Increased hippocampal blood flow in people at clinical high risk for psychosis and effects of cannabidiol.

BACKGROUND: Hippocampal hyperperfusion has been observed in people at Clinical High Risk for Psychosis (CHR), is associated with adverse longitudinal outcomes and represents a potential treatment target for novel pharmacotherapies. Whether cannabidiol (CBD) has ameliorative effects on hippocampal blood flow (rCBF) in CHR patients remains unknown. METHODS: Using a double-blind, parallel-group design, 33 CHR patients were randomized to a single oral 600 mg dose of CBD or placebo; 19 healthy controls did not receive any drug. Hippocampal rCBF was measured using Arterial Spin Labeling. We examined differences relating to CHR status (controls v. placebo), effects of CBD in CHR (placebo v. CBD) and linear between-group relationships, such that placebo > CBD > controls or controls > CBD > placebo, using a combination of hypothesis-driven and exploratory wholebrain analyses. RESULTS: Placebo-treated patients had significantly higher hippocampal rCBF bilaterally (all pFWE<0.01) compared to healthy controls. There were no suprathreshold effects in the CBD v. placebo contrast. However, we found a significant linear relationship in the right hippocampus (pFWE = 0.035) such that rCBF was highest in the placebo group, lowest in controls and intermediate in the CBD group. Exploratory wholebrain results replicated previous findings of hyperperfusion in the hippocampus, striatum and midbrain in CHR patients, and provided novel evidence of increased rCBF in inferior-temporal and lateral-occipital regions in patients under CBD compared to placebo. CONCLUSIONS: These findings suggest that hippocampal blood flow is elevated in the CHR state and may be partially normalized by a single dose of CBD. CBD therefore merits further investigation as a potential novel treatment for this population.

The neuropharmacology of cannabinoid receptor ligands in central signaling pathways.

The endocannabinoid system is a complex neuronal system involved in a number of biological functions, like attention, anxiety, mood, memory, appetite, reward, and immune responses. It is at the centre of scientific interest, which is driven by therapeutic promise of certain cannabinoid ligands and the changing legalization of herbal cannabis in many countries. The endocannabinoid system is a modulatory system, with endocannabinoids as retrograde neurotransmitters rather than direct neurotransmitters. Neuropharmacology of cannabinoid ligands in the brain can therefore be understood in terms of their modulatory actions through other neurotransmitter systems. The CB1 receptor is chiefly responsible for effects of endocannabinoids and analogous ligands in the brain. An overview of the neuropharmacology of several cannabinoid receptor ligands, including endocannabinoids, herbal cannabis and synthetic cannabinoid receptor ligands is given in this review. Their mechanism of action at the endocannabinoid system is described, mainly in the brain. In addition, effects of cannabinoid ligands on other neurotransmitter systems will also be described, such as dopamine, serotonin, glutamate, noradrenaline, opioid, and GABA. In light of this, therapeutic potential and adverse effects of cannabinoid receptor ligands will also be discussed.

Altered relationship between cortisol response to social stress and mediotemporal function during fear processing in people at clinical high risk for psychosis: a preliminary report.

Evidence suggests that people at Clinical High Risk for Psychosis (CHR) have a blunted cortisol response to stress and altered mediotemporal activation during fear processing, which may be neuroendocrine-neuronal signatures of maladaptive threat responses. However, whether these facets are associated with each other and how this relationship is affected by cannabidiol treatment is unknown. We examined the relationship between cortisol response to social stress and mediotemporal function during fear processing in healthy people and in CHR patients. In exploratory analyses, we investigated whether treatment with cannabidiol in CHR individuals could normalise any putative alterations in cortisol-mediotemporal coupling. 33 CHR patients were randomised to 600 mg cannabidiol or placebo treatment. Healthy controls (n = 19) did not receive any drug. Mediotemporal function was assessed using a fearful face-processing functional magnetic resonance imaging paradigm. Serum cortisol and anxiety were measured immediately following the Trier Social Stress Test. The relationship between cortisol and mediotemporal blood-oxygen-level-dependent haemodynamic response was investigated using linear regression. In healthy controls, there was a significant negative relationship between cortisol and parahippocampal activation (p = 0.023), such that the higher the cortisol levels induced by social stress, the lower the parahippocampal activation (greater deactivation) during fear processing. This relationship differed significantly between the control and placebo groups (p = 0.033), but not between the placebo and cannabidiol groups (p = 0.67). Our preliminary findings suggest that the parahippocampal response to fear processing may be associated with the neuroendocrine (cortisol) response to experimentally induced social stress, and that this relationship may be altered in patients at clinical high risk for psychosis.

