Étude du système endocannabinoïde et ses implications dans la schizophrénie

La schizophrénie est une maladie complexe et a une prévalence approximative de 1% dans la population générale. Au sein des paradigmes neurochimiques, la théorie étiologique de la dopamine est celle qui prévaut alors que sont de plus en plus impliqués d’autres circuits de neurotransmission comme celui du glutamate. En clinique, les patients atteints de schizophrénie ont une grande propension à consommer des substances, particulièrement du cannabis. Nous avons cherché à étayer l’hypothèse d’un désordre du système cannabinoïde endogène, un important neuromodulateur. Ce mémoire propose d’abord dans un premier article une revue exhaustive de la littérature explorant le système endocannabinoïde et ses implications dans la schizophrénie. Puis, nous exposons dans un second article les résultats d’une recherche clinique sur les endocannabinoïdes plasmatiques dans trois groupes de sujets avec schizophrénie et/ou toxicomanie, pendant 12 semaines. Nous avons observé un effet miroir de deux ligands endocannabinoïdes, l’anandamide et l’oleylethanolamide, qui étaient élevés chez les patients avec double diagnostic et abaissés chez les toxicomanes, au début de l’étude. Au terme de l’étude, l’élévation des endocannabinoïdes s’est maintenue et nous avons supposé un marqueur de vulnérabilité psychotique dans un contexte de consommation. Finalement, nous avons analysé les résultats en les intégrant aux connaissances moléculaires et pharmacologiques ainsi qu’aux théories neurochimiques et inflammatoires déjà développées dans la schizophrénie. Nous avons aussi tenu compte des principales comorbidités observées en clinique: la toxicomanie et les troubles métaboliques. Cela nous a permis de proposer un modèle cannabinoïde de la schizophrénie et conséquemment des perspectives de recherche et de traitement.

Validation of the Cannabis Expectancy Questionnaire (CEQ) in adult cannabis users in treatment

Background Outcome expectancies are a key cognitive construct in the etiology, assessment and treatment of Substance Use Disorders. There is a research and clinical need for a cannabis expectancy measure validated in a clinical sample of cannabis users. Method The Cannabis Expectancy Questionnaire (CEQ) was subjected to exploratory (n = 501, mean age 27.45, 78% male) and confirmatory (n = 505, mean age 27.69, 78% male) factor analysis in two separate samples of cannabis users attending an outpatient cannabis treatment program. Weekly cannabis consumption was clinically assessed and patients completed the Severity of Dependence Scale-Cannabis (SDS-C) and the General Health Questionnaire (GHQ-28). Results Two factors representing Negative Cannabis Expectancies and Positive Cannabis Expectancies were identified. These provided a robust statistical and conceptual fit for the data. Internal reliabilities were high. Negative expectancies were associated with greater dependence severity (as measured by the SDS) and positive expectancies with higher consumption. The interaction of positive and negative expectancies was consistently significantly associated with self-reported functioning across all four GHQ-28 scales (Somatic Concerns, Anxiety, Social Dysfunction and Depression). Specifically, within the context of high positive cannabis expectancy, higher negative expectancy was predictive of more impaired functioning. By contrast, within the context of low positive cannabis expectancy, higher negative expectancy was predictive of better functioning. Conclusions The CEQ is the first cannabis expectancy measure to be validated in a sample of cannabis users in treatment. Negative and positive cannabis expectancy domains were uniquely associated with consumption, dependence severity and self-reported mental health functioning.

