{"site":"Methylene Blue Bio","url":"https://methylenebluebio.com","format":"evidence-manifest/v1","claim_count":58,"claims":[{"id":"clm-001","text":"Methylene blue (methylthioninium chloride) is a synthetic phenothiazine-derived dye and oxidation-reduction agent, molecular formula C16H18ClN3S, molecular weight 319.86 g/mol (anhydrous), CAS 61-73-4. Industrial synonyms include basic blue 9; the FDA-approved brand is ProvayBlue.","source_url":"https://pubchem.ncbi.nlm.nih.gov/compound/6099","grade":"chemical-reference","grade_label":"Chemical reference","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/entity"]},{"id":"clm-002","text":"Methylene blue is described in the medical literature as the first synthetic drug, with more than a century of diverse medical use including staining, antimalarial treatment, and methemoglobinemia.","source_url":"https://pubmed.ncbi.nlm.nih.gov/21316815/","grade":"review","grade_label":"Review or guideline","used_on":["https://methylenebluebio.com/monograph"]},{"id":"clm-003","text":"The only FDA-approved methylene blue product is ProvayBlue (NDA 204630), an intravenous injection approved for the treatment of acquired methemoglobinemia in pediatric and adult patients.","source_url":"https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=204630","grade":"regulatory","grade_label":"Regulatory record","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/entity","https://methylenebluebio.com/faq"]},{"id":"clm-004","text":"There is no FDA-approved oral methylene blue product, and oral nootropic use is not an approved use. Disclosure (verbatim, from the run's verified FDA-status table): Methylene blue is FDA-approved only as an intravenous drug (ProvayBlue) for methemoglobinemia. Oral 'nootropic' methylene blue is not an FDA-approved product or use.","source_url":"https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=204630","grade":"regulatory","grade_label":"Regulatory record","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com","https://methylenebluebio.com/entity","https://methylenebluebio.com/faq"]},{"id":"clm-005","text":"The current ProvayBlue label carries a boxed warning, FDA's most prominent label warning: methylene blue may cause serious or fatal serotonin syndrome when combined with serotonergic drugs and opioids, and concomitant use with SSRIs, SNRIs, MAOIs, and opioids should be avoided.","source_url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4f6848e5-35ed-4046-b13c-3032b5ba3232","grade":"fda-label","grade_label":"FDA label","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com","https://methylenebluebio.com/faq","https://methylenebluebio.com/tools"]},{"id":"clm-006","text":"On July 26, 2011 FDA issued a Drug Safety Communication warning of serious CNS reactions when methylene blue is given to patients taking serotonergic psychiatric medications, and updated it on October 20, 2011.","source_url":"https://web.archive.org/web/20191213203653/https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-serious-cns-reactions-possible-when-methylene-blue-given-patients","grade":"regulatory","grade_label":"Regulatory record","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com","https://methylenebluebio.com/faq"]},{"id":"clm-007","text":"The interaction mechanism is monoamine oxidase inhibition: methylene blue is a potent, tight-binding, reversible inhibitor of MAO-A in vitro, inhibits MAO-B only at much higher concentrations, and at blood concentrations reported after clinical intravenous dosing MAO-A would be completely inhibited.","source_url":"https://pubmed.ncbi.nlm.nih.gov/17721552/","grade":"in-vitro","grade_label":"In vitro","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/faq","https://methylenebluebio.com/tools"]},{"id":"clm-008","text":"A 2010 systematic review identified 26 reported cases of acute confusional state after methylene blue infusion; 24 of the 26 were taking a serotonin reuptake inhibitor and 1 was taking clomipramine, and serotonin syndrome was a possible diagnosis in all 25 of those cases.","source_url":"https://pubmed.ncbi.nlm.nih.gov/20484716/","grade":"systematic-review","grade_label":"Systematic review","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/studies"]},{"id":"clm-009","text":"A 