History and discovery of methylene blue

A fortuitous invention: 1876

Heinrich Caro and the BASF laboratories

The discovery of methylene blue belongs to a precise historical context. In 1876, the chemistry of synthetic dyes was undergoing remarkable ferment in Germany. Scientists were competing to synthesise new organic compounds, in particular aniline derivatives capable of replacing costly and scarce natural dyes.

Heinrich Caro, a German chemist working for BASF (Badische Anilin- & Soda-Fabrik), one of the largest chemical groups in the world at the time, was conducting systematic experiments in organic synthesis. During a series of trials involving oxidation reactions, Caro accidentally synthesised a compound with extraordinary properties: a crystalline powder of an intense blue-green colour, possessing unrivalled water solubility and a remarkable tinctorial capacity.

This synthesis was not the fruit of deliberate planning, but rather of attentive observation of an unexpected phenomenon. Scientific genius often consists in recognising the importance of an anomaly and investigating it rather than dismissing it.

Swift patenting and commercial development

Aware of the importance of its discovery, BASF proceeded to patent the compound rapidly. The patent was filed in 1876 and swiftly exploited. From the 1880s onwards, methylene blue became a major industrial dye in Europe.

The flourishing textile industry of the late nineteenth century constituted an ideal market. Unlike natural dyes — costly, unpredictable in quality, often perishable — synthetic methylene blue was:

• Reproducible at will in large quantities
• Stable in storage
• Capable of dyeing wool, cotton and silk effectively
• Economically competitive

Commercial success was swift. The textile mills of Europe and America adopted this new dye on a massive scale. BASF became the leading global producer and the compound generated substantial profits for the company.

The medical era: 1890-1950

The first therapeutic applications

Even as methylene blue was conquering the textile industry, researchers recognised its medical potential. Paul Ehrlich, an internationally renowned German microbiologist and chemist, took a particular interest in the properties of the compound.

Ehrlich observed that methylene blue possessed antimicrobial and antiparasitic properties. In 1891, he tested it against Plasmodium malariae, the causative agent of malaria. The results proved promising — the compound effectively inhibited the multiplication of the parasite in infected patients.

This discovery was of capital importance. Malaria killed millions of people annually in the nineteenth and twentieth centuries. An effective therapy, however imperfect, represented a major advance. Methylene blue quickly came to be used as an antimalarial in tropical regions.

In parallel, Ehrlich and his successors tested the compound against other infections:

• Bacterial urinary tract infections (where it proved effective)
• Internal parasites (worms, protozoa)
• Infected wounds and chronic sores

These initially promising applications placed methylene blue at the heart of the emerging medical pharmacopoeia.

The height of medical confidence (1920-1940)

Between the 1920s and the 1940s, methylene blue enjoyed an almost legendary reputation in European and North American medical circles. The compound was:

• Prescribed regularly by clinical physicians
• Included in official pharmaceutical formularies
• Produced by the largest pharmaceutical laboratories (Merck, Bayer, Rhône-Poulenc)
• Studied intensively by pharmacology researchers

Scientific articles abounded, proposing new applications: treatment of mood disorders, support of cognitive functions, improvement of physical endurance. Although many of these claims lacked rigorous foundation, they reflected the general confidence in the compound.

During this period, methylene blue represented an example of scientific success: a molecule discovered in the laboratory, validated by empirical observations, adopted by industry and medicine, and generating tangible benefits for patients.

The emergence of superior alternatives (1940-1970)

The medical ascent of methylene blue underwent an inexorable decline from the 1940s onwards. Three factors converged to relegate it to the background:

The antibiotic revolution: in 1928, Alexander Fleming discovered penicillin. During the 1940s and 1950s, antibiotics — penicillin, streptomycin, tetracyclines — proved to be of unprecedented effectiveness against bacterial infections. These molecules rapidly eclipsed methylene blue which, although moderately active, could not compete.

Synthetic antimalarials: natural quinine (an alkaloid extracted from cinchona bark) was the reference treatment for malaria. In the 1930s and 1940s, chemists synthesised chloroquine and synthetic quinine, molecules more potent, better tolerated and easier to produce than methylene blue.

The rise of rational pharmacology: medicine advanced by adopting a more rigorous approach to therapies. Randomised controlled trials became the norm. Many of the earlier claims about methylene blue did not withstand this new critical scrutiny. Its real effectiveness for most indications proved marginal or non-existent.

By 1970, methylene blue had practically disappeared from everyday medical practice. A single indication survived and endures to this day: the treatment of methaemoglobinaemia, a rare condition in which haemoglobin is oxidised into a non-functional form. Methylene blue proved capable of reducing this aberrant form and remains the reference antidote.

Residual status: 1970-2000

For three decades, methylene blue remained confined to niches:

Specialised medicine: treatment of methaemoglobinaemia, the only indication approved by the health authorities.

