ArticleLiterature Review

Role of the endocannabinoid system in brain functions relevant for schizophrenia: An overview of human challenge studies with cannabis or ∆9-tetrahydrocannabinol (THC)

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... 25,104,105,106 CB1 receptors are widely expressed in brain with the highest concentrations in mesocorticolimbic regions. [107][108][109][110] Consistent with this distribution, based on human experimental studies involving cannabinoid administration, CB1 receptors appear to be involved in numerous cognitive processes subserved by corticolimbic circuitry, 44,111 such as learning and memory, 24,47 salience processing, 39,40 and response inhibition, 24 which are also known to be impaired in patients with psychosis. 111 Abundant evidence from experimental studies of healthy volunteers shows that CBD modulates brain function (in the opposite direction to THC) during each of these cognitive processes in their respective neural substrates. ...
... [107][108][109][110] Consistent with this distribution, based on human experimental studies involving cannabinoid administration, CB1 receptors appear to be involved in numerous cognitive processes subserved by corticolimbic circuitry, 44,111 such as learning and memory, 24,47 salience processing, 39,40 and response inhibition, 24 which are also known to be impaired in patients with psychosis. 111 Abundant evidence from experimental studies of healthy volunteers shows that CBD modulates brain function (in the opposite direction to THC) during each of these cognitive processes in their respective neural substrates. 24,39,40,47 This suggests that, at the brain systems level, the mechanism of the antipsychotic effects of CBD may be mediated through modulation of function of these neural substrates. ...
Article
Full-text available
Psychotic disorders such as schizophrenia are heterogeneous and often debilitating conditions that contribute substantially to the global burden of disease. The introduction of dopamine D2 receptor antagonists in the 1950s revolutionised the treatment of psychotic disorders and they remain the mainstay of our treatment arsenal for psychosis. However, traditional antipsychotics are associated with a number of side effects and a significant proportion of patients do not achieve an adequate remission of symptoms. There is therefore a need for novel interventions, particularly those with a non-D2 antagonist mechanism of action. Cannabidiol (CBD), a non-intoxicating constituent of the cannabis plant, has emerged as a potential novel class of antipsychotic with a unique mechanism of action. In this review, we set out the prospects of CBD as a potential novel treatment for psychotic disorders. We first review the evidence from the perspective of preclinical work and human experimental and neuroimaging studies. We then synthesise the current evidence regarding the clinical efficacy of CBD in terms of positive, negative and cognitive symptoms, safety and tolerability, and potential mechanisms by which CBD may have antipsychotic effects.
... Accumulating evidence suggests that the ECS plays a role in the pathophysiology of schizophrenia spectrum disorders (SSD) (Bossong & Niesink, 2010;Bossong, Jansma, Bhattacharyya, & Ramsey, 2014), which makes the ECS a potential target for novel treatments. Minichino et al. (2019) demonstrated, in a whole-group analysis, increased anandamide concentrations in the blood and cerebrospinal fluid (CSF) of patients with psychotic disorders compared to healthy controls (HC). ...
Article
Full-text available
Background Interactions between the endocannabinoid system (ECS) and neurotransmitter systems might mediate the risk of developing a schizophrenia spectrum disorder (SSD). Consequently, we investigated in patients with SSD and healthy controls (HC) the relations between (1) plasma concentrations of two prototypical endocannabinoids (N-arachidonoylethanolamine [anandamide] and 2-arachidonoylglycerol [2-AG]) and (2) striatal dopamine synthesis capacity (DSC), and glutamate and y-aminobutyric acid (GABA) levels in the anterior cingulate cortex (ACC). As anandamide and 2-AG might reduce the activity of these neurotransmitters, we hypothesized negative correlations between their plasma levels and the abovementioned neurotransmitters in both groups. Methods Blood samples were obtained from 18 patients and 16 HC to measure anandamide and 2-AG plasma concentrations. For all subjects, we acquired proton magnetic resonance spectroscopy scans to assess Glx (i.e. glutamate plus glutamine) and GABA + (i.e. GABA plus macromolecules) concentrations in the ACC. Ten patients and 14 HC also underwent [ ¹⁸ F]F-DOPA positron emission tomography for assessment of striatal DSC. Multiple linear regression analyses were used to investigate the relations between the outcome measures. Results A negative association between 2-AG plasma concentration and ACC Glx concentration was found in patients ( p = 0.008). We found no evidence of other significant relationships between 2-AG or anandamide plasma concentrations and dopaminergic, glutamatergic, or GABAergic measures in either group. Conclusions Our preliminary results suggest an association between peripheral 2-AG and ACC Glx levels in patients.
... Over the last decade, the acute effects of THC have been investigated in neuroimaging studies, most of them involving a cognitive paradigm (Bossong et al., 2014;Bloomfield et al., 2019). However, limited research has been done on the effects of THC using resting state functional connectivity, and studies that are conducted often consist of small sample size. ...
Article
Full-text available
Background: Cannabis produces various acute psychotropic effects, with marked individual differences. Cannabis use is a risk factor for developing psychotic disorders. The main component responsible for these effects is Δ9-tetrahydrocannabinol (THC). Here we investigated the neural basis of acute THC effects and its modulation by catechol-methyl-transferase (COMT) Val158Met genotype. Methods: Resting state functional MRI data of healthy occasional cannabis users were combined and re-analyzed from three double-blind, placebo-controlled, within-subject pharmacological functional magnetic resonance imaging studies (total N=87). Functional connectivity after placebo and THC was compared in three functional networks (salience, executive and default mode network) and a network implicated in psychosis (the hippocampus-midbrain-striatum network). COMT genotype modulation of subjective effects and connectivity was examined. Results: THC reduced connectivity in the salience network, specifically from the right insula to both the left insula and anterior cingulate cortex. We found a trend towards decreased connectivity in the hippocampus-midbrain-striatum network after THC. COMT genotype modulated subjective effects of THC, with strongest dysphoric reactions in Met/Met individuals. In addition, reduced connectivity after THC was demonstrated in the hippocampus-midbrain-striatum network of Met/Met individuals only. Conclusions: In this large multisite study we found that THC robustly decreases connectivity in the salience network, involved in processing awareness and salient information. Connectivity changes in the hippocampus-midbrain-striatum network may reflect the acute psychotic-like effects of THC. COMT genotype modulation of THC's impact on subjective effects and functional connectivity provides further evidence for involvement of prefrontal dopamine levels in the acute effects of cannabis.
... Actually, attention deficit has become a landmark task in the study of cognitive deficits in schizophrenia, and is often used to assess executive function (Bossong et al. 2014). The results of our correlation analysis, where CPT_IT scores gradually decreased with decreasing GMV in right fusiform gyrus and right lingual gyrus of EOS, also suggest that abnormal GMV in the ventral stream of visual pathway is associated with decreased cognitive function (Fig. 3B, C). ...
Article
Full-text available
Objectives Schizophrenia is a neurodevelopmental disorder characterized by progressive and widespread gray matter (GM) atrophy. Studies have shown that normal brain development has an impact on schizophrenia-induced GM alterations. However, the neuropathology and underlying molecular mechanisms of interaction between age and schizophrenia are unclear. Methods This study enrolled 66/84 first-episode drug-naïve patients with early-onset/adult-onset schizophrenia ((EOS)/(AOS)) and matched normal controls (NC) (46 adolescents/73 adults), undergoing T1-weighted high-resolution magnetic resonance imaging. Gray matter volume (GMV) in four groups was detected using 2-way analyses of variance with diagnosis and age as factors. Then, factors-related volume maps and neurotransmitter maps were spatially correlated using JuSpace to determine the relationship to molecular structure. Results Compared to AOS, EOS and adult NC had larger GMV in right middle frontal gyrus. Compared to adolescent NC, EOS and adult NC had smaller GMV in right lingual gyrus, right fusiform gyrus, and right cerebellum_6. Disease-induced GMV reductions were mainly distributed in frontal, parietal, thalamus, visual, motor cortex, and medial temporal lobe structures. Age-induced GMV alterations were mainly distributed in visual and motor cortex. The changed GMV induced by schizophrenia, age, and their interaction was related to dopaminergic and serotonergic receptors. Age is also related to glutamate receptors, and schizophrenia is also associated with GABAaergic and noradrenergic receptors. Conclusions Our results revealed the multimodal neural mechanism of interaction between disease and age. We emphasized age-related GM abnormalities of ventral stream of visual perceptual pathways and high-level cognitive brain in EOS, which may be affected by imbalance of excitatory and inhibitory neurotransmitters.
... Cannabis sativa is the most widely used drug in the world. It contains over 70 different constituents, including delta-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) [152]. CBD can interfere with the detrimental actions of Δ9-THC in terms of psychotic proneness and cognitive dysfunction [153]. ...
Chapter
Cognitive impairment, in past decades, has been consistently reported in patients with schizophrenia [1]. Neurocognitive disability appears early in the course of the disease, even in prodromal phases, and these deficits are widely present in different stages of the illness whether in patients or in their first-degree family members [2]. In 2004, the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) project has identified seven distinct cognitive domains that are impaired in patients with schizophrenia: speed of processing, attention/vigilance, working memory, verbal and visual learning, reasoning and problem solving, and social cognition [3–5]. Moreover, in the third meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) project, it was cleared that six areas of cognitive domains are damaged in patients with schizophrenia: perception, working memory, attention, executive functions, long-term memory, and social cognition [6]. Regarding social cognitive deficits, they include impairments in facial affect recognition, in perceiving and interpreting social cues, in theory of mind (ToM), and in the ability to make appropriate causal attributions for events [7]. Several studies have shown that both neurocognitive and social cognitive deficits are among the major causes of severe functional disabilities in patients with schizophrenia and they are also related to a worse outcome of the disorder [8–10]. In a comprehensive literature review, Green et al. [10] underlined that different cognitive deficits might have an impact on specific areas of psychosocial functioning. As a matter of fact, cognitive deficits seem to explain 20–60% of the variance of everyday functioning [3, 4, 11]. The influence of cognition on functional outcomes may happen through its influence on functional capacity, the ability to perform critical everyday living skills [12]. Thus, functional capacity may actually be considered as a proxy measure between neurocognition and everyday functioning and it has been found to be quite strongly associated with cognitive performance [13]. Recent studies have shown how cognitive impairment predicts functional outcomes even more than positive and negative symptoms and how it is associated with disability in phases of clinical remission too [2, 14]. From the greater and detailed knowledge of the role and meaning of cognitive impairment in schizophrenia, its improvement became an essential target in the treatment and in the clinical management of the illness [15]. In order to restore cognitive deficits in schizophrenic patients, there are different pharmacological and non-pharmacological approaches developed. Whereas pharmacological interventions include approved treatments (e.g., antipsychotics and antidepressants) and under-study treatments, non-pharmacological interventions include cognitive remediation, noninvasive brain stimulation techniques, and physical activity techniques [16–20].
... On the contrary, no significant association between cannabis use and emotions with negative valence (i.e., fearful and angry) was observed. This finding provides further support to the hypothesis that cannabinoids interact with emotional content, inducing a shift from a bias for negative emotional content towards positive emotional content ( Bossong et al., 2014( Bossong et al., , 2013. On the one hand, they suggest a possible role for the ECS in abnormal emotional processing; on the other hand, they provide indirect evidence for an involvement of ECS in FER deficits experienced by patients with schizophrenia ( Bossong et al., 2013 ). ...
Article
Full-text available
Schizophrenia is frequently accompanied with social cognitive disturbances. Cannabis represents one established environmental factor associated with the onset and progression of schizophrenia. The present cross-sectional study aimed to investigate the association of facial emotion recognition (FER) performance with cannabis use in 2039 patients with schizophrenia, 2141 siblings, and 2049 healthy controls (HC). FER performance was measured using the Degraded Facial Affect Recognition Task (DFAR). Better FER performance as indicated by higher DFAR-total scores was associated with lifetime regular cannabis use in schizophrenia (B = 1.36, 95% CI 0.02 to 2.69), siblings (B = 2.17, 95% CI 0.79 to 3.56), and HC (B = 3.10, 95% CI 1.14 to 5.06). No associations were found between DFAR-total and current cannabis use. Patients with schizophrenia who started to use cannabis after the age of 16 showed better FER performance than patients who started earlier (B = 2.50, 95% CI 0.15 to 4.84) and non-users (B = 3.72, 95 CI 1.96 to 5.49). Better FER performance was found also in siblings who started to use cannabis after 16 compared to non-users (B = 2.37, 95% CI 0.58 to 4.16), while HC using cannabis performed better than non-users at DFAR-total regardless of the age at onset. Our findings suggest that lifetime regular cannabis use may be associated with better FER regardless of the psychosis risk, but that FER might be moderated by age at first use in people with higher genetic risk. Longitudinal studies may clarify whether there is a cause-and-effect relationship between cannabis use and FER performance in psychotic and non-psychotic samples.
