Search

While the legal status and public perception of cannabis are currently changing in many countries, one of the important considerations from a public health viewpoint is its potential association with adverse health outcomes such as the development of psychosis. This has not only led to an increasing number of systematic reviews and meta-analyses that have been published on this topic but also to a concomitant increase in conflicting results which complicates evidence-based decision-making. To address this issue, we conducted an umbrella review of systematic reviews and meta-analyses using the AMSTAR-2 to assess the quality of included reviews. We further created an evidence map to visualize and facilitate the overview of the published evidence synthesis on the association between cannabis use and all psychosis-related outcomes and risk moderators in healthy, high-risk, and clinical populations. Overall, we found 32 systematic reviews and meta-analyses. Based on a synthesis of current evidence, cannabis use is associated with subclinical psychosis states (psychotic-like experiences) and traits (schizotypal personality) in the healthy population, as well as earlier onset and development of psychosis. The effects of cannabis use in the clinical high-risk population remain unclear, however, its effects in those with established psychosis seem robust in terms of an increased risk of relapse. A dose-response effect and an increased risk of clinically relevant adverse outcomes with earlier cannabis use in adolescents, frequency of use and potentially, potency of cannabis used have also been consistently shown across the psychosis continuum. The existence of childhood trauma may further increase the risk of development of psychosis, while single nucleotide polymorphisms such as on the AKT1-gene, DRD2-gene, CHRM3-gene and PRX- gene may serve as genetic moderators. Genetic mendelian randomization studies further implicate a bi-directional association between cannabis use and psychosis, however, further research using polygenetic risk scores and epigenetic analyses is warranted. It currently remains unclear whether concurrent substance use in combination with cannabis use may further potentiate the risk of adverse psychosis outcomes. A critical and systematic synthesis of extant evidence provided here may help highlight areas where there is optimal evidence as well as identify gaps in evidence and inform decision-making with clinical and public health implication

BackgroundPreclinical and human data suggest that the onset of psychosis involves hippocampal glutamatergic dysfunction, driving hyperactivity/hyperperfusion in a hippocampal-midbrain-striatal circuit. Whether glutamatergic dysfunction is related to cerebral perfusion in patients at Clinical High Risk (CHR) for psychosis, and whether cannabidiol (CBD) has ameliorative effects on glutamate or its relationship with blood flow remains unknown.MethodsUsing a double-blind, parallel-group design, 33 CHR patients were randomised to 600mg CBD or placebo; 19 healthy controls did not receive any drug. Proton magnetic resonance spectroscopy was used to measure glutamate concentrations in left hippocampus. We examined differences relating to CHR status (controls vs placebo), effects of CBD (placebo vs CBD) and linear between-group effects, such that placebo>CBD>controls or controls>CBD>placebo. We also examined group x glutamate x cerebral perfusion (measured using arterial spin labelling) interactions.ResultsCompared to controls, CHR-placebo patients had significantly lower hippocampal glutamate (p=.015) and a significant linear relationship was observed across groups, such that glutamate was highest in controls, lowest in CHR-placebo and intermediate in patients under CBD (p=.031). There was also a significant interaction between group (controls vs CHR-placebo), hippocampal glutamate and perfusion in the putamen and insula (pFWE=.012), driven by a strong positive correlation in the CHR-placebo group vs a negative correlation in controls.ConclusionsOur findings suggest that hippocampal glutamate is lower in CHR patients and may be partially normalised by CBD treatment. Furthermore, we provide the firstin vivoevidence of an abnormal relationship between hippocampal glutamate and resting perfusion in the striatum and insula in these patients.