2011 pharmacology review concluded 13 of 14 reported methylene blue CNS toxicity cases met Hunter criteria for serotonin toxicity, that severe serotonin toxicity has occurred in humans at methylene blue doses as low as 1 mg/kg IV, and that an IV dose of only 0.75 mg/kg produced a peak plasma concentration (about 500 ng/mL, 1.6 microM) sufficient to inhibit MAO-A.","source_url":"https://pubmed.ncbi.nlm.nih.gov/20142303/","grade":"review","grade_label":"Review or guideline","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/tools"]},{"id":"clm-010","text":"The ProvayBlue label instructs: avoid concomitant use with drugs that enhance serotonergic transmission including SSRIs, SNRIs, MAOIs, bupropion, buspirone, clomipramine, mirtazapine, linezolid, opioids, and dextromethorphan; if IV methylene blue cannot be avoided in a patient on serotonergic drugs, use the lowest possible dose and observe closely for CNS effects for up to 4 hours; and do not take serotonergic drugs within 72 hours after the last dose.","source_url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4f6848e5-35ed-4046-b13c-3032b5ba3232","grade":"fda-label","grade_label":"FDA label","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/tools","https://methylenebluebio.com/faq","https://methylenebluebio.com/decision_aid"]},{"id":"clm-011","text":"Label-listed serotonin syndrome symptoms include mental status changes (agitation, hallucinations, delirium, coma), autonomic instability (tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (nausea, vomiting, diarrhea); some reported cases were fatal.","source_url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4f6848e5-35ed-4046-b13c-3032b5ba3232","grade":"fda-label","grade_label":"FDA label","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/tools","https://methylenebluebio.com/medical_disclaimer"]},{"id":"clm-012","text":"ProvayBlue is contraindicated in glucose-6-phosphate dehydrogenase (G6PD) deficiency because of the risk of hemolytic anemia; the label also warns that G6PD-deficient patients may not reduce methylene blue to its active form, so it may not work in exactly the patients it can harm.","source_url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4f6848e5-35ed-4046-b13c-3032b5ba3232","grade":"fda-label","grade_label":"FDA label","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/tools","https://methylenebluebio.com/faq","https://methylenebluebio.com/decision_aid"]},{"id":"clm-013","text":"An evidence-based review of drug safety in G6PD deficiency, a condition whose causative mutations are carried by an estimated 400 million people worldwide, found solid evidence to prohibit only seven currently used medications, and methylthioninium chloride (methylene blue) is one of the seven.","source_url":"https://pubmed.ncbi.nlm.nih.gov/20701405/","grade":"systematic-review","grade_label":"Systematic review","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com","https://methylenebluebio.com/faq","https://methylenebluebio.com/tools"]},{"id":"clm-014","text":"The approved dosage is 1 mg/kg IV over 5-30 minutes; if methemoglobin remains above 30% or symptoms persist, a repeat dose of up to 1 mg/kg may be given one hour after the first; the maximum recommended number of doses is two; patients with moderate or severe renal impairment (eGFR 15-59) receive a single 1 mg/kg dose; subcutaneous administration is prohibited.","source_url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4f6848e5-35ed-4046-b13c-3032b5ba3232","grade":"fda-label","grade_label":"FDA label","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/tools","https://methylenebluebio.com/studies"]},{"id":"clm-015","text":"In the label's clinical studies, 31 adults with acquired methemoglobinemia received ProvayBlue (mean baseline methemoglobin 18.4%, range 4.1% to 74.4%); 26 of 28 evaluable subjects (92.9%) had at least a 50% reduction in methemoglobin from baseline at first post-baseline assessment, and outcomes across 14 pediatric cases in two retrospective series were consistent with adults.","source_url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4f6848e5-35ed-4046-b13c-3032b5ba3232","grade":"fda-label","grade_label":"FDA label","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/studies"]},{"id":"clm-016","text":"High