Download Spice/K2 drugs – more than innocent substitutes for marijuana

International Journal of Neuropsychopharmacology (2014), 17, 509–525.
doi:10.1017/S1461145713001247
© CINP 2013
REVIEW
Spice/K2 drugs – more than innocent substitutes
for marijuana
Jolanta B. Zawilska and Jakub Wojcieszak
Department of Pharmacodynamics, Medical University of Lodz, Lodz, Poland
Abstract
Smokeable herbal mixtures containing synthetic agonists of cannabinoid receptors, known under brand names
such as Spice, K2 and Kronic, represent a relatively new type of designer psychoactive drugs that has recently
emerged on the recreational drug market. Although the Spice packages are labelled ‘not for human consumption’
or ‘for aromatherapy only’ and declared to be purely herbal, these herbal mixtures produce cannabis-like effects
after smoking. This review surveys the current state of knowledge regarding the pharmacological properties
of synthetic cannabimimetics and the prevalence and pattern of their use. Special emphasis is given to the
negative consequences of using these products, including, among others, hallucinations, psychoses with
delusions, seizures, cardiovascular symptoms and acute kidney injury.
Received 19 July 2013; Reviewed 16 August 2013; Revised 27 September 2013; Accepted 27 September 2013;
First published online 29 October 2013
Key words: Abuse, adverse effects, Spice, synthetic cannabimimetics, THC.
Introduction
Synthetic agonists of cannabinoid receptors (hereafter
‘synthetic cannabimimetics’) represent a relatively new
type of designer psychoactive drugs that has recently
emerged on the recreational drug market (Fattore and
Fratta, 2011; Zawilska, 2011; Winstock and Barratt,
2013). Smokeable herbal mixtures containing synthetic
cannabimimetics are sold under a variety of brand
names; the most common are Spice in Europe, K2 in the
United States, Kronic in Australia and New Zealand.
Around 2004, in various European countries, herbal
mixtures of the Spice-type, advertised as meditation
potpourris, bath additives, air refreshers or tropical car
perfumes (Fattore and Fratta, 2011), became available
on the internet and in specialized ‘head shops’, which
sell paraphernalia for cannabis users. They gained significant popularity in 2008, and at that time sales of these
mixtures dramatically increased in Germany (Dresen
et al., 2010). Growing suspicion that synthetic psychoactive compounds could have been added to these herbal
mixtures was finally confirmed at the end of 2008 by
the detection of two synthetic cannabimimetic agents in
Spice, namely the cyclohexylphenol CP 47,497-C8 and
the aminoalkylindole JWH-018 (Auwärter et al., 2009;
Uchiyama et al., 2010). As compared to traditional illicit
psychoactive compounds of abuse, very little information
exists in the medical literature concerning new designer
recreational drugs, including synthetic cannabimimetics.
Spice products are usually sold in metal-foil sachets,
typically containing 1–3 g of dried vegetable matter
(leaves, flowers, resin) to which one or more synthetic
cannabimimetics have been added. They are relatively inexpensive, roughly €9–12 g−1 ($10–20 g−1), and €26–30 for
sachets sufficient for around eight joints (EMCDDA, 2009;
Johnson et al., 2013). The Spice packages are labelled ‘not
for human consumption’ or ‘for aromatherapy only’ and
declared to be purely herbal, containing plant ingredients
considered inert, and rarely list plants that naturally
contain psychoactive compounds, such as wild dagga
(Leonotis leonurus) or Indian warrior (Pedicularis densiflora)
(Dresen et al., 2010; Zuba et al., 2011). It has to be emphasized that the multicoloured packaging of the Spice-type
products is very attractive and highly sophisticated.
Many of them have a wide-open-eye imprint and circulate under such exotic names as Bombay Blue, Ex-ses,
Experience-Chill, Ice Bud Extra Cold, Herbal Dream,
Mojo, Moon Rocks, Red Magic, Space Truckin’, Spice
Gold Spirit, Spice Tropical Synergy, SpiceWorld420 and
Yucatan Fire (Harris and Brown, 2013). Because of their
packaging and very attractive scent, Spice products are
not easily identified by non-users as drugs.
Synthetic cannabimimetics – the major biologically
active components of Spice
Address for correspondence: Professor J. B. Zawilska, Department of
Pharmacodynamics, Medical University of Lodz, ul. Muszynskiego 1,
PL90-151 Lodz, Poland.
Tel.: +48-42-6779294 Fax: +48-42-6788398
Email: [email protected]
At present, over 150 synthetic cannabimimetics are
known, and the list is constantly growing. Some of the
first compounds detected in Spice were synthesized
and named after John W. Huffman, a medicinal chemist
510
J. B. Zawilska and J. Wojcieszak
0
0
0
N
JWH-015
N
0
JWH-018
CI
N
0
JWH-081
N
JWH-122
O
O
F
I
O
O
N
JWH-203
N
JWH-250
O
O
N
AM-694
N
RCS-4
OH
OH
H
OH
H
O
CP 47,497-C8
HU-210
Fig. 1. Chemical structures of synthetic cannabimimetics.
at Clemenson University, USA (Huffman et al.,
1994). Notably, JWH-018 (1-pentyl-1H-indol-3-yl)-1naphthalenyl-methanone), the most studied and best
characterized synthetic cannabinoid to date, was one of
the first compounds to be abused due to its high pharmacological activity and ease of synthesis (Huffman et al.,
1994; Atwood et al., 2009; Huffman, 2009). Today, aminoalkylindoles, phenacetylindoles and naphthoylpyrolles designed by J. W. Huffman represent the
dominant cannabimimetic compounds detected in the
Spice products (Hudson and Ramsey, 2011; Carroll
et al., 2012). The other chemically distinct groups of synthetic cannabimimetics include: (1) the cyclohexylphenol
(CP) compounds synthesized by Pfizer in the 1970s
(e.g. CP 47,497 and its modified version CP 47,497-C8),
(2) the HU-compounds, synthesized in the 1960s
by Raphael Mechoulam at the Hebrew University
(e.g. HU-210) and (3) the benzoylindoles, such as
AM-694 and AM-2201 synthesized by Alexandros
Makriyannis, or RCS-4 and RCS-8 produced by
Research Chemical Suppliers (EMCDDA, 2009;
Lindigkeit et al., 2009; Hudson et al., 2010; Uchiyama
et al., 2010, 2011a, b; Seely et al., 2011). With the exception
of HU-210, synthetic cannabimimetics are structurally
distinct from Δ9-tetrahydrocannabinol (Δ9-THC), the
primary psychoactive component of natural cannabis
(Fig. 1).
