Difference between revisions of "Methylene blue" - New World Encyclopedia

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Methylene blue

Chemical name	3,7-bis(Dimethylamino)- phenothiazin-5-ium chloride or Tetramethyl thionine
Empirical formula	C₁₆H₁₈ClN₃S
Molecular mass	319.86 g/mol
CAS number	[61-73-4]
EC number	200-515-2
Melting point	at 100-110 °C decomposes
Boiling point	Decomposes
Simplified molecular input line entry specification(SMILES)	CN(C)c3ccc2nc1ccc(N(C) C)cc1[s+]c2c3.[Cl-]
Disclaimer and references

Methylene blue, or MB, is a basic aniline dye with empirical formula: C₁₆H₁₈Cl N₃S. Its anhydrous molecular formula is C₁₆H₁₈H₃S Cl, and has many uses in a range of different fields, including biology, chemistry, medicine, as well as aquaculture. At room temperature it appears as a solid, odorless, dark green powder, that yields a blue solution when dissolved in water.

Other Names

Trade names for methylene blue include Desmoid piller, Desmoidpillen, Panatone, Urolene Blue, and Vitableu, while synonyms include: Phenothiazine-5-ium, 3,7-bis(dimethylamino)-, chloride (9CI); C.I. Basic Blue 9 (8CI); methylthionine chloride; methylthioninium chloride; tetramethylthionine chloride; swiss blue; aizen methylene blue; C.I. 52015. 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.

Uses

Chemistry

Methylene blue is widely used a redox indicator in analytical chemistry meaning that it indicates the presence or absence of oxygen. Oxygen-rich environments are said to be oxidizing. Oxidizing chemicals, such as oxygen and chlorine, strip electrons away from atoms of other elements. Chemical elements that have such a strong attraction for electrons that they can take electrons away from other types of atoms are known as oxidizing agents, and are very useful in chemistry. Methylene blue indicates the presence of oxidizing agents because it is oxidized itself by these compounds. When electrons are stripped from methylene blue, the resulting molecule imparts a blue color to the solution—giving a clear sign of a chemical change. ^[1]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, 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 oxygen is entirely consumed, the solution will turn colorless. ^[2]Methylene blue is also used to make the reaction between Fehling's solution and reducing sugars more visible, and as a reagent in redox titrations in volumetric analysis. ^[3]

Biology

Methylene blue is commonly used by biologists as a dye that assists in the identification of bacteria. Because bacteria are practically colorless, adding a drop or two of methylene blue to a microscope slide enables the biologists to see bacterial shapes and structures. Dyes like methylene blue (referred to as stains in biology) work by binding to biological tissues as a result of chemical attractions. Methylene blue is at its deepest shade of blue when in contact with acids, which makes it very useful in the identification of nucleic acids, like DNA and RNA.^[4] It can also work as an alternative to the chemical crystal violet in cellular structure|gram's staining procedures. ^[5] As a result of this attraction to nucleic acids, methylene blue has also been used in procedures such as northern blotting/ northern hybridization (which is used for the detection of specific RNA sequences), in order to visualize RNA.^[6] In addition, methylene blue is used as a safer alternative for another chemical called ethidium bromide (normally used in the visualization of DNA on gels in blotting procedures western blot. This is because ethidium bromide is a potent carcinogen and mutagen, and also because the short-length UV light that is required for ethidium bromide to fluroresce (and thereby aid in visualizing the DNA) can cause unwanted mutations in the DNA sample itself. Drawbacks of using methylene blue as a replacement are that it is less sensitive than ethidium bromide, and also fades rapidly after staining. This makes methylene blue an unideal replacement (though suitable for school contexts, due to it's less harmful nature). ^[7] Methylene blue has also been used as a way to obtain a quick estimate of the percentage of viable cells in a yeast sample, since viable yeast cells contain an enzyme that decolorizes methylene blue, whereas dead cells do not. As a result, when cells from a yeast are suspended in the dye, it penetrates all the cells, and leaves the dead cells blue, and the living cells unstained. Despite this, it must be noted that this method simply indicates whether an enzyme is present in the yeast cells (not whether the cells are incapable of dividing), and therefore is less accurate than other methods, and should be used to simply provide a rapid estimate. ^[8]

