ArticleLiterature Review

Is cannabis neurotoxic for the healthy brain? A meta-analytical review of structural brain alterations in non-psychotic users

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Abstract

Despite growing research in the field of cannabis imaging, mostly in those with a psychotic illness, the possible neurotoxic effects of smoked cannabis on the healthy brain have yet to be fully understood. There appears to be a need to evaluate the existing imaging data on the neuroanatomical effects of cannabis use on non-psychotic populations. We conducted a meta-analytical review to estimate the putative neurotoxic effect of cannabis in non-psychotic subjects who were using or not using cannabis. We specifically tested the hypothesis that cannabis use can alter grey and white matter in non-psychotic subjects. Our systematic literature search uncovered 14 studies meeting the inclusion criteria for the meta-analysis. The overall database comprised 362 users and 365 non-users. At the level of the individual studies there is limited and contrasting evidence supporting a cannabis-related alteration on the white and grey matter structures of non-psychotic cannabis users. However, our meta-analysis showed a consistent smaller hippocampus in users as compared to non-users. Heterogeneity across study designs, image acquisition, small sample sizes and limited availability of regions of interest to be included in the meta-analysis may undermine the core findings of this study. Our results suggest that in the healthy brain, chronic and long-term cannabis exposure may exert significant effects in brain areas enriched with cannabinoid receptors, such as the hippocampus, which could be related to a neurotoxic action.

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... Changes to the structure of brain tissue related to the consumption of a drug have the potential to change cognitive functioning, mood regulation, and overt behaviour. Evidence for such changes exists for many drugs, with examples including cannabis [16,[77][78][79][80], ecstasy (MDMA) [81], and alcohol [82][83][84]. However, a problem exists in the attribution of causality for structural changes to the administration of the drug due to a shortage of prospective studies showing no differences between the brains of drug users and nonusers prior to the start of drug consumption by the users. ...
... This problem is discussed further in relation to cannabis use by Murphy [16], although the issues arising relate to the consumption of other drugs. Structural differences in the brains of cannabis users have been reported in the hippocampus, amygdala, and prefrontal cortex, with these regions of structural difference having a relatively high density of CB1 and CB2 receptors [16,[77][78][79][80], and performance deficits being reported in some verbal memory and some executive functions [16,85]. Ecstasy (MDMA) use has been reported to be related to structural differences in the cerebral cortex (e.g. ...
... Evidence from psychobiological studies, and from studies from other biomedical disciplines, has shown that changes to certain structural features of the brain can arise from the use of some substances such as cannabis, ecstasy (MDMA), and alcohol [77][78][79][80][81][82][83][84]. These changes may be associated with impairments in such things as cognitive functioning and mood regulation compared to nonusers, or in the case of alcohol, comparisons between moderate users and heavy users [16,81,[85][86]. ...
Chapter
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This chapter reflects upon the relationship of psychobiological knowledge concerning substance use behaviours to knowledge coming from the domains of social psychology and clinical psychology practice, with regard to the personal and socially based interpretations which substance users themselves have of these behaviours. Current knowledge regarding psychobiological structures and processes relevant to substance use were briefly reviewed. These included pharmacokinetic processes regulating the bioavailability of a consumed drug, pharmacodynamics processes occurring at neuronal membranes, activity in the neural substrates of reward in response to both drug administration and to social rewards, genetic predispositions to develop substance use behaviours, and the determinants of individual differences in the effects of drugs on psychological functioning. By contrast, social psychological perspectives generally highlighted the role of cognitions associated with these behaviours, with these cognitions providing a medium for the representation of meaning associated with substance use. Clinical psychological literature was then briefly reviewed concerning the specific meaning of ‘self-medication’ which may sometimes be attached to substance use. It was concluded that psychobiological approaches to substance use provided knowledge at a different level of explanation to perspectives focussing upon the meaning of such behaviours, but that no particular level of explanation was inherently superior or more adequate than another. The important consideration was that levels of explanation needed to be appropriate for the specific questions to which answers were being sought. Keywords: Substance Use Behaviours, Psychobiology, Social Psychology, Self-Medication Hypothesis, Levels of Explanation.
... The frequency of cannabis use usually peaks in early adulthood (Copeland et al., 2013), a period of extensive neuroanatomical remodeling (Østby et al., 2009;Raznahan et al., 2014), particularly in some brain regions with high levels of the cannabinoid receptors through which cannabinoid compounds act (Jacobus and Tapert, 2014). Tetrahydrocannabinol (THC) is the main psychoactive cannabinoid compound, and the connentration is increasing (Fedotov, 2016), and it may be neurotoxic (Rocchetti et al., 2013). Young adults with high levels of cannabis exposure may be particularly sensitive to the potential neurotoxic effects of cannabis (Jacobus and Tapert, 2014). ...
... One effect of cannabinoid exposure on the brain that has been repeatedly documented is a smaller hippocampal volume (Rocchetti et al., 2013). One study based on a larger sample (N=111) reported that the differences in the volume of the hippocampus in cannabis users did not appear among previous users, suggesting that alterations in the hippocampal volume due to cannabis use might be reversed over time (Yucel et al., 2016). ...
... The subregions of the hippocampus play different roles in the memory system; for example, the dentate gyrus and third section of the cornu ammonis (CA3) are involved in memory encoding (Acsady and Kali, 2007) and early retrieval, while the first section of the cornu ammonis (CA1) has been linked to episodic memory (La et al., 2019), memory consolidation and recognition (Hunsaker and Kesner, 2008;Kesner and Hunsaker, 2010;Kesner and Rolls, 2015;Nakazawa et al., 2004;O'Reilly and Rudy, 2001). Although one effect of cannabinoid exposure on the brain that has been repeatedly documented is a smaller hippocampal volume among cannabis users (Rocchetti et al., 2013), researchers have not clearly whether this decrease in volume is driven by the changes in specific hippocampal subregions (Van Leemput et al., 2009). This difference is important because the different hippocampal subregions have unique functions in the learning and memory system (Gabrieli et al., 1997), as well as in the regulation of emotional behavior and hypothalamic function (Narr et al., 2004). ...
Article
Cannabis exposure is related to neuroanatomical changes in brain regions rich in cannabinoid receptors, such as the hippocampus. However, researchers have not clearly determined whether persistent heavy cannabis use leads to morphological changes in the hippocampus or whether an earlier age of onset of first cannabis use and/or higher doses of cannabis exposure exacerbate these alterations. In this longitudinal study, we investigated whether continued heavy cannabis use in young adults is associated with an altered hippocampal volume. Twenty heavy cannabis users (CBs) and 22 healthy controls (HCs) underwent a comprehensive psychological assessment and a T1 structural scan at baseline and at a 3-year follow-up visit. Volumes of the hippocampus and its subregions were estimated using volBrain software. Except for the cornu ammonis 2 (CA2)/CA3 subregions, age had significant effects on all hippocampal subregions in both the CB and HC groups. The relative right hippocampal volume and absolute and relative right CA1 volumes displayed a greater rate of decrease in CBs compared to HCs. In addition, we explored the relationship between alterations in hippocampal volume and cannabis use characteristics. Changes in the relative right hippocampal volume and the relative right CA1 volume were related to age at first cannabis use but not to age at onset of frequent cannabis use. Alterations in the relative right hippocampal volume and absolute and relative right CA1 volumes were associated with Cannabis Use Disorder Identification Test (CUDIT) scores. Based on these results, heavy cannabis use in early adulthood is a risk factor for a greater rate of decrease in the volume of the right hippocampus (particularly the right CA1).
... Most (n = 13) examined neuroimaging primary studies, including structural, functional and volumetric magnetic resonance imaging; 18 18 and computed tomography. 18 In otherwise healthy users, changes were observed in amygdala, 44,48,52 hippocampal, 44,48,52 and white and grey matter volume 44,48,56 and blood flow, 48,49,54,56 but there were no changes to whole brain volume, 41,52 intracranial volume 52 or the corpus callosum. 41 Changes in learning, 49 attention, 48,54 memory 48,49,54 and overall activity 18 were observed. ...
... Most (n = 13) examined neuroimaging primary studies, including structural, functional and volumetric magnetic resonance imaging; 18 18 and computed tomography. 18 In otherwise healthy users, changes were observed in amygdala, 44,48,52 hippocampal, 44,48,52 and white and grey matter volume 44,48,56 and blood flow, 48,49,54,56 but there were no changes to whole brain volume, 41,52 intracranial volume 52 or the corpus callosum. 41 Changes in learning, 49 attention, 48,54 memory 48,49,54 and overall activity 18 were observed. ...
Article
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Background: With impending marijuana legislation in Canada, a broad understanding of the harms associated with marijuana use is needed to inform the clinical community and public, and to support evidence-informed public policy development. The purpose of the review was to synthesize the evidence on adverse health effects and harms of marijuana use. Methods: We searched MEDLINE, The Cochrane Database of Systematic Reviews, Embase, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature, and the Health Technology Assessment Database from the inception of each database to May 2018. Given that systematic reviews evaluating one or other specific harm have been published, this is an overview review with the primary objective of assessing a health effect or harm. Data on author, country and year of publication, search strategy and results, and outcomes were extracted. Quality was assessed using the AMSTAR (A Measurement Tool to Assess Systematic Reviews) checklist. Results: The final analysis included 68 reviews. Evidence of harm was reported in 62 reviews for several mental health disorders, brain changes, cognitive outcomes, pregnancy outcomes and testicular cancer. Inconclusive evidence was found for 20 outcomes (some mental health outcomes, other types of cancers and all-cause mortality). No evidence of harm was reported for 6 outcomes. Interpretation: Harm was associated with most outcomes assessed. These results should be viewed with concern by physicians and policy-makers given the prevalence of use, the persistent reporting of a lack of recognition of marijuana as a possibly harmful substance and the emerging context of legalization for recreational use.
... Along with this, cannabis users have shown volume reductions in the medial temporal cortex, particularly in the parahippocampal gyrus and temporal pole [14], as well as decreased cortical thickness in the orbital frontal cortex [14][15][16][17], frontal gyrus [17], and prefrontal cortex [18]. Other evidence suggests that structural alterations are not robust in the hippocampus [17,[19][20][21], the orbitofrontal cortex [13,22,23], frontal gyrus [23], or prefrontal regions [17], or for overall grey matter volumes [19,[24][25][26][27][28], even following meta-analysis [29]. Therefore, proposed cognitive deficits in cannabis users may be better explained by alterations in the functioning of relevant brain regions. ...
... The detrimental effects of cannabis may be due to CB1-receptor-mediated disruption of hippocampal plasticity, a finding supported by animal histological investigations. Although there is a lack of evidence of significant effects on hippocampal activation from human studies, changes in hippocampal cerebral blood flow and ERPs [90,93] as well as structural differences [29] have been observed in CU compared to NU. Functional activation in other brain regions that express a high density of CB1 receptors were also found to be altered during memory processing tasks in cannabis users, possibly due to disruption of the normal functioning of the endocannabinoid system as suggested by overlap between brain regions with high CB1 receptor distribution [31] regions showing altered functioning in cannabis users (regions highlighted in [35]). ...
Article
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Cannabis has been associated with deficits in memory performance. However, the neural correlates that may underpin impairments remain unclear. We carried out a systematic review of functional magnetic resonance imaging (fMRI) studies investigating brain functional alterations in cannabis users (CU) compared to nonusing controls while performing memory tasks, complemented with focused narrative reviews of relevant preclinical and human studies. Twelve studies employing fMRI were identified finding functional brain activation during memory tasks altered in CU. Memory performance studies showed CU performed worse particularly during verbal memory tasks. Longitudinal studies suggest that cannabis use may have a causal role in memory deficits. Preclinical studies have not provided conclusive evidence of memory deficits following cannabinoid exposure, although they have shown evidence of cannabinoid-induced structural and histological alteration. Memory performance deficits may be related to cannabis use, with lower performance possibly underpinned by altered functional activation. Memory impairments may be associated with the level of cannabis exposure and use of cannabis during developmentally sensitive periods, with possible improvement following cessation of cannabis use.