BackgroundHippocampal hyperperfusion has been observed in people at Clinical High Risk for Psychosis (CHR), is implicated in the pathophysiology driving psychosis onset and represents a potential disease-modifying treatment target. Whether cannabidiol (CBD) has ameliorative effects on hippocampal blood flow (rCBF) in CHR patients remains unknown.MethodsUsing a randomised, double-blind, parallel-group design, 33 CHR patients were randomised to a single oral 600mg dose of CBD or placebo. Nineteen healthy controls were studied under identical conditions but did not receive any drug. Hippocampal rCBF was measured using Arterial Spin Labelling. We examined differences relating to CHR status (controls vs placebo), effects of CBD in CHR (placebo vs CBD) and linear between-group relationships, such that placebo>CBD>controls or controls>CBD>placebo, using a combination of hypothesis-driven and exploratory wholebrain analyses.ResultsPlacebo-treated patients had significantly higher hippocampal rCBF bilaterally (all pFWEFWE=.035) such that rCBF was highest in the placebo group, lowest in controls and intermediate in the CBD group. Exploratory wholebrain results replicated previous findings of hyperperfusion in the hippocampus, striatum and midbrain in CHR patients, and provided novel evidence of increased rCBF in inferior-temporal and lateral-occipital regions in patients under CBD compared to placebo.ConclusionsOur findings suggest that CBD may partially normalise alterations in hippocampal blood flow associated with the CHR state and therefore merits further investigation as a potential novel treatment for this population.

This systematic review aims at bringing together and discussing all available data from clinical evidence regarding the role of integrated hypothalamic-pituitary-adrenocortical (HPA) axis and endocannabinoid (eCB) system modulation in psychosis clinical high-risk (CHR) state and psychosis at different stages of illness.

This review aims at gathering and discussing all available data from clinical and preclinical evidence regarding the role of palmitoylethanolamide (PEA) in psychosis and related conditions by conducting a systematic literature search for all such data.

This systematic review aims at bringing together and discussing all available data from preclinical evidence regarding the role of integrated hypothalamic-pituitary-adrenal (HPA) axis and endocannabinoid (eCB) system modulation, with reference to psychosis animal models and psychosis-related preclinical evidence.

Neural underpinnings of Parkinson’s Disease psychosis (PDP) remain unclear to this day with relatively few studies and reviews available. Using a systematic review approach, here we aimed to qualitatively synthesize evidence from studies investigating PD psychosis-specific alterations in brain structure, function or chemistry using different neuroimaging modalities. PubMed, Web of Science and Embase databases were searched for fMRI, rsfMRI, DTI, PET, and SPECT studies comparing PDP patients with PD patients without psychosis (PDnP). We report findings from 18 studies (291 PDP patients, mean age ± SD = 68.65 ± 3.76 years; 48.5% males; 433 PDnP patients, mean age ± SD = 66.97 ± 3.80 years; 52% males). Qualitative synthesis revealed widespread patterns of altered brain function across task-based and resting-state fMRI studies in PDP compared to PDnP patients. Similarly, white matter abnormalities were reported in parietal, temporal, and occipital regions. Hypometabolism and reduced dopamine transporter binding were also reported whole brain and in subcortical areas. This suggests extensive alterations affecting regions involved in high order visual processing and attentional networks.

BackgroundCognitive and executive deficits lead to worsening of quality of life and are a risk factor for developing dementia in Parkinson’s Disease (PD) patients with psychosis. However, which key cognitive domains are differentially affected in PD patients with psychosis (PDP) compared to those without (PDnP), remains unclear. Here we examined this using a Bayesian meta-analytic approach.MethodsSearches were conducted on PubMed, Web of Science, SCOPUS, Medline and PsycINFO. Hedges’ g effect-size estimates were extracted from eligible studies as a measure of standard mean differences between PDP and PDnP patients. Meta-analyses were conducted separately for each cognitive domain and sub-domain, we examined the effect of age, PD medications, PD duration and severity, depression and psychosis severity for all major domains with meta-regressions.ResultsEffect-size estimates suggest worse performance on all major domains (k=105 studies) in PDP compared to PDnP patients, with global cognition (k=103 studies,g=-0.57), processing speed (k=29 studies,g=-0.58), executive functions (k=33,g=-0.56), episodic memory (k=30 studies,g=-0.58), and perception (k=34 studies,g=-0.55) as the most likely affected domains. Age, depression, and PD duration had moderating effects on task-related performance across most of the major nine domains.ConclusionsWe report extensive deficits across nine domains as well as sub-domains in PD psychosis, with global cognition, processing speed and executive functions as the most likely impaired. Presence of depression may influence task-related performance in PDP, alongside age and PD duration, but not dose of dopamine replacement treatments.

