Glutethimide

{{short description|Medication}} {{drugbox | Watchedfields = changed | verifiedrevid = 416746257 | IUPAC_name = 3-ethyl-3-phenyl-piperidine-2,6-dione | image = Glutethimide.svg | image_class = skin-invert-image | width = 150 | image2 = Glutethimide ball-and-stick model.png | image_class2 = bg-transparent | width2 = 180  | pronounce = {{IPAc-en|g|l|uː|ˈ|t|ɛ|θ|ɪ|ˌ|m|aɪ|d}}<br />{{respell|gloo|TE|thi|MYDE}} | tradename = Doriden, Elrodorm, Noxyron, others | Drugs.com = | pregnancy_category = C: (United States) | legal_status = | legal_AU = S8 | legal_BR = B1 | legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=Diário Oficial da União |language=pt-BR |publication-date=2023-04-04}}</ref> | legal_CA = Schedule IV | legal_US = Schedule II | legal_UK = Class B | legal_UN = P III | legal_DE = Anlage II | routes_of_administration = By mouth | dependency_liability = Moderate - high | bioavailability = Variable (T<sub>max</sub> = 1–6 hours)<ref>{{cite book|last1=Barceloux|first1=Donald G. | name-list-style = vanc |title=Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants|date=2012|publisher=John Wiley & Sons, Inc.|location=Hoboken, N.J.|isbn=978-0-471-72760-6|pages=492–493|oclc=814224300}}</ref> | protein_bound = ~50% | metabolism = Extensive hepatic | elimination_half-life = 8–12 hours | excretion = Renal | IUPHAR_ligand = 7192 | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 77-21-4 | ATC_prefix = N05 | ATC_suffix = CE01 | PubChem = 3487 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB01437 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 3367 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = C8I4BVN78E | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D00532 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 1102 | C = 13 | H = 15 | N = 1 | O = 2 | SMILES = O=C1NC(CCC1(CC)C2=CC=CC=C2)=O | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C13H15NO2/c1-2-13(10-6-4-3-5-7-10)9-8-11(15)14-12(13)16/h3-7H,2,8-9H2,1H3,(H,14,15,16) | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = JMBQKKAJIKAWKF-UHFFFAOYSA-N | density = | melting_point = 84 | solubility = 999 mg/L (30 °C/86 °F) }}

'''Glutethimide''' (brand names included '''Doriden''', '''Elrodorm''', and '''Noxyron''') is a central nervous system (CNS) depressant drug of the piperidine chemical class, one of many non-barbiturate, "barbiturate-like" GABAergic medications exhibiting general calming, relaxing, or "tranquilizing" properties in addition to relieving anxiety and promoting sleep. As such, "nerve pills" or "sleeping pills" were common vernacular descriptions of these types of medications.

thumb | left| alt=Doriden

==History== 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 '''Noxyron'''.<ref name = "US2673205">{{ cite patent | title = 3-Disubstituted Dioxopiperidines and the Manufacture thereof | country = US | number = 2673205 | status = patent | inventor = Hoffmann K, Tagmann E | assign1 = CIBA | gdate = 23 March 1954 }}</ref> 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.

==Chemical composition and synthesis== The (R) isomer has a faster onset of action and more potent anticonvulsant activity in animal models than the (S) isomer.<ref>{{cite journal | vauthors = Houlihan WJ, Bennett GB | title = Anti-Anxiety Agents, Anticonvulsants and Sedative-Hypnotics. | journal = Annual Reports in Medicinal Chemistry | date = January 1977 | volume = 12 | pages = 10–19 | publisher = Academic Press | doi=10.1016/S0065-7743(08)61540-7 }}</ref> [[File:Glutethimide synthesis.svg|class=skin-invert-image|500px|center|thumb|[https://pharmaceutical-substances.thieme.com/ps/search-results?docUri=KD-07-0034 Thieme] Synthesis:<ref> {{Cite journal | vauthors = Tagmann E, Sury E, Hoffmann K | title = Über Alkylenimin-Derivate. 2. Mitteilung | doi = 10.1002/hlca.19520350516 | journal = Helvetica Chimica Acta | volume = 35 | issue = 5 | pages = 1541–1548 | year = 1952 | bibcode = 1952HChAc..35.1541T }}</ref><ref>{{cite journal | vauthors = Salmon-Legagneur F, Neveu C | title = Sur Les Acides Alpha-Phenyl Alpha-Alcoyl (Ou Phenoalcoyl) Glutariques. | journal = Comptes Rendus Hebdomadaires des Séances de l'Académie des Sciences | date = January 1952 | volume = 234 | issue = 10 | pages = 1060–2}}</ref><ref>{{ cite journal | vauthors = Salmon-Legagneur F, Neveu C | title = Sur Les Acides Alpha-Phenyl Alpha-Alcoyl (Ou Phenoalcoyl) Glutariques | journal = Bull. Soc. Chim. France | year = 1953|page=70 }}</ref> Patent:<ref>{{cite patent | country = DE | status = patent | number = 950193 | invent1 = Hoffmann K Tagmann E | assign1 = CIBA | title = Verfahren zur Herstellung neuer Dioxopiperidine | gdate = 4 October 1956 }}</ref><ref name = "US2673205" />]]

The base catalyzed conjugate addition of 2-phenylbutyronitrile [769-68-6] ('''1''') to ethyl acrylate ('''2''') gives ethyl 4-cyano-4-phenylhexanoate, [https://pubchem.ncbi.nlm.nih.gov/compound/139890735 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''').