doses invert the drug's own therapeutic effect: single IV doses of 3 mg/kg or more have caused hypotension, wheezing, and reduced oxygenation; large cumulative doses (7 mg/kg or more) caused a symptom cluster lasting 2-12 hours that includes mild methemoglobinemia up to 7 percent, blue staining of urine, skin and mucous membranes, chest pain, tremor, and ECG changes; a single dose of 20 mg/kg or more caused severe intravascular hemolysis, hyperbilirubinemia, and death.","source_url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4f6848e5-35ed-4046-b13c-3032b5ba3232","grade":"fda-label","grade_label":"FDA label","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/tools","https://methylenebluebio.com/faq"]},{"id":"clm-017","text":"The most common adverse reactions (over 2%) in the ProvayBlue clinical experience were headache, hypokalemia, diarrhea, hypomagnesemia, myoclonus, nausea, and seizure-like phenomena; serious adverse reactions occurred in 3.2% of treated patients.","source_url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4f6848e5-35ed-4046-b13c-3032b5ba3232","grade":"fda-label","grade_label":"FDA label","used_on":["https://methylenebluebio.com/monograph"]},{"id":"clm-018","text":"Blue-green urine discoloration is an expected, benign effect of methylene blue: roughly 40% of a dose is excreted unchanged in urine, the label documents blue staining of urine, skin, and mucous membranes at higher exposures, and StatPearls describes the urine discoloration as expected and benign.","source_url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4f6848e5-35ed-4046-b13c-3032b5ba3232","grade":"fda-label","grade_label":"FDA label","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/faq","https://methylenebluebio.com/tools"]},{"id":"clm-019","text":"Methylene blue interferes with monitoring: it can cause pulse oximeters to underestimate oxygen saturation, and it can artifactually lower Bispectral Index readings during anesthesia.","source_url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4f6848e5-35ed-4046-b13c-3032b5ba3232","grade":"fda-label","grade_label":"FDA label","used_on":["https://methylenebluebio.com/monograph"]},{"id":"clm-020","text":"Pregnancy and lactation: ProvayBlue may cause fetal harm; intra-amniotic injection of methylene blue during the second trimester was associated with neonatal intestinal atresia and fetal death; oral methylene blue produced adverse developmental outcomes in rats and rabbits at doses at least 32 and 16 times the 1 mg/kg clinical dose; and the label advises discontinuing breastfeeding during and for up to 8 days after treatment because of the potential for serious adverse reactions including genotoxicity.","source_url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4f6848e5-35ed-4046-b13c-3032b5ba3232","grade":"fda-label","grade_label":"FDA label","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/decision_aid","https://methylenebluebio.com/faq"]},{"id":"clm-021","text":"Label pharmacokinetics: human half-life approximately 24 hours; steady-state volume of distribution 255 L (2 mg/kg IV); plasma protein binding about 94% in vitro; metabolized by CYP1A2, 2C19, and 2D6 with UGT-mediated conjugation (UGT1A4, UGT1A9) as the predominant in vitro pathway; about 40% excreted unchanged in urine; azure B is both a minor impurity of methylene blue and a human metabolite (parent-to-metabolite AUC ratio greater than 6:1, azure B about 8-fold less potent); renal impairment raises methylene blue AUC by 52% (mild) to 192% (severe).","source_url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4f6848e5-35ed-4046-b13c-3032b5ba3232","grade":"fda-label","grade_label":"FDA label","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/tools","https://methylenebluebio.com/pk"]},{"id":"clm-022","text":"In a human PK study (n=7 volunteers, 100 mg IV vs oral), IV methylene blue showed a multiphasic whole-blood time course with an estimated terminal half-life of 5.25 hours; oral administration of that formulation produced a roughly 15-fold lower whole-blood AUC (9 vs 137 nmol x min/mL); urinary excretion of methylene blue plus its leuco form was 18% (oral) vs 28% (IV) of dose; and in rats, intraduodenal dosing concentrated