Methylene Blue (methylthioninium chloride) is a synthetic compound used as a nootropic to increase memory, mood and longevity.
Soon after Methylene Blue was synthesized as a textile dye in the late 1800’s, it became the first synthetic drug to be used in humans. It was used for the treatment of malaria.
In the early 20th century, psychiatrists were using Methylene Blue in the experimental treatment of schizophrenia.[i]
Methylene Blue is currently being studied as potential therapy for mild cognitive impairment, Alzheimer’s and Parkinson’s disease, and other neurodegenerative disorders. All sharing a common problem with mitochondrial function.
Your brain’s neurons rely almost entirely on mitochondria-derived energy. Failure of mitochondrial function can affect the rest of your body. But it’s particularly detrimental to your brain.
This is where Methylene Blue steps in as possibly one of the most important anti-aging and neurological disease preventing nootropics we have available today.
As a nootropic, Methylene Blue quickly crosses the blood-brain barrier. It improves mitochondrial efficiency and respiration, acts as an antioxidant, and increases brain cell lifespan. Resulting in improved memory and mood.
Here we’ll dive into over 140 years of research on how Methylene Blue helps your brain.
Methylene Blue helps:
- Neurotransmitters: Methylene Blue inhibits monoamine oxidase and acetylcholinesterase activity which increases levels of catecholamines and acetylcholine. And boosts serotonin and norepinephrine affecting anxiety, depression and memory.
- Mitochondrial Energy: Methylene Blue assists brain cell respiration by increasing oxygen. And donating electrons to the electron transport chain within mitochondria. This same process is used to feed mitochondrial ATP when you eat. So MB provides this fuel without you having to eat. Increasing cellular energy positively effects mood and memory.
- Neuroprotectant: Methylene Blue is a potent antioxidant. Reactive oxygen species are produced inside mitochondria. The first free radical that is formed inside a cell is superoxide. MB will bind to superoxide and reduce it to water. It stops the oxidative cascade at its very beginning. Before it gets a chance to do damage.
Methylene Blue (methylthioninium chloride) was first synthesized in 1876 by German chemist Heinrich Caro at BASF as an aniline-based dye for cotton staining.
In 1891, German physician and Noble Prize recipient Paul Ehrlich pioneered the use of Methylene Blue in the treatment of malaria.[ii]
Ehrlich discovered that when MB was injected into animals in the lab, it would quickly concentrate in the brain. And had an uncanny ability to selectively target diseased tissues in the body.
It was Ehrlich who coined the term “Magic Bullet” for this unique action displayed by Methylene Blue. A term still in use today.
Methylene Blue has since been used to treat dementia, cancer chemotherapy, malaria, methemoglobinemia, urinary tract injections, cyanide and carbon monoxide poisoning.[iii]
How does Methylene Blue work in the brain?
Methylene Blue boosts brain health and function in several ways. But two in particular stand out.
- Methylene Blue improves memory. Unlike other nootropics which often work by increasing neurotransmitter synthesis and neural signaling, MB improves memory by increasing brain cell respiration. Or how the brain cell utilizes oxygen.
Studies show dramatic increases of cellular oxygen consumption and glucose uptake when using Methylene Blue. MB increases CMRO2 (cerebral metabolic rate) through increased activity in the mitochondrial electron transport chain.
Methylene Blue also stimulates glucose metabolism. Taken together, increases in CMRO2 and glucose uptake means that MB elevates oxygen consumption which helps glucose increase ATP production.
Increases in ATP production provides more cellular energy for better overall brain function including cognition, mood and memory.
- Methylene Blue is an antioxidant. MB has a unique mechanism of action that is fundamentally different from traditional antioxidants. During cellular respiration, the first free radical formed inside a cell is superoxide (O2).
So think of Methylene Blue as having a unique dual property. First, it increases cellular energy production which normally leads to oxidative stress. And second, it eliminates this oxidative stress. Making it a metabolic enhancer and an antioxidant.
Researchers tested Methylene Blue in animal models of neurological disease. First, researchers used rotenone (a potent pesticide) which causes severe dopamine depletion in the part of the brain associated with Parkinson’s.
