Etizolam

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Etizolam
Etizolam.svg
Etizolam.png
Clinical data
Trade namesEtilaam, Etizest, Etivan-2
Dependence
liability
Moderate
Routes of
administration
Oral, sublingual, rectal
ATC code
Legal status
Legal status
  • DE: Anlage III (Special prescription form required)
  • UK: Class C
  • US: Schedule I in Alabama, Arkansas, Florida, Louisiana, Mississippi, Ohio, Oregon, and Virginia; Schedule IV in Georgia, Texas, and South Carolina;[1] scheduled in Arizona[2] and Indiana;[3] not FDA approved. Unscheduled in the remaining states.
  • UN: Psychotropic Schedule IV
Pharmacokinetic data
Bioavailability93%
MetabolismHepatic
Elimination half-life3.4 hours[4][5] (main metabolite is 8.2 hours)[6]
Duration of action5-7 hours, 10-12 hours controlled release (CR)[7]
Onset of action: 15-30 min. (IR), 0.25 - 3 mg; and 45 - 60 min (CR) in 1.5 mg & 3 mg
ExcretionKidney
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.188.773 Edit this at Wikidata
Chemical and physical data
FormulaC17H15ClN4S
Molar mass342.85 g·mol−1
3D model (JSmol)
 ☒NcheckY (what is this?)  (verify)
~98% pure Etizolam powder. This pictured amount is roughly 150mg, and is thus around 150 standard doses.
Four blister packs of Etizex brand etizolam tablets
Etizex brand etizolam tablets

Etizolam (marketed under many brand names) is a thienodiazepine derivative[8] which is a benzodiazepine analog.[9] The etizolam molecule differs from a benzodiazepine in that the benzene ring has been replaced by a thiophene ring and triazole ring has been fused, making the drug a thienotriazolodiazepine.[10][11] It possesses amnesic, anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties.[12]

It was patented in 1972[13] and approved for medical use in 1983.[14]

Medical uses[edit]

Side effects[edit]

Long term use may result in blepharospasms.[16] Doses of 4 mg or more may cause anterograde amnesia.[citation needed]

In rare cases, erythema annulare centrifugum skin lesions have resulted.[17]

Tolerance, dependence and withdrawal[edit]

Abrupt or rapid discontinuation from etizolam, as with benzodiazepines, may result in the appearance of the benzodiazepine withdrawal syndrome, including rebound insomnia.[18] Neuroleptic malignant syndrome, a rare event in benzodiazepine withdrawal, has been documented in a case of abrupt withdrawal from etizolam.[19] 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.[20]

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.[21] Administering .5 mg etizolam twice daily did not induce cognitive deficits over 3 weeks when compared to placebo.[22]

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).[23]  Tolerance to the anticonvulsant effects of lorazepam was observed, but no significant tolerance to the anticonvulsant effects of etizolam was observed.[23] Etizolam therefore has a reduced liability to induce tolerance, and dependence, compared with classic benzodiazepines.[23]

Pharmacology[edit]

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.[24][25][26] Etizolam possesses potent hypnotic properties,[27] and is comparable with other short-acting benzodiazepines.[28] Etizolam acts as a full agonist at the benzodiazepine/GABAa receptor to produce its range of therapeutic and adverse effects.[29]

According to the Italian P.I. 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 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.[30][31]

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.[32]

Interactions[edit]

Itraconazole and fluvoxamine slow down the rate of elimination of etizolam, leading to accumulation of etizolam, therefore increasing its pharmacological effects.[33][34] Carbamazepine speeds up the metabolism of etizolam, resulting in reduced pharmacological effects.[35]

Overdose[edit]

Cases of intentional suicide by overdose using etizolam in combination with GABA agonists have been reported.[32][36] 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.[37]

Etizolam overdose deaths are rising - for instance, the National Records of Scotland report on drug-related deaths, implicated 548 deaths from 'street' Etizolam in 2018, almost double the number from 2017 (299) and only six years from the first recorded death (in 2012). The 548 deaths were 45% of all drug-related deaths in Scotland in 2018.[38]

