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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.
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Canabidiol , Transtornos Psicóticos , Humanos , Canabidiol/farmacologia , Transtornos Psicóticos/diagnóstico por imagem , Transtornos Psicóticos/tratamento farmacológico , Hipocampo/diagnóstico por imagem , Corpo Estriado , Método Duplo-CegoRESUMO
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.
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Cannabis , Alucinógenos , Humanos , Dronabinol/farmacologia , Imageamento por Ressonância Magnética , Encéfalo , Catecol O-Metiltransferase/genética , Catecol O-Metiltransferase/farmacologia , Alucinógenos/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , GenótipoRESUMO
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.
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Antipsicóticos , Canabidiol , Transtornos Psicóticos , Humanos , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Encéfalo , Canabidiol/efeitos adversos , Imageamento por Ressonância Magnética/métodos , Transtornos Psicóticos/diagnóstico por imagem , Transtornos Psicóticos/tratamento farmacológicoRESUMO
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.
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Background: Preclinical and human data suggest that psychosis onset involves hippocampal glutamatergic dysfunction, driving hyperactivity and hyperperfusion in a hippocampal-midbrain-striatal circuit. Whether glutamatergic dysfunction is related to cerebral perfusion in patients at clinical high risk (CHR) for psychosis, and whether cannabidiol (CBD) has ameliorative effects on glutamate or its relationship with perfusion remains unknown. Methods: Using a double-blind, parallel-group design, 33 CHR patients were randomized to a single 600 mg dose of CBD or placebo; 19 healthy controls did not receive any drug. Proton magnetic resonance spectroscopy was used to measure glutamate concentrations in left hippocampus. We examined differences relating to CHR status (controls vs placebo), effects of CBD (placebo vs CBD), and linear between-group effects, such that placebo>CBD>controls or controls>CBD>placebo. We also examined group × glutamate × cerebral perfusion (measured using Arterial Spin Labeling) interactions. Results: Compared to controls, CHR-placebo patients had significantly lower hippocampal glutamate (P =.015) and a significant linear relationship was observed across groups, such that glutamate was highest in controls, lowest in CHR-placebo, and intermediate in CHR-CBD (P =.031). Moreover, there was a significant interaction between group (controls vs CHR-placebo), hippocampal glutamate, and perfusion in the putamen and insula (P FWE =.012), with a strong positive correlation in CHR-placebo vs a negative correlation in controls. Conclusions: Our findings suggest that hippocampal glutamate is lower in CHR patients and may be partially normalized by a single dose of CBD. Furthermore, we provide the first in vivo evidence of an abnormal relationship between hippocampal glutamate and perfusion in the striatum and insula in CHR.
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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.
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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.
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Encéfalo , Dronabinol , Expressão Gênica , Humanos , Neuroimagem , Receptores de Canabinoides , Análise de RegressãoRESUMO
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.
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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.
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Canabidiol , Transtornos Psicóticos , Canabidiol/farmacologia , Medo , Humanos , Hidrocortisona , Sistema Hipotálamo-Hipofisário , Transtornos Psicóticos/tratamento farmacológico , Estresse Psicológico/tratamento farmacológicoRESUMO
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.
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Canabinoides , Endocanabinoides , Agonistas de Receptores de Canabinoides/farmacologia , Moduladores de Receptores de Canabinoides/metabolismo , Moduladores de Receptores de Canabinoides/farmacologia , Canabinoides/metabolismo , Canabinoides/farmacologia , Humanos , Ligantes , Neurofarmacologia , Receptor CB1 de Canabinoide , Receptor CB2 de Canabinoide , Receptores de Canabinoides/metabolismo , Transdução de SinaisRESUMO
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.
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Síndrome da Deleção 22q11/patologia , Conectoma/estatística & dados numéricos , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Rede Nervosa/fisiopatologia , Vias Neurais/fisiopatologia , Descanso/fisiologia , Síndrome da Deleção 22q11/genética , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Adulto JovemAssuntos
Cannabis , Alucinógenos , Preparações Farmacêuticas , Humanos , Legislação de Medicamentos , Saúde Pública , Política PúblicaRESUMO
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.
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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.
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Transtornos Psicóticos , Esquizofrenia , Hipocampo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Mesencéfalo , Vias Neurais/diagnóstico por imagem , Transtornos Psicóticos/diagnóstico por imagem , Esquizofrenia/diagnóstico por imagemRESUMO
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.