... Case-control studies of adult cannabis users and comparison individuals have shown evidence of neuroanatomical differences, particularly in brain regions enriched with cannabinoid receptors, such as the hippocampus (Ashtari et al., 2011;Lorenzetti et al., 2015;Schacht et al., 2012;Yücel et al., 2008), amygdala (Lorenzetti et al., 2015;Schacht et al., 2012;Yücel et al., 2008), striatum (Pagliaccio et al., 2015), and prefrontal cortex (Battistella et al., 2014;Filbey et al., 2014). The most consistent finding is that cannabis users have lower hippocampal volume (Batalla et al., 2013;Brumback et al., 2016;Lorenzetti et al., 2014;Lorenzetti et al., 2016;Rocchetti et al., 2013). Some of these studies examined associations between retrospectivelyreported age-of-onset of cannabis use and adult brain structure (e.g., (Ashtari et al., 2011;Battistella et al., 2014;Cousijn et al., 2012;Filbey et al., 2015;Gilman et al., 2014;Matochik et al., 2005;Pagliaccio et al., 2015;Wilson et al., 2000). ...
... Third, neuroimaging data were collected only once in adulthood. Thus, it is unclear if cannabis-related structural brain differences were apparent in adolescence or early adulthood, as some (Batalla et al., 2013;Brumback et al., 2016;Churchwell et al., 2010;Gilman et al., 2014;Lopez-Larson et al., 2011), but not all (Rocchetti et al., 2013;Weiland et al., 2015), studies have found. ...
Article
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Background: Few studies have tested the hypothesis that adolescent cannabis users show structural brain alterations in adulthood. The present study tested associations between prospectively-assessed trajectories of adolescent cannabis use and adult brain structure in a sample of boys followed to adulthood. Methods: Data came from the Pittsburgh Youth Study - a longitudinal study of ˜1000 boys. Boys completed self-reports of cannabis use annually from age 13-19, and latent class growth analysis was used to identify different trajectories of adolescent cannabis use. Once adolescent cannabis trajectories were identified, boys were classified into their most likely cannabis trajectory. A subset of boys (n = 181) subsequently underwent structural neuroimaging in adulthood, when they were between 30-36 years old on average. For this subset, we grouped participants according to their classified adolescent cannabis trajectory and tested whether these groups showed differences in adult brain structure in 14 a priori regions of interest, including six subcortical (volume only: amygdala, hippocampus, nucleus accumbens, caudate, putamen, and pallidum) and eight cortical regions (volume and thickness: superior frontal gyrus; caudal and rostral middle frontal gyrus; inferior frontal gyrus, separated into pars opercularis, pars triangularis, and pars orbitalis; lateral and medial orbitofrontal gyrus). Results: We identified four adolescent cannabis trajectories: non-users/infrequent users, desisters, escalators, and chronic-relatively frequent users. Boys in different trajectory subgroups did not differ on adult brain structure in any subcortical or cortical region of interest. Conclusions: Adolescent cannabis use is not associated with structural brain differences in adulthood.
... Even in studies that did not find significant reductions in users compared to non-users, there was evidence of a negative correlation between cannabis exposure and dependence severity with hippocampal volume (Chye et al., 2018;Cousijn et al., 2012). Since the lack of regional effects may be influenced by lateralisation, a metaanalysis found that when the left and right hippocampi are combined there was evidence of hippocampal reduction (Rocchetti et al., 2013). However, a longitudinal study of hippocampal volume in heavy cannabis users (mean age 21 years) compared to non-users (Koenders et al., 2016;Koenders et al., 2017) did not find cannabis-induced effects at baseline or 39-month follow-up using voxel-based and manual tracing approaches. ...
... Recent work has shown that CB 1 Rs are involved in midbrain threat processing (Back & Carobrez, 2018) and further work is needed to understand the potential involvement of these pathways in the pathophysiology of psychosis. Structurally, changes associated with early onset heavy use include hippocampal (Rocchetti et al., 2013) and amygdalar atrophy (Lorenzetti et al., 2015) alongside aberrant selfprocessing and executive network connectivity (Cheng et al., 2014;Filbey & Dunlop, 2014;Lopez-Larson et al., 2015;Orr et al., 2016), which map conceptually onto schizophreniform symptomatology. At the molecular level, heavy cannabis use is associated with perturbations of the endocannabinoid system (D'Souza et al., 2016). ...
Article
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The laws governing cannabis are evolving worldwide and associated with changing patterns of use. The main psychoactive drug in cannabis is Δ9-tetrahydrocannabinol (THC), a partial agonist at the endocannabinoid CB1 receptor. Acutely, cannabis and THC produce a range of effects on several neurocognitive and pharmacological systems. These include effects on executive, emotional, reward and memory processing via direct interactions with the endocannabinoid system and indirect effects on the glutamatergic, GABAergic and dopaminergic systems. Cannabidiol, a non-intoxicating cannabinoid found in some forms of cannabis, may offset some of these acute effects. Heavy repeated cannabis use, particularly during adolescence, has been associated with adverse effects on these systems, which increase the risk of mental illnesses including addiction and psychosis. Here, we provide a comprehensive state of the art review on the acute and chronic neuropsychopharmacology of cannabis by synthesizing the available neuroimaging research in humans. We describe the effects of drug exposure during development, implications for understanding psychosis and cannabis use disorder, and methodological considerations. Greater understanding of the precise mechanisms underlying the effects of cannabis may also give rise to new treatment targets.
... The effects of cannabis use should also conform to a vulnerability hypothesis, particularly with respect to inhibitory function (1), but additional cognitive consequences of adolescent cannabis use are hypothesized on measures of memory function and general IQ, such as perceptual reasoning (7,18). Considering results from animal studies showing that chronic administration of THC causes dosedependent neurotoxic changes in brain regions that are rich in cannabinoid receptors, such as the hippocampus, amygdala, septum, and cortex (17), and that abnormalities in hippocampal and temporal structures seem particularly linked to human cannabis use (16), we hypothesized that additional visual-spatial memory deficits will be consequential to cannabis use in adolescence, where both neuroplasticity and neurotoxicity models are considered, as the literature relating to the degree to which these effects last beyond the consumption period in humans remains inconclusive. A fourth model will also be tested-the developmental sensitivity model, informed by current neurodevelopmental theories (19) suggesting that cognitive functions linked to the prefrontal cortex (executive cognitive functions such as working memory, response inhibition, and perceptual reasoning) should show age-dependent effects, with earlier onset of substance use being linked to greater impairment. ...
... Three within-subject effects reflect processes that are consequential to substance use. The neurotoxicity hypothesis suggests that past substance use causes impairment in cognitive function in some lasting way, regardless of whether the substance use continues (blue arrows) (16). The neuroplasticity hypothesis suggests that consumption is associated with impaired cognitive performance, but only in the short term, and that through mechanisms of neuroplasticity, abstinence, or reduction in consumption, the cognitive impairment subsides (hashed lines). ...
Article
Objective:: Alcohol and cannabis misuse are related to impaired cognition. When inferring causality, four nonexclusive theoretical models can account for this association: 1) a common underlying vulnerability model; 2) a neuroplasticity model in which impairment is concurrent with changes in substance use but temporary because of neuroplastic brain processes that restore function; 3) a neurotoxicity model of long-term impairment consequential to substance use; and 4) a developmental sensitivity hypothesis of age-specific effects. Using a developmentally sensitive design, the authors investigated relationships between year-to-year changes in substance use and cognitive development. Method:: A population-based sample of 3,826 seventh-grade students from 31 schools consisting of 5% of all students entering high school in 2012 and 2013 in the Greater Montreal region were assessed annually for 4 years on alcohol and cannabis use, recall memory, perceptual reasoning, inhibition, and working memory, using school-based computerized assessments. Multilevel regression models, performed separately for each substance, were used to simultaneously test vulnerability (between-subject) and concurrent and lagged within-subject effects on each cognitive domain. Results:: Common vulnerability effects were detected for cannabis and alcohol on all domains. Cannabis use, but not alcohol consumption, showed lagged (neurotoxic) effects on inhibitory control and working memory and concurrent effects on delayed memory recall and perceptual reasoning (with some evidence of developmental sensitivity). Cannabis effects were independent of any alcohol effects. Conclusions:: Beyond the role of cognition in vulnerability to substance use, the concurrent and lasting effects of adolescent cannabis use can be observed on important cognitive functions and appear to be more pronounced than those observed for alcohol.
... A well-established modulator of THC is Cannabidiol (CBD) -a non-psychoactive constituent of cannabis that is often considered to account for some effects of cannabis. Evidence suggests that CBD administration in healthy adults lowers anxiety (Zuardi, Cosme, Graeff et al., 1993) and attenuates emotional processing (Fusar-Poli et al., 2009), as well as having an antagonistic effect to THC (Bhattacharyya et al., 2010;Rocchetti et al., 2013). However, other studies failed to replicate such results (Arndt & Wit, 2017;Haney et al., 2016). ...
... Systematic reviews are inconsistent in finding an association between CCU and gray matter volume changes in the amygdala. Some studies found that intense cannabis use is associated with reduced amygdala volume (Yücel et al., 2008;Cousijn et al., 2012;Pagliaccio et al., 2015), whereas others failed to replicate this result (Ashtari et al., 2011;Orr, Paschall & Banich, 2016;Rocchetti et al., 2013). ...
Thesis
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Blunted emotion is a side effect of cannabis use reported by chronic users. Past studies have established a link between chronic cannabis use and deficits in emotional face processing. However, changes in neurofunction underlying such deficits remain unknown. We selected 64 cannabis users who reported severe life problems from cannabis use (abuser), 64 cannabis users who did not report cannabis-related problems (user), and 64 non-users from the Human Connectome Project (HCP). The 3 groups of participants were matched on age, gender, and educational attainment. We examined the functional MRI data of an emotional processing task which required participants to match one of two faces to a presented target face that displayed either anger or fear. Results indicated that cannabis users exhibited increased activation in the inferior frontal cortex, the left amygdala, and the left putamen. Cannabis abusers exhibited increased activation in the middle cingulate cortex, the orbitofrontal cortex, the piriform cortex, the putamen, and the thalamus. These results suggest that the brain is more active during emotional processing in chronic cannabis users.
... The absence of significant variations that survived FDR correction in CUD participants is interesting given the debate on the potential neurotoxic impact of cannabis dependence on the hippocampus and the medial orbitofrontal cortex (Lorenzetti et al., 2019b;Rocchetti et al., 2013). This could be partly explained by the substantial heterogeneity observed within the included studies (Supporting Information - Figure 5). ...
