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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.

BackgroundRecent evidence suggests that cannabidiol (CBD), a non-intoxicating ingredient present in cannabis extract, has an antipsychotic effect in people with established psychosis. However, the effect of CBD on the neurocognitive mechanisms underlying psychosis is unknown.MethodsPatients with established psychosis on standard antipsychotic treatment were studied on separate days at least one week apart, to investigate the effects of a single dose of orally administered CBD (600 mg) compared to a matched placebo (PLB), using a double-blind, randomized, PLB-controlled, repeated-measures, within-subject cross-over design. Three hours after taking the study drug participants were scanned using a block design functional magnetic resonance imaging (fMRI) paradigm, while performing a verbal paired associate learning task. Fifteen psychosis patients completed both study days, 13 completed both scanning sessions. Nineteen healthy controls (HC) were also scanned using the same fMRI paradigm under identical conditions, but without any drug administration. Effects of CBD on brain activation measured using the blood oxygen level-dependent hemodynamic response fMRI signal were studied in the mediotemporal, prefrontal, and striatal regions of interest.ResultsCompared to HC, psychosis patients under PLB had altered prefrontal activation during verbal encoding, as well as altered mediotemporal and prefrontal activation and greater mediotemporal-striatal functional connectivity during verbal recall. CBD attenuated dysfunction in these regions such that activation under its influence was intermediate between the PLB condition and HC. CBD also attenuated hippocampal-striatal functional connectivity and caused trend-level symptom reduction in psychosis patients.ConclusionsThis suggests that normalization of mediotemporal and prefrontal dysfunction and mediotemporal-striatal functional connectivity may underlie the antipsychotic effects of CBD.

ObjectiveThe relationship between cannabis use and the onset of psychosis is well established. Aberrant salience processing is widely thought to underpin many of these symptoms. Literature explicitly investigating the relationship between aberrant salience processing and cannabis use is scarce; with those few studies finding that acute tetrahydrocannabinol (THC) administration (the main psychoactive component of cannabis) can result in abnormal salience processing in healthy cohorts, mirroring that observed in psychosis. Nevertheless, the extent of and mechanisms through which cannabis has a modulatory effect on aberrant salience, following both acute and chronic use, remain unclear.MethodsHere, we systematically review recent findings on the effects of cannabis use – either through acute THC administration or in chronic users – on brain regions associated with salience processing (through functional MRI data); and performance in cognitive tasks that could be used as either direct or indirect measures of salience processing. We identified 13 studies either directly or indirectly exploring salience processing. Three types of salience were identified and discussed – incentive/motivational, emotional/affective, and attentional salience.ResultsThe results demonstrated an impairment of immediate salience processing, following acute THC administration. Amongst the long-term cannabis users, normal salience performance appeared to be underpinned by abnormal neural processes.ConclusionsOverall, the lack of research specifically exploring the effects of cannabis use on salience processing, weaken any conclusions drawn. Additional research explicitly focussed on salience processing and cannabis use is required to advance our understanding of the neurocognitive mechanisms underlying the association between cannabis use and development of psychosis.

The aim of this article is to summarize current evidence regarding alterations in the neuroendocrine stress response system and endocannabinoid system and their relationship in psychotic disorders such as schizophrenia. Exposure to stress is linked to the development of a number of psychiatric disorders including psychosis. However, the precise role of stress in the development of psychosis and the possible mechanisms that might underlie this are not well understood. Recently the cannabinoid hypothesis of schizophrenia has emerged as a potential line of enquiry. Endocannabinoid levels are increased in patients with psychosis compared with healthy volunteers; furthermore, they increase in response to stress, which suggests another potential mechanism for how stress might be a causal factor in the development of psychosis. However, research regarding the links between stress and the endocannabinoid system is in its infancy. Evidence summarized here points to an alteration in the baseline tone and reactivity of the hypothalamic–pituitary–adrenal (HPA) axis as well as in various components of the endocannabinoid system in patients with psychosis. Moreover, the precise nature of the inter-relationship between these two systems is unclear in man, especially their biological relevance in the context of psychosis. Future studies need to simultaneously investigate HPA axis and endocannabinoid alterations both at baseline and following experimental perturbation in healthy individuals and those with psychosis to understand how they interact with each other in health and disease and obtain mechanistic insight as to their relevance to the pathophysiology of schizophrenia.

