Methylene blue activates signaling pathways involved in the mitochondrial pool renewal (mitochondrial biogenesis and autophagy), and prevents aggregation of misfolded proteins (28). Methylene blue can improve mitochondrial and cell function via multiple mechanisms including enhancing energy production, reducing oxidative stress and reducing inflammation (29). Although clinical trials are needed to validate this hypothesis, Methylene blue has been proposed as an “anti-aging” drug to help mitigate neurologic deterioration, skin aging, and other processes related to aging (30).

Methylene blue has been used in psychiatric medicine for over a century based on it’s antidepressant, anxiolytic (reducing anxiety), and neuroprotective effects which have been documented in animal and human studies (3,17,59,60).  Methylene blue has several proposed mechanisms for improving mood and brain function including inhibiting of monoamine oxidase A (MAO-A), inhibiting nitric oxide synthase (NO), restoring mitochondrial function, improving neuronal energy production and inhibiting the formation of superoxides (3).

Methylene blue has been shown to attenuate the formations of amyloid plaques and neurofibrillary tangles in Alzheimer’s disease (4). In both in vitro and in vivo studies, Methylene blue has shown efficacy in mitigating neurodegeneration after stroke, global cerebral ischemia, Alzheimer’s disease, Parkinson’s disease, and traumatic brain injury. Methylene blue has also been found to improve cognition due to age-related cognitive decline, and it is considered to be neuro-protective (5). A double blinded placebo controlled trial found that Methylene blue increased functional MR imaging activity during memory tasks (23). Methylene blue moieties have been developed for Alzheimer’s disease treatment and have been shown in double blind placebo controlled trials to benefit Alzheimer’s patients including improvement in cognition and blood flow to the brain. (24-27)

Methylene blue has demonstrated in test tube model activity against growing (log phase) and persister (stationary phase) forms of Bartonella bacteria and was Methylene blue + rifampin was active against Bartonella biofilms (7,8). Out of several agents tested in a test tube model, Methylene blue was found to have the most potent activity against Babesia bovis (19) however it had low activity against Babesia microti in an in vivo assay (20). In a high-throughput study screening a panel of FDA approved medications, Methylene blue has been shown to effectively treat persister Borrelia cells (the bacteria that causes Lyme disease) (6).

Brain photobiomodulation (PBM) therapy using red to near-infrared (NIR) light is an innovative treatment for a wide range of neurological and psychological conditions. Red/NIR light is able to stimulate mitochondrial respiration chain ATP synthesis (it supports the “energy engines” in the cells). Brain PBM therapy enhances the metabolic capacity of neurons and stimulates anti-inflammatory, anti-apoptotic (cell-death), and antioxidant responses, as well as neurogenesis (growth of new nerves) and synaptogenesis (growth of new synapses in the brain). The therapeutic role of PBM in treating dementia, Parkinson’s disease, stroke, brain trauma, and depression has gained increasing interest (29). There is data that both Methylene blue and PBM can treat persistent candida infections. The combination of Methylene blue and PBM appear to be synergistic for treating methicillin resistant staphylococcus aureus (MRSA) in superficial and deep excisional wounds (11), hepatitis-C, human immunodeficiency virus (HIV-1) (12) and to treat resistant plaque psoriasis lesions (10, 11, 13).

1.) Methylene blue often turns your urine blue and may also turn your stool blue or green as well. This is a normal, non-harmful side effect that will resolve whenever the medication is discontinued. Be sure to clean your toilets regularly to avoid any blue staining of your toilet bowl.

2.) Methylene blue is not safe during pregnancy or breast feeding. You must discontinue Methylene blue immediately if you become pregnant and notify your doctor at Aspen if you plan to become pregnant or breast feed.

3.) You understand taking methylene blue can, but rarely, result in any of the following potential side effects.

Serious side effects: anaphylaxis or other allergic reaction with hives, difficulty breathing, swelling of face, lips, tongue or throat; severe nausea, vomiting or stomach pain, pain in your chest, pale or blue/green skin, high fever, racing heart, confusion, hemolytic anemia, passing out or feeling like you could pass out, death.

Less serious side effects: mild bladder irritation, mild nausea, vomiting, diarrhea, upset stomach, dizziness, headache, increased sweating, sun sensitivity.

4.) Methylene blue in combination with caffeine can cause elevations in blood pressure, so please monitor your blood pressure daily if you consume caffeine while taking Methylene blue and notify your doctor  at Aspen if BP is >130/90.

5.) Avoid drinking alcohol while taking Methylene blue as it can increase MAO toxicity.

