Substance evidence
Methylene Blue
An MAO-A inhibitor sold as a nootropic, and the serotonin-syndrome record.
What Its Legal Status Actually Means
Read this before anything below it. Legal to sell is not the same fact as reviewed, verified, or approved.
There is no FDA-approved psychiatric indication — not for depression, bipolar disorder, anxiety, cognition, or "mitochondrial support". Methylene blue is an FDA-approved drug, but only for one thing: ProvayBlue (methylene blue injection, NDA 204630, Provepharm) is indicated for the treatment of pediatric and adult patients with acquired methemoglobinemia. Methylene blue also appears as a component of some FDA-listed prescription urinary combination products for irritative voiding symptoms. Everything sold as oral methylene blue drops, capsules, or "pharmaceutical grade USP" powder for wellness or nootropic use is an unapproved product with no premarket review of purity or dose; non-pharmaceutical-grade methylene blue is an industrial dye and can carry heavy-metal contamination. Any psychiatric use is off-label and unstudied at the doses people self-administer.
Quoted whole from the 2026-08-18 study harvest. Not summarized, not shortened.
What the Research Shows
5 records from the 2026-08-18 harvest, each checked against PubMed and Europe PMC on that date. How a study was designed, how many people were in it, and who paid for it are printed above what it found, because those three facts decide how much the finding is worth.
Study 1 · 2025
- Regulatory action
- Government body
- No funding reported
strong82/100Well-supported by good-quality research.
FDA-approved labeling states that methylene blue is indicated only for acquired methemoglobinemia and carries a boxed warning that it "may cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs and opioids", instructing prescribers to avoid concomitant use with SSRIs, SNRIs, MAOIs, and opioids. The labeling attributes this to methylene blue being a potent reversible inhibitor of monoamine oxidase, and notes that some reported cases were fatal.
How this record was checked
openFDA drug-label API record for PROVAYBLUE (set_id 4f6848e5-35ed-4046-b13c-3032b5ba3232, effective 2025-05-28) fetched 2026-08-18; the boxed warning, section 5.1 (Serotonin Syndrome with Concomitant Use of Serotonergic Drugs and Opioids), section 7 drug interactions, and the sole indication for acquired methemoglobinemia were read verbatim from that record. Application NDA 204630 (sponsor Provepharm SAS) confirmed via the openFDA Drugs@FDA API the same day, and the FDA-hosted prescribing-information PDF at the cited accessdata.fda.gov URL confirmed live (HTTP 200) on 2026-08-18.
Study 2 · 2014
- Randomized trial
- 42 participants
- Top-tier journal
- Independently funded
- Declared conflicts of interest
strong81/100Well-supported by good-quality research.
Read this first: Blinding was almost certainly compromised: 95.6% of methylene blue participants reported blue-green urine discoloration versus 21.1% on placebo. The subgroup finding that drives the headline result was predicted in advance but comes from splitting 42 people by post-training fear level, so it needs replication before it means much.
42 adults with marked claustrophobic fear were randomised to 260 mg of methylene blue or placebo immediately after six exposure trials. The drug did not simply improve outcomes: participants whose fear was low by the end of the session had less fear at one-month follow-up on methylene blue, while those still moderately or highly fearful tended to do worse on it than on placebo. Methylene blue appears to consolidate whatever was learned in the session, good or bad.
How this record was checked
PubMed record 25018057 fetched via NCBI efetch 2026-08-18; title, authors, journal, year, DOI, and the allocation (23 methylene blue, 19 placebo; n=42) confirmed from the abstract. PMC full text 4467026 fetched the same day via NCBI efetch (db=pmc) states "This work was supported in part by NIH grant R01 MH076847" and "The authors report no financial relationships with commercial interests", hence funding INDEPENDENT and conflicts disclosed; the side-effect table in that full text is the source of the urine-discoloration figures.
Study 3 · 2017
- Randomized trial
- 37 participants
- Reputable journal
- Funding not established
- Preregistered
moderate63/100Reasonable evidence with real limitations.
