Etizolam

Last updated

Etizolam
Etizolam.svg
Etizolam-from-xtal-3D-bs-17.png
Clinical data
Trade names Etizest, Etilaam, Etizex, Depas, Sedekopan, Pasaden
Dependence
liability 		Moderate
Routes of
administration 		Oral, sublingual, rectal
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 93%
Metabolism Hepatic
Elimination half-life 3.4 hours [2] [3] (main metabolite is 8.2 hours) [4]
Duration of action 5-7 hours
Excretion Kidney
Identifiers
  • 4-(2-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.188.773 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C17H15ClN4S
Molar mass 342.85 g·mol−1
3D model (JSmol)
  • ClC1=CC=CC=C1C2=NCC3=NN=C(C)N3C4=C2C=C(CC)S4
  • InChI=1S/C17H15ClN4S/c1-3-11-8-13-16(12-6-4-5-7-14(12)18)19-9-15-21-20-10(2)22(15)17(13)23-11/h4-8H,3,9H2,1-2H3 Yes check.svgY
  • Key:VMZUTJCNQWMAGF-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)
Etizolam powder. Pictured is roughly 150 mg; a standard dose is around 1 mg PureEtizolam.jpg
Etizolam powder. Pictured is roughly 150 mg; a standard dose is around 1 mg
Etizex brand etizolam tablets Etizex brand etizolam tablets.jpg
Etizex brand etizolam tablets

Etizolam (marketed under numerous brand names) is a thienodiazepine derivative [5] which is a benzodiazepine analog. [6] The etizolam molecule differs from a benzodiazepine in that the benzene ring has been replaced by a thiophene ring and triazole ring has been fused, making the drug a thienotriazolodiazepine. [7] [8]

Contents

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. [5]

It possesses anxiolytic, amnesic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. [9]

It was patented in 1972 [10] and first approved for medical use in Japan in 1984. [11]

As of April 2021, the export of etizolam has been banned in India. [12]

Medical uses

Side effects

Long term use may result in blepharospasms, [14] especially in women. [14] Doses of 4 mg or more may cause anterograde amnesia.[ citation needed ]

In rare cases, erythema annulare centrifugum skin lesions have resulted. [15]

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. [16] Neuroleptic malignant syndrome, a rare event in benzodiazepine withdrawal, has been documented in a case of abrupt withdrawal from etizolam. [17] 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. [18]

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. [19] Administering .5 mg etizolam twice daily did not induce cognitive deficits over 3 weeks when compared to placebo. [20]

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). [21] Tolerance to the anticonvulsant effects of lorazepam was observed, but no significant tolerance to the anticonvulsant effects of etizolam was observed. [21] Etizolam therefore has a reduced liability to induce tolerance, and dependence, compared with classic benzodiazepines. [21]

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. [22]

Pharmacology

Etizolam pills Etizolam.jpg
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. [4] [2] [3] Etizolam possesses potent hypnotic properties, [23] and is comparable with other short-acting benzodiazepines. [4] Etizolam acts as a positive allosteric modulator of the GABAA receptor by agonizing the receptor's benzodiazepine site. [24]

According to the Italian prescribing information sheet,[ citation needed ] 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. [25] [26]

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. [27]

Interactions

Itraconazole and fluvoxamine slow down the rate of elimination of etizolam, leading to accumulation of etizolam, therefore increasing its pharmacological effects. [28] [29] Carbamazepine speeds up the metabolism of etizolam, resulting in reduced pharmacological effects. [30]

Overdose

Cases of intentional suicide by overdose using etizolam in combination with GABA agonists have been reported. [27] [31] Although etizolam has a lower LD50 than certain benzodiazepines, the LD50 is still far beyond the prescribed or recommended dose. 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. [32]

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. [33]

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. [34] 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. [35] This recommendation was followed by the placement of Etizolam into Schedule IV in March 2020. [36]

Australia

Etizolam is not used medically in Australia but has been found in counterfeit Xanax pills. [37]

Denmark

Etizolam is controlled in Denmark under the Danish Misuse of Drugs Act. [38]

Germany

Etizolam was controlled in Germany in July 2013 [39] [40] but is not used medically.

