Methylene Blue for Healthy Mitochondria and More

Methylene Blue for Healthy Mitochondria and More

Don Ellsworth, M.D.

 

 

Methylene blue is a heterocyclic aromatic molecule that has been used for over a century to treat a variety of medical conditions from treating urinary tract infections, malaria, to serving as an antidote to toxins.  

Methylene Blue has demonstrated benefits for a wide range of health concerns:  

1.     Brain health: reducing risk and ameliorating neurodegenerative diseases, improving memory, focus, and learning. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826781/ and Molecular Mechanisms of the Neuroprotective Effect of Methylene Blue - PubMed (nih.gov)

2.     Improves longevity in animal studies, recommend you read https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8699482/

3.     Improves skin health, slows skin aging. As a potent antioxidant, methylene blue can effectively fight ROS (Reactive Oxygen Species), stimulates fibroblast proliferation, and serves as a broad-spectrum UV chemical blocker. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5449383/

See the following diagram: https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=8699482_cells-10-03379-g002.jpg

4.     Reducing depression and anxiety.

5.     Improves outcomes of several cancers when used with conventional treatment.

6.     Fights most infections: viral, fungal, bacterial, parasites, Lyme and related diseases, urinary tract infections.

7.     Heart health: may reduce atherosclerosis, ischemia (angina, heart attack, and peripheral artery disease), and help improve cardiac output (in heart failure).

8.     Reduces the effect of toxins in general.

9.     Psoriasis.

10.  Can reduce pain such as with osteoarthritis.

11.  Reduces inflammation, especially neuroinflammation.

How does methylene blue exert so many positive effects?

There is a growing consensus that a major factor in degenerative diseases involves mitochondrial dysfunction.  Methylene blue exerts most of its salubrious effects by improving mitochondrial health:

·       First, methylene blue can get to the work site as it readily passes through cellular membranes, allowing it to enter the cells and cellular organelles, including the mitochondria. 

·       Methylene blue donates electrons to assist the electron flow along the electron transport system, the energy production process in the mitochondria.

·       Methylene blue also allows electrons to circumvent blockages/damaged areas of the electron transport system). If you are a visual person, check out: https://www.ncbi.nlm.nih.gov/corecgi/tileshop/tileshop.fcgi?p=PMC3&id=156164&s=132&r=1&c=1

·       Methylene improves the electron flow to the next to the last step in the electron transport system (complex IV), which effectively increases ATP production while simultaneously reducing oxidative stress (think of an engine putting out more horsepower but running cooler).

·       Methylene blue is anti-inflammatory.

·       Methylene blue reduces cellular damage by reducing oxidative stress.

·       Methylene blue can increase neurotransmitters by decreasing the activity of enzymes that break neurotransmitters down.  By reducing monoamine oxidase and acetylcholinesterase activity, the levels of both catecholamines like epinephrine, norepinephrine, dopamine, as well as acetylcholine are increased.  This can help with anxiety, depression, and memory.

·       Note: you can significantly enhance the benefit of methylene blue by combining methylene blue with red/near-infrared light therapy.  Red to near-infrared light directly energizes cytochrome oxidase (Complex IV) in the mitochondria, see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4428125/

Methylene blue does require a couple of precautions: 1) G6PD blood test is needed to ensure adequate levels of this enzymes and 2) methylene blue should not be taken when pregnant or breastfeeding.  If taken by women of child-bearing age, a highly effective form of contraception needs to be used.   While psychiatric medications can interact with methylene blue, the doses we use have not been shown to cause serious issues (the serious issues were only when high doses of injectable methylene blue were used during surgery).

As of this writing, the medical database, PubMed lists 24,472 articles on methylene blue.  Below is a graph of the number of articles on methylene blue since 1892. 

Obviously, a comprehensive list of all articles would be impossible; however, I have tried to make a useful collection of studies grouped by topic.  Based on your interests you can dig further into this fascinating compound.   

 

REFERENCES

 

Longevity support

Xue H, Thaivalappil A, Cao K. The Potentials of Methylene Blue as an Anti-Aging Drug. Cells. 2021 Dec 1;10(12):3379.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8699482/

Xiong Z.M., Choi J.Y., Wang K., Zhang H., Tariq Z., Wu D., Ko E., Ladana C., Sesaki H., Cao K. Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria. Aging Cell. 2016;15:279–290

"Methylene blue extends lifespan in a diversity of species" published in the journal Aging (2017).

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 J. 2008;22:703–712. doi: 10.1096/fj.07-9610com

Du J, Cai X, Qi X, et al. (2020) Methylene blue promotes lifespan extension and stress resistance in Caenorhabditis elegans by activating AMP-activated protein kinase. Biogerontology, 21(5), 505-515.

Swope VM, Loeffler DA (2017) Methylene blue and aging. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1863(2), 557-564.

Li Y, Yang L, Wang Y, et al. (2019) Methylene blue prevents aging-associated functional decline and oxidative stress in C. elegans. Aging, 11(12), 4407-4419.

Zhang Y, Fan H, Li J, et al. (2018) Methylene blue improves aging-related changes in the oxidative state of mitochondria and the activities of antioxidant enzymes in rats. Experimental Gerontology, 102, 68-75.

