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

Sample

The study was part of the early developmental stages of psychopathology (EDSP) study,7 in which data were collected on the prevalence, incidence, risk factors, comorbidity, and four year course of mental disorders in a random regional representative population sample of adolescents and young adults aged 14-24 years. The EDSP study is prospective, consisting of a baseline survey in 1995, an assessment of a subsample in 1996-7, and a four year follow up of the total sample in 1999.7 The current analyses used the baseline and four year follow up data. The study sample was randomly drawn from the respective population registry offices of the city and each of the 29 counties of Munich. The base population were all those born between 1 June 1970 and 31 May 1981 who were registered as living in these areas as their primary place of residence and were German citizens. At baseline 3021 participants were interviewed face to face in their homes by using a computer assisted method (response rate 71%). An average of 42 months after the baseline investigations 2548 (response rate 84%) participants were successfully followed up. Of these, 90 participants did not want to respond to questions about illicit drug use at baseline or follow up, and data on the psychosis section of the Munich version of the international composite interview were incomplete for 21 participants. Our analyses were therefore of 2437 participants. To have 80% power to detect an odds ratio of 2.5 at the 5% level, given a base rate of psychotic experiences of 10% and a ratio of unexposed to exposed of 6:1,2 8 we needed a sample size of 616. As around four times as many subjects are required for an interaction such as between cannabis use and predisposition for psychosis,9 the sample size of 2437 was large enough.

Instruments

Participants were interviewed by trained psychologists using the Munich version of the composite international diagnostic interview (M-CIDI).10 At baseline, they used the lifetime version of the interview. The interval version was used at follow up, which refers to the period of assessment between baseline and follow up. We assessed data on the psychosis (G) section only at follow up and these represent lifetime ratings. At baseline and at follow up, participants additionally completed the self report symptom checklist (SCL-90-R)11 to screen for a broad range of psychopathological experiences including psychosis.

We used the “paranoid ideation” and “psychoticism” subscales of the symptom checklist to explore predisposition for psychosis at baseline and at follow up. Total scores of both subscales were added into a total score. Participants with total scores above the 90th centile were considered as having a predisposition for psychosis, both at baseline and at follow up.

We defined an outcome of psychosis as at least one (broad psychosis outcome) or at least two (narrow psychosis outcome) positive ratings on any of the 15 core psychosis items of the M-CIDI. We used the narrow outcome to exclude the possibility of spurious results due to false positive misclassification. None of these psychotic symptoms was due to acute effects of medication, drugs, or alcohol.

To assess symptoms of depression at baseline and follow up we calculated a mean score of the ratings on the 28 items of the depression section (E) of the M-CIDI. We divided this into two groups at the 90th centile, yielding a measure of significant symptoms at both baseline and follow up.

We assessed use of cannabis and other substances using the L-section of the M-CIDI. Individuals with lifetime cannabis use of five times or more at baseline were considered as exposed to cannabis. Cannabis exposure at baseline was defined as lifetime cannabis use of five times or more (any use) and frequency of use (use during the period of heaviest use: no use; less than once a month; three to four times a month; once to twice a week; three to four times a week; almost daily). Cannabis use at follow up was analysed as cannabis use of five times or more during the four years to follow up (any use at follow up). We combined psychostimulants, sedatives, opiates, cocaine, phencyclidine (PCP), and psychedelic drugs into a group of “other drugs.” Lifetime tobacco use at baseline was defined as daily use during at least one month. Alcohol use at baseline was analysed as frequency of use during the past 12 months (no use; less than once a month; three to four times a month; once to twice a week; three to four times a week; almost daily).

Statistical analyses

Associations between any use of cannabis or frequency of use at baseline and psychotic symptoms at follow up were expressed as odds ratios from logistic regression models in Stata, release 8.0 (StataCorp, College Station, TX). All analyses were a priori adjusted for age, sex, socioeconomic status, urbanicity,12 and experience of childhood trauma13 as well as for predisposition for psychosis at baseline. To test whether the effect of cannabis on psychosis was independent of other drugs, tobacco, alcohol, and symptoms of depression at baseline and at follow up, we entered these variables in the model with any cannabis use at baseline. We also adjusted the effect of baseline cannabis on psychotic symptoms according to the M-CIDI at follow up for predisposition for psychosis at follow up.

