Drug and Alcohol Dependence 157 (2015) 1–17 Contents lists available at ScienceDirect Drug and Alcohol Dependence j ournal homepage: www.elsevier.com/locate/drugalcdep Review Next generation of novel psychoactive substances on the horizon – A complex problem to face ∗ Jolanta B. Zawilska , Dariusz Andrzejczak Department of Pharmacodynamics, Medical University of Lodz, Poland a r t i c l e i n f o a b s t r a c t Article history: Background: The last decade has seen a rapid and continuous growth in the availability and use of novel Received 14 May 2015 psychoactive substances (NPS) across the world. Although various products are labeled with warnings Received in revised form “not for human consumption”, they are intended to mimic psychoactive effects of illicit drugs of abuse. 30 September 2015 Once some compounds become regulated, new analogues appear in order to satisfy consumers’ demands Accepted 30 September 2015 and at the same time to avoid criminalization. This review presents updated information on the second Available online 9 October 2015 generation of NPS, introduced as replacements of the already banned substances from this class, focusing on their pharmacological properties and metabolism, routes of administration, and effects in humans. Keywords: Methods: Literature search, covering years 2013–2015, was performed using the following keywords Novel psychoactive substances alone or in combination: “novel psychoactive substances”, “cathinones”, “synthetic cannabinoids”, Synthetic cannabimimetics Cathinones “benzofurans”, “phenethylamines”, “2C-drugs”, “NBOMe”, “methoxetamine”, “opioids”, “toxicity”, and Psychostimulants “metabolism”. NBOMe compounds Results: More than 400 NPS have been reported in Europe, with 255 detected in 2012–2014. The most Methoxetamine popular are synthetic cannabimimetics and psychostimulant cathinones; use of psychedelics and opioids Psychedelics is less common. Accumulating experimental and clinical data indicate that potential harms associated Opioids with the use of second generation NPS could be even more serious than those described for the already banned drugs. Conclusions: NPS are constantly emerging on the illicit drug market and represent an important health problem. A significant amount of research is needed in order to fully quantify both the short and long term effects of the second generation NPS, and their interaction with other drugs of abuse. © 2015 Elsevier Ireland Ltd. All rights reserved. Contents 1. Introduction . 2 2. Synthetic cannabimimetics (SCs) . 2 3. Synthetic cathinones . 8 4. Benzofuran analogues of amphetamines: 5-APB and 6-APB . 10 5. 4,4 -DMAR and MDMAR . 10 6. Hallucinogenic/psychedelic drugs . 10 6.1. NBOMes compounds – a second generation of 2C-phenethylamines . 10 6.2. Methoxetamine . 11 6.3. Diphenidine and 2-methoxydiphenidine . 12 7. Synthetic opioid-like drugs . 12 7.1. AH-7921 . 12 7.2. MT-45. .12 8. Conclusion . 13 ∗ Corresponding author at: Department of Pharmacodynamics, Medical University of Lodz, Muszynskiego´ 1, 90-151 Lodz, Poland. E-mail address: [email protected] (J.B. Zawilska). http://dx.doi.org/10.1016/j.drugalcdep.2015.09.030 0376-8716/© 2015 Elsevier Ireland Ltd. All rights reserved. Downloaded from ClinicalKey.com at Inova Fairfax Hospital - JCon January 07, 2017. For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved. 2 J.B. Zawilska, D. Andrzejczak / Drug and Alcohol Dependence 157 (2015) 1–17 Role of funding source . 13 Contributors. .13 Conflict of interest . 13 References . 14 1. Introduction the European Monitoring Centre for Drugs and Drug Addiction, EMCDDA (EMCDDA, 2015a). SCs are distributed under a variety The last decade has seen a rapid and continuous growth in of brand names; the most common are “Spice” in Europe, “K2” in the availability and use of novel psychoactive substances (NPS) the United States, “Kronic” in Australia and New Zealand (Zawilska across the world. They include a wide range of products that can and Wojcieszak, 2014). SCs containing products are typically sold be purchased online, from head shops, and drug dealers (EMCDDA, as smoking herbal mixtures in metal-foil sachets. Chemicals, most 2014a, 2015a; Papaseit et al., 2014; Vandrey et al., 2013; Zawilska, of them being manufactured in China, are mixed with or after dis- 2011). NPS are sold as ‘legal/herbal highs’, ‘bath salts’, ‘plant food’, solving in acetone, ethanol or methanol sprayed onto herbs such ‘insect repellents’, ‘research chemicals’, ‘air fresheners’, with the as Mellissa, Mentha, Thymus, and Damiana. The herbal material is disclaimer “not for human consumption” or “for research pur- then dried and packaged for sale (EMCDDA, 2015b). The presence poses only” to circumvent drug abuse legislation (EMCDDA, 2014a, of the herbal substrate gives consumers an impression that they are 2015a; Zawilska, 2011). The European Union (EU) Early Warning indeed smoking a natural product. Most products contain several System (EWS) noted the