Focus on Cannabinoids and Synthetic

Cannabinoids
R Le Boisselier1,2, J Alexandre2,3, V Lelong-Boulouard2,4 and D Debruyne1,2,5

The recent emergence of a multitude of synthetic cannabinoids (SCs) has generated a wealth of new information,
suggesting the usefulness of state-of-the-art on lato sensu cannabinoids. By modulating a plurality of neurotransmission
pathways, the endocannabinoid system is involved in many physiological processes that are increasingly explored. SCs
desired and adverse effects are considered to be more intense than those observed with cannabis smoking, which is partly
explained by the full agonist activity and higher affinity for cannabinoid receptors. Neurological and cardiovascular side
effects observed after cannabinoid poisoning generally respond to conventional supportive care, but severe outcomes may
occur in a minority of cases, mainly observed with SCs. The likelihood of severe abuse and addiction produced by SCs are of
concern for the scientific community also interested in the potential therapeutic value of cannabinoids.

The endocannabinoid system is involved in many physiological profits for underground laboratories. All have a wide range of
functions, including cognitive processes, behavior control, pharmacological activities that affect brain, immune, and vari-
memory, motor control, pain-sensation, appetite, homeostasis, ous other functions depending on which receptor subtype they
cardiovascular parameters, gastrointestinal motility, immunoreg- bind to and with which level of affinity.
ulation, etc., both in the central and peripheral nervous sys- Cannabis is globally the most widely used illicit drug, the
tems, peripheral organs, and immune tissues. Cannabinoids are World Health Organization estimating in 2013 that 181.8 mil-
a class of chemical compounds of diverse origins that act on lion people aged 15–64 years used cannabis for nonmedical pur-
the cell membrane cannabinoid receptors belonging to the poses.2 On the other hand, the medical use of cannabis products
rhodopsin-like G-protein coupled receptor (GPCR) family, and to treat disease or improve symptoms remains debated, even if
are subdivided into two subtypes: cannabinoid receptor 1 the benefits and risks of such medications have been investigated
(CB1R, mainly expressed in the brain and altering neurotrans- in a number of clinical trials on multiple sclerosis, cancer and
mitter release) and cannabinoid receptor 2 (CB2R, particularly noncancer pain, neurodegenerative disorders, and appetite sup-
abundant in immune tissues and modifying cytokine release) pression.3 In recent years, recreational use of SCs has grown and
receptors.1 Three major groups of cannabinoid receptor appears to be associated with potentially dangerous health effects,
ligands have been identified: endocannabinoids (the most probably due to higher binding affinities to CB1R.4 These newly
clearly defined, anandamide and 2-arachydonylglycerol) pro- developed SCs structures induce drug abuse and the scientific
duced by mammalians, phytocannabinoids (particularly D9- community is primarily concerned about the public health and
tetrahydrocannabinol (D9-THC), the most psychoactive, and safety aspects of abusive SCs use that have a major impact on
cannabidiol, nonpsychoactive) produced by the cannabis plant, human morbidity and mortality. At the same time, these substan-
and a number of synthetic cannabinoids (SCs) sold for recrea- ces offer new therapeutic potential.
tional drug use. Initially, SCs were developed as pharmacologi- The present contribution aims to provide a comprehensive
cal probes of the endogenous cannabinoid system, but the vast overview of the highly complex diverse nature and activity of can-
explosion of SCs aims to actually create compounds that will nabinoids, both natural and synthetic, using the more recent
be used abusively, to avoid legal restrictions, and to make large available data.
1
^te de Nacre, Centre for Evaluation and Information on Pharmacodependance – Addictovigilance (CEIP-A), F-14033, Caen, France;
University Hospital Centre Co
2
^te de Nacre, Department of Pharmacology, Caen, France; 3Normandy University, UNICAEN, University Hospital Centre Co
University Hospital Centre Co ^te de
Nacre, Caen, France; 4Normandy University, UNICAEN, University Hospital Centre Co ^te de Nacre, Inserm U 1075 COMETE Caen, France; 5Medical School,
Normandy University, Caen, France. Correspondence: R Le Boisselier (leboisselier-r@chu-caen.fr)
Received 19 August 2016; accepted 6 November 2016; advance online publication 9 November 2016. doi:10.1002/cpt.563

220 VOLUME 101 NUMBER 2 | FEBRUARY 2017 | www.wileyonlinelibrary/cpt

 OH
O O
OH OH
N O
H OH
Anandamide 2-arachidonoyl glycerol
Endocannabinoids
Figure 1 Chemical structure of the chief endo (anandamide and 2-arachidonoyl glycerol) and phyto (D9-THC and cannabidiol)-cannabinoids.
CHEMISTRY
Parent drugs
The first primary endocannabinoid to be identified was isolated
in 1992 from porcine brain extracts and was called anandamide
(chemical name: arachidonoyl ethanolamide, AEA). A second
main endocannabinoid, 2arachidonoyl glycerol (2-AG), was then
extracted from canine intestines.5 The chemical structure of these
endocannabinoids and those of the main active ingredients of
cannabis, D9-THC and cannabidiol, which had been clearly
identified well before by the 1960s, are shown in Figure 1. A
number of other minor cannabis plant constituents have also
been reported to bind to and functionally interact with CB recep-
tors. It must be stressed that although endo- and phytocannabi-
noids have different chemical structures, quantitative structure–
activity models show that the 3D structures have the ability to
interact in a similar way with cannabinoid receptors.6 In the
1970s, SCs were originally developed to investigate the endocanna-
binoid system in a research context. Since 2000, some have
emerged on the “legal highs” market as an alternative to phytocan-
nabinoids for recreational drug use.7 (As a remark, SCs are often
first experimented on by drug users unaware of their potential tox-
icity.) Eventually, SCs can be synthetic equivalents (i.e., dronabi-
nol, similar to D9-THC) or analogs of natural products (i.e.,
nabilone, HU-210), derivatives of endocannabinoids (i.e., metha-
nandamide), or new compounds belonging to diverse chemical
groups and subgroups. The latter SCs are emerging constantly and
have been roughly classified, as they appear on the recreational
drug market. The SCs structure commonly includes a main struc-
ture also called principal core (aromatic mono or heterocyclic
structures—frequently 3-indole—more or less substituted) linked
to a secondary moiety (alkyl chain—halogenated or not, aromatic
cyclic or alicyclic compounds—substituted or not) by a bridge
(carbon–carbon bond, carbonyl, carboxyl, carboxamide). The first
generation mainly included cyclohexylphenol, dibenzopyrane, and
numerous members (about 30 listed to date), naphthoyl indole
derivatives (Figure 2).
The second generation includes compounds again resulting
from a substituted indole core, but also from pyrrole, or indene
structures. The third and most recent generation is mainly repre-
sented by a carboxylate or carboxamide bridge linked to a
substituted indole or indazole core. Table 1 summarizes the
chemical classification of SCs as detailed by Debruyne and Le
Boisselier in a previous review.4
A large number of SCs have been rapidly synthesized, some-
times with few changes, and now represent several hundreds.
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 101 NUMBER 2 | FEBRUARY 2017
OH
H H
H H
O HO
Δ9-tetrahydrocannabinol Cannabidiol
Phytocannabinoids
Figure 2 Global structural scheme of SCs illustrated by some selected
members of the naphthoyl indole derivative family.
Currently, innovative compounds are still emerging, but at a
slower rate.
