Involvement of the endocannabinoid system in reward processing in the human brain

Rationale Disturbed reward processing in humans has been associated with a number of disorders, such as depression, addiction, and attention-deficit hyperactivity disorder. The endocannabinoid (eCB) system has been implicated in reward processing in animals, but in humans, the relation between eCB functioning and reward is less clear. Objectives The current study uses functional magnetic resonance imaging (fMRI) to investigate the role of the eCB system in reward processing in humans by examining the effect of the eCB agonist Δ9-tetrahydrocannabinol (THC) on reward-related brain activity. Methods Eleven healthy males participated in a randomized placebo-controlled pharmacological fMRI study with administration of THC to challenge the eCB system. We compared anticipatory and feedback-related brain activity after placebo and THC, using a monetary incentive delay task. In this task, subjects are notified before each trial whether a correct response is rewarded (“reward trial”) or not (“neutral trial”). Results Subjects showed faster reaction times during reward trials compared to neutral trials, and this effect was not altered by THC. THC induced a widespread attenuation of the brain response to feedback in reward trials but not in neutral trials. Anticipatory brain activity was not affected. Conclusions These results suggest a role for the eCB system in the appreciation of rewards. The involvement of the eCB system in feedback processing may be relevant for disorders in which appreciation of natural rewards may be affected such as addiction

Association of cannabis with glutamatergic levels in patients with early psychosis: Evidence for altered volume striatal glutamate relationships in patients with a history of cannabis use in early psychosis

The associative striatum, an established substrate in psychosis, receives widespread glutamatergic projections. We sought to see if glutamatergic indices are altered between early psychosis patients with and without a history of cannabis use and characterise the relationship to grey matter. 92 participants were scanned: Early Psychosis with a history of cannabis use (EPC\u2009=\u200929); Early Psychosis with minimal cannabis use (EPMC\u2009=\u200925); Controls with a history of cannabis use (HCC\u2009=\u200916) and Controls with minimal use (HCMC\u2009=\u200922). Whole brain T1 weighted MR images and localised proton MR spectra were acquired from head of caudate, anterior cingulate and hippocampus. We examined relationships in regions with known high cannabinoid 1 receptor (CB1R) expression (grey matter, cortex, hippocampus, amygdala) and low expression (white matter, ventricles, brainstem) to caudate Glutamine+Glutamate (Glx). Patients were well matched in symptoms, function and medication. There was no significant group difference in Glx in any region. In EPC grey matter volume explained 31.9% of the variance of caudate Glx (p\u2009=\u20090.003) and amygdala volume explained 36.9% (p\u2009=\u20090.001) of caudate Glx. There was no significant relationship in EPMC. The EPC vs EPMC interaction was significant (p\u2009=\u20090.042). There was no such relationship in control regions. These results are the first to demonstrate association of grey matter volume and striatal glutamate in the EPC group. This may suggest a history of cannabis use leads to a conformational change in distal CB1 rich grey matter regions to influence striatal glutamatergic levels or that such connectivity predisposes to heavy cannabis use

The effects of Δ9-tetrahydrocannabinol on the dopamine system

Δ(9)-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, is a pressing concern to global mental health. Patterns of use are changing drastically due to legalisation, availability of synthetic analogues (‘spice’), cannavaping and aggrandizements in the purported therapeutic effects of cannabis. Many of THC’s reinforcing effects are mediated by the dopamine system. Due to complex cannabinoid-dopamine interactions there is conflicting evidence from human and animal research fields. Acute THC causes increased dopamine release and neuron activity, whilst long-term use is associated with blunting of the dopamine system. Future research must examine the long-term and developmental dopaminergic effects of the drug

Early Onset Marijuana Use and Adult Mental Health

INTRODUCTION: The impact of marijuana use has become a national topic with the increase in state’s legalizing or decriminalizing the use of the drug. To understand the impact this new trend may have on the population, it is necessary to characterize the interaction between marijuana use and health outcomes. Previous research has focused on the acute effects of marijuana on mental health and longitudinal impacts of marijuana use in the adolescent population. However there are no previously published studies on the impact of early onset marijuana use on adult mental health. AIM: This study aims to determine the prevalence of early onset marijuana use and if there is a statically significant association between early onset marijuana use (\u3c14 years old) and increased prevalence of adverse mental health outcomes in adult life. METHODS: This study was conducted using data from the 2014 National Survey on Drug Use and Health. The study population included 41, 285 participants 18 or older at the time of the cross-sectional survey. Adult mental health outcomes were modeled for both early onset marijuana users and non-early onset marijuana users using a multiple logistic regression model to calculate both adjusted and unadjusted odds ratios (AOR’s, OR’s) with 95% confidence intervals. Statistical analysis was performed to examine the association between early onset marijuana use and negative adult mental health outcomes including serious mental illness, any mental illness and lifetime depressive episodes. RESULTS: This study found that in adults aged 18 and older the prevalence of early onset marijuana use was 8.3%. The prevalence of early onset marijuana use varies by gender, with a prevalence of 5.1(95% CI 4.7-5.2) for males and 3.3(95% CI 3.1-3.5) for females. Early onset marijuana use had a statistically significant association with all three indicators of poor adult mental health. The AOR for early onset marijuana use and serious mental illness was 2.3(95% CI 1.972-2.758). The association between early onset marijuana use and adult depressive episode had an AOR of 2.1(95% CI1.906-2.389). DISCUSSION: These findings suggest that early onset marijuana use is a risk factor for adverse mental health outcomes in adulthood. Consistent with findings from other nationally representative surveys, the prevalence of early onset marijuana use is higher in males than females. Early onset marijuana use is associated with increased odds of past year serious mental illness and past year any mental illness. This suggests that legislature considering marijuana legalization must also consider policies addressing under age use of the drug. Further longitudinal research is needed to father assess the association between early onset marijuana use and adult mental health

