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Emerging evidence suggests distinct neurobiological correlates of alcohol use disorder (AUD) between sexes, which however remain largely unexplored. This work from ENIGMA Addiction Working Group aimed to characterize the sex differences in gray matter (GM) and white matter (WM) correlates of AUD using a whole-brain, voxel-based, multi-tissue mega-analytic approach, thereby extending our recent surface-based region of interest findings on a nearly matching sample using a complementary methodological approach. T1-weighted magnetic resonance imaging (MRI) data from 653 people with AUD and 326 controls was analyzed using voxel-based morphometry. The effects of group, sex, group-by-sex, and substance use severity in AUD on brain volumes were assessed using General Linear Models. Individuals with AUD relative to controls had lower GM volume in striatal, thalamic, cerebellar, and widespread cortical clusters. Group-by-sex effects were found in cerebellar GM and WM volumes, which were more affected by AUD in females than males. Smaller group-by-sex effects were also found in frontotemporal WM tracts, which were more affected in AUD females, and in temporo-occipital and midcingulate GM volumes, which were more affected in AUD males. AUD females but not males showed a negative association between monthly drinks and precentral GM volume. Our results suggest that AUD is associated with both shared and distinct widespread effects on GM and WM volumes in females and males. This evidence advances our previous region of interest knowledge, supporting the usefulness of adopting an exploratory perspective and the need to include sex as a relevant moderator variable in AUD.

INTRODUCTION: There are growing concerns about commonly inflated effect sizes in small neuroimaging studies, yet no study has addressed recalibrating effect size estimates for small samples. To tackle this issue, we propose a hierarchical Bayesian model to adjust the magnitude of single-study effect sizes while incorporating a tailored estimation of sampling variance.METHODS: We estimated the effect sizes of case-control differences on brain structural features between individuals who were dependent on alcohol, nicotine, cocaine, methamphetamine, or cannabis and non-dependent participants for 21 individual studies (Total cases: 903; Total controls: 996). Then, the study-specific effect sizes were modeled using a hierarchical Bayesian approach in which the parameters of the study-specific effect size distributions were sampled from a higher-order overarching distribution. The posterior distribution of the overarching and study-specific parameters was approximated using the Gibbs sampling method.RESULTS: The results showed shrinkage of the posterior distribution of the study-specific estimates toward the overarching estimates given the original effect sizes observed in individual studies. Differences between the original effect sizes (i.e., Cohen's d) and the point estimate of the posterior distribution ranged from 0 to 0.97. The magnitude of adjustment was negatively correlated with the sample size (r = -0.27, p < 0.001) and positively correlated with empirically estimated sampling variance (r = 0.40, p < 0.001), suggesting studies with smaller samples and larger sampling variance tended to have greater adjustments. DISCUSSION: Our findings demonstrate the utility of the hierarchical Bayesian model in recalibrating single-study effect sizes using information from similar studies. This suggests that Bayesian utilization of existing knowledge can be an effective alternative approach t

Objectives The liberalisation of cannabis laws, the increasing availability and potency of cannabis has renewed concern about the risk of psychosis with cannabis. Methods The objective of the WFSBP task force was to review the literature about this relationship. Results Converging lines of evidence suggest that exposure to cannabis increases the risk for psychoses ranging from transient psychotic states to chronic recurrent psychosis. The greater the dose, and the earlier the age of exposure, the greater the risk. For some psychosis outcomes, the evidence supports some of the criteria of causality. However, alternate explanations including reverse causality and confounders cannot be conclusively excluded. Furthermore, cannabis is neither necessary nor sufficient to cause psychosis. More likely it is one of the multiple causal components. In those with established psychosis, cannabis has a negative impact on the course and expression of the illness. Emerging evidence also suggests alterations in the endocannabinoid system in psychotic disorders. Conclusions Given that exposure to cannabis and cannabinoids is modifiable, delaying or eliminating exposure to cannabis or cannabinoids, could potentially impact the rates of psychosis related to cannabis, especially in those who are at high risk for developing the disorder.

Brain asymmetry reflects left-right hemispheric differentiation, which is a quantitative brain phenotype that develops with age and can vary with psychiatric diagnoses. Previous studies have shown that substance dependence is associated with altered brain structure and function. However, it is unknown whether structural brain asymmetries are different in individuals with substance dependence compared with nondependent participants. Here, a mega-analysis was performed using a collection of 22 structural brain MRI datasets from the ENIGMA Addiction Working Group. Structural asymmetries of cortical and subcortical regions were compared between individuals who were dependent on alcohol, nicotine, cocaine, methamphetamine, or cannabis (n = 1,796) and nondependent participants (n = 996). Substance-general and substance-specific effects on structural asymmetry were examined using separate models. We found that substance dependence was significantly associated with differences in volume asymmetry of the nucleus accumbens (NAcc; less rightward; Cohen's d = 0.15). This effect was driven by differences from controls in individuals with alcohol dependence (less rightward; Cohen's d = 0.10) and nicotine dependence (less rightward; Cohen's d = 0.11). These findings suggest that disrupted structural asymmetry in the NAcc may be a characteristic of substance dependence.

Males and females show different patterns of cannabis use and related psychosocial outcomes. However, the neuroanatomical substrates underlying such differences are poorly understood. The aim of this study was to map sex differences in the neurobiology (as indexed by brain volumes) of dependent and recreational cannabis use. We compared the volume of a priori regions of interest (i.e., amygdala, hippocampus, nucleus accumbens, insula, orbitofrontal cortex (OFC), anterior cingulate cortex and cerebellum) between 129 regular cannabis users (of whom 70 were recreational users and 59 cannabis dependent) and 114 controls recruited from the ENIGMA Addiction Working Group, accounting for intracranial volume, age, IQ, and alcohol and tobacco use. Dependent cannabis users, particularly females, had (marginally significant) smaller volumes of the lateral OFC and cerebellar white matter than recreational users and controls. In dependent (but not recreational) cannabis users, there was a significant association between female sex and smaller volumes of the cerebellar white matter and OFC. Volume of the OFC was also predicted by monthly standard drinks. No significant effects emerged the other brain regions of interest. Our findings warrant future multimodal studies that examine if sex and cannabis dependence are specific key drivers of neurobiological alterations in cannabis users. This, in turn, could help to identify neural pathways specifically involved in vulnerable cannabis users (e.g., females with cannabis dependence) and inform individually tailored neurobiological targets for treatment.

