+100%-
Reflections in a flask of Methylene Blue

Used to dye fabrics for 150 years methylene blue was also the first synthetically engineered drug used in humans.

There’s a reason that methylene blue (MB) has a kind of space-age, industrial-type sound to it – its first use was as an industrial chemical. Check out the recent citations on the compound and you’ll find more discussions of nanowires, dye removal, and light degradation than of its health-enhancing properties.

For most of its long history (it was created in 1876), methylene blue has better been known for its ability to dye fabrics a rich blue color than anything else. (It’s now touted as an eco-friendly dye due to its easy biodegradability and is even being studied as a possible ecologically friendly energy source.)

Methylene blue is not some mad doctor’s good idea that has grabbed the public’s attention. It’s received quite a bit of study – albeit animal model study – over time and even played a fundamental role in the development of medicine. The first synthetically produced compound to be used as a drug, it’s helped open the door to our modern pharmacology.

It didn’t take long (1891) for methylene blue to be used (effectively in some patients) to treat malaria and it is still being explored as a treatment adjunct. (The fact that it turned the patient’s urine and feces bright blue was a turn-off.) In less picky animals (fish), methylene blue has long been used as an antifungal.

In the 1920s, MB’s use as an antipsychotic helped open the door to the development of antidepressants. Over time, this versatile compound has been used in medicine as a redox indicator, a stain used in medical testing, and is FDA-approved for use to enhance oxygen delivery in a disorder called methemoglobinemia.

Most recently, it’s been touted as a possible anti-aging, mitochondrial boosting, blood vessel enhancing, sepsis busting, anti-oxidant, anti-fungal, and anti-malaria drug.

Unique Mitochondrial Enhancer?

electron transport chain

Methylene blue may be able to enhance activity and protect against damage in the electron transport chain – where ATP is finally made.

Much of the interest in MB recently has evolved around its effects on the mitochondria. One review noted the “remarkable role” MB plays in its ability to stimulate mitochondrial respiration (reportedly by about 30%) and increase cellular oxygen consumption in the electron transport chain.

MB’s mitochondrial abilities lie in its ability to enhance the activity of the last stage of the ATP-making process in the electron transfer chain. The Krebs, or citric acid, cycle ends with the production of two compounds – NADH and FADH2 – that contribute electrons to the electron transport chain, which ultimately produces ATP.

MB is apparently to pick up electrons from NADH at the first part of the chain and quickly shunt them forward to the 3rd part. This potentially allows MB to bypass any damage that might be present in the first three parts of the chain and help the last part of the electron transport chain by increasing electron flows to it.

Fisher found that the last part of the electron transport chain was the one that was most disturbed in ME/CFS.

Emerging Insights #II: “The Cellular Equivalent of Chronic Fatigue” Found in ME/CFS

 

MB has also been shown to stimulate autophagy and reduce neuroinflammation in animal models. Autophagy is a mitochondrial cleanup process that may have gone awry in ME/CFS as well.

Cleaning Crisis? Defective Mitochondrial Cleanup In ME/CFS May Be Impairing Energy Production

Neuroprotective Agent?

The first three parts of the electron transport chain are massive producers of “reactive oxidative species (ROS)”; i.e. oxygenated free radicals including the highly reactive highly reactive peroxynitrite (ONOO−) which can cause extensive damage to the lipids covering our cells. (Martin Pall’s ONOO- hypothesis proposed that peroxynitrite was causing major damage in ME/CFS).

It’s thought that the mitochondrial degradation found in major neurodegenerative diseases such as Alzheimer’s and Parkinson’s Disease and traumatic brain injury probably occurs in the first three stages of the electron transport chain.

One paper suggested that MB’s unique ability to bypass the first three parts of the electron chain – and thus the parts of the chain that produce ROS – might make it a unique neuroprotective agent. Animal studies suggest that MB might be neuroprotective in a variety of neurodegenerative diseases including Parkinson’s, Alzheimer’s disease, and traumatic brain injury.

