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Official websites use. Share sensitive information only on official, secure websites. Collaborators listed in the appendix. Cannabis use is associated with increased risk of later psychotic disorder but whether it affects incidence of the disorder remains unclear. We aimed to identify patterns of cannabis use with the strongest effect on odds of psychotic disorder across Europe and explore whether differences in such patterns contribute to variations in the incidence rates of psychotic disorder. We included patients aged 18—64 years who presented to psychiatric services in 11 sites across Europe and Brazil with first-episode psychosis and recruited controls representative of the local populations. We applied adjusted logistic regression models to the data to estimate which patterns of cannabis use carried the highest odds for psychotic disorder. Assuming causality, we calculated the population attributable fractions PAFs for the patterns of cannabis use associated with the highest odds of psychosis and the correlation between such patterns and the incidence rates for psychotic disorder across the study sites. Between May 1, , and April 1, , we obtained data from patients with first-episode psychosis across 11 sites and population controls from those same sites. Differences in frequency of daily cannabis use and in use of high-potency cannabis contributed to the striking variation in the incidence of psychotic disorder across the 11 studied sites. Given the increasing availability of high-potency cannabis, this has important implications for public health. Many countries have legalised or decriminalised cannabis use, leading to concerns that this might result in an increase in cannabis use and associated harm, 1 , 2 even if the latter only affects a minority of the population. Meta-analysis shows a dose—response association with the highest odds of psychotic disorder in those with the heaviest cannabis use. A systematic review 11 has described a five-times variation in the incidence of schizophrenia worldwide. A transnational case-control study EU-GEI has reported an eight-times difference in the incidence of psychotic disorder across 16 European sites plus one in Brazil. The evidence reporting the dose-dependent association between cannabis use and psychotic disorders has been summarised in the meta-analysis by Marconi and colleagues. Finally, we searched for studies that reported the impact of any use of cannabis on the incidence of psychotic disorder or schizophrenia. Three studies met our inclusion criteria. Boydell and colleagues speculated that an increase in the incidence rates of schizophrenia between and in south London might be related to the increase, over the same period, in the prevalence of cannabis use in the year before first presentation. This multicentre case-control study across ten European and one Brazilian site replicates the strong effect of daily use of high-potency cannabis on the odds for psychotic disorder in the whole sample—which, to our knowledge, is the largest to date to address this question. This effect was particularly visible in London and Amsterdam. Most importantly, we provide the first direct evidence that cannabis use has an effect on variation in the incidence of psychotic disorders. We show that differences in the prevalence of daily use of cannabis, and in use of high-potency cannabis, among the controls from the different study sites made a major contribution to the striking variations in the incidence rates of psychotic disorder that we have previously reported across the same sites. In the context of the well reviewed epidemiological and biological evidence of a causal link between heavy cannabis use and psychotic disorders, our findings have substantial implications for mental health services and public health. Education is needed to inform the public about the mental health hazards of regular use of high-potency cannabis, which is becoming increasingly available worldwide. Therefore, using data from the EU-GEI case-control study of first-episode psychosis and the previously published data on incidence, 12 we sought to describe differences in patterns of cannabis use across sites, identify the measure of cannabis use with the strongest impact on odds of psychotic disorder across sites, calculate the population attributable fraction PAF for the patterns of cannabis use associated with the highest odds for psychosis, and test whether differences in patterns of cannabis use contribute to variations in the incidence of psychotic disorder across sites. The EU-GEI project set out to estimate the incidence of psychosis and recruit first-episode psychosis cases and controls to investigate risk factors for psychotic disorder. First, incidence rates were estimated 12 by identifying all individuals with a first episode of psychosis who presented to mental health services between May 1, , and April 1, , in 17 areas in England, France, the Netherlands, Italy, Spain, and Brazil appendix. Second, to investigate risk factors, we attempted to assess first-episode cases and population-based controls during the same period. Patients presenting with their first episode of psychosis were identified by trained researchers who carried out regular checks across the mental health services within