Metabolites
Many studies investigated the in vitro metabolism of SCs in
experiments using human hepatocytes, liver microsomes, or the
fungus Cunninghamella elagans and in authentic biological sam-
ples after SCs intake using liquid chromatography-tandem mass
spectrometry. Oxidative metabolic patterns of parent compounds
are dominated by hydroxylation, hydrolysis, N- and O-
dealkylation, deamination taking place on the aliphatic chains or
the substituted aromatic rings and mediated by the cytochrome
P450 enzymes (CYP3A4, major contributor).8 Secondary path-
ways primarily involve carboxylation and glucuronidation. This
extensive and complex metabolism leads to multiple derivatives
that may exhibit affinity for CB1/CB2 receptors or others, and
contribute to pharmacological and toxicological effects. For
example, the N-(3-hydroxypentyl) JWH-018 metabolite causes a
significant decrease in neuroblastoma and human kidney cell line
viability where the parent drug did not.9 However, for most SCs,
the contribution of the metabolites is unknown.
EXPERIMENTAL PHARMACOLOGY
Endocannabinoid system
The endocannabinoid system is a complex and multimodal sys-
tem involved in the regulation of many physiological processes. It
comprises two endogenous ligands, AEA and 2-AG, which can
bind to at least two GPCRs, known as CB1R and CB2R. Some
other targets have been highlighted over the last few years and
mainly include the transient receptor potential vanilloid-type 1
221
Table 1 Main chemical groups and subgroups of SCs4 Cannabinoid receptors binding
Group Subgroup Examples One way to differentiate cannabinoids is to study their affinity
First generation derivatives and selectivity for CB1R and CB2R. Regarding endocannabi-
noids that act as agonists, 2-AG binds to CB2R as well as to
3-indole naphtoyl JWH-018
CB1R with high affinity (inhibition constant (Ki) around 10-8 M
Dibenzopyrane HU-210 to 10-7 M), while AEA shows good CB1R but poor CB2R bind-
Cyclohexylphenol CP-47,497 ing.15 The natural phytocannabinoid D9-THC displays moderate
CB1R/CB2R affinities and acts as a CB1R partial agonist, where-
Second generation derivatives
as cannabidiol shows low affinities for either CB1R or CB2R,16
3-indole benzoyl AM-679, RCS-4 but might interact with alternative targets (inhibition of endo-
3-indole alkoyl UR-144, XLR-11 cannabinoid inactivation and/or activation of TRPV1). Among
the wide variety of SCs available to date, a large majority are non-
3-indole phenylacetyl JWH-250
specific CB1R/CB2R agonists but exhibit stronger affinity for
3-indole naphthylmethyl JWH-175 cannabinoid receptors compared to endo- and phytocannabi-
Indene naphthylmethyl JWH-176 noids (Ki 5 1029–1028 M, even 10210 M). Rimonabant
Pyrrole naphthoyl JWH-307
(5SR141716) and analogs are cannabinoid receptor blockers
expressing high potency (1–20 nM) and selectivity for the CB1
Third generation derivatives receptor. Only a few are selective CB2R antagonists.4
3-indole carboxylate PB-22 Even minor chemical modifications may change the structure–
3-indole carboxamide MMB-CHMINACA, STS-135
affinity/selectivity relationship. Valuable information has been
provided in the steric and electrostatic requirements for each
Indazole carboxylate NPB-22 receptor subtype17 and in silico prediction of SCs’ affinity to
Indazole carboxamide AB-CHMINACA, 5F-AKB-48 CB1R (without reference substances) by a recently developed
(5F-APINACA) quantitative structure–activity relationship model.18 This
Benzimidazole naphthoyl FUBIMINA research tool is interesting for the future development of new
structures, as Wiley et al. demonstrated in 2015, using a series of
SCs, that rank potency order was correlated with CB1R-binding
affinity, the strongest binding exhibiting the greatest efficacy.19
(TRPV1) and the orphan G-protein-coupled receptor called
GPR55.10 Some synthetic and degrading enzymes and transport- Interaction between cannabinoids and other
ers that regulate endocannabinoid levels and properties are also neurotransmission systems
involved in this system.11 The predominance of CB1R compared to CB2R in the CNS
CB1R are abundant in the CNS (central nervous system), with implies that CB1R is primarily responsible for the psychoactivity
particularly high density in the olfactory bulb, the cerebral cortex, of exogenous cannabinoids and physiological effects of endocan-
the hypothalamus, the hippocampus, the striatum, and the cere- nabinoids. The main synapses affected by the retrograde signaling
bellum. Their activation inhibits cyclic adenosine monophos- endocannabinoid system are the glutamatergic and GABAergic,
phate (cAMP) formation via Gi proteins, thus resulting in with strong CB1R expression in glutamatergic and GABAergic
reduced protein kinase A-dependent phosphorylation processes. cells. Through CB1R activation, the endocannabinoid system
Thus, they preferentially target the presynaptic elements that plays a relevant role in reducing N-methyl-D-aspartate (NMDA)
conferred on them a neuromodulator role, by acting mainly receptor activity and therefore limits the excitotoxicity resulting
through a retrograde signaling system that regulates synaptic from their excess activity.20 Thus, this endogenous system could
functions and suppresses neurotransmitter release. CB1R also be pharmacologically manipulated to reestablish the function of
modulates ion channels with inhibition of Ca21 channels and deregulated NMDA receptors, such as psychosis/schizophrenia
activation of several types of K1 channels.12 During the last or convulsive episodes. On the other hand, endocannabinoids
decade, an increasing number of studies also reported the pres- stimulate or inhibit GABA release, depending on the dose and
ence of CB1R in other CNS structures such as postsynaptic ter- brain regions, probably via dopaminergic modulation.21 Interac-
minals or astrocytes,13 although their functional roles are not tion of endocannabinoids and GABAergic cells may be crucial in
fully understood. Finally, CB1R are also found at a lower density regulating motor response, anxiety, and in alcohol or other drugs
in a variety of peripheral tissues and cells such as cardiovascular of abuse and dependence. In the brain reward pathways, the
tissue, the gastrointestinal tract, liver, reproductive system, endocannabinoid system interacts bidirectionally with the nico-
muscles, bones, and skin. CB2R are mainly found in peripheral tinic cholinergic system, and this interaction also plays a key role
tissue at similar sites as CB1R (nonparenchymal liver cells, endo- in modulating nicotine and cannabinoid intake dependence.22
crine pancreas, and bone), but play a significant role in the Indeed, many behavioral and neurochemical effects of nicotine,
immune system due to preponderant expression in immune cells which are related to its addictive potential, are reduced by phar-
and in the hematopoietic systems.14 CB2R were also seen to be macological blockade or genetic deletion of CB1R, by inhibition
found in the CNS, particularly in neurons and microglia. of endocannabinoid uptake, or by metabolic degradation and

222 VOLUME 101 NUMBER 2 | FEBRUARY 2017 | www.wileyonlinelibrary/cpt

activation of peroxisome proliferator-activated-receptor-alpha
(PPARa), which can also mediate cannabinoid effects.23 Con-
versely, cholinergic antagonists as well as endogenous negative
allosteric modulators appear to be effective in blocking the
dependence-related effects of cannabinoids. CB1R and cannabi-
noids also play a modulatory role in dopamine (DA) transmis-
sion, although CB1R do not appear to be located in
dopaminergic terminals, at least in the major brain regions receiv-
ing dopaminergic innervation, e.g., the caudate-putamen and the
nucleus accumbens/prefrontal cortex.24 Indeed, the effects of can-
nabinoids on DA transmission and DA-related behaviors are gen-
erally indirect and are exerted through modulation of GABA and
glutamate inputs received by dopaminergic neurons. However,
additional evidence suggests that CB2R may be located in nigros-
trial dopaminergic neurons and that certain eicosanoid-derived
cannabinoids may directly activate TRPV1, which has been
found in some dopaminergic pathways. Through this direct
mechanism or through indirect pathways involving GABA or
glutamate neurons, cannabinoids may therefore interact with DA
transmission in the CNS that has an important influence in vari-
ous DA-related neurobiological processes (e.g., control of move-
ment, motivation/reward) and, particularly, on different
pathologies affecting these processes such as basal ganglia disor-
ders, schizophrenia, and drug addiction.
