Chemistry:Etizolam

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Etizolam is a thienodiazepine derivative[1] which is a benzodiazepine analog.[2] The etizolam molecule differs from a benzodiazepine in that the benzene ring has been replaced by a thiophene ring and triazole ring has been fused, making the drug a thienotriazolodiazepine.[3][4]

Although a thienodiazepine, etizolam is clinically regarded as a benzodiazepine because of its mode of action via the benzodiazepine receptor and directly targeting GABAA allosteric modulator receptors.[1]

It possesses anxiolytic, amnesic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties.[5]

It was patented in 1972[6] and first approved for medical use in Japan in 1984.[7]

As of April 2021, the export of etizolam has been banned in India.[8]


Medical uses

  • Short-term treatment of insomnia.
  • Anxiety disorders such as OCD and generalized anxiety disorder, mostly as a short-term medication to be used purely on an at-need basis[9]

Side effects

Long term use may result in blepharospasms,[10] especially in women.[10] Doses of 4 mg or more may cause anterograde amnesia. In rare cases, erythema annulare centrifugum skin lesions have resulted.[11]

Tolerance, dependence and withdrawal

Abrupt or rapid discontinuation from etizolam, as with benzodiazepines, may result in the appearance of the benzodiazepine withdrawal syndrome, including rebound insomnia.[12] Neuroleptic malignant syndrome, a rare event in benzodiazepine withdrawal, has been documented in a case of abrupt withdrawal from etizolam.[13] This is particularly relevant given etizolam's short half-life relative to benzodiazepines such as diazepam resulting in a more rapid drug level decrease in blood plasma levels.[14]

In a study that compared the effectiveness of etizolam, alprazolam, and bromazepam for the treatment of generalized anxiety disorder, all three drugs retained their effectiveness over 2 weeks, but etizolam became more effective from 2 weeks to 4 weeks.[15] Administering .5 mg etizolam twice daily did not induce cognitive deficits over 3 weeks when compared to placebo.[16]

When multiple doses of etizolam, or lorazepam, were administered to rat neurons, lorazepam caused downregulation of alpha-1 benzodiazepine binding sites (tolerance/dependence), while etizolam caused an increase in alpha-2 benzodiazepine binding sites (reverse tolerance to anti-anxiety effects).[17] Tolerance to the anticonvulsant effects of lorazepam was observed, but no significant tolerance to the anticonvulsant effects of etizolam was observed.[17] Etizolam therefore has a reduced liability to induce tolerance, and dependence, compared with classic benzodiazepines.[17]

Etizolam may represent a possible anxiolytic of choice with reduced liability to produce tolerance and dependence after long-term treatment of anxiety and stress syndromes.[18]

Pharmacology

Etizolam pills

Etizolam, a thienodiazepine derivative, is absorbed fairly rapidly, with peak plasma levels achieved between 30 minutes and 2 hours. It has a mean elimination half-life of about 3.4 hours.[19][20][21] Etizolam possesses potent hypnotic properties,[22] and is comparable with other short-acting benzodiazepines.[19] Etizolam acts as a positive allosteric modulator of the GABAA receptor by agonizing the receptor's benzodiazepine site.[23]

According to the Italian prescribing information sheet, etizolam belongs to a new class of diazepines, thienotriazolodiazepines. This new class is easily oxidized, rapidly metabolized, and has a lower risk of accumulation, even after prolonged treatment. Etizolam has an anxiolytic action about 6-8 times greater than that of diazepam. Etizolam produces, especially at higher dosages, a reduction in time taken to fall asleep, an increase in total sleep time, and a reduction in the number of awakenings. During tests, there were no substantial changes in deep sleep; however, it may reduce REM sleep. In EEG tests of healthy volunteers, etizolam showed some similar characteristics to tricyclic antidepressants.[24][25]

Etizolam's main metabolites in humans are alpha-hydroxyetizolam and 8-hydroxyetizolam. alpha-Hydroxyetizolam is pharmacologically active and has a half-life of approximately 8.2 hours.[26]

Interactions

Itraconazole and fluvoxamine slow down the rate of elimination of etizolam, leading to accumulation of etizolam, therefore increasing its pharmacological effects.[27][28] Carbamazepine speeds up the metabolism of etizolam, resulting in reduced pharmacological effects.[29]

