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Second Cannabis and Mental Health conference
in Kings College, University of London, May 1-2 2007
central nervous system and endocannabinoids
Prof. Raphael Mechoulam, Israel
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.
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.
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.
(ARA-S) is an endogenous constituent of the endocannabionoid family, which we
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.
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.
Patrick Doherty. UK
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.
cognition and schizophrenia
Dr Nadia Sofowij, Australia
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.
functional MRI study of the effects of cannabis on the brain
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.
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.
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.
different symptomatic and cognitive effects of cannabis can be related to the
influence of THC and CBD on
specific brain regions.
exposure and the developing brain: long-term gateway effects?
L Hurd. USA
Marijuana (Cannabis sativa) is the illicit drug most
commonly used by teenagers.
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.
use: an important risk factor for psychosis?
Dr. Robert Ferdinand, Netherlands
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.
an dpsychotic symptoms, is htere a causal link?
Prof. David M Fergusson, New
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.
moderation of cannabis-induced psychosis
Dr Cecile Henquet, Netherlands
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.
of cannabis in a East-London first episode psychosis sample: data from the GAP,
genetics and psychosis study
Dr Marta Di Forti, UK
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
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
(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.
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).
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.
for cannabis use disorder: an overview
Prof. Jan Copeland, Australia
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.
cold sober: psychological interventions for cannabis and alcohol use among people
or major depression
Dr Amanda Baker, Australia
Co-existing cannabis, alcohol and other drug problems among people with psychosis
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.
interventions for cannabis abuse and/or dependence in outpatient settings
Dr. Cecile Denis, France
Cecile Denis, Marc Auriacombe
Psychiatry, JE2358, INSERM IFR 99, University Victor Segalen Bordeaux 2, Bordeaux,
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
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
concluded that this may enhance outcomes combined with CBT or motivational enhancement.
and Cannabis use
Dr. Emma Barkus, UK
Cannabis use has become
almost endemic in youth culture. The identification of personality traits which
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
response to cannabis as a possibility for identifying underlying proneness to
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
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
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,
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.
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.
data provide the first evidence in humans that we are aware of that cannabinoid
and dopamine systems have
interactive effects on attention and memory.
as an antipsychotic - new perspectives
Prof. Markus Leweke, Germany
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.
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
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.
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.