the drug in intestinal wall and liver with lower blood and brain levels than IV.","source_url":"https://pubmed.ncbi.nlm.nih.gov/10952480/","grade":"human-pk","grade_label":"Human PK","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/studies","https://methylenebluebio.com/pk"]},{"id":"clm-023","text":"Absolute oral bioavailability of methylene blue given as an aqueous oral formulation was 72.3% (+/- 23.9%) in 16 healthy volunteers (500 mg oral vs 50 mg IV crossover); co-administration of chloroquine significantly increased methylene blue plasma concentrations.","source_url":"https://pubmed.ncbi.nlm.nih.gov/18810398/","grade":"human-pk","grade_label":"Human PK","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/studies","https://methylenebluebio.com/pk","https://methylenebluebio.com/faq"]},{"id":"clm-024","text":"Oral kinetics are strongly formulation-dependent: with delayed-release MMX tablets (100-400 mg) peak blood concentrations occurred at a median of about 16 hours, half-life ranged from 6 to 27 hours, and cumulative urinary excretion ranged from about 23% to 40% of dose.","source_url":"https://pubmed.ncbi.nlm.nih.gov/22101227/","grade":"human-pk","grade_label":"Human PK","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/studies","https://methylenebluebio.com/pk"]},{"id":"clm-025","text":"In the only randomized placebo-controlled neuroimaging trial of oral methylene blue in healthy adults (n=26, ages 22-62, 13 per arm), a single 280 mg dose (approximately 4 mg/kg) of USP pharmaceutical-grade methylene blue increased fMRI response in the bilateral insular cortex during sustained attention and in prefrontal, parietal, and occipital cortex during short-term memory, and was associated with a 7% increase in correct responses during memory retrieval (p=0.01).","source_url":"https://pubmed.ncbi.nlm.nih.gov/27351678/","grade":"human-rct","grade_label":"Human RCT","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/studies","https://methylenebluebio.com/tools","https://methylenebluebio.com/faq"]},{"id":"clm-026","text":"In a double-blind trial in 42 adults with claustrophobia, 260 mg oral methylene blue given immediately after extinction training enhanced 1-month retention of fear extinction in participants whose fear was low by the end of training, tended to worsen outcomes in those with moderate-to-high end fear, and enhanced incidental contextual memory independent of fear outcomes.","source_url":"https://pubmed.ncbi.nlm.nih.gov/25018057/","grade":"human-rct","grade_label":"Human RCT","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/studies","https://methylenebluebio.com/tools"]},{"id":"clm-027","text":"In a randomized controlled trial in 42 adults with chronic PTSD, 260 mg methylene blue after each of 5 daily imaginal exposure sessions did not beat placebo on the primary symptom trajectory (both arms improved comparably to standard prolonged exposure), while showing better evaluator-rated treatment response (number needed to treat 7.5) and quality of life (d=0.58); the authors describe the efficacy as preliminary.","source_url":"https://pubmed.ncbi.nlm.nih.gov/28686823/","grade":"human-rct","grade_label":"Human RCT","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/studies"]},{"id":"clm-028","text":"A 2-year double-blind crossover trial in 31 people with bipolar disorder on lithium (17 completers) compared methylene blue 300 mg/day with 15 mg/day: participants were significantly less depressed during the 300 mg year, mania severity did not differ, and the authors themselves flagged major limitations including dropouts, simple rating scales, doubts about blinding, and uncertainty whether 15 mg/day is a true placebo.","source_url":"https://pubmed.ncbi.nlm.nih.gov/3091097/","grade":"human-crossover","grade_label":"Human crossover trial","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/studies"]},{"id":"clm-029","text":"A 6-month randomized double-blind crossover trial in 37 people with bipolar disorder on lamotrigine compared methylene blue 195 mg/day with 15 mg/day: the active dose significantly improved residual depression (MADRS p=0.02; HAM-D p=0.05, LOCF) and anxiety (HAM-A p=0.02); effects on cognitive symptoms were not significant; the drug was well tolerated