Next Generation of Novel Psychoactive Substances on the Horizon – A

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.

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

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

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 120–150 min (Gatch and Forster, 2015). In

as drugs of abuse during the mid-2000s. Since that time, their mice trained to discriminate -THC from vehicle, UR-144, XLR-

market has grown continuously (Castaneto et al., 2014; Zawilska 11, AKB-48, PB-22, 5F-PB-22, and AB-FUBINACA fully substituted

and Wojcieszak, 2014), and the consumption of SCs-containing for -THC, an observation suggesting that these second genera-

products has become a popular alternative to marijuana. A total tion SCs could produce marijuana-like effects in humans (Wiley

number of 134 SCs have been reported to the EWS by the end et al., 2013; Gatch and Forster, 2015). There are few published

of 2014, making the SCs the largest group of NPS monitored by data on toxicological properties of SCs at the cellular level. By

J.B. Zawilska, D. Andrzejczak / Drug and Alcohol Dependence 157 (2015) 1–17 3

Table 1

Representatives 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-yl

1-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

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

Table 1 (Continued)

Synonyms Formal name Chemical structure

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

J.B. Zawilska, D. Andrzejczak / Drug and Alcohol Dependence 157 (2015) 1–17 5

Table 1 (Continued)

Synonyms Formal name Chemical structure

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

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

Table 1 (Continued)

Synonyms Formal name Chemical structure

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

J.B. Zawilska, D. Andrzejczak / Drug and Alcohol Dependence 157 (2015) 1–17 7

Table 1 (Continued)

Synonyms Formal name Chemical structure

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

analogy to older compounds from this class: HU-210, CP- detailed molecular mechanisms underlying SCs-induced cell death

47,497-C8, JWH-018, JWH-073, JWH-122, JWH-210, and AM-2201, are still not fully understood.

representatives of the second generation, namely UR-144, 5F- Due to the appearance of the second generation SCs, metabolism

AKB-48, and 4-(methylnaphtyl)-AM-2201 (MAM-2201, a 5-ﬂuoro of these agents is a rapidly growing area of interest. UR-144 and

analogue of JWH-122), were cytotoxic to various cell types (Bileck XLR-11 are extensively metabolized in mice, mainly to mono-

et al., 2015; Koller et al., 2013, 2014, 2015; Tomiyama and Funada, hydroxylated glucuronides that are excreted with urine (Wiley

2014). Although several processes, like damage of cell membrane, et al., 2013). XLR-11 also undergoes deﬂuorination to UR-144,

DNA damage, interference with protein synthesis, activation of resulting in several metabolites that are common to subjects

caspase-3 and apoptosis, contributed to this action (Bileck et al., using both compounds. A similar phenomenon likely occurs in

2015; Koller et al., 2013, 2015; Tomiyama and Funada, 2014), the case of other ﬂuorinated analogues of SCs. This, in turn, could

Fig. 1. Examples of packaging for products containing second generation NPS.

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

have important analytical and pharmacokinetic consequences. fatal cases, in which 5F-PB-22 was detected in blood specimens,

Thus, identiﬁcation of unique metabolites as potential markers have been reported (Behonick et al., 2014).

for a ﬂuorinated analogue intake is crucial in the detection of a With the rising popularity of SCs as recreational drugs, an

suspected cannabimimetic consumption. Furthermore, duration increase of these compounds in driving cases has been notiﬁed. First

of psychoactive effects exerted by ﬂuorinated SCs could be longer reports on this issue presented 7 (Musshoff et al., 2014) and 16 (Tuv

than that of paternal compounds. In vitro studies with human liver et al., 2014) cases of driving under the inﬂuence of SCs, where the

microsomes identiﬁed 23 and 18 metabolites of AB-PINACA and presence of the following compounds was analytically conﬁrmed

5F-AB-PINACA, respectively (Wohlfarth et al., 2015). AB-PINACA in sera taken from subjects involved: AM-2201, JWH-018, JWH-

was primarily hydrolyzed to AB-PINACA carboxylic acid; two main 019, JWH-081, JWH-122, JWH-210, JWH-250, JWH-307, and RCS-4.

second generation metabolites of AB-PINACA carboxylic acid iden- AM-2201 and JWH-018 were the most frequently detected SCs.

tiﬁed are carbonyl-AB-PINACA and hydroxypentyl-AB-PINACA. With the appearance of the second generation SCs, driving cases

Most of AB-PINACA metabolites identiﬁed in vitro were also found positive for UR-144, XLR-11, APINACA, 5F-APINACA, AB-PINACA

in urine samples from suspected AB-PINACA cases (Wohlfarth and AB-CHMINACA have been recently reported (Adamowicz and

et al., 2015). Major metabolites of 5F-AB-PINACA were AB-PINACA Lechowicz, 2015; Karinen et al., 2015; Lemos, 2014; Louis et al.,

pentanoic acid, 5 -hydroxypentyl-AB-PINACA, and 5F-AB-PINACA 2014; Peterson and Couper, 2015). As the physical examination of

carboxylic acid (Wohlfarth et al., 2015). AKB-48 is predominantly the subjects revealed a delayed reaction of pupils to light, blurred

metabolized by human hepatocytes by mono-, di-, and trihydroxy- speech, dizziness, instable appearance and retarded sequence of

lation on the adamantyl ring followed by glucuronidation (Gandhi movements, it is assumed that the consumptions of SCs, like

et al., 2013; Holm et al., 2015). An observation that CYP3A4 is cannabis use (Hartman and Huestis, 2013), can lead to a potentially

the major enzyme involved in oxidative metabolism of AKB-48 dangerous impairment of driving skills and cognitive deﬁcits.

is of a clinical importance. It is assumed that CYP3A4 inhibitors, Legal status of the second generation SCs discussed above is

for example azole antifungal and anti-HIV drugs, could markedly given in Table 2.

decrease the rate of AKB-48 clearance, and potentiate its toxicity

(Holm et al., 2015). PB-22, 5F-PB-22, BB-22, AB-PINACA, and

AB-FUBINACA also undergo non-CYP-mediated biotransformation 3. Synthetic cathinones

by carboxylesterase 1 (Thomsen et al., 2015).

