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Drug and Alcohol Dependence 157 (2015) 1–17

Contents lists available at ScienceDirect

Drug and Alcohol Dependence

j ourna l h o me pa ge: www.elsev ier .com/ locate /drugalcdep

eview

ext generation of novel psychoactive substances on the horizon – Aomplex problem to face

olanta B. Zawilska ∗, Dariusz Andrzejczakepartment of Pharmacodynamics, Medical University of Lodz, Poland

r t i c l e i n f o

rticle history:eceived 14 May 2015eceived in revised form0 September 2015ccepted 30 September 2015vailable online 9 October 2015

eywords:ovel psychoactive substancesynthetic cannabimimeticsathinonessychostimulantsBOMe compoundsethoxetamine

sychedelicspioids

a b s t r a c t

Background: The last decade has seen a rapid and continuous growth in the availability and use of novelpsychoactive substances (NPS) across the world. Although various products are labeled with warnings“not for human consumption”, they are intended to mimic psychoactive effects of illicit drugs of abuse.Once some compounds become regulated, new analogues appear in order to satisfy consumers’ demandsand at the same time to avoid criminalization. This review presents updated information on the secondgeneration of NPS, introduced as replacements of the already banned substances from this class, focusingon their pharmacological properties and metabolism, routes of administration, and effects in humans.Methods: Literature search, covering years 2013–2015, was performed using the following keywordsalone or in combination: “novel psychoactive substances”, “cathinones”, “synthetic cannabinoids”,“benzofurans”, “phenethylamines”, “2C-drugs”, “NBOMe”, “methoxetamine”, “opioids”, “toxicity”, and“metabolism”.Results: More than 400 NPS have been reported in Europe, with 255 detected in 2012–2014. The mostpopular are synthetic cannabimimetics and psychostimulant cathinones; use of psychedelics and opioidsis less common. Accumulating experimental and clinical data indicate that potential harms associated
with the use of second generation NPS could be even more serious than those described for the alreadybanned drugs.Conclusions: NPS are constantly emerging on the illicit drug market and represent an important healthproblem. A significant amount of research is needed in order to fully quantify both the short and longterm effects of the second generation NPS, and their interaction with other drugs of abuse.
© 2015 Elsevier Ireland Ltd. All rights reserved.

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22. Synthetic cannabimimetics (SCs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23. Synthetic cathinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84. Benzofuran analogues of amphetamines: 5-APB and 6-APB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105. 4,4′-DMAR and MDMAR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106. Hallucinogenic/psychedelic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

6.1. NBOMes compounds – a second generation of 2C-phenethylamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106.2. Methoxetamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116.3. Diphenidine and 2-methoxydiphenidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

7. Synthetic opioid-like drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
7.1. AH-7921 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7.2. MT-45. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author at: Department of Pharmacodynamics, Medical University of LE-mail address: [email protected] (J.B. Zawilska).

ttp://dx.doi.org/10.1016/j.drugalcdep.2015.09.030376-8716/© 2015 Elsevier Ireland Ltd. All rights reserved.

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odz, Muszynskiego 1, 90-151 Lodz, Poland.

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2 J.B. Zawilska, D. Andrzejczak / Drug and Alcohol Dependence 157 (2015) 1–17

Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. Introduction

The last decade has seen a rapid and continuous growth inhe availability and use of novel psychoactive substances (NPS)cross the world. They include a wide range of products that cane purchased online, from head shops, and drug dealers (EMCDDA,014a, 2015a; Papaseit et al., 2014; Vandrey et al., 2013; Zawilska,011). NPS are sold as ‘legal/herbal highs’, ‘bath salts’, ‘plant food’,

insect repellents’, ‘research chemicals’, ‘air fresheners’, with theisclaimer “not for human consumption” or “for research pur-oses only” to circumvent drug abuse legislation (EMCDDA, 2014a,015a; Zawilska, 2011). The European Union (EU) Early Warningystem (EWS) noted the appearance of 418 new psychoactive sub-tances during the period of May 2005–December 2014, and aevenfold increase in reported seizures of NPS between 2008 and013 (EMCDDA, 2015a). In 2014 only, 101 new substances, aroundwo per week, were reported to the EWS; among them 31 designerathinones, 30 synthetic cannabimimetics, and 9 phenethylaminesEMCDDA, 2015a). A World Drug Report revealed in a world-wideurvey of 80 countries that 70 countries had reported the emer-ence of NPS in recent years (UNODC, 2013). It has been estimatedhat 2.9 million people aged 15–24 (around 5% of the total) in theU have already tried NPS (Corazza et al., 2014).

A growing interest in the use of NPS together with public healthangers posed by these drugs has forced a development of var-

ous sensitive analytical methods to identify and quantify theseompounds and their downstream metabolites in suspected prod-cts and human biological samples (blood, serum, urine, oral fluidsnd hair). They include liquid chromatography–tandem mass spec-rometry, liquid chromatography coupled to quadrupole-time-ofight mass spectrometry, gas chromatography/mass spectrome-ry, matrix-assisted/laser desorption/ionization time of flight masspectroscopy, direct analysis in real time mass spectrometry,uclear magnetic resonance, and immunoassays (e.g., Adamowicznd Tokarczyk, 2015; ElSohly et al., 2014; Johnson et al., 2014;anza et al., 2015; Poklis et al., 2014a, 2014b; Tang et al., 2014a).

NPS represent a heterogenous family of substances, including,mong others, synthetic cannabimimetics, synthetic cathinones,henethylamines, piperazines, ketamine- and phencyclidine-typeubstances, tryptamines, benzofuranes, and opioids (Papaseit et al.,014). Synthetic cannabimimetics and designer cathinones makep the largest groups of NPS, and in 2014 represented more thanwo thirds of compounds notified in the EU (EMCDDA, 2015a). Theim of the current contribution is to present updated informationn the second generation of NPS; compounds that have been intro-uced as replacements of the banned novel psychoactive drugs aseans to evade regulatory control. The list of NPS discussed in

his review is given in Table 1, and photographs of representativeacking for different classes of compounds are shown in Fig. 1.

. Synthetic cannabimimetics (SCs)

Originally developed for research purposes, SCs began to appears drugs of abuse during the mid-2000s. Since that time, theirarket has grown continuously (Castaneto et al., 2014; Zawilska

nd Wojcieszak, 2014), and the consumption of SCs-containingroducts has become a popular alternative to marijuana. A totalumber of 134 SCs have been reported to the EWS by the endf 2014, making the SCs the largest group of NPS monitored by

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the European Monitoring Centre for Drugs and Drug Addiction,EMCDDA (EMCDDA, 2015a). SCs are distributed under a varietyof brand names; the most common are “Spice” in Europe, “K2” inthe United States, “Kronic” in Australia and New Zealand (Zawilskaand Wojcieszak, 2014). SCs containing products are typically soldas smoking herbal mixtures in metal-foil sachets. Chemicals, mostof them being manufactured in China, are mixed with or after dis-solving in acetone, ethanol or methanol sprayed onto herbs suchas Mellissa, Mentha, Thymus, and Damiana. The herbal material isthen dried and packaged for sale (EMCDDA, 2015b). The presenceof the herbal substrate gives consumers an impression that they areindeed smoking a natural product. Most products contain severalSCs in a single preparation, thereby increasing a risk of overdoseand acute intoxication (EMCDDA, 2015b).