Spice products can be distinguished by the presence
of: (1) pronounced variations in the core structure of synthetic cannabimimetics, (2) considerable inter-and intrabatch variability in smoking mixtures, both in terms of
substances present and their quantity and (3) ever changing composition. Once some compounds became
regulated, new analogues appeared on the market in
order to satisfy demand and at the same time to avoid
criminalization (Lindigkeit et al., 2009; Hudson and
Ramsey, 2011; Dargan et al., 2011; Simolka et al., 2012;
Ernst et al., 2012; Langer et al., 2013; Uchiyama et al.,
2013). Despite modifications in the chemical structure, all
of the synthetic cannabimimetics are lipid soluble, nonpolar and typically consist of 20 to 26 carbon atoms,
which explains why they volatilize readily when smoked.
Synthetic cannabimimetics found in the Spice products
can be classified into one of the following groups
(Zawilska, 2011; Favretto et al., 2013):
• So called JWH compounds, at present including 146
members. This group has been divided into five
subgroups:
– naphthoylindoles, constituting the largest group of
74 compounds (e.g. JWH-015, JWH-018, JWH-019,
JWH-073, JWH-122, JWH-200, JWH-210, JWH-387,
JWH-398);
– naphthylmethylindoles, 9 compounds (e.g. JWH175);
– naphthoylpyrroles, 32 compounds (e.g. JWH-147);
– naphthylmethylindenes,
3
compounds
(e.g.
JWH-176);
– phenacetylindoles, 28 compounds (e.g. JWH-203,
JWH-250, JWH-253).
• Cyclohexylphenols (CP 47,497 and its homologues).
• Benzoylindoles (e.g. AM-694, AM-2201, AM-679,
RCS-4).
• Classical cannabinoids (e.g. HU-210).
• Other compounds, such as, for example, WIN 55,212-2,
UR-144 and TMCP series.
Synthetic cannabimimetics as drugs of abuse 511
UR-144 ((1-pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone), originally synthesized by Abbot
Laboratories, has recently been identified in various
herbal products obtained via online vendors in Russia
(Kavanagh et al., 2013) and in herbal incense seized
for drug trafficking in South Korea (Choi et al.,
2013). The TMCP compounds (TMCP-H, TMCP-018,
TMCP-020,
TMCP-2201,
TMCP-200,
TMCP-1220
and TMCP-1220-azepane), containing a 2,2,3,3-tetramethylcyclopropanecarbonyl
moiety,
represent
a
novel class of synthetic cannabimimetics. They have
been identified and detected in smoking mixtures
seized in Russia and Belarus (Shevyrin et al., 2012).
Interestingly, one of them, TMCP-2201 (1-(5fluoropentyl)-1H-indol-3-yl)-2,2,3,3-tetramethylcyclopropyl)
methanone, also known under the name of XLR-11, has
been detected in samples of ‘Mr. Happy’, ‘Clown Loyal’
and ‘Lava’ products, while its metabolite was identified
in clinical specimens from US patients suffering with
acute kidney injury associated with synthetic cannabimimetics use (CDC, 2013).
Other identified substances include (Lindigkeit et al.,
2009; Zuba et al., 2011):
• Amides of fatty acids: oleamide, palmitamide and
stearamide, which could mimic the action of natural
cannabinoids.
• Substances presumably originating from plants, e.g.
eugenol, eucalyptol, phytosterole, thymol, squalene,
persicol, fatty acids and their esters (ethyl linoleate,
linoleic acid, palmitic acid).
• Flavours (ethyl vanillin, acetyl vanillin).
• Preservatives (benzophenone, benzyl benzoate, hydroxybenzoic acid).
In addition, Spice products are supposed to contain
up to 15 different vegetal compounds, which gives rise
to a wide variety of drug combinations (Dresen et al.,
2010; Zuba et al., 2011). Moreover, they have been
found to contain large amounts of vitamin E, added to
hamper the analysis of the active cannabinoids (Dresen
et al., 2010; Zuba et al., 2011).
To create the herbal products, synthetic cannabimimetics are dissolved in an organic solvent (e.g. acetone)
and the resulting solution is sprayed on plant material.
The doped plant material is then dried and smoked in
a similar fashion to actual cannabis. Spice products typically have a pleasurable smell and taste, for example
honey or vanilla (Fattore and Fratta, 2011).
Spice – prevalance, pattern of use, users profile
Several factors contribute to the growing popularity of
synthetic cannabimimetics, namely the expectation to
achieve a more intense high than after cannabis, affordability, easy access, belief in the safety of use and avoidance of detection in standardized drug tests (Fattore
and Fratta, 2011). Among adolescents and young adults
lifetime use of Spice/K2 products was reported to be
around 10% (Hu et al., 2011; Forrester et al., 2012;
Vandrey et al., 2012), but the recently published results
of a self-reported study that included 14966 participants
from different countries around the world revealed lifetime use to be more prevalent (16.8%) (Winstock and
Barratt, 2013). In 2011, one-year prevalence of Spice use
by 12th grade students in USA was 11.4%. Thus, Spice
was the second most popular illicit substance used by
this group, behind marijuana (Office of National Drug
Control Policy, 2011).
Users are primarily male adolescents and young
adults, having at least a high school level of education
(Hu et al., 2011; Forrester et al., 2012; Vandrey et al.,
2012; Winstock and Barratt, 2013). Accumulating evidence demonstrates the increasing popularity of synthetic
cannabimimetics amongst soldiers (Loeffler et al., 2012)
and athletes (Heltsley et al., 2012). An analysis of 101
serum samples from 80 subjects, provided by several
medical and forensic centres in Germany, demonstrated
that 56.4% of them were positive for at least one synthetic
cannabimimetic. The most prevalent compound was
JWH-081 (found in 55% of samples), followed by
JWH-250 (47%), JWH-018 (9%) and JWH-073 (6%). Ten
serum samples were positive for only one compound,
35 samples contained two, eight samples three, and four
samples contained four (Dresen et al., 2011).
The primary reasons for the use of synthetic cannabimimetics are: curiosity, enjoyment of the effects, satisfaction, a desire to achieve marijuana-like psychoactive
effects while avoiding detection in drug tests and, less frequently, to aid the reduction or cessation of cannabis use
(Fattore and Fratta, 2011; Vandrey et al., 2012; Barratt
et al., 2013). Spice use was found to occur at a residence,
with the users alone or in small groups (Forrester et al.,
2012; Vandrey et al., 2012). Smoking as a joint or in a
water-pipe were the most common modes of synthetic
cannabimimetics administration, while oral consumption
as herbal tea was uncommon. The products were
obtained from retail vendors such as head shops or gas
stations/convenience stores, via the internet or from
friends and/or relatives (Vandrey et al., 2012). Data from
an anonymous internet-based survey conducted at the beginning of 2011 on 168 respondents demonstrated that the
mean number of days of Spice use in the previous year
was 67. A subset of respondents endorsed regular use,
with 55 and 39% reporting use in the past month and
past week, respectively. The mean number of uses per
day was four. During an average episode approximately
1 g of product (or 4.5 ‘hits’) was consumed, and the maximum amount consumed in a single episode was reported
to be 1.5 g (7.6 ‘hits’). The average duration of subjective
intoxication lasted 93 min, while the greatest one lasted
170 min (Vandrey et al., 2012). According to recent users
self-reports, synthetic cannabimimetics have a shorter
time until peak and shorter duration of action when compared with natural cannabis (Winstock and Barratt, 2013).
