Current Pharmaceutical Design, 2009, 15, 2603-2614 2603

Imaging the Neural Effects of Cannabinoids: Current Status and Future

Opportunities for Psychopharmacology

S. Bhattacharyya1,*, J.A. Crippa2, R. Martin-Santos3, T. Winton-Brown1 and P. Fusar-Poli1,4

1
Section of Neuroimaging, Box PO67, Division of Psychological Medicine & Psychiatry, Institute of Psychiatry, King's
College London, De Crespigny Park, London, SE5 8AF; 2Department of Behavioral Neurosciences, School of Medicine
of Ribeirão Preto, São Paulo University and INCT Translational Medicine, Brazil; 3Psychiatric Department, Institute of
Neuroscience, Hospital Clinico, IDIBAPS, CIBERSAM, Barcelona, Spain and 4Department of Psychobehavioural
Health Sciences, Section of Psychiatry, University of Pavia, Pavia, Italy

Abstract: Although recreational and medicinal use of cannabis has been known for many centuries, it is only in recent
decades that it has again attracted considerable systematic attention because of its adverse psychological and potential
beneficial effects. This has also been prompted by better understanding of the molecular targets of cannabinoids in the liv-
ing organism. While cannabis has attracted the attention of mental health professionals because of accumulating evidence
linking regular frequent use of cannabis to psychotic disorders like schizophrenia, neuroscientists and pharmacologists
have focused their attention on the potential beneficial effects of cannabinoids in neuropsychiatric diseases. However,
evidence regarding the neurobiological basis of these adverse psychological or potential beneficial effects has been mainly
derived from pre-clinical research. Developments in neuroimaging modalities now offer the unique opportunity to exam-
ine in vivo how the different cannabinoids may act on the human brain to mediate their effects. In this review, we focus on
research investigating the effects of cannabinoids in the human brain using neuroimaging techniques and explore how this
adds to the current understanding about the pathophysiological correlates of psychotic disorders and points towards newer
therapeutic candidates for psychotic and anxiety disorders. Further, we also discuss how combining neuroimaging and
pharmacological challenge with cannabinoids may open up newer avenues for target identification and validation in psy-
chopharmacology.
Key Words: Cannabis, delta-9-tetrahydrocannabinol, cannabidiol, endocannabinoid, functional magnetic resonance imaging,
psychosis, anxiety.

INTRODUCTION decreasing [7] and use of more potent forms of cannabis is

increasing [7, 8]. While epidemiological evidence has sug-
Although recreational use of Marijuana has been known
gested the link between cannabis use and psychotic out-
for over 4000 years and medicinal use at least since the 4th
comes, the biological mechanisms underlying that associa-
century BC [1], it is only in recent decades that it has again
tion have been less clear. Until recently, most of the avail-
attracted considerable scientific attention because of its ad-
able evidence regarding the mechanistic aspects of this link
verse psychological and beneficial effects [2-4]. Extracts has been obtained from basic research. Neuroimaging tech-
from the plant cannabis sativa have been hypothesized to be
niques provide a non-invasive way of exploring this in hu-
beneficial in a wide variety of medical conditions [4]. How-
mans in vivo. Recent research from our group and others
ever, it is only in conditions like multiple sclerosis, spinal
using neuroimaging tools now complement evidence from
cord injury and some neurological disorders that there is
basic research that help to understand the pathogenesis of the
some evidence of its beneficial effects [3]. On the other
link between cannabis use and psychosis. Understanding this
hand, what is increasingly being recognized is the link be- would be particularly important to the identification of pos-
tween regular cannabis use and increased risk for later de-
sible biological mechanisms of psychosis and critical to the
velopment of psychotic disorders like schizophrenia [2, 5].
identification of newer targets for the development of phar-
The public health importance of this association is stressed
macological treatments for schizophrenia [9], particularly
by the fact that cannabis is the third most popular recrea-
those that may target the endocannabinoid system [for a re-
tional drug after alcohol and tobacco and therefore is the
view see 10]. Moreover, there is accumulating evidence that
most commonly used illicit drug in the world [2, 6]. This is some of the chemical constituents of cannabis may have
compounded by worrying evidence that the prevalence of
therapeutic application in other mental health conditions.
cannabis use is increasing in some parts of Europe, USA,
Thus the aim of the present review is to focus on the evi-
Australia and New Zealand, while the age at first use is
dence pertaining to the use of neuroimaging in conjunction
with administration of cannabinoids or in the context of
*Address correspondence to this author at the Section of Neuroimaging, regular cannabis use that are relevant to a better understand-
Box PO67, Division of Psychological Medicine & Psychiatry, Institute of ing of the pathophysiology and developing newer pharma-
Psychiatry, King's College London, De Crespigny Park, London, SE5 8AF;
Tel: +44 20 7848 0355; Fax: +44 20 7848 0976;
cological treatments for psychotic and anxiety disorders.
E-mail: [email protected]

1381-6128/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd.

2604 Current Pharmaceutical Design, 2009, Vol. 15, No. 22 Bhattacharyya et al.

PHARMACOLOGY OF THE MAJOR CANNABI- and neuroprotective actions [53]. However, the mechanisms
NOIDS of action of CBD remain unclear. It displays low affinity for
CB1 receptors, though recent evidence suggests that it can
The extract of the cannabis plant has over 60 cannabi-
act as an antagonist/ inverse agonist at CB1 receptors even at
noids [11] and many other chemicals. However, the major
low concentrations [30, 54]. It also has various other effects,
psychoactive constituent of the cannabis plant is delta-9- including anti-oxidative effects [55], inhibition of anan-
tetrahydrocanabinol (THC) which is thought to be responsi-
damide uptake [56], enhancement of adenosine signaling
ble for most of its psychotropic effects [12]. Thus most of
[57], agonism at 5HT1A [58] and stimulated vanilloid recep-
the available evidence regarding the acute effects of cannabis
tors [56], and antagonism of cannabinoid receptors [59]
on cognition, behaviour and brain relates to evidence regard-
(GPR55) .
ing the effect of the crude extract or THC. Acute use of can-
nabis produces a number of effects which may be perceived CANNABIS USE AND SCHIZOPHRENIA
as desirable, such as relaxation, euphoria, intensification of
ordinary sensory experiences like appreciation of music or Following on from the initial epidemiological survey
films, decreased social inhibition and distortion of time sense carried out in Swedish transcripts [60], a large number of
[13, 14]. However, cannabis and THC also cause a number epidemiological studies that have been summarized in a re-
of undesirable effects in the form of impairments in atten- cent systematic review, suggest that regular cannabis may
tion, short-term memory, reaction time, psychomotor skills, increase the risk of developing schizophrenia de novo [5].
anxiety, paranoia and perceptual alterations like hallucina- There is also suggestion that an increase in the prevalence of
tions [13-16]. Systematic studies have shown that the main cannabis use may be associated with an increase in the inci-
cognitive domains impaired by the acute administration of dence of schizophrenia [61]. This is complemented by evi-
THC include learning and memory [13, 17 and for a recent dence of alteration of CB1 receptor expression in post-
review see 18], psychomotor control [19-22] and attention mortem brain specimens [62-65] and alteration of endocan-
[13, 23]. However, there is much less agreement regarding nabinoid levels in the CSF and blood [66-68] obtained from
the persistence of the longer term effects of cannabis use [13, patients with schizophrenia. In patients with psychotic disor-
24-28]. Interpretation of evidence emerging from studies that ders like schizophrenia, cannabis use is associated with
have examined the chronic effects of cannabis use is diffi- greater psychotic symptom severity [69], increased risk of
cult, because it is confounded by i) diversity in dose, potency relapse [70], earlier relapse [71], longer inpatient stay [72]
and composition of cannabis used, ii) inter-individual varia- and an increased risk of violence and criminal activity [73].
tion in the duration of cannabis use, iii) neuroadaptive proc- Similarly in people who are at high risk of psychotic disor-
esses related to tolerance, withdrawal and/ or sensitization ders, cannabis use is associated with higher rates of transi-
and iv) the fact that cannabis use seldom occurs in isolation. tion to psychosis [74]. In experimental settings acute admini-
stration of cannabis can provoke psychotic symptoms in
Most of the effects of THC on cognition and behaviour
healthy individuals [15]. Further experimental studies have
are mediated through its action on the neuronal CB1 receptor
clearly demonstrated that the induction of psychotic symp-
[29, 30], the main central cannabinoid receptor [31, 32]. This toms is specifically attributable to THC, which can induce
member of the family of G-protein-coupled receptors is
psychotic symptoms in healthy individuals [16, 46, 75] and
widely distributed throughout the brain [for reviews see 33,
exacerbate them in patients with schizophrenia [76].
34] and mediates the inhibition of the ongoing release of a
number of neurotransmitters like glutamate,
-aminobutyric Although activation of CB1 receptors by THC may affect
acid (GABA), acetylcholine, dopamine, noradrenaline, 5- various neurotransmitters, induction of psychotic symptoms
hydroxytrytamine (5-HT) and others [29, 30, 35] (Fig. 1A by THC has been hypothesized to be related to the modula-
and B). THC acts as a partial agonist at the CB1 receptors, tion of dopamine by THC [for a review see 2], as psychotic
with similar affinity but lower efficacy than endogenous symptoms in schizophrenia are thought to result from in-
CB1 ligands (endocannabinoids) like Anandamide and 2- creased dopamine activity in the striatum [77], resulting in
arachidonoylglycerol [reviewed in 30]. THC also exhibits the aberrant attribution of salience [78] to what would oth-
lower affinity and efficacy at CB1 receptors than some of the erwise be insignificant experiences or stimuli. This is consis-
synthetic agonists like HU-210, C55940 and R-(+)- tent with preclinical evidence that THC increases central
WIN55212 [30]. Activation of CB1 receptors by THC gen- dopamine synthesis [79, 80], inhibits dopamine uptake [81-
erally may result in the inhibition of ongoing neurotransmit- 84] and increases mesolimbic dopamine activity [85-89]. In
ter release, similar to, but in a less selective manner than is addition, the highest density of CB1 receptors [for reviews
mediated by endocannabinoids [for reviews see 30, 36]. see 33, 34] are found in the predominantly dopaminergic
THC can also result in CB1-mediated increase in the release areas of the brain [90] which are also most implicated in the
of dopamine, acetylcholine and glutamate in various brain generation of psychotic symptoms in schizophrenia [for re-
regions as shown in animal studies [37-41] (Fig. 1C). views see 91, 92].
On the other hand, Cannabidiol (CBD), the other major However, administration of THC not only induces psy-
ingredient of the extract of the cannabis plant [11], was ini- chotic symptoms in healthy individuals, it also reproduces
tially thought to be devoid of pharmacological activity. But it the other prominent domains of symptoms like negative and
is now considered to be a compound with a wide range of cognitive symptoms that are characteristic of schizophrenia
possible pharmacological effects [for a review see 42], in- [16, 75]. This is consistent with evidence that the cognitive
cluding anti-epileptic [43-45], anti-anxiety [46-49], antip- dysfunction associated with regular cannabis use is similar in
sychotic [50], anti-inflammatory [51], anti-parkinsonian [52] many respects to the cognitive endophenotypes that have
Imaging the Neural Effects of Cannabinoids Current Pharmaceutical Design, 2009, Vol. 15, No. 22 2605

