Methylene Blue Studied for Bipolar as FDA Issues Warning

Methylene blue By Kenneth J. Bender, PharmD, MA | October 5, 2011

A study presented by Canadian investigators at the 24th Congress of the European College of Neuropsychopharmacology (ECNP) in Paris, September 5 evaluated whether methylene blue can reduce residual symptoms of depression and mania in bipolar disorder.1

Weeks before, on July 26, the FDA issued a safety warning on the risk of serotonin syndrome when methylene blue is given concurrently with serotonergic psychiatric medications;2 and Health Canada issued a similar warning in February.

The compound is better known as a treatment for methemoglobinemia and as a dye in diagnostic applications, but it is also a potent, reversible monoamine oxidase inhibitor. Its potential to improve symptoms in bipolar disorder arises from other, possibly neuroprotective mechanisms including inhibition of nitric oxide synthase and guanylate cyclase, according to investigator Martin Alda, MD and colleagues, Dalhousie University, Halifax, Nova Scotia.

The investigators administered methylene blue to 37 subjects meeting criteria for bipolar disorder, while maintaining lamotrigine(Drug information on lamotrigine) as their primary mood stabilizer. Patients were randomized to receive 13 weeks treatment with either 195 mg methylene blue daily, or 15 mg as a putative subtherapeutic dose in lieu of a placebo that mimics the color in urine; with groups switching the regimen for an additional 13 weeks.

Alda reported that the active dose was associated with statistically significantly improved mood symptom scores from baseline on multiple measures, including the Montgomery-Asberg Depression Rating Scale (MADRS). There was no therapeutic effect apparent on cognitive performance, but no decrement observed with its use.

The compound was generally well tolerated in this controlled population, but this use remains investigational and, as the FDA warns, “methylene blue should generally not be given to patients taking serotonergic drugs unless the benefit is deemed to outweigh the risk.”


1. Alda M, MacQueen G, McKinnon M, et al. Methylene blue for residual symptoms and for cognitive dysfunction in bipolar disorder: Results of a double-blind trial. Presented at the 24th Congress of the European College of Neuropsychopharmacology (ECNP), Paris, September 5, 2011. Abstract P.2.e.001.

2. FDA. Drug Safety Communication: Serious CNS reactions possible when methylene blue is given to patients taking certain psychiatric medications. July 26, 2011. Accessed September 28, 2011.

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