Several other interactions with various systems are also
described. For example, adenosine A2A receptors can have an
opposite (permissive vs. inhibitory) influence on the CB1-
dependent synaptic effect.25 This interaction is widely repre-
sented in striatal glutamatergic synapses in which adenosine A2A
receptors are highly expressed. Some other evidence points in
favor of a functional interaction between the endocannabinoid
and serotonergic systems. Indeed, modulation of cannabinoid sig-
naling by interaction with various serotonergic receptors, such as
5-HT2A or 5-HT4 receptors, has been demonstrated.26,27 These
data suggest that the serotonergic system plays a role in anxiety/
depression side effects observed with cannabinoids, and may be a
basis for new approaches in the treatment of anxiety disorders.
Peripheral cannabinoid targets
Gastrointestinal localization. The endocannabinoid system is pre-
sent in the enteric nervous system.28 CB1R has been found on
both intrinsic and extrinsic neurons, with the enteric nervous sys-
tem serving as the major site of action. CB2Rs are expressed by
lamina propria plasma cells and activated macrophages, as well as
by the myenteric and submucosal plexus ganglia in the human ile-
um.29 The gastrointestinal effects of cannabinoids are mainly
mediated by CB1R. CB1R activation results in inhibition of gas-
tric acid secretion, lower esophageal sphincter relaxation,
impaired intestinal motility, visceral pain, and inflammation. The
antiemetic properties of THC on the CNS are well established.
Paradoxically, the effect of D9-THC on the gastrointestinal tract
results in a delay in gastric emptying that could cause nausea and
vomiting. To date, hyperemesis syndrome reported with cannabi-
noids remains unexplained. CB2Rs are also likely to be involved
in the inhibition of inflammation, visceral pain, and intestinal
motility in the inflamed gut.29
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 101 NUMBER 2 | FEBRUARY 2017
Cardiovascular localization. Functional CB1Rs are present in the
myocardium, where they mediate negative inotropy and also in
vascular tissues, where their activation leads to vasodilation. Both
of these effects appear to be involved in the hypotensive effect of
cannabinoids.30 CB2Rs are less important in cardiovascular regu-
lation, and are involved in ischemic preconditioning and
ischemia/reperfusion injury of the myocardium. The vasorelaxant
effect of endocannabinoids and synthetic cannabinoids in vitro is
complex and displays tissue and interspecies differences. It may
involve CB1R and TRPV1R and nitric oxide (NO)-mediated or
NO-independent mechanisms and also as yet undefined endothe-
lial site(s) of action.
Ocular localization. The wide existence of cannabinoid receptors
and their endogenous ligands in various eye tissues suggests a
physiological role for the cannabinoid system in ocular func-
tions.31 CB1R and CB2R are both present in retina, but CB1Rs
are also localized in the cornea, iris, and choroid. Endogenous
cannabinoids acting via cannabinoid receptors may have an
effect, for example, on aqueous humor production and outflow,
as well as on vision itself. This also provides an explanation for
the decrease in ocular pressure induced by topical cannabinoid
application. The hypothetical underlying mechanisms could be
that some cannabinoids may improve optic neuronal damage
through suppression of NMDA receptor hyperexcitability, stimu-
lation of neural microcirculation, and suppression of both apo-
ptosis and damaging free radical reactions.
Kidney localization. The endocannabinoid system is present in
the kidney, where it is involved in various renal functions.32 Nor-
mally, CB1R activation regulates renal vascular hemodynamics
and stimulates the transport of ions and proteins in different
nephron compartments. In various mouse and rat models of obe-
sity and diabetes, endocannabinoids generated in various renal
cells activate CB1R and contribute to the development of oxida-
tive stress, inflammation, and renal fibrosis. These effects can be
chronically improved by CB1R blockers. In contrast, activation
of renal CB2R reduces the harmful effects of these chronic
diseases.
MODALITIES OF RECREATIONAL USE
Availability
SCs were probably used as recreational drugs for the first time in
2004, when the first smokable herbal mixtures named “spice”
were marketed on the Internet as a legal alternative to cannabis,
in colorful attractive packaging. Initially, the blends were likened
to the plants traditionally used by shamans or “phyto-
toxicomania” adepts. However, it was only 4 years later that the
first evidence of SCs misuse appeared, with the discovery of
JWH-018, CP 47,497, and C6, C7, C8 analogs in herbal blends
by a German company. Nowadays, many “spice” products are
available under a wide variety of brand names on dedicated web-
sites (herbal-x.com, legalpuffs.com, . . .). Chemical analysis of dif-
ferent kinds of herbal mixtures showed considerable qualitative
variation in ingredients and quantitative differences in the
amount of active compound. The information listed on the
223
brand label seldom matches the analyzed contents of the package.
Chemical analysts noted the following discrepancies: more or less
product than announced, incorrect substance identity, variation
in the packages of up to 38%, range of one log unit between the
measured and announced concentration, both in older and recent
herbal mixtures.33,34 With the aim of adding it to tobacco, larger
amounts of “pure” powders, especially sold on Chinese gray mar-
ket websites, became available as “research chemicals,” with simi-
lar uncertainties concerning identification and quantification,
thus adding to the danger to users. More recently, original solu-
tions designed for use with an e-cigarette called “Buddha-blue,”
“C-liquid,” “Herbal liquid,” etc., were developed. This new meth-
od of consumption, discreet, is at high risk of SCs trivialization
(as for other synthetic drugs).
Prevalence
According to data in the scientific literature, mainly provided by
poison, toxicological, or epidemiological centers, the use of SCs is
common in the USA, with a prevalence that ranges from 1.4%
among military personnel (290 urine specimens positively con-
trolled on 20,017 analyzed samples for a period of 1 year, from
mid-2011 to mid-2012)35 up to about 10% among high school
seniors in 2011–2013 (11,863 students interviewed in 48
states)36. Note that 1) among Nevada students in 2013 alone
17.3% used SCs but only 4.3% used SCs frequently37; 2) among
patients (around 400 recruited in 2013) with substance use disor-
der, the prevalence rose up to 38%.38 In Europe, only a few stud-
ies showed a prevalence that can be estimated at around 2–5%:
2.2% in Norway (SCs detected in 16 cases over a total of 726
blood samples collected from Norwegian drivers during 7 weeks
in 2011–2012),39 2.8% in Germany (422, analysis in cases of traf-
fic and criminal offenses in 2010).40 From most of these reports,
typical SCs users are young males (M/F sex-ratio of 3:1).
EFFECTS IN HUMANS
Desired effects
Cannabis is sedative, anxiolytic, and induces thought disruption.
