Methylene blue
Human cognitive trials are few and small. In 26 healthy adults, one low oral dose raised correct memory answers by 7%. Two Alzheimer's trials of a related compound found no benefit on their primary outcomes. With SSRIs and similar drugs, case reports describe serotonin syndrome, and the label carries a boxed warning.
Add to Bio HackChecked 2026-11-09
- Status
- Prescription drug in the US. FDA-approved as ProvayBlue (intravenous injection) to treat acquired methemoglobinemia in children and adults. The label carries a boxed warning on serotonin syndrome with serotonergic drugs and opioids. It is not approved for cognition, mood or aging.
- Also called
- ProvayBlue, methylthioninium chloride, MB, LMTM, hydromethylthionine
- Taken for
- memory, focus, cognition, mood, energy, mitochondria, longevity
Strong several reviews agree · Moderate one review or consistent trials · Limited one or a few small studies · Untested no study in people, listed with what it rests on
Shown to help2
Reported risks3
- LimitedThe label warns methylene blue may cause serious or fatal serotonin syndrome with SSRIs, SNRIs, MAOIs and opioids. Case reports involve infusions.How often is not known
- LimitedThe label lists G6PD deficiency as a contraindication because of the risk of hemolytic anemia.How often is not known
- LimitedLimited evidence: gut and urinary effects were the most common reasons for stopping a related compound. The label warns it interferes with pulse oximetry readings.How often is not known
What people take it for, and what was found
Shown to help2
Memory and attention in healthy adults
Small trials found one low dose raised brain activity and memory retrieval 7% in healthy adults. No trial of repeated use was sourced.
The numbers and sources
- Effect
- One hour after a low oral dose, methylene blue raised functional MRI activity during attention and short-term memory tasks against placebo, and correct responses during memory retrieval rose 7% (P = 0.01) [3]. In adults with claustrophobia, 260 mg given after a fear-exposure session improved contextual memory at follow-up. People with low fear at the end of the session had less fear 1 month later on methylene blue, while people with moderate to high fear tended to do worse [4].
- Population
- 26 healthy adults aged 22 to 62 [3]; 42 adults with marked claustrophobic fear [4].
- Sources
- [3], [4]
- Caveats
- Two small single-dose trials, one measuring brain imaging more than behavior [3]. No trial of repeated use in healthy people was sourced.
Depression and anxiety in bipolar disorder
One trial found lower depression and anxiety scores in bipolar disorder when added to lamotrigine, against a low comparison dose.
The numbers and sources
- Effect
- Added to lamotrigine, methylene blue 195 mg lowered depression scores (MADRS P = 0.02, HAM-D P = 0.05) and anxiety scores (HAM-A P = 0.02) against a 15 mg comparison dose. Cognitive symptoms did not change significantly [5].
- Population
- 37 people with bipolar disorder in a 6-month crossover trial [5].
- Sources
- [5]
- Caveats
- One small trial using last observation carried forward. The abstract gives P values without effect sizes.
Not shown to help1
Alzheimer's disease
Not shown to change cognition or daily activities in Alzheimer's disease in two trials of a related compound. Later gains came only in a subgroup.
The numbers and sources
- Effect
- Over 15 months, LMTM, a reduced form of the methylthioninium molecule, at 75 mg or 125 mg twice daily did not differ from a 4 mg control on cognition (ADAS-Cog differences -0.02 and -0.43) or daily activities (ADCS-ADL differences -0.93 and -0.34) [1]. In a second phase 3 trial, the same compound under the name HMTM, at 8 or 16 mg per day, did not differ from control on its co-primary cognitive and daily-activity endpoints at 52 weeks. In the subgroup with mild cognitive impairment, starting 16 mg a year earlier was followed by less cognitive decline at 78 weeks (P 0.0291) and 104 weeks (P 0.0308). Plasma neurofilament light, a marker of nerve damage, rose less at 52 weeks (P 0.0291) [2].
- Population
- 891 people under 90 with mild to moderate Alzheimer's disease in 16 countries [1]; 598 people with amyloid on PET, 263 with mild cognitive impairment and 335 with mild to moderate dementia, at 82 centers [2].
- Sources
- [1], [2]
- Caveats
- LMTM is related to but not the same as methylene blue. In both trials the control arm received a low dose of methylthioninium to mask urine discoloration, and the authors of [2] attribute the lack of separation to activity in that arm. The later benefits in [2] come from a subgroup and a delayed-start comparison after all participants moved to 16 mg. Funded by TauRx Pharmaceuticals, the developer [1].
Claimed, not studied in people2
Energy and mitochondrial function in healthy people
Not studied in people. In human cells in the lab, methylene blue raised mitochondrial complex IV by 30% and oxygen use by 37 to 70%.
No study in people. This rests on lab studies, how it acts in the body.
The numbers and sources
- Effect
- In cultured human fibroblasts, nanomolar methylene blue increased mitochondrial complex IV by 30%, raised cellular oxygen consumption by 37 to 70% and increased heme synthesis. The authors propose this comes from methylene blue cycling between its oxidized and reduced forms inside mitochondria [8].
- Population
- Human IMR90 fibroblasts and HepG2 liver cells in culture, and rat liver mitochondria [8].
- Sources
- [8]
- Caveats
- Cell culture only. No trial was located that measured energy, fatigue or mitochondrial function in healthy people taking methylene blue.
Longevity
Not studied in people. In a multi-site mouse lifespan study it did not change median lifespan, with a 6% rise in maximum lifespan in females only.
