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 Δ-9-Tetrahydrocannabinol-Induced Effects on Psychosis and Cognition

“…In the current study, we did not replicate differences in THC sensitivity between patients and controls. However, rather than examining case-control differences, the design of the current study allowed for testing differential THC sensitivity at the level of psychometric psychosis liability, similar to earlier work (Henquet et al, 2005a;Verdoux et al, 2003). In agreement with these earlier studies, evidence for differential THC sensitivity was found, restricted to subjects with the Val/Val genotype.…”

“…Our diagnostic group was heterogeneous, including schizo-affective disorder and psychosis not otherwise specified apart from schizophrenia. The rationale for this relatively broad inclusion was that the effects of cannabis on psychotic symptoms and cognition, as well the interaction with prior psychometric psychosis liability, have been demonstrated both in populations of patients with a psychotic disorder and in nonpatient populations (D'Souza et al, 2005;Henquet et al, 2005a;Verdoux et al, 2003), suggesting relative nonspecificity across diagnostic groups and validating our approach of showing quantitative differences in sensitivity to cannabis between groups. Four relatives had diagnoses of affective disorder.…”

“…Thus, in patients, cannabis use predicts higher relapse rates and higher likelihood of a continuous illness course (Linszen et al, 1994). In young people with higher than average expression of psychometric psychosis liability, the likelihood to develop overt psychotic states is higher with additional exposure to cannabis use (Henquet et al, 2005a;Verdoux et al, 2003). These results suggest that at least part of the pathway of risk from psychometric psychosis liability to overt psychotic disorder may be mediated by an abnormal sensitivity to the psychotropic effects of cannabis.…”

“…THC, COMT Val 158 Met Genotype, and Psychosis D'Souza et al (2005) demonstrated greater sensitivity to THC effects on psychosis outcomes in patients with schizophrenia compared to healthy controls, whereas Verdoux et al (2003) and Henquet et al (2005a) found that higher levels of psychometric psychosis liability moderated the effect of cannabis in terms of 'switching on' psychotic symptoms. In the current study, we did not replicate differences in THC sensitivity between patients and controls.…”

“…Increased COMT activity may result in a combination of (i) reduced dopamine neurotransmission in the prefrontal cortex, hypothesized to result in poorer performance of frontally mediated cognitive tasks, in particular working memory and attention (Egan et al, 2001;Meyer-Lindenberg et al, 2005;Rosa et al, 2004) and (ii) increased levels of meso-limbic dopamine signaling hypothesized to result in increased risk for delusions and hallucinations, the core symptoms of psychosis (Akil et al, 2003;Bilder et al, 2004). The work to date therefore suggests that COMT genotype, psychometric psychosis liability, and being a patient with a psychotic disorder moderate the effect of cannabis on psychosis outcomes in the community (Caspi et al, 2005;Henquet et al, 2005a) and that differential sensitivity to cannabis not only involves the positive symptoms of psychosis, but also cognition, in particular memory (D'Souza et al, 2005). It is unlikely that the moderating effects of psychometric psychosis liability and COMT on the association between cannabis and expression of psychosis represent one and the same underlying mechanism, because psychometric psychosis liability is strongly associated with psychotic disorder whereas recent systematic reviews show only weak evidence of an association between COMT genotype and psychotic disorders (Fan et al, 2005;Munafo et al, 2005).…”