... We show, for the first time, that a linear relationship exists between the effect of THC on increases in brain signal (as indexed by the pooled effect-size estimate) and CNR1 gene expression levels (as estimated on the basis of an average from 6 post-mortem brains of healthy individuals obtained from Allen Human Brain Atlas), a proxy measure of CB1R availability, across the whole brain(41). These findings are important as the CB1R is the main molecular target of THC in the human brain, where it has partial-agonist effects (46,99). Our findings thus provide novel -albeit indirect-evidence that the effects of THC on human brain function are in part related to local CB1 receptor availability, and complement independent experimental evidence that the acute effects of THC on human behaviour may be mediated by its effects on CB1R. ...
Article
The neurobiological mechanisms underlying the effects of delta-9-tetrahydrocannabinol (THC) remain unclear. Here, we examined the spatial acute effect of THC on human on regional brain activation or blood flow (hereafter called ‘activation signal’) in a ‘core’ network of brain regions from 372 participants, tested using a within-subject repeated measures design under experimental conditions was used. We also investigated whether the neuromodulatory effects of THC are related to the local expression of the cannabinoid-type-1 (CB1R) and type-2 (CB2R) receptor. Finally, we investigated the dose-response relationship between THC and key brain substrates. These meta-analytic findings shed new light on the localisation of the effects of THC in the human brain, suggesting that THC has neuromodulatory effects in regions central to many cognitive tasks and processes, related to dose, with greater effects in regions with higher levels of CB1R expression.
... Like all drugs of abuse, cannabis increases dopamine levels in the nucleus accumbens (NAcc) (Zehra et al. 2018), which would generally be expected to increase willingness to exert effort (Di Chiara 1988;Salamone et al. 2007). However, it is true that the effect of cannabis on dopamine is weaker than other classic drugs of abuse (Bossong et al. 2014), which might also justify a null effect on effort. However, both our study and previous studies in humans suggest cannabis Fig. 4 Effects of oral THC (7.5 mg, 15 mg) on EEfRT task performance (% hard task choices). ...
Article
Full-text available
Background The use of cannabis has been clinically associated with decreased motivation to engage in normally rewarding activities. However, evidence from previous controlled studies is mixed. Method In this study, we examined the effects of acute delta-9-tetrahydrocannabinol (THC) versus placebo on a task measuring willingness to exert effort for rewards. This is a secondary analysis of a larger study examining interactions between ovarian hormones and THC. In this within-subjects study, oral THC and placebo were administered under double-blind conditions in counterbalanced order to healthy young adult (M age = 24 years) women with previous cannabis experience who were not regular users. Forty subjects completed three 4-h sessions with PL, 7.5 and 15 mg THC, while an additional 18 completed only PL and 15 mg THC sessions (design abridged due to pandemic). At each session, they completed a task consisting of making repeated choices between a hard and an easy task, which were worth varying amounts of money at varying probabilities. Results THC dose-dependently decreased hard task choices (drug effect, b = − 0.79, SE = 0.29, z = − 2.67, p < 0.01), especially at moderate to high expected values of reward (drug × probability × amount interaction, b = 0.77, SE = 0.38, z = 1.99, p = 0.04). THC also slowed task performance (drug effect, b = 0.01, SE = 0.005, t(5.24) = 2.11, p = 0.04), but the effect of THC on choice was still significant after controlling for this psychomotor slowing. Conclusions These findings support the idea that cannabis acutely reduces motivation to earn non-drug rewards. Still to be determined are the neurochemical mechanisms underlying this effect.
... There is a growing body of evidence that the endocannabinoid system is implicated in the pathophysiology of psychosis (Bossong et al., 2014;Zamberletti et al., 2012), thus CBD has been proposed as a candidate pharmacotherapy (Davies and Bhattacharyya, 2019). Preclinical work indicates that CBD inhibits the degradation of anandamide (Bisogno et al., 2001), an endocannabinoid which plays a major role in mood regulation, cognition, and behavior (Di Marzo and Petrosino, 2007). ...
Article
Cannabidiol (CBD) has become a fast-growing avenue for research in psychiatry, and clinicians are challenged with understanding the implications of CBD for treating mental health disorders. The goal of this review is to serve as a guide for mental health professionals by providing an overview of CBD and a synthesis the current evidence within major psychiatric disorders. PubMed and PsycINFO were searched for articles containing the terms “cannabidiol” in addition to major psychiatric disorders and symptoms, yielding 2,952 articles. Only randomized controlled trials or within-subject studies investigating CBD as a treatment option for psychiatric disorders (N=16) were included in the review. Studies were reviewed for psychotic disorders (n =6), anxiety disorders (n =3), substance use disorders (tobacco n= 3, cannabis n= 2, opioid n= 1), and insomnia (n= 1). There were no published studies that met inclusion criteria for alcohol or stimulant use disorder, PTSD, ADHD, autism spectrum disorder, or mood disorders. Synthesis of the CBD literature indicates it is generally safe and well tolerated. The most promising preliminary findings are related to the use of CBD in psychotic symptoms and anxiety. There is currently not enough high-quality evidence to suggest the clinical use of CBD for any psychiatric disorder.
... It is thought to play a critical role in regulating glutamatergic signalling, modulating NMDA receptor activity in order to prevent excitotoxicity (Sanchez-Blazquez et al., 2014). The endocannabinoid system has also been strongly implicated in the pathophysiology of psychosis in both clinical and pre-clinical studies (Appiah-Kusi et al., 2016;Bhattacharyya et al., 2012b;Bossong et al., 2014;Dalton et al., 2011;D'Souza et al., 2004;Leweke et al., 2016;Muguruza et al., 2013). It follows that aberrant activity of the endocannabinoid system resulting in NMDA receptor hypofunction could support the glutamatergic model of psychosis (Sanchez-Blazquez et al., 2014). ...
Article
Full-text available
Background Emerging evidence supports the antipsychotic effect of cannabidiol, a non-intoxicating component of cannabis, in people with psychosis. Preclinical findings suggest that this antipsychotic effect may be related to cannabidiol modulating glutamatergic signalling in the brain. Aim The purpose of this study was to investigate the effects of cannabidiol on the neurochemical mechanisms underlying psychosis. Methods We investigated the effects of a single oral dose of cannabidiol (600 mg) in patients with psychosis, using a double-blind, randomised, placebo-controlled, repeated-measures, within-subject cross-over design. After drug administration, 13 patients were scanned using proton magnetic resonance spectroscopy to measure left hippocampal glutamate levels. Symptom severity was rated using the Positive and Negative Syndrome Scale 60 min before drug administration (pre-scan), and 270 min after drug administration (post-scan). Effects of cannabidiol on hippocampal glutamate levels, symptom severity, and correlations between hippocampal glutamate and symptoms were investigated. Results Compared to placebo, there was a significant increase in hippocampal glutamate ( p=0.035), and a significantly greater decrease in symptom severity ( p=0.032) in the psychosis patients under cannabidiol treatment. There was also a significant negative relationship between post-treatment total Positive and Negative Syndrome Scale score and hippocampal glutamate ( p=0.047), when baseline Positive and Negative Syndrome Scale score, treatment (cannabidiol vs placebo), and interaction between treatment and glutamate levels were controlled for. Conclusions These findings may suggest a link between the increase in glutamate levels and concomitant decrease in symptom severity under cannabidiol treatment observed in psychosis patients. Furthermore, the findings provide novel insight into the potential neurochemical mechanisms underlying the antipsychotic effects of cannabidiol.
... For instance, interactions between disease states and stimulation may lead to illness-specific side effects, such as the increased risk of mania induction in patients with bipolar disorder, the increased risk of seizure induction in patients with cortical lesions, or the influence of brain atrophy on electrical current distribution in patients with prior traumatic brain injuries or co-morbid neurodegenerative conditions (Iriarte & George, 2018;Rossi et al., 2009). Relatedly, frequent, heavy cannabis use is known to exacerbate the risk of psychosis or schizophrenia in individuals with predispositions to these conditions (Bossong et al., 2014;Di Forti et al., 2015;2019), though the psychotomimetic effects of cannabis exposure have also been shown in otherwise healthy individuals with no pre-existing risk factors (Bhattacharyya et al., 2012;Marconi et al. 2016). As such, the potential for mania-related side effects of rTMS represents an important potential contraindication to rTMS therapy for individuals with CUD, which should be studied further in future research, and ultimately, weighed carefully against the potential benefits of this treatment option relative to other modalities. ...
Article
The expanding legalization of cannabis across the United States is associated with increases in cannabis use, and accordingly, an increase in the number and severity of individuals with cannabis use disorder (CUD). The lack of FDA-approved pharmacotherapies and modest efficacy of psychotherapeutic interventions means that many of those who seek treatment for CUD relapse within the first few months. Consequently, there is a pressing need for innovative, evidence-based treatment development for CUD. Preliminary evidence suggests that repetitive transcranial magnetic stimulation (rTMS) may be a novel, non-invasive therapeutic neuromodulation tool for the treatment of a variety of substance use disorders (SUDs), including recently receiving FDA clearance (August 2020) for use as a smoking cessation aid in tobacco cigarette smokers. However, the potential of rTMS for CUD has not yet been reviewed. This paper provides a primer on therapeutic neuromodulation techniques for SUDs, with a particular focus on reviewing the current status of rTMS research in people who use cannabis. Lastly, future directions are proposed for rTMS treatment development in CUD, with suggestions for study design parameters and clinical endpoints based on current gold-standard practices for therapeutic neuromodulation research.
... Along with observations of morphological and functional changes to anterior cingulate cortex (ACC) function (11)(12)(13)(14)(15)(16), evidence suggests that dysregulation of glutamate metabolism in this brain region and neurotransmission plays a key role in the development and maintenance of substance use disorders (17). Glutamate metabolism is regulated by astrocytes which are responsible for clearance of synaptic glutamate and provide glutamine to neurons (18). ...
Article
Full-text available
There is evidence that long-term cannabis use is associated with alterations to glutamate neurotransmission and glial function. In this study, 26 long-term cannabis users (males=65.4%) and 47 non-cannabis using healthy controls (males=44.6%) underwent proton magnetic resonance spectroscopy (¹H-MRS) of the anterior cingulate cortex (ACC) in order to characterize neurometabolite alterations in cannabis users and to examine associations between neurometabolites, cannabis exposure, and cannabis use behaviors. Myo-inositol, a marker of glial function, and glutamate metabolites did not differ between healthy controls and cannabis users or cannabis users who met criteria for DSM5 cannabis use disorder (n=17). Lower myo-inositol, a putative marker of glial function, was related to greater problematic drug use (F1,22 = 11.95, p=.002; Cohen’s f=0.59, large effect; Drug Abuse Screening Test) and severity of cannabis dependence (F1,22 = 6.61, p=.17; Cohen’s f=0.44, large effect). Further, past-year cannabis exposure exerted different effects on glutamate and glutamate+glutamine in males and females (glutamate: F1,21 = 6.31, p=.02; glutamate+glutamine: F1,21 = 7.20, p=.014), such that greater past-year cannabis exposure was related to higher concentrations of glutamate metabolites in male cannabis users (glutamate: F1,14 = 25.94, p=.00016; Cohen’s f=1.32, large effect; glutamate+glutamine: F1,14 = 23.24, p=.00027, Cohen’s f=1.24, large effect) but not in female cannabis users (glutamate: F1,6 = 1.37, p=0.78; glutamate+glutamine: F1,6 = 0.001, p=.97). The present results extend existing evidence of altered glial function and glutamate metabolism with cannabis use by providing evidence linking problematic drug use behaviors with glial function as measured with myo-inositol and recent chronic cannabis exposure to alterations in glutamate metabolism. This provides novel directions for the interrogation of the impact of cannabis use on brain neurochemistry.
... Interestingly, anandamide is involved in key functions that are known to be altered in schizophrenia, including reward processing, stress regulation and memory (14,15). Moreover, CB 1 receptors are distributed in high densities in brain regions known to be impaired in schizophrenia, such as the prefrontal cortex, the hippocampus and the basal ganglia (7,16). ...