Commonly reported reasons to use cannabis include relaxation,
enjoyment, euphoria, lowering of inhibitions, aid in social rela-
tions, and are quite similar to those evoked for alcohol consump-
tion. The main motives for SCs consumption do not
significantly differ in terms of recreational or relaxing objectives,
with the additional desire to experiment higher and/or different
psychoactive effects without unlawful risk-taking (no detection
in drug screening or nonbanned substances, for most).38 Users’
perceptions of SCs in comparison to natural cannabis were
explored in a study including 2,513 participants from around the
world.7 SCs were reported to require a shorter time to peak onset
of effect and to have a shorter duration of action. In the mean-
time, SCs were associated with more negative effects, inducing a
strong preference for natural cannabis in the population surveyed.
The rapid efficacy is corroborated by pharmacokinetic data show-
ing peak JWH-018/JWH-073 concentration 5 min after smok-
ing, followed by a rapid drop to below 10% of the peak
concentration within 3 h in subjects who smoked herbal
incenses.41 In addition, it must be emphasized that SCs are
224
frequently not used alone but are often combined with other sub-
stances, usually alcohol, cannabis, and tobacco.
Undesired effects
Different reports from poison centers or information services
have described exposure to SCs and a recent review listed a series
of cases and reports identified in the literature.42 All indicate pre-
dominance of neurological (37%), psychiatric (25.6%), cardiore-
spiratory (44.1%), and gastrointestinal (13.2%) effects, with
different degrees of seriousness.43 The clinical features the most
commonly reported in clinical practice with some consistency
among studies were tachycardia (40%) > agitation (20%) >
drowsiness > vomiting/nausea > hallucinations. Confusion,
hypertension, chest pain, and dizziness/vertigo, all less than 5%,
were also observed. Most of these effects were not life-
threatening and did not persist more than 8 h; they generally
respond to conventional supportive care, with only a few deaths
attributed directly to SCs use. Nevertheless, compared to canna-
bis, SCs exposure seems to result in more severe outcomes.42–44
(Note: we intentionally exclude the less specific, frequent, or seri-
ous signs affecting the skin or the metabolism.)
Neurological effects. Cannabinoids induce a combination of
stimulant and depressive effects with euphoria, talkativeness, easy
laughing, increased perception of external stimuli alternating
with drowsiness, dizziness, a decrease in psychomotor activity,
and sedation. Other neurological signs such as headache, pares-
thesia, and tremor also occurred,42,45 and in <5% seizures were
noted.43
Psychiatric effects. D9-THC produces transient psychomimetic
effects including paranoid and grandiose delusion, suspiciousness,
and disorganization of thinking, perceptual alterations, anxiety,
and hallucinations. In heavy chronic smokers, cannabis can
induce depersonalization and amotivational syndrome.45 The evi-
dence supports the fact that cannabinoids can cause psychotic
disorders or exacerbate symptoms of schizophrenia. The risk is
dose- and time-dependent and several factors, such as early age of
exposure or genetic factors, may increase vulnerability to psycho-
sis.46 Interestingly, cannabidiols have positive effects on attenuat-
ing psychotic-, anxious-, and depressive-like behaviors.47 In case
series, SCs intake induces hallucinations, severe anxiety, agitation,
and paranoia. Due to their full agonist activity with higher affini-
ty, combined with the nonpresence of cannabidiol, use of SCs
could carry an increasing risk of psychiatric complications.46,47
More modestly, epidemiological studies associated cannabis use
with depression and suicide, and several case reports involving
SCs are emerging.48
Cardiovascular effects. Endocannabinoids seem to play a minor
role in the regulation of cardiovascular function in normal condi-
tions, but are altered in most cardiovascular disorders.49 The
most prevalent effect of smoking marijuana is tachycardia, fol-
lowed by hypotension in about 30% of cases. It also increases
myocardial oxygen demand and therefore can induce several seri-
ous cardiac adverse events including myocardial ischemia,
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coronary thrombosis, or vasospasm.50 Acute and chronic canna-
bis effects are still unresolved, as some human and animal models
suggested that these effects may be due to acute effects (particu-
larly coronary vasospasm and the risk of myocardial ischemia)
while longitudinal studies have indicated that marijuana use may
not have a significant effect on long-term mortality.50 Following
SCs intake, sinus tachycardia is the most frequent incident
reported, with an overall 40% prevalence. Hypertension is often
concomitant, up to one-fourth of cases.51 Based on experimental
data and compared to the effects of smoking marijuana, hyper-
tension was not the more frequent change in blood pressure that
is expected and the exact mechanism of occurrence remains to be
clarified. Electrocardiogram (ECG) modifications, especially ST-
segment elevation associated with chest pain, are reported but the
exact etiologies of these ST-segment modifications remain
unclear.52 Although the etiology of SCs-induced cardiac events
has been questionable at times,53 tachycardia and hypertension
have to be considered as increasing the risk of cardiovascular
events.48
Cerebrovascular disorders. Cerebral vasospasm, cardio-
embolization, and systemic hypotension with impaired cerebral
autoregulation are mechanisms proposed by Moussouttas to
explain a number of cases of cerebral ischemia and infarction
linked to cannabis consumption.54 Similarly, SCs may carry a risk
for acute cerebrovascular events. Acute ischemic stroke has been
reported in young adults within hours of first SCs use.55 Other
stroke risk factors were oral contraceptives or tobacco/cannabis
smoking.
Gastrointestinal effects. Nausea and vomiting are widely reported
as frequent effects after acute SCs use. Cannabinoid hyperemesis
syndrome is defined as cyclical nausea and vomiting relieved by
hot bathing after chronic cannabis or SCs intake, and may be
associated with abdominal complaints and weight loss.56,57 Also,
dronabinol (D9-THC) is used in the medical treatment of
chemotherapy-induced vomiting. The paradoxical antiemetic and
proemetic effects of cannabinoids should be considered by medi-
cal staff, as they can have effects on health, lead to unnecessary
and invasive health investigations, or, conversely, mask other
medical symptoms. (To comment, almost no pancreatitis or hep-
atitis has been clearly highlighted to date in the literature.)
Nephrotoxic effects. There is no evidence, to our knowledge, of
direct renal toxicity linked to cannabis intake. Publication by the
Wyoming Department of Health of a report on 16 patients hav-
ing recently used SCs and suffering from acute kidney injury in
2012 was therefore a bombshell. Further sporadic cases were pub-
lished later.58 Patients were all young. Some cases of acute tubular
necrosis or acute interstitial nephritis (with two showing oxalate
crystals) were confirmed by biopsy findings. No immune complex
deposition or proliferative changes were displayed. Kidney func-
tion continued to improve until fully resolved, within 3 days in
most patients. Kidney dialysis was even required in some patients.
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Ophthalmological effects. Changes in the pupils, such as mydriasis
(and sometimes myosis) is regularly but inconsistently reported
in cases of SCs intoxication. The typical redness affecting the
eyes and due to the dilatation of the conjunctival vessels in mari-
juana consumers is also described among SCs users. Blurred
vision and light sensitivity can also occur.59
Pulmonary effects. Hyperventilation or apnea, pneumonia, alveo-
lar infiltrates are reported in case series.60 Ferk et al.61 showed
that in human lung and buccal cell lines, DNA damage occurs
from SCs exposure (XRL-11 and RCS-4 in this study). This indi-
cates that SCs may be directly genotoxic to lung epithelium cells,
independently of tobacco and/or pyrogens brought on by smok-
ing practices.
