From Dye to Drug: Methylene Blue, Ehrlich’s Staining and the 1891 Malaria Cures

In 1876 a German dye chemist named Heinrich Caro made a new blue colour for cotton. Fifteen years later, in a Berlin city hospital run by the physician Paul Guttmann, the same blue powder was given by mouth to two people with malaria, and both recovered. Between those two moments sits one of the most important chains of ideas in the history of medicine: a textile dye that stained living nerves, a microscope stain that coloured the malaria parasite more strongly than the blood around it, and a young physician-scientist, Paul Ehrlich, who asked whether a chemical that picked out a germ under the microscope might also pick it out inside the body.

This page follows that chain step by step, from the dye works to the sickbed and on to the drugs that grew out of it. Historians of pharmacology often describe methylene blue as the first synthetic drug used against a specific disease, and the 1891 report as an early case of a man-made chemical being chosen for an infection because of what it was seen to do to the germ. The story of the two men themselves is told on the companion page Two Lives Behind Methylene Blue; the redox chemistry and the antidote years are covered in The Science of Methylene Blue.

Table of Contents

  1. A Blue for Cotton: The 1876 Synthesis
  2. The 1877 Patent and the German Dye Industry
  3. Working Out the Structure: Bernthsen’s Studies
  4. Ehrlich’s 1886 Discovery: A Dye That Stains Living Nerves
  5. Staining the Malaria Parasite
  6. The 1891 Moabit Report by Guttmann and Ehrlich
  7. Methylene Blue Against Malaria into the First World War
  8. Selective Staining and the Idea of a Magic Bullet
  9. The Lead Structure: Pamaquine, Chloroquine and the Phenothiazines
  10. Key Research Papers
  11. Connections
  12. Featured Videos

1. A Blue for Cotton: The 1876 Synthesis

The 1870s were the golden age of coal-tar dyes. Since William Perkin’s mauve of 1856, chemists in Britain, France and Germany had learned that the black, sticky residue left over from making coal gas could be turned into colours brighter than anything madder root, indigo leaves or cochineal insects had ever given. Heinrich Caro had spent his working life in that world. Trained as a dyer and textile colourist in Berlin, he had improved the manufacture of Perkin’s mauve during seven years in Manchester, and since 1868 he had led the research laboratory of the Badische Anilin- und Soda-Fabrik (BASF) in Ludwigshafen on the Rhine.

Wool and silk take up most dyes readily; cotton, a plant fibre, is far harder to colour well. A strong, clean blue that would hold on cotton was therefore a prize. In 1876, while experimenting with a new chemical intermediate built from dimethylaniline (a coal-tar derivative), Caro obtained a pure blue dye for cotton. It was given the name methylene blue. Reviews of the compound’s history, such as the 2002 survey by Wainwright and Crossley, date its first synthesis to that year.

Nothing about the new dye suggested medicine. It was one product in a run of colours credited to Caro in those years, alongside induline, eosin and his work on synthetic alizarin, the red that replaced madder root in the dye vats. It is worth noting what this means for the “natural medicine” side of the story: methylene blue has no plant or mould ancestor. It was made from coal tar. Its importance in medicine came from the opposite direction to the herbal tradition, as the first sign that a chemist could design a substance in the laboratory and then find a disease it acted on.

A dye that changes colour

One property of the new blue would later matter enormously. In the presence of reducing substances, methylene blue loses its colour and turns into a colourless form (leucomethylene blue); in air it turns blue again. This reversible behaviour is central to how the dye acts in the body, and physicians would later rely on it, both in staining and in the antidote uses described on the chemistry and antidote page.

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2. The 1877 Patent and the German Dye Industry

In 1877 the company was granted a German patent for methylene blue. The company’s own published history describes it as the first German patent for a coal-tar dye. The timing was not an accident: 1877 was the year a single patent law came into force across the new German Empire, replacing the patchwork of state rules that had let firms copy one another freely. The exact patent number and date are often quoted in popular accounts, but they could not be confirmed from a primary source for this page and are left out.

