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First episode psychosis (FEP) patients who use cannabis experience more frequent psychotic and euphoric intoxication experiences compared to controls. It is not clear whether this is consequent to patients being more vulnerable to the effects of cannabis use or to their heavier pattern of use. We aimed to determine whether extent of use predicted psychotic-like and euphoric intoxication experiences in patients and controls and whether this differs between groups.
We analysed data on patients who had ever used cannabis (n = 655) and controls who had ever used cannabis (n = 654) across 15 sites from six countries in the EU-GEI study (2010–2015). We used multiple regression to model predictors of cannabis-induced experiences and to determine if there was an interaction between caseness and extent of use.
Caseness, frequency of cannabis use and money spent on cannabis predicted psychotic-like and euphoric experiences (p ⩽ 0.001). For psychotic-like experiences (PEs) there was a significant interaction for caseness × frequency of use (p < 0.001) and caseness × money spent on cannabis (p = 0.001) such that FEP patients had increased experiences at increased levels of use compared to controls. There was no significant interaction for euphoric experiences (p > 0.5).
FEP patients are particularly sensitive to increased psychotic-like, but not euphoric experiences, at higher levels of cannabis use compared to controls. This suggests a specific psychotomimetic response in FEP patients related to heavy cannabis use. Clinicians should enquire regarding cannabis related PEs and advise that lower levels of cannabis use are associated with less frequent PEs.
Recent 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.
Patients 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.
Compared 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.
This suggests that normalization of mediotemporal and prefrontal dysfunction and mediotemporal-striatal functional connectivity may underlie the antipsychotic effects of CBD.
Evidence regarding the association between cannabis use and depression remain conflicting, especially as studies have not typically adopted a longitudinal design with a follow-up period that was long enough to adequately cover the risk period for onset of depression.
Males from the Cambridge Study in Delinquent Development (CSDD) (N = 285) were assessed seven times from age 8 to 48 years to prospectively investigate the association between cannabis use and risk of major depressive disorder (MDD). A combination of multiple analyses (logistic regression, Cox regression, fixed-effects analysis) was employed to explore the strength and direction of effect within different developmental stages.
Multiple regression analyses revealed that early-onset cannabis use (before age 18) but not late-onset cannabis use (after age 27) was associated with a higher risk and shorter time until a subsequent MDD diagnosis. This effect was present in high-frequency [(odds ratio (OR) 8.83, 95% confidence interval (CI) 1.29–70.79]; [hazard ratio (HR) 8.69, 95% CI 2.07–36.52)] and low-frequency early-onset users (OR 2.41, 95% CI 1.22–4.76; HR 2.09, 95% CI 1.16–3.74). Effect of increased frequency of cannabis use on increased risk of subsequent MDD was observed only for use during adolescence (age 14–18) but not at later life stages, while controlling for observed and non-unobserved time-invariant factors. Conversely, MDD in adulthood (age 18–32) was linked to a reduction in subsequent cannabis use (age 32–48).
The present findings provide evidence implicating frequent cannabis use during adolescence as a risk factor for later life depression. Future studies should further examine causality of effects in larger samples.
Evidence suggests that cannabis-induced psychotic-like experiences may be a marker of psychosis proneness. The effect of such experiences on cannabis use has not systematically been examined.
We undertook a mixed-methods online survey of 1231 cannabis users (including 926 continued users) using the Cannabis Experiences Questionnaire. We examined the effect of psychotic-like and pleasurable experiences on cessation of cannabis and intention to quit. Socio-demographic variables, cannabis use parameters and substance misuse history were included as covariates. Free-text data explored subjective reasons for changes in use.
Cessation of cannabis use was associated with greater psychotic-like experiences [p < 0.001, Exp(B) 1.262, 95% confidence interval (CI) 1.179–1.351], whilst continued cannabis users were more likely to report pleasurable experiences [p < 0.001, Exp(B) 0.717, 95% CI 0.662–0.776]. Intention to quit cannabis in continued users was associated with greater psychotic-like experiences [p < 0.003, Exp(B) 1.131, 95% CI 1.044–1.225], whilst intention to not quit was significantly associated with increased pleasurable experiences [p < 0.015, Exp(B) 0.892, 95% CI 0.814–0.978]. Whereas former users clearly ascribed cessation to negative experiences, continued users who expressed intention to quit less readily ascribed the intention to negative experiences.