The population attributable fraction was derived from the associations between any use of cannabis and psychotic symptoms according to the M-CIDI at follow up (adjusted for demographics and trauma during childhood) in the logistic regression models, both for the whole dataset and for the individuals with expression of baseline predisposition, using the aflogit procedure in Stata. This parameter gives a measure of the proportion of cases in participants with psychotic symptoms according to the M-CIDI at follow up that could have been prevented, assuming causality, had the exposure to cannabis been eliminated completely from the baseline population.

We calculated the interaction between predisposition for psychosis at baseline and any cannabis use (adjusted for demographics, childhood trauma, and predisposition at follow up) under an additive model rather than a multiplicative model because an additive model is more likely to yield information on the degree of synergism between causes—that is, the extent to which both causes depend on each other or coparticipate in disease causation.14 15

We investigated the self medication hypothesis by calculating the association between predisposition for psychosis at baseline and cannabis use at follow up, both for the whole dataset and for the individuals who had not used cannabis at baseline. We used sensitivity analyses to examine whether differential attrition in the sample as a whole (3021 at baseline, 2437 at follow up) could have biased the findings. This was done by multiple imputation of missing values of cannabis use at baseline, predisposition for psychosis at baseline, and psychotic symptoms according to the M-CIDI at follow up with the hotdeck command in Stata.

Strengths and weaknesses

We examined psychotic symptoms according to the M-CIDI at follow up in a non-clinical sample. Symptoms were more prevalent than psychotic disorders defined according to the Diagnostic and Statistic Manual of Mental Disorders, fourth edition, but nevertheless have been shown to be on the same continuum of experiences as more severe states of psychosis, such as schizophrenia.8 16 Established risk factors for schizophrenia, such as urbanicity and familial predisposition, also affect the occurrence of psychotic symptoms.15 17 Our results confirm those from three previous studies that showed that exposure to cannabis plays a part not only in the expression of psychotic disorder but also in the emergence of less severe psychotic experiences.2 6 18

At baseline we used self reported psychotic experiences on the symptom checklist to determine predisposition for psychosis, whereas at follow up four years later we used the M-CIDI to determine psychosis outcome. In the group with predisposition for psychosis at baseline, any effect of cannabis can thus be interpreted as psychosis persisting from baseline to follow up (if we assume that the two measures of psychosis are identical), rather than an effect of transition from expression of predisposition at baseline to expression of overt symptoms at follow up. Although both explanations would be equally important, adjustment for the effect of the follow up equivalent of the baseline measure of predisposition for psychosis did not change the observed association between cannabis and psychotic symptoms according to the M-CIDI, indicating that the effect of cannabis can be interpreted as onset of clinical psychosis outside the continuity between the measure of predisposition for psychosis at baseline and follow up. In addition, cannabis also had a significant effect on psychotic symptoms in the group without predisposition for psychosis at baseline, albeit of smaller effect.

Synergistic interaction between cannabis and predisposition for psychosis

Findings from earlier research suggest biological plausibility, involving the endocannabinoid CB1 receptor system in close interaction with the dopamine neurotransmitter system. For example, delta-9-tetrahydrocannabinol (the major psychoactive component of cannabis) increases presynaptic dopamine efflux and utilisation in the prefrontal cortex in rats.19 Increased concentrations of CB1 receptors were found in the dorsolateral prefrontal cortex of patients with schizophrenia,20 and concentrations of anandamide (an endogenous cannabinoid that binds to the CB1 receptor) were found to be higher in the cerebrospinal fluid of these patients.21 Furthermore, there is evidence from animal studies that puberty in rats is a vulnerable period with respect to the adverse effects of cannabinoids.22 The longlasting behavioural disturbances observed in this animal study are consistent with impairments generally found in patients with schizophrenia, and the changes in these rats were reversed by the acute administration of the dopamine antagonist haloperidol.22 Repeated exposure to cannabis may cause initial increases in synaptic dopamine and then lead to more prolonged changes in the endogenous cannabinoid systems. These changes might be most profound after exposure to cannabis during adolescence and in individuals with a pre-existing vulnerability to dysregulation of the cannabinoid system and related neurotransmission systems.