Opioid dependence: Brain structure and function : a magnetic resonance imaging, neuropsychological, and electromagnetic study

Background: Opiod dependence is a chronic severe brain disorder associated with enormous health and social problems. The relapse back to opioid abuse is very high especially in early abstinence, but neuropsychological and neurophysiological deficits during opioid abuse or soon after cessation of opioids are scarcely investigated. Also the structural brain changes and their correlations with the length of opioid abuse or abuse onset age are not known. In this study the cognitive functions, neural basis of cognitive dysfunction, and brain structural changes was studied in opioid-dependent patients and in age and sex matched healthy controls. Materials and methods: All subjects participating in the study, 23 opioid dependents of whom, 15 were also benzodiazepine and five cannabis co-dependent and 18 healthy age and sex matched controls went through Structured Clinical Interviews (SCID) to obtain DSM-IV axis I and II diagnosis and to exclude psychiatric illness not related to opioid dependence or personality disorders. Simultaneous magnetoencephalography (MEG) and electroencephalography (EEG) measurements were done on 21 opioid-dependent individuals on the day of hospitalization for withdrawal therapy. The neural basis of auditory processing was studied and pre-attentive attention and sensory memory were investigated. During the withdrawal 15 opioid-dependent patients participated in neuropsychological tests, measuring fluid intelligence, attention and working memory, verbal and visual memory, and executive functions. Fifteen healthy subjects served as controls for the MEG-EEG measurements and neuropsychological assessment. The brain magnetic resonance imaging (MRI) was obtained from 17 patients after approximately two weeks abstinence, and from 17 controls. The areas of different brain structures and the absolute and relative volumes of cerebrum, cerebral white and gray matter, and cerebrospinal fluid (CSF) spaces were measured and the Sylvian fissure ratio (SFR) and bifrontal ratio were calculated. Also correlation between the cerebral measures and neuropsychological performance was done. Results: MEG-EEG measurements showed that compared to controls the opioid-dependent patients had delayed mismatch negativity (MMN) response to novel sounds in the EEG and P3am on the contralateral hemisphere to the stimulated ear in MEG. The equivalent current dipole (ECD) of N1m response was stronger in patients with benzodiazepine co-dependence than those without benzodiazepine co-dependence or controls. In early abstinence the opioid dependents performed poorer than the controls in tests measuring attention and working memory, executive function and fluid intelligence. Test results of the Culture Fair Intelligence Test (CFIT), testing fluid intelligence, and Paced Auditory Serial Addition Test (PASAT), measuring attention and working memory correlated positively with the days of abstinence. MRI measurements showed that the relative volume of CSF was significantly larger in opioid dependents, which could also be seen in visual analysis. Also Sylvian fissures, expressed by SFR were wider in patients, which correlated negatively with the age of opioid abuse onset. In controls the relative gray matter volume had a positive correlation with composite cognitive performance, but this correlation was not found in opioid dependents in early abstinence. Conclusions: Opioid dependents had wide Sylvian fissures and CSF spaces indicating frontotemporal atrophy. Dilatation of Sylvian fissures correlated with the abuse onset age. During early withdrawal cognitive performance of opioid dependents was impaired. While intoxicated the pre-attentive attention to novel stimulus was delayed and benzodiazepine co-dependence impaired sound detection. All these changes point to disturbances on frontotemporal areas.

Subclinical Depressive Symptoms and Continued Cannabis Use: Predictors of Negative Outcomes in First Episode Psychosis

Background Although depressive symptoms in first episode psychosis have been associated with cannabis abuse, their influence on the long-term functional course of FEP patients who abuse cannabis is unknown. The aims of the study were to examine the influence of subclinical depressive symptoms on the long-term outcome in first episode-psychosis patients who were cannabis users and to assess the influence of these subclinical depressive symptoms on the ability to quit cannabis use. Methods 64 FEP patients who were cannabis users at baseline were followed-up for 5 years. Two groups were defined: (a) patients with subclinical depressive symptoms at least once during follow-up (DPG), and (b) patients without subclinical depressive symptoms during follow-up (NDPG). Psychotic symptoms were measured using the Positive and Negative Syndrome Scale (PANSS), depressive symptoms using the Hamilton Depression Rating Scale (HDRS)-17, and psychosocial functioning was assessed using the Global Assessment of Functioning (GAF). A linear mixed-effects model was used to analyze the combined influence of cannabis use and subclinical depressive symptomatology on the clinical outcome. Results Subclinical depressive symptoms were associated with continued abuse of cannabis during follow-up (beta=4.45; 95% confidence interval [CI]: 1.78 to 11.17; P=.001) and with worse functioning (beta=-5.50; 95% CI: -9.02 to -0.33; P=.009). Conclusions Subclinical depressive symptoms and continued cannabis abuse during follow-up could be predictors of negative outcomes in FEP patients.

