Methylene Blue and Antidepressants: The Serotonin Syndrome Rule
Most of what is written about methylene blue online treats it as a supplement with an unusual color. It is not a supplement. It is a drug with a specific, potentially dangerous interaction that the FDA issued a formal warning about, and that interaction involves some of the most commonly prescribed medications in the country.
This page is the one place on this site that interaction is set out in full. It is a page about a flat no — and about why a provider who does not ask the question before prescribing methylene blue has not done the job.
Methylene blue is an MAO inhibitor
Among its several actions, methylene blue is a potent, reversible inhibitor of monoamine oxidase A — the enzyme that breaks down serotonin. That is the same mechanism as the older antidepressants known as MAOIs, which carry some of the strictest interaction warnings in pharmacology.
The clinical consequence: methylene blue raises serotonin levels. Combine it with anything else that raises serotonin, and the level can rise past what the nervous system tolerates. The result is serotonin syndrome — agitation, confusion, racing heart, high temperature, muscle rigidity and twitching, and in severe cases seizures, coma and death. It can develop within hours.
This is not a theoretical interaction. It was identified from cases of serotonin syndrome in patients given intravenous methylene blue during surgery while taking an SSRI, and in 2011 the FDA issued a Drug Safety Communication warning of "serious CNS reactions" when methylene blue is given with serotonergic psychiatric medications. The warning has been on the label of approved methylene blue products since.
The list
Any of the following, taken with methylene blue, is a combination we will not prescribe:
SSRIs — sertraline, fluoxetine, escitalopram, citalopram, paroxetine, fluvoxamine.
SNRIs — venlafaxine, desvenlafaxine, duloxetine.
Other serotonergic antidepressants — vortioxetine, vilazodone, clomipramine and other tricyclics, mirtazapine, trazodone at antidepressant strengths.
MAOIs — phenelzine, tranylcypromine, selegiline, linezolid (an antibiotic that is also an MAOI).
Others that raise serotonin — tramadol, meperidine, fentanyl, dextromethorphan (in many cough remedies), lithium, buspirone, the triptans used for migraine, St John's wort, and some stimulants and illicit drugs.
The list is long because serotonin is everywhere. A person who has never taken an antidepressant may still be on tramadol for a back, a triptan for migraines, or a cough syrup with dextromethorphan. The assessment asks about all of it.
Why "I'll just stop my SSRI for a while" is not an answer
Two reasons.
First, stopping an antidepressant is a clinical decision with its own risks, to be made with the prescriber, over time, and never in order to take an unproven cognitive enhancer. We will not suggest it and we will not prescribe methylene blue on the promise of it.
Second, several of these drugs persist. Fluoxetine and its active metabolite take about five weeks to clear. A person who stopped it last week is not clear of it. The washout periods are drug-specific and long, and they are another reason this is a question for the prescribing clinician, not a switch to flip.
What we ask, and what we do
Every methylene blue assessment asks for the complete medication list — prescription, over-the-counter, supplements — and asks specifically about mood and migraine medications, painkillers and cough remedies. A yes to any of the above is a no to methylene blue, and we say so, and we mean it.
We also ask that the list be kept current. A new prescription for an antidepressant, a triptan or tramadol after starting methylene blue is a reason to stop it and tell us, the same day.
Where methylene blue is prescribed, it is at the pharmaceutical grade the main page describes, with the G6PD screen the other safety page describes. None of that is optional either.
Frequently asked questions
No. Methylene blue inhibits MAO-A and raises serotonin; combined with an SSRI it can cause serotonin syndrome, which can be fatal. The FDA issued a formal warning on this interaction in 2011.
A toxic excess of serotonin: agitation, confusion, rapid heart rate, high temperature, muscle rigidity and twitching, and in severe cases seizures and death. It develops over hours and is a medical emergency.
SSRIs, SNRIs, MAOIs, most other antidepressants, tramadol and some other opioids, triptans, dextromethorphan, lithium, buspirone, St John's wort and linezolid, among others. The full list is above.
That is not a trade we will suggest or support. Stopping an antidepressant is a decision for your prescriber, and several of these drugs take weeks to clear.
The documented cases involved intravenous use, but MAO-A inhibition occurs at the exposures used orally, and the FDA warning does not carve out an exception. We treat the interaction as absolute.
Yes. Tell us. Occasional use of a serotonergic drug is still a serotonergic drug.
Where this fits in your plan
The Methylene Blue page covers what the drug is and what we will and will not claim for it. If you take anything on the list above, this is where the methylene blue conversation ends — and we would rather you knew that before the assessment than after.
We measure first. Then we act.
References
- FDA Drug Safety Communication: Serious CNS reactions possible when methylene blue is given to patients taking certain psychiatric medications. July 26 2011 (updated October 2011).
- Provayblue (methylene blue injection) prescribing information — Section 5, Warnings: serotonin syndrome with concomitant use of serotonergic drugs.
- Gillman PK. Methylene blue implicated in potentially fatal serotonin toxicity. Anesthesia 2006;61:1013–1014.
- Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity: inhibition of monoamine oxidase A (MAO A) confirms a theoretical prediction. British Journal of Pharmacology 2007;152:946–951.
- Boyer EW, Shannon M. The serotonin syndrome. NEJM 2005;352:1112–1120.
How we write and review our content
ACT 2 Health provides clinician-led care. Treatments are available only to eligible patients following clinical evaluation and within applicable regulations. This content is educational and is not medical advice. Individual results vary.
Compounded medication. Prepared by a licensed compounding pharmacy under a prescription written for you. Compounded medications are not FDA-approved, are not reviewed by the FDA for safety or effectiveness, and are not equivalent to or interchangeable with any branded product. Prescribed only when a licensed provider determines it is medically appropriate.
Care is delivered via telemedicine by healthcare professionals licensed in the state where the patient is located. Services are available only in states where our providers are licensed.
If you have taken methylene blue with a serotonergic medication and develop agitation, confusion, fever or muscle twitching, seek emergency care.