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Cannabinoid-related Agents in the Treatment of Anxiety Disorders: Current Knowledge and Future Perspectives

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Cannabinoid-related Agents in the Treatment of Anxiety Disorders: Current Knowledge and Future Perspectives

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Rich evidence has shown that cannabis products exert a broad gamut of effects on emotional regulation. The main psychoactive ingredient of hemp, Δ9-tetrahydrocannabinol (THC), and its synthetic cannabinoid analogs have been reported to either attenuate or exacerbate anxiety and fear-related behaviors in humans and experimental animals. The heterogeneity of cannabis-induced psychological outcomes reflects a complex network of molecular interactions between the key neurobiological substrates of anxiety and fear and the endogenous cannabinoid system, mainly consisting of the arachidonic acid derivatives anandamide and 2-arachidonoylglycerol (2-AG) and two receptors, respectively termed CB1 and CB2. The high degree of interindividual variability in the responses to cannabis is contributed by a wide spectrum of factors, including genetic and environmental determinants, as well as differences in the relative concentrations of THC and other alkaloids (such as cannabidiol) within the plant itself. The present article reviews the currently available knowledge on the herbal, synthetic and endogenous cannabinoids with respect to the modulation of anxiety responses, and highlights the challenges that should be overcome to harness the therapeutic potential of some of these compounds, all the while limiting the side effects associated with cannabis consumption. In addition the article presents some promising patents on cannabinoid-related agents.
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Recent Patents on CNS Drug D iscovery, 2012, 7, 25-40 25
2212-3954/12 $100.00+.00 © 2012 Bentham Science Publishers
Cannabinoid-related Agents in the Treatment of Anxiety Disorders:
Current Knowledge and Future Perspectives
Simone Tambaro and Marco Bortolato*
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California,
Los Angeles (CA), USA
Received: July 13, 2011; Accepted: July 29, 2011; Revised: August 29, 2011
Abstract: Rich evidence has shown that cannabis products exert a broad gamut of effects on emotional regulation. The
main psychoactive ingredient of hemp, 9-tetrahydrocannabinol (THC), and its synthetic cannabinoid analogs have been
reported to either attenuate or exacerb ate anxiety and fear-related behaviors in humans and experim ental animals. The
heterogeneity of cannabis-induced psychological outcomes reflects a complex network of molecular interactions between
the key neurobiological substrates of anxiety and fear and the end ogenous cannabinoid system, mainly consisting of the
arachidonic acid derivatives anandamide and 2-ar achidonoylglycerol (2-AG) and two receptors, respectively termed CB1
and CB2. The high degree o f interindividual variability in the responses to cannabis is contributed by a w ide spectrum of
factors, including genetic and environmental determinants, as well as differences in the relative concentrations of THC
and other alkaloids (su ch as cannabidiol) within the plant itself. The present article review s the currently available knowl-
edge on the herbal, synthetic and endogenous cannabinoids with respect to the modulation of anxiety responses, and high-
lights the challenges that should be overcome to harness the therapeutic poten tial of some of these compounds, all the
while limiting the side effects associated with cannabis consumption. In addition the article presents some promising pat-
ents on cannabinoid-related agents.
Keywords: Anxiety, cannabis, CB receptors, cannabidiol, endocannabinoids, 9-tetrahydrocannabinol.
INTRODUCTION
Anxiety is generally defined as an emotional state char-
acterized by maladaptive and excessive emotional respon-
siveness to potentially dangerous circumstances. The patho-
logical expression of anxiety leads to enduring emotional
perturbations with a consistent apprehension towards the
possibility of future, vaguely defined negative events [1].
According to the current classification of anxiety disorders in
the fourth edition of the Diagnostic and Statistical Manual of
Mental Disorders (DSM-IV) [2], the main diagnostic entities
in this category are:
- generalized anxiety disorder (GAD), featuring general
irritability, anxiety attacks, chronic apprehension, anx-
ious expectation and secondary phobic avoidance;
- panic disorder, characterized by brief (2-10 min) spells
of overwhelming anxiety or fear, accompanied by so-
matic and cognitive symptoms;
- social anxiety disorder (or social phobia), defined as
extreme agitation in social contexts and avoidance of
social situations;
- obsessive-compulsive disorder (OCD), characterized by
recurrent and intrusive anxiogenic thoughts (obses-
sions), and stereotyped behaviors (compulsions) aimed
at the reduction of the distress caused by the obsessions;
*Address correspondence to this author at the Dept. of Pharmacology and
Pharmaceutical Sciences Sch ool of Pharmacy University of Southern Cali-
fornia 1985 Zonal Ave PSC 527, Los Angeles, CA 90089;
Tel: 323-44 2-3225; Fax: 323-442-3229; E-mail: bortolat@usc.edu
- post-traumatic stress disorder (PTSD), in which a prior
intense trauma r esults in a long-lasting anxious re-
sponse, with re-experiencing/flashback phenomena,
avoidance and emotional numbing.
In keeping with their different clinical features and phe-
nomenological presentations, these disorders are under-
pinned by divergent neurobiological alterations and respond
to partially different pharmacotherapeutic strategies (outlined
in Table 1). A fundamental contribution in our understanding
of the neural bases of anxiety disorders and in the develop-
ment of novel therapies has been afforded by animal models
and testing paradigms for anxiety-like behaviors (summa-
rized in Table 2).
Over the last decades, converging epidemiological, clini-
cal and preclinical data have pointed to a key implication of
cannabis and its endogenous system in the regulation of
anxiety. In the following sections, we will present a brief
synopsis on cannabinoids and the available classes of related
agents, with a specific focus on their anxiolytic potential,
and the scientific challenges that should be overcome to fully
establish the applicability of such drugs in the therapy of
anxiety disorders.
