Synthetic cathinones – From natural plant stimulant to new drug of abuse
Introduction
Many new psychoactive substances (NPSs) were created throughout the 1960s and the remainder of the 20th century. While they may not have been referred to specifically as NPSs, drug analogues have been continually developed for decades. As recreational substances, NPSs started to be used on a large scale at the beginning of the 21st century. United Nations Office on Drugs and Crime (UNODC) defines NPSs as ‘substances of abuse, either in a pure form or a preparation, that are not controlled by the 1961 Single Convention on Narcotic Drugs or the 1971 Convention on Psychotropic Substances, but which may pose a public health threat’. This definition, therefore, excludes all internationally classified substances, including 3,4-methylenedioxymethamphetamine (MDMA) and amphetamines. The term ‘new’ does not necessarily refer to new inventions—several NPSs were first synthesized 40 years ago—but to substances that have recently become available on the market (UNODC). These compounds affect the human central nervous system (CNS) in a manner similar to drugs that have been known for a long time, such as amphetamine, cannabis, heroin, or LSD. NPSs are a heterogeneous group of natural, semi-synthetic, and synthetic compounds. The most popular NPSs include synthetic cathinones and synthetic cannabinoids. Over the past few years, the illicit drug market has seen an increase in the number of psychostimulants known as NPSs psychoactive substances, designer drugs, bath salts, plant food, research chemicals, vacuum freshener, pond cleaner, jewelry cleaner, or insect repellent (Zawilska et al., 2013).
In order to avoid criminal liability, preparations containing synthetic cathinones are usually labelled ‘substance not suitable for human consumption’, ‘not tested for safety or toxicity’, ‘keep out of reach of children’, etc. These preparations are purchased mainly in online stores and less often in brick-and-mortar shops or directly from people who distribute them. The composition of products offered under the same trade names may vary with regard to the amount (concentration) of psychoactive substances affecting the CNS and they may even contain other types of substances than those specified on their labels, which means that their users do not always know what substance they consume and in what quantity. Both quality and quantity of synthetic cathinones available on the drug market are inadequate (Adamowicz et al, 2016a,b; Odoardi et al., 2016). Many products increasingly contain not only single active ingredients but also combinations of two or more derivatives. They often include admixtures, e.g. caffeine and lidocaine (Capriola, 2013). Synthetic cathinones are sometimes sold as cocaine or ecstasy (MDMA) (EMCDDA, 2015b).
On the illicit market, synthetic cathinones are usually distributed in the forms of white powder, crystals, or capsules, while the tablet form is less popular. Synthetic cathinones are usually taken orally (capsules, water solutions, and tablets) and nasally (snorting of a powdered substance and its absorption through the nasal mucosa). In order to absorb a single large dose of a synthetic cathinone, users swallow the substance wrapped in cigarette paper (so-called ‘bombing’) (German et al., 2014; Prosser et al., 2012). Due to high water solubility, synthetic cathinones are also taken by intravenous and intramuscular injections and used in the form of enemas. It has been reported that in some cases intravenous injections were followed by venous thromboses and embolisms as well as local infections, abscesses, scabs, and scars (EMCDDA, 2015a). Opioid injectors also often declare injecting synthetic cathinones (EMCDDA, 2015b; Péterfi et al., 2014). There have been several reports warning of the rising popularity of intravenous use of synthetic cathinones (EMCDDA, 2015a). Synthetic cathinones are sometimes used in so-called ‘mephedrone sessions’, which means taking substances in several repeated doses within a few hours and usually in a specific social situation (e.g. at friends' homes, at a home party, or in nightclubs) (German et al., 2014).
Users of synthetic cathinones give a number of reasons for taking these substances, including the legal status (legality), availability (purchased mainly via the Internet), acceptable price (lower compared to conventional drugs), lack of rapid screening tests to confirm their intake, or user preferences for specific pharmacological properties, e.g. they are taken to enhance social and sexual experiences (Benschop et al., 2017).