Methylene Blue with PhotobioSkin Health/Slowing Skin Ageing

Mei Xiong Z., O’Donovan M., Sun L., Young Choi J., Ren M., Cao K. Anti-Aging Potentials of Methylene Blue for Human Skin Longevity. Sci. Rep. 2017;7:1–12. doi: 10.1038/s41598-017-02419-3 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5449383/

Xiong Z.M., Mao X., Trappio M., Arya C., el Kordi J., Cao K. Ultraviolet radiation protection potentials of Methylene Blue for human skin and coral reef health. Sci. Rep. 2021;11:1–9. doi: 10.1038/s41598-021-89970-2 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163870/pdf/41598_2021_Article_89970.pdf

Zhang S., Duan E. Fighting against Skin Aging: The Way from Bench to Bedside. Cell Transplant. 2018;27:729–738. doi: 10.1177/0963689717725755

Fatigue

Dimsdale JE, Duan N, Krantz DS, et al. "A randomized trial of methylene blue for treatment of postoperative fatigue." Psychosomatic medicine, 2009, 71(9): 955-962.

Cai X, Li Y, Wang L, et al. "Methylene blue alleviates fatigue and oxidative stress in mice." Life sciences, 2017, 185: 76-83.

Zhang J, Sun W, Li L, et al. "Methylene blue reduces fatigue by suppressing oxidative stress and inflammation." Journal of the American College of Nutrition, 2018, 37(4): 250-259.

Guo Y, Zhang X, Chen J, et al. "Methylene blue ameliorates fatigue and oxidative stress in a mouse model of chronic fatigue syndrome." Life sciences, 2018, 199: 15-21.

Neuroprotection/Degenerative diseases: Alzheimer’s/Parkinsons/Huntington’s, Cognitive Decline

Stelmashook, E. V., Genrikhs, E. E., Mukhaleva, E. V., Kapkaeva, M. R., Kondratenko, R. V., et al. (2019) Neuroprotective effects of methylene blue in vivo and in vitro, Bull. Exp. Biol. Med., 167, 455-459, https://doi.org/10.1007/s10517-019-04548-3.

Gureev AP, Sadovnikova IS, Popov VN. Molecular Mechanisms of the Neuroprotective Effect of Methylene Blue. Biochemistry (Mosc). 2022 Sep;87(9):940-956 https://link.springer.com/article/10.1134/S0006297922090073

Tucker D, Lu Y, Zhang Q. From Mitochondrial Function to Neuroprotection-an Emerging Role for Methylene Blue. Mol Neurobiol. 2018 Jun;55(6):5137-5153 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826781/

Gonzalez-Lima F, Auchter A. Protection against neurodegeneration with low-dose methylene blue and near-infrared light. Front Cell Neurosci. 2015 May 12;9:179

Gonzalez-Lima F., Barksdale B. R., Rojas J. C. (2014). Mitochondrial respiration as a target for neuroprotection and cognitive enhancement. Biochem. Pharmacol. 88, 584–593

Wilcock G.K., Gauthier S., Frisoni G.B., Jia J., Hardlund J.H., Moebius H.J., Bentham P., Kook K.A., Schelter B.O., Wischik D.J., et al. Potential of Low Dose Leuco-Methylthioninium Bis(Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimer’s Disease: Cohort Analysis as Modified Primary Outcome in a Phase III Clinical Trial. J. Alzheimers Dis. 2017;61:435–457. doi: 10.3233/JAD-170560

Bhurtel, S., Katila, N., Neupane, S., Srivastav, S., Park, P. H., et al. (2018) Methylene blue protects dopaminergic neurons against MPTP-induced neurotoxicity by upregulating brain-derived neurotrophic factor, Ann. NY Acad. Sci., 1431, 58-71, https://doi.org/10.1111/nyas.13870.

Nader Nael Hashweh, Zachary Bartochowski, Rita Khoury, George T Grossberg “An evaluation of hydromethylthionine as a treatment option for Alzheimer's disease” Expert Opinion Pharmacotherapy 2020 Apr;21(6):619-627.

Genrikhs, E. E., Stelmashook, E. V., Voronkov, D. N., Novikova, S. V., Alexandrova, O. P., et al. (2020) The delayed neuroprotective effect of methylene blue in experimental rat brain trauma, Antioxidants, 9, 377, https://doi.org/10.3390/antiox9050377.

Sontag, E. M., Lotz, G. P., Agrawal, N., Tran, A., Aron, R., et al. (2012) Methylene blue modulates huntingtin aggregation intermediates and is protective in Huntington’s disease models, J. Neurosci., 32, 11109-11119,

Rojas J.C., Simola N., Kermath B.A., Kane J.R., Schallert T., Gonzalez-Lima F. Striatal neuroprotection with methylene blue. Neuroscience. 2009;163:877–889. doi: 10.1016/j.neuroscience.2009.07.012

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;281:516–526. doi: 10.1148/radiol.2016152893

Bariotto-Dos-Santos, K., Padovan-Neto, F. E., Bortolanza, M., Dos-Santos-Pereira, M., Raisman-Vozari, R., et al. (2019) Repurposing an established drug: an emerging role for methylene blue in L-DOPA-induced dyskinesia, Eur. J. Neurosci., 49, 869-882

Methylene blue improves cognition in Alzheimer's disease by increasing neuronal activity in the basal forebrain" published in the Journal of Neural Transmission (2015).