appearance of 418 new psychoactive sub- SCs in a single preparation, thereby increasing a risk of overdose stances during the period of May 2005–December 2014, and a and acute intoxication (EMCDDA, 2015b). sevenfold increase in reported seizures of NPS between 2008 and SCs belong to at least 14 chemically diverse families, have struc- 9 9 2013 (EMCDDA, 2015a). In 2014 only, 101 new substances, around tures unrelated to -tetrahydrocannabinol ( -THC), different two per week, were reported to the EWS; among them 31 designer metabolism, and often greater toxicity (e.g., Castaneto et al., 2014; cathinones, 30 synthetic cannabimimetics, and 9 phenethylamines ElSohly et al., 2014; Fantegrossi et al., 2014). Despite of marked (EMCDDA, 2015a). A World Drug Report revealed in a world-wide differences in their chemical structure, all SCs are lipid soluble, non- survey of 80 countries that 70 countries had reported the emer- polar, and typically consist of 20–26 carbon atoms, which explains gence of NPS in recent years (UNODC, 2013). It has been estimated why they volatilize readily when smoked (Castaneto et al., 2014). that 2.9 million people aged 15–24 (around 5% of the total) in the First-generation SCs primarily constituted of JWH compounds, EU have already tried NPS (Corazza et al., 2014). originally synthesized by John W. Huffman, the medicinal A growing interest in the use of NPS together with public health chemist at the Clemson University, Clemson, USA (Zawilska and dangers posed by these drugs has forced a development of var- Wojcieszak, 2014). Over the past few years several new SCs ious sensitive analytical methods to identify and quantify these have been identified, including, among others, UR-144, 5F-UR- compounds and their downstream metabolites in suspected prod- 144 (XLR-11), PB-22 (QUPIC; an analogue of JWH 018 which ucts and human biological samples (blood, serum, urine, oral fluids differs by having 8-hydroxyquinoline replacing the naphthalene and hair). They include liquid chromatography–tandem mass spec- group of JWH 018), 5F-PB-22, BB-22 (QUCHIC; structurally sim- trometry, liquid chromatography coupled to quadrupole-time-of ilar to PB-22), AB-PINACA, 5F-AB-PINACA, ADB-PINACA, AKB-48 flight mass spectrometry, gas chromatography/mass spectrome- (APINACA), 5F-AKB-48, and AB-FUBINACA (DEA, 2014a, 2015a, try, matrix-assisted/laser desorption/ionization time of flight mass 2015b; EMCDDA, 2015b; Uchiyama et al., 2013). It should be spectroscopy, direct analysis in real time mass spectrometry, emphasized that fluorine substitution at the 5-pentyl position of nuclear magnetic resonance, and immunoassays (e.g., Adamowicz pentylindole/pentylindazole, recently a popular structural modi- and Tokarczyk, 2015; ElSohly et al., 2014; Johnson et al., 2014; fication of SCs, generally enhances compounds potency, stability Lanza et al., 2015; Poklis et al., 2014a, 2014b; Tang et al., 2014a). and prolongs half-life time. UR-144 (‘KM X-1’) has been designed NPS represent a heterogenous family of substances, including, by Abbott Laboratories in a search for selective agonists of cannabi- among others, synthetic cannabimimetics, synthetic cathinones, noid CB2 receptors (Frost et al., 2010). The compound preferentially phenethylamines, piperazines, ketamine- and phencyclidine-type binds to peripheral CB2 receptors over brain CB1 receptors (Wiley substances, tryptamines, benzofuranes, and opioids (Papaseit et al., et al., 2013). 5F-UR-144 (XLR-11), a 5-fluorinated analogue of 2014). Synthetic cannabimimetics and designer cathinones make UR-144, is a potent full agonist of CB1 and CB2 receptors. In a up the largest groups of NPS, and in 2014 represented more than battery of tests (rectal temperature, warm water tail withdrawal, two thirds of compounds notified in the EU (EMCDDA, 2015a). The spontaneous locomotor activity, and ring immobility) both com- aim of the current contribution is to present updated information pounds produced characteristic cannabinoid tetrad of effects, i.e., on the second generation of NPS; compounds that have been intro- hypothermia, analgesia, catalepsy, and suppression of locomotor duced as replacements of the banned novel psychoactive drugs as activity, that were blocked by rimonabant, an inverse agonist of means to evade regulatory control. The list of NPS discussed in cannabinoid receptors. The potency of UR-144 and XLR-11 was 9 this review is given in Table 1, and photographs of representative several-fold greater than that of -THC (Wiley et al., 2013). PB-22, packing for different classes of compounds are shown in Fig. 1. its fluorinated analogue 5F-PB-22, and BB-22 were first reported in Japan in early 2013. An increasing prevalence of PB-22 and 2. Synthetic cannabimimetics (SCs) 5F-PB-22 indicates that they could replace UR-144 and XLR-11 (Wohlfarth et al., 2014). PB-22 and 5F-PB-22 potently decreased Originally developed for research purposes, SCs began to appear locomotor activity up to.