Methylene Blue Capsules

Methylene blue was first created in the 1800s as a textile dye, but it has since been discovered to have additional uses in medicine, such as methemoglobinemia, malaria, and surgical staining.^[1]Animal studies have shown that this FDA-grandfathered medication, which is used to treat cyanide and carbon monoxide poisoning, can raise blood oxygen consumption.^[2]

Its antioxidant qualities have led to a recent increase in its popularity as a component of overall wellness in longevity care and age management.^[1] Additionally, this data has demonstrated its potential to assist wellness regimens that target the body’s production of energy and cellular health.^[1] As a medicine, it was originally intended and continues to be used as a water-soluble thiazine dye for acquired methemoglobinemia.^[3] Additional applications include the use of bacteriological stains, indicator dyes, and tracers in the assessment of fistulas in the gastrointestinal tract. ^[3] There is a black box warning regarding the potential for serotonin syndrome when using serotonergic medications with methylene blue; this should be avoided.^[3]

By lowering the production of reactive oxygen species through a process involving electron transfer within the cell’s mitochondria, methylene blue may be able to shield cells from oxidative stress.^[1] It is a phenothiazine derivative that contributes to improving mitochondrial function, particularly in the cellular energy production process.^[1] Reactive oxygen species, or free radicals, can rise and ATP production can fall as a result of mitochondrial dysfunction.^[1] The potential of methylene blue to fend off harmful molecules in the body may benefit cells’ energy centers and break the cycle of cell damage brought on by these harmful molecules.^[1]

It has been shown in small studies that, when the human brain is at rest, Methylene Blue potentially alters neural networks.^[2] Further research is required, as the study that found this had limitations due to its small sample size.^[2] But this is only a small step toward its neuroprotective potential as part of longevity care, supporting mental clarity and possibly supporting cognitive function.

Additionally, a 2022 overview of hundreds of clinical trials mentioned Methylene Blue’s potential benefits for depression, anxiety reduction, and brain protection, which have been shown in both human and animal studies.^[4]These features place it in the context of a larger plan to support vitality and longevity in people pursuing health and wellness.

As a topical age management therapy for skin damage, an increasing amount of research is being conducted. UV exposure, a decline in fibroblast migration and proliferation, and a breakdown of collagen and elastin are all factors in the aging process of the skin.^[1] Methylelne Blue was found to be a successful treatment for these problems in early research. ^[1][5] Methylene Blue treatment resulted in increased cell proliferation in skin fibroblasts when compared to common antioxidants such as vitamin C and retinol.^[1][5] Furthermore, it has been shown in certain studies to protect against UV-induced damage and promote the synthesis of collagen and elastin.^[1] In a 2017 study, it was even found to be a more effective antioxidant for long-term use on skin fibroblasts when compared to three other antioxidants.^[5]

As noted earlier, Methylene blue is a water-soluble thiazine dye used to treat acquired methemoglobinemia.^[3] Other uses include bacteriological staining, as an indicator dye, and as a tracer in the evaluation of gastrointestinal fistulas.^[3] Methylene blue carries a black box warning for the risk of serotonin syndrome with concomitant use of serotonergic medications; concurrent use of serotonergic medications should be avoided.^[3]

It received FDA approval for the treatment of methemoglobinemia, a condition when Fe2+ of hemoglobin gets oxidized to Fe3+, reducing the oxygen-carrying capacity of hemoglobin, and typically presents with cyanosis of the lips and extremities, characteristic “chocolate-colored urine,” and hypoxia.^[6] Methemoglobinemia results from exposure to certain drugs such as dapsone, a drug indicated for the treatment of Mycoplasma leprae and Pneumocystis jirovecii prophylaxis, benzocaine (a local anesthetic), high altitude water sources, and nitrites such as nitroglycerin or amyl nitrite used for treating coronary artery disease.^[6]

