# Glutethimide

Glutethimide (brand name Doriden) is a sedative-hypnotic medication introduced by Ciba Specialty Chemicals in 1954, initially thought to be a safer alternative to barbiturates in the treatment of insomnia, but soon found to have a similar dependency liability as barbiturates and similar depressants (e.g. methaqualone [Quaalude]); cessation of glutethimide use presents with symptoms similar to barbiturate withdrawal.
Doriden was manufactured as a scored, white tablet dosed at 500 mg. Commercial production of glutethimide was discontinued in 1993, and in Hungary in 2006. Since 2013, the United States Drug Enforcement Administration has limited annual production of the substance to three grams (equivalent to six Doriden tablets), suggesting current usage is limited small-scale research.

## Mechanism of Action

Glutethimide is a CYP2D6 enzyme inducer, therefore enabling the body to convert higher amounts of codeine to morphine.

## Usage
### Long-term Prescription

Following long-term use, cessation of glutethimide can produce rebound effects resembling those seen in barbiturate withdrawal; anecdotally, patients consistently taking stable doses of the drug long-term have reported symptoms including delirium, hallucinosis, convulsions and fever.

### Recreational Use

Glutethimide is a CYP2D6 enzyme inducer and was often recreationally, taken alongside codeine – a combination referred to on the streets as "hits", "Cibas and codeine", and "Dors and Fours" (as in "Doriden with Tylenol 4) – as it enables the body to convert higher amounts of the codeine to morphine. In conjunction with glutethimide's inherent sedative properties, this was a highly potent and often fatal combination.
The demand for this combination in Philadelphia and Pittsburgh, PA; Newark, New Jersey; New York City; Boston, MA; and Baltimore, MD led to small-scale clandestine synthesis of glutethimide since 1984,$^{:203}$ a process that is difficult and potentially explosive relative synthesizing similar depressants like ethchlorvynol, methyprylon, or barbiturates.

### Clinical Use and Research

Glutethimide's effect on quickening the transition of codeine to morphine was used and studied clinically, including some research in the 1970s in various countries of using it under carefully monitored circumstances as a form of oral opioid agonist substitution therapy, e.g. as a Substitutionmittel that may be a useful alternative to methadone.

## Discontinuation

Commercial production of glutethimide was discontinued in the U.S. in 1993 and in several eastern European countries, notably Hungary, in 2006. Analysis of confiscated glutethimide seems to invariably show the drug or the results of attempted synthesis, as opposed to being "laced" with similar depressants.

## Legal status
### United States

Glutethimide is a Schedule II drug under the Convention on Psychotropic Substances. It was originally a Schedule III drug in the United States under the Controlled Substances Act, but in 1991 it was upgraded to Schedule II, several years after it was discovered that misuse combined with codeine increased the effect of the codeine and deaths had resulted from the combination. It has a DEA ACSCN of 2550 and a 2013 production quota of 3 g.

## Synthesis

The (R) isomer has a faster onset and more potent anticonvulsant activity in animal models than the (S) isomer.
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).