Methylene Blue

what its legal status means, and does not mean

methylene blue is an fda-approved drug for exactly one thing. provayblue, a 5 mg per ml solution for intravenous infusion, is indicated for acquired methemoglobinemia in adults and children, at 1 mg per kilogram over 5 to 30 minutes, with one repeat dose allowed an hour later [label 1, 2.1, 11]. there is no fda-approved psychiatric use: not depression, not bipolar disorder, not anxiety, not cognition, not "mitochondrial support" [status]. the oral drops, capsules and "pharmaceutical grade usp" powders sold for wellness are unapproved products with no premarket review of purity or dose, and methylene blue that is not pharmaceutical grade is an industrial dye that can carry heavy-metal contamination [status]. legal to buy is not the same fact as reviewed, verified or approved, and this is not a dietary supplement: it is a drug being sold for uses no regulator has examined.

one date matters for reading the fda’s statements. when the agency issued its two 2011 communications, it wrote that "methylene blue is not an fda-approved drug at this time" [fda-2011-10]; provayblue was approved on april 8, 2016 [approval], and its label has carried the serotonin-syndrome boxed warning since. both fda communications, and the label, concern the intravenous drug given in hospitals. the agency said in october 2011 that it was "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" [fda-2011-10]. that is an absence of data about oral use, not a finding of safety, and the trials on this page gave 15 to 300 mg a day by mouth.

what the trials measured, in whom, and for how long

the entire controlled human record for mood is four trials. in 1986, 31 people with bipolar disorder, all on lithium, took 300 mg a day of methylene blue for a year and 15 mg a day for a year in a double-blind crossover; 17 completed [naylor-1986]. in 1987 the same group compared 15 mg a day with placebo for three weeks in severe depression; the published abstract gives no sample size, no effect size and no confidence interval [naylor-1987]. in 2017, 37 people with bipolar disorder on lamotrigine took 195 mg a day and 15 mg a day for six months in a double-blind crossover, registered as nct00214877, measuring depression, mania, anxiety and cognition [alda-2017]. and in 2014, 42 adults with claustrophobia took a single 260 mg dose or placebo immediately after a session of exposure therapy, with fear measured a month later [telch-2014]. a two-page 1988 report on methylene blue in mania by the 1986 group exists in pubmed without an abstract and is not a study record here.

two design facts travel with every one of these. first, the drug turns urine blue-green: in the 2014 trial 95.6% of people on methylene blue noticed it against 21.1% on placebo, so blinding was almost certainly broken [telch-2014]. second, to protect blinding, the two bipolar trials used 15 mg a day as the "placebo", while the 1987 trial reported that 15 mg a day was itself "a potent antidepressant". if the 1987 result is right, the bipolar trials compared two active doses; if it is wrong, the only placebo-controlled depression trial of methylene blue is wrong [naylor-1987; alda-2017; exclusions]. no trial has resolved this in four decades.

what the research says, in both directions

in favour. during the 300 mg year, the 1986 patients were significantly less depressed than during the 15 mg year, with no difference in manic symptoms [naylor-1986]. the 1987 trial reported significantly greater improvement on methylene blue than on placebo and called it "a potent antidepressant" [naylor-1987]. the 2017 trial found the 195 mg dose improved depression on both scales used (p = 0.02 on the madrs, p = 0.05 on the hamilton) and anxiety (p = 0.02), mania stayed low and stable, and side effects were transient and mild [alda-2017]. in the claustrophobia trial, people whose fear was low by the end of the exposure session had less fear a month later on methylene blue than on placebo [telch-2014]. the mechanism is real: in purified human enzyme, methylene blue is a potent, tight-binding reversible inhibitor of monoamine oxidase a, and at the blood levels reached after intravenous dosing it would be expected to inhibit that enzyme completely [ramsay-2007].

against, or smaller than it sounds. the 1986 authors listed their own limitations: small numbers, heavy dropout, crude rating scales, doubts about blinding, and uncertainty whether 15 mg a day was a placebo at all [naylor-1986]. the 1987 abstract reports no sample size and no effect size, so its strength cannot be judged from the record, and its call for further evaluation has not been answered by an adequately powered trial in nearly forty years [naylor-1987]. the 2017 trial is 37 people, the depression result sits at the conventional threshold on one of its two scales, cognition did not improve, funding is not recorded, and it was an add-on to lamotrigine, so it says nothing about methylene blue alone [alda-2017]. the claustrophobia trial cuts both ways by design: people still moderately or highly fearful at the end of the session tended to do worse on methylene blue than on placebo, which the authors read as the drug consolidating whatever the session taught, good or bad [telch-2014]. none of the four trials tested the oral products people buy, their doses, or their purity, and the harvest records that the "nootropic" and wellness marketing has no controlled trial behind it at all [exclusions].