Article
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Alcohol use disorder (AUD) and cannabis use disorder (CUD) are associated with brain alterations particularly involving fronto-cerebellar and meso-cortico-limbic circuitry. However, such abnormalities have additionally been reported in other psychiatric conditions , and until recently there has been few large-scale investigations to compare such findings. The current study uses the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium method of standardising structural brain measures to quantify case–control differences and to compare brain-correlates of substance use disorders with those published in relation to other psychiatric disorders. Using the ENIGMA protocols, we report effect sizes derived from a meta-analysis of alcohol (seven studies, N = 798, 54% are cases) and cannabis (seven studies, N = 447, 45% are cases) dependent cases and age- and sex-matched controls. We conduct linear analyses using harmonised methods to process and parcellate brain data identical to those reported in the literature for ENIGMA case–control studies of major depression disorder (MDD), schizophrenia (SCZ) and bipolar disorder so that effect sizes are optimally comparable across disorders. R elationships between substance use disorder diagnosis and subcortical grey matter volumes and cortical thickness were assessed with intracranial volume, age and sex as co-variates . After correcting for multiple comparisons, AUD case–control meta-analysis of subcortical regions indicated significant differences in the thalamus, hippocampus, amygdala and accumbens, with effect sizes (0.23) generally equivalent to, or larger than |0.23| those previously reported for other psychiatric disorders (except for the pallidum and putamen). On measures of cortical thickness, AUD was associated with significant differences bilaterally in the fusiform gyrus, inferior temporal gyrus, temporal pole, superior frontal gyrus, and rostral and caudal anterior cingulate gyri. Meta-analysis of CUD case–control studies indicated reliable reductions in amygdala, accumbens and hippocampus volumes, with the former effect size comparable to, and the latter effect size around half of that reported for alcohol and SCZ. CUD was associated with lower cortical thickness in the frontal regions, particularly the medial orbitofrontal region, but this effect was not significant after correcting for multiple testing. This study allowed for an unbiased cross-disorder comparison of brain correlates of substance use disorders and showed alcohol-related brain anomalies equivalent in effect size to that found in SCZ in several subcortical and cortical regions and significantly greater alterations than those found in MDD in several subcortical and cortical regions. Although modest, CUD results overlapped with findings reported for AUD and other psychiatric conditions, but appear to be most robustly related to reduce thickness of the medial orbitofrontal cortex.
... Les troubles cognitifs sont corrélés à des anomalies cérébrales chez les consommateurs réguliers de grandes quantités de cannabis durant des périodes prolongées (consommation quotidienne pendant au moins 19 ans en moyenne), mais pas chez les consommateurs occasionnels. Les études d'imagerie cérébrale ont retrouvé chez ces sujets une diminution dose-dépendante de la densité de substance grise au niveau de l'hippocampe, des régions parahippocampiques et de l'amygdale par rapport aux sujets témoins [8,18]. Ces anomalies sont d'autant plus marquées (par exemple perte de substance grise de 12 % au niveau de l'hippocampe, 7 % au niveau de l'amygdale dans l'étude de Yücel et al. [19], que l'âge de début de la consommation de cannabis était précoce et les quantités fumées importantes. ...
... Accompanying its legalization, the prevalence of cannabis use has risen by 15% in Canada [66] and 25% in the United States [67]. Long-term cannabis use is a risk factor for the development of schizophrenia [68] and neurocognitive impairments [69], and leads to structural changes such as increased cortical thickness [70][71][72] and cerebellar volume [73,74], and reduced hippocampal [75][76][77] and prefrontal cortex volume [77]. As such, it is essential to further our understanding of the impact that cannabis has on TMS measures. ...
Article
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1) Background: Transcranial magnetic stimulation (TMS) approaches are widely used to study cortical and corticospinal function. However, responses to TMS are subject to significant intra-and inter-individual variability. Acute and chronic exposure to recreational substances alters the excitability of the sensorimotor system and may contribute to the variability in TMS outcome measures. The increasing prevalence of recreational substance use poses a significant challenge for executing TMS studies, but there is a lack of clarity regarding the influence of these substances on sensorimotor function. (2) Methods: The literature investigating the influence of alcohol, nicotine, caffeine and cannabis on TMS outcome measures of corticospinal, intracortical and interhemispheric excitability was reviewed. (3) Results: Both acute and chronic use of recreational substances modulates TMS measures of excitability. Despite the abundance of research in this field, we identify knowledge gaps that should be addressed in future studies to better understand the influence of these substances on TMS outcomes. (4) Conclusions: This review highlights the need for TMS studies to take into consideration the history of participant substance use and to control for acute substance use prior to testing.
... These include both the gray matter (neuronal cells) and white matter (nerve axons responsible for communication). 34,35 Structural changes to the brain include reductions in the hippocampus [34][35][36][37][38] (12.1% in the left and 11.9% in the right, relative to controls) 38 and amygdala 37,38 (6.0% in the left and 8.2% in the right, relative to controls) 38 ...
Article
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Cannabis legalization has led to significant health consequences, particularly to patients in emergency departments and hospitals in Colorado. The most concerning include psychosis, suicide, and other substance abuse. Deleterious effects on the brain include decrements in complex decision-making, which may not be reversible with abstinence. Increases in fatal motor vehicle collisions, adverse effects on cardiovascular and pulmonary systems, inadvertent pediatric exposures, cannabis contaminants exposing users to infectious agents, heavy metals, and pesticides, and hash-oil burn injuries in preparation of drug concentrates have been documented. Cannabis dispensary workers ("budtenders") without medical training are giving medical advice that may be harmful to patients. Cannabis research may offer novel treatment of seizures, spasticity from multiple sclerosis, nausea and vomiting from chemotherapy, chronic pain, improvements in cardiovascular outcomes, and sleep disorders. Progress has been slow due to absent standards for chemical composition of cannabis products and limitations on research imposed by federal classification of cannabis as illegal. Given these factors and the Colorado experience, other states should carefully evaluate whether and how to decriminalize or legalize non-medical cannabis use.
... Non-remitting symptoms will inevitably affect the perceived efficacy of antipsychotic medication concordant with negative attitudes towards medication being an often-cited reason for non-adherence (Velligan et al., 2017). Prolonged cannabis use is additionally associated with neuroanatomical changes in several major areas associated with memory function (Batalla et al., 2013;Lorenzetti et al., 2016;Rigucci et al., 2016;Rocchetti et al., 2013). Interestingly, effects such as those on prospective memory may interfere with an individual's ability to regularly adhere to prescribed medications. ...
... Larger orbitofrontal volume also predated cannabis use and predicted regular cannabis use by age 22 years. Two meta-regressions of these studies ( Lorenzetti et al., 2019 ;Rocchetti et al., 2013 ) failed to find significant associations between the volumes of selected brain areas (i.e. hippocampus, whole brain size) and duration of cannabis use. ...
Article
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We review the findings of systematic reviews and meta-analyses of case-control studies that examine brain functioning and cognitive correlates of adolescent cannabis use using structural and functional neuroimaging tools and standardised neuropsychological tests. We also examine prospective epidemiological studies on the possible effects of adolescent and young adult cannabis use on cognitive performance in adult life and the completion of secondary education. We summarize the findings of studies in each of these areas that have been published since the most recent systematic review. Systematic reviews find that adolescent cannabis use is inconsistently associated with alterations in the structure of prefrontal and temporal brain regions. Meta-analyses reveal functional alterations in the parietal cortex and putamen. Differences in the orbitofrontal cortex predate cannabis use; it is unclear if they are affected by continued cannabis use and prolonged abstinence. Longitudinal and twin studies report larger declines in IQ among cannabis users than their non-using peers but it is unclear whether these findings can be attributed to cannabis use or to genetic, mental health and environmental factors. Several longitudinal studies and a meta-analysis of cross-sectional studies suggest that there is some cognitive recovery after abstinence from cannabis. Longitudinal studies and some twin studies have found that cannabis users are less likely to complete secondary school than their non-using controls. This association might reflect an effect of cannabis use and/or the social environment of cannabis users and their cannabis using peers. Cognitive performance is altered in some domains (e.g. IQ, verbal learning) in young people while they are regularly using cannabis. There are two important messages to adolescents and young adults: First, cannabis has potentially detrimental effects on cognition, brain and educational outcomes that persist beyond acute intoxication. Second, impaired cognitive function in cannabis users appears to improve with sustained abstinence.
... Some studies have shown atrophy in medial temporal regions rich in cannabinoid receptors, like the hippocampus and amygdala [7] , while others have shown a lack of any morphometric changes [8][9][10] between cannabis users and controls. The conflicting results, in part, may be due to smaller sample sizes and a range of different imaging techniques utilized [11] [12] . There is also, the possibility that cannabis use is often accompanied by simultaneous use of other substances like tobacco, alcohol and other narcotics. ...
Article
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The psychoactive effects of cannabis, one of the most commonly used narcotics, have been documented extensively. Despite multiple studies being undertaken, there have been only a few longitudinal studies investigating the effect of long term usage of cannabis on various subcortical structures. This study aims at looking deeper into the effects of long term usage of cannabis on different hippocampus subfields.¹ Participants were split into two groups, cannabis users and healthy controls. All the test subjects filled out the Cannabis Usage and Disorder Identification Test (CUDIT) and underwent T1-structural MRI scans twice, at a baseline and a followup 3 years later. The subfield volumes were measured using the software package Freesurfer with the LongitudinalHippocampalSubfields (v6.0) Module. Lifetime usage in grams was calculated for each participant until baseline and followup, independently, using linear interpolation. Usage of cannabis (lifetime consumption score) was correlated to increased volumes in certain subfields: the CA3 and CA4 in the right hemisphere and the presubiculum in both, the left and right hemispheres at baseline. Other tests including student's t-test and multivariate analysis of covariance were performed. Tests to understand the effects of varying consumption were also performed. Persistent usage of cannabis, however, did not result in atrophy of the subfields over time. Rather, there were lower growth rates observed in the healthy controls group as compared to that of the cannabis users in certain subfields.
... Repeated and regular exogenous cannabis exposure can affect CB1 binding [10] and downregulation [11], as well as effects on the brain structure and function (e.g., white matter integrity, functional connectivity, and cerebral blood flow) [12]. Frequent cannabis use, especially high-potency THC products, is associated with structural alterations in medial-temporal, frontal, limbic, and cerebellar regions [7,8,13], however, the extant literature regarding definitive effects on brain structure have garnered mixed findings [14]. Specific investigations into volumetric indices (i.e., cortical thickness and volume) has shown differences between cannabis users and non-users in several areas, including, the hippocampus [15,16], prefrontal cortex [17], right amygdala [18,19], right fusiform [20], orbitofrontal cortex [21,22], inferior parietal cortex [21], anterior cingulate [23,24], precentral gyrus [23,25], superior frontal gyrus [23], right thalamus [25], and cerebellum [26]; see review [27]. ...
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Cannabis use in adolescents and young adults is linked with aberrant brain structure, although findings to date are inconsistent. We examined whether aerobic fitness moderated the effects of cannabis on cortical surface structure and whether gender may play a moderating role. Seventy-four adolescents and young adults completed three-weeks of monitored abstinence, aerobic fitness testing, and structural magnetic resonance imaging (sMRI). Whole-sample linear regressions examined the effects of gender, VO 2 max, cannabis use, and their interactions on the surface area (SA) and local gyrification index (LGI). Cannabis use was associated with greater cuneus SA. Gender-by-cannabis predicted precuneus and frontal SA, and precentral, supramarginal, and frontal LGI; female cannabis users demonstrated greater LGI, whereas male cannabis users demonstrated decreased LGI compared to non-users. Aerobic fitness was positively associated with various SA and LGI regions. Cannabis-by-aerobic fitness predicted cuneus SA and occipital LGI. These findings demonstrate that aerobic fitness moderates the impact of cannabis on cortical surface structure, and gender differences are evident. These moderating factors may help explain inconsistencies in the literature and warrant further investigation. Present findings and aerobic fitness literature jointly suggest aerobic intervention may be a low-cost avenue for improving cortical surface structure, although the impact may be gender-specific.
