Methylene blue
updated
Methylene blue is an established IV rescue drug for acquired methemoglobinemia. In cognition research, a 26-person acute oral experiment found 7 percent more correct memory-retrieval responses, and a 248-person Chinese perioperative IV trial reduced early postoperative delirium and cognitive dysfunction. A 12-week registry was inconclusive, and a six-month bipolar trial found no cognitive benefit. These studies do not establish chronic healthy nootropic use; the label warns about serotonin syndrome and hemolysis.
Redox-active phenothiazinium dye and reversible MAO-A inhibitor
- ProvayBlue is approved for acquired methemoglobinemia, not cognitive enhancement.
- The label says IV use and explicitly says not to administer the product subcutaneously.
- One 26-person oral study measured effects about an hour after a single exposure.
- A posted 12-week registry had heavy attrition and no inferential comparisons.
- Methylene blue inhibits MAO-A and has a boxed serotonin-syndrome warning.
- G6PD deficiency is a contraindication because severe hemolysis can occur.
Which methylene blue claim are you evaluating?
The US approval covers acute IV rescue treatment for acquired methemoglobinemia. Oral cognition experiments, perioperative IV prevention, an oral colonoscopy dye, and retail nootropic products use different formulations, routes, populations, and outcomes.
| Lane | What is actually established |
|---|---|
| US ProvayBlue | IV treatment of acquired methemoglobinemia |
| Healthy cognition | One 26-person acute oral experiment plus an inconclusive 12-week registry |
| Perioperative cognition | One Shanghai IV open-label RCT in older surgical patients |
| China colonoscopy product | Enteric sustained-release oral dye used to improve lesion detection |
| Retail nootropic | Identity, exposure, repeated benefit, and interaction risk must be established separately |
US label · methemoglobinemia and major risks
FDA prescribing information
DailyMed. PROVAYBLUE (methylene blue) injection. Updated May 28, 2025; prescribing information revised February 2024.
The IV product treats acquired methemoglobinemia in adults and children. The label carries a boxed warning for serious or fatal serotonin syndrome with serotonergic drugs and opioids, contraindicates G6PD deficiency and prior severe hypersensitivity, warns about hemolysis, pulse-oximeter and laboratory interference, fetal harm, driving impairment, and higher exposure in renal impairment, and says not to administer subcutaneously.
- Participants / model
- Adults and children with acquired methemoglobinemia
- Treatment
- Sterile methylene blue injection, 5 mg/mL, administered intravenously
- Follow-up
- Acute rescue treatment
- Study design
- Regulatory prescribing information
- Funding
- Manufacturer regulatory program
This indication, exposure, and approximately 24-hour half-life belong to the labeled IV product. They do not establish chronic oral cognitive benefit.
Read the original sourceFDA approval · acquired methemoglobinemia
FDA regulatory record
US Food and Drug Administration. Orphan Drug Designations and Approvals, record 385512.
Records approval of methylene blue for treatment of acquired methemoglobinemia. It does not list cognitive enhancement as the approved indication.
- Participants / model
- Patients with acquired methemoglobinemia
- Treatment
- Methylene blue
- Follow-up
- Regulatory action
- Study design
- FDA orphan-drug approval record
An approval record establishes regulatory scope, not efficacy for unrelated uses.
Read the original source26 adults · one oral exposure
Randomized double-blind placebo-controlled trial
Rodriguez P et al. Radiology. 2016. PMID 27351678; NCT01836094.
Twenty-six healthy adults aged 22 to 62 completed task fMRI before and one hour after one low-dose oral exposure or placebo. Methylene blue changed task-related activation and was associated with 7 percent more correct responses during memory retrieval (P=.01). The experiment did not test repeated use, daily function, disease prevention, or long-term safety.
- Participants / model
- 26 healthy adults aged 22 to 62
- Treatment
- One low-dose oral methylene blue exposure or placebo
- Follow-up
- Approximately one hour to post-dose testing
- Study design
- Prospective randomized double-blind placebo-controlled task-fMRI experiment
- Funding
- NIH grants reported
The 26-person acute experiment tested several imaging and task endpoints; it did not measure daily function or durable clinical benefit.
Read the original sourceShanghai RCT · perioperative IV context
Randomized open-label controlled trial
Deng Y et al. Journal of Clinical Anesthesia. 2021. PMID 33091706; NCT04341844.
At two Fudan-affiliated Shanghai centers, 248 older surgical patients were randomized 124 per group to 2 mg/kg IV methylene blue after anesthesia induction or saline. Postoperative delirium was 7.3 percent versus 24.2 percent (OR 0.24, 95% CI 0.11 to 0.53), and cognitive dysfunction at day 7 was 16.1 percent versus 40.2 percent (OR 0.30, 95% CI 0.16 to 0.57).
- Participants / model
- 248 older adults undergoing major noncardiac surgery in Shanghai, China
- Treatment
- One 2 mg/kg IV infusion after anesthesia induction versus saline
- Follow-up
- In-hospital delirium follow-up and early cognitive assessment at postoperative day 7
- Study design
- Prospective randomized open-label controlled trial
- Funding
- Fudan University registry sponsor
Open-label, acute perioperative prevention in high-risk surgical patients is not evidence for oral daily enhancement. Longer-term registered outcomes were not reported in the PubMed abstract.
Read the original sourceChina product · colonoscopy detection aid
Chinese government reimbursement evidence dossier
National Healthcare Security Administration of China. Methylene blue enteric sustained-release tablet evidence slides, 2025.
