46 Recent Patents on CNS Drug Discovery, 2010, 5, 46-52

Pharmacology and Toxicology of Cannabis Derivatives and Endo-

cannabinoid Agonists

Gilberto Gerra1,*, Amir Zaimovic2, Maria L. Gerra3, Roberto Ciccocioppo4, Andrea Cippitelli4,
Giovanni Serpelloni5 and Lorenzo Somaini6

1
Health and Human Development Section, United Nations Office on Drugs, and Crime, Vienna, 2Programma
Dipendenze “Ser.T”, Azienda Unitá Sanitaria Locale, Parma, Italy, 3Student, University of Parma, School of Medicine,
Italy, 4Department of Experimental Medicine and Public Health, University of Camerino, Italy. 5Dipartimento
Dipendenze ASL Verona, Italy, 6Dipartimento Dipendenze Ser.T Cossato, ASL BI, Biella, Italy

Received: July 7, 2009; Accepted: August 21, 2009; Revised: October 6, 2009
Abstract: For centuries Cannabis sativa and cannabis extracts have been used in natural medicine.
9-
tetrahydrocannabinol (THC) is the main active ingredient of Cannabis. THC seems to be responsible for most of the
pharmacological and therapeutic actions of cannabis. In a few countries THC extracts (i.e. Sativex®) or THC derivatives
such as nabilone, and dronabinol are used in the clinic for the treatment of several pathological conditions like
chemotherapy-induced nausea and vomiting, multiple sclerosis and glaucoma. On the other hand the severe side effects
and the high abuse liability of these agents represent a serious limitation in their medical use. In addition, diversion in the
use of these active ingredients for recreational purpose is a concern. Over recent years, alternative approaches using
synthetic cannabinoid receptor agonists or agents acting as activators of the endocannabinoid systems are under scrutiny
with the hope to develop more effective and safer clinical applications. Likely, in the near future few of these new
molecules will be available for clinical use.
The present article reviews recent study and patents with focus on the cannabinoid system as a target for the treatment of
central nervous system disorders with emphasis on agonists.
Keywords: Cannabis, endocannabinoids, receptor agonists, abuse.

INTRODUCTION
In the early nineties the existence of receptors for the
psychoactive compounds of Cannabis sativa [1, 2] and the
isolation of their endogenous ligands, anandamide [3] and 2-
arachidonoylglycerol [4, 5] was described. Since then,
several thousands of scientific reports have explored in depth
the main aspects of the so called “endocannabinoid system”.
This system emerges nowadays as a relevant modulator of
physiological functions not only in the central nervous
system but also in the autonomic nervous system, the
endocrine network, the immune system, the gastrointestinal
tract, the reproductive system and the cardiovascular system
[6-11]. Pharmacological studies reveal that there are at least
two types of cannabinoid receptors, CB1 and CB2, and a
wide range of CB1 and CB2 ligands with diverse chemical
structures are now available [12]. Several series of com-
pounds have been developed as cannabinoid CB1 receptor
agonists. In addition, in recent years several molecules acting
as modulators (i.e., inhibitors of endocannabinoids degra-
dation or re-uptake) of the endocannabinoid system have
been also developed [13]. The present article will review,
with emphasis on the central nervous system (CNS), the
major pharmacological and toxicological characteristics of
the different classes of molecules with agonistic properties at
*Address correspondence to this author at the Health and Human
Development Section, Division for Operations, United Nations Office on
Drugs and Crime, Room D1438, P.O. Box 500, 1400 Vienna, Austria;
Tel: (+43-1) 26060-4123; Fax: (+43-1) 26060-5928;
E-mail: gilberto.gerra@unodc.org
the cannabinoid CB1 receptor system that have been or are
under current development.
CLINICAL USE OF CANNABIS & DERIVATIVES
The medical and recreational use of Cannabis sativa
derivatives has been practised for thousands of years and
nowadays marijuana is the most commonly used illicit drug
in the United States and in many other countries throughout
the world. Cannabis effects in humans include disruption of
short-term memory, cognitive impairments, enhanced body
awareness, in coordination, sleepiness, reflex tachycardia,
hypothermia and mood alterations with euphoria or dys-
phoria depending on prior experience of the user, mood state
at the time of onset, drug dose and route of administration
[14]. The main cannabis active ingredient responsible for
these effects is
9-tetrahydrocannabinol (THC) that in
addition to these acute actions possesses abuse liability
properties leading to addiction following chronic use [7, 14].
