Review
Piperazine compounds as drugs of abuse

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Abstract

Synthetic drugs are among the most commonly abused drugs in the world. This abuse is widespread among young people, especially in the dance club and rave scenes. Over the last several years, piperazine derived drugs have appeared, mainly available via the internet, and sold as ecstasy pills or under the names of Frenzy”, Bliss”, Charge”, Herbal ecstasy”, A2”, Legal X” and Legal E”. Although in the market piperazine designer drugs have the reputation of being safe, several experimental and epidemiological studies indicate risks for humans. Piperazine designer drugs can be divided into two classes, the benzylpiperazines such as N-benzylpiperazine (BZP) and its methylenedioxy analogue 1-(3,4-methylenedioxybenzyl)piperazine (MDBP), and the phenylpiperazines such as 1-(3-chlorophenyl)piperazine (mCPP), 1-(3-trifluoromethylphenyl)piperazine (TFMPP), and 1-(4-methoxyphenyl)piperazine (MeOPP). Toxicokinetic properties, including metabolic pathways, actions and effects in animals and humans, with some hypothesis of mechanism of action, and analytical approaches for the identification of these drugs are summarized in this review.

Introduction

The abuse of drugs is widespread all over the world. Synthetic drugs are among the most commonly abused and they have been consumed mainly at parties and night clubs by young people. The so-called designer drugs are a heterogeneous group of psychoactive substances obtained through the modification of chemical structure of some natural products or drugs (Mustata et al., 2009). The most common designer drugs are derived from phenylethylamine, as 3,4-methylenedioxymethamphetamine (MDMA). However, as these drugs become forbidden, new derivatives appear in the market to evade the law. In this context, piperazine derived drugs appeared on the market, mainly in the internet, sold as ecstasy pills or under the names of “Rapture,” “Frenzy,” “Bliss,” “Charge,” “Herbal ecstasy,” “A2,” “Legal X” and “Legal E.” Generally, they are consumed as capsules, tablets or pills but also in powder or liquid forms (Gee et al., 2005). They can also appear as an adulterant of MDMA and cocaine (Staack et al., 2007).

The first documented abuse of a piperazine derived drug occurred with N-benzylpiperazine (BZP) in the USA in 1996 (Austin and Monasterio, 2004). In September 2004, the new ecstasy-like substance 1-(3-chlorophenyl)piperazine (mCPP) was detected in street drugs in Sweden and in the Netherlands by the Drug Information and Monitoring System (DIMS). mCPP has been found in 26 member states of European Union (EU) and in Norway (Bossong et al., 2005, Kovaleva et al., 2008). It was estimated that in 2006, approximately 823,000 tablets of mCPP were seized in the EU (Kovaleva et al., 2008). In the Netherlands, the number of mCPP tablets seized alone or in combination with MDMA increased significantly from 2004 to 2007 (Bossong et al., 2010). A recent survey in the UK, found that piperazines are among the most common active drugs in tablets purchased from internet supplier sites (Davies et al., 2010). In New Zealand, the piperazine designer drugs known as party pills became a recent phenomenon (Gee et al., 2005, Sheridan et al., 2007). Piperazine designer drugs have also been detected in Japan (Takahashi et al., 2009) and Brazil (Lanaro et al., 2010). Markets for these drugs have also been developed in Bulgaria, Sweden and South Africa (Cohen and Butler, 2011). Nowadays, piperazine derived drugs including BZP and mCPP are under control in the EU, USA and New Zealand. In Brazil, besides BZP and mCPP, 1-(3-trifluoromethylphenyl)piperazine (TFMPP) is also under control. In competitive sports, the use of these substances is forbidden by the World Anti-Doping Agency (WADA).

Although in the corresponding drug scene the designer drugs have the reputation of being safe, several experimental, clinical, and epidemiological studies indicate risks to humans including a life-threatening serotonin syndrome, hepatotoxicity, neurotoxicity, psychopathology, and abuse potential of such drugs (Maurer et al., 2004).

Chemically, the piperazinic compounds are derived from piperazine, a cyclic molecule containing two nitrogens in opposite positions and four carbons distributed between the two nitrogen atoms (Fig. 1). They were originally used as anti-helmintic agents in the 1950s, and presently remain in human and veterinary pharmacotherapy (Haroz and Greenberg, 2006). Piperazine designer drugs can be divided into two classes, the benzylpiperazines such as N-benzylpiperazine (BZP) and its methylenedioxy analogue 1-(3,4-methylenedioxybenzyl)piperazine (MDBP), and the phenylpiperazines such as 1-(3-chlorophenyl)piperazine (mCPP), 1-(3-trifluoromethylphenyl)piperazine (TFMPP), and 1-(4-methoxyphenyl)piperazine (MeOPP) (Fig. 1). A third group of piperazine-like drugs includes the thienylmethylpiperazines.