Frequent Cannabis Use Among 14/15 Year Olds in Northern Ireland

The relatively high levels of cannabis use among young people is a cause of concern because of the positive relationship between its early onset use, antisocial behaviours and associated lifestyle. Amongst a survey of 3919 young people at school year 11 in Northern Ireland (aged 14/15 years) 142 reported daily cannabis use. These young people also reported particularly high levels of legal and illegal drug use and accounted for a high proportion of use of hard drugs such as cocaine and heroin for the full school cohort. Daily cannabis users also reported high levels of antisocial behaviour and disaffection with school. The findings perhaps raise questions about the existence of a potentially ‘hidden’ high risk school based group of young people during adolescence who require specific targeted prevention strategies.

Fitness to drive and cannabis: Validation of two blood THCCOOH thresholds to distinguish occasional users from heavy smokers.

Many studies based on either an experimental or an epidemiological approach, have shown that the ability to drive is impaired when the driver is under the influence of cannabis. Baseline performances of heavy users remain impaired even after several weeks of abstinence. Symptoms of cannabis abuse and dependence are generally considered incompatible with safe driving. Recently, it has been shown that traffic safety can be increased by reporting the long-term unfit drivers to the driver licensing authorities and referring the cases for further medical assessment. Evaluation of the frequency of cannabis use is a prerequisite for a reliable medical assessment of the fitness to drive. In a previous paper we advocated the use of two thresholds based on 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THCCOOH) concentration in whole blood to help to distinguish occasional cannabis users (≤3μg/L) from heavy regular smokers (≥40μg/L). These criteria were established on the basis of results obtained in a controlled cannabis smoking study with placebo, carried out with two groups of young male volunteers; the first group was characterized by a heavy use (≥10 joints/month) while the second group was made up of occasional users smoking at most 1 joint/week. However, to date, these cutoffs have not been adequately assessed under real conditions. Their validity can now be evaluated and confirmed with 146 traffic offenders' real cases in which the whole blood cannabinoid concentrations and the frequency of cannabis use are known. The two thresholds were not challenged by the presence of ethanol (40% of cases) and of other therapeutic and illegal drugs (24%). Thus, we propose the following procedure that can be very useful in the Swiss context but also in other countries with similar traffic policies: if the whole blood THCCOOH concentration is higher than 40μg/L, traffic offenders must be directed first and foremost toward medical assessment of their fitness to drive. This evaluation is not recommended if the THCCOOH concentration is lower than 3μg/L and if the self-rated frequency of cannabis use is less than 1 time/week. A THCCOOH level between these two thresholds cannot be reliably interpreted. In such a case, further medical assessment and follow-up of the fitness to drive are also suggested, but with lower priority.

Le cannabis, le tabac et le changement d’adiposité chez les jeunes hommes et femmes : une étude longitudinale 2005-2012

Exposé de la situation : Des études menées sur les animaux démontrent que le système endocannabinoide est important dans le maintien de l’homéostasie de l’énergie et que les effets de sa modulation sont différents selon le sexe et l’exposition à la nicotine. Deux études longitudinales ont étudié l’association entre l’usage du cannabis (UC) et le changement de poids et ont obtenus des résultats contradictoires. L’objectif de ce mémoire est de décrire la modification de l’association entre l’UC et le changement de poids par la cigarette chez les jeunes hommes et femmes. Méthodes : Des donnés de 271 hommes et 319 femmes ont été obtenues dans le cadre de l’étude NICO, une cohorte prospective (1999-2013). L’indice de masse corporelle (IMC) et la circonférence de taille (CT) ont été mesurés à l’âge de 17 et 25 ans. L’UC dans la dernière année et de cigarette dans les derniers trois mois ont été auto-rapportées à 21 ans. Les associations entre l’UC et le changement d’IMC et de CT ont été modélisées dans une régression polynomiale stratifiée par sexe avec ajustement pour l’activité physique, la sédentarité et la consommation d’alcool. Résultats : Uniquement, chez les hommes, l’interaction de l’UC et cigarettes était statistiquement significative dans le model de changement IMC (p=0.004) et celui de changement de CT (p=0.043). L’UC était associé au changement d’adiposité dans une association en forme de U chez les homes non-fumeurs et chez les femmes, et dans une association en forme de U-inversé chez les hommes fumeurs. Conclusion : La cigarette semble modifier l’effet du cannabis sur le changement d’IMC et CT chez les hommes, mais pas chez les femmes.

