Treating Long COVID Neurological Symptoms with Methylene Blue
As the cases of Long COVID continue to increase, it is important for the medical community to begin focusing on long-term therapeutic strategies that target the chronic ischemic and inflammatory environment seen in the brains of those infected or previously infected by COVID-19. One of the pharmacological agents that the medical community is starting to take notice of for this purpose is Methylene Blue.
What is Methylene Blue?
Methylene Blue (MB) has a long history of use, although it has not always been utilized for pharmaceutical purposes. It was first synthesized in 1876 for use as a textile dye, but as early as 1891, it was investigated for its medicinal applications. One of its first applications in the medical field was as a medical strain, but it soon expanded to be used in treatments.
Explore the photos below to get an in-depth view of IV Methylene Blue.
Its classic uses in the medical field include treatment for malaria, carbon monoxide poisoning, and methemoglobinemia. However, its effect on mitochondria has been receiving growing interest. There is also growing interest in the connection between mitochondrial dysfunction and Long COVID symptoms, adding to the appeal of MB as a potential pharmacological agent and treatment.
The Role of Methylene Blue in the Treatment of Long COVID
MB plays a significant role in the mitochondria due to its ability to act as a catalytic redox cycler. This mechanism allows it to reroute electrons in the mitochondrial electron transfer chain from NADH to cytochrome c. When this occurs, the activity of complex IV is increased, which promotes mitochondrial activity while mitigating oxidative stress.
Since oxidative damage, which is caused by mitochondrial dysfunction, impairs complex IV, the ability of MB to increase complex IV activity plays an important role in its ability to address and correct mitochondrial dysfunction.
What are Mitochondria?
Because of MB’s ability to influence the mitochondria and increase their functioning, it is important to consider what the role of the mitochondria is, and why their dysfunction plays a central role in Long COVID symptoms.
The mitochondria are organelles that generate most of the adenosine triphosphate (ATP) used by the cell. Virtually every ounce of energy generated in your body comes from the Krebs Cycle and the Electron Transport Chain both found in the mitochondria.
Virtually every biochemical reaction requires the input of energy in the form of ATP. Without ATP all it takes is six seconds for the cell to start deteriorating. The first thing that deteriorates in the cell without ATP is the mitochondria Itself.
Some of the other cellular biological processes in which mitochondria play essential roles include apoptosis, calcium signaling, cell growth, reactive oxygen species (ROS) generation, and cell cycle.
The mitochondria are very often denoted as the “powerhouse” of the cell due to their role in ATP production, but the truth is that they play a much more important role in the body, particularly affecting immunity.
The mitochondria sense the cellular environment and control inflammation, growth, senescence, and death. With these roles, the mitochondria balance metabolic priorities between growth, energy production, defense, and oxidative stress management. There are many tasks handled by the mitochondria, and having a good mitochondrial reserve ensures that the cell can remain flexible and multi-task. The loss of this flexibility can contribute to aging-related changes in the immune system.
Beyond Unfathomable Complexity
The average cell in the human body has between 1000-2000 mitochondria depending on the metabolic energy it needs to:
- Maintain its own health.
- Provide for the rest of the body what it was designed to provide.
In contrast, cardiomyocyte cells have 6-8000 mitochondria, and neurological cells are by far the most metabolically active cells in human physiology and contain on average between 2 – 3 million mitochondria in order to:
- Maintain their own health.
- Provide for the body a functioning neural network.
Given the vital importance of mitochondria as the generator of all of your biochemical “life” energy, that without healthy mitochondria your damaged neural network cannot be repaired.
Mitochondrial dysfunction occurs when there is a loss of function in mitochondria, and is a common observance in many neurological disorders that possess both chronic and acute neural injury. Some diseases that show mitochondrial dysfunction include neurodegenerative diseases and brain injuries from a lack of blood and oxygen supply.
