METHYLENE BLUE

Brain Behav. 2016 May 4;6(7):e00478. doi: 10.1002/brb3.478. eCollection 2016 Jul.

Methylene blue and normobaric hyperoxia combination therapy in experimental ischemic stroke.

Rodriguez P1, Zhao J2, Milman B3, Tiwari YV4, Duong TQ3.

Author information

Abstract

INTRODUCTION:

Ischemic stroke is a global burden that contributes to the disability and mortality of millions of patients. This study aimed to evaluate the efficacy of combined MB (methylene blue) and NBO (normobaric hyperoxia) therapy in experimental ischemic stroke.

METHODS:

Rats with transient (60 min) MCAO (middle cerebral artery occlusion) were treated with: (1) air + vehicle (N = 8), (2) air + MB (N = 8), (3) NBO + vehicle (N = 7), and (4) NBO + MB (N = 9). MB (1 mg/kg) was administered at 30 min, again on days 2, 7, and 14 after stroke. NBO was given during MRI (30-150 min) on day 0, and again 1 h each during MRI on subsequent days. Serial diffusion, perfusion and T2 MRI were performed to evaluate lesion volumes. Foot-fault and cylinder tests were performed to evaluate sensorimotor function.

RESULTS:

The major findings were: (1) NBO + MB therapy showed a greater decrease in infarct volume compared to NBO alone, but similar infarct volume compared to MB alone, (2) NBO + MB therapy accelerated sensorimotor functional recovery compared to NBO or MB alone, (3) Infarct volumes on day 2 did not change significantly from those on day 28 for all four groups, but behavioral function continued to show improved recovery in the NBO + MB group.

CONCLUSIONS:

These findings support the hypothesis that combined NBO + MB further improves functional outcome and reduces infarct volume compared to either treatment alone and these improvements extended up to 28 days.

Introduction to Methylene Blue

https://www.selfhacked.com/blog/methylene-blue-the-cheapest-cognitive-enhancer/?_ga=2.101967304.876108291.1518919069-95750936.1518566885

  • Methylene blue, also known as methylthioninium chloride, is a medication and dye.

  • Methylene blue benefits mitochondria and energy formation, increases cytochrome c oxidase, lowers oxidative stress, lowers amyloid and tau, modulates the glutamate system, and inhibits MAO.

  • Methylene Blue Snapshot

Pros

  • Acts as an antioxidant to mitochondria

  • Improves memory consolidation.

  • Protects the brain.

  • Enhances mood

  • is anti-cancer

  • is anti-microbial

 

Cons

  • Possible negative impact on the gut microbiome at large doses.

  • Should be careful with MAOIs and taking it with lots of sun

  • Can cause higher blood pressure, so people with already high blood pressure should be wary.

  • Doesn’t taste the best.

Benefit Scores:

  • Longevity = 8.0/10

  • Inflammation = 7.0/10

  • Mood = 8.5/10

  • Cognition = 8.5/10

  • Energy = 8.5/10

Benefits of Methylene Blue

1) Methylene Blue is an Anti-Depressant

  • Methylene Blue (MB) is a monoamine oxidase inhibitor (MAOI) (R).

  • MB inhibits MAO-A more than MAO-B, but it inhibits both at large doses (R).

  • At doses exceeding 5 mg/kg, it may cause serious serotonin toxicity/serotonin syndrome, if combined with any SSRIs or other serotonin reuptake inhibitor (R).

2) Methylene Blue is Anti-Cancer

  • Methylene blue appears to induce selective cancer cell apoptosis by the NQO1-dependent generation of cellular oxidative stress (R).

 

3) Methylene Can Help Alzheimer’s, Dementia and Parkinson’s and Huntington’s

  • Methylene blue has been investigated for the treatment of Alzheimer’s dementia (RR2).

  • Methylene blue is proposed to affect neurodegeneration in Alzheimer’s disease via inhibition of tau protein aggregation and amyloids (RR2).

  • It also may help Alzheimer’s by increasing acetylcholine (via acetylcholinesterase inhibition) (R).

