Cannabis is the world's most widely used illicit drug. It can impair verbal learning and induce psychosis, both acutely and possibly following long term use. But, where cannabis acts in the brain to impair verbal learning and induce psychotic symptoms is unclear. The aim of this study was to clarify how one of the main psychoactive ingredients of cannabis, delta-9-tetrahydrocannabinol (THC) acts on the brain to impair verbal learning and induce psychotic symptoms.

15 healthy males with minimal exposure to cannabis, were studied on 2 occasions approximately 1 month apart, following oral administration of 10mg of THC or placebo 1 hour prior to scanning, in a double-blind design. MR images were acquired on a 1.5T GE camera while subjects performed a Verbal paired associates task with separate encoding followed by retrieval conditions, with the conditions repeated in the same sequence 4 times. We examined the main effects of drug, task and drug- task interactions.

Administration of THC abolished the normal linear decrement in parahippocampal activation across successive encoding blocks and was associated with a trend for impaired word recall. Administration of THC also altered the normal time-dependent change in ventral striatal activation during retrieval of word pairs which was directly correlated with concurrently induced psychotic symptoms.

These results suggest that impairment in learning and verbal memory associated with cannabis use may be mediated through its action in the medial temporal cortex while psychotic symptoms may be induced through its action in the ventral striatum.

Cannabis has well established effects on cognitive processing but the neural basis of these is unclear. We used functional neuroimaging to investigate this, focusing on tasks that engaged verbal memory and response inhibition.

Subjects were 15 healthy males who had used cannabis < 25 times in their lifetime. Each subject was studied on 3 occasions, and was given either THC, CBD or placebo 1 hour prior to scanning, in a double-blind design. The order of drug administration was randomised and there was 1 month between each scanning session. During each session, images were acquired on a 1.5T GE camera while subjects performed a verbal paired associates memory task and a Go/No Go task. The modulatory effects of THC and CBD relative to placebo were examined by comparing activation during each task.

During the encoding phase of the memory task THC attenuated activation in the left temporal cortex compared to placebo. During the go-no go task, THC attenuated activation in the right inferior frontal cortex. Neither of these effects were attributable to differences in behavioural performance, sedation, or intoxication. The severity of psychotic symptoms provoked by THC was a function of its effect on right inferior frontal activation during response inhibition.

The effects of cannabis on verbal memory and motor control may be mediated through the influence of THC on left temporal and right inferior frontal activity, respectively. The induction of psychotic symptoms by cannabis may reflect an effect of THC on right inferior frontal activity.

The study sought to examine the neurophysiological effects of cannabidiol (CBD) on the emotional processing using functional Magnetic Resonance Imaging (fMRI).

Fifteen healthy male participants (age range 18-35) with a lifetime exposure to cannabis of 15 times or less were recruited in a double blind event-related fMRI design. Prior to each scanning session, participants were given an oral dose of either 600mg CBD or a placebo. The blood levels of drugs were monitored via an intravenous line, while systolic and diastolic blood pressure and heart rate (beats per minute) were recorded manually. During the scan, subjects were presented with 10 different facial identities, each identity expressing 50% or 100% intensities of fear or a neutral expression. Neuropsychological performance and symptoms ratings were recorded at baseline, immediately before scanning (1 hr), immediately after scanning (2 hr), and one hour post scanning (3 hr).

CBD had no significant effect on the gender discrimination task. Reaction times were significantly faster when processing 100% fearful faces than compared to 50% fearful and neutral faces. CBD had a significant effect on brain activation in response to faces with emotional expressions, decreasing activation in the right posterior cingulate gyrus and in the right cerebellum, when compared to placebo. Furthermore, a significant interaction effect was observed. In the right cingulate gyrus CBD attenuated activation during the processing of intense fearful faces but had no effect of neural response to neutral or mild fearful faces.

CBD significantly modulates the neurophysiological response associated with anxiety.

This study examined the effect of Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on brain activation during a motor inhibition task.

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.

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.

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.

Neuropsychological and neuroimaging studies of response inhibition in cannabis users have reported inconsistent results. The age of onset of cannabis use and individual genetic differences may play a critical role in the regulation of inhibition in cannabis users.