The patent marks a turning point in how dyes were made. Up to then, much of the German coal-tar industry had grown by imitation. Caro’s laboratory, which the Dictionary of Scientific Biography calls probably the first true industrial research organisation, worked differently: trained chemists were paid to invent new molecules, test them, and protect them. That system of salaried chemists, patent lawyers and large-scale manufacture is the model from which the modern pharmaceutical industry grew. When the dye firms later turned to medicines, they brought the same machinery with them.

Why a dye company mattered to medicine

The firms that made dyes were also the firms that could supply pure, consistent chemicals in quantity. A physician in 1880 who wanted to test a compound needed exactly that. Medical researchers of the period, Ehrlich above all, used the dye catalogues as a library of ready-made molecules. Methylene blue was one of hundreds of coal-tar colours on offer; what set it apart was what happened when it was placed on living tissue.

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3. Working Out the Structure: Bernthsen’s Studies

Caro made methylene blue years before anyone could draw its molecule. The structure was worked out by the chemist August Bernthsen, who published his Studien in der Methylenblaugruppe (“Studies in the methylene blue group”) in the Justus Liebigs Annalen der Chemie in 1885. The first part runs to more than sixty pages, and a second part followed in the same volume.

Bernthsen showed that methylene blue is built on a three-ring framework: two benzene rings joined by a bridge of one sulfur atom and one nitrogen atom. That parent ring system is called phenothiazine. In methylene blue, each outer ring carries a dimethylamino group, and the molecule carries a positive charge that is spread across the rings. The charge helps explain why the dye clings to negatively charged parts of cells, such as the acids of the cell nucleus, and why it dissolves in water.

The importance of this work went far beyond one dye. Once the phenothiazine skeleton was known, chemists could make relatives of methylene blue on purpose, changing one side group at a time. Decades later, as Section 9 describes, that skeleton became what Ohlow and Moosmann have called “pharmacology’s first lead structure.” Bernthsen later wrote the long memorial biography of Caro published in the Berichte der deutschen chemischen Gesellschaft in 1912.

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4. Ehrlich’s 1886 Discovery: A Dye That Stains Living Nerves

Paul Ehrlich had been fascinated by dyes since his student days. Most microscopists of his time stained tissue after it was dead and fixed. In 1886, in the Deutsche Medizinische Wochenschrift, Ehrlich reported something new: methylene blue, introduced into a living animal, coloured nerve tissue while the tissues around it stayed comparatively pale. His paper’s title, “Ueber die Methylenblaureaction der lebenden Nervensubstanz,” translates as “On the methylene blue reaction of living nerve substance.” The technique became known as vital (living) staining, and methylene blue became a standard tool for tracing fine nerve endings.

The finding was a puzzle with a large meaning. If a dye could travel through the whole body and settle in one kind of tissue rather than another, then the body’s tissues must differ chemically in ways that a molecule could “recognise.” Ehrlich spent the rest of his career developing that thought. His later theories of side chains and receptors, traced by the historian Anthony Travis in a 2019 review, grew directly out of the behaviour of dyes in tissue.

The 1890 report on pain relief

A dye drawn to nerves might also act on them. In 1890 Ehrlich and his colleague A. Leppmann published a short report in the same journal, “Ueber schmerzstillende Wirkung des Methylenblau” (“On the pain-relieving action of methylene blue”), describing an analgesic effect in patients. It was one of the first attempts to use a synthetic dye as a medicine, and it shows the line of reasoning that led, a year later, to malaria: start from where a dye goes in the body, and ask what it might do there.

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5. Staining the Malaria Parasite

Malaria had been treated for more than two centuries with a plant medicine: the bark of the South American cinchona tree and, after 1820, its purified alkaloid quinine. The disease itself was still poorly understood. Only in 1880 had the French army surgeon Alphonse Laveran seen the parasite in human blood, and its life cycle in the mosquito was not worked out until the late 1890s (the full story is told on the site’s history of malaria page).