Fig. (1). Putative effects of endocannabinoids and THC on neurotransmission.

A). Endocannabinoids like N- arachidonoylethanolamine or Anandamide (AEA) and 2- arachidonoylglycerol (2-AG) are synthesized on
demand in response to elevation of intracellular calcium and are released into the synaptic cleft. They act on presynaptic CB1 receptors to
inhibit the release of various neurotransmitters like glutamate (Glu),
-aminobutyric acid (GABA), acetylcholine (Ach), dopamine,
noradrenaline (NA) and serotonin (5-HT). Thus they serve as retrograde synaptic messengers to modulate neurotransmitter release in a man-
ner that helps maintain homeostasis and prevent the development of excessive neuronal activity. Exogeneous cannabinoids like delta-9-
tetrahydrocannabinol (THC) act as partial agonist at CB1 receptors and generally result in a less selective inhibition of neurotransmitter re-
lease.
B). Following release into the synaptic cleft, the endocannabinoids are rapidly removed from the extracellular space by a membrane-based
cannabinoid transporter (that is not yet fully characterized). Within the cell, Anandamide (AEA) is hydrolysed to Arachidonic acid (AA) and
Ethanolamine (EA) by the microsomal enzyme, fatty acid amide hydrolase (FAAH). 2- arachidonoylglycerol (2-AG) can also be hydrolysed
enzymically by FAAH or monoacylglycerol lipase (MAGL) to AA and glycerol (G).
C). Although administration of THC can generally result in inhibition of ongoing neurotransmitter release, it may also produce CB1 recep-
tor-mediated increase in the release of dopamine, glutamate (Glu) and acetylcholine (Ach) in certain brain regions, possibly by inhibiting the
release of an inhibitory neurotransmitter like GABA onto dopamine, glutamate or acetylcholine-releasing neurons.

been proposed as vulnerability markers for schizophrenia NEUROIMAGING OF THE EFFECTS OF CANNABIS
[for a review see 93]. Hence, human experimental admini- – IMPLICATIONS FOR DRUG DISCOVERY IN
stration of THC can be a more valid model for schizophre- SCHIZOPHRENIA
nia, as it more closely reproduces the different domains of
Neuroimaging provides a direct and noninvasive way of
symptoms characteristic of schizophrenia, than some of the
other existing pharmacological models [94, 95]. exploring the functional state of the brain in health, disease
or conditions of pharmacological or behavioral manipula-
2606 Current Pharmaceutical Design, 2009, Vol. 15, No. 22 Bhattacharyya et al.

tion. This section will focus first on the long-term effects of trast MRI, Sneider et al. [112, 113] reported increased re-
regular cannabis use on the brain in healthy individuals and gional blood volume in the right frontal, left temporal and
patients with schizophrenia, and discuss them in light of cur- cerebellar areas in chronic cannabis users 6-36 hours after
rent understanding of the neural correlates of schizophrenia. abstinence [112] relative to healthy controls. However, while
Subsequently, results of studies describing the neural corre- studies investigating rCBF or blood volume provide valuable
lates of acute administration of cannabis or THC will be dis- information regarding the effects of chronic cannabis use on
cussed to examine how pharmacological challenge studies brain function, they do not shed any light on how the long-
involving administration of THC may be used as a model for term effects of cannabis use on various cognitive processes
understanding the pathophysiology of schizophrenia and aid are mediated at the neural level. Various studies have inves-
in the discovery of newer treatments. tigated this by comparing the brain activation between
chronic cannabis users and controls while performing cogni-
I. Long-Term Effects of Cannabis on the Brain tive tasks that involve processes known to be modulated by
cannabis use. As the effects of cannabis on memory are well-
Different groups have examined chronic cannabis users
recognized, this has been investigated by various groups. In
using neuroimaging techniques to explore the long-term ef-
one of the earliest studies, Block et al. [114] used 15[O] posi-
fects of cannabis on brain structure and function. While ex-
tron emission tomography (PET) to demonstrate that poorer
amining structural changes, studies that used a whole brain
analysis approach using voxel-based morphometric (VBM) performance during an associative memory task in chronic
cannabis users relative to healthy controls was associated
methods did not detect any significant changes in grey mat-
with lower right prefrontal activation and greater posterior
ter volume in chronic cannabis users relative to controls [96-
cerebellar activation. More recently, using functional MRI
98]. The application of VBM methodology to structural
(fMRI) Jager et al. [98] demonstrated reduced bilateral para-
magnetic resonance imaging (MRI) permits the comparison
hippocampal and right dorsolateral prefrontal activation dur-
of the volume of the gray and white matter between groups
of interest for each voxel of the cerebral volume after auto- ing an associative memory task in chronic cannabis users
relative to healthy controls even when their performance was
matic image segmentation, without the need to define re-
matched. Studies investigating the effects of chronic canna-
gions of interest (ROI) in advance. Studies using an ROI-
bis use on the working memory network have consistently
based approach, which is more powerful in detecting subtle
reported increased activation in chronic users relative to con-
structural alterations in predefined anatomical regions, did
trols despite matched performance, either in the right supe-
however detect grey matter changes in temporal areas [99,
100] in chronic cannabis users relative to controls. This is rior, middle and inferior frontal gyri, bilateral anterior cingu-
late, right precentral and superior temporal gyri and basal
consistent with evidence that cannabis use or dependence in
ganglia [115, 116] or in the left superior parietal cortex
patients with schizophrenia is associated with smaller ante-
[116]. Effects of cannabis use on the neural network for psy-
rior [101] and posterior cingulate cortex [102] and that those
chomotor control have also been examined in two studies.
patients with schizophrenia who continue to use cannabis
Eldreth and colleagues [28] used a modified version of the
show greater loss of grey matter volume than those who do
not [103]. Two of the early studies that investigated the ef- Stroop task and PET to show that abstinent cannabis users
have hypoactivity in the left anterior cingulate and prefrontal
fect of chronic cannabis use on the integrity of white matter
cortex and hyperactivity in the hippocampus bilaterally, rela-
tracts using diffusion tensor imaging (DTI) found no signifi-
tive to control subjects, in the absence of any difference in
cant differences between users and controls [104, 105], but a
performance. They interpreted this as suggestive of an alter-
recent study found corpus callosal damage associated with
native neural network to overcome persistent functional
heavy cannabis use [106]. The inconsistency in findings re-
ported by the various studies that have examined the effects deficits. Gruber and Yurgelun-Todd [104] also used a similar
task to find lower anterior cingulate but higher mid-cingulate
of chronic cannabis use on brain structure possibly suggest
activity in chronic cannabis users relative to control subjects,
that the effects on brain structure are too subtle to be de-
despite similar task performance. Normal controls also dem-
tected using current approaches unless studies involve very
onstrated increased activity within the right dorsolateral pre-
large numbers of subjects or very heavy cannabis users who
frontal cortex (DLPFC) during the interference condition,
may be slightly atypical compared to the regular chronic
cannabis users [100]. However, it is interesting to note that while cannabis smokers, who made more errors of commis-
sion than controls during the interference condition, demon-
the effects of cannabis use on brain structure and integrity
strated a more diffuse, bilateral pattern of DLPFC activation.
are consistent with studies showing similar alterations in
patients with schizophrenia [107, 108]. The results of these neuroimaging studies that have em-
ployed cognitive tasks are difficult to compare because of
Majority of the studies examining the effect of chronic
cannabis use on the functional state of the brain, detected a the different imaging techniques and cognitive paradigms
used. Additionally, the inconsistency in results even in stud-
reduction in global cerebral blood flow (CBF) in chronic
ies that examined similar cognitive processes may reflect
users relative to controls [109, 110] without [109] or with
confounding effects of differences between substance users
[96, 110] associated reduced regional CBF (rCBF) in cere-
and volunteers, and of variation in the duration of cannabis
bellar [96] or frontal regions [96, 110]. Block et al. [96] also
use, its dose and pharmacological composition because of
reported greater rCBF in the right anterior cingulate in
chronic cannabis users relative to controls. However, an the various psychoactive ingredients in cannabis [117]. Nev-
ertheless, they are in keeping with the general pattern of neu-
early study by Mathew et al. [111] did not detect any differ-
ral dysfunction noted in patients with schizophrenia [91, 92,
ences in global or regional rCBF between cannabis users and
118].
controls. More recently, using dynamic susceptibility con-
Imaging the Neural Effects of Cannabinoids Current Pharmaceutical Design, 2009, Vol. 15, No. 22 2607

