Comment on “Methylene Blue and Serotonin Syndrome: A Caution Against Intravenous Use”

The US Food and Drug Administration (FDA) has approved the intravenous (IV) use of methylene blue (MB) for patients with acquired methemoglobinemia, and it is also widely used off-label as a dye during cystoscopy associated with abdominal, pelvic, and genitourinary procedures. This article is a commentary on the use of MB for this off-label purpose and highlights the potential risk for serotonin syndrome when MB is used in combination with other medications. Off-label MB use for genitourinary and pelvic surgical procedures became more common during a period of relative unavailability of indigo carmine between 2014 and 2022, and was considered standard of care for the visualization of ureteral efflux. One of the dangers of MB use is its inhibitory effect on monoamine oxidase (MAO), causing interactions with some other drugs that can be life-threatening. MB interacts with many commonly prescribed medications, and the FDA has issued a black box warning due to reports of serious central nervous system reactions in individuals taking serotonergic psychiatric medications. Considering this and the fact that there are safer alternative dyes that can be used, the authors caution against the IV use of MB in off-label contexts due to these risks and the existence of safer alternatives. MAO is responsible for the breakdown of serotonin and other monoamine neurotransmitters, so its inhibition can result in the accumulation of neurotransmitters in the brain and the peripheral nervous system. This prevention of breakdown has a therapeutic intent in anxiety and depression, but excess serotonin can cause life-threatening conditions such as serotonin syndrome (SS). SS is due to the presence of high levels of serotonin in the central nervous system that result in symptoms such as altered mental status, autonomic hyperactivity, and neuromuscular abnormalities; these can range in severity from mild to life-threatening. Milder cases can also present with symptoms such as tachycardia, tremor, and diarrhea, and more severe cases can present with delirium, neuromuscular rigidity, and hyperthermia. Currently, there is no treatment for SS other than discontinuing serotonergic medications and providing supportive care. Intravenous use of MB in patients using serotonergic medications dramatically increases the risk of serotonin syndrome and should be avoided. As the prevalence of depressive and anxiety disorders has risen, the number of individuals who regularly take serotonergic medications has risen steadily, meaning that a larger number of individuals are at risk of intravenous MB. Awareness of these interactions and risks should be advocated, and clinicians should be educated on identifying serotonin syndrome in both mild and severe forms. (Summarized from Brown O, Mou T, Barker MA. Methylene blue and serotonin syndrome: A caution against intravenous use. Urogynecology (Phila). 2026;32:90-93. doi: 10.1097/SPV.0000000000001785).