The remaining indications are non-FDA approved.^[6] The first indication is for vasoplegic syndrome, a type of distributive shock that occurs during coronary procedures (specifically coronary artery bypass grafting) as a means to increase systemic vascular resistance when the use of epinephrine is refractory.^[6] Another indication for methylene blue is during either a lumpectomy/mastectomy with sentinel lymph node biopsy, as it applied as a dye to map out which lymph nodes, if any, have any signs of malignancy.^[6] It can also reduce post-injection pain when used 45 seconds before the administration of propofol.^[6] Indications for methylene blue also include the treatment of Plasmodium falciparum in areas that have shown resistance to chloroquine and pyrimethamine-sulfadoxine.^[6] Methylene blue is also used to treat ifosfamide-induced encephalopathy due to the drug’s ability to prevent the formation of neurotoxic metabolites that cause the encephalopathy.^[6] Another indication for the use of methylene blue is to identify the parathyroid glands during parathyroidectomy procedures.^[6]

The mechanism of action for the oral administration of methylene blue involves a series of steps facilitated by NADPH reductase.^[7] Methylene blue is initially converted to leucomethylene blue, as facilitated by the enzyme NADPH reductase. ^[7] Leucomethylene blue plays a crucial role in the transition of hemoglobin from the ferric state to the ferrous state. ^[3] This transition is essentially a change in the oxidation state of hemoglobin. ^[3] The transition of hemoglobin to the ferrous state is associated with an enhanced ability to bind and release oxygen. ^[3] Consequently, this promotes the efficient transfer of oxygen to the tissues. ^[3]

In summary, NADPH reductase catalyzes the conversion of methylene blue to leucomethylene blue. ^[7] The subsequent action of leucomethylene blue on hemoglobin facilitates its transition to a state that optimally binds and releases oxygen, thereby enhancing the overall transfer of oxygen to the tissues. ^[7]

Methemoglobinemia arises when hemoglobin undergoes oxidation to produce methemoglobin. ^[7] In contrast to hemoglobin, methemoglobin lacks the ability to transport oxygen, potentially resulting in tissue hypoxia. ^[7] The conversion of methylene blue to leucomethylene blue is facilitated by NADPH reductase. Leucomethylene blue, in turn, expedites the transition of hemoglobin from the ferric state to the ferrous state, promoting the efficient transfer of oxygen to the tissues. ^[7]

Patients who have experienced severe hypersensitivity reactions to methylene blue or any other thiazine dye should not use methylene blue.^[8] Methylene blue use has been linked to anaphylactic reactions. In patients receiving methylene blue treatment, watch for signs of anaphylaxis.^[8] Stop using methylene blue and start supportive care if anaphylaxis or another severe hypersensitivity reaction (such as urticaria, bronchospasm, or edema) happens. ^[8]

Pulse oximetry may underestimate the oxygen saturation reading if there is methylene blue present in the blood. ^[8] Measurement from arterial blood sampling is advised if oxygen saturation is needed during or soon after the administration of methylene blue. ^[8] Furthermore, there have been reports of a decline in the Bispectral Index (BIS) after methylene blue administration. ^[8] If methylene blue is used during surgery, there should be other ways to determine the depth of anesthesia. Any urine test that uses a blue indicator, like the leucocyte esterase dipstick test, may yield unreliable results because methylene blue is easily absorbed into the urine. ^[8]

Methylene blue injections intrathecally or subcutaneously should not be performed.^[8] Necrotic ulcers may result from extravasation or subcutaneous administration.^[8] To avoid localized high concentrations of the product generating more methemoglobin, administer intravenously slowly over a few minutes.^[8]

Methylene blue treatment may result in hemolysis.^[8] Heinz bodies, high indirect bilirubin, low haptoglobin, and a negative Coombs test may be observed in laboratory testing. ^[8] Blood transfusions might be necessary if anemia doesn’t start to show symptoms for one or more days after treatment. Utilize the fewest methylene blue doses that work well. ^[8] If severe hemolysis develops, stop using methylene blue and think about other options.^[8] Methylene blue is contraindicated for use in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency) due to the risk of severe hemolysis and severe anemia.^[8] Additionally, patients with G6PD deficiency may not reduce methylene blue to its active form, and therefore, methylene blue may be ineffective in these patients.^[8]