Gender-related differences in the susceptibility, progression and clinical outcomes of alcohol dependence are well-known. However, the neurobiological substrates underlying such differences remain unclear. Therefore, this study aimed to investigate gender differences in the neuroanatomy (i.e. regional brain volumes) of alcohol dependence. We examined the volume of a priori regions of interest (i.e., orbitofrontal cortex, hippocampus, amygdala, nucleus accumbens, caudate, putamen, pallidum, thalamus, corpus callosum, cerebellum) and global brain measures (i.e., total grey matter (GM), total white matter (WM) and cerebrospinal fluid). Volumes were compared between 660 people with alcohol dependence (228 women) and 326 controls (99 women) recruited from the ENIGMA Addiction Working Group, accounting for intracranial volume, age and education years. Compared to controls, individuals with alcohol dependence on average had (3-9%) smaller volumes of the hippocampus (bilateral), putamen (left), pallidum (left), thalamus (right), corpus callosum, total GM and WM, and cerebellar GM (bilateral), the latter more prominently in women (right). Alcohol-dependent men showed smaller amygdala volume than control men, but this effect was unclear among women. In people with alcohol dependence, more monthly standard drinks predicted smaller amygdala and larger cerebellum GM volumes. The neuroanatomical differences associated with alcohol dependence emerged as gross and widespread, while those associated with a specific gender may be confined to selected brain regions. These findings warrant future neuroscience research to account for gender differences in alcohol dependence to further understand the neurobiological effects of alcohol dependence.

Brain asymmetry reflects left-right hemispheric differentiation, which is a quantitative brain phenotype that develops with age and can vary with psychiatric diagnoses. Previous studies have shown that substance dependence is associated with altered brain structure and function. However, it is unknown whether structural brain asymmetries are different in individuals with substance dependence compared with nondependent participants. Here, a mega-analysis was performed using a collection of 22 structural brain MRI datasets from the ENIGMA Addiction Working Group. Structural asymmetries of cortical and subcortical regions were compared between individuals who were dependent on alcohol, nicotine, cocaine, methamphetamine, or cannabis (n = 1,796) and nondependent participants (n = 996). Substance-general and substance-specific effects on structural asymmetry were examined using separate models. We found that substance dependence was significantly associated with differences in volume asymmetry of the nucleus accumbens (NAcc; less rightward; Cohen's d = 0.15). This effect was driven by differences from controls in individuals with alcohol dependence (less rightward; Cohen's d = 0.10) and nicotine dependence (less rightward; Cohen's d = 0.11). These findings suggest that disrupted structural asymmetry in the NAcc may be a characteristic of substance dependence.

While imaging studies have demonstrated volumetric differences in subcortical structures associated with dependence on various abused substances, findings to date have not been wholly consistent. Moreover, most studies have not compared brain morphology across those dependent on different substances of abuse to identify substance-specific and substance-general dependence effects. By pooling large multinational datasets from 33 imaging sites, this study examined subcortical surface morphology in 1628 nondependent controls and 2277 individuals with dependence on alcohol, nicotine, cocaine, methamphetamine, and/or cannabis. Subcortical structures were defined by FreeSurfer segmentation and converted to a mesh surface to extract two vertex-level metrics-the radial distance (RD) of the structure surface from a medial curve and the log of the Jacobian determinant (JD)-that, respectively, describe local thickness and surface area dilation/contraction. Mega-analyses were performed on measures of RD and JD to test for the main effect of substance dependence, controlling for age, sex, intracranial volume, and imaging site. Widespread differences between dependent users and nondependent controls were found across subcortical structures, driven primarily by users dependent on alcohol. Alcohol dependence was associated with localized lower RD and JD across most structures, with the strongest effects in the hippocampus, thalamus, putamen, and amygdala. Meanwhile, nicotine use was associated with greater RD and JD relative to nonsmokers in multiple regions, with the strongest effects in the bilateral hippocampus and right nucleus accumbens. By demonstrating subcortical morphological differences unique to alcohol and nicotine use, rather than dependence across all substances, results suggest substance-specific relationships with subcortical brain structures.

Objectives: We aimed to investigate whether severity of cannabis dependence is associated with the neuroanatomy of key brain regions of the stress and reward brain circuits. Methods: To examine dependence-specific regional brain alterations, we compared the volumes of regions relevant to reward and stress, between high-dependence cannabis users (CD+, n = 25), low-dependence cannabis users (CD−, n = 20) and controls (n = 37). Results: Compared to CD− and/or controls, the CD+ group had lower cerebellar white matter and hippocampal volumes, and deflation of the right hippocampus head and tail. Conclusion: These findings provide initial support for neuroadaptations involving stress and reward circuits that are specific to high-dependence cannabis users.

Objectives: We aimed to investigate whether severity of cannabis dependence is associated with the neuroanatomy of key brain regions of the stress and reward brain circuits. Methods: To examine dependence-specific regional brain alterations, we compared the volumes of regions relevant to reward and stress, between high-dependence cannabis users (CD+, n = 25), low-dependence cannabis users (CD−, n = 20) and controls (n = 37). Results: Compared to CD− and/or controls, the CD+ group had lower cerebellar white matter and hippocampal volumes, and deflation of the right hippocampus head and tail. Conclusion: These findings provide initial support for neuroadaptations involving stress and reward circuits that are specific to high-dependence cannabis users.

While imaging studies have demonstrated volumetric differences in subcortical structures associated with dependence on various abused substances, findings to date have not been wholly consistent. Moreover, most studies have not compared brain morphology across those dependent on different substances of abuse to identify substance-specific and substance-general dependence effects. By pooling large multinational datasets from 33 imaging sites, this study examined subcortical surface morphology in 1628 nondependent controls and 2277 individuals with dependence on alcohol, nicotine, cocaine, methamphetamine, and/or cannabis. Subcortical structures were defined by FreeSurfer segmentation and converted to a mesh surface to extract two vertex-level metrics-the radial distance (RD) of the structure surface from a medial curve and the log of the Jacobian determinant (JD)-that, respectively, describe local thickness and surface area dilation/contraction. Mega-analyses were performed on measures of RD and JD to test for the main effect of substance dependence, controlling for age, sex, intracranial volume, and imaging site. Widespread differences between dependent users and nondependent controls were found across subcortical structures, driven primarily by users dependent on alcohol. Alcohol dependence was associated with localized lower RD and JD across most structures, with the strongest effects in the hippocampus, thalamus, putamen, and amygdala. Meanwhile, nicotine use was associated with greater RD and JD relative to nonsmokers in multiple regions, with the strongest effects in the bilateral hippocampus and right nucleus accumbens. By demonstrating subcortical morphological differences unique to alcohol and nicotine use, rather than dependence across all substances, results suggest substance-specific relationships with subcortical brain structures.

