Librium, Valium and the benzodiazepines

Through the 1950s anxiety was treated with meprobamate and with barbiturates such as phenobarbital. The margin between a useful dose and a dangerous one was narrow, and overdoses brought heavy sedation, coma, respiratory failure and sometimes death.

Leo Sternbach, a chemist at Hoffmann-La Roche in Nutley, New Jersey, had made a family of compounds in the early 1930s as a postgraduate in Cracow, looking for synthetic dyes. In 1954, drawn by the success of chlorpromazine and early reports on meprobamate, he went back to them in search of drugs for the mind and made about 40. Every one tested proved inert. He treated one with methylamine instead, labeled it Ro 5-0690 and put it on the shelf untested. In 1957 it turned up during a laboratory cleanup and was sent for testing, which showed effects like those of meprobamate. Its structure proved to be a 1,4-benzodiazepine. It entered clinical use in 1960 as chlordiazepoxide, sold as Librium.

Diazepam, first synthesized in 1959, reached the market as Valium in 1963. It was more potent and also treated epilepsy, muscle spasm and alcohol withdrawal. From 1968 to 1982 it was the top-selling drug in the United States, with a peak of 2.3 billion tablets sold in 1978. The benzodiazepines bind their own site on the GABA-A receptor and strengthen the receptor's response to the transmitter GABA.

Serious or fatal reactions to diazepam alone proved rare; most followed combination with other drugs such as opioids or alcohol. Long use, though, brought tolerance, dependence and withdrawal, and stopping high doses abruptly could cause seizures, psychosis and death. Calcaterra and Barrow trace the misuse of the 1970s to early, overly optimistic views of diazepam's safety that led to prescribing where no drug was needed. Diazepam is a Schedule IV controlled substance in the United States.

In September 2020 the FDA required an updated boxed warning for every benzodiazepine, covering abuse, addiction, physical dependence and withdrawal reactions. The agency noted that dependence can develop after several days to weeks of steady use, even as prescribed. In 2019 about 92 million benzodiazepine prescriptions were dispensed from US outpatient pharmacies, alprazolam most often.