imaging the neural effects of cannabinoids current status and future

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Imaging the Neural Effects of Cannabinoids: Current Status and FutureOpportunities for Psychopharmacology

S. Bhattacharyya1,*, J.A. Crippa

2, R. Martin-Santos

3, T. Winton-Brown

1and P. Fusar-Poli

1,4

1Section of Neuroimaging, Box PO67, Division of Psychological Medicine & Psychiatry, Institute of Psychiatry, King's

College London, De Crespigny Park, London, SE5 8AF;2 Department 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 4 Department 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 imagingpsychosis, anxiety.

INTRODUCTION

Although recreational use of Marijuana has been known

for over 4000 years and medicinal use at least since the 4thcentury BC [1], it is only in recent decades that it has againattracted considerable scientific attention because of its ad-verse psychological and beneficial effects [2-4]. Extractsfrom the plant cannabis sativa have been hypothesized to bebeneficial in a wide variety of medical conditions [4]. How-ever, it is only in conditions like multiple sclerosis, spinalcord injury and some neurological disorders that there issome evidence of its beneficial effects [3]. On the otherhand, what is increasingly being recognized is the link be-tween regular cannabis use and increased risk for later de-velopment of psychotic disorders like schizophrenia [2, 5].The public health importance of this association is stressedby the fact that cannabis is the third most popular recrea-

tional drug after alcohol and tobacco and therefore is themost commonly used illicit drug in the world [2, 6]. This iscompounded by worrying evidence that the prevalence of cannabis use is increasing in some parts of Europe, USA,Australia and New Zealand, while the age at first use is

*Address correspondence to this author at the Section of Neuroimaging,

Box PO67, Division of Psychological Medicine & Psychiatry, Institute of

Psychiatry, King's College London, De Crespigny Park, London, SE5 8AF;

Tel: +44 20 7848 0355; Fax: +44 20 7848 0976;

E-mail: [email protected]

decreasing [7] and use of more potent forms of cannabis isincreasing [7, 8]. While epidemiological evidence has suggested the link between cannabis use and psychotic out-

comes, the biological mechanisms underlying that association have been less clear. Until recently, most of the avail-able evidence regarding the mechanistic aspects of this linkhas been obtained from basic research. Neuroimaging techniques provide a non-invasive way of exploring this in humans in vivo. Recent research from our group and othersusing neuroimaging tools now complement evidence frombasic research that help to understand the pathogenesis of thelink between cannabis use and psychosis. Understanding thiwould be particularly important to the identification of possible biological mechanisms of psychosis and critical to theidentification of newer targets for the development of phar-macological treatments for schizophrenia [9], particularlythose that may target the endocannabinoid system [for a review see 10]. Moreover, there is accumulating evidence thatsome of the chemical constituents of cannabis may havetherapeutic application in other mental health conditionsThus the aim of the present review is to focus on the evidence pertaining to the use of neuroimaging in conjunctionwith administration of cannabinoids or in the context ofregular cannabis use that are relevant to a better understand-ing of the pathophysiology and developing newer pharma-cological treatments for psychotic and anxiety disorders.



2604 Current Pharmaceutical Design, 2009 , Vol. 15, No. 22 Bhattach

PHARMACOLOGY OF THE MAJOR CANNABI-

NOIDS

The extract of the cannabis plant has over 60 cannabi-noids [11] and many other chemicals. However, the majorpsychoactive constituent of the cannabis plant is delta-9-tetrahydrocanabinol (THC) which is thought to be responsi-ble for most of its psychotropic effects [12]. Thus most of the available evidence regarding the acute effects of cannabis

on cognition, behaviour and brain relates to evidence regard-ing the effect of the crude extract or THC. Acute use of can-nabis produces a number of effects which may be perceivedas desirable, such as relaxation, euphoria, intensification of ordinary sensory experiences like appreciation of music orfilms, decreased social inhibition and distortion of time sense[13, 14]. However, cannabis and THC also cause a numberof undesirable effects in the form of impairments in atten-tion, short-term memory, reaction time, psychomotor skills,anxiety, paranoia and perceptual alterations like hallucina-tions [13-16]. Systematic studies have shown that the maincognitive domains impaired by the acute administration of THC include learning and memory [13, 17 and for a recentreview see 18], psychomotor control [19-22] and attention[13, 23]. However, there is much less agreement regardingthe persistence of the longer term effects of cannabis use [13,24-28]. Interpretation of evidence emerging from studies thathave examined the chronic effects of cannabis use is diffi-cult, because it is confounded by i) diversity in dose, potencyand composition of cannabis used, ii) inter-individual varia-tion in the duration of cannabis use, iii) neuroadaptive proc-esses related to tolerance, withdrawal and/ or sensitizationand iv) the fact that cannabis use seldom occurs in isolation.

Most of the effects of THC on cognition and behaviourare mediated through its action on the neuronal CB1 receptor[29, 30], the main central cannabinoid receptor [31, 32]. Thismember of the family of G-protein-coupled receptors is

widely distributed throughout the brain [for reviews see 33,34] and mediates the inhibition of the ongoing release of anumber of neurotransmitters like glutamate, -aminobutyricacid (GABA), acetylcholine, dopamine, noradrenaline, 5-hydroxytrytamine (5-HT) and others [29, 30, 35] (Fig. 1A and B). THC acts as a partial agonist at the CB1 receptors,with similar affinity but lower efficacy than endogenousCB1 ligands (endocannabinoids) like Anandamide and 2-arachidonoylglycerol [reviewed in 30]. THC also exhibitslower affinity and efficacy at CB1 receptors than some of thesynthetic agonists like HU-210, C55940 and R-(+)-WIN55212 [30]. Activation of CB1 receptors by THC gen-erally may result in the inhibition of ongoing neurotransmit-ter release, similar to, but in a less selective manner than is

mediated by endocannabinoids [for reviews see 30, 36].THC can also result in CB1-mediated increase in the releaseof dopamine, acetylcholine and glutamate in various brainregions as shown in animal studies [37-41] (Fig. 1C).

On the other hand, Cannabidiol (CBD), the other majoringredient of the extract of the cannabis plant [11], was ini-tially thought to be devoid of pharmacological activity. But itis now considered to be a compound with a wide range of possible pharmacological effects [for a review see 42], in-cluding anti-epileptic [43-45], anti-anxiety [46-49], antip-sychotic [50], anti-inflammatory [51], anti-parkinsonian [52]

and neuroprotective actions [53]. However, the mechanismof action of CBD remain unclear. It displays low affinity foCB1 receptors, though recent evidence suggests that it canact as an antagonist/ inverse agonist at CB1 receptors even alow concentrations [30, 54]. It also has various other effectsincluding anti-oxidative effects [55], inhibition of anandamide uptake [56], enhancement of adenosine signaling[57], agonism at 5HT1A [58] and stimulated vanilloid recep

tors [56], and antagonism of cannabinoid receptors [59(GPR55) .

CANNABIS USE AND SCHIZOPHRENIA

Following on from the initial epidemiological surveycarried out in Swedish transcripts [60], a large number ofepidemiological studies that have been summarized in a recent systematic review, suggest that regular cannabis mayincrease the risk of developing schizophrenia de novo [5]There is also suggestion that an increase in the prevalence ocannabis use may be associated with an increase in the inci-dence of schizophrenia [61]. This is complemented by evidence of alteration of CB1 receptor expression in post-mortem brain specimens [62-65] and alteration of endocannabinoid levels in the CSF and blood [66-68] obtained frompatients with schizophrenia. In patients with psychotic disorders like schizophrenia, cannabis use is associated withgreater psychotic symptom severity [69], increased risk ofrelapse [70], earlier relapse [71], longer inpatient stay [72and an increased risk of violence and criminal activity [73]Similarly in people who are at high risk of psychotic disor-ders, cannabis use is associated with higher rates of transition to psychosis [74]. In experimental settings acute administration of cannabis can provoke psychotic symptoms inhealthy individuals [15]. Further experimental studies haveclearly demonstrated that the induction of psychotic symptoms is specifically attributable to THC, which can inducepsychotic symptoms in healthy individuals [16, 46, 75] andexacerbate them in patients with schizophrenia [76].

Although activation of CB1 receptors by THC may affecvarious neurotransmitters, induction of psychotic symptomsby THC has been hypothesized to be related to the modula-tion of dopamine by THC [for a review see 2], as psychoticsymptoms in schizophrenia are thought to result from increased dopamine activity in the striatum [77], resulting inthe aberrant attribution of salience [78] to what would oth-erwise be insignificant experiences or stimuli. This is consistent with preclinical evidence that THC increases centradopamine synthesis [79, 80], inhibits dopamine uptake [8184] and increases mesolimbic dopamine activity [85-89]. Inaddition, the highest density of CB1 receptors [for reviews

see 33, 34] are found in the predominantly dopaminergicareas of the brain [90] which are also most implicated in thegeneration of psychotic symptoms in schizophrenia [for reviews see 91, 92].

