Heinrich Caro and Paul Guttmann: Methylene Blue, from Textile Dye to the First Synthetic Antimalarial

In 1876 a German dye chemist named Heinrich Caro (1834–1910), working at a dye works in Ludwigshafen on the Rhine, made a clean, bright blue dye for cotton out of coal-tar chemicals. It was called methylene blue. Fifteen years later, in 1891, the Berlin physician Paul Guttmann (1834–1893; some sources give 1833) and the younger Paul Ehrlich gave the same dye to two patients with malaria at the Moabit municipal hospital, and both recovered. Historians of medicine often describe methylene blue as the first synthetic drug used against a specific disease, and a 2018 systematic review calls it the first synthetic antimalarial.

The two men were born in the same year in Prussia’s eastern provinces, but as far as the record shows they never worked together: Ehrlich, who had spent years staining cells and tissues with the new aniline dyes, is the bridge between the chemist and the clinician. This wing tells their two stories, the chain of discovery that turned a textile colour into a medicine, the chemistry behind the dye and its later career as an antidote, and what modern research and safety studies have found. Methylene blue is the one medicine in this series with no plant or mould behind it; its “natural” story is the contrast with cinchona bark and quinine, the plant medicine it was measured against.

Table of Contents

  1. Deep-Dive Articles
  2. 1. Who They Were
  3. 2. The Discovery on One Page
  4. 3. A Coal-Tar Medicine in a World of Plant Remedies
  5. 4. The Chemistry and the Antidote Years
  6. 5. Timeline at a Glance
  7. 6. Later Significance and Safety Findings
  8. Key Research Papers
  9. Connections

Deep-Dive Articles

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Heinrich Caro and Paul Guttmann: Two Lives Behind Methylene Blue

The Posen-born dyer-chemist who led one of the first industrial research laboratories, and the Ratibor-born physician who ran Berlin’s Moabit hospital — two biographies side by side.

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

From the 1876 synthesis and Ehrlich’s nerve staining to the 1891 Moabit malaria report and the line of drugs that grew from the dye’s structure.

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The Science of Methylene Blue: Coal Tar, Redox Chemistry and the Antidote Years

The blue and colourless forms of the dye, why it reverses methaemoglobinaemia, and Matilda Moldenhauer Brooks’s 1930s cyanide and carbon monoxide studies.

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Methylene Blue Today: Mitochondria, Brain Research and Safety Findings

Modern malaria trials, mitochondrial and brain-imaging research, the negative Alzheimer’s trial, mood-disorder studies, and the serotonin and G6PD safety findings.

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1. Who They Were

Heinrich Caro was born in Posen, Prussia (today Poznań, Poland) in February 1834, into a family of Sephardic Jewish origin. He trained as a dyer and textile colourist at the Gewerbeinstitut (Royal Trades Institute) in Berlin while attending chemistry lectures at the university. In 1859 he went to Manchester as analytical chemist to a dye-making firm, where he improved the production of William Perkin’s mauve, the first aniline dye, and became a partner. He returned to Germany in 1866, and on 1 November 1868 he joined the Badische Anilin- & Soda-Fabrik in Ludwigshafen as head of research — what the Dictionary of Scientific Biography calls “probably the first true industrial research organization.” Dyes credited to him include induline, alizarin (patented with Carl Graebe and Carl Liebermann, 1869–70), eosin and methylene blue; peroxymonosulfuric acid is still called “Caro’s acid.” He moved to the company’s supervisory board in 1889 and died in Dresden in 1910.

Paul Guttmann was born in Ratibor, Prussian Silesia (today Racibórz, Poland); Wikipedia gives 9 September 1834, while the 1906 Jewish Encyclopedia gives 1833. He studied medicine in Berlin, Würzburg and Vienna, took his MD in 1858, worked as an assistant to the psychiatrist Wilhelm Griesinger, and became a Privatdozent at the University of Berlin in 1867. In 1879 he succeeded Heinrich Curschmann as director of the Moabit municipal hospital. He wrote a widely translated textbook of clinical examination (1884; in English, A Handbook of Physical Diagnosis), co-wrote a book on the sympathetic nervous system with Albert Eulenburg, edited the Journal für praktische Aerzte from 1885, and died in Berlin on 24 May 1893.

