Methylene blue is used as a cognitive and mitochondrial enhancer. It also has several other beneficial effects that have come to light over the last decade. Read on to learn how methylene blue can benefit you and which type is the best to use.

What is Methylene Blue?

Methylene blue (MB), also known as methylthioninium chloride, is a bioactive substance and dye.

Its benefits span across several important aspects of cellular function. They include improved mitochondrial function, decreased amyloid and tau protein formation, as well as monoamine oxidase (MAO), nitric oxide (NO) synthase, and guanylate cyclase inhibition [1, 2].

Methylene Blue Snapshot

PROs
  • Improves mitochondrial function
  • Improves memory consolidation
  • Protects the brain
  • Enhances Mood
  • Anti-cancer
  • Anti-microbial
CONs
  • Possible negative impact on the gut microbiome at large doses
  • Should be used with caution in those taking monoamine oxidase inhibitors (MAOIs)
  • Can cause higher blood pressure, so caution is advised in those with high blood pressure
  • Poor tasting

Benefits of Methylene Blue

1) Improves Mitochondrial Function

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 [1].

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 [4, 5].

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 [1].

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) [1, 2].

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].

2) Improves Cognitive Performance in Healthy People

A clinical trial of twenty-six subjects (age range, 22-62 years) was conducted on “low dose” methylene blue (MB) [8].

In this randomized study, “low-dose” MB increased functional MR imaging activity during sustained attention and short-term memory tasks and potentiated memory retrieval. Compared with control subjects, oral administration of “low-dose” 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 [8].

The insular cortex is important for sustained attention and administration of MB increased response (more brain activity) in the bilateral insular cortex during a psychomotor vigilance task and functional MR imaging response during a short-term memory task involving the prefrontal, parietal, and occipital cortex. MB was also associated with a 7% increase in correct responses during memory retrieval [8].

MB has also been shown to support memory consolidation and be neuroprotective with a portion of the cognitive-enhancing effects being mediated through improvements in mitochondrial function [3].

In rat hippocampal slices, glutamate-mediated synaptic transmission is abolished by relatively high concentrations (5 – 50 mM) of MB [9].

On the other hand, MB is known to enhance memory retention and other brain functions in which ionotropic glutamate receptors are involved. It is possible that MB benefits cognitive function by modulating AMPA/kainate and NMDA-type ionotropic glutamate receptors [9].

3) May Help in Alzheimer’s, Dementia, Parkinson’s and Huntington’s

Methylene blue (MB) has been investigated for the treatment of Alzheimer’s dementia and is proposed to affect neurodegeneration via the inhibition of tau protein aggregation and decreasing amyloid formation [10, 11, 12].

It also may help Alzheimer’s by increasing acetylcholine (via acetylcholinesterase inhibition) [13].

By acting as an electron carrier and mitochondrial enhancer, MB also has promise in treating Parkinson’s disease [14].

MB helps Huntington’s by increasing autophagy and activating AMPK [15].

4) Anti-Depressant Activity

Methylene Blue (MB) is a potent monoamine oxidase inhibitor (MAOI) [16].

MB inhibits MAO-A more than MAO-B, but it inhibits both at large doses, therefore caution would be advised when taking MB as an MAOI. At doses exceeding 5 mg/kg, it may cause serious serotonin toxicity/serotonin syndrome, if combined with any SSRIs or other serotonin reuptake inhibitor [16, 17].

5) May Be Anti-Cancer

Methylene blue (MB) appears to induce selective cancer cell apoptosis by the NQO1-dependent generation of cellular oxidative stress [18].

6) Increases Blood Pressure

In diseased states, blood pressure often drops too low.

Methylene blue (MB), an inhibitor of nitric oxide synthase and guanylate cyclase has been found to improve the hypotension associated with various clinical states [19, 20].

7) Is Antimicrobial

Methylene blue (MB) was first used in 1891 to treat malaria [21].

Photodynamic therapy using the light-activated antimicrobial agent, MB kills methicillin-resistant Staphylococcus aureus (MRSA) in superficial and deep excisional wounds [20].

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 [20].

MB is an antifungal agent and can inhibit candida by causing mitochondrial dysfunction in this species [22].

8) Can Extinguish Fear

Preclinical studies have shown that low-dose methylene blue (MB) increases memory retention after learning tasks, including fear extinction [23].

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 [23].

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 [23].

9) Can Slow Skin Aging

A study showed MB to be an effective antioxidant in connective tissue cells. This was true whether the cells were taken from healthy donors or from patients with a premature aging disease [24].

MB was more effective at building connective tissue and delaying cell death than other common mitochondrial-targeting antioxidants [24].

MB treatment changed the expression of some of the proteins in the skin. For example, the expression of elastin and collagen, essential elements of healthy skin, was increased [24].

10) Improves 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 [25].

Methylene blue (MB) improves methemoglobinemia by decreasing the amount of methemoglobin in the body [26].

Utilizing Methylene Blue

Methylene Blue Dosage

MB has wildly different effects depending on the dose. In the milligram doses, it shows some MAOI properties and can kill certain infections.

In the microgram doses, however, it acts via hormetic mechanisms and likely won’t kill an infection or have MAOI properties.

My Experience

Methylene blue definitely has an effect and I’ve subjectively noticed that it does so by increasing mitochondrial function, as it’s supposed to.

After lots of experimentation with mitochondrial enhancers, you begin to know what mitochondrial enhancement feels like. Anyway, I find it’s a great antidepressant and a nice tool for enhancement over the long term.

I take it once a day and I cycle with other mitochondrial enhancers. I end up taking it about 3 – 4 X a week because I have many other mitochondrial enhancers in my toolkit.

Instructions for Preparing a Solution

Safe Dosage

The recommended safe dose appears to be between 1 and 4 mg/kg, depending on the source [9].

Most side effects of MB appear to be dose-dependent and do not occur with doses < 2 mg/ kg, a dose range that is widely used in the clinical applications of MB [9].

In in vitro studies, MB demonstrates biological actions at a wide range of concentrations, from 0.1 nM to 10 mM, and toxic effects have only been reported at concentrations higher than 100 mM [9].

Furthermore, when combined with rivastigmine, a cholinesterase inhibitor, the effect of MB was potentiated [9].

For nootropic and everyday health uses, people often take 1-5mg/day.

Joe personally takes much lower dosages of methylene blue – about 100 mcg/day.

Side Effects of Methylene Blue

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 [20].

As mentioned, it should not be taken with an SSRI or serotonin increasing drug, if you’re taking a high dosage [20].

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 [20].

MB also interferes with the pulse oximeter’s light emission resulting in falsely depressed oxygen saturation reading [20].

It can cause higher blood pressure [20].

Caution When Buying

It is important to note that even pharmaceutical (USP) grade methylene blue may contain impurities, such as arsenic, aluminum, cadmium, mercury, and lead [3].

At low doses, the presence of contaminants is not of great concern, but at higher doses, non-specific effects due to the accumulation of various toxic and other bioactive substances are possible [3].

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 [3].

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 [3].

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