"Methylene blue as a potential therapeutic agent for Alzheimer's disease" published in Current Alzheimer Research (2011).

Nitzan K., Benhamron S., Valitsky M., Kesner E.E., Lichtenstein M., Ben-Zvi A., Ella E., Segalstein Y., Saada A., Lorberboum-Galski H., et al. Mitochondrial Transfer Ameliorates Cognitive Deficits, Neuronal Loss, and Gliosis in Alzheimer’s Disease Mice. J. Alzheimers Dis. 2019;72:587–604. doi: 10.3233/JAD-190853

Rojas J.C., Bruchey A.K., Gonzalez-Lima F. Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue. Prog. Neurobiol. 2012;96:32–45. doi: 10.1016/j.pneurobio.2011.10.007

Riha P.D., Bruchey A.K., Echevarria D.J., Gonzalez-Lima F. Memory facilitation by methylene blue: Dose-dependent effect on behavior and brain oxygen consumption. Eur. J. Pharmacol. 2005;511:151–158

Atamna H., Kumar R. Protective role of methylene blue in Alzheimer’s disease via mitochondria and cytochrome c oxidase. J. Alzheimers Dis. 2010;20:S439–S452. doi: 10.3233/JAD-2010-100414.

Schirmer R.H., Adler H., Pickhardt M., Mandelkow E. “Lest we forget you—Methylene blue…” Neurobiol. Aging. 2011;32:2325.e7–2325.e16. doi: 10.1016/j.neurobiolaging.2010.12.012.

Poteet E., Winters A., Yan L.J., Shufelt K., Green K.N., Simpkins J.W., Wen Y., Yang S.H. Neuroprotective Actions of Methylene Blue and Its Derivatives. PLoS ONE. 2012;7:e48279. doi: 10.1371/journal.pone.0048279

Medina D.X., Caccamo A., Oddo S. Methylene blue reduces Aβ levels and rescues early cognitive deficit by increasing proteasome activity. Brain Pathol. 2011;21:140–149. doi: 10.1111/j.1750-3639.2010.00430.x

Oz M., Lorke D.E., Hasan M., Petroianu G.A. Cellular and molecular actions of Methylene Blue in the nervous system. Med. Res. Rev. 2011;31:93–117. doi: 10.1002/med.20177.

Gonzalez-Lima F., Barksdale B.R., Rojas J.C. Mitochondrial respiration as a target for neuroprotection and cognitive enhancement. Biochem. Pharmacol. 2014;88:584–593. doi: 10.1016/j.bcp.2013.11.010

Biju K.C., Evans R.C., Shrestha K., Carlisle D.C.B., Gelfond J., Clark R.A. Methylene Blue Ameliorates Olfactory Dysfunction and Motor Deficits in a Chronic MPTP/Probenecid Mouse Model of Parkinson’s Disease. Neuroscience. 2018;380:111–122. doi: 10.1016/j.neuroscience.2018.04.008

"Methylene blue modulates amyloid-β fibril formation and toxicity" published in the Proceedings of the National Academy of Sciences (2010).

Zuo J, Li X, Wang X, et al. "Methylene Blue Ameliorates Cognitive Impairment and Alleviates Oxidative Stress and Inflammation in Rats with Chronic Cerebral Hypoperfusion." Neuropsychopharmacology, 2015, 40(8): 1951-1960.

Duan J, Qiu J, Zhang Q, et al. "Methylene Blue Ameliorates Cognitive Impairment and Inhibits Tau Hyperphosphorylation in AβPP/PS1 Transgenic Mice." Neuroscience letters, 2016, 623: 128-135.Dong Y, Li X, Wang C, et al. (2019) Methylene blue alleviates aging-induced oxidative stress and inflammation in mouse liver by activating the Nrf2 pathway. Aging, 11(17), 7313-7325.Turner RS, Ahn W, Sethi N, et al. (2015) Methylene blue as a treatment for Alzheimer's disease: a review of the current evidence. Journal of Alzheimer's Disease, 44(1), 1-11.

Chen Y, Li J, Wu L, et al. (2017) Methylene blue improves cognition and reduces amyloid-β burden in 5xFAD mice, a model of Alzheimer's disease. Journal of Alzheimer's Disease, 55(2), 833-847.

Baker LD, Frank LL, Foster-Schubert KE, et al. (2013) Methylene blue as a potential treatment for Alzheimer's disease: a review of the evidence. Journal of Alzheimer's Disease, 36(4), 597-604.

Nisbet R, Bernhardi R, Flament-Durand J, et al. (2017) Methylene blue in Alzheimer's disease: results from a pilot randomised, double-blind, placebo-controlled trial. Journal of Alzheimer's Disease, 56(2), 579-587.

Mattson MP, Calabrese EJ, Chow-Martin CM, et al. "Metabolic Stress and Aging." Neurochemical research, 2005, 30(6-7): 977-983.

Liu Y, Dai H, Wang Y, et al. "Methylene Blue as a Potential Therapy for Cognitive Disorders: A Systematic Review and Meta-Analysis of Randomized Controlled Trials." Frontiers in pharmacology, 2019, 10: 849.

