Fix Your Gut Ultimate Guide To Methylene Blue

Methylene blue supplementation is all the rage now thanks to Robert F. Kennedy Junior, Alex Jones, and Joe Rogan, but can it improve your health? Methylene blue is a synthetic dark blue dye discovered in 1876 by German chemist Heinrich Caro. Initially intended for textiles and histology, it has since been repurposed for medicinal applications. Methylene blue is used to treat methemoglobinemia, chemotherapy medication ifosfamide toxicity, cyanide poisoning, neuropsychiatric disorders (including bipolar disorder, depression, and schizophrenia as a potent monoamine oxidase inhibitor), Alzheimer’s disease, and malaria. In alternative medicine, it is believed to enhance mitochondrial function and health and is even claimed to have cancer-curing properties. Methylene blue can be administered intravenously and orally, with an oral bioavailability of about seventy percent when in an aqueous suspension. The question arises: should methylene blue be used to enhance your mitochondrial health, or should it only be used by prescription for specific treatment protocols?[1] [2] [3] [4] [5] [6]

Methylene blue is approved by the United States Food and Drug Administration (FDA) for treating methemoglobinemia. In this condition, the iron within hemoglobin (Fe2+) is oxidized to its ferric form (Fe3+), which reduces the oxygen-carrying capacity of hemoglobin. Hemoglobin is a protein within your red blood cells that transports oxygen from your lungs throughout your bloodstream and carbon dioxide back to your lungs to be exhaled. Methemoglobinemia typically presents with symptoms such as cyanosis (a bluish discoloration) of our lips, nail beds, tongue, and limbs, dark-colored urine, fatigue (sometimes severe), tachycardia, rapid breathing, slurred speech, confusion, weakness, seizures, headache, and hypoxia (low oxygen levels within our body). The primary action of methylene blue in the treatment of methemoglobinemia is to reduce the oxidized Fe3+ form of hemoglobin back to the ferrous form (Fe2+) as an antioxidant; this conversion restores the oxygen-binding capacity of hemoglobin, thereby increasing oxygen delivery back to our tissues. Additionally, intravenous buffered vitamin C is another treatment option for methemoglobinemia, and it can also reduce oxidized hemoglobin as an antioxidant.[7] [8] [9]

Conditions in Which You Might Want to Supplement [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25]

Alzheimer’s Disease
Brain fog
Burns
Cancer
Cardiovascular disease (high blood pressure, cardiomyopathy, myocardial infarction, vasoplegic syndrome)
Cerebral vascular disease (encephalopathy, stroke, traumatic brain injury edema)
Chronic fatigue syndrome
Chronic pain
Covid infection, Covid vaccine injury recovery, and Covid post viral syndrome (long Covid)
Dementia
Dysbiosis
High blood pressure – low doses might lower elevated blood pressure.
Low blood pressure (below 90/60 mm Hg) – higher doses might be needed to raise blood pressure.
Malaria
Methemoglobinemia
Migraines
Neuropsychiatric disorders (including bipolar disorder, depression, and schizophrenia)
NNEMF sensitivity – methylene blue’s inhibition of nitric oxide synthase may prevent excessive nitric oxide release triggered by nnEMF-induced calcium dysregulation, thereby preserving mitochondrial membrane potential and preventing apoptotic signaling.
Optic neuropathy
Parkinson’s Disease
Photosensitivity – if sunlight exposure causes you to get sunburn more easily.
Psoriasis
Septic shock

How Proper Supplementation Might Help Improve Mitochondrial Function

Methylene blue has a strong affinity for our mitochondria. Its hydrophilic/lipophilic properties and positive charge contribute to its accumulation within these organelles, driven by our mitochondrial membrane potential. Once inside our mitochondria, methylene blue is predominantly retained and can interact with nucleic acids, proteins, and lipids, thereby modulating their functions. Methylene blue acts as a redox cycling agent, meaning it can accept and donate electrons within our mitochondrial electron transport chain, functioning as an “electron shuttle.” Methylene blue accepts electrons from Complex I and donates them to Complex IV, effectively “moving” electrons down our mitochondria’s electron transport chain and increasing the activity of Complex IV. Methylene blue’s unique redox cycling capability allows it to donate electrons directly to cytochrome c, bypassing complex II and III. This process enhances mitochondrial adenosine triphosphate (ATP) production and improves the efficiency of the electron transport chain, reducing mitochondrial oxide generation. Please refer to chapter one for more information about how mitochondria produce energy.[26] [27] [28]