Take monoamine oxidase inhibitors (MAOI therapy), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) sparingly combined with methylene blue.^[8] When using serotonergic medications, wait 72 hours after the last methylene blue dose. ^[8] Methylene blue use has been linked to cases of serotonin syndrome, some of which have been fatal. ^[8] The majority of reports linked concurrent use of serotonergic medications. ^[8] The signs and symptoms of serotonin syndrome can include any combination of the following: tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, and hyperthermia; neuromuscular symptoms, such as tremor, rigidity, myoclonus, hyperreflexia, and incoordination; mental status changes, such as agitation, hallucinations, delirium, and coma; seizures; and/or gastrointestinal symptoms, such as nausea, vomiting, and diarrhea. ^[8] Keep an eye out for serotonin syndrome symptoms in all medication users. If symptoms appear, stop using methylene blue and start receiving supportive care. ^[8]

The kidneys are the main organ through which methylene blue is eliminated. ^[8] Patients who have impaired kidney function should use methylene blue with caution. In clinical studies, subjects with renal impairment (eGFR 15 to 89 mL/minute/1.73 m2) had significantly higher concentrations of methylene blue. Patients with moderate to severe renal impairment (eGFR 15 to 59 mL/minute/1.73 m2) should have their methylene blue dosage adjusted. ^[8] For patients with mild renal impairment (eGFR 60 to 89 mL/minute/1.73 m2), there is no need to change the dosage. ^[8] Following treatment with methylene blue, patients with renal impairment or failure should have their toxicities and possible drug interactions closely monitored for a prolonged duration because of the delayed clearance. ^[8]

Patients with hepatic disease or failure should use methylene blue with caution as it is heavily metabolized in the liver.^[8] Following methylene blue treatment, patients with hepatic impairment should be closely watched for toxicities and possible drug interactions for a prolonged duration because of the delayed clearance. ^[8]

Patients should be advised against driving or engaging in hazardous occupations, such as driving or operating machinery, until such adverse reactions to methylene blue have resolved, due to the possibility of confusion, dizziness, and vision disturbances with the drug. ^[8]

When giving methylene blue to elderly patients, use the fewest doses required to produce a reaction. Since the kidneys excrete methylene blue in large quantities, elderly patients may be more susceptible to negative reactions because of the possibility of age-related declines in renal function. ^[8]

Methylene blue can interact with opioids, anti-depressants, psychedelics, some antihistamines, lithium, St. John Worts, tyramine rich foods. Always check with a healthcare provider before taking this drug and always gain full knowledge of a patients medical history before prescribing. Severe adverse effects involving the central nervous system (CNS) in patients receiving serotonin-based psychiatric drugs (also known as serotonergic psychiatric treatments).^[9] These include the following drugs:

Selective Serotonin Reuptake Inhibitors (SSRIs)^[9]

Generic Name — Found in Brand Name(s)

Paroxetine — Paxil, Paxil CR, Pexeva
Fluvoxamine — Luvox, Luvox CR
Fluoxetine — Prozac, Sarafem, Symbyax
Sertraline — Zoloft
Citalopram — Celexa
Escitalopram — Lexapro
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)^[9]

Generic Name — Found in Brand Name(s)

Venlafaxine — Effexor, Effexor XR
Desvenlafaxine — Pristiq
Duloxetine — Cymbalta
Tricyclic Antidepressants (TCAs)^[9]

Generic Name — Found in Brand Name(s)

Amitriptyline — Amitid, Amitril, Elavil, Endep, Etrafon, Limbitrol, Triavil
Desipramine — Norpramin, Pertofrane
Clomipramine — Anafranil
Imipramine — Tofranil, Tofranil PM, Janimine, Pramine, Presamine
Nortriptyline — Pamelor, Aventyl hydrochloride
Protriptyline — Vivactil
Doxepin — Sinequan, Zonalon, Silenor
Trimipramine — Surmontil
Monoamine Oxidase Inhibitors (MAOIs)^[9]

Generic Name — Found in Brand Name(s)

Isocarboxazid — Marplan
Phenelzine — Nardil
Selegiline — Emsam, Eldepryl, Zelapar
Tranylcypromine Parnate
Other Psychiatric Medication^[9]

Generic Name — Found in Brand Name(s)