Traditional fishkeeping: aquarists used methylene blue empirically to treat fungal infections in fish, a tradition perpetuated without a solid scientific basis.

Biological research: laboratories continued to employ the blue as a laboratory stain, notably for the modified Gram stain and histological labelling.

Artisanal dyeing: the compound remained in use in professional textile dyeing and by craftspeople.

During this period, methylene blue was not forgotten — it simply no longer held any major clinical importance. It was a marginalised compound, surviving through inertia rather than through contemporary merit.

The pre-clinical resurgence: 2000-2020s

A renewal of scientific interest

From the 2000s onwards, a new wave of scientific research rediscovered methylene blue. Unlike the unverified historical claims, this new research rested on modern molecular biology and advanced analytical techniques.

Researchers observed that methylene blue:

• Possesses antioxidant properties (accepts free radicals and neutralises them)
• Interacts with mitochondria (selective accumulation)
• Shows neuroprotective activities in animal models (reduction of neurotoxicity)
• Possesses photosensitiser properties (generates reactive oxygen species under illumination)

These findings rest on solid biological data and not on anecdotes. They reinvigorate a legitimate scientific interest in the compound.

Current state of research (2020-2025)

At present, methylene blue is the subject of active pre-clinical studies in several fields:

• Neuroprotection in Alzheimer's and Parkinson's disease
• Anticancer photodynamic therapy
• Mitochondrial restoration in metabolic conditions
• Antioxidation and mitigation of oxidative stress

Status of the results: in vitro (test-tube) and animal studies (rodents, cellular models) generally prove promising. However, no rigorous clinical trial in humans has clearly demonstrated the effectiveness of methylene blue for any of these indications.

This distinction between pre-clinical promise and established clinical efficacy is crucial. Scientists recognise that methylene blue possesses an interesting biological potential, but that clinical translation is not guaranteed — which is precisely what justifies the continuation of research.

Laurent Schwartz and the metabolic theory (2010s)

Schwartz's approach

In the 2010s, Laurent Schwartz, a French researcher, articulated an innovative theory founded on the observation that mitochondrial dysfunction may constitute a significant underlying mechanism in carcinogenesis. From this point of view, methylene blue — which accumulates preferentially in the mitochondria and possesses characteristic reversible redox properties — could represent a therapeutic avenue for restoring the impaired mitochondrial functions in malignant cells.

This approach is rooted in the Warburg effect, a fundamental observation dating from 1924: cancer cells favour anaerobic glycolysis even in the presence of abundant oxygen, a phenomenon distinct from normal energy metabolism. Schwartz proposes that this metabolic dysfunction reflects a primordial rather than secondary mitochondrial failure — a perspective that reverses the traditional causality of metabolic cancer and opens up new therapeutic avenues.

Recognition and constructive scientific debate

Schwartz's metabolic theory has generated significant interest within the international scientific community. It offers an alternative perspective on cancer mechanisms and has inspired research exploring the links between mitochondria, energy metabolism and malignant transformation — fields that conventional approaches did not grasp as directly.

At the same time, the theory has prompted rigorous debate — a healthy and expected situation in the normal scientific process. Researchers raise important questions that refine and sharpen understanding:

• Is the Warburg effect a cause or a consequence of cancer?
• Is mitochondrial dysfunction sufficient to explain multifactorial carcinogenesis?
• How can the predictions of this theory be experimentally validated in humans?
• Which clinical protocols would make it possible to evaluate the effectiveness of methylene blue in cancers rigorously?

These legitimate questions do not disqualify the research but rather sharpen its scientific contours. The current clinical trials assessing the effectiveness of methylene blue in cancers remain limited to date, which represents a gap in knowledge — an opportunity for future research — rather than a definitive conclusion on the validity of the theory.

This dynamic illustrates the ordinary scientific process: innovative hypotheses, constructive debate between researchers of good faith, and the gradual accumulation of empirical data to validate, modulate or refute theoretical proposals. For further detail, consult our in-depth analysis of the Warburg effect and of the presentation of the Schwartz approach.

Summary timeline

Current perspectives

Methylene blue in the twenty-first century embodies a balanced position: a century-old compound with a prestigious legacy and a validated clinical status for certain indications, combined with interesting pre-clinical scientific promise currently undergoing rigorous investigation.

For professionals and patients, this reality means that:

• Methylene blue possesses a legitimate scientific potential justifying continued research
• Innovative therapeutic claims require rigorous clinical evidence — a healthy and classic requirement
• Current use should favour validated indications (methaemoglobinaemia) or established practical applications (fishkeeping, dyeing)
• The future of the compound will depend on the quality of the clinical trials and the robustness of the proposed mechanisms

Conclusion

The history of methylene blue — from accidental discovery to commercial success, then to medical marginalisation and scientific resurgence — illustrates how synthetic organic chemistry has transformed the world since 1876. This compound remains a fascinating example of the way in which scientific innovation evolves in response to the available technologies, biological understandings and changing societal needs.