B tier · viable
It is a genuinely approved drug with a real FDA label, WHO essential-medicines status and well-characterised pharmacology and toxicology — but that evidence belongs to methaemoglobinaemia, and the cognitive claim rests on a single 26-participant crossover imaging trial.
methylene blue
Methylene blue is an approved medicine for acquired methaemoglobinaemia with a well-characterised pharmacology, an FDA label and inclusion on the WHO Model List of Essential Medicines. Its use as a nootropic or longevity compound is entirely off-label and rests on a small human imaging trial plus mechanistic reasoning, while its documented interaction and contraindication profile is genuinely serious.
the explanation
Methylene blue is an old blue dye that became a real approved drug for a specific blood disorder, and it has decades of medical use behind it. Using it for memory or ageing is off-label and supported by one small study, and it is dangerous to combine with antidepressants and is contraindicated in people with G6PD deficiency.
regulatory status
FDA-approved (ProvayBlue, 2016) for acquired methaemoglobinaemia; all cognitive and longevity use is off-label
ProvayBlue (methylene blue injection) received FDA accelerated approval in 2016 for pediatric and adult patients with acquired methaemoglobinaemia, with continued approval contingent on verification of clinical benefit. Methylene blue is on the WHO Model List of Essential Medicines. No regulator has approved methylene blue for cognition, neuroprotection or longevity, and consumer 'USP grade' oral products sold for those purposes are not approved medicines and are not subject to the controls that apply to the approved injection.
how it works · proposed mechanism
Methylene blue cycles between oxidised and reduced forms, which lets it move electrons in biological systems — and that single property explains both its approved use and its risks.
Alternative electron carrier
At low concentrations methylene blue can accept electrons from NADH and pass them to cytochrome c, bypassing part of the respiratory chain. This is the mechanistic argument behind claims about brain energy metabolism and is the basis for the fMRI findings.
Methaemoglobin reduction
In its approved indication, methylene blue is reduced to leucomethylene blue, which reduces the ferric iron of methaemoglobin back to ferrous haemoglobin. This can shorten methaemoglobin half-life from hours to minutes and is why it is an essential medicine.
Potent reversible MAO-A inhibition
Methylene blue inhibits monoamine oxidase A reversibly at nanomolar concentrations, and reviews note that even doses below 1 mg/kg produce clinically significant inhibition. This is not a high-dose-only property, which is why the serotonergic interaction applies across the dose range people actually use.
what’s reported
evidence shape
6 sourcesThe composition of the cited literature by study type. This describes the shape of the evidence, not its quality — and it does not by itself set the grade.
⚠ the catch
This is the only compound in this index with a real FDA label, and that fact does a lot of work in marketing that the underlying evidence does not support — the approval is for a blood disorder, not for memory or ageing. The cognitive evidence is one randomised crossover study in 26 people using imaging endpoints, while the interaction and contraindication risks are documented well enough to appear in an FDA safety communication and a boxed section of the product label.
key published findings
- Human trial: a double-blind randomised placebo-controlled study in 26 healthy adults aged 22-62 given a single oral low dose reported a 7% increase in correct responses during memory retrieval versus placebo, with increased fMRI response in bilateral insular cortex, prefrontal cortex, parietal lobe and occipital cortex (Rodriguez et al., Radiology, 2016).
- Official: the ProvayBlue label carries the approved indication for acquired methaemoglobinaemia, states the product 'may cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs', and contraindicates use in patients with G6PD deficiency due to the risk of haemolytic anaemia.
- Human pharmacology: methylene blue is a potent reversible MAO-A inhibitor at nanomolar concentrations, with reviews concluding that even doses below 1 mg/kg produce clinically significant MAO inhibition; at least 14 published cases of probable or definite serotonin toxicity have been documented, including one fatal case (Anesthesia Patient Safety Foundation review).
- Human trial: the methylene blue derivative TRx0237 / LMTX (a stable reduced leuco-methylthioninium salt) failed to meet its primary endpoint in phase 3 Alzheimer's disease, with results reported in July 2016; post-hoc monotherapy subgroup claims were challenged on statistical grounds and criticised for an inappropriate comparator group.
- Pharmacokinetics: bioavailability differs sharply by formulation — oral solution reported at 72.3 ± 23.9% versus only 6.5% for a dry gelatin capsule — so 'oral methylene blue' is not one exposure.
limitations of the evidence
- The cognitive evidence is a single 26-participant single-dose crossover study using imaging and short-task endpoints, with no large replication and no data on sustained use.
- There is no long-term human data supporting any longevity or neuroprotective claim, and the most advanced attempt to translate this chemistry into a neurodegenerative indication (LMTX) failed its phase 3 primary endpoint.
- The dose-response is reported as hormetic, so results at low concentrations do not extrapolate upward, and the very large difference in bioavailability between oral formulations makes cross-study comparison unreliable.
documented safety signals
- Serotonin toxicity: in July 2011 the FDA issued a safety announcement on the risk of central nervous system toxicity when methylene blue is given to patients taking serotonergic psychiatric medications; the ProvayBlue label warns of serious or fatal serotonergic syndrome and advises against serotonergic drugs within 72 hours of the last dose. At least 14 published cases of probable or definite toxicity are documented, including a fatality.
- G6PD deficiency: contraindicated per the ProvayBlue label because treatment may cause severe haemolysis and severe anaemia; onset can be delayed by a day or more and red blood cell transfusion may be required. A 2018 meta-analysis of African malaria trials reported no association between methylene blue and haemolysis in G6PD-deficient patients, so the literature is not entirely uniform, but the label contraindication stands.
- MAO-A inhibition is potent at low doses, which means the interaction risk is not confined to high or intravenous exposure and extends to SSRIs, SNRIs and MAO inhibitors.
- Documented adverse effects include hypertension, headache, nausea, vomiting, dizziness, mental confusion, fever, and blue staining of skin and urine.
- Products sold outside the pharmaceutical supply chain are not subject to the identity, purity and contaminant controls that apply to the approved injection.
identity
| full name | Methylene blue (methylthioninium chloride) |
| category | Cognitive |
| modality | small molecule |
| formula | C16H18ClN3S |
| molar mass | 319.85 g/mol |
| cas | 61-73-4 |
| half-life | Approximately 18.5 ± 11.8 hours intravenously and 18.3 ± 7.2 hours for oral solution in more recent data; older estimates give a 5-24 hour range |
laboratory handling
| storage | The approved injection is stored per its label at controlled room temperature and protected from light. Methylene blue in any form is light-sensitive and should be kept in closed, light-protected containers. |
| solubility | Readily water-soluble, forming a deep blue solution; also soluble in ethanol. Aqueous solubility is high relative to the other compounds in this index. |
| co-studied with | The single most important documented interaction is with serotonergic drugs — SSRIs, SNRIs and MAO inhibitors — where the FDA and the product label both warn of serious or fatal serotonin syndrome, with the label advising a 72-hour separation after the last dose. This is a documented interaction rather than a theoretical one, and it applies at low doses because MAO-A inhibition is potent. |
Handling information describes laboratory practice for a research reagent. It is not a preparation guide for use in humans.
the receipts
6 citedU.S. Food and Drug Administration · 2016 · official
Radiological Society of North America · 2016 · official
Radiology 2016 · 2016 · randomized
Anesthesia Patient Safety Foundation Newsletter · 2019 · reviews
Wikipedia · 2026 · reviews
Wikipedia · 2026 · reviews
others in Cognitive