in kids with G6PD deficiency, should be closely watched.
Certain Types of Methemoglobinemia
Methylene blue may not work well for methemoglobinemia caused by specific agents, like arylamines or sulfa drugs. Other treatments might be needed.
Allergic Reactions
Patients who have had allergic reactions to methylene blue or similar drugs should not use it.
Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
People with G6PD deficiency should not take methylene blue because of the risk of serious side effects.
Legal Considerations
Methylene blue is FDA-approved for methemoglobinemia. Its off-label uses are not FDA-approved, and consumers should discuss potential risks and benefits with their healthcare providers.
The FTC and FDA regulate claims related to supplements containing methylene blue to prevent misleading health claims.
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Key Takeaways
- Methylene blue is FDA-approved for treating methemoglobinemia and is studied for other potential medical uses.
- Works by improving oxygen transport in the blood, supporting mitochondrial function, and acting as an antioxidant.
- Used in surgeries as a dye for locating lymph nodes and parathyroid glands.
- Potential off-label uses include vasoplegic syndrome, septic shock, malaria, and cognitive health, though more research is needed.
- Safety concerns – Avoid in people with G6PD deficiency, serotonin-related conditions, or certain types of methemoglobinemia.
- Possible side effects – Nausea, dizziness, sweating, blue urine, and, in rare cases, serotonin syndrome or hemolysis.
- Pregnancy and breastfeeding – Not recommended due to potential risks to the baby.
- Legal status – FDA regulates its approved use; off-label applications require medical supervision.
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