Methylene Blue rescued brain cell mitochondria from the damaging effects of this toxin. By donating electrons in the electron transport chain broken by rotenone. Essentially bypassing the broken transport chain with donated electrons as an alternative electron carrier.
Methylene Blue also countered cerebral ischemia reperfusion damage. The tissue damage caused when blood supply returns to tissue after a lack of oxygen. As can occur with Traumatic Brain Injury. MB accomplished this by rerouting mitochondrial electron transfer.
This means that Methylene Blue dramatically countered the behavioral, neurochemical, and neuropathological impairment found in Parkinson’s disease.[vi]
How things go bad
As we live life, our brain chemistry and metabolism changes.
↓ Mitochondrial energy levels decline
↓ Attention, memory and mental agility decline
↓ Tau proteins and amyloid plaques clog the brain
↓ Free radicals damage brain cell mitochondria
↓ Cerebral blood flow declines
All of these changes can happen at any age. And are a product of the food we eat, what we drink, lifestyle habits, the air we breathe and more.
So Methylene Blue can help for age-related cognitive decline, as well as a student looking to do better in school. By boosting brain cell mitochondria energy levels. And improving cerebral blood flow.
Methylene Blue to the rescue
Low dose Methylene Blue supplementation provides memory enhancing effects in animals and humans. It works as an antidepressant, is anti-aging, helps dementia, Huntington’s and Alzheimer’s.
Methylene Blue increases low blood pressure, improves cognition in healthy people, boosts mitochondrial function, is anti-microbial, can eliminate fear and even slow skin aging.
Methylene Blue boosts acetylcholine
Research shows that Methylene Blue is an acetylcholinesterase inhibitor with a preference for muscarinic acetylcholine receptors. Meaning MB prevents the breakdown of acetylcholine and making more available in your brain.[vii]
Methylene Blue is an antidepressant
One study in 1987 showed that 15 mg per day of Methylene Blue was a potent antidepressant in those with severe depression.[ix]
Another study with 31 bipolar disorder patients compared 300 mg per day of Methylene Blue with 15 mg per day. The patients were also on lithium treatment. The study showed that the 300 mg dose of Methylene Blue was a “useful addition to lithium in the long-term treatment of manic-depressive psychosis”. And patients were significantly less depressed.[x]
Methylene Blue resists Alzheimer’s Disease
Alzheimer’s disease and other forms of dementia are associated with a buildup of the protein Tau. Clinical trials show that Methylene Blue inhibits Tau formation. And is under consideration as a treatment for Alzheimer’s.[xi]
Methylene Blue has an inhibitory action on the cGMP pathway, and affects other molecular events closely related to the progression of Alzheimer’s.
Research also shows that cholinergic, serotonergic and glutamatergic systems all play important roles in the development of Alzheimer’s and other cognitive disorders. Methylene Blue provides beneficial effects in mediating these pathways.[xii]
This is particularly significant because most existing treatments for Alzheimer’s can only prevent the disease before it is diagnosed. But Methylene Blue shows promise in delaying the effects of Alzheimer’s and dementia after it is diagnosed.
Methylene Blue is anti-aging
Research shows that Methylene Blue is an effective anti-aging nootropic. MB increases mitochondrial complex IV by 30%, enhances cellular oxygen consumption by 37-70%, increases heme synthesis, and reverses premature senescence caused by H2O2 or cadmium.
Methylene Blue is considered a redox agent. Meaning it cycles between oxidized and reduced forms. This cycling by MB helps block oxidant production in brain cell mitochondria.[xiii]
Mitochondrial complex IV is the last enzyme in the respiratory electron transport chain of mitochondria. The last step in synthesizing ATP. Your cellular and mitochondrial source of energy.
Iron (heme) is an essential element and participates in oxygen transport, DNA synthesis and electron transport. Heme synthesis begins in mitochondria. Every cell requires heme to function properly.[xiv]
Senescence or biological aging is the gradual deterioration of cellular function. And is caused by telomere shortening that triggers DNA damage in response to reactive oxygen species, hydrogen peroxide (H2O2), cadmium and other toxins. Methylene Blue helps prevent premature senescence or premature cell death.