HERBAL AND SYNTHETIC CANNABINOIDS
Herbal cannabinoids
The three species included in the Cannabis genus (or
sub-species, depending on the taxonomic classification; see
[3], for a detailed discussion on the issue), sativa, indica and
ruderalis, feature at least 85 unique terpenophenolic
26 Recent Patents on CNS Drug Discovery, 2012, Vol. 7, No. 1 Tambaro and Bortolato
Table 1. Current Pharmacological Strategies for the Treat-
ment of Anxiety Disorders
1. Generalized anxiety disorder
a. Benzodiazepines
b. Buspirone
c. Selective serotonin reup take inhibitors
2. Panic attack
a. High-potency benzodiazepines
b. Tricyclic antidepressants
c. Selective serotonin reup take inhibitors
d. Monoamine oxidase inhibitors
3. Post-traumatic stress disorder
a. Selective serotonin reup take inhibitors
b. Low-dose antipsychotic agents
4. Obsessive-compulsive disorder
a. Tricyclic antidepressants
b. Selective seroton in reuptake inhibitors
compounds, collectively named phytocannabinoids [4]. The
main classes of phytocannabinoids are outlined in Fig (1).
Quantitative analyses of cannabis constituents are usually
performed by chromatographic techniques (generally Gas
Chromatography, but also Thin-Layer Chromatography, or
High-Performance Liquid Chromatography), often coupled
with Mass Spectrometry. A detailed description of the
instrum ental methods used for classification and source
tracing of cannabis products (including DNA identification
for forensic and intelligence purposes) is beyond the scope
of this review, but can be found in [5-7].
The chemical fingerprinting of hemp products has
revealed that the two most abundant phytocannabinoids are
9-tetrahydrocannabinol (THC, also named dronabinol) and
cannabidiol (CBD).
The main psychoactive constituent of cannabis, THC is a
highly lipophilic alkaloid produced mainly in the leaves,
flowers and glandular trichomes of the plant. Most of the
pharmacological effects elicited by hemp products, including
emotional and cognitive changes, analgesia, hypothermia
and appetite stimulation, are considered to be reflective of
the action of THC as a partial agonist of cannabinoid CB1
and CB2 receptors (see below). Additionally, THC has been
shown to act as an acetylcholinesterase inhibitor [8-10].
In contrast with THC, CBD is not psychotropic, but has
nevertheless been shown to play a role in the modulation of
behavioral effects of cannabis [11]. In fact, the THC:CBD
ratio is the main criterion to define different cannabis
chemotypes [12] and has been posited to contribute to the
variability in neurobehavioral outcomes of marijuana or
hashish consumption [13,14]. Interestingly, most cannabis
strains encountered in the illegal markets generally have
elevated amounts of THC [15].
The different characteristics of THC and CBD are
underpinned by their distinct mechanisms of action. Whereas
Table 2. Paradigms for Testing of Anxiety-like Behaviors in
Rodents
1. Unconditioned anxiety
a. Tests for social anxiety
i. Maternal separation-induced ul-
trasonic vocalizations (for pups)
ii. Social interaction
b. Tests based on approach/avoidance conflict
i. Novel open field
ii. Defensive withdrawal
iii. Elevated plus maze
iv. Elevated T-maze
v. Zero maze
vi. Light/dark box
vii. Emergence test
c. Tests based on antipredator defensive be-
havior
i. Mouse defense test battery
ii. Predator urine exposure test
iii. Predator exposure test
d. Other tests
i. Novelty-induced feeding sup-
pression
ii. Marble buryin g
iii. Defensive burying
2. Conditioned anxiety
a. Tests on conditional fear
i. Fear- conditioned freezing
ii. Fear-p otentiated startle
iii. Conditional fear-induced analge-
sia
b. Operant conflict test
i. Geiller-Seifter test (conditioned
suppression of eating)
ii. Vogel test (conditioned suppres-
sion of drinking)
THC has nanomolar affinity for both CB1 (Ki = 25.1
nmol/L) and CB2 (Ki = 35.2 nmol/L) receptors, CBD exhib-
its much lower affinity for either target [16-20]; however, the
latter phytocannabinoid was recently found to act as a highly
potent antagonist/inverse agonist of both CB receptors [21],
possibly due to a non-competitive mechanism of receptor
blockade [22]. Additionally, CBD has been shown to exert
some of its actions through other receptors, including the
vanilloid receptor VR1 and the serotonin receptor 5-HT
1A
(for a general overview of the topic, see [11]).
The other main phytocannabinoids, including cannabi-
gerol (CBG), cannabichromene (CBC) and cannabinol
Current Knowledge and Future Perspectives Recent Patents on CNS Drug Discovery, 2012, Vol. 7, No. 1 27
(CBN) (Fig. 1) [4, 23], have been shown to exert antibiotic
and antiinflammatory properties, but have not been strongly
associated with the behavioral effects of cannabis; never-
theless, the recent discovery that CBG is a highly potent
agonist for 2 adrenoceptor and a blocker of serotonin 5-
HT1A receptor [24] underscores the potential importance of
these and other alkaloids in the psychoactive profile of
cannabis.
Synthetic cannabinoids
In addition to phytocannabinoids, several classes of
synthetic CB receptor agonists have been developed; among
these families, the best characterized are the synthetic
analogs of THC - such as the biciclic compounds CP 47,497,
CP 55,244, CP 55,940 and the benxopyrans HU-210 and
nabilone Fig. (2) - and the aminoalkylindole derivatives -
including WIN 55,212-2, JWH-015, JWH-018, JWH-073,
JWH-081 and JWH-398 (for a general review, see [23]). Of
these agents, only nabilone has been approved for clinical
use as an antiemetic treatment and an adjunct analgesic for
neuropathic pain [25]. Other more potent synthetic canna-
binoids, such as CP 47,497, HU-210 and most JWH com-
pounds, have regrettably gained great popularity in the
market of recreational substances during the last decade,
under the generic brand names of “Spice” or “K2”. Unlike
THC, which is a partial agonist of CB1 receptors, these
agents are full, high-potency CB1 receptor activators [26,
27], thereby eliciting greater psychotropic effects than THC
(as CB1 receptors are the key mediators of the psychotropic
actions of cannabis). This characteristic, together with their
legal status (recently revoked across most Western countries,
including USA as of March 2011) and lack of available
testing procedures for the detection of urinary metabolites,
has unfortunately contributed to the great diffusion of
“Spice” blends in Central and Western Europe, as well as
Australasia.