Associations between regular cannabis use and brain resting-state functional connectivity in adolescents and adults

Background/aim: Cannabis use is highly prevalent in adolescents; however, little is known about its effects on adolescent brain function. Method: Resting-state functional magnetic resonance imaging was used in matched groups of regular cannabis users (N = 70, 35 adolescents: 16–17 years old, 35 adults: 26–29 years old) and non-regular-using controls (N = 70, 35 adolescents/35 adults). Pre-registered analyses examined the connectivity of seven major cortical and sub-cortical brain networks (default mode network, executive control network (ECN), salience network, hippocampal network and three striatal networks) using seed-based analysis methods with cross-sectional comparisons between user groups and age groups. Results: The regular cannabis use group (across both age groups), relative to controls, showed localised increases in connectivity only in the ECN analysis. All networks showed localised connectivity differences based on age group, with the adolescents generally showing weaker connectivity than adults, consistent with the developmental effects. Mean connectivity across entire network regions of interest (ROIs) was also significantly decreased in the ECN in adolescents. However, there were no significant interactions found between age group and user group in any of the seed-based or ROI analyses. There were also no associations found between cannabis use frequency and any of the derived connectivity measures. Conclusion: Regular cannabis use is associated with changes in connectivity of the ECN, which may reflect allostatic or compensatory changes in response to regular cannabis intoxication. However, these associations were not significantly different in adolescents compared to adults.</p

Associations between regular cannabis use and brain resting-state functional connectivity in adolescents and adults

BACKGROUND/AIM: Cannabis use is highly prevalent in adolescents; however, little is known about its effects on adolescent brain function. METHOD: Resting-state functional magnetic resonance imaging was used in matched groups of regular cannabis users (N = 70, 35 adolescents: 16-17 years old, 35 adults: 26-29 years old) and non-regular-using controls (N = 70, 35 adolescents/35 adults). Pre-registered analyses examined the connectivity of seven major cortical and sub-cortical brain networks (default mode network, executive control network (ECN), salience network, hippocampal network and three striatal networks) using seed-based analysis methods with cross-sectional comparisons between user groups and age groups. RESULTS: The regular cannabis use group (across both age groups), relative to controls, showed localised increases in connectivity only in the ECN analysis. All networks showed localised connectivity differences based on age group, with the adolescents generally showing weaker connectivity than adults, consistent with the developmental effects. Mean connectivity across entire network regions of interest (ROIs) was also significantly decreased in the ECN in adolescents. However, there were no significant interactions found between age group and user group in any of the seed-based or ROI analyses. There were also no associations found between cannabis use frequency and any of the derived connectivity measures. CONCLUSION: Regular cannabis use is associated with changes in connectivity of the ECN, which may reflect allostatic or compensatory changes in response to regular cannabis intoxication. However, these associations were not significantly different in adolescents compared to adults

Do the effects of cannabis on the hippocampus and striatum increase risk for psychosis?

Cannabis use is associated with increased risk of psychotic symptoms and in a small number of cases it can lead to psychoses. This review examines the neurobiological mechanisms that mediate the link between cannabis use and psychosis risk. We use an established preclinical model of psychosis, the methylazoxymethanol acetate (MAM) rodent model, as a framework to examine if psychosis risk in some cannabis users is mediated by the effects of cannabis on the hippocampus, and this region's role in the regulation of mesolimbic dopamine. We also examine how cannabis affects excitatory neurotransmission known to regulate hippocampal neural activity and output. Whilst there is clear evidence that cannabis/cannabinoids can affect hippocampal and medial temporal lobe function and structure, the evidence that cannabis/cannabinoids increase striatal dopamine function is less robust. There is limited evidence that cannabis use affects cortical and striatal glutamate levels, but there are currently too few studies to draw firm conclusions. Future work is needed to test the MAM model in relation to cannabis using multimodal neuroimaging approaches

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.Schizophrenia is a complex disease that has 1% worldwide prevalence. Dopamine etiological theory leads neurochemical paradigms although glutamate hypothesis is gaining in importance among several neurotransmission circuits involved. Schizophrenia patients are more prone to substance use disorders, particularly to cannabis dependence, than the general population. Therefore, we have aimed to explain the hypothesis of a deregulation in the endogenous cannabinoid system, a very important neurodulator.  First, this thesis proposes in the first article an exhaustive literature review on the endocannabinoid system and its implications in schizophrenia. Then, we present results from our clinical research on plasmatic endocannabinoids in three groups of subjects with schizophrenia and/or substance use disorders, during twelve weeks. We have observed a mirror effect involving two endocannabinoid ligands, anandamide and oleylethanolamide, which were elevated in patients with dual diagnosis and reduced in patients with only substance use disorders. At the end of the study, it seems that endocannabinoid elevation was maintained and we supposed a vulnerability to psychosis in a substance use disorder context.   Finally, we analyzed our results by integrating explanations from molecular biology and neuropharmacology and also from neurochemical and inflammatory theories already well-known in schizophrenia. We also considered the main comorbidities observed in clinic such as substance use and metabolic disorders. Then, we proposed an endogenous cannabinoid model of schizophrenia. Ultimately, this thesis suggested research perspectives and potential treatments