Read this first: The comparator was not inert: the "placebo" arm was 15 mg/day of methylene blue, chosen to preserve blinding because the drug discolours urine. Since a 1987 trial by Naylor reported that 15 mg/day itself acted as an antidepressant, the true drug-versus- nothing effect could be either larger or smaller than the reported difference.
37 people with bipolar disorder already on lamotrigine took 195 mg/day of methylene blue and 15 mg/day in a six-month double-blind crossover. The active dose modestly improved depression (MADRS p=0.02, HAM-D p=0.05) and anxiety (HAM-A p=0.02) but not cognition, and was well tolerated. This is the only modern controlled psychiatric trial of methylene blue, and 37 people is not enough to establish an effect size anyone should plan treatment around.
How this record was checked
PubMed record 27284082 fetched via NCBI efetch 2026-08-18; title, authors, journal (Br J Psychiatry 2017;210(1):54-60, epub 9 June 2016), year, DOI, n=37 enrolled, the 195 mg versus 15 mg design, six-month duration, trial registration NCT00214877, and all reported p-values confirmed from the abstract. Europe PMC core record checked the same day: not open access, not in PMC, no grant or funding statement retrievable, so funding is recorded UNKNOWN and independence left unchecked.
Study 4 · 1986
- Randomized trial
- 31 participants
- Reputable journal
- Funding not established
moderate57/100Reasonable evidence with real limitations.
Read this first: Nearly half the enrolled participants did not complete, the comparator was a low dose of the same drug rather than an inert placebo, and methylene blue's blue-green urine makes blinding difficult at any dose — all conceded in the paper. Everyone was also on lithium, so this tests methylene blue only as an add-on.
31 people with bipolar disorder, all maintained on lithium, spent one year on 300 mg/day of methylene blue and one year on 15 mg/day in a double-blind crossover; only 17 completed. They were significantly less depressed during the high-dose year, with no difference in manic symptoms. The authors themselves listed the limitations: small numbers, heavy dropout, crude rating scales, doubtful blinding, and no certainty that 15 mg/day was really a placebo.
How this record was checked
PubMed record 3091097 fetched via NCBI efetch 2026-08-18; title, authors, journal, year, DOI, n=31 enrolled with 17 completers, the 300 mg versus 15 mg crossover design, and the authors' stated limitations confirmed from the abstract. Europe PMC core record checked the same day: not open access, no grant or funding statement available for a 1986 paper, so funding is UNKNOWN and independence left unchecked.
Study 5 · 1987
- Randomized trial
- Reputable journal
- Funding not established
moderate58/100Reasonable evidence with real limitations.
Read this first: The published abstract gives no sample size, no effect size, and no confidence intervals, so the strength of the result cannot be assessed from the record; sample size is recorded as unknown rather than guessed. The dose it found effective, 15 mg/day, is the same dose the same group's 1986 trial and Alda's 2017 trial both used as the comparator — a direct internal contradiction in this small literature that has never been resolved.
A three-week controlled trial compared 15 mg/day of methylene blue with placebo in severe depressive illness and reported significantly greater improvement on methylene blue, concluding it "appears to be a potent antidepressant". Nearly forty years later that call for further clinical evaluation has still not been answered by an adequately powered trial.
How this record was checked
PubMed record 3555627 fetched via NCBI efetch 2026-08-18; title, authors, journal, year, DOI, the 15 mg/day dose, three-week duration, and placebo comparison confirmed from the abstract. No sample size is reported anywhere in the record, and the paper is not open access or in PMC, so sampleSize is null and funding UNKNOWN.
The Risks
Nobody checks this purchase the way a prescription is checked. No prescriber reviews it against the rest of what you take, no pharmacist screens the interaction, and no regulator confirms the dose in the capsule before it is sold. That is why this section sits here at full length rather than as a footnote.