Integrated metastate functional connectivity networks predict change in symptom severity in clinical high risk for psychosis.

The ability to identify biomarkers of psychosis risk is essential in defining effective preventive measures to potentially circumvent the transition to psychosis. Using samples of people at clinical high risk for psychosis (CHR) and Healthy controls (HC) who were administered a task fMRI paradigm, we used a framework for labelling time windows of fMRI scans as 'integrated' FC networks to provide a granular representation of functional connectivity (FC). Periods of integration were defined using the 'cartographic profile' of time windows and k-means clustering, and sub-network discovery was carried out using Network Based Statistics (NBS). There were no network differences between CHR and HC groups. Within the CHR group, using integrated FC networks, we identified a sub-network negatively associated with longitudinal changes in the severity of psychotic symptoms. This sub-network comprised brain areas implicated in bottom-up sensory processing and in integration with motor control, suggesting it may be related to the demands of the fMRI task. These data suggest that extracting integrated FC networks may be useful in the investigation of biomarkers of psychosis risk.

Human Striatal Response to Reward Anticipation Linked to Hippocampal Glutamate Levels.

Background: Dysfunctional reward processing is associated with a number of psychiatric disorders, such as addiction and schizophrenia. It is thought that reward is regulated mainly by dopamine transmission in the ventral striatum. Contemporary animal models suggest that striatal dopamine concentrations and associated behaviors are related to glutamatergic functioning in the ventral hippocampus. However, in humans the association between reward-related ventral striatal response and hippocampal glutamate levels is unclear. Methods: Nineteen healthy participants were studied using proton magnetic resonance spectroscopy to measure hippocampal glutamate levels, and functional magnetic resonance imaging to assess striatal activation and functional connectivity during performance of a monetary incentive delay task. Results: We found that ventral striatal activation related to reward processing was correlated with hippocampal glutamate levels. In addition, context-dependent functional coupling was demonstrated between the ventral striatum and both the lingual gyrus and hippocampus during reward anticipation. Elevated hippocampal glutamate levels were inversely related to context-dependent functional connectivity between the ventral striatum and the anterior hippocampus while anticipating reward. Conclusions: These findings indicate that human striatal responses to reward are influenced by hippocampal glutamate levels. This may be relevant for psychiatric disorders associated with abnormal reward processing such as addiction and schizophrenia.

The acute effects of cannabis on human executive function.

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.

Acute effects of Δ9-tetrahydrocannabinol (THC) on resting state connectivity networks and impact of COMT genotype: A multi-site pharmacological fMRI study.

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.

Therapeutic effect of psilocybin in addiction: A systematic review.

Background: Psychedelic-assisted therapy [e.g., with lysergic acid diethylamide (LSD)] has shown promising results as treatment for substance use disorders (SUDs). Previous systematic reviews assessing the efficacy of psilocybin in SUDs only included clinical trials conducted in the last 25 years, but they may have missed clinical trials assessing the efficacy of psilocybin that were conducted before the 1980s, given much research has been done with psychedelics in the mid-20th century. In this systematic review, we specifically assessed the efficacy of psilocybin in patients with a SUD or non-substance-related disorder with no publication date restrictions in our search strategy. Methods: A systematic literature search was performed according to Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines from the earliest published manuscript up to September 2, 2022, in seven electronic databases, including clinical trials in patients with a SUD or non-substance-related disorder evaluating the efficacy of psilocybin. Results: A total of four studies (six articles, of which two articles were long-term follow-up results from the same trial) were included in this systematic review. Psilocybin-assisted therapy was administered to n = 151 patients in a dose ranging from 6 to 40 mg. Three studies focused on alcohol use disorder, and one study on tobacco use disorder. In a pilot study (n = 10), the percentage of heavy drinking days decreased significantly between baseline and weeks 5-12 (mean difference of 26.0, 95% CI = 8.7-43.2, p = 0.008). In another single-arm study (n = 31), 32% (10/31) became completely abstinent from alcohol (mean duration of follow-up 6 years). In a double-blind, placebo-controlled randomized controlled trial (RCT, n = 95), the percentage of heavy drinking days during the 32-week double-blind period was significantly lower for psilocybin compared to placebo (mean difference of 13.9, 95% CI = 3.0-24.7, p = 0.01). In a pilot study (n = 15), the 7-day point prevalence of smoking abstinence at 26 weeks was 80% (12/15), and at 52 weeks 67% (10/15). Conclusion: Only one RCT and three small clinical trials were identified assessing the efficacy of psilocybin combined with some form of psychotherapy in patients with alcohol and tobacco use disorder. All four clinical trials indicated a beneficial effect of psilocybin-assisted therapy on SUD symptoms. Larger RCTs in patients with SUDs need to evaluate whether psilocybin-assisted therapy is effective in patients with SUD.