However, administration of THC not only induces psychotic symptoms in healthy individuals, it also reproducesthe other prominent domains of symptoms like negative andcognitive symptoms that are characteristic of schizophrenia[16, 75]. This is consistent with evidence that the cognitivedysfunction associated with regular cannabis use is similar inmany respects to the cognitive endophenotypes that have



Imaging the Neural Effects of Cannabinoids Current Pharmaceutical Design,2009 , Vol. 15, No. 22 260

been proposed as vulnerability markers for schizophrenia[for a review see 93]. Hence, human experimental admini-stration of THC can be a more valid model for schizophre-nia, as it more closely reproduces the different domains of symptoms characteristic of schizophrenia, than some of theother existing pharmacological models [94, 95].

NEUROIMAGING OF THE EFFECTS OF CANNABIS– IMPLICATIONS FOR DRUG DISCOVERY INSCHIZOPHRENIA

Neuroimaging provides a direct and noninvasive way ofexploring the functional state of the brain in health, diseaseor conditions of pharmacological or behavioral manipula

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 hydrolysedenzymically 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 therelease of an inhibitory neurotransmitter like GABA onto dopamine, glutamate or acetylcholine-releasing neurons.




tion. This section will focus first on the long-term effects of regular cannabis use on the brain in healthy individuals andpatients with schizophrenia, and discuss them in light of cur-rent understanding of the neural correlates of schizophrenia.Subsequently, results of studies describing the neural corre-lates of acute administration of cannabis or THC will be dis-cussed to examine how pharmacological challenge studiesinvolving administration of THC may be used as a model for

understanding the pathophysiology of schizophrenia and aidin the discovery of newer treatments.

I. Long-Term Effects of Cannabis on the Brain

Different groups have examined chronic cannabis usersusing neuroimaging techniques to explore the long-term ef-fects of cannabis on brain structure and function. While ex-amining structural changes, studies that used a whole brainanalysis approach using voxel-based morphometric (VBM)methods did not detect any significant changes in grey mat-ter volume in chronic cannabis users relative to controls [96-98]. The application of VBM methodology to structuralmagnetic resonance imaging (MRI) permits the comparisonof the volume of the gray and white matter between groupsof interest for each voxel of the cerebral volume after auto-matic image segmentation, without the need to define re-gions of interest (ROI) in advance. Studies using an ROI-based approach, which is more powerful in detecting subtlestructural alterations in predefined anatomical regions, didhowever detect grey matter changes in temporal areas [99,100] in chronic cannabis users relative to controls. This isconsistent with evidence that cannabis use or dependence inpatients with schizophrenia is associated with smaller ante-rior [101] and posterior cingulate cortex [102] and that thosepatients with schizophrenia who continue to use cannabisshow greater loss of grey matter volume than those who donot [103]. Two of the early studies that investigated the ef-fect of chronic cannabis use on the integrity of white mattertracts using diffusion tensor imaging (DTI) found no signifi-cant differences between users and controls [104, 105], but arecent study found corpus callosal damage associated withheavy cannabis use [106]. The inconsistency in findings re-ported by the various studies that have examined the effectsof chronic cannabis use on brain structure possibly suggestthat the effects on brain structure are too subtle to be de-tected using current approaches unless studies involve verylarge numbers of subjects or very heavy cannabis users whomay be slightly atypical compared to the regular chroniccannabis users [100]. However, it is interesting to note thatthe effects of cannabis use on brain structure and integrityare consistent with studies showing similar alterations in

patients with schizophrenia [107, 108].Majority of the studies examining the effect of chronic

cannabis use on the functional state of the brain, detected areduction in global cerebral blood flow (CBF) in chronicusers relative to controls [109, 110] without [109] or with[96, 110] associated reduced regional CBF (rCBF) in cere-bellar [96] or frontal regions [96, 110]. Block et al. [96] alsoreported greater rCBF in the right anterior cingulate inchronic cannabis users relative to controls. However, anearly study by Mathew et al. [111] did not detect any differ-ences in global or regional rCBF between cannabis users andcontrols. More recently, using dynamic susceptibility con-

trast MRI, Sneider et al. [112, 113] reported increased regional blood volume in the right frontal, left temporal andcerebellar areas in chronic cannabis users 6-36 hours afteabstinence [112] relative to healthy controls. However, whilestudies investigating rCBF or blood volume provide valuableinformation regarding the effects of chronic cannabis use onbrain function, they do not shed any light on how the longterm effects of cannabis use on various cognitive processe

are mediated at the neural level. Various studies have inves-tigated this by comparing the brain activation betweenchronic cannabis users and controls while performing cognitive tasks that involve processes known to be modulated bycannabis use. As the effects of cannabis on memory are wellrecognized, this has been investigated by various groups. Inone of the earliest studies, Block et al. [114] used

15[O] posi

tron emission tomography (PET) to demonstrate that poorerperformance during an associative memory task in chroniccannabis users relative to healthy controls was associatedwith lower right prefrontal activation and greater posteriorcerebellar activation. More recently, using functional MR(fMRI) Jager et al. [98] demonstrated reduced bilateral parahippocampal and right dorsolateral prefrontal activation dur

ing an associative memory task in chronic cannabis userrelative to healthy controls even when their performance wasmatched. Studies investigating the effects of chronic cannabis use on the working memory network have consistentlyreported increased activation in chronic users relative to controls despite matched performance, either in the right supe-rior, middle and inferior frontal gyri, bilateral anterior cingulate, right precentral and superior temporal gyri and basaganglia [115, 116] or in the left superior parietal cortex[116]. Effects of cannabis use on the neural network for psychomotor control have also been examined in two studiesEldreth and colleagues [28] used a modified version of theStroop task and PET to show that abstinent cannabis usershave hypoactivity in the left anterior cingulate and prefronta

cortex and hyperactivity in the hippocampus bilaterally, relative to control subjects, in the absence of any difference inperformance. They interpreted this as suggestive of an alter-native neural network to overcome persistent functionadeficits. Gruber and Yurgelun-Todd [104] also used a similatask to find lower anterior cingulate but higher mid-cingulateactivity in chronic cannabis users relative to control subjectsdespite similar task performance. Normal controls also demonstrated increased activity within the right dorsolateral prefrontal cortex (DLPFC) during the interference conditionwhile cannabis smokers, who made more errors of commission than controls during the interference condition, demonstrated a more diffuse, bilateral pattern of DLPFC activation.

The results of these neuroimaging studies that have employed cognitive tasks are difficult to compare because othe different imaging techniques and cognitive paradigmsused. Additionally, the inconsistency in results even in studies that examined similar cognitive processes may reflecconfounding effects of differences between substance usersand volunteers, and of variation in the duration of cannabisuse, its dose and pharmacological composition because othe various psychoactive ingredients in cannabis [117]. Nevertheless, they are in keeping with the general pattern of neural dysfunction noted in patients with schizophrenia [91, 92118].




II. Acute Effects of Cannabis on the Brain

a. Acute Effects of THC on Resting State Activity/Blood Flow in Brain

The earlier studies investigating the acute effects of can-nabis or THC on the brain have mainly examined this usingan experimental design in chronic or recreational cannabisusers, employing various imaging techniques ranging from133

Xe- single photon emission computed tomography(SPECT) [119-121],

15[O] H2O-PET [122-124] to

18[F] fluo-

rodeoxyglucose (FDG)-PET [125].

Relative to baseline, acute administration of THC-richcannabis extract or pure THC caused an increase in restingglobal cerebral blood flow (CBF) [120, 122, 126] as well asincreased activity in the anterior cingulate cortex and theinsula [122-124, 127], the prefrontal and orbitofrontal corti-ces [125], the cerebellum [123, 127] and the left temporallobe [119]. The effect of administration of THC-rich canna-bis extracts on activity in the basal ganglia, thalamus,amygdala and hippocampus [122, 124, 125] was less consis-tent. Again, results from these studies are difficult to com-pare and integrate because of differences in the severity andduration of cannabis use in the subjects recruited in the vari-ous studies, presence of psychiatric and drug misuse comor-bidities as well as variation in the mode, dose and purity of cannabis administered, notwithstanding the different imagingmodalities used. Other confounding factors such as toler-ance, withdrawal and sensitization to repeated use furthercomplicate the interpretation and generalization of these re-sults. However, the evidence suggests that acute cannabisadministration modulates brain function as measured usingmetabolic rate or blood flow in a wide network that includesprefrontal cortex, limbic and paralimbic areas, basal gangliaand cerebellum, consistent with the distribution of the CB1receptors in the brain [33].

b. Acute Effects of THC on Activation During CognitiveTasks

Although studies examining the acute effect of cannabisadministration on CBF and regional brain metabolism pro-vide valuable information regarding where cannabis acts inthe brain, they do not inform us about how the effects of cannabis on various cognitive and emotional processes aremediated at the neural level. Fewer studies have examinedthis in the context of cannabis research. They are summa-rized below based on the cognitive and emotional processesexamined in the context of acute administration of cannabisor THC.

