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Methylene blue

Methylene blue
Systematic (IUPAC) name
3,7-bis(Dimethylamino)-phenothiazin-5-ium chloride
Clinical data
Legal status
  • investigational
Routes of
CAS Registry Number  Y
ATC code None
PubChem CID:
ChemSpider  Y
Chemical data
Formula C16H18ClN3S
Molecular mass 319.85 g/mol

Methylene blue (CI 52015) is a heterocyclic aromatic chemical compound with the molecular formula C16H18N3SCl. It has many uses in biology and chemistry; for example, it can be used as a stain and as a pharmaceutical drug. At room temperature it appears as a solid, odorless, dark green powder, that yields a blue solution when dissolved in water. The hydrated form has 3 molecules of water per molecule of methylene blue.[1] Methylene blue should not be confused with methyl blue, another histology stain, new methylene blue, nor with the methyl violets often used as pH indicators.

The International Nonproprietary Name (INN) of methylene blue is methylthioninium chloride.[2][3]

Methylene blue was first prepared in 1876 by German chemist health system.[5]


  • Medical uses 1
    • Combined with light 1.1
    • Methemoglobinemia 1.2
    • Cyanide poisoning 1.3
    • Dye or stain 1.4
    • Placebo 1.5
    • Ifosfamide neurotoxicity 1.6
    • Vasoplegic syndrome after cardiac surgery 1.7
  • Side effects 2
  • Preparation 3
  • Light absorption properties 4
  • Other uses 5
    • Redox indicator 5.1
    • Peroxide generator 5.2
    • Sulfide analysis 5.3
    • Water testing 5.4
    • Methylene Blue Value of Fine Aggregate 5.5
    • Biology 5.6
    • Aquaculture 5.7
  • History 6
  • Research 7
    • Malaria 7.1
    • Clinical trials 7.2
  • See also 8
  • References 9
  • External links 10

Medical uses

Methylene blue is a component of a frequently prescribed urinary analgesic/anti-infective/anti-spasmodic known as "Prosed", a combination of drugs which also contains phenyl salicylate, benzoic acid, hyoscyamine sulfate, and methenamine (aka hexamethylenetetramine and not to be confused with 'methanamine').[6]

Combined with light

Methylene blue combined with light has been used to treat resistant plaque psoriasis,[7] AIDS-related Kaposi's sarcoma,[8] West Nile virus,[9] and to inactivate staphylococcus aureus,[10] HIV-1,[11] Duck hepatitis B,[12] adenovirus vectors,[13] and hepatitis C.[14] Phenothiazine dyes and light have been known to have virucidal properties for over 70 years.[15] In some circumstances, the combination can cause DNA damage that may lead to cancer.[16][17]


While many texts indicate that methylene blue has oxidizing agent properties, its effects as an oxidizing agent occur only at very high doses. At pharmacologic doses it has reducing agent properties. It is owing to this reason that methylene blue is employed as a medication for the treatment of methemoglobinemia. This can arise from ingestion of certain pharmaceuticals, toxins, or broad beans.[18] Normally, through the NADH or NADPH dependent methemoglobin reductase enzymes, methemoglobin is reduced back to hemoglobin. When large amounts of methemoglobin occur secondary to toxins, methemoglobin reductases are overwhelmed. Methylene blue, when injected intravenously as an antidote, is itself first reduced to leucomethylene blue, which then reduces the heme group from methemoglobin to hemoglobin. Methylene blue can reduce the half life of methemoglobin from hours to minutes.[19] At high doses, however, methylene blue actually induces methemoglobinemia, reversing this pathway.[19]

Methylene blue also blocks accumulation of cyclic guanosine monophosphate (cGMP) by inhibiting the enzyme guanylate cyclase: this action results in reduced responsiveness of vessels to cGMP-dependent vasodilators like nitric oxide and carbon monoxide. Cardiac surgical teams have found this very useful in the treatment of extremely low blood pressure (hypotension) which may occur during heart surgery requiring cardiac bypass.[20] Similar use is noted in the treatment of hypotension associated with overwhelming infections (sepsis).[21]