Article
Full-text available
Background The endogenous cannabinoid system mediates the psychoactive effects of cannabis in the brain. It has been argued that this system may play a key role in the pathophysiology of schizophrenia. While some studies have consistently shown that the levels of anandamide, an endogenous cannabinoid ligand, are increased in the cerebrospinal fluid of schizophrenia patients, inconsistent results have been observed in studies measuring anandamide levels in the periphery. Here, we sought to determine if the assessment of peripheral anandamide levels in patients evaluated in a psychiatric emergency setting would show robust increases. Methods One hundred seven patients with a schizophrenia-spectrum disorder from the psychiatric emergency settings of the Institut Universitaire en Santé Mentale de Montréal and 36 healthy volunteers were included in the study. A subsample of thirty patients were assessed at two time points: at the emergency and at their discharge from the hospital. Anxious and depressive symptoms, sleep and substance use were assessed using self-report questionnaires. In addition to anandamide, the levels of oleoylethanolamide (OEA), an anorexigenic fatty-acid ethanolamide, were also measured, since the prevalence of the metabolic syndrome is increased in schizophrenia. Plasma levels of anandamide and OEA were measured using liquid chromatography and mass spectrometry. Results Plasma anandamide and OEA levels were significantly increased in schizophrenia patients, relative to controls (Cohen’s d=1.0 and 0.5, respectively). Between-group differences remained significant after controlling for metabolic measures. No differences were observed between schizophrenia patients with and without a comorbid substance use disorder at baseline. Importantly, the levels of both endocannabinoids significantly decreased after discharge from the emergency setting. Conclusion The current results add to the growing body of evidence of endocannabinoid alterations in schizophrenia. The strong elevation of plasma anandamide levels in schizophrenia patients assessed in the psychiatric emergency setting suggests that anandamide and OEA area potential biomarkers of the psychological turmoil associated with this context.
... Previous reports have suggested both a potentially beneficial effect, as well as a potentially negative effect [23][24][25][26][27][28][29][30], for cannabis use in the context of human disease. The food and drug administration (FDA) has approved a number of cannabis-related therapies, including synthetic THC compounds, as well as plant-derived CBD [23][24][25][26]. ...
Article
Full-text available
Relatively little is known in terms of patient demographics, indications, previous cannabis use, or the forms and dosages of medical marijuana (MM) dispensed for patients at MM dispensaries. Even less is known in terms of how male and female patients may differ in each of these aspects. The goal of the current study was to examine each of these variables using a retrospective analysis of deidentified patient data from MM dispensaries in Louisiana. Deidentified data were analyzed from web-based pharmacist–patient consultations at MM dispensaries throughout Louisiana. Data were collected during the first 6 months following the initiation of the MM dispensing program in Louisiana. A total of 1195 MM patients (598 male/597 female) were included in the analyses. The average age of the sample was 51.9 years (±14.8) and it was composed primarily of white patients (86.7%). Males and females were nearly identical in terms of average age, race, previous cannabis use, indication profile, and MM recommendations. Differences between males and females were observed in terms of opioid use, history of psychosis, presence of more than one indication, and the duration of previous cannabis use. Our data indicate that, in MM dispensaries of the Deep South state, there are numerous similarities—and some potentially important differences—between male and female MM patients. The importance of these differences, and the importance of continued data collection/analysis, for improving MM dispensing are discussed.
... There is growing evidence that supports the relationship between the endocannabinoid system and schizophrenia (Bossong et al., 2014;Fakhoury, 2017;Gupta et al., 2014;Ibarra-Lecue et al., 2018;Saito et al., 2013). Moreover, the activation of this system produces the release of circulating cytokines and different neurotransmitters, including dopamine (Foster et al., 2016;Kucerova et al., 2014). ...
Article
There is evidence for increased rates of drug use among schizophrenic patients. However, the causality in this relationship remains unclear. In the present work, we use a maternal immune activation model to test whether animals at high risk of developing a schizophrenia-like condition are more prone to acquire cocaine self-administration, show enhanced sensitivity to the reinforcing actions of cocaine or if they are resistant to extinction or vulnerable to relapse. Also, given that D3 and CB2 receptor expression in immune cells is altered in patients with schizophrenia, we examined the populations of immune cells expressing these receptors. Pregnant rats were injected with lipopolysaccharide (LPS) (2 mg/kg s.c.) or saline every other day during pregnancy, and we tested prepulse inhibition –PPI- in the offspring. After this, one group of rats was submitted to cocaine self-administration (0.5 mg/kg) under fixed and progressive ratio schedules, dose-response testing, extinction and cue-induced drug-seeking. Another group was sacrificed to study the immune blood cells by flow cytometry. While rats born to LPS-treated mothers showed impaired PPI, there were no differences in cocaine self-administration acquisition, responsiveness to dose shifts, extinction or cue-induced reinstatement. Finally, there were fewer D3R⁺ granulocytes in the LPS-offspring and an exciting trend for CB2R⁺ lymphocytes to be more abundant in LPS-exposed rats. Our results indicate that the higher prevalence of cocaine abuse among people with schizophrenia is not due to a pre-existing pathology and suggest that D3R⁺ granulocytes and possibly CB2R⁺ lymphocytes could be potential biomarkers of schizophrenia.
... This could account, at least in part, for some of the discrepancies reported in studies assessing exclusively the behavioral component of cognitive processing (Pope et al., 2001). In line with evidence that cannabis-induced cognitive impairments tend to map on some of the domains affected in psychosis patients, similarities have been reported between the neurophysiological alterations underlying cognitive dysfunction in cannabis users and those underlying the cognitive deficits observed in psychosis (Bossong et al., 2014b;Blest-Hopley et al., 2018). p0200 ...
Chapter
Accumulating evidence suggests an association between cannabis use and psychosis. However, some concerns have been raised about the nature of this association, particularly whether it might be driven by other factors such as use of other substances. Another explanation would bring into play preexisting differences among cannabis users and nonusers in terms of psychosis-related symptomatology that would make cannabis users more prone to develop psychosis. Moreover, it has been argued that people with psychosis may use cannabis more in an attempt to self-medicate, thus implying that psychosis may itself predispose to cannabis use. Finally, evidence of a common genetic background predisposing to both psychosis and cannabis use would weaken the strength of any direct detrimental effect of cannabis use on later development of psychosis. The aim of this chapter is to bring together the available evidence specifically exploring the causality of the association between cannabis use and psychosis and to discuss it along with cause–effect criteria such as magnitude of the association, consistency of findings from other studies, specificity of the association, temporal sequence of association, biological gradient, coherence and experimental proof, and biological plausibility. Collectively, there is robust evidence for an association between cannabis use and psychosis. Convergent evidence from prospective and experimental studies points in the direction of a causal relationship. Although the size of the effect appears modest, the psychosis-inducing effects of cannabis may be particularly high among frequent users, users of potent forms of cannabis, and in the context of specific genetic or neurobiological vulnerability.
... Characteristics of psychosis include positive symptoms, such as hallucinations and delusions; negative and affective symptoms, such as a lack of motivation and depression; and neurocognitive alterations [2]. Although one of the most robust pathophysiological features of psychosis is an increase in the striatal dopamine function, accumulating evidence indicates abnormalities in the endocannabinoid system of patients with a psychotic disorder [3][4][5]. For example, patients exhibit enhanced levels of endogenous cannabinoid ligands in cerebrospinal fluid [6,7], as well as increased post-mortem CB1 receptor densities [8,9] and in vivo CB1 receptor availability in the brain [10,11]. ...
Article
Full-text available
Increasing evidence indicates a relationship between cannabis use and psychosis risk. Specific factors, such as determinants of cannabis use or the genetic profile of cannabis users, appear to moderate this association. The present systematic review presents a detailed and up-to-date literature overview on factors that influence the relationship between cannabis use and psychosis risk. A systematic search was performed according to the PRISMA guidelines in MEDLINE and Embase, and 56 studies were included. The results show that, in particular, frequent cannabis use, especially daily use, and the consumption of high-potency cannabis are associated with a higher risk of developing psychosis. Moreover, several genotypes moderate the impact of cannabis use on psychosis risk, particularly those involved in the dopamine function, such as AKT1. Finally, cannabis use is associated with an earlier psychosis onset and increased risk of transition in individuals at a clinical high risk of psychosis. These findings indicate that changing cannabis use behavior could be a harm reduction strategy employed to lower the risk of developing psychosis. Future research should aim to further develop specific biomarkers and genetic profiles for psychosis, thereby contributing to the identification of individuals at the highest risk of developing a psychotic disorder.
... There is growing evidence that supports the relationship between the endocannabinoid system and schizophrenia (Bossong et al., 2014;Fakhoury, 2017;Gupta et al., 2014;Ibarra-Lecue et al., 2018;Saito et al., 2013). Moreover, the activation of this system produces the release of circulating cytokines and different neurotransmitters, including dopamine (Foster et al., 2016;Kucerova et al., 2014). ...
Preprint
Full-text available
There is evidence for increased rates of drug use among schizophrenic patients. However, the causality in this relationship remains unclear. In addition, biomarkers of schizophrenia are vital, given the heterogeneous nature of the disorder that can lead to difficulties in the early diagnosis. In the present work, we use a maternal immune activation model to experimentally test whether animals at high risk of developing a schizophrenia-like condition are more prone to acquire cocaine self-administration, show enhanced sensitivity to the reinforcing actions of cocaine or if they are resistant to extinction or vulnerable to relapse. Pregnant rats were injected with lipopolysaccharide (LPS) (2 mg/kg s.c.) or saline every other day during pregnancy, and the offspring was tested for sensorimotor gating (prepulse inhibition or PPI). After this test, one group of rats was submitted to cocaine self-administration (0.5 mg/kg) under fixed and progressive ratio schedules, dose-response testing, extinction and cue-induced drug-seeking. Another group was sacrificed to study potential biomarkers in the immune blood cells by flow cytometry. While rats born to LPS-treated mothers showed impaired PPI, there were no differences in cocaine self-administration acquisition, responsiveness to dose shifts, extinction or cue-induced reinstatement. Finally, there were fewer DRD3+ granulocytes in the LPS-offspring and an exciting trend for CNR2+ lymphocytes to be more abundant in LPS-exposed rats. Our results indicate that the higher prevalence of cocaine abuse among people with schizophrenia is not due to a pre-existing pathology and suggest that DRD3+ granulocytes and possibly CNR2+ lymphocytes could be potential biomarkers of schizophrenia.
... Cannabinoid receptors are as abundant as glutamate, gamma-aminobutyric acid (GABA), or dopamine receptors in the brain (Katona & Freund, 2012), and consequently are involved in a wide range of functions including regulation of mood, memory and reward processing (Bossong, Jansma, Bhattacharyya, & Ramsey, 2014; J o u r n a l P r e -p r o o f 7 2000; Solowij et al., 2019). CBD (400-600mg oral) administered alone is also associated with anxiolytic effects (Crippa et al., 2011;Hundal et al., 2018;Zuardi et al., 1993), however, in a recent study of emotional processing tasks, CBD (300-900mg oral) induced minimal behavioural and subjective effects (Arndt & De Wit, 2017). ...
Article
The recent liberalisation of cannabis regulation has increased public and scientific debate about its potential benefits and risks. A key focus has been the extent to which cannabidiol (CBD) might influence the acute effects of delta-9-tetrahydrocannabinol (THC), but this has never been reviewed systematically. In this systematic review of how CBD influences the acute effects of THC we identified 16 studies involving 466 participants. Ten studies were judged at low risk of bias. The findings were mixed, although CBD was found to reduce the effects of THC in several studies. Some studies found that CBD reduced intense experiences of anxiety or psychosis-like effects of THC and blunted some of the impairments on emotion and reward processing. However, CBD did not consistently influence the effects of THC across all studies and outcomes. There was considerable heterogeneity in dose, route of administration and THC:CBD ratio across studies and no clear dose-response profile emerged. Although findings were mixed, this review suggests that CBD may interact with some acute effects of THC.
... The eCB system is a retrograde messenger system that regulates both excitatory glutamate and inhibitory GABA neurotransmission according to an 'on-demand' principle: Endocannabinoids are released when and where they are needed [10,11,13]. This endocannabinoid-mediated regulation of synaptic transmission is a widespread phenomenon in the brain and is thought to play an important role in higher brain functions, such as cognition, motor function, and processing of sensory input, reward, and emotions [14][15][16][17]. eCB receptors are also present on immune cells in the central nervous system (i.e., microglia), which suggests their involvement in processes such as cytokine release, immune suppression, and induction of both cell migration and apoptosis [18,19]. ...
Article
Full-text available
The endogenous cannabinoid (eCB) system plays an important role in the pathophysiology of both psychotic disorders and substance use disorders (SUDs). The non-psychoactive cannabinoid compound, cannabidiol (CBD) is a highly promising tool in the treatment of both disorders. Here we review human clinical studies that investigated the efficacy of CBD treatment for schizophrenia, substance use disorders, and their comorbidity. In particular, we examined possible profiles of patients who may benefit the most from CBD treatment. CBD, either as monotherapy or added to regular antipsychotic medication, improved symptoms in patients with schizophrenia, with particularly promising effects in the early stages of illness. A potential biomarker is the level of anandamide in blood. CBD and THC mixtures showed positive effects in reducing short-term withdrawal and craving in cannabis use disorders. Studies on schizophrenia and comorbid substance use are lacking. Future studies should focus on the effects of CBD on psychotic disorders in different stages of illness, together with the effects on comorbid substance use. These studies should use standardized measures to assess cannabis use. In addition, future efforts should be taken to study the relationship between the eCB system, GABA/glutamate, and the immune system to reveal the underlying neurobiology of the effects of CBD.
