Clinician’s Corner

Rapid Synthesis – Etizolam: A rapid review on pharmacology, non‐medical use and harms

In December 2019 NSW Health published a warning that counterfeit alprazolam tablets were being sold that contained the benzodiazepine etizolam. Etizolam is considered a new psychoactive substance, sometimes referred to as a ‘research chemical’, ‘street benzodiazepine’ or a ‘designer benzodiazepine’, although it is licenced for therapeutic use for anxiety in Italy, India and Japan, but is used non-medically in many other countries. Etizolam contributed to 548 deaths in 2018 in Scotland, more than three-quarters of all "street benzodiazepine" deaths. Despite these considerable harms, there were no published reviews that describe the non-medical use of etizolam (i.e. use outside a medical context), how it might be different from other benzodiazepines or what appropriate harm reduction advice might be. We wrote this rapid synthesis article to address this gap.

First, we considered whether the pharmacological or toxicological profile of etizolam differed from other benzodiazepines. Etizolam is a very short-acting benzodiazepine with a half-life of 5-7 hours (compared with 8-15 hours for alprazolam and 20-70 hours for diazepam). Although it is short acting, etizolam is metabolised into α-hydroxyetizolam, which has a longer half-life and may mean that the actual effects of etizolam last for longer than its half-life might imply.

Etizolam’s main effects are anxiolytic (i.e. to reduce anxiety) rather than sedative. A usual therapeutic dose is 0.5mg twice a day, with a maximum of 3mg per day. As an anxiolytic, etizolam is also considered to be more potent than other benzodiazepines – for example, 1mg of etizolam is considered roughly equivalent to about 5mg of diazepam.

This greater potency as an anxiolytic doesn’t necessarily translate to more harms in clinical use. Animal studies show that etizolam appears less lethal than benzodiazepines like diazepam. Some older clinical trials compared etizolam with other benzodiazepines, such as lorazepam, and showed that etizolam may be less likely to cause dependence, though these studies did not recruit people with substance use disorders. These studies did not test doses of etizolam that reflect the higher doses that are typically consumed with illicitly manufactured etizolam, so we still don’t know a lot about the relative safety profile for etizolam compared to other benzodiazepines when used non- medically.

We then sought to understand the context of non-medical etizolam use, and describe the nature of etizolam-related harms. In Scotland, etizolam is commonly sold as illegally manufactured pills, so the dose per tablet and the quality of the manufacturing process is unknown. Etizolam is available for as low as 5p per tablet (equivalent to about 10c in Australia). There are reports of people taking multiple tablets at a time (which can equate to large doses).

Etizolam, like other benzodiazepines, can cause dependence. Dependence is rarely reported with therapeutic use, though there are numerous reports describing tolerance and withdrawal on websites such as Bluelight, where people share experiences of using drugs. There now seems to be widespread non-medical use among people who use drugs in Scotland and Ireland.

Etizolam toxicity symptoms include central nervous system depression, slurred speech, severe sedation and unconsciousness (much like toxicity with other benzodiazepines). The benzodiazepine antagonist flumazenil has been shown to effectively reverse these symptoms. The most significant harms associated with etizolam use typically occur when etizolam is taken with other drugs, for example, in combination with opioids. Overdose mortality involving etizolam alone is rare. The low price of etizolam tablets, the unknown strength of the tablets, and the practice of taking etizolam in large doses with other drugs probably explains the high mortality associated with its use in Scotland, where etizolam use is now implicated in the majority of drug-related deaths (see figure below).

Figure 1 - Benzodiazepine-related deaths in Scotland 2009-2018

Summary for clinicians

Most harms with etizolam seem to be linked to the wide availability of cheap, illicitly manufactured pills, which are taken in unknown doses in combination with other substances. Current harm reduction advice, including avoiding combining benzodiazepines with other sedatives (e.g. opioids or alcohol), remains relevant and increasingly important. Where benzodiazepines are taken, the use of regulated benzodiazepines with known content may be less harmful than illicitly manufactured etizolam, though the best advice is to avoiding combining benzodiazepines with alcohol or opioids.

Suzanne Nielsen BPharm (Hons) PhD Deputy Director, Monash Addiction Research Centre, Monash University and NHMRC Career Development Fellow.

Dr Andrew McAuley PhD Senior Research Fellow, School of Health and Life Sciences, Glasgow Caledonian University

*A complimentary PDF of the article is available to APSAD members by emailing [email protected].