Overdose

See also: Medicine:Benzodiazepine overdose

Cases of intentional suicide by overdose using etizolam in combination with GABA agonists have been reported.[26][30] Etizolam has a lower LD50 than certain benzodiazepines. Flumazenil, a GABA antagonist agent used to reverse benzodiazepine overdoses, inhibits the effect of etizolam as well as classical benzodiazepines such as diazepam and chlordiazepoxide.[31]

Etizolam overdose deaths are rising in Scotland, especially among women - for instance, the National Records of Scotland report on drug-related deaths have, "have increased significantly in Scotland in recent years, with a much greater percentage increase in deaths among women than among men". By 2018, 1,187 overdoses were officially recorded, a 107% increase from 2008, this means that this has been the highest peak to date. Although, men still outnumber women in drug-related deaths.[32]

Society and culture

Brand names

Etilaam, Sedekopan, Etizest, Etizex, Pasaden or Depas

International drug control conventions

In 1990, it was recommended that Etizolam not be placed under international control.[33] However, this attitude has changed due to increased abuse. On December 13, 2019, the World Health Organization recommended Etizolam be placed in Schedule 4 of the 1971 Convention on Psychotropic Substances.[34] This recommendation was followed by the placement of Etizolam into Schedule IV in March 2020.[35]

Australia

Etizolam is not used medically in Australia but has been found in counterfeit Xanax pills.[36]

Denmark

Etizolam is controlled in Denmark under the Danish Misuse of Drugs Act.[37]

Germany

Etizolam was controlled in Germany in July 2013[38][39] but is not used medically.

Italy

Etizolam is licensed for the treatment of anxiety, insomnia and neurosis as a prescription-only medication.[40][41]

India

In India, it is a Narcotics prescription-only (NRx) medication used for anxiety disorders, sometimes in combination with other drugs, i.e. the beta blocker propranolol.

United Kingdom

In the UK, etizolam has been classified as a Class C drug by the May 2017 amendment to The Misuse of Drugs Act 1971 along with several other designer benzodiazepine drugs.[42]

United States

Etizolam is not authorized by the FDA for medical use in the U.S. As of March 2016, etizolam is a controlled substance in the following states: Alabama,[43] Arkansas,[44] Florida,[45] Georgia (as Schedule IV, whereas all other states listed here prohibit it as a Schedule I substance), Louisiana, Mississippi,[46] Texas,[47] South Carolina,[48] and Virginia.[49] It is controlled in Indiana as of July 1, 2017.[50] It is controlled in Ohio as of February 2018.

On December 23, 2022, the DEA announced it had begun consideration on the matter of placing Etizolam under temporary Schedule I status.[51]

Later on July 25, 2023, the DEA published a pre-print notice that Etizolam would become temporarily scheduled as a Schedule I controlled substance from 26 July 2023 to 26 July 2025.[52] On July 25, 2025, and effective the following day, the DEA extended the temporary scheduling until July 26, 2026.[53]

Misuse

Etizolam is a drug of potential misuse. Cases of etizolam dependence have been documented in the medical literature.[54] Since 1991, cases of etizolam misuse and addiction have substantially increased,[55] due to varying levels of accessibility and cultural popularity.[56] Pills being sold as Xanax or other benzodiazepines that are illicitly manufactured may often contain etizolam rather than their listed ingredient[57][36]