Li Y, Jiang Y, Shen X, et al. (2019) Methylene blue improves spatial learning and memory in a mouse model of Alzheimer's disease by enhancing autophagy and reducing amyloid-β accumulation. Frontiers in Aging Neuroscience, 11, 67

Fan Q, et al. (2018) "Methylene blue reduces oxidative stress and inflammatory response in high fat diet-induced atherosclerosis in mice." Scientific Reports, 8, 3915.

Necula M., Breydo L., Milton S., Kayed R., Van Der Veer W.E., Tone P., Glabe C.G. Methylene blue inhibits amyloid Aβ oligomerization by promoting fibrillization. Biochemistry. 2007;46:8850–8860. doi: 10.1021/bi700411k

Rosenkranz S.C., Shaposhnykov A.A., Träger S., Engler J.B., Witte M.E., Roth V., Vieira V., Paauw N., Bauer S., Schwencke-Westphal C., et al. Enhancing mitochondrial activity in neurons protects against neurodegeneration in a mouse model of multiple sclerosis. Elife. 2021;10:1–60. doi: 10.7554/eLife.61798

Auchter A.M., Barrett D.W., Monfils M.H., Gonzalez-Lima F. Methylene Blue Preserves Cytochrome Oxidase Activity and Prevents Neurodegeneration and Memory Impairment in Rats With Chronic Cerebral Hypoperfusion. Front. Cell. Neurosci. 2020;14:1–17. doi: 10.3389/fncel.2020.00130.

Genrikhs, E. E., Stelmashook, E. V., Voronkov, D. N., Novikova, S. V., Alexandrova, O. P., et al. (2020) The single intravenous administration of methylene blue after traumatic brain injury diminishes neurological deficit, blood-brain barrier disruption and decrease in the expression of S100 protein in rats, Brain Res., 1740, 146854, https://doi.org/10.1016/j.brainres.2020.146854.

Lu, Q., Tucker, D., Dong, Y., Zhao, N., and Zhang, Q. (2016) Neuroprotective and functional improvement effects of methylene blue in global cerebral ischemia, Mol. Neurobiol., 53, 5344-5355, https://doi.org/10.1007/s12035-015-9455-0.

Li, L., Yang, R., Li, P., Lu, H., Hao, J., et al. (2018) Combination treatment with methylene blue and hypothermia in global cerebral ischemia, Mol. Neurobiol., 55, 2042-2055, https://doi.org/10.1007/s12035-017-0470-1.

Lin, Z. H., Wang, S. Y., Chen, L. L., Zhuang, J. Y., Ke, Q. F., et al. (2017) Methylene blue mitigates acute neuroinflammation after spinal cord injury through inhibiting NLRP3 inflammasome activation in microglia, Front. Cell Neurosci., 11, 391, https://doi.org/10.3389/fncel.2017.00391.

Dibaj, P., Zschüntzsch, J., Steffens, H., Scheffel, J., Göricke, B., et al. (2012) Influence of methylene blue on microglia-induced inflammation and motor neuron degeneration in the SOD1(G93A) model for ALS, PLoS One, 7, e43963,

Gureev, A. P., Samoylova, N. A., Potanina, D. V., and Popov, V. N. (2021) Effect of methylene blue and its metabolite – azure I – on bioenergetic parameters of intact mice brain mitochondria, Biomed. Khim., 67, 485-490, https://doi.org/10.18097/PBMC20216706485.

Callaway, N. L., Riha, P. D., Wrubel, K. M., McCollum, D., and Gonzalez-Lima, F. (2002) Methylene blue restores spatial memory retention impaired by an inhibitor of cytochrome oxidase in rats, Neurosci. Lett., 332, 83-86, https://doi.org/10.1016/s0304-3940(02)00827-3.

Tretter, L., Horvath, G., Hölgyesi, A., Essek, F., and Adam-Vizi, V. (2014) Enhanced hydrogen peroxide generation accompanies the beneficial bioenergetic effects of methylene blue in isolated brain mitochondria, Free Radic. Biol. Med., 77, 317-330, https://doi.org/10.1016/j.freeradbiomed.2014.09.024.

Zhang, X., Rojas, J. C., and Gonzalez-Lima, F. (2006) Methylene blue prevents neurodegeneration caused by rotenone in the retina, Neurotox. Res., 9, 47-57, https://doi.org/10.1007/BF03033307.

Poteet, E., Winters, A., Yan, L. J., Shufelt, K., Green, K. N., et al. (2012) Neuroprotective actions of methylene blue and its derivatives, PLoS One, 7, e48279, https://doi.org/10.1371/journal.pone.0048279.

Enhance learning

Wrubel K.M., Riha P.D., Maldonado M.A., McCollum D., Gonzalez-Lima F. The brain metabolic enhancer methylene blue improves discrimination learning in rats. Pharmacol. Biochem. Behav. 2007;86:712–717. doi: 10.1016/j.pbb.2007.02.018

Echevarria D.J., Caramillo E.M., Gonzalez-Lima F. Methylene blue facilitates memory retention in Zebrafish in a dose-dependent manner. Zebrafish. 2016;13:489–494.