Cannabidiol, a Cannabis sativa constituent, as an anxiolytic drug

Objectives: To review and describe studies of the non-psychotomimetic constituent of Cannabis sativa, cannabidiol (CBD), as an anxiolytic drug and discuss its possible mechanisms of action. Method: The articles selected for the review were identified through searches in English,articles, and book chapters were handsearched for additional references. Experimental animal and human studies were included, with no time restraints. Results: Studies using animal models of anxiety and involving healthy volunteers clearly suggest an anxiolytic-like effect of CBD. like", and "cannabidiol and anxiety". The reference lists of the publications included, review Portuguese, and Spanish in the electronic databases ISI Web of Knowledge, SciELO, PubMed, and PsycINFO, combining the search terms "cannabidiol and anxiolytic", "cannabidiol and anxiolytic-articles, and book chapters were handsearched for additional references. Experimental animal and human studies were included, with no time restraints. Results: Studies using animal models of anxiety and involving healthy volunteers clearly suggest an anxiolytic-like effect of CBD. Moreover, CBD was shown to reduce anxiety in patients with social anxiety disorder. Conclusion: like", and "cannabidiol and anxiety". The reference lists of the publications included, review Future clinical trials involving patients with different anxiety disorders are warranted, especially of panic disorder, obsessive-compulsive disorder, social anxiety disorder, and post-traumatic stress disorders. The adequate therapeutic window of CBD and the precise mechanisms involved in its anxiolytic action remain to be determined.

The mental health risks of adolescent cannabis use

Since the early 1970s, when cannabis first began to be widely used [1], the proportion of young people who have used cannabis has steeply increased and the age of first use has declined [2, 3]. Most cannabis users now start in the mid-to-late teens [1], an important period of psychosocial transition when misadventures can have large adverse effects on a young person's life chances.

Representações Sociais da Cannabis no Concelho de Góis

A cannabis permanece como a substância ilícita mais consumida no mundo. Defendida por uns e “diabolizada” por outros, constitui uma das substâncias psicoactivas mais polémicas. Alguns autores destacaram já, a importância do estudo das representações sociais das substâncias psicoactivas. No entanto, desconhecem-se investigações que abordem a representação social desta substância num espaço rural. São objectivos deste estudo: 1) conhecer as representações sociais da cannabis no que diz respeito à substância, ao consumidor e ao contexto da utilização, 2) identificar as diferenças existentes entre utilizadores e não utilizadores desta substância da amostra em estudo. Para concretizar estes objectivos, foi realizado um estudo qualitativo que recorreu a uma dupla abordagem etno-metodológica e fenomenológica. Foram realizadas 30 entrevistas a indivíduos residentes nas duas maiores freguesias do concelho de Góis que, depois de transcritas, foram objecto de análise de conteúdo. No espaço rural considerado, a cannabis é maioritariamente representada como uma “droga”, indutora de uma sensação de mal-estar e causadora de dependência. Para os participantes o utilizador é percebido como detentor de características de personalidade negativas, que o induzem ao consumo. Relativamente ao eixo espacial, o espaço rural, e mais especificamente o concelho de Góis é representado como local de consumo e de produção da cannabis herbácea. Há uma distinção clara entre a representação social dos participantes que não utilizam a substância e os que utilizam. O último grupo representa-a como uma “droga leve”, e mostra-se esclarecido sobre as possíveis consequências da sua utilização. Neste grupo é ainda evidente a valorização da cannabis herbácea, em detrimento dos seus derivados. /