Methylene Blue improves memory
Animal studies have shown that a single low dose of Methylene Blue enhances long-term contextual memory. This type of memory is the conscious recall of the source and circumstances of a specific memory.
Other studies show that Methylene Blue in low doses taken after the event helps memory retention of the event. A study done with rats revealed why this works.
In this study, rats received 1 mg/kg of MB post-training for 3 days. The researchers then measured cytochrome c oxidation in participants brains. The idea was to determine if an increase in metabolic energy was behind the memory enhancing qualities of MB.
The study found that in the Methylene Blue treated group, brain cytochrome oxidase activity was 70% higher than in the placebo-treated group.
The findings suggest that repeated post-training supplementation of Methylene Blue improves memory consolidation. And this memory boost is due to the increased metabolic capacity in brain regions that require more energy during discrimination learning.[xv]
How does Methylene Blue feel?
When reading or studying, once you’re done, you should feel like you fully understand the subject material. And you’ll be able to use what you learned in the future.
Methylene Blue seems to facilitate a full understanding of something on the first try.
Many neurohackers report the biggest nootropic effect they experience with Methylene Blue is “after the fact learning”. You take in the information. And it’s like your brain sorts through the material. Then stores it in a form you can easily access later.
Methylene Blue has this uncanny ability to rewire your brain to forget about any negative associations you have of a situation. And only retains the positive aspects of that memory.
Some report that Methylene Blue makes you “feel young again”. It eliminates social anxiety. You’ll feel focused and more confident.
Workouts seem easier because you have more energy. Your mitochondria are energized. And you may find that recovery from workouts is easier.
Methylene Blue helps eliminate stress. So you have more energy in any situation with a relaxed state of mind.
And one recurring theme from many is improved sleep while using Methylene Blue.
Research into Methylene Blue for its therapeutic value goes back to the late 1800’s. But it’s only in the last couple of decades that scientists have been able to decode exactly how Methylene Blue works in the brain. All the way down to the molecular level in mitochondria.
A study in 2017 found that Alzheimer’s Disease could be caused by more than the accumulation of amyloid beta in the brain. The scientists looked into the two main components that produce energy in cells.
- Glycolysis is the mechanism used to convert glucose into fuel for consumption by mitochondria.
- Burning this fuel in mitochondria uses oxygen in a process called mitochondrial respiration.
The researchers found that as the brain ages, mitochondrial metabolism deteriorates. Resulting in a reduction in the molecules needed for energy production. And possibly the main culprit behind many neurological diseases including Alzheimer’s and Parkinson’s.[xvi]
A study conducted at Children’s Hospital Oakland Research Institute may have found the solution to this mitochondrial energy problem in brain cells.
The researchers found that Methylene Blue can prevent or slow the decline of mitochondrial function.
One of the key aspects of Alzheimer’s is mitochondrial dysfunction. Specifically complex IV dysfunction. And this is where Methylene Blue steps in.
The study found that Methylene Blue enhances complex IV in mitochondria. It increases oxygen consumption. And it reverses premature cell death.
The researchers concluded that Methylene Blue may be useful to delay mitochondrial dysfunction with aging and the decrease in complex IV in Alzheimer’s disease.[xvii]
Methylene Blue Improves Memory
26 healthy volunteers aged 22 – 62 participated in a double-blind, randomized, placebo-controlled clinical trial. Purpose of the study was to measure the effects of Methylene Blue on working memory and sustained attention.
Study results showed that a single low-dose of Methylene Blue resulted in an increase in short-term memory ability. In an area of the brain associated with the senses and visual processing.
Timothy Duong, Ph.D., the study author concluded Methylene Blue showed promise “in healthy aging, cognitive impairment, dementia and other conditions that might benefit from drug-induced memory enhancement”.[xviii]
Another study published in the American Journal of Psychiatry tested fear extinction (elimination of fear) and contextual memory. Both are forms of long-term memory.
In this study, participants received either Methylene Blue or a placebo after being placed in a small dark chamber for a couple of minutes to address their fear.