␤

The increasing number of recent SCs together with their higher Synthetic cathinones represent a large family of -keto

potency of action strongly suggests that these drugs pose an emerg- amphetamine compounds derived from cathinone, an active

ing public health treat. A number of adverse health effects related stimulant in a khat plant (Catha edulis). In the mid-2000s,

to SCs use reported to the National Poison Data USA had increased they appeared on the recreational drug market as alter-

from 349 in January 2015 to 1501 in April 2015 (Law et al., 2015). In natives to the controlled psychostimulants: amphetamine,

a two-week period in July 2015, over 200 people were hospitalized 3,4-methylenedioxymethamphetamine (MDMA), and metham-

in Poland following use of “MOCARZ” (“the Mighty One”); some of phetamine, and were commonly referred to as ‘plant food’,

them were in a very serious condition, and one died. The forensic ‘research chemical’, or ‘bath salts’ (Zawilska and Wojcieszak,

examination of samples revealed the presence of UR-144, BB-22, 2013; Karila et al., 2015). Between 2005 and 2014, more

5F-PB-22, XLR-144, and AB-CHMINACA (SOS Polonia, 2015). than 80 cathinone derivatives were reported to the EWS

Few clinical data on the effects of the second generation SCs (EMCDDA, 2015a). Of numerous synthetic cathinones, the

in humans have been published so far. Case series of acute kid- most commonly abused were mephedrone, methylone, and

ney injury associated with smoking of SCs have recently been 3,4-dimethoxypyrovalerone (MDPV). After regulatory control of

reported in patients without known preexisting renal disease. Ini- popular cathinones, they have been quickly replaced by newly

tial symptoms of a toxidrome were described by the patients as synthesized compounds, that include, but are not limited to,

an acute onset of intense nausea, vomiting, and ﬂank or abdom- analogues of mephedrone: 4-methyl-N-ethylcathinone (4-MEC)

inal pain (CDC, 2013a; Buser et al., 2014). Clinical examination and 4 -methyl-␣-pyrrolidinopropiophenone (4-MePPP; 4-MPPP),

revealed hypertension, elevated serum creatinine and blood urea and ␣-pyrrolidinovalerophenone (␣-PVP), an analogue of MDPV

nitrogen concentrations, and in renal biopsy samples acute tubular (DEA, 2014b; EMCDDA, 2015c). It is suggested that tablets con-

injury. Analysis of implicated products demonstrated the presence taining ␣-PVP are sold as ecstasy (EMCDDA, 2015c). Products

of UR-144 and XLR-11, and in available clinical specimens – XLR- containing ␣-PVP have several street names that vary among

11 N-pentanoic acid metabolite (CDC, 2013a; Buser et al., 2014). different countries, for example “Ocean Breath”, “Fire Ball”, “Total

It should be emphasized that acute kidney injury, irrespective of speed”, “Sensation”, “Speedway”, “Guarana Coco jumbo”, “Energy

its cause, can predispose to chronic and end-stage kidney disease, 3 (NRG-3)” and “Sextasy” (EMCDDA, 2015c).

later in life (Coca et al., 2012). Smoking of ADB-PINACA-containing Synthetic cathinones exert their action by increasing extracellu-

product “Crazy Clown” resulted in a wide-spectrum of adverse lar levels of noradrenaline (NA), dopamine (DA), and serotonin (5-

effects, including anxiety, delirium, aggressive behavior, psychosis, HT), primarily via two mechanisms. First, these compounds interact

confusion/disorientation, seizures, somnolence, unresponsiveness, with monoamine transporter proteins, namely NET, DAT and SERT,

tachycardia, hypertension, acidosis, and hypokalemia. One patient inhibiting reuptake of NA, DA and 5-HT, respectively. Their selectiv-

had myocardial infarction, and another one developed rhabdomy- ity for these transporters varies considerably (Simmler et al., 2013,

olysis (CDC, 2013b; Schwartz et al., 2015). In 7 out of 22 individuals 2014). Second, some compounds also act as transporter substrates

ADB-PINACA and ADB-PINACA 5-pentanoic acid were identiﬁed in and promote the release of neurotransmitters from intracellular

plasma (Schwartz et al., 2015). A case of acute cerebral ischemia stores by reversal of transporter ﬂux, and inhibition of the vesicu-

and infarction (Takematsu et al., 2014), and two fatal cases (Shanks lar monoamine transport receptor, VMAT2 (Simmler et al., 2013,

et al., 2015b) related to analytically conﬁrmed use of XLR-11 have 2014). Determining precise molecular mechanism of action for

been reported. Exposure to PB-22 containing product “Crazy Mon- monoamine transporter drugs is critical to predict their putative

key” (see Fig. 1) lead to seizures in a man and his dog; laboratory toxic potential, as it is suggested that transporter’s substrates, but

analysis of human and canine plasma revealed the presence of PB- not blockers, are endowed with neurotoxic potential. Whether syn-

22 (Gugelmann et al., 2014). PB-22 was suspected to be involved in thetic cathinones are neurotoxic, to what extend, and under which

three deaths in Australia (Gerostamoulos et al., 2015). Recently four conditions remains to be elucidated. Another issue important from

J.B. Zawilska, D. Andrzejczak / Drug and Alcohol Dependence 157 (2015) 1–17 9

Table 2

Legal 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.