ENDOCANNABINOIDS AND THEIR RECEPTORS
Following the identification of THC in the 1960s [28],
extensive research was devoted to the identification of its
biological targets and endogenous counterparts. Both objec-
tives were met around 30 years later, with the characteri-
zation of the two major cannabinoid receptors, CB1 [29] and
CB2 [30] as well as the discovery of two most prominent
Fig. (1). Chemical structures of the major phytocannabinoids. For more details, see text.
28 Recent Patents on CNS Drug Discovery, 2012, Vol. 7, No. 1 Tambaro and Bortolato
endocannabinoids N-arachidonoylethanolamine (commonly
named anandamide from the Sanskrit nanda, bliss) [31] and
2-arachidonoylglycerol (2-AG) [32, 33] Fig. (3).
CB receptors
Although CB
1 and CB
2 receptors only share 44% se-
quence identity (68% in the transmembrane domains), they
are both coupled to Gi/o proteins [34] and activated by both
anandamide and 2-AG. In line with their metabotropic na-
ture, CB receptors mediate their intracellular response
through a number of changes affecting signaling cascades,
such as inhibition of adenylyl cyclase, activation of G-
protein-activated inwardly rectifying potassium channels
(GIRKs) and phosphorylation of extracellular signal-related
kinases (ERKs) [35, 36].
The distribution pattern of CB
1 and CB
2 receptors is
strikingly divergent, indicating diverse physiological func-
tions: CB1 is the most abundant metabotropic receptor in the
brain, and is primarily distributed in the synaptic terminals of
neurons across all the major structures that regulate emo-
tional responsiveness, perception and memory, including
prefrontal cortex, amygdala, septo-hippocampal system,
striatum, thalamus, brainstem nuclei etc. [37-41]. CB1 recep-
tors are typically located on presynaptic terminals [42,43],
but they have also been identified in postsynaptic locations
[44,45]. Presynaptic CB1 receptors are posited to serve criti-
cal functions for the regulation of synaptic plasticity and
neurotransmitter release; in particular, they mediate the de-
polarization-induced suppression of inhibition (DSI) and
depolarization-induced suppression of excitation (DSE),
consisting in the reduction of -amino-butyric acid (GABA)
or glutamate release, respectively, from presynaptic boutons
following stimulation of the postsynaptic terminals [46-49].
In general, CB1 activation has been shown to inhibit the neu-
rotransmission of other mediators, including glycine, acetyl-
choline, norepinephrine and serotonin [50], but the under-
pinnings of these phenomena have not been completely elu-
cidated. Additionally, CB1 receptors have been implicated in
short- and long-term synaptic depression, in relation to pha-
sic or tonic endocannabinoid release (for a review on these
topics, see [51]).
The function of CB
1 receptors may vary depending on
the specific interactions that they entertain with other mo -
lecular targets. For example, CB1 receptors have been found
to associate with other G-protein complex receptors, su ch as
dopamine D2, orexin Ox1, μ opioid and adenosine A
2a, to
form heteromeric complexes (reviewed in [52, 53]).
The key role of CB
1 receptors as mediators of neuro-
chemical homeostasis in the brain is maintained through a
complex regulation of their expression. For example, these
receptors are subjected to a rapid internalization (via
clathrin-coated pits) following their binding with full ago-
nists; on the other hand, the receptors are also recycled, with
a process that requires endosomal acidification and dephos-
phorilation [54].
While CB
2 receptors are abundantly expressed in most
peripheral organs (and particularly in immune cells, where
they regulate cytokine secretion and modulate cell traffick-
ing) [55], their distribution in the brain appears to be sparse
and particularly confined to microglial cells; nevertheless,
recent evidence has revealed the presence of CB2 receptors
in several areas of the brain [56-58]. Inter estingly, a number
of studies suggest that neuronal CB2 receptors may be
mainly located in postsynaptic terminals [58,59]; neverthe-
less, the functional role of these targets in the brain remains
largely elusive and awaits further characterization.
The existence of cannabinoid receptors other than CB
1
and CB2 has been postulated based on ample experimental
Fig. (2). Chemical structures of the synthetic THC analogs CP55,94 0, CP55,244, CP 47,497 and HU-210. For more details, see text.
Current Knowledge and Future Perspectives Recent Patents on CNS Drug Discovery, 2012, Vol. 7, No. 1 29
evidence [60-62]. Interestingly, a number of investigations
have pointed to GPR55 as a novel putative cannabinoid re-
ceptor [63,64]; nevertheless, evidence on the specificity of
this receptor for endocannabinoid is still in conclusive [65].
Endocannabino ids
Both anandamide and 2-AG are derivatives of arachi-
donic acid, an unsaturated C20 fatty acid with 4 double
bonds, which also serves as the precursor for synthesis of
other eicosanoids, including prostaglandins and leukotriens.
Anandamide is found in picomolar concentrations and acts
as a high-affinity partial agonist for both CB1 and CB2 recep-
tors. It is synthesized on demand by enzymatic hydrolysis of
the membrane phospholipid N-arachidonoyl phosphatidyle-
thanolamine (NAPE), a process catalyzed by several phos-
pholipases [66-68]. Following release and activation of CB
receptors, anandamide is rapidly removed from the synaptic
cleft by a carrier-mediated system [69-72] and subsequently
hydrolyzed by the membrane enzyme fatty acid amide hy-
drolase (FAAH) [73-75]. FAAH serves the catabolism of
other substrates, including oleoylethanolamine (OEA) and
palmitoylethanolamine (PEA). Both these compounds do not
activate CB1 receptors [76], although they may reduce or
slow down anandamide degradation by competing with it for
FAAH activity.
In comparison with anandamide, 2-AG is much more
abundant (occurring in nanomolar concentrations across
most tissues) and acts as a full agonist of both CB receptors.
It is produced from 1,2diacylglycerol (DAG) by diacylglyc-
erol lipase (DAGL) [77] and degraded mainly by the cytoso-
lic serine hydrolase monoacylglycerol lipase (MAGL) [78],
although other enzymes are known to contribute to this proc-
ess [79].