... Interestingly, anandamide is involved in key functions that are known to be altered in schizophrenia, including reward processing, stress regulation and memory (14,15). Moreover, CB 1 receptors are distributed in high densities in brain regions known to be impaired in schizophrenia, such as the prefrontal cortex, the hippocampus and the basal ganglia (7,16). ...
... In recent years, neuroimaging studies have increasingly demonstrated acute effects of THC on brain function, the vast majority of them involving a cognitive challenge ( Bossong et al., 2014b ). For example, without affecting performance accuracy, THC caused reductions in activity during encoding of information in temporal and prefrontal areas, but increases in activity during recall, which suggests neural compensation to meet the cognitive demands of a task ( Bhattacharyya et al., 2009;Bossong et al., 2012 ). ...
Article
Cannabis produces a broad range of acute, dose-dependent psychotropic effects. Only a limited number of neuroimaging studies have mapped these effects by examining the impact of cannabis on resting state brain neurophysiology. Moreover, how genetic variation influences the acute effects of cannabis on resting state brain function is unknown. Here we investigated the acute effects of ∆9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, on resting state brain neurophysiology, and their modulation by catechol-methyl-transferase (COMT) Val158Met genotype. Thirty-nine healthy volunteers participated in a pharmacological MRI study, where we applied Arterial Spin Labelling (ASL) to measure perfusion and functional MRI to assess resting state connectivity. THC increased perfusion in bilateral insula, medial superior frontal cortex, and left middle orbital frontal gyrus. This latter brain area showed significantly decreased connectivity with the precuneus after THC administration. THC effects on perfusion in the left insula were significantly related to subjective changes in perception and relaxation. These findings indicate that THC enhances metabolism and thus neural activity in the salience network. Furthermore, results suggest that recruitment of brain areas within this network is involved in the acute effects of THC. Resting state perfusion was modulated by COMT genotype, indicated by a significant interaction effect between drug and genotype on perfusion in the executive network, with increased perfusion after THC in Val/Met heterozygotes only. This finding suggests that prefrontal dopamine levels are involved in the susceptibility to acute effects of cannabis.
... Cannabis use during adolescence has also been sug- gested to affect late brain maturation, resulting in the ob- served increased risk for psychosis associated with use of the drug ( Cohen et al., 2008;Di Forti et al., 2009;Gage et al., 2016 ). This evidence, together with findings from imaging, epidemiological and genetic studies, support a hypothesis that changes in the eCB system may underlie perturbed cognitive and emotional processing relevant to schizophrenia ( Bossong et al., 2014;Leweke et al., 2007;Volk and Lewis, 2016 ). Our findings that adolescent off- spring from LPS-exposed pregnant rats exhibited changes in eCB-mediated inhibitory mechanisms and in eCB signaling and levels support this hypothesis. ...
Article
There is strong evidence that immune activation from prenatal infection increases the risk for offspring to develop schizophrenia. The endocannabinoid (eCB) system has been implicated in the pathophysiology of schizophrenia while models of cortical dysfunction postulate an imbalance between neuronal excitation and inhibition in the disorder. The current study examined the impact of prenatal immune activation on eCB-mediated inhibitory mechanisms. We compared two forms of eCB-related plasticity of evoked inhibitory postsynaptic currents, namely depolarization-induced suppression of inhibition (DSI) and metabotropic glutamate receptor-induced long term depression (mGluR-iLTD), in both the dorsal and ventral hippocampus between adolescent offspring from rat dams that received either saline or bacterial lipopolysaccharide (LPS) during pregnancy. Compared to prenatal saline offspring, prenatal LPS offspring displayed prolonged DSI and stronger mGluR-iLTD in the dorsal and ventral hippocampus, respectively. The sensitivity of mGluR-iLTD to the CB1 receptor antagonist AM251 was also lower in the dorsal hippocampus of prenatal LPS compared to prenatal saline offspring. Testing whether changes in eCB receptor signaling or levels could contribute to these changes in inhibitory transmission, we found region specific increases in 2-arachidonoylglycerol-stimulated signaling and in basal and mGluR-induced levels of anandamide in prenatal LPS offspring when compared to prenatal saline offspring. Our findings indicate that prenatal immune activation can lead to long-term changes in eCB-related plasticity of hippocampal inhibitory synaptic transmission in adolescent rat offspring. Perturbation of the eCB system resulting from prenatal immune activation could represent a mechanism linking early life immune events to the development of psychopathology in adolescence.
... In addition, cannabis has been shown to acutely induce increased heart rate, perceptual alterations, time distortion, infectious laughter, talkativeness and intensification of ordinary experiences such as eating and listening to music (Ashton, 2001;Hall and Degenhardt, 2009). Most cognitive functions seem to be reduced during acute cannabis intoxication, with impairments in learning and memory, attention and executive function among the most consistently demonstrated effects (Solowij and Michie, 2007;Crean et al., 2011;Bossong et al., 2014aBossong et al., , 2014bBroyd et al., 2016; Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website, www.behaviouralpharm.com. ...
Article
Cannabis remains the most frequently used illicit drug worldwide. It produces a broad range of acute effects, such as euphoria, increased heart rate and perceptual alterations. Over the last few decades, a substantial number of experiments have been conducted to provide insight into the acute effects of cannabis on cognition. Here, we systematically review studies that investigated the impact of administration of cannabis or [INCREMENT]-tetrahydrocannabinol, the main psychoactive constituent of cannabis, on human executive function, in particular, on the three principal domains of inhibition, working memory and reasoning/association. Our findings suggest that cannabis use results in acute impairment of inhibition, with the strongest effects after pulmonary administration of higher doses of [INCREMENT]-tetrahydrocannabinol. Results from neuroimaging studies indicate that these effects are predominantly modulated through neural processes in the inferior frontal gyrus. Working memory and reasoning/association are less clearly affected by cannabis administration, possibly because of compensational neural mechanisms to overcome the effects of cannabis intoxication on performance accuracy. Factors that may account for the variation in results are the extent to which a paradigm involves attentional processes, differences between studies in administration methods and variation in the patients' history of cannabis use.
... Schizophrenia is an idiopathic chronic psychosis that causes hallucinations, delusions, thought and speech disorders, emotional and affective disturbances, and cognitive deficits [95]. Some scientists have proposed that a dysfunction in the EC system underlies these symptoms [96,97]. ...
Article
Endocannabinoids (ECs) are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors [cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2)]. Many ECs have been characterized; anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) are still considered the primary ECs signaling mediators. Dysregulation of ECs has been implicated in a wide range of pathologies, including neurodegenerative diseases. Understanding how ECs participate in neurological diseases is important to describe the pathology and to establish new treatments. Considering the physicochemical properties of ECs, liquid chromatography coupled to tandem mass spectrometry has become the reference method to determine these endogenous substances, in trace levels, in different biological samples. This review describes the recent advances in LC-MS/MS methods designed to determine ECs in complex biological matrixes. The advantages, limitations, selectivity, matrix effect, and sensitivity associated with each approach are emphasized. This article comprises three sections: (I) sample preparation techniques (conventional, microextraction, and online systems), (II) chromatographic methods (especially LC-MS/MS), and (III) relationship between ECs levels and neurodegenerative diseases.
... Résultats de la méta-analyse comparant des patients schizophrènes consommateurs de cannabis vs non-consommateurs(Rabin et al. 2011) Le fait que les performances cognitives des patients schizophrènes consommateurs de cannabis soient supérieures à celles de patients non consommateurs dans les études précédemment citées pourrait être attribué à des effets neurobiologiques.Cette hypothèse est étayée par le rôle que pourrait avoir le système endocannabinoïde dans la régulation des circuits neuronaux impliqués dans la neurocognition(132,181). Les recherches actuelles suggèrent que l'exposition auxcannabinoïdes pourrait entraîner des modifications fonctionnelles au niveau de régions cérébrales riches en récepteurs CB1, telles que des variations de la perfusion cérébrale et des modifications dans les modulations des systèmes de neurotransmission dopaminergique, gabaergique et glutamatergique (152,182). ...
... The acute effects of cannabis, Δ9-tetrahydrocannabinol (THC), or of the THC analog nabilone in nonpsychotic individuals mimic positive, negative, and cognitive symptoms of schizophrenia, [22][23][24] as well as neurophysiological phenomena associated with psychosis. [25][26][27][28] In PSZ, THC acutely worsens psychotic symptoms and cognitive functions, 29 and there is evidence that individuals with a predisposition for psychosis are more vulnerable to these acute psychotomimetic and cognitive-impairing effects. ...
Article
A major factor associated with poor prognostic outcome after a first psychotic break is cannabis misuse, which is prevalent in schizophrenia and particularly common in individuals with recent-onset psychosis. Behavioral interventions aimed at reducing cannabis use have been unsuccessful in this population. Cannabidiol (CBD) is a phytocannabinoid found in cannabis, although at low concentrations in modern-day strains. CBD has a broad pharmacological profile, but contrary to ∆9-tetrahydrocannabinol (THC), CBD does not activate CB1 or CB2 receptors and has at most subtle subjective effects. Growing evidence indicates that CBD acts as an antipsychotic and anxiolytic, and several reports suggest neuroprotective effects. Moreover, CBD attenuates THC's detrimental effects, both acutely and chronically, including psychotogenic, anxiogenic, and deleterious cognitive effects. This suggests that CBD may improve the disease trajectory of individuals with early psychosis and comorbid cannabis misuse in particular-a population with currently poor prognostic outcome and no specialized effective intervention.
... 38,39 Evidence that modulation of these brain regions and cognitive processes by acute administration of Δ9-THC resembles aspects of the neural abnormalities and psychopathology that are also observed in schizophrenia further support a role for alterations in the eCB system in the pathophysiology of the disorder, and highlight it as an important target for further research. 20 Independent of its role in modulating the psychoactive and psychotomimetic effects of cannabis, the eCB system has also been implicated in schizophrenia in other ways. 40 One potential contributing element to the overall role of the eCB system in schizophrenia may be the relationship between eCB dysfunction and abnormal dopamine levels. ...
Article
Full-text available
Accumulating evidence suggests that dysfunction within the endocannabinoid (eCB) system may play a role in psychosis. However, little is understood about how this may be related to the neurocognitive abnormalities and symptoms of psychosis. In this paper, we summarize some of the evidence supporting the role of eCB system in psychosis, as well as the current understanding of the neurocognitive underpinnings of psychosis. We particularly focus on neuroimaging evidence pertaining to alteration in the functional integration between different brain regions in patients with psychosis, and then relate this to evidence from neuroimaging studies of the effects of cannabis and its main ingredients, such as delta-9-tetrahydrocannainol and cannabidiol. Specifically, we explore this in the context of the hypothesis that psychosis is a disorder of dysconnectivity between different brain regions, focusing particularly on three large scale functional networks (the default mode, central executive, and salience networks), alterations in which have been implicated in psychosis, and we discuss the gaps in this research thus far. Finally, we propose that an approach to investigating the role of the eCB system in psychosis may be to employ a pharmacological cannabinoid challenge paradigm to examine how experimental perturbation of the eCB system may be related to abnormalities in the brain networks implicated in psychosis. We discuss challenges associated with this approach, and suggest safe and practical options to overcome the main issues involved with such an experimental approach. Studies employing such an approach have the potential of offering insight into the neurocognitive mechanisms underlying psychosis, and identifying novel therapeutic targets.
... Multiple lines of evidence have indicated a role for the endocannabinoid system in the pathophysiology of schizophrenia (Bossong, Jansma, Bhattacharyya, & Ramsey, 2014;Gupta, Cahill, Ranganathan, & Correll, 2014). Therefore, in addition to inducing nonphysiological states in healthy individuals, laboratory-based THC challenge studies can be used to probe abnormalities in the endocannabinoid systems of individuals with schizophrenia in order to identify markers of disease. ...
... The substantial psychiatric documentation on this matter has been reviewed multiple times in the past two decades (Manseau and Goff, 2015). Concomitantly, a literature has emerged on the neurobiology underlying cannabis psychosis, including genetics, pathology, physiology, and imaging approaches in humans (Batalla et al., 2014;Bossong et al., 2014), as well as neurochemistry and behavioral pharmacology approaches in other animals, primarily rodents (Zamberletti et al., 2012;Zuardi et al., 2012). This literature has also been regularly reviewed by authors like Esteban and García-Sevilla (2012), El Khoury et al. (2012), and López-Moreno et al. (2008. ...