The Chinese-language dossier describes a randomized double-blind phase 3 trial in 1,802 adults undergoing screening or diagnostic colonoscopy. In analyzed groups of 872 versus 879, non-polypoid colorectal lesion detection was 51.0 versus 41.2 percent, and non-polypoid adenoma detection was 39.1 versus 30.9 percent. The formulation is an oral enteric sustained-release dye used to improve lesion visualization.
- Participants / model
- Adults aged 50 to 75 undergoing colorectal screening or colonoscopy in China
- Treatment
- Oral enteric sustained-release methylene blue formulation versus placebo before colonoscopy
- Follow-up
- Single colonoscopy preparation context
- Study design
- Randomized double-blind multicenter placebo-controlled phase 3 study summarized in an official dossier
- Funding
- Manufacturer-submitted evidence within government reimbursement review
The dossier describes a diagnostic dye formulation and lesion-detection outcomes, not nootropic use; it does not report a complete clinical dataset.
Read the original sourceWhat does the FDA-approved product actually do?
ProvayBlue treats acquired methemoglobinemia in adults and children. In that condition, too much hemoglobin iron is in a ferric state that cannot carry oxygen normally. The drug’s reduced form helps return methemoglobin toward functional hemoglobin.
The product is a sterile 5 mg/mL IV solution. The label explicitly says not to administer it subcutaneously. If methemoglobinemia does not resolve after two label doses, the label directs clinicians toward alternative interventions rather than unlimited repeat exposure.
US label · methemoglobinemia and major risks
FDA prescribing information
DailyMed. PROVAYBLUE (methylene blue) injection. Updated May 28, 2025; prescribing information revised February 2024.
The IV product treats acquired methemoglobinemia in adults and children. The label carries a boxed warning for serious or fatal serotonin syndrome with serotonergic drugs and opioids, contraindicates G6PD deficiency and prior severe hypersensitivity, warns about hemolysis, pulse-oximeter and laboratory interference, fetal harm, driving impairment, and higher exposure in renal impairment, and says not to administer subcutaneously.
- Participants / model
- Adults and children with acquired methemoglobinemia
- Treatment
- Sterile methylene blue injection, 5 mg/mL, administered intravenously
- Follow-up
- Acute rescue treatment
- Study design
- Regulatory prescribing information
- Funding
- Manufacturer regulatory program
This indication, exposure, and approximately 24-hour half-life belong to the labeled IV product. They do not establish chronic oral cognitive benefit.
Read the original sourceFDA approval · acquired methemoglobinemia
FDA regulatory record
US Food and Drug Administration. Orphan Drug Designations and Approvals, record 385512.
Records approval of methylene blue for treatment of acquired methemoglobinemia. It does not list cognitive enhancement as the approved indication.
- Participants / model
- Patients with acquired methemoglobinemia
- Treatment
- Methylene blue
- Follow-up
- Regulatory action
- Study design
- FDA orphan-drug approval record
An approval record establishes regulatory scope, not efficacy for unrelated uses.
Read the original sourceWhat did the acute healthy-adult cognition trial measure?
It measured task performance and brain activation about one hour after one oral exposure. Among 26 healthy adults aged 22 to 62, methylene blue was associated with 7 percent more correct memory-retrieval responses and changed fMRI activation during attention and memory tasks.
The trial used multiple task and imaging outcomes with correction for imaging comparisons. It did not measure weeks of everyday concentration, school or work performance, dementia prevention, tolerance, withdrawal, or long-term adverse effects. The fMRI result measures task-related activation; it does not establish an everyday functional benefit.
26 adults · one oral exposure
Randomized double-blind placebo-controlled trial
Rodriguez P et al. Radiology. 2016. PMID 27351678; NCT01836094.
Twenty-six healthy adults aged 22 to 62 completed task fMRI before and one hour after one low-dose oral exposure or placebo. Methylene blue changed task-related activation and was associated with 7 percent more correct responses during memory retrieval (P=.01). The experiment did not test repeated use, daily function, disease prevention, or long-term safety.
- Participants / model
- 26 healthy adults aged 22 to 62
- Treatment
- One low-dose oral methylene blue exposure or placebo
- Follow-up
- Approximately one hour to post-dose testing
- Study design
- Prospective randomized double-blind placebo-controlled task-fMRI experiment
- Funding
- NIH grants reported
The 26-person acute experiment tested several imaging and task endpoints; it did not measure daily function or durable clinical benefit.
Read the original sourceDoes the repeated-use human record establish chronic cognitive benefit?
Repeated-use studies have not established cognitive benefit. The 12-week registry had heavy attrition and no posted between-group analyses, while a six-month bipolar crossover found no significant cognitive improvement.
NCT02380573 reports 117 enrolled, but its arm flow shows 98 started and 55 completed. The healthy-aging arms completed 12 of 22 versus 13 of 21; the MCI arms completed 12 of 28 versus 16 of 24. Descriptive means were posted without inferential comparisons. The bipolar trial enrolled 37 people on lamotrigine and compared 195 mg with a 15 mg low-dose condition; mood ratings moved, cognition did not.
12-week registry · attrition and no analyses
Results-posted randomized trial registry
ClinicalTrials.gov. NCT02380573. Results posted September 19, 2024.
