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The Second Cannabis and Mental Health conference
Held in Kings College, University of London, May 1-2 2007

Conference abstracts

The central nervous system and endocannabinoids
Prof. Raphael Mechoulam, Israel

The major endocannabionoid 2-arachidonoyl glycerol (2-AG) has been identified both in the central nervous system and in the periphery. Stressful stimuli-traumatic brain injury (TBI) for example - enhance brain 2-AG levels in mice.

2-AG, both of endogenous and exogenous origin, has been shown to be neuroprotective in in-vivo models of closed head injury, ischemia and excitotoxicity. These effects may derive from the ability of cannabinoids to act through various biochemical mechanisms including inhibition of glutamate release or direct blockade of NMDA receptors, inhibition of intracellular calcium mobilization, action as reactive oxygen species (ROS) scavengers, inhibition of pro- flammatory cytokines and inhibition of NF-kB activation. 2-AG also helps repair the blood brain barrier after TBI.

The endocannabinoids act via multiple receptors, of which the CB1 receptors are most abundant in the CNS. We
have shown that CB1 knockout mice display slower functional recovery after TBI and do not respond to treatment
with 2-AG. Recently however CB2 receptors have also been found to be formed in the brain, particularly in various pathological states.

Arachidonoyl-L-serine (ARA-S) is an endogenous constituent of the endocannabionoid family, which we recently
isolated from bovine brain. ARA-S binds very weakly to the known cannabinoid receptors. It was found to be a
vasorelaxant in an endothelium-dependent manner and to suppress formation of reactive oxygen intermediates, NO and TNF-a in a murine macrophage cell line, as well as TNF-a in vivo. We assume that ARA-S, due to its vasorelaxant, anti-inflammatory and antioxidant properties, could be a candidate neuroprotective agent in our animal model.

Indeed, a preliminary study revealed that mice, injected with ARA-S after injury, displayed a significantly greater
recovery of the neurobehavioral function, as compared with vehicle-treated mice. which sustained for at least 60 days. We assumed that the endocannabionoid system may be involved in the pathogenesis of hepatic encephalopathy, a neuropsychiatric syndrome induced by fulminant hepatic failure. Indeed in an animal model we found that the levels of 2-AG are elevated and administration of 2-AG improved a neurological score, activity and cognitive function. Apparently here 2-AG acts via the CB2 receptor as a specific CB2 receptor agonist had the same effect, while CB1 agonists were inactive.

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Endocannabinoids and development
Dr Patrick Doherty. UK

The active components of cannabis function by stimulating the CB1 cannabinoid receptor in the brain. These receptors have normal functions, and the brain makes its own molecules (called endocannabinoids) to activate them. Diacylglycerol lipase (DAGL) activity generates 2-arachidonyl glycerol (2-AG), the most abundant endocannabinoid in the nervous system. Insights into novel roles for endocannabinoids during development, and in the adult, are emerging based on a full understanding of where and when the DAGLs are expressed. The enzymes are first expressed by newly differentiated neurons, supporting an important role for the enzymes in axonal growth and guidance. The enzymes become restricted to post-synaptic sites at all CB1 positive synapses in the adult nervous system where they are well placed to synthesize, on demand, an endocannabinoid for the retrograde control of synaptic strength and neuroprotection. The enzymes are also expressed by neural stem cells in the adult brain where they play a role in the generation of new neurons throughout life. The cloning and characterisation of these enzymes paves the way for a better understanding of the factors that regulate endocannabinoid signalling, a pathway that can now be viewed as having multiple functions throughout the developing and adult brain.

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Cannabis, cognition and schizophrenia
Dr Nadia Sofowij, Australia


Long-term, heavy cannabis use is associated with specific cognitive impairments, similar to the cognitive endophenotypes proposed as vulnerability markers of schizophrenia. The endogenous cannabinoid system is involved in memory, attention and other cognitive functions, expresses altered functionality following exposure to cannabis, and is implicated in the pathophysiology of schizophrenia. This presentation will provide an overview of what is known about the long term cognitive effects of cannabis in the general population and present new research on cognition and brain structure and function in cannabis users and in people with schizophrenia who also use cannabis.

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A functional MRI study of the effects of cannabis on the brain
Prof. Philip McGuire, UK

Cannabis use can induce psychotic symptoms and anxiety and can alter cognitive and emotional processing. We used functional neuroimaging to investigate the neurocognitive basis of these effects, using experimental tasks that engage processes known to be modulated by cannabis use.

