A two-year double-blind crossover trial of the prophylactic effect of methylene blue in manic-depressive psychosis.
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?
Reasonable evidence with real limitations. how we score evidence
Caveat on this rating: 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.
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.
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.
Worth asking
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?
Source
A two-year double-blind crossover trial of the prophylactic effect of methylene blue in manic-depressive psychosis. — Naylor GJ, Martin B, Hopwood SE, Watson Y. (1986)
Reputable peer-reviewed journal
Read the source: https://doi.org/10.1016/0006-3223(86)90265-9
DOI: 10.1016/0006-3223(86)90265-9
How this was scored
- Study design
- Randomised controlled trial
- Funding
- Funding not disclosed
- Published in
- Reputable peer-reviewed journal
- Sample size
- 31
- Preregistered
- No
- Conflicts disclosed
- No
- Independent of proponent
- not recorded
- Retracted
- No
Read the full scoring rubric, including what it can't tell you.
Published August 19, 2026.
Questions
How strong is the evidence behind this?
Resolv rates this source "moderate evidence". Reasonable evidence with real limitations. It scores 57 out of 100 on our published rubric. One caveat travels with that badge: 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. 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?
A two-year double-blind crossover trial of the prophylactic effect of methylene blue in manic-depressive psychosis. — Naylor GJ, Martin B, Hopwood SE, Watson Y. (1986). Published in: Reputable peer-reviewed journal. DOI: 10.1016/0006-3223(86)90265-9. 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: Randomised controlled trial. Funding: Funding not disclosed. 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 methylene-blue, provayblue, methylthioninium chloride, methylene blue usp, mb FDA approved for this use?
No. Its current status is: Not FDA-evaluated for this use. 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.
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.