Our mitochondria are the primary sites for generating reactive oxygen species (ROS) and reactive nitrogen species (RNS), which can create oxidative stress and lead to poor mitochondrial health and cell death. Complex I and Complex III are the main areas where electron leakage occurs within our mitochondrial transport chain. The electrons that leak from Complex I and Complex III are transferred to oxygen (O2), forming superoxide radicals (O2•). This excess of reactive oxygen species primarily damages Complex I and Complex IV by oxidizing iron, which contributes to further mitochondrial dysfunction and can even damage mitochondrial DNA. Methylene blue is an “electron shuttle” that bypasses Complex I and Complex III, effectively reducing electron leakage and the formation of reactive oxygen species. This action leads to anti-inflammatory effects. The immune modulation effects that help reduce inflammation include inhibition of caspase-6 activity, restoration of Plasma Membrane Ca2+-ATPase pump function, reduction of pro-inflammatory cytokines through the Phosphoinositide 3-Kinase/Protein Kinase B/Glycogen Synthase Kinase 3 betapathway, attenuation of brain synaptic toxicity, and inhibition of Microtubule Affinity-Regulating Kinase 4/ Partitioning defective 1-mediated tau phosphorylation. Additionally, methylene blue activates the Nuclear factor erythroid 2-related factor 2/antioxidant responsive element signaling pathway and induces the Myocyte Enhancer Factor 2D protein-associated survival pathway, reducing and relieving inflammation.[29] [30] [31]

Methylene blue has a unique pharmacokinetic profile that allows it to effectively cross our blood-brain barrier (BBB), providing direct access to our central nervous system (CNS). Its amphipathic nature and lipophilicity enable it to passively diffuse through our BBB, where it accumulates in our neuronal mitochondria, attracted by their high membrane potential and metabolic activity. Methylene blue enhances mitochondrial respiration through increased redox cycling while also reducing electron leakage and the subsequent production of reactive oxygen species within our brain, which are significant contributors to neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Additionally, methylene blue exhibits neuroprotective properties by stabilizing mitochondrial membrane potential, inhibiting nitric oxide synthase (thereby decreasing the formation of nitrogen reactive species within our mitochondria), and modulating neuroinflammatory pathways. These combined effects help to preserve neuronal integrity and function.[32] [33]

Methylene blue has been shown to alleviate mitochondrial dysfunction induced by non-native electromagnetic fields (nnEMFs), primarily by modulating calcium homeostasis. nnEMFs disrupt mitochondrial function by affecting voltage-gated calcium channels and destabilizing the electrochemical gradients across mitochondrial membranes. This disruption leads to excessive intracellular calcium influx and impaired oxidative phosphorylation. Methylene blue counteracts these effects by stabilizing the mitochondrial membrane potential and inhibiting nitric oxide synthase (NOS). This inhibition reduces the overproduction of nitric oxide and the subsequent increase in reactive nitrogen species within mitochondria, improving the health of our mitochondrial membranes and allowing them to regulate calcium properly. Elevated nitric oxide levels, often caused by nnEMF exposure, activate soluble guanylate cyclase (sGC) and increase cyclic GMP (cGMP). This process promotes calcium release from intracellular stores and contributes to mitochondrial permeability transition. Methylene blue’s inhibition of the NO-sGC-cGMP pathway has been shown to restore cellular calcium balance and protect mitochondrial integrity. In clinical scenarios such as calcium channel blocker toxicity and vasoplegic shock, administering methylene blue significantly reduces the need for vasopressors by reversing pathological vasodilation and addressing calcium mismanagement. These findings suggest that methylene blue’s ability to regulate calcium signaling and redox balance may also help protect mitochondrial function from the bioenergetic disruptions caused by chronic nnEMF exposure. This protection may be enhanced with red light therapy, proper fasting, adequate sunlight exposure, good sleep hygiene, and a healthy circadian rhythm.[34] [35]