Due to the initial legal status of synthetic cathinones, they were regarded as ‘legal highs’ and often considered by users as safe alternatives to other commonly abused stimulants. The first drugs from this group on the illicit market were methcathinone and 4-methylmethcathinone (4-MMC, mephedrone), followed by 3,4-methylenedioxymethcathinone (MDMC, methylone), 3,4-methylenedioxypyrovalerone (MDPV), 4-methoxymethcathinone (methedrone), and α-pyrrolidinopropiophenone (PPP) (EMCDDA, 2015b). Initially, mephedrone and MDPV were cathinones most commonly found in ‘bath salt’ products in Europe. Mephedrone gained its popularity due to, among others, the low quality and difficulties in obtaining cocaine or MDMA (EMCDDA, 2016). The speed with which synthetic cathinones emerged among the wider population of drug users and the scale of their adverse health effects resulted in introduction of legal control over these compounds.
Currently, synthetic cathinones are the second largest group of new psychoactive substances among over 670 NPSs identified in Europe and monitored by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). According to an EMCDDA report, a total of 130 synthetic cathinones were registered in Europe by the end of 2017 and 12 such substances were identified for the first time that year (EMCDDA, 2018). In 2016, synthetic cathinones accounted for almost one-third (over 23,000) of the overall number of seizures of NPSs. The total number of seized synthetic cathinones approaches 1.9 tonnes, putting them in the first place on the list of seized NPSs in 2016 (EMCDDA, 2016).
Reports assessing the demographic data on synthetic cathinone users conclude that the respondents are mostly young males. A review of data collected from six EU countries (Germany, Hungary, Ireland, the Netherlands, Poland, and Portugal) found out that the Internet community interested in the subject of synthetic cathinones consisted of people aged 18 to 25 years; however, the profile of synthetic cathinone users was most likely in the age group of 18–35 years (Benschop et al., 2017).
Section snippets
Chemical properties
Synthetic cathinones are structural analogues of cathinone, a psychostimulant alkaloid present in khat (Catha edulis). Khat has been known and used for centuries by the people of East Africa and north-eastern part of the Arabian Peninsula due to its psychoactive properties. It was discovered in Yemen in the 18th century by the botanist Peter Forskal. According to historical references, the practice of chewing khat leaves for their euphoric and stimulant effects dates back many centuries; today,
Pharmacoclinical effects
Each year, up to several dozen psychoactive substances enter the drug market on which there is little or no literature data concerning their physicochemistry, pharmacology, or toxicity. There is a lack of detailed data on the effects of synthetic cathinones on the human body, although they are known to exhibit many structural, pharmacological, and behavioural effects similar to amphetamine and its derivatives (Simmler et al., 2014).
Some cathinones, for example pyrovalerone derivatives, were
Toxicity
Toxicity of synthetic cathinones is directly related to the structure (chemical composition) of a given substance (Glennon and Dukat, 2016) and also depends on the taken dose of a single substance or mixture. Mechanisms of action of synthetic cathinones are studied in experimental animal models and in in vitro cell cultures. However, only a limited number of these compounds have been tested (Table 2). Analysis of the results of these studies is complex not only because of differences in
Non-fatal intoxications and interpretation of concentrations
The most important aspect of forensic toxicological detection of acute intoxication cases are cathinone levels determined in serum. For example, Beck at al. presented 114 cases of intoxication with synthetic cathinones, confirmed analytically in the urine or serum of the patients. Apart from MDPV and α-PVP, which were the most popular, eleven other pyrovalerone derivatives were found (Beck et al., 2018). The following were determined most often: 4′-fluoro-α-pyrrolidinopentiophenone
Combined effects of synthetic cathinones and other psychoactive substances
One of the main problems of modern forensic toxicology is invariably the abuse of several psychoactive substances at the same time. The exact reasons why users combine several types of psychoactive substances remain unknown. Unfortunately, people abuse synthetic cathinones along with synthetic cannabinoids or cannabis and animal studies on the effects of these combinations are still lacking.
Some studies allow to compare the pharmacological mechanisms of action between NPSs and amphetamines,
Summary
Despite the tightening and changing legal regulations concerning production, processing, selling, and possessing substances from the group of synthetic cathinones, abuse of these compounds for recreational purposes still remains at a high level. Although the first synthetic cathinones were synthesized in the 1920s, a rapid increase in the popularity of these substances on the illicit drug market has been recorded after the year 2000 and is probably fuelled by the legality of these substances.
Author contributions
Piotr Czekaj, Ewelina Pieprzyca, Rafał Skowronek: concept, desig, review & editing.
Ewelina Pieprzyca, Rafał Skowronek, Ľuboš Nižnanský and Piotr Czekaj: writing original draft.
Declaration of competing interest
The authors declare no conflict of interest.
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