The divergent neurochemical profiles of anandamide and
2-AG underscore their different physiological roles. Al-
though our current understanding of the different function s
entertained by each endocannabinoid is still rudimentary, the
development of FAAH and MAGL inhibitors [80,81] has
been instrumental to elucidate the implication of each media-
tor in synaptic and neurochemical regulation. While 2-AG is
known as the retrograde mediator of DSI [82, 83] and DSE
[84-87], a number of studies suggest that anandamide may
serve as an activity-dependent regulator of monoaminergic
transmission [88-90]. Recent evidence points to a potential
biological antagonism between anandamide and 2-AG
[91,92]; on the other hand, emerging evidence points to a
similar role of anandamide and 2-AG in the regulation of
anxiety (albeit in relation to different receptors) and pain
[93]. The development of JZL195, a potent FAAH/MAGL
inhibitor, has in turn revealed that the b ehavioral effects of
CB1 receptor agonists can be only recapitulated by the com-
bination of both endocannabinoid-mediated functions [94].
Other lipids have been indicated as putative endocan-
nabinoids, including 2-arachidonoylglycerylether (noladin
ether) [95] and O-arachidonoylethanolamine (virodhamine)
[96] Fig. (3). Additionally, recent evidence has identified
that CB receptors may be modulated by peptidic ligands,
such as hemopressin and its derivatives [97,98].
EFFECTS OF CANNABIS AND CANNABINOID
AGENTS ON ANXIETY
Cannabis, THC and CB1 Receptor Agonists
The employment of cannabis for its medicinal, relaxing
and mood-enhancing properties has been documented across
most ancient civilizations. Originally introduced in Chinese
pharmacopoeia during the third millennium BCE [99,100],
cannabis became a popular remedy throughout Asia and
Europe in the following centuries [99,101]. The inclusion of
cannabis in the medical treatises by Dioscorides and Galen
secured the herb a stable reputation in the Roman Empire
and the Arabic world [101]. Until the early 20th century, the
plant remained a valuable therapy for a large number of dis-
Fig. (3). Chemical structures of the major endocannabinoids. For more details, see text.
30 Recent Patents on CNS Drug Discovery, 2012, Vol. 7, No. 1 Tambaro and Bortolato
eases [102]; however, growing concerns about the psychoac-
tive and narcotic effects of cannabis led to a progressive re-
striction and ultimate ban of its usage in the United States
and several European countries [100,103]. Despite its illicit
status, cannabis remains one of the most popular recreational
drugs, particular among adolescents and young adults, in
view of its mood-enhancing and euphoriant characteristics
[104-106].
Most psychological and behavioral effects of marijuana
and other hemp products are induced by THC through acti-
vation of CB1 brain receptors. In fact, although THC and
most synthetic cannabinoids are known to activate both CB1
and CB2 receptors, their actions on anxiety-like behaviors
and emotional regulation are efficiently countered by selec-
tive CB1 receptor antagonists, such as rimonabant (see next
section) [107].
The studies on the psychological effects of cannabis and
THC have unfolded a highly complex and often contradic-
tory scen ario, fostering a long-standing debate on the poten-
tial harms and benefits of its products. An important aspect
of this discussion (particularly in consideration of its legal
aspects and the potential therapeutic applications of hemp
derivatives), revolves around the distinction between use and
misuse of cannabis. In particular, whereas the abuse and de-
pendence liability of cannabis is generally well-recognized
[108,109], the definition of these phenomena has been heav-
ily criticized as reflective of political agendas rather than
scientific bases. For instance, the diagnosis of substance
abuse, according to the criteria listed by the DSM–IV TR, is
based on the manifestation of at least one of four symptoms:
interference with major professional or personal obligations;
intoxication in hazardous settings; substance-related legal
problems; continued use in the face of persistent social or
interpersonal problems [110]. The applicability of some of
these standards to marijuana and other cannabis deriv atives,
however, has been questioned [99], also in view of their
lower potential to induce physical harm in comparison with
other legal substances, such as alcohol and tobacco [111].
While the controversies surrounding cannabis are far
from subdued (and are often permeated and masked by con-
flicting ideological credos), standardized studies on cannabi-
noids have highlighted that the psychological and behavioral
outcomes of this substance are highly variable and range
from relaxation, euthymia and heightened sociability to
panic, paranoid ideation and psychosis [112-116]. A corol-
lary of this observation is that the high comorbidity rate be-
tween cannabis use disorders and psychiatric conditions
[100-105] may indicate that cannabis consumption is either a
concurring cause or a “self-therapeutic” strategy for anxiety
and mood disorders [117-123]. The latter interpretation is
supported by the observation that anxiety-spectrum distur-
bances and traumas in early developmental stages are a
strong predictor for later cannabis use disorders [124-127];
furthermore, several lines of evidence suggest that the anx-
iolytic effects of THC may partially account for the hig h
prevalence of cannabis use in patients affected by PTSD
[128-131] and OCD [132]. Accordingly, recent clinical stud-
ies have shown that THC elicits therapeutic effects in OCD
[133] and trichotillomania, an impulse-control disorder char-
acterized by compulsive hair-pulling [134].
Nevertheless, prospective analyses show that cannabis
use and dependence increase the risk for development of
panic disorder [135], suggesting that the effect of cannabis
may vary with respect to the nosological entities within the
spectrum of anxiety disorders. Of note, chronic consumption
of cannabis has been hypothesized to exacerbate depressive
or anxious manifestations, and reduce the therapeutic effi-
cacy of anxiolytic agents [122,136-138]; an interesting theo-
retical implication of this finding is that long-term exposure
to cannabinoid agents may lead to profound alterations of
synaptic plasticity and neurochemical homeostasis and alter
the pathophysiological trajectory of anxiety and mood disor-
ders. Thus, while cannabis may be initially used as a self-
therapy for certain anxiety disorders, the prolonged exposure
to this substance in vulnerable individuals may in turn alter
or aggravate the clinical course of these conditions and ren-
der the patients refractory to standard treatments.
