Methylene blue

Why this drug is interesting

Methaemoglobin is haemoglobin whose iron has been oxidised from the ferrous to the ferric state. It cannot bind oxygen, and it shifts the dissociation curve of the remaining normal haemoglobin leftward, so the patient is both carrying less oxygen and releasing less of what they carry. The result is a cyanosed patient with a normal arterial oxygen tension who does not improve with oxygen.

Methylene blue reverses this by acting as an electron shuttle: NADPH methaemoglobin reductase reduces it to leucomethylene blue, which then non-enzymatically reduces methaemoglobin back to haemoglobin. It is an elegant mechanism, and it explains almost everything difficult about the drug — because a patient who cannot generate NADPH cannot use it, and a dose large enough to exceed the reducing capacity oxidises haemoglobin instead.

Dosing

The licence is for "acute symptomatic treatment of medicinal and chemical products-induced methaemoglobinaemia", in adults, children and adolescents aged 0 to 17 years.¹

The product is hypotonic and may be diluted in 50 mL of 5% glucose to avoid local pain, particularly in children. It must not be given subcutaneously or intrathecally.

Renal impairment

Methylene blue is predominantly renally eliminated, and the label reduces the ceiling accordingly:

In infants of 3 months or younger and newborns with moderate to severe renal impairment there are no data, and lower maximum cumulative doses — below 0.5 mg/kg — may be considered.

Contraindications — including the one that catches people

Serotonin syndrome

Recognition and monitoring

Other monitoring

• ECG and blood pressure during and after treatment — hypotension and arrhythmia are potential adverse reactions
• The drug "imparts a blue-green colour to urine, faeces and a blue colour to skin which may hinder a diagnosis of cyanosis" — warn the patient and the team, and do not rely on skin colour afterwards
• BIS (bispectral index) interference — anaesthetists should be aware, and vigilant for methaemoglobinaemia in patients on dapsone

Common causes of acquired methaemoglobinaemia

• Local anaesthetics — prilocaine and benzocaine especially; see lidocaine for the related toxicity
• Dapsone — and note the reduced 4 mg/kg ceiling
• Nitrates and nitrites, including amyl nitrite and contaminated water
• Aniline dyes and nitrobenzene — again a 4 mg/kg ceiling
• Metoclopramide, sulfonamides, phenazopyridine, chloroquine

Adverse effects

• Paradoxical methaemoglobinaemia above the ceiling dose or with rapid injection
• Haemolytic anaemia, particularly in G6PD deficiency and with aniline or dapsone
• Serotonin syndrome with serotonergic co-medication
• Hypotension and cardiac arrhythmia
• Blue-green discolouration of urine, faeces and skin
• Pain at the injection site; local necrosis on extravasation
• Photosensitivity — the label warns of cutaneous photosensitivity on exposure to strong light including phototherapy, theatre lights and illuminating devices such as pulse oximeters, and advises patients to take protective measures
• Nausea, vomiting, abdominal pain
• Heinz body formation in aniline poisoning

Critical appraisal

1. The evidence is entirely observational and that is unlikely to change. Methaemoglobinaemia severe enough to need treatment is rare, the mechanism is understood, and the response is usually rapid and obvious. This is an antidote whose warrant is physiological rather than trial-based, and legitimately so.
2. The dose ceiling is the part most likely to be forgotten under pressure. A drug that reverses a condition at one dose and causes it at another is unusual, and the ceiling has to be tracked cumulatively across repeat doses rather than checked once.
3. The serotonin syndrome interaction is a modern problem imposed on an old drug. Methylene blue has been in use for over a century; SSRIs have not. The interaction is real and serious, and it is not something the drug's long safety record can reassure you about.
4. Failure to respond is diagnostically informative and often mismanaged. The instinct is to give more. The label's list — G6PD deficiency, cytochrome b5 reductase deficiency, sulfhaemoglobinaemia — is a better response than a second dose, because in all three of those the second dose does harm without benefit.

References

1. 1
   Methylthioninium chloride Proveblue 5 mg/ml solution for injection — Summary of Product Characteristics, Provepharm UK Ltd. electronic Medicines Compendium. Sections 4.1–4.5, 4.8. Verified 24 Aug 2026.
2. 2
   TOXBASE — methaemoglobinaemia; methylthioninium chloride. National Poisons Information Service. toxbase.org (NHS login required. NPIS: 0344 892 0111.)
3. 3
   Barker SJ, Tremper KK, Hyatt J. Effects of methemoglobinemia on pulse oximetry and mixed venous oximetry. Anesthesiology 1989;70(1):112–17 — the origin of the ~85% plateau, which sets in once methaemoglobin exceeds roughly 30–35%; summarised in StatPearls, Methemoglobinemia, NCBI Bookshelf.
4. 4
   Ash-Bernal R, Wise R, Wright SM. Acquired methemoglobinemia: a retrospective series of 138 cases at 2 teaching hospitals. Medicine (Baltimore) 2004;83(5):265–73. PubMed
5. 5
   Medicines and Healthcare products Regulatory Agency. Methylthioninium chloride (methylene blue): risk of serious or fatal serotonergic syndrome with concomitant use of serotonergic drugs. gov.uk