Methylene Blue: Benefits, Dosage and Side Effects 2022

Methylene blue (MB), also known as methylthioninium chloride, is a bioactive substance and a blue dye. Methylene blue (MB), as the first fully man-made medicine, has a wide range of clinical applications. Apart from its well-known FDA approved applications in surgical staining, malaria, and methemoglobinemia, the anti-oxidative properties of MB recently brought new attention to this century-old drug.

Some researchers believe that it can directly improve cellular and mitochondrial function and decrease the production of proteins linked to Alzheimer’s. It is also being studied for its potential to inhibit monoamine oxidase (MAO), nitric oxide (NO) synthase, and guanylate cyclase [Rojas, 2013Tucker, 2017].

Methylene Blue

Mitochondrial Mechanisms

During brain aging, mitochondrial dysfunction has been associated with neuronal loss. It has also been observed in many brain diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and brain injuries [Nitzan, 2019]. MB is highly lipophilic and able to effectively cross the blood-brain barrier (BBB) [Rojas, 2012].

At low doses, methylene blue (MB) has been shown to protect the brain from disease by acting as an electron donor to complex I-IV of the mitochondria which increases adenosine triphosphate (ATP) production. ATP is the currency of life and the energy that powers humans. If our production of ATP declines, our physical and mental performance declines. Even healthy individuals can benefit from a boost in ATP production [Rojas, 2013].

More specifically, MB can donate electrons to coenzyme Q and possibly to cytochrome C, thus increasing cytochrome oxidase (complex IV) activity and oxygen consumption. MB also increases heme synthesis [3].

MB is also able to stimulate glucose metabolism in conditions without oxygen and increase the amount of NAD+ produced by mitochondria [45].

Low dose MB also acts as an antioxidant in mitochondria. MB interacts with oxygen to form water, which would decrease the superoxide radicals produced during the process of oxidative phosphorylation. MB can also trap leaking electrons produced by mitochondrial inhibitors and preserve the metabolic rate by bypassing blocked points of electron flow, thus improving mitochondrial respiration [Rojas, 2013].

However, at high concentrations, MB can promote oxidative stress. Therefore, it is expected that low MB doses or concentrations will be, in general, more effective than large ones at facilitating physiological effects within mitochondria. In fact, at high local concentrations, MB can potentially “steal” electrons away from the electron transport chain complexes, disrupting the redox balance and acting as a pro-oxidant. This is thought to a result of excess electrons saturating the electron transport chain, producing reactive oxygen species (ROS) [12].

In a rat model of cerebral ischemia, MB was able to speed up the removal of damaged mitochondria from a cell prior to cell death (mitophagy) [6].

MB is also capable of reducing the mitochondrial damaging effects of amyloid beta in animal models [7].

Clinical Use

1) Methemoglobinemia

Methemoglobinemia is a blood disorder where an abnormal amount of methemoglobin is produced. Methemoglobin is an oxidized type of hemoglobin (carries oxygen throughout the body) that does not release oxygen efficiently [8].

This condition can cause troublesome symptoms like blue skin, shortness of breath, weakness, headache, and psychological changes. Severe, untreated cases can cause changes in heart rhythm, coma, and death [9].

Methylene blue (MB) binds to methemoglobin and converts it to a more efficient form, thereby improving the symptoms of methemoglobinemia [Umbreit, 2007].

A doctor may administer methylene blue intravenously to patients with methemoglobinemia. Do not under any circumstances attempt this treatment yourself. If you have symptoms of methemoglobinemia, seek medical attention immediately.

Other Uses (Likely Effective)

2) Septic Shock

During septic shock, blood pressure can drop dangerously low. Methylene blue has been found to restore blood pressure and heart function during these dangerous episodes. While methylene blue may prevent hypotension on its own, some researchers believe that it is most promising as a complement to other medications used to treat septic shock [111213].

The evidence for methylene blue’s effectiveness against the hypotension and heart problems associated with septic shock is quite strong. However, it has not been approved by the FDA for this purpose, and clinical trials are still ongoing [14].

3) Antimicrobial Action

Methylene blue (MB) was first used in 1891 to treat malaria, and it is considered safe and effective. Current studies have been investigating whether MB treatment alongside other antiparasitic drugs could prevent the parasites from developing drug resistance [15].

Photodynamic therapy using the light-activated antimicrobial agent, MB kills methicillin-resistant Staphylococcus aureus (MRSA) in superficial and deep excisional wounds [12].

MB in combination with light also inactivates viral nucleic acid of hepatitis-C and human immunodeficiency virus (HIV-1) and treats cases of resistant plaque psoriasis [12].

MB is an antifungal agent and may inhibit candida by causing mitochondrial dysfunction in this species [16].

Potential Benefits (Possibly Effective)

Methylene blue has not been approved by the FDA for the purpose of cognitive enhancement, neuroprotection, or any medical purpose other than methemoglobinemia. Despite promising early results, existing clinical studies have not been large or powerful enough to determine effectiveness for any of the potential benefits in this section. Talk to your doctor before attempting to use methylene blue.

4) Neuroprotection

Cognitive Performance

A clinical trial of twenty-six adults was conducted to investigate whether low doses (0.5 – 4.0 mg/kg) of methylene blue (MB) could increase brain activity and improve performance in memory tasks [17].