See also

References

  1. ↑ 1.0 1.1 "Molecular and neurochemical evaluation of the effects of etizolam on GABAA receptors under normal and stress conditions". Arzneimittel-Forschung 49 (2): 88–95. February 1999. doi:10.1055/s-0031-1300366. PMID 10083975. 
  2. ↑ "Experimental versus theoretical log D7.4, pKa and plasma protein binding values for benzodiazepines appearing as new psychoactive substances". Drug Testing and Analysis 10 (8): 1258–1269. March 2018. doi:10.1002/dta.2387. PMID 29582576. https://pure.hud.ac.uk/ws/files/13273614/logDpKaPPB_13thMar2018.pdf. 
  3. ↑ "Contribution of human hepatic cytochrome p450 isoforms to the metabolism of psychotropic drugs". Biological & Pharmaceutical Bulletin 28 (9): 1711–6. September 2005. doi:10.1248/bpb.28.1711. PMID 16141545. 
  4. ↑ "Separation of 1,4-Benzodiazepines and Analogues Using Cholesteryl-10-Undecenoate Bonded Phase in Microcolumn Liquid Chromatography". Journal of Chromatographic Science 36 (3): 111–118. 1 March 1998. doi:10.1093/chromsci/36.3.111. 
  5. ↑ "Benzodiazepine metabolism: an analytical perspective". Current Drug Metabolism 9 (8): 827–844. October 2008. doi:10.2174/138920008786049258. PMID 18855614. https://zenodo.org/record/1067769. 
  6. ↑ "Triazolothienodiazepine compounds" US patent 3904641
  7. ↑ Yamawaki, Shigeto (December 1999). "The use and development of anxiolytics in Japan". European Neuropsychopharmacology 9: S413–S419. 2000-04-25. doi:10.1016/s0924-977x(99)00053-x. ISSN 0924-977X. PMID 10622688. http://dx.doi.org/10.1016/s0924-977x(99)00053-x. 
  8. ↑ "EGazette Home". 2021-03-21. http://egazette.nic.in/WriteReadData/2021/226041.pdf. 
  9. ↑ "Effects of different cyclodextrins on the morphology, loading and release properties of poly (DL-lactide-co-glycolide)-microparticles containing the hypnotic agent etizolam". Journal of Microencapsulation 24 (3): 214–24. May 2007. doi:10.1080/02652040601058152. PMID 17454433. 
  10. ↑ 10.0 10.1 "Etizolam and benzodiazepine induced blepharospasm". Journal of Neurology, Neurosurgery, and Psychiatry 75 (3): 506–507. March 2004. doi:10.1136/jnnp.2003.019869. PMID 14966178. 
  11. ↑ "Etizolam-induced superficial erythema annulare centrifugum". Clinical and Experimental Dermatology 27 (1): 34–6. January 2002. doi:10.1046/j.0307-6938.2001.00943.x. PMID 11952667. 
  12. ↑ "Rebound insomnia induced by abrupt withdrawal of hypnotics in sleep-disturbed rats". European Journal of Pharmacology 597 (1–3): 46–50. November 2008. doi:10.1016/j.ejphar.2008.08.024. PMID 18789918. 
  13. ↑ "[A patient with Parkinson's disease complicated by hypothyroidism who developed malignant syndrome after discontinuation of etizolam"] (in ja). Rinsho Shinkeigaku = Clinical Neurology 42 (2): 136–9. February 2002. PMID 12424963. https://www.neurology-jp.org/Journal/cgi-bin/journal.cgi?lg=jp&pg=smry&vl=42&no=2&tp=136. 
  14. ↑ "Elimination half-life of drugs: value and limitations". Annual Review of Medicine 36 (1): 421–7. February 1985. doi:10.1146/annurev.me.36.020185.002225. PMID 3994325. 
  15. ↑ "Etizolam in the treatment of generalized anxiety disorder: a controlled clinical trial". The Journal of International Medical Research 17 (5): 455–60. 25 June 2016. doi:10.1177/030006058901700507. PMID 2572494. 
  16. ↑ "Effects of treatment with etizolam 0.5 mg BID on cognitive performance: a 3-week, multicenter, randomized, double-blind, placebo-controlled, two-treatment, three-period, noninferiority crossover study in patients with anxiety disorder". Clinical Therapeutics 31 (12): 2851–9. December 2009. doi:10.1016/j.clinthera.2009.12.010. PMID 20110024. 
  17. ↑ 17.0 17.1 17.2 "Low tolerance and dependence liabilities of etizolam: molecular, functional, and pharmacological correlates". European Journal of Pharmacology 519 (1–2): 31–42. September 2005. doi:10.1016/j.ejphar.2005.06.047. PMID 16107249. 