The registry reports actual enrollment of 117, while participant-flow arms show 98 started and 55 completed. Healthy-aging arms started 22 versus 21 and completed 12 versus 13; MCI arms started 28 versus 24 and completed 12 versus 16. Outcomes were posted as descriptive means at baseline, two weeks, and 12 weeks, but no between-group statistical analyses were posted. Only three people entered the Alzheimer arms and no middle-age participant started.
- Participants / model
- Adults aged 45 to 89 in healthy-aging, MCI, Alzheimer, and planned middle-age cohorts
- Treatment
- Oral USP methylene blue 282 mg daily versus blue-dye placebo; all arms also listed phenazopyridine as a blinding aid
- Follow-up
- 12 weeks
- Study design
- Phase 2 randomized quadruple-masked registry with results
- Funding
- University of Texas Health Science Center at San Antonio; Texas Alzheimer’s Research and Care Consortium
Flow counts conflict with the registry enrollment total, attrition was high, and absence of posted analyses prevents a benefit conclusion from the descriptive table.
Read the original source37 people · six-month cognition result null
Randomized double-blind crossover trial
Alda M et al. British Journal of Psychiatry. 2017. PMID 27284082; NCT00214877.
Thirty-seven people with bipolar disorder taking lamotrigine entered a six-month crossover comparison of 195 mg methylene blue with a 15 mg low-dose comparison. Depression and anxiety ratings improved in last-observation-carried-forward analyses, but cognitive symptoms did not improve significantly.
- Participants / model
- 37 people with bipolar disorder and residual symptoms while treated with lamotrigine
- Treatment
- 195 mg active methylene blue versus 15 mg low-dose comparison in a crossover design
- Follow-up
- 6 months
- Study design
- Randomized double-blind crossover trial
Disease-specific adjunctive treatment with an active low-dose comparator does not establish enhancement in healthy people.
Read the original sourceRepeated-use cognition · no healthy chronic benefit established
PubMed and trial registry records
PubMed, ClinicalTrials.gov, ChiCTR, and Russian-language records for repeated methylene-blue use.
The cited records include the 12-week NCT02380573 registry, the six-month bipolar crossover, acute perioperative Chinese trials, and studies of related tau-targeting derivatives. They include no published controlled trial establishing durable everyday cognitive enhancement from chronic unmodified methylene blue in healthy adults.
- Participants / model
- Repeated-use human cognition studies sought
- Treatment
- Unmodified methylene blue, with derivative drugs kept separate
What does the Shanghai postoperative-cognition trial establish?
It supports a narrow acute perioperative signal. In 248 older adults having major noncardiac surgery, one 2 mg/kg IV infusion after anesthesia induction reduced reported delirium from 24.2 to 7.3 percent and day-7 cognitive dysfunction from 40.2 to 16.1 percent.
The trial was randomized but open label, used saline control, and occurred in a high-risk surgical setting. Its outcome is prevention of early postoperative neurocognitive complications. It cannot answer whether a healthy person thinks better after chronic oral self-use.
Shanghai RCT · perioperative IV context
Randomized open-label controlled trial
Deng Y et al. Journal of Clinical Anesthesia. 2021. PMID 33091706; NCT04341844.
At two Fudan-affiliated Shanghai centers, 248 older surgical patients were randomized 124 per group to 2 mg/kg IV methylene blue after anesthesia induction or saline. Postoperative delirium was 7.3 percent versus 24.2 percent (OR 0.24, 95% CI 0.11 to 0.53), and cognitive dysfunction at day 7 was 16.1 percent versus 40.2 percent (OR 0.30, 95% CI 0.16 to 0.57).
- Participants / model
- 248 older adults undergoing major noncardiac surgery in Shanghai, China
- Treatment
- One 2 mg/kg IV infusion after anesthesia induction versus saline
- Follow-up
- In-hospital delirium follow-up and early cognitive assessment at postoperative day 7
- Study design
- Prospective randomized open-label controlled trial
- Funding
- Fudan University registry sponsor
Open-label, acute perioperative prevention in high-risk surgical patients is not evidence for oral daily enhancement. Longer-term registered outcomes were not reported in the PubMed abstract.
Read the original sourceAre IV ProvayBlue, oral methylene blue, and China’s colonoscopy tablet interchangeable?
No. The US product is a sterile IV trihydrate-strength solution. PubChem’s formula and molecular weight describe the anhydrous chloride identity. China’s enteric sustained-release tablet was studied as a colonoscopy dye. Route, hydrate expression, release profile, purity, and intended use all change what can be inferred.
The Chinese phase 3 dossier reports 1,802 participants and analyzed groups of 872 versus 879. Non-polypoid lesion detection was 51.0 versus 41.2 percent. The trial studied lesion visualization during colonoscopy, not cognition.
US label · methemoglobinemia and major risks
FDA prescribing information
DailyMed. PROVAYBLUE (methylene blue) injection. Updated May 28, 2025; prescribing information revised February 2024.
The IV product treats acquired methemoglobinemia in adults and children. The label carries a boxed warning for serious or fatal serotonin syndrome with serotonergic drugs and opioids, contraindicates G6PD deficiency and prior severe hypersensitivity, warns about hemolysis, pulse-oximeter and laboratory interference, fetal harm, driving impairment, and higher exposure in renal impairment, and says not to administer subcutaneously.
- Participants / model
- Adults and children with acquired methemoglobinemia
- Treatment
- Sterile methylene blue injection, 5 mg/mL, administered intravenously
- Follow-up
- Acute rescue treatment
- Study design
- Regulatory prescribing information
- Funding
- Manufacturer regulatory program
This indication, exposure, and approximately 24-hour half-life belong to the labeled IV product. They do not establish chronic oral cognitive benefit.