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2. The Discovery on One Page

Caro made methylene blue in 1876 while experimenting with a new chemical intermediate; he was looking for a dye, not a drug. His employer received a German patent for it in 1877. In 1885 the chemist August Bernthsen published the structural studies that showed what the molecule was — the same Bernthsen who later wrote Caro’s long memorial biography in 1912.

The medical story began with Paul Ehrlich. In 1886 he reported that methylene blue, injected into a living animal, picked out living nerve tissue and coloured it blue while leaving most other tissue pale. In 1890 he and A. Leppmann reported that the dye had a pain-relieving effect. Ehrlich had also used methylene blue to stain malaria parasites in blood, and the parasites took up the dye strongly. If a dye could single out a parasite, he reasoned, perhaps it could also harm it.

In 1891 Guttmann and Ehrlich published “Über die Wirkung des Methylenblau bei Malaria” (On the action of methylene blue in malaria) in the Berliner klinische Wochenschrift. Two patients with malaria at Moabit were treated with methylene blue and both were cured; the paper was later reprinted in Ehrlich’s collected papers. According to a 2018 systematic review, methylene blue went on to be used against all types of malaria during the late nineteenth and early twentieth centuries, and in the First World War some soldiers received large amounts over several weeks, with mainly urogenital side effects. Historians also trace to this selective staining the seed of Ehrlich’s later “magic bullet” idea: a chemical that finds and harms only the cause of a disease.

The full chain is told in From Dye to Drug.

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3. A Coal-Tar Medicine in a World of Plant Remedies

Most of the early medicines in this series came from a plant or a mould — willow bark, foxglove, opium, the cinchona tree. Methylene blue did not. It is a synthetic thiazine dye built from aniline-type chemicals distilled from coal tar, the black by-product of gas-making that fed the new dye industry of the 1850s and 1860s.

The natural thread runs around it rather than through it. The dye chemists of Caro’s generation were trying to replace natural colours with synthetic ones: alizarin, which Caro helped bring to industry, is the red colour of madder root, and indigo, whose long industrial synthesis Caro directed until he left the research post, came from the indigo plant. In medicine, the standard malaria remedy of the time was quinine, an alkaloid from the bark of the South American cinchona tree. Methylene blue was the first synthetic challenger to that plant medicine, and the later synthetic antimalarials — pamaquine and, in time, chloroquine — were built partly on the chemical lessons it taught. In the 1970s, about eighty years after the Moabit report, a plant came back to the front of malaria treatment with artemisinin from sweet wormwood, described on the site’s Tu Youyou wing.

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4. The Chemistry and the Antidote Years

Methylene blue exists in two forms. The oxidised form is deep blue; when it accepts electrons it becomes the colourless leucomethylene blue, and it can give those electrons up again. This easy back-and-forth (a redox couple) is the key to most of its medical uses. Inside red blood cells, the colourless form can hand electrons to methaemoglobin — haemoglobin whose iron has been oxidised so that it can no longer carry oxygen — and turn it back into working haemoglobin. That is why a 2021 review describes methylene blue as best known as an antidote for acquired methaemoglobinaemia, and why a New York City poison centre reported improvement in 98% of 185 treated cases over twenty-four years, with adverse effects in 4.9%.

In 1932 and 1933 Matilda Moldenhauer Brooks, a physiologist at the University of California, Berkeley, reported that methylene blue protected animals against cyanide and carbon monoxide poisoning, and proposed it as an antidote; her reports set off a lively exchange in the medical and scientific journals of the 1930s. The cyanide use later faded, and a 2018 study revisiting it in rats concluded that the dye’s protective effect works through its redox properties rather than through the mechanism proposed in the 1930s. One well-known visible sign of the dye in the body is that it turns the urine blue or green.

The details are in The Science of Methylene Blue, and the clinical side is covered on the site’s methaemoglobinaemia and G6PD page.

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5. Timeline at a Glance

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6. Later Significance and Safety Findings

Methylene blue’s chemical skeleton, the phenothiazine ring, has been called pharmacology’s first lead structure. Reviews trace from it not only the synthetic antimalarials but also, through the 1940s and 1950s, phenothiazine antihistamines, sedatives and antipsychotics such as chlorpromazine — a line of work connected to the site’s Daniel Bovet wing. The dye-to-drug idea also ran forward to Gerhard Domagk’s sulfonamides of the 1930s.