==Mechanism of action and uses== 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.<ref>{{cite journal | vauthors = Shamoian CA | title = Codeine and glutethimide. Euphoretic, addicting combination | journal = New York State Journal of Medicine | volume = 75 | issue = 1 | pages = 97–99 | date = 1975| pmid = 1053824 }}</ref><ref name="hav">{{cite journal | vauthors = Havier RG, Lin R | s2cid = 45780806 | title = Deaths as a result of a combination of codeine and glutethimide | journal = Journal of Forensic Sciences | volume = 30 | issue = 2 | pages = 563–6 | date = April 1985 | pmid = 3998703 | doi = 10.1520/JFS11840J }}</ref>

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 continued 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 withdrawn from the U.S. market and classified a Schedule I drug.<ref>{{cite book | first = Paul | last = Gahlinger | name-list-style = vanc | title = Illegal Drugs: A Complete Guide to Their History, Chemistry, Use, and Abuse | chapter = Methaqualone and Glutethimide |oclc=52269170|isbn=9780452285057| date = 2003 | publisher = Penguin }}</ref>{{rp|203}}

===Clinical research=== Glutethimide's effect on quickening the conversion of codeine to morphine was studied clinically, including some research in the 1970s in various countries. In these studies, it was used under carefully monitored circumstances as a form of oral opioid agonist substitution therapy, particularly as a ''Substitutionmittel''{{clarify|date=April 2025}} that may be a useful alternative to methadone.<ref>{{cite journal | vauthors = Popa D, Loghin F, Imre S, Curea E | title = The study of codeine-gluthetimide pharmacokinetic interaction in rats | journal = Journal of Pharmaceutical and Biomedical Analysis | volume = 32 | issue = 4–5 | pages = 867–77 | date = August 2003 | pmid = 12899973 | doi = 10.1016/s0731-7085(03)00189-4 }}</ref><ref>{{cite journal | vauthors = Khajawall AM, Sramek JJ, Simpson GM | title = 'Loads' alert | journal = The Western Journal of Medicine | volume = 137 | issue = 2 | pages = 166–8 | date = August 1982 | pmid = 7135952 | pmc = 1274052 }}</ref>

Glutethimide was available in the United States until 1993, when production ceased and it was withdrawn from the market. Since 2013, the U.S. DEA has limited annual production to three grams, equivalent to six Doriden tablets, suggesting that current use is limited to small-scale research.{{Citation needed|date=March 2025}}

==Legal status== ===United States=== Glutethimide is a Schedule II drug under the Convention on Psychotropic Substances.<ref>{{cite web |url= http://www.incb.org/pdf/e/list/green.pdf |publisher=International Narcotics Control Board |title=List of psychotropic substances under international control |url-status=dead |archive-url=https://web.archive.org/web/20120831222336/http://www.incb.org/pdf/e/list/green.pdf |archive-date=2012-08-31 }}</ref> 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,<ref>{{cite web | url = http://www.deadiversion.usdoj.gov/21cfr/cfr/1308/1308_12.htm | publisher = Drug Enforcement Administration | work = Title 21 Code of Federal Regulations | title = Section 1308.12 Schedules of Controlled Substances | access-date = 2011-10-07 | archive-date = 2015-08-04 | archive-url = https://web.archive.org/web/20150804042821/http://www.deadiversion.usdoj.gov/21cfr/cfr/1308/1308_12.htm | url-status = dead }}</ref> several years after it was discovered that misuse combined with codeine increased the effect of the codeine and deaths had resulted from the combination.<ref name="hav"/><ref>{{cite journal | vauthors = Feuer E, French J | title = Descriptive epidemiology of mortality in New Jersey due to combinations of codeine and glutethimide | journal = American Journal of Epidemiology | volume = 119 | issue = 2 | pages = 202–7 | date = February 1984 | pmid = 6695899 | doi = 10.1093/oxfordjournals.aje.a113738 }}</ref> It has a DEA ACSCN of 2550 and a 2013 production quota of 3 g.

== See also == *Aminoglutethimide, close relative to this substance *Piperidione *Methyprylon, sometimes spelled methyprylone and branded as Noludar and Dimeran *Pyrithyldione

== References == {{Reflist|2}}

Category:Abandoned drugs Category:CYP2D6 inducers Category:Sedatives Category:Piperidines Category:Glutarimides Category:GABAA receptor positive allosteric modulators