II. Acute Effects of Cannabis on the Brain regions, visual cortex, and in an attentional network compris-
ing the parietal lobe, frontal lobe and thalamus, which they
a. Acute Effects of THC on Resting State Activity/Blood
interpreted as underlying the perceptual and cognitive altera-
Flow in Brain
tions caused by cannabis. In a recent study [130] occasional
The earlier studies investigating the acute effects of can- cannabis users performed a reaction time baseline task and
nabis or THC on the brain have mainly examined this using dichotic listening task with attend-right- and attend-left-ear
an experimental design in chronic or recreational cannabis instructions. Using PET, the authors demonstrated that rela-
users, employing various imaging techniques ranging from tive to placebo, acute cannabis administration resulted in
133
Xe- single photon emission computed tomography increase in normalized regional CBF in the orbital frontal
(SPECT) [119-121], 15[O] H2O-PET [122-124] to 18[F] fluo- cortex, anterior cingulate, temporal pole, insula, and cerebel-
rodeoxyglucose (FDG)-PET [125]. lum and decrease in regional CBF in the visual and auditory
cortices. Although cannabis lowered regional CBF in the
Relative to baseline, acute administration of THC-rich
auditory cortices compared to placebo, it did not alter the
cannabis extract or pure THC caused an increase in resting
normal pattern of attention-related regional CBF asymmetry
global cerebral blood flow (CBF) [120, 122, 126] as well as
(i.e., greater regional CBF in the temporal lobe contralateral
increased activity in the anterior cingulate cortex and the
to the direction of attention) that was also observed after
insula [122-124, 127], the prefrontal and orbitofrontal corti-
placebo. The authors interpreted these results as indicating
ces [125], the cerebellum [123, 127] and the left temporal that while cannabis had dramatic direct effects on regional
lobe [119]. The effect of administration of THC-rich canna-
CBF, it caused relatively little change in the normal pattern
bis extracts on activity in the basal ganglia, thalamus,
of task-related regional CBF during this auditory focused
amygdala and hippocampus [122, 124, 125] was less consis-
attention task.
tent. Again, results from these studies are difficult to com-
pare and integrate because of differences in the severity and Time Perception
duration of cannabis use in the subjects recruited in the vari- In another study [129], O’Leary and colleagues examined
ous studies, presence of psychiatric and drug misuse comor-
the effect of acute cannabis administration in recreational
bidities as well as variation in the mode, dose and purity of
and chronic cannabis users while they performed a self-
cannabis administered, notwithstanding the different imaging
paced counting task during PET imaging. Relative to pla-
modalities used. Other confounding factors such as toler-
cebo, cannabis increased regional CBF in the ventral fore-
ance, withdrawal and sensitization to repeated use further
brain and cerebellar cortex in both groups, but resulted in
complicate the interpretation and generalization of these re- significantly less frontal lobe activation in chronic users. The
sults. However, the evidence suggests that acute cannabis
rate of counting increased after smoking cannabis in both
administration modulates brain function as measured using
groups, as did a behavioral measure of self-paced tapping.
metabolic rate or blood flow in a wide network that includes
Both these increases correlated with regional CBF in the
prefrontal cortex, limbic and paralimbic areas, basal ganglia
cerebellum, which the authors interpreted as evidence of
and cerebellum, consistent with the distribution of the CB1
cannabis accelerating the cerebellar clock resulting in altera-
receptors in the brain [33]. tion in self-paced behaviours.
b. Acute Effects of THC on Activation During Cognitive Response Inhibition
Tasks
Borgwardt et al. [131] used a task that involved the inhi-
Although studies examining the acute effect of cannabis bition of prepotent motor responses in conjunction with
administration on CBF and regional brain metabolism pro- fMRI and found that acute administration of THC attenuated
vide valuable information regarding where cannabis acts in activation in the right inferior frontal and anterior cingulated
the brain, they do not inform us about how the effects of gyrus, part of the normal inhibitory control network. This is
cannabis on various cognitive and emotional processes are of interest not just in the context of understanding how can-
mediated at the neural level. Fewer studies have examined nabis modulates these processes in the brain, but also be-
this in the context of cannabis research. They are summa- cause neurophysiological studies [132, 133] suggest an in-
rized below based on the cognitive and emotional processes hibitory deficit as a central pathophysiologic mechanism in
examined in the context of acute administration of cannabis psychotic disorders and as abnormal activation of the net-
or THC. work underlying motor response inhibition is well docu-
Attention mented in schizophrenia [134, 135]. Although psychomotor
control is a prominent acute effect of cannabis [13, 19, 20,
In a series of studies, O’Leary and colleagues [128-130] 136], modulation of its neural correlates by THC have never
used 15[O] H2O PET to examine how acute cannabis chal- been investigated before. Both the neuroimaging studies that
lenge modulated neural activation related to different cogni- have examined this in the context of cannabis use [28, 104],
tive processes. They demonstrated that in recreational can- have employed modified versions of the classic Stroop task,
nabis users [128] relative to placebo, acute cannabis admini- which is not a pure response inhibition task as it also meas-
stration increased the regional CBF in the orbital and mesial ures cognitive inhibition, i.e. inhibition of interference and
frontal lobes, insula, temporal poles, anterior cingulate and selective attention.
cerebellum despite intact performance during an auditory
attention (dichotic listening) task. They interpreted these Verbal Learning
effects as being related to the effects of cannabis on mood. Although impairment in learning and memory is one of
They also noted reduced CBF in the temporal lobe auditory the most prominent acute cognitive effects of cannabis and
2608 Current Pharmaceutical Design, 2009, Vol. 15, No. 22 Bhattacharyya et al.

THC in healthy individuals [16, 17] and possibly the only nism of action of the drug, thus allowing a systems level
domain that continues to be impaired in chronic users [26], it evaluation of the circuit underlying a specific cognitive
is not known where cannabis or its main psychoactive ingre- process or behaviour modulated by the drug [144]. Used in
dient, THC acts in the human brain to cause these impair- conjunction with pharmacological challenge involving psy-
ments. This is also critical to understanding the neurobiology choactive drugs that have specific symptomatic effects like
of the cannabis- psychosis link as verbal memory is one of psychotic or mood symptoms as in the case of cannabis or
the key neuropsychological impairments in schizophrenia ecstasy, they can help understand the neurobiological sub-
[137]. As the main central cannabinoid (CB1) receptors have strate for psychotic or mood disorders respectively. fMRI
a high density in the medial temporal and prefrontal cortex studies of the effects of cannabinoids may thus provide a
[33], areas critical to learning and memory [138, 139] and ‘neural signature’ of a specific cognitive process or behav-
THC affects both medial temporal and memory function in iour modulated by the specific cannabinoid in health or dis-
experimental animals [140], it may thus influence learning ease. For example, work by Bhattacharyya et al. [75] sug-
and memory by modulating function in these regions. How- gests that the attenuation of ventral striatal activation may be
ever, this has never been experimentally demonstrated in considered as a ‘neural signature’ of the psychotic symptoms
humans. Bhattacharyya et al. [75] used fMRI in conjunction induced by THC.When combined with other molecular im-
with oral administration of THC in a group of occasional aging techniques like PET or magnetic resonance spectros-
cannabis users to investigate this. They demonstrate that the copy (MRS) which allow measurement of neurotransmitters
normal linear decremental response in activation in the me- like dopamine and its receptors or glutamate and GABA
dial temporal cortex during verbal learning and its relation- respectively, such studies can help characterize the neuro-
ship to memory performance was disrupted by THC, such cognitive and neurochemical underpinnings of the specific
that there was an augmentation of medial temporal activation cognitive processes or behaviours in health or disease. This
and the relationship between medial temporal activation and may in turn help in the identification of newer targets for
memory performance was no longer evident. THC also at- drug discovery in schizophrenia. As human experimental
tenuated ventral striatal activation such that the effect of administration of THC closely models the different symptom
THC on ventral striatal activation correlated with the sever- domains characteristic of schizophrenia, human pharmacol-
ity of psychotic symptoms induced by it concurrently. This is ogical imaging studies involving experimental administra-
possibly of more direct relevance to understanding the neu- tion of THC may complement existing animal models, and
robiology of the cannabis- psychosis link. Although it has inform our understanding about the neurobiology of schizo-
been hypothesized that the induction of psychotic symptoms phrenia. Additionally, such studies may not only help deline-
by cannabis reflects a secondary effect of THC on dopamine ate the neurobiology of the cognitive and symptomatic ef-
release in the striatum [2] and recent evidence obtained using fects of cannabis and inform our understanding of the
PET suggests that THC may acutely modulate dopamine mechanistic link between cannabis use and schizophrenia,
release in this area [141], it was not clear until recently but critically, may also help in the development of a more
whether the effect of THC on the human striatum underlie reliable and accurate pharmacological model for schizophre-
the acute induction of psychotic symptoms by cannabis and nia. ‘Neural signatures’ of specific cognitive and sympto-
THC. matic effects of THC may be characterized by combining
pharmacological challenge in healthy volunteers and fMRI
Emotional Processing
using specific, reproducible and well-characterized stimuli
Phan et al. [142] employed an emotional face processing that engage processes modulated by THC and known to be
task to examine the acute effect of THC to social signals of impaired in schizophrenia.
threat (fearful and angry faces) in healthy recreational can- Traditionally, initial identification of a therapeutic candi-
nabis users using a placebo-controlled design. The authors
date molecule for a neuropsychiatric condition is influenced
reported reduced amygdala reactivity to social signals of
mainly by existing knowledge about its pharmacological
threat in the absence of modulation of activity in the primary
properties in terms of the receptors and/or neurotansmitters
visual and motor cortex and interpreted this as indicative of
modulated by it. However, it is seldom possible to describe a
the anxiolytic effect of low dose of THC. Lack of measur-
specific cognitive process or behaviour in terms of change in
able behavioural effects on anxiety reduction in the study by a specific receptor or neurotransmitter in the brain, let alone
Phan et al. [142] however limits the interpretability of their
complex and heterogeneous neuropsychiatric disorders like
findings, especially as THC commonly increases anxiety in
schizophrenia, which not only involve abnormalities in mul-
occasional users, similar to the subjects used in their study.
tiple behavioral and cognitive domains, but may have multi-
However, this apparently conflicting result may also reflect
ple and as yet unclear aetiologies [9]. As modulation of a
the bimodal effect of cannabinoids on anxiety, with lower
specific central receptor or neurotransmitter seldom occurs in
doses of THC having anxiolytic and higher doses having isolation in the human brain, therapeutic candidate molecules
anxiogenic effects [143].
chosen on the basis of specific characterization of their re-
ceptor and neurotransmitter profiles in animal and in vitro
III. Potential for Drug Discovery
models often fail during clinical trials. Thus, although sup-
Most psychoactive drugs act on multiple receptors in the ported by preclinical evidence that predicted efficacy [145],
CNS with differing levels of efficacy and thus modulate initial clinical trial data suggest that CB1 antagonists may
multiple neurotransmitter systems. fMRI allows the exami- not be efficacious in schizophrenia [146]. fMRI used in con-
nation of the combined or integrated effects on these neuro- junction with pharmacological challenge may play an impor-
transmitters independent of the specific molecular mecha- tant role by helping in identifying such potential candidates
Imaging the Neural Effects of Cannabinoids Current Pharmaceutical Design, 2009, Vol. 15, No. 22 2609

