A 70 year old male comes to the ED with fever and confusion. He has a hx of HT and depression.

What clue does the urine provide?

hint: green urine can be the result of a blue dye

Our patient was on an SSRI but recently started taking  methylene blue to improve his cognitive function.  He developed serotonin syndrome with confusion and fever.

Methylene blue is a monoamine oxidase inhibitor; preventing the breakdown of serotonin in neural synapses. Since SSRIs also increase serotonin in the synapse dangerous levels of serotonin can build up causing serotonin syndrome when taking both drugs.

Serotonin toxicity manifests with neuromuscular abnormalities, autonomic hyperactivity and mental status changes. Clinically,  this leads to tremors , clonus and confusion. Since serotonin syndrome is a clinical diagnosis; guidelines suggest it is present if any one of the following syndrome exists.

criteria for serotonin syndrome

Methylene blue  was originally synthesized as a textile dye  but it  is also an FDA approved drug with many uses. It is an antioxidant (reducing to leucomethylene blue)  It has been used to treat malaria, methemoglobinemia, CO poisoning, ifosfamide-induced encephalopathy,   calcium channel blocker toxicity,  and cyanide poisoning.  It is used IV as a marker dye in urologic surgery and as a dye marker in parathyroidectomies.  It is also  used  IV for distributive shock.

Since methylene blue is a dye, in higher doses it dyes the brain.  Below is the brain of a patient treated with methylene blue before death, in a case of shock/vasoplegic syndrome. During his last few days, the ordered dosage of methylene blue was 1mg/kg/hr, and the dosage given was 74 ml of 0.5% methylene blue. The standard dose for methemoglobinemia  is  1 mg/kg of a 1% solution over 5 to 30 minutes

More recently,  it is being used as a neuroprotectant to prevent cognitive decline .  It reduces oxidative stress, and improves mitochondrial energy production as well as reverses signs of aging in skin.  For these reasons,  It has also recently been touted as a longevity drug by Mel Gibson and Bryan Johnson in popular media. Bryan Johnson who takes 25 mg tid to increase his life span.

 

Methylene blue may have long term health benefits in terms of neuroprotection. There are no long term studies of the optimum dose.  It is recommended  that  it should be taken at low doses and it should be taken for five days at a time followed by two days off.

Our patient was given cyproheptadine (a serotonin blocker) and told to avoid methylene blue in the future. He recovered unevenfully.

FUN FACTS

Vitamin C is also an antioxidant and is an alternative treatment for methemoglobinemia if methylene blue is unavailable.

Methylene blue should not be given to someone taking methamphetamines since both increase serotonin levels.

 

Rodriguez P, Singh A, Malioy K, et al. Methylene blue modulates functional connectivity in the human brain. Brain Imaging Behav. 2017 Jun;11(3):640-648.

Scheindlin S. Something old… something blue. Molecular Interventions. 2008;8(6):268–273. 

Atamna H, Kumar R. Protective role of methylene blue in Alzheimer's disease via mitochondria and cytochrome c oxidase. J Alzheimers Dis. 2010; 20: S439–S452. 10.3233/JAD-2010-100414 

 Xue H, Thaivalappil A, Cao K. the potentials of methylene blue as an anti-aging drug. Cells. 2021 De 1:10(12):3379

 Salman AE, Salman MA, Saricaoglu F, Akinci SB, Aypar Ü. Pain on injection of propofol: a comparison of methylene blue and lidocaine. J Clin Anesth. 2011 Jun;23(4):270-4.

Rosanne NaunheimComment