Cannabis 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.

A 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.

The 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.

The interindividual differences in transient psychosis-like effects of Δ9-THC are the result of its differential impact on glial function and stress response.

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.

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.

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.

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?

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.

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 the AKT1 rs1130233 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, where AKT1 genotype modulated the effect of THC.

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.

Cannabis 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.

Lifetime 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.

Lifetime 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).

In 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.

Cannabis can induce transient psychotic symptoms, but not all users experience these adverse effects. We compared the neural response to Δ9-tetrahydrocannabinol (THC) in healthy volunteers in whom the drug did or did not induce acute psychotic symptoms.

In a double-blind, placebo-controlled, pseudorandomized design, 21 healthy men with minimal experience of cannabis were given either 10 mg THC or placebo, orally. Behavioural and functional magnetic resonance imaging measures were then recorded whilst they performed a go/no-go task.

The sample was subdivided on the basis of the Positive and Negative Syndrome Scale positive score following administration of THC into transiently psychotic (TP; n = 11) and non-psychotic (NP; n = 10) groups. During the THC condition, TP subjects made more frequent inhibition errors than the NP group and showed differential activation relative to the NP group in the left parahippocampal gyrus, the left and right middle temporal gyri and in the right cerebellum. In these regions, THC had opposite effects on activation relative to placebo in the two groups. The TP group also showed less activation than the NP group in the right middle temporal gyrus and cerebellum, independent of the effects of THC.

In this first demonstration of inter-subject variability in sensitivity to the psychotogenic effects of THC, we found that the presence of acute psychotic symptoms was associated with a differential effect of THC on activation in the ventral and medial temporal cortex and cerebellum, suggesting that these regions mediate the effects of the drug on psychotic symptoms.

Interpersonal sensitivity is a personality trait described as excessive awareness of both the behaviour and feelings of others. Although interpersonal sensitivity has been found to be one of the vulnerability factors to depression, there has been little interest in its relationship with the prodromal phase of psychosis. The aims of this study were to examine the level of interpersonal sensitivity in a sample of individuals with an at-risk mental state (ARMS) for psychosis and its relationship with other psychopathological features.

Method. Sixty-two individuals with an ARMS for psychosis and 39 control participants completed a series of self-report questionnaires, including the Interpersonal Sensitivity Measure (IPSM), the Prodromal Questionnaire (PQ), the Ways of Coping Questionnaire (WCQ) and the Depression and Anxiety Stress Scale (DASS).

Individuals with an ARMS reported higher interpersonal sensitivity compared to controls. Associations between interpersonal sensitivity, positive psychotic symptoms (i.e. paranoid ideation), avoidant coping and symptoms of depression, anxiety and stress were also found.

This study suggests that being ‘hypersensitive’ to interpersonal interactions is a psychological feature of the putatively prodromal phase of psychosis. The relationship between interpersonal sensitivity, attenuated positive psychotic symptoms, avoidant coping and negative emotional states may contribute to long-term deficits in social functioning. We illustrate the importance, when assessing a young client with a possible ARMS, of examining more subtle and subjective symptoms in addition to attenuated positive symptoms.

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.