Glutethimide

Glutethimide was developed Ciba Specialty Chemicals in 1954, and approved for medical use in the United States by the U.S. FDA in 1957. It was indicated for treating insomnia, and branded Doriden by Ciba. Generic trade names that followed included Elrodorm and Noxyrom.^[3] Following the passage of the Controlled Substances Act of 1970 in the U.S., followed by the creation of the U.S. Drug Enforcement Agency (DEA) in 1973, the "War on Drugs" began to prioritize the criminalization of combination drugs containing controlled substances.

The DEA declared glutethimide to be as habit-forming and addicting as barbiturates and other highly-regulated CNS depressants such as Quaalude and Placidyl. Abrupt cessation of this substance can result in rebound effects similar to those in withdrawal from any GABAergic substance, including alcohol, barbiturates and benzodiazepines.

The (R) isomer has a faster onset of action and more potent anticonvulsant activity in animal models than the (S) isomer.^[4]

The base catalyzed conjugate addition of 2-phenylbutyronitrile [769-68-6] (1) to ethyl acrylate (2) gives ethyl 4-cyano-4-phenylhexanoate, CID:139890735 (3). Alkaline hydrolysis of the nitrile group into an amide group, and subsequent acidic cyclization of the product affords the desired glutethimide (4).

Glutethimide is a CYP2D6 enzyme inducer, enabling the body to convert higher amounts of codeine to morphine, frequently leading to ingestion of glutethimide alongside codeine-containing products, such as Tylenol No. 3 or No. 4, and widespread misuse, overdose, and fatalities. Colloquially called "hits," "pancakes and syrup," or "Dors and 4s", this combination is highly potent and often lethal due to extreme respiratory depression.^[9][10]

In recreational quantities, any form of glutethimide was colloquially called a "Ciba" and all trade names of the medicine were manufactured as a white pill/tablet with a score line directed to be taken by mouth, and containing 500mg of the active ingredient.

During the 1980s, glutethimide became increasingly harder to access and subject to many restrictions as a CSA-classified Schedule II substance, but market demand for the product constinued to exist among northeastern U.S. states and metropolitan centers, leading to the substance's clandestine "underground" manufacturing and sale, which only increased when methaqualone was fully withdrawan from the U.S. market and classified a Schedule I drug.^[11]: 203

• Aminoglutethimide, close relative to this substance
• Piperidione
• Methyprylon, sometimes spelled methyprylone and branded as Noludar and Dimeran
• Pyrithyldione