We examine the influence of COMT Val158Met functional polymorphism on the response inhibition brain network in a group of early-onset chronic cannabis users compared with healthy controls.

fMRI data was acquired from 27 chronic cannabis users who began use cannabis before 16 years of age, and 29 non-using control subjects matched in terms of age, educational level and intelligence quotient while undergoing the Multi-Source Interference Task (MSIT). Participants were male, Caucasians aged between 18 and 30 years. All were assessed by a structured psychiatric interview (PRISM) to exclude any lifetime Axis-I disorder (DSM-IV). COMT genotyping was performed and resonance imaging data was analysed by voxel-based morphometry (VBM).

Both groups did not differ on their behavioural performance and brain responses during the MSIT task. A significant group-by-genotype interaction was observed on task-related brain activation (and on MSIT reaction times), in which met carrier load was associated with increased activation in cannabis users and val carrier load with increased activation in controls. The interaction pattern included the medial frontal cortex, ACC, inferior frontal gyrus, ventral striatum, anterior mesencephalon, inferior parietal and superior temporal cortices and the PCC.

Chronic cannabis exposure interacts with the genetically driven dopamine function in the modulation of the neural mechanisms related to response inhibition.

Grants:PNSD/2011/050, PNSD2006/101, SGR2009/1435.

Increased psychotomimetic response to cannabis is demonstrated in psychosis-prone individuals. Early use of cannabis has poorer prognostic outcomes. However, as yet no cut-off age for early use has been established.

To determine, if age at first use affects later cannabis experiences and to determine if a “critical age” of first use exists for psychotomimetic cannabis experiences.

The cannabis experiences questionnaire (CEQ) (EUGEI version) was administered to a large internet-based non-clinical sample. Regression analysis was conducted of age at first use against CEQ scores controlling for gender, age frequency of use and duration of use. To determine cut-off age: independent ‘t’ tests (parametric) and Mann–Whitney-U tests (non-parametric) were used to determine significance of differences in CEQ scores at cut-off ages from 12-25.

We obtained data for 1115 participants. Younger age at first use was significantly associated with increased psychotomimetic experiences (adjusted P < 0.001). All cannabis experiences were increased in in those commencing at younger age at every cut off age from 17 to 22 (P < 0.001) with maximal difference at 22. Psychotic experiences significantly varied from age of first use of 19 to 22 with maximal difference at cut-off ages 20, 21 and 22 (P < 0.001). Pleasurable experiences were significantly reduced in those commencing later at every cut-off age from age of use 17 to 22 (P < 0.001) with maximal difference between groups at age 20.

Later onset of use is associated with reduced cannabis experiences till the early 1920s. This may have public health implications.

The authors have not supplied their declaration of competing interest.

Evidence has been accumulating regarding alterations in components of the endocannabinoid system in patients with psychosis. Of all the putative risk factors associated with psychosis, being at clinical high-risk for psychosis (CHR) has the strongest association with the onset of psychosis, and exposure to childhood trauma has been linked to an increased risk of development of psychotic disorder. We aimed to investigate whether being at-risk for psychosis and exposure to childhood trauma were associated with altered endocannabinoid levels.

We compared 33 CHR participants with 58 healthy controls (HC) and collected information about previous exposure to childhood trauma as well as plasma samples to analyse endocannabinoid levels.

Individuals with both CHR and experience of childhood trauma had higher N-palmitoylethanolamine (p < 0.001) and anandamide (p < 0.001) levels in peripheral blood compared to HC and those with no childhood trauma. There was also a significant correlation between N-palmitoylethanolamine levels and symptoms as well as childhood trauma.

Our results suggest an association between CHR and/or childhood maltreatment and elevated endocannabinoid levels in peripheral blood, with a greater alteration in those with both CHR status and history of childhood maltreatment compared to those with either of those risks alone. Furthermore, endocannabinoid levels increased linearly with the number of risk factors and elevated endocannabinoid levels correlated with the severity of CHR symptoms and extent of childhood maltreatment. Further studies in larger cohorts, employing longitudinal designs are needed to confirm these findings and delineate the precise role of endocannabinoid alterations in the pathophysiology of psychosis.

