Summary

Etizolam (Fig.1) is a thienodiazepine derivative, also known to be a benzodiazepine through its action via the benzodiazepine receptor [1; 2]. In the United States, it is available for purchase through the internet for the purpose of research [3]. However, etizolam has not been approved by the FDA for medicinal use [4], and it cannot be imported, sold or prescribed in the US. In addition, etizolam is marketed in only some countries as a medicinal product; Table 1 highlights countries authorised to sell etizolam. Etizolam – legal production – has been described as ‘[readily] available by the internet’ by the 39^th ECDD (2017) Agenda item 4.13. Furthermore, no reports exist on the illicit manufacturing of etizolam. Data – which is limited – suggests that over 5% of Americans purchased benzodiazepine in 2013 [5].

Figure 1. Etizolam (C17H15CIN4S)

Figure 1. Etizolam (C₁₇H₁₅CIN₄S) is a thienodiazepine derivative sold commercially (in some countries) and on the internet for research purposes [4]. Eizolam was patented in 1978 and was more recently reported to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) in 2011 [5]. Right: etizolam structure showing chemical groups [3].

Table 1. Etizolam is only sold commercially in some countries. Etizolam is registered for use as a medicine in Japan, Italy and India [2].

Detailed

Etizolam is considered a new psychoactive substance (NPS), and in this regard the internet vendors have contributed to the increasing popularity of online crypto-markets [6]. Further, the legality – legal status – of NPS across Europe, for example, has been recently addressed with the UK introducing the Psychoactive Substances Act 2016 [6]. This Act enables the prevention of importing, exporting and supplying of some NPS. Efforts are currently focused around safe-guarding legal markets against street-level and/or crypto market places [6; 7]. Recent data has revealed that NPS sales are dominated by the online market; the crypto market is emerging [6]. In a study investigating online vendors selling NPS, and assessing the reliability of NPS on the crypto market results found that the number of vendors selling NPS had increased from October 2015 to October 2016: one year [6].

Dosage

Etizolam has been previously described as eliciting anxiolytic, euphoric, muscle relaxant, and sleep aiding effects on an individual [5; 8]. Furthermore, Etizolam has been described as having anxiolytic, hypnotic, sedative, amnesic, along with muscle relaxing properties [2; 8]. In addition, a typical etizolam recreational dose has been reported at between 0.25-3mg [5]. One study, assessing the tolerability and efficacy of etizolam found that a random administration of etizolam – 0.50mg or 0.25mg –alleviated anxiety and depressive symptoms [9]. More specifically, the 0.50mg dose was more effective than the 0.25mg and placebo dose [9]. A single-dose etizolam was used in order to understand the activity of cytochrome P450 [10] to Japanese men. Participants of the study received a single 1mg oral etizolam dose, and results concluded that a single-dose etizolam was influence by cytochrome enzyme activity [10]. Lastly, etizolam was administered to patients with chronic subdural hematoma (CSH) to measure the effects of etizolam post-surgery [11]. Remarkably, etizolam significantly reduced the size of the assessed subdural hematomas in 15 patients when compared to the control group (24 patients) [11]. Authors of this study suggested that etizolam might be useful for the prevention of reoccurring chronic subdural hematoma (CSH) [11].

Safety

Etizolam has been associated with adverse drug events (ADE), in which etizolam belongs to class of benzodiazepines with 63 adverse events in the past [12]. This class also includes triazolam and alprazolam [12]. Safety and use of etizolam was evaluated in adolescents and children [2]. Interestingly, results of this retrospective chart review study found that, in children and adolescents, etizolam was effective and well-tolerated [2]. Etizolam is currently not controlled under stipulated United Nations Conventions [4]. So far, it is legal for use in research settings; however, it is unscheduled [4]. It is important to note that etizolam is 6-10 times potent in comparison to diazepam [8]. An online survey study which included 619 NPS users found that 55 respondents who used GABA activating drugs commonly used etizolam [13]. Authors also noted that respondents – GABA users – were motivated the most by coping with pain, boredom, anxiety and emotional problems, along with price and legal status [13]. In evaluating the cross-reactivity of potentially abused drugs with a detection kit, O’Connor et al (2015) found that the immune-analysis ELISA kit assay was successful at detecting etizolam [3]. Crucially, results from this cross-reactivity assay are important for providing toxicological data on etizolam to safely monitor this drug in the future [3].

Side Effects

-hydroxyetizolam is one particular metabolite of etizolam which has a half-life of around 8 hours [2]. Etizolam is used mainly in adults who have been diagnosed with generalised anxiety disorder, panic disorder and depressive and somatic symptoms [2]. Described adverse effects include: drowsiness and weakening of the muscles [2; 5]. Etizolam has been classified as a ‘short-acting benzodiazepine’ according to the authors [12] who referenced the Japan Pharmacotherapeutic Classification. What is known of etizolam’ efficacy in the literature has been reported as being ‘minimal’ [2]. Details of the adverse effects of etizolam is limited [4]. In evaluating if etizolam can induce blepharospasm (the tight closing of the eyelids), research concluded that amongst participants etizolam can cause blepharospasms [14]. Importantly, benzodiazepines are capable of developing cognitive impairments [15], and this class of NPS has seen an increase in drug-related harms [16].