Mitochondrial dysfunction plays a role in the induction of factors that lead to brain disorders, such as inflammation, oxidative stress, transcriptional alterations, and excitotoxicity. For neurological disorders such as traumatic brain injury, Alzheimer’s disease, depression, Parkinson’s disease, and stroke, mitochondrial dysfunction contributes to the disease’s pathophysiology because of decreased energy production and excessive reactive oxygen species (ROS) production. Excessive ROS production leads to oxidative stress, which is a major contributing factor to many neurodegenerative diseases.
Watch the video : I’m No Longer the Walking Dead
Further studies into the effect of mitochondrial dysfunction on these neurological disorders have found that restoring mitochondrial function may serve as a treatment method, with many studies showing improvements in brain mitochondrial function after treatment for the neurological illness.
Long-Term Effects of COVID-19 on The Brain Mitochondria
Studies have found that COVID-19 can directly or indirectly affect the central nervous system (CNS). These effects on the CNS can contribute to the symptoms seen in those with long-COVID, such as serious long-term mental and cognitive changes, including “brain fog.”
With infection, the SARS-CoV-2 RNA genome integrates into the host mitochondrial matrix, which leads to virus replication and increased viral load. The viral RNA then hijacks the mitochondrial function to suppress the body’s immune response and further promote viral replication. As the infection continues, the infected cells (which can include neurons) may experience oxidative stress and calcium ion influx that can lead to necrosis, apoptosis, or dysfunction, along with impaired mitochondrial function.
The tissues in the brain require an immediate and constant supply of oxygen to keep up with their significant metabolism. However, the SARS-CoV-2 virus may cause hypoxia in some regions of the brain to benefit its reproductive abilities. This hypoxia can then compromise neuronal cell energy metabolism, leading to mitochondrial dysfunction in the cerebral tissue.
This theory of the effect of the SARS-CoV-2 virus on the CNS has been confirmed with autopsies showing the presence of the coronavirus in the CNS, especially in the brain.
The Spike Protein
SARS-COV-2 infects cells through its spike protein, which binds to a surface receptor on the target cell. Many people who have been infected will develop antibodies that neutralize the spike protein. However, those who produce antibodies that neutralize one COVID-19 strain but not another are known to have increased chances of antibody-dependent enhancement (ADE) to the new strain, which may explain Long COVID symptoms.
There’s more to the spike protein than its ability to let the virus connect to a target cell, though, with the spike proteins themselves being toxic to human physiology. Free spike protein can have several direct pathologic actions on cells, including stimulating pro-inflammatory and vasoactive mediators, especially platelet-activating factors.
The spike protein can also damage the blood-brain barrier (BBB) and change its function by inducing the inflammatory response of microvascular endothelial cells. These findings support the observances that SARS-CoV-2 can alter the BBB and pass through it to enter the brain. The SARS-CoV-2 spike protein-binding receptor (ACE2) is also widely expressed in brain microvascular endothelial cells, which is why it often targets these cells, causing inflammation and the neurological symptoms associated with COVID-19.
Not only does the observance of the spike protein damaging and passing through the BBB support clinical reports detailing early neurological changes, but it also serves as a basis for long-term neurological symptoms.
Neurological Symptoms Commonly Seen in Long-COVID
Those with a COVID-19 infection can show neurologic symptoms such as:
- Loss of sense of taste and smell
- Brief loss of consciousness
Some of these symptoms are common in other neurological conditions, such as Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease, causing those with long-COVID to be potentially misdiagnosed because of the mimicking of symptoms. Additionally, there is a growing concern about the long-term effects of SARS-CoV-2 on the CNS and cognitive function. Specifically, if SARS-CoV-2 causes neurodegenerative diseases or if it accelerates their occurrence prematurely.
Spike Protein from Other Sources
Research also shows that the spike protein can have these same effects from other sources of the spike protein, not just from the infection itself. A 2021 study found that those with long-COVID and who had obtained the spike protein from another source both showed retained spike protein in monocytes.