512
J. B. Zawilska and J. Wojcieszak
Almost all recent synthetic cannabimimetics users admitted to having used natural cannabis. The vast majority
of them also consumed alcohol (90.5% of the users in the
previous month), tobacco (67.9%) and energy drinks
(61.4%). Some of them reported consumption of other
psychoactive compounds, mainly MDMA (26.2% in the
previous month), benzodiazepines (18.5%), cocaine
(14.8%), LSD and hallucinogenic mushrooms (around
12%). Among respondents who recently used both cannabis and synthetic cannabimimetics, almost 80% reported
far more frequent use of the former (Winstock and
Barratt, 2013).
Although data collected from online surveys broaden
our knowledge on the use of synthetic cannabimimetics
as well as their desired and unwanted effects (see
below), they should be interpreted with caution due to
several methodological limitations. The most significant
limitations include: (1) groups are not representative of
the general population (e.g. students from one university,
people having access to the internet, willing to complete a
survey without compensation), (2) surveys are retrospective, so the data are subject to recall bias, (3) respondents
are not certain of the chemical compounds actually contained in the Spice-type products and (4) high levels of
poly-drug use and confounding effects from other
compounds.
Analysis
To our knowledge, at present neither synthetic cannabimimetics nor their metabolites can be detected by standard and extended drug tests. Since various synthetic
cannabimimetics are controlled in several countries, including Austria, Australia, Belgium, Canada, Denmark,
Estonia, Finland, France, Italy, Japan, Latvia, Lithuania,
Poland, Romania, Russia, Spain, South Korea, Sweden
and the USA (UNODC, 2010; EMCDDA, 2011; National
Conference of State Legislatures, 2012), great effort has recently been given to developing testing strategies capable
of identifying and quantifying these compounds and
their downstream metabolites in suspected products
and human biological samples (blood, serum, urine,
oral fluids and hair). The applied analytical methods include liquid chromatography tandem mass spectrometry
(LC-MS/MS), gas chromatography-mass spectrometry
(GC-MS), high mass resolution techniques like matrixassisted laser desorption/ionization-time of flight mass
spectrometry (MALDI-TOF) and direct analysis in real
time mass spectrometry (DART-MS) (Dresen et al., 2010,
2011; Hudson et al., 2010; Sobolevsky et al., 2010; Teske
et al., 2010; Uchiyama et al., 2010, 2011a; Chimalakonda
et al., 2011a, b, 2012; Coulter et al., 2011; ElSohly et al.,
2011; Grigoryev et al., 2011, 2012, 2013; Möller et al.,
2011; Moran et al., 2011; Gottardo et al., 2012; Hutter
et al., 2012a, b; Kneisel and Auwäter, 2012; Musah
et al., 2012; Denooz et al., 2013; Kavanagh et al., 2013).
However, these analytic methods are currently limited
to a few laboratories. It has to be emphasized that even
with the aid of these highly sophisticated analytical methods, the ever-changing composition of the Spice-type products and their complex metabolism combined with the
very limited available information on the chromatographic characteristics and spectral features of the newest
compounds and their metabolites, create a major obstacle
to effective detection of cannabimimetics, especially in
biological samples (Favretto et al., 2013).
Synthetic cannabimimetics – mode of action,
biodisposition and metabolism
Cannabinoids exert their biological effects primarily by
interacting with specific membrane bound G proteincoupled cannabinoid receptors, termed CB1 and CB2.
Both cannabinoid receptors inhibit adenylyl cyclase and
activate a mitogen-activated protein kinase (MAP) cascade by interacting with Gi/o-subtype of G proteins. The
CB1 receptor can also activate an A-type and inwardly
rectifying potassium channel and inhibit N- and P/
Q-type calcium channels. In addition, the CB1 receptor
can be coupled to the Gs protein (Pertwee et al., 2010).
Accumulating experimental evidence indicate that the
actions of cannabinoids are not restricted to the CB1 and
CB2 receptors. Other postulated molecular targets for cannabinoids include additional GPCR (e.g. opioid receptors,
muscarinic acetylcholine receptors and the GPR55 receptor), transient receptor potential cation channel receptors,
such as transient receptor potential cation channel vanilloid receptors (TRPV), and nuclear perixisome
proliferation-activated receptors (PPAR) (Pertwee et al.,
2010).
Activation of CB1 receptors by endocannabinoids
occurs mainly via a retrograde signaling process. CB1
receptors are found on the axon terminals of neurons,
where they usually mediate the inhibition of neurotransmitters release (Lovinger, 2008). They are abundantly
expressed in brain regions associated with cognition,
memory, reward, anxiety, pain sensory perception, food
intake, body temperature and motor coordination, such
as the cerebral cortex, hippocampus, basal ganglia, cerebellum and hypothalamus. In addition to the central nervous system (CNS), CB1 receptors are also expressed in
the peripheral nervous system, both on sensory nerve
fibres and in the autonomic nervous system. CB2 receptors are located predominantly in multiple lymphoid
organs, such as the spleen, tonsils, thymus and lymphoid
nodes, as well as immune cells, including lymphocytes,
macrophages, microglia, mast cells and natural killing
cells. It has been shown that the psychoactive effects of
Δ9-THC are mediated through CB1 receptors in the
brain (Howlett et al., 2002).
At present, little is known about the detailed pharmacology and toxicology of synthetic cannabimimetics, and
no systematic studies on humans have been published.
It is widely known that most Spice drugs are endowed
Synthetic cannabimimetics as drugs of abuse 513
with potent cannabimimetic activity. Table 1 presents
synthetic cannabimimetics with defined receptor profiles
most commonly detected in products and biological samples. Behavioural studies performed on animals demonstrate that synthetic cannabimimetics are potent agonists
of CB1 and CB2 receptors. CP-47,497 and JWH-018
given intraperitoneally to rats suppressed spontaneous
locomotor activity for longer duration and more potently
than Δ9-THC (Uchiyama et al., 2012). Nasal exposure of
mice to smoke from ‘Buzz’ (containing 2.7 mg JWH-018)
resulted in a dose-dependent antinociception, hypothermia, catalepsy and reduced spontaneous locomotor
activity (Wiebelhaus et al., 2012). Δ9-THC-like discriminative stimulus effects were observed in mice after
administration of JWH-204, JWH-205, JWH-018 and
JWH-073 (Vann et al., 2009; Brents et al., 2013), and in
monkeys treated with JWH-018 and JWH-073 (Ginsburg
et al., 2012). By analogy to Δ9-THC, JWH-018 and
JWH-073 dose-dependently attenuated the withdrawal
symptoms produced by rimonabant, a CB1 receptor antagonist (Ginsburg et al., 2012). Chronic exposure of
mice to JWH-015, a CB2-selective agonist, has been associated with increased vulnerability to drug abuse and depression (Onaivi et al., 2008), while systemic, intranasal
administration of another CB2-selective cannabimimetic
compound, JWH-133, or its direct injection to the nucleus
accumbens, dose-dependently inhibited intravenous cocaine self-administration, cocaine-enhanced locomotion
and cocaine-enhanced extracellular dopamine level in
the nucleus accumbens (Xi et al., 2011). In electrophysiological studies CP-47,497 and JWH-018 increased the EEG
power spectra in the frequency range of 5.0–6.0 Hz, while
Δ9-THC decreased the power spectra in the wide range of
7.0–20.0 Hz (Uchiyama et al., 2012). As prolonged cannabis use is associated with immune suppression (Klein and
Cabral, 2006; Grotenhermen, 2007), it can be anticipated
that the long-term use of Spice drugs containing synthetic
cannabimimetics with affinity for CB2 receptors
(Huffman, 2009; Uchiyama et al., 2011b: Rajasekaran
et al., 2013; see Table 1) may also affect the function of
the immune system. The very recent paper by Lewis
et al. (2012) demonstrated that both short- and long-term
administration to male rats of HU-210 had negative
effects on spermatogenesis, being associated with
decreased sperm production and a reduced number of
Sertoli cells, as well as fragmentation of sperm DNA
and reduction in sperm motility. Whether recreational
use of synthetic cannabimimetics might affect the fertility
of man remains to be elucidated.