Cyanide poisoning

Since its reduction potential is similar to that of oxygen and can be reduced by components of the electron transport chain, large doses of methylene blue are sometimes used as an antidote to potassium cyanide poisoning, a method first successfully tested in 1933 by Dr. Matilda Moldenhauer Brooks in San Francisco,[22] although first demonstrated by Bo Sahlin of Lund University, in 1926.[22][23]

Dye or stain

Methylene blue is used in endoscopic polypectomy as an adjunct to saline or epinephrine, and is used for injection into the submucosa around the polyp to be removed. This allows the submucosal tissue plane to be identified after the polyp is removed, which is useful in determining if more tissue needs to be removed, or if there has been a high risk for perforation. Methylene blue is also used as a dye in chromoendoscopy, and is sprayed onto the mucosa of the gastrointestinal tract in order to identify dysplasia, or pre-cancerous lesions. Intravenously injected methylene blue is readily released into the urine and thus can be used to test the urinary tract for leaks or fistulas.

In surgeries such as sentinel lymph node dissections, methylene blue can be used to visually trace the lymphatic drainage of pertinent tissues. Similarly, methylene blue is added to bone cement in orthopedic operations to provide easy discrimination between native bone and cement. Additionally, methylene blue accelerates the hardening of bone cement, increasing the speed at which bone cement can be effectively applied. Methylene blue is used as an aid to visualisation/orientation in a number of medical devices, including a Surgical sealant film, TissuePatch.

When methylene blue is "polychromed" (oxidized in solution or "ripened" by fungal metabolism,[24] as originally noted in the thesis of Dr D L Romanowsky in 1890s), it gets serially demethylated and forms all the tri, di, mono and non methyl intermediates - which are Azure B, Azure A, Azure C and thionine respectively.[25] This is the basis of the basophilic part of the spectrum of Romanowski-Giemsa effect. If only synthetic Azure B and Eosin Y is used, it may serve as a standardized Giemsa stain; but, without methylene blue, the normal neutrophilic granules tend to overstain and look like toxic granules. On the other hand, if methylene blue is used it might help to give the normal look of neutrophil granules and may additionally also enhances the staining of nucleoli and polychromatophilic RBCs (reticulocytes).[26]

A traditional application of methylene blue is the intravital or supravital staining of nerve fibers, an effect first described by