Read the original sourcePubChem · anhydrous chloride identity
Government chemical database
National Library of Medicine. PubChem Compound Summary for CID 6099, methylene blue.
Identifies anhydrous methylthioninium chloride as C16H18ClN3S, molecular weight 319.9 g/mol, CAS 61-73-4. The ProvayBlue label separately expresses product strength as methylene blue trihydrate equivalent.
- Participants / model
- Not applicable
- Treatment
- Not applicable
- Follow-up
- Database record
- Study design
- Curated chemical identity record
Chemical identity does not verify purity or equivalence of a retail product.
Read the original sourceChina product · colonoscopy detection aid
Chinese government reimbursement evidence dossier
National Healthcare Security Administration of China. Methylene blue enteric sustained-release tablet evidence slides, 2025.
The Chinese-language dossier describes a randomized double-blind phase 3 trial in 1,802 adults undergoing screening or diagnostic colonoscopy. In analyzed groups of 872 versus 879, non-polypoid colorectal lesion detection was 51.0 versus 41.2 percent, and non-polypoid adenoma detection was 39.1 versus 30.9 percent. The formulation is an oral enteric sustained-release dye used to improve lesion visualization.
- Participants / model
- Adults aged 50 to 75 undergoing colorectal screening or colonoscopy in China
- Treatment
- Oral enteric sustained-release methylene blue formulation versus placebo before colonoscopy
- Follow-up
- Single colonoscopy preparation context
- Study design
- Randomized double-blind multicenter placebo-controlled phase 3 study summarized in an official dossier
- Funding
- Manufacturer-submitted evidence within government reimbursement review
The dossier describes a diagnostic dye formulation and lesion-detection outcomes, not nootropic use; it does not report a complete clinical dataset.
Read the original sourceWhy do antidepressants, opioids, and cough medicine matter?
Methylene blue inhibits MAO-A. The current label carries a boxed warning because serious or fatal serotonin syndrome has occurred with serotonergic drugs and opioids; it also names dextromethorphan as a risk.
- Relevant drug categories include SSRIs, SNRIs, MAO inhibitors, bupropion, buspirone, clomipramine, mirtazapine, linezolid, opioids, and dextromethorphan.
- Symptoms can combine agitation or delirium, unstable blood pressure or temperature, tremor or rigidity, seizures, and gastrointestinal distress.
- The boxed warning applies to clinician-managed rescue treatment, and no lower oral amount has been established as safe with serotonergic drugs or opioids.
US label · methemoglobinemia and major risks
FDA prescribing information
DailyMed. PROVAYBLUE (methylene blue) injection. Updated May 28, 2025; prescribing information revised February 2024.
The IV product treats acquired methemoglobinemia in adults and children. The label carries a boxed warning for serious or fatal serotonin syndrome with serotonergic drugs and opioids, contraindicates G6PD deficiency and prior severe hypersensitivity, warns about hemolysis, pulse-oximeter and laboratory interference, fetal harm, driving impairment, and higher exposure in renal impairment, and says not to administer subcutaneously.
- Participants / model
- Adults and children with acquired methemoglobinemia
- Treatment
- Sterile methylene blue injection, 5 mg/mL, administered intravenously
- Follow-up
- Acute rescue treatment
- Study design
- Regulatory prescribing information
- Funding
- Manufacturer regulatory program
This indication, exposure, and approximately 24-hour half-life belong to the labeled IV product. They do not establish chronic oral cognitive benefit.
Read the original sourceHuman enzyme study · MAO-A inhibition
In-vitro human enzyme study
Ramsay RR et al. British Journal of Pharmacology. 2007. PMCID PMC2078225.
Purified human enzyme experiments found methylene blue to be a potent reversible inhibitor of MAO-A. This pharmacology provides a plausible basis for the label’s serious serotonergic interaction warning.
- Participants / model
- Purified human MAO-A and MAO-B, not clinical participants
- Treatment
- Methylene blue in enzyme assays
- Follow-up
- Acute in-vitro assays
- Study design
- Mechanistic enzyme kinetics study
Enzyme potency supports interaction mechanism, not a cognitive benefit.
Read the original sourceWhy can methylene blue worsen the problem it is meant to treat?
People with G6PD deficiency may not reduce the drug to its active form, and treatment can cause severe hemolysis and severe anemia. ProvayBlue is contraindicated in G6PD deficiency. Hemolytic anemia can also occur outside that group and may be delayed by a day or more.
Treatment depends on G6PD status and exposure. Higher IV exposures also produced hypotension, wheezing, reduced oxygenation, chest symptoms, tachycardia, confusion, and even mild methemoglobinemia in label reports.
US label · methemoglobinemia and major risks
FDA prescribing information
DailyMed. PROVAYBLUE (methylene blue) injection. Updated May 28, 2025; prescribing information revised February 2024.
The IV product treats acquired methemoglobinemia in adults and children. The label carries a boxed warning for serious or fatal serotonin syndrome with serotonergic drugs and opioids, contraindicates G6PD deficiency and prior severe hypersensitivity, warns about hemolysis, pulse-oximeter and laboratory interference, fetal harm, driving impairment, and higher exposure in renal impairment, and says not to administer subcutaneously.