Additionally, this study examined patients who showed symptoms of long-COVID after being given the spike protein and found that they responded to treatments intended for long-COVID, supporting the observance that other sources of the spike protein can cause long-COVID.
Studies also show that the spike protein from other sources selectively and potently drives pro-inflammatory cytokine secretion in human monocytes. This supports our belief that the spike protein is causing the inflammation and mitochondria problems seen in those with long-COVID, and this research explains why we are seeing patients with similar symptoms no matter if they got the spike protein from the infection or from another source.
Methylene Blue as a Long-COVID Treatment
A significant amount of evidence shows that changes induced by mitochondria, such as oxidative stress, dysfunctional electron transport, Ca2+ imbalance, impaired mitochondrial trafficking, defective mitophagy, and altered mitochondrial dynamics, show some involvement in various brain diseases.
Since MB is able to correct mitochondrial dysfunction, it shows promise as a treatment for Long COVID. It can target and improve many areas of mitochondrial damage, although the two most notable areas in regard to Long COVID treatment include oxidative stress and neuro-inflammation because they have the greatest impact on neurons.
The benefits of MB on other neurological diseases that are related to mitochondrial dysfunction, such as stroke and Parkinson’s disease, have been well documented. We have also seen improvements in our patients when treating Long COVID with MB, further supporting the use of MB to correct cases of mitochondrial dysfunction for those with neurological conditions.
How MB Is Administered
The ideal method for administering MB is intravenously since it allows for a higher available drug concentration compared to oral delivery.
Once administered, MB accumulates in tissues at significant concentrations. This includes the brain tissue, and the high concentration allows it to cross the BBB and potentially enter neuronal mitochondria. However, the mechanism by which it penetrates mitochondria remains unclear.
Light Based Therapies + Methylene Blue
In general, photo-biomodulation (PBM) and photodynamic therapy (PDT) are two primary methods, which use light in medicine and dentistry.
- PBM uses low-level laser light to induce healthy cellular activity including proliferation and repair.
- In contrast, PDT uses low level laser light combined with a photosensitizing compound (PS) to cause cell death.
Due to similar, but not fully understood mechanisms and biphasic response of light, unexpected and complex outcomes that as yet defy explanation may be observed. Thus, step-by-step protocols have yet to be developed that produce thorough, reliable, and reproducible results for a majority of conditions.
What is clear however, is that the low-level energy of the lasers and LED light being used are safe and easy to use.
Regarding COVID, both of these modalities should theoretically be useful, perhaps even critically important if they can be combined.
Photodynamic Therapy (PDT)
We need to kill the virus as soon and as quickly as possible. For this, Photodynamic Therapy with a Photosensitizing agent that can target and become concentrated in the virus, and a laser with a corresponding frequency of energy (wavelength) that is readily absorbed by the Photosensitizing agent.
The energized Photosensitizing agent will now release ROS that are deadly to the virus. Ideally a properly constructed protocol that takes advantage of these properties will clear a patient of an entire viral load quickly, and before systemic damage is created.
Photodynamic Therapy (PDT) – The Basics
- For reasons that remain obscure, certain Photosensitizing compounds possess a powerful affinity for unhealthy cells or specific components therein, especially but not limited to malignancy. For example: Methylene Blue is powerfully attracted to Malaria.
- Once administered to the body, the targeted malignant/pathogenic cells will retain the Photosensitizing compound, while healthy cells are able to clear themselves of the Photosensitizing compound over a specified period of time – “incubation”.
- The Photosensitizing compound must also contain the needed molecular components that when stimulated by the correct light are able to release the needed ROS, that will kill neighboring malignant or pathogenic cells.
Photo-biomodulation (PBM) is another therapeutic approach targeting mitochondria, but its underlying mechanism differs from MB. Because of these differences in mechanisms, combining PBM and MB can offer better results than either therapy individually.