Over recent years intensive research on the molecular mode
of action of Cannabis sativa derivatives has been carried out
and our knowledge of the physiology and pharmacology of
the cannabinoid system have greatly expanded. Clinical
studies have shown, for example, that some effects of
cannabinoids may be therapeutically useful and currently
nabilone, a structural analogue of THC, is used in parts of
the USA and the UK for treatment of chemotherapy induced
nausea and vomiting. THC itself and its analogue Dronabinol
are used as appetite stimulators in AIDS patients [15] but
also to reduce intraocular pressure in patients with glaucoma.
Clinical trials of standardized cannabis extracts have been

1574-8898/10 $100.00+.00 © 2010 Bentham Science Publishers Ltd.

Pharmacology and Toxicology of Cannabis Derivatives
undertaken for these indications [16, 17], and a new drug
based on cannabis extracts (Sativex A) has recently been
approved in Canada as adjunctive treatment for the symp-
tomatic relief of neuropathic pain associated with multiple
sclerosis. Nonetheless, the usefulness as therapeutic agents
of such extracts, of THC itself, or of synthetic compounds
with the same pharmacological actions as THC, is greatly
hampered by their psychotropic effects and by their abuse
potential [18].
ACUTE TOXICITY OF CANNABIS & CANNABIS
DERIVATIVES
Learning & Memory
Learning and memory skills are severely affected by
acute cannabis use. For example acute cannabis intoxication
has been repeatedly reported to cause marked changes in
subjective mental status with negative effects on neuro-
psychological performance such as learning performances
and leading to reduced attention, and reduction in working
memory [19-22].
In studies investigating acute effects among non severe
heavy users, higher doses of tetrahydrocannabinol THC have
been found associated to with impairments in planning and
control impulse tasks, with effects persisting over 4 weeks
from drug use [23]. Compared to abstinent individuals,
cannabis users showed deficits on verbal skills, visual
recognition, delayed visual recall, and short- and long-inter-
val prospective memory tasks [24].
Although cannabis-associated cognitive deficit seems
reversible and related to recent cannabis exposure rather than
irreversible and related to cumulative lifetime use [25], long-
term heavy cannabis use (more than 15 years) has been
demonstrated to lead to a subtle and permanent impairment
in cognitive performance, mainly in the capacity to retain
new information [26].
At neuron-anatomical levels these cannabis effects can be
explained with the ability of cannabinoid agonists to
interfere with the expression of long term potentiation (LTP)
and long term depression (LTD), the two major molecular
mechanisms of learning and memory, in key areas such as
the prefrontal cortex, the striatum, hippocampus and the
amygdala, nucleus accumbens [27].
Electro-physiological and neurochemical data have, in
fact, clearly shown that in these brain structures activation of
cannabinoid CB1 receptors by natural as well as synthetic
agonists may lead to a marked alteration of both inhibitory
GABAergic and excitatory glutamatergic neurotransmission
which play a critical role in LTP and LTD [28].
Finally, integrated studies combining brain imaging
techniques and neuropsychological tasks evidenced that
cannabis users performed significantly worse in a “face-
name task”, and that this deficit is associated to parahippo-
campal hyperactivity and frontocortical hypo-activity [29].
In a PET study, it was also shown that heavy marijuana users
tested for a modified Stroop Task have persistent deficits in
cognitive functioning associated with hypo-activity in the
left perigenual anterior cingulate cortex and the left lateral
prefrontal cortex and hyperactivity in the hippocampus. It
Recent Patents on CNS Drug Discovery, 2010, Vol. 5, No. 1 47
was suggested that these differences in brain activity may
play a role in the development of neuropsychiatric disorders
referable to chronic cannabis use including addiction [30].
Of interest, there is evidence that while cannabinoid receptor
agonists impair memory formation, antagonists reverse these
deficits or even act as memory enhancers [31]. At the
neurobiological level these data are supported by findings
indicating reduction in neural plasticity following canna-
binoid-agonists treatment, and increased plasticity following
antagonist exposure [32].