The impact of cannabidiol treatment on resting state functional connectivity, prefrontal metabolite levels and reward processing in recent-onset patients with a psychotic disorder.

The first clinical trials with cannabidiol (CBD) as treatment for psychotic disorders have shown its potential as an effective and well-tolerated antipsychotic agent. However, the neurobiological mechanisms underlying the antipsychotic profile of CBD are currently unclear. Here we investigated the impact of 28-day adjunctive CBD or placebo treatment (600 mg daily) on brain function and metabolism in 31 stable recent-onset psychosis patients (<5 years after diagnosis). Before and after treatment, patients underwent a Magnetic Resonance Imaging (MRI) session including resting state functional MRI, proton Magnetic Resonance Spectroscopy (1H-MRS) and functional MRI during reward processing. Symptomatology and cognitive functioning were also assessed. CBD treatment significantly changed functional connectivity in the default mode network (DMN; time × treatment interaction p = 0.037), with increased connectivity in the CBD (from 0.59 ± 0.39 to 0.80 ± 0.32) and reduced connectivity in the placebo group (from 0.77 ± 0.37 to 0.62 ± 0.33). Although there were no significant treatment effects on prefrontal metabolite concentrations, we showed that decreased positive symptom severity over time was associated with both diminishing glutamate (p = 0.029) and N-acetyl-aspartate (NAA; neuronal integrity marker) levels (p = 0.019) in the CBD, but not the placebo group. CBD treatment did not have an impact on brain activity patterns during reward anticipation and receipt or functional connectivity in executive and salience networks. Our results show that adjunctive CBD treatment of recent-onset psychosis patients induced changes in DMN functional connectivity, but not prefrontal metabolite concentrations or brain activity during reward processing. These findings suggest that DMN connectivity alteration may be involved in the therapeutic effects of CBD.

Effects of Δ9-tetrahydrocannabinol administration on human encoding and recall memory function: a pharmacological FMRI study.

Deficits in memory function are an incapacitating aspect of various psychiatric and neurological disorders. Animal studies have recently provided strong evidence for involvement of the endocannabinoid (eCB) system in memory function. Neuropsychological studies in humans have shown less convincing evidence but suggest that administration of cannabinoid substances affects encoding rather than recall of information. In this study, we examined the effects of perturbation of the eCB system on memory function during both encoding and recall. We performed a pharmacological MRI study with a placebo-controlled, crossover design, investigating the effects of Δ9-tetrahydrocannabinol (THC) inhalation on associative memory-related brain function in 13 healthy volunteers. Performance and brain activation during associative memory were assessed using a pictorial memory task, consisting of separate encoding and recall conditions. Administration of THC caused reductions in activity during encoding in the right insula, the right inferior frontal gyrus, and the left middle occipital gyrus and a network-wide increase in activity during recall, which was most prominent in bilateral cuneus and precuneus. THC administration did not affect task performance, but while during placebo recall activity significantly explained variance in performance, this effect disappeared after THC. These findings suggest eCB involvement in encoding of pictorial information. Increased precuneus activity could reflect impaired recall function, but the absence of THC effects on task performance suggests a compensatory mechanism. These results further emphasize the eCB system as a potential novel target for treatment of memory disorders and a promising target for development of new therapies to reduce memory deficits in humans.

Structural Brain Volumes of Individuals at Clinical High Risk for Psychosis: A Meta-analysis.