BackgroundCommon neural underpinning of Parkinson’s Disease (PD) psychosis across different structural magnetic resonance imaging (MRI) studies remains unclear to this day with few studies and even fewer meta-analyses available.ObjectivesOur meta-analysis aimed to identify and summarise studies using MRI approach to identify PD psychosis-specific brain regions and examine the relation between cortical volume loss and dopaminergic and serotonergic receptor density.MethodsPubMed, Web of Science and Embase were searched for MRI studies of PD psychosis (PDP) compared to PD patients without psychosis (PDnP). Seed-baseddMapping with Permutation of Subject Images was applied in the meta-analysis where coordinates were available. Multiple linear regressions to examine the relationship between grey matter volume loss in PDP and receptor gene expression density (extracted from the Allen Human Brain Atlas) were conducted in R.ResultsWe observed lower grey matter volume in parietal-temporo-occipital regions from our meta-analysis (N studies =10, PDP n=211, PDnP, n=298). These results remained significant after adjusting for PD medications and for cognitive scores. Grey matter volume loss in PDP was associated with local expression of 5-HT1a (b=0.109,p=0.012) and 5-HT2a receptors (b=-0.106,p=0.002) also after adjusting for PD medications (5-HT1a,p= 0.005; 5-HT2a,p= 0.001).ConclusionsWidespread cortical volume loss in the parieto-temporo-occipital regions involved in information processing and integration, as well as attention, could result in PD psychosis symptoms. Neurobiological mechanisms implicating serotonergic receptors may also contribute to this condition.

Background Cannabidiol (CBD) is a non-intoxicating substance present in the extract of Cannabis sativa popularised by its therapeutic potential. A limited number of neuroimaging studies have investigated CBD effects on brain function primarily in healthy individuals, people with early/ clinical high risk of psychosis, and social anxiety disorder. As a result of heterogeneity in the population examined, imaging modality and neurocognitive paradigm, the acute brain effects of CBD and the molecular mechanisms that may underlie its effects remain unclear. Methods We meta-analysed neuroimaging studies that examined the acute effects of CBD, relative to placebo, on human brain function using SPECT and fMRI while performing diverse cognitive tasks. Subsequently, we examined the relationship between the spatially distributed pooled effects of CBD on brain signal and the distribution of candidate mechanistic targets for the effects of CBD including fatty acid amide hydrolase (FAAH), dopamine D2, serotonin and cannabinoid-type-1 receptors as indexed by their gene expression data. Results CBD modulated the function of several brain regions, including the medial frontoparietal, midcingulo-insular, pericentral, lateral frontoparietal, and dorsal frontoparietal networks as well as the striatum and cerebellum. There was a significant inverse relationship between the magnitude of pooled CBD effect on brain activation and expression of FAAH but not the other targets. Discussion These preliminary findings suggest that the effect of CBD in the human brain may be linked to local FAAH availability and suggests that there is a strong case for directly examining whether the effects of CBD on FAAH underlie its effects on brain function and behaviour.

SummaryCannabinoids are commonly perceived by the public as safe and effective for improving mental health, despite limited evidence to support their use. We discuss reasons why cannabinoids may be particularly compelling for our patients and provide strategies for how psychiatrists can counsel and educate patients on the evidence regarding cannabinoids.

Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) have been the most investigated cannabinoids at the human and preclinical levels, although the neurobiological mechanisms underlying their effects remain unclear. Human experimental evidence complemented by observational studies suggests that THC may have psychotogenic effects while CBD may have antipsychotic effects. However, whether their effects on brain function are consistent with their opposing behavioral effects remains unclear. To address this, here we synthesize neuroimaging evidence investigating the acute effects of THC and CBD on human brain function using a range of neuroimaging techniques, with an aim to identify the key brain substrates where THC and CBD have opposing effects. After a systematic search, a review of the available studies indicated marked heterogeneity. However, an overall pattern of opposite effect profiles of the two cannabinoids was evident with some degree of consistency, primarily attributed to the head-to-head challenge studies of THC and CBD. While head-to-head comparisons are relatively few, collectively the evidence suggests that opposite effects of THC and CBD may be present in the striatum, parahippocampus, anterior cingulate/medial prefrontal cortex, and amygdala, with opposite effects less consistently identified in other regions. Broadly, THC seems to increase brain activation and blood flow, whereas CBD seems to decrease brain activation and blood flow. Given the sparse evidence, there is a particular need to understand the mechanisms underlying their opposite behavioral effects because it may not only offer insights into the underlying pathophysiological mechanisms of psychotic disorders but also suggest potentially novel targets and biomarkers for drug discovery.

