Glutethimide

Glutethimide is a synthetic central nervous system depressant belonging to the piperidine chemical class. It is one of several non-barbiturate, barbiturate-like medications that exert their effects through γ-aminobutyric acid (GABA)–mediated pathways. Clinically, glutethimide was used primarily as a hypnotic for the treatment of insomnia and possessed additional anxiolytic and general tranquillising properties. During the mid-twentieth century, drugs of this type were commonly referred to in everyday language as “sleeping pills” or “nerve pills”.
Glutethimide was marketed under several brand names, most notably Doriden, as well as Elrodorm and Noxyrom. Although initially regarded as a safer alternative to barbiturates, its high abuse potential, risk of dependence, and involvement in fatal drug combinations ultimately led to its withdrawal from medical use.

History and Development

Glutethimide was developed in 1954 by Ciba Specialty Chemicals during a period of intensive pharmaceutical research aimed at producing non-barbiturate sedative–hypnotics. It was approved for medical use in the United States by the Food and Drug Administration (FDA) in 1957 and introduced under the brand name Doriden. The drug was indicated primarily for short-term management of insomnia.
In the decades following its introduction, glutethimide gained popularity as a prescription hypnotic, particularly in patients who were considered unsuitable for barbiturate therapy. However, by the late 1960s and early 1970s, growing evidence of misuse, tolerance, and dependence began to mirror the concerns already associated with barbiturates.
The passage of the Controlled Substances Act (CSA) of 1970 and the establishment of the Drug Enforcement Administration (DEA) in 1973 marked a shift in regulatory attitudes toward sedative–hypnotics. Glutethimide was recognised as having abuse and dependence potential comparable to barbiturates and other highly regulated depressants such as methaqualone and ethchlorvynol. Abrupt discontinuation was found to produce withdrawal symptoms similar to those seen with other GABAergic substances, including alcohol, barbiturates, and benzodiazepines.

Chemical Composition and Stereochemistry

Glutethimide is a piperidine-derived compound that exists as a pair of optical isomers. The R-isomer has been shown in animal models to exhibit a faster onset of action and greater anticonvulsant potency than the S-isomer. Commercial pharmaceutical preparations contained the racemic mixture.
The compound’s sedative–hypnotic properties arise from its ability to modulate inhibitory neurotransmission in the central nervous system, producing dose-dependent sedation, hypnosis, and respiratory depression.

Synthesis and Patenting

The synthesis of glutethimide was described in mid-twentieth-century pharmaceutical patents. A key step involves the base-catalysed conjugate addition of 2-phenylbutyronitrile to ethyl acrylate, yielding an intermediate ethyl cyanoester. Subsequent alkaline hydrolysis converts the nitrile group into an amide, followed by acidic cyclisation to form the glutethimide ring structure.
This synthetic pathway was protected under US patents filed during the 1950s, reflecting the commercial importance of the compound at the time.

Mechanism of Action and Pharmacology

Glutethimide exerts its pharmacological effects primarily through GABAergic mechanisms, enhancing inhibitory neurotransmission within the brain. Although structurally distinct from barbiturates, its functional effects are broadly similar, including sedation, hypnosis, anxiolysis, and at higher doses, profound central nervous system and respiratory depression.
A distinctive and clinically significant property of glutethimide is its role as an enzyme inducer, particularly of cytochrome P450 2D6 (CYP2D6). This induction accelerates the metabolic conversion of codeine into morphine, substantially increasing opioid potency in individuals taking both substances.
This interaction led to widespread misuse, especially in combination with codeine-containing analgesics. The resulting drug mixtures were known colloquially by names such as “Dors and 4s”, “hits”, “pancakes and syrup”, reflecting combinations of Doriden tablets with codeine preparations. These combinations were extremely dangerous and frequently fatal due to synergistic respiratory depression.

Patterns of Misuse and Decline

By the late 1970s and 1980s, glutethimide had become increasingly difficult to obtain legally due to tighter prescribing controls and its classification under the CSA. Nevertheless, demand persisted in certain regions of the United States, particularly in large metropolitan areas. This demand contributed to clandestine synthesis and diversion, a trend that intensified after methaqualone was withdrawn from the US market and reclassified as a Schedule I substance.
In recreational contexts, glutethimide tablets were often referred to simply as “Cibas”, a reference to the original manufacturer. Standard tablets were white, scored, intended for oral use, and typically contained 500 mg of active ingredient.

Clinical Research and Experimental Uses

During the 1970s, glutethimide was investigated in clinical research settings for its potential role in opioid agonist substitution therapy. Because of its ability to enhance the conversion of codeine to morphine, it was studied under carefully controlled conditions as an experimental alternative to methadone in certain contexts, particularly in parts of Europe. These studies were limited and did not result in widespread clinical adoption.

Withdrawal from the Market

Glutethimide remained available by prescription in the United States until 1993, when production ceased and the drug was formally withdrawn from the market. Concerns over safety, abuse, and the availability of safer hypnotic agents, such as benzodiazepines and later non-benzodiazepine “Z-drugs”, contributed to its discontinuation.
Since 2013, the DEA has permitted only extremely limited annual production, amounting to approximately three grams per year, equivalent to six Doriden tablets. This quota suggests that glutethimide is now restricted to small-scale laboratory or research use rather than clinical application.

Legal Status

Under international drug control frameworks, glutethimide is classified as a Schedule II substance under the Convention on Psychotropic Substances. In the United States, it was originally placed in Schedule III of the Controlled Substances Act but was reclassified to Schedule II in 1991 following evidence of severe misuse and fatal interactions with opioids.
The drug has a designated DEA Administrative Controlled Substances Code Number (ACSCN) of 2550, reflecting its continued regulatory oversight despite the absence of routine medical use.