Cécile Henquet

Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people

Abstract Objective To investigate the relation between cannabis use and psychotic symptoms in individuals with above average predisposition for psychosis who first used cannabis during adolescence. Design Analysis of prospective data from a population based sample. Assessment of substance use, predisposition for psychosis, and psychotic symptoms was based on standardised personal interviews at baseline and at follow up four years later. Participants 2437 young people (aged 14 to 24 years) with and without predisposition for psychosis. Main outcome measure Psychotic symptoms at follow up as a function of cannabis use and predisposition for psychosis at baseline. Results After adjustment for age, sex, socioeconomic status, urbanicity, childhood trauma, predisposition for psychosis at baseline, and use of other drugs, tobacco, and alcohol, cannabis use at baseline increased the cumulative incidence of psychotic symptoms at follow up four years later (adjusted odds ratio 1.67, 95% confidence interval 1.13 to 2.46). The effect of cannabis use was much stronger in those with any predisposition for psychosis at baseline (23.8% adjusted difference in risk, 95% confidence interval 7.9 to 39.7, P = 0.003) than in those without (5.6%, 0.4 to 10.8, P = 0.033). The risk difference in the “predisposition” group was significantly greater than the risk difference in the “no predisposition” group (test for interaction 18.2%, 1.6 to 34.8, P = 0.032). There was a dose-response relation with increasing frequency of cannabis use. Predisposition for psychosis at baseline did not significantly predict cannabis use four years later (adjusted odds ratio 1.42, 95% confidence interval 0.88 to 2.31). Conclusion Cannabis use moderately increases the risk of psychotic symptoms in young people but has a much stronger effect in those with evidence of predisposition for psychosis.

An experimental study of catechol-o-methyltransferase Val158Met moderation of delta-9-tetrahydrocannabinol-induced effects on psychosis and cognition.

Observational studies have suggested that psychometric psychosis liability and a functional polymorphism in the catechol-O-methyltransferase (COMT Val158Met) gene moderate the psychosis-inducing effect of cannabis. To replicate and extend this finding, a double-blind, placebo-controlled cross-over design was used in which patients with a psychotic disorder (n=30), relatives of patients with a psychotic disorder (n=12), and healthy controls (n=32) were exposed to Δ-9-tetrahydrocannabinol (Δ-9-THC, the principal component of cannabis) or placebo, followed by cognitive assessment and assessment of current psychotic experiences. Previous expression of psychometric psychosis liability was also assessed. Models of current psychotic experiences and cognition were examined with multilevel random regression analyses to assess (i) main effects of genotype and condition, (ii) interactions between condition and genotype, and (iii) three-way interactions between condition, genotype, and psychometric psychosis liability. Carriers of the Val allele were most sensitive to Δ-9-THC-induced psychotic experiences, but this was conditional on prior evidence of psychometric psychosis liability. Δ-9-THC impacted negatively on cognitive measures. Carriers of the Val allele were also more sensitive to Δ-9-THC-induced memory and attention impairments compared to carriers of the Met allele. Experimental effects of Δ-9-THC on cognition and psychosis are moderated by COMT Val158Met genotype, but the effects may in part be conditional on the additional presence of pre-existing psychosis liability. The association between cannabis and psychosis may represent higher order gene–environment and gene–gene interactions.

Continued cannabis use and risk of incidence and persistence of psychotic symptoms: 10 year follow-up cohort study

Objective To determine whether use of cannabis in adolescence increases the risk for psychotic outcomes by affecting the incidence and persistence of subclinical expression of psychosis in the general population (that is, expression of psychosis below the level required for a clinical diagnosis). Design Analysis of data from a prospective population based cohort study in Germany (early developmental stages of psychopathology study). Setting Population based cohort study in Germany. Participants 1923 individuals from the general population, aged 14-24 at baseline. Main outcome measure Incidence and persistence of subthreshold psychotic symptoms after use of cannabis in adolescence. Cannabis use and psychotic symptoms were assessed at three time points (baseline, T2 (3.5 years), T3 (8.4 years)) over a 10 year follow-up period with the Munich version of the composite international diagnostic interview (M-CIDI). Results In individuals who had no reported lifetime psychotic symptoms and no reported lifetime cannabis use at baseline, incident cannabis use over the period from baseline to T2 increased the risk of later incident psychotic symptoms over the period from T2 to T3 (adjusted odds ratio 1.9, 95% confidence interval 1.1 to 3.1; P=0.021). Furthermore, continued use of cannabis increased the risk of persistent psychotic symptoms over the period from T2 to T3 (2.2, 1.2 to 4.2; P=0.016). The incidence rate of psychotic symptoms over the period from baseline to T2 was 31% (152) in exposed individuals versus 20% (284) in non-exposed individuals; over the period from T2 to T3 these rates were 14% (108) and 8% (49), respectively. Conclusion Cannabis use is a risk factor for the development of incident psychotic symptoms. Continued cannabis use might increase the risk for psychotic disorder by impacting on the persistence of symptoms.