While imaging studies have demonstrated volumetric differences in subcortical structures associated with dependence on various abused substances, findings to date have not been wholly consistent. Moreover, most studies have not compared brain morphology across those dependent on different substances of abuse to identify substance-specific and substance-general dependence effects. By pooling large multinational datasets from 33 imaging sites, this study examined subcortical surface morphology in 1628 nondependent controls and 2277 individuals with dependence on alcohol, nicotine, cocaine, methamphetamine, and/or cannabis. Subcortical structures were defined by FreeSurfer segmentation and converted to a mesh surface to extract two vertex-level metrics-the radial distance (RD) of the structure surface from a medial curve and the log of the Jacobian determinant (JD)-that, respectively, describe local thickness and surface area dilation/contraction. Mega-analyses were performed on measures of RD and JD to test for the main effect of substance dependence, controlling for age, sex, intracranial volume, and imaging site. Widespread differences between dependent users and nondependent controls were found across subcortical structures, driven primarily by users dependent on alcohol. Alcohol dependence was associated with localized lower RD and JD across most structures, with the strongest effects in the hippocampus, thalamus, putamen, and amygdala. Meanwhile, nicotine use was associated with greater RD and JD relative to nonsmokers in multiple regions, with the strongest effects in the bilateral hippocampus and right nucleus accumbens. By demonstrating subcortical morphological differences unique to alcohol and nicotine use, rather than dependence across all substances, results suggest substance-specific relationships with subcortical brain structures.

While imaging studies have demonstrated volumetric differences in subcortical structures associated with dependence on various abused substances, findings to date have not been wholly consistent. Moreover, most studies have not compared brain morphology across those dependent on different substances of abuse to identify substance-specific and substance-general dependence effects. By pooling large multinational datasets from 33 imaging sites, this study examined subcortical surface morphology in 1628 nondependent controls and 2277 individuals with dependence on alcohol, nicotine, cocaine, methamphetamine, and/or cannabis. Subcortical structures were defined by FreeSurfer segmentation and converted to a mesh surface to extract two vertex-level metrics-the radial distance (RD) of the structure surface from a medial curve and the log of the Jacobian determinant (JD)-that, respectively, describe local thickness and surface area dilation/contraction. Mega-analyses were performed on measures of RD and JD to test for the main effect of substance dependence, controlling for age, sex, intracranial volume, and imaging site. Widespread differences between dependent users and nondependent controls were found across subcortical structures, driven primarily by users dependent on alcohol. Alcohol dependence was associated with localized lower RD and JD across most structures, with the strongest effects in the hippocampus, thalamus, putamen, and amygdala. Meanwhile, nicotine use was associated with greater RD and JD relative to nonsmokers in multiple regions, with the strongest effects in the bilateral hippocampus and right nucleus accumbens. By demonstrating subcortical morphological differences unique to alcohol and nicotine use, rather than dependence across all substances, results suggest substance-specific relationships with subcortical brain structures.

While imaging studies have demonstrated volumetric differences in subcortical structures associated with dependence on various abused substances, findings to date have not been wholly consistent. Moreover, most studies have not compared brain morphology across those dependent on different substances of abuse to identify substance-specific and substance-general dependence effects. By pooling large multinational datasets from 33 imaging sites, this study examined subcortical surface morphology in 1628 nondependent controls and 2277 individuals with dependence on alcohol, nicotine, cocaine, methamphetamine, and/or cannabis. Subcortical structures were defined by FreeSurfer segmentation and converted to a mesh surface to extract two vertex-level metrics—the radial distance (RD) of the structure surface from a medial curve and the log of the Jacobian determinant (JD)—that, respectively, describe local thickness and surface area dilation/contraction. Mega-analyses were performed on measures of RD and JD to test for the main effect of substance dependence, controlling for age, sex, intracranial volume, and imaging site. Widespread differences between dependent users and nondependent controls were found across subcortical structures, driven primarily by users dependent on alcohol. Alcohol dependence was associated with localized lower RD and JD across most structures, with the strongest effects in the hippocampus, thalamus, putamen, and amygdala. Meanwhile, nicotine use was associated with greater RD and JD relative to nonsmokers in multiple regions, with the strongest effects in the bilateral hippocampus and right nucleus accumbens. By demonstrating subcortical morphological differences unique to alcohol and nicotine use, rather than dependence across all substances, results suggest substance-specific relationships with subcortical brain structures.

Objectives: We aimed to investigate whether severity of cannabis dependence is associated with the neuroanatomy of key brain regions of the stress and reward brain circuits. Methods: To examine dependence-specific regional brain alterations, we compared the volumes of regions relevant to reward and stress, between high-dependence cannabis users (CD+, n = 25), low-dependence cannabis users (CD−, n = 20) and controls (n = 37). Results: Compared to CD− and/or controls, the CD+ group had lower cerebellar white matter and hippocampal volumes, and deflation of the right hippocampus head and tail. Conclusion: These findings provide initial support for neuroadaptations involving stress and reward circuits that are specific to high-dependence cannabis users.

Objectives: We aimed to investigate whether severity of cannabis dependence is associated with the neuroanatomy of key brain regions of the stress and reward brain circuits. Methods: To examine dependence-specific regional brain alterations, we compared the volumes of regions relevant to reward and stress, between high-dependence cannabis users (CD+, n = 25), low-dependence cannabis users (CD−, n = 20) and controls (n = 37). Results: Compared to CD− and/or controls, the CD+ group had lower cerebellar white matter and hippocampal volumes, and deflation of the right hippocampus head and tail. Conclusion: These findings provide initial support for neuroadaptations involving stress and reward circuits that are specific to high-dependence cannabis users.

Objectives: We aimed to investigate whether severity of cannabis dependence is associated with the neuroanatomy of key brain regions of the stress and reward brain circuits. Methods: To examine dependence-specific regional brain alterations, we compared the volumes of regions relevant to reward and stress, between high-dependence cannabis users (CD+, n = 25), low-dependence cannabis users (CD−, n = 20) and controls (n = 37). Results: Compared to CD− and/or controls, the CD+ group had lower cerebellar white matter and hippocampal volumes, and deflation of the right hippocampus head and tail. Conclusion: These findings provide initial support for neuroadaptations involving stress and reward circuits that are specific to high-dependence cannabis users.

