Methylene Blue - a wonder nootropic with strong longevity benefits?

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Disclaimer - not medical advise

This article is based on my research of information from publicly available sources and my personal experience. The information, opinions, and references provided in this article are for informational purposes only. This article does not endorse any products. This article is not a medical advise and is not intended to treat, diagnose or prescribe for any illness or condition. Under no circumstances should you attempt self-diagnosis or treatment based on anything you have seen or read in this article.  Please consult your doctor or healthcare provider for your specific diagnosis and treatment.

What is methylene blue?

Methylene blue has been around in the medicinal use for over 120 years:

• Antiviral & antibacterial: During the late 19th and early 20th centuries against, it was used as malaria treatment. It is used as a treatment for urinary tract infections (most of which are caused by bacteria rather than viruses). Relevant today: it is being studied in relation to SARS-CoV-2 (it may have a role in the treatment of COVID-19 and in combination with red light, it has been shown to inactivate the virus on N95 respirators and masks).
• Neurodegenerative disorders: It is currently being studied as a potential therapy for a variety of neurodegenerative disorders including mild cognitive impairment, Alzheimer’s disease, Parkinson’s disease, Huntignton’s disease and others. All of them share a common problem - mitochondrial function impairment.

That’s a nice spiel but unless you have a genetic mutation which predisposes you to a neurodegenerative disorder (such a double copy of Apoe4 gene which increases risk of Alzheimer’s disease by 10-fold), you probably don’t care that much about neurodegenerative disease prevention.

I certainly do care about minimizing my risks of neurodegenerative disorders (one of the top-5 killers) that’s why methylene blue has been on my radar.  But I also don’t like to take things for granted and prefer to dive deeper myself. The good news is that methylene blue is a potent nootropic (disclosure: this article is written with a healthy dose of methylene blue).

How does methylene blue work?

Methylene blue acts by enhancing the mitochondrial function in the brain:

• First of all, it preferentially enters neuronal mitochondria as opposed to mitochondria of other cell types and has a high (~73%) bioavailability.
• Secondly, at low doses it has a unique auto oxidizing redox chemical property - it can both donate and accept electrons. This supercharges your mitochondria increasing oxygen consumption, ATP (energy) production, and the NAD+/NADH ratio.

Methylene blue has a hormetic response curve - at low doses it produces a beneficial type of stress called hormesis but at high doses it loses its effectiveness. Hormesis is activated via PGC-1a pathway which leads to growth of new mitochondria in a process called mitochondrial biogenesis. Higher density of mitochondria in a cell has been linked with stronger health and longer lifespan. You can read more about mitochondrial biogenesis including PGC-1a pathway in the longevity principle #4.

Why do I like methylene blue?

Methylene blue is different from other nootropics which often work by increasing neurotransmitter synthesis and neural signaling.

Methylene blue improves attention, memory, and concentration by increasing energy production by mitochondria in neurons and improving oxygen delivery.

In two human clinical trials in 2016 and 2017, low dose Methylene blue has been shown to enhance resting-state functional connectivity in brain regions associated with a visuomotor task and linking perception and memory functions.

To say that simply - it connects the left and the right parts of the brain. This makes you both more creative and more logical.

Methylene blue also reduces the activity of the default mode network (DMN). This is a part of the brain that’s most active when we are at rest and least active when we concentrate on a task. So methylene blue reduces the activity of this brain region, thus, helping us concentrate. Modafinil has been shown to have a similar effect.

By reducing the activity of the default mode network, you get into the flow state.

In addition, methylene blue may improve motivation and have antidepressant effects by leading to increased levels of dopamine and serotonin, respectively. It does this by inhibiting the monoamine oxidase A (MOA), responsible for a breakdown of neurotransmitters, and, thus, increasing the levels of neurotransmitters.