One month later, participants that had used Methylene Blue had less retained fear than those given a placebo. The study authors concluded, “Methylene Blue enhances memory and the retention of fear extinction”.[xix]
Methylene Blue helps Bipolar Disorder
A study at Dalhousie University in Halifax compared the effectiveness of lamotrigine (Lamictal®) along with daily supplementation of either 195 mg or 15 mg of Methylene Blue in patients with bipolar disorder.
Patients took a dose (Lamictal and either 195 mg or 15 mg of Methylene Blue) for three months. Then switched to the other dose for 3 months. The team found that bipolar participants had reduced depression and anxiety when taking the higher dose of Methylene Blue compared to when they were on the lower dose.
Several bipolar disorder patients in the study chose to continue using Methylene Blue after the study concluded.[xx]
Recommended safe doses based on clinical studies with animals and humans ranges from 0.5 – 4 mg/kg. So a 90 kg (200 lb.) body weight translates to 45 – 360 mg of Methylene Blue.
The bottom line is there is no true recommended dose for Methylene Blue. My recommendation is start with the lowest dose of 0.5 mg/kg and see how you react.
Methylene Blue is water-soluble so you don’t need to take it with a meal, or healthy fat like some nootropics.
Methylene Blue has a half-life of about 5 hours. So you can dose twice a day.
Methylene Blue is famous for turning urine blue. But for most neurohackers, your urine will only stain blue at doses roughly exceeding 500 mcg. Some recommend preventing blue urine by mixing Methylene Blue with ascorbic acid for 3 hours before taking it.
Methylene Blue is also available as a doctor-administered injection for therapeutic use. Typically used to treat diseases like malaria or with anti-cancer therapy.
Methylene Blue shows a hormetic dose-response, with opposite effects at low and high doses.
In other words, lower doses of Methylene Blue work well as a nootropic. But high doses do not because MB can potentially “steal” electrons away from the electron transport chain. Disrupting the redox balance and acting as a pro-oxidant (instead of an antioxidant).[xxi]
At low doses, these contaminants are not that big of a problem. But higher doses will result in the accumulation of these toxins in your cells.
Side effects with Methylene Blue are rare when doses are under 2 mg/kg. But can include stomach pain, chest pain, dizziness, headache, sweating, confusion, high blood pressure, shortness of breath, accelerated heartbeat, tremor, skin turning blue, urine turning blue or green, reduction of red blood cells, or jaundice (only reported in infants).
Monoamine Oxidase (MAOI) inhibition becomes a big problem at around 2 mg/kg of Methylene Blue. So if you are using antidepressants or antianxiety medications that affect serotonin, you should NOT use Methylene Blue. Because using Methylene Blue with one of these medications could cause Serotonin Syndrome.
This includes SSRI’s and MAOI’s such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, zimelidine, bupropion, buspirone, clomipramine, mirtazapine and venlafaxine.
Do not use Methylene Blue if you are pregnant or breast-feeding.
Methylene Blue is sold as a liquid, and in crystalline powder form.
Industrial-grade and chemical-grade Methylene Blue is sold as a dye or stain. And can consist of more than 8% – 11% of various contaminants. And should NOT be used as a nootropic.
Only pharmaceutical (USP) grade Methylene Blue should be used as a nootropic. Ask for a Certificate of Analysis which should include the amount of contaminants such as arsenic, aluminum, cadmium, mercury and lead.
Nootropics Expert Recommendation
We recommend using Methylene Blue as a nootropic supplement.
Your body does not make Methylene Blue on its own. So to get its benefits you must take it as a supplement.
Methylene Blue is especially helpful for those dealing with anxiety and depression.
Methylene Blue is a fast-acting nootropic that can also help prevent brain mitochondrial degeneration. Providing potential as an anti-aging nootropic.
Methylene Blue donates electrons in the electron transport chain in your mitochondria. So experienced neurohackers suggest avoiding CoQ-10 or idebenone when using MB because it seems to make Methylene Blue much less effective.