Access to cannabis and cannabinoid products is increasing worldwide for recreational and medicinal use. Two primary compounds within cannabis plant matter, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are both psychoactive, but only THC is considered intoxicating. There is significant interest in potential therapeutic properties of these cannabinoids and of CBD in particular. Some research has suggested that CBD may ameliorate adverse effects of THC, but this may be dose dependent as other evidence suggests possible potentiating effects of THC by low doses of CBD. We conducted a randomised placebo controlled trial to examine the acute effects of these compounds alone and in combination when administered by vaporisation to frequent and infrequent cannabis users. Participants (n = 36; 31 male) completed 5 drug conditions spaced one week apart, with the following planned contrasts: placebo vs CBD alone (400 mg); THC alone (8 mg) vs THC combined with low (4 mg) or high (400 mg) doses of CBD. Objective (blind observer ratings) and subjective (self-rated) measures of intoxication were the primary outcomes, with additional indices of intoxication examined. CBD showed some intoxicating properties relative to placebo. Low doses of CBD when combined with THC enhanced, while high doses of CBD reduced the intoxicating effects of THC. The enhancement of intoxication by low-dose CBD was particularly prominent in infrequent cannabis users and was consistent across objective and subjective measures. Most effects were significant at p < .0001. These findings are important to consider in terms of recommended proportions of THC and CBD in cannabis plant matter whether used medicinally or recreationally and have implications for novice or less experienced cannabis users.

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Cognitive impairment is a major source of disability in schizophrenia and current antipsychotic drugs (APDs) have minimal efficacy for this symptom domain. Cannabidiol (CBD), the major non-intoxicating component of Cannabis sativa L., exhibits antipsychotic and neuroprotective properties. We recently reported the effects of CBD on cognition in male offspring of a maternal immune activation (polyinosinic-polycytidilic acid (poly I:C)) model relevant to the aetiology of schizophrenia; however, the effects of CBD treatment in females are unknown. Sex differences are observed in the onset of schizophrenia symptoms and response to APD treatment. Furthermore, the endogenous cannabinoid system, a direct target of CBD, is sexually dimorphic in humans and rodents. Therefore, the present work aimed to assess the therapeutic impact of CBD treatment on behaviour and neurochemical signalling markers in female poly I:C offspring. Time-mated pregnant Sprague-Dawley rats (n = 16) were administered poly I:C (4 mg/kg; i.v.) or saline (control) on gestational day 15. From postnatal day 56, female offspring received CBD (10 mg/kg, i.p.) or vehicle treatment for approximately 3 weeks. Following 2 weeks of CBD treatment, offspring underwent behavioural testing, including the novel object recognition, rewarded alternation T-maze and social interaction tests to assess recognition memory, working memory and sociability, respectively. After 3 weeks of CBD treatment, the prefrontal cortex (PFC) and hippocampus (HPC) were collected to assess effects on endocannabinoid, glutamatergic and gamma-aminobutyric acid (GABA) signalling markers. CBD attenuated poly I:C-induced deficits in recognition memory, social interaction and glutamatergic N-methyl-D-aspartate receptor (NMDAR) binding in the PFC of poly I:C offspring. Working memory performance was similar between treatment groups. CBD also increased glutamate decarboxylase 67, the rate-limiting enzyme that converts glutamate to GABA, and parvalbu

The mainstay treatment for schizophrenia is antipsychotic drugs (APDs), which are mostly effective against the positive symptoms (e.g. hallucinations), but provide minimal benefits for the negative symptoms (e.g. social withdrawal) and cognitive deficits. We have recently shown that treatment with the non-intoxicating phytocannabinoid, cannabidiol (CBD), can improve cognition and social interaction deficits in a maternal immune activation (MIA) model relevant to the aetiology of schizophrenia, however, the mechanisms underlying this effect are unknown. An imbalance in the main excitatory (glutamate) and inhibitory (GABA) neurotransmitter systems in the brain plays a role in the pathophysiology of schizophrenia. Therefore, the endocannabinoid system could represent a therapeutic target for schizophrenia as a regulator of glutamate and GABA release via the CB1 receptor (CB1R). This study investigated the effects of chronic CBD treatment on markers of glutamatergic, GABAergic and endocannabinoid signalling in brain regions implicated in social behaviour and cognitive function, including the prefrontal cortex (PFC) and hippocampus (HPC). Time-mated pregnant Sprague-Dawley rats (n = 16) were administered poly I:C (4 mg/kg, i.v.) or saline (control) on gestational day 15. Male offspring were injected with CBD (10 mg/kg, i.p.) or vehicle twice daily from postnatal day 56 for 3 weeks. The prefrontal cortex (PFC) and hippocampus (HPC) were collected for post-mortem receptor binding and Western blot analyses (n = 8 per group). CBD treatment attenuated poly I:C-induced deficits in cannabinoid CB1 receptor binding in the PFC and glutamate decarboxylase 67, the enzyme that converts glutamate to GABA, in the HPC. CBD treatment increased parvalbumin levels in the HPC, regardless of whether offspring were exposed to poly I:C in utero. Conversely, CBD did not affect N-methyl-d-aspartate receptor and gamma-aminobutyric acid (GABA) A receptor binding or protein levels of fatty acid am

Background: The US National Institutes of Mental Health Research Domain Criteria (RDoC) seek to stimulate research into biologically validated neuropsychological dimensions across mental illness symptoms and diagnoses. The RDoC framework comprises 39 functional constructs designed to be revised and refined, with the overall goal of improving diagnostic validity and treatments. This study aimed to reach a consensus among experts in the addiction field on the 'primary' RDoC constructs most relevant to substance and behavioural addictions. Methods: Forty-four addiction experts were recruited from Australia, Asia, Europe and the Americas. The Delphi technique was used to determine a consensus as to the degree of importance of each construct in understanding the essential dimensions underpinning addictive behaviours. Expert opinions were canvassed online over three rounds (97% completion rate), with each consecutive round offering feedback for experts to review their opinions. Results: Seven constructs were endorsed by ≥ 80% of experts as 'primary' to the understanding of addictive behaviour: five from the Positive Valence System (reward valuation, expectancy, action selection, reward learning, habit); one from the Cognitive Control System (response selection/inhibition); and one expert-initiated construct (compulsivity). These constructs were rated to be related differentially to stages of the addiction cycle, with some linked more closely to addiction onset and others more to chronicity. Experts agreed that these neuropsychological dimensions apply across a range of addictions. Conclusions: The study offers a novel and neuropsychologically informed theoretical framework, as well as a cogent step forward to test transdiagnostic concepts in addiction research, with direct implications for assessment, diagnosis, staging of disorder, and treatment.