Locomotor performances Central cannabinoid receptors
are densely located in the caudate putamen, in output nuclei
of the basal ganglia (i.e., globus pallidus and the substantia
nigra pars reticulate) and in the cerebellum [33]. Thought the
important role of these brain structures in motor control and
coordination, it is not surprising that cannabis use is asso-
ciated with significant locomotor skill impairment [34].
Locomotor effects of cannabinoids have been well docu-
mented in laboratory animals and in humans [35-37]. In
addition, the significance of cannabis use in driving impair-
ment and motor vehicle crashes has traditionally been
established in experimental and epidemiological studies.
Surveys that established recent use of cannabis by directly
measuring THC in blood showed that THC positives,
particularly at higher doses, are about three to seven times
more likely to be responsible for their crash as compared to
drivers that had not used drugs or alcohol [38].
Impairment of cognitive functions and psychomotor
skills associated with cannabis use could last longer than a
measurable THC blood concentration, with the risk for
marijuana users to become responsible in fatal or injurious
traffic accidents, even with low blood concentrations of THC
[39]. Smoking of 17mg THC has been recently demonstrated
to result in impairment of cognitive motor skills that could
be important for coordinated movement and driving, whereas
the lower dose of 13mg THC appears to cause less impair-
ment of such skills in regular users of marijuana [40],
possibly in relationship to tolerance effects. Dose-related
effects of THC in motor control impairment and deterio-
ration of response-reaction time tasks has been well docu-
mented also in recreational cannabis users [41].
Chronic Toxicity of Cannabis & Cannabis Derivatives
Drug Dependence
Addiction is one of the most serious consequences of
chronic cannabis use. Epidemiological data indicate that
early initiation of cannabis consumption is a significant risk
factor for abuse progression. Moreover, regular or heavy
cannabis use was found associated with an increased risk of
using other illicit drugs, abusing or becoming dependent
upon other illicit drugs, and using a wider variety of other
illicit drugs. The risks of use, abuse/dependence, and use of a
diversity of other drugs declined with increasing age [42-44].
The findings may support a general causal model such as the
cannabis gateway hypothesis in which the cannabis exposure
has an enduring impact on hedonic processing resulting in
future enhanced risk of abusing other drugs of addiction.
Despite this phenomenon has been described, the actual
causal mechanisms underlying the gateway remain unclear
and therefore its significance is debated [42-44].
48 Recent Patents on CNS Drug Discovery, 2010, Vol. 5, No. 1
Cross-tolerance and cross-sensitization between canna-
binoid agents and opiates have been clearly demonstrated in
laboratory animal studies [45, 46]. Elective blockade of
cannabinoid receptors has been demonstrated to prevent
seeking behavior for a variety of drugs including heroin,
cocaine nicotine and alcohol [45-48].
Psychiatric Comorbidity
Recent research showed that the emotional responses to
cannabinoids are not always pleasant and delightful. Rather,
anxiety and panic may also occur after activation of CB1
receptors [49]. Diagnoses of depression, with suicidal idea-
tion and anhedonia, and agoraphobia were reported signi-
ficantly associated with increased likelihood of cannabis use
[50-52]. In addition epidemiological data indicates that
almost 90% of cannabis dependent adults have been found
affected by concomitant personality disorders, more than
half had a paranoid disorder and more than a third suffers
from a borderline personality disorder [53]. Evidence from
longitudinal studies in different countries showed that
regular cannabis use predicts an increased risk of a schizo-
phrenia diagnosis or of reporting symptoms of psychosis
[54]. These relations were found to persist after controlling
for confounding variables, such as personal characteristics
and other drug use. It is unclear whether co-morbid cannabis
use occurs to self-medicate from the negative symptoms of
psychosis [55]. However data showing that a dose dependent
relationship exists between cannabis and the development of
psychiatric disorders, may suggest that cannabis use
constitutes a causal factor in the expression of psychotic
symptoms [56]. The risk of chronic psychoses like schizo-
phrenia seems to be related to genetic vulnerability predis-
posing a subgroup of cannabis users to a higher risk [57].
Studies focusing on children and adolescents who have
hallucinations in response to cannabis use showed that
psychotic-like reaction were associated with depressive
disorder and cannabis exposure extent [58, 59]. The complex
neuro-pharmacological mechanism underlying cannabis-
induced psychotic symptoms is unclear and controversial
data are available. On one side THC could be considered
responsible of the risk for psychotic symptoms induced by
marijuana; on the other, different cannabinoids, such as
cannabidiol, could be able to attenuate the risk of psychiatric
disorders [60].
