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Methylene Blue toxicity with serotonin reuptake inhibitors (SRIs)

New data now indicates strongly that Methylene Blue has significant potency as an MAOI and that it can precipitate potentially fatal serotonin toxicity if combined with SRIs.

Serotonin toxicity (ST) is an iatrogenic drug-induced toxidrome displaying the characteristics of a synaptic serotonin concentration-related phenomenon. The term ST is preferable because serotonin syndrome (SS) insinuates an idiosyncratic reaction like malignant hyperthermia (MH) or neuroleptic malignant syndrome (NMS). ST is important because potentially fatal combinations of therapeutic drugs are sometimes inadvertently combined. Also, many texts contain incomplete and erroneous information concerning which drugs are capable of precipitating ST, and its mechanism, symptoms and treatment. Such texts include the British National Formulary, Australian Medicines Handbook, and even ‘Goodman and Gilman’ and Rang & Dale.

The generally poor understanding of serotonin toxicity has been highlighted, more recently, by the availability of several drugs, not used as antidepressants, that posses the property of monoamine oxidase inhibition. It was the accidental discovery of the mood elevating properties of iproniazid, in the trials for tuberculosis around 1955, that led to the discovery of the monoamine inhibiting properties of those drugs, and to the developement of the original MAOI antidepressants. The first patient to die as a result of serotonin toxicity was a doctor, in the original trials of iproniazid, who was given pethidine (1).

The wheel has now gone full circle, in that the latest new drug causing this problem is again and anti-microbial, linezolid, that also has significant activity as an MAOI. Thus history repeats itself, and we demonstrate how slowly and painfully we learn from history, and how quickly we forget its lessons. Students of the history of medicine may, by this time, be exhibiting wry smiles as they recollect the original work, going back to the nineteenth century, following the discovery of inorganic dyes from petroleum, and how Paul Erhlich studied their antimicrobial properties. These eventually lead to the discovery of all the tricyclic psychotropics, including antihistamines, and the tricyclic antidepressants, and the Neuroleptics (all based on the Methylene Blue nucleus).

The evidence relating to serotonin toxicity from Professor Whyte's research group (HATS) series of 2,222 serotonergic overdoses has been published in a seminal series of papers (2-9). Other recommended papers concerning serotonin toxicity are:(10-23)

The clinical features of serotonin toxicity

The typical clinical features of ST in humans, are:--

1. neuromuscular hyperactivity: tremor, clonus, myoclonus and hyperreflexia, and, in the advanced stage, pyramidal rigidity;
2. autonomic hyperactivity: diaphoresis, fever, tachycardia, tachypnoea and mydriasis;
3. altered mental status: agitation, excitement, with confusion in the advanced stage only.

Descriptions of the clinical presentation may be found elsewhere (2,16). Whyte concludes …‘only clonus (inducible, spontaneous or ocular), agitation, diaphoresis, tremor and hyperreflexia were needed for accurate prediction of ST as diagnosed by a clinical toxicologist.’ If, in the presence of a serotonergic agent, the single sign of spontaneous clonus is present, then ST may be reliably diagnosed.

The spectrum concept explains ST as a progression of serotonergic effects mediated by the degree of elevation of intra-synaptic serotonin. These range from serotonin-related side effects (at therapeutic doses) through to toxicity, and culminate in death with MAOI / SRI combinations. The three important mechanisms are serotonin reuptake inhibition (SRI), MAO inhibition and pre-synaptic release. The only therapeutic drugs implicated in severe reactions are: over-dose of MAOIs-alone, combinations of MAOIs with either SRIs, or the only clinically available serotonin releaser, amphetamine (methylphenidate is not a risk (24,25)).

The data suggests that about 50 per cent of patients who have ingested the weak ‘RIMA’ moclobemide, in combination with SRIs, will exhibit at least moderately severe ST. SSRIs alone do not result in severe ST or pyrexia in excess of 38.5c (11) which indicates they have a ceiling effect.

Understanding ST as a form of poisoning reveals the importance of knowing the degree to which different drugs are capable of elevating brain serotonin, indeed the relative frequency and severity of ST with different drugs (and combinations) is useful in refining hypotheses about the potency and actions of those drugs (24).