Amoxapine — Asendin
Maprotiline — Ludiomil
Nefazodone — Serzone
Trazodone — Desyrel, Oleptro, Trialodine
Bupropion — Wellbutrin, Wellbutrin SR, Wellbutrin XL, Zyban, Aplenzin
Buspirone — Buspar
Vilazodone — Viibryd
Mirtazapine — Remeron, Remeron Soltab
Methylene blue can cause skin discoloration, which can be removed by using a hypochlorite solution.^[10] During clinical trials, skin discoloration was reported in 13% of patients.^[10]

Urine discoloration can occur when urine from patients receiving methylene blue is exposed to air. Oxidation produces methylene azure, which is blue or green in color.^[10] During clinical trials, urine discoloration occurred in 74% of patients.^[10]

Gastrointestinal adverse reactions associated with methylene blue include dysgeusia (20%), nausea (13%), anorexia (4%), vomiting (2%), diarrhea (2%), lower abdominal pain, flatulence, xerostomia, glossodynia, and tongue eruption. Some reactions were classified as moderate to severe treatment-emergent adverse events for dysgeusia (1%), nausea (2%), and vomiting (1%).^[10]

Methylene blue is indicated for acquired methemoglobinemia; it is not effective in the treatment of methemoglobinemia resulting from glucose-6-phosphate dehydrogenase (G6PD) deficiency, and administration can precipitate an acute hemolytic episode in these patients.^[10] Hemolytic anemia, hemolysis, hyperbilirubinemia, and methemoglobinemia have been reported following use of methylene blue class products.^[10]

During clinical trials, dizziness (16%), postural dizziness (2%), syncope (4%), presyncope (2%), headache (10%), and anxiety (4%) were reported with the use of methylene blue.^[10] Some reactions were classified as moderate to severe treatment-emergent adverse events for dizziness (4%), postural dizziness (1%), presyncope (1%), and headache (7%)^[10]

During clinical trials, pain in the extremity was reported in 84% of patients.^[10] Other musculoskeletal adverse reactions include musculoskeletal pain (9%), paresthesia (9%), back pain (2%), muscle cramps (spasms) (2%), arthralgia (2%), and limb discomfort (2%).^[10] Some reactions were classified as moderate to severe treatment-emergent adverse events for pain in extremity (56%), back pain (2%), muscle spasms (1%), and arthralgia (1%).^[10] Myalgia has also been reported following administration of methylene blue class products.^[10]

Anaphylactoid reactions have been reported with the use of intravenous methylene blue.^[10] During clinical trials, pruritus was reported in 4% of patients; of these events, 1 (1%) was classified as a moderate to severe treatment-emergent adverse reaction.^[10] Monitor patients for anaphylaxis when treated with methylene blue.^[10] If anaphylaxis or other severe hypersensitivity reaction (e.g., angioedema, urticaria, bronchospasm) occur, discontinue treatment and initiate supportive treatment.^[10]

During clinical trials of intravenous methylene blue, chest pain (unspecified) was reported in 4% of patients.^[10] Palpitations, sinus tachycardia, and hypertension have also been reported following administration of methylene blue class products.^[10]

Infusion-related reactions have been reported with the intravenous use of methylene blue.^[10] During clinical trials, infusion site pain was reported in 6% of patients (1% moderate to severe treatment-emergent), and erythema, catheter site pain, and infusion site discomfort were each reported in 2% of patients.^[10] Infusion site extravasation, induration, pruritus, edema, and urticaria, and peripheral edema have also been reported following administration of methylene blue class products.^[10]

Adverse reactions related to the special senses have been reported with the intravenous use of methylene blue.^[10] During clinical trials, oral paresthesias were reported in 9% of patients.^[10] Oral discomfort and oral hypoesthesia were reported in 2% of patients.^[10] Blurred vision, eye pruritus, ocular hyperemia, nasal congestion, oropharyngeal pain, rhinorrhea, and sneezing have also been reported following administration of methylene blue class products.^[10]

During clinical trials of intravenous methylene blue, hot flashes (reported as feeling hot) were reported in 17% of patients while feeling cold was reported in 6% of patients.^[10] Hyperhidrosis was reported in 13% of patients; pallor and contact dermatitis were each reported in 5% of patients, and ecchymosis, cold sweat, and chills were each reported in 2% of patients. Some reactions were classified as moderate to severe treatment-emergent adverse events for feeling hot (6%), hyperhidrosis (2%), and cold sweat (1%).^[10] Photosensitivity, necrotic ulcer, and papule have also been reported following the administration of methylene blue class products.^[10]