Others
Other general or metabolic signs such as hyperthermia, rhabdo-
myolisis, hyperglycemia, acidosis, and hypokaliemia can also
occur. The well-known appetite-stimulating effect of cannabis is
reported but is lower with SCs.59
Dependence/withdrawal
Nine percent of cannabis users are at risk of becoming depen-
dent. The risk is higher when use began in childhood, and in
chronic or heavy users.45 As SCs have just recently become avail-
able, epidemiological data have not been collected for long
enough to be able to quantify the risk for SCs. Nevertheless, con-
sidering the more highly potent CB1R activity and shorter time
to effect, SCs could carry a major risk of dependence. To support
this, in a New Zealand detoxification center, 41 out of a total of
47 patients spoke of difficulties in stopping SCs use due to the
development of withdrawal symptoms.61 These included anxiety,
mood swings, nausea, and loss of appetite.
Mortality
In a cohort of Swedish male subjects followed from 1969 to
2011, Manrique-Garcia et al.63 found that subjects with a base-
line history of heavy cannabis use had an overall increased risk of
death compared to nonusers, even after excluding early exposure
to tobacco or at-risk alcohol use with a 1.4 hazard ratio (95%
confidence interval (CI) 5 1.1, 1.9). This risk persists when a
stratified analysis by psychosis diagnosis during follow-up is per-
formed. To date, there are still no large studies available on
deaths related to SCs consumption. Until 2016 and at the most,
31 deaths associated with SCs use have been reported in the liter-
ature in the form of small case series or isolated reports, analyti-
cally documented. Fatalities were considered as caused by SCs,
directly (sudden cardiac dysrhythmia, seizures) or indirectly
(hypothermia, self-injury).42
CANNABINOIDS AS POTENTIAL THERAPEUTIC AGENTS
Use of cannabinoids in cancer treatment
Numerous studies have demonstrated that dronabinol and nabi-
lone are effective in the prevention and treatment of
chemotherapy-induced nausea and vomiting and, therefore, they
have been both approved by the US Food and Drug
225
Administration for this indication in patients who have failed to
respond to conventional antiemetic therapy. A recent study
reviewed the effectiveness and tolerability of cannabis-based med-
ications for chemotherapy-induced nausea and vomiting in adults
with cancer.63 This review included 23 randomized controlled
trials and found that fewer people who received cannabis-based
medicines experienced nausea and vomiting than people who
received the placebo, and the authors concluded that cannabis-
based medications may be useful for treating refractory
chemotherapy-induced nausea and vomiting. However, the
authors also highlighted some methodological limitations, mainly
that the trials included were generally of low to moderate quality,
and reflected chemotherapy treatments and antisickness medi-
cines that were around in the 1980s and 1990s, and probably do
not reflect current chemotherapy regimens and newer antiemetic
agents. In the field of cancer treatment, the clinical approval of
cannabinoids is largely restricted to palliative uses in various dis-
eases, but since the emergence of promising preclinical data, the
antitumor effects of cannabinoids are beginning to be clinically
assessed. In a phase I clinical study, nine patients with glioblasto-
ma having escaped standard therapy underwent intracranial D9-
THC administration with favorable results.64 Also, a recent
phase II study evaluated cannabidiol as a treatment for acute
graft-versus-host disease in patients who have undergone alloge-
neic hematopoietic stem cell transplantation in addition to stan-
dard therapy (NCT01596075).65 Cannabidiol 300 mg/day was
administrated orally 7 days before transplantation, and was main-
tained for 30 days after transplantation in 48 patients. None of
the patients developed acute graft-versus-host disease while con-
suming cannabidiol and did not present with severe toxicity dur-
ing a median follow-up of 16 months. The authors concluded
that adding cannabidiol to standard graft-versus-host disease pro-
phylaxis is safe and promising in order to reduce the occurrence
of acute graft-versus-host disease.
Use of cannabinoids in pain management
Pain management improves a patient’s quality of life. Previous
studies of small groups of patients found D9-THC to have a
potential analgesic effect. However, D9-THC administration was
associated with side effects including drowsiness, dizziness, ataxia,
and blurred vision. In a multicenter, double-blind, placebo-
controlled study, THC:CBD extract and D9-THC extract alone
were also effective for management of pain resistant to strong
opioids.66 Cannabinoid use for pain management has also been
evaluated in a few clinical studies, especially for the treatment of
both neuropathic and chronic rheumatic pain. A study tested the
impact of vaporized cannabis in 21 patients with chronic pain
treated with sustained-release morphine or oxycodone.67 Patients
who received vaporized cannabis combined with sustained-release
morphine exhibited more controlled pain than those who
received vaporized cannabis and oxycodone.
Use of cannabinoids in central nervous diseases
Neuroinflammatory diseases, including multiple sclerosis, Alz-
heimer’s and Parkinson’s diseases, and amyotrophic lateral sclero-
sis, are characterized by hyperactive glial cells accompanied by
226
infiltration of blood leukocytes. There is growing evidence that
cannabinoid receptors and endocannabinoids play a crucial role
in this context.68 Some countries have approved the combination
of THC:CBD in the current 1:1 ratio as an add-on therapy to
prevent central pain and spasticity in multiple sclerosis. A recent
clinical study reviewed the safety and the efficacy of this combina-
tion in 1,615 patients with multiple sclerosis between January
2014 and February 2015 from the mandatory Italian medicines
agency e-registry.69 After an initial 4-week single-blind
THC:CBD trial period, 47% of patients experienced initial
improvement in spasticity. During the second phase, consisting
of double-blinded randomization of the initial responders to con-
tinue either with THC:CBD treatment or the placebo, a signifi-
cantly higher proportion of patients receiving THC:CBD still
saw an improvement in spasticity. Almost 47% of patients
reported adverse events including dizziness and fatigue. Regarding
other neuroinflammatory diseases, only a few clinical studies are
underway and seem to show promising results, particularly
regarding Alzheimer’s disease. Cannabinoids, including SCs such
as WIN 55,212-2 and the most CB2R-selective JWH-133, exhib-
it interesting antiinflammatory properties that are underpinned
by the presence of CB2R in glial cells, astrocytes, and microglial
cells, and the upregulation response that they undergo when these
cells become reactive during an inflammatory process.68 Although
large clinical trials are missing, the available experimental data are
encouraging in demonstrating the presence of upregulation of
CB2R in glial elements in postmortem tissues of Parkinson’s dis-
ease patients, and the potential benefit of modulation of these
receptors by cannabinoid ligands in this context.70 Considering
the additional neuroprotective properties of some cannabinoids,
treatment or management of several neuroinflammatory diseases
could be usefully investigated.
Recently, the use of medical synthetic cannabinoids as antiepi-
leptic agents has emerged. Cannabis-based treatment for epilepsy
has recently received major attention with reports of improve-
ments in seizure control in children with severe epilepsy. In
response, many states have legalized cannabis for the treatment of
epilepsy in children and adults. Although several studies reported
the efficacy of cannabinoids in seizure prevention, to date there
are no well-controlled clinical studies of the effectiveness of
cannabidiol-THC combinations, only anecdotal reports, explain-
ing that recent reviews assumed that no reliable conclusions can
be drawn.71 The role of the endocannabinoid system in the path-
ogenesis of schizophrenia has been a subject of controversy over
the last few years.46 As stated above, D9-THC produced positive
and negative psychotic symptoms, euphoria, anxiety, attention,
and working/verbal memory disorders. Patients with schizophre-
nia respond more fiercely to D9-THC than healthy subjects.