The ability of cannabis to either exacerbate or attenuate
emotional reactivity is highly influenced by numerous fac-
tors, including its chemotype, as well as the inf luence of ge-
netic, developmental and contextual variables. Unfortu-
nately, little is still known about the susceptibility factors
that govern the behav ioral outcomes of cannabis in patients
affected by anxiety-spectrum disorders. Indeed, several
components have been shown to play a role in this link, in-
cluding genetic background, age, gender, environmental
stress and concurrent use of other drugs; a detailed analysis
of these determinants is outside the scope of the present
work, but the interested reader should refer to [139].
Aside from the influence of vulnerability factors, the
available evidence indicates that cannabis, THC and other
CB1 receptor agonists exercise a bidirectional influence on
anxiety responses as a function of the dosage. The majority
of users report that consumption of modest amounts of can-
nabis and CB1 receptor agonists results in euphoria, relaxa-
tion, heightened perception, sociability and creativity, mod-
erate to high doses have been reported to elicit phobia, agita-
tion, panic, dysphoria, psychotic manifestations and cogni-
tive impairmen ts [112-116,124,140-143]. In line with these
premises, early studies showed a robust anxiolytic efficacy
of low-dose nabilone in comparison with placebo [144,145].
Additionally, the few available reports on the clinical out-
comes of recreational cannabinoids show that a moderate
consumption of “Spice” blends is generally associated with
euphoria and disinhibition [146], but the abuse of these sub-
stances is conducive to high levels of anxiety, panic, para-
noid ideation and mood disturbances [147-151].
The biphasic effects of cannabinoids on anxiety-related
responses have been extensively documented in rodents. In
agreement with human eviden ce, preclinical studies have
elucidated that the acute administration of low doses of CB1
receptor agonists elicits anxiolytic-like in approach/avoi-
dance tasks [152-156]; conversely, high concentrations of
the same compounds are generally associated with the oppo-
site outcomes [157-162] (for complete reviews of the topic,
see [163,164]).
The bidirectional action of CB
1 receptors on anxiety re-
sponses may be related to the modulatory role of these tar-
gets on GABA and glutamate release across amygdala and
other forebrain areas [41,165,166]. As these two major neu-
Current Knowledge and Future Perspectives Recent Patents on CNS Drug Discovery, 2012, Vol. 7, No. 1 31
rotransmitters affect anxiety in an opposite fashion, different
doses of cannabinoids and synthetic CB1 receptor agonists
may indeed produce highly divergent effects, in relation to
their ability to affect the homeostasis and the balance of
GABA and glutamate (for a review on these issues, see
[163]). Furthermore, CB1 receptors have been shown to play
critical roles in the regulation of most neurochemical sub-
strates of anxiety, including the neurotransmitters serotonin,
norepinephrine and acetylcholine, as well as stress hor-
mones, colecystokynin and opioid peptides [50,163].
In line with this concept, the infusion in the periaqueduc-
tal grey of arachidonyl-2-chloroethylamide (ACEA), an
anandamide synthetic analog with high CB1 receptor selec-
tivity, elicited anxiolytic-like effects in rats in an elevated
plus maze, with a bell-shaped dose-response curve [167], the
highest doses being associated to no significant behavioral
change.
Novel categories of compounds have been patented for
potential efficacy as selective CB1 receptor modulators, in-
cluding sulfonyl-benzamides [168] and tetrasubstituted imi-
dazole derivatives [169]. To the best of our knowledge,
however, no findings on the action of these compounds in
anxiety regulation have been reported to date.
CB1 Receptor Antagonists/Inverse Agonists
The cannabinoid CB
1 receptor antagonists/inverse ago-
nist rimonabant was introduced into clinical practice by
Sanofi-Aventis in 2006 as a treatment for obesity [170] and
smoking cessation [171]. The majority of preclinical studies
found that these compounds are anxiogenic at high doses
[158,159,172,173] and ineffective at low doses [174,175].
The anxiogenic properties of CB1 receptor antagonists, were
unequivocally confirmed by clinical data on the psychiatric
side effects of rimonabant. The significant increase in anxi-
ety, depression and suicidality in patients under treatment
with rimonabant [176-179], in particular, led to the with-
drawal of the drug from the European market in October
2008. As a consequence, several pharmaceutical companies
announced the interruption of their clinical research on CB1
receptor antagonists, including taranabant (from Merck) and
otenabant (from Pfizer), both in Phase 3 of development.
Some of the anxiogenic properties of rimonabant and ana-
logs have been speculated to be due to their activity as in-
verse agonists; as a result, the therapeutic use of newly-
developed neutral CB1 antagonists has been proposed, with
the hypothesis that these compounds would not elicit the
untoward psychological effects observed with rimonabant
and its analogs [180,181]; this idea is supported by recent
findings, showing that unlike CB1 receptor inverse agonists,
the neutral antagonists of this targets fail to facilitate the ac-
quisition or consolidation of fear [182].
CB2 Receptor Ligands
Few studies have actually evaluated the role of CB
2 re-
ceptor in anxiety and stress response. While this receptor
was posited to be mainly expressed mainly in immune cells
and peripheral areas, its identification in the brain under
pathological conditions, such as Alzheimer’s disease, multi-
ple sclerosis and amyotrophic lateral sclerosis spinal cord
[183-185], led to a number of studies aimed at the assess-
ment of its potential role in brain function and behavioral
regulation. Some of these investigations indicated that the
suppression of CB2 receptor in the brain, through intracere-
broventricular injection of antisense nucleotide sequences,
elicited anxiolytic effects in rodents [186]. In contrast, Gar-
cia-Gutierrez and Manzanares [187] recently described that
the overexpression of CB2 receptors reduced anxiogenic-
related behaviors in the light-dark box and elevated plus
maze. These premises point to the possibility that CB2 recep-
tor ligands may also play a role in the modulation of anxiety
disorders. This hypothesis, however, awaits further examina-
tion with proper pharmaco logical tools.
