How Victorian Dyes Evolved Into Modern Psychiatric Medicines
The colorful common ancestors of today's treatments.
Posted Aug 08, 2020
Modern antipsychotics, antidepressants, and tranquilizers seem like very different kinds of drugs, and of course in practice they are. Surprisingly, though, many of them stem from the same source—Victorian fabric dyes—which in turn resulted from a student’s spring break project which went awry. Here is the story; along the way, I’ll try to put into context the discoveries of these various medicines covered in earlier blogs.
William Henry Perkin, an 18-year-old student at the Royal College of Chemistry, had an ambitious goal for Easter vacation in 1856. Working in the attic of his home in East London, he was attempting to synthesize the antimalarial drug quinine. Instead, he got a dark gooey substance in the bottom of his glassware, usually not a very happy outcome.
But when he tried to clean it out with alcohol, it turned a bright purple color, and Perkin, with a background in photography and art, had the idea that it might be useful as a dye. He raised the idea with his professor, but was told that this was frivolous, and was urged to return to his regular work.
Undaunted, Perkin and friends set up a laboratory in his backyard. He applied the liquid, which he called aniline purple, to silk, and after further tests at a Scottish fabric works, patented his new dye and founded a company. Initially, the public was little interested, but after Queen Victoria wore a silk dress colored with aniline purple to the Great Exhibition of 1862, it became very popular.
Perkin had inadvertently founded the field of synthetic organic chemistry, and soon there were a number of companies using their new techniques to make dyes, and later cosmetics, paints, food colorings, explosives—and medicines. This was the beginning of the road that among other things, led to chlorpromazine (Thorazine) and many of the modern medicines used in psychiatry (1).
One of the results of the newly developing skills in organic chemistry was methylene blue, a phenothiazine compound synthesized in 1876 by Heinrich Caro, a calico printer and chemist who later was also one of the discoverers of indigo (as in blue jeans). There it might have remained, but for two events.
The first was that the German pharmacologist Paul Ehrlich was using it to stain bacteria, when in 1891 he realized that it immobilized the microscopic Plasmodium parasites which cause malaria. In a leap from the laboratory to the bedside, he gave it to malaria patients, who seemed to get better, and ultimately methylene blue became the world’s first fully synthetic drug, used widely to treat allied troops in World War II, until it was ultimately replaced by newer medicines.
The second discovery came from antihistamine research. After the success of diphenhydramine (now Benadryl and other brands) in 1945, chemists were looking for other antihistamines. Among them was Paul Charpentier at the Rhône-Poulenc company, who came up with the methylene blue derivative promazine. He sent some to Henri Laborit, a French surgeon who believed that decreasing histamine release might aid in preventing surgical shock. It turned out that it was such a success in sedating presurgical patients and complementing anesthetics that Laborit asked for others.
As it happened, Charpentier had been testing these same compounds as antimalarials. One of them—chlorpromazine—was ineffective for malaria, but had significant antihistaminic properties. He sent it on to Laborit, who noticed that it made patients seem more tranquil and to enter a state of "indifference." It was a natural jump to wonder if this might have psychiatric uses, and as they say, the rest is history. Chlorpromazine (Largactil) was released in France in 1952 and later in the U.S. with the brand name Thorazine. It revolutionized the care of psychotic patients, and led to an efflux of inpatients from institutions back into the communities, who were not always prepared to receive them.
In response to the success of chlorpromazine, other drug companies began studying variations on the molecule. As we described in another blog, researchers at the Geigy company sent one of the variants to Roland Kuhn, a Swiss psychiatrist, who gave it to schizophrenics without benefit, but who also had the idea of giving it to depressed patients, who responded. The result was imipramine (Tofranil), the first tricyclic antidepressant, released in Europe in 1957 and the U.S. in 1959.
The success of imipramine led other companies to make variations and test their properties in animals. One of them seemed to have behavioral effects more like chlorpromazine, but wasn’t as sedating and, interestingly, had seemed to make them more resistant to pain. This led to further testing as a new antipsychotic compound. Ironically, the finding about pain had been mistaken, due to faulty electrodes, but the end result was the marketing in 1989 of clozapine (Clozaril), which remains one of the most effective medicines for treatment-resistant schizophrenia.
As for benzodiazepines: the success of meprobamate (Miltown) as a tranquilizer in the early 1950s led other companies to search for new ones. Leo Sternbach, a chemist at Hoffman LaRoche, was working on alternative tranquilizing agents, but since competitors were already making variants on the meprobamate molecule, he was tasked with using completely different compounds. He fell back on a group of fabric dyes he had worked on years earlier during his training in Poland. He tried different ones, and later, in a story full of both chance events and perseverance, found that one of them, chlordiazepoxide, was a clinically useful tranquilizer (2). Marketed in 1960, it was the first of the benzodiazepines, which for many years were for the most widely used tranquilizers and sleeping pills.
The use of fabric dyes as medicines wasn’t confined to psychiatry. The dye prontosil red became the first sulfonamide antibiotic, which later was modified to make the tuberculosis drug isoniazid. (Later, iproniazid, a chemical cousin of isoniazid derived from a different source, became the first MAO inhibitor antidepressant.) A yellow acridine dye developed from methylene blue became the antimalarial quinacrine in 1931. It, in turn, was modified to make chloroquine (used widely since the late 1940s) and hydroxychloroquine (1955), treatments much in the news today in another context.
As for methylene blue, it is still with us. It is used to treat the blood illness methemoglobinemia, and is being studied as a possible treatment for Alzheimer’s disease.
These many different kinds of drugs, used in psychiatry and for infectious diseases, have something in common—they are all the outgrowth of synthetic organic chemistry, with roots in the mid-nineteenth century discovery of synthetic fabric dyes. And it all began with a student’s wayward chemistry project.
This post was excerpted and adapted from Molecules, Madness, and Malaria: How Victorian fabric dyes evolved into modern medicines for mental illness and infectious disease.
1. Mendelson, W.B.: Molecules, Madness, and Malaria: How Victorian fabric dyes evolved into modern medicines for mental illness and infectious disease. Pythagoras Press, 2020.
2. Mendelson, W.B.: The Curious History of Medicines in Psychiatry. Pythagoras Press, 2020.