  • NIH - Methylene blue test
  • Methylene blue at stainsfile

External links

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  3. ^ Linz A.J., Greenham R.K., Fallon L.F. (May 2006). "Methemoglobinemia: an industrial outbreak among rubber molding workers". J. Occup. Environ. Med. 48 (5): 523–8.  
  4. ^ Badische Anilin- und Sodafabrik [BASF] (Mannheim, Germany), "Verfahren zur Darstellung blauer Farbstoffe aus Dimethylanilin und anderen tertiaren aromatischen Monaminen" (Method for preparation of blue dyes from dimethylaniline and other tertiary aromatic monoamines), Deutsches Reich Patent no. 1886 (December 15, 1877). Available on-line at: P. Friedlaender, Fortschritte der Theerfarbenfabrikation und verwandter Industriezweige (Progress of the manufacture of coal-tar dyes and related branches of industry), volume 1 (Berlin, Germany: Julius Springer, 1888), pages 247-249.
    See also:
    • British patent no. 3751 (October 9, 1877).
    • Heinrich Caro, "Improvement in the production of dye-stuffs from methyl-aniline," U.S. Patent no. 204,796 (filed: March 28, 1878 ; issued: June 11, 1878).
  5. ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014. 
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  7. ^ Salah M., Samy N., Fadel M. (January 2009). "Methylene blue mediated photodynamic therapy for resistant plaque psoriasis".  
  8. ^ Tardivo J.P., Del Giglio A., Paschoal L.H., Baptista M.S. (August 2006). "New photodynamic therapy protocol to treat AIDS-related Kaposi's sarcoma".  
  9. ^ Papin J.F., Floyd R.A., Dittmer D.P. (November 2005). "Methylene blue photoinactivation abolishes West Nile virus infectivity in vivo".  
  10. ^ Zolfaghari P.S., Packer S., Singer M., Nair S.P., Bennett J., Street C., Wilson M. (2009). "In vivo killing of Staphylococcus aureus using a light-activated antimicrobial agent".  
  11. ^ Floyd R.A., Schneider J.E., Dittmer D.P. (March 2004). "Methylene blue photoinactivation of RNA viruses".  
  12. ^ Wagner S.J., Skripchenko A., Pugh J.C., Suchmann D.B., Ijaz M.K. (September 2001). "Duck hepatitis B photoinactivation bydimethylmethylene blue in RBC suspensions".  
  13. ^ Schagen F.H., Moor A.C., Cheong S.C., Cramer S.J., van Ormondt H., van der Eb A.J., Dubbelman T.M., Hoeben R.C. (May 1999). "Photodynamic treatment of adenoviral vectors with visible light: an easy and convenient method for viral inactivation".  
  14. ^ Müller-Breitkreutz K., Mohr H. (November 1998). "Hepatitis C and human immunodeficiency virus RNA degradation by methylene blue/light treatment of human plasma".  
  15. ^ Wagner S.J., Skripchenko A., Robinette D., Mallory D.A., Hirayama J., Cincotta L., Foley J. (2000). "The use of dimethylmethylene blue for virus photoinactivation of red cell suspensions".  
  16. ^ Sturmey R.G., Wild C.P., Hardie L.J. (May 2009). "Removal of red light minimizes methylene blue-stimulated DNA damage in oesophageal cells: implications for chromoendoscopy".  
  17. ^ Olliver J.R., Wild C.P., Sahay P., Dexter S., Hardie L.J. (August 2003). "Chromoendoscopy with methylene blue and associated DNA damage in Barrett's oesophagus".  
  18. ^ Manual of Clinical Hematology, Joseph Mazza
  19. ^ a b Brent J. (2005). Critical care toxicology: diagnosis and management of the critically poisoned patient.  
  20. ^
  21. ^
  22. ^ a b Matilda Moldenhauer Brooks (1936). "Methylene blue as an antidote for cyanide and carbon monoxide poisoning". The  
  23. ^
  24. ^ p172What is Giemsa's stain and how does it color blood cells, bacteria and chromosomes? by John A. Kiernan, Subsection On Chemical Reactions and Staining MechanismsDako Education Guide - Special Stains and H & E " second edition Chapter 19:
  26. ^ Dacie and Lewis Practical Haematology 10th ed, p61
  27. ^ Ehrlich,P. (1887) Biol. Centralblatt 6: 214, cited from Baker JR (1958) Principles of Biological Microtechnique (Reprinted 1970, with corrections). Methuen, London.
  28. ^ Wilson JG (1910) Intra vitam staining with methylene blue. Anatomical Record 4: 267-277.
  29. ^ Schabadasch A (1930) Untersuchungen zur Methodik der Methylenblaufarbung des vegetativen Nervensystems. Zeitschrift fur Zellforschung 10: 221-243.
  30. ^ Zacks Zacks SI (1973) The Motor Endplate, 2nd ed. Huntington, NY: Krieger
