Designer Benzodiazepines: A Review of Toxicology and Public Health Risks

Abstract

The rising use of designer benzodiazepines (DBZD) is a cat-and-mouse game between organized crime and law enforcement. Non-prohibited benzodiazepines are introduced onto the global drug market and scheduled as rapidly as possible by international authorities. In response, DBZD are continuously modified to avoid legal sanctions and drug seizures and generally to increase the abuse potential of the DBZD. This results in an unpredictable fluctuation between the appearance and disappearance of DBZD in the illicit market. Thirty-one DBZD were considered for review after consulting the international early warning database, but only 3-hydroxyphenazepam, adinazolam, clonazolam, etizolam, deschloroetizolam, diclazepam, flualprazolam, flubromazepam, flubromazolam, meclonazepam, phenazepam and pyrazolam had sufficient data to contribute to this scoping review. A total of 49 reports describing 1 drug offense, 2 self-administration studies, 3 outpatient department admissions, 44 emergency department (ED) admissions, 63 driving under the influence of drugs (DUID) and 141 deaths reported between 2008 and 2021 are included in this study. Etizolam, flualprazolam flubromazolam and phenazepam were implicated in the majority of adverse-events, drug offenses and deaths. However, due to a general lack of knowledge of DBZD pharmacokinetics and toxicity, and due to a lack of validated analytical methods, total cases are much likely higher. Between 2019 and April 2020, DBZD were identified in 48% and 83% of postmortem and DUID cases reported to the UNODC, respectively, with flualprazolam, flubromazolam and etizolam as the most frequently detected substances. DBZD toxicology, public health risks and adverse events are reported.

The Psychonauts’ Benzodiazepines; Quantitative Structure-Activity Relationship (QSAR) Analysis and Docking Prediction of Their Biological Activity

“…They are usually ingested with other sedatives, primarily opioids, to potentiate their effects; promote ‘come down’ after stimulant use; or unintentionally, as counterfeits of prescription benzodiazepines [ 20 ]. Safety/toxicity profiles for most of the known DBZDs are not described yet, with limited knowledge of their pharmacodynamics and pharmacokinetics [ 15 , 25 , 26 ]. To date, the consumption of these new and unknown molecules is regarded as a serious threat to public health and society [ 20 , 27 , 28 ].…”

The blood-to-plasma ratio and predicted GABAA-binding affinity of designer benzodiazepines

“…Knowledge of the pharmacology of these designer benzodiazepines is important for harm reduction around the world as due to their illicit nature, they have not gone through the standard research and clinical testing of licensed medicines [10]. Although there has been a large amount of research into the physicochemical and pharmacological properties of benzodiazepines [11][12][13].…”

The alprazolam analogue 4′‐chloro deschloroalprazolam identified in seized capsules

“…Ten of these 30 designer benzodiazepines have been reported by the EMCDDA in the past 5 years, 12 indicating recent growth in the illicit benzodiazepine trade. Schedule IV of the Convention of Psychotropic Substances of 1971 lists 33 benzodiazepines 13,14 while the United Nations Office on Drugs and Crime (UNODC) lists 38 benzodiazepines under international control 15 . Each list encompasses both designer and commercially available compounds.…”

“…12 The first designer benzodiazepine with this structural moiety was flubromazepam listed in 2013, and the most recent was flualprazolam in 2018. 12 Flualprazolam is common in the current designer benzodiazepine market, 12,13 and as such, similar structures are likely to follow suite. Alprazolam is commonly prescribed for anxiety and panic disorders 17 under several prescription brands including the well-known Xanax.…”