By Danielle Wojcik, PharmD
Methylene blue (MB) is a phenothiazine derivative with effects on redox reactions that is used for a myriad of indications, including methemoglobinemia, vasoplegia, refractory shock, and ifosfamide toxicity. Its blue color provides additional utility as medical dye. Outside of its prescribed indications, MB is available for purchase without a prescription and has increasing popularity in nootropics. Nootropic agents include prescription medications (such as methylphenidate or dextroamphetamine) and dietary supplements with proposed mechanisms of supporting and enhancing brain functions such as attention, memory, wakefulness, and self-control. MB is purported to enhance mitochondrial function to boost energy, support physical health, and improve cognitive performance, though these claims have not been evaluated by the FDA.
Although it is available as a dietary supplement, MB use is not without risks. Administration of MB is not recommended in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency due to the risk of hemolysis. Deficiency of G6PD is a genetic predisposition most common in patients of African, Mediterranean, or Asian descent. Many patients with G6PD deficiency will remain asymptomatic during their lifetime, and may not know they have this deficiency, as testing for this genetic condition is not routine. Discovery of G6PD deficiency may be incidental upon administration of medications which require functional G6PD enzymatic activity.
G6PD converts NADP to the reduced form, NADPH. NADPH is crucial in oxygen-free radical scavenging to prevent cellular damage. The reduction of MB to leucomethylene blue is facilitated by NADPH. Leucomethylene blue is the active form of MB and is responsible for converting ferric hemoglobin to ferrous hemoglobin to reverse methemoglobinemia. Patients with G6PD deficiency do not have sufficient quantities of NADPH for this reduction reaction. In absence of NADPH, erythrocytes are subject to oxidative stress from MB, which may result in hemolysis.
Regardless of G6PD deficiency, chronic use of MB can precipitate methemoglobinemia when the redox reaction becomes oversaturated, shifting the reaction in the opposite direction. Instead of facilitating the conversion of ferric hemoglobin to ferrous hemoglobin, the overabundance of MB can cause a ferrous to ferric hemoglobin conversion and the production of methemoglobin.
Recently, a previously healthy patient presented to a local hospital and was found to be in acute renal failure with an admission SCr of 7.73 mg/dL. The patient reported outpatient use of oral methylene blue supplementation for the past several months as a general health aid. The patient reported blue-green urine which had since resolved. Initial workup revealed anemia with a hemoglobin and hematocrit of 6.8 and 19, respectively, for which they received two units of packed red blood cells. Additionally, their haptoglobin resulted at 18. A methemoglobin percentage was obtained which resulted <1%. Given the patient’s acute renal injury, anemia, and haptoglobin, there was concern for hemolytic anemia which has since resolved. This patient remained admitted for dialysis and monitoring kidney and blood count recovery.
Treatment of MB-induced hemolytic anemia, as described in the above patient, includes cessation of MB administration and supportive care for anemia complications, such as blood product administration. This is a rare potential complication of methylene blue administration, which may be increasingly seen with the rise of nootropic agent promotion and the availability of methylene blue products to the general public.
For treatment recommendations for methylene blue toxicity or any other poisoning, call your local poison center at 1-800-222-1222.
References
Malík M, Tlustoš P. Nootropics as Cognitive Enhancers: Types, Dosage and Side Effects of Smart Drugs. Nutrients. 2022;14(16):3367. Published 2022 Aug 17. doi:10.3390/nu14163367
Richardson SR, O’Malley GF. Glucose-6-Phosphate Dehydrogenase Deficiency. [Updated 2022 Sep 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470315/
Ludlow JT, Wilkerson RG, Nappe TM. Methemoglobinemia. [Updated 2023 Aug 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537317/
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