with transient mild side effects.","source_url":"https://pubmed.ncbi.nlm.nih.gov/27284082/","grade":"human-crossover","grade_label":"Human crossover trial","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/studies","https://methylenebluebio.com/tools"]},{"id":"clm-030","text":"In an exploratory phase 2 dose-finding trial of methylthioninium chloride in 321 people with mild or moderate Alzheimer's disease (69, 138, or 228 mg/day), the 138 mg/day dose showed treatment benefits at 24 weeks in two independent populations (ADAS-cog effect -5.42 units in moderate disease, corrected p=0.047; regional cerebral blood flow decline reduced in mild disease, corrected p<0.001), while delivery of the highest dose was impaired by dose-dependent dissolution and absorption limitations.","source_url":"https://pubmed.ncbi.nlm.nih.gov/25550228/","grade":"human-rct","grade_label":"Human RCT","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/studies","https://methylenebluebio.com/tools","https://methylenebluebio.com/faq"]},{"id":"clm-031","text":"The first phase 3 trial of the reduced form LMTM (leuco-methylthioninium bis(hydromethanesulfonate)) in 891 people with mild to moderate Alzheimer's disease was negative on both co-primary endpoints: neither 75 mg twice daily nor 125 mg twice daily differed from the 4 mg twice daily control on ADAS-Cog (p=0.98 and p=0.93) or ADCS-ADL at 65 weeks, and the authors stated the results do not suggest benefit as an add-on treatment.","source_url":"https://pubmed.ncbi.nlm.nih.gov/27863809/","grade":"human-rct","grade_label":"Human RCT","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/studies","https://methylenebluebio.com/faq","https://methylenebluebio.com/limits"]},{"id":"clm-032","text":"The second phase 3 trial (LMTM 100 mg twice daily vs 4 mg twice daily in 800 people with mild Alzheimer's disease) reported significant differences favoring monotherapy subgroups on ADAS-cog, ADCS-ADL, MRI atrophy, and glucose uptake, but these came from a Statistical Analysis Plan revised before unblinding into non-randomized cohort comparisons (for example 100 mg monotherapy n=79 vs 4 mg as randomized n=396), not from the original randomized comparison.","source_url":"https://pubmed.ncbi.nlm.nih.gov/29154277/","grade":"human-obs","grade_label":"Human observational","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/studies","https://methylenebluebio.com/limits"]},{"id":"clm-033","text":"The confirmatory phase 3 LUCIDITY trial (NCT03446001; 598 amyloid-PET-positive participants, 44% with MCI due to AD; hydromethylthionine mesylate 16 mg/day or 8 mg/day vs methylthioninium chloride 4 mg twice weekly as a urinary-colourant control) could not demonstrate significant differences on its co-primary clinical endpoints (ADAS-cog11, ADCS-ADL23) at 52 weeks; the authors attribute this to symptomatic activity in the control arm; delayed-start differences in the MCI subgroup appeared at 78 and 104 weeks, alongside NfL, grey-matter atrophy, and pTau217 biomarker differences.","source_url":"https://pubmed.ncbi.nlm.nih.gov/41570392/","grade":"human-rct","grade_label":"Human RCT","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/studies","https://methylenebluebio.com/faq","https://methylenebluebio.com/limits"]},{"id":"clm-034","text":"A 2026 sponsor-affiliated population pharmacokinetic analysis (710 participants, 7784 plasma measurements) reported U-shaped time-varying clearance with 12-month plasma levels about 3-fold (HMTM) and 5-fold (MTC) above linear-model predictions, concluding the low-dose MTC control arm was not pharmacologically inert; this is the sponsor's explanation for the failed 52-week primary endpoints, and it has not been tested in a trial with a truly inert placebo.","source_url":"https://pubmed.ncbi.nlm.nih.gov/41917677/","grade":"human-pk","grade_label":"Human PK","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/limits","https://methylenebluebio.com/studies_note"]},{"id":"clm-035","text":"In a single-center randomized controlled trial in 91 adults with septic shock, methylene blue started within 24 hours shortened time to vasopressor discontinuation (69 vs 94 hours, p<0.001), added one vasopressor-free day at day 28 (p=0.008), and shortened ICU stay by 1.5 