  31. ^ Kiernan JA (1974) Effects of metabolic inhibitors on vital staining with methylene blue. Histochemistry 40: 51-57.
  32. ^ Novella Steve. "The ethics of deception in medicine". Science Based Medicine. Retrieved 2008-01-24. 
  33. ^ "Methylene blue for cognitive dysfunction in bipolar disorder".  
  34. ^ Alici-Evcimen Y., Breitbart W.S. (October 2007). "Ifosfamide neuropsychiatric toxicity in patients with cancer". Psychooncology 16 (10): 956–960.  
  35. ^ Patel P.N. (2006). "Methylene blue for management of ifosfamide induced encephalopathy". Annals of Pharmacotherapy 40 (2): 266–303.  
  36. ^ Dufour C., Grill J., Sabouraud P., et al. (February 2006). "Ifosfamide induced encephalopathy: 15 observations". Arch. Pediatr. (in French) 13 (2): 140–145.  
  37. ^ Aeschlimann T.; Cerny, T; Küpfer, A (1996). "Inhibition of (mono)amine oxidase activity and prevention of ifosfamide encephalopathy by methylene blue". Drug. Metab. Dispos. 24 (12): 1336–1339.  
  38. ^ Levin RL, Degrange MA, Bruno GF, Del Mazo CD, Taborda DJ, Griotti JJ, Boullon FJ (February 2004). "Methylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery.". Ann Thorac Surg 77 (2): 496–9.  
  39. ^ "BestBets: Is Methylene Blue of benefit in treating adult patients who develop vasoplegic syndrome during Cardiac Surgery". 
  40. ^ Stawicki SP, Sims C, Sarani B, Grossman MD, Gracias VH (May 2008). "Methylene blue and vasoplegia: who, when, and how?". Mini Rev Med Chem 8 (5): 472–90.  
  41. ^ Mokhlesi B., Leikin J.B., Murray P., Corbridge T.C. (March 2003). "Adult toxicology in critical care: Part II: specific poisonings".  
  42. ^ Harvey J.W., Keitt A.S. (May 1983). "Studies of the efficacy and potential hazards of methylene blue therapy in aniline-induced methaemoglobinaemia".  
  43. ^ Ramsay RR; Dunford, C.; Gillman, C.K. (August 2007). "Methylene blue and serotonin toxicity: inhibition of monoamine oxidase A (MAO A) confirms a theoretical prediction.". Br J Pharmacol 152 (6): 946–951.  
  44. ^ Gillman P.K. (October 2006). "Methylene blue implicated in potentially fatal serotonin toxicity".  
  45. ^ L. Michaelis; M. P. Schubert; S. Granick (1940). "Semiquinone Radicals of the Thiazines". J. Am. Chem. Soc. 62 (1): 204–211.  
  46. ^ J. Cenens and R. A. Schoonheydt (1988). "VISIBLE SPECTROSCOPY OF METHYLENE BLUE ON HECTORITE, LAPONITE B, AND BARASYM IN AQUEOUS SUSPENSION" (PDF). Clay and Clay Minerals 36 (3): 214–224. 
  47. ^ 2−Spectroquant 114779 Sulfide Test. Method: photometric 0.020 - 1.50 mg/l S
  48. ^ Standard Test Method for Rapid Determination of the Methylene Blue Value for Fine Aggregate or Mineral Filler Using a Colorimeter
  49. ^ Construction Standard CS3:2013 – Aggregates for Concrete
  50. ^ [2] Aquarium Chemical Treatments
  51. ^
  52. ^ a b Schirmer H.; Coulibaly B.; Stich A.; et al. (2003). "Methylene blue as an antimalarial agent—past and future". Redox Rep 8 (5): 272–276.  
  53. ^ Guttmann, P. and Ehrlich. P. (1891) "Über die Wirkung des Methylenblau bei Malaria" (On the effect of methylene blue on malaria), Berliner Klinische Wochenschrift, 28 : 953-956.
  54. ^ Meissner P.E.; Mandi G.; Coulibaly B.; et al. (2006). "Methylene blue for malaria in Africa: results from a dose-finding study in combination with chloroquine". Malaria Journal 5: 84.  
  55. ^ "Alzheimer's drug 'halts' decline".  
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  57. ^ Medina DX, C. A., Oddo S (2011). "Methylene blue reduces Aβ levels and rescues early cognitive deficit by increasing proteasome activity". Brain Pathology 21 (2): 140–149.  
  58. ^ "Potential Efficacy". 
  59. ^ "Phase III". 
  60. ^ Atamna H., Nguyen A., Schultz C., Boyle K., Newberry J., Kato H., Ames B.N. (March 2008). "Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways". FASEB J. 22 (3): 703–712.  
  61. ^ Bonda, D. J., Lee, H.-P., Lee, H., Friedlich, A. L., Perry, G., Zhu, X., & Smith, M. A. (2010). "Novel therapeutics for Alzheimer's disease: An update". Current Opinion in Drug Discovery & Development 13 (2): 235–246.  
  62. ^ Wondrak GT (2007). "NQO1-activated phenothiazinium redox cyclers for the targeted bioreductive induction of cancer cell apoptosis". Free Radic Biol Med 43 (2): 178–90.  
  63. ^ "Enhancing the Efficacy of Photodynamic Cancer Therapy by Radicals from Plant Auxin (Indole-3-Acetic Acid)". Cancer Res 63: 776. 2003. 