Our knowledge on the tissue distribution and metabolism of inhaled synthetic cannabimimetics is, at present,
limited. Wiebelhaus et al. (2012) analysed biodisposition
of JWH-018 in mice exposed (a nose-only exposure) to
smoke from 50 mg of the herbal product called ‘Buzz’
containing 5.4% of JWH-018, and found significant
JWH-018 levels in blood, brain, heart, lung, liver, kidney
and spleen. Furthermore, mice exposed to 20 mg of ‘Buzz’
demonstrated elevated levels of JWH-018 in the heart and
lungs. The highest concentrations of JWH-018 were found
in tissues associated with absorption (lung), metabolism
(liver) and elimination (kidney), while the lowest were
found in blood. In another study mice were exposed to
smoke from 50 mg ‘Magic Gold’ containing 3.6%
JWH-018 and 5.7% JWH-073 and the time course of disposition of these two cannabimimetics in the blood and
the brain was evaluated. Concentrations of JWH-018
and JWH-073 increased quickly. Twenty minutes after exposure the mean blood concentration was 88 ng/ml for
JWH-018 and 134 ng/ml for JWH-073. At the same
time the mean brain concentration was 317 ng/g and
584 ng/g, for JWH-018 and JWH-073, respectively.
Within 20 h, blood and brain concentrations of both compounds dropped to very low or undetectable levels
(Poklis et al., 2012). Data from animal studies are in accordance with the results published by Teske et al.
(2010). In two human subjects who consumed a dose of
c.50 μg/kg body mass JWH-018 by smoking, the maximum blood concentrations of the drug were in the
range of 10 ng/ml 5 min post-inhalation. Within 3 h, the
serum level rapidly dropped, and after 24 h merely
trace findings were present. It might be expected that
the time course of synthetic cannabimimetics action is
similar to that of cannabis, as following inhalation, maximum plasma concentration of Δ9-THC was found to
occur within minutes after inhalation, its psychotropic
effects start within seconds to a few minutes, reach a
maximum after 15–30 min and cease within 2–3 h
(Grotenhermen, 2003).
It is suggested that both phase I (oxidation, and to a
lower extent, carboxylation) and phase II (conjugation
with glucuronic acid) processes are involved in the
metabolism of synthetic cannabimimetics (Sobolevsky
et al., 2010; Wintermeyer et al., 2010; Chimalakonda
et al., 2011a; Moran et al., 2011). Final metabolites are predominantly excreted with urine (Gronewold and Skopp,
2011). Monohydroxylation is the major metabolic pathway of compounds containing in their structure the
indole ring, such as naphtoylindoles, phenacetylindoles
and benzoylindoles. For some of them, metabolites with
carboxylated alkyl chains were also identified (Hutter
et al., 2012a). It was demonstrated that JWH-018 is metabolized to at least nine monohydroxylated metabolites
and one primary carboxy metabolite (Brents et al.,
2011). Kinetic studies identified CYP2C9 and CYP1A2
as major isoenzymes involved in the oxidation of
JWH-018 and AM-2201 (Chimalakonda et al., 2012),
whereas UGT1A1, UGT1A3, UGT1A9, UGT1A10 and
UGT2B7 were the major UDP-glucuronosyltransferases
responsible for conjugation of hydroxylated metabolites
of JWH-018 and JWH-073 (Chimalakonda et al., 2011a).
Very recently, it was demonstrated that typical metabolites of JWH-018 and JWH-073 are formed in humans
after AM-2201 consumption (Hutter et al., 2013), making
a correct identification of synthetic cannabimimetics
514
Substance
Chemical name
CB1 Ki
(nM)
CB2 Ki
(nM)
References
Δ9-tetrahydro-cannabinol
(Δ9-THC)
AM-694
(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol
40.7
36.4
(Showalter et al., 1996)
[1-(5-fluoropentyl)-1H-indol-3-yl](2-iodophenyl)-methanone
0.08
1.44
AM-1220
[1-(1-methyl-2-piperidinyl)methyl]-1-naphthaleyl-methanone
3.88
73.4
AM-2201
[1-(5-fluoropentyl)-1H-indol-3-yl]-1-naphthalenyl-methanone
1.00
2.60
CP 47,497-C8
JWH-007
JWH-015
JWH-018
JWH-019
JWH-073
JWH-081
JWH-122
rel-2-[(1S,3R)-3-hydroxycyclohexyl]-5-(2-methylnonan-2-yl)phenol
(2-methyl-1-pentyl-1H-indol-3-yl)-1-naphthalenyl-methanone
(2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenyl-methanone
(1-pentyl-1H-indol-3-yl)-1-naphthalenyl-methanone
(1-hexyl-1H-indol-3-yl)-1-naphthalenyl-methanone
(1-butyl-1H-indol-3-yl)-1-naphthalenyl-methanone
(4-methoxy-1-naphthalenyl)(1-pentyl-1H-indol-3-yl)-methanone
(4-methyl-1-naphthalenyl)(1-pentyl-1H-indol-3-yl)-methanone
0.83
9.50
383
9.50
9.80
8.90
1.20
0.69
2.90
13.8
2.94
5.55
38.0
12.4
1.20
JWH-133
JWH-175
JWH-200 (WIN 55,225)
JWH-203
JWH-210
JWH-250
JWH-251
JWH-303
JWH-369
(+)-WIN 55,212-2
(6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran
3-(1-naphthalenylmethyl)-1-pentyl-3H-indole
[1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl]-1-naphthalenyl-methanone
2-(2-chlorophenyl)-1-(1-pentyl-1H-indol-3-yl)-ethanone
(4-ethyl-1-naphthalenyl)(1-pentyl-1H-indol-3-yl)-methanone
1-(1-pentyl-1H-indol-3-yl)-2-(2-methoxyphenyl)-ethanone
2-(2methylphenyl)-1-(1-pentyl-1H-indol-3-yl)-ethanone
[5-(2-fluorophenyl)-1-pentyl-pyrrol-3-yl]-1-naphthalenyl-methanone
[5-(2-chlorophenyl)-1-pentyl-1H-pyrrol-3-yl]-1-naphthalenyl-methanone
[(3R)-2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo
[1,2,3,4-de]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone
677
14.0
42.0
8.00
0.46
11.0
29.0
7.7
7.9
62.3
(Makriyannis and Deng,
2001)
(Makriyannis and Deng,
2001)
(Makriyannis and Deng,
2001)
(Melvin et al., 1993)
(Aung et al., 2000)
(Aung et al., 2000)
(Huffman et al., 1994)
(Aung et al., 2000)
(Aung et al., 2000)
(Aung et al., 2000)
(Aung et al., 2000; Huffman
et al., 2003)
(Huffman et al., 1999)
(Huffman et al., 2003)
(Huffman et al., 2003)
(Huffman et al., 2005)
(Huffman et al., 2005)
(Huffman et al., 2005)
(Huffman et al., 2005)
(Huffman et al., 2006)
(Huffman et al., 2006)
(Showalter et al., 1996)
3.4
6.40
7.00
0.69
33.0
146
3.3
5.2
3.30
J. B. Zawilska and J. Wojcieszak
Table 1. Affinities of synthetic cannabimimetics most commonly detected in products and biological samples to cannabinoid CB1 and CB2 receptors
Synthetic cannabimimetics as drugs of abuse 515
ingested far more difficult than originally thought.
