FDA's 2011 methylene blue warnings: serotonin syndrome with SSRIs and SNRIs, and the label changes that followed
In July 2011 the FDA warned of serious CNS reactions when methylene blue is given to people on serotonergic psychiatric drugs. Its October update said most cases followed IV doses in parathyroid surgery; oral risk was unknown.
We have not finished checking this source. No judgement either way. how we score evidence
Caveat on this rating: Built from case reports without a rate; the FDA said risk by oral or low-dose routes was unknown, not absent.
Two FDA drug safety communications, now offline at fda.gov, and the 2012 class label change they led to.
Significant findings
On 26 July 2011 the FDA announced it "has received reports of serious central nervous system (CNS) reactions when the drug methylene blue is given to patients taking psychiatric medications that work through the serotonin system of the brain". It explained that methylene blue "is a potent, reversible monoamine oxidase inhibitor (MAOI)" and that "Methylene blue should generally not be given to patients taking serotonergic drugs", except in life-threatening or urgent situations. For planned use, it advised that most serotonergic psychiatric drugs be stopped at least 2 weeks ahead, fluoxetine at least 5 weeks, with "Safety information about these potential drug interactions... being added to the drug labels for serotonergic psychiatric medications."
On 20 October 2011 it narrowed the picture: "Most cases... occurred in the context of parathyroid surgery, which involved the intravenous administration of methylene blue as a visualizing agent. Methylene blue doses ranged from 1 mg/kg to 8 mg/kg." The cases involved an SSRI, an SNRI or clomipramine; for other psychiatric drugs with lesser serotonergic activity the risk was "unclear".
The follow-through is this row's anchor: FDA's 18 December 2012 approval of class labeling revisions to Zoloft (sertraline) "regarding serotonin toxicity associated with the co-administration of linezolid and methylene blue". Current SSRI and SNRI labels carry the same language.
The other direction
The October update is the restraint: "it is not known whether there is a risk of serotonin syndrome in patients taking serotonergic psychiatric medications who are given methylene blue by other routes (e.g., orally or by local tissue injection) or at intravenous doses lower than 1 mg/kg." Current antidepressant labels likewise say "No reports involved the administration of methylene blue by other routes". The warnings were built from case reports, not trials, and give no rate.
What this does not show
It does not say oral methylene blue is safe with an antidepressant; it says that was not known. It is not a reason to stop an antidepressant on your own; the FDA's own advice was to make any change with a clinician.
Worth asking
I take an antidepressant; before any procedure or supplement, does everyone know, and has methylene blue come up?
Source
Supplement approval letter, NDA 19839/S-073/S-081 and NDA 20990/S-034/S-040 (Zoloft): class labeling revisions on serotonin toxicity with linezolid and methylene blue — US Food and Drug Administration, Center for Drug Evaluation and Research (2012)
Regulator or national health body
How this was scored
- Study design
- Regulatory safety determination
- Funding
- not recorded
- Published in
- Regulator or national health body
- Sample size
- not recorded
- Preregistered
- not recorded
- Conflicts disclosed
- not recorded
- Independent of proponent
- not recorded
- Retracted
- No
We have not finished checking this source, so there is no scoring to show yet. “We have not checked this yet” and “this is disputed” are different statements, so no scored band is shown rather than a low one.
Read the full scoring rubric, including what it can't tell you.
Published October 21, 2026.
Questions
How strong is the evidence behind this?
veisund rates this source "not yet assessed". We have not finished checking this source. No judgement either way. One caveat travels with that badge: Built from case reports without a rate; the FDA said risk by oral or low-dose routes was unknown, not absent. The score is calculated from recorded facts about the source — study design, funding, publication venue, sample size, preregistration — not typed in by an editor.
What is the source for this?
Supplement approval letter, NDA 19839/S-073/S-081 and NDA 20990/S-034/S-040 (Zoloft): class labeling revisions on serotonin toxicity with linezolid and methylene blue — US Food and Drug Administration, Center for Drug Evaluation and Research (2012). Published in: Regulator or national health body. The full source is linked on this page so you can read it yourself.
Who paid for this research, and does that matter?
Study design: Regulatory safety determination. Funding: not recorded. Independence from the proponent is not recorded. Industry sponsorship is one of the most reliably measured biases in medicine, which is why funding carries real weight in the score rather than sitting in a footnote.
Is this medical advice?
This is information to bring to your prescriber, not medical advice and not a reason to change anything on your own. Nothing here is an instruction to stop or reduce a medication. If you are in crisis, call or text 988.
This is information to bring to your prescriber, not medical advice and not a reason to change anything on your own. Nothing here is an instruction to stop or reduce a medication. If you are in crisis, call or text 988.