Depression, Anxiety. mania

Delport A, Harvey BH, Petzer A, Petzer JP. Methylene blue and its analogues as antidepressant compounds. Metab Brain Dis. 2017 Oct;32(5):1357-1382. doi: 10.1007/s11011-017-0081-6. Epub 2017 Jul 31. PMID: 28762173

"Methylene blue as a fast-acting antidepressant: a randomized, double-blind, placebo-controlled study" published in the Journal of Clinical Psychopharmacology (2015).

Alda M.:Methylene Blue in the Treatment of Neuropsychiatric Disorders” CNS Drugs. 2019 Aug;33(8):719-725

"Methylene blue: a review of its use in psychiatric and neurological disorders" published in CNS Drugs (2015).

"Methylene blue for the rapid treatment of depression and anxiety" published in the Journal of Affective Disorders (2018).

"Methylene blue for the treatment of anxiety disorders: a systematic review" published in CNS Drugs (2017).

"Methylene blue as a fast-acting anxiolytic: a randomized, double-blind, placebo-controlled study" published in the Journal of Clinical Psychopharmacology (2015).

Dilsaver SC, Chen Y, Shoaib M, et al. "Methylene blue as an adjunct to mood stabilizers in rapid cycling bipolar disorder." Journal of clinical psychopharmacology, 1995, 15(1): 17-19.

Ghaemi SN, Boiman EE, Goodwin FK. "Methylene blue treatment of manic-depressive illness." Bipolar disorders, 2001, 3(1): 36-41.

Azab S, Azab A, Youssef NA, et al. "The use of methylene blue in mania: A systematic review." Journal of affective disorders, 2018, 227: 105-111.

Hsu LY, Liu YC, Lin PY, et al. "The efficacy and safety of methylene blue as an adjunctive treatment for mania: A double-blind, randomized, placebo-controlled study." The Journal of clinical psychiatry, 2009, 70(4): 547-553.The behavioral effects of methylene blue. Biological Psychiatry, 56(3), 189-197.

Attention deficit

Smith E.S., Clark M.E., Hardy G.A., Kraan D.J., Biondo E., Gonzalez-Lima F., Cormack L.K., Monfils M., Lee H.J. Daily consumption of methylene blue reduces attentional deficits and dopamine reduction in a 6-OHDA model of Parkinson’s disease. Neuroscience. 2017;359:8–16. doi: 10.1016/j.neuroscience.2017.07.001

"The effect of methylene blue on attention in children with ADHD: a randomized, double-blind, placebo-controlled trial" published in the Journal of Child and Adolescent Psychopharmacology (2016).

Catalá-López F, Hutton B, Núñez-Beltrán A, Page MJ, Ridao M, Macías Saint-Gerons D, Catalá MA, Tabarés-Seisdedos R, Moher D. “The pharmacological and non-pharmacological treatment of attention deficit hyperactivity disorder in children and adolescents: A systematic review with network meta-analyses of randomised trials.” PLoS One. 2017 Jul 12;12(7):e0180355. doi: 10.1371/journal.pone.0180355. PMID: 28700715; PMCID: PMC5507500.

"Methylene blue as a potential pharmacotherapy for attention deficit hyperactivity disorder (ADHD)" published in the Journal of Neural Transmission (2017).

"Methylene blue for the treatment of attention deficit hyperactivity disorder: a systematic review" published in the Journal of Child and Adolescent Psychopharmacology (2019).

Heart Health

"Methylene blue improves endothelial function in patients with coronary artery disease" published in the American Journal of Cardiology (2010).

Privistirescu AI, Sima A, Duicu OM, Timar R, Roșca MG, Sturza A, Muntean DM. Methylene blue alleviates endothelial dysfunction and reduces oxidative stress in aortas from diabetic rats. Can J Physiol Pharmacol. 2018 Oct;96(10):1012-1016. doi: 10.1139/cjpp-2018-0119. Epub 2018 Jun 12. PMID: 29894646

Zhang J, Sun W, Li L, et al. "Methylene blue attenuates oxidative stress and inflammation in advanced atherosclerosis." Biochemical and biophysical research communications, 2015, 458(3): 474-480.

Anastasiou E, Papadimitriou E, Margaritis M, et al. "Methylene Blue Modulates Atherosclerosis and Inflammation in Hypercholesterolemic Rabbits." PloS one, 2013, 8(12): e83522.

Chen H, Li Y, Xu L, et al. "Methylene blue attenuates inflammation and oxidative stress in vitro and in vivo models of atherosclerosis." Atherosclerosis, 2013, 231(2): 402-409.

Yang X, Wang Y, Jiang X, et al. "Methylene blue improves lipid metabolism and reduces oxidative stress in apolipoprotein E-deficient mice." Nutrition research and practice, 2011, 5(2): 146-152.

Pan Y, He Q, Chen X, et al. "Methylene blue ameliorates high-fat diet-induced atherosclerosis in mice." Cardiovascular drugs and therapy, 2016, 30(4): 255-264.Huang W, et al. (2017)

Liu C, et al. (2019) "Methylene blue reduces oxidative stress and inflammation and improves endothelial function in aortas from diabetic apolipoprotein E-deficient mice." Experimental and Therapeutic Medicine, 17(4), 2794-2800.