Does normal developmental expression of psychosis combine with environmental risk to cause persistence of psychosis ? A psychosis proneness-persistence model

BACKGROUND Research suggests that low-grade psychotic experiences in the general population are a common but transitory developmental phenomenon. Using two independent general population samples, the hypothesis was examined that common, non-clinical developmental expression of psychosis may become abnormally persistent when synergistically combined with developmental exposures that may impact on behavioural and neurotransmitter sensitization such as cannabis, trauma and urbanicity. METHOD The amount of synergism was estimated from the additive statistical interaction between baseline cannabis use, childhood trauma and urbanicity on the one hand, and baseline psychotic experiences on the other, in predicting 3-year follow-up psychotic experiences, using data from two large, longitudinal, random population samples from the Netherlands [The Netherlands Mental Health Survey and Incidence Study (NEMESIS)] and Germany [The Early Developmental Stages of Psychopathology (EDSP) study]. RESULTS The 3-year persistence rates of psychotic experiences were low at 26% in NEMESIS and 31% in EDSP. However, persistence rates were progressively higher with greater baseline number of environmental exposures in predicting follow-up psychotic experiences (chi2=6.9, df=1, p=0.009 in NEMESIS and chi2=4.2, df=1, p=0.04 in EDSP). Between 21% and 83% (NEMESIS) and 29% and 51% (EDSP) of the subjects exposed to both environmental exposures and psychotic experiences at baseline had persistence of psychotic experiences at follow-up because of the synergistic action of the two factors. CONCLUSION The findings suggest that environmental risks for psychosis act additively, and that the level of environmental risk combines synergistically with non-clinical developmental expression of psychosis to cause abnormal persistence and, eventually, need for care.

Gene-Environment Interplay Between Cannabis and Psychosis

Cannabis use is considered a contributory cause of schizophrenia and psychotic illness. However, only a small proportion of cannabis users develop psychosis. This can partly be explained by the amount and duration of the consumption of cannabis and by its strength but also by the age at which individuals are first exposed to cannabis. Genetic factors, in particular, are likely to play a role in the short- and the long-term effects cannabis may have on psychosis outcome. This review will therefore consider the interplay between genes and exposure to cannabis in the development of psychotic symptoms and schizophrenia. Studies using genetic, epidemiological, experimental, and observational techniques will be discussed to investigate gene-environment correlation gene-environment interaction, and higher order interactions within the cannabis-psychosis association. Evidence suggests that mechanisms of gene-environment interaction are likely to underlie the association between cannabis and psychosis. In this respect, multiple variations within multiple genes--rather than single genetic polymorphisms--together with other environmental factors (eg, stress) may interact with cannabis to increase the risk of psychosis. Further research on these higher order interactions is needed to better understand the biological pathway by which cannabis use, in some individuals, may cause psychosis in the short- and long term.

Evidence that the COMTVal158Met polymorphism moderates sensitivity to stress in psychosis: An experience‐sampling study

Gene–environment interactions involving the catechol‐O‐methyltransferase Val158Met polymorphism (COMTVal158Met) have been implicated in the causation of psychosis. Evidence from general population studies suggests that Met/Met subjects are sensitive to stress, a trait associated with psychosis. We hypothesized that the Met allele would moderate the effects of stress on negative affect (NA) in controls, and on NA and psychosis in patients with a psychotic disorder. Thirty‐one patients with a psychotic disorder and comorbid cannabis misuse and 25 healthy cannabis users were studied with the experience sampling method (ESM), a structured diary technique assessing current context and emotional and psychotic experiences in daily life. A significant interaction between COMTVal158Met genotype and ESM stress in the model of NA was found for patients (interaction χ2 = 7.4, P = 0.02), but not for controls (interaction χ2 = 3.8, P = 0.15). In the model of ESM psychosis, a significant interaction between COMTVal158Met genotype and ESM stress was also apparent (interaction χ2 = 11.6, P < 0.01), with Met/Met patients showing the largest increase in psychotic experiences as well as NA in reaction to ESM stress. The findings suggest that the COMTVal158Met polymorphism moderates affective and psychotic responses to stress in patients with psychosis, providing evidence for gene–environment interaction mechanisms in the formation of psychotic symptoms.