- Participants / model
- Adults and children with acquired methemoglobinemia
- Treatment
- Sterile methylene blue injection, 5 mg/mL, administered intravenously
- Follow-up
- Acute rescue treatment
- Study design
- Regulatory prescribing information
- Funding
- Manufacturer regulatory program
This indication, exposure, and approximately 24-hour half-life belong to the labeled IV product. They do not establish chronic oral cognitive benefit.
Read the original sourceWhich practical safety effects are easy to miss?
The dye can make pulse oximetry underestimate oxygen saturation, interfere with blue-indicator urine tests, and discolor skin and body fluids. The label also reports confusion, dizziness, visual disturbance, phototoxicity, and seizure-like phenomena.
- Pregnancy: the label warns of fetal harm.
- Breastfeeding: the label calls for interruption during treatment and for up to eight days afterward.
- Driving: avoid it until neurologic and visual symptoms have resolved.
- Kidney function: after a single IV dose, AUC rose 52, 116, and 192 percent with mild, moderate, and severe renal impairment.
- Liver impairment: delayed clearance can extend toxicity and interaction monitoring.
US label · methemoglobinemia and major risks
FDA prescribing information
DailyMed. PROVAYBLUE (methylene blue) injection. Updated May 28, 2025; prescribing information revised February 2024.
The IV product treats acquired methemoglobinemia in adults and children. The label carries a boxed warning for serious or fatal serotonin syndrome with serotonergic drugs and opioids, contraindicates G6PD deficiency and prior severe hypersensitivity, warns about hemolysis, pulse-oximeter and laboratory interference, fetal harm, driving impairment, and higher exposure in renal impairment, and says not to administer subcutaneously.
- Participants / model
- Adults and children with acquired methemoglobinemia
- Treatment
- Sterile methylene blue injection, 5 mg/mL, administered intravenously
- Follow-up
- Acute rescue treatment
- Study design
- Regulatory prescribing information
- Funding
- Manufacturer regulatory program
This indication, exposure, and approximately 24-hour half-life belong to the labeled IV product. They do not establish chronic oral cognitive benefit.
Read the original sourceWhat does the roughly 24-hour half-life actually apply to?
It comes from the human pharmacokinetic section for the IV product. It is not a validated interval for repeated oral nootropic use, a different salt or formulation, or a retail product of uncertain identity.
Methylene blue has concentration-dependent redox behavior, extensive distribution, metabolism through several pathways, and exposure that rises with renal impairment. A single half-life cannot settle formulation equivalence, accumulation, or safe repeated use.
US label · methemoglobinemia and major risks
FDA prescribing information
DailyMed. PROVAYBLUE (methylene blue) injection. Updated May 28, 2025; prescribing information revised February 2024.
The IV product treats acquired methemoglobinemia in adults and children. The label carries a boxed warning for serious or fatal serotonin syndrome with serotonergic drugs and opioids, contraindicates G6PD deficiency and prior severe hypersensitivity, warns about hemolysis, pulse-oximeter and laboratory interference, fetal harm, driving impairment, and higher exposure in renal impairment, and says not to administer subcutaneously.
- Participants / model
- Adults and children with acquired methemoglobinemia
- Treatment
- Sterile methylene blue injection, 5 mg/mL, administered intravenously
- Follow-up
- Acute rescue treatment
- Study design
- Regulatory prescribing information
- Funding
- Manufacturer regulatory program
This indication, exposure, and approximately 24-hour half-life belong to the labeled IV product. They do not establish chronic oral cognitive benefit.
Read the original sourcePubChem · anhydrous chloride identity
Government chemical database
National Library of Medicine. PubChem Compound Summary for CID 6099, methylene blue.
Identifies anhydrous methylthioninium chloride as C16H18ClN3S, molecular weight 319.9 g/mol, CAS 61-73-4. The ProvayBlue label separately expresses product strength as methylene blue trihydrate equivalent.
- Participants / model
- Not applicable
- Treatment
- Not applicable
- Follow-up
- Database record
- Study design
- Curated chemical identity record
Chemical identity does not verify purity or equivalence of a retail product.
Read the original sourceWhich uses have human evidence?
The US rescue indication and major label risks are established. The healthy cognition signal is acute. Repeated-use evidence is incomplete and does not establish chronic healthy enhancement. Chinese trials add meaningful perioperative and diagnostic-formulation context, not a general nootropic result.
US label · methemoglobinemia and major risks
FDA prescribing information
DailyMed. PROVAYBLUE (methylene blue) injection. Updated May 28, 2025; prescribing information revised February 2024.
The IV product treats acquired methemoglobinemia in adults and children. The label carries a boxed warning for serious or fatal serotonin syndrome with serotonergic drugs and opioids, contraindicates G6PD deficiency and prior severe hypersensitivity, warns about hemolysis, pulse-oximeter and laboratory interference, fetal harm, driving impairment, and higher exposure in renal impairment, and says not to administer subcutaneously.
- Participants / model
- Adults and children with acquired methemoglobinemia
- Treatment
- Sterile methylene blue injection, 5 mg/mL, administered intravenously
- Follow-up
- Acute rescue treatment
- Study design
- Regulatory prescribing information
- Funding
- Manufacturer regulatory program
This indication, exposure, and approximately 24-hour half-life belong to the labeled IV product. They do not establish chronic oral cognitive benefit.
Read the original sourceFDA approval · acquired methemoglobinemia
FDA regulatory record
US Food and Drug Administration. Orphan Drug Designations and Approvals, record 385512.
