Playing the methylene blues

Part 1: Origin story

Recently, a subscriber reached out to ask me for my take on methylene blue. This dazzling blue chemical has been taking the weird and wacky world of ‘wellness’ (whatever the heck that term means) by storm, ever since US Secretary for Health and Human Services, Robert F. Kennedy, Jnr was filmed squirting a blue liquid - widely assumed to be methylene blue - into his drinking water during a plane flight.

Methylene blue has joined the ever-expanding roster of substances promoted by biohackers, as part of their increasingly elaborate and costly regimes for (supposedly) enhancing physical and cognitive health. Biohacking, for those unfamiliar with the term, is the practice of making adjustments to one’s nutrition, exercise regime, sleep routine, and environment, in order to improve - and ideally, optimise - every conceivable (and ideally, measurable) aspect of health, performance and lifespan.

These adjustments might include dietary change, fasting practices, nutritional supplementation, off-label pharmaceuticals, physical training protocols, saunas and ice baths, wearables such as continuous glucose monitors and smartwatches, nearables such as sleep tracking mats, and even implanted subdermal devices such as lights, magnets, and RFID chips.

Now, as a health practitioner, I’m all in favour of people making better choices when it comes to their health and lifestyle behaviours. But where I part company with the biohackers is that I believe that health is the means to an end, not the end in itself. Hence, I advise people to work intelligently on their health, so that they can get, and keep, themselves in the best position to enjoy what life is truly about for as long as possible - cultivating deep and fulfilling relationships with other human beings, experiencing the beauty of this wonderful planet, and utilising the skills, talents and interests that are uniquely yours to make a worthwhile contribution to other beings, before you shuffle off your mortal coil.

For biohackers, however, optimising performance is their raison d’être. It’s not done in service of some other, higher goal; it is the goal in itself. Biohacking, in essence, is a cult, with a soteriology¹ of self-improvement for its own sake, and an eschatology² of immortality through technological innovation. Frankly, I find it repugnant on every level - the domain of narcissistic, solipsistic, spiritually bankrupt wankers. As a consequence, my first instinct is to dismiss any practice that biohackers are promoting, with the same reflexive disgust with which I would brush off a cockroach that was crawling up my leg.

However, the scientific mindset requires us to put aside our prejudices and consider all hypotheses as objectively as we possibly can. So, with that in mind, let’s take a good, hard look at the claims made for methylene blue, and how well - or otherwise - they’re supported by the scientific literature. In Part 1 of this series, I’ll cover methylene blue’s admittedly pretty cool origin story, and summarise the medical applications for which there’s good evidence of efficacy. Then in Part 2, I’ll discuss the side effects, and set methylene blue within the broader context of the commodification of ‘wellness’.

Methylene blue: From dye to drug

Methylene blue was first synthesised in 1876 by the German company Badische Anilin und Soda Fabrik (BASF) - yes, that BASF. The world’s largest chemical producing company began its life as a manufacturer of textile dyes made from aniline, a derivative of coal tar. Methylene blue wasn’t that crash hot as a textile dye, but the brilliant German scientist and doctor, Paul Ehrlich, quickly recognised its potential as a biological staining agent that could be used to highlight particular cellular structures, making them easier to identify and study. This discovery quickly led to another: methylene blue selectively inhibited certain microbial species. In 1891, Ehrlich published a paper demonstrating the efficacy of methylene blue in the treatment of malaria and thus, the substandard fabric dye became the first ever synthetic drug. Subsequently, methylene blue and its derivatives were explored in the treatment of a diverse array of tropical diseases, and bacterial and viral infections.

In the course of his experiments with the use of methylene blue as a live tissue stain, Ehrlich stumbled across its neuroleptic, or dopamine-blocking properties. This led to its experimental use in psychotic patients, which subsequently spurred the development of phenothiazines, the very first class of antipsychotic drugs. These first-generation antipsychotics, which gained widespread use in the late 1950s, quickly became notorious for their horrendous adverse effects, including motor-related issues called extrapyramidal symptoms (EPS) - such as muscle stiffness, tremors, and slowed movement - and tardive dyskinesia, an involuntary movement condition which causes uncontrollable, repetitive body movements such as grimacing, sticking out the tongue or smacking the lips.

If you’ve never witnessed someone suffering with tardive dyskinesia, I urge you to watch this short video made by a courageous man whose life has been devastated by this godawful condition:

Definitely something to bear in mind if you decide to experiment with methylene blue, the OG phenothiazine.

Current medical uses of methylene blue

Eager to discover new applications for Ehrlich’s mystical inky liquid, doctors proceeded to try it out on everything from cancer to cyanide poisoning. In the case of some of these applications, it was superseded by more effective drugs, while in others, its side effects and drug interaction profile rendered it too hazardous to use. Currently, it is an approved or widely accepted treatment, or experimental agent which has shown promise in case series and small-scale human trials, for treatment of the following conditions:

1. Methemoglobinaemia

Methylene blue is an FDA-approved treatment for this rare and potentially life-threatening condition, in which the ability of haemoglobin to transport oxygen around the body is compromised by oxidation, inducing functional anaemia. Methemoglobinaemia can be caused by certain anaesthetics, prescription or recreational drugs, chemical exposure or genetic factors. Methylene blue rapidly restores haemoglobin to its reduced state, reversing the functional anaemia.