Attention

In a series of studies, O’Leary and colleagues [128-130]used

15[O] H2O PET to examine how acute cannabis chal-

lenge modulated neural activation related to different cogni-tive processes. They demonstrated that in recreational can-nabis users [128] relative to placebo, acute cannabis admini-stration increased the regional CBF in the orbital and mesialfrontal lobes, insula, temporal poles, anterior cingulate andcerebellum despite intact performance during an auditoryattention (dichotic listening) task. They interpreted theseeffects as being related to the effects of cannabis on mood.They also noted reduced CBF in the temporal lobe auditory

regions, visual cortex, and in an attentional network comprising the parietal lobe, frontal lobe and thalamus, which theyinterpreted as underlying the perceptual and cognitive alterations caused by cannabis. In a recent study [130] occasionacannabis users performed a reaction time baseline task anddichotic listening task with attend-right- and attend-left-eainstructions. Using PET, the authors demonstrated that relative to placebo, acute cannabis administration resulted in

increase in normalized regional CBF in the orbital frontacortex, anterior cingulate, temporal pole, insula, and cerebellum and decrease in regional CBF in the visual and auditorycortices. Although cannabis lowered regional CBF in theauditory cortices compared to placebo, it did not alter thenormal pattern of attention-related regional CBF asymmetry(i.e., greater regional CBF in the temporal lobe contralaterato the direction of attention) that was also observed afterplacebo. The authors interpreted these results as indicatingthat while cannabis had dramatic direct effects on regionaCBF, it caused relatively little change in the normal patternof task-related regional CBF during this auditory focusedattention task.

Time Perception

In another study [129], O’Leary and colleagues examinedthe effect of acute cannabis administration in recreationaand chronic cannabis users while they performed a selfpaced counting task during PET imaging. Relative to pla-cebo, cannabis increased regional CBF in the ventral forebrain and cerebellar cortex in both groups, but resulted insignificantly less frontal lobe activation in chronic users. Therate of counting increased after smoking cannabis in bothgroups, as did a behavioral measure of self-paced tappingBoth these increases correlated with regional CBF in thecerebellum, which the authors interpreted as evidence ofcannabis accelerating the cerebellar clock resulting in alteration in self-paced behaviours.

Response Inhibition

Borgwardt et al. [131] used a task that involved the inhi-bition of prepotent motor responses in conjunction withfMRI and found that acute administration of THC attenuatedactivation in the right inferior frontal and anterior cingulatedgyrus, part of the normal inhibitory control network. This iof interest not just in the context of understanding how cannabis modulates these processes in the brain, but also because neurophysiological studies [132, 133] suggest an in-hibitory deficit as a central pathophysiologic mechanism inpsychotic disorders and as abnormal activation of the network underlying motor response inhibition is well documented in schizophrenia [134, 135]. Although psychomotor

control is a prominent acute effect of cannabis [13, 19, 20136], modulation of its neural correlates by THC have nevebeen investigated before. Both the neuroimaging studies thahave examined this in the context of cannabis use [28, 104]have employed modified versions of the classic Stroop taskwhich is not a pure response inhibition task as it also meas-ures cognitive inhibition, i.e. inhibition of interference andselective attention.

Verbal Learning

Although impairment in learning and memory is one ofthe most prominent acute cognitive effects of cannabis and




THC in healthy individuals [16, 17] and possibly the onlydomain that continues to be impaired in chronic users [26], itis not known where cannabis or its main psychoactive ingre-dient, THC acts in the human brain to cause these impair-ments. This is also critical to understanding the neurobiologyof the cannabis- psychosis link as verbal memory is one of the key neuropsychological impairments in schizophrenia[137]. As the main central cannabinoid (CB1) receptors have

a high density in the medial temporal and prefrontal cortex[33], areas critical to learning and memory [138, 139] andTHC affects both medial temporal and memory function inexperimental animals [140], it may thus influence learningand memory by modulating function in these regions. How-ever, this has never been experimentally demonstrated inhumans. Bhattacharyya et al. [75] used fMRI in conjunctionwith oral administration of THC in a group of occasionalcannabis users to investigate this. They demonstrate that thenormal linear decremental response in activation in the me-dial temporal cortex during verbal learning and its relation-ship to memory performance was disrupted by THC, suchthat there was an augmentation of medial temporal activationand the relationship between medial temporal activation and

memory performance was no longer evident. THC also at-tenuated ventral striatal activation such that the effect of THC on ventral striatal activation correlated with the sever-ity of psychotic symptoms induced by it concurrently. This ispossibly of more direct relevance to understanding the neu-robiology of the cannabis- psychosis link. Although it hasbeen hypothesized that the induction of psychotic symptomsby cannabis reflects a secondary effect of THC on dopaminerelease in the striatum [2] and recent evidence obtained usingPET suggests that THC may acutely modulate dopaminerelease in this area [141], it was not clear until recentlywhether the effect of THC on the human striatum underliethe acute induction of psychotic symptoms by cannabis andTHC.

Emotional Processing

Phan et al. [142] employed an emotional face processingtask to examine the acute effect of THC to social signals of threat (fearful and angry faces) in healthy recreational can-nabis users using a placebo-controlled design. The authorsreported reduced amygdala reactivity to social signals of threat in the absence of modulation of activity in the primaryvisual and motor cortex and interpreted this as indicative of the anxiolytic effect of low dose of THC. Lack of measur-able behavioural effects on anxiety reduction in the study byPhan et al. [142] however limits the interpretability of theirfindings, especially as THC commonly increases anxiety inoccasional users, similar to the subjects used in their study.

However, this apparently conflicting result may also reflectthe bimodal effect of cannabinoids on anxiety, with lowerdoses of THC having anxiolytic and higher doses havinganxiogenic effects [143].

III. Potential for Drug Discovery

Most psychoactive drugs act on multiple receptors in theCNS with differing levels of efficacy and thus modulatemultiple neurotransmitter systems. fMRI allows the exami-nation of the combined or integrated effects on these neuro-transmitters independent of the specific molecular mecha-

nism of action of the drug, thus allowing a systems leveevaluation of the circuit underlying a specific cognitiveprocess or behaviour modulated by the drug [144]. Used inconjunction with pharmacological challenge involving psychoactive drugs that have specific symptomatic effects likepsychotic or mood symptoms as in the case of cannabis orecstasy, they can help understand the neurobiological substrate for psychotic or mood disorders respectively. fMRI

studies of the effects of cannabinoids may thus provide a‘neural signature’ of a specific cognitive process or behaviour modulated by the specific cannabinoid in health or dis-ease. For example, work by Bhattacharyya et al. [75] suggests that the attenuation of ventral striatal activation may beconsidered as a ‘neural signature’ of the psychotic symptominduced by THC.When combined with other molecular imaging techniques like PET or magnetic resonance spectroscopy (MRS) which allow measurement of neurotransmitterlike dopamine and its receptors or glutamate and GABArespectively, such studies can help characterize the neurocognitive and neurochemical underpinnings of the specificcognitive processes or behaviours in health or disease. Thimay in turn help in the identification of newer targets fo

drug discovery in schizophrenia. As human experimentaadministration of THC closely models the different symptomdomains characteristic of schizophrenia, human pharmacological imaging studies involving experimental administration of THC may complement existing animal models, andinform our understanding about the neurobiology of schizo-phrenia. Additionally, such studies may not only help delineate the neurobiology of the cognitive and symptomatic effects of cannabis and inform our understanding of themechanistic link between cannabis use and schizophreniabut critically, may also help in the development of a morereliable and accurate pharmacological model for schizophrenia. ‘Neural signatures’ of specific cognitive and symptomatic effects of THC may be characterized by combining

pharmacological challenge in healthy volunteers and fMRusing specific, reproducible and well-characterized stimulthat engage processes modulated by THC and known to beimpaired in schizophrenia.

Traditionally, initial identification of a therapeutic candidate molecule for a neuropsychiatric condition is influencedmainly by existing knowledge about its pharmacologicaproperties in terms of the receptors and/or neurotansmittermodulated by it. However, it is seldom possible to describe aspecific cognitive process or behaviour in terms of change ina specific receptor or neurotransmitter in the brain, let alonecomplex and heterogeneous neuropsychiatric disorders likeschizophrenia, which not only involve abnormalities in mul

tiple behavioral and cognitive domains, but may have multiple and as yet unclear aetiologies [9]. As modulation of aspecific central receptor or neurotransmitter seldom occurs inisolation in the human brain, therapeutic candidate moleculechosen on the basis of specific characterization of their re-ceptor and neurotransmitter profiles in animal and in vitro

models often fail during clinical trials. Thus, although sup-ported by preclinical evidence that predicted efficacy [145]initial clinical trial data suggest that CB1 antagonists maynot be efficacious in schizophrenia [146]. fMRI used in conjunction with pharmacological challenge may play an impor-tant role by helping in identifying such potential candidates




with greater accuracy and speed [144, 147]. By comparingthe effects of potential therapeutic candidate molecules onthe ‘neural signatures’ of THC against the effects of knowntherapeutic agents (eg. antipsychotics) with proven clinicalutility, it may be possible to identify with greater accuracyand reliability preclinical candidates which are likely toprove efficacious in clinical trials. Thus this may hasten thespeed of identification of potential candidate molecules and

substantially reduce the failure rates of such candidates inclinical trials.