Methods

Subjects were 15 healthy males who were not regular cannabis users. Each subject was studied on 3 occasions,
and was given either THC, CBD or placebo 1 hour prior to scanning, in a double-blind design. The order of drug
administration was randomised and there was 1 month between each scanning session. During each session, images were acquired on a 1.5T GE camera while subjects performed a verbal paired associates memory task, a Go/ No Go task, visual processing of anxious faces and listening to speech. The modulatory effects of THC and CBD relative to placebo were examined by comparing activation during each task.

Results

During the encoding phase of the memory task THC attenuated activation in the left temporal cortex compared to
placebo. During the go-no go task, THC attenuated activation in the right inferior frontal cortex and its effect in
this region predicted the severity of psychotic symptoms induced by THC. THC attenuated activation in the auditory cortex while subjects listened to speech. CBD attenuated activation in the amygdala in response to fearful faces and this effect was correlated with the effect of CBD on skin conductance.

Conclusions

The different symptomatic and cognitive effects of cannabis can be related to the influence of THC and CBD on
specific brain regions.

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Cannabis exposure and the developing brain: long-term gateway effects?
Prof. Yasmin L Hurd. USA


Marijuana (Cannabis sativa) is the illicit drug most commonly used by teenagers.

Epidemiological studies suggest that early regular use of cannabis increases the risk of initiating the use of other illicit drugs. Whether there is a causal relationship between early cannabis exposure and the progression to the use of other illicit drugs is still highly debated. One strategy to directly evaluate the neurobiological relationship of prior cannabis experience with other illicit drugs independent of cultural and social factors is the use of experimental animal models. The presentation will provide results from animal models showing long-term cannabis-induced disturbances of reward neural systems.

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Cannabis use: an important risk factor for psychosis?
Dr. Robert Ferdinand, Netherlands

This presentation is based on findings from an epidemiological study among 2,076 children and adolescents from the general population who were followed up into adulthood. In young adulthood, information on lifetime cannabis (and other illicit drug) use and lifetime psychotic features was obtained. At previous assessments behavioural and emotional problems were assessed. Cannabis use predicted future psychotic symptoms. However, the reverse, psychotic symptoms predicting cannabis use, was also found. The prediction of psychotic symptoms by cannabis use could not be explained by high levels of behavioural or emotional problems in general. Remarkably, MDMA use predicted psychotic symptoms as well. Implications for mental health policies will be discussed.

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Cannabis an dpsychotic symptoms, is htere a causal link?
Prof. David M Fergusson, New Zealand

This presentation will use data from the Christchurch Health & Development Study (CHDS) to examine the linkages between exposure to cannabis use and rates of psychosis/psychotic symptoms. The CHDS is a longitudinal study of a birth cohort of 1,265 children born in 1977 that has been studied to the age of 30. Key issues to be examined include: confounding; reverse causality; and the pathways linking cannabis use to the development of psychotic symptoms. The implications of these findings for the regulation of cannabis use and supply will be considerable.

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Genetic moderation of cannabis-induced psychosis
Dr Cecile Henquet, Netherlands

Observational studies have shown that gene X environment interactions may underlie the association between cannabis use and psychosis. A double-blind placebo controlled study in which patients with a psychotic illness, relatives of patients and healthy controls were exposed to delta-9-THC, showed that a functional polymorphism in the cathechol-0-methyltransferase gene moderates the acute effects of cannabis on cognition and psychosis outcome. A momentary assessment technique was furthermore used to assess differences between patients and controls in the effects of cannabis in daily life. These data show that psychosis liability is associated with differential sensitivity to both the psychosis-inducing and mood-enhancing effects of cannabis. The temporal dissociation between acute rewarding effects and sub-acute psychotogenic effects may be instrumental in explaining the circle of deleterious use in patients with psychotic illness.

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Use of cannabis in a East-London first episode psychosis sample: data from the GAP, genetics and psychosis study
Dr Marta Di Forti, UK

Background: Exposure to cannabis is associated with a risk of developing psychosis. Individual sceptibility depends on age of onset of cannabis abuse and on genotype (Arseneault et al., 2004; Caspi et al., 2005). In the general population cannabis use is associated with lower educational achievement (Macleod et al, 2004). There are not study addressing this association in individuals with psychosis. In this study we investigate whether early age at first cannabis use is associated with longer and regular use and whether cannabis use predicts level of educational achievement in a first-episode psychotic population.

Method:

We collected demographic, clinical and cannabis use (age at first use, frequency, length of use) information
in a sample of 200 first-episode psychosis patients. All the subjects were recruited as part of the Genetic And
sychosis (GAP) study.

Results:

110 (55%) smoked cannabis, eighty-nine were male and 21 female. We collected data on age at first use on
sventy subjects, of whom 44 (62,8%) began their use before age 16. The mean age at first use of cannabis was 16,24 years. The mean age of onset of psychosis in the cannabis users group was 2 years earlier (mean 23,2; SD 4,575) than in the non cannabis users group (mean 25,3; SD 7,004), p= 0.014. However there was not significant difference in age of onset between genders.

