Piperazine designer drugs elicit toxicity in the alternative in vivo model Caenorhabditis elegans

Abstract

Piperazine designer drugs are a group of synthetic drugs of abuse that have appeared on the illicit market since the second half of the 1990s. The most common derivatives are 1‐benzylpiperazine (BZP), 1‐(4‐methoxyphenyl)piperazine (MeOPP) and 1‐(3,4‐methylenedioxybenzyl)piperazine (MDBP). They can be consumed as capsules, tablets, but also in powder or liquid forms. Generally, although less potent than amphetamines, piperazines have dopaminergic and serotonergic activities. The aim of this work was to evaluate the toxic effects of BZP, MeOPP and MDBP using Caenorhabditis elegans as in vivo model for acute toxicity, development, reproduction and behavior testing. The LC50 for BZP, MeOPP and MDBP were 52.21, 5.72 and 1.22 mm, respectively. All concentrations induced a significant decrease in the body surface of the worms, indicating developmental alterations, and decrease in the brood size. Worms exposed to piperazine designer drugs also presented a decrease in locomotor activity and mechanical sensitivity, suggesting the possible dysfunction of the nervous system. Neuronal damage was confirmed through the decrease in fluorescence of BY200 strains, indicating loss of dopaminergic transporters. In conclusion, we suggest that piperazine designer drugs lead to neuronal damage, which might be the underlying cause of the altered behavior observed in humans.

An Update on the Implications of New Psychoactive Substances in Public Health

“…They are completely synthetic and have been widely sold as legal party pills, powder of pure substances, and adulterants due to their stimulant pharmacological properties. Piperazine (Figure 1) is an N-heterocyclic bioactive natural product extensively present in biologically active compounds [13,[31][32][33], and was used as anti-helminthic [34]. The two main structural groups that form the piperazine-based compounds are 1benzylpiperazine and 1-phenylpiperazine (Supplementary Material Table S1 and Figure 1) [10,13,31,32,[35][36][37][38][39][40].…”

“…Piperazine (Figure 1) is an N-heterocyclic bioactive natural product extensively present in biologically active compounds [13,[31][32][33], and was used as anti-helminthic [34]. The two main structural groups that form the piperazine-based compounds are 1benzylpiperazine and 1-phenylpiperazine (Supplementary Material Table S1 and Figure 1) [10,13,31,32,[35][36][37][38][39][40]. The two main structural groups that form the piperazine-based compounds are 1benzylpiperazine and 1-phenylpiperazine (Supplementary Material Table S1 and Figure 1) [10,13,31,32,[35][36][37][38][39][40].…”

“…In the second half of the 1990s, piperazine designer drugs emerged in the illicit market, but the United States and Scandinavia were the only regions reporting high consumption rates [31,35,41]. N-benzylpiperazine (BZP) was the first consumed derivative of piperazines in 1996 in the United States.…”

“…In England and Wales, between 2008 and 2009, deaths caused by drugs of abuse mainly involved piperazines. Currently, these compounds have spread worldwide, and around 10% of the population from developed countries has already used these types of designer drugs [31,35]. Piperazines are among the leading deaths caused by synthetic psychoactive stimulants and hallucinogens [43].…”

“…Piperazine derived drugs can be consumed as capsules, tablets, loose powders, or in liquid forms, and can also appear as adulterants of MDMA and cocaine [13,31,35]. Therefore, they can enter the system through oral ingestion, nasal insufflation, injection, and smoking [35].…”