What the paragraph below covers:
- Serotonin syndrome
- Drug interactions
The central risk is pharmacological, not hypothetical: methylene blue is a potent reversible inhibitor of monoamine oxidase A. The FDA-approved labeling for ProvayBlue carries a boxed warning that it may cause serious or fatal serotonin syndrome when combined with serotonergic drugs and opioids, and directs clinicians to avoid concomitant use with SSRIs, SNRIs, MAOIs, and opioids; the labeling also names bupropion, buspirone, clomipramine, mirtazapine, linezolid, and dextromethorphan, and states that some reported cases were fatal. Anyone taking an antidepressant is in the interaction zone. Beyond that: methylene blue causes haemolytic anaemia in people with G6PD deficiency and can worsen methemoglobinemia at high doses; it interferes with pulse oximetry; it turns urine and sometimes stool blue-green, which makes genuine blinding in trials nearly impossible; and it can cause hypersensitivity reactions, and neurologic and visual symptoms affecting driving. Doses used in the psychiatric studies (195-300 mg/day) are far above the amounts in consumer products, and neither has been shown safe for long-term self-administration.
What Is Not Known
The boundaries of the section above, in the harvest’s own words. What it excluded, why, and where it looked and found nothing. An absence of evidence is not evidence of absence, and it is not evidence of benefit either.
What Was Left Out, and Why
Quoted from the harvest, where these notes sat above the study list rather than after it. Where a note says “below” it means the studies in the section above.
- Alzheimer's/frontotemporal dementia trials of the methylene blue derivative leuco-methylthioninium (LMTM/TRx0237) excluded: different molecule, different indication, and the pivotal trials were industry-sponsored and failed their primary endpoints.
- Animal and mechanistic work on methylene blue as a mitochondrial/cytochrome-oxidase enhancer excluded; only human controlled evidence is included.
- Wellness and "nootropic" marketing of oral methylene blue has no controlled trial behind it at all. The entire human psychiatric evidence base is the four small trials below, three of which are 30-40 years old.
The Retraction Check
PubMed efetch records for all four PMIDs (3091097, 3555627, 27284082, 25018057) inspected 2026-08-18 for "Retraction in" flags; none present. The FDA labeling record was checked against the live openFDA drug-label API the same day.
Questions for a Prescriber or Pharmacist
This page does not tell anyone to take Methylene Blue or to avoid it. It is not able to: it does not know what else you take, what you have tried, or what you are treating. These are the questions each study above raises, written to be asked out loud.
- I am taking methylene blue (or thinking about it) while on an antidepressant — given the FDA boxed warning about fatal serotonin syndrome, is there any dose of this that is safe for me?
- This drug seems to strengthen whatever the exposure session taught — including a bad session. If I am doing exposure therapy, is that a risk worth taking?
- The only recent controlled trial of methylene blue in bipolar disorder had 37 people and was an add-on to lamotrigine — is there a better-supported add-on for my residual depression?
- The original methylene blue bipolar trial is from 1986, had 17 completers, and its authors doubted their own blinding — is there any reason to prefer it over treatments with modern evidence?
- A 1987 trial called methylene blue a potent antidepressant and nobody has run a proper trial since — does that absence of follow-up tell us something?
And the one to ask at the counter, whatever the answers above turn out to be: given everything I am already taking, what would you want to know about Methylene Blue before I put it in the same body?
Where This Page Comes From
Transcribed from the study-harvest-2026-08-18 record for methylene-blue, built into this page by scripts/supplement-ingest.mjs on 2026-09-07. Nothing here is fetched at page load, and nothing here was written by a model without a citation behind it.
| Source file | study-harvest/2026-08-18/methylene-blue.yaml |
|---|---|
| Source repo | REPTechnologies/avalo-backend |
| SHA-256 | 188fa48dbe1d02bcf30ee50b69154cae70bd481192282a40f417a82fb4de288e |
| Also searched as | ProvayBlue, methylthioninium chloride, methylene blue USP, MB |
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