What are the side effects of methylene blue?

Side Effects of Methylene Blue

Methylene blue's most serious side effect is serotonin syndrome when combined with serotonergic medications, and it can cause hemolytic anemia in patients with G6PD deficiency, while common benign effects include blue-green discoloration of urine and stool. 1, 2

Critical and Life-Threatening Side Effects

Serotonin Syndrome

• Methylene blue acts as a potent monoamine oxidase inhibitor and can precipitate severe, potentially fatal serotonin syndrome when combined with serotonergic medications (SSRIs, SNRIs, other antidepressants), resulting in severe CNS toxicity 1, 2
• This interaction occurs even at low doses of 1 mg/kg IV, as plasma concentrations reach levels sufficient to inhibit monoamine oxidase A in the central nervous system 3
• All 50 reported cases of methylene blue-induced serotonin syndrome involved concurrent use of serotonergic antidepressants, with symptoms ranging from mild to severe, including one fatality 4
• Serotonin syndrome can occur with both parenteral and oral administration of methylene blue-containing agents 4

Hemolytic Anemia in G6PD Deficiency

• G6PD deficiency is an absolute contraindication to methylene blue use due to risk of severe hemolytic anemia and paradoxical worsening of methemoglobinemia 1, 2
• This occurs because methylene blue's mechanism requires adequate NADPH production, which is impaired in G6PD deficiency 1

Paradoxical Methemoglobinemia

• Total cumulative dosing should not exceed 7 mg/kg, as higher doses paradoxically worsen methemoglobinemia rather than treating it 1, 2

Cardiovascular Side Effects

Hemodynamic Effects

• Methylene blue may inhibit guanylate cyclase, decreasing nitric oxide-mediated vasodilation, which can lead to systemic and pulmonary hypertension 1
• Hemodynamic instability has been reported as a serious adverse event, particularly with intravenous administration 5

Drug Interactions

Opioid Interactions

• The FDA warns against using hydromorphone within 14 days of methylene blue exposure due to risk of serotonin syndrome or opioid toxicity, creating a clinical dilemma when methylene blue is needed emergently 1

Other Serotonergic Medications

• Compazine should be held before methylene blue administration due to serotonin syndrome risk 1

Common and Benign Side Effects

Discoloration Effects

• Blue-green discoloration of urine and stool is a common, expected, and harmless side effect 2

Pregnancy and Teratogenicity Concerns

• Use methylene blue with caution in pregnancy due to concerns about teratogenicity and possible intestinal atresia 1, 2

Safety Profile with Oral Administration

• When used orally in small amounts (as during swallowing examinations), serious adverse events are rare (0.16% in pooled analysis of 1902 patients) 5
• Non-serious adverse events with oral administration are typically mild, self-limiting, and show a dose-related trend 5

Clinical Pitfalls to Avoid

• Always screen for concurrent serotonergic medication use before administering methylene blue - this is the most common preventable cause of serious toxicity 1, 3, 4
• Always screen for G6PD deficiency before administration to prevent hemolytic crisis 1, 2
• Never exceed 7 mg/kg cumulative dosing to avoid paradoxical worsening of methemoglobinemia 1, 2
• Monitor patients for at least one hour after administration 1, 2