CYP2C9, together with CYP3A4, also play a key role in
the metabolism of ∆9-THC by human hepatic microsomes
(Watanabe et al., 2007).
Unlike ∆9-THC metabolites, metabolites of synthetic
cannabimimetics retain varying amounts of biologic activity, and can act as full agonists, partial agonists, neutral
antagonists or inverse agonists of cannabinoid receptors.
Thus, for example, some of the hydroxylated metabolites
of JWH-018 and JWH-073 have been demonstrated to
bind to CB1 and CB2 receptors with high or intermediate
affinity, and potently stimulate G-proteins (Brents et al.,
2011, 2012; Rajasekaran et al., 2013). Furthermore, one
of them, M1, produced a marked depression of locomotor
activity and core body temperature in mice that were
blocked by CB1 receptor-preferring antagonists (Brents
et al., 2011, 2012).
Effects of synthetic cannabimimetics in humans
The consumption of cannabis leads to numerous effects
within the CNS and peripheral organs. Their spectrum,
severity and duration heavily depend on the dose, the individual threshold of the user and psychobiological factors. The most commonly reported CNS effects include
feeling of euphoria, relaxation, changes in sensory perception, especially with regard to visual stimuli, altered
perception of time, transient hallucination, anxiolysis,
sedation, disturbances of short-term memory, lack of coordination and reduction in psychomotor activity. Panic
reactions, that occur most often in naïve users or at high
doses, and psychotic symptoms have also been described.
Physical effects include vasodilation, hyposalivation
and dry mouth, decreased respiratory rate and relaxation
of muscles (Grotenhermen, 2007). Δ9-THC exerts complex cardiovascular effects in humans. It produces a
rapid increase in the heart rate (with a peak occurring
10–30 min after the onset of smoking) that may be accompanied by a modest increase in blood pressure.
Marijuana smoking has also been demonstrated to
evoke orthostatic hypotension and a chronic use of cannabis may elicit a long lasting decrease in the heart rate and
blood pressure (Malinowska et al., 2012). On the contrary,
synthetic cannabimimetics have been consistently shown
to increase blood pressure (see below).
The most frequent side effects observed during clinical
trials of Sativex® (multiple sclerosis medication containing cannabis extract) were: fatigue (11.4%), nausea
(10.2%), dry mouth (7.8%), application site pain (7.8%),
oral pain (6.6%), diarrhea (6%), abnormal taste (4.2%),
pharyngitis (3.6%), increased appetite (3.6%), weakness
(3.6%), vertigo (3%), mouth ulceration (3%), fall (3%),
lethargy (3%), thirst (3%), vomiting (2.4%), cough (2.4%)
and sensation of heaviness (2.4%). The main intoxication
type reactions included: dizziness (41.6%), somnolence
(8.4%), feeling drunk (7.2%), disturbance in attention
(6.6%), euphoric mood (5.4%), disorientation (4.8%) and
dissociation (3%) (Sativex monograph).
Human users of synthetic cannabimimetics report that
these products share some but not all of the ‘subjective’
effects of cannabis (Vardakou et al., 2010; Schneir et al.,
2011). After smoking a cigarette containing CP 47,497
(Auwärter et al., 2009) or JWH-018 (Teske et al., 2010),
healthy volunteers reported sickness, sedation, xerostomia, hot flushes, burning eyes and deterioration of
mood and perception. Results from a large anonymous
survey indicate that synthetic cannabimimetics produce
more negative effects, including hangover and paranoia,
than natural cannabis (Winstock and Barratt, 2013). In
line with this, emerging evidence accumulated mainly
during the last two years shows a wide range of harmful
responses to Spice, including hallucinations, psychoses
with delusions, agitation, aggressive behaviour, anxiety,
panic attacks, seizures, short-term memory deficits,
hypertension, acute myocardial infarction, acute kidney
injury and respiratory depression (Auwärter et al., 2009;
Müller et al., 2010a, b; Vardakou et al., 2010; Vearrier
and Osterhoudt, 2010; Benford and Caplan, 2011;
Every-Palmer, 2011; Hurst et al., 2011; Lapoint et al.,
2011; Mir et al., 2011; Schneir et al., 2011; Simmons
et al., 2011; Bebarta et al., 2012; Faircloth et al., 2012;
Heath et al., 2012; Hermanns-Clausen et al., 2012, 2013;
Jinwala and Gupta, 2012; Pant et al., 2012; Peglow et al.,
2012; Schneir and Baumbacher, 2012; Thomas et al., 2012;
Tung et al., 2012; Young et al., 2012; Alhadi et al., 2013;
Berry-Cabán et al., 2013; Bhanushali et al., 2013; CDC,
2013; Harris and Brown, 2013; McQuade et al., 2013).
Treatment of Spice-induced intoxication is mainly supportive, and consists of intravenous application of fluids and,
additionally, depending on the type and severity of symptoms, benzodiazepines, non-benzodiazepine sedatives and
antipsychotic drugs. Most symptoms resolved themselves
within several hours. Case reports of adverse effects of synthetic cannabimimetics are listed in Table 2.