References

[1] K. Araki, N. Yasui-Furukori, T. Fukasawa, T. Aoshima, A. Suzuki, Y. Inoue, T. Tateishi K. Otani, 2004. Inhibition of the metabolism of etizolam by itraconazole in humans: evidence for the involvement of CYP3A4 in etizolam metabolism. European Journal of Clinical Pharmacology, 60: 427-430.

[2] R.B. Nayak, S. Lohit, S.S. Chate, N.M. Patil and M. Mahesh, 2016. Etizolam: Use and safety profile in children and adolescent. Al Ameen Journal of Medical Science, 9(3): 206-209.

[3] Lauren C. O’Connor, Hazel J. Torrance, and Denise A. McKeown, 2015. ELISA Detection of Phenazepam, Etizolam, Pyrazolam, Flubromazepam, Diclazepam and Delorazepam in Blood Using Immunalysis Benzodiazepine Kit. Journal of Analytical Toxicology, 40:159-161.

[4] World Health Organization, 2017. Etizolam: critical review report Agenda Item 4.13. Expert Committee on Drug Dependence Thirty-ninth Meeting, Geneva, 6-10 November 2-17.

[5] Kieran R. Manchester, Emma C. Lomas, Peter D. Maskell, 2017. The emergence of new psychoactive substance (NPS) benzodiazepines: A review. Drug Test Analysis, 10: 37-53.

[6] Elle Wadsworth, Colin Drummond and Paolo Deluca, 2018. The Dynamic Environment of Crypto Markets: The Lifespan of New Psychoactive Substances (NPS) and Vendors Selling NPS. Brain Science, 8(46): doi:10.3390/brainsci8030046.

[7] Van Hout MC, Hearne E, 2017. New psychoactive substances (NPS) on cryptomarket fora: An exploratory study of characteristics of forum activity between NPS buyers and vendors. International Journal of Drug Policy, 40: 102-110. doi: 10.1016/j.drugpo.2016.11.007.

[8] P V Devi Swapna, Paramita Das, S H.Chetan, Jitender Reddy, 2014. ANALYTICAL METHOD DEVELOPMENT AND VALIDATION FOR THE SIMULTANEOUS ESTIMATION OF PROPRANOLOL HYDROCHLORIDE AND ETIZOLAM IN THEIR COMBINED DOSAGE FORM BY VIERODT’S METHOD. International Journal of Pharmaceutical Biological and Chemical Sciences, 3(2): 46-50.

[9] Massimo Casacchia, Francesca Bolino & Ugo Ecari (1990) Etizolam in the treatment of generalized anxiety disorder: a double-blind study versus placebo, Current Medical Research and Opinion, 12:4, 215-223, DOI: 10.1185/03007999009111650.

[10] T. Fukasawa, N. Yasui–Furukori, A. Suzuki, Y. Inoue, T. Tateishi, K. Otani, 2005. Pharmacokinetics and pharmacodynamics of etizolam are influenced by polymorphic CYP2C19 activity. European Journal of Clinical Pharmacology, 61: 791-795.

[11] Yutaka HIRASHIMA, Naoya KUWAYAMA, Hideo HAMADA, Nakamasa HAYASHI, and Shunro ENDO, 2002. Etizolam, an Anti-anxiety Agent, Attenuates Recurrence of Chronic Subdural Hematoma. Neurol. Med. Chir (Tokyo), 42.

[12] Mitsuko Onda, Hirohisa Imai, Yurina Takada, Shingo Fujii, Takako Shono, Yoko Nanaumi, 2015. Identification and prevalence of adverse drug events caused by potentially inappropriate medication in homebound elderly patients: a retrospective study using a nationwide survey in Japan. BMJ Open, 5: :e007581. doi:10.1136/bmjopen-2015-007581.

[13] Christophe Soussan, Anette Kjellgren, 2016. The users of Novel Psychoactive Substances: Online survey about their characteristics, attitudes and motivations. International Journal of Drug Policy, 32: 77-84.

[14] M Wakakura, T Tsubouchi, J Inouye, 2004. Etizolam and benzodiazepine induced blepharospasm. Journal of Neurology Neurosurgical Psychiatry; 75: 506-509.

[15] Goro Fukami, Tasuku Hashimoto, Yukihiko Shirayama, Tadashi Hasegawa, Hiroyuki Watanabe, Mihisa Fujisaki, Kenji Hashimoto, Masaomi Iyo, 2010. Effects of etizolam and ethyl loflazepate on the P300 event-related potential in healthy subjects. Annals of General Psychiatry, 9:37. http://www.annals-general-psychiatry.com/content/9/1/37.

[16] Amira Guirguis, 2018. Novel psychoactive substances: understanding the new illegal drug market. The Pharmaceutical Journal. pharmaceutical-journal.com/opinion/insight/novel-psychoactive-substances-understanding-the-new-illegal-drug- market/20205503.article.