SCs belong to at least 14 chemically diverse families, have struc-tures unrelated to �9-tetrahydrocannabinol (�9-THC), differentmetabolism, and often greater toxicity (e.g., Castaneto et al., 2014;ElSohly et al., 2014; Fantegrossi et al., 2014). Despite of markeddifferences in their chemical structure, all SCs are lipid soluble, non-polar, and typically consist of 20–26 carbon atoms, which explainswhy they volatilize readily when smoked (Castaneto et al., 2014).

First-generation SCs primarily constituted of JWH compounds,originally synthesized by John W. Huffman, the medicinalchemist at the Clemson University, Clemson, USA (Zawilska andWojcieszak, 2014). Over the past few years several new SCshave been identified, including, among others, UR-144, 5F-UR-144 (XLR-11), PB-22 (QUPIC; an analogue of JWH 018 whichdiffers by having 8-hydroxyquinoline replacing the naphthalenegroup of JWH 018), 5F-PB-22, BB-22 (QUCHIC; structurally sim-ilar to PB-22), AB-PINACA, 5F-AB-PINACA, ADB-PINACA, AKB-48(APINACA), 5F-AKB-48, and AB-FUBINACA (DEA, 2014a, 2015a,2015b; EMCDDA, 2015b; Uchiyama et al., 2013). It should beemphasized that fluorine substitution at the 5-pentyl position ofpentylindole/pentylindazole, recently a popular structural modi-fication of SCs, generally enhances compounds potency, stabilityand prolongs half-life time. UR-144 (‘KM X-1’) has been designedby Abbott Laboratories in a search for selective agonists of cannabi-noid CB2 receptors (Frost et al., 2010). The compound preferentiallybinds to peripheral CB2 receptors over brain CB1 receptors (Wileyet al., 2013). 5F-UR-144 (XLR-11), a 5-fluorinated analogue ofUR-144, is a potent full agonist of CB1 and CB2 receptors. In abattery of tests (rectal temperature, warm water tail withdrawal,spontaneous locomotor activity, and ring immobility) both com-pounds produced characteristic cannabinoid tetrad of effects, i.e.,hypothermia, analgesia, catalepsy, and suppression of locomotoractivity, that were blocked by rimonabant, an inverse agonist ofcannabinoid receptors. The potency of UR-144 and XLR-11 wasseveral-fold greater than that of �9-THC (Wiley et al., 2013). PB-22,its fluorinated analogue 5F-PB-22, and BB-22 were first reportedin Japan in early 2013. An increasing prevalence of PB-22 and5F-PB-22 indicates that they could replace UR-144 and XLR-11(Wohlfarth et al., 2014). PB-22 and 5F-PB-22 potently decreasedlocomotor activity up to 120–150 min (Gatch and Forster, 2015). Inmice trained to discriminate �9-THC from vehicle, UR-144, XLR-11, AKB-48, PB-22, 5F-PB-22, and AB-FUBINACA fully substituted
for �9-THC, an observation suggesting that these second genera-tion SCs could produce marijuana-like effects in humans (Wileyet al., 2013; Gatch and Forster, 2015). There are few publisheddata on toxicological properties of SCs at the cellular level. By
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J.B. Zawilska, D. Andrzejczak / Drug and Alcohol Dependence 157 (2015) 1–17 3

Table 1Representatives of the second generation NPS.

Synonyms Formal name Chemical structure

Cannabimimetics

UR-144 (1-Pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)-methanone

5F-UR-144 (XLR-11) (1-(5-Fluoropentyl)-1H-indol-3-yl)(2,2,3,3-tetramethyl-cyclopropyl)methanone

PB-22 (QUPIC) Quinolin-8-yl1-pentyl-1H-indole-3-carboxylate

5F-PB-22 Quinolin-8-yl 1-(5-fluoropentyl)-1H-indole-3-carboxylate

BB-22 (QUCHIC) 8-Quinolinyl 1-(cyclohexylmethyl)-1H-indole-3-carboxylate

AB-PINACA N-(1-Amino-3-methyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide

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Table 1 (Continued)


5F-AB-PINACA N-(1-Amino-3-methyl-1-oxobutan-2-yl)-1-(5-fluoropentyl)-1H-indazole-3-carboxamide

AKB-48 (APINACA) N-(1-Adamantyl)-1-pentyl-1H-indazole-3-carboxamide

5F-AKB-48 N-(1-Adamantyl)-1-(5-fluoropentyl)-1H-indazole-3-carboxamide

ADB-PINACA N-(1-Amino-3,3′-dimethyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide



Table 1 (Continued)


AB-FUBINACA N-(1-Amino-3-methyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indazole-3-carboxamide

Synthetic cathinones

4-Methyl-N-ethyl cathinone (4-MEC) 2-(Ethylamino)-1-(4-methylphenyl)-1-propanone

4′-Methyl-�-pyrrolidino-propiophenone (4-MePPP) (RS)-1-(4-Methylphenyl)-2-(1-pyrrolidinyl)-1-propanone

�-Pyrrolidinovalerophenone (�-PVP, O-2387) (RS)-1-Phenyl-2-(1-pyrrolidinyl)-1-pentanone

Benzofurans

5-APB 5-(2-Aminopropyl)benzofuran

6-APB 6-(2-Aminopropyl)benzofuran

Hallucinogens/psychedelics

25B-NBOMe; 2C-B-NBOMe 2-(4-Bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine



Table 1 (Continued)


25C-NBOMe; 2C-C-NBOMe 2-(4-Chloro-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine

25I-NBOMe; 2C-I-NBOMe 2-(4-Iodo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine

Methoxetamine (MXE) 2-(3-Methoxyphenyl)-2-(ethylamino)cyclohexan-1-one

Diphenidine 1-(1,2-Diphenylethyl)piperidine

2-Methoxydiphenidine (MXP, 2-MXP) 1-[1-(2-Methoxyphenyl)-2-phenylethyl]piperidine

Opioids

AH-7921 3,4-Dichloro-N{[1-(dimethylamino)cyclohexyl]methyl}benzamide



Table 1 (Continued)


MT-45 1-Cyclohexyl-4-(1,2-diphenylethyl)piperazine

Other

para-Methyl-4-methyl-aminorex (4,4′-DMAR) 4-Methyl-5-(4-methylphenyl)-4,5-dihydrooxazol-2-amine

a4rAae2Dc2

nalogy to older compounds from this class: HU-210, CP-7,497-C8, JWH-018, JWH-073, JWH-122, JWH-210, and AM-2201,epresentatives of the second generation, namely UR-144, 5F-KB-48, and 4-(methylnaphtyl)-AM-2201 (MAM-2201, a 5-fluoronalogue of JWH-122), were cytotoxic to various cell types (Bileckt al., 2015; Koller et al., 2013, 2014, 2015; Tomiyama and Funada,014). Although several processes, like damage of cell membrane,
NA damage, interference with protein synthesis, activation ofaspase-3 and apoptosis, contributed to this action (Bileck et al.,015; Koller et al., 2013, 2015; Tomiyama and Funada, 2014),
Fig. 1. Examples of packaging for products


detailed molecular mechanisms underlying SCs-induced cell deathare still not fully understood.

Due to the appearance of the second generation SCs, metabolismof these agents is a rapidly growing area of interest. UR-144 andXLR-11 are extensively metabolized in mice, mainly to mono-hydroxylated glucuronides that are excreted with urine (Wileyet al., 2013). XLR-11 also undergoes defluorination to UR-144,
resulting in several metabolites that are common to subjectsusing both compounds. A similar phenomenon likely occurs inthe case of other fluorinated analogues of SCs. This, in turn, could
containing second generation NPS.