Article
Full-text available
Much of our knowledge of the endocannabinoid system in schizophrenia comes from behavioral measures in rodents, like prepulse inhibition of the acoustic startle and open-field locomotion, which are commonly used along with neurochemical approaches or drug challenge designs. Such methods continue to map fundamental mechanisms of sensorimotor gating, hyperlocomotion, social interaction, and underlying monoaminergic, glutamatergic, and GABAergic disturbances. These strategies will require, however, a greater use of neurophysiological tools to better inform clinical research. In this sense, electrophysiology and viral vector-based circuit dissection, like optogenetics, can further elucidate how exogenous cannabinoids worsen (e.g., tetrahydrocannabinol, THC) or ameliorate (e.g., cannabidiol, CBD) schizophrenia symptoms, like hallucinations, delusions, and cognitive deficits. Also, recent studies point to a complex endocannabinoid-endovanilloid interplay, including the influence of anandamide (endogenous CB1 and TRPV1 agonist) on cognitive variables, such as aversive memory extinction. In fact, growing interest has been devoted to TRPV1 receptors as promising therapeutic targets. Here, these issues are reviewed with an emphasis on the neurophysiological evidence. First, we contextualize imaging and electrographic findings in humans. Then, we present a comprehensive review on rodent electrophysiology. Finally, we discuss how basic research will benefit from further combining psychopharmacological and neurophysiological tools.
... Additionally, PEA, OEA and LEA have been identified as structural analogs of endocannabinoids (ECs). The endocannabinoid system is known to play an important role in some neurological diseases such as schizophrenia, stroke, and AD [39][40][41] . Although these EC-like ligands cannot bind to cannabinoid receptors with high affinity, they may influence endocannabinoid function via competition for catabolic enzymes 42 . ...
Article
Full-text available
High fat diet (HFD)-induced metabolic disorders may lead to emotional disorders. This study aimed to explore the effect of simvastatin (SMV) and bezafibrate (BZ) on improving HFD-induced emotional changes, and tried to identify their different mechanisms. The intraperitoneal glucose tolerance test (IPGTT) was used to evaluate glucose control ability; and behavior tests including open field tests (OFT), forced swimming tests (FST), tail suspension tests (TST) and sucrose preference (SPT), were then performed to evaluate emotional changes. Serum samples were collected for the LC-MS based metabolomics analysis to explore the emotional-related differential compounds; we then evaluated the effect of the drugs. The abnormal serum metabolic profiling and emotional changes caused by HFD in mice was alleviated by SMV treatment, whereas BZ only affected the emotional disorder. The improvement of cannabinoid analogues and then produced influences on the endocannabinoid system, which may be a potential mechanism SMV action. BZ promoted tryptophan-serotonin pathway and inhibited tryptophan-kynurenine pathway, which may be its mechanism of action. Here, we proposed a shed light on the biological mechanisms underlying the observed effects, and identified an important drug candidate for the treatment of emotional disorders induced by HFD.
... On the other hand, chronic cannabis use is associated with modest impairments in cognitive performance, with the most reliable and marked effects on prospective memory, verbal learning, verbal immediate and delayed recall, and recognition memory (Ranganathan and D'Souza, 2006;Solowij and Battisti, 2008;Broyd et al., 2016;Schoeler et al., 2016). Impairments of working memory are less reliably observed in chronic cannabis users, perhaps because such deficits are detected only at higher cognitive loads or in tasks requiring manipulation rather than mere repetition of information (Bossong et al., 2014). Typically, working memory recruits network activity across regions of the posterior and superior parietal cortex, the prefrontal cortex, and the anterior cingulate cortex (Cabeza and Nyberg, 2000). ...
Article
Studies from preclinical animal models indicate that sustained activation of CB1 receptor signaling is a major contributing factor for the onset of cognitive deficits associated to chronic cannabis use, in particular within the working memory and decision-making domains. Yet, very few studies have been designed to directly assess the role of CB1 receptors in mediating the effects of cannabis on human brain function. This perspective review article provides an overview of current state of knowledge on possible neurobiological mechanisms accounting for the detrimental effects of chronic cannabis use on cognition and related changes in brain structure and functional connectivity. This article is part of the Special Issue entitled “A New Dawn in Cannabinoid Neurobiology”.
... Similarly, since the use of cannabinoid agonists in humans has been linked to a higher incidence of schizophrenia, and other psychotic disorders, it is further hypothesized that the neural mechanism of these untoward effects is related to dysregulated information processing via altered cortical oscillations by these drugs (Nottage et al., 2015;Robbe et al., 2006;Skosnik et al., 2016;Uhlhaas and Singer, 2010). Thus, a wide range of studies have noted abnormalities in evoked gamma and theta band cortical oscillations in schizophrenia (Bossong et al., 2014;Light et al., 2006;Pittman-Polletta et al., 2015;Shin et al., 2011;Spencer et al., 2004;Uhlhaas and Singer, 2010), and it has been suggested that these abnormalities may be useful to distinguish treatment-sensitive from insensitive forms of this psychiatric disorder (Gandal et al., 2012). Moreover, disrupted cortical network oscillations such as these are positively correlated with memory impairments that are associated with schizophrenia (Haenschel et al., 2009;Haenschel and Linden, 2011). ...
Article
Extensive pioneering studies performed in the hippocampus have greatly contributed to our knowledge of an endogenous cannabinoid system comprised of the molecular machinery necessary to process these endocannabinoid lipid messengers and their associated cannabinoid receptors. Moreover, a foundation of knowledge regarding the function of hippocampal circuits, and its role in supporting synaptic plasticity has facilitated our understanding of the roles cannabinoids play in the diverse behaviors in which the hippocampus participates in both normal and pathological states. In this review, we present an historical overview of research pertaining to the hippocampal cannabinoid system to provide context in which to understand the participation of the hippocampus in cognition, behavior, and epilepsy. We also examine potential roles for the hippocampal formation in mediating dysfunctional behavior, and assert that these phenomena reflect disordered physiological activity within the hippocampus and its interactions with other brain regions after exposure to synthetic cannabinoids, and the phytocannabinoids found in marijuana, such as Δ9-THC and cannabidiol. In this regard, we examine contemporary hypotheses concerning the hippocampal endocannabinoid system's participation in psychotic disorders, schizophrenia, and epilepsy, and examine cannabinoid-sensitive cellular mechanisms contributing to coherent network oscillations as a potential contributor to these disorders.
... Neuro-imaging studies performed on individuals without psychiatric disorders have shown that acute ∆ 9 -THC intoxication and chronic cannabis smoking both produce neurofunctional alterations echoing the neurophysiologic disturbances seen in schizophrenia (Bossong, Jansma, Bhattacharyya, & Ramsey, 2014). Indeed, cannabinoids have been shown to disrupt working memory-related activity in dorso-lateral prefrontal and parietal cortices; to impair amygdala reactivity during the viewing of fearful or angry faces; to alter the functioning of frontal and striatal regions during response inhibition tasks; and finally, to disrupt prefrontal and medial temporal regions during episodic memory tasks. ...
Chapter
Full-text available
Cognitive dysfunctions are core features in schizophrenia, and they have a significant negative impact on social and occupational functioning. Highly prevalent in schizophrenia, substance use disorders can impair cognition, both in schizophrenia and in the normal population. However, in the specific case of cannabis, findings have been paradoxical, as most studies have shown that cannabis smoking impairs cognition in nonpsychosis individuals, while it seems to be associated with better cognitive functioning in individuals with schizophrenia. Preliminary functional magnetic resonance imaging studies have also produced results echoing these paradoxical findings. The potential reasons behind those findings include the neuroprotective effects of cannabis, the social lifestyle associated with cannabis smoking, as well as premorbid differences. Studies in the field have limitations that cannot be neglected, and methodological recommendations are made for future studies that will be performed on the topic.
... Clinical studies show that cannabinoids may exert mixed effects on emotional learning and memory (Ballard et al., 2013;Bossong et al., 2014). Indeed, cannabinoid CB1 receptors are largely expressed within brain areas that are mainly involved in cognitive and emotional processing, such as the mammalian neocortex, hippocampus, amygdala and striatum (Marsicano and Lutz, 1999;Oropeza et al., 2007;Rey et al., 2012;Fitzgerald et al., 2013;Cannizzaro et al., 2006;D'Amico et al., 2004). ...
Article
Background: Emotionally salient experiences induce the formation of explicit memory traces, besides eliciting automatic or implicit emotional memory in rodents. This study aims at investigating the implementation of a novel task for studying the formation of limbic memory engrams as a result of the acquisition- and retrieval- of fear-conditioning - biased declarative memory traces, measured by animal discrimination of an "emotional-object". Moreover, by using this new method we investigated the potential interactions between stimulation of cannabinoid transmission and integration of emotional information and cognitive functioning. New method: The Emotional-Object Recognition task is composed of 3 following sessions: habituation; cued fear-conditioned learning; emotional recognition. Rats are exposed to Context "B chamber" for habituation and cued fear-conditioning, and tested in Context "A chamber" for emotional-object recognition. Results: Cued fear-conditioning induces a reduction in emotional-object exploration time during the Emotional-Object Recognition task in controls. The activation of cannabinoid signalling impairs limbic memory formation, with respect to vehicle. Comparison to existing methods: The Emotional-Object Recognition test overcomes several limitations of commonly employed methods that explore declarative-, spatial memory and fear-conditioning in a non-integrated manner. It allows the assessment of unbiased cognitive indicators of emotional learning and memory. Conclusions: The Emotional-Object: Recognition task is a valuable tool for investigating whether, and at what extent, specific drugs or pathological conditions that interfere with the individual affective/emotional homeostasis, can modulate the formation of emotionally salient explicit memory traces, thus jeopardizing control and regulation of animal behavioural strategy.
... The endogenous cannabinoid system (ECS) is extensive, with receptors exerting multiple regulatory functions in both immune and central nervous systems. This system can impact motor function, appetite, pain sensitivity, emotional processing, and cognitionspecifically attention, learning and memory (DeRosse et al., 2010;Rabin et al., 2011;Greineisen and Turner, 2010;Bossong et al., 2014). Signaling is initiated by two subtypes of cannabinoid receptors, CB1R and CB2R. ...
Preprint
Full-text available
the present paper describes the preliminary results of a study centered on the effect of salience alterations and cannabis use on the intensity of psychotic symptoms in adolescent and adult cohorts. The exploratory analysis focused on cross-sectional scores at psychometric questionnaires of 64 participants allocated to 4 different subgroups. A hierarchical pattern in the psychopathology measures was observed in the adult subgroups, with Psychotic patients scoring higher in several domains than other patients from the Psychiatric and Neurologic Units; in turn, adolescents reported a more severe intensity of psychotic symptoms at the Positive and Negative Syndrome Scale subscales (p-value: < 0.05) when compared to adult one, while no significant difference was observed in cannabis exposure or Aberrant Salience Inventory scores (p-value: 0.22). These results suggest that aberrant salience and, to a lesser degree, cannabis use might play a role in determining psychotic symptoms severity, especially in more at-risk life phases. Public Significance Statement: the present study displays how salience alterations in younger patients might lead to intensified psychotic symptoms, while exploring parallel psychopathological domains and explaining the layout of a wider project. The role of cannabis use in this equation is still to be clarified.
Article
ZUSAMMENFASSUNG Hintergrund Bei Patienten mit Störungen aus dem schizophrenen Formenkreis ist der Konsum von Cannabis und anderen psychoaktiven Substanzen weit verbreitet. Es besteht eine wissenschaftliche Evidenz, dass der hochdosierte und regelmäßige Freizeitkonsum von Cannabis mit nachteiligen Langzeitfolgen assoziiert ist. Und dennoch könnte die physiologische Bedeutung des Endocannabinoidsystems (ECS) den Einsatz von Cannabispräparaten – womöglich mit einem hohen Gehalt an Cannabidiol (CBD) – zur Therapie neuropsychiatrischer Erkrankungen als nützlich erscheinen lassen. Ziel Darstellung der Grundlagen für die Wirksamkeit von medizinischem Cannabis bei neuropsychiatrischen Erkrankungen – insbesondere Störungen aus dem schizophrenen Formenkreis – und kritische Nutzen-Risiko-Bewertung. Ergebnisse und Diskussion Die beiden wichtigsten neuroaktiven Bestandteile von Cannabis sind CBD und Tetrahydrocannabinol (THC). THC scheint psychose- und angstfördernd zu wirken und die Kognition zu beeinträchtigen. Basierend auf einer Recherche aktueller Literatur ist anzunehmen, dass CBD im Gegensatz zu THC nicht euphorisierend, sondern antikonvulsiv, analgetisch, angstlösend und antipsychotisch wirken könnte und möglicherweise die kognitive Leistungsfähigkeit verbessern kann. Somit wäre CBD ein natürlicher Antagonist von THC. Während es eine hinreichende Evidenz gibt, dass der Freizeitkonsum von meist THC-lastigem Cannabis die psychische Gesundheit nachteilig beeinflusst und Psychosen fördert, gibt es Studien, die darauf hindeuten, dass CBD protektiv sein könnte. Allerdings mangelt es an hochwertigen kontrollierten klinischen Studien mit größeren Patientenzahlen und guter Methodik, um eine ausreichende Evidenz für den Einsatz von Cannabidiol in der klinischen Praxis zu begründen.