with greater accuracy and speed [144, 147]. By comparing trodermal responses to fearful stimuli. More recently, Crippa
the effects of potential therapeutic candidate molecules on et al. (2009)1 carried out the first study investigating the neu-
the ‘neural signatures’ of THC against the effects of known ral correlates of the anxiolytic effects of CBD in a clinical
therapeutic agents (eg. antipsychotics) with proven clinical sample, using a similar design as in their previous study [48].
utility, it may be possible to identify with greater accuracy They show that a single oral dose of CBD (400 mg) reduced
and reliability preclinical candidates which are likely to subjective measures of anxiety without increasing sedation
prove efficacious in clinical trials. Thus this may hasten the in patients with Social Anxiety disorder, which was associ-
speed of identification of potential candidate molecules and ated with decreased activity in the left parahippocampal
substantially reduce the failure rates of such candidates in gyrus and hippocampus, extending to the inferior temporal
clinical trials. gyrus. They also found a positive correlation between the
effects of CBD on activity in the amygdala bilaterally and a
NEUROIMAGING EVIDENCE OF THE BENEFICIAL clear reduction in subjective ratings of anxiety. Taken to-
EFFECTS OF OTHER CANNABINOIDS IN MENTAL gether, the modulatory effects of CBD on limbic and para-
ILLNESSES limbic activation as demonstrated in these studies are consis-
tent with current understanding regarding the neural sub-
Although THC in high doses is known to induce anxiety
strate of anxiety in health and psychiatric disorders [154] and
and psychotic symptoms and impair various cognitive func-
tions, not all cannabinoids present in cannabis sativa are bad a potential role for CBD in ameliorating clinically significant
anxiety. However, future double-blind placebo-controlled
for mental health. As noted earlier, there is accumulating
studies would be necessary to further confirm these observa-
evidence for the potential beneficial effects of CBD in vari-
tions in patients with anxiety disorders.
ous neuropsychiatric conditions. This section will briefly
describe the preclinical evidence and then discuss the com-
II. Evidence for Antipsychotic Potential of CBD
plementary evidence emerging from neuroimaging studies
involving the administration of CBD that support these hy- Evidence for the potential antipsychotic effect of CBD
potheses. first came from two simultaneous but separate observations.
Zuardi et al. [46] observed that it reduced the psychotic-like
I. Evidence for Anxiolytic Potential of CBD symptoms induced by THC in healthy individuals. Around
the same time, Rottanburg et al. [155] reported the associa-
Preclinical evidence regarding the anxiolytic potential of
CBD have come from observations in laboratory animals tion between psychosis and consumption of a South African
variant of cannabis sativa with high levels of THC and ab-
that this cannabinoid had effects similar to known anxiolytic
sent CBD. Subsequently, in studies using standard animal
drugs in conditioned emotional paradigms [148], the Vogel
models of antipsychotic activity, CBD has been shown to
conflict test [149], and the elevated plus maze test [47, 150,
have a profile similar to that of an atypical antipsychotic
151]. CBD was also found to attenuate the anxiogenic effect
drug [156-158]. CBD was also found to attenuate the disrup-
of THC in healthy human volunteers [46] and to reduce
anxiety in volunteers submitted to the simulation of public tion of prepulse inhibition induced by NMDA antagonists in
mice [159] and the CBD content of cannabis extracts was
speaking test [152]. These effects did not appear to involve
related to greater amplitude of auditory evoked mismatch
any pharmacokinetic interaction [46, 153]. Although the
negativity [160], further suggestive of a potential antipsy-
precise molecular mechanisms underlying the anxiolytic
chotic effect. A recent fMRI study carried out in conjunction
effect of cannabidiol are far from clear, a series of studies
with pharmacological challenge with cannabinoids further
now provide complementary evidence that not only supports
the anxiolytic potential, but also delineates the neural corre- supports the antipsychotic potential of CBD, as the net effect
of CBD on brain function and behaviour was observed to be
lates of such effect. Crippa et al. [48] carried out the first
opposite to that of THC in healthy individuals [Bhattach-
neuroimaging study investigating the neural correlates of the
aryya et al., 2008]2. This is consistent with complementary
anxiolytic effects of this constitutent of cannabis. Using sin-
evidence suggesting its efficacy in reducing the psychotic
gle photon emission computed tomography (SPECT) in con-
symptoms in Parkinson’s disease [52] and is also supported
junction with oral administration of CBD (400 mg) in a dou-
ble-blind placebo-controlled, cross-over design, they showed by evidence that individuals smoking strains of cannabis
containing CBD in addition to THC were less likely to expe-
that the anxiolytic effect of CBD in healthy volunteers was
rience psychotic-like symptoms than those smoking cannabis
associated with increased activity in the left parahippocam-
without CBD [161]. However, double-blind randomised con-
pal gyrus, as well as reduced activity in the left amygdala-
trolled trials need to demonstrate the efficacy of CBD either
hippocampus complex and left posterior cingulate gyrus.
as an antipsychotic in individuals with pre-existing psychotic
More recently, Fusar-Poli et al. [49] used fMRI, which per-
mitted the acquisition of greater numbers of images with conditions like schizophrenia or in ameliorating the psychiat-
ric consequences of cannabis use.
better spatial and temporal resolution, to investigate the neu-
ral correlates of the anxiolytic effects of CBD in healthy hu-
man volunteers. They observed that CBD (600mg) modu-
_____________________________
lated brain activity patterns when healthy subjects were 1
processing intensely fearful stimuli, attenuating responses in Jose A Crippa, personal communication, 2009.
2
Bhattacharyya S, Fusar-Poli P, Borgwardt S, Martin-Santos R, O’Carroll C, Seal M,
the amygdala and the anterior and posterior cingulate corti- Crippa J, Atakan Z, McGuire PK. Opposite effects of cannabis ingredients in the brain-
ces. Also, the attenuation of activation in the amygdala and neural basis for potential antipsychotic effect of cannabidiol. Presented at the 21st
the posterior cingulate gyrus were directly correlated with European College of Neuropsychopharmacology Congress, Barcelona, September,
2008.
the concomitant effect of CBD in modulating the elec-
2610 Current Pharmaceutical Design, 2009, Vol. 15, No. 22 Bhattacharyya et al.

