Etizolam (marketed under numerous brand names) is a

thienodiazepine A thienodiazepine is a heterocyclic compound containing a diazepine ring fused to a thiophene ring. If R1 and R2 are part of a triazole ring, the substance is called a "thienotriazolodiazepine." The thienodiazepine structure forms the central ...

derivative which is a

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...

analog. The etizolam molecule differs from a benzodiazepine in that the

benzene Benzene is an Organic compound, organic chemical compound with the Chemical formula#Molecular formula, molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar hexagonal Ring (chemistry), ring with one hyd ...

ring has been replaced by a

thiophene Thiophene is a heterocyclic compound with the formula C4H4S. Consisting of a planar five-membered ring, it is aromatic as indicated by its extensive substitution reactions. It is a colorless liquid with a benzene-like odor. In most of its reacti ...

ring and

triazole A triazole is a heterocyclic compound featuring a five-membered ring of two carbon atoms and three nitrogen atoms with molecular formula C2H3N3. Triazoles exhibit substantial Isomer, isomerism, depending on the positioning of the nitrogen atoms w ...

ring has been fused, making the drug a

thienotriazolodiazepine A thienotriazolodiazepine is a heterocyclic compound containing a diazepine ring fused to thiophene and triazole rings. Thienotriazolodiazepine forms the central core of several pharmaceutical drugs including: * α-Hydroxyetizolam * Brotizolam ...

. Although a thienodiazepine, etizolam is clinically regarded as a benzodiazepine because of its mode of action via the benzodiazepine receptor and directly targeting GABA_A allosteric modulator receptors. It possesses

anxiolytic An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...

amnesic Amnesia is a deficit in memory caused by brain damage or brain diseases,Gazzaniga, M., Ivry, R., & Mangun, G. (2009) Cognitive Neuroscience: The biology of the mind. New York: W.W. Norton & Company. but it can also be temporarily caused by t ...

anticonvulsant Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatme ...

hypnotic A hypnotic (from Ancient Greek, Greek ''Hypnos'', sleep), also known as a somnifacient or soporific, and commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to sleep induction, induce sleep and to trea ...

sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or Psychomotor agitation, excitement. They are central nervous system (CNS) Depressant, depressants and interact with brain activity, causing its decelera ...

and

skeletal muscle relaxant A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeu ...

properties. It was patented in 1972 and first approved for medical use in Japan in 1984. As of April 2021, the export of etizolam has been banned in India.

Medical uses

* Short-term treatment of

insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...

. * Anxiety disorders such as OCD and general anxiety disorder, mostly as a short-term medication to be used purely on an at-need basis

Side effects

Long term use may result in

blepharospasm Blepharospasm is a neurological disorder characterized by intermittent, involuntary spasms and contractions of the orbicularis oculi muscle, orbicularis oculi (eyelid) muscles around both eyes. These result in abnormal twitching or blinking, an ...

s, especially in women. Doses of 4 mg or more may cause

anterograde amnesia In neurology, anterograde amnesia is the inability to create new memories after an event that caused amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. Thi ...

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

Tolerance, dependence and withdrawal

Abrupt or rapid discontinuation from etizolam, as with

benzodiazepines Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat co ...

, may result in the appearance of the

benzodiazepine withdrawal syndrome Benzodiazepine withdrawal syndrome (BZD withdrawal) is the cluster of signs and symptoms that may emerge when a person who has been taking benzodiazepines as prescribed develops a physical dependence on them and then reduces the dose or stop ...

, including

rebound insomnia The rebound effect, or rebound phenomenon, is the emergence or re-emergence of symptoms that were either absent or controlled while taking a medication, but appear when that same medication is discontinued or reduced in dosage. In the case of re- ...

Neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS) is a rare but life-threatening reaction that can occur in response to antipsychotics (neuroleptic) or other drugs that block the effects of dopamine. Symptoms include high fever, confusion, rigid muscles, va ...

, a rare event in benzodiazepine withdrawal, has been documented in a case of abrupt withdrawal from etizolam. This is particularly relevant given etizolam's short half life relative to benzodiazepines such as

diazepam Diazepam, sold under the brand name Valium among others, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is used to treat a range of conditions, including anxiety disorder, anxiety, seizures, alcohol withdrawal syndr ...

resulting in a more rapid drug level decrease in blood plasma levels. In a study that compared the effectiveness of etizolam,

alprazolam Alprazolam, sold under the brand name Xanax among others, is a fast-acting, potent tranquilizer of moderate duration within the triazolobenzodiazepine group of chemicals called benzodiazepines. Alprazolam is most commonly prescribed in the ...

, and

bromazepam Bromazepam, sold under many brand names, is a benzodiazepine. It is mainly an anxiolytic, anti-anxiety agent with similar side effects to diazepam. In addition to being used to treat anxiety or panic states, bromazepam may be used as a premedica ...

for the treatment of

generalized anxiety disorder Generalized anxiety disorder (GAD) is an anxiety disorder characterized by excessive, uncontrollable and often irrational worry about events or activities. Worry often interferes with daily functioning. Individuals with GAD are often overly con ...

, all three drugs retained their effectiveness over 2 weeks, but etizolam became more effective from 2 weeks to 4 weeks. Administering .5 mg etizolam twice daily did not induce cognitive deficits over 3 weeks when compared to placebo. When multiple doses of etizolam, or

lorazepam Lorazepam, sold under the brand name Ativan, Tavor among others, is a benzodiazepine medication. It is used to treat anxiety (including anxiety disorders), insomnia, severe agitation, active seizures including status epilepticus, alcoh ...

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

of choice with reduced liability to produce tolerance and dependence after long-term treatment of anxiety and stress syndromes.