Regular cannabis use is associated with adverse cognitive and mental health outcomes that have been ascribed to aberrant neuroanatomy in brain regions densely innervated with cannabinoid receptors. Neuroanatomical differences between cannabis users and controls have been assessed in multiple structural magnetic resonance imaging (sMRI) studies. However, there is heterogeneity in the results leading to cautious interpretation of the data so far. We examined the sMRI evidence to date in human cannabis users, to establish more definitely whether neuroanatomical alterations are associated with regular cannabis use. The regional specificity and association with cannabis use indices (i.e. cumulative dosage, duration) were also explored. We systematically reviewed and meta-analysed published sMRI studies investigating regional brain volumes (cortical, subcortical and global) in cannabis users and non-user controls. Three electronic databases were searched (PubMed, Scopus, and PsycINFO). A total of 17 meta-analyses were conducted (one for each cortical, subcortical and global volume) using the generic inverse variance method, whereby standardised mean difference in volume was calculated between users and non-users. Exploratory meta-regressions were conducted to investigate the association between cannabis use indices and regional brain volumes. A total of 30 articles were eligible for inclusion, contributing 106 effect sizes across 17 meta-analyses. Regular cannabis users had significantly smaller volumes of the hippocampus (SMD = 0.14, 95% CIs [0.02, 0.27]; Z = 2.29, p = 0.02, I2 = 74%) and orbitofrontal cortex {medial (SMD = 0.30, 95% CIs [0.15, 0.45]; Z = 3.89, p = 0.0001, I2 = 51%), lateral (SMD = 0.19, 95% CIs [0.07, 0.32]; Z = 3.10, p = 0.002, I2 = 26%)} relative to controls. The volumes of the hippocampus and orbitofrontal cortex were not significantly associated with cannabis duration and dosage. Our findings are consistent with evidence of aberrance in brain region

Cognitive impairment is a major source of disability in schizophrenia and current antipsychotic drugs (APDs) have minimal efficacy for this symptom domain. Cannabidiol (CBD), the major non-intoxicating component of Cannabis sativa L., exhibits antipsychotic and neuroprotective properties. We recently reported the effects of CBD on cognition in male offspring of a maternal immune activation (polyinosinic-polycytidilic acid (poly I:C)) model relevant to the aetiology of schizophrenia; however, the effects of CBD treatment in females are unknown. Sex differences are observed in the onset of schizophrenia symptoms and response to APD treatment. Furthermore, the endogenous cannabinoid system, a direct target of CBD, is sexually dimorphic in humans and rodents. Therefore, the present work aimed to assess the therapeutic impact of CBD treatment on behaviour and neurochemical signalling markers in female poly I:C offspring. Time-mated pregnant Sprague-Dawley rats (n = 16) were administered poly I:C (4 mg/kg; i.v.) or saline (control) on gestational day 15. From postnatal day 56, female offspring received CBD (10 mg/kg, i.p.) or vehicle treatment for approximately 3 weeks. Following 2 weeks of CBD treatment, offspring underwent behavioural testing, including the novel object recognition, rewarded alternation T-maze and social interaction tests to assess recognition memory, working memory and sociability, respectively. After 3 weeks of CBD treatment, the prefrontal cortex (PFC) and hippocampus (HPC) were collected to assess effects on endocannabinoid, glutamatergic and gamma-aminobutyric acid (GABA) signalling markers. CBD attenuated poly I:C-induced deficits in recognition memory, social interaction and glutamatergic N-methyl-D-aspartate receptor (NMDAR) binding in the PFC of poly I:C offspring. Working memory performance was similar between treatment groups. CBD also increased glutamate decarboxylase 67, the rate-limiting enzyme that converts glutamate to GABA, and parvalbu

The mainstay treatment for schizophrenia is antipsychotic drugs (APDs), which are mostly effective against the positive symptoms (e.g. hallucinations), but provide minimal benefits for the negative symptoms (e.g. social withdrawal) and cognitive deficits. We have recently shown that treatment with the non-intoxicating phytocannabinoid, cannabidiol (CBD), can improve cognition and social interaction deficits in a maternal immune activation (MIA) model relevant to the aetiology of schizophrenia, however, the mechanisms underlying this effect are unknown. An imbalance in the main excitatory (glutamate) and inhibitory (GABA) neurotransmitter systems in the brain plays a role in the pathophysiology of schizophrenia. Therefore, the endocannabinoid system could represent a therapeutic target for schizophrenia as a regulator of glutamate and GABA release via the CB1 receptor (CB1R). This study investigated the effects of chronic CBD treatment on markers of glutamatergic, GABAergic and endocannabinoid signalling in brain regions implicated in social behaviour and cognitive function, including the prefrontal cortex (PFC) and hippocampus (HPC). Time-mated pregnant Sprague-Dawley rats (n = 16) were administered poly I:C (4 mg/kg, i.v.) or saline (control) on gestational day 15. Male offspring were injected with CBD (10 mg/kg, i.p.) or vehicle twice daily from postnatal day 56 for 3 weeks. The prefrontal cortex (PFC) and hippocampus (HPC) were collected for post-mortem receptor binding and Western blot analyses (n = 8 per group). CBD treatment attenuated poly I:C-induced deficits in cannabinoid CB1 receptor binding in the PFC and glutamate decarboxylase 67, the enzyme that converts glutamate to GABA, in the HPC. CBD treatment increased parvalbumin levels in the HPC, regardless of whether offspring were exposed to poly I:C in utero. Conversely, CBD did not affect N-methyl-d-aspartate receptor and gamma-aminobutyric acid (GABA) A receptor binding or protein levels of fatty acid am

Background: The US National Institutes of Mental Health Research Domain Criteria (RDoC) seek to stimulate research into biologically validated neuropsychological dimensions across mental illness symptoms and diagnoses. The RDoC framework comprises 39 functional constructs designed to be revised and refined, with the overall goal of improving diagnostic validity and treatments. This study aimed to reach a consensus among experts in the addiction field on the 'primary' RDoC constructs most relevant to substance and behavioural addictions. Methods: Forty-four addiction experts were recruited from Australia, Asia, Europe and the Americas. The Delphi technique was used to determine a consensus as to the degree of importance of each construct in understanding the essential dimensions underpinning addictive behaviours. Expert opinions were canvassed online over three rounds (97% completion rate), with each consecutive round offering feedback for experts to review their opinions. Results: Seven constructs were endorsed by ≥ 80% of experts as 'primary' to the understanding of addictive behaviour: five from the Positive Valence System (reward valuation, expectancy, action selection, reward learning, habit); one from the Cognitive Control System (response selection/inhibition); and one expert-initiated construct (compulsivity). These constructs were rated to be related differentially to stages of the addiction cycle, with some linked more closely to addiction onset and others more to chronicity. Experts agreed that these neuropsychological dimensions apply across a range of addictions. Conclusions: The study offers a novel and neuropsychologically informed theoretical framework, as well as a cogent step forward to test transdiagnostic concepts in addiction research, with direct implications for assessment, diagnosis, staging of disorder, and treatment.