the interaction the fda warned about, from the agency and the label

on july 26, 2011 the fda said it had 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", listed the drugs concerned (every ssri and snri, the tricyclics, the maois, and bupropion, buspirone, mirtazapine, trazodone, nefazodone and vilazodone), and stated the mechanism: methylene blue "is a potent, reversible monoamine oxidase inhibitor (maoi)", and "healthcare professionals and patients may not realize" it. the reported events were lethargy, confusion, delirium, agitation, aggression and coma, often with muscle jerking, speech loss, rigidity, seizures, fever or raised blood pressure. its instruction for planned use was that most serotonergic drugs should be stopped at least two weeks before methylene blue, fluoxetine five weeks, and not restarted until 24 hours after the last dose [fda-2011-07]. on october 20, 2011 it added that most of the reports came from parathyroid surgery, where methylene blue is injected intravenously as a visualising agent at 1 to 8 mg per kilogram, that the cases involved people on an ssri, an snri or clomipramine, and that the risk with other psychiatric drugs, by mouth, or below 1 mg per kilogram was not known [fda-2011-10]. the antidepressant labels were changed to match: the trintellix label, for one, contraindicates starting the drug in anyone being given intravenous methylene blue and adds that "no reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection)" [antidepressant-label].

the provayblue label says the same thing in a box. its boxed warning: it "may cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs and opioids. avoid concomitant use of provayblue with selective serotonin reuptake inhibitors (ssris), serotonin norepinephrine reuptake inhibitors (snris), monoamine oxidase inhibitors (maois) and opioids" [label, boxed warning]. section 5.1 adds that "some of the reported cases were fatal", that opioids and dextromethorphan raise the risk, and that patients should not take serotonergic drugs within 72 hours after the last dose; section 7 names bupropion, buspirone, clomipramine, mirtazapine and linezolid as well, and calls the drug "a potent reversible inhibitor of monoamine oxidase" [label 5.1, 7; label-row]. a 2011 review of the published cases found that 13 of 14 reports of cns toxicity with methylene blue met the hunter criteria for serotonin toxicity, that an intravenous dose of only 0.75 mg per kilogram produced blood levels high enough to inhibit monoamine oxidase a, and that severe toxicity had occurred at 1 mg per kilogram [gillman-2011]. the hunter criteria themselves are seven signs built from 2,222 overdoses: inducible muscle jerking, agitation, sweating, tremor, overactive reflexes, and in severe cases rigidity and fever [hunter-2003]. the arithmetic for a reader on an antidepressant: 1 mg per kilogram is 70 mg for a 70 kg adult, the 2017 trial gave 195 mg a day by mouth, nobody has measured what oral dose with an ssri is safe, and the only regulator to speak has said it does not know [fda-2011-10; risks].

the rest of the label. provayblue is contraindicated in g6pd deficiency, an inherited enzyme condition, because it can cause hemolytic anemia, and hemolysis can occur even without it [label 4, 5.4]; it makes pulse oximeters under-read oxygen [5.5]; it can cause confusion, dizziness and blurred vision [5.6]; it turns urine blue and interferes with urine dipstick tests [5.7]; its half-life is about 24 hours [12.3]; and intra-amniotic exposure in pregnancy has been associated with intestinal atresia and fetal death [8.1]. in overdose, 7 mg per kilogram and above brought nausea, chest pain, breathlessness, racing heart, tremor, confusion and blue staining of skin and urine, and 20 mg per kilogram and above caused severe hemolysis and death [label 10]. the common reactions in its own 31-patient trial were headache, low potassium, diarrhea, low magnesium, muscle jerking, nausea and seizure-like episodes [label 6.1].

questions people ask

does methylene blue work for depression?

not shown. the controlled evidence is four small trials: a 1986 bipolar trial with 17 completers whose authors doubted their own blinding, a 1987 three-week trial of 15 mg a day whose abstract reports no sample size, a 2017 trial of 195 mg a day in 37 people with bipolar disorder on lamotrigine that found modest improvement in depression and anxiety and none in cognition, and a 2014 single-dose trial in claustrophobia. the two bipolar trials used 15 mg a day as the placebo, the dose the 1987 trial called an antidepressant. no trial has tested the oral products sold for mood, and no adequately powered trial has been run.

is methylene blue fda approved?

yes, for one use. provayblue, an intravenous injection, was approved on april 8, 2016 for acquired methemoglobinemia, a blood disorder. there is no approved use for depression, bipolar disorder, anxiety or cognition, and no oral methylene blue product has an fda label for anything. the drops and capsules sold online for wellness are unapproved products with no review of purity or dose.

can you take methylene blue with an ssri or other antidepressant?