Elevated hepatic enzymes have been reported following the use of methylene blue class products.^[10]

During clinical trials of intravenous methylene blue, influenza-like illness was reported in 4% of patients (1% moderate to severe treatment-emergent), and dyspnea was reported in 2% of patients. Discomfort (unspecified) was reported in 2% of patients.^[10]

Dysuria and thirst have been reported following the administration of methylene blue class products.^[10]

Serotonin syndrome, including fatal cases, has been reported in patients receiving methylene blue.^[10] Most reports were associated with the concomitant use of serotonergic drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs).^[10] Serotonin syndrome may include the following combination of signs and symptoms: autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, and hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, and incoordination), mental status changes (e.g., agitation, hallucinations, delirium, and coma), seizures, or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea).^[10] Monitor all drug recipients for symptoms of serotonin syndrome. If symptoms occur, discontinue methylene blue and begin supportive treatment.^[10]

Methylene blue is contraindicated in women who are or may become pregnant. Methylene blue may cause fetal harm when administered during pregnancy.^[7] Epidemiologic evidence exists that methylene blue is a teratogen. Intra-amniotic injection of pregnant women with methylene blue during the second trimester was associated with neonatal intestinal atresia and fetal death.^[7] Methylene blue should not be administered during amniocentesis due to the risk of teratogenicity and other newborn adverse effects.^[7] Intra-amniotic injection of methylene blue hours to days prior to birth can result in hyperbilirubinemia, hemolytic anemia, skin staining, methemoglobinemia, respiratory distress, and photosensitivity in the neonate.^[7] If methylene blue is administered to a pregnant woman at term, monitor the neonate for adverse reactions.^[7] If methylene blue is used during pregnancy or if the patient becomes pregnant while taking this drug, advise the woman of the potential risk to the fetus.^[7]

There is no information regarding the presence of methylene blue in human milk, the effects on the breastfed infant, or the effects on milk production.^[7] Discontinue breast-feeding during methylene blue administration and for up to 8 days after treatment with methylene blue due to the potential for serious adverse effects, including genotoxicity.^[7]

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

1. Xue H, Thaivalappil A, Cao K. The Potentials of Methylene Blue as an Anti-Aging Drug. Cells. 2021 Dec 1;10(12):3379. doi: 10.3390/cells10123379. PMID: 34943887; PMCID: PMC8699482. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8699482/
2. Rodriguez P, Singh AP, Malloy KE, Zhou W, Barrett DW, Franklin CG, Altmeyer WB, Gutierrez JE, Li J, Heyl BL, Lancaster JL, Gonzalez-Lima F, Duong TQ. Methylene blue modulates functional connectivity in the human brain. Brain Imaging Behav. 2017 Jun;11(3):640-648. doi: 10.1007/s11682-016-9541-6. PMID: 26961091; PMCID: PMC5018244. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5018244/
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5. Xiong ZM, O’Donovan M, Sun L, Choi JY, Ren M, Cao K. Anti-Aging Potentials of Methylene Blue for Human Skin Longevity. Sci Rep. 2017 May 30;7(1):2475. doi: 10.1038/s41598-017-02419-3. PMID: 28559565; PMCID: PMC5449383. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5449383/
6. Bistas E, Sanghavi DK. Methylene Blue. [Updated 2023 Jun 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557593/
7. Elsevier. (2021, June 4). Methylene Blue. Clinical Pharmacology. https://www.clinicalkey.com/pharmacology/monograph/390?sec=monmech
8. Elsevier. (2021, June 4). Methylene Blue. Clinical Pharmacology. https://www.clinicalkey.com/pharmacology/monograph/390?sec=moncontr
9. Center for Drug Evaluation and Research. (n.d.). CNS reactions possible when methylene blue is given to patients T… U.S. Food and Drug Administration. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-serious-cns-reactions-possible-when-methylene-blue-given-patients#table
10. Elsevier. (2021, June 4). Methylene Blue. Clinical Pharmacology. https://www.clinicalkey.com/pharmacology/monograph/390?sec=monadve