Records approval of methylene blue for treatment of acquired methemoglobinemia. It does not list cognitive enhancement as the approved indication.
- Participants / model
- Patients with acquired methemoglobinemia
- Treatment
- Methylene blue
- Follow-up
- Regulatory action
- Study design
- FDA orphan-drug approval record
An approval record establishes regulatory scope, not efficacy for unrelated uses.
Read the original source26 adults · one oral exposure
Randomized double-blind placebo-controlled trial
Rodriguez P et al. Radiology. 2016. PMID 27351678; NCT01836094.
Twenty-six healthy adults aged 22 to 62 completed task fMRI before and one hour after one low-dose oral exposure or placebo. Methylene blue changed task-related activation and was associated with 7 percent more correct responses during memory retrieval (P=.01). The experiment did not test repeated use, daily function, disease prevention, or long-term safety.
- Participants / model
- 26 healthy adults aged 22 to 62
- Treatment
- One low-dose oral methylene blue exposure or placebo
- Follow-up
- Approximately one hour to post-dose testing
- Study design
- Prospective randomized double-blind placebo-controlled task-fMRI experiment
- Funding
- NIH grants reported
The 26-person acute experiment tested several imaging and task endpoints; it did not measure daily function or durable clinical benefit.
Read the original source12-week registry · attrition and no analyses
Results-posted randomized trial registry
ClinicalTrials.gov. NCT02380573. Results posted September 19, 2024.
The registry reports actual enrollment of 117, while participant-flow arms show 98 started and 55 completed. Healthy-aging arms started 22 versus 21 and completed 12 versus 13; MCI arms started 28 versus 24 and completed 12 versus 16. Outcomes were posted as descriptive means at baseline, two weeks, and 12 weeks, but no between-group statistical analyses were posted. Only three people entered the Alzheimer arms and no middle-age participant started.
- Participants / model
- Adults aged 45 to 89 in healthy-aging, MCI, Alzheimer, and planned middle-age cohorts
- Treatment
- Oral USP methylene blue 282 mg daily versus blue-dye placebo; all arms also listed phenazopyridine as a blinding aid
- Follow-up
- 12 weeks
- Study design
- Phase 2 randomized quadruple-masked registry with results
- Funding
- University of Texas Health Science Center at San Antonio; Texas Alzheimer’s Research and Care Consortium
Flow counts conflict with the registry enrollment total, attrition was high, and absence of posted analyses prevents a benefit conclusion from the descriptive table.
Read the original source37 people · six-month cognition result null
Randomized double-blind crossover trial
Alda M et al. British Journal of Psychiatry. 2017. PMID 27284082; NCT00214877.
Thirty-seven people with bipolar disorder taking lamotrigine entered a six-month crossover comparison of 195 mg methylene blue with a 15 mg low-dose comparison. Depression and anxiety ratings improved in last-observation-carried-forward analyses, but cognitive symptoms did not improve significantly.
- Participants / model
- 37 people with bipolar disorder and residual symptoms while treated with lamotrigine
- Treatment
- 195 mg active methylene blue versus 15 mg low-dose comparison in a crossover design
- Follow-up
- 6 months
- Study design
- Randomized double-blind crossover trial
Disease-specific adjunctive treatment with an active low-dose comparator does not establish enhancement in healthy people.
Read the original sourceShanghai RCT · perioperative IV context
Randomized open-label controlled trial
Deng Y et al. Journal of Clinical Anesthesia. 2021. PMID 33091706; NCT04341844.
At two Fudan-affiliated Shanghai centers, 248 older surgical patients were randomized 124 per group to 2 mg/kg IV methylene blue after anesthesia induction or saline. Postoperative delirium was 7.3 percent versus 24.2 percent (OR 0.24, 95% CI 0.11 to 0.53), and cognitive dysfunction at day 7 was 16.1 percent versus 40.2 percent (OR 0.30, 95% CI 0.16 to 0.57).
- Participants / model
- 248 older adults undergoing major noncardiac surgery in Shanghai, China
- Treatment
- One 2 mg/kg IV infusion after anesthesia induction versus saline
- Follow-up
- In-hospital delirium follow-up and early cognitive assessment at postoperative day 7
- Study design
- Prospective randomized open-label controlled trial
- Funding
- Fudan University registry sponsor
Open-label, acute perioperative prevention in high-risk surgical patients is not evidence for oral daily enhancement. Longer-term registered outcomes were not reported in the PubMed abstract.
Read the original sourceChina product · colonoscopy detection aid
Chinese government reimbursement evidence dossier
National Healthcare Security Administration of China. Methylene blue enteric sustained-release tablet evidence slides, 2025.
The Chinese-language dossier describes a randomized double-blind phase 3 trial in 1,802 adults undergoing screening or diagnostic colonoscopy. In analyzed groups of 872 versus 879, non-polypoid colorectal lesion detection was 51.0 versus 41.2 percent, and non-polypoid adenoma detection was 39.1 versus 30.9 percent. The formulation is an oral enteric sustained-release dye used to improve lesion visualization.
- Participants / model
- Adults aged 50 to 75 undergoing colorectal screening or colonoscopy in China
- Treatment
- Oral enteric sustained-release methylene blue formulation versus placebo before colonoscopy
- Follow-up
- Single colonoscopy preparation context
- Study design
- Randomized double-blind multicenter placebo-controlled phase 3 study summarized in an official dossier
- Funding
- Manufacturer-submitted evidence within government reimbursement review
The dossier describes a diagnostic dye formulation and lesion-detection outcomes, not nootropic use; it does not report a complete clinical dataset.