According to data from the US National Poison Data
Center, collected in 2010 (1898 cases), the most frequently
reported adverse effects of synthetic cannabimimetics use
were: tachycardia (40%) and hypertension (8.1%), agitation/irritability (23.4%), drowsiness/lethargy (13.5%),
confusion (12%), hallucinations or delusions (9.4%) and
dizziness (7.3%). Two patients developed status epilepticus (Hoyte et al., 2012). Similar results were obtained by
the New Zealand National Poisons Centre (Schep et al.,
2011). An analysis of 29 clinical reports on analytically
confirmed intoxication with synthetic cannabimimetics
selected from the database of the Poisons Information
Centre Freiburg, Germany, has shown that the most common adverse effects were symptoms associated with
(1) the cardiovascular system, i.e. tachycardia (76%),
hypertension (34%), dyspnea (21%) and thoracic pain
(10%), (2) the CNS, i.e. restlessness/agitation (41%),
changes in perception/hallucinations (38%), vertigo
(24%), anxiousness/panic attack (21%), somnolence
Male, 25
Male, 21
Symptoms
Compound identified
Comments
References
Reddened conjunctivae, increase in pulse rate,
xerostomia, alteration in mood and perception.
Symptoms lasted up to 6 h.
Increased anxiety over the previous month. Paranoid
hallucinations, paranoid delusions.
Serum samples positive for homolog
of CP 47,497.
Self-experiment conducted by two of the
authors who smoked one cigarette containing
0.3 g of ‘Spice diamond’.
Recurrent psychotic episodes for 7 years,
long-lasting cannabis use, smoking of ‘Spice’
prior to admission to a hospital.
Patient suffered from ADHD. Anxiety resolved
after lorazepam.
(Auwärter et al., 2009)
Female, 20
Panic attacks (for 2 h), irritability, anxiety, fear, blurred
vision, unsteady gait, weakness, diaphoresis,
palpitations, tachycardia.
Visual hallucinations, anxiety, mild increase in blood
pressure (135/85 mm Hg), tachycardia (120 beats/
min), occasional muscle fasciculations, mild
hypokalemia (2.9 mEq/l).
Anxiety.
Female, 22
Anxiety, palpitations, tachycardia (126 beats/min).
Male, 19
Male, 25
Generalized 1–2 min convulsion while smoking
‘Happy Tiger Incense’. On admission to ED: blood
pressure 177/82 mm Hg, heart rate 84 beats/min.
Severe anxiety, paranoia, halting speech, avoidance of
eye contact, tachycardia, diaphoresis.
Generalized seizures, temperature of 37.7 °C, CPK
2649 U/l, mild sinus tachycardia.
Tachycardia, acidosis, unresponsiveness.
Male, 21
Hypertension, agitation, unresponsiveness.
Male, 19
Paranoia, delusions
Male, 19
Female, 19
Male, 23
Paranoia, agitation, visual hallucinations.
Agitation, sedation, amnesia.
Delusions, paranoia. Patient complained of ‘monsters
on his back’.
Visual hallucinations, chest pain, ‘pounding on chest’,
dyspnea on exertion. Initial tachycardia (140 beat/
min) progressed into sinus bradycardia (48 beats/min)
with episodes of functional bradycardia at 30 to 40
beats/min.
Female, 17
Male, 20
Male, 48
Male, 17
Screening for cannabis (urine, hair)
and other drugs (urine) – negative.
Identification not conducted.
Identification not conducted.
JWH-018 and JWH-073 identified in
the smoked product.
JWH-018 and JWH-073 identified in
the smoked product
JWH-018, JWH-081, JWH-250 and
AM-2201 identified in the smoked
product.
THC not detected in urine sample.
JWH-018 in the ingested powder,
JWH-018 metabolite in urine sample.
Urine sample positive for JWH-018
metabolite.
Urine sample positive for JWH-018
and JWH-073 metabolites.
Urine sample positive for JWH-018
and JWH-073 metabolites.
Screening of urine sample – negative.
Levorphanol in urine sample.
Screening of urine sample – negative.
JWH-018 and JWH-073 identified in
the smoked K9 product.
Symptoms resolved 2 h after administration of
lorazepam.
(Müller et al., 2010b)
(Müller et al., 2010a)
(Vearrier and Osterhoudt,
2010)
(Schneir et al., 2011)
(Schneir and Baumbacher,
2012)
Patient admitted to smoking ‘Spice’.
(Benford and Caplan, 2011)
Consumption of an alcohol mixture containing
white powder 30 min before seizures.
Patient admitted smoking a ‘Spice’ product.
Symptoms resolved with benzodiazepines and
iv fluids.
Symptoms resolved with iv fluids.
(Lapoint et al., 2011)
Patient was brought to ED 1 h after smoking a
‘Spice’ product.
Smoking the ‘Space’ brand of Spice.
Smoking the ‘Space’ brand of Spice.
(Simmons et al., 2011)
(Bebarta et al., 2012)
(Young et al., 2012)
J. B. Zawilska and J. Wojcieszak
Gender, age
516
Table 2. Case reports on the adverse effects of synthetic cannabimimetics
Male, 17
Male, 59
Male, 36
Male, 16
Male, 16
Male, 16
Male, 17
Male, 20
Male, 48
Male, 22
Identification not conducted.
Patient admitted to smoking K2.
(Faircloth et al., 2012)
Identification not conducted.
Patient admitted to smoking ‘Spice’.
(Peglow et al., 2012)
Identification not conducted.
Mental disturbances after 4 weeks of daily
K2 use
(Tung et al., 2012)
Identification not conducted.
Patient admitted to using K2.
(Mir et al., 2011)
Urine sample negative for cannabis
and cocaine.
Patient admitted to smoking K2.
Urine sample positive for THC.
Patient admitted to using K2.
Identification not conducted.
Patient admitted to smoking K2 an hour prior to
admission.
Identification not conducted.
Patient admitted to smoking K2 an hour prior to
admission.
Identification not conducted.
Symptoms appeared after smoking K2.
(Thomas et al., 2012)
Urine sample positive for JWH-018
metabolite.
Patient confirmed drinking vodka the night
before and smoking 3 g of ‘Spice’ before work.
(Pant et al., 2012)
Identification not conducted.
Patient admitted to long-term regular use of
Spice. His negative symptoms, disorganized
behaviour and speech persisted despite
abstinence from Spice for 2 months.
(Berry-Cabán et al., 2013)
(Heath et al., 2012)
Synthetic cannabimimetics as drugs of abuse 517
Male, 15
Dizziness, confusion, emesis (multiple episodes), blood
pressure 158/86 mm Hg, sinus tachycardia (132 beats/
min), mild hypokalemia.
Three admissions to the hospital due to psychotic
symptoms (vivid visual hallucinations and
disorganized, bizarre behaviour).
Restless, agitation, irritation, irrelevant speech that
persisted for 2 wk. At admission to a hospital blood
pressure of 150/90 mm Hg, heart rate – 95 beats/min,
profuse sweating.
Patient presented with a 3 d history of midsternal chest
pain. EEG revealed ST-segment elevation in the
inferolateral leads; increased troponin level (initially
3 ng/ml, then 25 ng/ml). Diagnosis: acute myocardial
infarction.
