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Methylene Blue Nootropics Reviews

Methylene Blue as a Nootropic? (Review)

Methylene blue supports mitochondrial respiration and strengthens synaptic connections, which may lead to decreased fatigue and enhanced cognition & recall.

Since its initial synthesis in 1886, the phenothiazine derivative methylene blue (MB) has been established as a highly versatile chemical agent with a diverse span of uses, ranging from treating malaria to dying textiles[1]. Within the past few years, preclinical research has suggested a possible neuroprotective benefit from MB administration. MB is believed to promote neuronal cell health by supporting mitochondrial function. Animal studies have yielded promising results in neurocognitive tests[2][3]. Here is what you need to know if you’re interested in using methylene blue.

How does Methylene Blue work?

Mitochondria are organelles within cells that play the key role of energy production. Cellular energy is stored in the form of adenosine triphosphate (ATP), one of the most important molecules in the cell. As the name suggests, ATP contains three linked phosphate groups. Removal of each group releases a large amount of energy, which is expended in supporting cellular function. Subsequent removal of ATP produces ADP (adenosine diphosphate) & AMP (adenosine monophosphate). ATP is produced within mitochondria as a final product of respiration, a series of biochemical reactions that extract energy from glucose. These biochemical reactions require oxygen & electron carriers (e.g. NADH).

Poteet E, Winters A, Yan L, Shufelt K, Green KN, Simpkins JW, et al. Neuroprotective actions of methylene blue & its derivatives. PLoS One. 2012;7(10):e48279-.
Methylene blue acts as an artificial electron carrier, promoting mitochondrial respiration. The net outcome is more energy available as ATP for cellular processes.[4]
Methylene blue supports mitochondrial respiration by functioning as an additional electron carrier[5]. MB receives electrons from NADH through mitochondrial complex I, itself being reduced to leuco-MB (MBH2). Leuco-MB then donates the electrons to cytochrome C, upon which it is recycled back to MB. These reactions serve to create a high proton (H+) concentration in the space between the inner & outer mitochondrial membranes. This leads to the passage of H+ down the concentration gradient, through mitochondrial complex V. In doing so, ADP & a phosphate (Pi) are joined to form ATP. Leuco-MB can also act as a free radical scavenger, neutralising superoxides by accepting electrons & itself becoming oxidized back to MB[6]. In this way, leuco-MB acts to prevent direct oxidative damage caused by free radicals.

Rojas JC, Bruchey AK, Gonzalez-Lima F. Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue. Prog Neurobiol. 2012 Jan;96(1):32-45.
Methylene blue preferentially accumulates in more active neurones (A), & potentiates mitochondrial & synaptic activity (B). These processes result in increased & improved neurotransmission (C), which is thought to be the mechanism behind the neurocognitive benefits associated with MB.[7]
MB has been observed to preferentially localise in neurones that are more active[3]. Stimulated mitochondria in these neurones modulate genomic expression of proteins that further potentiate mitochondrial respiration via nuclear respiratory transcription factor (NRF-1), resulting in increased expression of cytochrome oxidase (COX), nitric oxide synthase (NOS-1), NMDA receptors, & AMPA receptors. Strengthened synaptic connections as a result of these processes result in improved memory.

The pharmacologic mechanism behind the neuroprotective activity of methylene blue is unique in that it does not involve a receptor-ligand interaction, as do most drugs. In addition, MB also exhibits an atypical dose-response curve– one that has been described as hormetic[8]. Hormesis is a phenomenon where lower doses produce optimum responses while higher doses or exposures may actually produce the opposite effect. Hormesis is an intriguing pattern that may explain the dose-responses associated with exercise & oxidative stress, where the right amount of exercise-induced oxidative stress induces a cascade of favourable physiologic adaptations that can mitigate more severe stressors[9].

Rojas JC, Bruchey AK, Gonzalez-Lima F. Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue. Prog Neurobiol. 2012 Jan;96(1):32-45.
An example hormetic dose-response curve. Note the inverse response caused with higher doses.[10]
As previously mentioned, metabolism of MB involves reduction to leukomethylene blue (MBH2). MB is primarily eliminated in the urine (75%)[11].

What is it like?

I have tested BlueBrainBoost’s formulation with the following results. I have noticed increased energy and decreased fatigue, with an onset of up to 1 hour and duration of 2-4 hours. The only adverse effects were discolouration of the mouth and urine. I used a dosage of 10 mg (20 drops) in the morning sublingually before brushing my teeth. During this time, I was also taking 30 mg/day coluracetam, 500 mg/day ashwagandha, & 600 mg/day NAC. I suspect that coadministration of CoQ10 and creatine may have a synergistic effect based on the pharmacologic site and mechanism of action.