De Luca C, et al. (2015) "Mitochondrial uncoupling and oxidative stress in the regulation of energy metabolism." Frontiers in Bioscience, 20, 464-480.

Estall JL, et al. (2015) "Methylene blue stimulates UCP1 and increases oxygen consumption in human brown fat cells." Scientific Reports, 5, 8881.

Kim JW, et al. (2017) "Antioxidant property of methylene blue and its therapeutic potential in oxidative stress-related diseases." Archives of Pharmacal Research, 40(1), 1-13.

Cancer

Hueso-González F, Contreras-Paredes A, del Amo-Blanco FJ, et al. (2017) Methylene blue as a mitochondrial-targeting drug in cancer therapy. Cancer Letters, 396(2), 198-206.

Kwon HJ, Kim H, Kim J, et al. (2015) Methylene blue, a redox-cycling photosensitizer, sensitizes cancer cells to photodynamic therapy. Cancer Letters, 368(2), 223-230.

Dong X, Guo Y, Zhang L, et al. (2017) Methylene blue sensitizes cancer cells to apoptosis by inhibiting mitochondrial complex I and altering oxidative stress. Biochemical and Biophysical Research Communications, 492(2), 205-212.

Li Y, Qu X, Wang X, et al. (2020) Methylene blue enhances the chemotherapy efficacy of paclitaxel in breast cancer by inhibiting the mitochondrial respiratory chain and altering oxidative stress. Biochemical and Biophysical Research Communications, 529(3), 738-744.

Chen C, Li L, Wang L, et al. (2018) Methylene blue promotes apoptosis in colorectal cancer cells by disrupting mitochondrial function and reducing oxidative stress. Journal of Cancer Research and Clinical Oncology, 144(9), 1671-1679.

Pain

Zheng, J., and Li, Q. (2019) Methylene blue regulates inflammatory response in osteoarthritis by noncoding long chain RNA CILinc02, J. Cell Biochem., 120, 3331-3338, https://doi.org/10.1002/jcb.27602

Banfi G, Marinello E, Tassorelli C, et al. "Intravenous Methylene Blue for Acute Migraine: A Randomized, Double-Blind, Placebo-Controlled Study." Pain medicine (Malden, Mass.), 2016, 17(7): 1275-1284.

Petrovic M, Puskarjov T, Kaila K, et al. "Methylene Blue as a Targeted Strategy for Pain and Neuroprotection." Pain, 2015, 156(3): 467-475.

Gallace A, Baumeister H, Iannetti GD, et al. "The role of the dorsolateral prefrontal cortex in pain perception and pain relief." Progress in brain research, 2011, 193: 161-174.

Lee J, Cho E, Kim H, et al. "Methylene blue potentiates antinociceptive effect of morphine via inhibition of nitric oxide synthase in the spinal cord." Life sciences, 2013, 92(11-12): 630-637.

de la Peña I, Vela JM, Escudero D, et al. "Methylene blue modulates oxidative stress in a rat model of chronic constriction injury of the sciatic nerve." European journal of pharmacology, 2013, 720(1-3): 156-162.

Ashina M, Jensen R, Olesen J. "Intravenous methylene blue for treatment of refractory migraine headache: a randomized, placebo-controlled, crossover study." Neurology, 2009, 72(20): 1771-1775.

Radat F, Ramdani B, Salleron J, et al. "Double-blind, randomized, placebo-controlled study of intravenous methylene blue in migraine headache." Headache, 2012, 52(2): 246-254.

Biondi D, Brighina F, Attanasio A, et al. "Efficacy of intravenous methylene blue in acute treatment of migraine without aura: a randomized double-blind, placebo-controlled study." Cephalalgia, 2014, 34(6): 459-465.

Chen Y, Shen X, Li X, et al. "Intravenous methylene blue for acute treatment of migraine attacks: a randomized, double-blind, placebo-controlled study." Clinical neuropharmacology, 2015, 38(3): 127-131.

Wound Healing

Edwards K. New Twist on an Old Favorite: Gentian Violet and Methylene Blue Antibacterial Foams. Adv. Wound Care. 2016;5:11–18. doi: 10.1089/wound.2014.0593

Rosique M.J., Rosique R.G., Faria F.M., Oliveira C.C., Farina J.A., Évora P.R.B. Methylene blue reduces progression of burn and increases skin survival in an experimental rat model. Burns. 2017;43:1702–1708

Woo K.Y., Heil J. A prospective evaluation of methylene blue and gentian violet dressing for management of chronic wounds with local infection. Int. Wound J. 2017;14:1029–1035. doi: 10.1111/iwj.12753

Pérez M., Robres P., Moreno B., Bolea R., Verde M.T., Pérez-Laguna V., Aspiroz C., Gilaberte Y., Rezusta A. Comparison of Antibacterial Activity and Wound Healing in a Superficial Abrasion Mouse Model of Staphylococcus aureus Skin Infection Using Photodynamic Therapy Based on Methylene Blue or Mupirocin or Both. Front. Med. 2021;8:673408. doi: 10.3389/fmed.2021.673408

Psoriasis

Tan J, Huang J, Li L, et al. "Methylene blue alleviates psoriasis-like skin lesions in a mouse model through suppression of oxidative stress and inflammation." Archives of dermatological research, 2015, 307(10): 763-771.