CBD
Several studies suggest that THC and CBD may exert
opposite actions on brain function and psychopathology
[188], possibly in relation to the action of CBD as a potent
CB1 receptor antagonist/inverse agonist [21] (see above).
Several lines of preclinical work have shown that CBD re-
duces the effects of THC on several behavioral functions
[189-191]. In line with these data, CBD has been found to
reduce the anxiety and improve the sensation of well being
induced by an acute, high THC dose in healthy volunteers
[192].
In contrast with these data, a number of studies have
shown that CBD pretreatment potentiated the behavioral
effects induced by THC [193-195]. These actions may sig-
nify the ability of CBD to inhibit cytochrome P450-mediated
drug metabolism [196,197], which may increase THC blood
and brain concentrations [193,195].
Notably, the behavioral outcomes of CBD do not appear
to be only due to potential pharmacodynamic/pharma-
cokynetic competition with THC; indeed, recent studies have
shown that CBD exerts inherent anxiolytic effects, both in
rodent models [157,198-201] and, more recently, in patients
affected by social phobia [202, 203]. Th e anxiolytic action of
CBD may be linked to 5-HT1A receptor, but not through ben-
zodiazepine receptors [204]. Of note, the anxiolytic action of
CBD also appears to be bidirectional, as only low to moder-
ate doses, but not high doses, have been associated with anx-
iolytic effects [200,205].
The anxiolytic action of CBD do not appear to be medi-
ated by benzodiazepine receptors [204], but rather by 5-HT1A
serotonin receptors in the bed nucleus of the stria terminalis
[206], a critical component of the amygdaloid complex in-
volved in the regulation of stress response. Accordingly,
CBD has been shown to reduce amygdalar responses to fear-
ful stimuli [207]; this mechanism may be essential for the
anxiolytic effects of this compound in social phobia [203].
Furthermore, CBD has been shown to elicit antipanic effects
through the activation of 5-HT1A receptors in the dorsal
periaqueductal gray, a critical area for the modulation of
emotional reactivity to stress [208, 209].
Endocannabino id Transport Blockers
The systemic administration of the endocannabinoid
transport blocker AM404 (Fig. 4) was shown to elicit anx-
iolytic-like behaviors in the elevated plus maze and defen-
sive withdrawal in adult rats, as well as an attenuation of
ultrasonic vocalizations in rat pups [175]. The same com-
32 Recent Patents on CNS Drug Discovery, 2012, Vol. 7, No. 1 Tambaro and Bortolato
pound was shown to attenuate marble burying (a paradigm
for compulsivity testing) in mice, suggesting that this com-
pound may have some potential efficacy for OCD [206].
Interestingly, the anxiolytic effects of AM404 were shown to
be contributed by both CB1 and 5-HT1A receptors [152, 210],
in a fashion similar to the potent CB1 receptor agonist CP
55,940 [160]. Additionally, AM404 has been suggested to
act as a FAAH inhibitor [211], although evidence in this
respect is controversial [72]. Indeed, despite the identifica-
tion of potential candidate endocannabinoid binding sites
[212], no final evidence is currently available on the exis-
tence and/or molecular identity of the endocannabinoid
transporter.
Although the possibility of targeting the endocannabinoid
carrier for the developmen t of anxiolytic compounds is ap-
pealing and has been targeted by a patent proposing these
compounds as a pharmacological support for psychotherapy
[213], the elusive molecular identity of the transporter itself
has greatly limited the studies. Furthermore, preliminary data
indicate that AM404 elicits reward in animals and is self-
administered by squirrel monkeys [175, 214], raising the
possibility that endocannabinoid transport blockers may be
addictive.
FAAH Inhibitors
The prototypical FAAH inhibitor URB597 (Fig. 4) has
been shown to reduce anxiety-like behaviors in rats, in a
rimonabant-sensitive fashion [155,163, 215-217]. In addition
to its anxiolytic-like properties, URB597 was found to exert
also antidepressant-like effects in several animal models
with high face and predictive validity, such as the forced
swim, tail suspension and chronic mild stress paradigms [89,
210, 216, 218]. The anxiolytic action of FAAH inhibitors has
been suggested to depend on the enhancement of anan-
damide in the dorsolateral periaqueductal gray [219]; inter-
estingly, however, only low doses of URB597 in the prefron-
tal cortex were found to elicit anxiolytic-like effects, through
CB1 receptor activation. However, higher doses ceased to
elicit anx iolysis, in view of their interaction with TPRV1
vanilloid receptors [220]. Furthermore, the anxiolytic and
antidepressant actions of FAAH inhibitors were observed
only under conditions of high environmental aversiveness,
but not under normal conditions [163 ,218, 221]. Impor-
tantly, the psychotropic effects of FAAH inhibitors are par-
tially distinct from those associated with cannabinoids, in
that they appear to fail to reproduce the hedonic and intero-
ceptive states produced by CB receptor agonists [89] and to
induce self-ad ministration in squirrel monkeys [222]. Taken
together, these data suggest that FAAH inhibitors may be
promising tools in the therapy of anxiety and mood disorders
with a safer profile than cannabinoid direct agonists. This
idea has been recently endorsed by several authors in recent
articles and patents, featuring novel categories of highly se-
lective and potent FAAH inhibitors [223-227]. However, it
should be noted that recent data have recently shown that
URB597 induce a number of side effects in rats, including
social withdrawal, working memory deficits [228] and im-
pairments in auditory discrimination and reversal of olfac-
tory discrimination [229].
Fig. (4). Chemical structures of endocannabinoid degradation inac-
tivators. For more details, see text.
MAGL Inhibitors
The role of 2-AG in emotional regulation has been diffi-
cult to ascertain until the recent development of highly selec-
tive monoacylglycerol lipase (MAGL) inhibitors [35, 223].
Several lines of evidence have suggested that 2-AG plays a
pivotal role in the pathophysiology of anxiety and defensive
behaviors. The prototypical MAGL inhibitor, JZL184 (Fig.
4), has been shown to enhance the levels of 2-AG, but not
anandamide; this effect is due to its extremely high selectiv-
ity for MAGL over FAAH and other brain serine hydrolases.