PBM is also known as low-level laser therapy and involves the application of red-beam (400-720 nm) or near-infrared (700-1000 nm) laser on biological tissues. PBM can modulate various biological processes due to its ability to target the mitochondria. The low-level laser donates photons to complex IV, which increases its activity and thus oxygen consumption.
Photo-biomodulation (PBM) – The Basics
- Using a specific wavelength of light that is absorbed by particular components of healthy cells, vital metabolic activity, healthy and balanced cellular turnover and internal cellular functions can be stimulated and enhanced. In cases such as COVID with severe mitochondrial disruption the photons of the correct light will stimulate ATP production.
- Given the ubiquitous cellular damage caused by the COVID spike protein’s disruption of the Electron Transport Chain in mitochondria of otherwise healthy cells, and because of ischemic tissue damage caused by systemic inflammation, stimulating healthy cellular activity as well as proliferation might prove to enhance and accelerate a COVID patient’s recovery.
Growing research on the effect of the SARS-CoV-2 spike protein on mitochondrial dysfunction, and thus the role of the mitochondria in Long COVID symptoms, has led to an increasing need for pharmacological treatments that repair the mitochondrial function.
Methylene blue is a pharmacological agent showing appealing results as a treatment for Long COVID, which we suspect is due to its ability to correct mitochondrial dysfunction. When combined with photo-biomodulation, another therapeutic approach targeting mitochondria, the treatment becomes even more effective.
- National Center for Biotechnology Information (2022). PubChem Compound Summary for CID 6099, Methylene blue. Retrieved July 5, 2022
- Tucker, D., Lu, Y., & Zhang, Q. (2017). From Mitochondrial Function to Neuroprotection—an Emerging Role for Methylene Blue. Molecular Neurobiology, 55(6), 5137-5153. doi: 10.1007/s12035-017-0712-2
- Zhao, X., Lu, M., Yuan, D., Xu, D., Yao, P., & Ji, W. et al. (2019). Mitochondrial Dysfunction in Neural Injury. Frontiers In Neuroscience, 13. doi: 10.3389/fnins.2019.00030
- Nunn, A., Guy, G., Botchway, S., & Bell, J. (2021). SARS-CoV-2 and EBV; the cost of a second mitochondrial “whammy”?. Immunity &Amp; Ageing, 18(1). doi: 10.1186/s12979-021-00252-x
- Aw, D., Silva, A., & Palmer, D. (2007). Immunosenescence: emerging challenges for an ageing population. Immunology, 120(4), 435-446. doi: 10.1111/j.1365-2567.2007.02555.x
- Nicolson GL. Mitochondrial Dysfunction and Chronic Disease: Treatment With Natural Supplements. Integr Med (Encinitas). 2014 Aug;13(4):35-43. PMID: 26770107; PMCID: PMC4566449.