... These compound alterations are important as preclinical evidence suggests neurotoxic effects of THC on CB1 rich areas [45]. In humans, volumetric reductions and gray matter density alterations are consistently noted in the hippocampus, which relate to duration of use and cannabis dosage [45,47,48]. There are also links with compound composition; THC levels are inversely related to volumetric reductions while higher THC/cannabidiol ratios are associated with reduced volume and gray matter [45]. ...
... Initial findings on brain morphometry mostly report a decreased hippocampal and amygdala volume Murray et al., 2017;Rocchetti et al., 2013), but these have largely been superseded by recent large-scale studies that did not identify cannabis effects on cortical thickness or subcortical volumes Gillespie et al., 2018;Meier, Schriber, Beardslee, Hanson, & Pardini, 2019;J. M. Orr, Paschall, & Banich, 2016;Thayer et al., 2017). ...
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Although previous studies have highlighted associations of cannabis use with cognition and brain morphometry, critical questions remain with regard to the association between cannabis use and brain structural and functional connectivity. In a cross‐sectional community sample of 205 African Americans (age 18–70) we tested for associations of cannabis use disorder (CUD, n = 57) with multi‐domain cognitive measures and structural, diffusion, and resting state brain‐imaging phenotypes. Post hoc model evidence was computed with Bayes factors (BF) and posterior probabilities of association (PPA) to account for multiple testing. General cognitive functioning, verbal intelligence, verbal memory, working memory, and motor speed were lower in the CUD group compared with non‐users (p < .011; 1.9 < BF < 3,217). CUD was associated with altered functional connectivity in a network comprising the motor‐hand region in the superior parietal gyri and the anterior insula (p < .04). These differences were not explained by alcohol, other drug use, or education. No associations with CUD were observed in cortical thickness, cortical surface area, subcortical or cerebellar volumes (0.12 < BF < 1.5), or graph‐theoretical metrics of resting state connectivity (PPA < 0.01). In a large sample collected irrespective of cannabis used to minimize recruitment bias, we confirm the literature on poorer cognitive functioning in CUD, and an absence of volumetric brain differences between CUD and non‐CUD. We did not find evidence for or against a disruption of structural connectivity, whereas we did find localized resting state functional dysconnectivity in CUD. There was sufficient proof, however, that organization of functional connectivity as determined via graph metrics does not differ between CUD and non‐user group.
... To our knowledge, only one previous meta-analysis and meta-regression of sMRI studies in cannabis users versus controls exists [72]. This work focused on whole brain, intracerebroventricular, hippocampal, and amygdala volumes as regions of interest (ROIs), finding significant reduction in hippocampal and amygdala volumes in cannabis users. ...
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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 regions involved in reward, learning and memory, and motivation circuits in the regular use of substances other than cannabis, pointing to commonality in neurobiological abnormalities between regular users of cannabis and of other substances.
... A recent study has found that even minimal incidental use of cannabis in adolescence is associated with morphological brain volume changes (Orr et al., 2019). A meta-analysis of cross-sectional MRI studies found replicated evidence of reduced grey matter in the CB1R rich areas of the hippocampus and the amygdala associated with cannabis use (Rocchetti et al., 2013). ...
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Previous systematic reviews and meta-analyses of cross-sectional data assessing the effect of cannabis on cognitive functioning and intelligence show inconsistent results. We hypothesized that frequent and dependent cannabis use in youth would be associated with Intelligence Quotient (IQ) decline. This study is a systematic review and meta-analysis. We searched Embase, PubMed and PsychInfo from inception to 24 January 2020. We included studies with non-treatment seeking samples and pre- and post-exposure measures of IQ. We requested data from authors if summary data was not available from published work. We preregistered our review with PROSPERO (ID no. CRD42019125624). We found seven cohort studies including 808 cases and 5308 controls. We found a significant effect for the association between frequent or dependent cannabis use in youth and IQ change, Cohen's d = −0.132 (95% CI −0.198 to −0.066) p < 0.001. Statistical heterogeneity between studies was also low at I ² = 0.2%. Study quality was moderate to high. This translates to an average decline of approximately 2 IQ points following exposure to cannabis in youth. Future studies should have longer periods of follow up to assess the magnitude of developmental impact.
... *NPS -neuro-psychiatric symptoms While some evidence suggests that there may be a small reduction in the hippocampal volume in cannabis users vs. non-users, but with no clinical manifestations, other data show that chronic, heavy use of smoked cannabis is associated with a decline in some cognitive abilities (decision-making and conceptual planning) (48,49). ...
Article
Both phytocannabinoids (Δ9-tetrahydrocannabinol, cannabidiol) and synthetic derivatives (nabilone, dronabinol) showed therapeutic benefits in some neurological disorders. Cannabis inhalation was reported to attenuate several symptoms (rigidity, bradykinesia, tremor) in Parkinson’s disease. A significant reduction in monthly seizures in patients with epilepsy has been noted for cannabidiol, while administration of Δ9-tetrahydrocannabinol resulted in benefits on psychomotor agitation in patients suffering from Alzheimer’s disease. Although there are clinical studies supporting the use of cannabis preparations as adjuvant therapy in neurological disorders, more investigations are needed to assess their safety and efficacy.
... Cinnamomum camphora [163], Cannabis sativa [164], Myristica fragrans [165], and many others have neurotoxic effects. The current study was conducted to investigate the developmental neurotoxicity of S. guineense on PND 70 rats. ...
... Regular cannabis use exerts changes in brain structure (Ceccarini et al., 2015;Lorenzetti, Chye, Silva, Solowij, & Roberts, 2019;Rocchetti et al., 2013) and neurofunctional connectivity (Scott et al., 2018), negatively affecting cognitive function (Scott et al., 2018), such as memory (Prini et al., 2020;Schoeler et al., 2016). Chronic and long-term cannabis exposure may exert differential, region-specific effects in brain areas enriched with cannabinoid receptors, such as the hippocampus, orbitofrontal cortex volume (Lorenzetti et al., 2019;Yanes et al., 2018), and decreased activation in the anterior cingulate cortex and in the dorsolateral prefrontal cortex (Chang, Yakupov, Cloak, & Ernst, 2006). ...
Article
Attention allows us to select relevant information from the background. Although several studies have described that cannabis use induces deleterious effects on attention, it remains unclear if cannabis dependence affects the attention network systems differently. Objectives To evaluate whether customary consumption of cannabis or cannabis dependence impacts the alerting, orienting, and executive control systems in young adults; to find out whether it is related to tobacco or alcohol dependence and if cannabis use characteristics are associated with the attention network systems. Method One-hundred and fifty-four healthy adults and 102 cannabis users performed the Attention Network Test (ANT) to evaluate the alerting, orienting, and executive control systems. Results Cannabis use enhanced the alerting system but decreased the orienting system. Moreover, those effects seem to be associated with cannabis dependence. Out of all the cannabis-using variables, only the age of onset of cannabis use significantly predicted the efficiency of the orienting and executive control systems. Conclusion Cannabis dependence favors tonic alertness but reduces selective attention ability; earlier use of cannabis worsens the efficiency of selective attention and resolution of conflicts.
... The effects of cannabis use on brain structure are more variable than those observed with alcohol use disorders, but increased severity of cannabis use is associated with greater structural changes in the hippocampus, prefrontal cortex, amygdala, insula, cerebellum, and striatum (Lorenzetti et al., 2016). Decreased hippocampal volume is the most consistently found structural alteration in cannabis users relative to non-users, with a medium effect size (Rocchetti et al., 2013). Current evidence suggests that alcohol and cannabis use disorders produce partially overlapping effects on the brain and the extent of changes in brain structure depends on the severity of use in nonpsychotic individuals. ...
Article
Substance use may confound the study of brain structure in schizophrenia. We used voxel-based morphometry (VBM) to examine whether differences in regional gray matter volumes exist between schizophrenia patients with (n = 92) and without (n = 66) clinically significant cannabis and/or alcohol use histories compared to 88 healthy control subjects. Relative to controls, patients with schizophrenia had reduced gray matter volume in the bilateral precentral gyrus, right medial frontal cortex, right visual cortex, right occipital pole, right thalamus, bilateral amygdala, and bilateral cerebellum regardless of substance use history. Within these regions, we found no volume differences between patients with schizophrenia and a history of cannabis and/or alcohol compared to patients with schizophrenia without a clinically significant substance use history. Our data support the idea that a clinically meaningful history of alcohol or cannabis use does not significantly compound the gray matter deficits associated with schizophrenia.
... This is also inconsistent with meta-analyses showing that greater cannabis dosage is associated with altered brain integrity (i.e. function and structure; Blest-Hopley et al. 2018;Rocchetti et al. 2013). It could be that exposure to cannabis is not consistently assessed across the reviewed studies and was examined by few studies, so this evidence might not be conclusive and needs to be corroborated by future work with sound assessment of cannabis exposure (e.g. ...
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Rationale Regular cannabis use (i.e. ≥ monthly) is highly prevalent, with past year use being reported by ~ 200 million people globally.High reactivity to cannabis cues is a key feature of regular cannabis use and has been ascribed to greater cannabis exposure and craving, but the underlying neurobiology is yet to be systematically integrated. Objectives We aim to systematically summarise the findings from fMRI studies which examined brain function in cannabis users while exposed to cannabis vs neutral stimuli during a cue-reactivity fMRI task. Methods A systematic search of PsycINFO, PubMed and Scopus databases was pre-registered in PROSPERO (CRD42020171750) and conducted following PRISMA guidelines. Eighteen studies met inclusion/exclusion criteria. Samples comprised 918 participants (340 female) aged 16–38 years. Of these, 603 were regular cannabis users, and 315 were controls. Results The literature consistently reported greater brain activity in cannabis users while exposed to cannabis vs neutral stimuli in three key brain areas: the striatum, the prefrontal (anterior cingulate, middle frontal) and the parietal cortex (posterior cingulate/precuneus) and additional brain regions (hippocampus, amygdala, thalamus, occipital cortex). Preliminary correlations emerged between cannabis craving and the function of partially overlapping regions (amygdala, striatum, orbitofrontal cortex ). Conclusions Exposure to cannabis-cues may elicit greater brain function and thus trigger cravings in regular cannabis users and thus trigger cannabis craving. Standardised and longitudinal assessments of cannabis use and related problems are required to profile with greater precision the neurobiology of cannabis cue-reactivity, and its role in predicting cravings and relapse.
... Evidence strongly indicates that the hippocampus is involved in learning and memory and the hippocampus has been implicated in neural circuitry models of substance use/addiction (Koob & Volkow, 2010 playing a role in drug-related contextual processing and anticipation/craving. In human neuroimaging studies, lower hippocampal volume is associated with greater use of alcohol (Fein & Fein, 2013; see Wilson, Bair, Thomas, & Iacono, 2017 for a meta-analysis), cannabis (Filbey, McQueeny, Kadamangudi, Bice, & Ketcherside, 2015;Yücel et al., 2008; see Rocchetti et al., 2013 for a meta-analysis), nicotine (Janowitz et al., 2014) and other illicit substances (Thompson et al., 2004). While most studies offer evidence in support of lower hippocampal volume in relation to substance use (Mackey et al., 2018), some recent studies report null associations (Filbey et al., 2015;Gillespie et al., 2018;Mashhoon, Sava, Sneider, Nickerson, & Silveri, 2015). ...