Among those who commenced cannabis use before age 16, the mean length of cannabis use was 9,5 years
compared to 5,4 years among those whose use began after 17 years. We had data on frequency of cannabis use
on sixty-three subjects. Forty-one began their use before age 16, and of these 33 (70,2%) used cannabis three or
more times a week compared to the 14 (29,8%) of those who started after 16 years. Applying a multiple regression, we found that age at first use predicted years of cannabis use (p=0,008) independent of age of onset of psychosis and showed a trend towards significance for frequency of cannabis use (p=0,07). We had available data on level of education achieved on 81 patients, 55 (67.9%) male and 26 female (32.1%), mean age: 31.0yrs, range 19-59yrs (SD: 7.7). Of these 81 cases 54 (66.7%) were cannabis users, with mean age of 29.2 y (SD 5.9) and 27 cases (33.3%) were not cannabis users, mean age 34.7 y (SD 9.5). Applying linear regression analysis using level of education as the dependant variable and frequency of use as the independent variable we found that frequency of cannabis use predicts level of education achieved (p=0.03).

Condusion:

Early age at first use of cannabis is associated with longer and regular use in patients with their first episode of psychosis. Counterintuitively, our data also show that frequent cannabis use is associated with higher academic achievement in a first episode psychotic population. This is not due to the non-users being of lower age. Further analyses will be conducted to explore this interesting finding.

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Day 2

Interventions for cannabis use disorder: an overview
Prof. Jan Copeland, Australia

Cannabis is the most widely used illicit substance in the Western world with more than one in four young people in the UK having ever used it. Worldwide, its use is increasingly recognised as a source of morbidity, with recent concerns focusing on its contribution to psychosis in young people. In 1996 it was estimated in Australia, that more disability-adjusted healthy years of life were lost due to cannabis use and dependence than to HIV, Hepatitis B and Hepatitis C combined. In addition, there is a growing demand for cannabis dependence treatment locally and internationally. This paper will provide an overview of the evidence to support psycho-social interventions for cannabis use disorder and discuss the promising pharmacotherapies, and specific interventions for co-occurring cannabis dependence and other psychological disorders, currently under investigation internationally.

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Stoned, cold sober: psychological interventions for cannabis and alcohol use among people with psychosis
or major depression
Dr Amanda Baker, Australia


Co-existing cannabis, alcohol and other drug problems among people with psychosis or major
depression are very common in clinical practice. Screening, assessing and intervening with co-existing problems is
core business for mental health, drug and alcohol and other clinicians. As people with co-existing problems have
usually been excluded from research trials, as yet there are no clear indications for 'best treatment'. This presentation reviews the small but growing evidence base for psychological interventions for cannabis and alcohol use problems among people with co-existing psychosis or major depression. Several randomised controlled trials conducted at the Centre for Brain and Mental Health Research, University of Newcastle, NSW, are reviewed in detail. The growing research base suggest that: (i) minimal interventions in the form of assessment, the provision of self-help materials and regular follow-up; (ii) brief motivational interventions; and (iii) cognitive behaviour therapy are useful for people with co-existing problems, with some evidence of differential effectiveness for alcohol versus cannabis use problems. The high prevalence of co-existing problems and evidence for the utility of briefer interventions for some people implies that a 'stepped' model of care may be useful.

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Psychotherapeutic interventions for cannabis abuse and/or dependence in outpatient settings
Dr. Cecile Denis, France

Cecile Denis, Marc Auriacombe
"Addiction Psychiatry, JE2358, INSERM IFR 99, University Victor Segalen Bordeaux 2, Bordeaux, France."

Cannabis use disorder is the most commonly occurring illicit substance use disorder in the general population.
Despite the large number of cannabis users who seek or may need treatment only a few randomized clinical trials
exist that explore the most effective interventions. The six studies included in this review show that cannabis
dependence is not easily treated by psychotherapies in outpatient settings. Cognitive-behavioral (CB) both in
individual or group sessions, motivational enhancement in individual sessions have been demonstrated to be
effective to reduce cannabis use. The most recent, best quality and largest controlled trial, found extended individul
CBT to be more effective than brief individual motivational therapy. The two studies on contingency-management
treatments concluded that this may enhance outcomes combined with CBT or motivational enhancement.