6.) Methylene blue is contraindicated with certain medications, so please let your physician at Aspen if you are currently taking any of the following: MAO Inhibitors, Aclidinium, alpha or beta agonists, amphetamines/ADHD medication, Apraclonidine, Atomoxetine, Benzhydrocodone, Bezafibrate, Buprenorphine, BuPROPion, BusPIRone, Butorphanol, CarBAMazepine, Carbinoxamine, Cimetropium, CloZAPine, Codeine, Cyclobenzaprine, Dapoxetine, Deutetrabenazine, Dexmethylphenidate, Dextromethorphan, Diamorphine, Diethylpropion, Dihydrocodeine, Diphenoxylate, DOPamine, Droxidopa, Eluxadoline, Fenfluramine, Glycopyrrolate, Guanethidine, HYDROcodone, HYDROmorphone, Indoramin, Iobenguane, Iohexol, Iomeprol, Iopamidol, Ipratropium, Isometheptene, Levodopa-Foslevodopa, Levomethadone, Levonordefrin, Levosulpiride, Linezolid, Lithium, Maprotiline, Meptazinol, Mequitazine, Methadone, Methotrimeprazine, Methyldopa, Methylphenidate, Metoclopramide, Mianserin, Morphine, Nefazodone, Nefopam, Normethadone, Opicapone, Opium, Oxatomide, OxyCODONE, OxyMORphone, Ozanimod, Pheniramine, Pholcodine, Pramlintide, Reboxetine, Remifentanil, Reserpine (or Carditone), Revefenacin, Secretin, Triptans, Solriamfetol, Hypericum (St. John’s Wort), Sufentanil, Tapentadol, Tetrabenazine, Tetrahydrozoline, Tianeptine, Tiotropium, Tricyclic Antidepressants (Amitriptyline), Tryptophan/5-HTP, Tyrosine, Umeclidinium, Valbenazine, Viloxazine.

7.) Taking Methylene blue in addition to an SSRI (i.e. Prozac, Lexapro etc.) or SNRI medication (i.e. Cymbalta etc.) increases the risk of serotonin syndrome, a potentially life-threatening condition. You agree to inform your prescribing provider if you are on an SSRI or SNRI, or if you wish to begin one of these medications. Main symptoms of serotonin syndrome include: agitation or restlessness, confusion or disorientation, anxiety, rapid heart rate, high blood pressure, sweating, shivering, fever, tremors, muscle rigidity, seizures, clonus, tremor, sweating, fever, diarrhea, nausea, vomiting, and dilated pupils. Changes in dream state is often the first sign of increased serotonin with more intense or memorable dreams.

Methylene Blue can be prescribed and used safely, even when a patient is on potentially contraindicated medications, under the right circumstances. These include:

1.) The patient is under close supervision by the prescribing physician, and the medication is gradually tapered to minimize the risk of significant side effects.

2.) The medication, dose, patient size (BMI), and duration of treatment are carefully considered before tapering Methylene Blue.

1.) You understand Methylene blue is an FDA approved drug, but can be used as an “off-label” therapy to treat tickborne disease and/or mitochondrial dysfunction. This “off-label” application is considered to be experimental and therefore there is no guarantee of outcome as there is no clinical trial (human studies) data specific to tickborne disease patients.
2.) Methylene blue is a medication and medical dye currently FDA approved to treat methemoglobinemia and used “off label” for Ifosfamide-induced encephalopathy, Onychomycosis (topical), sentinel node mapping in breast cancer, cyanide poisoning, vagoplegia, hepatopulmonary syndrome, and arsenic poisoning.

1.) You understand that you need to have your quantitative G6PD enzyme levels checked via a blood test before starting this medication to ensure you do not have a genetic mutation that could cause anemia while taking Methylene blue.
2.) Your physician may request you to have regular appointments every 6-8 weeks to ensure you are tolerating the medication well. This may be a condition of treatment and inability to follow up on the prescribed schedule may result in discontinuation of further prescriptions for Methylene Blue.
3.) Your physician may request to have your blood drawn for lab testing every 4-6 weeks to aid in monitoring the effects to your body from taking Methylene Blue. This may be a condition of treatment and inability to follow up on the prescribed schedule may result in discontinuation of further prescriptions for Methylene Blue.

Methylene Blue Subduing the Post Covid-19 Blues

Methylene Blue Providing Brain Protection Benefits

Effects of Methylene Blue on Brain Function as Seen in MRI

Effects of Methylene Blue For Reducing Pain

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