the 17 catchment areas one site per catchment area. Patients were eligible if they were aged 18—64 years and resident within the study areas at the time of their first presentation with a diagnosis of psychosis by ICD criteria F20—33 ; details are provided in the supplementary methods and in previous publications. Using the Operational Criteria Checklist algorithm, all cases interviewed received a research-based diagnosis. We adopted quota sampling strategies to guide the recruitment of controls. Accurate local demographic data were used to set quotas for controls to ensure the samples' representativeness of each catchment area's population at risk in terms of age, gender, and ethnicity. Potential controls were initially identified on the basis of locally available sampling strategies, most commonly random sampling from lists of all postal addresses and from general practitioner lists from randomly selected surgeries. To achieve representation of hard-to-reach groups eg, young men , we then tried to oversample them using more ad-hoc approaches such as internet and newspaper advertisements, and leaflets at local stations, shops, and job centres. Controls were excluded if they had received a diagnosis of, or treatment for, psychotic disorder. All participants provided informed, written consent. Ethical approval was provided by research ethics committees in each site. We obtained sociodemographic data using the Medical Research Council Sociodemographic Schedule, as described previously. To minimise recall bias, none of the recruitment materials for cases or controls mentioned cannabis or referred to its potential role as risk factor for psychotic disorder. Participants were asked if they had ever used cannabis in their lifetime; if the answer was yes, they were then asked to give details on their pattern of use. Questions on the type of cannabis used made no reference to its potency and allowed participants to report the colloquial name, in any language, of the cannabis they used. We included six measures of cannabis use in the initial analyses, including lifetime cannabis use ie, whether or not the individual had ever used cannabis , currently using cannabis, age at first use of cannabis, 16 lifetime frequency of use ie, the frequency that characterised the individual's most consistent pattern of use , and money spent weekly on cannabis during their most consistent pattern of use. We used complete case analyses for all analyses using Stata version We used inverse probability weights to account for any oversampling of controls relative to the populations at risk appendix ; we gave each control's data a weight inversely proportional to their probability of selection given their key demographics age, gender, and ethnicity using census data on relevant populations. These weights were applied in all analyses. All sociodemographic and drug-use variables associated with case-control status were controlled for in all analyses appendix. We applied adjusted logistic regression models to estimate the effect of each of the six measures of cannabis use on the odds of a psychotic disorder ie, case status. The data have a multilevel structure because cases and controls are nested within sites. To take account of this clustering in the logistic regression analysis, we used the cluster option in Stata. We fitted interaction terms to logistic models. These interaction models, using likelihood ratio tests, were run to investigate whether individual measures of cannabis use interacted with each other to significantly increase the odds ratios ORs for psychotic disorder and whether the ORs for psychotic disorder of the individual measures of cannabis use varied significantly by site. The PAF measures the population effect of an exposure by providing an estimate of the proportion of disorder that would be prevented if the exposure were removed, assuming causality. To account for potential selection bias, we did a probabilistic sensitivity analysis using the STATA episensi command. Finally, we used Pearson's correlation to test for an association between the incidence rates for psychotic disorder adjusted for ethnic minority status in each site and the prevalence of daily cannabis use and use of high-potency cannabis in the controls as representing the general population for each site. Study funders contributed to the salaries of the research workers employed but did not participate in the study design, data analyses, data interpretation, or writing of the manuscript. All authors had full access to the study data and had final responsibility for the decision to submit for publication. Thus, cases took part. All 17 sites contributed to the recruitment of population controls except for Maison Blanche, which was consequently excluded from the analysis appendix. This resulted in cases and controls for analysis. Compared with controls, cases were younger, more often men, and from ethnic minorities, than the controls table 1. Sociodemographics and lifetime history of substance misuse across all included cases and controls. More cases than controls reported having ever used cannabis, having smoked ten tobacco cigarettes or more a day, or having tried other recreational drugs table 1. An adjusted logistic regression model showed that those who had ever used cannabis had a modest increase in odds of