Medicine

Methylene blue has wide use in the medical community. It is employed as a treatment for the treatment of methemoglobinemia, a disorder in which methemoglobin (oxidized hemoglobin) levels rise above their normal 1% in blood. Methemoglobin lacks the electron that is needed to form a bond with oxygen and, thus, is incapable of oxygen transport, meaning that, if there is too much methemoglobin in the blood, a person can die because of lack of oxygen to vital tissues and organs. Because of methylene blue's reducing abilities, it can reduce the excess methemoglobin to hemoglobin, thereby restoring normal methemoglobin levels. ^[9] Methylene blue can also be used as a stain for surgical and medical marking (though it can cause localized tissue inflammation), as well as a diagnostic agent in renal function tests and in vital nerve staining. It has also been used as an antidote for cyanide poisoning, but it should be used carefully, because it may make cyanide toxicity worse by increasing the amount of cyanide in the blood. ^[10] Sodium nitrite is considered to be a safer and more effective antidote.

The drug has also been used for the treatment of manic-depressive psychosis, the herpes simplex, chronic urolithiasis (formation of kidney and bladder stones), and glutaricaciduria (a rare hereditary metabolic disorder, that results in the accumulation of excess organic acids in the blood and urine). Methylene blue was formerly used as as a urinary antiseptic, a treatment for cystitis (bladder infection) and urethritis (infection of the urethra), as well as an analgesic (painkiller) and antipyretic (fever reducer); however, there are more effective agents used now. In terms of its effectiveness as an antiparasitic, methylene blue has shown to have effects against malaria.

Aquaculture

Methylene blue is used in aquaculture and by tropical fish hobbyists as a bacterial and fungal infection preventative on freshwater fish eggs. It is also commonly used as a additive in a solution in which infected (or newly purchased) fish are dipped (commonly called a dip). In the dip, the methylene blue serves to fight and kill the offending organisms, as well as increase the oxygen carrying capacity of the fish's hemoglobin. ^[11] While some hobbyists use methylene blue to treat fish infected with ich, the parasitic[protozoa]] Ichthyophthirius multifiliis, methylene blue has shown to not be the most effective solution, and other solutions, such as ionized copper, are instead suggested. ^[12] While methylene blue is non-toxic to fish if used in the proper dosage, it is toxic to live plants, and also will harm fish if placed in long-term contact with them.

Other uses

Methylene blue has also been used as a dye for temporary hair colorants, cotton, wool, leather, and paper.

Misuse

While methylene blue has many uses in the medicine, it has also been used inappropriately by pranksters, due to it's ability to alter urine with a green-blue color. About 75% of an oral dose of methylene blue is released into the urine (mostly in its reduced form - leucomethylene blue), thereby adding a blue-green hue to the urine (some of the remaining methylene blue is excreted via the bile). However, use of this substance in such a way is dangerous, because methylene blue is a biologically active substance^[13], and if administered inappropriately, can lead to a number of health complications, including gastrointestinal disturbances and dysuria. Large doses of methylene blue can can produce methaemoglobinaemia, as well as chest pain, dyspnoea, restlessness, apprehension, tremors, a sense of oppression, urinary tract irritation, as well as a mild haemolysis with moderate hyperbilirubinaemia, reticulosis and slight anaemia.^[14]

Notes

References
ISBN links support NWE through referral fees

Schirmer H, Coulibaly B, Stich A, et al. (2003). Methylene blue as an antimalarial agent—past and future. Redox Rep. 8: 272–76.