  18. ↑ "Low tolerance and dependence liabilities of etizolam: molecular, functional, and pharmacological correlates". European Journal of Pharmacology 519 (1–2): 31–42. September 2005. doi:10.1016/j.ejphar.2005.06.047. PMID 16107249. 
  19. ↑ 19.0 19.1 Cite error: Invalid <ref> tag; no text was provided for refs named auto1
  20. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named auto
  21. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named DEADiv-etiz-factsheet
  22. ↑ "Effects of thienodiazepine derivatives, etizolam and clotiazepam on the appearance of Fm theta". The Japanese Journal of Psychiatry and Neurology 46 (4): 927–31. December 1992. doi:10.1111/j.1440-1819.1992.tb02862.x. PMID 1363923. 
  23. ↑ "Effects of benzodiazepines and non-benzodiazepine compounds on the GABA-induced response in frog isolated sensory neurones". British Journal of Pharmacology 98 (3): 735–40. November 1989. doi:10.1111/j.1476-5381.1989.tb14600.x. PMID 2574062. 
  24. ↑ "Depas". http://www.carloanibaldi.com/terapia/schede/DEPAS.htm. 
  25. ↑ "Etizolam" (in en). PubChem. U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/compound/3307. 
  26. ↑ 26.0 26.1 "Case report: Etizolam and its major metabolites in two unnatural death cases". Forensic Science International 182 (1–3): e1-6. November 2008. doi:10.1016/j.forsciint.2008.08.012. PMID 18976871. 
  27. ↑ "Inhibition of the metabolism of etizolam by itraconazole in humans: evidence for the involvement of CYP3A4 in etizolam metabolism". European Journal of Clinical Pharmacology 60 (6): 427–30. August 2004. doi:10.1007/s00228-004-0789-1. PMID 15232663. 
  28. ↑ "Effects of concomitant fluvoxamine on the plasma concentration of etizolam in Japanese psychiatric patients: wide interindividual variation in the drug interaction". Therapeutic Drug Monitoring 26 (6): 638–42. December 2004. doi:10.1097/00007691-200412000-00009. PMID 15570188. 
  29. ↑ "Induction of the metabolism of etizolam by carbamazepine in humans". European Journal of Clinical Pharmacology 61 (3): 185–8. May 2005. doi:10.1007/s00228-005-0904-y. PMID 15776275. 
  30. ↑ "Blood concentrations of new designer benzodiazepines in forensic cases". Forensic Science International 268: 35–38. November 2016. doi:10.1016/j.forsciint.2016.09.006. PMID 27685473. 
  31. ↑ "Effects of several benzodiazepines, alone and in combination with flumazenil, in rhesus monkeys trained to discriminate pentobarbital from saline". Psychopharmacology 122 (3): 230–6. December 1995. doi:10.1007/bf02246544. PMID 8748392. 
  32. ↑ Tweed, E. J., Miller, R. G., Schofield, J., Barnsdale, L., & Matheson, C. (2020). Why are drug-related deaths among women increasing in Scotland? A mixed-methods analysis of possible explanations. Drugs: Education, Prevention and Policy, 29(1), 62–75. https://doi.org/10.1080/09687637.2020.1856786
  33. ↑ "Expert Committee on Drug Dependence's Twenty Seventh Report". September 28, 1990. https://apps.who.int/iris/bitstream/handle/10665/40616/WHO_TRS_808.pdf?sequence=1&isAllowed=y. 
  34. ↑ "Letter of WHO Director-General to UN Secretary-General dated November 15th 2019". https://www.who.int/medicines/access/controlled-substances/UNSG_letter_42ECDD_recommendations_15Nov19.pdf. 
  35. ↑ "News: Recently scheduled benzodiazepines Flualprazolam and Etizolam associated with multiple post-mortem and DUID cases in UNODC EWA". United Nations Office on Drugs and Crime. March 2020. https://www.unodc.org/LSS/Announcement/Details/ad0c279b-b4d4-49f3-b638-cd87755d2d42. 
  36. ↑ 36.0 36.1 "Warnings over counterfeit benzodiazepines". https://www.health.nsw.gov.au/news/Pages/20191212_02.aspx. 
  37. ↑ "Bekendtgørelse om euforiserende stoffer" (in da). https://www.retsinformation.dk/Forms/R0710.aspx?id=137169. 