FUTURE DIRECTION MRI = Magnetic resonance imaging

Neuroimaging studies examining the acute and chronic fMRI = Functional magnetic resonance imaging
effects of cannabinoids have informed our understanding of MRS = Magnetic resonance spectroscopy
the biological basis of the link between cannabis use and
schizophrenia. However, the neurochemical and specific DTI = Diffusion tensor imaging
neurocognitive underpinnings of this association are still CBF = Cerebral blood flow
unclear. Understanding these mechanisms is critical as,
among the known aetiological factors of schizophrenia, can- rCBF = Regional cerebral blood flow
nabis use is arguably the most potentially modifiable. Mo- ROI = Regions of interest
lecular imaging techniques like MRS and PET in conjunc-
tion with pharmacological challenge of cannabinoids can VBM = Voxel-based morphometry
help unravel the perturbation of glutamate and dopamine GABA =
Aminobutyric acid
levels respectively that may be related to the induction of
5-HT = 5-Hydroxytryptamine (serotonin)
psychotic symptoms by cannabis and THC. Newer PET ra-
dioligands like 11[C] MePPEP [162] which bind to CB1 re- FDG = Fluorodeoxyglucose
ceptors allow in vivo characterization of the human endocan-
nabinoid system in health as well as in diseases like schizo- REFERENCES
phrenia, thus allowing the examination of any possible
References 167-169 are related articles recently published.
pathogenetic link [163]. Used in conjunction with pharma-
cological challenge involving THC this may also help under- [1] Ameri A. The effects of cannabinoids on the brain. Prog Neurobiol
1999; 58(4): 315-48.
stand the relationship between the symptomatic effects of [2] Murray RM, Morrison PD, Henquet C, Di Forti M. Cannabis, the
THC and CB1 receptor function in healthy individuals. Un- mind and society: the hash realities. Nat Rev Neurosci 2007; 8(11):
ravelling these links and mechanisms may help identify po- 885-95.
tential targets for the development of newer drugs for [3] Di Marzo V, De Petrocellis L. Plant, synthetic, and endogenous
schizophrenia, particularly those that may target the can- cannabinoids in medicine. Annu Rev Med 2006; 57: 553-74.
[4] Watson SJ, Benson JA, Jr., Joy JE. Marijuana and medicine: as-
nabinoid or glutamatergic system. Further studies using mul- sessing the science base: a summary of the 1999 Institute of Medi-
timodal neuroimaging are also warranted that explore the cine report. Arch Gen Psychiatry 2000; 57(6): 547-52.
neurochemical mechanisms underlying the potential benefi- [5] Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB,
cial effects of CBD as an anxiolytic or antipsychotic agent. Burke M, et al. Cannabis use and risk of psychotic or affective
mental health outcomes: a systematic review. Lancet 28 2007;
They may also indicate a role for CBD as a treatment for the 370(9584): 319-28.
adverse psychiatric consequences of cannabis use in the gen- [6] World Drug Report UNODC. United Nations Office on Drugs and
eral population [42] or in those with pre-existing psychiatric Crime [online]. http: //www.unodc.org/documents/wdr/WDR_
disorders, particularly as conventional antipsychotic medica- 2008_eng_web.pdf. [Accessed on Jan 1, 2009].
tions may be ineffective for such conditions [165]. Its neuro- [7] Ashton H. Cannabis or health? Curr Opin Psych 2002; 15: 247-53.
[8] Potter DJ, Clark P, Brown MB. Potency of delta 9-THC and other
protective effects and favourable safety profile [42, 165, cannabinoids in cannabis in England in 2005: implications for psy-
166] suggest that CBD might be particularly useful in indi- choactivity and pharmacology. J Forensic Sci 2008; 53(1): 90-4.
viduals with neuropsychiatric conditions, in whom use of [9] Carpenter WT, Koenig JI. The evolution of drug development in
dopaminergic antipsychotics is unsatisfactory because of schizophrenia: past issues and future opportunities. Neuropsycho-
pharmacology 2008; 33(9): 2061-79.
their side-effect profile. Pharmacological imaging studies [10] Pacher P, Batkai S, Kunos G. The endocannabinoid system as an
utilizing an experimental design involving CBD challenge emerging target of pharmacotherapy. Pharmacol Rev 2006; 58(3):
may thus provide proof of concept of the therapeutic benefit 389-462.
of this molecule that can serve as a basis for future clinical [11] Mechoulam R, Gaoni Y. Recent advances in the chemistry of hash-
trials. ish. Fortschr Chem Org Naturst 1967; 25: 175-213.
[12] Mechoulam R, Shani A, Edery H, Grunfeld Y. Chemical basis of
hashish activity. Science 1970; 169(945): 611-2.
ACKNOWLEDGEMENTS [13] Hall W, Solowij N. Adverse effects of cannabis. Lancet 1998;
352(9140): 1611-6.
Sagnik Bhattacharyya is supported by a Joint MRC/ Pri- [14] Tart CT. Marijuana intoxication common experiences. Nature
ory Clinical research training fellowship from the Medical 1970; 226(5247): 701-4.
Research Council, UK. Jose A Crippa is recipient of a Con- [15] Talbott JA, Teague JW. Marihuana psychosis. Acute toxic psycho-
selho Nacional de Desenvolvimento Científico e Tec- sis associated with the use of Cannabis derivatives. JAMA 1969;
210(2): 299-302.
nológico (CNPq, Brazil) Productivity fellowship.The authors [16] D'Souza DC, Perry E, MacDougall L, Ammerman Y, Cooper T,
declare no competing interests. Wu YT, et al. The psychotomimetic effects of intravenous delta-9-
tetrahydrocannabinol in healthy individuals: implications for psy-
ABBREVIATIONS chosis. Neuropsychopharmacology 2004; 29(8): 1558-72.
[17] Curran HV, Brignell C, Fletcher S, Middleton P, Henry J. Cogni-
THC = Delta-9-tetrahydrocannabinol tive and subjective dose-response effects of acute oral Delta 9-
tetrahydrocannabinol (THC) in infrequent cannabis users. Psycho-
CBD = Cannabidiol pharmacology (Berl) 2002; 164(1): 61-70.
[18] Ranganathan M, D'Souza DC. The acute effects of cannabinoids on
DLPFC = Dorsolateral prefrontal cortex memory in humans: a review. Psychopharmacology (Berl) 2006;
PET = Positron emission tomography 188(4): 425-44.
[19] Hart CL, van Gorp W, Haney M, Foltin RW, Fischman MW. Ef-
SPECT = Single photon emission computed tomography fects of acute smoked marijuana on complex cognitive perform-
ance. Neuropsychopharmacology 2001; 25(5): 757-65.
Imaging the Neural Effects of Cannabinoids Current Pharmaceutical Design, 2009, Vol. 15, No. 22 2611