The dye itself has returned to research again and again. Trials in Burkina Faso tested it as a partner drug against falciparum malaria and found a strong effect on gametocytes, the parasite stage that infects mosquitoes. Laboratory work describes it as an electron cycler in the mitochondrial respiratory chain with a hormetic dose response (opposite effects at low and high doses), and a 2016 randomised fMRI study in 26 healthy adults reported increased brain responses and a 7% rise in correct memory-retrieval answers after a low oral dose. A 2016 phase 3 trial of a related compound in 891 people with mild to moderate Alzheimer’s disease, by contrast, found no benefit in its primary analysis.

Two safety findings stand out. Methylene blue is a potent reversible inhibitor of monoamine oxidase A, which explains reports of serotonin toxicity when it is given to people taking serotonergic antidepressants; a fatal case was reported in 2014. And in a pooled analysis of four trials in 1,005 West African children, those with full G6PD deficiency showed a small drop in haemoglobin, with two episodes of haemolysis; the authors judged this of limited clinical relevance but called for monitoring. These findings are set out in Methylene Blue Today and on the site’s drug interactions and serotonin syndrome page.

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Key Research Papers

  1. Guttmann P, Ehrlich P. Über die Wirkung des Methylenblau bei Malaria. In: The Collected Papers of Paul Ehrlich. Elsevier; 1960:9-14. (Reprint of the 1891 Berliner klinische Wochenschrift paper.) DOI: 10.1016/b978-0-08-009056-6.50006-3
  2. Ehrlich P. Ueber die Methylenblaureaction der lebenden Nervensubstanz. Deutsche Medizinische Wochenschrift. 1886;12(4):49-52. DOI: 10.1055/s-0028-1139684
  3. Bernthsen A. Heinrich Caro. Berichte der deutschen chemischen Gesellschaft. 1912;45(2):1987-2042. DOI: 10.1002/cber.19120450278
  4. 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
  5. Wainwright M, Crossley KB. Methylene Blue--a therapeutic dye for all seasons? J Chemother. 2002;14(5):431-43. PubMed PMID: 12462423
  6. 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
  7. 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
  8. 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
  9. Brooks MM. Methylene blue as antidote for cyanide and carbon monoxide poisoning. JAMA. 1933;100(1):59. DOI: 10.1001/jama.1933.02740010061028
  10. Rothenberg R, Biary R, Hoffman RS. Effectiveness and tolerability of methylthioninium chloride (methylene blue) for the treatment of methemoglobinemia: twenty-four years of experience at a single poison center. Clin Toxicol (Phila). 2025;63(4):284-291. PubMed PMID: 40062661
  11. Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity: inhibition of monoamine oxidase A (MAO A) confirms a theoretical prediction. Br J Pharmacol. 2007;152(6):946-51. PubMed PMID: 17721552
  12. Müller O, Mockenhaupt FP, Marks B, Meissner P, Coulibaly B, Kuhnert R, Buchner H, Schirmer RH, Walter-Sack I, Sié A, Mansmann U. Haemolysis risk in methylene blue treatment of G6PD-sufficient and G6PD-deficient West-African children with uncomplicated falciparum malaria: a synopsis of four RCTs. Pharmacoepidemiol Drug Saf. 2013;22(4):376-85. PubMed PMID: 23135803
  13. Gauthier S, Feldman HH, Schneider LS, Wilcock GK, Frisoni GB, Hardlund JH, Moebius HJ, Bentham P, Kook KA, Wischik DJ, Schelter BO, Davis CS, Staff RT, Bracoud L, Shamsi K, Storey JM, Harrington CR, Wischik CM. Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer’s disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial. Lancet. 2016;388(10062):2873-2884. PubMed PMID: 27863809

PubMed Topic Searches

  1. Methylene blue history
  2. Methylene blue and malaria
  3. Methylene blue and methemoglobinemia
  4. Methylene blue and cyanide
  5. Methylene blue and serotonin toxicity

Further Reading

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Connections