  38. ↑ "Verordnungsentwurf der Bundesregierung" (in de). Bundesministerium für Gesundheit (Federal Ministry of Health). http://www.bundesgesundheitsministerium.de/fileadmin/dateien/Downloads/B/Betaeubungsmittelgesetz/27_BtMAEndV.pdf. 
  39. ↑ "Gesetz über den Verkehr mit Betäubungsmitteln" (in de). Bundesministerium der Justiz und für Verbraucherschutz (Federal Ministry of Justice and Consumer Protection). http://www.gesetze-im-internet.de/btmg_1981/index.html. 
  40. ↑ "DEPAS - Etizolam". 2017-08-31. https://www.codifa.it/farmaci/d/depas-etizolam-ansiolitici-benzodiazepinici. 
  41. ↑ PubChem. "Etizolam" (in en). https://pubchem.ncbi.nlm.nih.gov/compound/3307. 
  42. ↑ "The Misuse of Drugs Act 1971 (Amendment) Order 2017". http://www.legislation.gov.uk/uksi/2017/634/contents/made. 
  43. ↑ "Alabama Code Title 20. Food, Drugs, and Cosmetics § 20-2-23". https://codes.findlaw.com/al/title-20-food-drugs-and-cosmetics/al-code-sect-20-2-23.html. 
  44. ↑ "List of Controlled Substances". State of Arkansas. http://www.healthy.arkansas.gov/aboutadh/rulesregs/controlled_substances_list.pdf. 
  45. ↑ "Statutes & Constitution: Online Sunshine". http://www.leg.state.fl.us/Statutes/index.cfm?App_mode=Display_Statute&URL=0800-0899/0893/Sections/0893.03.html. 
  46. ↑ "HB1231 (As Sent to Governor) - 2014 Regular Session". http://billstatus.ls.state.ms.us/documents/2014/html/HB/1200-1299/HB1231SG.htm. 
  47. ↑ "Health and Safety Code Chapter 481. Texas Controlled Substances Act". https://statutes.capitol.texas.gov/Docs/HS/htm/HS.481.htm. 
  48. ↑ "Controlled Substance Schedule | SCDHEC". https://www.scdhec.gov/health-regulation/drug-control-register-verify/controlled-substance-schedule. 
  49. ↑ "18VAC110-20-322. Placement of Chemicals in Schedule I" (in en). Commonwealth of Virginia. 2 December 2015. http://law.lis.virginia.gov/admincode/title18/agency110/chapter20/section322/. 
  50. ↑ "Ellington's bill banning two deadly drugs could soon be law - State of Indiana House of Representatives". http://www.indianahouserepublicans.com/news/press-releases/ellington-s-bill-banning-two-deadly-drugs-could-soon-be-law/. 
  51. ↑ "(Proposed Rule) Schedules of Controlled Substances: Temporary Placement of Etizolam, Flualprazolam, Clonazolam, Flubromazolam, and Diclazepam in Schedule I". DEA. December 23, 2022. https://www.federalregister.gov/documents/2022/12/23/2022-27278/schedules-of-controlled-substances-temporary-placement-of-etizolam-flualprazolam-clonazolam. 
  52. ↑ "Schedules of Controlled Substances: Temporary Placement of Etizolam, Flualprazolam, Clonazolam, Flubromazolam, and Diclazepam in Schedule I". DEA. July 25, 2023. https://public-inspection.federalregister.gov/2023-15748.pdf. 
  53. ↑ "Schedules of Controlled Substances: Extension of Temporary Placement of Clonazolam, Diclazepam, Etizolam, Flualprazolam, and Flubromazolam in Schedule I of the Controlled Substances Act" (in en). 2025-07-25. https://www.federalregister.gov/documents/2025/07/25/2025-14037/schedules-of-controlled-substances-extension-of-temporary-placement-of-clonazolam-diclazepam. 
  54. ↑ "A case of etizolam dependence". Indian Journal of Pharmacology 46 (6): 655–6. 2014. doi:10.4103/0253-7613.144943. PMID 25538342. 
  55. ↑ "How to tackle Dundee's fake valium epidemic". BBC News. 20 April 2018. https://www.bbc.com/news/uk-scotland-43822454. 
  56. ↑ "Novel psychoactive substances: understanding the new illegal drug market". https://www.pharmaceutical-journal.com/opinion/insight/novel-psychoactive-substances-understanding-the-new-illegal-drug-market/20205503.article. 
  57. ↑ "Drug Data Xanax". https://www.ecstasydata.org/results.php?start=0&search_field=all&s=xanax. 



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