Forms of cannabis that contain a higher D9-THC content, such
as the “skunk-like” or sensemilla cannabis, have been shown to
cause more severe psychotic symptoms and increase the risk of
schizophrenia to a greater degree.72 Because of the ability of D9-
THC to induce psychotic syndrome, as well as evidence associat-
ing cannabis use with the development of schizophrenia, the
potential antipsychotic properties of cannabinoid-based com-
pounds that may counter the effects of D9-THC have drawn
VOLUME 101 NUMBER 2 | FEBRUARY 2017 | www.wileyonlinelibrary/cpt
great interest. In a small, 16-week, placebo-controlled, double-
blind, randomized trial of 15 obese patients with schizophrenia,
CB1R antagonist as rimonabant was associated with a decrease in
anxiety, depression, and hostility compared with placebo.73 Can-
nabidiol impact in this context was also examined in patients
with resistant schizophrenia, with nonconclusive results. A large
clinical study tested the effects of cannabidiol (n 5 20) on psy-
chosis compared to the antipsychotic amisulpride (n 5 19) and
did not show any differences between the two groups. However,
the cannabidiol group experienced significantly fewer side
effects.74
Use of cannabinoids in ocular diseases
The endocannabinoid system is present in both anterior and pos-
terior ocular tissue, including the retina, and application of can-
nabinoids to the eye produces several effects, including
hyperemia, reduced tear production, and intraocular pressure.
These intraocular pressure-lowering properties of cannabinoids
have therefore attracted considerable attention with the view of
developing cannabinoid-based agents to treat glaucoma. Clinical
results are conflicting and suffer from a small sample size and
potential bias. Porcella et al. found that the SCs “WIN 55,212-2”
was effective in lowering intraocular pressure in patients with
resistant glaucoma76 with effects that may persist 4 weeks in the
event of chronic administration. For both D9-THC and WIN
55,212-2, the ocular hypotensive effect appears to be due to
CB1R activation.77 Large clinical studies are therefore needed,
regarding both the type of cannabinoids used (phytocannabinoids
or SCs) and the dose used.
CONCLUSION
Over the last decade, SCs have continued to emerge as popular
drugs of abuse as an alternative to phytocannabinoids. Knowledge
of SCs, mainly used as popular recreational drugs, was generated
primarily by users; it is now based on case reports or small series
including admissions to emergency services or poison control cen-
ters. To date, numerous in vitro and experimental data, but still
no large randomized clinical trials on cannabinoid effects, are
emerging in the scientific literature. Cannabinoids have a phar-
macological effect by binding to CB1R and/or CB2R, with CB1
agonists responsible for the recreational effects of SCs. Despite
activation of CB1R, the endocannabinoid system also interferes
with other neurotransmission systems, thus accounting for some
diverse adverse effects. Moreover, the wide variety of chemical
compounds likely to activate or interact with a number of phar-
macological pathways, resulting in serotoninergic, sympathomi-
metic, or other nonelucidated modulations at the time, may lead
to more various and unexpected adverse effects. SCs effects are
considered to be more intense and faster than those observed
with cannabis smoking, explained partly by the full agonist activi-
ty and high affinity for cannabinoid receptors. In addition to
unpleasant CNS effects, several physical adverse effects including
kidney damage, pulmonary, gastrointestinal, and cardiovascular
side effects can make consumption unsafe. This phenomenon of
synthetic drug use is still recent and unknown in most countries,
in which prevalence of use is still low compared to the US.
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 101 NUMBER 2 | FEBRUARY 2017
Meanwhile, medical practitioners, when faced with a patient
with unexplained symptoms, including common symptoms such
as agitation, anxiety, tachycardia, or hypertension, etc., the toxico-
logical analysis remaining negative, should bear synthetic drugs as
SCs in mind. Regrettably, if these clinical effects generally
respond to conventional supportive care, severe outcomes may
occur in a minority of cases. Finally, the influx of “nonmedicinal”
SCs produced by “drug designers” may bring additional responses
due to the higher affinity to cannabinoid receptors than D9-
THC, but also render the message confusing due to the signifi-
cant heterogeneity and the limited information available on each
specific compound. Recreational cannabinoid abuse is a growing
public health problem, with serious physical and mental health
consequences. The interest taken by the scientific community in
the potential therapeutic value of cannabinoids is great, but the
strong likelihood of abuse and addiction produced by SCs is of
concern. While findings from several clinical studies showed sig-
nificant benefits from cannabinoids in different contexts, perma-
nent conclusions are limited by the low to moderate quality of
the trials (small sample sizes, short trial duration, and lack of pla-
cebo control in the majority of studies). Moreover, the majority
of these studies are on natural cannabinoids or analogs, are old,
and therefore reflect therapeutic strategies that were around in
the 1980s and 1990s, involving modifications in standard therapy
and making it impossible to come to any conclusions to date.
Meanwhile, current experimental studies provide sufficiently
promising results to consider clinical development especially in
the field of cancer care, pain management, or neuroinflammatory
disease treatment that must be confirmed for phytocannabinoids
and remains to be carefully explored for SCs.
CONFLICT OF INTEREST
The authors declare no conflicts of interest.
C 2016 American Society for Clinical Pharmacology and Therapeutics
V
1. Pertwee, R.G. Targeting the endocannabinoid system with
cannabinoid receptor agonists: pharmacological strategies and
therapeutic possibilities. Philos. Trans. R. Soc. Lond. B Biol. Sci. 367,
3353–3363 (2012).
2. The health and social effects of nonmedical cannabis use (World
Health Organization 2016). <http://www.who.int/substance_abuse/
publications/cannabis_report/en/>.
3. Whiting, P.F. et al. Cannabinoids for medical use. A systematic review
and meta-analysis. JAMA 313, 2456–2473 (2015)
4. Debruyne, D. & Le Boisselier, R. Emerging drugs of abuse: current
perspectives on synthetic cannabinoids. Subst. Abuse Rehabil. 6,
113–129 (2015).
5. Mechoulam, R., Hanus, L.O. & Pertwee, R. Early phytocannabinoid
chemistry to endocannabinoids and beyond. Nat. Rev. Neurosci. 15,
757–764 (2014).
6. Reggio, P.H. The Cannabinoid Receptors, 203–234 (Humana Press,
New York, 2009).
7. Winstock, A.R. & Barratt M.J. Synthetic cannabis: a comparison of
patterns of use and effect profile with natural cannabis in a large
global sample. Drug Alcohol Depend. 131, 106–111 (2013).
8. Watanabe, S., Kuzhiumparambil, U., Winiarski, Z. & Fu, S. Data on
individual metabolites of synthetic cannabinoids JWH-018, JWH-073
and AM2201 by Cunninghamela elegans. Forensic Sci. Int. 261, 33–
42 (2016).
227
9. Couceiro, J. et al. Toxicological impact of JWH-018 and its phase I
metabolite N-(-3hydroxypentyl) on human cell lines. Forensic Sci. Int.
264, 100–105 (2016).
10. vez, A.E. & Hashimotodani, Y.
Castillo, P.E., Younts, T.J., Cha
Endocannabinoid signaling and synaptic function. Neuron. 76, 70–81
(2012).
11. Piomelli, D. The molecular logic of endocannabinoid signalling. Nat.
Rev. Neurosci. 4, 873–884 (2003).
12. Turu, G. & Hunyady, L. Signal transduction of the CB1 cannabinoid
receptor. J. Mol. Endocrinol. 44, 75–85 (2010).
13. Oliveira da Cruz, J.F., Robin, L.M., Drago, F., Marsicano, G. & Metna-
Laurent, M. Astroglial type-1 cannabinoid receptor (CB1): A new
player in the tripartite synapse. Neuroscience 323, 35–42 (2016).
14. Maccarrone, M. et al. Endocannabinoid signaling at the periphery: 50
years after THC. Trends Pharmacol. Sci. 36, 277–296 (2015).
