by Sara Hover, RPh, FAARM, PCCA Director of Clinical Services

The history of methylene blue dates back to the late 19th century, when it was first synthesized by German chemist Heinrich Caro in 1876. Initially developed as a textile dye, it quickly gained popularity in the textile industry for its vibrant blue color. However, its journey from a dye to a versatile chemical agent was just the beginning.

In the 1890s, researchers began exploring potential medical applications of methylene blue. Paul Ehrlich, a German physician and Nobel laureate, investigated its antimicrobial properties and found methylene blue was effective in patients with certain bacterial and protozoal infections. These early findings laid the foundation for its future use in pharmaceutical therapies.¹

Diagnostic, Antimicrobial & Antiviral Properties

Methylene blue’s staining properties quickly caught the attention of the medical community. Surgeons realized its potential as a valuable tool in surgical procedures, particularly in enhancing visualization and precision. It subsequently was used in techniques such as lymph node mapping, where it helped identify cancerous cells in lymph nodes.²

Additionally, methylene blue exhibits potent antimicrobial properties, making it an effective option for patients with various infections. One of the most significant breakthroughs in the pharmaceutical application came with its use in patients suffering from malaria.¹ In the early 20th century, researchers discovered that methylene blue, when combined with specific antimalarial drugs, exhibited potent anti-parasitic effects. It was found to be effective against the Plasmodium genus — the parasites responsible for malaria. Methylene blue reduced the severity of malaria symptoms and accelerated recovery, saving countless lives in malaria-endemic regions.³

Methylene blue has also shown efficacy in patients with urinary tract infections caused by certain bacteria. It acts by inhibiting bacterial growth and reducing the recurrence of infections.⁴

Given its broad-spectrum antiviral activity, methylene blue may potentially be used in patients with viral infections. It is important to note that further research is needed to establish efficacy in specific viral diseases, but it has shown promise in combating respiratory viral infections such as influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). In experimental studies, researchers learned methylene blue demonstrated inhibitory effects on viral replication and reduced severity of respiratory viral symptoms.⁵

Methemoglobinemia Management

Methylene blue’s role in patients with methemoglobinemia, a rare blood disorder that is characterized by reduced oxygen-carrying capacity in red blood cells, is another significant milestone. By converting methemoglobin, a dysfunctional form of hemoglobin, back to functional hemoglobin, methylene blue was proven to help restore normal oxygenation and save lives in critical situations.¹

Antioxidant, Anti-Inflammatory & Anti-Apoptotic Properties

In recent years, methylene blue has garnered attention for its potential in neuroprotection and mitochondrial support. Research has shown that it possesses antioxidant, anti-inflammatory and anti-apoptotic properties, making it a promising candidate for various neurological disorders.

Methylene blue’s ability to enhance mitochondrial function and stimulate mitochondrial biogenesis opened up new avenues for addressing age-related cognitive decline and neurodegenerative diseases. Researchers have explored its potential in Alzheimer’s disease, Parkinson’s disease, depression and other mental health conditions.⁶

Mitochondrial Support

Mitochondria are essential cellular organelles responsible for generating energy in the form of adenosine triphosphate (ATP). Dysfunction of mitochondria is a common feature in neurodegenerative diseases. Methylene blue has shown remarkable effects on mitochondrial function,⁷ in particular as an electron carrier in the electron transport chain, facilitating the flow of electrons and enhancing ATP production. This property helps optimize mitochondrial function and improve cellular energy metabolism.

Methylene blue has also been found to promote the growth and replication of mitochondria — a process known as mitochondrial biogenesis. By increasing the number of healthy mitochondria, methylene blue enhances energy production and cellular resilience.⁷

Mitochondrial dysfunction can lead to the overproduction of reactive oxygen species (ROS), causing oxidative damage. Methylene blue helps reduce ROS production and prevents oxidative stress, preserving mitochondrial integrity.

The neuroprotective and mitochondrial support properties of methylene blue potentially have broad implications for patients with neurological disorders. While more research is needed, promising studies have highlighted its potential in conditions such as Alzheimer’s disease and Parkinson’s disease, as well as Huntington’s disease and ischemic stroke.