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J.B. Zawilska, D. Andrzejczak / Drug

ave important analytical and pharmacokinetic consequences.hus, identification of unique metabolites as potential markersor a fluorinated analogue intake is crucial in the detection of auspected cannabimimetic consumption. Furthermore, durationf psychoactive effects exerted by fluorinated SCs could be longerhan that of paternal compounds. In vitro studies with human liver

icrosomes identified 23 and 18 metabolites of AB-PINACA andF-AB-PINACA, respectively (Wohlfarth et al., 2015). AB-PINACAas primarily hydrolyzed to AB-PINACA carboxylic acid; two main

econd generation metabolites of AB-PINACA carboxylic acid iden-ified are carbonyl-AB-PINACA and hydroxypentyl-AB-PINACA.

ost of AB-PINACA metabolites identified in vitro were also foundn urine samples from suspected AB-PINACA cases (Wohlfartht al., 2015). Major metabolites of 5F-AB-PINACA were AB-PINACAentanoic acid, 5′-hydroxypentyl-AB-PINACA, and 5F-AB-PINACAarboxylic acid (Wohlfarth et al., 2015). AKB-48 is predominantlyetabolized by human hepatocytes by mono-, di-, and trihydroxy-

ation on the adamantyl ring followed by glucuronidation (Gandhit al., 2013; Holm et al., 2015). An observation that CYP3A4 ishe major enzyme involved in oxidative metabolism of AKB-48s of a clinical importance. It is assumed that CYP3A4 inhibitors,or example azole antifungal and anti-HIV drugs, could markedlyecrease the rate of AKB-48 clearance, and potentiate its toxicityHolm et al., 2015). PB-22, 5F-PB-22, BB-22, AB-PINACA, andB-FUBINACA also undergo non-CYP-mediated biotransformationy carboxylesterase 1 (Thomsen et al., 2015).

The increasing number of recent SCs together with their higherotency of action strongly suggests that these drugs pose an emerg-

ng public health treat. A number of adverse health effects relatedo SCs use reported to the National Poison Data USA had increasedrom 349 in January 2015 to 1501 in April 2015 (Law et al., 2015). In

two-week period in July 2015, over 200 people were hospitalizedn Poland following use of “MOCARZ” (“the Mighty One”); some ofhem were in a very serious condition, and one died. The forensicxamination of samples revealed the presence of UR-144, BB-22,F-PB-22, XLR-144, and AB-CHMINACA (SOS Polonia, 2015).

Few clinical data on the effects of the second generation SCsn humans have been published so far. Case series of acute kid-ey injury associated with smoking of SCs have recently beeneported in patients without known preexisting renal disease. Ini-ial symptoms of a toxidrome were described by the patients asn acute onset of intense nausea, vomiting, and flank or abdom-nal pain (CDC, 2013a; Buser et al., 2014). Clinical examinationevealed hypertension, elevated serum creatinine and blood ureaitrogen concentrations, and in renal biopsy samples acute tubular

njury. Analysis of implicated products demonstrated the presencef UR-144 and XLR-11, and in available clinical specimens – XLR-1 N-pentanoic acid metabolite (CDC, 2013a; Buser et al., 2014).

t should be emphasized that acute kidney injury, irrespective ofts cause, can predispose to chronic and end-stage kidney disease,ater in life (Coca et al., 2012). Smoking of ADB-PINACA-containingroduct “Crazy Clown” resulted in a wide-spectrum of adverseffects, including anxiety, delirium, aggressive behavior, psychosis,onfusion/disorientation, seizures, somnolence, unresponsiveness,achycardia, hypertension, acidosis, and hypokalemia. One patientad myocardial infarction, and another one developed rhabdomy-lysis (CDC, 2013b; Schwartz et al., 2015). In 7 out of 22 individualsDB-PINACA and ADB-PINACA 5-pentanoic acid were identified inlasma (Schwartz et al., 2015). A case of acute cerebral ischemiand infarction (Takematsu et al., 2014), and two fatal cases (Shankst al., 2015b) related to analytically confirmed use of XLR-11 haveeen reported. Exposure to PB-22 containing product “Crazy Mon-
ey” (see Fig. 1) lead to seizures in a man and his dog; laboratorynalysis of human and canine plasma revealed the presence of PB-2 (Gugelmann et al., 2014). PB-22 was suspected to be involved inhree deaths in Australia (Gerostamoulos et al., 2015). Recently four

cohol Dependence 157 (2015) 1–17

fatal cases, in which 5F-PB-22 was detected in blood specimens,have been reported (Behonick et al., 2014).

With the rising popularity of SCs as recreational drugs, anincrease of these compounds in driving cases has been notified. Firstreports on this issue presented 7 (Musshoff et al., 2014) and 16 (Tuvet al., 2014) cases of driving under the influence of SCs, where thepresence of the following compounds was analytically confirmedin sera taken from subjects involved: AM-2201, JWH-018, JWH-019, JWH-081, JWH-122, JWH-210, JWH-250, JWH-307, and RCS-4.AM-2201 and JWH-018 were the most frequently detected SCs.With the appearance of the second generation SCs, driving casespositive for UR-144, XLR-11, APINACA, 5F-APINACA, AB-PINACAand AB-CHMINACA have been recently reported (Adamowicz andLechowicz, 2015; Karinen et al., 2015; Lemos, 2014; Louis et al.,2014; Peterson and Couper, 2015). As the physical examination ofthe subjects revealed a delayed reaction of pupils to light, blurredspeech, dizziness, instable appearance and retarded sequence ofmovements, it is assumed that the consumptions of SCs, likecannabis use (Hartman and Huestis, 2013), can lead to a potentiallydangerous impairment of driving skills and cognitive deficits.

Legal status of the second generation SCs discussed above isgiven in Table 2.

3. Synthetic cathinones

Synthetic cathinones represent a large family of �-ketoamphetamine compounds derived from cathinone, an activestimulant in a khat plant (Catha edulis). In the mid-2000s,they appeared on the recreational drug market as alter-natives to the controlled psychostimulants: amphetamine,3,4-methylenedioxymethamphetamine (MDMA), and metham-phetamine, and were commonly referred to as ‘plant food’,‘research chemical’, or ‘bath salts’ (Zawilska and Wojcieszak,2013; Karila et al., 2015). Between 2005 and 2014, morethan 80 cathinone derivatives were reported to the EWS(EMCDDA, 2015a). Of numerous synthetic cathinones, themost commonly abused were mephedrone, methylone, and3,4-dimethoxypyrovalerone (MDPV). After regulatory control ofpopular cathinones, they have been quickly replaced by newlysynthesized compounds, that include, but are not limited to,analogues of mephedrone: 4-methyl-N-ethylcathinone (4-MEC)and 4′-methyl-�-pyrrolidinopropiophenone (4-MePPP; 4-MPPP),and �-pyrrolidinovalerophenone (�-PVP), an analogue of MDPV(DEA, 2014b; EMCDDA, 2015c). It is suggested that tablets con-taining �-PVP are sold as ecstasy (EMCDDA, 2015c). Productscontaining �-PVP have several street names that vary amongdifferent countries, for example “Ocean Breath”, “Fire Ball”, “Totalspeed”, “Sensation”, “Speedway”, “Guarana Coco jumbo”, “Energy3 (NRG-3)” and “Sextasy” (EMCDDA, 2015c).