the provayblue label says to avoid it: its boxed warning says the combination with ssris, snris, maois and opioids "may cause serious or fatal serotonergic syndrome", and section 7 adds bupropion, buspirone, clomipramine, mirtazapine, linezolid and dextromethorphan. the fda’s 2011 communications told prescribers to stop most serotonergic drugs two weeks before intravenous methylene blue, fluoxetine five weeks, and said it did not know whether oral doses or doses below 1 mg per kilogram carried the same risk. that is a prescriber question before it is a shelf question, and nothing here is a reason to stop an antidepressant on your own.

is methylene blue an maoi?

yes. the fda called it "a potent, reversible monoamine oxidase inhibitor" in 2011, the provayblue label calls it "a potent reversible inhibitor of monoamine oxidase", and a 2007 enzyme study found it a tight-binding inhibitor of monoamine oxidase a, the enzyme that breaks down serotonin, at the levels reached after intravenous dosing. that is why it interacts with antidepressants the way the old maoi drugs do.

what did the fda say about methylene blue in 2011?

on july 26, 2011 it reported serious central nervous system reactions in people given methylene blue while taking serotonergic psychiatric drugs, listed those drugs, explained the maoi mechanism, and told prescribers to stop most of them two weeks beforehand. on october 20, 2011 it added that most cases came from parathyroid surgery with intravenous doses of 1 to 8 mg per kilogram, involved ssris, snris or clomipramine, and that the risk by mouth or at lower doses was unknown. both communications concern the intravenous drug.

what are the side effects of methylene blue?

from the provayblue label: serotonin syndrome with serotonergic drugs, which has been fatal; hemolytic anemia, and it is contraindicated in g6pd deficiency; confusion, dizziness and blurred vision; blue-green urine and interference with pulse oximeters and urine tests; and in its own 31-patient trial, headache, low potassium, diarrhea, low magnesium, muscle jerking, nausea and seizure-like episodes. in overdose, 7 mg per kilogram and above caused chest pain, breathlessness and confusion, and 20 mg per kilogram and above caused severe hemolysis and death. the trials on this page reported mostly mild, transient effects at 15 to 300 mg a day by mouth, in small numbers of people.

sources for this section

the library rows link to our one-page summary of each study, with the original paper, its funding and our evidence grade on that page.

1. the legal-status paragraph on this page (provayblue as the one approved product and use; no psychiatric indication; oral products unapproved with no premarket review; non-pharmaceutical grades as industrial dye), written from the regulator’s documents in the 2026-08-18 study harvest and quoted whole above
2. the risks paragraph on this page (the 2026-08-18 study harvest’s known-risks record for methylene blue: monoamine oxidase a inhibition, the boxed warning, g6pd hemolysis, pulse oximetry, blinding, trial doses against consumer products)
3. the "what is not known" notes on this page: the dementia trials of a different molecule excluded, animal and mechanistic work excluded, no controlled trial behind the wellness marketing; retraction check 2026-08-18
4. provayblue (methylene blue) injection prescribing information, fda label on dailymed (set id 4f6848e5-35ed-4046-b13c-3032b5ba3232, version 28, effective may 28, 2025): boxed warning; sections 1, 2.1, 4, 5.1 to 5.7, 6.1, 7, 8.1, 10, 11, 12.3
5. drugs@fda, nda 204630 (provayblue, provepharm), approved april 8, 2016
6. fda drug safety communication, july 26, 2011: serious cns reactions possible when methylene blue is given to patients taking certain psychiatric medications (archived copy; the original fda.gov page, ucm263190, no longer resolves)
7. fda drug safety communication, october 20, 2011: updated information about the drug interaction between methylene blue (methylthioninium chloride) and serotonergic psychiatric medications (archived copy; the original fda.gov page, ucm276119, no longer resolves)
8. the provayblue label’s boxed warning and serotonin-syndrome sections, read for the library (openfda record, effective may 28, 2025) (library row)
9. naylor gj, martin b, hopwood se, watson y. a two-year double-blind crossover trial of the prophylactic effect of methylene blue in manic-depressive psychosis. biological psychiatry 1986 (library row)
10. naylor gj, smith ah, connelly p. a controlled trial of methylene blue in severe depressive illness. biological psychiatry 1987 (library row)
11. alda m, mckinnon m, blagdon r, et al. methylene blue treatment for residual symptoms of bipolar disorder: randomised crossover study. british journal of psychiatry 2017 (library row)
12. telch mj, bruchey ak, rosenfield d, et al. effects of post-session administration of methylene blue on fear extinction and contextual memory in adults with claustrophobia. american journal of psychiatry 2014 (library row)
13. 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 (abstract read via pubmed 17721552; not yet a library row)
14. gillman pk. cns toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity. journal of psychopharmacology 2011;25(3):429-436 (abstract read via pubmed 20142303; not yet a library row)
15. dunkley ej, et al. the hunter serotonin toxicity criteria. qjm 2003 (library row)
16. the trintellix (vortioxetine) label’s contraindication and serotonin-syndrome wording on intravenous methylene blue, quoted on this site’s vortioxetine explainer