days and hospital stay by 2.7 days, with no serious adverse effects attributed to the drug; mortality and ventilator days did not differ.","source_url":"https://pubmed.ncbi.nlm.nih.gov/36915146/","grade":"human-rct","grade_label":"Human RCT","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/studies"]},{"id":"clm-036","text":"A 2024 systematic review and meta-analysis of randomized trials of methylene blue in sepsis and septic shock (3 RCTs, 141 participants) found shorter ICU stay (mean difference -1.58 days), fewer days on mechanical ventilation (-0.72 days), and a 31.5-hour shorter time to vasopressor discontinuation, with no association with abnormal methemoglobin levels; the proposed mechanism is guanylate cyclase inhibition reducing nitric-oxide-driven vasodilation.","source_url":"https://pubmed.ncbi.nlm.nih.gov/38698779/","grade":"systematic-review","grade_label":"Systematic review","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/studies"]},{"id":"clm-037","text":"In a randomized trial embedded in 638 consecutive cardiac surgery patients, vasoplegic syndrome occurred in 56 (8.8%); patients randomized to 1.5 mg/kg IV methylene blue had zero deaths versus 21.4% mortality (6 of 28) with placebo (p=0.01), and vasoplegia resolved within 6 hours in all treated patients.","source_url":"https://pubmed.ncbi.nlm.nih.gov/14759425/","grade":"human-rct","grade_label":"Human RCT","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/studies","https://methylenebluebio.com/tools"]},{"id":"clm-038","text":"A randomized phase 2 trial (n=60) of methylene blue oral rinse (0.025% to 0.1% every 6 hours for 2 days) for intractable oral mucositis pain in cancer care found significant pain-score reductions versus conventional therapy alone and improved oral function, with no serious adverse events; 8 participants reported oral burning with the first dose.","source_url":"https://pubmed.ncbi.nlm.nih.gov/36324139/","grade":"human-rct","grade_label":"Human RCT","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/studies","https://methylenebluebio.com/faq"]},{"id":"clm-039","text":"In rats, low-dose methylene blue (1 mg/kg IP post-training) increased brain cytochrome c oxidation at 24 hours and improved spatial memory retention (66% vs 31% correct probe visits versus saline); higher concentrations did not enhance brain cytochrome c oxidation in vitro.","source_url":"https://pubmed.ncbi.nlm.nih.gov/14724055/","grade":"animal","grade_label":"Animal","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/studies","https://methylenebluebio.com/tools"]},{"id":"clm-040","text":"The rodent dose-response is U-shaped: in rats, 1-10 mg/kg did not alter locomotion or feeding, 4 mg/kg improved habituation and object recognition memory, 50-100 mg/kg reduced running-wheel behavior, and low but not high doses increased brain oxygen consumption.","source_url":"https://pubmed.ncbi.nlm.nih.gov/15792783/","grade":"animal","grade_label":"Animal","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/studies","https://methylenebluebio.com/tools","https://methylenebluebio.com/faq"]},{"id":"clm-041","text":"In rats, methylene blue 4 mg/kg daily for 5 days after extinction training improved retention of fear extinction and increased cytochrome oxidase activity in prefrontal cortical regions.","source_url":"https://pubmed.ncbi.nlm.nih.gov/15466319/","grade":"animal","grade_label":"Animal","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/studies"]},{"id":"clm-042","text":"A 2012 mechanistic review describes methylene blue as showing a hormetic dose-response with opposite effects at low and high doses: at low doses it acts as an electron cycler in the mitochondrial electron transport chain with cytochrome-oxidase-linked memory effects, while high doses have opposite effects; the review's in vivo evidence base is predominantly rodent.","source_url":"https://pubmed.ncbi.nlm.nih.gov/22067440/","grade":"review","grade_label":"Review or guideline","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/studies","https://methylenebluebio.com/tools","https://methylenebluebio.com/faq"]},{"id":"clm-043","text":"Methylene blue is converted by NADPH reductase to leucomethylene blue, which reduces the ferric iron of methemoglobin back to the