Synthetic cathinones exert their action by increasing extracellu-lar levels of noradrenaline (NA), dopamine (DA), and serotonin (5-HT), primarily via two mechanisms. First, these compounds interactwith monoamine transporter proteins, namely NET, DAT and SERT,inhibiting reuptake of NA, DA and 5-HT, respectively. Their selectiv-ity for these transporters varies considerably (Simmler et al., 2013,2014). Second, some compounds also act as transporter substratesand promote the release of neurotransmitters from intracellularstores by reversal of transporter flux, and inhibition of the vesicu-lar monoamine transport receptor, VMAT2 (Simmler et al., 2013,2014). Determining precise molecular mechanism of action formonoamine transporter drugs is critical to predict their putative
toxic potential, as it is suggested that transporter’s substrates, butnot blockers, are endowed with neurotoxic potential. Whether syn-thetic cathinones are neurotoxic, to what extend, and under whichconditions remains to be elucidated. Another issue important from


Table 2Legal status of second generation NPS representatives.

Compound Legal status

UR-144 Controlled substance in Germany, Denmark, Hungary, New Zealand, Poland, Portugal, Russia, Slovakia, Slovenia, Turkey, UK (class B) and USA(Schedule I).

XLR-11 Controlled substance in New Zealand, Poland and USA (Schedule I).PB-22 Controlled substance in Germany, Hungary, New Zealand, Poland and USA (Schedule I).5F-PB-22 Controlled substance in Hungary, Poland and USA (Schedule I).BB-22 Controlled substance in Poland.AB-PINACA Controlled substance in Germany, Singapore and USA (Schedule I).5F-AB-PINACA Controlled substance in Germany and Singapore.AKB-48 (APINACA) Controlled substance in Germany, Japan, Latvia, New Zealand, Poland, Singapore and USA (Schedule I).5F-AKB-48 Controlled substance in Germany and Poland.ADB-PINACA Controlled substance in Singapore and USA (Schedule I). Alert report from the EMCDDA in 2014.AB-FUBINACA Controlled substance in Germany and USA (Schedule I).4-MEC Controlled substance in New Zealand, Poland, UK (class B) and USA (Schedule I).4-MePPP Controlled substance in USA (Schedule I). Sweden’s public health agency suggested to classify 4-MePPP as hazardous substance on November

10, 2014.�-PVP Controlled substance in Poland and USA (Schedule I). Risk assessment report by the EMCDDA, September 2015.5-APB/6-APB Controlled substance in Canada, Germany. New Zealand, Poland, and UK. Alert report by the Europol-EMCDDA, February 2015.25B-NBOMe Controlled substance in Israel, Poland, Sweden, and USA (Schedule I).25C-NBOMe Controlled substance in Israel, Poland, Sweden and USA (Schedule I).25I-NBOMe Controlled substance in Australia, Israel, Poland, Romania, Russia, Serbia, Sweden, UK (class A) and USA (Schedule I). Risk assessment report

by the EMCDDA, May 2014.Methoxetamine Controlled substance in Brazil, Israel, Japan, Poland, Russia, Sweden, Switzerland, UK (class B) and USA (Schedule I). Risk assessment report by

the EMCDDA, May 2014.AH-7921 Controlled substance in Australia, Brazil, Israel, Poland, Russia, UK (class A) and USA (schedule I). Risk assessment report by the EMCDDA, May

2014.ng not

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he clinical point of view is a risk of cathinones-induced hepato-oxicity. The first experimental data demonstrating hepatotoxicityf four synthetic cathinones, including 4-MEC, have been just pub-ished (Araújo et al., 2015). In studies on primary culture of rat hepa-ocytes, 4-MEC reduced cell viability in a concentration-dependent

anner. Hepatotoxic activity of 4-MEC (EC50 = 1.29 mM) waseaker from that of MDMA (EC50 = 0.745 mM), used as a reference

ompound (Araújo et al., 2015). It is suggested that oxidative stresss one of factors involved of cathinones’ hepatotoxicity.

Structure–activity data have demonstrated that changing an N-lkyl substituent of cathinone drugs can profoundly influence theirharmacology. 4-MEC and 4-MePPP maintain the 4-methyl ring-ubstitution of mephedrone: 4-MEC has an N-ethyl group, whereas-MePPP has an N-butyl group that is cyclized to form a pyrroli-ine ring (see Table 1). 4-MePPP acted only as a DAT blocker with

ittle activity at SERT (Saha et al., 2015), whereas 4-MEC was aonselective inhibitor of DAT, NET and SERT. Interestingly, 4-MECisplayed so-called hybrid activity, acting as a SERT substrate (i.e. 5-T releaser) and DAT/NET blocker (Saha et al., 2015; Simmler et al.,014). The potency of 4-MEC to inhibit uptake at SERT and DATas similar to that exerted by mephedrone. By analogy to MDPV,-PVP displayed negligible activity at SERT but was potent cate-holamine uptake inhibitor (Marusich et al., 2014). In vivo studiesemonstrated that �-PVP produced psychomotor stimulant effectsMarusich et al., 2014), 4-MEC potently increased extracellular 5-T level in rat nucleus accumbens, had weak effect on DA, andvoked minimal motor stimulation, whereas 4-MePPP producedarge increases in DA and robust motor stimulation (Saha et al.,015). In discriminative-stimulus studies performed on rats, �-VP and 4-MePPP fully substituted for methamphetamine, whereas-MEC was inactive (Gatch et al., 2015; Naylor et al., 2015). In addi-ion, �-PVP produced a discriminative stimulus effect similar tohat of cocaine (Gatch et al., 2015). Both �-PVP and 4-MEC markedlyeduced intracranial self-stimulation thresholds in rats with a
otency comparable to that of methamphetamine (Watterson et al.,014). These observations suggest that the discussed above secondeneration synthetic cathinones are endowed with abuse poten-ial.

ification by the EMCDDA, February 2014.

Studies on human liver microsomes identified six phase Imetabolites of �-PVP, which were formed with the aid of CYP2D6,CYP2B6, and CYP2C19. The compound was primarily metabolizedby monohydroxylation after �-keto group reduction to OH-�-PVP (Negreira et al., 2015). In human urine specimens, bothunchanged �-PVP and OH-�-PVP were found (Shima et al., 2014;Uralets et al., 2014). Breakdown of 4-MEC follows metabolicpath of mephedrone, and involves reduction of �-keto groupwith consequent N-dealkylation (Uralets et al., 2014). In rat 4-MePPP was extensively metabolized by oxidative desamination,and hydroxylation of the 4′-methyl group followed by oxidation to4-carboxy-pyrrolidinopropiophenone, the main drug’s metabolite(Springer et al., 2003).

Accumulating evidence indicate that both desired andunwanted effects of newer synthetic cathinones are similar to thoseobserved for the first generation drugs (Zawilska and Wojcieszak,2013). According to records posted on Internet fora analyzed byVan Hout (2014), 4-MEC is primarily used by insufflation andorally, with a frequent combination of these two routes due tothe extensive nasal burning, clogging of nasal passages, and nasaldripping. The drug produced quick but short lasting, up to 2–3 heffects, namely euphoria, deep relaxation, sensual enhancement,and increased appreciation of music. Negative effects describedby users included heart palpitations, insomnia, sweating, muscletwitching, bruxism, dizziness, nausea, and vomiting (Van Hout,2014). �-PVP can be taken orally, sublingually, by insufflation,smoking/inhalation, intravenously, and rectally (EMCDDA, 2015c).The reported doses are 5–20 mg (low) and 30–40 mg (high) forinsufflation, 5–25 mg (low) and 45–70 mg (high) for oral admin-istration, and 2–5 mg (low) and 10–20 mg (high) for intravenousinjection (Drugs Forum). The most common adverse effects weretachycardia, mydriasis, hallucinations, anxiety, agitation, tremor,hyperthermia, diaphoresis, and paranoia (Drugs Forum; EMCDDA,2015c). Recently a case of neonatal withdrawal syndrome, with
increased jitteriness, irritability, high pitched cry, hypertoniain the limbs, and brisk tendon reflexes, after chronic maternalconsumption of 4-MEC has been reported (Pichini et al., 2014).There were more than one hundred analytically confirmed fatal

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ases involving �-PVP (EMCDDA, 2015c; Nagai et al., 2014; Gilt al., 2015; Potocka-Banas et al., 2015; Sykutera et al., 2015). Legaltatus of 4-MEC, 4-MePPP, and �-PVP is given in Table 2.

