[sunote notecolor=”#F2F2F2″ textcolor=”#66666″]Methylene blue by itself is unlikely to cause serotonin syndrome, and could only contribute to serotonin syndrome when used in high doses along with another serotonergic drug. Serotongeric classes of medications include SSRIs, tricyclic antidepressants, MAOIs, and miscellaneous drugs like Demerol or dextromethorphan. [/sunote]
Can methylene blue precipitate serotonin syndrome?
Before addressing this question, we’ll first define serotonin syndrome and discuss common prescription drugs associated with serotonin syndrome.
Since methylene blue reversibly inhibits monoamine oxidase A (MAO-A) in the brain, which metabolizes serotonin and other monoamines, it is often wondered whether methylene blue could therefore increase the risk of serotonin syndrome.
Serotonin syndrome (aka serotonin toxicity) occurs when the concentration of serotonin rises sharply in the brain. This phenomenon can result in a potentially fatal toxidrome, involving hyperthermia (fever), hyperreflexia, altered mental status, coma and a constellation of other signs and symptoms.
The stage is set for serotonin syndrome to occur when two or more serotonergic drugs are combined. Probably the most dangerous combination would consist of a selective-serotonin reuptake inhibitor (SSRI, e.g., zoloft or prozac) in conjunction with a potent and irreversible monoamine oxidase inhibitor (MAOI), like Parnate. This combination is probably more dangerous than an SSRI plus a tricyclic.
The SSRI inhibits the removal of serotonin from the synapse, while the MAOI impairs the metabolism of serotonin. Serotonin is then toxically increased via this two-pronged mechanism.
Methylene Blue And Serotonin Syndrome
Unlike the MAOI antidepressant Parnate, Methylene blue is a reversible and competitive inhibitor of monoamine oxidase-A (MAO-A), making it less likely to provoke serotonin syndrome.
Methylene blue by itself is highly unlikely to cause serotonin syndrome. However, methylene blue could contribute to serotonin syndrome when combined with other serotonergic drugs.
While methylene blue was originally considered to be a significant risk factor for serotonin syndrome, that view has been recently revised.
Consider the following safety information about methylene blue:
MB is an FDA-grandfathered drug that has already been rigorously studied and used in humans for over 120 years. PubMed lists 4908 human studies of MB (searched 2013). MB’s pharmacokinetics, side effect profile, and contraindications are well-known and most importantly, minimal in humans  and . MB has been used in parathyroid surgery to aid in lymphatic mapping since the early 1970s at doses of 3.5–10 mg/kg. A safety announcement from the FDA warned physicians about possible serious serotonin reactions in patients who received intravenous MB during parathyroid surgery if taking serotonergic psychiatric drugs. A subsequent report by Mayo Clinic surgeons and pharmacologists summarized the FDA evidence and literature and concluded “that the use of methylene blue dye at low doses for lymphatic mapping likely carries very little risk for serotonin neurotoxicity” . Furthermore, none of the FDA cases are based on oral MB. Daily 300 mg oral MB (4.28 mg/kg/day based on a body weight of 70 kg) has been used safely for one year in clinical trials . Thus, low-dose MB has a long history of safe usage that supports its translational relevance to human populations.