Pharmacokinetics, pharmacodynamics and toxicology of new psychoactive substances (NPS): 2C-B, 4-fluoroamphetamine and benzofurans

Highlights

• A number of new psychoactive substances (NPS) enter the European drug market yearly.

• Frequently detected NPS are 4-bromo-2,5-dimethoxyphenethylamine (2C-B), 4-fluoroamphetamine (4-FA) and benzofurans.

• 2C-B, 4-FA and benzofurans can cause sympathomimetic effects.

• In contrast to 4-FA, 2C-B and benzofurans can cause severe psychological symptoms.

Abstract

Background

Recently, the number of new psychoactive substances (NPS) appearing on the illicit drug market has shown a marked increase. Although many users perceive the risk of using NPS as medium or low, these substances can pose a serious health risk and several NPS have been implicated in drug-related deaths. In Europe, frequently detected NPS are 4-bromo-2,5-dimethoxyphenethylamine (2C-B), 4-fluoroamphetamine (4-FA) and benzofurans (5-(2-aminopropyl)benzofuran (5-APB) or 6-(2-aminopropyl)benzofuran (6-APB)). However, little is known about the health risks of these specific NPS.

Methods

In this paper, existing literature on the pharmacokinetics and pharmacodynamics of 2C-B, 4-FA and benzofurans (5-APB/6-APB) was reviewed.

Results

Our review showed that the clinical effects of 2C-B, 4-FA and benzofurans (5-APB/6-APB) are comparable with common illicit drugs like amphetamine and 3,4-methylenedioxymethamphetamine (MDMA). Therefore, NPS toxicity can be handled by existing treatment guidelines that are based on clinical effects instead of the specific drug involved. Even so, information on the health risks of these substances is limited to a number of case reports that are complicated by confounders such as analytical difficulties, mislabelling of drugs, concomitant exposures and interindividual differences.

Conclusion

To aid in early legislation, data on clinical effects from poisons centres and user fora should be combined with (in vitro) screening methods and collaboration on an (inter)national level is essential. As a result, potentially hazardous NPS could be detected more quickly, thereby protecting public health.

Introduction

Over the past years, an increasing number of new psychoactive substances (NPS) has become available on the worldwide illicit drug market. The presence of NPS on the European drug market is monitored by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) which has reported an ongoing increase of newly detected NPS every year. The number of first time notified NPS reported to the EMCDDA increased from 15 in 2007 to 101 in 2014 (EMCDDA, 2007, EMCDDA, 2015a), bringing the total number of presently monitored NPS to more than 450.

NPS are defined as new narcotic or psychotropic drugs, in pure form or preparation, that are not controlled by the 1961 United Nations Single Convention on Narcotic Drugs or the 1971 United Nations Convention on Psychotropic Substances, but which may pose a public health threat comparable to substances that are listed in these two conventions (EMCDDA, 2006). Many NPS were developed years ago and are therefore not newly designed but are in fact, newly introduced on the user's market. NPS can be divided in several groups based on their chemical structure or mechanism of action. These groups include: piperazines, benzodiazepines, arylamines, tryptamines, opioids, phenethylamines, synthetic cannabinoids, synthetic cathinons and other substances (EMCDDA, 2015a).

One of the main groups of NPS that are notified to the EMCDDA by European member states are synthetic phenethylamines (EMCDDA, 2014). The interest in these substances increased with the publication of the book ‘Phenethylamines I Have Known and Loved (PIHKAL)’ in 1991 (Shulgin and Shulgin, 1991). From that time onwards, mainly ring-substituted phenethylamines like 4-bromo-2,5-dimethoxyphenethylamine (2C-B) were encountered on the international drug market. However, in recent years, other phenethylamines have started to appear. Since 2005, the most commonly encountered phenethylamines in the EU include 4-fluoroamphetamine (4-FA) and 2C-related substances like 2,5-dimethoxy-4-iodophenethylamine (2C-I) and 2,5-dimethoxy-4-ethylphenethylamine (2C-E). Because 2C-B was added to Schedule II of the 1971 Convention on Psychotropic Substances, it is by definition not an NPS. Nevertheless, 2C-B is still the most frequently reported “new” phenethylamine to the EMCDDA (King, 2014).

Like in the EU, 2C-B and 4-FA were the most frequently detected NPS in the Netherlands in 2013. In addition, benzofurans (5-(2-aminopropyl)benzofuran (5-APB) or 6-(2-aminopropyl)benzofuran (6-APB)) were also frequently detected (Hondebrink et al., 2015). 5-APB and 6-APB were first reported to the EMCDDA in 2010 (5-APB, United Kingdom) and 2011 (6-APB, Hungary) (EMCDDA, 2010a, EMCDDA, 2011). Since then, their presence on the illicit drug market has rapidly increased. For instance, 6-APB was amongst the most frequently offered NPS in online shops in 2012, indicating widespread (online) availability (EMCDDA, 2012).

