CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity

Methylene blue has only recently been noted to cause severe central nervous system toxicity. Methylene blue is used for various conditions, including, intravenously, in methemoglobinemia, vasoplegia and as an aid to parathyroidectomy (at doses of 1-7.5 mg kg(-1)). This review of the current evidence concludes that 13 of 14 of the reported cases of CNS toxicity were serotonin toxicity that met the Hunter Serotonin Toxicity Criteria. That has important preventative and treatment implications. Serotonin toxicity is precipitated by the monoamine oxidase inhibitor (MAOI) property of methylene blue interacting with serotonin reuptake inhibitors. Serotonin toxicity is reviewed, using the lessons inherent in the methylene blue story and experience, to illustrate how the mechanisms and potency of serotonergic drugs interact to determine severity. Recent human data showed that an intravenous dose of only 0.75 mg kg(-1) of methylene blue produced a peak plasma concentration of 500 ng ml(-1) (1.6 mu M), indicating that the concentration in the central nervous system reaches a level that inhibits monoamine oxidase A. That is consonant with the actual occurrence of severe serotonin toxicity in humans at the dose of only 1mg kg(-1). It seems that all proposed uses of methylene blue entail levels that block monoamine oxidase, so cessation of serotonin reuptake inhibitors should be very carefully considered before using methylene blue.