Background While current cannabis research has advanced our understanding into the effects of its individual components, there is a pressing need to identify simple terminology that is understood in the same way by researchers and users of cannabis. Current categorisation in research focuses on the two main cannabinoids: delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD); and two different species of cannabis: indica and sativa. Recreational cannabis has also been categorised by researchers as ‘skunk’ or ‘hash’. Focusing on individuals who use cannabis frequently, this study aimed to identify views on current terms used to denote different types of cannabis and to identify terms validated by participants. These views were extracted from responses of the Cannabis Experiences Questionnaire (CEQ), a widely used instrument in the literature. Methods We qualitatively analysed 236 free-text responses from Question 23 of the CEQ survey (using Iterative Categorisation) relating to categorization and consumption methods. Data was used from a previous study (Sami et al., Psychol Med 49:103–12, 2019), which recruited a convenience sample of 1231 participants aged 18 years and above who had previously used cannabis. Results Regarding type of cannabis used, specific strain names (n = 130), concentrates (n = 37), indica/sativa (n = 22) and THC/CBD terms (n = 22) were mentioned. Other terms used were hybrids (n = 10), origins of specific strains (n = 17), edibles (n = 8), and herbal cannabis (n = 7). Regarding problems with specific terms, participants were skeptical about terms such as skunk and super skunk (n = 78) preferring terms like THC/CBD, indica/sativa, specific marketed strains and references to preparation methods. Conclusions The results suggest a disparity between the common terms used by researchers in academia and those used by cannabis consumers. While there are advantages and limitations of using these terms to bridge views of researchers and individuals who use cannabis, this study underscores the importance of formally assessing chemical constituents rather than relying on self-report data and of incorporating cannabis user views on current terms used in research, potentially also incorporating descriptors of preparation and consumption methods.

Background Evidence suggests that an overlap exists between the neurobiology of psychotic disorders and the effects of cannabinoids on neurocognitive and neurochemical substrates involved in reward processing. Aims We investigate whether the psychotomimetic effects of delta-9-tetrahydrocannabinol (THC) and the antipsychotic potential of cannabidiol (CBD) are underpinned by their effects on the reward system and dopamine. Methods This narrative review focuses on the overlap between altered dopamine signalling and reward processing induced by cannabinoids, pre-clinically and in humans. A systematic search was conducted of acute cannabinoid drug-challenge studies using neuroimaging in healthy subjects and those with psychosis Results There is evidence of increased striatal presynaptic dopamine synthesis and release in psychosis, as well as abnormal engagement of the striatum during reward processing. Although, acute THC challenges have elicited a modest effect on striatal dopamine, cannabis users generally indicate impaired presynaptic dopaminergic function. Functional MRI studies have identified that a single dose of THC may modulate regions involved in reward and salience processing such as the striatum, midbrain, insular, and anterior cingulate, with some effects correlating with the severity of THC-induced psychotic symptoms. CBD may modulate brain regions involved in reward/salience processing in an opposite direction to that of THC. Conclusions There is evidence to suggest modulation of reward processing and its neural substrates by THC and CBD. Whether such effects underlie the psychotomimetic/antipsychotic effects of these cannabinoids remains unclear. Future research should address these unanswered questions to understand the relationship between endocannabinoid dysfunction, reward processing abnormalities, and psychosis.