psychotic disorder compared with those who had never used it table 2 ; the odds were slightly greater in those who started to use cannabis at age 15 years or younger. Crude ORs are adjusted only for age, gender, and ethnicity whereas fully adjusted ORs are additionally adjusted for level of education, employment status, tobacco, stimulants, ketamine, legal highs, and hallucinogenics. Reference group for both crude and adjusted ORs is the never users unless specified otherwise. Frequency of use and type of cannabis used were combined to generate a single-measure of frequency plus type of use because these two measures had the highest ORs. Crude and fully adjusted ORs of psychotic disorders for the combined measure of frequency plus type of cannabis use in the whole sample. Crude ORs are adjusted only for age, gender and ethnicity and fully adjusted ORs are additionally adjusted for level of education, employment status, and use of tobacco, stimulants, ketamine, legal highs, and hallucinogenics. In the three sites with the greatest consumption of high-potency cannabis, daily use of high-potency cannabis was associated with the greatest increase in the odds for psychotic disorder compared with never having used: four times greater in Paris, five times greater in London, and more than nine times greater in Amsterdam figure 2. Fully adjusted ORs of psychotic disorders for the combined measure of frequency plus type of cannabis use in three sites. Data are shown for the three sites with the greatest consumption of cannabis: London cases, controls , Amsterdam 96 cases, controls , and Paris 54 cases, controls. Based on the prevalence of daily cannabis use, and use of high potency cannabis, in cases and controls and the corresponding adjusted ORs, we estimated the PAFs for the whole sample and for each of the sites table 3. We did not calculate the PAF for Palermo because there was no main effect of use of high-potency cannabis on the odds for psychotic disorder. The probabilistic sensitivity analyses we ran suggest that selection bias is unlikely to explain our findings appendix. The results of the probabilistic sensitivity analysis to estimate the potential effects of selection bias on high potency cannabis use were similar appendix. The EU-GEI incidence study reported an eight-times variation in the incidence rates of psychotic disorder adjusted for age, gender, and ethnic minority status across the study sites. Adjusted incidence rates for all psychosis for the 11 sites plotted against the prevalence of daily use in the population controls A and prevalence of use of high-potency cannabis in the population controls B. Incidence rates are adjusted for age, gender, and ethnicity. Our main findings show that among the measures of cannabis use tested, the strongest independent predictors of whether any given individual would have a psychotic disorder or not were daily use of cannabis and use of high-potency cannabis. Starting to use cannabis by 15 years of age modestly increased the odds for psychotic disorder but not independently of frequency of use or of the potency of the cannabis used. These measures of extent of exposure did not interact with each other, nor did they interact with the sites. This lack of interaction between degree of cannabis use ie, daily use of cannabis or use of high-potency cannabis and site might reflect insufficient power in our study; however, it could also indicate that although the magnitude of the effect might vary depending on the degree of cannabis use, there is a consistent effect of daily use and use of high-potency cannabis on the ORs for psychotic disorders across all study sites. We replicated our previous finding 28 that daily use of high-potency cannabis is most strongly associated with case-control status. Compared with never users, participants who used high-potency cannabis daily had four-times higher odds of psychosis in the whole sample, with a five-times increase in London and a nine-times increase in Amsterdam. We also saw that, in the whole sample, daily use of high-potency cannabis was associated with a doubling in the OR for psychotic disorder. The large sample size and the different types of cannabis available across Europe have allowed us to report that the dose—response relationship characterising the association between cannabis use and psychosis 7 reflects not only the use of high-potency cannabis but also the daily use of types with an amount of THC consistent with more traditional varieties. Use of high-potency cannabis was a strong predictor of psychotic disorder in Amsterdam, London, and Paris where high-potency cannabis was widely available, by contrast with sites such as Palermo where this type was not yet available. Thus our findings are consistent with previous epidemiological and experimental evidence suggesting that the use of cannabis with a high concentration of THC has more harmful effects on mental health than does use of weaker forms. The novelty of this study is its multicentre structure and the availability of incidence rates for psychotic disorder for all the sites. This has allowed us, for the first time, to show how the association between cannabis use and risk of psychosis varies geographically depending on prevailing patterns of use, and how the latter contributes to variation in incidence rates for