2. Vasodilatory shock (including septic shock and vasoplegia)

Vasodilatory shock is a medical emergency in which conditions such as sepsis, severe allergic reactions, or spinal cord injuries cause blood vessels to relax excessively, resulting in diminished blood flow to vital organs including the brain, heart, and kidneys. Adding methylene blue to the standard treatment regimen of intravenous fluids and blood pressure-raising drugs (vasopressors), improves blood flow dynamics, reduces the need for vasopressors and increases survival, although the quality of evidence for these benefits was rated as low by reviewers.

3. Malaria

Methylene blue was, as you’ll recall, the first synthetic drug ever used in medicine, and the first condition it was used to treat was malaria. The development of chloroquine dethroned methylene blue as a malaria treatment, but the rapid increase in treatment resistance to chloroquine drugs has prompted researchers to turn back to methylene blue. In combination with artemesinin (a compound derived from the sweet wormwood plant, Artemisia annua, which was traditionally used for malarial symptoms), methylene blue effectively clears the malaria parasite from the blood. It also reduces the intensity of transmission of the malaria parasite and curtails the development and spread of treatment resistance.

4. Cancer diagnosis

The light spectrum properties of methylene blue are utilised in diagnosis of several types of cancer. For example, methylene blue can be used to identify sentinel lymph nodes into which cancer can spread, with greater speed and less pain than the standard procedure. Women undergoing axillary lymph node dissection to check for the spread of breast cancer into surrounding lymph nodes have reduced incidence of arm lymphoedema if methylene blue is used to identify sentinel lymph nodes. Use of methylene blue during colonoscopy aids in detection of polyps that may become cancerous, and is especially useful in people with inflammatory bowel disease. And methylene blue can be used during cancer surgery, to accurately identify tumour margins and hence reduce the need for revision surgery.

5. Photodynamic therapy for skin diseases and cancer treatment

Photodynamic therapy uses a combination of light-activated drugs and specific wavelengths of light to combat skin and mucous membrane infections and to kill cells that are behaving abnormally, either due to a proliferative disease, or because they have turned cancerous. When combined with near infrared light, methylene blue triggers apoptosis. Apoptosis is programmed cell death - an orderly process in which damaged cells ‘commit suicide’ without harming their neighbours, as distinct from necrosis - an uncontrolled and accidental cell death caused by external factors, which often leads to inflammation and damage to surrounding tissues.

Photodynamic therapy using methylene blue has been shown to be effective for psoriasis, oral candidiasis, fungal nail infections (onychomycosis), acne, antibiotic-resistant staph infections of wounds, and malignant melanoma.

6. Oral pain

A methylene blue mouth rinse has been shown to relieve the pain of burning mouth syndrome, and oral mucositis from cancer treatment, in pilot studies and case series.

7. Ifosfamide-induced neurotoxicity

Ifosfamide is a cancer chemotherapy agent, used for treatment of sarcomas, lymphomas, germ-cell tumours, head-and-neck cancers, and paediatric cancers including neuroblastoma and Wilms tumour. It causes a type of neurotoxicity (damage to the nervous system) dubbed ifosfamide-induced encephalopathy, in up to 30 per cent of adult patients who receive it intravenously, and 8 per cent of children with non-nervous system tumours. Retrospective chart reviews of both adults and children suggest that methylene blue is effective for the management of ifosfamide-induced neurotoxicity, although the authors of these reviews acknowledge that the treatment has never been prospectively studied or subjected to controlled trials.

Other potential applications of methylene blue

Cancer treatment

In vitro studies suggest that methylene blue may induce apotosis in certain human cancer cell lines, suggesting it may have potential as part of treatment protocols for some cancer types, for example, melanoma.

Alzheimer’s disease

Methylene blue reduces the formation of two of the hallmarks of Alzheimer’s disease: amyloid plaques and neurofibrillary tangles of tau protein. It also appears to increase the mitochondrial function of neurons, hence boosting the supply of cellular energy within the brain, and to reverse some of the disturbances to neurotransmitter function that are seen in Alzheimer’s patients. A phase 2 study of methylene blue in 321 patients with mild to moderate Alzheimer’s disease noted improved cerebral blood flow and better scores on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog), after 50 weeks of treatment.

In a 15 month randomised, controlled, double-blind, parallel-arm, multi-centre phase 3 trial, involving 891 participants and using a better-absorbed form of methylene blue, no improvement was seen in ADAS-Cog scores of participants who took the methylene blue-derived drug in addition to other Alzheimer’s medications. Intriguingly though, participants who were only taking the methylene blue-derived drug did have improved cognitive function, suggesting that other Alzheimer’s drugs might interfere with the activity of methylene blue.

---

By this point, you might be well be thinking, ‘This stuff sounds amazing! Where can I get some?’ Whoa there, cowboy. Take another look at that long list of current and potential applications. Notice something? Most of them are for treatment of serious, even life-threatening conditions. When faced with a high probability of death or catastrophic cognitive degeneration either without treatment, or with a standard-of-care treatment that is known to be quite ineffective, most people are willing to try a risky treatment if it holds out even a small prospect of saving them. But what about minor illnesses, or even non-illness applications such as the enhancement of cognitive capacity that biohackers are obsessed with? The risk calculus is vastly different in such cases. And methylene blue has some serious hazards. We’ll dive into those in Part 2 of this series.

For information on my private practice, please visit Empower Total Health. I am a Certified Lifestyle Medicine Practitioner, with an ND, GDCouns, BHSc(Hons) and Fellowship of the Australasian Society of Lifestyle Medicine.

1. Soteriology refers to doctrines of salvation.

2. Eschatology is the term used for religious doctrines of last things or end times.