MB’s neuroprotective properties and its ability to boost serotonin and dopamine levels have also led it to be explored as an antidepressant.

Cognition Enhancer?

Brain helper?

Animal studies suggest MB can help with cognition but few human studies have been done.

A lab culture study suggested that MB can increase cellular oxygen consumption rates and reduce anaerobic glycolysis in neurons potentially giving in neuroprotective properties.

An interesting animal study suggested that MB might be beneficial for conditions involving chronic cerebral hypoperfusion; i.e. conditions associated with chronically low blood flows in the brain which can cause “mild cognitive impairment” – a category of illness that ME/CFS may fit. Another animal study asserted that MB “provides a novel strategy for neuroprotection against both chronic and acute neurological diseases involving mitochondrial dysfunction.” Using both low-level laser therapy and MB improved cognition in sleep-deprived mice.

Note that while five studies over the past year suggest that methylene blue has positive effects in neuroinflammation, cognition, etc., none involved humans and all were lab or animal studies. One small study did suggest it might have modest cognitive benefits.

THE GIST

  • Methylene blue (MB) has a kind of space-age, industrial-type sound to it for a reason – its first use was as an industrial chemical.
  • For most of its long history (it was created in 1876), methylene blue has better been known for its ability to dye fabrics a rich blue color than anything else but it’s not some mad doctor’s good idea. The first synthetically produced compound to be used as a drug, it’s helped open the door to our modern pharmacology.
  • In the 1920s, MB’s use as an antipsychotic helped open the door to the development of antidepressants. Over time, this versatile compound has been used in medicine as a redox indicator, a stain used in medical testing, and is FDA-approved for use to enhance oxygen delivery in a disorder called methemoglobinemia.
  • Most recently, it’s been touted as a possible anti-aging, mitochondrial boosting, blood vessel enhancing, sepsis busting, anti-oxidant, anti-fungal, and anti-malaria drug.
  • This strange compound appears to have unique mitochondrial-enhancing capabilities. One review noted the “remarkable role” MB plays in its ability to stimulate mitochondrial respiration (reportedly by about 30%) and increase cellular oxygen consumption in the electron transport chain. Its ability to reduce the production of free radicals in the mitochondria suggests it may be particularly helpful in neurodegenerative diseases.
  • Animal studies and a few human studies suggest methylene blue or MB may be able to help with cognition, improve energy levels and mood.  While anecdotal reports suggest MB  can help with memory, energy, mental clarity, and sleep, with only a few small human studies available its effects in humans are unclear.
  • Still, MB is not expensive, is readily available, and when purchased from labs that provide certifications of purity and is NOT being used with in conjunction with SSRI antidepressants see blog) it appears to be quite safe. See the end of the blog for dosage.

Nootropicsexperts.com reports that “neurohackers” find MB particularly helps with “after-the-fact learning”; i.e. remembering what you learned and easily using it. They also report experiencing more calmness, putting less focus on negative associations, having more energy, and improved sleep.

Combination Therapy?

One review recommended combining methylene blue with “normobaric hyperoxia treatment”, which involves breathing air with higher than usual levels of oxygen – and is similar, but different, from hyperbaric oxygen therapy which takes place in a pressurized environment. One study found that the combination further reduced neuroinflammation and increased mitochondrial functioning.

Another animal study suggested that using MB with “hypothermia” (cold treatment) improved its ability to reduce neuroinflammation and increase mitochondrial activity and cognition.

Side Effects and Warnings

Methylene Blue appears to be quite safe at the dosages recommended, with one proviso. Because it’s a potent MAO (monamine oxidase) inhibitor that blocks the breakdown of neurotransmitters if used in conjunction with SSRI antidepressants such as Prozac, Zoloft, Paxil, Celexa, Lexapro, and others, it could cause a dangerous condition called serotonin syndrome. Nootropicsexpert.com states serotonin syndrome “becomes a big problem” at about 2 mg/kg. This is not an idle threat – case reports exist in the literature of methylene blue causing this.