ferrous state of normal hemoglobin; this redox couple is the basis of its approved use.","source_url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4f6848e5-35ed-4046-b13c-3032b5ba3232","grade":"fda-label","grade_label":"FDA label","used_on":["https://methylenebluebio.com/monograph"]},{"id":"clm-044","text":"Azure B, a demethylated analog, is the major metabolite of methylene blue in a validated rat plasma assay and is also documented in the human label as both an impurity and a metabolite.","source_url":"https://pubmed.ncbi.nlm.nih.gov/24122875/","grade":"animal","grade_label":"Animal","used_on":["https://methylenebluebio.com/monograph"]},{"id":"clm-045","text":"A thorough QT study found ProvayBlue 2 mg/kg IV had no effect on QT, PR, or QRS intervals; a clinical cocktail study found no effect on the exposure of midazolam (CYP3A4), caffeine (CYP1A2), warfarin (CYP2C9), or dextromethorphan (CYP2D6); in vitro, methylene blue inhibits multiple CYPs and UGT1A4/1A9 and inhibits the renal transporters OCT2, MATE1, and MATE2-K, with clinical significance not established.","source_url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4f6848e5-35ed-4046-b13c-3032b5ba3232","grade":"fda-label","grade_label":"FDA label","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/tools"]},{"id":"clm-046","text":"Hypersensitivity: anaphylactic reactions to methylene blue class products have been reported, and ProvayBlue is contraindicated after previous severe hypersensitivity to methylene blue or any other thiazine dye.","source_url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4f6848e5-35ed-4046-b13c-3032b5ba3232","grade":"fda-label","grade_label":"FDA label","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/tools"]},{"id":"clm-047","text":"Methemoglobinemia caused by aryl amines (such as aniline) or sulfa drugs (such as dapsone) may not resolve or may rebound after methylene blue treatment.","source_url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4f6848e5-35ed-4046-b13c-3032b5ba3232","grade":"fda-label","grade_label":"FDA label","used_on":["https://methylenebluebio.com/monograph"]},{"id":"clm-048","text":"Treatment with methylene blue may cause confusion, dizziness, and disturbed vision; the label advises refraining from driving or hazardous activities until neurologic and visual symptoms resolve.","source_url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4f6848e5-35ed-4046-b13c-3032b5ba3232","grade":"fda-label","grade_label":"FDA label","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/tools"]},{"id":"clm-049","text":"ProvayBlue storage: store at 20 to 25 C (68 to 77 F) with excursions permitted to 15 to 30 C; do not refrigerate or freeze; keep in the original package to protect from light. Supplied as 5 mg/mL solution in 10 mL (50 mg) and 2 mL (10 mg) single-dose ampules and vials, USP grade.","source_url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4f6848e5-35ed-4046-b13c-3032b5ba3232","grade":"fda-label","grade_label":"FDA label","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/tool-data"]},{"id":"clm-050","text":"The only randomized human cognition trial of oral methylene blue used USP pharmaceutical-grade material dispensed through a compounding pharmacy, and the FDA-approved product is manufactured to the USP injection monograph; a USP drug standard for methylene blue therefore exists and is what separates drug-grade material from industrial dye.","source_url":"https://pubmed.ncbi.nlm.nih.gov/27351678/","grade":"fda-label","grade_label":"FDA label","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/tools","https://methylenebluebio.com/faq"]},{"id":"clm-051","text":"Aquarium and industrial methylene blue products are not FDA-approved drugs and are not part of any FDA-reviewed manufacturing or purity framework; the run's verified FDA-status disclosure applies: oral 'nootropic' methylene blue is not an FDA-approved product or use. Statements about the specific contaminant content of any given non-drug product cannot be verified from primary sources and are not made on this site.","source_url":"https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=204630","grade":"absence-of-evidence","grade_label":"Absence of