In general, early cannabis use during adolescence seems
to be closely related to an increased risk of schizophrenia-
like psychoses [61, 62], and there is now sufficient evidence
to warn young people that using cannabis could increase
their risk of developing a psychotic illness later in life [63].
Natural Cannabinoid Agonists & their Derivatives
Therapeutic properties of Cannabis sativa are known
since thousands of years. The earliest archeological evidence
of cannabis use dates back 10000 years. Between 2700 and
2000 BC, Cannabis was used in Cina to treat rheumatic pains
and other conditions, In India and in Central America its use
played an important role in religion [64].
As mentioned before the main cannabis active ingredient
is 9-tetrahydrocannabinol, however, at least other 66
canna-binoids have been isolated from cannabis [65]. In
Gerra et al.
addition cannabis contains sever other noncannabinoid
biologically active agents.
Due to the presence of all these chemicals cannabis
herbal forms or raw extracts, despite showing therapeutic
efficacy cannot be recommended because side effects and
toxicity can be higher that of single connabinoid agents; it
can be the result of the exposure to several biologically
active chemical together, and it is difficult to control or
predict.
Important advances in the therapeutic use of cannabis
came from the development of preparations containing single
active ingredients or of purified extracts. For example, the
therapeutic efficacy of synthetic D9-THC analogs (e.g.,
Marinol, Cesamet) and medicinal cannabis preparations
containing both D9-THC and cannabidiol (e.g., Sativex,
Cannador) in the treatment of chronic pain, vomiting,
cachexia have been well documented offers important
advantages over [66, 67]. Recently, the use of these cannabis
derivatives for the treatment of CNS disorders has been
extensively explored and new patents have been published
disclosing the use of these agents in the treatment of
epilepsia, neurodegenerative disorder and psychiatric
conditions for these cannabis derivatives have been explored
[68-70].
CANNABINOID CB1 RECEPTOR SYNTHETIC
AGONISTS
More than 20 years have now passed from the identi-
fication of THC as the main psychoactive constituent of
Cannabis sativa [71, 72], the characterization and molecular
cloning [1, 2, 73] of the cannabinoid CB1 and CB2 receptors.
The extensive research on the structure and activity of the
natural constituents of cannabis and the development of
synthetic compounds with high potency and stereo-selec-
tivity have now opened new possibilities to target the
cannabinoid system using selective receptor agonists with
improved pharmacotherapeutic potential and reduced toxi-
city. These new molecules consists of agonists that binds
directly to cannabinoid receptors and to agents able to
increase endocannabinoid function by increasing the syn-
thesis or by reducing reuptake and the degradation of endo-
genous ligands at cannabinoid receptors.
Selective CB1 and CB2 receptor agonists: According to
the International Union of Pharmacology [reviewed in 74],
cannabinoid agonists can be divided into classical canna-
binoids, non-classical cannabinoids, aminoalkylindoles and
eicosanoids. New series of compounds have been recently
described, including diarylether sulfonylesters [75] and
pyrrole derivatives [76].
Classical cannabinoids are tricyclic dibenzopyran
derivatives that are either compounds occurring naturally in
the plant Cannabis sativa, or synthetic analogues of these
compounds. The most representative forms are THC, a
partial agonist at both the CB1 and CB2 receptors and the
main psychoactive constituent of Cannabis, along with 11-
hydroxy-
8-THC-dimethylheptyl (HU-210), a synthetic
compound that displays the highest potency at the CB1
receptor [74]. Classical cannabinoids are usually CB1/CB2
agonists, although changes in the THC molecule have led to
Pharmacology and Toxicology of Cannabis Derivatives
the synthesis of selective CB2 receptor agonists such as HU-
308 [77, 78].
Non-classical cannabinoids are synthetic THC analogues
that lack the dihydropyran ring. The most representative
form is the Pfizer compound CP-55 940, a potent and
complete agonist at both the CB1 and CB2 receptors, which
was used to characterize the CB1 receptor for the first time
[1, 79]. Aminoalkylindoles were the first non-cannabinoid
molecules that displayed cannabimimetic activity [80]. R-
(+)-WIN-55,212–2 is the most representative form, and it
behaves as a complete agonist at both the CB1 and CB2
receptors, with higher intrinsic activity at the CB2 receptor.
