Methylene Blue

What methylene blue is

Methylene blue was developed in the 19th century as a textile dye. Toward the end of that century, Paul Ehrlich noticed that it kills malaria parasites and used it to work on his idea of the magic bullet, an agent that hits the disease specifically and spares everything else. This makes methylene blue one of the very first synthetic drugs.

Today it is an ordinary medication for a very specific situation. In methemoglobinemia, the red blood pigment can no longer transport oxygen, for example after certain poisonings. The European Commission approved Methylthioninium chloride Proveblue in 2011 for the acute treatment of drug- or chemical-induced methemoglobinemia, and the US Food and Drug Administration approved ProvayBlue in 2016 for acquired methemoglobinemia. It is given as an injection in a clinical setting. Taking small amounts sublingually, as is common in the scene, lies outside these approvals.

How it is supposed to work

The cell's energy is produced in the mitochondria on a kind of assembly line on which electrons are passed from station to station. Methylene blue can itself accept and donate electrons. At low concentrations, it can thereby bypass weakened stations and pass electrons directly to cytochrome c oxidase, complex IV of the respiratory chain. Cell studies show more complex IV activity and more oxygen consumption. A 2012 review describes it as an electron carrier with antioxidant properties and derives from this effects on memory and neuroprotection that have been shown mainly in animals.

The same review emphasizes a special feature: methylene blue has a hormetic dose-response curve, that is, opposite effects at low and high doses. At low doses it acts as an electron shuttle and antioxidant; at high doses it becomes a stressor for the cell itself. Here, more is explicitly not better.

Why the scene uses it

Biohackers are interested in methylene blue as a tool for focus and mental energy, especially with age, when the mitochondria decline. Many users report more clarity, less brain fog and better concentration. That may be real, but these are user reports, not controlled evidence. Most commonly, diluted drops are taken under the tongue. Because the dye stains teeth and mucous membranes, some use a straw, and because it can be activating, people tend to take it in the morning rather than late in the evening.

Viewed soberly, methylene blue is therefore an option for a fairly clearly defined group: healthy, curious adults who do not take antidepressants or other serotonergic medications, do not have G6PD deficiency and use only tested pharmaceutical-grade product, ideally with a doctor keeping an eye on things. For everyone else, especially during ongoing treatment with psychiatric medications, it is not a substance to experiment with.

What the studies show

Functional imaging in 26 healthy adults, Radiology 2016

Rodriguez and colleagues studied 26 healthy adults aged 22 to 62 in a randomized, double-blind, placebo-controlled study. Before and 1 hour after a low oral single dose of methylene blue or placebo, participants completed attention and short-term memory tasks in an MRI scanner. Methylene blue increased activity in the insular cortex during the attention task and in the frontal, parietal and occipital cortex during the memory task. In memory retrieval, there were 7 percent more correct answers.

Alzheimer's trial of a methylene blue derivative, Lancet 2016

Gauthier and colleagues tested LMTM, a stable reduced form of methylthioninium, in a randomized, double-blind phase 3 trial over 15 months in 891 patients with mild to moderate Alzheimer's disease. The prespecified main analyses showed no benefit on cognition or daily functioning at either of the two doses tested. The authors write that the results do not support LMTM as an add-on treatment.

MAO-A inhibition, British Journal of Pharmacology 2007

Using purified human enzyme, Ramsay and colleagues measured that methylene blue strongly and reversibly inhibits monoamine oxidase A, and MAO-B only at considerably higher concentrations. At concentrations such as those described after intravenous administration, MAO-A would be completely inhibited. This explains the cases of serotonin toxicity in patients who were also taking serotonin reuptake inhibitors.

Where the data stop

The human data on biohacking use essentially consist of one single-dose study with 26 participants. It measures brain activity and a memory task 1 hour after intake. Whether regular intake over weeks or months improves concentration, energy or mental performance in everyday life has not been studied. Longer controlled studies on cognitive effects in healthy people are lacking.

The great hope for Alzheimer's disease was not fulfilled in the phase 3 trial with 891 patients. A later subgroup analysis of another trial hinted at effects, but these comparisons were redefined only during the ongoing trial, before unblinding, and are not randomized comparisons. The cell biology data on senescence, mitochondria and neuroprotection also come from cell culture and animal models. For long COVID, dementia prevention or anti-aging, for which methylene blue is promoted online, there are no robust human data.

Status, approval and legal situation

Methylene blue has been approved in the EU as Methylthioninium chloride Proveblue since 2011, for the acute treatment of drug- or chemical-induced methemoglobinemia in adults, children and adolescents. In the US, ProvayBlue has been approved since 2016 for acquired methemoglobinemia. Both approvals concern injection in a clinical setting. Taking small amounts for performance enhancement is not approved and is therefore off-label. Besides pharmaceutical-grade product, technical-grade dye is also sold, which according to reports from the scene may be contaminated with heavy metals and has no place in the body. Methylene blue is not on the doping list.

Safety

The US prescribing information carries a boxed warning: in combination with serotonergic drugs and opioids, methylene blue can trigger a serious or fatal serotonin syndrome. The reason is the strong inhibition of MAO-A. If you take SSRI or SNRI antidepressants, MAO inhibitors or other serotonergic medications, methylene blue is not for you. In G6PD deficiency, an inherited enzyme defect of the red blood cells, it is contraindicated because severe hemolysis and anemia can result, and many people do not know they have this deficiency without a test. Harmless but noticeable is the blue discoloration of urine, skin and body fluids. Important for hospital care and surgery: methylene blue in the blood can cause the fingertip pulse oximeter to show oxygen saturation as too low. If you take it, you should mention this before any procedure.

Sources

• Rodriguez P et al., Radiology 2016 — randomized fMRI study in 26 healthy adults
• Rojas JC, Bruchey AK, Gonzalez-Lima F, Progress in Neurobiology 2012 — review of the mechanism and hormetic dose response
• Atamna H, Kumar R, Journal of Alzheimers Disease 2010 — mitochondria and cytochrome c oxidase
• Ramsay RR et al., British Journal of Pharmacology 2007 — inhibition of MAO-A
• Gauthier S et al., Lancet 2016 — phase 3 trial of LMTM in Alzheimer's disease
• US prescribing information ProvayBlue, FDA 2023 — warnings on serotonin syndrome, G6PD deficiency and pulse oximetry
• European Medicines Agency, EPAR Methylthioninium chloride Proveblue
• Atamna H et al., Biochemical Pharmacology 1996 — antimalarial action, Paul Ehrlich