Is it safe?

methylene blue nootropicMethylene blue is associated with a very favourable safety profile. It is generally well-tolerated at doses lower than 2 mg/kg.[12] The most noticeable side effect of MB is blue discolouration of the oral cavity and blue or blue-green discoloration of the urine. These effects are reversible and not harmful. [13] Staining of the teeth can be removed with repeated tooth-brushing, and discolouration of the urine ceases after the drug is fully removed from the system. Other reported adverse effects include a mild headache and dizziness[14].

MB does exhibit some serotonergic activity. This is due to its inhibition of enzymatic degradation of serotonin by MAO-A. Intravenous doses higher than 5 mg/kg have led to the development of serotonin syndrome. This risk is increased in individuals already taking other serotonergic agents (e.g. tianeptine, St. John’s Wort, common antidepressants, dextromethorphan, tramadol). For these reasons, individuals at risk should avoid coadministration of MB with serotonergic agents by at least 2 weeks (or more depending upon the agent), start at low doses, & increase carefully to an effective dose.

Neurotoxicity has been associated with some preparations of MB as a result of chemical impurities. The presence of heavy metals used in the synthesis of MB can have adverse effects on neurones. Thus, only pharmaceutical grade formulations are recommended for human consumption – not lab grade, & not aquarium grade. These formulations may not meet USP standards and may contain up to 11% contaminants.

How should I take it?

Because MB’s role as a neuroprotective agent in humans is still being studied, there is as yet no recommended dosage. The animal doses used in preclinical trials roughly converts to a human equivalent dose of 0.16–0.64 mg/kg administered sublingually. Sublingual administration may produce higher bioavailability than oral administration, but causes more staining of the mouth. I calculated my dose like so:

  1. 0.16 to 0.64 mg/kg × 54.43 kg = 8.71 mg to 34.84 mg per dose
  2. 10 mg/1 mL = 8.71 mg/x mL → 0.87 mL × 20 gtt/1 mL = 17 gtt to 3.5 mL per dose SL (gtt = drops)

It should be noted that due to the hormetic dose-response curve, the response to MB may decrease with higher doses. MB is typically formulated as a 10 mg/mL solution, where 1 drop = 0.05 mL = 0.5 mg. The bottle should be shaken well before administration.

Summary

Overall, I would recommend methylene blue to individuals looking for an inexpensive extra boost in energy. I have not tested MB long enough to notice changes in cognition or memory, but the pre-clinical studies & pharmacologic literature seem to support this benefit.

  • Methylene blue supports mitochondrial respiration & strengthens synaptic connections, which may lead to decreased fatigue and enhanced cognition & recall. MB exhibits a hormetic dose-response curve.
  • The safety profile has been well-characterised, and MB has generally been shown to be well-tolerated. I believe the most important warnings are those concerning serotonin syndrome and chemical impurities.
  • The best-estimated dosage is only an approximation from animal studies. MB is not yet recommended for human consumption for the purpose of improving cognition and memory.
  • Only pharmaceutical grade formulations of MB should be used.
Methylene Blue
7.5
Focus
8
Mood
7.5
Memory
8
Stimulation
5.5
Relaxation
6.5
Safety
Reviewer 8.3
Summary
Methylene Blue improves mood, memory and energy levels, as well as mitochondrial function (and may also delay aging). I think it is a powerful tool to have in your arsenal, and the BBB solution is cheap and convenient, therefore I highly recommend it to anyone.

References   [ + ]