Regular cannabis use is associated with adverse cognitive and mental health outcomes that have been ascribed to aberrant neuroanatomy in brain regions densely innervated with cannabinoid receptors. Neuroanatomical differences between cannabis users and controls have been assessed in multiple structural magnetic resonance imaging (sMRI) studies. However, there is heterogeneity in the results leading to cautious interpretation of the data so far. We examined the sMRI evidence to date in human cannabis users, to establish more definitely whether neuroanatomical alterations are associated with regular cannabis use. The regional specificity and association with cannabis use indices (i.e. cumulative dosage, duration) were also explored. We systematically reviewed and meta-analysed published sMRI studies investigating regional brain volumes (cortical, subcortical and global) in cannabis users and non-user controls. Three electronic databases were searched (PubMed, Scopus, and PsycINFO). A total of 17 meta-analyses were conducted (one for each cortical, subcortical and global volume) using the generic inverse variance method, whereby standardised mean difference in volume was calculated between users and non-users. Exploratory meta-regressions were conducted to investigate the association between cannabis use indices and regional brain volumes. A total of 30 articles were eligible for inclusion, contributing 106 effect sizes across 17 meta-analyses. Regular cannabis users had significantly smaller volumes of the hippocampus (SMD = 0.14, 95% CIs [0.02, 0.27]; Z = 2.29, p = 0.02, I2 = 74%) and orbitofrontal cortex {medial (SMD = 0.30, 95% CIs [0.15, 0.45]; Z = 3.89, p = 0.0001, I2 = 51%), lateral (SMD = 0.19, 95% CIs [0.07, 0.32]; Z = 3.10, p = 0.002, I2 = 26%)} relative to controls. The volumes of the hippocampus and orbitofrontal cortex were not significantly associated with cannabis duration and dosage. Our findings are consistent with evidence of aberrance in brain region

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BACKGROUND: The U.S. National Institutes of Mental Health Research Domain Criteria (RDoC) seek to stimulate research into biologically validated neuropsychological dimensions across mental illness symptoms and diagnoses. The RDoC framework comprises 39 functional constructs designed to be revised and refined, with the overall goal to improve diagnostic validity and treatments. This study aimed to reach a consensus among experts in the addiction field on the 'primary' RDoC constructs most relevant to substance and behavioural addictions. METHODS: Forty-four addiction experts were recruited from Australia, Asia, Europe and the Americas. The Delphi technique was used to determine a consensus as to the degree of importance of each construct in understanding the essential dimensions underpinning addictive behaviours. Expert opinions were canvassed online over three rounds (97% completion rate), with each consecutive round offering feedback for experts to review their opinions. RESULTS: Seven constructs were endorsed by >/=80% of experts as 'primary' to the understanding of addictive behaviour: five from the Positive Valence System (Reward Valuation, Expectancy, Action Selection, Reward Learning, Habit); one from the Cognitive Control System (Response Selection/Inhibition); and one expert-initiated construct (Compulsivity). These constructs were rated to be differentially related to stages of the addiction cycle, with some more closely linked to addiction onset, and others more to chronicity. Experts agreed that these neuropsychological dimensions apply across a range of addictions. CONCLUSIONS: The study offers a novel and neuropsychologically informed theoretical framework, as well as a cogent step forward to test transdiagnostic concepts in addiction research, with direct implications for assessment, diagnosis, staging of disorder, and treatment.

Contains fulltext : 204600.pdf (publisher's version ) (Closed access)

BACKGROUND: The U.S. National Institutes of Mental Health Research Domain Criteria (RDoC) seek to stimulate research into biologically validated neuropsychological dimensions across mental illness symptoms and diagnoses. The RDoC framework comprises 39 functional constructs designed to be revised and refined, with the overall goal to improve diagnostic validity and treatments. This study aimed to reach a consensus among experts in the addiction field on the 'primary' RDoC constructs most relevant to substance and behavioural addictions. METHODS: Forty-four addiction experts were recruited from Australia, Asia, Europe and the Americas. The Delphi technique was used to determine a consensus as to the degree of importance of each construct in understanding the essential dimensions underpinning addictive behaviours. Expert opinions were canvassed online over three rounds (97% completion rate), with each consecutive round offering feedback for experts to review their opinions. RESULTS: Seven constructs were endorsed by >/=80% of experts as 'primary' to the understanding of addictive behaviour: five from the Positive Valence System (Reward Valuation, Expectancy, Action Selection, Reward Learning, Habit); one from the Cognitive Control System (Response Selection/Inhibition); and one expert-initiated construct (Compulsivity). These constructs were rated to be differentially related to stages of the addiction cycle, with some more closely linked to addiction onset, and others more to chronicity. Experts agreed that these neuropsychological dimensions apply across a range of addictions. CONCLUSIONS: The study offers a novel and neuropsychologically informed theoretical framework, as well as a cogent step forward to test transdiagnostic concepts in addiction research, with direct implications for assessment, diagnosis, staging of disorder, and treatment.

ObjectiveAlthough lower brain volume has been routinely observed in individuals with substance dependence compared with nondependent control subjects, the brain regions exhibiting lower volume have not been consistent across studies. In addition, it is not clear whether a common set of regions are involved in substance dependence regardless of the substance used or whether some brain volume effects are substance specific. Resolution of these issues may contribute to the identification of clinically relevant imaging biomarkers. Using pooled data from 14 countries, the authors sought to identify general and substance-specific associations between dependence and regional brain volumes.MethodBrain structure was examined in a mega-analysis of previously published data pooled from 23 laboratories, including 3,240 individuals, 2,140 of whom had substance dependence on one of five substances: alcohol, nicotine, cocaine, methamphetamine, or cannabis. Subcortical volume and cortical thickness in regions defined by FreeSurfer were compared with nondependent control subjects when all sampled substance categories were combined, as well as separately, while controlling for age, sex, imaging site, and total intracranial volume. Because of extensive associations with alcohol dependence, a secondary contrast was also performed for dependence on all substances except alcohol. An optimized split-half strategy was used to assess the reliability of the findings.ResultsLower volume or thickness was observed in many brain regions in individuals with substance dependence. The greatest effects were associated with alcohol use disorder. A set of affected regions related to dependence in general, regardless of the substance, included the insula and the medial orbitofrontal cortex. Furthermore, a support vector machine multivariate classification of regional brain volumes successfully classified individuals with substance dependence on alcohol or nicotine relative to nondependent control subje