BZP can be manufactured by reacting piperazine monohydrochloride with benzyl chloride. Other methods described include mixing of piperazine hexahydrate, piperazine dihydrochloride monohydrate and benzyl chloride, leading to the predominant product 1-BZP dihydrochloride, and the mixture of equal molar amounts of piperazine hexahydrate and benzyl chloride (Yeap et al., 2010).

BZP was originally synthesized by researchers from Burroughs, Wellcome & Co. as a de-worming agent for cattle. However, there is no published data about the use of BZP as a treatment for intestinal parasites. In the 1970s, BZP was investigated as an anti-depressant agent. Clinical trials were performed but they were abandoned due to reinforcing effects similar to dexamphetamine. Despite this finding, in the 1980s, BZP-derived compounds were once more tested as anti-depressant agents, namely Trelibet (EGYT-475) and befuraline (DIV-145). There is evidence that they reached phases I and II clinical trials and were found to act as a pro-drug, being metabolized to active BZP in humans (Kerr and Davis, 2011).

The aim of this review is to summarize current knowledge on dynamics, kinetics, and analytical methodologies for the identification of piperazine derivatives, including BZP, MDBP, mCPP, TFMPP, and MeOPP.

Section snippets

In vitro studies

Among the piperazinic compounds used as drugs of abuse, BZP is the most studied. It has been reported that the combination of BZP and TFMPP (2:1, in most of cases) in pills mimics the effects of MDMA in humans (de Boer et al., 2001). Studies in synaptosomes demonstrated that BZP is a releaser of 1-methyl-4-phenylpyridinium ion ([3H]MPP+), whereas TFMPP is a releaser of serotonin ([3H]-5-HT). These releasing properties are mediated by substrate activity at dopamine (DATs) and serotonin (SERTs)

Kinetics

Piperazines are readily absorbed from the gastrointestinal tract. A portion of the absorbed drug is metabolized and excreted in urine. There is wide variation in the rates at which piperazines are excreted by different individuals, which adds to the variability of their toxicity (Austin and Monasterio, 2004). The piperazine designer drugs are mainly metabolized in liver, being the phenylpiperazines more extensively metabolized than the benzylpiperazines, and excreted almost exclusively as

Clinical studies

Wilkins et al. (2008) realized a survey in New Zealand about patterns of uses and side effects of BZP/TFMPP party pills with 2010 participants. The users were characterized as being mainly male (60%), from European origin (75%), and with mean age of 23 years. The majority of consumers (89%) used party pills in combination with other drugs such as alcohol (91%), tobacco (37%), and cannabis (21%). The most reported adverse physical symptoms were insomnia (54%), headaches (26%) and nausea (21%).

Case-reports

The case-reports of documented piperazine-related intoxications are summarized in Table 2.

There is a case report of a male young adult who attended a party and ingested four tablets of a substance called Rapture. Twelve hours after the ingestion, he developed an acute psychotic episode associated with intense persecutory delusional beliefs and auditory and visual hallucinations. The symptoms completely abated within 48 h, with only benzodiazepines treatment (Austin and Monasterio, 2004).

A case

Analysis

There are several techniques used to detect piperazine designer drugs, from colorimetric tests to chromatographic analysis in different matrices.

Special concerns and treatment of intoxications

Patients with seizure disorders, psychiatric illness or coronary disease should avoid BZP as should those taking prescription sympathomimetics or anticholinergics. Coingestion with MDMA or amphetamine should also be cautioned against, as this combination could lead to fatal toxicity (Gee et al., 2005).

When patients present to healthcare-facilities with BZP toxicity, an electrocardiogram and an estimation of plasma sodium should be done. Those with moderate to severe toxicity may require

Conclusion

Piperazine-derived compounds are emerging designer drugs, whose abuse has increased remarkably worldwide. They are sold with the reputation of being safe. Nevertheless, they present stimulating and hallucinogenic effects, and cause unusual perceptions and experiences after ingestion. Also, there are several reports of toxic symptoms experienced by users after drug intake, including a fatal case, mainly when these drugs are taken in association. Toxicokinetic and toxicodynamic knowledge on the

Role of funding source

M.D. Arbo is the recipient of Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES Foundation – Brazil) fellowship (Proc BEX 0593/10-9).

Contributors

Author Marcelo Dutra Arbo wrote the first draft of the manuscript. Authors Maria de Lourdes Bastos and Helena Ferreira Carmo improved and corrected the version. All authors contributed to and have approved the final manuscript.

Conflict of interest

The authors declare that there are no conflicts of interest.

Acknowledgement

We would like to thank CAPES Foundation – Brazil for the fellowship.

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