Etizolam (original) (raw)

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Benzodiazepine analog drug

Etizolam
Clinical data
Trade names Etizest, Etilaam, Etizex, Depas, Sedekopan, Pasaden
Dependence liability Moderate
Routes of administration Oral, sublingual, rectal
ATC code N05BA19 (WHO)
Legal status
Legal status BR: Class B1 (Psychoactive drugs)[1] DE: Anlage III (Special prescription form required) UK: Class C US: Schedule I UN: Psychotropic Schedule IV
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
IUPAC name 4-(2-Chlorophenyl)-2-ethyl-9-methyl-6_H_-thieno[3,2-_f_][1,2,4]triazolo[4,3-_a_][1,4]diazepine
CAS Number 40054-69-1 checkY
PubChem CID 3307
ChemSpider 3191 checkY
UNII A76XI0HL37
KEGG D01514 checkY
ChEMBL ChEMBL1289779 ☒N
CompTox Dashboard (EPA) DTXSID0023030 Edit this at Wikidata
ECHA InfoCard 100.188.773 Edit this at Wikidata
Chemical and physical data
Formula C17H15ClN4S
Molar mass 342.85 g·mol−1
3D model (JSmol) Interactive image
SMILES ClC1=CC=CC=C1C2=NCC3=NN=C(C)N3C4=C2C=C(CC)S4
InChI 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 checkYKey:VMZUTJCNQWMAGF-UHFFFAOYSA-N checkY
☒NcheckY (what is this?) (verify)

Etizolam powder. Pictured is roughly 150 mg; a standard dose is around 1 mg

Four blister packs of Etizex brand etizolam tablets

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which is a benzodiazepine analog.[6] The etizolam molecule differs from a benzodiazepine in that the benzene ring has been replaced by a thiophene ring and triazole ring has been fused, making the drug a thienotriazolodiazepine.[7][8]

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 approved for medical use[_where?_] in 1983.[11]

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

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

[edit]

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]

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]

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]

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 - for instance, the National Records of Scotland report on drug-related deaths, 'street' Etizolam was a factor in ("implicated in, or potentially contributed to") 752, or 59%, of drug-related deaths in Scotland in 2019. It is important to highlight that more than one drug contributed to the vast majority of the deaths (by way of comparison, opiates and opioids were a factor in 1092, or 86%, of drug-related deaths).[33]

Society and culture

[edit]

Etilaam, Sedekopan, Etizest, Etizex, Pasaden or Depas

International drug control conventions

[edit]

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]

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

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

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

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

[42]

In India, it is a Narcotics prescription-only (NRx) medication used for anxiety disorders, sometimes in combination with other drugs like 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]

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]

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][37]

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