Preprint
Full-text available
Background The neurobiological mechanisms underlying the effects of delta-9-tetrahydrocannabinol (THC) remain unclear. Here, we examined the spatial acute effect of THC on human on regional brain activation or blood flow (hereafter called ‘activation signal’) in a ‘core’ network of brain regions that subserve a multitude of processes. We also investigated whether the neuromodulatory effects of THC are related to the local expression of its key molecular target, cannabinoid-type-1 (CB1R) but not type-2 (CB2R) receptor. Methods A systematic search was conducted of acute THC-challenge studies using fMRI, PET, and arterial spin labelling in accordance with established guidelines. Using pooled summary data from 372 participants, tested using a within-subject repeated measures design under experimental conditions, we investigated the effects of a single dose (6-42mg) of THC, compared to placebo, on brain signal. Findings As predicted, THC augmented the activation signal, relative to placebo, in the anterior cingulate, superior frontal cortices, middle temporal and middle and inferior occipital gyri, striatum, amygdala, thalamus, and cerebellum crus II and attenuated it in the middle temporal gyrus (spatially distinct from the cluster with THC-induced increase in activation signal), superior temporal gyrus, angular gyrus, precuneus, cuneus, inferior parietal lobule, and the cerebellum lobule IV/V. Using post-mortem gene expression data from an independent cohort from the Allen Human Brain atlas, we found a direct relationship between the magnitude of THC-induced brain signal change, indexed using pooled effect-size estimates, and CB1R gene expression, a proxy measure of CB1R protein distribution, but not CB2R expression. A dose-response relationship was observed with THC dose in certain brain regions. Interpretation These meta-analytic findings shed new light on the localisation of the effects of THC in the human brain, suggesting that THC has neuromodulatory effects in regions central to many cognitive tasks and processes, with greater effects in regions with higher levels of CB1R expression.
Article
Anecdotal reports of the benefits of cannabis and its components in the treatment of epilepsy have been reported for millennia. However, only recently randomized controlled trial data in support of cannabidiol (CBD) became available resulting in its FDA approval for the treatment of seizures and epilepsy. One of the most common and debilitating comorbidities of epilepsy is cognitive impairment. This impairment has a multifactorial etiology including network dysfunction due to seizures, negative cognitive side effects from anti-seizure medications (ASMs), and mood disturbances. Knowing the effects of a particular ASM (either positive or negative) is vital for providers to counsel patients on expected side effects, and may result in choosing a particular regimen over the other if the patient already suffers from significant cognitive deficits. Unlike most other ASMs and other well-studied cannabinoids such as Δ9-tetrahydrocannabinol, CBD has been shown to have additional mechanisms of action (MOA) that result in neuroprotective, anti-inflammatory, anti-oxidant, and neurogenesis effects. These additional MOAs suggest that the use of CBD could lead to other actions including positive effects on cognition that may be independent of seizure control. This targeted review discusses the currently available data on CBD's effects on cognition in epilepsy. First, we review the proposed mechanisms by which CBD could exert effects on cognition. Then, we present the pre-clinical/animal data investigating cognitive effects of CBD in seizure/epilepsy models. Finally, we discuss the available human data, including the studies in people with epilepsy that included cognitive evaluations pre- and on-CBD, and studies investigating if CBD has any effects on brain structure or function in areas pertinent to memory and cognitive functions.
Article
Cannabis use by adolescents is a public health problem because it can cause cognitive impairment and educational deterioration. The objective of this study was to assess the prevalence and correlates of cognitive impairment among male adolescents with cannabis use in comparison with a control group. This is a case-control study that included 1682 adolescents who just finished their secondary school. A drug screen was made for all participants. Cognitive assessment using Montreal Cognitive Assessment (MoCA) scale was carried out for adolescents with positive urine screen for cannabis and a control group of adolescents with negative urine screen for drugs. The prevalence of cannabis use among adolescents was 2.14%. About one third of the cases started to use cannabis before the age of 15 years. Fifty-six percent used cannabis frequently (>4 times/wk). Adolescents with cannabis use were more likely to have cognitive impairment based on MoCA than controls (78% vs. 44%, P =0.004). Cases were more likely to have impairment in naming, abstraction, orientation, and total MoCA score than controls. Adolescents who started cannabis use early (below 15 y) had impairment in visuospatial/executive, attention, language, abstraction, delayed recall, and total MoCA score compared with those who started late (above 15 y). In addition, adolescents who use cannabis frequently had impairment in all cognitive domains except naming compared with those who used it occasionally. To conclude, the current study found that adolescents with cannabis use were more likely to have cognitive impairment than controls and this impairment was associated with age of onset and frequency of cannabis use.
Article
Cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) have been the most investigated cannabinoids at the human and preclinical level, although the neurobiological mechanisms underlying their effects remain unclear. Human experimental evidence complemented by observational studies suggest that THC may have psychotogenic effects while CBD may have antipsychotic effects. However, whether their effects on brain function are consistent with their opposing behavioural effects remains unclear. To address this, here we synthesise neuroimaging evidence investigating the acute effects of THC and CBD on human brain function using a range of neuroimaging techniques, with an aim to identify the key brain substrates where THC and CBD have opposing effects. Following a systematic search, a review of the available studies indicated marked heterogeneity. However, an overall pattern of opposite effect profiles of the two cannabinoids was evident with some degree of consistency, primarily attributed to the head-to-head challenge studies of THC and CBD. While head-to-head comparisons are relatively few, collectively the evidence suggests that opposite effects of THC and CBD may be present in the striatum, parahippocampus, anterior cingulate/medial prefrontal cortex and amygdala, with opposite effects less consistently identified in other regions. Broadly, THC seems to increase, while CBD seems to decrease brain activation and blood flow. Given the sparse evidence, there is a particular need to understand the mechanisms underlying their opposite behavioural effects, as it may not only offer insights into the underlying pathophysiological mechanisms of psychotic disorders but may also suggest potentially novel targets and biomarkers for drug discovery.
Article
Background The brain’s endocannabinoid system, the primary target of cannabis, has been implicated in psychosis. The endocannabinoid, anandamide, is elevated in cerebrospinal fluid of patients with schizophrenia. Fatty acid amide hydrolase (FAAH) controls brain anandamide levels, however, it is unknown if FAAH is altered in vivo in psychosis or related to positive psychotic symptoms. Methods Twenty-seven patients with schizophrenia-spectrum disorders and 36 healthy control participants completed high-resolution positron emission tomography (PET) scans with the novel FAAH radioligand, [¹¹C]CURB, and structural MRI. Data were analyzed using the validated irreversible two-tissue compartment model with a metabolite-corrected arterial input function. Results FAAH did not differ significantly between patients with psychotic disorders and healthy controls (F1,62.85=0.48, p=.49). In contrast, lower FAAH predicted greater positive psychotic symptom severity, with the strongest effect observed for the positive symptom dimension, which includes suspiciousness, delusions, unusual thought content, and hallucinations (F1,26.69=12.42, p=.002; Cohen’s f=0.42, large effect). Shorter duration of illness (F1,26.95=13.78, p=.001; Cohen’s f=0.39; medium-to-large effect) and duration of untreated psychosis predicted lower FAAH (F1,26.95=6.03, p=.021, Cohen’s f=0.27, medium effect). These results were not explained by past cannabis exposure or current intake of antipsychotic medications. FAAH exhibited marked differences across brain regions (F7,112.62=175.85, p<1x10⁻⁵⁶; Cohen’s f>1). Overall, FAAH was higher in females than in males (F1,62.84=10.05, p=.002; Cohen’s f=0.37). Conclusions This first study of brain FAAH in psychosis indicates that FAAH may represent a biomarker of disease state of potential utility for clinical studies targeting psychotic symptoms or as a novel target for interventions to treat psychotic symptoms.
Article
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.
Article
Full-text available
Importance Cannabis is the most commonly used illicit drug in the world. Cannabinoids have been shown to modulate immune responses; however, the association of cannabis with neuroimmune function has never been investigated in vivo in the human brain. Objective To investigate neuroimmune activation or 18-kDa translocator protein (TSPO) levels in long-term cannabis users, and to evaluate the association of brain TSPO levels with behavioral measures and inflammatory blood biomarkers. Design, Setting, and Participants This cross-sectional study based in Toronto, Ontario, recruited individuals from January 1, 2015, to October 30, 2018. Participants included long-term cannabis users (n = 24) and non–cannabis-using controls (n = 27). Cannabis users were included if they had a positive urine drug screen for only cannabis and if they used cannabis at least 4 times per week for the past 12 months and/or met the criteria for cannabis use disorder. All participants underwent a positron emission tomography scan with [¹⁸F]FEPPA, or fluorine F 18–labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide. Main Outcomes and Measures Total distribution volume was quantified across regions of interest. Stress and anxiety as well as peripheral measures of inflammatory cytokines and C-reactive protein levels were also measured. Results In total, 24 long-term cannabis users (mean [SD] age, 23.1 [3.8] years; 15 men [63%]) and 27 non–cannabis-using controls (mean [SD] age, 23.6 [4.2] years; 18 women [67%]) were included and completed all study procedures. Compared with the controls, cannabis users had higher [¹⁸F]FEPPA total distribution volume (main group effect: F1,48 = 6.5 [P = .01]; ROI effect: F1,200 = 28.4 [P < .001]; Cohen d = 0.6; 23.3% higher), with a more prominent implication for the cannabis use disorder subgroup (n = 15; main group effect: F1,39 = 8.5 [P = .006]; ROI effect: F1,164 = 19.3 [P < .001]; Cohen d = 0.8; 31.5% higher). Greater TSPO levels in the brain were associated with stress and anxiety and with higher circulating C-reactive protein levels in cannabis users. Conclusions and Relevance The results of this study suggest that TSPO levels in cannabis users, particularly in those with cannabis use disorder, are higher than those in non–cannabis-using controls. The findings emphasize the need for more complementary preclinical systems for a better understanding of the role of cannabinoids and TSPO in neuroimmune signaling.
Chapter
Clinical Staging in Psychiatry - edited by Patrick D. McGorry August 2019
Article
Recent interest for the use of cannabis-derived products as therapeutic agents in the treatment of epilepsies has necessitated a reevaluation of their effects on brain and behavior. Overall, prolonged cannabis use is thought to result in functional and structural brain alterations. These effects may be dependent on a number of factors: e.g., which phytocannabinoid is used (e.g., cannabidiol (CBD) vs. tetrahyrocannabinol (THC)), the frequency of use (occasional vs. heavy), and at what age (prenatal, childhood, adulthood) the use began. However, due to the fact that there are over seven hundred constituents that make up the Cannabis sativa plant, it is difficult to determine which compound or combination of compounds is responsible for specific effects when studying recreational users. Therefore, this review focuses only on the functional MRI studies investigating the effects of specific pharmacological preparations of cannabis compounds, specifically THC, tetrahydrocannabivarin (THCV), and CBD, on brain function in healthy individuals and persons with epilepsy with references to non-epilepsy studies only to underline the gaps in research that need to be filled before cannabis-derived products are considered for a wide use in the treatment of epilepsy. This article is part of a Special Issue entitled "Cannabinoids and Epilepsy"
Chapter
Systematic reviews of prospective studies have consistently evidenced the role of cannabis use as a risk factor for the emergence of psychosis. However, as expected in multifactorial complex diseases, cannabis use is not sufficient or necessary to cause schizophrenia or related disorders The sensitivity to the cannabis effects is proposed to be mediated by the genetic variability observed in human populations for the Catecol-O-methyltransferase gene (COMT), one of several enzymes that degrade catecholamines, such as, dopamine. The Dunedin Multidisciplinary Health and Development Study reported for the first time that the relationship between adolescent cannabis use and the risk of developing psychotic disorders is modulated by COMT Val158Met genotype. These results have triggered several other studies, however, only some have replicated the interaction, while others have failed or have offered controversial results. Environmental factors, other genetic interactions and several methodological concerns and challenges are discussed in the present chapter.