evidence","used_on":["https://methylenebluebio.com/monograph","https://methylenebluebio.com/tools","https://methylenebluebio.com/faq","https://methylenebluebio.com/comparisons"]},{"id":"clm-052","text":"NAD+ (nicotinamide adenine dinucleotide) has no FDA-approved drug product: an openFDA Drugs@FDA query for the ingredient returns no records.","source_url":"https://api.fda.gov/drug/drugsfda.json?search=products.active_ingredients.name:%22nicotinamide%20adenine%20dinucleotide%22&limit=3","grade":"absence-of-evidence","grade_label":"Absence of evidence","used_on":["https://methylenebluebio.com/comparisons"]},{"id":"clm-053","text":"No published head-to-head trial compares methylene blue with NAD+ precursors or any other mitochondria-marketed compound on cognitive outcomes; and no randomized trial of low-dose generic oral methylene blue has been published in people with mild cognitive impairment (the only MCI evidence is the LUCIDITY trial of the salt hydromethylthionine mesylate, whose MCI findings are delayed-start subgroup results).","source_url":"https://pubmed.ncbi.nlm.nih.gov/41570392/","grade":"absence-of-evidence","grade_label":"Absence of evidence","used_on":["https://methylenebluebio.com/comparisons","https://methylenebluebio.com/limits","https://methylenebluebio.com/monograph"]},{"id":"clm-054","text":"No PubMed-indexed comparison of methylene blue with ifenprodil exists; a search for both terms returns no study comparing them.","source_url":"https://pubmed.ncbi.nlm.nih.gov/27351678/","grade":"absence-of-evidence","grade_label":"Absence of evidence","used_on":["https://methylenebluebio.com/honesty_log"]},{"id":"clm-055","text":"Hospital and trial dosing spans, by indication: methemoglobinemia 1 mg/kg IV (label, max 2 doses); vasoplegia after cardiac surgery 1.5 mg/kg IV (Levin); septic shock adjunct per RCT protocol (Ibarra-Estrada); single-dose cognition imaging 280 mg oral, about 4 mg/kg (Rodriguez); fear-extinction augmentation 260 mg oral (Telch, Zoellner); bipolar adjunct 195-300 mg/day oral (Alda, Naylor); dementia program 69-228 mg/day MTC (phase 2) and 8-16 mg/day HMTM (LUCIDITY), different salts that are not interchangeable with methylene blue milligrams.","source_url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4f6848e5-35ed-4046-b13c-3032b5ba3232","grade":"human-rct","grade_label":"Human RCT","used_on":["https://methylenebluebio.com/tools","https://methylenebluebio.com/monograph"]},{"id":"clm-056","text":"There are no published human trials of long-term daily low-dose generic oral methylene blue for cognitive enhancement in healthy people: the randomized human evidence is one single-dose imaging trial (n=26), post-session augmentation trials in claustrophobia and PTSD, small bipolar adjunct crossover trials, and the dementia-program trials of modified salts; none establishes long-term efficacy or safety of the influencer-style daily low-dose protocol.","source_url":"https://pubmed.ncbi.nlm.nih.gov/27351678/","grade":"absence-of-evidence","grade_label":"Absence of evidence","used_on":["https://methylenebluebio.com/limits","https://methylenebluebio.com","https://methylenebluebio.com/faq","https://methylenebluebio.com/decision_aid"]},{"id":"clm-057","text":"Methylene blue is used intravenously in hospitals, beyond its approved indication, in vasoplegia and septic shock (randomized evidence summarized in this pack) and historically to prevent ifosfamide-induced encephalopathy; clinical IV use spans roughly 1 to 7.5 mg/kg in the published literature.","source_url":"https://pubmed.ncbi.nlm.nih.gov/20142303/","grade":"review","grade_label":"Review or guideline","used_on":["https://methylenebluebio.com/monograph"]},{"id":"clm-058","text":"Pack self-counts for the hero and machine layer, computed from this pack's own files: 22 rows in the graded study table, 18 of them human, 3 rat, 1 in vitro; 38 fetch-verified citations, 100% peer-reviewed or government; 1 FDA boxed warning; 10 label-named interacting drugs or drug classes on the avoid list.","source_url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4f6848e5-35ed-4046-b13c-3032b5ba3232","grade":"chemical-reference","grade_label":"Chemical reference","used_on":["https://methylenebluebio.com","https://methylenebluebio.com/copy","https://methylenebluebio.com/llms"]}]}