Moreover, recently a number of different chemical structures
have been disclosed and described as preferential ligands for
CB2 receptors [81, 82].
Eicosanoids are the prototypic endocannabinoids, of
which anandamide (a partial agonist at both the cannabinoid
receptors) and 2-AG (a complete agonist at both the CB1 and
CB2 receptors) are the most representative compounds.
Based on the structure of anandamide, minor chemical
changes have led to the development of the first generation
of CB1-selective agonists, of which R(+)- methanandamide
and arachidonyl-2’-chloroethylamiden (ACEA) is the most
representative forms [83]. To date these molecules have been
tested only preclinically and their therapeutic potential has
not been entirely exploited yet. There is expectation that this
second waive of cannabinoid agonists will offer important
therapeutic advantages over the first generation classical
cannabis derivatives. However, laboratory animal studies
have clearly shown that these molecules may retain the
toxicity profile of THC. For example it has been shown that
agonist at CB1 receptors like WIN-55,212–2 and CP-55 940
may cause locomotor impairment, may disrupt memory and
have abuse liability. It is known, for example, that in rodents
direct activation of CB1 receptors by CP 55,940 and WIN
55,212-2 dose-dependently increase voluntary alcohol
consumption [84, 85] and alcohol drinking motivation [86],
while THC significantly reinstates responding previously
reinforced with beer [87]. Administration of the CB1
receptor agonist WIN 55,212-2 during abstinence was also
shown to increase alcohol consumption when the alcoholic
solution was made available again [88]. In light of the abuse
liability and the toxicological effects found with these
agents, the clinical development of molecules acting as direct
cannabinoid CB1 receptor agonist remains challenging. New
possibilities have very recently exploited with the
development of synthetic cannabinoid agonists that do not
cross the blood brain barrier. These molecules do not show
abuse liability and can be used to treat peripheral-related
disorders such as inflammation or glaucoma [89]. Efforts
have also been made to develop molecules that selectively
activates CB2 receptors. In facts these agents do not appear
to show the same abuse liability and toxicity of non selective
cannabinoid agonists or molecules that activates CB1 recep-
tors for detailed review see [89].
MODULATORS OF THE ENDOCANNABINOID
SYSTEM
In 1992, the first endogenous ligand to exert THC-like
activity, the lipid arachidonylethanolamide, was extracted
Recent Patents on CNS Drug Discovery, 2010, Vol. 5, No. 1 49
from pig brain and named anandamide, from the Sanskrit
word for bliss, ananda [3]. Anandamide has been shown to
mimic in vivo pharmacological and behavioural effects of
THC. In 1995 2-arachidonoyl glycerol (2-AG), a monoacyl-
glycerol involved as an intermediate in a variety of signalling
pathways, was reported to interact with cannabinoid recep-
tors [4, 6]. Following this, other endogenous compounds
including dihomo-g-linolenoylethanolamide and docosa-
tetraenoylethanolamide [90], 2-arachidonoylglyceryl ether
[91], O-arachidonoyl-ethanolamine [92], N-arachidonoyl-
dopamine [93] were shown to bind to the cannabinoid
receptors.
Anandamade and 2-AG are the two endocannabinoid
ligands most abundantly expressed in the brain [6, 94].
Different pathways are involved in the synthesis and release
on demand of anandamide and 2-AG. Anandamide is formed
by the cleavage of the phospholipid precursor, N-arachi-
donoyl-phosphatidylethanolamine (NAPE) [6, 95]. The 2-
AG, on the other hand, is a monoglyceride and its formation
is closely associated with the metabolism of triacylglycerol,
mainly by the receptor-dependent activation of phos-
phatidylinositol- specific phospholipase C [6, 94]. Once
anandamide and 2-AG are formed, they target the CB1
receptors in the same cell where they were formed, via
diffusion within the plasmalemma, or they can be released to
the extracellular fluid where they act as a retrograde trans-
mitter to activate presynaptic cannabinoid receptors [6].
Endocannabinoid signalling is terminated by a two-step
process that includes transport into cells and hydrolysis by
two specific enzymatic systems. Both steps exert a tight
control of endocannabinoid levels in tissues, rapidly elimi-
nating these signalling molecules. Endocannabinoid uptake
is mediated by a transporter [96], which is widely distributed
throughout the brain [97]. The transporter is an elusive
molecule which works in a manner that is similar to other
lipid carriers: it facilitates the uptake of both anandamide and
2-AG in an energy-independent fashion [96]. The anan-
damide transporter is saturable, displays substrate specificity
and can be blocked by specific drugs such as AM404 [97].