NEUROIMAGING EVIDENCE OF THE BENEFICIALEFFECTS OF OTHER CANNABINOIDS IN MENTALILLNESSES

Although THC in high doses is known to induce anxietyand psychotic symptoms and impair various cognitive func-tions, not all cannabinoids present in cannabis sativa are badfor mental health. As noted earlier, there is accumulatingevidence for the potential beneficial effects of CBD in vari-ous neuropsychiatric conditions. This section will brieflydescribe the preclinical evidence and then discuss the com-plementary evidence emerging from neuroimaging studiesinvolving the administration of CBD that support these hy-potheses.

I. Evidence for Anxiolytic Potential of CBD

Preclinical evidence regarding the anxiolytic potential of CBD have come from observations in laboratory animalsthat this cannabinoid had effects similar to known anxiolyticdrugs in conditioned emotional paradigms [148], the Vogelconflict test [149], and the elevated plus maze test [47, 150,151]. CBD was also found to attenuate the anxiogenic effectof THC in healthy human volunteers [46] and to reduceanxiety in volunteers submitted to the simulation of publicspeaking test [152]. These effects did not appear to involve

any pharmacokinetic interaction [46, 153]. Although theprecise molecular mechanisms underlying the anxiolyticeffect of cannabidiol are far from clear, a series of studiesnow provide complementary evidence that not only supportsthe anxiolytic potential, but also delineates the neural corre-lates of such effect. Crippa et al. [48] carried out the firstneuroimaging study investigating the neural correlates of theanxiolytic effects of this constitutent of cannabis. Using sin-gle photon emission computed tomography (SPECT) in conjunction with oral administration of CBD (400 mg) in a dou-ble-blind placebo-controlled, cross-over design, they showedthat the anxiolytic effect of CBD in healthy volunteers wasassociated with increased activity in the left parahippocam-pal gyrus, as well as reduced activity in the left amygdala-

hippocampus complex and left posterior cingulate gyrus.More recently, Fusar-Poli et al. [49] used fMRI, which per-mitted the acquisition of greater numbers of images withbetter 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 wereprocessing intensely fearful stimuli, attenuating responses inthe amygdala and the anterior and posterior cingulate corti-ces. Also, the attenuation of activation in the amygdala andthe posterior cingulate gyrus were directly correlated withthe concomitant effect of CBD in modulating the elec-

trodermal responses to fearful stimuli. More recently, Crippaet al. (2009)

1carried out the first study investigating the neu

ral correlates of the anxiolytic effects of CBD in a clinicasample, using a similar design as in their previous study [48]They show that a single oral dose of CBD (400 mg) reducedsubjective measures of anxiety without increasing sedationin patients with Social Anxiety disorder, which was associated with decreased activity in the left parahippocampa

gyrus and hippocampus, extending to the inferior temporagyrus. They also found a positive correlation between theeffects of CBD on activity in the amygdala bilaterally and aclear reduction in subjective ratings of anxiety. Taken to-gether, the modulatory effects of CBD on limbic and para-limbic activation as demonstrated in these studies are consistent with current understanding regarding the neural sub-strate of anxiety in health and psychiatric disorders [154] anda potential role for CBD in ameliorating clinically significananxiety. However, future double-blind placebo-controlledstudies would be necessary to further confirm these observations in patients with anxiety disorders.

II. Evidence for Antipsychotic Potential of CBD

Evidence for the potential antipsychotic effect of CBDfirst came from two simultaneous but separate observationsZuardi et al. [46] observed that it reduced the psychotic-likesymptoms induced by THC in healthy individuals. Aroundthe same time, Rottanburg et al. [155] reported the association between psychosis and consumption of a South Africanvariant of cannabis sativa with high levels of THC and absent CBD. Subsequently, in studies using standard animamodels of antipsychotic activity, CBD has been shown tohave a profile similar to that of an atypical antipsychoticdrug [156-158]. CBD was also found to attenuate the disruption of prepulse inhibition induced by NMDA antagonists inmice [159] and the CBD content of cannabis extracts wasrelated to greater amplitude of auditory evoked mismatchnegativity [160], further suggestive of a potential antipsychotic effect. A recent fMRI study carried out in conjunctionwith pharmacological challenge with cannabinoids furthersupports the antipsychotic potential of CBD, as the net effecof CBD on brain function and behaviour was observed to beopposite to that of THC in healthy individuals [Bhattach-aryya et al., 2008]

2. This is consistent with complementary

evidence suggesting its efficacy in reducing the psychoticsymptoms in Parkinson’s disease [52] and is also supportedby evidence that individuals smoking strains of cannabiscontaining CBD in addition to THC were less likely to experience psychotic-like symptoms than those smoking cannabiwithout CBD [161]. However, double-blind randomised con

trolled trials need to demonstrate the efficacy of CBD eitheras an antipsychotic in individuals with pre-existing psychoticconditions like schizophrenia or in ameliorating the psychiatric consequences of cannabis use.

_____________________________1

Jose A Crippa, personal communication, 2009.2 Bhattacharyya S, Fusar-Poli P, Borgwardt S, Martin-Santos R, O’Carroll C, Seal M

Crippa J, Atakan Z, McGuire PK. Opposite effects of cannabis ingredients in the brain

neural basis for potential antipsychotic effect of cannabidiol. Presented at the 21

European College of Neuropsychopharmacology Congress, Barcelona, September2008.




FUTURE DIRECTION

Neuroimaging studies examining the acute and chroniceffects of cannabinoids have informed our understanding of the biological basis of the link between cannabis use andschizophrenia. However, the neurochemical and specificneurocognitive underpinnings of this association are stillunclear. Understanding these mechanisms is critical as,among the known aetiological factors of schizophrenia, can-

nabis use is arguably the most potentially modifiable. Mo-lecular imaging techniques like MRS and PET in conjunc-tion with pharmacological challenge of cannabinoids canhelp unravel the perturbation of glutamate and dopaminelevels respectively that may be related to the induction of psychotic symptoms by cannabis and THC. Newer PET ra-dioligands like

11[C] MePPEP [162] which bind to CB1 re-

ceptors allow in vivo characterization of the human endocan-nabinoid system in health as well as in diseases like schizo-phrenia, thus allowing the examination of any possiblepathogenetic link [163]. Used in conjunction with pharma-cological challenge involving THC this may also help under-stand the relationship between the symptomatic effects of THC and CB1 receptor function in healthy individuals. Un-ravelling these links and mechanisms may help identify po-tential targets for the development of newer drugs forschizophrenia, particularly those that may target the can-nabinoid or glutamatergic system. Further studies using mul-timodal neuroimaging are also warranted that explore theneurochemical mechanisms underlying the potential benefi-cial effects of CBD as an anxiolytic or antipsychotic agent.They may also indicate a role for CBD as a treatment for theadverse psychiatric consequences of cannabis use in the gen-eral population [42] or in those with pre-existing psychiatricdisorders, particularly as conventional antipsychotic medica-tions may be ineffective for such conditions [165]. Its neuro-protective effects and favourable safety profile [42, 165,166] suggest that CBD might be particularly useful in indi-viduals with neuropsychiatric conditions, in whom use of dopaminergic antipsychotics is unsatisfactory because of their side-effect profile. Pharmacological imaging studiesutilizing an experimental design involving CBD challengemay thus provide proof of concept of the therapeutic benefitof this molecule that can serve as a basis for future clinicaltrials.

ACKNOWLEDGEMENTS

Sagnik Bhattacharyya is supported by a Joint MRC/ Pri-ory Clinical research training fellowship from the MedicalResearch Council, UK. Jose A Crippa is recipient of a Con-selho Nacional de Desenvolvimento Científico e Tec-

nológico (CNPq, Brazil) Productivity fellowship.The authorsdeclare no competing interests.

ABBREVIATIONS

THC = Delta-9-tetrahydrocannabinol

CBD = Cannabidiol

DLPFC = Dorsolateral prefrontal cortex

PET = Positron emission tomography

SPECT = Single photon emission computed tomography

MRI = Magnetic resonance imaging

fMRI = Functional magnetic resonance imaging

MRS = Magnetic resonance spectroscopy

DTI = Diffusion tensor imaging

CBF = Cerebral blood flow

rCBF = Regional cerebral blood flow

ROI = Regions of interest

VBM = Voxel-based morphometry

GABA = Aminobutyric acid

5-HT = 5-Hydroxytryptamine (serotonin)

FDG = Fluorodeoxyglucose

REFERENCES

References 167-169 are related articles recently published.

[1] Ameri A. The effects of cannabinoids on the brain. Prog Neurobio1999; 58(4): 315-48.

[2] Murray RM, Morrison PD, Henquet C, Di Forti M. Cannabis, th

mind and society: the hash realities. Nat Rev Neurosci 2007; 8(11)885-95.[3] Di Marzo V, De Petrocellis L. Plant, synthetic, and endogenou

cannabinoids in medicine. Annu Rev Med 2006; 57: 553-74.[4] Watson SJ, Benson JA, Jr., Joy JE. Marijuana and medicine: as

sessing the science base: a summary of the 1999 Institute of Medicine report. Arch Gen Psychiatry 2000; 57(6): 547-52.