MK-45 Controlled substance in Poland and UK (class A). Warning notiﬁcation by the EMCDDA, February 2014.

the clinical point of view is a risk of cathinones-induced hepato- Studies on human liver microsomes identiﬁed six phase I

toxicity. The ﬁrst experimental data demonstrating hepatotoxicity metabolites of ␣-PVP, which were formed with the aid of CYP2D6,

of four synthetic cathinones, including 4-MEC, have been just pub- CYP2B6, and CYP2C19. The compound was primarily metabolized

lished (Araújo et al., 2015). In studies on primary culture of rat hepa- by monohydroxylation after ␤-keto group reduction to OH-␣-

tocytes, 4-MEC reduced cell viability in a concentration-dependent PVP (Negreira et al., 2015). In human urine specimens, both

manner. Hepatotoxic activity of 4-MEC (EC50 = 1.29 mM) was unchanged ␣-PVP and OH-␣-PVP were found (Shima et al., 2014;

weaker from that of MDMA (EC50 = 0.745 mM), used as a reference Uralets et al., 2014). Breakdown of 4-MEC follows metabolic

compound (Araújo et al., 2015). It is suggested that oxidative stress path of mephedrone, and involves reduction of ␤-keto group

is one of factors involved of cathinones’ hepatotoxicity. with consequent N-dealkylation (Uralets et al., 2014). In rat 4-

Structure–activity data have demonstrated that changing an N- MePPP was extensively metabolized by oxidative desamination,

alkyl substituent of cathinone drugs can profoundly inﬂuence their and hydroxylation of the 4 -methyl group followed by oxidation to

pharmacology. 4-MEC and 4-MePPP maintain the 4-methyl ring- 4-carboxy-pyrrolidinopropiophenone, the main drug’s metabolite

substitution of mephedrone: 4-MEC has an N-ethyl group, whereas (Springer et al., 2003).

4-MePPP has an N-butyl group that is cyclized to form a pyrroli- Accumulating evidence indicate that both desired and

dine ring (see Table 1). 4-MePPP acted only as a DAT blocker with unwanted effects of newer synthetic cathinones are similar to those

little activity at SERT (Saha et al., 2015), whereas 4-MEC was a observed for the ﬁrst generation drugs (Zawilska and Wojcieszak,

nonselective inhibitor of DAT, NET and SERT. Interestingly, 4-MEC 2013). According to records posted on Internet fora analyzed by

displayed so-called hybrid activity, acting as a SERT substrate (i.e. 5- Van Hout (2014), 4-MEC is primarily used by insufﬂation and

HT releaser) and DAT/NET blocker (Saha et al., 2015; Simmler et al., orally, with a frequent combination of these two routes due to

2014). The potency of 4-MEC to inhibit uptake at SERT and DAT the extensive nasal burning, clogging of nasal passages, and nasal

was similar to that exerted by mephedrone. By analogy to MDPV, dripping. The drug produced quick but short lasting, up to 2–3 h

␣

-PVP displayed negligible activity at SERT but was potent cate- effects, namely euphoria, deep relaxation, sensual enhancement,

cholamine uptake inhibitor (Marusich et al., 2014). In vivo studies and increased appreciation of music. Negative effects described

demonstrated that ␣-PVP produced psychomotor stimulant effects by users included heart palpitations, insomnia, sweating, muscle

(Marusich et al., 2014), 4-MEC potently increased extracellular 5- twitching, bruxism, dizziness, nausea, and vomiting (Van Hout,

HT level in rat nucleus accumbens, had weak effect on DA, and 2014). ␣-PVP can be taken orally, sublingually, by insufﬂation,

evoked minimal motor stimulation, whereas 4-MePPP produced smoking/inhalation, intravenously, and rectally (EMCDDA, 2015c).

large increases in DA and robust motor stimulation (Saha et al., The reported doses are 5–20 mg (low) and 30–40 mg (high) for

2015). In discriminative-stimulus studies performed on rats, ␣- insufﬂation, 5–25 mg (low) and 45–70 mg (high) for oral admin-

PVP and 4-MePPP fully substituted for methamphetamine, whereas istration, and 2–5 mg (low) and 10–20 mg (high) for intravenous

4-MEC was inactive (Gatch et al., 2015; Naylor et al., 2015). In addi- injection (Drugs Forum). The most common adverse effects were

tion, ␣-PVP produced a discriminative stimulus effect similar to tachycardia, mydriasis, hallucinations, anxiety, agitation, tremor,

that of cocaine (Gatch et al., 2015). Both ␣-PVP and 4-MEC markedly hyperthermia, diaphoresis, and paranoia (Drugs Forum; EMCDDA,

reduced intracranial self-stimulation thresholds in rats with a 2015c). Recently a case of neonatal withdrawal syndrome, with

potency comparable to that of methamphetamine (Watterson et al., increased jitteriness, irritability, high pitched cry, hypertonia

2014). These observations suggest that the discussed above second in the limbs, and brisk tendon reﬂexes, after chronic maternal

generation synthetic cathinones are endowed with abuse poten- consumption of 4-MEC has been reported (Pichini et al., 2014).

tial. There were more than one hundred analytically conﬁrmed fatal

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

cases involving ␣-PVP (EMCDDA, 2015c; Nagai et al., 2014; Gil is available in both powder and tablet form. Some of the tablets

et al., 2015; Potocka-Banas´ et al., 2015; Sykutera et al., 2015). Legal have non-speciﬁc motifs (e.g., “Specked Cherry”, “Speckled Cross”),

status of 4-MEC, 4-MePPP, and ␣-PVP is given in Table 2. logos associated with numerous recreational drugs (e.g., “Playboy”,

“Mitsubishi”, “Heart”, “Transformers”) or marks (e.g., “ST” referring

to the street name “Serotoni”; Fig. 1) (EMCDDA, 2014b; Glanville

4. Benzofuran analogues of amphetamines: 5-APB and

et al., 2015). Although in most cases 4,4 -DMAR was reported as

6-APB

the only active substance, other psychoactive substances (mainly

synthetic cathinones) were also detected (EMCDDA, 2014b).