See also

Methylene blue, toluidine blue, and other 3,7-diaminophenothiazinium-based redox cyclers appear to induce selective cancer cell apoptosis by NAD(P)H:quinone oxidoreductase (NQO1)-dependent bioreductive generation of cellular oxidative stress.[62] Combined with plant auxin (indole-3-acetic acid), methylene blue is has been investigated for the photodynamic treatment of cancer.[63]

Methylene blue might also delay senescence as one study has shown that it extended the lifespan of IMR90 fibroblasts by more than 20 population doublings.[60] LMTX addresses some of the concerns about dose-response which were raised earlier in the study.[61]

Methylene blue, under the brand name Rember, has been investigated for treatment of Alzheimer's dementia.[55][56] Methylene blue is proposed to affect neurodegeneration in Alzheimer's disease via inhibition of tau protein aggregation. Methylene blue also affects dissociation of amyloids[57][58] TauRx Therapeutics have reformulated the drug, under the brand name LMTX, which has been prioritized ahead of rember due-to better outcome expected with the newer product.[59]

Clinical trials

Methylene blue was identified by Paul Ehrlich about 1891 as a possible treatment for malaria.[53] It disappeared as an anti-malarial during the Pacific War in the tropics, since American and Allied soldiers disliked its two prominent, but reversible side effects: turning the urine blue or green, and the sclera (the whites of the eyes) blue. Interest in its use as an anti-malarial has recently been revived,[52] especially due to its low price. Several clinical trials are in progress, trying to find a suitable drug combination. According to studies on children in Africa, Methylene Blue appears to have efficacy against malaria, but the attempts to combine methylene blue with chloroquine were disappointing.[54]



Methylene blue has been described as "the first fully synthetic drug used in medicine." Its use in the treatment of malaria was pioneered by Paul Guttmann and Paul Ehrlich in 1891. During this period before the first World War, researchers like Ehrlich believed that drugs and dyes worked in the same way, by preferentially staining pathogens and possibly harming them. Methylene blue continued to be used in the second World War, where it was not well liked by soldiers, who observed, "Even at the loo, we see, we pee, navy blue." Antimalarial use of the drug has recently been revived.[51] The blue urine was used to monitor psychiatric patients' compliance with medication regimes. This led to interest - from the 1890s to the present day - in the drug's antidepressant and other psychotropic effects. It became the lead compound in research leading to the discovery of chlorpromazine.[52]


Methylene blue is used in aquaculture and by tropical fish hobbyists as a treatment for fungal infections. It can also be effective in treating fish infected with ich although a combination of malachite green and formaldehyde is far more effective against the parasitic protozoa Ichthyophthirius multifiliis. It is usually used to protect newly laid fish eggs from being infected by fungus or bacteria. This is useful when the hobbyist wants to artificially hatch the fish eggs. Methylene Blue is also very effective when used as part of a "medicated fish bath" for treatment of ammonia, nitrite, and cyanide poisoning as well as for topical and internal treatment of injured or sick fish as a "first response".[50]


In neuroscience, methylene blue can also serve as a non-selective inhibitor of NO synthase.