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Background Alcohol, cannabis, and nicotine use are highly comorbid and alarmingly prevalent in young adults. The hippocampus may be particularly sensitive to substance exposure. This remains largely untested in humans and familial risk may confound exposure effects. We extend prior work on alcohol and hippocampal volume in women by testing common and unique substance use effects and the potential moderating role of sex on hippocampal volume during emerging adulthood. A quasi-experimental cotwin control (CTC) design was used to separate familial risk from exposure consequences. Methods In a population-based sample of 435 24-year-old same-sex twins (58% women), dimensional measures (e.g. frequency, amount) of alcohol, cannabis, and nicotine use across emerging adulthood were assessed. Hippocampal volume was assessed using MRI. Results Greater substance use was significantly associated with lower hippocampal volume for women but not men. The same pattern was observed for alcohol, cannabis, and nicotine. CTC analyses provided evidence that hippocampal effects likely reflected familial risk and the consequence of substance use in general and alcohol and nicotine in particular; cannabis effects were in the expected direction but not significant. Within-pair mediation analyses suggested that the effect of alcohol use on the hippocampus may reflect, in part, comorbid nicotine use. Conclusions The observed hippocampal volume deviations in women likely reflected substance-related premorbid familial risk and the consequences of smoking and, to a lesser degree, drinking. Findings contribute to a growing body of work suggesting heightened risk among women toward experiencing deleterious effects of substance exposure on the still-developing young adult hippocampus.
... While prior research suggests male and female cannabis users may differ in neural networks (Noorbakhsh et al., 2020) and brain development trajectories (Herting et al., 2019), the vast majority of the literature fails to directly compare male and female users (vs non-users). Therefore, it still remains unclear if recreational cannabis use is neurotoxic (Adam et al., 2020;Pillay et al., 2008;Rocchetti et al., 2013) or neuroprotective (Alexander, 2016;Appendino et al., 2011;Campos et al., 2016;Fernández-Ruiz et al., 2011;Hartsel et al., 2016;Izzo et al., 2009) to males and females and what neural networks (if any) may be impacted with cannabis use. Given the recent increase in cannabis research, it is imperative a timely comprehensive review on exisiting sex, cannabis use and neuroimaging research needs to be completed. ...
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Cannabis has been shown to cause structural and functional neurocognitive changes in heavy users. Cannabis use initiation aligns with brain development trajectories; therefore, it is imperative that the potential neurological implications of cannabis use are understood. Males and females reach neurodevelopmental milestones at different rates making it necessary to consider biological sex in all cannabis and brain-based research. Through use of a systamatic review in accordance with PRISMA guidelines, we aimed to understand the interaction between biological sex and cannabis use on brain-based markers. In total, 18 articles containing a sex-based analysis of cannabis users were identified. While the majority of studies ( n = 11) reported no sex by cannabis use interactions on brain-based markers, those that reported findings ( n = 8) suggest females may be more susceptible to cannabis’ neurotoxic effects. Unfortunately, a large portion of the literature was excluded due to no sex-based analysis. In addition, studies that reported no sex differences often contained a reduced number of females which may result in some studies being underpowered for sex-based analyses, making it difficult to draw firm conclusions. Suggestions to improve cannabis and sex-based reseach are proposed.
... Structural changes that appear in connection with the early initiation and intensity of cannabis use include the hippocampus bilaterally [11,12] and the amygdala [13]. Simultaneously, such changes alter the connectivity between processing and executive systems [14][15][16][17], which reflects the concept of schizophrenia symptomatology. ...
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The rising popularity of medical marijuana and its potential therapeutic uses has resulted in passionate discussions that have mainly focused on its possible benefits and applications. Although the concept itself seems promising, the multitude of presented information has noticeable ramifications-terminological chaos being one. This work aimed to synthesize and critically analyze scientific evidence on the therapeutic uses of cannabinoids in the field of psychiatry. Emphasis was placed on the anxiolytic effects of cannabis constituents and their effects on post-traumatic stress disorder, anxiety disorders, schizophrenia spectrum, and other psychotic disorders. The review was carried out from an addictological perspective. A database search of interchangeably combined keywords resulted in the identification of subject-related records. The data were then analyzed in terms of relevance, contents, methodologies, and cited papers. The results were clear in supporting one common conclusion: while most findings provide support for beneficial applications of medical marijuana in psychiatry, no certain conclusions can be drawn until larger-scaled, more methodo-logically rigorous, and (preferably) controlled randomized trials verify these discoveries.
... This indicates that the slower molecular adaptation of CB1Rs to THC in hippocampus suggests that it is more susceptible to molecular degeneration associated with cannabis use. This is further supported by a meta-analysis across 14 studies showing significant volumetric reduction of the hippocampus in cannabis users (Rocchetti et al., 2013). Berrendero et al. (1998) noted the age-related reduction of mRNA levels in hippocampal CB1R. ...
Article
Given the aging Baby Boomer generation, changes in cannabis legislation, and the growing acknowledgment of cannabis for its therapeutic potential, it is predicted that cannabis use in the older population will escalate. It is, therefore, important to determine the interaction between the effects of cannabis and aging. The aim of this report is to describe the link between cannabis use and the aging brain. Our review of the literature found few and inconsistent empirical studies that directly address the impact of cannabis use on the aging brain. However, research focused on long-term cannabis use points toward cumulative effects on multimodal systems in the brain that are similarly affected during aging. Specifically, the effects of cannabis and aging converge on overlapping networks in the endocannabinoid, opioid, and dopamine systems that may affect functional decline particularly in the hippocampus and prefrontal cortex, which are critical areas for memory and executive functioning. To conclude, despite the limited current knowledge on the potential interactive effects between cannabis and aging, evidence from the literature suggests that cannabis and aging effects are concurrently present across several neurotransmitter systems. There is a great need for future research to directly test the interactions between cannabis and aging.
Article
Cannabis use is widespread among people at ultra-high risk (UHR) for psychosis. The causal link as well as the temporal link between cannabis use and further occurrence of psychosis in UHR people remain inconclusive. Current science data supported an increased risk of transition to psychosis in cannabis users who are genetically predisposed to psychosis. This risk would be even greater in the presence of a family history of psychosis, in case of a strong use and an early onset use. Several models have been cited to explain the link between cannabis use and the subsequent onset of psychosis or prepsychotic states: cannabis-induced modifications of some brain structures, a dysregulation of the hypothalamic-pituitary axis and an alteration of normal neurological development via the endocannabinoid system. Cannabis represents a modifiable risk for psychosis. Current interventions aim to reduce or stop the cannabis use in order to reduce the risk of transition to psychosis. Copyright © 2019 Elsevier Masson SAS. All rights reserved.
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Zur gezielten Aufnahme, Verarbeitung und Speicherung der komplexen sensorischen Informationen unserer Umwelt benötigen wir kognitive Fähigkeiten. Unter „Kognition” versteht man dabei eine Vielzahl bewusster sowie unbewusster neuronaler Prozesse des Gehirns, die bei der Verarbeitung externer und interner Informationen ablaufen.
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Background Converging lines of evidence from diffusion tensor imaging (DTI) studies reveal significant alterations in white matter (WM) microstructure in the prefrontal cortex of chronic stimulant users compared to controls, suggesting compromised axonal microstructure and/or myelin. Methods A meta-analysis of DTI-based WM integrity was conducted for white matter regions across the corpus callosum and association fibers. Articles were sourced and selected using PRISMA guidelines for systematic review and meta-analysis. Inclusion and exclusion criteria were determined by the authors in order to best capture WM integrity among individuals with primary stimulant use in comparison to healthy control subjects. Results Eleven studies that focused on region-of-interest (ROI)-based analysis of WM integrity were extracted from an initial pool of 113 independent studies. Analysis across ROIs indicated significantly lower fractional anisotropy (FA) values in stimulant use groups compared to controls with a small to moderate overall effect (Hedges’ g = -0.37, 95% CI [-0.54, -0.20]). Eigenvalues were also analyzed, revealing a significant effect for radial diffusivity (RD; Hedges’ g = 0.24, 95% CI [0.01, 0.47]) but not axial diffusivity (AD; Hedges’ g = 0.05, 95% CI [-0.20, 0.29]) or mean diffusivity (MD; Hedges’ g = 0.20, 95% CI [-0.01, 0.41]). Subgroup analyses based on specific ROIs, primary substance use, poly-substance use, and imaging technology were also explored. Conclusion Results of the present study suggest a consistent effect of compromised WM integrity for individuals with stimulant use disorders. Furthermore, no significant differences were found between cocaine and methamphetamine-based groups.
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Objective: Amidst the evolving policy surrounding cannabis legalization in the United States, cannabis use is becoming increasingly prevalent as perceptions of harm decrease, particularly among adolescents. Cannabis and alcohol are commonly used by adolescents and are often used together. However, developmental research has historically taken a “single substance” approach to examine the association of substance use and adolescent brain and behavior rather than examining co-(or poly-substance) use of multiple substances, such as cannabis and alcohol. Thus, the acute effects of cannabis and alcohol, and the impact of co-use of cannabis and alcohol on the adolescent brain, cognitive function and subsequent psychosocial outcomes remains understudied. This narrative review aims to examine the effects of cannabis and alcohol on adolescents across a number of behavioral and neurobiological outcomes. Methods: The PubMed and Google Scholar databases were searched for the last 10 years to identify articles reporting on acute effects of cannabis and alcohol administration, and the effects of cannabis and alcohol on neuropsychological, neurodevelopmental, neural (e.g., structural and functional neuroimaging), and psychosocial outcomes in adolescents. When adolescent data were not available, adult studies were included as support for potential areas of future direction in adolescent work. Results: Current studies of the impact of cannabis and alcohol on adolescent brain and behavior have yielded a complicated pattern. Some suggest that the use of cannabis in addition to alcohol during adolescence may have a “protective” effect, yielding neuropsychological and structural brain outcomes that are better than those for adolescents who use only alcohol. However, other adolescent studies suggest that cannabis and alcohol co-use is associated with negative health and social outcomes such as poorer academic performance and impaired driving. Conclusion: Variation in study methodologies, policy-level limitations and our limited understanding of the developmental neurobiological effects of cannabis preclude the straightforward interpretation of the existing data on adolescent cannabis and alcohol use. Further research on this topic is requisite to inform the development of effective intervention and prevention programs for adolescent substance users, which hinge on a more comprehensive understanding of how cannabis—and its intersection with alcohol—impacts the developing brain and behavior.
Article
Objectives: Cannabinoids have gained popularity recently with special emphasis on their use for chronic pain. Although NICE guidelines advise against their usage for management of chronic pain, almost all rheumatologists encounter a few patients in their daily practice who either use them or are curious about them. We reviewed the mechanism of action of cannabinoids, current knowledge about their role in rheumatology and potential drug interactions with common drugs used in Rheumatology. We attempted to answer the question "If cannabinoids are friend, foe or just a mere bystander?" Methods: We adhered to a search strategy for writing narrative reviews as per available guidelines. We searched PubMed with the search terms "Cannabinoids", "Rheumatology" and "Chronic pain" for published articles and retrieved 613 articles. The abstracts and titles of these articles were screened to identify relevant studies focusing on mechanism of actions, adverse effects and drug interactions. We also availed the services of a musculoskeletal librarian. Results: Despite the NHS guidelines against the usage of cannabinoids and associated significant stigma, cannabinoids are increasingly used for the management of pain in rheumatology without prescription. Cannabinoids act through two major receptors CB1 and CB2, which are important modulators of the stress response with potential analgesic effects. Their role in various rheumatological diseases including Rheumatoid arthritis, Osteoarthritis and Fibromyalgia have been explored with some benefits. However, in addition to the adverse effects, cannabinoids also have some potential interactions with common drugs used in rheumatology, which many users are unaware of. Conclusion: While the current studies and patient reported outcomes suggest cannabinoids to be a "friend" of rheumatology, their adverse events and drug interactions prove to be a "Foe". We were unable to arrive at a definite answer for our question posed, however on the balance of probabilities we can conclude cannabinoids to be a "foe". Under these circumstances, a disease and drug focussed research is need of the hour to answer the unresolved question.
