Methylene blue is a potent reversible inhibitor of monoamine oxidase A
Mark Kemp · 9 October 2026
Methylene blue is a potent, reversible inhibitor of monoamine oxidase A, the enzyme that breaks down serotonin. That explains the serotonin toxicity reported when it is combined with SSRIs. A plain summary of Ramsay, Dunford & Gillman, Br J Pharmacol 2007.
In kinetic assays on purified human monoamine oxidase, methylthioninium chloride (methylene blue) inhibited MAO-A potently, tightly and reversibly, while inhibiting MAO-B only at much higher concentrations (Ramsay, Dunford & Gillman, Br J Pharmacol 2007). MAO-A is the enzyme that breaks down serotonin. The authors concluded that at concentrations reached after intravenous dosing, MAO-A would be fully inhibited, which explains the serotonin toxicity reported in patients taking SSRIs.
Citation: Ramsay RR, Dunford C, Gillman PK. Br J Pharmacol 2007;152(6):946–951. doi:10.1038/sj.bjp.0707430. PMID 17721552. PMC2078225.
What the study did
By 2007 there were clinical reports of serotonin toxicity — sometimes severe — in patients given methylene blue during surgery while taking SSRIs. The authors had predicted that methylene blue's structure made it a likely MAO inhibitor. This paper tested the prediction directly.
They measured inhibition of purified human MAO-A and MAO-B using kinetic assays and spectral analysis, and looked at how methylene blue interacts with the enzyme's active site.
What it found
Methylene blue was a potent, tight-binding, reversible inhibitor of MAO-A. It inhibited MAO-B too, but only at much higher concentrations — the effect is selective. Spectral evidence showed it binding in the active site, behaving as both an oxidising substrate and a one-electron reductant.
Monoamine oxidase A is the enzyme chiefly responsible for breaking down serotonin. Inhibit it, and serotonin accumulates. Add an SSRI, which blocks serotonin reuptake, and the two mechanisms compound. That is the pharmacological basis of serotonin toxicity, and the paper confirmed that methylene blue can supply the MAO-inhibition half of it.
The authors concluded that at blood concentrations reached after intravenous administration, MAO-A would be fully inhibited and MAO-B partially, and that this is the likely explanation for the clinical reports.
| Model | Purified human MAO-A and MAO-B, in vitro |
| Compound | Methylthioninium chloride |
| Measured | Enzyme inhibition kinetics; spectral changes at the active site |
| Result | Potent, tight-binding, reversible MAO-A inhibition; MAO-B inhibited only at much higher concentration |
| Not tested | Oral dosing in people; any supplement; any threshold below which the interaction is absent |
What it means, and what it doesn't
This paper is why Is methylene blue safe? says what it says about antidepressants. It is the mechanism behind the warning: methylene blue inhibits the enzyme that clears serotonin, and that is a well-characterised route to a serious interaction with any serotonergic medicine.
What the paper does not do is define a safe amount. The clinical reports were intravenous, surgical doses; the authors note that oral dosing could affect amine uptake in the gut but did not test it, and no threshold below which the interaction disappears has been established. The right reading is that the interaction is real at the enzyme level and that anyone taking a serotonergic medicine should treat it as present until a clinician says otherwise.
Read the paper
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(6):946–951.
This summarises a laboratory study on purified enzyme. It is not a claim about any product. If you take any serotonergic medication, speak to a healthcare professional before using methylene blue.