It can also be used as an indicator to determine if eukaryotic cells such as yeast are alive or not. The methylene blue is reduced in viable cells leaving them unstained. However dead cells are unable to reduce the oxidized methylene blue and the cells are stained blue. Methylene blue can interfere with the respiration of the yeast as it picks up hydrogen ions made during the process and the yeast cell cannot then use those ions to release energy.

In biology methylene blue is used as a dye for a number of different staining procedures, such as Wright's stain and Jenner's stain. Since it is a temporary staining technique, methylene blue can also be used to examine RNA or DNA under the microscope or in a gel: as an example, a solution of methylene blue can be used to stain RNA on hybridization membranes in northern blotting to verify the amount of nucleic acid present. While methylene blue is not as sensitive as ethidium bromide, it is less toxic and it does not intercalate in nucleic acid chains, thus avoiding interference with nucleic acid retention on hybridization membranes or with the hybridization process itself.


Methylene Blue Value reflects the amount of the clay minerals in the aggregate samples.[48] Methylene Blue solution is successively added to fine aggregate which is being agitating in water. The presence of free dye solution can be checked with stain test on a filter paper.[49]

Methylene Blue Value of Fine Aggregate

The MBAS assay cannot distinguish between specific surfactants, however. Some examples of anionic surfactants are carboxylates, phosphates, sulfates, and sulfonates.

A color reaction in an acidified, aqueous methylene blue solution containing chloroform can detect anionic surfactants in a water sample. Such a test is known as an MBAS assay (methylene blue active substances assay).

Water testing

The addition of a strong reducing agent, such as ascorbic acid, to a sulfide-containing solution is sometimes used to prevent sulfide oxidation from atmospheric oxygen. Although it is certainly a sound precaution for the determination of sulfide with an ion selective electrode, it might however hamper the development of the blue color if the freshly formed methylene blue is also reduced, as described here above in the paragraph on redox indicator.

The formation of methylene blue after the reaction of hydrogen sulfide with dimethyl-p-phenylenediamine and iron(III) at pH 0.4 – 0.7 is used to determine by photometric measurements sulfide concentration in the range 0.020 to 1.50 mg/L (20 ppb to 1.5 ppm). The test is very sensitive and the blue coloration developing upon contact of the reagents with dissolved H2S is stable for 60 min. Ready-to-use kits such as the Spectroquant sulfide test[47] facilitate routine analyses. The methylene blue sulfide test is a convenient method often used in soil microbiology to quickly detect in water the metabolic activity of sulfate reducing bacteria (SRB). It should be observed that in this test, methylene blue is a product of reaction and not a reagent.

Sulfide analysis

Methylene blue is also a peroxides by a Diels-Alder reaction which is spin forbidden with normal atmospheric triplet oxygen.

Peroxide generator

Methylene blue is widely used as a redox indicator in analytical chemistry. Solutions of this substance are blue when in an oxidizing environment, but will turn colorless if exposed to a reducing agent. The redox properties can be seen in a classical demonstration of chemical kinetics in general chemistry, the "blue bottle" experiment. Typically, a solution is made of glucose (dextrose), methylene blue, and sodium hydroxide. Upon shaking the bottle, oxygen oxidizes methylene blue, and the solution turns blue. The dextrose will gradually reduce the methylene blue to its colorless, reduced form. Hence, when the dissolved dextrose is entirely consumed, the solution will turn blue again.

