Methylene Blue
Also known as: Methylthioninium chloride, MB, ProvayBlue
Evidence: Clinical
Overview
Phenothiazine redox dye (not a peptide) that can act as an alternative electron carrier in mitochondria; low oral doses studied in humans for memory and cerebral metabolism.
Methylene blue is a phenothiazine dye, not a peptide. In the US it is an approved prescription drug, ProvayBlue (NDA 204630, approved 2016-04-08), given intravenously for acquired methemoglobinemia, with a boxed warning for serotonin syndrome. At low oral doses it has been studied in small human trials of memory and fear extinction with mixed results. A related reduced form, LMTM, failed a phase 3 trial in Alzheimer's disease. The cognitive uses are research uses, not approved indications.
Benefits
Acquired methemoglobinemia (approved IV drug, ProvayBlue), memory and fear-extinction effects (small human RCTs, mixed), mitochondrial electron carrier (preclinical)
Dosing reference
- Research dose
- 0.5-20 mg daily (oral, low dose)
- Range
- 500 to 20000 mcg, 1x daily
0.5-20mg oral, start low. Pharmaceutical/USP grade only - industrial or aquarium dye contains heavy-metal contaminants. DO NOT combine with SSRIs, SNRIs, MAOIs, triptans or other serotonergic drugs: methylene blue is a potent MAO-A inhibitor and has caused serotonin syndrome at clinical doses. Avoid in G6PD deficiency (hemolysis) and in pregnancy. Effects are hormetic - high doses become pro-oxidant. Temporarily stains urine blue.
Mechanism
Methylene blue is a redox-active phenothiazine. In methemoglobinemia it is reduced to leucomethylene blue, which converts methemoglobin back to hemoglobin. In mitochondria it can accept electrons from NADH and pass them to cytochrome c, bypassing complex I to III blockade, and at low doses it increased mitochondrial respiration in preclinical work. It also inhibits monoamine oxidase A, the basis of the serotonin syndrome warning on the US label, and nitric oxide synthase.
Evidence
Clinical: at least one published human trial or an approved drug
- Approved in the US in 2016 as ProvayBlue (NDA 204630) for acquired methemoglobinemia, IV, with a boxed warning for serotonin syndrome with serotonergic drugs; still marketed
- An aqueous oral formulation had 72.3% absolute bioavailability in healthy volunteers (Walter-Sack et al., 2009)
- A randomized placebo-controlled fMRI study gave healthy adults a single low oral dose and measured memory and brain activation (Rodriguez et al., 2016)
- In adults with claustrophobia, post-session methylene blue improved fear extinction when the exposure session ended with low fear and worsened it when fear stayed high (Telch et al., 2014)
- Low-dose methylene blue improved extinction memory in rats (Gonzalez-Lima and Bruchey, 2004)
- Human-trial status beyond the approved use: small trials only. LMTM, a reduced methylthioninium form, failed its phase 3 trial in mild to moderate Alzheimer's disease (Gauthier et al., 2016)
References
- Extinction Memory Improvement by the Metabolic Enhancer Methylene Blue. Gonzalez-Lima F, Bruchey AK, Learning & Memory, 2004
- High absolute bioavailability of methylene blue given as an aqueous oral formulation. Walter-Sack I, Rengelshausen J, Oberwittler H, et al., European Journal of Clinical Pharmacology, 2009
- Multimodal Randomized Functional MR Imaging of the Effects of Methylene Blue in the Human Brain. Rodriguez P, Zhou W, Barrett DW, et al., Radiology, 2016
- Effects of post-session administration of methylene blue on fear extinction and contextual memory in adults with claustrophobia. Telch MJ, Bruchey AK, Rosenfield D, et al., American Journal of Psychiatry, 2014
- 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. Gauthier S, Feldman HH, Schneider LS, et al., The Lancet, 2016
Side effects
The US label carries a boxed warning: methylene blue inhibits MAO-A and can cause serotonin syndrome with SSRIs, SNRIs, MAOIs, triptans and other serotonergic drugs, a documented cause of hospitalization and death. It causes hemolysis in G6PD deficiency and turns urine and stool blue-green. High doses can paradoxically cause methemoglobinemia.
Storage
- Storage
- Room temperature, away from light
- Lyophilized
- 24+ months
Pharmacology
- Half-life
- About 24 h (human, IV; ProvayBlue label)
- Bioavailability
- Oral: 72.3% absolute (healthy volunteers, aqueous solution vs IV; Walter-Sack et al., 2009)
- Molecular weight
- 319.85 Da
- Sequence
- N/A - small molecule phenothiazine (not a peptide)