Italy

Etizolam is licensed for the treatment of anxiety, insomnia and neurosis as a prescription-only medication. [41] [42]

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. [43]

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, [44] Arkansas, [45] Florida, [46] Georgia (as Schedule IV, whereas all other states listed here prohibit it as a Schedule I substance), Louisiana, Mississippi, [47] Texas, [48] South Carolina, [49] and Virginia. [50] It is controlled in Indiana as of July 1, 2017. [51] 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. [52]

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. [53] On July 25, 2025, and effective the following day, the DEA extended the temporary scheduling until July 26, 2026. [54]

Misuse

Etizolam is a drug of potential misuse. Cases of etizolam dependence have been documented in the medical literature. [55] Since 1991, cases of etizolam misuse and addiction have substantially increased, [56] due to varying levels of accessibility and cultural popularity. [57] Pills being sold as Xanax or other benzodiazepines that are illicitly manufactured may often contain etizolam rather than their listed ingredient [58] [37]

See also

References

  1. ↑ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  2. 1 2 "Etizolam". www.drugbank.ca. Retrieved 2020-09-03.
  3. 1 2 "Drug & Chemical Evaluation - Etizolam" (PDF). U.S. Drug Enforcement Administration. U.S. Department of Justice. March 2020. Archived (PDF) from the original on 2020-09-03.
  4. 1 2 3 Fracasso C, Confalonieri S, Garattini S, Caccia S (1991-02-01). "Single and multiple dose pharmacokinetics of etizolam in healthy subjects". European Journal of Clinical Pharmacology. 40 (2): 181–185. doi:10.1007/BF00280074. PMID   2065698. S2CID   10176681.
  5. 1 2 Sanna E, Pau D, Tuveri F, Massa F, Maciocco E, Acquas C, et al. (February 1999). "Molecular and neurochemical evaluation of the effects of etizolam on GABAA receptors under normal and stress conditions". Arzneimittel-Forschung. 49 (2): 88–95. doi:10.1055/s-0031-1300366. PMID   10083975. S2CID   19732765.
  6. ↑ Manchester KR, Maskell PD, Waters L (March 2018). "Experimental versus theoretical log D7.4, pKa and plasma protein binding values for benzodiazepines appearing as new psychoactive substances" (PDF). Drug Testing and Analysis. 10 (8): 1258–1269. doi:10.1002/dta.2387. PMID   29582576. S2CID   31098917.
  7. ↑ Niwa T, Shiraga T, Ishii I, Kagayama A, Takagi A (September 2005). "Contribution of human hepatic cytochrome p450 isoforms to the metabolism of psychotropic drugs". Biological & Pharmaceutical Bulletin. 28 (9): 1711–6. doi: 10.1248/bpb.28.1711 . PMID   16141545.
  8. ↑ Catabay A, Taniguchi M, Jinno K, Pesek JJ, Williamsen E (1 March 1998). "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. doi: 10.1093/chromsci/36.3.111 .
  9. ↑ Mandrioli R, Mercolini L, Raggi MA (October 2008). "Benzodiazepine metabolism: an analytical perspective". Current Drug Metabolism. 9 (8): 827–844. doi:10.2174/138920008786049258. PMID   18855614.
  10. ↑ US 3904641,"Triazolothienodiazepine compounds"
  11. ↑ Yamawaki S (December 1999). "The use and development of anxiolytics in Japan" . European Neuropsychopharmacology. 9 (published 2000-04-25): S413 –S419. doi:10.1016/s0924-977x(99)00053-x. ISSN   0924-977X. PMID   10622688 – via Elsevier Science Direct.
  12. ↑ "EGazette Home" (PDF). The Gazette of India. 2021-03-21. Archived from the original (PDF) on 2022-10-10.
  13. ↑ Lopedota A, Cutrignelli A, Trapani A, Boghetich G, Denora N, Laquintana V, et al. (May 2007). "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. doi:10.1080/02652040601058152. PMID   17454433. S2CID   31434550.
  14. 1 2 Wakakura M, Tsubouchi T, Inouye J (March 2004). "Etizolam and benzodiazepine induced blepharospasm". Journal of Neurology, Neurosurgery, and Psychiatry. 75 (3): 506–507. doi:10.1136/jnnp.2003.019869. PMC   1738986 . PMID   14966178.