[5] Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PBBurke M, et al. Cannabis use and risk of psychotic or affectiv

mental health outcomes: a systematic review. Lancet 28 2007370(9584): 319-28.

[6] World Drug Report UNODC. United Nations Office on Drugs anCrime [online]. http: //www.unodc.org/documents/wdr/WDR_

2008_eng_web.pdf. [Accessed on Jan 1, 2009].[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 othecannabinoids in cannabis in England in 2005: implications for psy

choactivity and pharmacology. J Forensic Sci 2008; 53(1): 90-4.[9] Carpenter WT, Koenig JI. The evolution of drug development in

schizophrenia: past issues and future opportunities. Neuropsychopharmacology 2008; 33(9): 2061-79.

[10] Pacher P, Batkai S, Kunos G. The endocannabinoid system as anemerging target of pharmacotherapy. Pharmacol Rev 2006; 58(3)

389-462.[11] Mechoulam R, Gaoni Y. Recent advances in the chemistry of hash

ish. Fortschr Chem Org Naturst 1967; 25: 175-213.[12] Mechoulam R, Shani A, Edery H, Grunfeld Y. Chemical basis o

hashish activity. Science 1970; 169(945): 611-2.[13] Hall W, Solowij N. Adverse effects of cannabis. Lancet 1998

352(9140): 1611-6.[14] Tart CT. Marijuana intoxication common experiences. Natur

1970; 226(5247): 701-4.[15] Talbott JA, Teague JW. Marihuana psychosis. Acute toxic psycho

sis associated with the use of Cannabis derivatives. JAMA 1969

210(2): 299-302.[16] D'Souza DC, Perry E, MacDougall L, Ammerman Y, Cooper TWu YT, et al. The psychotomimetic effects of intravenous delta-9

tetrahydrocannabinol in healthy individuals: implications for psychosis. Neuropsychopharmacology 2004; 29(8): 1558-72.

[17] Curran HV, Brignell C, Fletcher S, Middleton P, Henry J. Cognitive and subjective dose-response effects of acute oral Delta 9

tetrahydrocannabinol (THC) in infrequent cannabis users. Psychopharmacology (Berl) 2002; 164(1): 61-70.

[18] Ranganathan M, D'Souza DC. The acute effects of cannabinoids onmemory in humans: a review. Psychopharmacology (Berl) 2006

188(4): 425-44.[19] Hart CL, van Gorp W, Haney M, Foltin RW, Fischman MW. Ef

fects of acute smoked marijuana on complex cognitive performance. Neuropsychopharmacology 2001; 25(5): 757-65.




[20] McDonald J, Schleifer L, Richards JB, de Wit H. Effects of THC

on behavioral measures of impulsivity in humans. Neuropsycho-pharmacology 2003; 28(7): 1356-65.

[21] Ramaekers JG, Moeller MR, van Ruitenbeek P, Theunissen EL,Schneider E, Kauert G. Cognition and motor control as a function

of Delta9-THC concentration in serum and oral fluid: limits of im-pairment. Drug Alcohol Depend 2006; 85(2): 114-22.

[22] Ramaekers J, Kauert G, Theunissen E, Toennes S, Moeller M.Neurocognitive performance during acute THC intoxication in

heavy and occasional cannabis users. J Psychopharmacol 2008.

[23] Ilan AB, Smith ME, Gevins A. Effects of marijuana on neuro-physiological signals of working and episodic memory. Psycho-pharmacology (Berl) 2004; 176(2): 214-22.

[24] Pope HG, Jr., Yurgelun-Todd D. The residual cognitive effects of heavy marijuana use in college students. JAMA 1996; 275(7): 521-

7.[25] Pope HG, Jr., Gruber AJ, Hudson JI, Huestis MA, Yurgelun-Todd

D. Neuropsychological performance in long-term cannabis users.Arch Gen Psychiatry 2001; 58(10): 909-15.

[26] Solowij N, Stephens RS, Roffman RA, Babor T, Kadden R, MillerM, et al. Cognitive functioning of long-term heavy cannabis users

seeking treatment. Jama 2002; 287(9): 1123-31.[27] Pope HG, Jr. Cannabis, cognition, and residual confounding.

JAMA 2002; 287(9): 1172-4.[28] Eldreth DA, Matochik JA, Cadet JL, Bolla KI. Abnormal brain

activity in prefrontal brain regions in abstinent marijuana users.Neuroimage 2004; 23(3): 914-20.

[29] Howlett AC. The cannabinoid receptors. Prostagland Lipid Mediat2002; 68-69: 619-31.

[30] Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol

and delta9-tetrahydrocannabivarin. Br J Pharmacol 2008; 153(2):199-215.

[31] Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI.Structure of a cannabinoid receptor and functional expression of

the cloned cDNA. Nature 1990; 346(6284): 561-4.[32] Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de

Costa BR, et al. Cannabinoid receptor localization in brain. ProcNatl Acad Sci USA 1990; 87(5): 1932-6.

[33] Elphick MR, Egertova M. The neurobiology and evolution of can-nabinoid signalling. Philos Trans R Soc Lond B Biol Sci 2001;

356(1407): 381-408.[34] Eggan SM, Lewis DA. Immunocytochemical distribution of the

cannabinoid CB1 receptor in the primate neocortex: a regional and

laminar analysis. Cereb Cortex 2007; 17(1): 175-91.[35] Szabo B, Schlicker E. Effects of cannabinoids on neurotransmis-

sion. Handb Exp Pharmacol 2005(168): 327-65.

[36] Kreitzer AC. Neurotransmission: emerging roles of endocannabi-noids. Curr Biol 2005; 15(14): R549-51.

[37] Pertwee RG, Ross RA. Cannabinoid receptors and their ligands.Prostaglandins Leukot Essent Fatty Acids 2002; 66(2-3): 101-21.

[38] Pistis M, Ferraro L, Pira L, Flore G, Tanganelli S, Gessa GL, et al.

Delta(9)-tetrahydrocannabinol decreases extracellular GABA and

increases extracellular glutamate and dopamine levels in the ratprefrontal cortex: an in vivo microdialysis study. Brain Res 2002;

948(1-2): 155-8.[39] Gardner EL. Endocannabinoid signaling system and brain reward:

emphasis on dopamine. Pharmacol Biochem Behav 2005; 81(2):263-84.

[40] Nagai H, Egashira N, Sano K, Ogata A, Mizuki, K, Iwasaki K, et

al. Antipsychotics improve Delta9-tetrahydrocannabinol-induced

impairment of the prepulse inhibition of the startle reflex in mice.Pharmacol Biochem Behav 2006; 84(2): 330-6.

[41] Pisanu A, Acquas E, Fenu S, Di Chiara G. Modulation of Delta(9)-THC-induced increase of cortical and hippocampal acetylcholine

release by micro opioid and D(1) dopamine receptors. Neurophar-macology 2006; 50(6): 661-70.

[42] Zuardi AW. Cannabidiol: from an inactive cannabinoid to a drugwith wide spectrum of action. Rev Bras Psiquiatr 2008; 30(3): 271-

80.[43] Carlini EA, Leite JR, Tannhauser M, Berardi AC. Letter: Can-

nabidiol and Cannabis sativa extract protect mice and rats againstconvulsive agents. J Pharm Pharmacol 1973; 25(8): 664-5.

[44] Izquierdo I, Orsingher OA, Berardi AC. Effect of cannabidiol andof other cannabis sativa compounds on hippocampal seizure dis-

charges. Psychopharmacologia 1973; 28(1): 95-102.

[45] Cunha JM, Carlini EA, Pereira AE, Ramos OL, Pimentel C, Ga

gliardi R, et al. Chronic administration of cannabidiol to healthyvolunteers and epileptic patients. Pharmacology 1980; 21(3): 175

85.[46] Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG. Action of can

nabidiol on the anxiety and other effects produced by delta 9-THCin normal subjects. Psychopharmacology (Berl) 1982; 76(3): 245

50.[47] Guimaraes FS, Chiaretti TM, Graeff FG, Zuardi AW. Antianxiety

effect of cannabidiol in the elevated plus-maze. Psychopharma

cology (Berl) 1990; 100(4): 558-9.[48] Crippa JA, Zuardi AW, Garrido GE, Wichert-Ana L, Guarnieri R

Ferrari L, et al. Effects of cannabidiol (CBD) on regional cerebra

blood flow. Neuropsychopharmacology 2004; 29(2): 417-26.[49] Fusar-Poli P, Crippa JA, Bhattacharyya S, Borgwardt SJ, Allen P

Martin-Santos R, et al. Distinct effects of {delta}9tetrahydrocannabinol and cannabidiol on neural activation during

emotional processing. Arch Gen Psychiatry 2009; 66(1): 95-105.[50] Zuardi AW, Hallak JE, Dursun SM, Morais SL, Sanches RF

Musty RE, et al. Cannabidiol monotherapy for treatment-resistanschizophrenia. J Psychopharmacol 2006; 20(5): 683-6.