Society and culture[edit]

Brand names[edit]

Etilaam, Sedekopan, Etizest, Etizex, Pasaden or Depas

Legal status[edit]

International drug control conventions[edit]

On December 13th 2019, the World Health Organization recommended Etizolam be placed in Schedule 4 of the 1971 Convention on Psychotropic Substances.[39] This recommendation was followed by the placement of Etizolam into Schedule IV in March 2020 [40]

Australia[edit]

Etizolam is a Schedule 4 substance under the Poisons Standard June 2018 as it is classed as a benzodiazepine derivative.[41] A schedule 4 drug is outlined in the Poisons Act 1964 as "Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription."[41]

Denmark[edit]

Etizolam is controlled in Denmark under the Danish Misuse of Drugs Act.[42]

The Netherlands[edit]

Etizolam is not controlled and therefore sold in Headshops all over The Netherlands.

Germany[edit]

Etizolam was controlled in Germany in July 2013.[43][44]

Italy[edit]

Etizolam is licensed for the treatment of anxiety, insomnia and neurosis as a prescription-only medication.[45]

Japan[edit]

Etizolam also called Depas, is restricted as a benzodiazepine analog in Japan from October 2016 onwards.

United Kingdom[edit]

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.[46]

United States[edit]

Etizolam is not authorized by the FDA for medical use in the U.S. However, it currently remains unscheduled at the federal level and is legal for research purposes. As of March 2016, etizolam is a controlled substance in the following states: Alabama,[47] Arkansas,[48] Florida,[49] Georgia (as Schedule IV, whereas all other states listed here prohibit it as a Schedule I substance), Louisiana, Mississippi,[50] Texas,[51] South Carolina,[1] and Virginia.[52] It is controlled in Indiana as of July 1, 2017.[3] It is controlled in Ohio as of February 2018.

Misuse[edit]

Etizolam is a drug of potential misuse. Cases of etizolam dependence have been documented in the medical literature.[53] However, conflicting reports from the World Health Organization, made public in 1991, dispute the misuse claims.[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]

See also[edit]

References[edit]

  1. ^ a b "Controlled Substance Schedule | SCDHEC". www.scdhec.gov. Retrieved 2019-03-20.
  2. ^ "Arizona HB2033 | 2017 | Fifty-third Legislature 1st Regular". LegiScan.
  3. ^ a b "Ellington's bill banning two deadly drugs could soon be law - State of Indiana House of Representatives". www.indianahouserepublicans.com.
  4. ^ "Etizolam". www.drugbank.ca. Retrieved 2020-09-03.
  5. ^ U.S. Drug Enforcement Administration (March 2020). "Drug & Chemical Evaluation - Etizolam" (PDF). U.S. Department of Justice. Archived (PDF) from the original on September 2020.
  6. ^ 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 (inactive 2020-10-13). ISSN 1432-1041. PMID 2065698.CS1 maint: DOI inactive as of October 2020 (link)
  7. ^ https://mentalhealthdaily.com/2018/07/17/etizolam-vs-xanax-alprazolam/
  8. ^ 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.
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  26. ^ U.S. Drug Enforcement Administration (March 2020). "Drug & Chemical Evaluation - Etizolam" (PDF). U.S. Department of Justice. Archived (PDF) from the original on September 2020.
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  35. ^ 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.
  36. ^ 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.
  37. ^ 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.
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  40. ^ "News: March 2020 – Recently scheduled benzodiazepines Flualprazolam and Etizolam associated with multiple post-mortem and DUID cases in UNODC EWA".
  41. ^ a b "Poisons Standard June 2018". www.legislation.gov.au. Archived from the original on March 2, 2017.
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  52. ^ "18VAC110-20-322. Placement of Chemicals in Schedule I". Commonwealth of Virginia. 2 December 2015. Retrieved 11 March 2016.
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External links[edit]