Death can result from a single dose of an SRI when errors are made in a patient already on an MAOI, as two recent deaths illustrate. The Otte case (imipramine 225 mg), in a European teaching hospital (26), and also Cassens (27). Neither were treated with 5-HT2A antagonists. It is entirely possible the same thing would happen if linezolid or Methylene Blue achieved substantial MAO inhibition, which they might in special circumstances.

In 2005 the editor of the journal Anaesthesia kindly invited me to write an editorial concerning case reports and serotonin toxicity. They had already published an interesting case report by Martindale et al of ‘Neurological sequelae following methylene blue injection for parathyroidectomy’, although it had not been recognised as a possible example of ST (28). I was alerted to this report via a google search that led me to a report on the internet by Rosenbaum (29), who, most astutely, suggested the symptoms and signs he had observed in his patient might be serotonin toxicity (ST) resulting from an interaction between methylene blue and a serotonin reuptake inhibitor (SRI). Rosenbaum noted the similarities to the Martindale report, see: http://www.mhaus.org/index.cfm/fuseaction/Content.Display/PagePK/Jan06CaseOfTheMonth13.cfm I corresponded with him, in order to encourage him to publish his case in a peer reviewed Journal, and to let him know that in my opinion he was correct and that this strongly suggested methylene blue must have activity as a monoamine-oxidase inhibitor. I hope he will publish his case, at any rate I believe the report is still available at the above internet address.

I had searched for information concerning methylene blue and MAOI activity, with moderate success, and submitted a comment concerning this to the same journal. As they were preparing to go to press with my letter the editor contacted me to say they had received yet another report that he thought I might wish to comment on. Indeed, it seemed very likely that this was indeed another case of ST (30). A further subsequent report is one involving venlafaxine (31). There is also a recent report by Bach et al (32), that, in light of this analysis, might also be noted.

Severe degrees of ST involving therapeutic doses of SRIs occur only following combination with monoamine oxidase inhibitors (MAOIs) (24), but not with other serotonergic drugs (with other mechanisms of action). These cases therefore indicated that methylene blue can exhibit significant potency as an MAOI.

A search of the existing standard texts (Goodman and Gilman, Rang and Dale, British National Formulary, Martindale etc) reveals no information or suggestion that Methylene Blue is an MAOI: however other recent literature does support an MAOI effect (33-35), but one of uncertain potency and relevance in relation to humans. I have communicated with an expert in the field of assessing MAOI potency who has kindly agreed to assay methylene blue, and these results will be published in due course.

SRIs have been in use for more than three decades (clomipramine has been in use since 1968, well before fluoxetine, (1988)). It would be astonishing if substantial numbers of patients taking them had not been operated on with procedures that utilize the infusion of methylene blue. If it was a potent MAOI there would probably be a number of reports of life-threatening toxicity; and there are not. That leads to the supposition that it is a relatively weak MAOI, and the risk of ST is low. This is similar to the situation with linezolid, the antibiotic with MAOI effects (36,37). It is perhaps only when large doses are infused, or in susceptible individuals (e.g. cytochrome P450 2D6 poor metabolisers), or as a result of pharmacokinetic drug-drug interactions (raising Methylene Blue levels), that an interaction might occur. It is probably significant that in one case the SRI concerned, fluoxetine, is potent inhibitor of several cytochrome P450 sub-types.

It may well be that ST has occurred and not been recognised, or the relevance has not been appreciated (cf. pethidine, linezolid (10)). It would be most interesting to know if, in retrospect, experienced practitioners recognise that they have indeed seen serotonergic symptoms (particularly clonus, hyperreflexia, pyrexia and altered mental state) in such cases. Please let me know, using the 'contact me' button on this page.

If you learn of any other cases, not referenced herein please let me know .

Until the evidence is more clear, in my opinion, adherence to the lower dose range (< 5mg/kg) of methylene blue and ceasing the SRIs, especially paroxetine fluvoxamine, fluoxetine and clomipramine, as well as any other potent cytochrome P450 2D6 inhibitors, is almost certainly sufficient precaution.

Post script (28/7/2006): in the two weeks since my letter, referred to above, has been available on the Journal website I have already had two emails describing cases that appear likely to represent moderately severe serotonin toxicity with methylene blue and an SRI. It is also notable that I have not had any communications, or located any reports, describing similar symptoms with methylene blue by itself, in the absence of an SRI.

As the old expression goes, watch this space.

All text ©Dr Ken Gillman MRC Psych - PsychoTropical Research®


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