[51] Malfait AM, Gallily R, Sumariwalla PF, Malik AS, Andreakos EMechoulam R, et al. The nonpsychoactive cannabis constituen

cannabidiol is an oral anti-arthritic therapeutic in murine collageninduced arthritis. Proc Natl Acad Sci USA 2000; 97(17): 9561-6.

[52] Zuardi A, Crippa J, Hallak J, Pinto J, Chagas M, Rodrigues G, e

al. Cannabidiol for the treatment of psychosis in Parkinson's dis

ease. J Psychopharmacol 2008.[53] Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO. Can

nabidiol--recent advances. Chem Biodivers 2007; 4(8): 1678-92.[54] Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA

Pertwee RG. Cannabidiol displays unexpectedly high potency as anantagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharma

col 2007; 150(5): 613-23.[55] Hampson AJ, Grimaldi M, Axelrod J, Wink D. Cannabidiol and (

)Delta9-tetrahydrocannabinol are neuroprotective antioxidantsProc Natl Acad Sci USA 1998; 95(14): 8268-73.

[56] Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DEBrandi I, et al. Molecular targets for cannabidiol and its syntheti

analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmaco

2001; 134(4): 845-52.[57] Carrier EJ, Auchampach JA, Hillard CJ. Inhibition of an equilibra

tive nucleoside transporter by cannabidiol: a mechanism of can

nabinoid immunosuppression. Proc Natl Acad Sci USA 2006103(20): 7895-900.

[58] Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties o

cannabidiol at 5-HT1a receptors. Neurochem Res 2005; 30(8)1037-43.

[59] Ryberg E, Larsson N, Sjogren S, Hjorth S, Hermansson NOLeonova J, et al. The orphan receptor GPR55 is a novel cannabi

noid receptor. Br J Pharmacol 2007; 152(7): 1092-101.[60] Andreasson S, Allebeck P, Engstrom A, Rydberg U. Cannabis and

schizophrenia. A longitudinal study of Swedish conscripts. Lance1987; 2(8574): 1483-6.

[61] Boydell J, van Os J, Caspi A, Kennedy N, Giouroukou E, Fearon Pet al. Trends in cannabis use prior to first presentation with schizo

phrenia, in South-East London between 1965 and 1999. PsychoMed 2006; 36(10): 1441-6.

[62] Dean B, Sundram S, Bradbury R, Scarr E, Copolov D. Studies on[3H]CP-55940 binding in the human central nervous system: re

gional specific changes in density of cannabinoid-1 receptors associated with schizophrenia and cannabis use. Neuroscience 2001

103(1): 9-15.[63] Zavitsanou K, Garrick T, Huang XF. Selective antagonis

[3H]SR141716A binding to cannabinoid CB1 receptors is increased in the anterior cingulate cortex in schizophrenia. Prog Neu

ropsychopharmacol Biol Psychiatry 2004; 28(2): 355-60.[64] Newell KA, Deng C, Huang XF. Increased cannabinoid recepto

density in the posterior cingulate cortex in schizophrenia. ExpBrain Res 2006; 172(4): 556-60.

[65] Eggan SM, Hashimoto T, Lewis DA. Reduced cortical cannabinoid1 receptor messenger RNA and protein expression in schizophre

nia. Arch Gen Psychiatry 2008; 65(7): 772-84.




[66] Leweke FM, Giuffrida A, Wurster U, Emrich HM, Piomelli D.

Elevated endogenous cannabinoids in schizophrenia. Neuroreport1999; 10(8): 1665-9.

[67] De Marchi N, De Petrocellis L, Orlando P, Daniele F, Fezza F, DiMarzo V. Endocannabinoid signalling in the blood of patients with

schizophrenia. Lipids Health Dis 2003; 2: 5.[68] Giuffrida A, Leweke FM, Gerth CW, Schreiber D, Koethe D, Faul-

haber J, et al. Cerebrospinal anandamide levels are elevated inacute schizophrenia and are inversely correlated with psychotic

symptoms. Neuropsychopharmacology 2004; 29(11): 2108-14.

[69] Henquet C, Krabbendam L, Spauwen J, Kaplan C, Lieb R, Witt-chen HU, et al. Prospective cohort study of cannabis use, predispo-sition for psychosis, and psychotic symptoms in young people. Bmj

2005; 330(7481): 11.[70] Linszen DH, Dingemans PM, Nugter MA, Van der Does AJ,

Scholte WF, Lenior MA. Patient attributes and expressed emotionas risk factors for psychotic relapse. Schizophr Bull 1997; 23(1):

119-30.[71] Hides L, Dawe S, Kavanagh DJ, Young RM. Psychotic symptom

and cannabis relapse in recent-onset psychosis. Prospective study.Br J Psychiatry 2006; 189: 137-43.

[72] Isaac M, Isaac M, Holloway F. Is cannabis an anti-antipsychotic?The experience in psychiatric intensive care. Hum Psychopharma-

col 2005; 20(3): 207-10.[73] Miles H, Johnson S, Amponsah-Afuwape S, Finch E, Leese M,

Thornicroft G. Characteristics of subgroups of individuals withpsychotic illness and a comorbid substance use disorder. Psychiatr

Serv 2003; 54(4): 554-61.[74] Kristensen K, Cadenhead KS. Cannabis abuse and risk for psycho-

sis in a prodromal sample. Psychiatry Res 30 2007; 151(1-2): 151-4.

[75] Bhattacharyya S, Fusar-Poli P, Borgwardt S, Martin-Santos R,Nosarti C, O' Carroll C, et al. Delta-9-tetrahydrocannabinol modu-

lates medial temporal and striatal function in humans: a neural ba-sis for the effects of cannabis on learning and psychosis. Archives

of General Psychiatry ( In Press). [76] D'Souza DC, Abi-Saab WM, Madonick S, Forselius-Bielen K,

Doersch A, Braley G, et al. Delta-9-tetrahydrocannabinol effects inschizophrenia: implications for cognition, psychosis, and addiction.

Biol Psychiatry 2005; 57(6): 594-608.[77] Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers

M, et al. Increased striatal dopamine transmission in schizophrenia:confirmation in a second cohort. Am J Psychiatry 1998; 155(6):

761-7.

[78] Kapur S. Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophre-nia. Am J Psychiatry 2003; 160(1): 13-23.

[79] Bloom AS, Dewey WL. A comparison of some pharmacologicalactions of morphine and delta9-tetrahydrocannabinol in the mouse.

Psychopharmacology (Berl) 1978; 57(3): 243-8.[80] Maitre L, Staehelin M, Bein HJ. Effect of an extract of cannabis

and of some cannabinols on catecholamine metabolism in rat brainand heart. Agents Actions 1970; 1(3): 136-43.

[81] Banerjee SP, Snyder SH, Mechoulam R. Cannabinoids: influenceon neurotransmitter uptake in rat brain synaptosomes. J Pharmacol

Exp Ther 1975; 194(1): 74-81.[82] Hershkowitz M, Szechtman H. Pretreatment with delta 1-

tetrahydrocannabinol and psychoactive drugs: effects on uptake of biogenic amines and on behavior. Eur J Pharmacol 1979; 59(3-4):

267-76.[83] Poddar MK, Dewey WL. Effects of cannabinoids on catecholamine

uptake and release in hypothalamic and striatal synaptosomes. JPharmacol Exp Ther 1980; 214(1): 63-7.

[84] Sakurai-Yamashita Y, Kataoka Y, Fujiwara M, Mine K, Ueki S.Delta 9-tetrahydrocannabinol facilitates striatal dopaminergic

transmission. Pharmacol Biochem Behav 1989; 33(2): 397-400.[85] Chen JP, Paredes W, Li J, Smith D, Lowinson J, Gardner EL. Delta

9-tetrahydrocannabinol produces naloxone-blockable enhancementof presynaptic basal dopamine efflux in nucleus accumbens of con-

scious, freely-moving rats as measured by intracerebral microdialy-sis. Psychopharmacology (Berl) 1990; 102(2): 156-62.

[86] Chen JP, Paredes W, Lowinson JH, Gardner EL. Strain-specificfacilitation of dopamine efflux by delta 9-tetrahydrocannabinol in

the nucleus accumbens of rat: an in vivo microdialysis study. Neu-rosci Lett 1991; 129(1): 136-80.

[87] French ED. delta9-Tetrahydrocannabinol excites rat VTA dopa

mine neurons through activation of cannabinoid CB1 but not opioireceptors. Neurosci Lett 1997; 226(3): 159-62.

[88] Tanda G, Pontieri FE, Di Chiara G. Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu

opioid receptor mechanism. Science 1997; 276(5321): 2048-50.[89] Robledo P, Trigo JM, Panayi F, de la Torre R, Maldonado R. Be

havioural and neurochemical effects of combined MDMA andTHC administration in mice. Psychopharmacology (Berl) 2007

195(2): 255-64.

[90] Seamans JK, Yang CR. The principal features and mechanisms odopamine modulation in the prefrontal cortex. Prog Neurobiol. Sep2004; 74(1): 1-58.