Elucidation of psychotic-like experiences may form the basis of a therapeutic intervention for those who wish to quit. Cessation in those with cannabis-induced psychotomimetic experiences may offset the risk for the development of a psychotic disorder, in this higher risk group.
Cannabis and its main psychoactive ingredient δ-9-tetrahydrocannibidiol (THC) can induce transient psychotic symptoms in healthy individuals and exacerbate them in those with established psychosis. However, not everyone experience these effects, suggesting that certain individuals are particularly susceptible. The neural basis of this sensitivity to the psychotomimetic effects of THC is unclear.
We investigated whether individuals who are sensitive to the psychotomimetic effects of THC (TP) under experimental conditions would show differential hippocampal activation compared with those who are not (NP). We studied 36 healthy males under identical conditions under the influence of placebo or THC (10 mg) given orally, on two separate occasions, in a pseudo-randomized, double-blind, repeated measures, within-subject, cross-over design, using psychopathological assessments and functional MRI while they performed a verbal learning task. They were classified into those who experienced transient psychotic symptoms (TP; n = 14) following THC administration and those who did not (NP; n = 22).
Under placebo conditions, there was significantly greater engagement of the left hippocampus (p < 0.001) in the TP group compared with the NP group during verbal encoding, which survived leave-one-out analysis. The level of hippocampal activation was directly correlated (Spearman's ρ = 0.44, p = 0.008) with the severity of transient psychotic symptoms induced by THC. This difference was not present when we compared two subgroups from the same sample that were defined by sensitivity to anxiogenic effects of THC.
These results suggest that altered hippocampal activation during verbal encoding may serve as a marker of sensitivity to the acute psychotomimetic effects of THC.
Although alterations in medial temporal lobe structures have been previously associated with use of cannabis, one of the most widely used illicit drugs, whether such alterations are a cause or effect of cannabis use has been unclear.
In this cross-sectional observational study involving 404 twins/siblings, we have compared cortical thickness and surface area between groups of gender-matched sibling-pairs (concordant cannabis unexposed, concordant exposed and discordant for cannabis exposure) using permutation tests after controlling for potential confounds. Bi-variate polygenic model was used to assess the genetic and environmental contributions underlying cortical morphological phenotypes and frequency of cannabis use.
Cortical thickness of the right entorhinal cortex was significantly lower in the concordant exposed siblings compared to both discordant unexposed and discordant exposed groups [false discovery rate (FDR)-corrected, q < 0.05]. The association between the right entorhinal cortex thickness and frequency of cannabis use is due to the contribution of significant shared additive genetic (ρg = −0.19 ± 0.08; p = 0.02) factors but not unique environment (ρe = 0.05 ± 0.09; p = 0.53). Significantly lower surface area of the right entorhinal cortex in discordant exposed group compared with the discordant unexposed group furnishes preliminary evidence in support of causal effect of cannabis use (FDR-corrected, q < 0.05). However, bi-variate polygenic model-based analysis did not show any significant effect.
Shared genetic liability may underlie the association between cannabis exposure and thinner right entorhinal cortex. Prospective longitudinal studies are necessary to definitively disentangle the cause–effect relationships of cannabis use.
The 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.
Here, 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.
The 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.
Overall, 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.
This chapter surveys possible lasting consequences of cannabinoid exposure during crucial periods of pubertal and adolescent maturation reported from animal studies. Endocannabinoids and their cannabinoid receptors, CB1 and CB2, are present from the early stages of gestation and play a number of vital roles for the developing organism. Beside direct alterations in the endocannabinoid or other neurotransmitter systems, adolescent/pubertal cannabinoid exposure has been reported to affect cortical and limbic systems in particular. Global evidence indicates that cannabis use/abuse acts as a risk factor for the emergence of schizophrenia, especially among early-onset cannabis users. Similar indications were observed in animal studies, where chronic pubertal, but not adult, cannabinoid treatment resulted in lasting behavioral deficits, resembling at least some aspects of schizophrenia. Data from animal research point out clearly that the age at which an individual is exposed to cannabinoids has major impact on subsequent effects of this drug.