Article
Background and objectives: Cognitive impairment is a core symptom domain of schizophrenia, neurological disorders and substance abuse. It is characterised by deficits in learning, memory, attention and executive functioning and can severely impact daily living. Antipsychotic drugs prescribed to treat schizophrenia provide limited cognitive benefits and novel therapeutic targets are required. Cannabidiol (CBD), a component of the cannabis plant, has anti-inflammatory and antipsychotic-like properties; however, its ability to improve cognitive impairment has not been thoroughly explored. The aim of this systematic review was to evaluate preclinical and clinical literature on the effects of CBD in cognitive domains relevant to schizophrenia. Methods: A systematic literature search was performed across numerous electronic databases for English language articles (January 1990 to March 2016), with 27 articles (18 preclinical and 9 clinical studies) included in the present review. Results: CBD improves cognition in multiple preclinical models of cognitive impairment, including models of neuropsychiatric (schizophrenia), neurodegenerative (Alzheimer's disease), neuro-inflammatory (meningitis, sepsis and cerebral malaria) and neurological disorders (hepatic encephalopathy and brain ischemia). To-date, there is one clinical investigation into the effects of CBD on cognition in schizophrenia patients, with negative results for the stroop test. CBD attenuates Δ(9)-THC-induced cognitive deficits. Conclusions: The efficacy of CBD to improve cognition in schizophrenia cannot be elucidated due to lack of clinical evidence; however, given the ability of CBD to restore cognition in multiple studies of impairment, further investigation into its efficacy in schizophrenia is warranted. Potential mechanisms underlying the efficacy of CBD to improve cognition are discussed.
Article
Objective The relationship between cannabis use and the onset of psychosis is well established. Aberrant salience processing is widely thought to underpin many of these symptoms. Literature explicitly investigating the relationship between aberrant salience processing and cannabis use is scarce; with those few studies finding that acute tetrahydrocannabinol (THC) administration (the main psychoactive component of cannabis) can result in abnormal salience processing in healthy cohorts, mirroring that observed in psychosis. Nevertheless, the extent of and mechanisms through which cannabis has a modulatory effect on aberrant salience, following both acute and chronic use, remain unclear. Methods Here, we systematically review recent findings on the effects of cannabis use – either through acute THC administration or in chronic users – on brain regions associated with salience processing (through functional MRI data); and performance in cognitive tasks that could be used as either direct or indirect measures of salience processing. We identified 13 studies either directly or indirectly exploring salience processing. Three types of salience were identified and discussed – incentive/motivational, emotional/affective, and attentional salience. Results The results demonstrated an impairment of immediate salience processing, following acute THC administration. Amongst the long-term cannabis users, normal salience performance appeared to be underpinned by abnormal neural processes. Conclusions Overall, the lack of research specifically exploring the effects of cannabis use on salience processing, weaken any conclusions drawn. Additional research explicitly focussed on salience processing and cannabis use is required to advance our understanding of the neurocognitive mechanisms underlying the association between cannabis use and development of psychosis.
Article
Full-text available
A potent, synthetic cannabinoid was radiolabeled and used to characterize and precisely localize cannabinoid receptors in slide-mounted sections of rat brain and pituitary. Assay conditions for 3H-CP55,940 binding in Tris-HCl buffer with 5% BSA were optimized, association and dissociation rate constants determined, and the equilibrium dissociation constant (Kd) calculated (21 nM by liquid scintillation counting, 5.2 nM by quantitative autoradiography). The results of competition studies, using several synthetic cannabinoids, add to prior data showing enantioselectivity of binding and correlation of in vitro potencies with potencies in biological assays of cannabinoid actions. Inhibition of binding by guanine nucleotides was selective and profound: Nonhydrolyzable analogs of GTP and GDP inhibited binding by greater than 90%, and GMP and the nonhydrolyzable ATP analog showed no inhibition. Autoradiography showed great heterogeneity of binding in patterns of labeling that closely conform to cytoarchitectural and functional domains. Very dense 3H-CP55,940 binding is localized to the basal ganglia (lateral caudate-putamen, globus pallidus, entopeduncular nucleus, substantia nigra pars reticulata), cerebellar molecular layer, innermost layers of the olfactory bulb, and portions of the hippocampal formation (CA3 and dentate gyrus molecular layer). Moderately dense binding is found throughout the remaining forebrain. Sparse binding characterizes the brain stem and spinal cord. Densitometry confirmed the quantitative heterogeneity of cannabinoid receptors (10 nM 3H-CP55,940 binding ranged in density from 6.3 pmol/mg protein in the substantia nigra pars reticulata to 0.15 pmol/mg protein in the anterior lobe of the pituitary). The results suggest that the presently characterized cannabinoid receptor mediates physiological and behavioral effects of natural and synthetic cannabinoids, because it is strongly coupled to guanine nucleotide regulatory proteins and is discretely localized to cortical, basal ganglia, and cerebellar structures involved with cognition and movement.
Article
Full-text available
Presented letters visually with an occasional stop signal (tone), which told Ss not to respond on that trial, in 4 studies with 56 undergraduates, high school students, and laboratory assistants. The studies were conducted in 2 halves, with 12 Ss performing the tasks in a single session in one half and 2 Ss performing the task for 6 sessions in the other half. Dependent variables in Exps I–IV were (1) probability of inhibiting a response when the signal occurred, (2) mean and standard deviation of RT on no-signal trials, (3) mean RT on trials on which the signal occurred but Ss failed to inhibit, and (4) estimated RT to stop signal, respectively. Results, formulated in terms of a proposed model to estimate RT to the stop signal and to account for the relations among the variables, show that transformations of stop-signal delay were successful in group and individual conditions, regardless of how delays were selected. (19 ref)
Chapter
Full-text available
Much effort has been made to understand the role of attention in perception; much less effort has been placed on the role attention plays in the control of action. Our goal in this chapter is to account for the role of attention in action, both when performance is automatic and when it is under deliberate conscious control. We propose a theoretical framework structured around the notion of a set of active schemas, organized according to the particular action sequences of which they are a part, awaiting the appropriate set of conditions so that they can become selected to control action. The analysis is therefore centered around actions, primarily external actions, but the same principles apply to internal actions—actions that involve only the cognitive processing mechanisms. One major emphasis in the study of attentional processes is the distinction between controlled and automatic processing of perceptual inputs (e.g., Shiffrin & Schneider, 1977). Our work here can be seen as complementary to the distinction between controlled and automatic processes: we examine action rather than perception; we emphasize the situations in which deliberate, conscious control of activity is desired rather than those that are automatic.
Article
Full-text available
Investigating the effects of cannabis use on memory function appears challenging. While early observational investigations aimed to elucidate the longer-term effects of cannabis use on memory function in humans, findings remained equivocal and pointed to a pattern of interacting factors impacting on the relationship between cannabis use and memory function, rather than a simple direct effect of cannabis. Only recently, a clearer picture of the chronic and acute effects of cannabis use on memory function has emerged once studies have controlled for potential confounding factors and started to investigate the acute effects of delta-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), the main ingredients in the extract of the cannabis plant in pharmacological challenge experiments. Relatively consistent findings have been reported regarding the acute impairments induced by a single dose of Δ9-THC on verbal and working memory. It is unclear whether they may persist beyond the intoxication state. In the long-term, these impairments seem particularly likely to manifest and may also persist following abstinence if regular and heavy use of cannabis strains high in Δ9-THC is started at an early age. Although still at an early stage, studies that employed advanced neuroimaging techniques have started to model the neural underpinnings of the effects of cannabis use and implicate a network of functional and morphological alterations that may moderate the effects of cannabis on memory function. Future experimental and epidemiological studies that take into consideration individual differences, particularly previous cannabis history and demographic characteristics, but also the precise mixture of the ingredients of the consumed cannabis are necessary to clarify the magnitude and the mechanisms by which cannabis-induced memory impairments occur and to elucidate underlying neurobiological mechanisms.
Article
Full-text available
Evidence is increasing for involvement of the endocannabinoid system in cognitive functions including attention and executive function, as well as in psychiatric disorders characterized by cognitive deficits, such as schizophrenia. Executive function appears to be associated with both modulation of active networks and inhibition of activity in the default mode network. In the present study, we examined the role of the endocannabinoid system in executive function, focusing on both the associated brain network and the default mode network. A pharmacological functional magnetic resonance imaging (fMRI) study was conducted with a placebo-controlled, cross-over design, investigating effects of the endocannabinoid agonist Δ9-tetrahydrocannabinol (THC) on executive function in 20 healthy volunteers, using a continuous performance task with identical pairs. Task performance was impaired after THC administration, reflected in both an increase in false alarms and a reduction in detected targets. This was associated with reduced deactivation in a set of brain regions linked to the default mode network, including posterior cingulate cortex and angular gyrus. Less deactivation was significantly correlated with lower performance after THC. Regions that were activated by the continuous performance task, notably bilateral prefrontal and parietal cortex, did not show effects of THC. These findings suggest an important role for the endocannabinoid system in both default mode modulation and executive function. This may be relevant for psychiatric disorders associated with executive function deficits, such as schizophrenia and ADHD.
Article
Full-text available
The authors highlight the utility of distribution-analytical techniques in the study of individual differences and clinical disorders. Cognitive deficits associated with attention-deficit/hyperactivity disorder (AD/HD) were examined by using delta-plot analyses of performance data (reaction time and accuracy) obtained through the use of a prototypical conflict task, the Eriksen flanker task. In 20 children with AD/HD (compared with matched control participants), overall performance measures indicated a marginal performance deficit. Delta-plot analyses indicated that performance deficits associated with AD/HD involve response inhibition but not automatic response activation. In a within-subjects titration study, the response inhibition deficit was eliminated by methylphenidate treatment, but these effects were highly dose specific. The beneficial effect of methylphenidate was clarified further after correcting for inter-individual variation in sensitivity to medicine dosage.
Article
Full-text available
Background Evidence indicates involvement of the endocannabinoid (eCB) system in both the pathophysiology of schizophrenia and working memory (WM) function. Additionally, schizophrenia patients exhibit relatively strong WM deficits. These findings suggest the possibility that the eCB system is also involved in WM deficits in schizophrenia. In the present study, we examined if perturbation of the eCB system can induce abnormal WM activity in healthy subjects. Methods A pharmacological functional magnetic resonance imaging study was conducted with a placebo-controlled, cross-over design, investigating effects of the eCB agonist Δ9-tetrahydrocannabinol on WM function in 17 healthy volunteers, by means of a parametric Sternberg item-recognition paradigm with five difficulty levels. Results Performance accuracy was significantly reduced after Δ9-tetrahydrocannabinol. In the placebo condition, brain activity increased linearly with rising WM load. Δ9-Tetrahydrocannabinol administration enhanced activity for low WM loads and reduced the linear relationship between WM load and activity in the WM system as a whole and in left dorsolateral prefrontal cortex, inferior temporal gyrus, inferior parietal gyrus, and cerebellum in particular. Conclusions Δ9-Tetrahydrocannabinol enhanced WM activity network-wide for low loads, while reducing the load-dependent response for increasing WM loads. These results indicate that a challenged eCB system can induce both abnormal WM activity and WM performance deficits and provide an argument for the possibility of eCB involvement in WM deficits in schizophrenia
Article
Full-text available
The influence of cannabis on mental health receives growing scientific and political attention. An increasing demand for treatment of cannabis dependence has refueled the discussion about the addictive potential of cannabis. A key feature of all addictive drugs is the ability to increase synaptic dopamine levels in the striatum, a mechanism involved in their rewarding and motivating effects. However, it is currently unknown if cannabis can stimulate striatal dopamine neurotransmission in humans. Here we show that Δ9-tetrahydrocannabinol (THC), the main psychoactive component in cannabis, induces dopamine release in the human striatum. Using the dopamine D2/D3 receptor tracer [11C]raclopride and positron emission tomography in seven healthy subjects, we demonstrate that THC inhalation reduces [11C]raclopride binding in the ventral striatum and the precommissural dorsal putamen but not in other striatal subregions. This is consistent with an increase in dopamine levels in these regions. These results suggest that THC shares a potentially addictive property with other drugs of abuse. Further, it implies that the endogenous cannabinoid system is involved in regulating striatal dopamine release. This allows new directions in research on the effects of THC in neuropsychiatric disorders, such as schizophrenia.
Article
Full-text available
Recent evidence has implicated the endocannabinoid (eCB) system in nicotine addiction. The eCB system also has an important role in reward mechanisms, and nicotine addiction has been associated with aberrant reward processing. Motivated by this evidence, we tested the hypothesis that eCB modulation of reward processing is altered in subjects with a nicotine addiction (NAD). For this purpose, we compared reward-related activity in NAD with healthy controls (HC) in a pharmacological magnetic resonance imaging (MRI) study using Δ(9)-tetrahydrocannabinol (THC) administration to challenge the eCB system. Eleven HC and 10 NAD participated in a 3-T functional MRI (fMRI) study with a double-blind, cross-over, placebo-controlled design, using a Monetary Incentive Delay (MID) paradigm with three reward levels. Reward activity in the nucleus accumbens (NAcc) and caudate putamen during anticipation and feedback of reward was compared after THC and placebo. fMRI results indicated a significant reduction of reward anticipation activity in the NAcc in NAD after THC administration, which was not present in HC. This is indicated by a significant group by drug by reward interaction. Our data show that THC significantly reduces the NAcc response to monetary reward anticipation in NAD. These results suggest that nicotine addiction is associated with altered eCB modulation of reward processing in the NAcc. This study adds important human data to existing evidence implicating the eCB system in nicotine addiction.