Under the microscope the malaria parasite, which lives inside red blood cells, is small and hard to see. Ehrlich and others found that methylene blue coloured it strongly. Ohlow and Moosmann, in their 2011 history of the phenothiazine family, note that the phenothiazine structure was “initially used for histochemical stains of plasmodia by Paul Ehrlich.” The parasite took up the blue; much of the surrounding blood did not. Methylene blue and its oxidation products later became basic ingredients of the blood stains used for decades to diagnose malaria on a glass slide.

For Ehrlich the stain was more than a convenience. If the parasite soaked up the dye more eagerly than human cells did, perhaps the dye could be used to reach the parasite inside a patient, and perhaps it would harm the parasite more than the person. In the account given by Krafts and colleagues in their 2012 review of antimalarial history, this line of thought runs straight from the identification of the parasite to the first synthetic antimalarial treatment.

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6. The 1891 Moabit Report by Guttmann and Ehrlich

The test took place at the Moabit municipal hospital in Berlin, where Paul Guttmann had been director since 1879. Guttmann was a senior clinician and the author of a widely translated textbook of physical examination. In 1891 the two published “Ueber die Wirkung des Methylenblau bei Malaria” (“On the action of methylene blue in malaria”) in the Berliner klinische Wochenschrift.

The report was brief and described just two patients. Both had malaria confirmed under the microscope, both were given methylene blue by mouth, and both were recorded as cured. In the summary table of the 2018 systematic review by Lu and colleagues, the two patients are recorded as receiving 500 mg of methylene blue a day for 12 to 24 days and being followed for one to two months, with both cured. One patient had urogenital symptoms (irritation of the bladder and urethra, which became the best-known side effect of the treatment), and the table notes that nutmeg was given with the dye in an attempt to reduce them. These figures are reported here as history, as recorded by the review authors; they are not a description of modern practice.

Why this small report mattered

Two patients would not count as evidence today. What made the paper historic was its logic. Quinine was a natural product whose action no one understood. Methylene blue was a synthetic chemical, chosen because of a known, visible property: it was taken up by the parasite. Lu and colleagues describe methylene blue as “the first synthetic antimalarial to be discovered,” and Schirmer and colleagues, in their 2011 history, call it “the first synthetic drug.” That shorthand needs care. Other synthetic chemicals had been used as medicines earlier (the sedative chloral hydrate, for example, entered use in 1869), so the claim is better put as historians generally frame it: methylene blue was among the first synthetic drugs aimed at a particular disease, chosen for a reason that could be stated in advance.

A note on the source

The page numbers of the original 1891 article differ between sources. The citation given in the Key Research Papers list below is the 1960 reprint of the paper in The Collected Papers of Paul Ehrlich, and it is labelled there as a reprint. Guttmann died two years after the report, in 1893.

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7. Methylene Blue Against Malaria into the First World War

News of the Berlin result travelled quickly. Physicians in Europe and the Americas tried methylene blue in their own malaria patients, and through the 1890s and 1900s it was used, in Lu and colleagues’ words, “during the late 19th and early 20th centuries against all types of malaria.” Their review tabulates the early reports. Among them is a series of seven patients published in the United States in 1892, in which four were recorded as cured and three as treatment failures. In 1904 an early analysis pooled 425 malaria cases from eleven publications and concluded that methylene blue had been effective in 85 percent of patients.

What patients noticed

The treatment was hard to miss. Methylene blue passes into the urine and turns it green-blue, and the historical reports describe that colour change in almost every patient. The other common complaints were urogenital irritation and, especially with higher doses, stomach upset. In the historical studies the dye was usually given by mouth, often in high doses and for long periods.

The First World War

During the First World War methylene blue was still being used for malaria among troops. Lu and colleagues, citing a 1920 letter in the Lancet by D. G. Marshall on its “toxicity,” report that some European soldiers received more than 400 grams of methylene blue over several weeks, without major side effects apart from moderate urogenital symptoms. The number is reported as a historical observation; it describes wartime practice, not a modern regimen.