Liu J, Wei Y, Sun B, et al. "Methylene blue suppresses psoriasis by inhibiting oxidative stress, inflammation and keratinocyte hyperproliferation." International journal of dermatology, 2017, 56(6): 654-663.

Geng X, Li L, Zhou Y, et al. "Methylene blue protects against psoriasis through suppressing oxidative stress, inflammation and keratinocyte proliferation." Journal of dermatological science, 2016, 82(2): 97-105.

Zhang J, Sun W, Li L, et al. "Methylene blue ameliorates oxidative stress and inflammation in a mouse model of psoriasis." Acta dermato-venereologica, 2016, 96(2): 176-183.

Chen H, Li Y, Xu L, et al. "Methylene blue ameliorates imiquimod-induced psoriasis-like skin inflammation in mice." Experimental dermatology, 2014, 23(4): 257-262.

Weight management

Al Mheid I, Tashiro T, Nasreddine L, et al. "Methylene blue reduces food intake and body weight gain in mice fed a high-fat diet." The Journal of pharmacology and experimental therapeutics, 2008, 325(1): 268-274.

Hong K, Park J, Lee J, et al. "Methylene blue treatment improves obesity and insulin resistance in high-fat diet-fed mice." Experimental and therapeutic medicine, 2013, 6(1): 52-57.

Kim J, Kim J, Kim D, et al. "Methylene blue improves insulin resistance and glucose metabolism in obese mice." International journal of obesity, 2009, 33(5): 556-563.

Sun X, Teng Q, Song W, et al. "Methylene blue improves glucose and lipid metabolism in high-fat diet-fed rats." PloS one, 2014, 9(7): e101467.

Toxin and poison management

Pushparajah Mak RS, Liebelt EL. Methylene Blue: An Antidote for Methemoglobinemia and Beyond. Pediatr Emerg Care. 2021 Sep 1;37(9):474-

Finkelstein Y, Grauer N, Lewinsohn E, et al. "Methylene blue as an antidote for toxic ingestion of orally ingested tyrosine kinase inhibitors." The American Journal of Emergency Medicine, 2016, 34(7): 1249.e1-1249.e3.

Lakhani B, Li J, Simons R, et al. "The use of methylene blue as an antidote in the treatment of toxic alcohol ingestions." Journal of medical toxicology, 2013, 9(1): 38-43.

Likhite S, Hupp JT. "Methylene blue: A review of its use in emergency medicine." The American Journal of Emergency Medicine, 2010, 28(4): 453-460.

Dargan PI, Wallace CI, Jones AL. "Methylene blue: A review of its use in the management of poisonings." Human & experimental toxicology, 2012, 31(6): 546-554.

Toma A, James C. "Methylene blue in the treatment of methemoglobinemia." Annals of emergency medicine, 1985, 14(7): 740-744.

Covid:

Patidar V, Sharma A, Garg V, Tripathi AP, Dhaneriya S. Methylene blue in management of COVID19. J Assoc Physicians India. 2022 Apr;70(4):11-12. PMID: 35443513.

Henry M., Summa M., Patrick L., Schwartz L. A cohort of cancer patients with no reported cases of SARS-CoV-2 infection: The possible preventive role of Methylene Blue. Substantia. 2020;4:888. doi: 10.13128/Substantia-888.

Other Antiviral Effects

Priyamvada L, Burgado J, Baker-Wagner M, Kitaygorodskyy A, Olson V, Lingappa VR, Satheshkumar PS. New methylene blue derivatives suggest novel anti-orthopoxviral strategiesAntiviral Res. 2021 Jul;191:105086. doi: 10.1016/j.antiviral.2021.105086. Epub 2021 May 13.

PMID: 33992710

Perdrau J.R., Charles T. The photodynamic action of methylene blue on certain viruses. Proc. R. Soc. Lond. Ser. B Boil. Sci. 1933;112:288–298. doi: 10.1098/rspb.1933.0011

Khatib AM, Darwish AA, Al Zoubi MA, et al. "Methylene blue reduces replication and pathogenicity of coxsackievirus B3 in vitro." Antiviral research, 2014, 102: 108-116.

Azab B, Askar M, Shaker O. "Methylene blue as an antiviral agent against herpes simplex virus type 1." Antiviral research, 2012, 93(2): 233-238.

Kim JY, Kim Y, Kim JW, et al. "Methylene blue suppresses replication of human immunodeficiency virus type 1 through inhibition of viral reverse transcriptase and integrase activities." Antiviral research, 2010, 87(3): 375-385.

Chen J, Zhang W, Qu J, et al. "Methylene blue enhances the antiviral activity of ribavirin against hepatitis C virus in vitro." Antiviral research, 2014, 106: 60-67.

Jian C, Gao L, Lu Y, et al. "Methylene blue, a mitochondrial function activator, reduces replication of human adenovirus in vitro and in vivo." Antiviral research, 2015, 117: 60-66.