15. Reggio, P.H. Endocannabinoid binding to the cannabinoid receptors:
what is known and what remains unknown. Curr. Med. Chem. 17,
1468–1486 (2010)
16. Vemuri, V.K. & Makriyannis, A. Medicinal chemistry of cannabinoids.
Clin. Pharmacol. Ther. 97, 553–558 (2015).
17. Mella-Raipan, J., Hernandez-Pino, S., Morales-Verdejo, C. & Pessoa-
Mahana, D. 3D-QSAR/CoMFA-based structure-affinity/selectivity
relationships of aminoalkylindoles in the cannabinoid CB1 and CB2
receptors. Molecules 19, 2842–2861 (2014).
18. Paulke, A., Proschak, E., Sommer, K., Achenbach, J., Wunder, C.,
Toennes, S.W. Synthetic cannabinoids: in silico prediction of the
cannabinoid receptor 1 affinity by a quantitative structure-activity
relationship model. Toxicol. Lett. 245, 1–6 (2016).
19. Wiley, J.L. et al. AB-CHMINACA, AB-PINACA, and FUBIMINA: affinity
and potency of novel synthetic cannabinoids in producing D9-
tetrahydroccanbinol-like effects in mice. Pharmacol. Exp. Ther. 354,
328–339 (2015).
20. Rodrıguez-Mun ~oz, M., Sa nchez-Bla
zquez, P., Merlos, M. & Garzon-
Nin~o, J. Endocannabinoid control of glutamate NMDA receptors: the
therapeutic potential and consequences of dysfunction. Oncotarget
(2016); e-pub ahead of print.
21. Chiu, C.Q., Puente, N., Grandes, P. & Castillo, P.E. Dopaminergic
modulation of endocannabinoid-mediated plasticity at GABAergic
synapses in the prefrontal cortex. J. Neurosci. 30, 7236–7248
(2010).
22. Scherma, M. et al. Interactions between the endocannabinoid and
nicotinic cholinergic systems: preclinical evidence and therapeutic
perspectives. Psychopharmacology (Berl). 233, 1765–1777 (2016).
23. O’Sullivan, S.E. An update on PPAR activation by cannabinoids. Br. J.
Pharmacol. 173, 1899–1910 (2016).
24. Garcıa, C., Palomo-Garo, C., Go mez-Galvez, Y. & Ferna
ndez-Ruiz, J.
Cannabinoid-dopamine interactions in the physiology and
physiopathology of the basal ganglia. Br. J. Pharmacol. 173, 2069–
2079 (2016).
25. Tebano, M.T., Martire, A. & Popoli, P. Adenosine A(2A)-cannabinoid
CB(1) receptor interaction: an integrative mechanism in striatal
glutamatergic neurotransmission. Brain Res. 1476, 108–118
(2012).
26. Franklin, J.M. & Carrasco, G.A. Cannabinoid receptor agonists
upregulate and enhance serotonin 2A (5-HT(2A)) receptor activity via
ERK1/2 signaling. Synapse 67, 145–159 (2013).
27. Nasehi, M., Farrahizadeh, M., Ebrahimi-Ghiri, M. & Zarrindast, M.R.
Modulation of cannabinoid signaling by hippocampal 5-HT4
serotonergic system in fear conditioning. J. Psychopharmacol.
(2016); e-pub ahead of print.
28. Duncan, M., Davison, J.S. & Sharkey, K.A. Review article:
endocannabinoids and their receptors in the enteric nervous system.
Aliment. Pharmacol. Ther. 22, 667–683 (2005).
29. Galli, J.A., Sawaya, R.A. & Friedenberg, F.K. Cannabinoid
hyperemesis syndrome. Curr. Drug Abuse Rev. 4, 241–249 (2011).
30. O’Sullivan, S.E. Endocannabinoids and the cardiovascular system
in health and disease. Handb. Exp. Pharmacol. 231, 393–422
(2015).
31. €rvinen, T., Pate, D.W. & Laine, K. Cannabinoids in the treatment of
Ja
glaucoma. Pharmacol. Ther. 95, 203–220 (2002).
32. Tam, J. The emerging role of the endocannabinoid system in the
pathogenesis and treatment of kidney diseases. J. Basic Clin. Physiol.
Pharmacol. 27, 267–276 (2016).
228
33. Uchiyama, N., Kikura-Hanajiri, R., Ogata, J. & Goda, Y. Chemical
analysis of synthetic cannabinoids as designer drugs in herbal
products. Forensic Sci. Int. 198, 31–38 (2010).
34. Frinculescu, A., Lyall, CL., Ramsey, J. & Miserez, B. Variation in
commercial smoking mixtures containing third-generation synthetic
cannabinoids. Drug Test. Anal. (2016); e-pub ahead of print.
35. Wohlfarth, A. et al. Urinary prevalence, metabolite detection rates,
temporal patterns and evaluation of suitable LC-MS/MS targets to
document synthetic cannabinoid intake in US military urine
specimens. Clin. Chem. Lab. Med. 53, 423–434 (2015).
36. Palamar, J.J., Acosta, P. Synthetic cannabinoid use in a nationally
representative sample of US high school seniors. Drug Alcohol
Depend. 149, 194–202 (2015).
37. Clements-Nolle, K., Lensch, T., Larson, S. & Yang, W. Prevalence and
correlates of any and frequent synthetic cannabinoid use in a
representative sample of high school students. Subst. Use Misuse
51, 1139–1146 (2016).
38. Bonar, E.E., Ashrafioun, L. & Llgen, M.A. Synthetic cannabinoid use
among patients in residential substance use disorder treatment:
prevalence, motives, and correlates. Drug Alcohol Depend. 143,
268–271 (2014).
39. Tuv, S.S., Krabseth, H., Karinen, R., Olsen, K.M., Øiestad, E.L.,
Vindenes, V. Prevalence of synthetic cannabinoids in blood samples
from Norwegian drivers suspected of impaired driving during a seven
weeks period. Accid. Anal. Prev. 62, 26–31 (2014).
40. Jaenicke, N.J., Pogoda, W., Paulke, A., Wunder, C., Toennes, S.W.
Retrospective analysis of synthetic cannabinoids in serum
samples—epidemiology and consumption patterns. Forensic. Sci. Int.
242, 81–87 (2014).
41. Adamowicz, P., Gieron ~, J., Gil, D., Lechowicz, W., Skulska, A. &
Tokarczyk, B. The prevalence of new psychoactive substances in
biological material — a three-year review of casework in Poland. Drug
Test. Anal. 8, 63–70 (2016)
42. Kacinko, S.L., Xu, A., Homan, J.W., McMullin, M.M. & Warrington,
D.M. Development and validation of a liquid chromatography-tandem
mass spectrometry method for the identification and quantification of
JWH-018, JWH-073, JWH-019, and JWH-250 in human whole blood.
J. Anal. Toxicol. (2016); e-pub ahead of print.
43. Tait, R.J., Caldicott, D., Mountain, D., Hill, S.L. & Lenton, S. A
systematic review of adverse events arising from the use of synthetic
cannabinoids and their associated treatment. Clin. Toxicol. 54, 1–13
(2016).
44. Waugh, J. et al. Epidemiology and clinical features of toxicity following
recreational use of synthetic cannabinoid receptor agonists: a report
from the United Kingdom National Poisons Information Service. Clin.
Toxicol. 54, 512–518 (2016).
45. Riederer, A.M. et al. Acute poisonings from synthetic cannabinoids —
50 U.S. Toxicology Investigators Consortium Registry Sites, 2010-
2015. MMWR Morb. Mortal. Wkly. Rep. 65, 692–695 (2016).
46. Panlilio, V.L., Goldberg, S.R. & Justinova, Z. Cannabinoid abuse and
addiction: Clinical and preclinical findings. Clin. Pharmacol. Ther. 97,
616–627 (2015).
