Feeling (Methylene) Blue Part I

Dispelling the misinformation surrounding a new Tik Tok craze.

This article is inspired by subscriber Rafaela inquiring about Methylene Blue, as well as the craziness that goes on on social media.

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It should come as no surprise that I find social media to be one of the worst things to have ever graced humanity. It requires no clarity of thought and feeds into the impulsive, dopamine fueled centers of our brain that make us crave more attention and more notoriety. Tik Tok is just one of the newest social media platforms that feeds into the need for affirmation, leading people to chase trends or whatever is popular to satisfy that attention itch. This form of “clout chasing”, as the young ones call it, has made many people, without any real marketable skills, celebrities over night.

In an era that feels the need to correct for misinformation through fact checking, social media has spawned their own reactionary critics that target these new found “influencers”. Ironically, many of these people who react to these so-called influencers end up engaging in the same practices that they criticize many of their detractors of doing.

Last week several journalists reported on a new Tik Tok fad where influencers encouraged their followers to try Methylene Blue for all of its therapeutic benefits, going so far as to tell people it can help fight COVID. Of course, this has led to reactionary doctors and YouTubers to try to quell the spread of the misinformation by ironically engaging in their own misinformation.

I honestly left the thought of Methylene Blue in the back of my mind after seeing a subscriber suggest I look into it for its benefits against COVID. Well, now seems like the perfect time to dive in a little into the literature and see what I can find about Methylene Blue. At the same time, I will also provide my own “fact checking” to dispel some of the misinformation put out by both the YouTube video above and the Daily Wire article that it referenced.

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Brief Introduction into Methylene Blue

Methylene Blue is a tricyclic phenothiazine dye that was developed during the late 1800s for use in textile work to dye cotton. However, it was later found to be an effective compound to use in bacteria staining and thus was adopted as a common staining method for bacteria.

Image taken from Glatz et. al. “Microscopic image of a Malassezia spp. culture. Methylene blue staining.”

It was only a few years after its development that researchers began to examine Methylene Blue for its other possible therapeutic benefits (Dabholkar et. al.):

MB has a long history of more than 140 years, but it has managed to revive itself because of its wide range of applications. It is one of the most famous drugs to be repurposed for different clinical applications several times. MB was prepared as a dye for textiles by Caro in 1876 [26], [27]. Further, Paul Ehrlich developed the staining activity of MB and formed the groundwork of modern chemotherapy in 1891 [28]. Then, in the late 19th century it was used in the treatment of malaria, however, its use was discontinued because of the inevitable adverse effects; blue sclera and green urine [29], [30]. In the 1920s, MB was used as an antidote for cyanide poisoning because the reduction potential of MB is equal to the reduction potential of oxygen, and MB is readily reduced by the elements of the electron transport chain [31], [32]. Further, MB was found to reverse toxic methemoglobinemia [33]. MB has been found to reverse hypotension in sepsis and is useful in cases of vasoplegia [34]. Due to its unique physicochemical characteristics including its ionic charges, redox chemistry, light spectrum properties, and planar structure, MB exerts a wide range of clinical applications on the nervous system [35], [36]. MB has been used in photodynamic therapy for excisional wounds, hepatitis C, HIV, and psoriasis [37], [38], [39]. MB has also been established as a diagnostic marker for oral cancer [40], [41] and breast cancer [42].

Methylene Blue is mostly used for the treatment of methemoglobinemia, a disorder in which the heme iron found within the hemoglobin of red blood cells is oxidized from the Fe+2 state to the Fe+3 state. The more oxidized iron serves as a poor oxygen carrier for hemoglobin, and thus reduces the oxygen levels carried in the blood. Methemoglobinemia is usually a side effect of other drugs or acute diseases, and thus Methylene Blue’s use has tended to be limited in nature.

Methylene Blue is heavily evolved in oxidation/reduction reaction and can help carry electrons to the heme iron and reduce it to the proper Fe+2 state.

Schematic for Methylene Blue in treating methemoglobinemia. NADPH is formed through one metabolic pathway. The electrons from NADPH are shuttled to Methylene Blue and reduces it to Leucomethylene Blue which is colorless. Leucomethylene Blue can then carry electrons to the Fe+3 iron and reduce it to the Fe+2 state. Afterwards, the Methylene Blue can be reused.

In fact, many of Methylene Blue’s therapeutic properties are derived from its ability to serve as an oxidative/reductive agent, and is where Methylene Blue’s activities stem from. Its wide ability to serve in redox reactions, aromatic nature, ionic properties, and irradiating capabilities provide it a host of different therapeutic properties.

Methylene Blue’s antioxidant properties should come as no surprise. There’s a strong relationship between the aromatic nature of molecules and their ability to serve as free radical sponges. Aromatic molecules have the ability to “delocalize” their electrons. Essentially, the electrons located within the double bonds and lone pairs of the molecule’s atoms can spread around a molecule. When antioxidants come into contact with a reactive oxygen species (ROS, molecules or agents that form free radicals) they can form a free radical intermediate. The ability to delocalize the free radical nature around the entire molecule allows these molecules to stabilize the new radical formation. This makes aromatic compounds good sponges to take the brunt of damage caused by ROS in place of our more sensitive DNA and cellular proteins, thus protecting many of our cellular functions from destruction oxidative damage.

A representation of free radical formation and resonance using Vitamin C. Vitamin C is not an aromatic compound since it cannot engage in resonance through the cyclic molecule. However, it can still engage in some form of resonance. When Vit. C comes into contact with an ROS a free radical may form on the molecule (left). Afterwards, the new radical character is now able to be shuttled through the molecule through resonance and spread the radical burden across several atoms. This ability to stabilize radical formation makes antioxidants very appealing molecules to serve as sacrificial agents to protect cellular DNA and proteins.

The aromatic nature is also what provides many of these compounds their different colors and hues. Not only does aromaticity provide free radical stabilization but the electrons within the molecule can become “excited” by light. The excited electrons can then release these photons and provides the color that we see. This is why flavanoids, which are aromatic compounds found in fruits and vegetables provide both color and antioxidant properties to these foods.

Strangely enough, this ability to capture light has allowed Methylene Blue to be used in forms of phototherapy (light therapy) where Methylene Blue is added to tissues, cuts, or bruises infected with bacteria. Light is then provided causing the Methylene Blue to oxidize and form ROS that help kill bacteria. Because antibiotic resistant bacteria are becoming a growing concern, such treatment options may help to bypass concerns caused by antibiotics (Sperandio et. al.).

All this to say that Methylene Blue’s denigration as a dye is actually derivative. It removes the more complex nature of colorful molecules. Just because Methylene Blue was first designed as a dye for clothing does not mean that removes its other possible effects. It underscores how so many people view things from a parochial viewpoint. Surely something that is used as a dyeing agent can’t be used for other purposes. Why would a dye do anything else other than be a dye? It reminds me of those D.A.R.E. commercials that tried to dissuade people from smoking by making such comparative arguments as cigarettes contain methane which is found in dog poop.

Considering that humans themselves, and really many living organisms produce methane that point is absolutely moot, and is extremely reductive. We should learn by now, at least through this Substack that, just as we should not judge a book by it’s cover, we can’t judge a molecule for its originally intended purpose. After all, we should know full well the importance of repurposing molecules when it comes to pharmaceuticals.

But that’s enough soapboxing for now. This post has been separated into two posts because I apparently can’t shorten things down. The next post will focus on fact checking the fact checkers and see if there’s any merit to the reactions to these influencers. Please stay tuned!