[20] McDonald J, Schleifer L, Richards JB, de Wit H. Effects of THC [45] Cunha JM, Carlini EA, Pereira AE, Ramos OL, Pimentel C, Ga-
on behavioral measures of impulsivity in humans. Neuropsycho- gliardi R, et al. Chronic administration of cannabidiol to healthy
pharmacology 2003; 28(7): 1356-65. volunteers and epileptic patients. Pharmacology 1980; 21(3): 175-
[21] Ramaekers JG, Moeller MR, van Ruitenbeek P, Theunissen EL, 85.
Schneider E, Kauert G. Cognition and motor control as a function [46] Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG. Action of can-
of Delta9-THC concentration in serum and oral fluid: limits of im- nabidiol on the anxiety and other effects produced by delta 9-THC
pairment. Drug Alcohol Depend 2006; 85(2): 114-22. in normal subjects. Psychopharmacology (Berl) 1982; 76(3): 245-
[22] Ramaekers J, Kauert G, Theunissen E, Toennes S, Moeller M. 50.
Neurocognitive performance during acute THC intoxication in [47] Guimaraes FS, Chiaretti TM, Graeff FG, Zuardi AW. Antianxiety
heavy and occasional cannabis users. J Psychopharmacol 2008. effect of cannabidiol in the elevated plus-maze. Psychopharma-
[23] Ilan AB, Smith ME, Gevins A. Effects of marijuana on neuro- cology (Berl) 1990; 100(4): 558-9.
physiological signals of working and episodic memory. Psycho- [48] Crippa JA, Zuardi AW, Garrido GE, Wichert-Ana L, Guarnieri R,
pharmacology (Berl) 2004; 176(2): 214-22. Ferrari L, et al. Effects of cannabidiol (CBD) on regional cerebral
[24] Pope HG, Jr., Yurgelun-Todd D. The residual cognitive effects of blood flow. Neuropsychopharmacology 2004; 29(2): 417-26.
heavy marijuana use in college students. JAMA 1996; 275(7): 521- [49] Fusar-Poli P, Crippa JA, Bhattacharyya S, Borgwardt SJ, Allen P,
7. Martin-Santos R, et al. Distinct effects of {delta}9-
[25] Pope HG, Jr., Gruber AJ, Hudson JI, Huestis MA, Yurgelun-Todd tetrahydrocannabinol and cannabidiol on neural activation during
D. Neuropsychological performance in long-term cannabis users. emotional processing. Arch Gen Psychiatry 2009; 66(1): 95-105.
Arch Gen Psychiatry 2001; 58(10): 909-15. [50] Zuardi AW, Hallak JE, Dursun SM, Morais SL, Sanches RF,
[26] Solowij N, Stephens RS, Roffman RA, Babor T, Kadden R, Miller Musty RE, et al. Cannabidiol monotherapy for treatment-resistant
M, et al. Cognitive functioning of long-term heavy cannabis users schizophrenia. J Psychopharmacol 2006; 20(5): 683-6.
seeking treatment. Jama 2002; 287(9): 1123-31. [51] Malfait AM, Gallily R, Sumariwalla PF, Malik AS, Andreakos E,
[27] Pope HG, Jr. Cannabis, cognition, and residual confounding. Mechoulam R, et al. The nonpsychoactive cannabis constituent
JAMA 2002; 287(9): 1172-4. cannabidiol is an oral anti-arthritic therapeutic in murine collagen-
[28] Eldreth DA, Matochik JA, Cadet JL, Bolla KI. Abnormal brain induced arthritis. Proc Natl Acad Sci USA 2000; 97(17): 9561-6.
activity in prefrontal brain regions in abstinent marijuana users. [52] Zuardi A, Crippa J, Hallak J, Pinto J, Chagas M, Rodrigues G, et
Neuroimage 2004; 23(3): 914-20. al. Cannabidiol for the treatment of psychosis in Parkinson's dis-
[29] Howlett AC. The cannabinoid receptors. Prostagland Lipid Mediat ease. J Psychopharmacol 2008.
2002; 68-69: 619-31. [53] Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO. Can-
[30] Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of nabidiol--recent advances. Chem Biodivers 2007; 4(8): 1678-92.
three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol [54] Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA,
and delta9-tetrahydrocannabivarin. Br J Pharmacol 2008; 153(2): Pertwee RG. Cannabidiol displays unexpectedly high potency as an
199-215. antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharma-
[31] Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. col 2007; 150(5): 613-23.
Structure of a cannabinoid receptor and functional expression of [55] Hampson AJ, Grimaldi M, Axelrod J, Wink D. Cannabidiol and (-
the cloned cDNA. Nature 1990; 346(6284): 561-4. )Delta9-tetrahydrocannabinol are neuroprotective antioxidants.
[32] Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Proc Natl Acad Sci USA 1998; 95(14): 8268-73.
Costa BR, et al. Cannabinoid receptor localization in brain. Proc [56] Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE,
Natl Acad Sci USA 1990; 87(5): 1932-6. Brandi I, et al. Molecular targets for cannabidiol and its synthetic
[33] Elphick MR, Egertova M. The neurobiology and evolution of can- analogues: effect on vanilloid VR1 receptors and on the cellular up-
nabinoid signalling. Philos Trans R Soc Lond B Biol Sci 2001; take and enzymatic hydrolysis of anandamide. Br J Pharmacol
356(1407): 381-408. 2001; 134(4): 845-52.
[34] Eggan SM, Lewis DA. Immunocytochemical distribution of the [57] Carrier EJ, Auchampach JA, Hillard CJ. Inhibition of an equilibra-
cannabinoid CB1 receptor in the primate neocortex: a regional and tive nucleoside transporter by cannabidiol: a mechanism of can-
laminar analysis. Cereb Cortex 2007; 17(1): 175-91. nabinoid immunosuppression. Proc Natl Acad Sci USA 2006;
[35] Szabo B, Schlicker E. Effects of cannabinoids on neurotransmis- 103(20): 7895-900.
sion. Handb Exp Pharmacol 2005(168): 327-65. [58] Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of
[36] Kreitzer AC. Neurotransmission: emerging roles of endocannabi- cannabidiol at 5-HT1a receptors. Neurochem Res 2005; 30(8):
noids. Curr Biol 2005; 15(14): R549-51. 1037-43.
[37] Pertwee RG, Ross RA. Cannabinoid receptors and their ligands. [59] Ryberg E, Larsson N, Sjogren S, Hjorth S, Hermansson NO,
Prostaglandins Leukot Essent Fatty Acids 2002; 66(2-3): 101-21. Leonova J, et al. The orphan receptor GPR55 is a novel cannabi-
[38] Pistis M, Ferraro L, Pira L, Flore G, Tanganelli S, Gessa GL, et al. noid receptor. Br J Pharmacol 2007; 152(7): 1092-101.
Delta(9)-tetrahydrocannabinol decreases extracellular GABA and [60] Andreasson S, Allebeck P, Engstrom A, Rydberg U. Cannabis and
increases extracellular glutamate and dopamine levels in the rat schizophrenia. A longitudinal study of Swedish conscripts. Lancet
prefrontal cortex: an in vivo microdialysis study. Brain Res 2002; 1987; 2(8574): 1483-6.
948(1-2): 155-8. [61] Boydell J, van Os J, Caspi A, Kennedy N, Giouroukou E, Fearon P,
[39] Gardner EL. Endocannabinoid signaling system and brain reward: et al. Trends in cannabis use prior to first presentation with schizo-
emphasis on dopamine. Pharmacol Biochem Behav 2005; 81(2): phrenia, in South-East London between 1965 and 1999. Psychol
263-84. Med 2006; 36(10): 1441-6.
[40] Nagai H, Egashira N, Sano K, Ogata A, Mizuki, K, Iwasaki K, et [62] Dean B, Sundram S, Bradbury R, Scarr E, Copolov D. Studies on
al. Antipsychotics improve Delta9-tetrahydrocannabinol-induced [3H]CP-55940 binding in the human central nervous system: re-
impairment of the prepulse inhibition of the startle reflex in mice. gional specific changes in density of cannabinoid-1 receptors asso-
Pharmacol Biochem Behav 2006; 84(2): 330-6. ciated with schizophrenia and cannabis use. Neuroscience 2001;
[41] Pisanu A, Acquas E, Fenu S, Di Chiara G. Modulation of Delta(9)- 103(1): 9-15.
THC-induced increase of cortical and hippocampal acetylcholine [63] Zavitsanou K, Garrick T, Huang XF. Selective antagonist
release by micro opioid and D(1) dopamine receptors. Neurophar- [3H]SR141716A binding to cannabinoid CB1 receptors is in-
macology 2006; 50(6): 661-70. creased in the anterior cingulate cortex in schizophrenia. Prog Neu-
[42] Zuardi AW. Cannabidiol: from an inactive cannabinoid to a drug ropsychopharmacol Biol Psychiatry 2004; 28(2): 355-60.
with wide spectrum of action. Rev Bras Psiquiatr 2008; 30(3): 271- [64] Newell KA, Deng C, Huang XF. Increased cannabinoid receptor
80. density in the posterior cingulate cortex in schizophrenia. Exp
[43] Carlini EA, Leite JR, Tannhauser M, Berardi AC. Letter: Can- Brain Res 2006; 172(4): 556-60.
nabidiol and Cannabis sativa extract protect mice and rats against [65] Eggan SM, Hashimoto T, Lewis DA. Reduced cortical cannabinoid
convulsive agents. J Pharm Pharmacol 1973; 25(8): 664-5. 1 receptor messenger RNA and protein expression in schizophre-
[44] Izquierdo I, Orsingher OA, Berardi AC. Effect of cannabidiol and nia. Arch Gen Psychiatry 2008; 65(7): 772-84.
of other cannabis sativa compounds on hippocampal seizure dis-
charges. Psychopharmacologia 1973; 28(1): 95-102.
2612 Current Pharmaceutical Design, 2009, Vol. 15, No. 22 Bhattacharyya et al.

