What are the side effects of Methylthioninium chloride (Methylene blue)?

Side Effects of Methylene Blue (Methylthioninium Chloride)

Methylene blue is generally well-tolerated at therapeutic doses (1-2 mg/kg), but carries serious, potentially life-threatening risks in specific patient populations, particularly those with G6PD deficiency, those taking serotonergic medications, pregnant women, and patients with renal failure. 1

Common/Benign Side Effects

At therapeutic doses, methylene blue commonly causes:

• Blue-green discoloration of urine and stool - This is harmless and resolves after medication cessation 1, 2
• Cardiovascular effects: Rapid heartbeat, flushing 2
• Central nervous system effects: Blurred vision, dizziness, drowsiness 2
• Gastrointestinal symptoms: Dry mouth, nausea, vomiting, diarrhea 2, 3
• Genitourinary effects: Difficult urination, acute urinary retention 2
• Respiratory symptoms: Shortness of breath or trouble breathing 2

Serious and Life-Threatening Adverse Effects

Hemolytic Anemia in G6PD Deficiency

Methylene blue is absolutely contraindicated in patients with G6PD deficiency because it can cause severe, potentially fatal hemolytic anemia. 1

• Methylene blue paradoxically worsens methemoglobinemia in G6PD-deficient patients rather than treating it 1
• The mechanism involves methylene blue acting as an oxidant at higher concentrations, and G6PD-deficient patients cannot produce sufficient NADPH to convert methylene blue to its active reducing form (leukomethylene blue) 1
• All patients should ideally be tested for G6PD deficiency before methylene blue administration; in emergencies, obtain a family history of G6PD deficiency 1
• Heinz body hemolytic anemia has been documented after methylene blue administration in G6PD-deficient patients 1

Serotonin Syndrome

Methylene blue acts as a potent monoamine oxidase inhibitor and can precipitate life-threatening serotonin syndrome in patients taking selective serotonin reuptake inhibitors (SSRIs) or other serotonergic antidepressants. 1, 4

• Serotonin toxicity can occur at doses as low as 1 mg/kg 4
• Peak plasma concentrations of 500 ng/mL (1.6 µM) achieved with only 0.75 mg/kg IV are sufficient to inhibit monoamine oxidase A 4
• 13 of 14 reported cases of CNS toxicity from methylene blue met Hunter Serotonin Toxicity Criteria 4
• Serotonin reuptake inhibitors should be carefully considered for cessation before methylene blue use 4

Risks in Pregnancy and Neonates

Methylene blue should be used with extreme caution in pregnant women due to concerns about teratogenicity and possible intestinal atresia. 1

• Intraamniotic injection and postnatal doses of 2-4 mg/kg in premature infants have caused hemolysis and methemoglobinemia in non-G6PD-deficient infants 1

Cardiovascular Complications

In anesthetized patients and those with renal failure, methylene blue can cause systemic and pulmonary hypertension by inhibiting guanylate cyclase and decreasing nitric oxide-mediated vasodilation. 1

Dose-Dependent Toxicity

• Toxic levels are reached at total doses >7 mg/kg 1
• Large doses (4 mg/kg) result in proportionately higher levels of the oxidizing form rather than the reducing form, potentially inducing hemolysis 1
• Worsening methemoglobinemia can occur with repeated doses due to a rebound phenomenon 1
• If methemoglobinemia worsens after methylene blue treatment, urgent exchange transfusion should be performed 1

Clinical Efficacy Data

Recent real-world data demonstrates that methylene blue is highly effective when used appropriately:

• In a 24-year poison center series of 185 cases, 98% of patients improved after methylene blue administration (95% CI: 96-100%) 5
• Adverse effects attributable to methylene blue were reported in only 4.9% of cases (95% CI: 4.6-5.1%), including one instance of hemolysis 5
• Most patients responded to a single dose of 1-2 mg/kg, supporting current treatment recommendations 5

Critical Pitfalls to Avoid

1. Never administer methylene blue without screening for G6PD deficiency when time permits 1
2. Always obtain medication history for SSRIs and serotonergic drugs before administration 1, 4
3. Do not exceed 7 mg/kg total dose to avoid toxicity 1
4. Use alternative treatments (ascorbic acid, exchange transfusion) in G6PD-deficient patients 1
5. Exercise extreme caution in pregnant women, neonates, and patients with renal failure 1