Idebenone is an Alzheimer’s drug that has some nootropic benefit. But it works similar to Methylene Blue because it acts as a transporter in the electron transport chain of mitochondria. Competing with Methylene Blue.
[i] Allexsaht W.J. “The use of methylene blue in the treatment of catatonic dementia praecox patients.” Psychiatric Quarterly. 1938;12:245–252.
[ii] Schirmer R.H., Coulibaly B., Stich A., Scheiwein M., Merkle H., Eubel J., Becker K., Becher H., Müller O., Zich T., Schiek W., Kouyaté B. “Methylene blue as an antimalarial agent.” Redox Report. 2003;8(5):272-5. (source)
[iv] Wen Y., Li W., Poteet E.C., Xie L., Tan C., Yan L.J., Ju X., Liu R., Qian H., Marvin M.A., Goldberg M.S., She H., Mao Z., Simpkins J.W., Yang S.H. “Alternative mitochondrial electron transfer as a novel strategy for neuroprotection.” Journal of Biological Chemistry. 2011 May 6; 286(18):16504-15. (source)
[vi] Wen Y., Li W., Poteet E.C., Xie L., Tan C., Yan L.J., Ju X., Liu R., Qian H., Marvin M.A., Goldberg M.S., She H., Mao Z., Simpkins J.W., Yang S.H. “Alternative mitochondrial electron transfer as a novel strategy for neuroprotection.” Journal of Biological Chemistry. 2011 May 6; 286(18):16504-15. (source)
[viii] Ramsay R.R., Dunford C., Gillman P.K. “Methylene blue and serotonin toxicity: inhibition of monoamine oxidase A (MAO A) confirms a theoretical prediction.” British Journal of Pharmacology. 2007 Nov;152(6):946-51 (source)
[x] Naylor G.J., Martin B., Hopwood S.E., Watson Y. “A two-year double-blind crossover trial of the prophylactic effect of methylene blue in manic-depressive psychosis.” Biological Psychiatry. 1986 Aug;21(10):915-20. (source)
[xi] Crowe A., James M.J., Lee V.M., Smith A.B. 3rd, Trojanowski J.Q., Ballatore C., Brunden K.R. “Aminothienopyridazines and methylene blue affect Tau fibrillization via cysteine oxidation.” Journal of Biological Chemistry. 2013 Apr 19;288(16):11024-37 (source)
[xiii] Atamna H., Nguyen A., Schultz C., Boyle K., Newberry J., Kato H., Ames B.N. “Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways.” FASEB Journal. 2008 Mar;22(3):703-12. (source)
[xvi] Sonntag K.C., Ryu W., Amirault K.M., Healy R.A., Siegel A.J., McPhie D.L., Forester B., Cohen B.M. “Late-onset Alzheimer’s disease is associated with inherent changes in bioenergetics profiles” Scientific Reports 2017; 7 (source)
[xvii] Atamna H., Nguyen A., Schultz C., Boyle K., Newberry J., Kato H., Ames B.N. “Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways.” FASEB Journal. 2008 Mar;22(3):703-12 (source)
[xviii] Rodriguez P., Zhou W., Barrett D.W., Altmeyer W., Gutierrez J.E., Li J., Lancaster J.L., Gonzalez-Lima F., Duong T.Q. “Multimodal Randomized Functional MR Imaging of the Effects of Methylene Blue in the Human Brain.” Radiology. 2016 Nov;281(2):516-526. (source)
[xix] Telch M.J., BRuchey A.K., Rosenfield D., Cobb A.R., Smits J., Pahl S., Gonzalez-Lima F. “Effects of Post-Session Administration of Methylene Blue on Fear Extinction and Contextual Memory in Adults With Claustrophobia” American Journal of Psychiatry Volume 171, Issue 10, October 2014, pp. 1091-1098 (source)
[xx] Alda M., McKinnon M., Blagdon R., Garnham J., MacLellan S., O'Donovan C., Hajek T., Nair C., Dursun S., MacQueen G. “Methylene blue treatment for residual symptoms of bipolar disorder: randomised crossover study.” British Journal of Psychiatry. 2017 Jan;210(1):54-60 (source)