  • It also partially repairs impairments in mitochondrial function and cellular metabolism (R).

  • By acting as an electron carrier and mitochondrial enhancer, it has promise in treating Parkinson’s disease (R).

  • Methylene blue helps Huntington’s by increasing autophagy and activating AMPK (R).

  • Methylene blue can alleviate mitochondrial abnormalities in a cellular model of progeria (R).

 

4) Methylene Blue Increases Blood Pressure

  • In diseased states, blood pressure often drops too low.

  • Methylene blue, an inhibitor of nitric oxide synthase and guanylate cyclase has been found to improve the hypotension associated with various clinical states (R).

 

5) Methylene Blue Improves Cognitive Performance in Health People

 

http://journal.frontiersin.org/article/10.3389/fphar.2015.00206/full

  • A randomized, double-blinded, placebo-controlled clinical trial of twenty-six subjects (age range, 22–62 years) was conducted on low dose methylene blue (~280mg, which is actually a high dose in my book) (R).

  • In this randomized study, low-dose methylene blue increased functional MR imaging activity during sustained attention and short-term memory tasks and potentiated memory retrieval (R).

  • Compared with control subjects, oral administration of low-dose methylene blue 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 (R).

  • Administration of methylene blue increased response (more brain activity) in the bilateral insular cortex during a psychomotor vigilance task (Z = 2.9–3.4, P= .01–.008) and functional MR imaging response during a short-term memory task involving the prefrontal, parietal, and occipital cortex (Z = 2.9–4.2, P = .03–.0003). Methylene blue was also associated with a 7% increase in correct responses during memory retrieval (P = .01) (R).

  • The insular cortex is important for sustained attention (R).

  • The study concluded: “Low-dose methylene blue can increase functional MR imaging activity during sustained attention and short-term memory tasks and enhance memory retrieval” (R).

  • Methylene blue has been shown to support memory consolidation and is neuroprotective as well (R).

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

  • 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 (R).

  • Part of the cognitive enhancing effects are mediated by improvements in mitochondrial function.

 

6) Methylene Blue Helps Mitochondrial Function

  • It also has been shown that in low doses methylene blue protects the brain from disease by acting as an antioxidant in the mitochondria. It also acts as an artificial electron donor to complex I-IV of the mitochondria.

  • MB increases heme synthesis, cytochrome c oxidase (complex IV), and mitochondrial respiration (R), all of which help cognitive function.

  • This means that it can increase 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.

  • High concentrations of MB 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 (R).

  • It is well established that reduced MB can donate electrons to coenzyme Qand possibly to cytochrome c, thus increasing cytochrome oxidase (complex IV) activity and oxygen consumption (R).

  • At low concentrations, MB can interact 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 (RR2R3).

  • 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) (R).

  • MB is capable of reducing the mitochondrial damaging effects of amyloid beta in animal models (R).

  • Thus, MB is a potential target for mitochondrial dysfunction (R).

 

  • MB is able to stimulate glucose metabolism in conditions without oxygen (R), and increase NAD+ by mitochondria (R).

  • Some of the outcomes of improved mitochondrial function include increased fat burning (βeta-oxidation) (R), glucose utilization, ATP synthesis and extracellular matrix production (R).

  • In rat models of pancreatitis, Methylene blue reduces mitochondrial dysfunction (R).

7) Methylene Blue is Antimicrobial

  • Methylene blue was first used in 1891 to treat malaria.

  • Photodynamic therapy using the light-activated antimicrobial agent, MB kills methicillin-resistant staphylococcus aureus (MRSA) in superficial and deep excisional wounds (R).

  • 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 (R).

  • MB is an antifungal agent and can inhibit candida by causing mitochondrial dysfunction in this species (R).

8) Methylene Blue Can Extinguish Fear

  • Preclinical studies have shown that low-dose methylene blue increases memory retention after learning tasks, including fear extinction (R).

  • Adult participants displaying marked claustrophobic fear were randomly assigned to double-blind administration of 260 mg of methylene blue (N=23) or administration of placebo (N=19) immediately following six 5-minute extinction trials in an enclosed chamber (R).