. Benzofuran analogues of amphetamines: 5-APB and-APB

Two benzofuran compounds, i.e., 5- and 6-APB, appearedn the recreational drug market in 2010–2011 under streetames “Benzo Fury” (Fig. 1), “Fury X”, and “Fury Extreme” (Chant al., 2013; Jebadurai et al., 2013). These two compounds aretructural isomers, structurally related to MDMA and MDA (3,4-ethylenedioxyamphetamine). The pharmacological profile of

hese benzofurans indicates that they have both psychostimulantnd hallucinogenic properties. It has been demonstrated that, likeathinones, 5-APB and 6-APB are potent inhibitors of DAT, NETnd SERT, similar to MDMA, and at high concentrations releasedA, 5-HT and NA (5-APB only). In addition, they bind to sero-

onin 5-HT2A receptors, well known for mediating hallucinogenicffects of such drugs as LSD and 1-(2-dimethoxy-4-iodophenyl--aminopropanone) – DOI (González-Maeso et al., 2007), 5-HT2Bnd 5-HT2C receptors (Dawson et al., 2014; Iversen et al., 2013;ickli et al., 2015b). As 5-HT2B receptors have been implicated in

substance-used heart valve fibrosis (Bhattacharyya et al., 2009),igh agonist activity of 5-APB and 6-APB at these receptors suggestshat their long term use could cause cardiotoxicity (Dawson et al.,014; Iversen et al., 2013). Both benzofuran compounds also bindo adrenergic �1A, �2A, �2B, and �2C receptors (Iversen et al., 2013;ickli et al., 2015b).

The main metabolites of 5-APB and 6-APB identified in rat urineamples were 3-carboxymethyl-4-hydroxy amphetamine and-carboxymethyl-3-hydroxy amphetamine, respectively (Weltert al., 2015a, 2015b).

Users report that effects of 5-APB and 6-APB resembled that ofDMA but were more intense (Jebadurai et al., 2013). A report

rom the United Kingdom National Poisons Information Serviceas shown that majority of users developed symptoms charac-eristic for sympathomimetic stimulation, such as tachycardia,ypertension, palpitations, mydriasis, insomnia, fever, diaphoresis,nd tremor. Mental health disturbances, i.e., anxiety, aggression,onfusion, psychosis, paranoia, hallucinations and delusion, werelso common (Kamour et al., 2014). The reported adverse effectsn users of benzofuran compounds were more pronounced thathose of mephedrone (Kamour et al., 2014). In three case reportstwo related to 5-APB- and one to 6-APB-induced intoxication),ll analytically confirmed, the dominant symptoms of intoxica-ions were severe psychomotor agitation, aggressiveness, paranoidhoughts, and behavior (Adamowicz et al., 2014; Chan et al., 2013;

cIntyre et al., 2015). Intoxications induced by consumption of-APB, taken together with 3-methyl-N-methylcathinone and alco-ol (Adamowicz et al., 2014) or with alcohol only (McIntyre et al.,015), were fatal. 5-APB and 6-APB have been classified as con-rolled substances by a few countries (Table 2).

. 4,4′-DMAR and MDMAR

4,4′-DMAR and MDMAR are analogues of aminorex, an anorex-genic compound with stimulant-like character. Aminorex wasriginally synthesized by McNeil Laboratories in the 1960s. In 1965t was registered in Europe as an appetite suppressant, and with-rawn shortly afterwards due to fatal complications related to
rimary pulmonary hypertension.
The presence of 4,4′-DMAR in Europe was first noted by theMCDDA at the end of 2012, and an official risk assessment was per-ormed by the EMCDDA in 2014 (EMCDDA, 2014b). The compound



is available in both powder and tablet form. Some of the tabletshave non-specific motifs (e.g., “Specked Cherry”, “Speckled Cross”),logos associated with numerous recreational drugs (e.g., “Playboy”,“Mitsubishi”, “Heart”, “Transformers”) or marks (e.g., “ST” referringto the street name “Serotoni”; Fig. 1) (EMCDDA, 2014b; Glanvilleet al., 2015). Although in most cases 4,4′-DMAR was reported asthe only active substance, other psychoactive substances (mainlysynthetic cathinones) were also detected (EMCDDA, 2014b).

Studies performed on rat brain synaptosomes have demon-strated that cis-4,4′-DMAR, cis-MDMAR and trans-MDMAR arepotent, efficacious substrate-type releasers at DAT, NET, and SERT(Brandt et al., 2014; McLaughlin et al., 2014). The potency of cis-4,4′-DMAR at DAT and NET was comparable to that of d-amphetamine,however, it exerted much more potent action at SERT (Brandt et al.,2014). Comparative studies with cis-MDMAR, trans-MDMAR andMDMA demonstrated that both isomers were more potent at DATand NET than MDMA (McLaughlin et al., 2014).

Information collected by the EMCDDA and from the user web-sites suggests that 4,4′-DMAR is taken by nasal insufflations andorally; in the latter case the reported doses were 10–20 mg(EMCDDA, 2014b). Oral ingestion is reported by direct swallow-ing of tablets or powder wrapped in cigarette papers (Glanvilleet al., 2015). At present, information on adverse effects of 4,4′-DMAR is limited to users’ self reports from Internet discussion fora.Commonly described effects include nausea, mydriasis, dysphoria,agitation, sweating, increased heart rate, dry mouth, psychosis, hal-lucinations, and hyperthermia (Glanville et al., 2015). A total of27 deaths, 8 in Hungary and 19 in the United Kingdom, involv-ing 4,4′-DMAR, were reported to the EMCDDA (EMCDDA, 2014b).In all of the cases 4,4′-DMAR has been detected in postmortemsamples. Intoxication symptoms included hyperthermia, agitation,confusion, intensive sweating, seizures, foaming from the mouth,cardiac and respiratory arrest. The autopsy findings demonstratedextensive bleeding in the muscles and organs, brain edema, andpulmonary edema (EMCDDA, 2014b).

6. Hallucinogenic/psychedelic drugs

6.1. NBOMes compounds – a second generation of2C-phenethylamines

The phenethylamine-based structure is shared among suchdiverse compounds as catecholamines, amphetamines, cathinones,and so-called 2C drugs. The name “2C”, originally created byAlexander Shulgin, refers to their chemical structure, wheretwo carbon atoms separate an amine group from a phenylring. The substituted phenethylamines (2C-X) contain methoxygroups on 2 and 5 positions of the phenyl ring and a varietyof substituents at position 4. They exert stimulating, hallucino-genic, and psychedelic effects, depending on the structure anddose (Dean et al., 2013; King, 2013). The first compound fromthis group was 2-(4-bromo-2,5-dimethoxyphenyl)ethanamine (4-bromo-2,5-dimethoxyphenethylamine; 2C-B; “Nexus”, “Toonies”,“Bromo”, “Venus”) sold in the 1980s and early 1990s as a MDMAreplacement (Dean et al., 2013). Since the scheduling of 2C-B bythe Drug Enforcement Agency (DEA) in 1995, several new 2C com-pounds have been synthesized and introduced on the drug market.Recent and highly active compounds are N-benzyl substitutedphenethylamines (NBOMes), namely 25B-NBOMe (2C-B-NBOMe),25C-NBOMe (2C-C-NBOMe), and 25I-NBOMe (2C-I-NBOMe; “N-bomb”, “Smiles”, “CIMBI-5”) (Bersani et al., 2014; DEA, 2013;
EMCDDA, 2014c). 25I-NBOMe, the most potent compound of thisgroup, was first synthesized by Ralf Heim at the Free University ofBerlin as one of a series of pharmacological tools to study 5-HT2Areceptors (Heim, 2003).