Social rewards or punishments motivate human learning and behaviour, and alterations in the brain circuits involved in the processing of these stimuli have been linked with several neuropsychiatric disorders. However, questions still remain about the exact neural substrates implicated in social reward and punishment processing. Here, we conducted four Anisotropic Effect Size Signed Differential Mapping voxel-based meta-analyses of fMRI studies investigating the neural correlates of the anticipation and receipt of social rewards and punishments using the Social Incentive Delay task. We found that the anticipation of both social rewards and social punishment avoidance recruits a wide network of areas including the basal ganglia, the midbrain, the dorsal anterior cingulate cortex, the supplementary motor area, the anterior insula, the occipital gyrus and other frontal, temporal, parietal and cerebellar regions not captured in previous coordinate-based meta-analysis. We identified decreases in the BOLD signal during the anticipation of both social reward and punishment avoidance in regions of the default-mode network that were missed in individual studies likely due to a lack of power. Receipt of social rewards engaged a robust network of brain regions including the ventromedial frontal and orbitofrontal cortices, the anterior cingulate cortex, the amygdala, the hippocampus, the occipital cortex and the brainstem, but not the basal ganglia. Receipt of social punishments increased the BOLD signal in the orbitofrontal cortex, superior and inferior frontal gyri, lateral occipital cortex and the insula. In contrast to the receipt of social rewards, we also observed a decrease in the BOLD signal in the basal ganglia in response to the receipt of social punishments. Our results provide a better understanding of the brain circuitry involved in the processing of social rewards and punishment. Furthermore, they can inform hypotheses regarding brain areas where disruption in activity may be associated with dysfunctional social incentive processing during disease

BackgroundCannabis use has been associated with psychosis through exposure to delta-9-tetrahydrocannabinol (Δ9-THC), its key psychoactive ingredient. Although preclinical and human evidence suggests that Δ9-THC acutely modulates glial function and hypothalamic-pituitary-adrenal (HPA) axis activity, whether differential sensitivity to the acute psychotomimetic effects of Δ9-THC is associated with differential effects of Δ9-THC on glial function and HPA-axis response has never been tested.MethodsA double-blind, randomized, placebo-controlled, crossover study investigated whether sensitivity to the psychotomimetic effects of Δ9-THC moderates the acute effects of a single Δ9-THC dose (1.19 mg/2 ml) on myo-inositol levels, a surrogate marker of glia, in the Anterior Cingulate Cortex (ACC), and circadian cortisol levels, the key neuroendocrine marker of the HPA-axis, in a set of 16 healthy participants (seven males) with modest previous cannabis exposure.ResultsThe Δ9-THC-induced change in ACC myo-inositol levels differed significantly between those sensitive to (Δ9-THC minus placebo; M = −0.251, s.d. = 1.242) and those not sensitive (M = 1.615, s.d. = 1.753) to the psychotomimetic effects of the drug (t(14) = 2.459, p = 0.028). Further, the Δ9-THC-induced change in cortisol levels over the study period (baseline minus 2.5 h post-drug injection) differed significantly between those sensitive to (Δ9-THC minus placebo; M = −275.4, s.d. = 207.519) and those not sensitive (M = 74.2, s.d. = 209.281) to the psychotomimetic effects of the drug (t(13) = 3.068, p = 0.009). Specifically, Δ9-THC exposure lowered ACC myo-inositol levels and disrupted the physiological diurnal cortisol decrease only in those subjects developing transient psychosis-like symptoms.ConclusionsThe interindividual differences in transient psychosis-like effects of Δ9-THC are the result of its differential impact on glial function and stress response.