- Yang, L., Youngblood, H., Wu, C., & Zhang, Q. (2020). Mitochondria as a target for neuroprotection: role of methylene blue and photobiomodulation. Translational Neurodegeneration, 9(1). doi: 10.1186/s40035-020-00197-z
- Wang, F., Kream, R., & Stefano, G. (2020). Long-Term Respiratory and Neurological Sequelae of COVID-19. Medical Science Monitor, 26. doi: 10.12659/msm.928996
- Swain, O., Romano, S., Miryala, R., Tsai, J., Parikh, V., & Umanah, G. (2021). SARS-CoV-2 Neuronal Invasion and Complications: Potential Mechanisms and Therapeutic Approaches. The Journal Of Neuroscience, 41(25), 5338-5349. doi: 10.1523/jneurosci.3188-20.2021
- Theoharides, T. (2022). Could SARS-CoV-2 Spike Protein Be Responsible for Long-COVID Syndrome?. Molecular Neurobiology, 59(3), 1850-1861. doi: 10.1007/s12035-021-02696-0
- Theobald, S., Simonis, A., Georgomanolis, T., Kreer, C., Zehner, M., & Eisfeld, H. et al. (2021). Long lived macrophage reprogramming drives spike protein mediated inflammasome activation in COVID-19. EMBO Molecular Medicine, 13(8). doi: 10.15252/emmm.202114150
- Patterson, B., Francisco, E., Yogendra, R., Long, E., Pise, A., & Rodrigues, H. et al. (2022). Persistence of SARS CoV-2 S1 Protein in CD16+ Monocytes in Post-Acute Sequelae of COVID-19 (PASC) up to 15 Months Post-Infection. Frontiers In Immunology, 12. doi: 10.3389/fimmu.2021.746021
- Shen, Q., Du, F., Huang, S., Rodriguez, P., Watts, L., & Duong, T. (2013). Neuroprotective Efficacy of Methylene Blue in Ischemic Stroke: An MRI Study. Plos ONE, 8(11), e79833. doi: 10.1371/journal.pone.0079833
- Wen, Y., Li, W., Poteet, E., Xie, L., Tan, C., & Yan, L. et al. (2011). Alternative Mitochondrial Electron Transfer as a Novel Strategy for Neuroprotection. Journal Of Biological Chemistry, 286(18), 16504-16515. doi: 10.1074/jbc.m110.208447
- 23.Fekrazad R, Asefi S, Pourhajibagher M, Vahdatinia F, Fekrazad S, Bahador A, Abrahamse H, Hamblin MR. Photobiomodulation and Antiviral Photodynamic Therapy in COVID-19 Management. Adv Exp Med Biol. 2021;1318:517-547. doi: 10.1007/978-3-030-63761-3_30. PMID: 33973198.
- Abrahamse H, Hamblin MR. New photosensitizers for photodynamic therapy. Biochem J. 2016 Feb 15;473(4):347-64. doi: 10.1042/BJ20150942. PMID: 26862179; PMCID: PMC4811612.
- Dos Santos AF, Terra LF, Wailemann RA, Oliveira TC, Gomes VM, Mineiro MF, Meotti FC, Bruni-Cardoso A, Baptista MS, Labriola L. Methylene blue photodynamic therapy induces selective and massive cell death in human breast cancer cells. BMC Cancer. 2017 Mar 15;17(1):194. doi: 10.1186/s12885-017-3179-7. PMID: 28298203; PMCID: PMC5353937.
- Tardivo JP, Del Giglio A, de Oliveira CS, Gabrielli DS, Junqueira HC, Tada DB, Severino D, de Fátima Turchiello R, Baptista MS. Methylene blue in photodynamic therapy: From basic mechanisms to clinical applications. Photodiagnosis Photodyn Ther. 2005 Sep;2(3):175-91. doi: 10.1016/S1572-1000(05)00097-9. Epub 2005 Nov 21. PMID: 25048768.
- Wang Y, Ren K, Liao X, Luo G, Kumthip K, Leetrakool N, Li S, Chen L, Yang C, Chen Y. Inactivation of Zika virus in plasma and derivatives by four different methods. J Med Virol. 2019 Dec;91(12):2059-2065. doi: 10.1002/jmv.25538. Epub 2019 Aug 31. PMID: 31389019.
- Ateş GB, Ak A, Garipcan B, Gülsoy M. Methylene blue mediated photobiomodulation on human osteoblast cells. Lasers Med Sci. 2017 Nov;32(8):1847-1855. doi: 10.1007/s10103-017-2286-7. Epub 2017 Aug 4. PMID: 28776111.
- Svyatchenko VA, Nikonov SD, Mayorov AP, Gelfond ML, Loktev VB. Antiviral photodynamic therapy: Inactivation and inhibition of SARS-CoV-2 in vitro using methylene blue and Radachlorin. Photodiagnosis Photodyn Ther. 2021 Mar;33:102112. doi: 10.1016/j.pdpdt.2020.102112. Epub 2020 Nov 26. PMID: 33249118; PMCID: PMC7690324.