Background: Structural magnetic resonance imaging studies in individuals at clinical high risk (CHR) for psychosis have yielded conflicting results. Methods: The aims of this study were to compare intracranial and structural brain volumes and variability of CHR individuals with those of healthy control (HC) subjects and to investigate brain volume differences and variability in CHR subjects with and without transition to psychosis. The PubMed and Embase databases were searched for relevant studies published before June 1, 2020. Results: A total of 34 studies were deemed eligible, which included baseline data of 2111 CHR and 1472 HC participants. In addition, data were included for 401 CHR subjects who subsequently transitioned to psychosis and 1023 nontransitioned CHR participants. Whole-brain and left, right, and bilateral hippocampal volume were significantly smaller in CHR subjects than in HC subjects. Cerebrospinal fluid and lateral ventricle volumes were significantly larger in CHR subjects than in HC subjects. Variability was not significantly different in CHR subjects compared with HC subjects. CHR individuals with and without subsequent transition to psychosis did not show significant differences in any of the volumetric assessments or in variability. Conclusions: This meta-analysis demonstrates reduced whole-brain and hippocampal volumes and increased cerebrospinal fluid and lateral ventricle volumes in CHR individuals. However, no significant differences were observed in any of the volumetric assessments between CHR individuals with and without subsequent transition to psychosis. These findings suggest that although structural brain alterations are present before the onset of the disorder, they may not significantly contribute to the identification of CHR individuals at the highest risk for the development of psychosis.

Task-independent acute effects of delta-9-tetrahydrocannabinol on human brain function and its relationship with cannabinoid receptor gene expression: A neuroimaging meta-regression analysis.

The neurobiological mechanisms underlying the effects of delta-9-tetrahydrocannabinol (THC) remain unclear. Here, we examined the spatial acute effect of THC on human 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. 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) receptors. 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.

The Relationship Between Grey Matter Volume and Clinical and Functional Outcomes in People at Clinical High Risk for Psychosis.

Objective: To examine the association between baseline alterations in grey matter volume (GMV) and clinical and functional outcomes in people at clinical high risk (CHR) for psychosis. Methods: 265 CHR individuals and 92 healthy controls were recruited as part of a prospective multi-center study. After a baseline assessment using magnetic resonance imaging (MRI), participants were followed for at least two years to determine clinical and functional outcomes, including transition to psychosis (according to the Comprehensive Assessment of an At Risk Mental State, CAARMS), level of functioning (according to the Global Assessment of Functioning), and symptomatic remission (according to the CAARMS). GMV was measured in selected cortical and subcortical regions of interest (ROI) based on previous studies (ie orbitofrontal gyrus, cingulate gyrus, gyrus rectus, inferior temporal gyrus, parahippocampal gyrus, striatum, and hippocampus). Using voxel-based morphometry, we analysed the relationship between GMV and clinical and functional outcomes. Results: Within the CHR sample, a poor functional outcome (GAF < 65) was associated with relatively lower GMV in the right striatum at baseline (P < .047 after Family Wise Error correction). There were no significant associations between baseline GMV and either subsequent remission or transition to psychosis. Conclusions: In CHR individuals, lower striatal GMV was associated with a poor level of overall functioning at follow-up. This finding was not related to effects of antipsychotic or antidepressant medication. The failure to replicate previous associations between GMV and later psychosis onset, despite studying a relatively large sample, is consistent with the findings of recent large-scale multi-center studies.

Evidence for involvement of the insula in the psychotropic effects of THC in humans: a double-blind, randomized pharmacological MRI study.