COMT ValMet moderation of cannabis-induced psychosis: a momentary assessment study of 'switching on' hallucinations in the flow of daily life

Objective:  A functional polymorphism in the catechol‐o‐methyltransferase gene (COMT Val158Met) may moderate the psychosis‐inducing effects of cannabis. In order to extend this finding to dynamic effects in the flow of daily life, a momentary assessment study of psychotic symptoms in response to cannabis use was conducted.

Does dopamine mediate the psychosis-inducing effects of cannabis? A review and integration of findings across disciplines

General population epidemiological studies have consistently found that cannabis use increases the risk of developing psychotic disorders in a dose-dependent manner. While the epidemiological signal between cannabis and psychosis has gained considerable attention, the biological mechanism whereby cannabis increases risk for psychosis remains poorly understood. Animal research suggests that delta-9-tetrahydrocannabinol (THC, the main psychoactive component of cannabis) increases dopamine levels in several regions of the brain, including striatal and prefrontal areas. Since dopamine is hypothesized to represent a crucial common final pathway between brain biology and actual experience of psychosis, a focus on dopamine may initially be productive in the examination of the psychotomimetic effects of cannabis. Therefore, this review examines the evidence concerning the interactions between THC, endocannabinoids and dopamine in the cortical as well as subcortical regions implicated in psychosis, and considers possible mechanisms whereby cannabis-induced dopamine dysregulation may give rise to delusions and hallucinations. It is concluded that further study of the mechanisms underlying the link between cannabis and psychosis may be conducted productively from the perspective of progressive developmental sensitization, resulting from gene-environment interactions.

Psychosis reactivity to cannabis use in daily life: an experience sampling study

BACKGROUND Little is known about the experiential dynamics of the interaction between cannabis and vulnerability to psychosis. AIMS To examine the effects of cannabis on psychotic symptoms and mood in patients with psychosis and healthy controls. METHOD Patients with a psychotic disorder (n = 42) and healthy controls (n = 38) were followed in their daily lives using a structured time-sampling technique. RESULTS Daily life cannabis use predicted subsequent increases in positive affect and in patients, but not in controls, decreases in negative affect. In patients, but not in controls, cannabis use predicted increased levels of hallucinatory experiences. Mood-enhancing properties of cannabis were acute, whereas psychosis-inducing effects were sub-acute. There was no direct evidence for self-medication effects in daily life. CONCLUSIONS Patients with psychosis are more sensitive to both the psychosis-inducing and mood-enhancing effects of cannabis. The temporal dissociation between acute rewarding effects and sub-acute toxic influences may be instrumental in explaining the vicious circle of deleterious use in these patients.

Replication in two independent population-based samples that childhood maltreatment and cannabis use synergistically impact on psychosis risk

BACKGROUND There may be biological plausibility to the notion that cannabis use and childhood trauma or maltreatment synergistically increase the risk for later development of psychotic symptoms. To replicate and further investigate this issue, prospective data from two independent population-based studies, the Greek National Perinatal Study (n=1636) and The Netherlands Mental Health Survey and Incidence Study (NEMESIS) (n=4842), were analyzed. METHOD Two different data sets on cannabis use and childhood maltreatment were used. In a large Greek population-based cohort study, data on cannabis use at age 19 years and childhood maltreatment at 7 years were assessed. In addition, psychotic symptoms were assessed using the Community Assessment of Psychic Experiences (CAPE). In NEMESIS, the Composite International Diagnostic Interview (CIDI) was used to assess psychotic symptoms at three different time points along with childhood maltreatment and lifetime cannabis use. RESULTS A significant adjusted interaction between childhood maltreatment and later cannabis use was evident in both samples, indicating that the psychosis-inducing effects of cannabis were stronger in individuals exposed to earlier sexual or physical mistreatment [Greek National Perinatal Study: test for interaction F(2, 1627)=4.18, p=0.02; NEMESIS: test for interaction χ2(3)=8.08, p=0.04]. CONCLUSIONS Cross-sensitivity between childhood maltreatment and cannabis use may exist in pathways that shape the risk for expression of positive psychotic symptoms.