Methylene blue demonstrates synergistic effects when combined with red and infrared (IR) light exposure, particularly in mitochondrial bioenergetics and neuroprotection. According to Doctor Jack Kruse, methylene blue is an electron cycler, donating electrons to cytochrome c in the mitochondrial electron transport chain. This process helps bypass dysfunctional complexes and restore redox balance. The therapeutic potential of methylene blue is enhanced when paired with red and IR light, which directly stimulates cytochrome c oxidase (Complex IV). This stimulation improves electron tunneling and increases adenosine triphosphate (ATP) synthesis. Doctor Kruse highlights that exposure to red light after methylene blue supplementation “shrinks cytochrome proteins,” optimizing electron flow through the electron transport chain, especially in conditions impacted by non-native electromagnetic fields (nnEMFs). These fields can disrupt proton spin dynamics, increase cellular calcium influx, and interfere with mitochondrial signaling. Peer-reviewed studies support this mechanism, showing that low-dose methylene blue and near-infrared light target the same cellular component, cytochrome c oxidase. Here, methylene blue donates electrons biochemically, while infrared light contributes photons biophysically. Together, they enhance mitochondrial respiration and reduce oxidative stress.[36] [37]

Methylene blue also promotes healthy mitochondrial biogenesis. Methylene blue promotes healthy mitochondrial biogenesis by activating Nuclear Factor Erythroid 2-related Factor 2 (NRF2), which is stimulated by increased hydrogen peroxide production from neutralized reactive oxygen species formation within our mitochondria. This change affects the ratio of NAD+ to NADH within our mitochondria, leading to the activation of Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (PGC-1α). This activation occurs through phosphorylation by AMP-activated protein kinase (AMPK), leading to more mitochondria being produced within our cells.[38] [39] [40]

Methylene Blue Over Supplementation Can Also Harm Our Mitochondrial Function

You may have heard the phrase, “the dosage makes the poison.” Taking too high a dose of methylene blue or using it too frequently can lead to mitochondrial dysfunction. Methylene blue is a low-dose redox buffer, helping reduce reactive oxygen species and support mitochondrial function. When taken at lower doses, methylene blue can also be a substrate for glutathione reductase. Still, when taken in higher doses, it can hinder glutathione synthesis and utilization and reduce cellular glutathione reserves. Higher doses of methylene blue can cause excessive redox cycling, taking electrons away from mitochondrial electron transport chain complexes and overwhelming our cell’s antioxidant defenses by causing them to produce less energy, hindering efficiency, and causing more mitochondrial leakage. The increased mitochondrial leakage generates too many superoxide radicals that cannot be effectively neutralized anymore. Excessive redox cycling can tip this balance toward increased oxidative stress when antioxidant systems like glutathione or superoxide dismutase (SOD) become overwhelmed. Too much energy generation within our mitochondria can also harm our health; mitochondrial homeostasis is crucial. Consequently, too much redox cycling leads to increased oxidation, inflammation, and mitochondrial and cellular apoptosis if severe enough.[41] [42] [43] [44] [45] [46] [47] [48]

“At low doses, there is MB–MBH₂ equilibrium (electron cycling) and MBH₂ can donate electrons to ETC complexes and oxygen, leading to enhanced energy metabolism and decreased superoxide formation. At high doses, equilibrium is impaired and MB can take electrons away from ETC complexes, leading to decreased activity of these complexes and more oxidative stress.”[49]

Common Side Effects From Taking Methylene Blue (More Common With Improper Dosage)[50] [51] [52] [53] [54] [55] [56] [57]