Article
Background: Cannabis use is increasing worldwide despite the various health effects of this substance. Methods: We report two cases of acute hippocampal encephalopathy in heavy cannabis users (>10 joints/day). Results: In both male patients, acute encephalitis was suspected. Brain MRI diffusion-weighted sequences showed bilateral high signal abnormalities in hippocampal regions. Patients had renal dysfunction, rhabdomyolysis and inflammatory syndrome. Investigations showed no evidence of infectious or autoimmune encephalitides. Repeated electroencephalograms revealed no epileptic activity. Clinical, biological and MRI acute abnormalities improved within weeks. New exposition to cannabis yielded a new episode of encephalopathy. In both patients, severe long-lasting episodic memory impairment associated with hippocampal atrophy were observed several months later. Conclusions: Health professionals should be aware of this cannabis-related syndrome given its severe and long-lasting effects.
Article
While medical and recreational cannabis use is becoming more frequent among older adults, the neurocognitive consequences of cannabis use in this age group are unclear. The aim of this literature review was to synthesize and evaluate the current knowledge on the association of cannabis use during older-adulthood with cognitive function and brain aging. We reviewed the literature from old animal models and human studies while focusing on the link of middle- and old-age use of cannabis with cognition. The report highlights the gap in knowledge on cannabis use in late-life and cognitive health, and discusses the limited findings in the context of substantial changes in attitudes and policies. Furthermore, we outline possible theoretical mechanisms and propose recommendations for future research. The limited evidence on this important topic suggests that use in older ages may not be linked with poorer cognitive performance, thus detrimental effects of early-life cannabis use may not translate to use in older ages. Rather, use in old ages may be associated with improved brain health, in accordance with the known neuroprotective properties of several cannabinoids. Yet, firm conclusions cannot be drawn from the current evidence-base due to lack of research with strong methodological designs.
Article
Cannabis is the most frequently used illicit drug in the world. Cross‐sectional neuroimaging studies have revealed that chronic cannabis exposure and the development of cannabis use disorders may affect cerebllar morphology. However, cross‐sectional studies cannot make a conclusive distinction between causes and consequences, and there is a lack of longitudinal neuroimaging studies. In the current study, we used longitudinal neuroimaging data to explore whether persistent cannabis use and higher levels of cannabis exposure in young adults are related to cerebellar thickness alterations. Twenty heavy cannabis users (CBs) and 22 non‐cannabis‐using controls (HCs) completed a comprehensive psychological assessment and a T1‐structural MRI scan at baseline and a 3‐year follow‐up. Except for lobuleVIIB, all cerebellar subregions showed significant effects of age in both the CB and HC groups. Both VI and CrusI had higher rates of increase in CBs than in HCs. In addition, we examined the relationship between changes in cerebellar thickness and cannabis use characteristics. We found that alterations in lobule VI and CrusI were related to the age at onset first cannabis use but not the age at onset frequent cannabis use. The changes in lobule VI and CrusI were associated with the CUDIT score, even when controlling for the AUDIT score. The results indicated that an increased rate of cerebellar thickness is a risk factor for heavy cannabis use in early adulthood. Cannabis use affects the cerebellar structure, and monitoring cerebellar structural alterations that could be used as biomarkers may help guide the development of clinical tools.
Article
Introduction: Cannabis use has a high prevalence in young youth and is associated with poor psychosocial outcomes. Such outcomes have been ascribed to the impact of cannabis exposure on the developing brain. However, findings from individual studies of volumetry in youth cannabis users are equivocal. Objectives: Our primary objective was to systematically review the evidence on brain volume differences between young cannabis users and nonusers aged 12-26 where profound neuromaturation occurs, accounting for the role of global brain volumes (GBVs). Our secondary objective was to systematically integrate the findings on the association between youth age and volumetry in youth cannabis users. Finally, we aimed to evaluate the quality of the evidence. Materials and Methods: A systematic search was run in three databases (PubMed, Scopus, and PsycINFO) and was reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We run meta-analyses (with and without controlling for GBV) of brain volume differences between young cannabis users and nonusers. We conducted metaregressions to explore the role of age on volumetric differences. Results: Sixteen studies were included. The reviewed samples included 830 people with mean age 22.5 years (range 14-26 years). Of these, 386 were cannabis users (with cannabis use onset at 15-19 years) and 444 were controls. We found no detectable group differences in any of the GBVs (intracranium, total brain, total white matter, and total gray matter) and regional brain volumes (i.e., hippocampus, amygdala, orbitofrontal cortex, and total cerebellum). Age and cannabis use level did not predict (standardized mean) volume group differences in metaregression. We found little evidence of publication bias (Egger's test p>0.1). Conclusions: Contrary to evidence in adult samples (or in samples mixing adults and youth), previous single studies in young cannabis users, and meta-analyses of brain function in young cannabis users, this early evidence suggests nonsignificant volume differences between young cannabis users and nonusers. While prolonged and long-term exposure to heavy cannabis use may be required to detect gross volume alterations, more studies in young cannabis users are needed to map in detail cannabis-related neuroanatomical changes.
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As more states legalize cannabis, more complications are becoming apparent. The emergency department (ED) tends to be the destination for most of the acute presentations. The purpose of this chapter is to introduce some of the major complications related to cannabis ingestion/exposures being seen currently. The acute issues being covered in this chapter include acute marijuana toxicity, acute mental illness (acute psychosis, depression, anxiety, and suicide/suicidal ideation), cannabinoid hyperemesis syndrome, pulmonary and cardiovascular complications, and, finally, issues related to conscious sedation.
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Recent structural MRI studies on gray matter (GM) volumes using group-level mass-univariate statistical analysis suggest that chronic and heavy cannabis exposure may affect brain region-based morphology. In this prospective study, we use a multivariate pattern analysis approach to investigate the voxel-level change of GM densities in chronic heavy cannabis users. Principal component analysis and linear support vector machine are used in this study, resulting in an 88.1% separation between chronic heavy cannabis users (N = 20) and non-cannabis healthy controls (HCs, N = 22) through leave-one-out cross-validation. The model's discriminative pattern showed that GM density decreases in the part of middle frontal gyrus, inferior frontal gyrus, middle temporal gyrus, inferior temporal gyrus and left occipital lobe in heavy cannabis users with respect to HCs and increases in the part of lentiform nucleus, left cerebellum and right parietal lobe. These results suggest that GM densities alteration has taken place on chronic heavy cannabis users compared with HCs at voxel level.
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Cannabinoids are chemicals that can be endogenous, natural, and synthetic substances which has the ability to bind to the cannabinoid receptors and exhibit a plethora of pharmacological and toxicological effects. Cannabinoids, the multipotent substance has a well-defined cellular signaling pathway that leads to a diverse physiological action in the body. Based on their chemical structural attributes, these substances can cross the blood–brain barrier, and hence, can exert an effect both in the central nervous system and the peripheral system in the body. Manipulation of the cannabinoid signaling with the natural and/or synthetic ligands can result in a plethora of pharmacological effects that can be used for various prophylactic and therapeutic treatment strategies in animals and humans. However, cannabinoids also induce severe adverse effects in the central and peripheral nervous systems. Hence, in this chapter, we review the current neuropharmacological and neurotoxicological properties of cannabinoids.
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Herbal products with potential therapeutic and nutritional values are gaining importance among people around the world. Herbal products are generally considered safe for human applications. Extracts from various herbal products or purified bioactive compounds are prepared and marketed in various forms. Polyherbal products are formulations with more than two herbal extracts. They are considered prophylactically or therapeutically effective on many occasions due to their complementary and/or potentiation activities due to each other’s benefits. In most of the incidents, these herbal products have not been scientifically validated. Hence, patients and/or consumers are at risk for various adverse effects, leading to acute and chronic toxicity. General toxicity tests are generally conducted for herbal products; however, the neurotoxicity tests are not routinely conducted. Heavy metals such as lead, mercury, and arsenic present in the polyherbal products often cause severe neurotoxicity. The major challenge of using polyherbal formulations products for prophylactic and/or therapeutic purposes is the nonavailability of valid scientific information on the complete metabolite profile, human equivalent dose, potential adverse effects, and possible antidotes. In this chapter, we look into the potentially toxic substances present in the polyherbal products, and various general toxicity and neurotoxicity tests of the herbal products are discussed.
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Objective: Systematically review the scientific literature to characterize the effects of cannabis use on brain structure, function, and neurodevelopmental outcomes in adolescents and young adults with ADHD. Method: Systematic review following PRISMA guidelines utilizing PubMed, Embase, PsycINFO, and Cochrane CENTRAL trials register from inception until 1 January 2020. Articles that examined the impact of cannabis use on youth with ADHD were included. Results: Eleven studies were identified that compared outcomes for individuals with ADHD who used cannabis or synthetic cannabinoids against those with ADHD who did not. Seven of these studies used neuroimaging techniques, including fMRI, structural MRI, and SPECT. Differential regions of activation were identified, including the right hippocampus and cerebellar vermis, and bilateral temporal lobes. Morphological differences were identified in the right precentral and postcentral gyri, left nucleus accumbens, right superior frontal and postcentral gyri. No study identified any additive or ADHD × cannabis use interaction on neuropsychological tasks of executive function. Two studies found adverse differential impacts of early-onset cannabis use in this population. Conclusion: A dearth of evidence is available on the impact of cannabis use on the developing brain and functioning for individuals with ADHD, despite the elevated risk for substance use in this population. The limited, potentially underpowered evidence does not support the hypothesis that cannabis use has a deleterious impact on neuropsychological tasks in transitional age youth with ADHD. Larger and longer-term studies are needed, however, to better inform clinicians and patients as to the impacts of cannabis use in youth with ADHD.
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Cannabis use has historically been thought to cause amotivation, but the relationship between cannabis and apathy, anhedonia, and reward processing remains poorly characterised. In this systematic review, we evaluated whether cannabis exposure acutely and/or non-acutely was associated with altered reward processing using questionnaire, behavioural, or functional neuroimaging measures. Questionnaire studies demonstrated greater anhedonia in adolescent cannabis users, and some indication of greater apathy in young adult cannabis users. Behavioural studies yielded some evidence of reduced reward learning in adolescent cannabis users, though there were too few studies in this category for reliable conclusions. Finally, longitudinal and acute functional neuroimaging studies showed an association between cannabis and blunted neural responses to reward, which did not emerge consistently in cross-sectional studies. The current results suggest that cannabis use is associated with specific impairments in reward and motivation. Future large-scale, longitudinal studies which use multiple behavioural and neuroimaging measures of reward processing may further clarify the impact of cannabis use on motivational and reward processes, and neural networks.
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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. In a large multisite dataset of 261 subjects, reduced hippocampal volume was found in cannabis‐dependent users relative to non‐dependent users and controls, irrespective of cannabis dosage. However, non‐dependent users did not differ from controls in hippocampal volume. Shape analysis indicated localized deflations in the superior‐medial body of the hippocampus, driving the findings in dependent users.
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Systematic reviews should build on a protocol that describes the rationale, hypothesis, and planned methods of the review; few reviews report whether a protocol exists. Detailed, well-described protocols can facilitate the understanding and appraisal of the review methods, as well as the detection of modifications to methods and selective reporting in completed reviews. We describe the development of a reporting guideline, the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols 2015 (PRISMA-P 2015). PRISMA-P consists of a 17-item checklist intended to facilitate the preparation and reporting of a robust protocol for the systematic review. Funders and those commissioning reviews might consider mandating the use of the checklist to facilitate the submission of relevant protocol information in funding applications. Similarly, peer reviewers and editors can use the guidance to gauge the completeness and transparency of a systematic review protocol submitted for publication in a journal or other medium.