Redox indicator

A volumetric flask of a methylene blue solution

Other uses

Species Absorption peak Extinction coefficient (dm3/mole·cm)
MB+ (solution) 664 95000
MBH2+ (solution) 741 76000
(MB+)2 (solution) 605 132000
(MB+)3 (solution) 580 110000
MB+ (adsorbed on clay) 673 116000
MBH2+ (adsorbed on clay) 763 86000
(MB+)2 (adsorbed on clay) 596 80000
(MB+)3 (adsorbed on clay) 570 114000

Methylene blue is a potent cationic dye with maximum absorption of light around 670 nm. The specifics of absorption depend on a number of factors, including protonation, adsorption to other materials, and metachromasy - the formation of dimers and higher-order aggregates depending on concentration and other interactions:[46]

Absorption spectrum of methylene blue, in terms of the molar extinction coefficient (base 10 logarithm). In this dataset a peak absorbance of 1.7 (i.e. 98% of transmitted light absorbed) was observed with 665 nm light passing through 1 cm of 10 micromolar methylene blue solution.

Light absorption properties

This compound may be prepared by treating dimethyl-4-phenylenediamine with hydrogen sulfide dissolved in hydrochloric acid, followed by oxidation with ferric chloride:[45]


It causes hemolytic anemia in carriers of the G6PD (favism) enzymatic deficiency.

Methylene blue is a monoamine oxidase inhibitor (MAOI),[43] and if infused intravenously at doses exceeding 5 mg/kg, may precipitate serious serotonin toxicity, serotonin syndrome, if combined with any selective serotonin reuptake inhibitors (SSRIs) or other serotonin reuptake inhibitor (e.g., duloxetine, sibutramine, venlafaxine, clomipramine, imipramine).[44]

Cardiovascular Central Nervous System Dermatologic Gastrointestinal Genito-urinary Hematologic
Precordial pain
• Mental confusion
• Staining of skin
• Injection site necrosis (SC)
• Fecal discoloration
Abdominal pain
• Discoloration of urine (doses over 80 µg)
Bladder irritation

Side effects

Some literature has reported the use of methylene blue as an adjunct in the management of patients experiencing vasoplegic syndrome after cardiac surgery.[38][39][40]

Vasoplegic syndrome after cardiac surgery

Another, less well-known use of methylene blue is its utility for treating ifosfamide neurotoxicity. Methylene blue was first reported for treatment and prophylaxis of ifosfamide neuropsychiatric toxicity in 1994. A toxic metabolite of ifosfamide, chloroacetaldehyde (CAA), disrupts the mitochondrial respiratory chain, leading to an accumulation of nicotinamide adenine dinucleotide hydrogen (NADH). Methylene blue acts as an alternative electron acceptor, and reverses the NADH inhibition of hepatic gluconeogenesis while also inhibiting the transformation of chloroethylamine into chloroacetaldehyde, and inhibits multiple amine oxidase activities, preventing the formation of CAA.[34] The dosing of methylene blue for treatment of ifosfamide neurotoxicity varies, depending upon its use simultaneously as an adjuvant in ifosfamide infusion, versus its use to reverse psychiatric symptoms that manifest after completion of an ifosfamide infusion. Reports suggest that methylene blue up to six doses a day have resulted in improvement of symptoms within 10 minutes to several days.[35] Alternatively, it has been suggested that intravenous methylene blue every six hours for prophylaxis during ifosfamide treatment in patients with history of ifosfamide neuropsychiatric toxicity.[36] Prophylactic administration of methylene blue the day before initiation of ifosfamide, and three times daily during ifosfamide chemotherapy has been recommended to lower the occurrence of ifosfamide neurotoxicity.[37]

Ifosfamide neurotoxicity

Methylene blue has been used as a placebo; physicians would tell their patients to expect their urine to change color and view this as a sign that their condition had improved.[32] This same side effect makes methylene blue difficult to test in traditional placebo-controlled clinical studies.[33]


[31] The mechanism of selective dye uptake is incompletely understood; vital staining of nerve fibers in skin is prevented by ouabain, a drug that inhibits the Na/K-ATPase of cell membranes.[30][29][28]

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