Nootropicsexpert.com includes 5-HTP, bupropion, buspirone, citalopram, clomipramine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, MAOIs like Marplan, Nardil, and Parnate, milnacipran, mirtazapine, paroxetine, rasagiline, sertraline, selegiline, St. John’s wort, trazodone, tryptophan, Zimelidine, and venlafaxine in the list of contraindicated drugs for MB.

MB may cause your urine to turn green or blue, may cause mild gut discomfort, which may be alleviated by taking it with food, and may (rarely) cause headaches. Nootropicsexpert.com reports that blue urine will usually occur at “doses roughly exceeding 500 mcg” and that mixing MB with ascorbic acid 3 hours before taking it might help with that.

Using Methylene Blue

Nootropicsexpert.com notes there is no recommended dosage but that the dosage ranges from 0.5 – 4 mg/kg(0.23 – 1.8 mg /lb.) of body weight per day. That would translate to about 360 mg/day for a 200 lb person at the high end – a dose they believe is probably too high. They recommend starting at the low end and then going from there. Note that taking too much MB can be counterproductive because at high doses, it can swipe electrons from the electron transport chain.

Lowest dose per day

  • 100 lbs / 45 kgs = 23 mg/day
  • 150 lb / 68 kgs = 34 mg/day
  • 200 lbs / 90 kgs = 46 mg/day

Because MB has a half-life of five hours, nootropicsexpert.com states it can be taken twice a day. It doesn’t need to be taken with a meal.

Finding Methylene Blue

CTZL Methylene blue

CTZL appears to provide a good source of MB. (Health Rising is not affiliated with CTZL)

Pharmaceutical-grade: because industrial-grade methylene blue can be full of toxic contaminants, you must use only pharmaceutical-grade methylene blue. Nootropicsexpert.com, however, states that even pharmaceutical-grade MB can contain heavy metals (but that they are not a problem at low doses). It recommends using brands such as CZTL Methylene Blue that have an independent, 3rd party Certificate of Analysis which shows the levels of contaminants.

CZTL ships in 1-gram containers of powder and states it provides detailed dosage and mixing instructions in each shipment. A Certificate of Analysis (CofA) that verifies the purity of the Methylene Blue is included in each purchase. Check out an FAQ from CZTL.

With 1 gram of MB costing $30 at CZTL, it appears to be fairly affordable if my numbers are correct (1,000 mg/46 mg/day [100-lb person] = 23-day supply of 2 doses a day at the lowest dose. Buying in larger doses (5 gms – $70) would bring the cost down to .65 cents a day for a 100-lb. person at the lowest dose.

Applying The Arseneau Test

The Arseneau test assesses the factors below to help decide whether or not to try a treatment:

  • The credibility of the source – animal studies and some good blogs – quality is pretty good.
  • Quality of the evidence – lacking. While quite a few lab and animal studies attest to MB’s possible effectiveness as a potential mitochondrial enhancer, neuroprotector, cognition helper, sleep enhancer, etc., only a few small human studies have been done.
  • The benefit, the cost, and the risk–benefit analysis – the benefit appears moderate, the cost is fairly low and the risk appears low (unless using it with SSRIs or other MAO-enhancing drugs or supplements) so long as MB is purchased from an independent, lab-certified source. Once those restrictions have been met, MB looks like a good shot.

Conclusion

Who knew that an industrial chemical (properly processed) might be helpful in diseases like ME/CFS and long COVID? I heard about it when I learned that an ME/CFS expert was recommending that his/her patients try it. Its potential ability to increase mitochondrial activity, protect neurons, tamp down neuroinflammation, and improve cognition and mood makes it an intriguing possibility for disorders like chronic fatigue syndrome (ME/CFS), fibromyalgia, and long COVID which share these issues.

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