Two benzofuran compounds, i.e., 5- and 6-APB, appeared

Studies performed on rat brain synaptosomes have demon-

on the recreational drug market in 2010–2011 under street

strated that cis-4,4 -DMAR, cis-MDMAR and trans-MDMAR are

names “Benzo Fury” (Fig. 1), “Fury X”, and “Fury Extreme” (Chan

potent, efﬁcacious substrate-type releasers at DAT, NET, and SERT

et al., 2013; Jebadurai et al., 2013). These two compounds are

(Brandt et al., 2014; McLaughlin et al., 2014). The potency of cis-4,4 -

structural isomers, structurally related to MDMA and MDA (3,4-

DMAR at DAT and NET was comparable to that of d-amphetamine,

methylenedioxyamphetamine). The pharmacological proﬁle of

however, it exerted much more potent action at SERT (Brandt et al.,

these benzofurans indicates that they have both psychostimulant

2014). Comparative studies with cis-MDMAR, trans-MDMAR and

and hallucinogenic properties. It has been demonstrated that, like

MDMA demonstrated that both isomers were more potent at DAT

cathinones, 5-APB and 6-APB are potent inhibitors of DAT, NET

and NET than MDMA (McLaughlin et al., 2014).

and SERT, similar to MDMA, and at high concentrations released

Information collected by the EMCDDA and from the user web-

DA, 5-HT and NA (5-APB only). In addition, they bind to sero-

sites suggests that 4,4 -DMAR is taken by nasal insufﬂations and

tonin 5-HT2A receptors, well known for mediating hallucinogenic

orally; in the latter case the reported doses were 10–20 mg

effects of such drugs as LSD and 1-(2-dimethoxy-4-iodophenyl-

(EMCDDA, 2014b). Oral ingestion is reported by direct swallow-

2-aminopropanone) – DOI (González-Maeso et al., 2007), 5-HT2B

ing of tablets or powder wrapped in cigarette papers (Glanville

and 5-HT2C receptors (Dawson et al., 2014; Iversen et al., 2013;

et al., 2015). At present, information on adverse effects of 4,4 -

Rickli et al., 2015b). As 5-HT2B receptors have been implicated in

DMAR is limited to users’ self reports from Internet discussion fora.

a substance-used heart valve ﬁbrosis (Bhattacharyya et al., 2009),

Commonly described effects include nausea, mydriasis, dysphoria,

high agonist activity of 5-APB and 6-APB at these receptors suggests

agitation, sweating, increased heart rate, dry mouth, psychosis, hal-

that their long term use could cause cardiotoxicity (Dawson et al.,

lucinations, and hyperthermia (Glanville et al., 2015). A total of

2014; Iversen et al., 2013). Both benzofuran compounds also bind

27 deaths, 8 in Hungary and 19 in the United Kingdom, involv-

to adrenergic ␣1A, ␣2A, ␣2B, and ␣2C receptors (Iversen et al., 2013;

ing 4,4 -DMAR, were reported to the EMCDDA (EMCDDA, 2014b).

Rickli et al., 2015b).

In all of the cases 4,4 -DMAR has been detected in postmortem

The main metabolites of 5-APB and 6-APB identiﬁed in rat urine

samples. Intoxication symptoms included hyperthermia, agitation,

samples were 3-carboxymethyl-4-hydroxy amphetamine and

confusion, intensive sweating, seizures, foaming from the mouth,

4-carboxymethyl-3-hydroxy amphetamine, respectively (Welter

cardiac and respiratory arrest. The autopsy ﬁndings demonstrated

et al., 2015a, 2015b).

extensive bleeding in the muscles and organs, brain edema, and

Users report that effects of 5-APB and 6-APB resembled that of

pulmonary edema (EMCDDA, 2014b).

MDMA but were more intense (Jebadurai et al., 2013). A report

from the United Kingdom National Poisons Information Service

has shown that majority of users developed symptoms charac-

6. Hallucinogenic/psychedelic drugs

teristic for sympathomimetic stimulation, such as tachycardia,

hypertension, palpitations, mydriasis, insomnia, fever, diaphoresis,

6.1. NBOMes compounds – a second generation of

and tremor. Mental health disturbances, i.e., anxiety, aggression,

2C-phenethylamines

confusion, psychosis, paranoia, hallucinations and delusion, were

also common (Kamour et al., 2014). The reported adverse effects

The phenethylamine-based structure is shared among such

in users of benzofuran compounds were more pronounced that

diverse compounds as catecholamines, amphetamines, cathinones,

those of mephedrone (Kamour et al., 2014). In three case reports

and so-called 2C drugs. The name “2C”, originally created by

(two related to 5-APB- and one to 6-APB-induced intoxication),

Alexander Shulgin, refers to their chemical structure, where

all analytically conﬁrmed, the dominant symptoms of intoxica-

two carbon atoms separate an amine group from a phenyl

tions were severe psychomotor agitation, aggressiveness, paranoid

ring. The substituted phenethylamines (2C-X) contain methoxy

thoughts, and behavior (Adamowicz et al., 2014; Chan et al., 2013;

groups on 2 and 5 positions of the phenyl ring and a variety

McIntyre et al., 2015). Intoxications induced by consumption of

of substituents at position 4. They exert stimulating, hallucino-

5-APB, taken together with 3-methyl-N-methylcathinone and alco-

genic, and psychedelic effects, depending on the structure and

hol (Adamowicz et al., 2014) or with alcohol only (McIntyre et al.,

dose (Dean et al., 2013; King, 2013). The ﬁrst compound from

2015), were fatal. 5-APB and 6-APB have been classiﬁed as con-

this group was 2-(4-bromo-2,5-dimethoxyphenyl)ethanamine (4-

trolled substances by a few countries (Table 2).

bromo-2,5-dimethoxyphenethylamine; 2C-B; “Nexus”, “Toonies”,

“Bromo”, “Venus”) sold in the 1980s and early 1990s as a MDMA

5. 4,4 -DMAR and MDMAR replacement (Dean et al., 2013). Since the scheduling of 2C-B by

the Drug Enforcement Agency (DEA) in 1995, several new 2C com-

4,4 -DMAR and MDMAR are analogues of aminorex, an anorex- pounds have been synthesized and introduced on the drug market.

