Methylene blue treatment for residual symptoms of bipolar disorder: randomised crossover study.
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?
Reasonable evidence with real limitations. how we score evidence
Caveat on this rating: 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.
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.
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.
Worth asking
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?
Source
Methylene blue treatment for residual symptoms of bipolar disorder: randomised crossover study. — Alda M, McKinnon M, Blagdon R, et al. (2017)
Reputable peer-reviewed journal
Read the source: https://doi.org/10.1192/bjp.bp.115.173930
DOI: 10.1192/bjp.bp.115.173930
How this was scored
- Study design
- Randomised controlled trial
- Funding
- Funding not disclosed
- Published in
- Reputable peer-reviewed journal
- Sample size
- 37
- Preregistered
- Yes
- 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.
Where we put this study in context
Questions
How strong is the evidence behind this?
Resolv rates this source "moderate evidence". Reasonable evidence with real limitations. It scores 63 out of 100 on our published rubric. One caveat travels with that badge: 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. 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?
Methylene blue treatment for residual symptoms of bipolar disorder: randomised crossover study. — Alda M, McKinnon M, Blagdon R, et al. (2017). Published in: Reputable peer-reviewed journal. DOI: 10.1192/bjp.bp.115.173930. 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.