The main reason for recreational use of cannabis is the 'high', the primary psychotropic effect of Δ9-tetrahydrocannabinol (THC). This psychoactive compound of cannabis induces a range of subjective, physical and mental reactions. The effect on heart rate is pronounced and complicates bloodflow-based neuroimaging of psychotropic effects of THC. In this study we investigated the effects of THC on baseline brain perfusion and activity in association with the induction of 'feeling high'. Twenty-three subjects participated in a pharmacological MRI study, where we applied arterial spin labelling (ASL) to measure perfusion, and resting-state functional MRI to assess blood oxygen level-dependent signal fluctuation as a measure of baseline brain activity. Feeling high was assessed with a visual analogue scale and was compared to the imaging measures. THC increased perfusion in the anterior cingulate cortex, superior frontal cortex, and insula, and reduced perfusion in the post-central and occipital gyrus. Baseline brain activity was altered, indicated by increased amplitude of fluctuations in resting-state functional MRI signal after THC administration in the insula, substantia nigra and cerebellum. Perfusion changes in frontal cortex were negatively correlated with ratings of feeling high, suggesting an interaction between cognitive control and subjective effects of THC. In conclusion, an acute THC challenge altered baseline brain perfusion and activity, especially in frontal brain areas involved in cognitive and emotional processes, and the insula, associated with interoceptive awareness. These changes may represent the THC-induced neurophysiological correlates of feeling high. The alterations in baseline brain perfusion and activity also have relevance for studies on task-related effects of THC on brain function.

Reduced resting state functional connectivity in the hippocampus-midbrain-striatum network of schizophrenia patients.

Contemporary preclinical models suggest that abnormal functioning of a brain network consisting of the hippocampus, midbrain and striatum plays a critical role in the pathophysiology of schizophrenia. Previous neuroimaging studies examined individual aspects of this model in schizophrenia patients and individuals at clinical high risk for psychosis. However, this exact preclinical brain network has not been translated to human neuroimaging studies with schizophrenia patients and therefore it is currently unknown how functioning of this network is altered in patients. Here we investigated resting state functional connectivity in the hippocampus-midbrain-striatum network of schizophrenia patients, using functional Magnetic Resonance Imaging. Based on preclinical models, a network of functionally validated brain regions comprising the anterior subiculum (SUB), limbic striatum (LS), ventral tegmental area (VTA) and associative striatum (AS) was examined in 47 schizophrenia patients and 51 healthy controls. Schizophrenia patients demonstrated significantly lower functional connectivity in this hippocampus-midbrain-striatum network compared with healthy controls (p = 0.036). Particular reductions in connectivity were found between the SUB and LS (0.002 ± 0.315 and 0.116 ± 0.224, p = 0.040) and between the VTA and AS (0.230 ± 0.268 and 0.356 ± 0.285, p = 0.026). In patients, functional connectivity was not significantly associated with positive, negative or general symptom scores. Reduced connectivity is consistent with the concept of functional brain dysconnectivity as a key feature of the disorder. Our results support the notion that functioning of the hippocampus-midbrain-striatum network is significantly altered in the pathophysiology of schizophrenia.

Abnormal nodal and global network organization in resting state functional MRI from subjects with the 22q11 deletion syndrome.

The 22q11 deletion syndrome is a genetic disorder associated with a high risk of developing psychosis, and is therefore considered a neurodevelopmental model for studying the pathogenesis of schizophrenia. Studies have shown that localized abnormal functional brain connectivity is present in 22q11 deletion syndrome like in schizophrenia. However, it is less clear whether these abnormal cortical interactions lead to global or regional network disorganization as seen in schizophrenia. We analyzed from a graph-theory perspective fMRI data from 40 22q11 deletion syndrome patients and 67 healthy controls, and reconstructed functional networks from 105 brain regions. Between-group differences were examined by evaluating edge-wise strength and graph theoretical metrics of local (weighted degree, nodal efficiency, nodal local efficiency) and global topological properties (modularity, local and global efficiency). Connectivity strength was globally reduced in patients, driven by a large network comprising 147 reduced connections. The 22q11 deletion syndrome network presented with abnormal local topological properties, with decreased local efficiency and reductions in weighted degree particularly in hub nodes. We found evidence for abnormal integration but intact segregation of the 22q11 deletion syndrome network. Results suggest that 22q11 deletion syndrome patients present with similar aberrant local network organization as seen in schizophrenia, and this network configuration might represent a vulnerability factor to psychosis.

Supporting Future Cannabis Policy - Developing a Standard Joint Unit: A Brief Back-Casting Exercise.