Patient presented with a 1-week history of chest pain,
described as approx. 30-min episodes of ‘soreness’.
EEG revealed ST-segment elevation in the
inferolateral leads; increased troponin level (11.6 ng/
ml). Diagnosis: acute myocardial infarction.
Patient presented with a 3 d history of retrosternal and
episodic chest pain, lasting for 1–2 h at a time. EEG
revealed ST-segment elevation; increased troponin
level (initially 7 ng/ml, then 12 ng/ml). Diagnosis:
acute myocardial infarction.
Faint, generalized muscular tone in extremities,
cyanosis, apnea, ocular redness, swelling.
Tachycardia (initially 180 beats/min, after 6 mg iv
adenosine decreased to 140 beats/min). At the
hospital – confused speech, somnolence, complaints
of chest and back pain.
Lost of consciousness. On admission – sinus
tachycardia (172 beats/min), blood pressure of 162/57
mm Hg. Amnesia, mild headache, fatigue.
Agitation, confusion, suicidal ideation, self-inflicted
trauma, sinus tachycardia.
Generalized tonic-clonic seizures. Sinus tachycardia
(106 beats/min), blood pressure 140/80 mm Hg,
temperature 37.7 °C, myadriasis, diaphoresis,
increased creatine phosphokinase level to 1200 U/l
Agitation, aggression, attention impairment consistent
with delirium, tachycardia (160 beats/min). On the
seventh hospital day the patient developed acute
psychosis with delusions.
518
Table 2. (cont.)
Symptoms
Compound identified
Comments
References
Female, 19
Seizure, agitation, altered mental status, blood pressure
153/84 mm Hg, pulse 116 beats/min. The patient was
somnolent, hyperreflexic, and periodically repeated
‘Is this real?’
Agitation, dangerous behaviour described as ‘running
in and out of traffic’, myoclonic jerking,
hallucinations. At admission: sinus tachycardia (134
beats/min), blood pressure 144/68 mm Hg, flushed
skin, dilated pupils, hyperflexia without clonus ,
occasional jerking of the limbs, inappropriate laughter
and silence when asked questions.
Anxiety, mild hyperreflexia, tachycardia (130 beats/
min). The patient complained of inability to move his
limbs.
Seizure-like activity, cyanosis, unresponsiveness.
Initial pulse 220 beats/min, at admission to a hospital
– 180 beats/min.
Chest pain, nausea, vomiting, syncope, pulse 95 beats/
min.
Mild agitation, hallucinations, pulse at admission to a
hospital 104 beats/min.
Urine sample negative for cannabis
and other drugs of abuse
Patient was smoking ‘Bayou Blaster®’ when
seizures started.
(Harris and Brown, 2013)
Urine sample negative for cannabis
and other drugs of abuse.
Patient was smoking ‘Humboldt Gold’ when
symptoms started. He described being in
multiple dreams that he could not get out.
Identification not conducted.
Patient admitted to smoking ‘Space’ several
minutes before symptoms occurred.
Urine sample positive for THC.
Patient admitted to smoking K2 approx. 20 min
before symptoms occurred.
Identification not conducted.
Patient admitted smoking 3 g of K2.
Identification not conducted.
Nausea and vomiting, flank pain. Diagnosed: acute
kidney injury.
Nausea and vomiting. Diagnosed: acute kidney injury.
Product: XLR-11. Urine: N-pentanoic
acid metabolite of XLR-11
Blood: N-pentanoic acid metabolite of
XLR-11.
Product: XLR-11 and UR-144. Serum:
XLR-11; UR-144, N-pentanoic acid
metabolite of XLR-11.
Product: XLR-11.
Patient admitted to smoking K2 herbal for the
first time and complained of being in a dream
state that he could not get out.
Symptoms appeared 2 d after smoking the
product.
Symptoms appeared 2 d after smoking
‘Phantom Wicked Dreams’.
Patient used ‘Mr. Happy’.
Male, 17
Male, 17
Male, 19
Male, 24
Male, 22
Male, 18
Male, 30
Male, 26
Nausea and vomiting, abdominal pain/back pain.
Diagnosed: acute kidney injury.
Male, 17
Nausea and vomiting, flank pain. Diagnosed: acute
kidney injury.
Nausea and vomiting, abdominal pain. Diagnosed:
acute kidney injury.
Nausea and vomiting, abdominal pain. Diagnosed:
acute kidney injury.
Nausea and vomiting, abdominal pain. Diagnosed:
acute kidney injury.
Male, 18
Male, 18
Male, 15
Symptoms appeared 9 d after smoking ‘Clown
Royal’.
Symptoms appeared 2 d after smoking ‘Lava’.
Product: XLR-11. Urine: N-pentanoic
acid metabolite of XLR-11.
Not detected
Symptoms appeared 2 d after smoking ‘Lava’.
Identification not conducted.
Patient admitted to smoking ‘Flame 2.0’.
(Centers for Disease Control
and Prevention, 2013)
J. B. Zawilska and J. Wojcieszak
Gender, age
Male, 20
Male, 23
Male, 26
Male, 30
Male, 17
Male, 17
Male, 20
Male, 19
Male, 21
Male, 20
Identification not conducted.
Patient admitted to using Spice for few weeks.
(Bhanushali et al., 2013)
Identification not conducted.
Identification not conducted.
Identification not conducted.
Blood: MAM-2201, UR-144. Urine:
metabolites of JWH-122, UR-144 and
JWH-018.
Blood: JWH-081. Urine: metabolites of
JWH-081, JWH-018 and JWH-073.
Patient admitted to using Spice over the last two
years.
Patient admitted to using Spice over the last
year.
Patient smoked an herbal mixture ordered via
the Internet, assuming that it contained ‘salvia
divinorum’.
Few minutes after smoking the herbal mixture
‘Jamaican Gold’. patient felt nauseous.
Blood: JWH-122. Urine: Metabolites of
JWH-122 and JWH-018.
Patient smoked the herbal mixture ‘Lava Red’
Blood: JWH-122, JWH-210, JWH-018.
Urine: Metabolites of JWH-122,
JWH-210, JWH-018, Δ9-THC.
Blood: AM-2201, JWH-122, JWH-210.
Urine: metabolites of JWH-018 and
AM-2201.
Patient smoked ‘Bonzai’ two times: in the
evening and in the morning. Seizures
developed after the second consumption.
Patient smoked several Spice products for the
last 4 months.
Urine: metabolites of AM-2201
Before convulsion patient smoked a ‘Black
Mamba’ Spice product.
(Hermanns-Clausen et al.,
2013)
(Alhadi et al., 2013)
(McQuade et al., 2013)
Synthetic cannabimimetics as drugs of abuse 519
Nausea and vomiting for 2 d. Diagnosed: oliguric acute
kidney injury
Nausea and vomiting for 2 d. Diagnosed: oliguric acute
kidney injury
Nausea, vomiting, diarrhea and lower abdominal pain
for 2 d. Diagnosed: oliguric acute kidney injury.