Methylene blue benefits are not limited by its nootropic effect. It attenuates neuroinflammation by improving integrity of the blood-brain barrier so that the bad inflammatory compounds from the blood do not enter the brain. It also protects neurons from potential damage caused by mitochondrial dysfunction and oxidative stress.

Long-term, it supports cognitive enhancement by promoting neurogenesis (birth of new neurons) and mitochondrial biogenesis (birth of new mitochondria), delaying cellular senescence (formation of old and dysfunctional cells), and potentially protecting from neurodegenerative diseases of aging.

The bottom line is that methylene blue provides both immediate benefits and long-term benefits.

Immediate benefits of methylene blue:

• Improves working memory and visual and motor coordination by increasing ATP generation by mitochondria in neurons and inhibiting cholinesterase, thus, increasing the amount of acetylcholine.
• Produces antidepressant effects by increasing levels of neurotransmitters (serotonin, dopamine, and melatonin).
• May attenuate neuroinflammation by improving integrity of the blood-brain barrier.
• May protect neurons from potential damage caused by mitochondrial dysfunction and oxidative stress.

Long-term benefits of methylene blue:

• May support long-term cognitive enhancement by promoting neurogenesis (birth of new neurons) and mitochondrial biogenesis (birth of new mitochondria) via hormesis (beneficial type of stress).
• May delay cellular senescence (formation of old and dysfunctional cells) in the brain by improving the activity of the mitochondrial electron transport chain, enhancing cellular oxygen consumption, and increasing heme synthesis.
• May protect from neurodegenerative diseases of aging (such as mild cognitive impairment (MCI), Alzheimer’s disease (AD), Parkinson’s disease) by preventing aggregation of a variety of neurodegenerative proteins, including tau, TDP-43, and huntingtin.

How to take and NOT to take methylene blue?

• Because methylene blue inhibits MAO and increases serotonin level, it should NOT be combined with MAO inhibitors, SSRIs, SNRIs, drugs or supplements that increase serotonin levels (e.g., 5-HTP), or any other psychiatric or neurological medicines to avoid a risk of serotonin syndrome. There is at least one documented case of serotonin syndrome associated with methylene blue (74-year old women on SSRIs who received 100 mg of methylene blue).
• There is no established safe dosage of methylene blue for humans. Based on the animal doses in preclinical trials, a safe human equivalent dose falls between 0.16 to 0.64 mg/kg administered sublingually. This converts to a dose range of 11 to 43 mg for a 150 lbs (68 kg) person. I usually take 20-50 mg per dose. The two clinical trials mentioned above (in 2016 and 2017) which demonstrated nootropic effects of methylene blue used a 280 mg of methylene blue and were tolerated well.
• Metabolic half-life of methylene blue is relative long and range from 5 to 24 hours. This means that methylene blue can have a prolonged effect.

How does methylene blue feel?

If you read methylene blue reviews on reddit, you will notice that many people report limited to no effects from taking methylene blue. That’s likely related to 2 issues:

• Low doses. Below 10 mg, you are unlikely to feel much.
• Expectation of “jittery” concentration. Many people expect nootropics to act like caffeine or nicotine giving them a “jittery” feeling. Methylene blue works differently: it increase energy production by mitochondria in neurons and improves oxygen delivery. Most nootropics often work by increasing neurotransmitter synthesis and neural signaling (such as nicotine which binds to acetylcholine receptors, increases dopamine and endorphin levels, and lead to immediate, but short-lived, euphoria).

I can describe concentration from taking methylene blue as being very smooth (as if you had a long walk and feel refreshed). As mentioned above, my doses range from 20 to 50 mg. Sometimes, I combine it with nicotine for an immediate effect from nicotine and prolonged effect from methylene blue.

Pro-tip: combine red-light therapy with low dose methylene blue to achieve synergistic effects. Both interventions act on Cytochrome c oxidase in mitochondria upregulating mitochondrial respiration.

