Etizolam

Etizolam, also known by various trade names such as Etizest and Etilaam, is a benzodiazepine analog, specifically a thienodiazepine, and one of the first designer benzodiazepine drugs to show up in the market around 2011.

Compared to other benzodiazepine drugs, etizolam displays a short-acting nature (5-7 hours) and considerable potency, with 1 mg roughly equivalent to 10 mg of diazepam.

Etizolam’s regulatory situation is somewhat of a mix-up. While it is an approved medication in places like Japan, Italy, and India, it has not received FDA approval in the United States as a medication. However, it is still legal to purchase online as a research chemical, which has led to a significant amount of misuse.

This has meant that although etizolam is federally unscheduled, individual states in the US like Alabama, Arkansas, Florida, Georgia, and others have scheduled it as a Schedule I compound, the most restrictive classification available.

IUPAC Name 

4-(2-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine

Other Names

Etizest, Wtilaam, Etizex, Depas, Sedekopan, Pasaden, Arophalm, Capsafe, Dezolam, Eticalm, Etidrale, Etisedan, Guperies, Medipeace, Mozun, Nonnerv, Palgin, Sylazepam

Metabolism

The biotransformation of etizolam is extensive and involves both hydroxylation and conjugation. The main metabolite formed via 1′-hydroxylation is α-hydroxyetizolam and has an elimination half-life of around 8.2 hours [1]. This metabolic byproduct retains pharmacological activity comparable to that of the parent drug, indicating that metabolite action may contribute to etizolam’s clinical effects.

CYP3A4 is predicted to be the main CYP enzyme responsible for mediating etizolam metabolism.

CYP2C18 and CYP2C19 are also involved in the metabolic pathways [2]. The kidneys excrete the drug.

Duration of Effects 

With a single oral dose of 0.5 mg, the average elimination half-life of etizolam is roughly 3.4 hours. However, this value may increase up to 17 hours, depending on the rate of metabolism.

How Does Etizolam Work?

Etizolam is known to exert its effects through the classic benzodiazepine pathway. This effect increases the natural inhibitory function of GABA and results in sedative, anxiolytic, and muscle-relaxant effects.

More specifically, etizolam is selectively a full, rather than a partial, GABA-A receptor agonist and enhances GABA-induced Cl- currents [3]. Etizolam shows high potency and affinity for the alpha-1 beta 2 gamma 2S subunit combination at GABA-A receptor sites. Alpha-1 receptors mediate the sedative effects of etizolam, while alpha-2 and alpha-3 mediate the anxiolytic effects [3].

Furthermore, etizolam is also a specific antagonist at the platelet-activating factor receptor. It inhibits PAF-induced platelet aggregation by inhibiting PAF binding to the receptors on the platelet surface. PAF antagonists do not provoke an inflammatory response upon binding but rather block or lessen the effects of PAF [2]. Lastly, studies have demonstrated that etizolam mediates imipramine-like neuropharmacological and behavioral effects and exerts only minor effects on cognitive functioning.

Is Etizolam Safe? Risks & Side Effects

Etizolam, like all other benzodiazepines, carries significant risk. If it were an approved medication in the United States, it would likely receive a Schedule IV designation, which would entail that despite its recognized medical uses, it still carries the potential for misuse and dependence.

In general, when misuse is avoided, benzodiazepines are not likely to cause serious health-related events. However, the possibility of misuse is a very real factor that must be considered. The recent explosion in drug overdose deaths in the United States should serve as a stark reminder of this. Nonetheless, when it comes to etizolam, there is plenty of evidence to suggest that, among benzodiazepines, it has rare qualities that make it safer to use than most.

Side Effects of Etizolam

Etizolam is generally considered to be well tolerated when compared to other benzodiazepine compounds. However, it produces the usual range of side effects associated with benzodiazepines.

Regarding etizolam use, some of the most commonly reported adverse effects have been: drowsiness, sedation, muscle weakness, loss of coordination, fainting, headaches, confusion, depression, slurred speech, visual disturbances, changes in libido, and tremors.

In rare cases, etizolam has also been linked to skin lesions, blepharospasm (especially in women), and anterograde amnesia. However, etizolam has been found to have no effects on fertility, development, and teratogenicity [4]. Overall, its adverse effects profile is less significant than most benzodiazepines.

Benzodiazepine Withdrawal & Dependence

As a possible consequence of benzodiazepine therapy, withdrawal symptoms and physical dependence are well-known factors. The full extent of these risks was unknown when they were first synthesized, and benzodiazepines were prescribed far too liberally. However, with time, doctors realized their mistakes and now take much care when it comes to hedging against this possibility.

In fact, it’s now standard practice for doctors to try and limit a benzodiazepine treatment to the shortest time frame, which will not affect the treatment’s likelihood of success. Doctors worry about the possibility of a benzodiazepine dependence because, if this were to happen, it would entail the patient would have to go through a long, drawn-out process of drug tapering to get off benzodiazepines safely. Drug tapering is considered a safe procedure when done under appropriate supervision, but complications can still develop.

Because of the dangers presented by benzodiazepine withdrawal, quitting these compounds “cold turkey” is not considered an option. Indeed, withdrawal symptoms stemming from benzodiazepines, as well as alcohol, are unique in that, if left untreated, they have the possibility of becoming fatal.

However, when it comes to etizolam, it seems that the particular qualities present in this compound make it less likely to engender dependence, although, obviously, it is still a possibility which becomes likelier the more the compound is taken.

In a rat study that compared etizolam to lorazepam, it was found that etizolam had fewer chances of resulting in tolerance and dependence. It was also found that rats developed a tolerance to the anticonvulsant actions of lorazepam but not those of etizolam [5]. More studies are needed to confirm this characteristic of etizolam, but in the countries where it is available, such as India and Japan, the notion that etizolam is less liable to cause dependence is widespread. It has made etizolam one of the most prescribed benzodiazepines.

Nonetheless, etizolam’s potent, short-acting nature still has to be considered. It is well known that short-acting, potent benzodiazepines have more potential to engender dependence because they are more likely to cause abuse-related habits due to inter-dose withdrawal symptoms and other related factors.