The standardization of cannabis doses is a priority for research, policy-making, clinical and harm-reduction interventions and consumer security. Scientists have called for standard units of dosing for cannabis, similar to those used for alcohol. A Standard Joint Unit (SJU) would facilitate preventive and intervention models in ways similar to the Standard Drink (SD). Learning from the SD experiences allows researchers to tackle emerging barriers to the SJU by applying modern forecasting methods. During a workshop at the Lisbon Addictions Conference 2019, a back-casting foresight method was used to address challenges and achieve consensus in developing an SJU. Thirty-two professionals from 13 countries and 10 disciplines participated. Descriptive analysis of the workshop was carried out by the organizers and shared with the participants in order to suggest amendments. Several characteristics of the SJU were defined: (1) core values: easy-to use, universal, focused on THC, accurate, and accessible; (2) key challenges: sudden changes in patterns of use, heterogeneity of cannabis compounds as well as in administration routes, variations over time in THC concentrations, and of laws that regulate the legal status of recreational and medical cannabis use); and (3) facilitators: previous experience with standardized measurements, funding opportunities, multi-stakeholder support, high prevalence of cannabis users, and widespread changes in legislation. Participants also identified three initial steps for the implementation of a SJU by 2030: (1) Building a task-force to develop a consensus-based SJU; (2) Expanded available national-level data; (3) Linking SJU consumption to the concept of "risky use," based on evidence of harms.

The Impact of Cannabidiol on Human Brain Function: A Systematic Review.

Background: Accumulating evidence suggests that the non-intoxicating cannabinoid compound cannabidiol (CBD) may have antipsychotic and anxiolytic properties, and thus may be a promising new agent in the treatment of psychotic and anxiety disorders. However, the neurobiological substrates underlying the potential therapeutic effects of CBD are still unclear. The aim of this systematic review is to provide a detailed and up-to-date systematic literature overview of neuroimaging studies that investigated the acute impact of CBD on human brain function. Methods: Papers published until May 2020 were included from PubMed following a comprehensive search strategy and pre-determined set of criteria for article selection. We included studies that examined the effects of CBD on brain function of healthy volunteers and individuals diagnosed with a psychiatric disorder, comprising both the effects of CBD alone as well as in direct comparison to those induced by ∆9-tetrahydrocannabinol (THC), the main psychoactive component of Cannabis. Results: One-ninety four studies were identified, of which 17 met inclusion criteria. All studies investigated the acute effects of CBD on brain function during resting state or in the context of cognitive tasks. In healthy volunteers, acute CBD enhanced fronto-striatal resting state connectivity, both compared to placebo and THC. Furthermore, CBD modulated brain activity and had opposite effects when compared to THC following task-specific patterns during various cognitive paradigms, such as emotional processing (fronto-temporal), verbal memory (fronto-striatal), response inhibition (fronto-limbic-striatal), and auditory/visual processing (temporo-occipital). In individuals at clinical high risk for psychosis and patients with established psychosis, acute CBD showed intermediate brain activity compared to placebo and healthy controls during cognitive task performance. CBD modulated resting limbic activity in subjects with anxiety and metabolite levels in patients with autism spectrum disorders. Conclusion: Neuroimaging studies have shown that acute CBD induces significant alterations in brain activity and connectivity patterns during resting state and performance of cognitive tasks in both healthy volunteers and patients with a psychiatric disorder. This included modulation of functional networks relevant for psychiatric disorders, possibly reflecting CBD's therapeutic effects. Future studies should consider replication of findings and enlarge the inclusion of psychiatric patients, combining longer-term CBD treatment with neuroimaging assessments.

Factors Moderating the Association Between Cannabis Use and Psychosis Risk: A Systematic Review.

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.

Glutamate in schizophrenia: Neurodevelopmental perspectives and drug development.

Research into the neurobiological processes that may lead to the onset of schizophrenia places growing emphasis on the glutamatergic system and brain development. Preclinical studies have shown that neurodevelopmental, genetic, and environmental factors contribute to glutamatergic dysfunction and schizophrenia-related phenotypes. Clinical research has suggested that altered brain glutamate levels may be present before the onset of psychosis and relate to outcome in those at clinical high risk. After psychosis onset, glutamate dysfunction may also relate to the degree of antipsychotic response and clinical outcome. These findings support ongoing efforts to develop pharmacological interventions that target the glutamate system and could suggest that glutamatergic compounds may be more effective in specific patient subgroups or illness stages. In this review, we consider the updated glutamate hypothesis of schizophrenia, from a neurodevelopmental perspective, by reviewing recent preclinical and clinical evidence, and discuss the potential implications for novel therapeutics.