The degradation of endocannabinoids is performed by two
specific enzymatic systems: the fatty acid amide hydrolase
(FAAH) [98] and the monoacylglyceride lipase (MAGL)
[99]. FAAH is a membrane enzyme that belongs to the serine
hydrolase family. FAAH is widely distributed throughout the
body, with high concentrations in the brain and liver. FAAH
can degrade many fatty acid amides, including
acylethanolamides such as anandamide and the sleep factor
oleamide. Although FAAH can inactivate 2-AG, the main
enzyme responsible for the inactivation of this
monoglyceride is MAGL [99, 100]. Interestingly, in a recent
study was also described the existence of fatty acid binding
proteins (FABPs) that are largely expressed in brain and that
works as a intracellular AEA carriers. FABPs proteins
facilitate AEA transport from the plasma membrane to
FAAH thus facilitating the inactivation of this endocanna-
binoid [101].
In the recent years several agents able to indirectly
increase the endocannabinoid tone have been developed. For
example a significant increase of brain endocannabinoid
(both anandamide and 2-AG) activity has been described
50 Recent Patents on CNS Drug Discovery, 2010, Vol. 5, No. 1
after selective inhibition of the transporter by AM404 [97].
Alternatively, selective increase of anandamide and 2-AG
has been described following specific inhibition of the
degradating enzymes FAAH or MAGL by several agents
including URB597 or JZL184 and OMDM169 [102, 103]
Lastly, the identification of FABPs proteins as intracellular
carrier of AEA has open to the possibility to develop FABPs
inhibitors to increase this endocannabinoid levels [101].
Interestingly, these modulators of the endocannabinoid
system not only appears to be devoid of abuse liability, but
under some experimental conditions they reduce addictive
related behaviours. For example, recent studies showed that
inhibition of FAAH by URB597 has neutral effects on the
reinforcing effects of ethanol, heroin, THC and cocaine
[104-106]. Moreover, additional, studies on nicotine showed
that URB597 blocks the expression of nicotine induced
conditioned place preference, and the acquisition of nicotine
self-administration and relapse [107, 108]. Consistent with
this latter finding it was shown that the increase of endo-
cannabinoid tone following transported inhibition by AM404
lowers ethanol self-administration as well as cocaine induced
reward in an intracranial self-stimulation paradigm [109,
110]. Given that endocannabinoids are synthesized and
released on demand, one would speculate that selective
inhibition of their reuptake, intracellular transport and degra-
dation would result in specific increases of endocannabinoid
neurotransmission in those brain areas where neurotrans-
mission is activated. On the contrary, administration of direct
receptor agonists would result in a generalized stimulation of
brain cannabinoid neurotransmission. These two different
modalities of activation of the system could explain the lack
of abuse potential observed with indirect modulators of
cannabinoid neurotransmission.
CURRENT & FUTURE DEVELOPMENTS
Although current clinical data support the efficacy of
THC and THC derivatives in the treatment of pathological
conditions like neuropathic pain, multiple sclerosis, anxiety,
glaucoma, nausea, and vomiting [111] caution should be
taken in the use of these medications because of their high
level of toxicity and abuse potential. Agents acting as
indirect modulators of the endocannabinoid system may
offer the benefit of obtaining the same therapeutic effects,
but in the absence of abuse liability and reduced toxicity.
Future clinical development of these molecules in the
treatment of the above mentioned pathological conditions is
envisioned. Moreover, emerging data suggests that drugs that
stimulate the endocannabinoid system may have therapeutic
potential in the treatment of psychiatric illness such as
anxiety, depression and addiction [112, 113]. Finally, a
growing body of evidence suggests that cannabinoid recep-
tors can play a major roles in the regulation of several
peripheral functions. Therefore, space for the development of
new agents with selective agonistic properties at peripheral
cannabinoid receptor system is envisioned [114].
CONFLICT OF INTEREST
There are no direct or indirect conflicts of interest for any
of the authors relevant to the subject of this article. The
Gerra et al.
views expressed herein are those of the author(s) and do not
necessarily reflect the views of the United Nations.
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