Read the original sourceHuman enzyme study · MAO-A inhibition
In-vitro human enzyme study
Ramsay RR et al. British Journal of Pharmacology. 2007. PMCID PMC2078225.
Purified human enzyme experiments found methylene blue to be a potent reversible inhibitor of MAO-A. This pharmacology provides a plausible basis for the label’s serious serotonergic interaction warning.
- Participants / model
- Purified human MAO-A and MAO-B, not clinical participants
- Treatment
- Methylene blue in enzyme assays
- Follow-up
- Acute in-vitro assays
- Study design
- Mechanistic enzyme kinetics study
Enzyme potency supports interaction mechanism, not a cognitive benefit.
Read the original sourcePubChem · anhydrous chloride identity
Government chemical database
National Library of Medicine. PubChem Compound Summary for CID 6099, methylene blue.
Identifies anhydrous methylthioninium chloride as C16H18ClN3S, molecular weight 319.9 g/mol, CAS 61-73-4. The ProvayBlue label separately expresses product strength as methylene blue trihydrate equivalent.
- Participants / model
- Not applicable
- Treatment
- Not applicable
- Follow-up
- Database record
- Study design
- Curated chemical identity record
Chemical identity does not verify purity or equivalence of a retail product.
Read the original sourceRepeated-use cognition · no healthy chronic benefit established
PubMed and trial registry records
PubMed, ClinicalTrials.gov, ChiCTR, and Russian-language records for repeated methylene-blue use.
The cited records include the 12-week NCT02380573 registry, the six-month bipolar crossover, acute perioperative Chinese trials, and studies of related tau-targeting derivatives. They include no published controlled trial establishing durable everyday cognitive enhancement from chronic unmodified methylene blue in healthy adults.
- Participants / model
- Repeated-use human cognition studies sought
- Treatment
- Unmodified methylene blue, with derivative drugs kept separate
Studies and sources
US label · methemoglobinemia and major risks
FDA prescribing information
DailyMed. PROVAYBLUE (methylene blue) injection. Updated May 28, 2025; prescribing information revised February 2024.
The IV product treats acquired methemoglobinemia in adults and children. The label carries a boxed warning for serious or fatal serotonin syndrome with serotonergic drugs and opioids, contraindicates G6PD deficiency and prior severe hypersensitivity, warns about hemolysis, pulse-oximeter and laboratory interference, fetal harm, driving impairment, and higher exposure in renal impairment, and says not to administer subcutaneously.
- Participants / model
- Adults and children with acquired methemoglobinemia
- Treatment
- Sterile methylene blue injection, 5 mg/mL, administered intravenously
- Follow-up
- Acute rescue treatment
- Study design
- Regulatory prescribing information
- Funding
- Manufacturer regulatory program
This indication, exposure, and approximately 24-hour half-life belong to the labeled IV product. They do not establish chronic oral cognitive benefit.
Read the original sourceFDA approval · acquired methemoglobinemia
FDA regulatory record
US Food and Drug Administration. Orphan Drug Designations and Approvals, record 385512.
Records approval of methylene blue for treatment of acquired methemoglobinemia. It does not list cognitive enhancement as the approved indication.
- Participants / model
- Patients with acquired methemoglobinemia
- Treatment
- Methylene blue
- Follow-up
- Regulatory action
- Study design
- FDA orphan-drug approval record
An approval record establishes regulatory scope, not efficacy for unrelated uses.
Read the original source26 adults · one oral exposure
Randomized double-blind placebo-controlled trial
Rodriguez P et al. Radiology. 2016. PMID 27351678; NCT01836094.
Twenty-six healthy adults aged 22 to 62 completed task fMRI before and one hour after one low-dose oral exposure or placebo. Methylene blue changed task-related activation and was associated with 7 percent more correct responses during memory retrieval (P=.01). The experiment did not test repeated use, daily function, disease prevention, or long-term safety.
- Participants / model
- 26 healthy adults aged 22 to 62
- Treatment
- One low-dose oral methylene blue exposure or placebo
- Follow-up
- Approximately one hour to post-dose testing
- Study design
- Prospective randomized double-blind placebo-controlled task-fMRI experiment
- Funding
- NIH grants reported
The 26-person acute experiment tested several imaging and task endpoints; it did not measure daily function or durable clinical benefit.
Read the original source12-week registry · attrition and no analyses
Results-posted randomized trial registry
ClinicalTrials.gov. NCT02380573. Results posted September 19, 2024.
The registry reports actual enrollment of 117, while participant-flow arms show 98 started and 55 completed. Healthy-aging arms started 22 versus 21 and completed 12 versus 13; MCI arms started 28 versus 24 and completed 12 versus 16. Outcomes were posted as descriptive means at baseline, two weeks, and 12 weeks, but no between-group statistical analyses were posted. Only three people entered the Alzheimer arms and no middle-age participant started.
- Participants / model
- Adults aged 45 to 89 in healthy-aging, MCI, Alzheimer, and planned middle-age cohorts
- Treatment
- Oral USP methylene blue 282 mg daily versus blue-dye placebo; all arms also listed phenazopyridine as a blinding aid
- Follow-up
- 12 weeks
- Study design
- Phase 2 randomized quadruple-masked registry with results
- Funding
- University of Texas Health Science Center at San Antonio; Texas Alzheimer’s Research and Care Consortium
Flow counts conflict with the registry enrollment total, attrition was high, and absence of posted analyses prevents a benefit conclusion from the descriptive table.