Recent evidence has shown that this compound exerts anx-
iolytic-like effects in the elevated plus maze and in marble
buyring, at doses that do not affect locomotor activity [93,
230, 231]. The anxiolytic proprieties of MGL inhibitors have
also been presented in some recent patents [232,233]. Simi-
larly to the effects described for FAAH inhibitors (see
above), the anxiolytic effects of this compound were ob-
served in highly aversive (or anxiogenic) contextual settings
[229]. The neurobiological role of 2-AG in anxiety is still
poorly understood, although several studies have shown that
Current Knowledge and Future Perspectives Recent Patents on CNS Drug Discovery, 2012, Vol. 7, No. 1 33
environmental stressors alter its biosynthesis and degradation
in key brain structures controlling emo tional regulation, in-
cluding periaqueductal grey, amygdala and hippocampus
[234, 235]. Interestingly, recent evidence has shown that the
anxiolytic properties of JZL184 appear to be mediated by
CB2, rather than CB1 receptors [93], pointing to a potential
implication of this receptor in the role of 2-AG in anxiety
regulation.
CURRENT AND FUTURE DEVELOPMENTS
In light of the limitations of our current pharmacological
armamentarium for anxiety disorders, the ability of cannabi-
noids to modulate emotional responses is extremely attrac-
tive for the development of novel anxiolytic agents [217]. At
the same time, great concern arises from the protean role of
cannabinoids on the regulation of these responses, as well as
their misuse liability and other side effects. The identifica-
tion of operational strategies for the employment of cannabi-
noids in the therapy of anxiety disorders is therefore a fun-
damental goal in psychiatry research.
As outlined above, clinical evidence strongly suggests
that acute administration of low doses of CB1 receptor ago-
nists results in anxiolytic effects, while excessive activation
of these targets elicits opposite outcomes, following a re-
verse U-shaped dose-response pattern. Hence, a primary
strategy to harness the anxiolytic properties of cannabinoids
could consist in the employment of partial, low-affinity CB1
receptor agonists, which may ensure a relatively high thera-
peutic index and the stabilization of the activation of this
target within a range associated with mood enhancement
and/or anxiolysis. This idea is indirectly supported by the
mirroring observation that anecdotal reports on highly po-
tent, high-affinity synthetic cannabinoids (such as those con-
tained in “Spice” blends) trigger greater psychoactive effects
than the partial CB receptor agonist THC [26]. This concep t
indicates a potential evolution in the search for direct CB
agonists, in sharp contrast with the previous trend aimed at
the identification of high-aff inity CB recep tor activators.
An alternative strategy to achieve a similar therapeutic
goal may lie in the combination of CB1 receptor agonists
with low dosages of antagonists (preferably neutral, in order
to avoid potential side effects linked to CB1 inverse ago-
nism); this intriguing approach, which has been indicated in
a recent patent [236], is based on the likely mechanism of
action of Sativex®, a cannab inoid mouth spray containing
THC and CBD (in a ratio of 1.08:1) and marketed for the
treatment of neuropathic pain, spasticity and overactive
bladder, in consideration of the action of CBD as a CB1 re-
ceptor antagonist. However, recent preliminary clinical stud-
ies have shown that this formulation did not significantly
reduce anxiety (in fact, it was reported to induce a mild, yet
not significant increase of this symptom) [237,238], and that
CBD did not appear to elicit a significant opposition to the
effect of dronabinol [238], plausibly indicating that a h igher
concentration of this ingredient (or lower relative amount of
THC) may be necessary to elicit anxiolytic effects.
A third, highly promising avenue for the development of
cannabinoid-based anxiolytic therapies may be afforded by
FAAH inhibitors. Unlike endocannabinoid transport blockers
and direct CB receptor agonists, these compounds exh ibit a
number of highly desirable properties for anxiolytic agents:
first, they appear to maintain their anxiolytic and antidepres-
sant effect not only under conditions of acute administration,
but also following long-term treatment [93,210]; second,
they appear to elicit their effects only in conditions of highly
aversive environmental circumstances (i.e., similar to those
that would in fact require an anxiolytic treatment); third, they
have no apparent addiction liability [89,222]. The neurobi-
ological bases of this phenomenon are not completely under-
stood, and may be related to the involvement of other FAAH
substrates, such as OEA or PEA; however, recent investiga-
tions suggest that the lack of 2-AG enhancement ensuing
FAAH inactivation may contribute to the lack of reinforcing
properties of URB597 [239], potentially suggesting a differ-
ent role of anandamide and 2-AG in the modulation of re-
ward; this idea is actually consistent with the recent finding
that 2-AG is induces self-admin istration in monkeys [240].
A key problem concerning the potential application of
cannabinoid-related agents and cannabinoids is the relatively
little information about their long-term effects following
chronic administration. Indeed, the subjective effects of can-
nabis have been shown to be typically different in chronic
users as compared to occasional marijuana smokers [241,
242]. Prolonged consumption of cannabis has been shown to
induce affective sequelae, including alexithymia and avoli-
tion [113, 243-245]. Interestingly, tolerance h as been shown
to the effects of THC [246, 247], while no information is
available on endocannabinoid-related agents. Long-term
administration of cannabinoids has been shown to result in a
number of neuroplastic adaptive processes, including CB
receptor down-regulation [248, 249]. Some of these phe-
nomena may indeed be critical in shaping the different emo-
tional responsiveness to cannabis throughout life and reflect
a potential pathophysiological loop which may compound
the severity of pre-existing anxiety and affective disorders.