Hormesis

In addition to its diverse clinical applications, methylene blue garnered attention for its hormetic properties. Hormesis refers to the phenomenon in which exposure to low or moderate doses of a compound elicits beneficial physiological responses, while higher doses may be detrimental. Methylene blue exemplifies this hormetic effect: at lower doses, methylene blue exhibits an enhanced effect on mitochondrial function, whereas excessive doses are associated with toxic effects including increases in oxidative stress.¹

Precautions and Considerations:
Pregnancy, Breastfeeding and G6PD Deficiency

While methylene blue has demonstrated a wide range of clinical applications and potential benefits, there are certain precautions and considerations that should be considered for specific patient populations. For example, there is limited safety data on the use of methylene blue during pregnancy and breastfeeding, and therefore it is not recommended. There is also a precaution for patients with a G6PD deficiency, an inherited condition that affects the red blood cells’ ability to properly function. So, caution is necessary when considering methylene blue in individuals with this deficiency. As is the case with any pharmaceutical, the practitioner must evaluate the risk versus benefit for each individual patient before prescribing a medication. Methylene blue is no exception.⁸

Evolutionary Agent

From its humble origins as a textile dye, methylene blue has transformed into a versatile clinical agent with a wide range of potential applications. Over the years, it evolved from a surgical aid and diagnostic tool to helping patients with malaria and methemoglobinemia. The journey of methylene blue exemplifies the serendipitous discoveries that shape medical progress, demonstrating the immense potential hidden within seemingly ordinary substances.

References

1. Bruchey, A. K., & Gonzalez-Lima, F. (2008). Behavioral, Physiological and Biochemical Hormetic Responses to the Autoxidizable Dye Methylene Blue. Am J Pharmacol Toxicol. 3(1):72-79. Accessed April 2023 at pubmed.ncbi.nlm.nih.gov/20463863/

2. Staniloaie, D., Budin, C., Vasile, D., et al. (2022). Role of methylene blue in detecting the sentinel lymph node in colorectal cancer: In vivo vs. ex vivo technique. Exp Ther Med. 23(1):72. Accessed April 2023 at pubmed.ncbi.nlm.nih.gov/34934443/

3. Calderón M., Weitzel T., Rodriguez M.F., et al. (2017) Methylene blue for treating malaria. Cochrane Database Syst Rev. (10):CD012837.

4. Huang, Y. Y., Wintner, A., Seed, P. C., et al. (2018). Antimicrobial photodynamic therapy mediated by methylene blue and potassium iodide to treat urinary tract infection in a female rat model. Sci Rep. 8(1):7257. Accessed April 2023 at pubmed.ncbi.nlm.nih.gov/29740035/

5. Dabholkar, N., Gorantla, S., Dubey, S. K., et al. (2021). Repurposing methylene blue in the management of COVID-19: Mechanistic aspects and clinical investigations. Biomed Pharmacother. Accessed April 2023 at pubmed.ncbi.nlm.nih.gov/34399199/

6. Gureev, A. P., Sadovnikova, I. S., & Popov, V. N. (2022). Molecular Mechanisms of the Neuroprotective Effect of Methylene Blue. Biochemistry (Mosc). 87(9):940-956. Accessed April 2023 at pubmed.ncbi.nlm.nih.gov/36180986/

7. Gureev, A. P., Syromyatnikov, M. Y., Gorbacheva, T. M., Starkov, A. A., & Popov, V. N. (2016). Methylene blue improves sensorimotor phenotype and decreases anxiety in parallel with activating brain mitochondria biogenesis in mid-age mice. Neurosci Res. 13:19-27. Accessed April 2023 at pubmed.ncbi.nlm.nih.gov/27515402/

8. Methylene Blue. (2023) Clinical Pharmacology powered by ClinicalKey. Philadelphia (PA): Elsevier. C2023. Accessed May 2023 at clinicalkey.com

The complete version of this article originally appeared in PCCA’s members-only magazine, the Apothagram.