How to buy and NOT to buy methylene blue + other issues to consider

Buying methylene blue is easy but finding a high quality product is not. Methylene blue has been traditionally used as an industrial dye where high level of impurities (namely, heavy metals) is not an issue. It’s certainly an issue if you plan to put it in your body. Never buy or consume methylene blue unless you’ve seen results of impurity testing or plan to test it yourself.

Generally, there are 3 available forms of methylene blue:

Liquid

Pros:

• Easy to take (you can add in a coffee or a smoothy).
• Easy to buy.

Cons:

• Leaves stains on your hands and dishes which are hard to clean.
• Makes your teeth blue.
• Takes a while (45-60 min) to kick in because it needs to go through the stomach first.

Powder

Pros:

• Will likely leave the least stains if you do it right (e.g., make your own capsules).

Cons:

• Harder to buy.
• Takes a while (45-60 min) to kick in because it needs to go through the stomach first.

Troches

Pros:

• Most convenient to take.
• Kicks in immediately because it is dissolved in the mouth (and, as mentioned above, methylene blue quickly crosses the blood brain barrier).

Cons:

• Expensive ($8 per 16 mg of methylene blue which becomes ~$24 if you want a more effective dose).
• Your tongue will look very blue for a very long time. Not practical for work settings.

As mentioned above, I do not endorse or recommend any products not do I recommend taking methylene blue. But folks might want to know which products I use, so here they are: science.bio for liquid and powder and troscriptions for troches.

My personal candies

Taking a liquid MB is quite impractical due to staining and taking troches is impractical due to high cost (for effective doses), I ended up creating my own recipe.

Step 1. Put these ingredients in a blender:

• Methylene Blue (liquid or powder). 20 mg per candy. MB takes ~30 minutes to start working and the effect feels for several hours (half-life of MB is 5-24 hours).
• Low dose nicotine. 0.5 mg per candy (I put lozenges in a blender). While I prefer to take 1-2 mg if I take nicotine separately, I found that this lower amount is enough for this candy to give a small concentration boost immediately.
• Low-dose caffeine. 20 mg per candy (1/10th of coffee cup). Caffeine at low doses may promote neurogenesis (formation of new neurons) and won’t make you jittery. I use Coffeberry Energy which is a patented formula by Futureceuticals (since I can’t buy the ingredient itself, I use Bulletproof Neuromaster capsules which also contain whole coffee fruit extract which has nootropic properties thanks to chlorogenic acid).
• D-Ribose to boost mitochondria. 2 grams per candy. You can learn more about the importance of D-Ribose for mitochondrial health in the longevity principle #3.
• MCT oil for ketones and to create shape. 5 grams per candy.
• Coconut cream for taste and to create shape. 5 grams per candy.

Step 2. Mix the ingredients in a blender for 60 seconds.

Step 3. Pour the resulting liquid into a candy mold and put in a freezer for 2 hours.

Step 4. Enjoy. I may take up to 3 candies per day.

Final words

Methylene blue is an interesting compound because it provides both immediate benefits and long-term benefits (including prevention or reduction of risks of neurodegenerative disorders; although it’s unlikely to treat neurodegenerative disorders). There are hundreds of studies on methylene blue including clinical trials.

Methylene blue is safe in low doses but should not be taken with drugs that increase serotonin levels (MAO inhibitors, SSRIs, SNRIs, psychedelics, etc.). Impurity with heavy metals is also a concern unless properly tested.

Methylene blue gives a nice concentration boost but, unfortunately, due to its coloring abilities is not practical to take if you take a lot of video calls. Let’s wait on more innovation in this area and hope that someone introduces a convenient form of this product. Though it may take a while - the issue is that a status of methylene blue is a grey area. Methylene blue is actually a drug that is commonly used to treat urinary tract infection and methemoglobinemia. It could be grand fathered by FDA if someone has taken or sold methylene blue prior to 1994 when the Dietary Supplement Health and Education Act has been established. However, it is unlikely that someone can prove that.

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