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Benzodiazepines: The Accidental Tranquilizers

How unsuccessful fabric dyes grew into one of the first medical blockbusters.

Benzodiazepines became one of the first blockbuster commercial drugs in the 1960s, and their use is remarkably persistent; approximately 1 in 8 adults in the U.S. consume them annually. Where did they come from? Like many of the psychiatric medicines developed in the 1950s and 1960s, their heritage is from the synthetic dye industry. Their discoverer was a remarkable individual named Leo Sternbach.

Sternbach (1908-2005) was the son of a pharmacist, born in what is now Croatia. After a number of moves due to the hard times after World War I, the family settled in Krakow, Poland. There he enrolled in the University of Krakow, which was closed to Jews, but which made an exception because his father had become a prominent pharmacist before the closing. He earned his Ph.D. in organic chemistry and taught there, and later moved to Switzerland in 1940, where he went to work for the Hoffmann-La Roche company in Basel. In 1941, when Germany invaded Greece and Yugoslavia and the situation felt more insecure in Switzerland, the company moved its headquarters to the U.S. Using travel documents provided by Roche, Sternbach and his wife escaped through France and Portugal, settling near the company’s laboratories in Nutley, New Jersey. He was known as a good chemist, but his habit of criticizing his bosses led him to be passed from one group to another. Fortunately, early on he found the first commercially successful method for synthesizing biotin (vitamin B7), which was included in multivitamin products. The discovery was also valuable for Sternbach politically; it secured his place while he lobbied to have more freedom in his work.

At the time, the success of the tranquilizer meprobamate (Miltown) in 1953 led Sternbach’s superiors at the Hoffman LaRoche laboratories to ask him to work on developing new drugs to reduce anxiety. Since several companies were working with small alterations on the meprobamate molecule, his task was to find an entirely new approach. In choosing his starting materials, he recalled that during his training in Krakow in the 1930s, he had studied azo dyes and derivatives, a family of compounds going back to the mid-nineteenth century dye industry. The particular ones Sternbach had examined (which were then called 4,5-benzo-[hept-1,2,6-oxdiazines]) had not been found to have good prospects as commercial dyes, and the work had been discontinued; in retrospect, though, he realized that they might be good building blocks in his new work. He proceeded to synthesize about 40 variations on these molecules, but on animal testing most did not appear to have the profile of tranquilizers. His boss began to feel that this would not be a fruitful project and reassigned him to work on antibiotics.

That would have been the end of the story, but later, in 1957, one of his assistants was cleaning out old unused bottles and found one which apparently was the 40th untested compound from his previous work. He asked Sternbach if it was OK to toss it out. Instead, Sternbach, who had been told to do other work, asked his colleagues to do animal testing on this one last sample. When the skeptical pharmacologists did so, it turned out to have sedative and muscle relaxant effects, and to differ from chlorpromazine, as it did not significantly alter autonomic nervous system function.

Testing in larger animals showed that chlordiazepoxide decreased aggression. Studies from the San Diego Zoo described combative monkeys who became docile, and a bellicose lynx who became playful as a pussycat. A well-known collage released by the company shows a 40-pound lynx with a ferocious expression in one frame, and in the next docilely sniffing a flower. The first study in humans involved high doses and made patients dizzy, with slurred speech. Roche interested Irvin Cohen, a private psychiatrist in Galveston, Texas, to use lower doses in outpatients, and he and two others reported success in decreasing anxiety, improving sleep, and giving a sense of well-being. As time went on, thousands of patients were studied in formal clinical trials.

Sternbach re-evaluated the chemistry of the compound, chlordiazepoxide, and determined that it was in a family known as benzodiazepines, which as the name suggests, were formed from the combination of a benzene ring with a diazepine nucleus. It was marketed in 1960 as Librium (as in ‘Equilibrium’) and was followed a few years later by Valium (in which the ‘Val’ came from the Latin valere, to be strong). He continued to develop new variations, and tested some on himself. On one notable occasion, a new prospective drug left him bed-ridden for two days, evoking in his wife "a little scare." His work produced seven more benzodiazepines, and ultimately about a dozen were marketed by various companies for use as tranquilizers, sleeping agents, muscle relaxants, anticonvulsants, and sedatives during procedures such as colonoscopy and mechanical ventilation. Their success was phenomenal, and by 1977 they were the most widely prescribed drugs in the world.

 Wikimedia Commons
Leo Sternbach’s fame spread back to his hometown in Opatija, Croatia, where this graffiti picture of him appeared in 2019.
Source: Wikimedia Commons

Much of the initial popularity of benzodiazepines came from the perception that they were much safer than the then-dominant barbiturates. With time, though, their many limitations also became apparent. Their potential for abuse became evident, and they were classified as Drug Enforcement Administration Schedule IV controlled substances. Reports came out of impaired driving, as well as confusional states in the elderly. Some data suggested an association of long-term use with the later development of dementia, though some other work did not. In 2016, the FDA issued a ‘black box’ warning of their potentially lethal effects when combined with opiates. For these reasons, treatment shifted to the newer selective serotonin reuptake inhibitors (SSRIs) for anxiety and the "Z drugs" such as zolpidem for sleep. But the story of the benzodiazepines began with a persistent chemist finding a new use for azo dyes.

As for Sternbach, he continued a productive career, developing other kinds of drugs as well, including ones to treat high blood pressure, and to minimize bleeding during brain surgery, ultimately holding 241 patents. Even though his discoveries led to 40 percent of the company’s sales at one point, he never became wealthy, earning one dollar per discovery, the fee paid to him for turning over the patent rights to his employers. But this never seemed to be his goal, which was freedom to pursue studies in medicinal chemistry. Even after his retirement in 1973, he worked as a consultant, coming to the office almost every day until two years before his death at the age of 97.

This blog is excerpted and adapted from The Curious History of Medicines in Psychiatry.


Wallace B. Mendelson: Molecules, Madness, and Malaria: How Victorian fabric dyes evolved into modern medicines for mental illness and infectious disease. Pythagoras Press, New York, 2020.

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