igenic compound with stimulant-like character. Aminorex was Recent and highly active compounds are N-benzyl substituted

originally synthesized by McNeil Laboratories in the 1960s. In 1965 phenethylamines (NBOMes), namely 25B-NBOMe (2C-B-NBOMe),

it was registered in Europe as an appetite suppressant, and with- 25C-NBOMe (2C-C-NBOMe), and 25I-NBOMe (2C-I-NBOMe; “N-

drawn shortly afterwards due to fatal complications related to bomb”, “Smiles”, “CIMBI-5”) (Bersani et al., 2014; DEA, 2013;

primary pulmonary hypertension. EMCDDA, 2014c). 25I-NBOMe, the most potent compound of this

The presence of 4,4 -DMAR in Europe was ﬁrst noted by the group, was ﬁrst synthesized by Ralf Heim at the Free University of

EMCDDA at the end of 2012, and an ofﬁcial risk assessment was per- Berlin as one of a series of pharmacological tools to study 5-HT2A

formed by the EMCDDA in 2014 (EMCDDA, 2014b). The compound receptors (Heim, 2003).

J.B. Zawilska, D. Andrzejczak / Drug and Alcohol Dependence 157 (2015) 1–17 11

In vitro receptor studies have demonstrated that NBOMe headache, sweating, and temporary dysuria. High doses can lead

compounds act as potent full agonists of 5-HT2A (a common to strong sound and time distortion, extreme unpleasant halluci-

site of action for hallucinogens) and 5-HT2C receptors. N-Benzyl nations, anxiety, panic and fear, severe agitation, aggressiveness,

substitution of 2C-phenylethylamines dramatically increased their acute psychosis, insomnia, seizures, rhabdomyolysis with subse-

afﬁnity at 5-HT2A receptors (Braden et al., 2006). Importantly, quent acidosis and renal failure, muscle rigidity, tremulousness,

25C-NBOMe and 25I-NBOMe show nanomolar agonist binding and excited delirium which can result in a sudden and unexpected

afﬁnity to 5-HT2A receptors (Braden et al., 2006; Rickli et al., cardiopulmonary arrest. Sympathomimetic signs, such as mydria-

2015a), and are pharmacologically active at very low submil- sis, tachycardia, hypertension, hyperthermia, and diaphoresis are

ligram doses (EMCDDA, 2014c; Nichols et al., 2008). In addition, also common (Bersani et al., 2014; EMCDDA, 2014c; Forrester,

NBOMe compounds showed high afﬁnity binding to adrener- 2014; Grautoff and Kähler, 2014; Hill et al., 2013a; Laskowski et al.,

gic ␣1A and ␣2A receptors, and H1 histamine receptors (Rickli 2015; Nikolaou et al., 2015; Poklis et al., 2014b; Rose et al., 2013;

et al., 2015a). 2-(4-Iodo-2,5-dimethoxyphenyl)ethanamine (2C- Stellpﬂug et al., 2014; Tang et al., 2014b; Wood et al., 2015). Anal-

I) and its two N-benzyl substituted derivatives, 25I-NBOMe ysis of acute intoxication with NBOMe and 2C-X drugs reported to

and 25I-NBMD (2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2,3- the National Poison Data System USA demonstrated that there had

methylenedioxyphenyl)methyl]ethanamine) produced the head been higher incidence of hallucinations/delusions, single episode

twitch response in mice that was completely blocked by a selective seizures and benzodiazepine administration in NBOMe exposures

5-HT2A receptor antagonist, M100,907 (Halberstadt and Geyer, that those in 2C exposures (Srisuma et al., 2014).

2014). In this behavioral test 25I-NBOMe displayed 14-fold higher During the last few years, more than a dozen fatalities have been

potency than 2C-I. As the head twitch response in rats and mice reported as a result of the ingestion of NBOMes, mainly 25I-NBOMe

after 5-HT2A receptors activation is widely used as a behavioral (ACMD, 2013; Andreasen et al., 2015; Bersani et al., 2014; EMCDDA,

proxy in rodent for human hallucinogenic effect, it is assumed that 2014c; Kueppers and Cooke, 2015; Lowe et al., 2015; Poklis et al.,

NBOMe compounds could produce hallucinations in man. 2014a; Shanks et al., 2015a; Srisuma et al., 2014; Tarpgaard et al.,

It has been demonstrated that 25I-NBOMe was extensively 2015; Walterscheid et al., 2014). At the end of the last year two

metabolized, mainly by O-demethylation, O,O-bis-demethylation, students died in Poland after oral ingestion of 25B-NBOMe and 4-

and hydroxylation (Caspar et al., 2015). Twenty-nine and 35 phase chloromethcathinone (Wiergowski et al., 2015). Legal status of the

I metabolites were identiﬁed in rat and human urine, respectively. three discussed NBOMe compounds is given in Table 2.

CYP1A2 and CYP3A4 were involved in the process of hydroxylation,

while CYP2C9 and CYP2C19 – in O-demethylation. The main phase I

metabolites underwent glucoronidation and sulfation (Caspar et al., 6.2. Methoxetamine

2015). In the case of 25B-NBOMe, the major detoxiﬁcation path-

ways in humans include oxidatation and glucoronidation, resulting Methoxetamine (MXE) is a structural analogue of ketamine,

in 12 phase I and 9 phase II metabolites (Boumrah et al., 2015). where a 2-chloro group on a phenyl ring and a N-methylamino

In a cross-sectional anonymous online survey conducted in 2012 group of ketamine have been replaced by a 3-methoxy and N-

on 22,289 respondents (mainly from Canada, USA, and the United ethylamino group, respectively. Since the ﬁrst report on effects

Kingdom), 2.6% of them reported having ever tried one of the three of methoxetamine, which appeared in May 2010, the drug has