Read the original source37 people · six-month cognition result null
Randomized double-blind crossover trial
Alda M et al. British Journal of Psychiatry. 2017. PMID 27284082; NCT00214877.
Thirty-seven people with bipolar disorder taking lamotrigine entered a six-month crossover comparison of 195 mg methylene blue with a 15 mg low-dose comparison. Depression and anxiety ratings improved in last-observation-carried-forward analyses, but cognitive symptoms did not improve significantly.
- Participants / model
- 37 people with bipolar disorder and residual symptoms while treated with lamotrigine
- Treatment
- 195 mg active methylene blue versus 15 mg low-dose comparison in a crossover design
- Follow-up
- 6 months
- Study design
- Randomized double-blind crossover trial
Disease-specific adjunctive treatment with an active low-dose comparator does not establish enhancement in healthy people.
Read the original sourceShanghai RCT · perioperative IV context
Randomized open-label controlled trial
Deng Y et al. Journal of Clinical Anesthesia. 2021. PMID 33091706; NCT04341844.
At two Fudan-affiliated Shanghai centers, 248 older surgical patients were randomized 124 per group to 2 mg/kg IV methylene blue after anesthesia induction or saline. Postoperative delirium was 7.3 percent versus 24.2 percent (OR 0.24, 95% CI 0.11 to 0.53), and cognitive dysfunction at day 7 was 16.1 percent versus 40.2 percent (OR 0.30, 95% CI 0.16 to 0.57).
- Participants / model
- 248 older adults undergoing major noncardiac surgery in Shanghai, China
- Treatment
- One 2 mg/kg IV infusion after anesthesia induction versus saline
- Follow-up
- In-hospital delirium follow-up and early cognitive assessment at postoperative day 7
- Study design
- Prospective randomized open-label controlled trial
- Funding
- Fudan University registry sponsor
Open-label, acute perioperative prevention in high-risk surgical patients is not evidence for oral daily enhancement. Longer-term registered outcomes were not reported in the PubMed abstract.
Read the original sourceChina product · colonoscopy detection aid
Chinese government reimbursement evidence dossier
National Healthcare Security Administration of China. Methylene blue enteric sustained-release tablet evidence slides, 2025.
The Chinese-language dossier describes a randomized double-blind phase 3 trial in 1,802 adults undergoing screening or diagnostic colonoscopy. In analyzed groups of 872 versus 879, non-polypoid colorectal lesion detection was 51.0 versus 41.2 percent, and non-polypoid adenoma detection was 39.1 versus 30.9 percent. The formulation is an oral enteric sustained-release dye used to improve lesion visualization.
- Participants / model
- Adults aged 50 to 75 undergoing colorectal screening or colonoscopy in China
- Treatment
- Oral enteric sustained-release methylene blue formulation versus placebo before colonoscopy
- Follow-up
- Single colonoscopy preparation context
- Study design
- Randomized double-blind multicenter placebo-controlled phase 3 study summarized in an official dossier
- Funding
- Manufacturer-submitted evidence within government reimbursement review
The dossier describes a diagnostic dye formulation and lesion-detection outcomes, not nootropic use; it does not report a complete clinical dataset.
Read the original sourceHuman enzyme study · MAO-A inhibition
In-vitro human enzyme study
Ramsay RR et al. British Journal of Pharmacology. 2007. PMCID PMC2078225.
Purified human enzyme experiments found methylene blue to be a potent reversible inhibitor of MAO-A. This pharmacology provides a plausible basis for the label’s serious serotonergic interaction warning.
- Participants / model
- Purified human MAO-A and MAO-B, not clinical participants
- Treatment
- Methylene blue in enzyme assays
- Follow-up
- Acute in-vitro assays
- Study design
- Mechanistic enzyme kinetics study
Enzyme potency supports interaction mechanism, not a cognitive benefit.
Read the original sourcePubChem · anhydrous chloride identity
Government chemical database
National Library of Medicine. PubChem Compound Summary for CID 6099, methylene blue.
Identifies anhydrous methylthioninium chloride as C16H18ClN3S, molecular weight 319.9 g/mol, CAS 61-73-4. The ProvayBlue label separately expresses product strength as methylene blue trihydrate equivalent.
- Participants / model
- Not applicable
- Treatment
- Not applicable
- Follow-up
- Database record
- Study design
- Curated chemical identity record
Chemical identity does not verify purity or equivalence of a retail product.
Read the original sourceRepeated-use cognition · no healthy chronic benefit established
PubMed and trial registry records
PubMed, ClinicalTrials.gov, ChiCTR, and Russian-language records for repeated methylene-blue use.
The cited records include the 12-week NCT02380573 registry, the six-month bipolar crossover, acute perioperative Chinese trials, and studies of related tau-targeting derivatives. They include no published controlled trial establishing durable everyday cognitive enhancement from chronic unmodified methylene blue in healthy adults.
- Participants / model
- Repeated-use human cognition studies sought
- Treatment
- Unmodified methylene blue, with derivative drugs kept separate
Why is Methylene blue in A tier?
The A tier reflects an approved rescue indication and additional human studies. Chronic nootropic use remains unestablished: healthy cognition data include one 26-person acute experiment and an incomplete 12-week registry, while IV label safety does not characterize repeated oral use.
read Methylene blue in the reptides guide, chapter 35: 8 pages, free to read.