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Systematic reviews should build on a protocol that describes the rationale, hypothesis, and planned methods of the review; few reviews report whether a protocol exists. Detailed, well-described protocols can facilitate the understanding and appraisal of the review methods, as well as the detection of modifications to methods and selective reporting in completed reviews. We describe the development of a reporting guideline, the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols 2015 (PRISMA-P 2015). PRISMA-P consists of a 17-item checklist intended to facilitate the preparation and reporting of a robust protocol for the systematic review. Funders and those commissioning reviews might consider mandating the use of the checklist to facilitate the submission of relevant protocol information in funding applications. Similarly, peer reviewers and editors can use the guidance to gauge the completeness and transparency of a systematic review protocol submitted for publication in a journal or other medium.
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It is unclear yet whether cannabis use is a moderating or causal factor contributing to grey matter alterations in schizophrenia and the development of psychotic symptoms. We therefore systematically reviewed structural brain imaging and post mortem studies addressing the effects of cannabis use on brain structure in psychosis. Studies with schizophrenia (SCZ) and first episode psychosis (FEP) patients as well as individuals at genetic (GHR) or clinical high risk for psychosis (ARMS) were included. We identified 15 structural magnetic resonance imaging (MRI) (12 cross sectional / 3 longitudinal) and 4 post mortem studies. The total number of subjects encompassed 601 schizophrenia or first episode psychosis patients, 255 individuals at clinical or genetic high risk for psychosis and 397 healthy controls. We found evidence for consistent brain structural abnormalities in cannabinoid 1 (CB1) receptor enhanced brain areas as the cingulate and prefrontal cortices and the cerebellum. As these effects have not consistently been reported in studies examining nonpsychotic and healthy samples, psychosis patients and subjects at risk for psychosis might be particularly vulnerable to brain volume loss due to cannabis exposure.
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Heavy cannabis users display smaller amygdalae and hippocampi than controls, and genetic variation accounts for a large proportion of variance in liability to cannabis dependence (CD). A single nucleotide polymorphism in the cannabis receptor-1 gene (CNR1), rs2023239, has been associated with CD diagnosis and intermediate phenotypes, including abstinence-induced withdrawal, cue-elicited craving, and parahippocampal activation to cannabis cues. This study compared hippocampal and amygdalar volumes (potential CD intermediate phenotypes) between heavy cannabis users and healthy controls, and analyzed interactions between group, rs2023239 variation, and the volumes of these structures. Ninety-four heavy cannabis users participated, of whom 37 (14 men, 23 women; mean age=27.8) were matched to 37 healthy controls (14 men, 23 women; mean age=27.3) for case-control analyses. Controlling for total intracranial volume and other confounding variables, matched cannabis users had smaller bilateral hippocampi (left, p=0.002; right, p=0.001) and left amygdalae (p=0.01) than controls. When genotype was considered in the case-control analyses, there was a group by genotype interaction, such that the rs2023239 G allele predicted lower volume of bilateral hippocampi among cannabis users relative to controls (both p<0.001). This interaction persisted when all 94 cannabis users were compared to controls. There were no group by genotype interactions on amygdalar volume. These data replicate previous findings of reduced hippocampal and amygdalar volume among heavy cannabis users, and suggest that CNR1 rs2023239 variation may predispose smaller hippocampal volume after heavy cannabis use. This association should be tested in future studies of brain volume differences in CD.
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Cannabis use typically begins during adolescence and early adulthood, a period when cannabinoid receptors are still abundant in white matter pathways across the brain. However, few studies to date have explored the impact of regular cannabis use on white matter structure, with no previous studies examining its impact on axonal connectivity. The aim of this study was to examine axonal fibre pathways across the brain for evidence of microstructural alterations associated with long-term cannabis use and to test whether age of regular cannabis use is associated with severity of any microstructural change. To this end, diffusion-weighted magnetic resonance imaging and brain connectivity mapping techniques were performed in 59 cannabis users with longstanding histories of heavy use and 33 matched controls. Axonal connectivity was found to be impaired in the right fimbria of the hippocampus (fornix), splenium of the corpus callosum and commissural fibres. Radial and axial diffusivity in these pathways were associated with the age at which regular cannabis use commenced. Our findings indicate long-term cannabis use is hazardous to the white matter of the developing brain. Delaying the age at which regular use begins may minimize the severity of microstructural impairment.
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Objective: Funnel plots (plots of effect estimates against sample size) may be useful to detect bias in meta-analyses that were later contradicted by large trials. We examined whether a simple test of asymmetry of funnel plots predicts discordance of results when meta-analyses are compared to large trials, and we assessed the prevalence of bias in published meta-analyses. Design: Medline search to identify pairs consisting of a meta-analysis and a single large trial (concordance of results was assumed if effects were in the same direction and the meta-analytic estimate was within 30
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The aberrant processing of salience is thought to be a fundamental factor underlying psychosis. Cannabis can induce acute psychotic symptoms, and its chronic use may increase the risk of schizophrenia. We investigated whether its psychotic effects are mediated through an influence on attentional salience processing. To examine the effects of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) on regional brain function during salience processing. Volunteers were studied using event-related functional magnetic resonance imaging on 3 occasions after administration of Δ9-THC, CBD, or placebo while performing a visual oddball detection paradigm that involved allocation of attention to infrequent (oddball) stimuli within a string of frequent (standard) stimuli. University center. Fifteen healthy men with minimal previous cannabis use. Symptom ratings, task performance, and regional brain activation. During the processing of oddball stimuli, relative to placebo, Δ9-THC attenuated activation in the right caudate but augmented it in the right prefrontal cortex. Δ9-Tetrahydrocannabinol also reduced the response latency to standard relative to oddball stimuli. The effect of Δ9-THC in the right caudate was negatively correlated with the severity of the psychotic symptoms it induced and its effect on response latency. The effects of CBD on task-related activation were in the opposite direction of those of Δ9-THC; relative to placebo, CBD augmented left caudate and hippocampal activation but attenuated right prefrontal activation. Δ9-Tetrahydrocannabinol and CBD differentially modulate prefrontal, striatal, and hippocampal function during attentional salience processing. These effects may contribute to the effects of cannabis on psychotic symptoms and on the risk of psychotic disorders.
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Background: Despite impressive advancements in early interventions in psychosis, there is an urgent need of robust neurobiological markers to improve the predictive value of psychosis transition. Available structural imaging literature in the field is undermined by several methodological caveats and a number of confounders such as exposure to antipsychotic treatment. Methods: Fourteen voxel-based morphometry studies of antipsychotic-naive subjects at enhanced clinical risk for psychosis (high risk [HR]) or experiencing a first-episode psychosis (FEP) were included. Formal meta-analysis of effect sizes and "signed differential mapping" voxel-based meta-analysis were combined to control the results for sample sizes, strength of individual findings, and confounding variables. Results: Formal effect size meta-analysis indicated consistent gray matter (GM) reductions both in subjects at enhanced clinical risk for psychosis and in first-episode subjects when compared with control groups. Voxel-based meta-analysis showed GM reductions in the temporal, limbic prefrontal cortex within the HR group and in the temporal insular cortex and cerebellum within the FEP group. Psychosis onset was characterized by GM decreases in temporal, anterior cingulate, cerebellar, and insular regions. GM alterations in the temporal regions directly related to severity of psychotic symptoms. There was no publication bias. Heterogeneity across studies was low. Sensitivity analyses confirmed robustness of the above results. Conclusions: Vulnerability to psychosis is associated with consistent GM decreases in prefrontal and temporolimbic areas. The onset of full disease is accompanied by temporoinsular, anterior cingulate, and cerebellar GM reductions. Neuroanatomical alterations in temporal regions may underlie the clinical onset of psychotic symptoms.
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Cannabis is the most widely used illicit drug in the developed world. Despite this, there is a paucity of research examining its long-term effect on the human brain. To determine whether long-term heavy cannabis use is associated with gross anatomical abnormalities in 2 cannabinoid receptor-rich regions of the brain, the hippocampus and the amygdala. Cross-sectional design using high-resolution (3-T) structural magnetic resonance imaging. Participants were recruited from the general community and underwent imaging at a hospital research facility. Fifteen carefully selected long-term (>10 years) and heavy (>5 joints daily) cannabis-using men (mean age, 39.8 years; mean duration of regular use, 19.7 years) with no history of polydrug abuse or neurologic/mental disorder and 16 matched nonusing control subjects (mean age, 36.4 years). Volumetric measures of the hippocampus and the amygdala combined with measures of cannabis use. Subthreshold psychotic symptoms and verbal learning ability were also measured. Cannabis users had bilaterally reduced hippocampal and amygdala volumes (P = .001), with a relatively (and significantly [P = .02]) greater magnitude of reduction in the former (12.0% vs 7.1%). Left hemisphere hippocampal volume was inversely associated with cumulative exposure to cannabis during the previous 10 years (P = .01) and subthreshold positive psychotic symptoms (P < .001). Positive symptom scores were also associated with cumulative exposure to cannabis (P = .048). Although cannabis users performed significantly worse than controls on verbal learning (P < .001), this did not correlate with regional brain volumes in either group. These results provide new evidence of exposure-related structural abnormalities in the hippocampus and amygdala in long-term heavy cannabis users and corroborate similar findings in the animal literature. These findings indicate that heavy daily cannabis use across protracted periods exerts harmful effects on brain tissue and mental health.
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David Moher and colleagues introduce PRISMA, an update of the QUOROM guidelines for reporting systematic reviews and meta-analyses
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There are limited data regarding the impact of marijuana (MJ) on cortical development during adolescence. Adolescence is a period of substantial brain maturation and cortical thickness abnormalities may be indicative of disruptions of normal cortical development. This investigation applied cortical-surface based techniques to compare cortical thickness measures in MJ using adolescents compared to non-using controls. Eighteen adolescents with heavy MJ use and 18 non-using controls similar in age received MRI scans using a 3T Siemens scanner. Cortical reconstruction and volumetric segmentation was performed with FreeSurfer. Group differences in cortical thickness were assessed using statistical difference maps covarying for age and gender. Compared to non-users, MJ users had decreased cortical thickness in right caudal middle frontal, bilateral insula and bilateral superior frontal cortices. Marijuana users had increased cortical thickness in the bilateral lingual, right superior temporal, right inferior parietal and left paracentral regions. In the MJ users, negative correlations were found between frontal and lingual regions for urinary cannabinoid levels and between age of onset of use and the right superior frontal gyrus. This is one of the first studies to evaluate cortical thickness in a group of adolescents with heavy MJ use compared to non-users. Our findings are consistent with prior studies that documented abnormalities in prefrontal and insular regions. Our results suggest that age of regular use may be associated with altered prefrontal cortical gray matter development in adolescents. Furthermore, reduced insular cortical thickness may be a biological marker for increased risk of substance dependence.
