Librium

The human search for a way to make the troubles of life more bearable has been a long one. Alcohol; opium; chloral hydrate; and, by the 1930s, barbiturates are chemicals that have been used as mood-altering drugs. These all have serious drawbacks, however, so the search for a perfect tranquilizer continues.

That search nearly came to a halt with the discovery of Librium. The first in a long line of psychotropic drugs called benzodiazepines, Librium--followed by its more effective cousin Valium and then dozens of analogs--has been described as a landmark in modern psychopharmacology. These compounds quickly became the most widely prescribed mood-altering drugs in history.

Librium's discovery was partly accidental. Leo Sternbach, a researcher in the New Jersey laboratory of Hoffmann-La Roche, had been looking for a new drug to replace the highly addictive barbiturates of the 1950s. He was testing derivatives of a class of compounds, benzoheptoxdiazines, which he had worked with years before. He discovered, however, that the compounds he was using had only six-membered rings, not seven-, and the 40 derivatives he made had no biological activity. He treated one derivative with methylamine and just stored the resulting white crystalline powder on a shelf.

A couple of years later, this compound--which might easily have been thrown out with the other useless compounds--was tested. It was chlordiazepoxide, and it was found to be biologically active and a strong central nervous system (CNS) depressant. The Food & Drug Administration approved chlordiazepoxide under the trade name Librium as a tranquilizer, finding it effective for relieving anxiety; treating insomnia, muscle spasms, and the symptoms of alcoholism; and preventing seizures.

Librium and Valium, which followed in 1963, were and continue to be extremely successful drugs. By the 1970s, Valium was the most highly prescribed pharmaceutical in the world. In 1987 alone, more than 2.8 billion Valium tablets were made. In 1981, Valium was succeeded by an even more effective benzodiazepine, Xanax, which also became a blockbuster product. Currently, scores of benzodiazepines are on the market, each prescribed for different conditions and in a variety of strengths.

Benzodiazepine's mechanism of action is not entirely understood. It apparently works by affecting the actions of the inhibitory neurotransmitter *-aminobutyric acid (GABA) in the brain. Benzodiazepines bind to a receptor near GABA binding sites, actually enhancing the affinity of these sites for GABA. Thus, brain activity is slowed as it releases fewer excitatory neurotransmitters, which results in the dampened emotions, relaxed muscles, and impaired memory seen with benzodiazepine use.

The great successes of Librium and its analogs were eroded by the emergence of some severe problems. The drugs quickly entered the recreational drug scene, and it is estimated that benzodiazepines may be abused by 90% of alcohol abusers and illicit drug users. One of the compounds, Rohypnol, considered about 10 times more potent than Valium as a CNS depressant, is known as the date-rape drug because of its association with that crime. Rohypnol is not sold or manufactured in the U.S., but it is available in other countries and is smuggled into the U.S. for illicit use.

But the main problem was that benzodiazepines were found to be addictive. Although the drugs are safe and effective for short-term relief of anxiety and other symptoms, extended use of the compounds results in increasing tolerance and strong physical dependence. It did not take many years before doctors discovered that these compounds, when discontinued, could cause dangerous withdrawal symptoms such as convulsions, tremors, abdominal and muscle cramps, vomiting, and sweating. So many people became addicted to these drugs that the problem appeared in novels, movies, jokes, and, eventually, congressional hearings.

Although Librium, Valium, and other benzodiazepines are still available, their popularity is greatly diminished. Only about 100 million prescriptions for benzodiazepines were written in 1999. They have been replaced in popularity by the newer selective serotonin reuptake inhibitor antidepressants such as Prozac. Still, benzodiazepines are effective drugs and will undoubtedly continue to be prescribed, carefully, for years to come.

Chlordiazepoxide Hydrochloride

Name
◾ 7-Chloro-N-methyl-5-phenyl-3H-1,4-benzodiazepin-2-amine 4-oxide hydrochloride

CAS Registry
◾ 438-41-5

Other Names
◾ Librium
◾ A-Poxide
◾ SK-Lygen

Introduced
1960, by Hoffmann-La Roche

Did you know that Librium and other benzodiazepines are the largest group of recreationally used drugs in the world?