Meissner PE, 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.

http://ntp.niehs.nih.gov/ntpweb/index.cfm?objectid=0004CBF9-F1F6-975E-7960ACB47153C2FC

http://eprints.hec.gov.pk/1102/

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=6222095&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

External links

Credits

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@@ Line 5: / Line 5: @@
 | align="center" colspan="2" bgcolor="#ffffff" | [[Image:Methylene blue.svg|200px|Methylene blue]]<br/>[[Image:Methylene-blue-ox-3D-vdW.png|200px|Space-filling model of methylene blue in its oxidised form]]
 |-
-| [[IUPAC nomenclature|Chemical name]]
+| Chemical name
 | 3,7-bis(Dimethylamino)-<br />phenothiazin-5-ium chloride<br /> or Tetramethyl thionine
 |-
@@ Line 11: / Line 11: @@
 | {{{formula|C<sub>16</sub>H<sub>18</sub>ClN<sub>3</sub>S}}}
 |-
-| [[Molecular mass]]
+| Molecular mass
 | {{{mol_mass|319.86}}} g/mol
 |-
-| [[CAS registry number|CAS number]]
+| CAS number
 | [{{{CAS|61-73-4}}}]
 |-
-| [[EC-No|EC number]]
+| EC number
 | 200-515-2
 |-
@@ Line 26: / Line 26: @@
 | Decomposes
 |-
-| [[Simplified molecular input line entry specification|SMILES]]
+| Simplified molecular input line entry specification(SMILES)
 | {{{SMILES|CN(C)c3ccc2nc1ccc(N(C)<br />C)cc1[s+]c2c3.[Cl-]}}}
 |-
@@ Line 33: / Line 33: @@
 |}
-'''Methylene blue''', or MB, is a basic aniline dye with [[empirical formula]]: [[carbon|C]]<sub>16</sub>[[hydrogen|H]]<sub>18</sub>[[chlorine|Cl]][[nitrogen|N]]<sub>3</sub>[[sulfur|S]].  Its anhydrous molecular formula is [[carbon|C]]<sub>16</sub>[[hydrogen|H]]<sub>18</sub>[[hydrogen|H]]<sub>3</sub>[[sulfur|S]][[chlorine|Cl]], and has many uses in a range of different fields, including [[biology]], [[chemistry]], medicine, as well as aquaculture.  At room temperature it appears as a solid, odorless, dark green powder, that yields a blue solution when dissolved in [[water (molecule)|water]].
+'''Methylene blue''', or MB, is a basic aniline dye with [[empirical formula]]: [[carbon|C]]<sub>16</sub>[[hydrogen|H]]<sub>18</sub>[[chlorine|Cl]][[nitrogen|N]]<sub>3</sub>[[sulfur|S]].  Its anhydrous molecular formula is [[carbon|C]]<sub>16</sub>[[hydrogen|H]]<sub>18</sub>[[hydrogen|H]]<sub>3</sub>[[sulfur|S]][[chlorine|Cl]], and has many uses in a range of different fields, including [[biology]], [[chemistry]], medicine, as well as aquaculture.  At room temperature it appears as a solid, odorless, dark green powder, that yields a blue solution when dissolved in [[water]].
 ==Other Names==
-Trade names for methylene blue include Desmoid piller, Desmoidpillen, Panatone, Urolene Blue, and Vitableu, while synonyms include: Phenothiazine-5-ium, 3,7-bis(dimethylamino)-, chloride (9CI); C.I. Basic Blue 9 (8CI); methylthionine chloride; methylthioninium chloride; tetramethylthionine chloride; swiss blue; aizen methylene blue; C.I. 52015.  Methylene blue should not be confused with [[methyl blue]], another [[histology]] stain, [[new methylene blue]], nor with the [[methyl violet]]s often used as [[pH indicator]]s.
+Trade names for methylene blue include Desmoid piller, Desmoidpillen, Panatone, Urolene Blue, and Vitableu, while synonyms include: Phenothiazine-5-ium, 3,7-bis(dimethylamino)-, chloride (9CI); C.I. Basic Blue 9 (8CI); methylthionine chloride; methylthioninium chloride; tetramethylthionine chloride; swiss blue; aizen methylene blue; C.I. 52015.  Methylene blue should not be confused with methyl blue, another histology stain, new methylene blue, nor with the methyl violets often used as [[pH indicator]]s.
 ==Uses==
 ===Chemistry===
-Methylene blue is widely used a [[redox indicator]] in [[analytical chemistry]] meaning that it indicates the presence or absence of oxygen.  Oxygen-rich environments are said to be "oxidizing." Oxidizing chemicals, such as oxygen and chlorine, strip electrons away from atoms of other elements. Chemical elements that have such a strong attraction for electrons that they can "rip" electrons away from other types of atoms are known as oxidizing agents, and are very useful in chemistry. Methylene blue indicates the presence of oxidizing agents because it is oxidized itself by these compounds. When electrons are stripped from methylene blue, the resulting molecule imparts a blue color to the solution—giving a clear sign of a chemical change. <ref>http://www.americanchemistry.com/s_chlorine/sec_content.asp?CID=1251&DID=4729&CTYPEID=113</ref>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 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 oxygen is entirely consumed, the solution will turn colorless. <ref>http://www.cci.ethz.ch/experiments/methylen/en/stat.html</ref>Methylene blue is also used to make the reaction between Fehling's solution and reducing sugars more visible, and as a reagent in redox titrations in volumetric analysis. <ref>http://www.starch.dk/isi/methods/27DE.htm</ref>