[91] Ross CA, Margolis RL, Reading SA, Pletnikov M, Coyle JT. Neurobiology of schizophrenia. Neuron 2006; 52(1): 139-53.

[92] Allen P, Aleman A, McGuire PK. Inner speech models of auditoryverbal hallucinations: evidence from behavioural and neuroimaging

studies. Int Rev Psychiatry 2007; 19(4): 407-15.[93] Solowij N, Michie PT. Cannabis and cognitive dysfunction: paral

lels with endophenotypes of schizophrenia? J Psychiatry Neurosc2007; 32(1): 30-52.

[94] Krystal JH, Perry EB, Jr., Gueorguieva R, Belger A, Madonick SHAbi-Darghum A, et al. Comparative and interactive human psy

chopharmacologic effects of ketamine and amphetamine: implications for glutamatergic and dopaminergic model psychoses an

cognitive function. Arch Gen Psychiatry 2005; 62(9): 985-94.[95] Fletcher PC, Honey GD. Schizophrenia, ketamine and cannabis

evidence of overlapping memory deficits. Trends Cogn Sci 200610(4): 167-74.

[96] Block RI, O'Leary DS, Ehrhardt JC, Augustinack JC, GhoneimMM, Arndt S, et al. Effects of frequent marijuana use on brain tis

sue volume and composition. Neuroreport 2000; 11(3): 491-6.[97] Tzilos GK, Cintron CB, Wood JB, Simpson NS, Young AD, Pop

HG Jr, et al. Lack of hippocampal volume change in long-termheavy cannabis users. Am J Addict 2005; 14(1): 64-72.

[98] Jager G, Van Hell HH, De Win MM, Kahn RS, Van Den Brink WVan Ree JM, et al. Effects of frequent cannabis use on hippocam

pal activity during an associative memory task. Eur Neuropsychopharmacol 2007; 17(4): 289-97.

[99] Matochik JA, Eldreth DA, Cadet JL, Bolla KI. Altered brain tissucomposition in heavy marijuana users. Drug Alcohol Depend 2005

77(1): 23-30.[100] Yucel M, Solowij N, Respondek C, Whittle S, Fornito A, Panteli

C, et al. Regional brain abnormalities associated with long-term

heavy cannabis use. Arch Gen Psychiatry 2008; 65(6): 694-701.[101] Szeszko PR, Robinson DG, Sevy S, Kumra S, Rupp CI, Betensky

JD, et al. Anterior cingulate grey-matter deficits and cannabis us

in first-episode schizophrenia. Br J Psychiatry 2007; 190: 230-6.[102] Bangalore SS, Prasad KM, Montrose DM, Goradia DD, Diwadka

VA, Keshavan MS. Cannabis use and brain structural alterations infirst episode schizophrenia--a region of interest, voxel based mor

phometric study. Schizophr Res 2008; 99(1-3): 1-6.[103] Rais M, Cahn W, Van Haren N, Schnack H, Caspers E, Hulshof

Pol H, et al. Excessive brain volume loss over time in cannabisusing first-episode schizophrenia patients. Am J Psychiatry 2008

165(4): 490-6.[104] Gruber SA, Yurgelun-Todd DA. Neuroimaging of marijuan

smokers during inhibitory processing: a pilot investigation. BrainRes Cogn Brain Res 2005; 23(1): 107-18.

[105] Delisi LE, Bertisch HC, Szulc KU, Majcher M, Brown K, BappaA, et al. A preliminary DTI study showing no brain structura

change associated with adolescent cannabis use. Harm Reduct 2006; 3: 17.

[106] Arnone D, Barrick TR, Chengappa S, Mackay CE, Clark CAAbou-Saleh MT. Corpus callosum damage in heavy marijuana use

preliminary evidence from diffusion tensor tractography and tractbased spatial statistics. Neuroimage 2008; 41(3): 1067-74.

[107] Honea R, Crow TJ, Passingham D, Mackay CE. Regional deficitin brain volume in schizophrenia: a meta-analysis of voxel-based

morphometry studies. Am J Psychiatry 2005; 162(12): 2233-45.[108] Kyriakopoulos M, Bargiotas T, Barker GJ, Frangou S. Diffusion

tensor imaging in schizophrenia. Eur Psychiatry 2008; 23(4): 25573.

[109] Tunving K, Thulin SO, Risberg J, Warkentin S. Regional cerebrablood flow in long-term heavy cannabis use. Psychiatry Res 1986

17(1): 15-21.




[110] Lundqvist T, Jonsson S, Warkentin S. Frontal lobe dysfunction in

long-term cannabis users. Neurotoxicol Teratol 2001; 23(5): 437-43.

[111] Mathew RJ, Tant S, Burger C. Regional cerebral blood flow inmarijuana smokers. Br J Addict 1986; 81(4): 567-71.

[112] Sneider JT, Pope HG, Jr., Silveri MM, Simpson NS, Gruber SA,Yurgelun-Todd DA. Altered regional blood volume in chronic can-

nabis smokers. Exp Clin Psychopharmacol 2006; 14(4): 422-8.[113] Sneider JT, Pope HG, Jr., Silveri MM, Simpson NS, Gruber SA,

Yurgelun-Todd DA. Differences in regional blood volume during a

28-day period of abstinence in chronic cannabis smokers. Eur Neu-ropsychopharmacol 2008; 18(8): 612-9.

[114] Block RI, O'Leary DS, Hichwa RD, Augustinack JC, Boles Ponto

LL, Ghoneim MM, et al. Effects of frequent marijuana use onmemory-related regional cerebral blood flow. Pharmacol Biochem

Behav 2002; 72(1-2): 237-50.[115] Kanayama G, Rogowska J, Pope HG, Gruber SA, Yurgelun-Todd

DA. Spatial working memory in heavy cannabis users: a functionalmagnetic resonance imaging study. Psychopharmacology (Berl)

2004; 176(3-4): 239-47.[116] Jager G, Kahn RS, Van Den Brink W, Van Ree JM, Ramsey NF.

Long-term effects of frequent cannabis use on working memoryand attention: an fMRI study. Psychopharmacology (Berl) 2006;

185(3): 358-68.[117] Mechoulam R. Marihuana chemistry. Science 1970; 168(936):

1159-66.[118] Velakoulis D, Wood SJ, Wong MT, McGorry PD, Yung A, Phillips

L, et al. Hippocampal and amygdala volumes according to psycho-sis stage and diagnosis: a magnetic resonance imaging study of

chronic schizophrenia, first-episode psychosis, and ultra-high-risk individuals. Arch Gen Psychiatry 2006; 63(2): 139-49.

[119] Mathew RJ, Wilson WH, Tant SR. Acute changes in cerebral bloodflow associated with marijuana smoking. Acta Psychiatr Scand

1989; 79(2): 118-28.[120] Mathew RJ, Wilson WH, Humphreys DF, Lowe JV, Wiethe KE.

Regional cerebral blood flow after marijuana smoking. J CerebBlood Flow Metab 1992; 12(5): 750-8.

[121] Mathew RJ, Wilson WH. Acute changes in cerebral blood flowafter smoking marijuana. Life Sci 1993; 52(8): 757-67.

[122] Mathew RJ, Wilson WH, Coleman RE, Turkington TG, DeGradoTR. Marijuana intoxication and brain activation in marijuana

smokers. Life Sci 1997; 60(23): 2075-89.[123] Mathew RJ, Wilson WH, Turkington TG, Coleman RE. Cerebellar

activity and disturbed time sense after THC. Brain Res 1998;

797(2): 183-9.[124] Mathew RJ, Wilson WH, Chiu NY, Turkington TG, Degrado TR,

Coleman RE. Regional cerebral blood flow and depersonalization

after tetrahydrocannabinol administration. Acta Psychiatr Scand1999; 100(1): 67-75.

[125] Volkow ND, Gillespie H, Mullani N, Tancredi L, Grant C, Valen-tine A, et al. Brain glucose metabolism in chronic marijuana users

at baseline and during marijuana intoxication. Psychiatry Res 1996;67(1): 29-38.

[126] Mathew RJ, Wilson WH, Humphreys D, Lowe JV, Weithe KE.Depersonalization after marijuana smoking. Biol Psychiatry 1993;

33(6): 431-41.[127] Mathew RJ, Wilson WH, Turkington TG, Hawk TC, Coleman RE,

DeGrado TR, et al. Time course of tetrahydrocannabinol-inducedchanges in regional cerebral blood flow measured with positron

emission tomography. Psychiatry Res 2002; 116(3): 173-85.[128] O'Leary DS, Block RI, Koeppel JA, Flaum M, Schultz SK, An-

dreasen NC, et al. Effects of smoking marijuana on brain perfusionand cognition. Neuropsychopharmacology 2002; 26(6): 802-16.