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Personality and Cannabis use
Dr. Emma Barkus, UK


Cannabis use has become almost endemic in youth culture. The identification of personality traits which precipitate
or maintain cannabis use have been identified in clinical samples. This approach may also be useful to highlight
risk of psychopathology or difficulties from substance use in non-clinical samples. In particular there is a continuing
debate surrounding whether there is a causal or association relationship between cannabis use and psychosis. The
presentation will highlight literature concerned with personality traits and cannabis use. Emphasis will be placed on
using response to cannabis as a possibility for identifying underlying proneness to psychiatric disease.

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CBD vs. THC: imaging differences
Dr Zerrin Atakan UK


This brief presentation will elicit and discuss the findings of a recently carried out fMRI study comparing the effects
of two major cannabis compounds, namely delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). The subjects were 15 male, healthy volunteers aged 20 - 42 years who had used cannabis less than 15 times in their lifetime. The compounds were also compared with placebo, using a randomised, double blind methodology. The effects of these two compounds on brain activation were studied when certain functions such as motor response inhibition, verbal memory and sensory tasks were carried out by the subjects. This is the first study showing how these two compounds differ in the way they activate different brain regions when the these tasks are carried out. The findings permit the integration of previous knowledge about the effects of cannabinoids at the level of neuroreceptors and at the behavioural level.

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he effects of delta-9-THC in healthy individuals and individuals with schizophrenia
Dr Deepak Cyril D'Souza, USA


Laboratory studies with delta-9-tetrahydrocannabinol (A-9-THC) have been a useful approach to investigate the association between cannabis and psychosis. We have characterized the behavioural, cognitive and endocrine effects of 0. 2.5 mg and 5 mg A-9-THC in a 3 day, double-blind, randomized and counterbalanced study, in healthy individuals who had been exposed to cannabis but had never been diagnosed with a cannabis abuse disorder. A-9-THC produced schizophrenia-like positive and negative symptoms, altered perception,
increased anxiety, produced euphoria, disrupted immediate and delayed word recall, impaired performance on tests of attention and working memory without impairing orientation. Interestingly, frequent users of cannabis appear to have blunted responses to some of the "negative" but not positive effects of A-9-THC. In a parallel study of identical design, we characterized the effects of A-9-THC in stable, anti psychotic-treated schizophrenia patients. A-9-THC transiently increased learning and recall deficits, positive, negative and general schizophrenia symptoms, perceptual alterations, akathisia, rigidity and dyskinesia, and deficits in vigilance. Schizophrenia patients were more vulnerable to A-9-THC effects on recall relative to controls suggesting that CB-1R dysfunction contributes to the pathophysiology of the cognitive deficits associated with schizophrenia.

In light of the growing preclinical evidence of cannabinoid-dopamine interactions, we then sought to determine
whether dopamine neurotransmission contributed to the psychotomimetic effects of A-9-THC. We studied the effects of pretreatment with haloperidol the dopamine receptor antagonist, on the behavioural and cognitive effects of the cannabinoid A-9-THC in humans. Interestingly, haloperidol did not reduce the psychotomimetic effects of A-9-THC. Rather, haloperidol and A-9-THC interacted to worsen verbal recall and several aspects of sustained attention.

These data provide the first evidence in humans that we are aware of that cannabinoid and dopamine systems have
interactive effects on attention and memory.

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Cannabidiol as an antipsychotic - new perspectives
Prof. Markus Leweke, Germany

Background: The human endocannabinoid system interacts with various neurotransmitter systems and the endocannabinoid anandamide was found significantly elevated in CSF and inversely correlated to psychopathology (Giuffrida et al. 2004) providing a link to the neurobiology of schizophrenia. While delta-9-tetrahydrocannabinol, the psychoactive compound of Cannabis sativa shows psychedelic properties, the major herbal cannabinoid compound cannabidiol was suggested recently a re- uptake inhibitor of anandamide. In addition potential antipsychotic properties have been hypothezised.

Methods.

We performed an explorative, 4-week, double-blind, controlled clinical trial on the effects of purified cannabidiol in acute schizophrenia compared to the antipsychotic amisulpride. The antipsychotic properties of bothwere the primary target of the study. Furthermore side effects and anxiolytic capabilities of both treatments were investigated.

Results:

42 patients fulfilling DSM-IV criteria of acute paranoid schizophrenia or schizophreniform psychosis participated in the study. Both treatments were associated with a significant decrease of psychotic symptoms after
2 and 4 weeks as assessed by BPRS and PANSS. However, there was no statistical difference between both treatment groups. In contrast, cannabidiol induced significantly less side effects (EPS. increase in prolactin, weight gain) when compared to amisulpride.

Conclusions:

Cannabidiol proved substantial antipsychotic properties in acute schizophrenia. This is in line with our suggestion of an adaptive role of the endocannabinoid system in paranoid schizophrenia, and raises further evidence that this adaptive mechanism may represent a valuable target for antipsychotic treatment strategies.

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