  15. ↑ Kuroda K, Yabunami H, Hisanaga Y (January 2002). "Etizolam-induced superficial erythema annulare centrifugum". Clinical and Experimental Dermatology. 27 (1): 34–6. doi:10.1046/j.0307-6938.2001.00943.x. PMID   11952667. S2CID   36251540.
  16. ↑ Hirase M, Ishida T, Kamei C (November 2008). "Rebound insomnia induced by abrupt withdrawal of hypnotics in sleep-disturbed rats". European Journal of Pharmacology. 597 (1–3): 46–50. doi:10.1016/j.ejphar.2008.08.024. PMID   18789918.
  17. ↑ Kawajiri M, Ohyagi Y, Furuya H, Araki T, Inoue N, Esaki S, et al. (February 2002). "[A patient with Parkinson's disease complicated by hypothyroidism who developed malignant syndrome after discontinuation of etizolam]" [A patient with Parkinson's disease complicated by hypothyroidism who developed malignant syndrome after discontinuation of etizolam]. Rinsho Shinkeigaku = Clinical Neurology (in Japanese). 42 (2): 136–9. PMID   12424963.
  18. ↑ Greenblatt DJ (February 1985). "Elimination half-life of drugs: value and limitations". Annual Review of Medicine. 36 (1): 421–7. doi:10.1146/annurev.me.36.020185.002225. PMID   3994325.
  19. ↑ Bertolino A, Mastucci E, Porro V, Corfiati L, Palermo M, Ecari U, Ceccarelli G (25 June 2016). "Etizolam in the treatment of generalized anxiety disorder: a controlled clinical trial". The Journal of International Medical Research. 17 (5): 455–60. doi:10.1177/030006058901700507. PMID   2572494. S2CID   43179840.
  20. ↑ De Candia MP, Di Sciascio G, Durbano F, Mencacci C, Rubiera M, Aguglia E, et al. (December 2009). "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. doi:10.1016/j.clinthera.2009.12.010. PMID   20110024.
  21. 1 2 3 Sanna E, Busonero F, Talani G, Mostallino MC, Mura ML, Pisu MG, et al. (September 2005). "Low tolerance and dependence liabilities of etizolam: molecular, functional, and pharmacological correlates". European Journal of Pharmacology. 519 (1–2): 31–42. doi:10.1016/j.ejphar.2005.06.047. PMID   16107249.
  22. ↑ Sanna E, Busonero F, Talani G, Mostallino MC, Mura ML, Pisu MG, et al. (September 2005). "Low tolerance and dependence liabilities of etizolam: molecular, functional, and pharmacological correlates". European Journal of Pharmacology. 519 (1–2): 31–42. doi:10.1016/j.ejphar.2005.06.047. PMID   16107249.
  23. ↑ Nakamura J, Mukasa H (December 1992). "Effects of thienodiazepine derivatives, etizolam and clotiazepam on the appearance of Fm theta". The Japanese Journal of Psychiatry and Neurology. 46 (4): 927–31. doi:10.1111/j.1440-1819.1992.tb02862.x. PMID   1363923. S2CID   11263866.
  24. ↑ Yakushiji T, Fukuda T, Oyama Y, Akaike N (November 1989). "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. doi:10.1111/j.1476-5381.1989.tb14600.x. PMC   1854765 . PMID   2574062.
  25. ↑ "Depas" . Retrieved October 31, 2015.
  26. ↑ "Etizolam". PubChem. U.S. National Library of Medicine. Retrieved 2020-09-03.
  27. 1 2 Nakamae T, Shinozuka T, Sasaki C, Ogamo A, Murakami-Hashimoto C, Irie W, et al. (November 2008). "Case report: Etizolam and its major metabolites in two unnatural death cases". Forensic Science International. 182 (1–3): e1-6. doi:10.1016/j.forsciint.2008.08.012. PMID   18976871.
  28. ↑ Araki K, Yasui-Furukori N, Fukasawa T, Aoshima T, Suzuki A, Inoue Y, et al. (August 2004). "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. doi:10.1007/s00228-004-0789-1. PMID   15232663. S2CID   22970567.
  29. ↑ Suzuki Y, Kawashima Y, Shioiri T, Someya T (December 2004). "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. doi:10.1097/00007691-200412000-00009. PMID   15570188. S2CID   12164244.
  30. ↑ Kondo S, Fukasawa T, Yasui-Furukori N, Aoshima T, Suzuki A, Inoue Y, et al. (May 2005). "Induction of the metabolism of etizolam by carbamazepine in humans". European Journal of Clinical Pharmacology. 61 (3): 185–8. doi:10.1007/s00228-005-0904-y. PMID   15776275. S2CID   9612361.