Allergic reactions (hives, rash, pruritus [itching], anaphylaxis)
Anxiety
Blue or green discoloration of urine, saliva, or skin
Coagulation (blood clot formation)
Diarrhea
Dysbiosis (may reduce probiotic Bifidobacteria levels after a few weeks of supplementation)
Dysgeusia – metallic taste in your mouth
Elevated blood pressure and/or heart rate (taken with caffeine, nicotine, or any vasoconstrictor might elevate your blood pressure further)
Fatigue
Headaches
Hemolytic anemia (especially if you have genetical glucose-6-phosphate dehydrogenase deficiency) – symptoms including fatigue, tachycardia, pale skin, jaundice, dark urine, shortness of breath, chills, gallstones, enlarged spleen, pulmonary hypertension, syncope (fainting), chest pain, peripheral edema, ascites.[58] [59]
Insomnia
Nausea
Migraines
Paradoxical methemoglobinemia
Photosensitivity – makes you more likely to sunburn.
Serotonin Syndrome (more likely when combined with serotonergic medications, (https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-serious-cns-reactions-possible-when-methylene-blue-given-patients) supplements, and herbs including selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, 5-HTTP, Saint John’s Wort) – symptoms include confusion, hyperactivity, brain fog, muscle twitching, excessive sweating, shivering, shaking, diarrhea, coordination issues when walking, muscle rigidity, and/or fever.[60] [61]
Vomiting

Recommended Methylene Blue Supplements

Recommended Methylene Blue Supplement: HEALTHLETIC Ultimate Methylene Blue

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Methylene Blue Dosage Supplementation Recommendations

Doctor Jack Kruse emphasizes the importance of individualized, low-dose titration to harness methylene blue’s mitochondrial benefits while hopefully avoiding its pro-oxidant risks. Doctor Jack Kruse advocates for a titration strategy beginning at approximately 0.5–1 mg/kg body weight in a glass of filtered or spring water, administered with red and infrared light exposure (preferably early morning sunlight exposure) while fasting. He also recommends using only pharmaceutical-grade USP-certified methylene blue. Sunlight exposure within reason after ten to twenty minutes of taking methylene blue might help it work better. I recommend starting at 0.25 mg/kg body weight; you can always increase the dosage after a few days to see if it improves your issues. Discuss with your healthcare professional before starting to supplement with methylene blue. Cautiously supplement with methylene blue if you suffer from stage two hypertension, a blood pressure of 140/90 mmHg or greater, or have a history of blood clot formation. I would not supplement with methylene blue if you are pregnant or breastfeeding.[62]

[1] https://my.clevelandclinic.org/health/diseases/24115-methemoglobinemia

[2] https://www.ncbi.nlm.nih.gov/books/NBK557593/#:~:text=Methylene%20blue%20is%20a%20medication,its%20ability%20to%20carry%20oxygen.

[3] https://www.basf.com/global/en/media/magazine/creatingchemistrystories/2015/pioneer-thinker-then-and-now-methlyene-blue

[4] https://www.yahoo.com/lifestyle/bryan-johnson-mel-gibson-possibly-200842038.html

[5] https://www.amazon.com/Ultra-Methylene-Blue-Fresh-Flavor/dp/B0F6Q2ZHL5

[6] https://www.cbc.ca/radio/whitecoat/methylene-blue-explainer-1.7531116

[7] https://www.ncbi.nlm.nih.gov/books/NBK557593/#:~:text=Methylene%20blue%20is%20a%20medication,its%20ability%20to%20carry%20oxygen.

[8] https://my.clevelandclinic.org/health/diseases/24115-methemoglobinemia

[9] https://renoja.com/methylene-blue-and-its-impact-on-mitochondrial-function-a-deep-dive/

[10] https://www.pfmjournal.org/journal/view.php?doi=10.23838/pfm.2022.00079#t1-pfm-2022-00079

[11] https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-020-00197-z

[12] https://jackkruse.com/biohacking-time-with-methylene-blue/