NBOMes, i.e. 25B-NBOMe, 25C-NBOMe, and 25I-NBOMe; the most been extensively advertised as a ‘legal’ and ‘bladder friendly’

popular was 25I-NBOMe (Lawn et al., 2014). NBOMe containing alternative to ketamine (EMCDDA, 2013; Kjellgren and Jonsson,

products are sold as tablets, capsules, powder, liquid, spray, and 2013). In light of experimental data demonstrating that prolonged

preloaded paper doses (blotters; see Fig. 1). NBOMes drugs are administration of methoxetamine to mice produced signiﬁcant

usually taken by holding in the mouth (sublingually or bucally) bladder and kidney toxicity (Dargan et al., 2014), an issue as to

or via nasal insufﬂations; oral administration is far less common whether, in humans, this drug is far less toxic than ketamine

(EMCDDA, 2014c; Lawn et al., 2014; Nikolaou et al., 2015). It is remains to be elucidated. In 2013, methoxetamine was one out of

suggested that formulation of NBOMe drugs with hydroxypropyl- four most frequently detected NPS by the Drugs Information and

cyclodextrin can improve their low oral bioavailability (Nikolaou Monitoring System in the Netherlands (Hondebrink et al., 2015).

et al., 2015). There is some evidence that 25C-NBOMe and 25I- Methoxetamine is typically sold as powder, under common street

NBOMe have been sold as a replacement of LSD (Bersani et al., names such as “MXE”, “Mexxy”, “M-ket”, “MEX”, “Kmax”, “Special

2014; EMCDDA, 2014c; Suzuki et al., 2014). However, unlike LSD, M”, “legal ketamine”, “Minx”, “Jippe”, and “Roﬂcoptr” (EMCDDA,

NBOMe drugs exert signiﬁcant sympathomimetic activity and can 2013; Fig. 1). Products often contain other psychoactive com-

lead to acute toxicity (see below). Mild hallucinogenic effects of pounds, including synthetic cathinones (methylone, mephedrone,

25C-NBOMe and 25I-NBOMe taken sublingually or intranasally can MDPV), synthetic cannabimimetics (AM-2201, JWH-018), benzo-

be achieved at doses as low as 50–200 ␮g, strong after 350–800 ␮g, diazepines, methylphenidate, ketamine, cannabis, amphetamine,

and very strong over 700–800 ␮g (Bersani et al., 2014; Halberstadt methamphetamine, MDMA, morphine, and heroin (EMCDDA,

and Geyer, 2013; Nikolaou et al., 2015; Zuba et al., 2013). The drugs 2013; Kamijo et al., 2014).

are only slightly less potent than LSD, which is usually taken in By analogy to ketamine, methoxetamine has a sub-micromolar

doses 25–250 ␮g. The duration of NBOMes actions depends on the afﬁnity for glutamate N-methyl-d-aspartate (NMDA) receptor, and

route of administration, ranging from 3 to 8 h and 4 to 6 h by insuf- binds to its phencyclidine site. In addition, methoxetamine exhibits

ﬂations of 25C-NBOMe and 25I-NBOMe, respectively, and 4 to 10 h a sub-micromolar afﬁnity for SERT, and so resembles phencycli-

(25C-NBOMe) and 6 to 10 h (25I-NBOMe) by sublingual or buccal dine (Roth et al., 2013). It has been shown that methoxetamine

consumption (Bersani et al., 2014; Halberstadt and Geyer, 2014). increases electrically-stimulated DA release from slices of rat

Psychotropic effects of NBOMes are individual-, dose- and nucleus accumbens and inhibits DA reuptake (Davidson et al.,

route of administration-dependent. Primary effects sought by 2014). Demonstration that methoxetamine produced conditioned

users include euphoria, feelings of love and empathy, sociability, place preference and was self-administered by rats indicates that

increased visual, auditory, olfactory, and tactile sensations, hal- the drug possesses abuse potential (Botanas et al., 2015).

lucinations, life-changing spiritual experiences, and psychedelic Methoxetamine is intensively metabolized in humans. Glu-

effects, such as depersonalization and derealization. Common curonide conjugates of phase I metabolites, mainly of O-

adverse effects of NBOMe drugs include nausea, vomiting, desmethylmethoxetamine, O-desmethylnormethoxetamine, and

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

O-desmethylhydroxymethoxetamine, are excreted with urine Hearne, 2015). Analysis of information related to MXP purchase,

(Menzies et al., 2014). use, desired and acute side-effects, posted on Internet fora has

The most common routes of administration for methoxetamine recently been published by Van Hout and Hearne (2015). The com-

include nasal insufﬂation and oral consumption, where it is swal- pound is purchased via online research chemical vendors in the

lowed either as a powder wrapped in a cigarette paper or dissolved form of powder. The most common routes of administration are

in a solution. On rare occasions, the drug is taken sublingually, rec- oral, nasal and sublingual; reported doses are between 30 and

tally, or by intramuscular/intravenous injections (Corazza et al., 80 mg. Users described effects of MXP as euphoric, empathogenic,

2013; Kjellgren and Jonsson, 2013). A typical dose of methoxe- stimulant and dissociative, lasting in a wavy way for a long time.

tamine reported by users was 20–60 mg for insufﬂation, 40–60 mg Auditory and visual hallucinations were also reported. Common

for oral administration, and 15–30 mg for intramuscular injection. acute side-effects included chest pain, palpitations, hyperthermia,

The duration of action depends on the route of administration: respiratory difﬁculties, seizures, disturbances in long-term mem-

2.5–4 h for nasal, 3–5 h for oral, and 2–3 h for intramuscular one ory, and limb numbness (Van Hout and Hearne, 2015). Three cases

(Kjellgren and Jonsson, 2013). of fatal intoxication have been recently presented by Elliott et al.