+Methylene blue is widely used a [[redox]] indicator in [[analytical chemistry]] meaning that it indicates the presence or absence of [[oxygen]].  [[Oxygen]]-rich environments are said to be oxidizing. Oxidizing chemicals, such as oxygen and chlorine, strip electrons away from atoms of other elements. Chemical elements that have such a strong attraction for electrons that they can take [[electron]]s away from other types of atoms are known as oxidizing agents, and are very useful in chemistry. Methylene blue indicates the presence of oxidizing agents because it is oxidized itself by these compounds. When [[electron]]s are stripped from methylene blue, the resulting molecule imparts a blue color to the solution—giving a clear sign of a chemical change. <ref>http://www.americanchemistry.com/s_chlorine/sec_content.asp?CID=1251&DID=4729&CTYPEID=113</ref>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]], 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 oxygen is entirely consumed, the solution will turn colorless. <ref>http://www.cci.ethz.ch/experiments/methylen/en/stat.html</ref>Methylene blue is also used to make the reaction between Fehling's solution and reducing sugars more visible, and as a reagent in [[redox]] [[titration]]s in volumetric analysis. <ref>http://www.starch.dk/isi/methods/27DE.htm</ref>
 ===Biology===
-Methylene blue is commonly used by biologists as a dye that assists in the identification of bacteria.  Because bacteria are practically colorless, adding a drop or two of methylene blue to a microscope slide enables the biologists to see bacterial shapes and structures.  Dyes like methylene blue (referred to as stains in biology) work by binding to biological tissues as a result of chemical attractions.  Methylene blue is at its deepest shade of blue when in contact with acids, which makes it very useful in the identification of nucleic acids, like DNA and RNA.<ref>http://www.americanchemistry.com/s_chlorine/sec_content.asp?CID=1252&DID=4730&CTYPEID=113</ref>  It can also work as an alternative to the chemical crystal violet in [[Bacteria|cellular structure|gram's staining procedures]]. <ref>http://www.eng.umd.edu/~nsw/ench485/lab9b.htm</ref>  As a result of this attraction to nucleic acids, methylene blue has also been used in procedures such as northern blotting/ northern hybridization (which is used for the detection of specific RNA sequences), in order to visualize RNA.<ref>http://wheat.pw.usda.gov/~lazo/methods/iubio/northgel.html</ref>  In addition, methylene blue is used as a safer alternative for another chemical called ethidium bromide (normally used in the visualization of DNA on gels in blotting procedures [[Antibody|western blot]].  This is because ethidium bromide is a potent carcinogen and mutagen, and also because the short-length UV light that is required for ethidium bromide to fluroresce (and thereby aid in visualizing the DNA) can cause unwanted mutations in the DNA sample itself.  Drawbacks of using methylene blue as a replacement are that it is less sensitive than ethidium bromide, and also fades rapidly after staining.  This makes methylene blue an unideal replacement (though suitable for school contexts, due to it's less toxic nature). <ref>http://www.bioscience-explained.org/EN1.2/schollar.html</ref>