Replaced but not forgotten

Quinine never disappeared, and methylene blue did not replace it. In the early twentieth century, according to Lu and colleagues, methylene blue “was gradually replaced by new synthetic antimalarials with different characteristics and finally without colouring properties.” A blue drug that stained the urine and irritated the bladder was not an easy sell to patients or armies. Its own successors, described in Section 9, were the reason it faded. Its return to malaria research in the 1990s and 2000s is covered on the page Methylene Blue Today.

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8. Selective Staining and the Idea of a Magic Bullet

For Ehrlich, the malaria result confirmed an idea he had been building since his student days: that a chemical can have a preference. A dye stains one cell and not its neighbour because it binds something chemically distinctive in that cell. If that binding could be made to happen with a poison, and only in the germ, the germ would die while the patient was spared. Ehrlich later called such a substance a Zauberkugel, a “magic bullet.”

In their 2008 tribute on the centenary of his Nobel Prize, Bosch and Rosich list among Ehrlich’s contributions to pharmacology the “magic bullet” concept, the terms chemoreceptor and chemotherapy, and the habit of linking the chemical structure of compounds to their effect in the body. They also credit him with a research system “based on the synthesis of multiple chemical structures for pharmacological screening in animal models of disease states,” a description that fits the modern drug laboratory as well as Ehrlich’s own. Strebhardt and Ullrich, writing in the same year, trace the targeted cancer drugs of the twenty-first century back to the same postulate.

From methylene blue to arsphenamine

Methylene blue was an early test of the magic-bullet approach in patients, but not its most famous success. That came in 1909–1910, when Ehrlich’s laboratory, after screening hundreds of arsenic compounds, introduced arsphenamine for syphilis (the full story is on the Paul Ehrlich page). A generation later, the sulfonamide story began with a red dye tested on infected mice, told on the Gerhard Domagk page. In both cases the starting point was the dye chemist’s catalogue, and the guiding idea was the one first tried with methylene blue: a molecule that seeks out its target.

The receptor idea

Travis, who is also Caro’s biographer, shows in his 2019 review how dye chemistry shaped Ehrlich’s thinking about the “side chains” of molecules, the attached groups of atoms that decide how a dye binds. Those side chains became, in Ehrlich’s hands, a model of immunity and then of drug action, and eventually the receptors on which twentieth-century drug design was built. The line runs from the stained nerve of 1886 to the receptor diagrams in a modern pharmacology textbook.

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9. The Lead Structure: Pamaquine, Chloroquine and the Phenothiazines

In drug research, a “lead structure” is a molecule that works well enough to be copied and changed until a better medicine emerges. Methylene blue became one of the first. Wainwright and Crossley summarise its place in history this way: methylene blue “formed the basis of antimicrobial chemotherapy—particularly in the area of antimalarials—and eventually led to the discovery of the neuroleptic drug families.”

The antimalarial line

Chemists in the German dye and drug industry took methylene blue as the starting point for a systematic programme of antimalarial testing of synthetic compounds. According to Lu and colleagues, “the first synthetic drug designed as an antimalarial, pamaquine, was derived from MB.” Pamaquine was followed by other synthetic antimalarials and, in time, by chloroquine. Krafts, Hempelmann and Skórska-Stania trace this whole line “from methylene blue to chloroquine” in their 2012 review, which they dedicate to Johann “Hans” Andersag, the chemist who developed chloroquine. Chloroquine went on to become one of the most widely used medicines of the twentieth century, until resistance in the parasite eroded it; the story of the drugs that followed, including artemisinin from sweet wormwood, is on the site’s antimalarial drugs page.

The phenothiazine line

The second line came from Bernthsen’s skeleton itself. Ohlow and Moosmann describe how phenothiazines, first used by Ehrlich as stains for malaria parasites, were exploited for their anti-worm and antibacterial properties in the 1930s and 1940s; how chemically modified phenothiazines then entered clinical use as antihistamines in the 1940s and as sedatives and antipsychotics in the 1950s; and how that use continues today. The best known of the antipsychotics is chlorpromazine. Kristiansen, in a 1989 review, follows the history of the phenothiazines “from methylene blue via chlorpromazine” to later derivatives, and relates it to Ehrlich’s receptor concept.