psychotic disorder. Variations in patterns of cannabis use across the sites translated into differences in the proportion of new cases of psychotic disorder attributable to cannabis use. Finally, we report what, to our knowledge, is the first evidence that differences in the prevalence of daily use and use of high-potency cannabis in the controls correlate with the variation in the adjusted incidence rates for psychotic disorder across the study sites. Our results show that in areas where daily use and use of high-potency cannabis are more prevalent in the general population, there is an excess of cases of psychotic disorder. Our findings need to be appraised in the context of limitations. Data on cannabis use are not validated by biological measures, such as urine, blood, or hair samples. However, such measures do not allow testing for use over previous years. Our potency variable does not include the proportion of another important cannabinoid, cannabidiol CBD , 34 because reliable data on this were available for only England and Holland. Given the much higher mean percentage of THC expected in types of cannabis commonly used in UK 24 , 29 and in Holland, 19 our dichotomous categorisation might have led to underestimation of the effect of potency on the ORs for psychotic disorder. Furthermore, a direct measure of the THC content of the cannabis samples used by our participants would have only provided data on THC value for a single timepoint rather than an estimate covering lifetime use. When setting quotas based on the main sociodemographics of the populations at risk for the recruitment of controls, we applied weights to account for undersampling or oversampling of some groups. For instance, most of the sites oversampled the age group 16—24 years appendix , which represents the part of the population most likely to consume cannabis 17 and the most likely to suffer associated harm. Moreover, none of the sites mentioned either cannabis, or other, drug use in the materials used for participant recruitment, thus avoiding selection and recall bias. First-episode studies minimise the effect of recall bias, which can be a source of error when history of exposure to environmental factors is collected retrospectively in patients with well established psychosis. This study design also reduces the chances of results being biased by illness course; therefore, it is preferred to investigate aetiology. In conclusion, our findings confirm previous evidence of the harmful effect on mental health of daily use of cannabis, especially of high-potency types. Importantly, they indicate for the first time how cannabis use affects the incidence of psychotic disorder. Therefore, it is of public health importance to acknowledge alongside the potential medicinal properties of some cannabis constituents the potential adverse effects that are associated with daily cannabis use, especially of high-potency varieties. MDF did the data analysis and wrote the findings in the initial manuscript. All authors had full access to all data including statistical reports and tables in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. MDF reports personal fees from Janssen, outside the submitted work. MB reports grants and personal fees from Adamed, Janssen-Cilag, Otsuka, and Abbiotics; personal fees from Angelini and Casen Recordati; and grants from Lundbeck and Takeda, outside of the submitted work. PBJ reports personal fees from being a member of the scientific advisory boards for Janssen and Ricordati, outside of the submitted work. All other authors declare no competing interests. This section collects any data citations, data availability statements, or supplementary materials included in this article. As a library, NLM provides access to scientific literature. Lancet Psychiatry. Find articles by Marta Di Forti. Find articles by Diego Quattrone. Find articles by Tom P Freeman. Find articles by Giada Tripoli. Find articles by Charlotte Gayer-Anderson. Find articles by Harriet Quigley. Find articles by Victoria Rodriguez. Find articles by Hannah E Jongsma. Find articles by Laura Ferraro. Find articles by Caterina La Cascia. Find articles by Daniele La Barbera. Find articles by Ilaria Tarricone. Find articles by Domenico Berardi. Find articles by Celso Arango. Find articles by Andrea Tortelli. Find articles by Eva Velthorst. Find articles by Miguel Bernardo. Find articles by Cristina Marta Del-Ben. Find articles by Paulo Rossi Menezes. Find articles by Jean-Paul Selten. Find articles by Peter B Jones. Find articles by James B Kirkbride. Find articles by Bart PF Rutten. Find articles by Lieuwe de Haan. Find articles by Pak C Sham. Find articles by Jim van Os. Find articles by Cathryn M Lewis. Find articles by Michael Lynskey. Find articles by Craig Morgan. Find articles by Robin M Murray. Published by Elsevier Ltd. See ' Cannabis and psychosis: triangulating the evidence. Self-reported ethnicity.. Employment status 1 year before assessment.. Lifetime cannabis use.. Lifetime tobacco use.. Open in a new tab. Measure of cannabis use and ORs for psychotic disorders for case-control sample across 11 sites. PAFs for daily use of cannabis and use of high-potency cannabis in the whole sample and by site. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel.

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