No study in people. This rests on animal studies, lab studies.
The numbers and sources
- Effect
- In genetically mixed mice tested at three sites, methylene blue did not alter median lifespan in males or females, and raised female maximum lifespan by 6% (P = 0.004) [9]. In culture, it extended the lifespan of human fibroblasts by more than 20 population doublings [8].
- Population
- Genetically heterogeneous mice at three sites [9]. Human IMR90 fibroblasts in culture [8].
- Sources
- [9], [8]
- Caveats
- Mouse and cell results do not show what happens to human lifespan. No study of methylene blue and aging outcomes in people was located.
Doses studied
The fear-extinction trial used a single 260 mg oral dose [4]. The first Alzheimer's trial used LMTM 75 mg or 125 mg twice daily against 4 mg twice daily [1]. The second used HMTM 8 mg or 16 mg per day against methylthioninium chloride 4 mg twice weekly [2]. The bipolar trial compared 195 mg with 15 mg [5]. The healthy-adult imaging trial describes its single oral dose as low [3].
Risks
Reported risks3
Serotonin syndrome with SSRIs and other serotonergic drugs (boxed warning)
The label warns methylene blue may cause serious or fatal serotonin syndrome with SSRIs, SNRIs, MAOIs and opioids. Case reports involve infusions.
The numbers and sources
- How common
- How often is not known: the sources give no rate.
- Effect
- The ProvayBlue label's boxed warning states methylene blue may cause serious or fatal serotonin syndrome with serotonergic drugs and opioids, naming SSRIs, SNRIs, MAOIs and opioids [6]. A systematic review of case reports and audits found 26 patients with an acute confusional state after methylene blue infusion. 24 were taking a serotonin reuptake inhibitor and 1 clomipramine, and serotonin syndrome was a possible diagnosis in all 25 [7].
- Population
- 9 case reports and 2 retrospective reviews, in people given intravenous infusions [7]; label [6].
- Sources
- [6], [7]
- Caveats
- Case reports cannot give a rate. The reports involve intravenous infusions, not oral doses.
Hemolytic anemia in G6PD deficiency
The label lists G6PD deficiency as a contraindication because of the risk of hemolytic anemia.
The numbers and sources
- How common
- How often is not known: the sources give no rate.
- Effect
- The label lists G6PD deficiency as a contraindication because of the risk of hemolytic anemia, and lists hemolytic anemia among its warnings [6]. In the Alzheimer's trial, dose-dependent falls in hemoglobin were the most common laboratory abnormality, described as not clinically significant [1].
- Population
- Label [6]; 891 trial participants [1].
- Sources
- [6], [1]
- Caveats
- [1] studied LMTM, not methylene blue.
Gut and urinary effects, discoloration and monitor interference
Limited evidence: gut and urinary effects were the most common reasons for stopping a related compound. The label warns it interferes with pulse oximetry readings.
The numbers and sources
- How common
- How often is not known: the sources give no rate.
- Effect
- Gastrointestinal and urinary effects were the most common adverse events at both higher LMTM doses and the most common reasons for stopping [1]. In the bipolar trial, side effects were described as transient and mild [5]. The label warns that methylene blue interferes with pulse oximetry readings [6].
- Population
- Trial participants in [1] and [5]; label [6].
- Sources
- [1], [5], [6]
- Caveats
- The trials were not designed to rank side effects.
Sources
- Gauthier S, Feldman HH, Schneider LS, et al. Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial. The Lancet. 2016. https://doi.org/10.1016/S0140-6736(16)31275-2
- Wischik CM, Stefanacci R, Bentham P, et al. Clinical, imaging and blood biomarker outcomes in a Phase 3 clinical trial of tau aggregation inhibitor hydromethylthionine mesylate in mild cognitive impairment and mild to moderate dementia due to Alzheimer's disease. The Journal of Prevention of Alzheimer's Disease. 2026. https://doi.org/10.1016/j.tjpad.2026.100480
- Rodriguez P, Zhou W, Barrett DW, et al. Multimodal Randomized Functional MR Imaging of the Effects of Methylene Blue in the Human Brain. Radiology. 2016. https://doi.org/10.1148/radiol.2016152893
- Telch MJ, Bruchey AK, Rosenfield D, et al. Effects of Post-Session Administration of Methylene Blue on Fear Extinction and Contextual Memory in Adults With Claustrophobia. American Journal of Psychiatry. 2014. https://doi.org/10.1176/appi.ajp.2014.13101407
- Alda M, McKinnon M, Blagdon R, et al. Methylene blue treatment for residual symptoms of bipolar disorder: Randomised crossover study. British Journal of Psychiatry. 2017. https://doi.org/10.1192/bjp.bp.115.173930
- U.S. Food and Drug Administration. PROVAYBLUE (methylene blue) injection, prescribing information. Revised 2024. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4f6848e5-35ed-4046-b13c-3032b5ba3232
- Ng BK, Cameron AJ. The Role of Methylene Blue in Serotonin Syndrome: A Systematic Review. Psychosomatics. 2010. https://doi.org/10.1176/appi.psy.51.3.194
- Atamna H, Nguyen A, Schultz C, et al. Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways. FASEB Journal. 2008. https://doi.org/10.1096/fj.07-9610com
- Harrison DE, Strong R, Allison DB, et al. Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Aging Cell. 2014. https://doi.org/10.1111/acel.12170