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In vitro receptor studies have demonstrated that NBOMeompounds act as potent full agonists of 5-HT2A (a commonite of action for hallucinogens) and 5-HT2C receptors. N-Benzylubstitution of 2C-phenylethylamines dramatically increased theirffinity at 5-HT2A receptors (Braden et al., 2006). Importantly,5C-NBOMe and 25I-NBOMe show nanomolar agonist bindingffinity to 5-HT2A receptors (Braden et al., 2006; Rickli et al.,015a), and are pharmacologically active at very low submil-

igram doses (EMCDDA, 2014c; Nichols et al., 2008). In addition,BOMe compounds showed high affinity binding to adrener-ic �1A and �2A receptors, and H1 histamine receptors (Ricklit al., 2015a). 2-(4-Iodo-2,5-dimethoxyphenyl)ethanamine (2C-) and its two N-benzyl substituted derivatives, 25I-NBOMend 25I-NBMD (2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2,3-ethylenedioxyphenyl)methyl]ethanamine) produced the head

witch response in mice that was completely blocked by a selective-HT2A receptor antagonist, M100,907 (Halberstadt and Geyer,014). In this behavioral test 25I-NBOMe displayed 14-fold higherotency than 2C-I. As the head twitch response in rats and micefter 5-HT2A receptors activation is widely used as a behavioralroxy in rodent for human hallucinogenic effect, it is assumed thatBOMe compounds could produce hallucinations in man.

It has been demonstrated that 25I-NBOMe was extensivelyetabolized, mainly by O-demethylation, O,O-bis-demethylation,

nd hydroxylation (Caspar et al., 2015). Twenty-nine and 35 phase metabolites were identified in rat and human urine, respectively.YP1A2 and CYP3A4 were involved in the process of hydroxylation,hile CYP2C9 and CYP2C19 – in O-demethylation. The main phase Ietabolites underwent glucoronidation and sulfation (Caspar et al.,

015). In the case of 25B-NBOMe, the major detoxification path-ays in humans include oxidatation and glucoronidation, resulting

n 12 phase I and 9 phase II metabolites (Boumrah et al., 2015).In a cross-sectional anonymous online survey conducted in 2012

n 22,289 respondents (mainly from Canada, USA, and the Unitedingdom), 2.6% of them reported having ever tried one of the threeBOMes, i.e. 25B-NBOMe, 25C-NBOMe, and 25I-NBOMe; the mostopular was 25I-NBOMe (Lawn et al., 2014). NBOMe containingroducts are sold as tablets, capsules, powder, liquid, spray, andreloaded paper doses (blotters; see Fig. 1). NBOMes drugs aresually taken by holding in the mouth (sublingually or bucally)r via nasal insufflations; oral administration is far less commonEMCDDA, 2014c; Lawn et al., 2014; Nikolaou et al., 2015). It isuggested that formulation of NBOMe drugs with hydroxypropyl-yclodextrin can improve their low oral bioavailability (Nikolaout al., 2015). There is some evidence that 25C-NBOMe and 25I-BOMe have been sold as a replacement of LSD (Bersani et al.,014; EMCDDA, 2014c; Suzuki et al., 2014). However, unlike LSD,BOMe drugs exert significant sympathomimetic activity and can

ead to acute toxicity (see below). Mild hallucinogenic effects of5C-NBOMe and 25I-NBOMe taken sublingually or intranasally cane achieved at doses as low as 50–200 �g, strong after 350–800 �g,nd very strong over 700–800 �g (Bersani et al., 2014; Halberstadtnd Geyer, 2013; Nikolaou et al., 2015; Zuba et al., 2013). The drugsre only slightly less potent than LSD, which is usually taken inoses 25–250 �g. The duration of NBOMes actions depends on theoute of administration, ranging from 3 to 8 h and 4 to 6 h by insuf-ations of 25C-NBOMe and 25I-NBOMe, respectively, and 4 to 10 h25C-NBOMe) and 6 to 10 h (25I-NBOMe) by sublingual or buccalonsumption (Bersani et al., 2014; Halberstadt and Geyer, 2014).

Psychotropic effects of NBOMes are individual-, dose- andoute of administration-dependent. Primary effects sought bysers include euphoria, feelings of love and empathy, sociability,

ncreased visual, auditory, olfactory, and tactile sensations, hal-ucinations, life-changing spiritual experiences, and psychedelicffects, such as depersonalization and derealization. Commondverse effects of NBOMe drugs include nausea, vomiting,


cohol Dependence 157 (2015) 1–17 11

headache, sweating, and temporary dysuria. High doses can leadto strong sound and time distortion, extreme unpleasant halluci-nations, anxiety, panic and fear, severe agitation, aggressiveness,acute psychosis, insomnia, seizures, rhabdomyolysis with subse-quent acidosis and renal failure, muscle rigidity, tremulousness,and excited delirium which can result in a sudden and unexpectedcardiopulmonary arrest. Sympathomimetic signs, such as mydria-sis, tachycardia, hypertension, hyperthermia, and diaphoresis arealso common (Bersani et al., 2014; EMCDDA, 2014c; Forrester,2014; Grautoff and Kähler, 2014; Hill et al., 2013a; Laskowski et al.,2015; Nikolaou et al., 2015; Poklis et al., 2014b; Rose et al., 2013;Stellpflug et al., 2014; Tang et al., 2014b; Wood et al., 2015). Anal-ysis of acute intoxication with NBOMe and 2C-X drugs reported tothe National Poison Data System USA demonstrated that there hadbeen higher incidence of hallucinations/delusions, single episodeseizures and benzodiazepine administration in NBOMe exposuresthat those in 2C exposures (Srisuma et al., 2014).

During the last few years, more than a dozen fatalities have beenreported as a result of the ingestion of NBOMes, mainly 25I-NBOMe(ACMD, 2013; Andreasen et al., 2015; Bersani et al., 2014; EMCDDA,2014c; Kueppers and Cooke, 2015; Lowe et al., 2015; Poklis et al.,2014a; Shanks et al., 2015a; Srisuma et al., 2014; Tarpgaard et al.,2015; Walterscheid et al., 2014). At the end of the last year twostudents died in Poland after oral ingestion of 25B-NBOMe and 4-chloromethcathinone (Wiergowski et al., 2015). Legal status of thethree discussed NBOMe compounds is given in Table 2.