Cognitive impairment is a major source of disability in schizophrenia and current antipsychotic drugs (APDs) have minimal efficacy for this symptom domain. Cannabidiol (CBD), the major non-intoxicating component of Cannabis sativa L., exhibits antipsychotic and neuroprotective properties. We recently reported the effects of CBD on cognition in male offspring of a maternal immune activation (polyinosinic-polycytidilic acid (poly I:C)) model relevant to the aetiology of schizophrenia; however, the effects of CBD treatment in females are unknown. Sex differences are observed in the onset of schizophrenia symptoms and response to APD treatment. Furthermore, the endogenous cannabinoid system, a direct target of CBD, is sexually dimorphic in humans and rodents. Therefore, the present work aimed to assess the therapeutic impact of CBD treatment on behaviour and neurochemical signalling markers in female poly I:C offspring. Time-mated pregnant Sprague-Dawley rats (n = 16) were administered poly I:C (4 mg/kg; i.v.) or saline (control) on gestational day 15. From postnatal day 56, female offspring received CBD (10 mg/kg, i.p.) or vehicle treatment for approximately 3 weeks. Following 2 weeks of CBD treatment, offspring underwent behavioural testing, including the novel object recognition, rewarded alternation T-maze and social interaction tests to assess recognition memory, working memory and sociability, respectively. After 3 weeks of CBD treatment, the prefrontal cortex (PFC) and hippocampus (HPC) were collected to assess effects on endocannabinoid, glutamatergic and gamma-aminobutyric acid (GABA) signalling markers. CBD attenuated poly I:C-induced deficits in recognition memory, social interaction and glutamatergic N-methyl-D-aspartate receptor (NMDAR) binding in the PFC of poly I:C offspring. Working memory performance was similar between treatment groups. CBD also increased glutamate decarboxylase 67, the rate-limiting enzyme that converts glutamate to GABA, and parvalbu

Cannabis exerts its psychoactive effect through cannabinoid receptors that are widely distributed across the cortical surface of the human brain. It is suggested that cannabis use may contribute to structural alterations across the cortical surface. In a large, multisite dataset of 120 controls and 141 cannabis users, we examined whether differences in key characteristics of the cortical surface - including cortical thickness, surface area, and gyrification index were related to cannabis use characteristics, including (i) cannabis use vs. non-use, (ii) cannabis dependence vs. non-dependence vs. non-use, and (iii) early adolescent vs. late adolescent onset of cannabis use vs. non-use. Our results revealed that cortical morphology was not associated with cannabis use, dependence, or onset age. The lack of effect of regular cannabis use, including problematic use, on cortical structure in our study is contrary to previous evidence of cortical morphological alterations (particularly in relation to cannabis dependence and cannabis onset age) in cannabis users. Careful reevaluation of the evidence on cannabis-related harm will be necessary to address concerns surrounding the long-term effects of cannabis use and inform policies in a changing cannabis regulation climate.

Cannabis exerts its psychoactive effect through cannabinoid receptors that are widely distributed across the cortical surface of the human brain. It is suggested that cannabis use may contribute to structural alterations across the cortical surface. In a large, multisite dataset of 120 controls and 141 cannabis users, we examined whether differences in key characteristics of the cortical surface - including cortical thickness, surface area, and gyrification index were related to cannabis use characteristics, including (i) cannabis use vs. non-use, (ii) cannabis dependence vs. non-dependence vs. non-use, and (iii) early adolescent vs. late adolescent onset of cannabis use vs. non-use. Our results revealed that cortical morphology was not associated with cannabis use, dependence, or onset age. The lack of effect of regular cannabis use, including problematic use, on cortical structure in our study is contrary to previous evidence of cortical morphological alterations (particularly in relation to cannabis dependence and cannabis onset age) in cannabis users. Careful reevaluation of the evidence on cannabis-related harm will be necessary to address concerns surrounding the long-term effects of cannabis use and inform policies in a changing cannabis regulation climate.

Cannabis exerts its psychoactive effect through cannabinoid receptors that are widely distributed across the cortical surface of the human brain. It is suggested that cannabis use may contribute to structural alterations across the cortical surface. In a large, multisite dataset of 120 controls and 141 cannabis users, we examined whether differences in key characteristics of the cortical surface - including cortical thickness, surface area, and gyrification index were related to cannabis use characteristics, including (i) cannabis use vs. non-use, (ii) cannabis dependence vs. non-dependence vs. non-use, and (iii) early adolescent vs. late adolescent onset of cannabis use vs. non-use. Our results revealed that cortical morphology was not associated with cannabis use, dependence, or onset age. The lack of effect of regular cannabis use, including problematic use, on cortical structure in our study is contrary to previous evidence of cortical morphological alterations (particularly in relation to cannabis dependence and cannabis onset age) in cannabis users. Careful reevaluation of the evidence on cannabis-related harm will be necessary to address concerns surrounding the long-term effects of cannabis use and inform policies in a changing cannabis regulation climate.

Cannabis use is highly prevalent and often considered to be relatively harmless. Nonetheless, a subset of regular cannabis users may develop dependence, experiencing poorer quality of life and greater mental health problems relative to non-dependent users. The neuroanatomy characterizing cannabis use versus dependence is poorly understood. We aimed to delineate the contributing role of cannabis use and dependence on morphology of the hippocampus, one of the most consistently altered brain regions in cannabis users, in a large multi-site dataset aggregated across four research sites. We compared hippocampal volume and vertex-level hippocampal shape differences (1) between 121 non-using controls and 140 cannabis users; (2) between 106 controls, 50 non-dependent users and 70 dependent users; and (3) between a subset of 41 controls, 41 non-dependent users and 41 dependent users, matched on sample characteristics and cannabis use pattern (onset age and dosage). Cannabis users did not differ from controls in hippocampal volume or shape. However, cannabis-dependent users had significantly smaller right and left hippocampi relative to controls and non-dependent users, irrespective of cannabis dosage. Shape analysis indicated localized deflations in the superior-medial body of the hippocampus. Our findings support neuroscientific theories postulating dependence-specific neuroadaptations in cannabis users. Future efforts should uncover the neurobiological risk and liabilities separating dependent and non-dependent use of cannabis.