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Encéfalo/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Rede Nervosa/diagnóstico por imagem , Sintomas Prodrômicos , Transtornos Psicóticos/diagnóstico por imagem , Adolescente , Adulto , Encéfalo/fisiologia , Conectoma/métodos , Feminino , Humanos , Estudos Longitudinais , Masculino , Rede Nervosa/fisiologia , Valor Preditivo dos Testes , Desempenho Psicomotor/fisiologia , Transtornos Psicóticos/psicologia , Fatores de Risco , Adulto JovemRESUMO
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.
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Antipsicóticos , Transtornos Psicóticos , Esquizofrenia , Antipsicóticos/uso terapêutico , Desenvolvimento de Medicamentos , Ácido Glutâmico , Humanos , Receptores de N-Metil-D-Aspartato , Esquizofrenia/tratamento farmacológicoRESUMO
Emotional dysregulation and anxiety are common in people at clinical high risk for psychosis (CHR) and are associated with altered neural responses to emotional stimuli in the striatum and medial temporal lobe. Using a randomised, double-blind, parallel-group design, 33 CHR patients were randomised to a single oral dose of CBD (600 mg) or placebo. Healthy controls (n = 19) were studied under identical conditions but did not receive any drug. Participants were scanned with functional magnetic resonance imaging (fMRI) during a fearful face-processing paradigm. Activation related to the CHR state and to the effects of CBD was examined using a region-of-interest approach. During fear processing, CHR participants receiving placebo (n = 15) showed greater activation than controls (n = 19) in the parahippocampal gyrus but less activation in the striatum. Within these regions, activation in the CHR group that received CBD (n = 15) was intermediate between that of the CHR placebo and control groups. These findings suggest that in CHR patients, CBD modulates brain function in regions implicated in psychosis risk and emotion processing. These findings are similar to those previously evident using a memory paradigm, suggesting that the effects of CBD on medial temporal and striatal function may be task independent.
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Canabidiol , Transtornos Psicóticos , Encéfalo , Mapeamento Encefálico , Corpo Estriado/diagnóstico por imagem , Método Duplo-Cego , Medo , Humanos , Imageamento por Ressonância Magnética , Transtornos Psicóticos/diagnóstico por imagem , Transtornos Psicóticos/tratamento farmacológicoRESUMO
Psychosis has been proposed to develop from dysfunction in a hippocampal-striatal-midbrain circuit, leading to aberrant salience processing. Here, we used functional magnetic resonance imaging (fMRI) during novelty salience processing to investigate this model in people at clinical high risk (CHR) for psychosis according to their subsequent clinical outcomes. Seventy-six CHR participants as defined using the Comprehensive Assessment of At-Risk Mental States (CAARMS) and 31 healthy controls (HC) were studied while performing a novelty salience fMRI task that engaged an a priori hippocampal-striatal-midbrain circuit of interest. The CHR sample was then followed clinically for a mean of 59.7 months (~5 y), when clinical outcomes were assessed in terms of transition (CHR-T) or non-transition (CHR-NT) to psychosis (CAARMS criteria): during this period, 13 individuals (17%) developed a psychotic disorder (CHR-T) and 63 did not. Functional activation and effective connectivity within a hippocampal-striatal-midbrain circuit were compared between groups. In CHR individuals compared to HC, hippocampal response to novel stimuli was significantly attenuated (P = .041 family-wise error corrected). Dynamic Causal Modelling revealed that stimulus novelty modulated effective connectivity from the hippocampus to the striatum, and from the midbrain to the hippocampus, significantly more in CHR participants than in HC. Conversely, stimulus novelty modulated connectivity from the midbrain to the striatum significantly less in CHR participants than in HC, and less in CHR participants who subsequently developed psychosis than in CHR individuals who did not become psychotic. Our findings are consistent with preclinical evidence implicating hippocampal-striatal-midbrain circuit dysfunction in altered salience processing and the onset of psychosis.
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Atenção/fisiologia , Conectoma , Corpo Estriado/fisiopatologia , Hipocampo/fisiopatologia , Mesencéfalo/fisiopatologia , Rede Nervosa/fisiopatologia , Reconhecimento Visual de Modelos/fisiologia , Transtornos Psicóticos/fisiopatologia , Esquizofrenia/fisiopatologia , Adulto , Corpo Estriado/diagnóstico por imagem , Feminino , Seguimentos , Hipocampo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Mesencéfalo/diagnóstico por imagem , Rede Nervosa/diagnóstico por imagem , Sintomas Prodrômicos , Desempenho Psicomotor/fisiologia , Transtornos Psicóticos/diagnóstico por imagem , Esquizofrenia/diagnóstico por imagem , Adulto JovemRESUMO
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.
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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.