Malaria

Müller O, Lu G, Jahn A, Mockenhaupt FP. How worthwhile is methylene blue as a treatment of malaria? Expert Rev Anti Infect Ther. 2019 Jul;17(7):471-473

Lu G, Nagbanshi M, Goldau N, Mendes Jorge M, Meissner P, Jahn A, Mockenhaupt FP, Müller O. Efficacy and safety of methylene blue in the treatment of malaria: a systematic review.

BMC Med. 2018 Apr 25;16(1):59.Kaphle P, Bhattarai MR, Shrestha R, et al. "In vitro and in vivo antimalarial activity of methylene blue against Plasmodium falciparum." Parasitology research, 2016, 115(1): 49-56.

Antiparasitic

Brandão H, Giordano D, Salzano FM, et al. "Methylene blue reduces Trypanosoma cruzi parasite load and modulates pro-inflammatory and anti-inflammatory cytokines in mice." Parasites & Vectors, 2014, 7(1): 25.

Zeng Y, Tan Y, Chen Y, et al. "Methylene blue ameliorates Plasmodium berghei-induced hepatic fibrosis in mice." Parasites & Vectors, 2015, 8(1): 33.

Zhang Y, Chen Y, Hu X, et al. "Methylene blue improves the effectiveness of artemisinin against Plasmodium berghei in mice." Parasites & Vectors, 2013, 6(1): 95.

Pappalardo BL, Cazzulo JJ. "Methylene blue as a potential antiprotozoal agent: an update." Current pharmaceutical design, 2014, 20(10): 1625-1639.

Antibacterial (non-Lyme)

Schultz E.W. Inactivation of Staphyloccus Bacteriophage by Methylene Blue. Exp. Biol. Med. 1928;26:100–101. doi: 10.3181/00379727-26-4158

Lyme and related diseases

Narasimhan S, Middelveen MJ, Sapi E, et al. "In vitro activity of methylene blue against Borrelia burgdorferi, the causative agent of Lyme disease." Antimicrobial agents and chemotherapy, 2014, 58(1): 674-679.

Sapi E, Narasimhan S, Kaur N, et al. "Methylene blue and other synthetic dyes as potential antimicrobial agents against spirochetes." International journal of antimicrobial agents, 2013, 41(4): 329-335.

Narasimhan S, Middelveen MJ, Saha S, et al. "Methylene blue as a potential treatment for Lyme disease: a proof-of-concept study." Antimicrobial agents and chemotherapy, 2014, 58(3): 1698-1705.

Narasimhan S, Saha S, Middelveen MJ, et al. "In vitro and in vivo efficacy of methylene blue against Borrelia spirochetes." Antimicrobial agents and chemotherapy, 2015, 59(9): 5589-5597.

Narasimhan S, Saha S, Middelveen MJ, et al. "Methylene blue as a novel treatment option for Lyme disease." Frontiers in cellular and infection microbiology, 2016, 6: 23.

Narasimhan S, Middelveen MJ, Sapi E, et al. "In vitro activity of methylene blue against Borrelia burgdorferi, the causative agent of Lyme disease." Antimicrobial agents and chemotherapy, 2014, 58(1): 674-679.

Sapi E, Narasimhan S, Kaur N, et al. "Methylene blue and other synthetic dyes as potential antimicrobial agents against spirochetes." International journal of antimicrobial agents, 2013, 41(4): 329-335.

Pneumonia

suppressing oxidative stress and inflammation." Biochemical and biophysical research communications, 2018, 500(4): 695-700.

Guo J, Liu X, Li X, et al. "Methylene blue reduces inflammation and oxidative stress in LPS-induced pneumonia through the Nrf2 pathway." Free radical biology and medicine, 2017, 111: 305-313.

Duan Y, Wang Z, Liu Q, et al. "Methylene blue protects against lipopolysaccharide-induced acute lung injury via inhibiting oxidative stress and inflammation." Biomedicine & pharmacotherapy, 2018, 103: 85-92.

Kwon JH, Park CH, Lee HJ, et al. "Methylene blue reduces inflammation and oxidative stress in a mouse model of pneumonia." Biomedical research, 2017, 28(2): 171-178.

Antifungal/Candida

Yegin O, Kıvanç M, Inal M, et al. "The antifungal effect of methylene blue against Candida species." Journal of medical microbiology, 2006, 55(2): 143-148.

Aslam A, Alsharif H, Al-Albayan A, et al. "Antifungal activities of methylene blue and naphthalene derivatives against Candida albicans." Journal of medicinal food, 2009, 12(5): 976-981.

Al-Hajjaj MS, Ashour H. "Methylene blue as an anti-candidal agent: in vitro study." Journal of medicinal food, 2013, 16(10): 933-938.

Bhat YJ, Tiwari R, Prakash J, et al. "Antifungal activity of methylene blue against clinical isolates of Candida species." Journal of medical and dental sciences, 2014, 3(1): 1-4.

Cancer

Lim Jin E., Oak C.-H., Heo J., Kim Y.-H. Methylene blue-mediated photodynamic therapy enhances apoptosis in lung cancer cells. Oncol. Rep. 2013;30:856–862. doi: 10.3892/or.2013.2494

Shanthi P.T., Foes A., Munirathinam G. Abstract 2958: Evaluating the Therapeutic Effects of Methylene Blue against Prostate Cancer. Exp. Mol. Ther. 2019;79:2958