  31. ↑ Høiseth G, Tuv SS, Karinen R (November 2016). "Blood concentrations of new designer benzodiazepines in forensic cases". Forensic Science International. 268: 35–38. doi:10.1016/j.forsciint.2016.09.006. PMID   27685473.
  32. ↑ Woolverton WL, Nader MA (December 1995). "Effects of several benzodiazepines, alone and in combination with flumazenil, in rhesus monkeys trained to discriminate pentobarbital from saline". Psychopharmacology. 122 (3): 230–6. doi:10.1007/bf02246544. PMID   8748392. S2CID   24836734.
  33. ↑ 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
  34. ↑ "Expert Committee on Drug Dependence's Twenty Seventh Report" (PDF). World Health Organization . September 28, 1990. Retrieved July 3, 2023.
  35. ↑ "Letter of WHO Director-General to UN Secretary-General dated November 15th 2019" (PDF). www.who.int.
  36. ↑ "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.
  37. 1 2 "Warnings over counterfeit benzodiazepines". NSW Health.
  38. ↑ "Bekendtgørelse om euforiserende stoffer". retsinformation.dk (in Danish). Retrieved 2016-11-21.
  39. ↑ "Verordnungsentwurf der Bundesregierung" [Federal draft regulation](PDF). Bundesministerium für Gesundheit (Federal Ministry of Health) (in German). Archived from the original (PDF) on 18 March 2016.
  40. ↑ "Gesetz über den Verkehr mit Betäubungsmitteln" [Law on traffic with tranquillizers]. Bundesministerium der Justiz und für Verbraucherschutz (Federal Ministry of Justice and Consumer Protection) (in German).
  41. ↑ "DEPAS - Etizolam". 2017-08-31. Retrieved 2018-05-14.
  42. ↑ PubChem. "Etizolam". pubchem.ncbi.nlm.nih.gov. Retrieved 2021-03-06.
  43. ↑ "The Misuse of Drugs Act 1971 (Amendment) Order 2017".
  44. ↑ "Alabama Code Title 20. Food, Drugs, and Cosmetics § 20-2-23". Findlaw.
  45. ↑ "List of Controlled Substances" (PDF). State of Arkansas. Archived from the original (PDF) on 2 February 2011.
  46. ↑ "Statutes & Constitution: Online Sunshine". www.leg.state.fl.us.
  47. ↑ "HB1231 (As Sent to Governor) - 2014 Regular Session". billstatus.ls.state.ms.us.
  48. ↑ "Health and Safety Code Chapter 481. Texas Controlled Substances Act". statutes.capitol.texas.gov. Retrieved 2019-07-12.
  49. ↑ "Controlled Substance Schedule | SCDHEC". www.scdhec.gov. Retrieved 2019-03-20.
  50. ↑ "18VAC110-20-322. Placement of Chemicals in Schedule I". Commonwealth of Virginia. 2 December 2015. Retrieved 11 March 2016.
  51. ↑ "Ellington's bill banning two deadly drugs could soon be law - State of Indiana House of Representatives". www.indianahouserepublicans.com.
  52. ↑ "(Proposed Rule) Schedules of Controlled Substances: Temporary Placement of Etizolam, Flualprazolam, Clonazolam, Flubromazolam, and Diclazepam in Schedule I". Federal Register . DEA. December 23, 2022.
  53. ↑ "Schedules of Controlled Substances: Temporary Placement of Etizolam, Flualprazolam, Clonazolam, Flubromazolam, and Diclazepam in Schedule I" (PDF). Federal Register . DEA. July 25, 2023. Retrieved 2023-07-25.
  54. ↑ "Schedules of Controlled Substances: Extension of Temporary Placement of Clonazolam, Diclazepam, Etizolam, Flualprazolam, and Flubromazolam in Schedule I of the Controlled Substances Act". Federal Register. 2025-07-25. Retrieved 2025-08-13.
  55. ↑ Gupta S, Garg B (2014). "A case of etizolam dependence". Indian Journal of Pharmacology. 46 (6): 655–6. doi: 10.4103/0253-7613.144943 . PMC   4264086 . PMID   25538342.
  56. ↑ Allison D (20 April 2018). "How to tackle Dundee's fake valium epidemic". BBC News.
  57. ↑ Guirguis A. "Novel psychoactive substances: understanding the new illegal drug market". Pharmaceutical Journal. Archived from the original on 2019-04-11. Retrieved 2018-10-18.
  58. ↑ "Drug Data Xanax". DrugData.org. Retrieved 9 April 2020.
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