Substance use may increase the risk of non-adherence to antipsychotics, resulting in negative outcomes in patients with psychosis.

We aimed to quantitatively summarize evidence regarding the effect of cannabis use, the most commonly used illicit drug amongst those with psychosis, on adherence to antipsychotic medication. Studies were identified through a systematic database search. Adopting random-effects models, pooled odds ratios (OR) for risk of non-adherence to antipsychotic medications were calculated comparing: cannabis-users at baseline v. non-users at baseline; non users v. continued cannabis users at follow-up; non-users v. former users at follow-up; former users v. current users.

Fifteen observational studies (n = 3678) were included. Increased risk of non-adherence was observed for cannabis users compared to non-users (OR 2.46, n = 3055). At follow-up, increased risk of non-adherence was observed for current users compared to non-users (OR 5.79, n = 175) and former users (OR 5.5, n = 192), while there was no difference between former users and non-users (OR 1.12, n = 187).

Cannabis use increases the risk of non-adherence and quitting cannabis use may help adherence to antipsychotics. Thus, cannabis use may represent a potential target for intervention to improve medication adherence in those with psychosis.

Although the association between cannabis use and violence has been reported in the literature, the precise nature of this relationship, especially the directionality of the association, is unclear.

Young males from the Cambridge Study of Delinquent Development (n = 411) were followed up between the ages of 8 and 56 years to prospectively investigate the association between cannabis use and violence. A multi-wave (eight assessments, T1–T8) follow-up design was employed that allowed temporal sequencing of the variables of interest and the analysis of violent outcome measures obtained from two sources: (i) criminal records (violent conviction); and (ii) self-reports. A combination of analytic approaches allowing inferences as to the directionality of associations was employed, including multivariate logistic regression analysis, fixed-effects analysis and cross-lagged modelling.

Multivariable logistic regression revealed that compared with never-users, continued exposure to cannabis (use at age 18, 32 and 48 years) was associated with a higher risk of subsequent violent behaviour, as indexed by convictions [odds ratio (OR) 7.1, 95% confidence interval (CI) 2.19–23.59] or self-reports (OR 8.9, 95% CI 2.37–46.21). This effect persisted after controlling for other putative risk factors for violence. In predicting violence, fixed-effects analysis and cross-lagged modelling further indicated that this effect could not be explained by other unobserved time-invariant factors. Furthermore, these analyses uncovered a bi-directional relationship between cannabis use and violence.

Together, these results provide strong indication that cannabis use predicts subsequent violent offending, suggesting a possible causal effect, and provide empirical evidence that may have implications for public policy.

Effect of cannabis use on memory function is a contentious issue, with effects being different in healthy individuals and patients with psychosis.

Employing a meta-analytic approach we investigated the effects of cannabis use on memory function in patients with psychosis and healthy individuals, and the effect of diagnosis, memory dimension and moderating factors. A total of 88 studies were identified through a systematic literature search, investigating healthy (n = 7697) and psychotic (n = 3261) individuals. Standardized mean differences between the cannabis user and non-user groups on memory tasks were estimated using random-effects models and the effect-size statistic Cohen's d. Effects of potential moderating factors were tested using mixed-effects models and subgroup analyses.

We found that cannabis use was associated with significantly (p ⩽ 0.05) impaired global (d = 0.27) and prospective memory (d = 0.61), verbal immediate (d = 0.40) and delayed (d = 0.36) recall as well as visual recognition (d = 0.41) in healthy individuals, but a better global memory (d = −0.11), visual immediate recall (d = −0.73) and recognition (d = −0.42) in patients. Lower depression scores and younger age appeared to attenuate the effects of cannabis on memory. Cannabis-using patients had lower levels of depression and were younger compared with non-using patients, whilst healthy cannabis-users had higher depression scores than age-matched non-users. Longer duration of abstinence from cannabis reduced the effects on memory in healthy and patient users.

These results suggest that cannabis use is associated with a significant domain-specific impairment in memory in healthy individuals but not in cannabis-using patients, suggesting that they may represent a less developmentally impaired subgroup of psychotic patients.