The information on effects of methoxetamine is largely lim- (2015). Postmortem analysis of bioﬂuids revealed the presence of

ited to self-reported experiences from user websites and case 2-MXP and its metabolites: hydroxy-2-MXP, O-desmethyl-2-MXP

reports/series. Methoxetamine exerts a wide range of effects, and hydroxylated O-desmethyl-2-MXP, as well as diphenidine and

some of which resemble actions of ketamine and phencyclidine, hydroxy-diphenidine (Elliott et al., 2015).

while others vary greatly. The desired effects include euphoria,

increased empathy and social interaction, feelings of peacefulness 7. Synthetic opioid-like drugs

and calmness, vivid visual hallucinations, intensiﬁcation of sensory

experiences (especially to the music), introspection, sense of disso- Two new synthetic opioids, AH-7921 and MT-45, have recently

ciation from the physical body, a sense of going deeper inside the appeared on the recreational drug market, and risk assessments by

self, spiritual and transcendental experiences, and at high doses the EMCDDA have been performed for both compounds (EMCDDA,

out-of-body or even near-death experiences (Corazza et al., 2013; 2014d, 2014e; Siddiqi et al., 2015). Their legal status is presented

Hofer et al., 2012; Kjellgren and Jonsson, 2013; Zawilska, 2014). In in Table 2.

some cases the dissociative effects of methoxetamine are described

as being ketamine-like, although user reports suggest they may last 7.1. AH-7921

for a markedly longer period of time, up to 24 h (Corazza et al.,

2013). At higher doses, methoxetamine produces a wide-range AH-7921 was originally synthesized by Allen and Handburys

of unwanted effects, among them slurred speech, impairment to Ltd., and patented in 1976 as an opioid analgesic. Since mid-2012

understand language, distortion of time perception, reduced abil- several European countries have reported the presence of AH-

ity to concentrate and focus, inability to coordinate movement, 7921, also known as “Doxylam”, in seizures by customers or police.

anxiety, fear, paranoia, changes in perception of distance, propor- The compound is an agonist of ␮- and ␬-opioid receptors with a

tion and of the body imagine, as well as psychomotor agitation moderate selectivity toward ␮-opioid receptors. In animal stud-

(Corazza et al., 2013; Elian and Hackett, 2014; Hill et al., 2013b; ies, AH-7921 was equipotent to morphine in inducing analgesia,

Hydzik et al., 2012; Kjellgren and Jonsson, 2013; Zawilska, 2014). hypothermia, sedation, respiratory depression, miosis, and addic-

Some self-reported experiences suggest compulsive re-dosing of tive behavior. Furthermore, like morphine, AH-7921 has a narrow

methoxetamine as well as the unintentional consumption of more therapeutic window, and doses that produce analgesia are close to

than initially planned. However, no data appear to have been pub- those producing adverse effects (EMCDDA, 2014d; Hayes and Tyers,

lished on dependence and abuse potential of methoxetamine in 1983).

humans (Zawilska, 2014). Little is known about the prevalence and pattern of AH-7921 use.

A total of 110 non-fatal intoxications with methoxetamine It is suggested that the primary route of AH-7921 administration

have been reported by the EMCDDA by the end of 2012, almost is oral consumption; the drug is also taken nasally, sublingually,

half of them being analytically conﬁrmed (EMCDDA, 2013). Clin- rectally, and by intravenous injection. Self-reported effects include

ical features of methoxetamine-induced toxicity include anxiety, relaxation, euphoria, analgesia, alertness, nausea, myosis, occa-

hallucinations, panic, profound agitation, aggression, violence, sional itching, and tremor at the end of the session (EMCDDA,

black-outs, confusion, disorientation, amnesia, lowered conscious- 2014d). A total of 6 non-fatal intoxications (EMCDDA, 2014d) and

ness, catatonic state, cerebral ataxia, mydriasis, slurred speech, 18 deaths (EMCDDA, 2014d; Karinen et al., 2014; Kronstrand et al.,

drowsiness, tremor, vertigo, insomnia, motor incoordination, 2014; Skowronek et al., 2014; Vorce et al., 2014) associated with

tachycardia, chest pain, hypertension, cardiac and respiratory AH-7921 have been reported. In addition to AH-7921, postmortem

depression (Zawilska, 2014). analysis of biological samples revealed the presence of benzo-

More than 20 deaths due to methoxetamine overdose have been diazepines, synthetic cathinones, alcohol, methoxetamine, and

disseminated. In all these cases, the presence of methoxetamine gabapentin. At autopsy, pulmonary edema was found in the major-

was analytically conﬁrmed. A conducted postmortem analysis also ity of victims (EMCDDA, 2014d; Karinen et al., 2014; Kronstrand

revealed the presence of other psychoactive drugs of abuse, such as et al., 2014; Vorce et al., 2014). In one case, the fatal intoxica-

alcohol, THC, amphetamines, cocaine, synthetic cannabimimetics, tion with a combination of AH-7921 and two synthetic cathinones

ketamine, and opioids (Adamowicz and Zuba, 2015; Chiappini et al., (N-ethylbuphedrone and 3-methylmethcathinone) led to a sudden

2015; EMCDDA, 2013; Wiergowski et al., 2014; Wikström et al., cardiac arrest (Skowronek et al., 2014).

2013). So far, nine countries have banned methoxetamine (Table 2).

7.2. MT-45

6.3. Diphenidine and 2-methoxydiphenidine

MT-45 was developed in the 1970s by the Japanese Dainippon

Following the control of methoxetamine, several new disso- Pharmaceutical Co. Ltd. as an opioid analgesic. The compound acts

ciative piperidine derivatives, antagonists of NMDA receptors, as an agonist of ␮-, ␦- and ␬-opioid receptors. In animal studies

including diphenidine and 2-methoxydiphenidine (MXP, 2-MXP), MT-45 caused analgesia, respiratory depression, sedation, memory

have appeared on the recreational drug market (Van Hout and impairment, and demonstrated dependence potential and abuse

J.B. Zawilska, D. Andrzejczak / Drug and Alcohol Dependence 157 (2015) 1–17 13

liability. Analgesic properties of MT-45 were comparable to those an urgent need for a development of highly sensitive analytical

exerted by morphine. Of note, R- and S-stereoisomers of MK-45 methods for detection and quantiﬁcation of metabolic constituents.

markedly differ in the potency of actions (Nozaki et al., 1983). Another critical area that awaits elucidation encompasses phar-