Background.What determines inter-individual variability to impairments in behavioural control that may underlie road-traffic accidents, and impulsive and violent behaviours occurring under the influence of cannabis, the most widely used illicit drug worldwide?Method.Employing a double-blind, repeated-measures design, we investigated the genetic and neural basis of variable sensitivity to cannabis-induced behavioural dyscontrol in healthy occasional cannabis users. Acute oral challenge with placebo or Δ9-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, was combined with functional magnetic resonance imaging, while participants performed a response inhibition task that involved inhibiting a pre-potent motor response. They were genotyped for rs1130233 single nucleotide polymorphisms (SNPs) of the protein kinase B (AKT1) gene.Results.Errors of inhibition were significantly (p = 0.008) increased following administration of THC in carriers of the A allele, but not in G allele homozygotes of theAKT1rs1130233 SNP. The A allele carriers also displayed attenuation of left inferior frontal response with THC evident in the sample as a whole, while there was a modest enhancement of inferior frontal activation in the G homozygotes. There was a direct relationship (r = − 0.327,p = 0.045) between the behavioural effect of THC and its physiological effect in the inferior frontal gyrus, whereAKT1genotype modulated the effect of THC.Conclusions.These results require independent replication and show that differing vulnerability to acute psychomotor impairments induced by cannabis depends on variation in a gene that influences dopamine function, and is mediated through modulation of the effect of cannabis on the inferior frontal cortex, that is rich in dopaminergic innervation and critical for psychomotor control.

BackgroundCannabis use is associated with an increased risk of developing a psychotic disorder but the temporal relationship between cannabis use and onset of illness is unclear. The objective of this study was to assess prospectively the influence of cannabis use on transition to psychosis in people at ultra-high risk (UHR) for the disorder.MethodLifetime and continued cannabis use was assessed in a consecutively ascertained sample of 182 people (104 male, 78 female) at UHR for psychosis. Individuals were then followed clinically for 2 years to determine their clinical outcomes.ResultsLifetime cannabis use was reported by 134 individuals (73.6%). However, most of these individuals had stopped using cannabis before clinical presentation (n = 98, 73.1%), usually because of adverse effects. Among lifetime users, frequent use, early-onset use and continued use after presentation were all associated with an increase in transition to psychosis. Transition to psychosis was highest among those who started using cannabis before the age of 15 years and went on to use frequently (frequent early-onset use: 25%; infrequent or late-onset use: 5%; χ21 = 10.971, p = 0.001). However, within the whole sample, cannabis users were no more likely to develop psychosis than those who had never used cannabis (cannabis use: 12.7%; no use: 18.8%; χ21 = 1.061, p = 0.303).ConclusionsIn people at UHR for psychosis, lifetime cannabis use was common but not related to outcome. Among cannabis users, frequent use, early-onset use and continued use after clinical presentation were associated with transition to psychosis.

Background:This study examined the effect of Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on brain activation during a motor inhibition task.Methods:Functional magnetic resonance imaging and behavioural measures were recorded while 15 healthy volunteers performed a Go/No-Go task following administration of either THC or CBD or placebo in a double-blind, pseudo-randomized, placebo-controlled repeated measures within-subject design.Results:Relative to placebo, THC attenuated activation in the right inferior frontal and the anterior cingulate gyrus. In contrast, CBD deactivated the left temporal cortex and insula. These effects were not related to changes in anxiety, intoxication, sedation, and psychotic symptoms.Conclusions:These data suggest that THC attenuates the engagement of brain regions that mediate response inhibition. CBD modulated function in regions not usually implicated in response inhibition.