Pharmacology

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. Etizolam possesses potent

properties, and is comparable with other short-acting

s. Etizolam acts as a

positive allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimuli. Some of them, like benzodiazepines or alcohol, function as psychoactive drugs. The site that ...

of the GABA_A receptor by agonizing the receptor's benzodiazepine site. According to the Italian prescribing information sheet, etizolam belongs to a new class of

diazepine Diazepine is a seven-membered heterocyclic compound with two nitrogen atoms (e.g., in ring positions 1 and 2). Types include: * 1,2-Diazepine * 1,3-Diazepine * 1,4-Diazepine ** Benzodiazepines Benzodiazepines (BZD, BDZ, BZs), colloquial ...

s. This new class is easily

oxidized Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...

, rapidly

metabolized Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

, and has a lower risk of accumulation, even after prolonged treatment. Etizolam has an

action about 6-8 times greater than that of

. 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 ''Deep Sleep'' is a series of point-and-click adventure games created by Polish indie developer Mateusz Sokalszczuk (also known by his online name scriptwelder). The series consists of three free browser games in which the player attempts to na ...

; however, it may reduce

REM sleep Rapid eye movement sleep (REM sleep or REMS) is a unique phase of sleep in mammals (including humans) and birds, characterized by random rapid movement of the eyes, accompanied by low muscle tone throughout the body, and the propensity of the s ...

. In

EEG Electroencephalography (EEG) is a method to record an electrogram of the spontaneous electrical activity of the brain. The bio signals detected by EEG have been shown to represent the postsynaptic potentials of pyramidal neurons in the neoc ...

tests of healthy volunteers, etizolam showed some similar characteristics to

tricyclic antidepressant Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains ...

s. 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.

Interactions

Itraconazole Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. It may be given ...

and

fluvoxamine Fluvoxamine, sold under the brand name Luvox among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is primarily used to treat major depressive disorder and, perhaps more-especially, obsessive–compu ...

slow down the rate of elimination of etizolam, leading to accumulation of etizolam, therefore increasing its pharmacological effects.

Carbamazepine Carbamazepine, sold under the brand name Tegretol among others, is an anticonvulsant medication used in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other medications and as ...

speeds up the metabolism of etizolam, resulting in reduced pharmacological effects.

Overdose

Cases of intentional suicide by

overdose A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. Retrieved on September 20, 2014.

using etizolam in combination with GABA agonists have been reported. Although etizolam has a lower

LD50 In toxicology, the median lethal dose, LD50 (abbreviation for "lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 is a toxic unit that measures the lethal dose of a given substance. The value of LD50 for a substance is the dose requ ...

than certain

, the LD50 is still far beyond the prescribed or recommended dose.

Flumazenil Flumazenil, also known as flumazepil, is a selective GABAA receptor, GABAA receptor antagonist administered via injection, otic insertion, or intranasally. Therapeutically, it acts as both an antagonist and antidote to benzodiazepines (partic ...

, a GABA antagonist agent used to reverse benzodiazepine overdoses, inhibits the effect of etizolam as well as classical benzodiazepines such as diazepam and chlordiazepoxide. 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.

Society and culture

Brand names

Etilaam, Sedekopan, Etizest, Etizex, Pasaden or Depas

Legal status

International drug control conventions

In 1990, it was recommended that Etizolam not be placed under international control. However, this attitude has changed due to increased abuse. On December 13, 2019, the

World Health Organization The World Health Organization (WHO) is a list of specialized agencies of the United Nations, specialized agency of the United Nations which coordinates responses to international public health issues and emergencies. It is headquartered in Gen ...

recommended Etizolam be placed in Schedule 4 of the

1971 Convention on Psychotropic Substances The Convention on Psychotropic Substances of 1971 is a United Nations treaty designed to control psychoactive drugs such as amphetamine-type stimulants, barbiturates, benzodiazepines, and psychedelics signed in Vienna, Austria on 21 February ...

. This recommendation was followed by the placement of Etizolam into Schedule IV in March 2020.

Australia

Etizolam is not used medically in Australia but has been found in counterfeit

Xanax Alprazolam, sold under the brand name Xanax among others, is a fast-acting, potent tranquilizer of moderate duration within the triazolobenzodiazepine group of chemicals called benzodiazepines. Alprazolam is most commonly prescribed in the ...

pills.

Denmark

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

Germany

Etizolam was controlled in Germany in July 2013 but is not used medically.

Italy

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

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 Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms ( arrhythmia), and to protect the heart from a second heart attack after a first heart attack ( secondary prevention ...

propranolol Propranolol is a medication of the beta blocker class. It is used to treat hypertension, high blood pressure, some types of cardiac dysrhythmia, irregular heart rate, thyrotoxicosis, capillary hemangiomas, akathisia, performance anxiety, and ...

. United Kingdom In the UK, etizolam has been classified as a

Class C drug The Misuse of Drugs Act 1971 (c. 38) is an act of the Parliament of the United Kingdom. It represents action in line with treaty commitments under the Single Convention on Narcotic Drugs, the Convention on Psychotropic Substances, and the Uni ...

by the May 2017 amendment to The Misuse of Drugs Act 1971 along with several other designer benzodiazepine drugs.

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, Arkansas, Florida, Georgia (as Schedule IV, whereas all other states listed here prohibit it as a Schedule I substance), Louisiana, Mississippi, Texas, South Carolina, and Virginia. It is controlled in Indiana as of July 1, 2017. 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. 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.

Misuse

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

References

External links

Inchem.org - Etizolam
{{PAF signaling 2-Chlorophenyl compounds Designer drugs GABAA receptor positive allosteric modulators Hypnotics Thienotriazolodiazepines