Eplerenona

J Psychopharmacol OnlineFirst, published on February 8, 2010 as doi:10.1177/0269881109359098

Review

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

Journal of Psychopharmacology
0(00) 1–8
! The Author(s) 2010
Reprints and permissions:
sagepub.co.uk/journalsPermissions.nav
DOI:10.1177/0269881109359098
jop.sagepub.com

P Ken Gillman

Abstract
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 kgÀ1). This review of the current evidence
concludes that 13 of 14 of the reportedcases 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 andexperience, 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 kgÀ1 of methylene blue produced a peak plasma concentration of 500 ng mlÀ1 (1.6 mM), indicating that the concentration in the central
nervous system reaches a level that inhibits monoamine oxidase A. That is consonantwith the actual occurrence of severe serotonin toxicity in humans
at the dose of only 1 mg kgÀ1. 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.

Keywords
methylene blue, monoamine oxidase inhibitor, serotonin reuptake inhibitor, serotoninsyndrome, serotonin toxicity

Introduction
Methylene blue (MB), now called methylthioninium chloride,
has recently been noted to cause central nervous system
(CNS) toxicity, variously described as encephalopathy, CNS
toxicity, serotonin syndrome (SS) or serotonin toxicity (ST),
but seemingly only when given to patients already on (selective) serotonin reuptake inhibitors ((S)SRIs). SeeTable 1. The
extent of the use of MB is unknown, much being ‘off-label’.
There are reviews of its intravenous (i.v.) use in methemoglobinemia (McRobb and Holt, 2008), parathyroidectomy
(Dudley, 1971; Han et al., 2007) and vasoplegia (Del Duca
et al., 2009; Stawicki et al., 2008). Also, there are (March
2009) 13 clinical trials involving MB registered at
ClinicalTrials.gov. These involve, interalia, dementia, bipolar
disorder and malaria. A warning has been issued by the UK
Medicines and Healthcare Products Regulatory Agency
(MHRA) (MHRA, 2008) that refers to CNS toxicity. It
does not discuss either ST or MB’s monoamine oxidase inhibitor (MAOI) potency. As a result of observations and predictions concerning MB toxicity (Gillman, 2006d) work was
initiated which has demonstrated it tobe a very potent
MAOI in vitro. MB’s Ki for MAO-A is 27 nM (Ramsay
et al., 2007). Recent evidence indicates tissue levels are sufficient to produce full MAO-A inhibition in humans at even the
lowest recommended dose (1–2 mg kgÀ1 intravenously for
methemoglobinemia). Recent reviews of the pharmacology
of MB discuss the evidence in relation to ST (Stanford
et al., 2009) and other aspects of itspharmacology

(Oz et al., 2009), including inhibition of inducible and constitutive nitric oxide synthase and the formation of L-citrulline.

The intricacies of serotonin toxicity
Serotonin toxicity is a moderately complex topic. This review
uses the history of the emergence of MB toxicity to illustrate
how to understand ST, and the probability of the degree of
severity with various drug...