The Evolution Toward Designer Benzodiazepines in Drug-Facilitated Sexual Assault Cases

Abstract

Drug-facilitated sexual assault (DFSA) is a crime where the victim is unable to provide sexual consent due to an incapacitation resulting from alcohol or drug consumption. Due to the large number of substances possibly used in DFSA, including illicit, prescription and over-the-counter drugs, DFSA faces many toxicological challenges. Benzodiazepines (BZDs) are ideal candidates for DFSA, as they are active at low doses, have a fast onset of action, and can be easily administered orally. The last decade has seen the emergence of designer benzodiazepines (DBZDs), which show slight modifications compared with BZDs and similar pharmacological effects, but are are not controlled under the international drug control system. DBZDs represent an additional challenge due to the number of new entities regularly appearing on the market, their possibly higher potency, and the limited knowledge available on their pharmacokinetic and pharmacodynamics properties. Many BZDs and DBZDs have a short half-life, leading to rapid metabolism and excretion. The low concentrations and short time windows for the detection of BZD in body fluids require the use of highly sensitive analysis methods to enable the detection of drugs and their respective metabolites. This review discusses the current state of the toxicological analysis of BZDs and DBZDs in forensic casework, their pharmacokinetic properties (i.e., absorption, distribution, metabolism, and elimination), as well as their analysis in biosamples typically encountered in DFSA (i.e., blood, urine and hair).

Designer Benzodiazepines: Effects, Toxicity, and Interactions

“…The log 1/c values predicted for several DBZDs (22 DBZDs in the study by Waters et al and 76 in the study by Catalaini et al) allowed the classification of molecules with predicted values higher than 8.0, considered to possess high GABA A R affinity. Interestingly, etizolam and flualprazolam, 2 of the most popular DBZDs 69 responsible for multiple fatalities, [70][71][72][73][74] showed predicted log 1/c values of 8.10 and 8.40, respectively. The top 10 predicted log 1/c values identified by Catalani et al showed putative biological activity levels up to 10 times higher (log 1/c = 9.40).…”

The use of prodrugs as drugs of abuse

“…While there are a number of available designer benzodiazepines that are the active metabolite of a known benzodiazepine (desmethylflunitrazepam is the active metabolite of flunitrazepam; 3‐hydroxyphenazepam is the active metabolite of phenazepam), little is known about the active pharmacology of those compounds, but it is inferred that they are similar to the parent drugs (Katselou et al, 2017; Wilde et al, 2021). Nordiazepam, a desmethyl metabolite of diazepam, and cloniprazepam, a prodrug of clonazepam, have also been implicated in criminal cases (Orsolini et al, 2020; Pérez Orts et al, 2023; Yu et al, 2023; Wilde et al, 2021; Zawilska & Wojcieszak, 2019).…”

“…The effects of designer benzodiazepines that are active metabolites of other benzodiazepines are thought to be similar to those of the parent drugs, although the exact pharmacology may still be unknown and half‐lives are a challenge to estimate (Wilde et al, 2021). Designer benzodiazepines have been implicated in drug‐facilitated sexual assaults, including nordiazepam (desmethyldiazepam) an active metabolite of diazepam (Morgillo et al, 2023; Pérez Orts et al, 2023).…”