Nausea, vomiting, diarrhea and lower abdominal pain
for 3 d. Diagnosed: acute kidney injury.
Sinus tachycardia (160 beats/min), mydriasis,
anisocoria, retrograde amnesia, mild somnolence,
leukocytosis.
Agitation, laugh attacks, panic attacks, massive
vomiting, myoclonig jerking, sinus tachycardia (112
beats/min), confusion, somnolence, hypokalemia.
Massive vomiting, pale skin, mydriasis, mild
tachycardia (100 beats/min), somnolence, mild
hypokalemia, leukocytosis, elevation of creatine
kinase.
Tonic-clinic seizures, repetitive vomiting, no sufficient
respiration. The next day: elevated levels of creatine
kinase, leukocytosis, trombolysis.
Dyspnea, 2-month history of chronic cough, occasional
hemoptysis, two episodes of syncope. Chest imaging
revealed diffuse, bilateral, subacute lung infiltrates.
Suspected: hypersensitivity pneumonitis.
Generalized tonic-clonic convulsion lasting for appr.
2–3 min, drowsiness, dry skin.
520
J. B. Zawilska and J. Wojcieszak
(17%), confusion, disorientation (14%), (3) the gastrointestinal system, i.e. nausea/vomiting (28%) and dry mouth/
globus sensation (14%) and (4) the eyes – mydriasis (38%)
and conjuctive hyperaemia (14%) (Hermanns-Clausen
et al., 2012). It should be noted that data collected from
Poison Centres reports may not be representative of all
synthetic cannabimimetics intoxications. The reported
cases are likely to have more severe symptoms than nonreported ones. Furthermore, exposure history and substance/product responsible for the symptoms are mainly
based on reports coming from individuals with no or limited qualified knowledge in the field, such as patients,
relatives and bystanders (e.g. Hermanns-Clausen et al.,
2012; Hoyte et al., 2012).
To our knowledge there is only one published report of
death following use of a synthetic cannabinoid. The decedent was a 23-year old male, with many blunt and
sharp force wounds; the fatal wound was a self-inflicted
stab wound to the neck. AM-2201 and its metabolites
were found in his blood (Patton et al., 2013).
A recent report of Musshoff et al. (2013) presents
seven cases of driving under the influence of synthetic
cannabimimetics, where the presence of the following
compounds was analytically confirmed in sera taken
from a total of eight subjects involved: AM-2201(two persons), JWH-018 (three persons), JWH-019 (one person),
JWH-122 (five persons), JWH-210 (four persons),
JWH-307 (one person). As the physical examination of
the subjects revealed a delayed reaction of pupils to
light, blurred speech, dizziness, unstable appearance
and retarded sequence of movements, it is assumed that
the consumptions of synthetic cannabimimetics, like cannabis use (Hartman and Huestis, 2013), can lead to a potentially dangerous impairment of driving skills and
cognitive deficits.
It is estimated that around 9% of cannabis users develop dependence with a withdrawal response that
occurs upon cessation of drug administration. The most
common symptoms of cannabis withdrawal are anger, irritability, depressed mood, anxiety, decreased appetite
and weight loss, restlessness, disturbances in sleep onset
and maintenance and cannabis craving. Symptoms do
not occur until about 24 h after the last use, peak in
2–3 d and last about 2–3 wk (Cooper and Haney, 2008;
Danovitch and Gorelick, 2012).
To our knowledge, there are only three published
reports of dependence on synthetic cannabimimetics.
Zimmermann et al. (2009) presented the case of a
20 yr-old patient who had developed a tolerance to
‘Spice Gold’. During the abstinence period he suffered
from a physical dependence syndrome with profound
sweating (especially in the night), internal unrest, tremor,
insomnia, nightmares, palpitations, headache, diarrhea,
nausea, and vomiting. While being treated in hospital
for Spice dependence, he displayed increased heart rate
and hypertension for several days. Nacca et al. (2013) described two cases of acute withdrawal syndrome in a
22 yr-old woman and a 20 yr-old man, presumably due
to prolonged synthetic cannabimimetics use. The syndrome was characterized by sinus tachycardia and severe
anxiety in the absence of any abnormal neurologic
findings. The patients also complained of headache, insomnia, sweats and chills and, in the woman’s case,
cramping pain in arms and legs, vivid dreams and potent
anorexia. The symptoms did not improve with marijuana,
but resolved with lorazepam or quetiapine. A severe
withdrawal syndrome with similar symptoms lasting
for 3–4 d and accompanied by significant craving, was
reported in the case of a 23 yr-old man who had consumed ‘Spice Gold’, containing JWH-018 and CP 47,497,
on a regular basis (Rominger et al., 2013). At the present
state of knowledge it appears that the withdrawal syndrome from synthetic cannabimimetics is similar but
more severe than that from natural cannabis (Gorelick
et al., 2013).
Conclusions
Although synthetic cannabimimetics were originally
synthesized to study the endocannabinoid system, with
the aim of developing therapeutically-effective compounds devoid of the unwanted effects of cannabis, several of them have become drugs of abuse. The
experience of recent years clearly shows that synthetic
cannabimimetics represent a significant potential hazard
to human health. As many of these compounds and
their metabolites have been found to possess higher binding affinity and higher efficacy at CB receptors than
Δ9-THC, it might be expected that both the acute and
chronic effects, including the adverse ones, of synthetic
cannabimimetics could be intensified when compared to
a similar level of exposure to Δ9-THC. None of these substances has been thoroughly tested for negative side effects. The unknown production practices, composition
and purity of the Spice-type products, as well as the concentration of active ingredients, are all associated with
risks which are hard to define. Accumulating clinical
evidence indicates that intoxication with Spice/K2-like
products produces symptoms similar to adverse effects
after high doses of cannabis. However, some symptoms,
such as pronounced agitation, epileptic seizures, hypokalemia and frequently occurring nausea/vomiting
seem to be unique to the synthetic cannabimimetics
(Hermanns-Clausen et al., 2012). According to expert opinions, the appearance of myoclonic and generalized
tonic-clonic seizures, and cases of acute myocardial infarction after the use of synthetic cannabimimetics are
particularly worrying. The growing popularity of Spice/
K2-products as recreational drugs highlights the urgent
need to further evaluate the effects of synthetic cannabimimetics in vivo in order to: (1) improve our understanding of how these compounds interact with cannabinoid
and non-cannabinoid receptors in the brain as well as in
peripheral organs and tissues, (2) better characterize
Synthetic cannabimimetics as drugs of abuse 521
their pharmacological, toxicological and pharmacokinetic
properties, (3) develop drug-specific treatments for intoxication and (4) create effective education and prevention
programmes.
Acknowledgments
Supported by the Medical University of Lodz
(503/3-011-01/503-01). Fruitful discussion with José
Miguel Honório from the Faculdade de Farmácia,
University of Lisbon, is highly appreciated.
Statement of Interest
None.
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