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The hippocampus is a vulnerable and plastic brain structure that is damaged by a variety of stimuli, e.g. hypoxia, hypoperfusion, hypoglycaemia, stress and seizures. Alzheimer’s disease is a common and important disorder in which hippocampal atrophy is reported. Indeed, the available evidence suggests that hippocampal atrophy is the starting point of the pathogenesis of Alzheimer’s disease and a significant number of patients with hippocampal atrophy will develop Alzheimer’s disease. Studies indicate that hippocampal atrophy has functional consequences, e.g. cognitive impairment. Deposition of tau protein, formation of neurofibrillary tangles and accumulation of β-amyloid (Aβ) contributes to hippocampal atrophy together with damage caused by several other factors. Some of the factors associated with the development of hippocampal atrophy in Alzheimer’s disease have been identified, e.g. hypertension, diabetes mellitus, hyperlipidaemia, seizures, affective disturbances and stress, and more is being learnt about other factors. Hypertension can potentially damage the hippocampus through ischaemia caused by atherosclerosis and cerebral amyloid angiopathy. Diabetes can produce hippocampal lesions via both vascular and non-vascular pathologies and can reduce the threshold for hippocampal damage. Carriers of the apolipoprotein E (ApoE)-ɛ4 genotype have been shown to have greater mesial temporal atrophy and poorer memory functions than non-carriers. In addition to giving rise to abnormal lipid metabolism, the ApoE-ε4 allele can affect the course of Alzheimer’s disease via both Aβ-dependent and -independent pathways. Repetitive seizures can increase Aβ-peptide production and cause neurotransmission dysfunction and cytoskeletal abnormalities or a combination of these. Affective disturbances and stress are proposed to increase corticosteroid-induced hippocampal damage in many different ways. In the absence of any specific markers for predicting Alzheimer’s disease progression, it seems appropriate to learn more about the various predictors of hippocampal atrophy that determine the progression of Alzheimer’s disease from mild cognitive impairment (MCI), and then attempt to address these. It would be interesting to know to what extent these predictors play a role in the development of MCI or hasten the conversion of MCI to fullblown Alzheimer’s disease. Finally, it would be useful to know the extent to which these predictors can worsen or aggravate existing Alzheimer’s disease. Of the clinically used drugs in Alzheimer’s disease, anticholinesterases have been shown to slow down the rate of progression of hippocampal atrophy. One study observed that the neuroprotective effect of these agents is possibly due to an anti-Aβ effect produced by cholinergic stimulation. Similarly, antihypertensive and antihyperglycaemic drugs (pioglitazone and insulin) have been shown to reduce the risk of Alzheimer’s disease or disease progression. Currently, there are no disease-modifying therapies available for Alzheimer’s disease. It has been suggested that for treatment to be most effective, the regimen must be started before significant downstream damage has occurred (i.e. before the clinical diagnosis of Alzheimer’s disease, at the stage of MCI or earlier). Since the hippocampus is a plastic structure and atrophy of this structure is closely related to the pathophysiology of Alzheimer’s disease, if we could control blood pressure, regulate blood sugar, treat behavioural and psychological symptoms, achieve satisfactory lipid lowering and maintain a seizure-free state in patients with Alzheimer’s disease, this may not only improve disease control but could also potentially affect the rate of disease progression.
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Animal and human studies indicate that cannabidiol (CBD), a major constituent of cannabis, has anxiolytic properties. However, no study to date has investigated the effects of this compound on human pathological anxiety and its underlying brain mechanisms. The aim of the present study was to investigate this in patients with generalized social anxiety disorder (SAD) using functional neuroimaging. Regional cerebral blood flow (rCBF) at rest was measured twice using (99m)Tc-ECD SPECT in 10 treatment-naïve patients with SAD. In the first session, subjects were given an oral dose of CBD (400 mg) or placebo, in a double-blind procedure. In the second session, the same procedure was performed using the drug that had not been administered in the previous session. Within-subject between-condition rCBF comparisons were performed using statistical parametric mapping. Relative to placebo, CBD was associated with significantly decreased subjective anxiety (p < 0.001), reduced ECD uptake in the left parahippocampal gyrus, hippocampus, and inferior temporal gyrus (p < 0.001, uncorrected), and increased ECD uptake in the right posterior cingulate gyrus (p < 0.001, uncorrected). These results suggest that CBD reduces anxiety in SAD and that this is related to its effects on activity in limbic and paralimbic brain areas.
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In animal studies, tetrahydrocannabinol (THC) has been found to affect brain morphology, particularly within areas rich in cannabinoid receptors (e.g., hippocampus, cerebral cortex). While cannabis remains the most widely used illicit drug worldwide, there has been limited work investigating its effects on human brain tissue. In this paper, we conducted a systematic review of existing structural magnetic resonance imaging studies to examine whether cannabis use is associated with significant changes in brain anatomy. We identified only 13 structural neuroimaging studies, which were diverse in terms of sample characteristics (e.g., age of participants, duration and frequency of use) and methodology (e.g., image analysis). No study found global structural changes in cannabis users, although six studies reported regional alterations. While changes in the hippocampus and parahippocampus were frequently identified, the findings were inconsistent across studies. The available literature also provides some evidence that regional structural changes are associated with cannabis use patterns (particularly cumulative dosage and frequency of use), as well as measures of psychopathology (e.g., measures of depressive and psychotic symptoms). Together, these structural imaging findings suggest that THC exposure does affect brain morphology, especially in medial-temporal regions. Given the small literature available and the limitations of studies to date, further research is clearly required, particularly given the prevalence of cannabis use worldwide.
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Converging lines of evidence suggest an association between cannabis use and impaired episodic memory as well as related associative learning. These deficits have been associated with the duration, frequency, and age of onset of cannabis use. However, it remains unclear whether these parameters of use differently impact memory-related hippocampal functioning. Forty-two cannabis users were examined by means of functional magnetic resonance imaging while they encoded and retrieved face-profession associations. Region of interest analysis was subsequently used to compare (para-)hippocampal functioning in users with (1) a longer and shorter duration of use, (2) a higher and lower frequency of use, and (3) an earlier and later onset. To further separate the effects of these parameters of use on performance and (para-)hippocampal activity, linear regression analysis was applied. Compared to low-frequency users, high-frequency users displayed stronger blood oxygenation level-dependent response during encoding in the left parahippocampal gyrus. No differences were obvious for the groups separated according to duration of use or an earlier and later onset of use. Linear regression analysis confirmed the association between a higher frequency of use and increased activity in the left parahippocampal gyrus. Our findings suggest that the frequency of use might have a particular critical impact on intact parahippocampal functioning in cannabis users. Increased activity within the encoding-related network might reflect functional compensation to maintain cognitive functioning.
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David Moher and colleagues introduce PRISMA, an update of the QUOROM guidelines for reporting systematic reviews and meta-analyses
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Delta-9-tetrahydrocannabinol (Delta-9-THC) and Cannabidiol (CBD), the two main ingredients of the Cannabis sativa plant have distinct symptomatic and behavioral effects. We used functional magnetic resonance imaging (fMRI) in healthy volunteers to examine whether Delta-9-THC and CBD had opposite effects on regional brain function. We then assessed whether pretreatment with CBD can prevent the acute psychotic symptoms induced by Delta-9-THC. Fifteen healthy men with minimal earlier exposure to cannabis were scanned while performing a verbal memory task, a response inhibition task, a sensory processing task, and when viewing fearful faces. Subjects were scanned on three occasions, each preceded by oral administration of Delta-9-THC, CBD, or placebo. BOLD responses were measured using fMRI. In a second experiment, six healthy volunteers were administered Delta-9-THC intravenously on two occasions, after placebo or CBD pretreatment to examine whether CBD could block the psychotic symptoms induced by Delta-9-THC. Delta-9-THC and CBD had opposite effects on activation relative to placebo in the striatum during verbal recall, in the hippocampus during the response inhibition task, in the amygdala when subjects viewed fearful faces, in the superior temporal cortex when subjects listened to speech, and in the occipital cortex during visual processing. In the second experiment, pretreatment with CBD prevented the acute induction of psychotic symptoms by Delta-9-tetrahydrocannabinol. Delta-9-THC and CBD can have opposite effects on regional brain function, which may underlie their different symptomatic and behavioral effects, and CBD's ability to block the psychotogenic effects of Delta-9-THC.
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Anxiety reactions and panic attacks are the acute symptoms most frequently associated with cannabis use. Understanding the relationship between cannabis and anxiety may clarify the mechanism of action of cannabis and the pathophysiology of anxiety. Aims of the present study were to review the nature of the relationship between cannabis use and anxiety, as well as the possible clinical, diagnostic and causal implications. Systematic review of the Medline, PsycLIT and EMBASE literature. Frequent cannabis users consistently have a high prevalence of anxiety disorders and patients with anxiety disorders have relatively high rates of cannabis use. However, it is unclear if cannabis use increases the risk of developing long-lasting anxiety disorders. Many hypotheses have been proposed in an attempt to explain these relationships, including neurobiological, environmental and social influences. The precise relationship between cannabis use and anxiety has yet to be established. Research is needed to fully clarify the mechanisms of such the association.
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We conducted a systematic review to assess the evidence for specific effects of cannabis on brain structure and function. The review focuses on the cognitive changes associated with acute and chronic use of the drug. We reviewed literature reporting neuroimaging studies of chronic or acute cannabis use published up until January 2009. The search was conducted using Medline, EMBASE, LILACS and PsycLIT indexing services using the following key words: cannabis, marijuana, delta-9-tetrahydrocannabinol, THC, cannabidiol, CBD, neuroimaging, brain imaging, computerized tomography, CT, magnetic resonance, MRI, single photon emission tomography, SPECT, functional magnetic resonance, fMRI, positron emission tomography, PET, diffusion tensor MRI, DTI-MRI, MRS and spectroscopy. Sixty-six studies were identified, of which 41 met the inclusion criteria. Thirty-three were functional (SPECT/PET/fMRI) and eight structural (volumetric/DTI) imaging studies. The high degree of heterogeneity across studies precluded a meta-analysis. The functional studies suggest that resting global and prefrontal blood flow are lower in cannabis users than in controls. The results from the activation studies using a cognitive task are inconsistent because of the heterogeneity of the methods used. Studies of acute administration of THC or marijuana report increased resting activity and activation of the frontal and anterior cingulate cortex during cognitive tasks. Only three of the structural imaging studies found differences between users and controls. Functional neuroimaging studies suggest a modulation of global and prefrontal metabolism both during the resting state and after the administration of THC/marijuana cigarettes. Minimal evidence of major effects of cannabis on brain structure has been reported.
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Cannabis sativa use can impair verbal learning, provoke acute psychosis, and increase the risk of schizophrenia. It is unclear where C. sativa acts in the human brain to modulate verbal learning and to induce psychotic symptoms. To investigate the effects of 2 main psychoactive constituents of C. sativa, Delta9-tetrahydrocannabinol (Delta9-THC) and cannabidiol, on regional brain function during verbal paired associate learning. Subjects were studied on 3 separate occasions using a block design functional magnetic resonance imaging paradigm while performing a verbal paired associate learning task. Each imaging session was preceded by the ingestion of Delta9-THC (10 mg), cannabidiol (600 mg), or placebo in a double-blind, randomized, placebo-controlled, repeated-measures, within-subject design. University research center. Fifteen healthy, native English-speaking, right-handed men of white race/ethnicity who had used C. sativa 15 times or less and had minimal exposure to other illicit drugs in their lifetime. Regional brain activation (blood oxygen level-dependent response), performance in a verbal learning task, and objective and subjective ratings of psychotic symptoms, anxiety, intoxication, and sedation. Delta9-Tetrahydrocannabinol increased psychotic symptoms and levels of anxiety, intoxication, and sedation, whereas no significant effect was noted on these parameters following administration of cannabidiol. Performance in the verbal learning task was not significantly modulated by either drug. Administration of Delta9-THC augmented activation in the parahippocampal gyrus during blocks 2 and 3 such that the normal linear decrement in activation across repeated encoding blocks was no longer evident. Delta9-Tetrahydrocannabinol also attenuated the normal time-dependent change in ventrostriatal activation during retrieval of word pairs, which was directly correlated with concurrently induced psychotic symptoms. In contrast, administration of cannabidiol had no such effect. The modulation of mediotemporal and ventrostriatal function by Delta9-THC may underlie the effects of C. sativa on verbal learning and psychotic symptoms, respectively.
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