Article
Full-text available
Background: Cannabis can induce transient psychotic symptoms, but not all users experience these adverse effects. We compared the neural response to Δ9-tetrahydrocannabinol (THC) in healthy volunteers in whom the drug did or did not induce acute psychotic symptoms. Method In a double-blind, placebo-controlled, pseudorandomized design, 21 healthy men with minimal experience of cannabis were given either 10 mg THC or placebo, orally. Behavioural and functional magnetic resonance imaging measures were then recorded whilst they performed a go/no-go task. Results: The sample was subdivided on the basis of the Positive and Negative Syndrome Scale positive score following administration of THC into transiently psychotic (TP; n = 11) and non-psychotic (NP; n = 10) groups. During the THC condition, TP subjects made more frequent inhibition errors than the NP group and showed differential activation relative to the NP group in the left parahippocampal gyrus, the left and right middle temporal gyri and in the right cerebellum. In these regions, THC had opposite effects on activation relative to placebo in the two groups. The TP group also showed less activation than the NP group in the right middle temporal gyrus and cerebellum, independent of the effects of THC. Conclusions: In this first demonstration of inter-subject variability in sensitivity to the psychotogenic effects of THC, we found that the presence of acute psychotic symptoms was associated with a differential effect of THC on activation in the ventral and medial temporal cortex and cerebellum, suggesting that these regions mediate the effects of the drug on psychotic symptoms.
Article
Full-text available
Cannabidiol is a component of marijuana that does not activate cannabinoid receptors, but moderately inhibits the degradation of the endocannabinoid anandamide. We previously reported that an elevation of anandamide levels in cerebrospinal fluid inversely correlated to psychotic symptoms. Furthermore, enhanced anandamide signaling let to a lower transition rate from initial prodromal states into frank psychosis as well as postponed transition. In our translational approach, we performed a double-blind, randomized clinical trial of cannabidiol vs amisulpride, a potent antipsychotic, in acute schizophrenia to evaluate the clinical relevance of our initial findings. Either treatment was safe and led to significant clinical improvement, but cannabidiol displayed a markedly superior side-effect profile. Moreover, cannabidiol treatment was accompanied by a significant increase in serum anandamide levels, which was significantly associated with clinical improvement. The results suggest that inhibition of anandamide deactivation may contribute to the antipsychotic effects of cannabidiol potentially representing a completely new mechanism in the treatment of schizophrenia.
Article
Full-text available
Introduction Cannabinoids produce a spectrum of effects in humans including euphoria, cognitive impairments, psychotomimetic effects, and perceptual alterations. The extent to which dopaminergic systems contribute to the effects of Δ-9-tetrahydrocannabinol (Δ-9-THC) remains unclear. This study evaluated whether pretreatment with a dopamine receptor antagonist altered the effects of Δ-9-THC in humans. Materials and methods In a 2-test-day double-blind study, 28 subjects including healthy subjects (n = 17) and frequent users of cannabis (n = 11) were administered active (0.057 mg/kg) or placebo oral haloperidol in random order followed 90 and 215 min later by fixed order intravenous administration of placebo (vehicle) and active (0.0286 mg/kg) Δ-9-THC, respectively. Results Consistent with previous reports, intravenous Δ-9-THC produced psychotomimetic effects, perceptual alterations, and subjective effects including “high.” Δ-9-THC also impaired verbal recall and attention. Haloperidol pretreatment did not reduce any of the behavioral effects of Δ-9-THC. Haloperidol worsened the immediate free and delayed free and cued recall deficits produced by Δ-9-THC. Haloperidol and Δ-9-THC worsened distractibility and vigilance. Neither drug impaired performance on a motor screening task, the Stockings of Cambridge task, or the delayed match to sample task. Frequent users had lower baseline plasma prolactin levels and blunted Δ-9-THC induced memory impairments. Conclusions The deleterious effects of haloperidol pretreatment on the cognitive effects of Δ-9-THC are consistent with the preclinical literature in suggesting crosstalk between DAergic and CBergic systems. However, it is unlikely that DA D2 receptor mechanisms play a major role in mediating the psychotomimetic and perceptual altering effects of Δ-9-THC. Further investigation is warranted to understand the basis of the psychotomimetic effects of Δ-9-THC and to better understand the crosstalk between DAergic and CBergic systems.
Article
Full-text available
Rationale Cannabis is one of the most frequently used substances. Cannabis and its constituent cannabinoids are known to impair several aspects of cognitive function, with the most robust effects on short-term episodic and working memory in humans. A large body of the work in this area occurred in the 1970s before the discovery of cannabinoid receptors. Recent advances in the knowledge of cannabinoid receptors’ function have rekindled interest in examining effects of exogenous cannabinoids on memory and in understanding the mechanism of these effects. Objective The literature about the acute effects of cannabinoids on memory tasks in humans is reviewed. The limitations of the human literature including issues of dose, route of administration, small sample sizes, sample selection, effects of other drug use, tolerance and dependence to cannabinoids, and the timing and sensitivity of psychological tests are discussed. Finally, the human literature is discussed against the backdrop of preclinical findings. Results Acute administration of Δ-9-THC transiently impairs immediate and delayed free recall of information presented after, but not before, drug administration in a dose- and delay-dependent manner. In particular, cannabinoids increase intrusion errors. These effects are more robust with the inhaled and intravenous route and correspond to peak drug levels. Conclusions This profile of effects suggests that cannabinoids impair all stages of memory including encoding, consolidation, and retrieval. Several mechanisms, including effects on long-term potentiation and long-term depression and the inhibition of neurotransmitter (GABA, glutamate, acetyl choline, dopamine) release, have been implicated in the amnestic effects of cannabinoids. Future research in humans is necessary to characterize the neuroanatomical and neurochemical basis of the memory impairing effects of cannabinoids, to dissect out their effects on the various stages of memory and to bridge the expanding gap between the humans and preclinical literature.
Article
Full-text available
There is growing evidence that drugs of abuse alter processing of emotional information in ways that could be attractive to users. Our recent report that Δ(9)-tetrahydrocannabinol (THC) diminishes amygdalar activation in response to threat-related faces suggests that THC may modify evaluation of emotionally-salient, particularly negative or threatening, stimuli. In this study, we examined the effects of acute THC on evaluation of emotional images. Healthy volunteers received two doses of THC (7.5 and 15 mg; p.o.) and placebo across separate sessions before performing tasks assessing facial emotion recognition and emotional responses to pictures of emotional scenes. THC significantly impaired recognition of facial fear and anger, but it only marginally impaired recognition of sadness and happiness. The drug did not consistently affect ratings of emotional scenes. THC's effects on emotional evaluation were not clearly related to its mood-altering effects. These results support our previous work, and show that THC reduces perception of facial threat. Nevertheless, THC does not appear to positively bias evaluation of emotional stimuli in general.
Article
Full-text available
It is generally agreed that schizophrenia patients show a markedly reduced ability to perceive and express facial emotions. Previous studies have shown, however, that such deficits are emotion-specific in schizophrenia and not generalized. Three kinds of studies were examined: decoding studies dealing with schizophrenia patients' ability to perceive universally recognized facial expressions of emotions, encoding studies dealing with schizophrenia patients' ability to express certain facial emotions, and studies of subjective reactions of patients' sensitivity toward universally recognized facial expressions of emotions. A review of these studies shows that schizophrenia patients, despite a general impairment of perception or expression of facial emotions, are highly sensitive to certain negative emotions of fear and anger. These observations are discussed in the light of hemispheric theory, which accounts for a generalized performance deficit, and social-cognitive theory, which accounts for an emotion-specific deficit in schizophrenia.
Article
The Continuous Performance Test (CPT) has become an essential constituent of the neuropsychological investigation of schizophrenia. Also, a vast number of brain imaging studies, mostly PET investigations, have employed the CPT as a cognitive challenge and established a relative hypofrontality in schizophrenics compared to controls. The aim of the present investigation was to clarify whether this predescribed hypofrontality could also be verified using functional magnetic resonance imaging (fMRI). 20 healthy volunteers and 14 schizophrenics on stable neuroleptic medication were included. Imaging was performed using the CPT-double-T-version and a clinical 1.5 T MRI-scanner with a single slice technique and a T 2 *-weighted gradient-echo-sequence. The schizophrenics exhibited a decreased activation in the right mesial prefrontal cortex, the right cingulate and the left thalamus compared to controls. These results obtained by fMRI are discussed in relation to published findings using PET.
Chapter
Hallucinations remain one of the most intriguing phenomena in psychopathology. The development of neuroimaging techniques has enabled investigators to examine the neural underpinnings of hallucinatory symptoms present in schizophrenia and other disorders. Here we provide an overview of positron emission tomography (PET) and single-photon emission computed tomography (SPECT) neuroimaging studies in patients with hallucinations. The majority of these studies have been in schizophrenia patients with auditory verbal hallucinations, and show increased metabolism or blood flow in auditory cortex and speech perception areas. A number of studies also implicate non-sensory brain regions such as the anterior cingulate cortex that may be involved in top-down attentional and speech monitoring processes. In patients with neurological disorders who experience visual hallucinations reduced activation in the ventral visual pathway is reported, again implicating a fundamental role for the modality-specific sensory cortex. In conclusion, findings from PET and SPECT neuroimaging studies might suggest that ‘imbalances’ between bottom-up sensory activation and top-down attentional modulation are the primary neurocognitive dysfunction that underpins the hallucinating brain.
Chapter
This chapter is divided into two parts. The first describes the effect of Pat Rabbitt's influence in encouraging the first author to use the increasingly sophisticated methods of ageing research to answer questions about the fundamental characteristics of working memory, together with reflections on why so little of this work reached publication. The second part presents a brief review of the literature on working memory and ageing, followed by an account of more recent work attempting to apply the traditional method of experimental dissociation to research on normal ageing and Alzheimer's disease. The discussion suggests that even such simple methods can throw light on both the processes of ageing and the understanding of working memory.
Article
We review evidence for partially segregated networks of brain areas that carry out different attentional functions. One system, which includes parts of the intraparietal cortex and superior frontal cortex, is involved in preparing and applying goal-directed (top-down) selection for stimuli and responses. This system is also modulated by the detection of stimuli. The other system, which includes the temporoparietal cortex and inferior frontal cortex, and is largely lateralized to the right hemisphere, is not involved in top-down selection. Instead, this system is specialized for the detection of behaviourally relevant stimuli, particularly when they are salient or unexpected. This ventral frontoparietal network works as a 'circuit breaker' for the dorsal system, directing attention to salient events. Both attentional systems interact during normal vision, and both are disrupted in unilateral spatial neglect.
Article
Objective We sought to examine the relation between cannabis abuse and the symptomatic course of recent-onset schizophrenia and related disorders. Design A prospective cohort study over a year using monthly Brief Psychiatric Rating Scale assessments. Participants Cannabis-abusing patients (n=24) were compared with nonabusers (n=69). Eleven patients were mild and 13 were heavy cannabis-abusing patients. Results Significantly more and earlier psychotic relapses occurred in the cannabis-abusing group (P=.03). This association became stronger when mild and heavy cannabis abuse were distinguished (P=.002). No confounding effect of other variables, eg, other street drugs, was found. In all but one patient, cannabis abuse preceded the onset of the first psychotic symptoms for at least 1 year. Conclusions Cannabis abuse and particularly heavy abuse can be considered a stressor eliciting relapse in patients with schizophrenia and related disorders and possibly a premorbid precipitant.
Article
Background Controversy remains as to whether cannabis acts as a causal risk factor for schizophrenia or other functional psychotic illnesses. Aims To examine critically the evidence that cannabis causes psychosis using established criteria of causality. Method We identified five studies that included a well-defined sample drawn from population-based registers or cohorts and used prospective measures of cannabis use and adult psychosis. Results On an individual level, cannabis use confers an overall twofold increase in the relative risk for later schizophrenia. At the population level, elimination of cannabis use would reduce the incidence of schizophrenia by approximately 8%, assuming a causal relationship. Cannabis use appears to be neither a sufficient nor a necessary cause for psychosis. It is a component cause, part of a complex constellation of factors leading to psychosis. Conclusions Cases of psychotic disorder could be prevented by discouraging cannabis use among vulnerable youths. Research is needed to understand the mechanisms by which cannabis causes psychosis.
Article
Tritiated haloperidol and tritiated dopamine label postsynaptic dopamine receptors in mammalian brain. Clinical potencies of butyrophenones, phenothiazines, and related drugs correlate closely with their ability to inhibit tritiated haloperidol binding. These binding methods provide a simple in vitro means for evaluating new drugs as potential antischizophrenic agents.