6.2. Methoxetamine

Methoxetamine (MXE) is a structural analogue of ketamine,where a 2-chloro group on a phenyl ring and a N-methylaminogroup of ketamine have been replaced by a 3-methoxy and N-ethylamino group, respectively. Since the first report on effectsof methoxetamine, which appeared in May 2010, the drug hasbeen extensively advertised as a ‘legal’ and ‘bladder friendly’alternative to ketamine (EMCDDA, 2013; Kjellgren and Jonsson,2013). In light of experimental data demonstrating that prolongedadministration of methoxetamine to mice produced significantbladder and kidney toxicity (Dargan et al., 2014), an issue as towhether, in humans, this drug is far less toxic than ketamineremains to be elucidated. In 2013, methoxetamine was one out offour most frequently detected NPS by the Drugs Information andMonitoring System in the Netherlands (Hondebrink et al., 2015).Methoxetamine is typically sold as powder, under common streetnames such as “MXE”, “Mexxy”, “M-ket”, “MEX”, “Kmax”, “SpecialM”, “legal ketamine”, “Minx”, “Jippe”, and “Roflcoptr” (EMCDDA,2013; Fig. 1). Products often contain other psychoactive com-pounds, including synthetic cathinones (methylone, mephedrone,MDPV), synthetic cannabimimetics (AM-2201, JWH-018), benzo-diazepines, methylphenidate, ketamine, cannabis, amphetamine,methamphetamine, MDMA, morphine, and heroin (EMCDDA,2013; Kamijo et al., 2014).

By analogy to ketamine, methoxetamine has a sub-micromolaraffinity for glutamate N-methyl-d-aspartate (NMDA) receptor, andbinds to its phencyclidine site. In addition, methoxetamine exhibitsa sub-micromolar affinity for SERT, and so resembles phencycli-dine (Roth et al., 2013). It has been shown that methoxetamineincreases electrically-stimulated DA release from slices of ratnucleus accumbens and inhibits DA reuptake (Davidson et al.,2014). Demonstration that methoxetamine produced conditionedplace preference and was self-administered by rats indicates that
the drug possesses abuse potential (Botanas et al., 2015).
Methoxetamine is intensively metabolized in humans. Glu-curonide conjugates of phase I metabolites, mainly of O-desmethylmethoxetamine, O-desmethylnormethoxetamine, and


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The most common routes of administration for methoxetaminenclude nasal insufflation and oral consumption, where it is swal-owed either as a powder wrapped in a cigarette paper or dissolvedn a solution. On rare occasions, the drug is taken sublingually, rec-ally, or by intramuscular/intravenous injections (Corazza et al.,013; Kjellgren and Jonsson, 2013). A typical dose of methoxe-amine reported by users was 20–60 mg for insufflation, 40–60 mgor oral administration, and 15–30 mg for intramuscular injection.he duration of action depends on the route of administration:.5–4 h for nasal, 3–5 h for oral, and 2–3 h for intramuscular oneKjellgren and Jonsson, 2013).

The information on effects of methoxetamine is largely lim-ted to self-reported experiences from user websites and caseeports/series. Methoxetamine exerts a wide range of effects,ome of which resemble actions of ketamine and phencyclidine,hile others vary greatly. The desired effects include euphoria,

ncreased empathy and social interaction, feelings of peacefulnessnd calmness, vivid visual hallucinations, intensification of sensoryxperiences (especially to the music), introspection, sense of disso-iation from the physical body, a sense of going deeper inside theelf, spiritual and transcendental experiences, and at high dosesut-of-body or even near-death experiences (Corazza et al., 2013;ofer et al., 2012; Kjellgren and Jonsson, 2013; Zawilska, 2014). In

ome cases the dissociative effects of methoxetamine are describeds being ketamine-like, although user reports suggest they may lastor a markedly longer period of time, up to 24 h (Corazza et al.,013). At higher doses, methoxetamine produces a wide-rangef unwanted effects, among them slurred speech, impairment tonderstand language, distortion of time perception, reduced abil-

ty to concentrate and focus, inability to coordinate movement,nxiety, fear, paranoia, changes in perception of distance, propor-ion and of the body imagine, as well as psychomotor agitationCorazza et al., 2013; Elian and Hackett, 2014; Hill et al., 2013b;ydzik et al., 2012; Kjellgren and Jonsson, 2013; Zawilska, 2014).ome self-reported experiences suggest compulsive re-dosing ofethoxetamine as well as the unintentional consumption of more

han initially planned. However, no data appear to have been pub-ished on dependence and abuse potential of methoxetamine inumans (Zawilska, 2014).

A total of 110 non-fatal intoxications with methoxetamineave been reported by the EMCDDA by the end of 2012, almostalf of them being analytically confirmed (EMCDDA, 2013). Clin-

cal features of methoxetamine-induced toxicity include anxiety,allucinations, panic, profound agitation, aggression, violence,lack-outs, confusion, disorientation, amnesia, lowered conscious-ess, catatonic state, cerebral ataxia, mydriasis, slurred speech,rowsiness, tremor, vertigo, insomnia, motor incoordination,achycardia, chest pain, hypertension, cardiac and respiratoryepression (Zawilska, 2014).

More than 20 deaths due to methoxetamine overdose have beenisseminated. In all these cases, the presence of methoxetamineas analytically confirmed. A conducted postmortem analysis also

evealed the presence of other psychoactive drugs of abuse, such aslcohol, THC, amphetamines, cocaine, synthetic cannabimimetics,etamine, and opioids (Adamowicz and Zuba, 2015; Chiappini et al.,015; EMCDDA, 2013; Wiergowski et al., 2014; Wikström et al.,013). So far, nine countries have banned methoxetamine (Table 2).

.3. Diphenidine and 2-methoxydiphenidine

Following the control of methoxetamine, several new disso-iative piperidine derivatives, antagonists of NMDA receptors,ncluding diphenidine and 2-methoxydiphenidine (MXP, 2-MXP),ave appeared on the recreational drug market (Van Hout and



Hearne, 2015). Analysis of information related to MXP purchase,use, desired and acute side-effects, posted on Internet fora hasrecently been published by Van Hout and Hearne (2015). The com-pound is purchased via online research chemical vendors in theform of powder. The most common routes of administration areoral, nasal and sublingual; reported doses are between 30 and80 mg. Users described effects of MXP as euphoric, empathogenic,stimulant and dissociative, lasting in a wavy way for a long time.Auditory and visual hallucinations were also reported. Commonacute side-effects included chest pain, palpitations, hyperthermia,respiratory difficulties, seizures, disturbances in long-term mem-ory, and limb numbness (Van Hout and Hearne, 2015). Three casesof fatal intoxication have been recently presented by Elliott et al.(2015). Postmortem analysis of biofluids revealed the presence of2-MXP and its metabolites: hydroxy-2-MXP, O-desmethyl-2-MXPand hydroxylated O-desmethyl-2-MXP, as well as diphenidine andhydroxy-diphenidine (Elliott et al., 2015).

7. Synthetic opioid-like drugs

Two new synthetic opioids, AH-7921 and MT-45, have recentlyappeared on the recreational drug market, and risk assessments bythe EMCDDA have been performed for both compounds (EMCDDA,2014d, 2014e; Siddiqi et al., 2015). Their legal status is presentedin Table 2.

7.1. AH-7921

AH-7921 was originally synthesized by Allen and HandburysLtd., and patented in 1976 as an opioid analgesic. Since mid-2012several European countries have reported the presence of AH-7921, also known as “Doxylam”, in seizures by customers or police.The compound is an agonist of �- and �-opioid receptors with amoderate selectivity toward �-opioid receptors. In animal stud-ies, AH-7921 was equipotent to morphine in inducing analgesia,hypothermia, sedation, respiratory depression, miosis, and addic-tive behavior. Furthermore, like morphine, AH-7921 has a narrowtherapeutic window, and doses that produce analgesia are close tothose producing adverse effects (EMCDDA, 2014d; Hayes and Tyers,1983).