[66] Leweke FM, Giuffrida A, Wurster U, Emrich HM, Piomelli D. [87] French ED. delta9-Tetrahydrocannabinol excites rat VTA dopa-
Elevated endogenous cannabinoids in schizophrenia. Neuroreport mine neurons through activation of cannabinoid CB1 but not opioid
1999; 10(8): 1665-9. receptors. Neurosci Lett 1997; 226(3): 159-62.
[67] De Marchi N, De Petrocellis L, Orlando P, Daniele F, Fezza F, Di [88] Tanda G, Pontieri FE, Di Chiara G. Cannabinoid and heroin activa-
Marzo V. Endocannabinoid signalling in the blood of patients with tion of mesolimbic dopamine transmission by a common mu1
schizophrenia. Lipids Health Dis 2003; 2: 5. opioid receptor mechanism. Science 1997; 276(5321): 2048-50.
[68] Giuffrida A, Leweke FM, Gerth CW, Schreiber D, Koethe D, Faul- [89] Robledo P, Trigo JM, Panayi F, de la Torre R, Maldonado R. Be-
haber J, et al. Cerebrospinal anandamide levels are elevated in havioural and neurochemical effects of combined MDMA and
acute schizophrenia and are inversely correlated with psychotic THC administration in mice. Psychopharmacology (Berl) 2007;
symptoms. Neuropsychopharmacology 2004; 29(11): 2108-14. 195(2): 255-64.
[69] Henquet C, Krabbendam L, Spauwen J, Kaplan C, Lieb R, Witt- [90] Seamans JK, Yang CR. The principal features and mechanisms of
chen HU, et al. Prospective cohort study of cannabis use, predispo- dopamine modulation in the prefrontal cortex. Prog Neurobiol. Sep
sition for psychosis, and psychotic symptoms in young people. Bmj 2004; 74(1): 1-58.
2005; 330(7481): 11. [91] Ross CA, Margolis RL, Reading SA, Pletnikov M, Coyle JT. Neu-
[70] Linszen DH, Dingemans PM, Nugter MA, Van der Does AJ, robiology of schizophrenia. Neuron 2006; 52(1): 139-53.
Scholte WF, Lenior MA. Patient attributes and expressed emotion [92] Allen P, Aleman A, McGuire PK. Inner speech models of auditory
as risk factors for psychotic relapse. Schizophr Bull 1997; 23(1): verbal hallucinations: evidence from behavioural and neuroimaging
119-30. studies. Int Rev Psychiatry 2007; 19(4): 407-15.
[71] Hides L, Dawe S, Kavanagh DJ, Young RM. Psychotic symptom [93] Solowij N, Michie PT. Cannabis and cognitive dysfunction: paral-
and cannabis relapse in recent-onset psychosis. Prospective study. lels with endophenotypes of schizophrenia? J Psychiatry Neurosci
Br J Psychiatry 2006; 189: 137-43. 2007; 32(1): 30-52.
[72] Isaac M, Isaac M, Holloway F. Is cannabis an anti-antipsychotic? [94] Krystal JH, Perry EB, Jr., Gueorguieva R, Belger A, Madonick SH,
The experience in psychiatric intensive care. Hum Psychopharma- Abi-Darghum A, et al. Comparative and interactive human psy-
col 2005; 20(3): 207-10. chopharmacologic effects of ketamine and amphetamine: implica-
[73] Miles H, Johnson S, Amponsah-Afuwape S, Finch E, Leese M, tions for glutamatergic and dopaminergic model psychoses and
Thornicroft G. Characteristics of subgroups of individuals with cognitive function. Arch Gen Psychiatry 2005; 62(9): 985-94.
psychotic illness and a comorbid substance use disorder. Psychiatr [95] Fletcher PC, Honey GD. Schizophrenia, ketamine and cannabis:
Serv 2003; 54(4): 554-61. evidence of overlapping memory deficits. Trends Cogn Sci 2006;
[74] Kristensen K, Cadenhead KS. Cannabis abuse and risk for psycho- 10(4): 167-74.
sis in a prodromal sample. Psychiatry Res 30 2007; 151(1-2): 151- [96] Block RI, O'Leary DS, Ehrhardt JC, Augustinack JC, Ghoneim
4. MM, Arndt S, et al. Effects of frequent marijuana use on brain tis-
[75] Bhattacharyya S, Fusar-Poli P, Borgwardt S, Martin-Santos R, sue volume and composition. Neuroreport 2000; 11(3): 491-6.
Nosarti C, O' Carroll C, et al. Delta-9-tetrahydrocannabinol modu- [97] Tzilos GK, Cintron CB, Wood JB, Simpson NS, Young AD, Pope
lates medial temporal and striatal function in humans: a neural ba- HG Jr, et al. Lack of hippocampal volume change in long-term
sis for the effects of cannabis on learning and psychosis. Archives heavy cannabis users. Am J Addict 2005; 14(1): 64-72.
of General Psychiatry (In Press). [98] Jager G, Van Hell HH, De Win MM, Kahn RS, Van Den Brink W,
[76] D'Souza DC, Abi-Saab WM, Madonick S, Forselius-Bielen K, Van Ree JM, et al. Effects of frequent cannabis use on hippocam-
Doersch A, Braley G, et al. Delta-9-tetrahydrocannabinol effects in pal activity during an associative memory task. Eur Neuropsycho-
schizophrenia: implications for cognition, psychosis, and addiction. pharmacol 2007; 17(4): 289-97.
Biol Psychiatry 2005; 57(6): 594-608. [99] Matochik JA, Eldreth DA, Cadet JL, Bolla KI. Altered brain tissue
[77] Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers composition in heavy marijuana users. Drug Alcohol Depend 2005;
M, et al. Increased striatal dopamine transmission in schizophrenia: 77(1): 23-30.
confirmation in a second cohort. Am J Psychiatry 1998; 155(6): [100] Yucel M, Solowij N, Respondek C, Whittle S, Fornito A, Pantelis
761-7. C, et al. Regional brain abnormalities associated with long-term
[78] Kapur S. Psychosis as a state of aberrant salience: a framework heavy cannabis use. Arch Gen Psychiatry 2008; 65(6): 694-701.
linking biology, phenomenology, and pharmacology in schizophre- [101] Szeszko PR, Robinson DG, Sevy S, Kumra S, Rupp CI, Betensky
nia. Am J Psychiatry 2003; 160(1): 13-23. JD, et al. Anterior cingulate grey-matter deficits and cannabis use
[79] Bloom AS, Dewey WL. A comparison of some pharmacological in first-episode schizophrenia. Br J Psychiatry 2007; 190: 230-6.
actions of morphine and delta9-tetrahydrocannabinol in the mouse. [102] Bangalore SS, Prasad KM, Montrose DM, Goradia DD, Diwadkar
Psychopharmacology (Berl) 1978; 57(3): 243-8. VA, Keshavan MS. Cannabis use and brain structural alterations in
[80] Maitre L, Staehelin M, Bein HJ. Effect of an extract of cannabis first episode schizophrenia--a region of interest, voxel based mor-
and of some cannabinols on catecholamine metabolism in rat brain phometric study. Schizophr Res 2008; 99(1-3): 1-6.
and heart. Agents Actions 1970; 1(3): 136-43. [103] Rais M, Cahn W, Van Haren N, Schnack H, Caspers E, Hulshoff
[81] Banerjee SP, Snyder SH, Mechoulam R. Cannabinoids: influence Pol H, et al. Excessive brain volume loss over time in cannabis-
on neurotransmitter uptake in rat brain synaptosomes. J Pharmacol using first-episode schizophrenia patients. Am J Psychiatry 2008;
Exp Ther 1975; 194(1): 74-81. 165(4): 490-6.
[82] Hershkowitz M, Szechtman H. Pretreatment with delta 1- [104] Gruber SA, Yurgelun-Todd DA. Neuroimaging of marijuana
tetrahydrocannabinol and psychoactive drugs: effects on uptake of smokers during inhibitory processing: a pilot investigation. Brain
biogenic amines and on behavior. Eur J Pharmacol 1979; 59(3-4): Res Cogn Brain Res 2005; 23(1): 107-18.
267-76. [105] Delisi LE, Bertisch HC, Szulc KU, Majcher M, Brown K, Bappal
[83] Poddar MK, Dewey WL. Effects of cannabinoids on catecholamine A, et al. A preliminary DTI study showing no brain structural
uptake and release in hypothalamic and striatal synaptosomes. J change associated with adolescent cannabis use. Harm Reduct J
Pharmacol Exp Ther 1980; 214(1): 63-7. 2006; 3: 17.
[84] Sakurai-Yamashita Y, Kataoka Y, Fujiwara M, Mine K, Ueki S. [106] Arnone D, Barrick TR, Chengappa S, Mackay CE, Clark CA,
Delta 9-tetrahydrocannabinol facilitates striatal dopaminergic Abou-Saleh MT. Corpus callosum damage in heavy marijuana use:
transmission. Pharmacol Biochem Behav 1989; 33(2): 397-400. preliminary evidence from diffusion tensor tractography and tract-
[85] Chen JP, Paredes W, Li J, Smith D, Lowinson J, Gardner EL. Delta based spatial statistics. Neuroimage 2008; 41(3): 1067-74.
9-tetrahydrocannabinol produces naloxone-blockable enhancement [107] Honea R, Crow TJ, Passingham D, Mackay CE. Regional deficits
of presynaptic basal dopamine efflux in nucleus accumbens of con- in brain volume in schizophrenia: a meta-analysis of voxel-based
scious, freely-moving rats as measured by intracerebral microdialy- morphometry studies. Am J Psychiatry 2005; 162(12): 2233-45.
sis. Psychopharmacology (Berl) 1990; 102(2): 156-62. [108] Kyriakopoulos M, Bargiotas T, Barker GJ, Frangou S. Diffusion
[86] Chen JP, Paredes W, Lowinson JH, Gardner EL. Strain-specific tensor imaging in schizophrenia. Eur Psychiatry 2008; 23(4): 255-
facilitation of dopamine efflux by delta 9-tetrahydrocannabinol in 73.
the nucleus accumbens of rat: an in vivo microdialysis study. Neu- [109] Tunving K, Thulin SO, Risberg J, Warkentin S. Regional cerebral
rosci Lett 1991; 129(1): 136-80. blood flow in long-term heavy cannabis use. Psychiatry Res 1986;
17(1): 15-21.
Imaging the Neural Effects of Cannabinoids Current Pharmaceutical Design, 2009, Vol. 15, No. 22 2613

