Meprobamate

Meprobamate—marketed as Miltown by Wallace Laboratories and Equanil by Wyeth, among others—is a carbamate derivative used as an anxiolytic drug. It was the best-selling minor tranquilizer for a time, but has largely been replaced by the benzodiazepines due to their wider therapeutic index (lower risk of toxicity at therapeutically prescribed doses) and lower incidence of serious side effects.

History Frank Berger was working in a laboratory of a British drug company, looking for a preservative for penicillin, when he noticed that a compound called mephenesin (or myanesin) calmed laboratory rodents without actually sedating them. Berger subsequently referred to this “tranquilizing” effect in a now-historic article, published by the British Journal of Pharmacology in 1946. However, three major drawbacks existed to the use of mephenesin as a tranquilizer: a very short duration of action, greater effect on the spinal cord than on the brain (resulting in a very low therapeutic index), and a weak activity.

In May 1950, after moving to Carter Products in New Jersey, Berger and a chemist, Bernard John Ludwig, synthesized a chemically related tranquilizing compound, meprobamate, that overcame these three drawbacks. Wallace Laboratories, a subsidiary of Carter Products, bought the license and named their new product "Miltown" after the borough of Milltown, New Jersey. Launched in 1955, it rapidly became the first blockbuster psychotropic drug in American history, becoming popular in Hollywood and gaining fame for its seemingly miraculous effects. It has since been marketed under more than 100 trade names, from Amepromat through Quivet to Zirpon. A December 1955 study of 101 patients at the Mississippi State Hospital in Whitfield, Rankin County, Mississippi, found meprobamate useful in the alleviation of "mental symptoms": 3% of patients made a complete recovery, 29% were greatly improved, 50% were somewhat better, while 18% realized little change. Self-destructive patients became cooperative and calmer, and experienced a resumption of logical thinking. In 50% of the cases, relaxation brought about more favorable sleep habits. Following the trial, hydrotherapy and all types of shock treatment were subsequently halted. Meprobamate was found to help in the treatment of alcoholics by 1956. By 1957, over 36 million prescriptions had been filled for meprobamate in the US alone, a billion pills had been manufactured, and it accounted for fully a third of all prescriptions written. Berger, clinical director of Wallace Laboratories, described it as a relaxant of the central nervous system, whereas other tranquilizers suppressed it. A University of Michigan study found that meprobamate affected driving skills. Though patients reported being able to relax more easily, meprobamate did not completely alleviate their tense feelings. The disclosures came at a special scientific meeting at the Barbizon Plaza Hotel in New York City, at which Aldous Huxley addressed an evening session. He predicted the development of many chemicals "capable of changing the quality of human consciousness", in the next few years. Meprobamate was one of the first drugs to be widely advertised to the general public, with user Milton Berle promoting the drug heavily on his television show, calling himself 'Uncle Miltown'. Miltown soon became ubiquitous in 1950s American life, with 1 in 20 Americans having used it by late 1956, and popular comedians making as many jokes about the drug as they did about Elvis Presley. In January 1960, Carter Products, Inc. and American Home Products Corporation (which marketed meprobamate as Equanil) were charged with having conspired to monopolize the market in mild tranquilizers. It was revealed that the sale of meprobamate earned $40,000,000 for the defendants. Of this amount, American Home Products accounted for about two-thirds and Carter about one-third. The U.S. government sought an order mandating that Carter make its meprobamate patent available at no charge to any company desiring to use it. In April 1965, meprobamate was removed from the list of tranquilizers when experts ruled that the drug was a sedative, instead. The U.S. Pharmacopoeia published the ruling. At the same time, the Medical Letter disclosed that meprobamate could be addictive at doses not much above recommended. In December 1967, meprobamate was placed under abuse control amendments to the Food, Drug and Cosmetic Act. Records on production and distribution were required to be kept. Limits were placed on prescription duration and refills. On January 19, 2012, the European Medicines Agency withdrew marketing authorization in the European Union for all medicines containing meprobamate, "due to serious side effects seen with the medicine." The Agency's Committee for Medicinal Products for Human Use "concluded that the benefits of meprobamate do not outweigh its risks." In October 2013, Canada also withdrew marketing authorization.

Pharmacology Although it was marketed as being safer, meprobamate has most of the pharmacological effects and dangers of barbiturates and acts at the barbiturate binding site (though it is less sedating at effective doses). It is reported to have some anticonvulsant properties against absence seizures, but can exacerbate generalized tonic-clonic seizures. Meprobamate's mechanism of action is not completely known. It has been shown in animal studies to have effects at multiple sites in the central nervous system, including the thalamus and limbic system. Meprobamate binds to GABAA receptors which interrupts neuronal communication in the reticular formation and spinal cord, causing sedation and altered perception of pain. Meprobamate has the ability to activate currents even in the absence of GABA. This relatively unique property makes meprobamate exceptionally dangerous when used in combination with other GABA-mediated drugs (including alcohol). It is also a potent adenosine reuptake inhibitor. Related drugs include carisoprodol and tybamate (prodrugs of meprobamate), phenprobamate, felbamate, mebutamate, and methocarbamol.

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