47. Rabin, R.A. & George, T.P. Understanding the link between
cannabinoids and psychosis. Clin. Pharmacol. Ther. (2016); e-pub
ahead of print.
48. Campos, A.C., Fogaça, M.V., Sonego, A.B. & Guimara ~es, F.S.
Cannabidiol, neuroprotection and neuropsychiatric disorders.
Pharmacol. Res. (2016); e-pub ahead of print.
49. Castaneto, M.S., Gorelick, D.A., Desrosiers, N.A., Hartman, R.L.,
Pirard, S. & Huestis, M.A. Synthetic cannabinoids: epidemiology,
pharmacodynamics, and clinical implications. Drug Alcohol Depend.
144, 12–41 (2014).
50. O’Sullivan, S.E. Endocannabinoids and the cardiovascular system in
health and disease. Handb. Exp. Pharmacol. 231, 393–422 (2015).
51. Franz, C.A. & Frishman, W.H. Marijuana use and cardiovascular
disease. Cardiol. Rev. 24, 158–162 (2016).
52. Helander, A., Beck, O., Ha €gerkvist, R. & Hulte
n P. Identification of
novel psychoactive drug use in Sweden based on laboratory
analysis—initial experiences from the STRIDA project Scand. J. Clin.
Lab. Invest. 73, 400–406 (2013).
53. Zaleta, S., Kumar, P. & Miller, S. Chest pain, troponin rise, and ST-
elevation in an adolescent boy following the use of the synthetic
cannabis product K2. Ann. Pediatr Cardiol. 9, 79–81 (2016).
VOLUME 101 NUMBER 2 | FEBRUARY 2017 | www.wileyonlinelibrary/cpt
54. Alexandre, J., Fedrizzi, S., Debruyne, D., Coquerel, A. & Le Boisselier,
R. Synthetic cannabinoid (K2) use in pediatric patients and
cardiovascular events: A place for pericarditis and myopericarditis?
J. Pediatr. 167, 1454 (2015).
55. Moussouttas, M. Cannabis use and cerebrovascular disease.
Neurologist 10, 47–53 (2004).
56. Bernson-Leung, M.E., Leung, L.Y. & Kumar, S.J. Synthetic cannabis
and acute ischemic stroke. Stroke Cerebrovasc. Dis. 23, 1239–1241
(2014).
57. Hopkins, C.Y. & Gilchrist, B.L. A case of cannabinoid hyperemesis
syndrome caused by synthetic cannabinoids. J. Emerg. Med. 45,
544–546 (2013).
58. Ukaigwe, A., Karmacharya, P. & Donato, A. A gut gone to pot: A Case
of cannabinoid hyperemesis syndrome due to K2, a synthetic
cannabinoid. Case Rep. Emerg. Med. 16, 1–3 (2014).
59. Centers for Disease Control and Prevention. Acute kidney injury
associated with synthetic cannabinoid use — multiple states.
<https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6206a1.
htm> (2012).
60. Castellanos, D. & Gralnik, L.M. Synthetic cannabinoids 2015: An
update for pediatricians in clinical practice. World J. Clin. Pediatr. 5,
16–24 (2016).
61. Ferk, F. et al. Genotoxic properties of XLR-11, a widely consumed
synthetic cannabinoid, and of the benzoyl indole RCS-4. Arch. Toxicol.
(2016); e-pub ahead of print.
62. Macfarlane, V. & Christie, G. Synthetic cannabinoid withdrawal: a
new demand on detoxification services. Drug Alcohol Rev. 34 147–
153 (2015).
63. Manrique-Garcia, E., Ponce de Leon, A., Dalman, C., Andre asson, S.
& Allebeck, P. Cannabis, psychosis, and mortality: a cohort study of
50,373 Swedish men. Am. J. Psychiatry. 173, 790–798 (2016).
64. Smith, L.A., Azariah, F., Lavender, V.T.C., Stoner, N.S. & Bettiol, S.
Cannabinoids for nausea and vomiting in adults with cancer receiving
chemotherapy. Cochrane Database Syst. Rev. CD009464 (2015).
65. Guzma n, M. et al. A pilot clinical study of delta9-tetrahydrocannabinol
in patients with recurrent glioblastoma multiforme. Br. J. Cancer 95,
197–203 (2006).
66. Yeshurun, M. et al. Cannabidiol for the prevention of graft-versus-
host-disease after allogeneic hematopoietic Cell Transplantation:
Results of a Phase II Study. Biol. Blood Marrow Transplant. 21,
1770–1775 (2015).
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 101 NUMBER 2 | FEBRUARY 2017
67. Johnson, J.R., Burnell-Nugent, M., Lossignol, D., Ganae-Motan, E.D.,
Potts, R. & Fallon, M.T. Multicenter, double-blind, randomized,
placebo-controlled, parallel-group study of the efficacy, safety, and
tolerability of THC:CBD extract and THC extract in patients with
intractable cancer-related pain. J. Pain Symptom Manage. 39, 167–
179 (2010).
68. Abrams, D.I., Couey, P., Shade, S.B., Kelly, M.E. & Benowitz, N.L.
Cannabinoid-opioid interaction in chronic pain. Clin. Pharmacol. Ther.
90, 844–851 (2011).
69. Chiurchiu , V., Leuti, A. & Maccarrone, M. Cannabinoid signaling and
neuroinflammatory diseases: a melting pot for the regulation of brain
immune responses. J. Neuroimmune Pharmacol. 10, 268–280
(2015).
70. Patti, F. et al. Efficacy and safety of cannabinoid oromucosal spray for
multiple sclerosis spasticity. J. Neurol. Neurosurg. Psychiatry (2016)
[Epub ahead of print].
71. Gomez-Ga lvez, Y., Palomo-Garo, C., Fernandez-Ruiz, J. & Garcıa, C.
Potential of the cannabinoid CB(2) receptor as a pharmacological
target against inflammation in Parkinson’s disease. Prog.
Neuropsychopharmacol. Biol. Psychiatry 64, 200–208 (2016).
72. Koppel, B.S. et al. Systematic review: efficacy and safety of medical
marijuana in selected neurologic disorders: report of the Guideline
Development Subcommittee of the American Academy of Neurology.
Neurology. 82, 1556–1563 (2014).
73. Di Forti, M. et al. Proportion of patients in south London with first-
episode psychosis attributable to use of high potency cannabis: a
case-control study. Lancet Psychiatry 2, 233–238 (2015).
74. Kelly, D.L. et al. Effects of the cannabinoid-1 receptor antagonist
rimonabant on psychiatric symptoms in overweight people with
schizophrenia: a randomized, double-blind, pilot study. J. Clin.
Psychopharmacol. 31, 86–91 (2011).
75. Leweke, F.M. et al. Cannabidiol enhances anandamide signaling and
alleviates psychotic symptoms of schizophrenia. Transl. Psychiatry 2,
e94 (2012).
76. Porcella, A., Maxia, C., Gessa, G.L. & Pani, L. The synthetic
cannabinoid WIN55212-2 decreases the intraocular pressure in
human glaucoma resistant to conventional therapies. Eur. J.
Neurosci. 13, 409–412 (2001).
77. Cairns, E.A., Baldridge, W.H. & Kelly, M.E.M. The endocannabinoid
system as a therapeutic target in glaucoma. Neural Plast. 9364091
(2016).
229