Maternal immune activation (MIA) during prenatal development is an environmental risk factor for psychiatric disorders including schizophrenia (SZ). Converging lines of evidence from human and animal model studies suggest that elevated cytokine levels in the maternal and fetal compartments are an important indication of the mechanisms driving this association. However, there is variability in susceptibility to the psychiatric risk conferred by MIA, likely influenced by genetic factors. How MIA interacts with a genetic profile susceptible to SZ is challenging to test in animal models. To address this gap, we examined whether differential gene expression responses occur in forebrain-lineage neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (hiPSC) generated from three individuals with a diagnosis of schizophrenia and three healthy controls. Following acute (24 h) treatment with either interferon-gamma (IFNγ; 25 ng/μl) or interleukin (IL)-1β (10 ng/μl), we identified, by RNA sequencing, 3380 differentially expressed genes (DEGs) in the IFNγ-treated control lines (compared to untreated controls), and 1980 DEGs in IFNγ-treated SZ lines (compared to untreated SZ lines). Out of 4137 genes that responded significantly to IFNγ across all lines, 1223 were common to both SZ and control lines. The 2914 genes that appeared to respond differentially to IFNγ treatment in SZ lines were subjected to a further test of significance (multiple testing correction applied to the interaction effect between IFNγ treatment and SZ diagnosis), yielding 359 genes that passed the significance threshold. There were no differentially expressed genes in the IL-1β-treatment conditions after Benjamini-Hochberg correction. Gene set enrichment analysis however showed that IL-1β impacts immune function and neuronal differentiation. Overall, our data suggest that a) SZ NPCs show an attenuated transcriptional response to IFNγ treatment compared to controls; b) Due to low IL-1β receptor expression in NPCs, NPC cultures appear to be less responsive to IL-1β than IFNγ; and c) the genes differentially regulated in SZ lines – in the face of a cytokine challenge – are primarily associated with mitochondrial, “loss-of-function”, pre- and post-synaptic gene sets. Our findings particularly highlight the role of early synaptic development in the association between maternal immune activation and schizophrenia risk.

The neurobiological mechanisms underlying the effects of delta-9-tetrahydrocannabinol (THC) remain unclear. Here, we examined the spatial acute effect of THC on human regional brain activation or blood flow (hereafter called 'activation signal') in a 'core' network of brain regions from 372 participants, tested using a within-subject repeated measures design under experimental conditions. We also investigated whether the neuromodulatory effects of THC are related to the local expression of the cannabinoid-type-1 (CB1R) and type-2 (CB2R) receptors. Finally, we investigated the dose-response relationship between THC and key brain substrates. These meta-analytic findings shed new light on the localisation of the effects of THC in the human brain, suggesting that THC has neuromodulatory effects in regions central to many cognitive tasks and processes, related to dose, with greater effects in regions with higher levels of CB1R expression.

Evidence indicates shared physiopathological mechanisms between autism and psychosis. In this regard, the endocannabinoid system has been suggested to modulate neural circuits during the early stage of neurodevelopment, with implications for both autism and psychosis. Nevertheless, such potential common markers of disease have been investigated in both autism and psychosis spectrum disorders, without considering the conundrum of differentiating the two groups of conditions in terms of diagnosis and treatment. Here, we systematically review all human and animal studies examining the endocannabinoid system and its biobehavioral correlates in the association between autism and psychosis. Studies indicate overlapping biobehavioral aberrancies between autism and schizophrenia, subject to correction by modulation of the endocannabinoid system. In addition, common cannabinoid-based pharmacological strategies have been identified, exerting epigenetic effects across genes controlling neural mechanisms shared between autism and schizophrenia. Interestingly, a developmental and transgenerational trajectory between autism and schizophrenia is supported by evidence that exogenous alteration of the endocannabinoid system promotes progression to inheritable psychosis phenotypes in the context of biobehavioral autism vulnerability. However, evidence for a diametral association between autism and psychosis is scant. Several clinical implications follow from evidence of a developmental continuum between autism and psychosis as a function of the endocannabinoid system dysregulation.

Around half of patients with early psychosis have a history of cannabis use. We aimed to determine if there are neurobiological differences in these the subgroups of persons with psychosis with and without a history of cannabis use. We expected to see regional deflations in hippocampus as a neurotoxic effect and regional inflations in striatal regions implicated in addictive processes. Volumetric, T1w MRIs were acquired from people with a diagnosis psychosis with (PwP + C = 28) or without (PwP − C = 26) a history of cannabis use; and Controls with (C + C = 16) or without (C − C = 22) cannabis use. We undertook vertex‐based shape analysis of the brainstem, amygdala, hippocampus, globus pallidus, nucleus accumbens, caudate, putamen, thalamus using FSL FIRST. Clusters were defined through Threshold Free Cluster Enhancement and Family Wise Error was set at p, Cannabis is often associated with the early course of psychotic disorders. The EfCIP study looked at four groups: People with psychosis with cannabis use, people with psychosis without cannabis use, controls with cannabis use and controls without cannabis use. We observe change in subcortical morphology in persons with psychosis with cannabis use versus persons with psychosis without cannabis use in the putamen and thalamus which may be due to compulsive use in this group.