[129] O'Leary DS, Block RI, Turner BM, Koeppel J, Magnotta VA,Ponto LB, et al. Marijuana alters the human cerebellar clock. Neu-

roreport 11 2003; 14(8): 1145-51.[130] O'Leary DS, Block RI, Koeppel JA, Schultz SK, Magnotta VA,

Ponto LB, et al. Effects of smoking marijuana on focal attentionand brain blood flow. Hum Psychopharmacol 2007; 22(3): 135-48.

[131] Borgwardt SJ, Allen P, Bhattacharyya S, Fusar-Poli P, Crippa JA,Seal ML, et al. Neural basis of Delta-9-tetrahydrocannabinol and

cannabidiol: effects during response inhibition. Biol Psychiatry2008; 64(11): 966-73.

[132] Freedman R, Adams CE, Adler LE, Bickford PC, Gault J, HarrisJG, et al. Inhibitory neurophysiological deficit as a phenotype for

genetic investigation of schizophrenia. Am J Med Genet 2000

97(1): 58-64.[133] Daskalakis ZJ, Christensen BK, Chen R, Fitzgerald PB, Zipursky

RB, Kapur S. Evidence for impaired cortical inhibition in schizophrenia using transcranial magnetic stimulation. Arch Gen

Psychiatry 2002; 59(4): 347-54.[134] Rubia K, Russell T, Bullmore ET, Soni W, Brammer MJ, Simmon

A, et al. An fMRI study of reduced left prefrontal activation inschizophrenia during normal inhibitory function. Schizophr Re

2001; 52(1-2): 47-55.

[135] Kaladjian A, Jeanningros R, Azorin JM, Grimault S, Anton JLMazzola-Pomietto P. Blunted activation in right ventrolateral prefrontal cortex during motor response inhibition in schizophrenia

Schizophr Res 2007; 97(1-3): 184-93.[136] Lamers CT, Bechara A, Rizzo M, Ramaekers JG. Cognitive func

tion and mood in MDMA/THC users, THC users and non-drug using controls. J Psychopharmacol 2006; 20(2): 302-11.

[137] Reichenberg A, Harvey PD. Neuropsychological impairments ischizophrenia: Integration of performance-based and brain imagin

findings. Psychol Bull 2007; 133(5): 833-58.[138] Wagner AD, Schacter DL, Rotte M, Koutstaal W, Maril A, Dale

AM, et al. Building memories: remembering and forgetting of verbal experiences as predicted by brain activity. Science 1998

281(5380): 1188-91.[139] Buckner RL, Wheeler ME. The cognitive neuroscience of remem

bering. Nat Rev Neurosci. Sep 2001; 2(9): 624-34.[140] Robbe D, Montgomery SM, Thome A, Rueda-Orozco PE

McNaughton BL, Buzsaki G. Cannabinoids reveal importance ospike timing coordination in hippocampal function. Nat Neurosc

2006; 9(12): 1526-33.[141] Bossong MG, van Berckel BN, Boellaard R, Zuurman L, Schui

RC, Windhorst AD, et al. Delta9-Tetrahydrocannabinol InduceDopamine Release in the Human Striatum. Neuropsychopharma

cology 2009; 34(3): 759-66.[142] Phan KL, Angstadt M, Golden J, Onyewuenyi I, Popovska A, d

Wit H. Cannabinoid modulation of amygdala reactivity to sociasignals of threat in humans. J Neurosci 2008; 28(10): 2313-9.

[143] Viveros MP, Marco EM, File SE. Endocannabinoid system andstress and anxiety responses. Pharmacol Biochem Behav 2005

81(2): 331-42.[144] Borsook D, Becerra L, Hargreaves R. A role for fMRI in optimiz

ing CNS drug development. Nat Rev Drug Discov 2006; 5(5): 41124.

[145] Scatton B, Sanger DJ. Pharmacological and molecular targets in th

search for novel antipsychotics. Behav Pharmacol 2000; 11(3-4)243-56.

[146] Meltzer HY, Arvanitis L, Bauer D, Rein W. Placebo-controlled

evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Am J Psychiatry 2004

161(6): 975-84.[147] Wong DF, Tauscher J, Grunder G. The role of imaging in proof o

concept for CNS drug discovery and development. Neuropsychopharmacology 2009; 34(1): 187-203.

[148] Zuardi AW, Karniol IG. Effects on variable-interval performancein rats of delta 9-tetrahydrocannabinol and cannabidiol, separately

and in combination. Braz J Med Biol Res 1983; 16(2): 141-6.[149] Musty RE, Conti LH, Mechoulam R. Anxiolytic properties of can

nabidiol. In: Harvey DJ, eds. Marihuana '84. Proceedings of theOxford Symposium on Cannabis. Oxford: IRL Press Limited

1984: 713-9.[150] Onaivi ES, Green MR, Martin BR. Pharmacological characteriza

tion of cannabinoids in the elevated plus maze. J Pharmacol ExpTher 1990; 253(3): 1002-9.

[151] Guimaraes FS, de Aguiar JC, Mechoulam R, Breuer A. Anxiolyticeffect of cannabidiol derivatives in the elevated plus-maze. Gen

Pharmacol 1994; 25(1): 161-4.[152] Zuardi AW, Cosme RA, Graeff FG, Guimarães FS. Effects o

ipsapirone and cannabidiol on human experimental anxiety. J Psychopharmacol 1993; 7: 82-8.

[153] Agurell S, Carlsson S, Lindgren JE, Ohlsson A, Gillespie HHollister L. Interactions of delta 1-tetrahydrocannabinol with can

nabinol and cannabidiol following oral administration in man. Assay of cannabinol and cannabidiol by mass fragmentography. Ex

perientia 1981; 37(10): 1090-2.




[154] Ferrari MC, Busatto GF, McGuire PK, Crippa JA. Structural mag-

netic resonance imaging in anxiety disorders: an update of researchfindings. Rev Bras Psiquiatr 2008; 30(3): 251-64.

[155] Rottanburg D, Robins AH, Ben-Arie O, Teggin A, Elk R. Canna-bis-associated psychosis with hypomanic features. Lancet 1982;

2(8312): 1364-6.[156] Zuardi AW, Rodrigues JA, Cunha JM. Effects of cannabidiol in

animal models predictive of antipsychotic activity. Psychopharma-cology (Berl) 1991; 104(2): 260-4.

[157] Guimaraes VM, Zuardi AW, Del Bel EA, Guimaraes FS. Can-

nabidiol increases Fos expression in the nucleus accumbens but notin the dorsal striatum. Life Sci. 2004; 75(5): 633-8.

[158] Moreira FA, Guimaraes FS. Cannabidiol inhibits the hyperlocomo-

tion induced by psychotomimetic drugs in mice. Eur J Pharmacol2005; 512(2-3): 199-205.

[159] Long LE, Malone DT, Taylor DA. Cannabidiol reverses MK-801-induced disruption of prepulse inhibition in mice. Neuropsycho-

pharmacology 2006; 31(4): 795-803.[160] Juckel G, Roser P, Nadulski T, Stadelmann AM, Gallinat J. Acute

effects of Delta9-tetrahydrocannabinol and standardized cannabisextract on the auditory evoked mismatch negativity. Schizophr Res

2007; 97(1-3): 109-17.[161] Morgan CJ, Curran HV. Effects of cannabidiol on schizophrenia-

like symptoms in people who use cannabis. Br J Psychiatry 2008;192(4): 306-7.

[162] Yasuno F, Brown AK, Zoghabi SS, Krushinski JH, Chernet E,Tauscher J, et al. The PET radioligand [11C]MePPEP binds re-

versibly and with high specific signal to cannabinoid CB1 receptor

in nonhuman primate brain. Neuropsychopharmacology 200833(2): 259-69.

[163] Cohen M, Solowij N, Carr V. Cannabis, cannabinoids and schizophrenia: integration of the evidence. Aust N Z J Psychiatry 2008

42(5): 357-68.[164] D'Souza DC, Braley G, Blaise R, Vendetti M, Oliver S, Pittman B

et al. Effects of haloperidol on the behavioral, subjective, cognitive, motor, and neuroendocrine effects of Delta-9-tetrahydro

cannabinol in humans. Psychopharmacology (Berl) 2008; 198(4)

587-603.[165] Mechoulam R, Spatz M, Shohami E. Endocannabinoids and neuro

protection. Sci STKE 2002; 2002(129): RE5.

[166] Lastres-Becker I, Molina-Holgado F, Ramos JA, Mechoulam RFernandez-Ruiz J. Cannabinoids provide neuroprotection against 6

hydroxydopamine toxicity in vivo and in vitro: relevance to Parkinson's disease. Neurobiol Dis 2005; 19(1-2): 96-107.

[167] Baker D, Pryce G. The endocannabinoid system and multiple sclerosis. Curr Pharm Des 2008; 14(23): 2326-36.

[168] Fowler CJ. "The tools of the trade"--an overview of the pharmacology of the endocannabinoid system. Curr Pharm Des 2008; 14(23)

2254-65.[169] Viso A, Cisneros JA, Ortega-Gutierrez S. The medicinal chemistr

of agents targeting monoacylglycerol lipase. Curr Top Med Chem2008; 8(3): 231-46.

imaging the neural effects of cannabinoids current status and future

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