The information from Internet discussion fora and clinical non- macological properties, genomic, cellular and systemic toxicity of

fatal intoxication cases indicates that MT-45 is typically taken NPS and their metabolites, particularly these from the second gen-

orally or by nasal insufﬂation. Other, less common routes of eration as well as new ones to come. Furthermore, knowledge of

intake include intravenous or intramuscular injection, inhalation, the speciﬁc enzymes involved in phase I metabolism will improve

and rectal administration. Typical doses reported by users are our ability to predict potential drug–drug interactions and possible

15–30 mg for insufﬂation and 25–75 mg for oral administration; impact of genetic polymorphism.

desired effects can last for up to 2 h. MT-45 was taken alone or The rapid emergency of NPS with a constantly increasing

in combination with other recreational compounds (ACMD, 2014; number of intoxication cases prompted numerous countries to

EMCDDA, 2014e; Siddiqi et al., 2015). Frequently reported sub- introduce various legal responses. However, constant modiﬁca-

jective desired effects were mild euphoria, relaxation, having a tions of chemical structures by clandestine laboratories allows

sense of well-being, whereas unwanted effects included itching, producers to stay one step ahead of the legal process, a situation

sedation, dizziness, nausea, anxiety, disorientation, and respira- that resembles a ‘cat and mouse game’. With an acceleration of

tory depression (EMCDDA, 2014e; Siddiqi et al., 2015). MT-45 speed new designer psychoactive compounds replace former ones,

appears to exert ototoxic effects as in a few cases signiﬁcant audi- it is not surprising that most of second generation NPS presented

tory symptoms with transient tinnitus and hearing loss have been in this review either have been already scheduled or put in for-

observed (Lindeman et al., 2014). A total of 18 non-fatal intoxi- mal risk assessments prepared by the EMCDDA. Another alarming

cations (all of them in Sweden), and 30 deaths (28 in Sweden, phenomenon is that scheduling individual substances may lead

2 in the USA) related to MT-45 use have been reported (ACMD, to a temporary increase in their sale, accompanied by a sudden

2014; Helander et al., 2014). In addition to MT-45, postmortem rise in emergency hospitalizations, around the time of legislation.

analysis of biological samples revealed the presence of alcohol, Such situation happened in Poland in July 2015, when after placing

psychostimulants, and psychotropic drugs from various thera- numerous NPS from different chemical groups (including second

peutic groups, such as anxiolytics, antiepileptics, antidepressants, generation SCs) into schedule of the Controlled Substance Act, more

antipsychotics, and opioids (EMCDDA, 2014e). Symptoms of acute than 320 cases of severe intoxications with NPS containing prod-

intoxications included mainly tachycardia, somnolence, uncon- ucts, a few of them fatal, have been notiﬁed over a two weeks period

sciousness, decreased respiratory rate, reduced oxygen saturation, (Rzeczpospolita, 2015).

and cyanosis. In a few cases parasthesia, blurred vision, bilat- Considering the ever changing market of NPS, both on the local

eral hearing loss, miosis, seizures, hypokalemia, hyperthermia, and global scale, we need to raise awareness of these compounds,

and vomiting were also observed (ACMD, 2014; EMCDDA, 2014e; as well as to substantially facilitate information sharing on cur-

Helander et al., 2014). rent recreational drugs trends, experience, and toxicity. Keeping

in mind that only 10 out of 28 countries reported to the EMCDDA

systematic collection of such information (Heyerdahl et al., 2014),

8. Conclusion an important condition to reach above goals is an improvement of

data collection on emergency department presentations with acute

During the last decade, NPS have extensively dominated the NPS toxicity at the national level. With this improvement in hand,

drug scene in different parts of the world. Several factors have creation of an effective data collection system across Europe seems

contributed to their increasing popularity, including aggressive feasible.

marketing strategies to attract consumers’ attention, such as attrac-

tive names, colorful packing, low prices, occasional sales, and

loyalty programs (e.g., buy one get one free), perception of being

Role of funding source

‘safe’ and free from risks possessed by classical drugs of abuse, eas-

ily access through Internet shops, and lack of detection on routine

Supported by grants from the National Research Center, Cracow,

urine drug screening.

Poland (2014/13/8/B/NZ7/02237) and Medical University of Lodz,

Many NPS were synthesized and patented a few decades ago,

Lodz, Poland (31-002).

but only recently their chemical structures have been modiﬁed

to produce new compounds with psychoactive effects similar to

scheduled drugs of abuse. Importantly, even small molecular dif-

Contributors

ferences from previously controlled compounds, not only narcotics

but also the ﬁrst generation of NPS, can result in a big difference

Jolanta B. Zawilska developed the overall structure of the

in terms of biological activity, pharmacokinetic parameters, and

manuscript, prepared Table 1, wrote parts on the manuscript

identiﬁcation. Second generation NPS, such as NBOMe compounds

related to synthetic cannabimimetics, designer cathinones, ana-

replacing ‘2C drugs’, and ﬂuorinated SCs analogues, are examples

logues of benzofuran and aminorex, and opioid-like drugs,

of such strategy.

and incorporated content written by Dariusz Andrzejczak on

There are several risk factors related to NPS use: inter- and

psychedelic drugs and that appeared in the Introduction. Dariusz

intra-product concentration variability, multiple psychoactive sub-

Andrzejczak prepared Table 2 and Fig. 1, and conducted the liter-

stances in single products, manufacturing different compounds

ature search. Both authors have contributed to and have approved

under the same commercial name, lack of information on active

the manuscript.

ingredients inside a package, paucity of scientiﬁc research based

data on adverse effects. Little is known about NPS metabolism and

interaction with other xenobiotics, including medicines. Examples

of the second generation NPS discussed in this review demonstrate Conﬂict of interest

that NPS could undergo extensive metabolism in the human body,

leading to very low or even negligible levels of the parent com- The authors have no conﬂict of interest in relationship to this

pound in examined biological ﬂuids. This situation emphasizes paper.

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

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