ETIZOLAM Critical Review Report Agenda Item 4.13 Expert Committee on Drug Dependence Thirty-ninth Meeting Geneva, 6-10 November 2017 39th ECDD (2017) Agenda item 4.13 Etizolam Page 2 of 20 39th ECDD (2017) Agenda item 4.13 Etizolam Contents Acknowledgements.................................................................................................................................. 5 Summary...................................................................................................................................................... 6 1. Substance identification ....................................................................................................................... 7 A. International Nonproprietary Name (INN).......................................................................................................... 7 B. Chemical Abstract Service (CAS) Registry Number .......................................................................................... 7 C. Other Chemical Names ................................................................................................................................................... 7 D. Trade Names ....................................................................................................................................................................... 7 E. Street Names ....................................................................................................................................................................... 8 F. Physical Appearance ....................................................................................................................................................... 8 G. WHO Review History ....................................................................................................................................................... 8 2. Chemistry ................................................................................................................................................... 8 A. Chemical Name .................................................................................................................................................................. 8 B. Chemical Structure ........................................................................................................................................................... 8 C. Stereoisomers ...................................................................................................................................................................... 9 D. Methods and Ease of Illicit Manufacturing ........................................................................................................... 9 E. Chemical Properties ......................................................................................................................................................... 9 F. Identification and Analysis ........................................................................................................................................... 9 3. Ease of Convertibility Into Controlled Substances ...................................................................... 10 4. General Pharmacology ........................................................................................................................ 10 A. Routes of administration and dosage ................................................................................................................... 10 B. Pharmacokinetics .......................................................................................................................................................... 10 C. Pharmacodynamics ....................................................................................................................................................... 10 5. Toxicology ................................................................................................................................................ 10 6. Adverse Reactions in Humans ........................................................................................................... 12 7. Dependence Potential .......................................................................................................................... 12 A. Animal Studies ................................................................................................................................................................. 12 B. Human Studies ................................................................................................................................................................. 12 8. Abuse Potential ...................................................................................................................................... 13 A. Animal Studies ................................................................................................................................................................. 13 B. Human Studies ................................................................................................................................................................. 13 9. Therapeutic Applications and Extent of Therapeutic Use and Epidemiology of Medical Use .............................................................................................................................................................. 13 10. Listing on the WHO Model List of Essential Medicines .............................................................. 13 11. Marketing Authorizations (as a Medicinal Product) ................................................................. 14 12. Industrial Use ......................................................................................................................................... 14 13. Non-Medical Use, Abuse and Dependence ..................................................................................... 14 Page 3 of 20 39th ECDD (2017) Agenda item 4.13 Etizolam 14. Nature and Magnitude of Public Health Problems Related to Misuse, Abuse and Dependence ............................................................................................................................................. 14 15. Licit Production, Consumption and International Trade ......................................................... 15 16. Illicit Manufacture and Traffic and Related Information ........................................................ 15 17. Current International Controls and Their Impact ...................................................................... 15 18. Current and Past National Controls ................................................................................................ 15 19. Other Medical and Scientific Matters Relevant for a Recommendation on the Scheduling of the Substance ..................................................................................................................................... 15 References ................................................................................................................................................ 16 Annex 1: Report on WHO Questionnaire for Review of Psychoactive Substances for the 39th ECDD: Evaluation of Etizolam ................................................................................................. 20 Page 4 of 20 39th ECDD (2017) Agenda item 4.13 Etizolam Acknowledgements This report has been drafted under the responsibility of the WHO Secretariat, Department of Essential Medicines and Health Products, Teams of Innovation, Access and Use and Policy, Governance and Knowledge. The WHO Secretariat would like to thank the following people for their contribution in producing this review report: Dr. Katia Gysling, Chile (literature search, review and drafting), Ms. Dilkushi Poovendran, Geneva, Switzerland (questionnaire analysis and report drafting) and Dr. Stephanie Kershaw, Adelaide, Australia (review report editing, questionnaire analysis and report drafting). Page 5 of 20 39th ECDD (2017) Agenda item 4.13 Etizolam Summary Etizolam is a thienodiazepine derivative, with high affinity for the benzodiazepine site in GABAA receptors. It was developed in the 1980’s as an alternative to known benzodiazepines. It is readily absorbed and it has a shorter half-life than benzodiazepines. It is sold commercially as a medicine to control generalized anxiety and other psychiatric pathologies in some countries. It is also sold in the internet by several companies for research purposes. There have been a few studies comparing the differential pharmacological profile of etizolam compared to benzodiazepines. A major difference with benzodiazepines is its shorter half-life. It also differs from benzodiazepines as it has lower sedative effects. It has been proposed that this could be due to a lower affinity for GABAA receptors containing alpha1-subunits. In the last few years there has been an increase in its misuse and abuse, with several cases of death reported. Page 6 of 20 39th ECDD (2017) Agenda item 4.13 Etizolam 1. Substance identification A. International Nonproprietary Name (INN) Etizolam B. Chemical Abstract Service (CAS) Registry Number 0040054-69-1 C. Other Chemical Names (4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepine2 6H-tieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine, 4-(2-chlorophenyl)-2-etyl-9- metyl- AHR 3219 Y 7131 D. Trade Names Arophalm (Nichi-Iko Pharmaceutical, Japan) Capsafe