1. Ginimuge PR, Jyothi SD. Methylene blue: revisited. J Anaesthesiol Clin Pharmacol.
2. Callaway NL, Riha PD, Bruchey AK, Munshi Z, Gonzalez-Lima F. Methylene blue improves brain oxidative metabolism & memory retention in rats. Pharmacol. Biochem. Behav. 2004; 77:175–181.
3, 7. Rojas JC, Bruchey AK, Gonzalez-Lima F. Neurometabolic mechanisms for memory enhancement & neuroprotection of methylene blue. Prog Neurobiol. 2012 Jan;96(1):32-45.
4. Poteet E, Winters A, Yan L, Shufelt K, Green KN, Simpkins JW, et al. Neuroprotective actions of methylene blue & its derivatives. PLoS One. 2012;7(10):e48279-.
5. Gonzalez-Lima F, Barksdale BR, Rojas JC. Mitochondrial respiration as a target for neuroprotection & cognitive enhancement. Biochem Pharmacol. 2014 Apr 15;88(4):584-93.
6. Miclescu A, Basu S, Wiklund L. Methylene blue added to a hypertonic-hyperoncotic solution increases short-term survival in experimental cardiac arrest. Crit. Care Med. 2006; 34:2806–2813.
8. Bruchey AK, Gonzalez-Lima F. Behavioral, physiological, and biochemical hormetic responses to the auto-oxidizable dye methylene blue. Am. J. Pharm. & Toxicol. 2008; 3:72–79.
9. Ji LL, Gomez-Cabrera MC, Vina J. Role of free radicals & antioxidant signaling in skeletal muscle health and pathology. Infect Disord Drug Targets. 2009;9(4):428–444.
10. Rojas JC, Bruchey AK, Gonzalez-Lima F. Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue. Prog Neurobiol. 2012 Jan;96(1):32-45.
11. Medscape® 5.1.2, (electronic version). Reuters Health Information, New York, New York.
12, 14. Ginimuge PR, Jyothi SD. Methylene blue: revisited. J Anaesthesiol Clin Pharmacol. 2010 Oct;26(4):517-20.
13. Gillett MJ, Burnett JR. Medications and green urine. Intern Med J. 2006 01;36(1):64-6.

8 replies on “Methylene Blue as a Nootropic? (Review)”

I feel that I must comment on your post. Although the nootropic effect of a common dye like Methylene Blue is certainly interesting, I have the impressing you seem to downplay the risks associated with this compound.

Methylene Blue is certainly not without risk, and in fact can lead to potential life-threatening situations. You have already mentioned serotonin syndrome, but from your description it’s implied that this results only from intravenous injection of a high dose, or the combination of methylene blue with SSRI anti-depressants. You also correctly mention that MB is a MAO-A inhibitor, but don’t underline the strict dietary restrictions that accompagny the prolonged intake of potent MAO-A inhibitors.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2078225/
Br J Pharmacol. 2007 Nov; 152(6): 946–951 confirms methylene blue is a potent reversible inhibitor of MAO A with implications for gut uptake of amines when administered orally. There have been several deaths or near deaths, reported recently where a single dose of a SSRI has been inadvertently added to a MAOI (Otte et al., 2003; Cassens et al., 2006; Zonneveld et al., 2006).

Schwiebert et al (2009), (DOI: 10.1111/j.1365-2044.2009.06029.x) reports that an intraoperative dose of 1mg/kg produced serotonin syndrome in one woman, so at that dose at least definite MAOI activity can be expected. That is 80mg for an average adult, while you stated it is generally well-tolerated at doses lower than 2mg/kg citing a paper from 2008. I realize that there is likely a potency difference between oral and intravenous use, yet as no in vivo data on MAO inhibition is known, but what we have points to MB being a very potent inhibitor, it is likely that doses as low as 10-20mg a day may be sufficient for full MAO-A inhibition.

Methylene blue is a close structural analog of the potent class of phenothiazine anti-psychotics (Thorazine, Haldol, etc…), so the fact that it is psychoactive is not really a surprise.

You combined it with coluracetam, ashwaganda and N-acetylcysteine. Ashwagandha (Withania somnifera) chief constituents are alkaloids, not something you ought to combine with a MAO-A inhibitor, if it is a dry extract. But coluracetam seems much more worrysome. When you look at the molecule, you see they just alkylated piracetam (actually piracet-COOH) with tacrine, so the molecule is so to say “N-tacrinyl-piracetam”. In the original article (PMID: 8740080) the researchers gave it orally to rats and reported their findings: improved learning deficits without tacrine-type adverse effects.

That is fine and dandy in a rat stomach, where the pH is 3-4 and stomach fluids volume low, but I want to bet that in a human with a stomach pH 1-2, which is 100x more acidic, and having comparatively larger volume of stomach digestive fluid, that a lot of hydrolysis of the N-alkylated amide will happen in your stomach. I looked up the rate of hydrolysis of an N-alkylated amide at various pH levels and it confirms my suspicion.

This would mean that the carboxylic acid corresponding to piracetam, and tactrine are formed in the stomach.

Tacrine, which got withdrawn from the market due to toxicity issues, with its bare 4-amino group in combination with a strong MAO-A inhibitor of undefined ED-50… You’re on very thin ice with that one.

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