In this randomized study, low-dose MB increased functional MR imaging activity during sustained attention and short-term memory tasks and potentiated memory retrieval [17].

Compared with control subjects, oral administration MB increased functional MR imaging response during the encoding, maintenance, and retrieval components of a short-term memory task in multiple clusters in the prefrontal, parietal, and occipital cortex. MB was also associated with a 7% increase in correct responses during memory retrieval [17].

In rat hippocampal slices, glutamate-mediated synaptic transmission is abolished by relatively high concentrations (5 – 50 mM) of MB [18].


Methylene blue (MB) has been investigated in people with Alzheimer’s dementia, Some researchers believe that it could affect neurodegeneration via the inhibition of tau protein aggregation and amyloid formation [192021].

Early studies have also begun to investigate methylene blue in models of Parkinson’s and Huntington’s diseases. However, these have not produced clinical evidence so far [2223].


In a 2021 review paper (Xue, 2021), the Potentials of Methylene Blue as an Anti-Aging Drug was discussed. In addition to having antioxidative properties, MB also crosses the BBB easily, making it a promising candidate for treatment. 

However, the results in phase 2 and phase 3 clinical trials are controversial [Lancet, 2016Wilcock, 2018Wischik, 2015].

Studies show that, even with physiological brain aging, MB treatment could still enhance memory by increasing cytochrome oxidase activity and decreasing oxidative stress [RRRRR].


Adult participants displaying marked claustrophobic fear were randomly assigned to double-blind administration of 260 mg of MB or administration of placebo immediately following six 5-minute extinction trials in an enclosed chamber [24].

The study concluded that MB enhances memory and the retention of fear extinction when administered after a successful exposure session but may have a deleterious effect on extinction when administered after an unsuccessful exposure session [24].

It is unclear whether these findings can be repeated in people with other types of phobias. Further clinical trials are needed.

Using Methylene Blue


The FDA has only approved methylene blue for the treatment of methemoglobinemia, and this treatment can only be carried out by a medical professional. There is no safe and effective dose for any other purpose because no sufficiently powerful study has been undertaken to find one. That being said, we can look at the doses which have provided benefits in clinical studies.

Various studies have used between 1 and 4 mg/kg, depending on the source [18].

Most side effects of MB appear to be dose-dependent and have not occurred with doses of less than 2 mg/ kg, a dose range that is widely used in clinical trials [18].

Side Effects

Methylene blue (MB) is contraindicated in patients who have developed hypersensitivity reactions to it and in severe renal insufficiency. It is relatively contraindicated in G6PD deficient patients as it can cause severe hemolysis and also in patients with Heinz body anemia [12].

As mentioned, it should not be taken with an SSRI or serotonin increasing drug, if you’re taking a high dosage [12].

Babies are particularly prone to the adverse effects of MB. It causes hyperbilirubinemia, meth-Hemoglobin formation, hemolytic anemia, respiratory distress, pulmonary edema, phototoxicity and bluish discoloration of tracheal secretions and urine [12].

MB also interferes with the pulse oximeter’s light emission resulting in falsely depressed oxygen saturation reading [12].

It may also cause higher blood pressure [12].

Safety Notes

There are three basic types of methylene blue: industrial, chemical and pharmaceutical-grade.

The only version you’ll want to use medicinally is pharmaceutical-grade. You won’t find methylene blue at your local pharmacy but many compounding pharmacies can obtain the pharmaceutical grade.

Do not ingest methylene blue from the pet store that is meant for fish tanks. Industrial-grade methylene blue has lots of impurities, and typically contain only 10% to 25% methylene blue.

Even pharmaceutical (USP) grade methylene blue may contain impurities such as arsenic, aluminum, cadmium, mercury, and lead. At higher doses, some researchers have warned of the danger of these contaminants accumulating in the patient’s tissues [Rojas, 2012].

Industrial-grade and chemical-grade MB sold as a dye or stain can consist of more than 8% or 11% of various contaminants (NTP, 2008, Sigma Chemical Co, St. Louis, MO) and should not be administered to humans or animals [Rojas, 2012].

For example, commercial chemical suppliers routinely warn that their non-USP MB products are of a chemical grade not suitable for use in living applications [Rojas, 2012as it typically has heavy metal contaminants like lead, cadmium and arsenic.

When combined with rivastigmine, a cholinesterase inhibitor, the effect of MB was potentiated. To avoid unexpected interactions, talk to your doctor before using methylene blue [Oz, 2009].

How do I find a compounding pharmacy in US?

There are a few ways to locate a compounding pharmacy in your local area.

First, ask your healthcare provider if they have any that they prefer to use. They may be able to direct you to a compounding pharmacy that they’ve worked with in the past or like to use. They may also refer you to a compounding pharmacy that specializes in a certain area.

Another way is by utilizing the Alliance for Pharmacy Compounding’s website. Enter your city and state, and their directory will point you to nearby compounding pharmacies.

You can also find a compounding pharmacy by using the Professional Compounding Centers of America’s website. Enter your zip code or your city and state to find one.

And remember, your local community pharmacy may be able to compound your medication. If you’re unsure, ask your pharmacist.

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