2019 Society for the Study of Addiction While imaging studies have demonstrated volumetric differences in subcortical structures associated with dependence on various abused substances, findings to date have not been wholly consistent. Moreover, most studies have not compared brain morphology across those dependent on different substances of abuse to identify substance-specific and substance-general dependence effects. By pooling large multinational datasets from 33 imaging sites, this study examined subcortical surface morphology in 1628 nondependent controls and 2277 individuals with dependence on alcohol, nicotine, cocaine, methamphetamine, and/or cannabis. Subcortical structures were defined by FreeSurfer segmentation and converted to a mesh surface to extract two vertex-level metrics-the radial distance (RD) of the structure surface from a medial curve and the log of the Jacobian determinant (JD)-that, respectively, describe local thickness and surface area dilation/contraction. Mega-analyses were performed on measures of RD and JD to test for the main effect of substance dependence, controlling for age, sex, intracranial volume, and imaging site. Widespread differences between dependent users and nondependent controls were found across subcortical structures, driven primarily by users dependent on alcohol. Alcohol dependence was associated with localized lower RD and JD across most structures, with the strongest effects in the hippocampus, thalamus, putamen, and amygdala. Meanwhile, nicotine use was associated with greater RD and JD relative to nonsmokers in multiple regions, with the strongest effects in the bilateral hippocampus and right nucleus accumbens. By demonstrating subcortical morphological differences unique to alcohol and nicotine use, rather than dependence across all substances, results suggest substance-specific relationships with subcortical brain structures.

Cognitive impairment is a major source of disability in schizophrenia and current antipsychotic drugs (APDs) have minimal efficacy for this symptom domain. Cannabidiol (CBD), the major non-intoxicating component of Cannabis sativa L., exhibits antipsychotic and neuroprotective properties. We recently reported the effects of CBD on cognition in male offspring of a maternal immune activation (polyinosinic-polycytidilic acid (poly I:C)) model relevant to the aetiology of schizophrenia; however, the effects of CBD treatment in females are unknown. Sex differences are observed in the onset of schizophrenia symptoms and response to APD treatment. Furthermore, the endogenous cannabinoid system, a direct target of CBD, is sexually dimorphic in humans and rodents. Therefore, the present work aimed to assess the therapeutic impact of CBD treatment on behaviour and neurochemical signalling markers in female poly I:C offspring. Time-mated pregnant Sprague-Dawley rats (n = 16) were administered poly I:C (4 mg/kg; i.v.) or saline (control) on gestational day 15. From postnatal day 56, female offspring received CBD (10 mg/kg, i.p.) or vehicle treatment for approximately 3 weeks. Following 2 weeks of CBD treatment, offspring underwent behavioural testing, including the novel object recognition, rewarded alternation T-maze and social interaction tests to assess recognition memory, working memory and sociability, respectively. After 3 weeks of CBD treatment, the prefrontal cortex (PFC) and hippocampus (HPC) were collected to assess effects on endocannabinoid, glutamatergic and gamma-aminobutyric acid (GABA) signalling markers. CBD attenuated poly I:C-induced deficits in recognition memory, social interaction and glutamatergic N-methyl-D-aspartate receptor (NMDAR) binding in the PFC of poly I:C offspring. Working memory performance was similar between treatment groups. CBD also increased glutamate decarboxylase 67, the rate-limiting enzyme that converts glutamate to GABA, and parvalbu

Background: The US National Institutes of Mental Health Research Domain Criteria (RDoC) seek to stimulate research into biologically validated neuropsychological dimensions across mental illness symptoms and diagnoses. The RDoC framework comprises 39 functional constructs designed to be revised and refined, with the overall goal of improving diagnostic validity and treatments. This study aimed to reach a consensus among experts in the addiction field on the 'primary' RDoC constructs most relevant to substance and behavioural addictions. Methods: Forty-four addiction experts were recruited from Australia, Asia, Europe and the Americas. The Delphi technique was used to determine a consensus as to the degree of importance of each construct in understanding the essential dimensions underpinning addictive behaviours. Expert opinions were canvassed online over three rounds (97% completion rate), with each consecutive round offering feedback for experts to review their opinions. Results: Seven constructs were endorsed by ≥ 80% of experts as 'primary' to the understanding of addictive behaviour: five from the Positive Valence System (reward valuation, expectancy, action selection, reward learning, habit); one from the Cognitive Control System (response selection/inhibition); and one expert-initiated construct (compulsivity). These constructs were rated to be related differentially to stages of the addiction cycle, with some linked more closely to addiction onset and others more to chronicity. Experts agreed that these neuropsychological dimensions apply across a range of addictions. Conclusions: The study offers a novel and neuropsychologically informed theoretical framework, as well as a cogent step forward to test transdiagnostic concepts in addiction research, with direct implications for assessment, diagnosis, staging of disorder, and treatment.

The mainstay treatment for schizophrenia is antipsychotic drugs (APDs), which are mostly effective against the positive symptoms (e.g. hallucinations), but provide minimal benefits for the negative symptoms (e.g. social withdrawal) and cognitive deficits. We have recently shown that treatment with the non-intoxicating phytocannabinoid, cannabidiol (CBD), can improve cognition and social interaction deficits in a maternal immune activation (MIA) model relevant to the aetiology of schizophrenia, however, the mechanisms underlying this effect are unknown. An imbalance in the main excitatory (glutamate) and inhibitory (GABA) neurotransmitter systems in the brain plays a role in the pathophysiology of schizophrenia. Therefore, the endocannabinoid system could represent a therapeutic target for schizophrenia as a regulator of glutamate and GABA release via the CB1 receptor (CB1R). This study investigated the effects of chronic CBD treatment on markers of glutamatergic, GABAergic and endocannabinoid signalling in brain regions implicated in social behaviour and cognitive function, including the prefrontal cortex (PFC) and hippocampus (HPC). Time-mated pregnant Sprague-Dawley rats (n = 16) were administered poly I:C (4 mg/kg, i.v.) or saline (control) on gestational day 15. Male offspring were injected with CBD (10 mg/kg, i.p.) or vehicle twice daily from postnatal day 56 for 3 weeks. The prefrontal cortex (PFC) and hippocampus (HPC) were collected for post-mortem receptor binding and Western blot analyses (n = 8 per group). CBD treatment attenuated poly I:C-induced deficits in cannabinoid CB1 receptor binding in the PFC and glutamate decarboxylase 67, the enzyme that converts glutamate to GABA, in the HPC. CBD treatment increased parvalbumin levels in the HPC, regardless of whether offspring were exposed to poly I:C in utero. Conversely, CBD did not affect N-methyl-d-aspartate receptor and gamma-aminobutyric acid (GABA) A receptor binding or protein levels of fatty acid am