In addition to national and international monitoring systems that detect the presence of NPS on the illicit drug market, data on actual NPS use can be obtained from survey studies, mainly on sub-population level. For example, a recent European survey amongst ∼13,000 young adults reported a lifetime and last year's prevalence of NPS use of 8% and 3%, respectively. Although NPS are not the most frequently used drugs of abuse, their use is increasing with a lifetime prevalence of 5% in 2011 to 8% in 2014 (Flash Eurobarometer, 2011, Flash Eurobarometer, 2014). In addition, a study amongst Spanish students reported an overall lifetime use of ‘legal highs’ of 0.7%, with the use of ‘research chemicals’, ‘Spice’ products and mephedrone, being 0.4%, 1.1% and 0.4%, respectively (Clinical Committee, 2011). Furthermore, the lifetime and last year's prevalence of use of ‘benzofury’ was reported to be 2.7% and 2.3% in nightlife visitors, mainly from the United Kingdom (EMCDDA, 2013). In the Netherlands, last year's prevalence of use of 2C-B and 4-FA was comparable to that of established drugs in 2013, like psychedelic mushrooms, GHB and ketamine (∼10%, Goossens et al., 2014). Recently, a novel method to investigate trends in drug use was applied, in which pooled urine samples collected from stand-alone urinals in central London were analysed. During a 6-month period, this resulted in the detection of 13 NPS, including mephedrone and 5-APB (Archer et al., 2012, Archer et al., 2014).

A recent US study combining several databases to provide insight in the characteristics of NPS users, showed that NPS users are primarily young male adults (Maxwell, 2014). Although this is consistent with other studies (Helander et al., 2013, Helander et al., 2014, Winstock et al., 2014, Vazirian et al., 2015, Hondebrink et al., 2015), NPS use has also been reported in teens and adults up to 73 years of age (Carhart-Harris et al., 2011). NPS use often takes place at a party or event (65%) and with friends (60%) (Flash Eurobarometer 401, 2014).

According to the Flash Eurobarometer survey, most users obtain NPS via a friend (70%), whereas a minority (30%) buy them from a drug dealer. Although NPS can readily be purchased on the Internet and in specialized smart- or headshops (EMCDDA, 2012), these sources of drug purchase were reported by only 13% of the respondents in this survey (Flash Eurobarometer 401, 2014). In contrast, a different study reported ‘purchased over the Internet’ (71%) followed by ‘received from a friend’ (10%) as the most common sources of NPS (Helander et al., 2013). These differences might be explained by the connectivity (rural or urban area) of NPS users to multiple sources of drug purchase (Bilinski et al., 2012, Flash Eurobarometer, 2011).

There is a perception that NPS are relatively safe; only 60% of young adults perceive the health risk of using NPS as high, whereas 40% perceive it as medium to low (Flash Eurobarometer 401, 2014). In addition, not all NPS dealers provide information on ingredients, advised dosage and negative side effects and many market their products as ‘herbal’ or ‘natural drugs’, implying there are no health risks (Hillebrand et al., 2010). Even so, NPS use can pose serious health threats resulting in hospitalization and deaths. The European Union Early Warning System for NPS has issued ∼80 public health alerts during the last five years to alert the network on serious and urgent issues regarding NPS use (EMCDDA, 2015a). In addition, approximately 10% of all drug-related emergency department visits in Europe involved NPS. Although systematic data on NPS-related deaths is difficult to find, some data is available. In Hungary, NPS were involved in roughly half of the reported drug-induced deaths in 2013. In addition, the Early Warning System indicated that methylenedioxypyrovalerone (MDPV, first detected in 2008) was involved in 99 deaths at the time of its risk assessment in 2014 (EMCDDA, 2015b). Also, forensic casework has recently shown an increased presence of benzofurans (5-APB/6-APB) (Elliott and Evans, 2014), indicating potential toxicity and mortality. Notably, benzofurans have been implicated in several deaths in recent years (Clemente et al., 2012), although analytical confirmation is often lacking. Furthermore, the Dutch Poisons Information Centre (DPIC) was consulted about 35 NPS exposures in 2013 and 77 in 2014, mostly involving 4-FA, mephedrone, methoxetamine, 2C-B and benzofurans (5-APB/6-APB) (Hondebrink et al., 2015, Mulder-Spijkerboer et al., 2015).

Despite the increasing use and presence of NPS on the illicit drug market, the health risks associated with the use of many frequently detected NPS are not well known. This information is not only of importance for healthcare professionals to provide appropriate treatment in case of an overdose, but is also crucial in the process of legislation, prevention and control (Wood and Dargan, 2012). Due to their structural resemblance, it is likely that clinical effects following NPS exposure partly overlap those following exposure to more common illicit drugs, like amphetamine or 3,4-methylenedioxy-methamphetamine (MDMA, the main active ingredient in ecstasy) (Table 1). Nevertheless, the need for peer-reviewed data is high. To investigate the clinical effects following NPS use, we performed a literature review for two of the most frequently detected new phenethylamines in the EU, 2C-B and 4-FA. In addition, we reviewed the literature on benzofurans, because of their increasing popularity and potential for serious health effects. Mephedrone and methoxetamine were excluded from this review, as their pharmacokinetics and pharmacodynamics have been recently reviewed elsewhere (Dybdal-Hargreaves et al., 2013, Miotto et al., 2013, Zawilska, 2014).