Little is known about the prevalence and pattern of AH-7921 use.It is suggested that the primary route of AH-7921 administrationis oral consumption; the drug is also taken nasally, sublingually,rectally, and by intravenous injection. Self-reported effects includerelaxation, euphoria, analgesia, alertness, nausea, myosis, occa-sional itching, and tremor at the end of the session (EMCDDA,2014d). A total of 6 non-fatal intoxications (EMCDDA, 2014d) and18 deaths (EMCDDA, 2014d; Karinen et al., 2014; Kronstrand et al.,2014; Skowronek et al., 2014; Vorce et al., 2014) associated withAH-7921 have been reported. In addition to AH-7921, postmortemanalysis of biological samples revealed the presence of benzo-diazepines, synthetic cathinones, alcohol, methoxetamine, andgabapentin. At autopsy, pulmonary edema was found in the major-ity of victims (EMCDDA, 2014d; Karinen et al., 2014; Kronstrandet al., 2014; Vorce et al., 2014). In one case, the fatal intoxica-tion with a combination of AH-7921 and two synthetic cathinones(N-ethylbuphedrone and 3-methylmethcathinone) led to a suddencardiac arrest (Skowronek et al., 2014).

7.2. MT-45

MT-45 was developed in the 1970s by the Japanese Dainippon
Pharmaceutical Co. Ltd. as an opioid analgesic. The compound actsas an agonist of �-, �- and �-opioid receptors. In animal studiesMT-45 caused analgesia, respiratory depression, sedation, memoryimpairment, and demonstrated dependence potential and abuse

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iability. Analgesic properties of MT-45 were comparable to thosexerted by morphine. Of note, R- and S-stereoisomers of MK-45arkedly differ in the potency of actions (Nozaki et al., 1983).The information from Internet discussion fora and clinical non-

atal intoxication cases indicates that MT-45 is typically takenrally or by nasal insufflation. Other, less common routes ofntake include intravenous or intramuscular injection, inhalation,nd rectal administration. Typical doses reported by users are5–30 mg for insufflation and 25–75 mg for oral administration;esired effects can last for up to 2 h. MT-45 was taken alone or

n combination with other recreational compounds (ACMD, 2014;MCDDA, 2014e; Siddiqi et al., 2015). Frequently reported sub-ective desired effects were mild euphoria, relaxation, having aense of well-being, whereas unwanted effects included itching,edation, dizziness, nausea, anxiety, disorientation, and respira-ory depression (EMCDDA, 2014e; Siddiqi et al., 2015). MT-45ppears to exert ototoxic effects as in a few cases significant audi-ory symptoms with transient tinnitus and hearing loss have beenbserved (Lindeman et al., 2014). A total of 18 non-fatal intoxi-ations (all of them in Sweden), and 30 deaths (28 in Sweden,

in the USA) related to MT-45 use have been reported (ACMD,014; Helander et al., 2014). In addition to MT-45, postmortemnalysis of biological samples revealed the presence of alcohol,sychostimulants, and psychotropic drugs from various thera-eutic groups, such as anxiolytics, antiepileptics, antidepressants,ntipsychotics, and opioids (EMCDDA, 2014e). Symptoms of acutentoxications included mainly tachycardia, somnolence, uncon-ciousness, decreased respiratory rate, reduced oxygen saturation,nd cyanosis. In a few cases parasthesia, blurred vision, bilat-ral hearing loss, miosis, seizures, hypokalemia, hyperthermia,nd vomiting were also observed (ACMD, 2014; EMCDDA, 2014e;elander et al., 2014).

. Conclusion

During the last decade, NPS have extensively dominated therug scene in different parts of the world. Several factors haveontributed to their increasing popularity, including aggressivearketing strategies to attract consumers’ attention, such as attrac-

ive names, colorful packing, low prices, occasional sales, andoyalty programs (e.g., buy one get one free), perception of beingsafe’ and free from risks possessed by classical drugs of abuse, eas-ly access through Internet shops, and lack of detection on routinerine drug screening.

Many NPS were synthesized and patented a few decades ago,ut only recently their chemical structures have been modifiedo produce new compounds with psychoactive effects similar tocheduled drugs of abuse. Importantly, even small molecular dif-erences from previously controlled compounds, not only narcoticsut also the first generation of NPS, can result in a big difference

n terms of biological activity, pharmacokinetic parameters, anddentification. Second generation NPS, such as NBOMe compoundseplacing ‘2C drugs’, and fluorinated SCs analogues, are examplesf such strategy.

There are several risk factors related to NPS use: inter- andntra-product concentration variability, multiple psychoactive sub-tances in single products, manufacturing different compoundsnder the same commercial name, lack of information on active

ngredients inside a package, paucity of scientific research basedata on adverse effects. Little is known about NPS metabolism and

nteraction with other xenobiotics, including medicines. Examples
f the second generation NPS discussed in this review demonstratehat NPS could undergo extensive metabolism in the human body,eading to very low or even negligible levels of the parent com-ound in examined biological fluids. This situation emphasizes


an urgent need for a development of highly sensitive analyticalmethods for detection and quantification of metabolic constituents.Another critical area that awaits elucidation encompasses phar-macological properties, genomic, cellular and systemic toxicity ofNPS and their metabolites, particularly these from the second gen-eration as well as new ones to come. Furthermore, knowledge ofthe specific enzymes involved in phase I metabolism will improveour ability to predict potential drug–drug interactions and possibleimpact of genetic polymorphism.

The rapid emergency of NPS with a constantly increasingnumber of intoxication cases prompted numerous countries tointroduce various legal responses. However, constant modifica-tions of chemical structures by clandestine laboratories allowsproducers to stay one step ahead of the legal process, a situationthat resembles a ‘cat and mouse game’. With an acceleration ofspeed new designer psychoactive compounds replace former ones,it is not surprising that most of second generation NPS presentedin this review either have been already scheduled or put in for-mal risk assessments prepared by the EMCDDA. Another alarmingphenomenon is that scheduling individual substances may leadto a temporary increase in their sale, accompanied by a suddenrise in emergency hospitalizations, around the time of legislation.Such situation happened in Poland in July 2015, when after placingnumerous NPS from different chemical groups (including secondgeneration SCs) into schedule of the Controlled Substance Act, morethan 320 cases of severe intoxications with NPS containing prod-ucts, a few of them fatal, have been notified over a two weeks period(Rzeczpospolita, 2015).

Considering the ever changing market of NPS, both on the localand global scale, we need to raise awareness of these compounds,as well as to substantially facilitate information sharing on cur-rent recreational drugs trends, experience, and toxicity. Keepingin mind that only 10 out of 28 countries reported to the EMCDDAsystematic collection of such information (Heyerdahl et al., 2014),an important condition to reach above goals is an improvement ofdata collection on emergency department presentations with acuteNPS toxicity at the national level. With this improvement in hand,creation of an effective data collection system across Europe seemsfeasible.

Role of funding source

Supported by grants from the National Research Center, Cracow,Poland (2014/13/8/B/NZ7/02237) and Medical University of Lodz,Lodz, Poland (31-002).

Contributors

Jolanta B. Zawilska developed the overall structure of themanuscript, prepared Table 1, wrote parts on the manuscriptrelated to synthetic cannabimimetics, designer cathinones, ana-logues of benzofuran and aminorex, and opioid-like drugs,and incorporated content written by Dariusz Andrzejczak onpsychedelic drugs and that appeared in the Introduction. DariuszAndrzejczak prepared Table 2 and Fig. 1, and conducted the liter-

Conflict of interest

The authors have no conflict of interest in relationship to thispaper.


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next generation of novel psychoactive substances on the ......only” to circumvent drug abuse...

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