Etizolam

Substance identification
Etizolam (4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2f][1,2,4] triazolo[4,3-a][1,4]diazepine) is a thienodiazepine derivative. It is used as a pharmaceutical for treatment of anxiety in some countries, but is also produced as an unapproved drug in tablet and powder forms.

WHO review history
The ECDD reviewed etizolam at its 26th meeting, in 1989, and at its 27th meeting, in 1990. At its 37th meeting, in 2015, the Committee pre-reviewed etizolam and recommended that a critical review be conducted at a future meeting. A critical review of etizolam was prepared for the 39th meeting, in 2017. At that meeting, the Committee noted that there were insufficient data on dependence, abuse and risks to public health posed and therefore recommended that it be kept under surveillance. A critical review was initiated at the 42nd meeting, as new information had been presented to the Committee on dependence, abuse and risks to public health.

Similarity to known substances and effects on the central nervous system
Etizolam is an agonist at the benzodiazepine site of the GABAA receptor. Its pharmacological effects are similar to those of other benzodiazepines such as diazepam, which is currently controlled under the Convention on Psychotropic Substances of 1971.

In animal models, etizolam induced effects characteristic of benzodiazepines, such as muscle relaxation, anticonvulsive effects and sedation.

Central nervous system depression has also been described in humans. The effects, which include drowsiness, sedation, muscle relaxation, ataxia, slurred speech and loss of consciousness, are reversed by the benzodiazepine receptor antagonist flumazenil.

Dependence potential
The dependence potential of etizolam in humans has been described in case reports and on drug information forums. Non-medical use is associated with the development of tolerance as well as craving and withdrawal on cessation of use. The withdrawal symptoms described in a case report were characteristic of benzodiazepine withdrawal and included palpitations, impaired sleep, agitation and tremors.

Actual abuse and/or evidence of likelihood of abuse
In the animal drug discrimination model, etizolam showed pentobarbital-like effects, suggesting that it may have subjective drug effects similar to those of sedative hypnotics.

Non-medical use of etizolam has been documented in a number of countries. It has been detected in impaired drivers and in biological samples from cases of fatal drug overdose, often in combination with other substances. In one country, it was reported to contribute to up to 46% of all drug-related deaths.

Therapeutic usefulness
Etizolam was patented in the 1970s and has been marketed since the early 1980s. It is not on the WHO Model List of Essential Medicines or the WHO Model List of Essential Medicines for Children, but it is sold commercially as a medicine in a few countries. Etizolam is also sold by several companies for research purposes. It has been used for the treatment of anxiety disorders and other psychiatric conditions.

Recommendation
Etizolam (4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2- f][1,2,4] triazolo[4,3a][1,4]diazepine) is a thienodiazepine derivative that has actions and effects very similar to those of benzodiazepines listed under Schedule IV in the Convention on Psychotropic Substances of 1971. It can produce a state of dependence and central nervous system depression, like other benzodiazepines. It has therapeutic indications and has marketing authorization in a few countries. There is sufficient evidence of its abuse so as to constitute a public health and social problem.

■ Recommendation: The Committee recommended that etizolam (4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2- f][1,2,4] triazolo[4,3a][1,4]diazepine) be added to Schedule IV of the 1971 Convention on Psychotropic Substances.