+Methylene blue is commonly used by biologists as a dye that assists in the identification of [[bacteria]].  Because [[bacteria]] are practically colorless, adding a drop or two of methylene blue to a [[microscope]] slide enables the biologists to see bacterial shapes and structures.  Dyes like methylene blue (referred to as stains in [[biology]]) work by binding to biological [[tissue]]s as a result of chemical attractions.  Methylene blue is at its deepest shade of blue when in contact with [[acid]]s, which makes it very useful in the identification of [[nucleic acid]]s, like DNA and RNA.<ref>http://www.americanchemistry.com/s_chlorine/sec_content.asp?CID=1252&DID=4730&CTYPEID=113</ref>  It can also work as an alternative to the chemical crystal violet in [[Bacteria|cellular structure|gram's staining procedures]]. <ref>http://www.eng.umd.edu/~nsw/ench485/lab9b.htm</ref>  As a result of this attraction to [[nucleic acid]]s, methylene blue has also been used in procedures such as northern blotting/ northern hybridization (which is used for the detection of specific RNA sequences), in order to visualize RNA.<ref>http://wheat.pw.usda.gov/~lazo/methods/iubio/northgel.html</ref>  In addition, methylene blue is used as a safer alternative for another [[chemical]] called ethidium bromide (normally used in the visualization of DNA on gels in blotting procedures [[Antibody|western blot]].  This is because ethidium bromide is a potent [[carcinogen]] and mutagen, and also because the short-length UV [[light]] that is required for ethidium bromide to fluroresce (and thereby aid in visualizing the DNA) can cause unwanted mutations in the DNA sample itself.  Drawbacks of using methylene blue as a replacement are that it is less sensitive than ethidium bromide, and also fades rapidly after staining.  This makes methylene blue an unideal replacement (though suitable for school contexts, due to it's less harmful nature). <ref>http://www.bioscience-explained.org/EN1.2/schollar.html</ref>
-Methylene blue has also been used as a way to obtain a quick estimate of the percentage of viable cells in a yeast sample, since viable yeast cells contain an enzyme that decolorizes methylene blue, whereas dead cells do not.  As a result, when cells from a yeast are suspended in the dye, it penetrates all the cells, and leaves the dead cells blue, and the living cells unstained.  Despite this, it must be noted that this method simply indicates whether an enzyme is present in the yeast cells (not whether the cells are incapable of dividing), and therefore is less accurate than other methods, and should be used to simply provide a rapid estimate. <ref>http://www.wfcc.info/tis/info2.html</ref>
+Methylene blue has also been used as a way to obtain a quick estimate of the percentage of viable [[cell]]s in a [[yeast]] sample, since viable yeast cells contain an [[enzyme]] that decolorizes methylene blue, whereas dead cells do not.  As a result, when cells from a [[yeast]] are suspended in the dye, it penetrates all the cells, and leaves the dead cells blue, and the living cells unstained.  Despite this, it must be noted that this method simply indicates whether an [[enzyme]] is present in the [[yeast]] [[cell]]s (not whether the cells are incapable of dividing), and therefore is less accurate than other methods, and should be used to simply provide a rapid estimate. <ref>http://www.wfcc.info/tis/info2.html</ref>
 ===Medicine===
-Owing to its reducing agent properties, methylene blue is employed as a medication for the treatment of [[methemoglobinemia]], which can arise from ingestion of certain pharmaceuticals or [[Vicia faba|broad beans]]. Basically, methylene blue acts to reduce the [[heme]] group from [[methemoglobin]] to [[hemoglobin]], however since methylene blue is toxic, any methemoglobinemia treatment with this substance should be strictly evaluated by a doctor.<br />
+Methylene blue has wide use in the medical community.  It is employed as a treatment for the treatment of methemoglobinemia, a disorder in which methemoglobin (oxidized hemoglobin) levels rise above their normal 1% in blood.  Methemoglobin lacks the electron that is needed to form a bond with oxygen and, thus, is incapable of oxygen transport, meaning that, if there is too much methemoglobin in the blood, a person can die because of lack of oxygen to vital tissues and organs.  Because of methylene blue's reducing abilities, it can reduce the excess methemoglobin to hemoglobin, thereby restoring normal methemoglobin levels.    <ref>http://www.emedicine.com/EMERG/topic313.htm</ref>  Methylene blue can also be used as a stain for surgical and medical marking (though it can cause localized tissue inflammation), as well as a diagnostic agent in renal function tests and in vital nerve staining.  It has also been used as an antidote for cyanide poisoning, but it should be used carefully, because it may make cyanide toxicity worse by increasing the amount of cyanide in the blood. <ref>http://www.drugs.com/cons/methylene-blue.html</ref>  Sodium nitrite is considered to be a safer and more effective antidote.  <br><br>The drug has also been used for the treatment of manic-depressive psychosis, the herpes simplex, chronic urolithiasis (formation of kidney and bladder stones), and  glutaricaciduria (a rare hereditary metabolic disorder, that results in the accumulation of excess organic acids in the blood and urine).  Methylene blue was formerly used as as a urinary antiseptic, a treatment for cystitis (bladder infection) and urethritis (infection of the urethra), as well as an analgesic (painkiller) and antipyretic (fever reducer); however, there are more effective agents used now.  In terms of its effectiveness as an antiparasitic, methylene blue has shown to have effects against malaria.
-Methylene blue also blocks accumulation of cyclic guanosine monophosphate ([[Cyclic guanosine monophosphate|cGMP]]) by inhibiting the enzyme [[guanylate cyclase]]: this action results in reduced responsiveness of vessels to cGMP-dependent [[vasodilator]]s like [[nitric oxide]] and [[carbon monoxide]].
-Methylene blue is used in [[colonoscopy|endoscopic]] [[polyp (medicine)|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 [[endoscopy|chromoendoscopy]], and is sprayed onto the mucosa of the [[gastrointestinal tract]] in order to identify [[dysplasia]], or pre-cancerous lesions.
-Methylene blue was used at the end of the century as a successful treatment for [[malaria]]. It disappeared as an anti-malarial during the wars in Asia, as U.S. soldiers disliked its two inevitable, fully reversible side effects: green [[urine]] and blue [[sclera]]. Interest in its use has recently been revived,<ref>{{cite journal | author=Schirmer H, Coulibaly B, Stich A, ''et al.'' | title=Methylene blue as an antimalarial agent&mdash;past and future | journal=Redox Rep. | year=2003 | volume=8 | pages=272&ndash;76 | doi=10.1179/135100003225002899}}</ref> especially because it is very cheap. Several clinical trials are in progress, trying to find a suitable drug combination. Initial attempts to combine methylene blue with [[chloroquine]] were disappointing;<ref>{{cite journal | title=Methylene blue for malaria in Africa: results from a dose-finding study in combination with chloroquine | author=Meissner PE, Mandi G, Coulibaly B, ''et al.'' | journal=Malaria Journal | year=2006 | volume=5 | pages=84 | doi=10.1186/1475-2875-5-84}}</ref> however, more recent attempts have appeared more promising.
-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 [[cyanide]] poisoning.
-Methylene blue is probably a [[monoamine oxidase inhibitor]], and if infused intravenously at doses exceeding 5&nbsp;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]]).<ref>{{cite journal | author=Gillman PK. | year=2006 | title=Methylene Blue implicated in potentially fatal serotonin toxicity | journal=Anaesthesia | volume=61 | pages=1013-14 | doi=10.1111/j.1365-2044.2006.04808.x}}</ref>
 ===Aquaculture===
@@ Line 72: / Line 65: @@
 ==References==
-<<'''This article needs at least 3 reliable references, properly formatted.'''>>
+#{{cite journal | author=Schirmer H, Coulibaly B, Stich A, ''et al.'' | title=Methylene blue as an antimalarial agent&mdash;past and future | journal=Redox Rep. | year=2003 | volume=8 | pages=272&ndash;76 | doi=10.1179/135100003225002899}}
+#{{cite journal | title=Methylene blue for malaria in Africa: results from a dose-finding study in combination with chloroquine | author=Meissner PE, Mandi G, Coulibaly B, ''et al.'' | journal=Malaria Journal | year=2006 | volume=5 | pages=84 | doi=10.1186/1475-2875-5-84}}
+# http://ntp.niehs.nih.gov/ntpweb/index.cfm?objectid=0004CBF9-F1F6-975E-7960ACB47153C2FC
+# http://eprints.hec.gov.pk/1102/
+# http://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=6222095&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
 ==External links==