One blue dye, many descendants

Seen from a distance, the result is striking. A cotton dye made in a Rhineland laboratory in 1876 led, through a stained nerve, a stained parasite and two patients in a Berlin hospital, to two of the great drug families of the twentieth century: the synthetic antimalarials and the phenothiazine medicines of psychiatry and allergy. Methylene blue itself never left medicine. Its later life as an antidote for methaemoglobinaemia, and the modern research on mitochondria and the brain, are described on the site’s Methylene Blue page, its Ehrlich and phenothiazines history page, and the wing’s own Methylene Blue Today.

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Key Research Papers

  1. Wainwright M, Crossley KB. Methylene Blue--a therapeutic dye for all seasons? J Chemother. 2002;14(5):431-43. PubMed PMID: 12462423
  2. Bernthsen A. Studien in der Methylenblaugruppe. Justus Liebigs Annalen der Chemie. 1885;230(1):73-136. DOI: 10.1002/jlac.18852300106
  3. Ehrlich P. Ueber die Methylenblaureaction der lebenden Nervensubstanz. Deutsche Medizinische Wochenschrift. 1886;12(4):49-52. DOI: 10.1055/s-0028-1139684
  4. Ehrlich P, Leppmann A. Ueber schmerzstillende Wirkung des Methylenblau. Deutsche Medizinische Wochenschrift. 1890;16(23):493-494. DOI: 10.1055/s-0029-1209911
  5. Guttmann P, Ehrlich P. Über die Wirkung des Methylenblau bei Malaria. Reprinted in: The Collected Papers of Paul Ehrlich. Elsevier; 1960:9-14 (originally published in Berliner klinische Wochenschrift, 1891). DOI: 10.1016/b978-0-08-009056-6.50006-3
  6. Marshall DG. The “toxicity” of methylene-blue. Lancet. 1920;195(5051):1334. DOI: 10.1016/S0140-6736(00)92632-1
  7. Lu G, Nagbanshi M, Goldau N, Mendes Jorge M, Meissner P, Jahn A, Mockenhaupt FP, Müller O. Efficacy and safety of methylene blue in the treatment of malaria: a systematic review. BMC Med. 2018;16(1):59. PubMed PMID: 29690878
  8. Schirmer RH, Adler H, Pickhardt M, Mandelkow E. “Lest we forget you--methylene blue...”. Neurobiol Aging. 2011;32(12):2325.e7-16. PubMed PMID: 21316815
  9. Krafts K, Hempelmann E, Skórska-Stania A. From methylene blue to chloroquine: a brief review of the development of an antimalarial therapy. Parasitol Res. 2012;111(1):1-6. PubMed PMID: 22411634
  10. Ohlow MJ, Moosmann B. Phenothiazine: the seven lives of pharmacology’s first lead structure. Drug Discov Today. 2011;16(3-4):119-31. PubMed PMID: 21237283
  11. Kristiansen JE. Dyes, antipsychotic drugs, and antimicrobial activity. Fragments of a development, with special reference to the influence of Paul Ehrlich. Dan Med Bull. 1989;36(2):178-85. PubMed PMID: 2651032
  12. Bosch F, Rosich L. The contributions of Paul Ehrlich to pharmacology: a tribute on the occasion of the centenary of his Nobel Prize. Pharmacology. 2008;82(3):171-9. PubMed PMID: 18679046
  13. Strebhardt K, Ullrich A. Paul Ehrlich’s magic bullet concept: 100 years of progress. Nat Rev Cancer. 2008;8(6):473-80. PubMed PMID: 18469827
  14. Travis AS. Chemical Modeling: From Paul Ehrlich’s Dyes to β-Blockers-A Brief History. J Comput Biol. 2019;26(7):726-734. PubMed PMID: 31066580

PubMed Topic Searches

  1. PubMed: methylene blue history
  2. PubMed: methylene blue malaria
  3. PubMed: phenothiazine history
  4. PubMed: Paul Ehrlich magic bullet

Further Reading

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