Finally, another important step for the employment of
cannabinoid-based anxiolytic therapies will be the analysis
of the vulnerability factors implicated in the differential re-
sponses and long-term sequelae induced by cannabis con-
sumption. For example, numerous meta-analyses and longi-
tudinal studies have established that cannabis consumption
in adolescence is conducive to an increased risk for psy-
chotic disorders [250-253]. This association is particularly
significant in the presence of other genetic factors, such as
the Val108Met allelic variant of the gene encoding catechol-
O-methyltransferase (COMT) [254,255], one of the main
enzymes for the degradation of the neurotransmitter dopa-
mine. Interestingly, it has been shown that the synergistic
effect of COMT haplotype and cannabis in adolescence is
more robust in conjunction with predisposing environmental
variables, such as the exposure to urbanicity and psychoso-
cial stress [256]. Ano ther gene that may modulate the behav-
ioral responsiveness to cannabinoids is Nrg1, which encodes
for the synaptic protein neuregulin 1. Indeed, the heterozy-
gous deletion of this gene ablates the development of toler-
ance to the anxiogenic effects of CB receptor agonists [257,
258]. These findings suggest that the employment of a phar-
macogenetic approach may be a critical screening instrument
to identify which patients may be treated with cannabis for
medical purposes without risks of neuropsychiatric side ef-
fects. Notably, the role of genes in the mental sequelae of
34 Recent Patents on CNS Drug Discovery, 2012, Vol. 7, No. 1 Tambaro and Bortolato
cannabis may also be contributed by epigenetic factors, in
consideration of the recent finding that THC induces expres-
sion of histone deacetylase 3 [259].
While studies on the biological determinants of different
responses to cannabis are still at their preliminary stages,
advances in this area may be essential to allow a personal-
ized approach for the employment of cannabinoid-based
therapies in anxiety and mood disorders.
CONFLICT OF INTEREST
N/A.
ACKNOWLEDGMENTS
The present work was supported by the National Institute
of Health grant R21HD070611 and the USC Zumberge Indi-
vidual Research Grant (to MB).
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... The reported high variability of the effects of cannabis in TS resembles the broad heterogeneity of outcomes reported by recreational users of marijuana: while cannabis is generally associated with relaxation, euthymia, and heightened sociability, some users have occasionally reported panic, paranoid ideation, and even psychotic reactions. It should also be remembered that THC and other CB 1 receptor agonists have been shown to exert a bidirectional influence on behavior as a function of the dosage: most users report that consumption of modest amounts of cannabis and CB 1 receptor agonists results in euphoria, relaxation, heightened perception, sociability, and creativity; conversely, moderate to high doses have been reported to elicit phobia, agitation, panic, dysphoria, psychotic manifestations and cognitive impairments (Tambaro & Bortolato, 2012). ...
... Au Maroc, Belghazi et al. affirme que l´hospitalisation psychiatrique concerne les cas graves de schizophrénie, de dépression, et troubles bipolaires [12]. Dans le contexte africain, les demandes de soins psychiatriques sont le plus souvent formulées devant des manifestations socialement peu tolérées, comme l´agitation, l´agressivité [13,20,32]. Nos résultats confirment ce constat; nous avons trouvé l´agressivité comme premier motif d´hospitalisation en psychiatrie suivi de l´agitation (Tableau 3). ...
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Introduction: in Mali, there are no data on the prevalence of mental disorders. The purpose of this study was to describe the clinical and epidemiological features of patients hospitalised in the Department of Psychiatry. Methods: we conducted a cross-sectional study in the Department of Psychiatry at the University Hospital of Point G between January 2014 and December 2018. Data were collected from the medical records of 1105 patients hospitalised for psychiatric disorders. Results: the average age of patients was 32.6 ± 11.1 years, ranging from 13 to 82 years. Male patients accounted for 83.8% (926/1105) of enrolled subjects, 53.2% (588/1105) were single, 18.8% (208/1105) were not employed and 28.2% (310/1105) had primary education. Seventy-four percent (818/1105) had a history of psychiatric disorders, 22.7% (251/1105) were born to consanguineous parents. Drug use was reported in 42.9% (474/1105) of cases, including tobacco 32.6% (361/1105), cannabis 26.0% (287/1105) and/or alcohol 15.6% (172/1105). The demand for care came from families in 87.5% (967/1105) of cases. Aggression was the most common reason for consultation (44.5%; 492/1105). In 67.8% (749/1105) of cases, the diagnosis was schizophrenia, schizotypic disorders or delusional disorders. The first use of care was traditional in 58.7% (649/1105) of cases. Conclusion: people hospitalised for psychiatric disorders from 2014 to 2018 were predominantly young and male with a history of psychiatric disorders. They mainly had schizophrenia, schizotypic disorders and delusional disorders.
... Characterization of the anxiolytic effects of the cannabinoids found in cannabis and hemp have focused mainly on CBD's activity in both rodents and humans. In pre-clinical rodent models of fear and anxiety-like behavior CBD has shown some evidence of anxiolytic, anti-stress, and anti-compulsive like effects [8]. In human trials CBD has shown in preliminary studies anxiolytic effects in individuals who suffer from social anxiety disorders [9,10]. ...
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Purpose of review Anxiety is a prevalent mental health condition which manifests as a disproportionate response of fear to a perceived threat. Different types of anxiety disorders vary in their pathophysiology, symptoms and treatments. The causes of anxiety disorders are complex and largely unknown; however, it has been suggested that a number of brain mechanisms and neurotransmitters are involved in the development of these conditions. While there are non-pharmacological treatments for anxiety, many patients are prescribed medications such as selective serotonin reuptake inhibitors, serotonin and noradrenaline reuptake inhibitors and/or benzodiazepines. Unfortunately, these medications have issues with efficacy and safety, and therefore, there is a continuing need for newer medicines. The cannabis constituents of tetrahydrocannabinol (THC), cannabidiol (CBD) and terpenes have been proposed as a potential treatment for anxiety conditions. Recent findings Medicinal cannabis constituents act on the endocannabinoid system (ECS) and other targets. The ECS affects several physiological functions through modulation of the central nervous system and inflammatory pathways. In particular, CBD has been suggested to exhibit anxiolytic properties, whereas THC can either have an anxiogenic or anxiolytic effect, depending on the dose, route of administration and individual genetic and environmental factors. There is also evidence that terpenes could be effective in anxiety management. Summary Currently, there is a gap in the literature as to whether standardised CBD and/or THC preparations can be used for anxiety disorders. Further information is required to know the precise doses and CBD-THC ratios from human clinical trials and real-world patient use.