  • The study concluded that Methylene blue 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 (R).

9) Methylene Blue Can Slow Skin Aging

  • A very recent 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 (R).

  • MB was more effective at building connective tissue and delaying cell death than other common mitochondrial-targeting antioxidants (R).

  • 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 (R).

Dosage for Different Effects

  • MB has wildly different effects depending on the dose.  In the milligram doses, it shows some MAO-I 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 MAO-I 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 3-4X a week because I have many other mitochondrial enhancers in my toolkit.

 

Instructions for Prepare a Solution

Safe Dosage of Methylene Blue

  • The recommended safe dose appears to be between 1 and 4 mg/kg, depending on the source (R).

  • 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 (R).

  • 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. (R)

  • Furthermore, when combined with rivastigmine, a cholinesterase inhibitor, the effect of MB was potentiated (R).

  • I personally take much lower dosages of methylene blue – about 90 mcg.

 

Contraindications of Methylene Blue

  • Methylene blue 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 (R).

  • As mentioned, it should not be taken with an SSRI or serotonin increasing drug, if you’re taking a high dosage (R).

  • Babies are particularly prone to adverse effects of Methylene blue. It causes hyperbilirubinemia, meth-Hemoglobin formation, hemolytic anemia, respiratory distress, pulmonary edema, phototoxicity and bluish discoloration of tracheal secretions and urine (R).

  • Methylene Blue also interferes with the pulse oximeter’s light emission resulting in falsely depressed oxygen saturation reading (R).

  • It can cause higher blood pressure (R).

 

Caution When Buying

  • It is important to note that even pharmaceutical (USP) grade Methylene Blue contains impurities, such as arsenic, aluminum, cadmium, mercury, and lead (R).

  • 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 bioactive substances are possible (R).

  • 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 (R).

  • 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 (R).

  • For this reason, I only recommend taking a USP grade Methylene Blue Powder or Methylene Blue Solution at low doses.

FDA Compliance

  • The information on this website has not been evaluated by the Food & Drug Administration or any other medical body. We do not aim to diagnose, treat, cure or prevent any illness or disease. Information is shared for educational purposes only. You must consult your doctor before acting on any content on this website, especially if you are pregnant, nursing, taking medication, or have a medical condition.

Brain Behav. 2016 May 4;6(7):e00478. doi: 10.1002/brb3.478. eCollection 2016 Jul.

Methylene blue and normobaric hyperoxia combination therapy in experimental ischemic stroke.

Rodriguez P1, Zhao J2, Milman B3, Tiwari YV4, Duong TQ3.

Author information

Abstract

INTRODUCTION:

Ischemic stroke is a global burden that contributes to the disability and mortality of millions of patients. This study aimed to evaluate the efficacy of combined MB (methylene blue) and NBO (normobaric hyperoxia) therapy in experimental ischemic stroke.

METHODS:

Rats with transient (60 min) MCAO (middle cerebral artery occlusion) were treated with: (1) air + vehicle (N = 8), (2) air + MB (N = 8), (3) NBO + vehicle (N = 7), and (4) NBO + MB (N = 9). MB (1 mg/kg) was administered at 30 min, again on days 2, 7, and 14 after stroke. NBO was given during MRI (30-150 min) on day 0, and again 1 h each during MRI on subsequent days. Serial diffusion, perfusion and T2 MRI were performed to evaluate lesion volumes. Foot-fault and cylinder tests were performed to evaluate sensorimotor function.

RESULTS:

The major findings were: (1) NBO + MB therapy showed a greater decrease in infarct volume compared to NBO alone, but similar infarct volume compared to MB alone, (2) NBO + MB therapy accelerated sensorimotor functional recovery compared to NBO or MB alone, (3) Infarct volumes on day 2 did not change significantly from those on day 28 for all four groups, but behavioral function continued to show improved recovery in the NBO + MB group.

CONCLUSIONS:

These findings support the hypothesis that combined NBO + MB further improves functional outcome and reduces infarct volume compared to either treatment alone and these improvements extended up to 28 days.