[110] Lundqvist T, Jonsson S, Warkentin S. Frontal lobe dysfunction in genetic investigation of schizophrenia. Am J Med Genet 2000;
long-term cannabis users. Neurotoxicol Teratol 2001; 23(5): 437- 97(1): 58-64.
43. [133] Daskalakis ZJ, Christensen BK, Chen R, Fitzgerald PB, Zipursky
[111] Mathew RJ, Tant S, Burger C. Regional cerebral blood flow in RB, Kapur S. Evidence for impaired cortical inhibition in schizo-
marijuana smokers. Br J Addict 1986; 81(4): 567-71. phrenia using transcranial magnetic stimulation. Arch Gen
[112] Sneider JT, Pope HG, Jr., Silveri MM, Simpson NS, Gruber SA, Psychiatry 2002; 59(4): 347-54.
Yurgelun-Todd DA. Altered regional blood volume in chronic can- [134] Rubia K, Russell T, Bullmore ET, Soni W, Brammer MJ, Simmons
nabis smokers. Exp Clin Psychopharmacol 2006; 14(4): 422-8. A, et al. An fMRI study of reduced left prefrontal activation in
[113] Sneider JT, Pope HG, Jr., Silveri MM, Simpson NS, Gruber SA, schizophrenia during normal inhibitory function. Schizophr Res
Yurgelun-Todd DA. Differences in regional blood volume during a 2001; 52(1-2): 47-55.
28-day period of abstinence in chronic cannabis smokers. Eur Neu- [135] Kaladjian A, Jeanningros R, Azorin JM, Grimault S, Anton JL,
ropsychopharmacol 2008; 18(8): 612-9. Mazzola-Pomietto P. Blunted activation in right ventrolateral pre-
[114] Block RI, O'Leary DS, Hichwa RD, Augustinack JC, Boles Ponto frontal cortex during motor response inhibition in schizophrenia.
LL, Ghoneim MM, et al. Effects of frequent marijuana use on Schizophr Res 2007; 97(1-3): 184-93.
memory-related regional cerebral blood flow. Pharmacol Biochem [136] Lamers CT, Bechara A, Rizzo M, Ramaekers JG. Cognitive func-
Behav 2002; 72(1-2): 237-50. tion and mood in MDMA/THC users, THC users and non-drug us-
[115] Kanayama G, Rogowska J, Pope HG, Gruber SA, Yurgelun-Todd ing controls. J Psychopharmacol 2006; 20(2): 302-11.
DA. Spatial working memory in heavy cannabis users: a functional [137] Reichenberg A, Harvey PD. Neuropsychological impairments in
magnetic resonance imaging study. Psychopharmacology (Berl) schizophrenia: Integration of performance-based and brain imaging
2004; 176(3-4): 239-47. findings. Psychol Bull 2007; 133(5): 833-58.
[116] Jager G, Kahn RS, Van Den Brink W, Van Ree JM, Ramsey NF. [138] Wagner AD, Schacter DL, Rotte M, Koutstaal W, Maril A, Dale
Long-term effects of frequent cannabis use on working memory AM, et al. Building memories: remembering and forgetting of ver-
and attention: an fMRI study. Psychopharmacology (Berl) 2006; bal experiences as predicted by brain activity. Science 1998;
185(3): 358-68. 281(5380): 1188-91.
[117] Mechoulam R. Marihuana chemistry. Science 1970; 168(936): [139] Buckner RL, Wheeler ME. The cognitive neuroscience of remem-
1159-66. bering. Nat Rev Neurosci. Sep 2001; 2(9): 624-34.
[118] Velakoulis D, Wood SJ, Wong MT, McGorry PD, Yung A, Phillips [140] Robbe D, Montgomery SM, Thome A, Rueda-Orozco PE,
L, et al. Hippocampal and amygdala volumes according to psycho- McNaughton BL, Buzsaki G. Cannabinoids reveal importance of
sis stage and diagnosis: a magnetic resonance imaging study of spike timing coordination in hippocampal function. Nat Neurosci
chronic schizophrenia, first-episode psychosis, and ultra-high-risk 2006; 9(12): 1526-33.
individuals. Arch Gen Psychiatry 2006; 63(2): 139-49. [141] Bossong MG, van Berckel BN, Boellaard R, Zuurman L, Schuit
[119] Mathew RJ, Wilson WH, Tant SR. Acute changes in cerebral blood RC, Windhorst AD, et al. Delta9-Tetrahydrocannabinol Induces
flow associated with marijuana smoking. Acta Psychiatr Scand Dopamine Release in the Human Striatum. Neuropsychopharma-
1989; 79(2): 118-28. cology 2009; 34(3): 759-66.
[120] Mathew RJ, Wilson WH, Humphreys DF, Lowe JV, Wiethe KE. [142] Phan KL, Angstadt M, Golden J, Onyewuenyi I, Popovska A, de
Regional cerebral blood flow after marijuana smoking. J Cereb Wit H. Cannabinoid modulation of amygdala reactivity to social
Blood Flow Metab 1992; 12(5): 750-8. signals of threat in humans. J Neurosci 2008; 28(10): 2313-9.
[121] Mathew RJ, Wilson WH. Acute changes in cerebral blood flow [143] Viveros MP, Marco EM, File SE. Endocannabinoid system and
after smoking marijuana. Life Sci 1993; 52(8): 757-67. stress and anxiety responses. Pharmacol Biochem Behav 2005;
[122] Mathew RJ, Wilson WH, Coleman RE, Turkington TG, DeGrado 81(2): 331-42.
TR. Marijuana intoxication and brain activation in marijuana [144] Borsook D, Becerra L, Hargreaves R. A role for fMRI in optimiz-
smokers. Life Sci 1997; 60(23): 2075-89. ing CNS drug development. Nat Rev Drug Discov 2006; 5(5): 411-
[123] Mathew RJ, Wilson WH, Turkington TG, Coleman RE. Cerebellar 24.
activity and disturbed time sense after THC. Brain Res 1998; [145] Scatton B, Sanger DJ. Pharmacological and molecular targets in the
797(2): 183-9. search for novel antipsychotics. Behav Pharmacol 2000; 11(3-4):
[124] Mathew RJ, Wilson WH, Chiu NY, Turkington TG, Degrado TR, 243-56.
Coleman RE. Regional cerebral blood flow and depersonalization [146] Meltzer HY, Arvanitis L, Bauer D, Rein W. Placebo-controlled
after tetrahydrocannabinol administration. Acta Psychiatr Scand evaluation of four novel compounds for the treatment of schizo-
1999; 100(1): 67-75. phrenia and schizoaffective disorder. Am J Psychiatry 2004;
[125] Volkow ND, Gillespie H, Mullani N, Tancredi L, Grant C, Valen- 161(6): 975-84.
tine A, et al. Brain glucose metabolism in chronic marijuana users [147] Wong DF, Tauscher J, Grunder G. The role of imaging in proof of
at baseline and during marijuana intoxication. Psychiatry Res 1996; concept for CNS drug discovery and development. Neuropsycho-
67(1): 29-38. pharmacology 2009; 34(1): 187-203.
[126] Mathew RJ, Wilson WH, Humphreys D, Lowe JV, Weithe KE. [148] Zuardi AW, Karniol IG. Effects on variable-interval performance
Depersonalization after marijuana smoking. Biol Psychiatry 1993; in rats of delta 9-tetrahydrocannabinol and cannabidiol, separately
33(6): 431-41. and in combination. Braz J Med Biol Res 1983; 16(2): 141-6.
[127] Mathew RJ, Wilson WH, Turkington TG, Hawk TC, Coleman RE, [149] Musty RE, Conti LH, Mechoulam R. Anxiolytic properties of can-
DeGrado TR, et al. Time course of tetrahydrocannabinol-induced nabidiol. In: Harvey DJ, eds. Marihuana '84. Proceedings of the
changes in regional cerebral blood flow measured with positron Oxford Symposium on Cannabis. Oxford: IRL Press Limited;
emission tomography. Psychiatry Res 2002; 116(3): 173-85. 1984: 713-9.
[128] O'Leary DS, Block RI, Koeppel JA, Flaum M, Schultz SK, An- [150] Onaivi ES, Green MR, Martin BR. Pharmacological characteriza-
dreasen NC, et al. Effects of smoking marijuana on brain perfusion tion of cannabinoids in the elevated plus maze. J Pharmacol Exp
and cognition. Neuropsychopharmacology 2002; 26(6): 802-16. Ther 1990; 253(3): 1002-9.
[129] O'Leary DS, Block RI, Turner BM, Koeppel J, Magnotta VA, [151] Guimaraes FS, de Aguiar JC, Mechoulam R, Breuer A. Anxiolytic
Ponto LB, et al. Marijuana alters the human cerebellar clock. Neu- effect of cannabidiol derivatives in the elevated plus-maze. Gen
roreport 11 2003; 14(8): 1145-51. Pharmacol 1994; 25(1): 161-4.
[130] O'Leary DS, Block RI, Koeppel JA, Schultz SK, Magnotta VA, [152] Zuardi AW, Cosme RA, Graeff FG, Guimarães FS. Effects of
Ponto LB, et al. Effects of smoking marijuana on focal attention ipsapirone and cannabidiol on human experimental anxiety. J Psy-
and brain blood flow. Hum Psychopharmacol 2007; 22(3): 135-48. chopharmacol 1993; 7: 82-8.
[131] Borgwardt SJ, Allen P, Bhattacharyya S, Fusar-Poli P, Crippa JA, [153] Agurell S, Carlsson S, Lindgren JE, Ohlsson A, Gillespie H,
Seal ML, et al. Neural basis of Delta-9-tetrahydrocannabinol and Hollister L. Interactions of delta 1-tetrahydrocannabinol with can-
cannabidiol: effects during response inhibition. Biol Psychiatry nabinol and cannabidiol following oral administration in man. As-
2008; 64(11): 966-73. say of cannabinol and cannabidiol by mass fragmentography. Ex-
[132] Freedman R, Adams CE, Adler LE, Bickford PC, Gault J, Harris perientia 1981; 37(10): 1090-2.
JG, et al. Inhibitory neurophysiological deficit as a phenotype for
2614 Current Pharmaceutical Design, 2009, Vol. 15, No. 22 Bhattacharyya et al.

[154] Ferrari MC, Busatto GF, McGuire PK, Crippa JA. Structural mag- versibly and with high specific signal to cannabinoid CB1 receptors
netic resonance imaging in anxiety disorders: an update of research in nonhuman primate brain. Neuropsychopharmacology 2008;
findings. Rev Bras Psiquiatr 2008; 30(3): 251-64. 33(2): 259-69.
[155] Rottanburg D, Robins AH, Ben-Arie O, Teggin A, Elk R. Canna- [163] Cohen M, Solowij N, Carr V. Cannabis, cannabinoids and schizo-
bis-associated psychosis with hypomanic features. Lancet 1982; phrenia: integration of the evidence. Aust N Z J Psychiatry 2008;
2(8312): 1364-6. 42(5): 357-68.
[156] Zuardi AW, Rodrigues JA, Cunha JM. Effects of cannabidiol in [164] D'Souza DC, Braley G, Blaise R, Vendetti M, Oliver S, Pittman B,
animal models predictive of antipsychotic activity. Psychopharma- et al. Effects of haloperidol on the behavioral, subjective, cogni-
cology (Berl) 1991; 104(2): 260-4. tive, motor, and neuroendocrine effects of Delta-9-tetrahydro-
[157] Guimaraes VM, Zuardi AW, Del Bel EA, Guimaraes FS. Can- cannabinol in humans. Psychopharmacology (Berl) 2008; 198(4):
nabidiol increases Fos expression in the nucleus accumbens but not 587-603.
in the dorsal striatum. Life Sci. 2004; 75(5): 633-8. [165] Mechoulam R, Spatz M, Shohami E. Endocannabinoids and neuro-
[158] Moreira FA, Guimaraes FS. Cannabidiol inhibits the hyperlocomo- protection. Sci STKE 2002; 2002(129): RE5.
tion induced by psychotomimetic drugs in mice. Eur J Pharmacol [166] Lastres-Becker I, Molina-Holgado F, Ramos JA, Mechoulam R,
2005; 512(2-3): 199-205. Fernandez-Ruiz J. Cannabinoids provide neuroprotection against 6-
[159] Long LE, Malone DT, Taylor DA. Cannabidiol reverses MK-801- hydroxydopamine toxicity in vivo and in vitro: relevance to Parkin-
induced disruption of prepulse inhibition in mice. Neuropsycho- son's disease. Neurobiol Dis 2005; 19(1-2): 96-107.
pharmacology 2006; 31(4): 795-803. [167] Baker D, Pryce G. The endocannabinoid system and multiple scle-
[160] Juckel G, Roser P, Nadulski T, Stadelmann AM, Gallinat J. Acute rosis. Curr Pharm Des 2008; 14(23): 2326-36.
effects of Delta9-tetrahydrocannabinol and standardized cannabis [168] Fowler CJ. "The tools of the trade"--an overview of the pharmacol-
extract on the auditory evoked mismatch negativity. Schizophr Res ogy of the endocannabinoid system. Curr Pharm Des 2008; 14(23):
2007; 97(1-3): 109-17. 2254-65.
[161] Morgan CJ, Curran HV. Effects of cannabidiol on schizophrenia- [169] Viso A, Cisneros JA, Ortega-Gutierrez S. The medicinal chemistry
like symptoms in people who use cannabis. Br J Psychiatry 2008; of agents targeting monoacylglycerol lipase. Curr Top Med Chem
192(4): 306-7. 2008; 8(3): 231-46.
[162] Yasuno F, Brown AK, Zoghabi SS, Krushinski JH, Chernet E,
Tauscher J, et al. The PET radioligand [11C]MePPEP binds re-