ADOLESCENT CANNABIS USE, BASELINE PRODROMAL SYMPTOMS AND THE RISK OF PSYCHOSIS ANTTI MUSTONEN, SOLJA NIEMELÄ, TANJA NORDSTRÖM, GRAHAM K. MURRAY, PIRJO MÄKI, ERIKA JÄÄSKELÄINEN, JOUKO MIETTUNEN Background: Association of cannabis use and the risk of psychosis has been studied extensively but the temporal order still remains controversial. Aim: To examine the association between cannabis use in adolescence and the risk of psychosis after adjustment for prodromal symptoms and other potential confounders. Methods: The sample (N=6,534) was composed of the prospective general population-based Northern Finland Birth Cohort of 1986. Information on prodromal symptoms of psychosis and cannabis use was collected using questionnaires at age 15-16 years. Subjects were followed up for ICD-10 psychotic disorders until age 30 years using nationwide registers. Results: The risk of psychosis was elevated in subjects who had tried cannabis 5 times or more (Hazard Ratio, HR=6.5; 95%CI=3.0-13.9). The association remained statistically significant even when adjusted for prodromal symptoms, other substance use and parental psychosis (HR=3.0; 1.1-8.0). Conclusions: Adolescent cannabis use is associated with increased risk of psychosis even after adjustment for baseline prodromal symptoms, parental psychosis and other substance use. Increasing evidence points towards a dose-response relationship between the level of cannabis use and the risk for psychotic outcomes (1-4), and also indicates that cannabis use results in earlier onset of psychosis (5,6). Most longitudinal studies have taken reverse causation into account by excluding individuals with pre-existing psychotic symptoms, which could have led to overestimates of the true association (7). Moreover, most of these previous studies have focused on psychotic symptoms rather than psychotic illness per se. Several studies have examined the impact of psychotic baseline severity in relation to the cannabis use-psychosis association, e.g. (8-11). To our knowledge, there is only one prospective study examining cannabis use and psychosis diagnosis (schizophreniform syndrome) that has taken baseline psychotic (prodromal) symptoms into account as a potential confounder before or at the time of cannabis use (8). Furthermore, cannabis use often co-occurs with other types of substance use, which may also have an impact on the psychosis outcome (12). The aim of this study was to examine the predictive association between adolescent cannabis use at age 15-16 years and the risk of subsequent psychosis by the age of 30 years in the Northern Finland Birth Cohort Study 1986 (NFBC 1986). An association between cannabis use and prodromal symptoms in adolescence has been reported previously in the NFBC 1986 (13). We hypothesized that cannabis use increases the risk for psychosis independently of baseline prodromal symptoms, parental psychosis, and other forms of substance use including daily tobacco smoking. METHODS Participants The Northern Finland Birth Cohort (NFBC) 1986 is an ongoing follow-up study including 99% of all births, comprising all the live born children (n=9,432) from the two northernmost provinces in Finland (14). In all, 7,344 (48.8% boys) participated in the follow-up study in 2001-2002, when the participants were aged 15-16 years. Participants who signed the informed consent form and answered the questions on cannabis use were included in the present study. Adolescents who had received a psychosis diagnosis before the 15-16-year follow-up (n=10) were excluded from the study. The final sample included 6,534 individuals (49.1% boys). Information on psychosis-related diagnoses was collected from the national registries until the end of 2015, i.e. by the age of 30 years. The study was approved by the Ethics committee of the Northern Ostrobothnia Hospital District in Finland (17 May 2006). The data flow is shown in Figure 1. **insert figure 1 here** Data collection Data collection started prospectively before birth and has continued since (14). A multidisciplinary NFBC field study was conducted when the adolescents were 15-16 years of age (15). Data on substance abuse was collected in 2001-2002, in two different surveys. First, they received a postal questionnaire, which included questions on smoking habits. Thereafter, all the participants were invited to a field study where they completed self-report questionnaires including questions on prodromal symptoms for psychosis (PROD-screen) (16), on alcohol use and illicit substance use. For more detailed information about the study design, see figure 1 and the NFBC webpage (15). Measures Cannabis use The data on adolescent cannabis use was collected using questionnaires which the participants received during the field study when they were aged 15 to 16 years. The participants were asked ‘Have you ever used marihuana or hashish?’ as dichotomized (no/yes) and with options: 1) never, 2) once, 3) 2-4 times, 4) 5 times or more, or 5) regularly. Options 4-5 were pooled due to small sample size in the two categories (13). Psychosis diagnoses Information on diagnosed non-organic psychoses (ICD-10: F20, F22-F29, F302, F312, F315, F323, F333) was gathered from nationwide registers: the Care Register for Health Care 2001-2015 and the Register of Primary Health Care Visits 2011-2015 of the National Institute for Health and Welfare, disability pensions of the Finnish Centre for Pensions 2001-2015, and the medication reimbursement register of the Social Insurance Institution of Finland 2001-2005. The Care Register contains data on patients discharged from inpatient care, and since 1998 also data on specialized outpatient care. The Register of Primary Health Care Visits covers all outpatient primary health care delivered in Finland. For more comprehensive information about the registers see Filatova et al. 2016 Supplement 1 (17). Age at the time when psychosis was first detected was estimated as the onset age of psychosis. Cumulative incidence of psychoses was calculated. Prodromal symptoms The occurrence of prodromal symptoms during the previous six months were asked (no/yes) using the PROD-screen (16) when the cohort members were 15-16 years old. The PROD-questionnaire has 12 specific items (no/yes) rating e.g. feelings that something strange or inexplicable is taking place within oneself or in the environment, feelings that one is being followed or influenced in some special way, experience of thoughts running wild or difficulty in controlling the speed of thoughts. The sum of the questionnaire was used as a continuous variable in the analyses. Smoking and substance use other than cannabis Data on tobacco smoking, alcohol use, and use of illicit drugs or other intoxicants was collected at two points during the 15–16-year follow-up: information on regular tobacco smoking was ascertained in postal questionnaires and other data on substance use were collected in the questionnaire that the participants received during the field study. Daily tobacco smoking was studied with the question ‘Are you currently smoking tobacco daily (no/yes)’. Frequent drunkenness was questioned as subjective measure ‘Have you been drunk during the past year (0, 1-2, 3-5, 6-9, 10-19, 20-39 or 40 times or more)’, but we categorized this as ‘Have you been drunk during the past year 10 times or more (no/yes)’. Data were also collected on any use of other substances with several questions (no/yes), e.g. prescription drug use, use of inhalants and illicit drugs. Because of the low number of users in each group, these were combined as ’Other substance use (no/yes)’. Family structure Information on family structure was gathered by combining information collected from parents at birth and when the cohort member was aged 15–16. The classification of the family pattern included families with (1) both parents living with the subject all the time (intact families) and (2) other (non-intact) families (13). Place of residence Data were collected based on the population density of the residential area at age 15–16 years in order to account for possible confounding due place of residence. The variable was dichotomized in the analyses (urban vs. non-urban). Socio-economic status of the family The socio-economic status of the family was estimated by the highest education level achieved by either parent when the child was aged 15–16. This variable was categorized as: professionals (professionals, entrepreneurs and other white-collar workers) and non-professionals (13). Parental psychosis Information on parental psychosis (no/yes) was based on parental diagnoses in the nationwide registers. These registers include: 1) Register of Health Care during the years 1972-2015 (Hospital Discharge Register until 1994). This register also includes visits to specialized outpatient health care since 1998; 2) disability pensions of the Finnish Centre for Pensions (1965-2013), and 3) The Register of Primary Health Care Visits (2011-2015). Statistical methods We used logistic regression analysis with Cox regression analysis (Hazard Ratio, HR; with 95% CI) to assess the effect of cannabis use on the risk of psychosis. Times of emigration and death were used as censoring points in the analyses. We conducted also additional Cox regression analyses on cannabis use and separate psychosis diagnoses. Cannabis use was included in the analyses as dichotomized (no/yes) and categorized (never, once, 2-4 times, 5 times or more). Logistic regression analysis with odds ratios (OR; 95% confidence interval, CI) was used to study the associations between a) covariates (i.e. family characteristics, smoking, alcohol use and other drug use) and cannabis use (dichotomized), and b) covariates and psychosis diagnosis. We also studied dose-response with a trend test, in which cannabis use was entered to the regression analysis as a continuous variable. In the final Cox-regression analyses, we included covariates that had statistically significant effects (p<0.05) on both the outcome of cannabis use and psychosis diagnosis. Additionally, we also included parental psychosis (no/yes) because it is known to be a potential risk factor for psychosis although it reached statistical significance only for psychosis risk and thus did not fulfill the inclusion criteria as described above. All statistical analyses were performed using SPSS 21.0. Results Background variables, cannabis use and occurrence of prodromal symptoms and psychosis The background variables under study and their relation to cannabis use and occurrence of psychosis during the follow-up are presented in Table 1. In all, there were 375 (5.7%) ever users of cannabis of which 66 (1.0%) had used cannabis more than five times. Girls reported cannabis use more commonly than boys (6.3% vs. 5.1%, p<0.05). Among those who had tried cannabis once, 58.9% were female (112/190). The respective figures for 2-4 times and 5 times or more were 55.5% (66/119) and 48.5% (32/66). Daily smokers were more likely to use cannabis than non-daily smokers (22.2% vs. 3.3%, p<0.05, see Table 1). In total, 1993 adolescents (30.5% of the study sample) reported frequency of 3 or more items in PROD-screen. **insert table 1 here** Altogether 124 psychoses emerged in the sample population (29 narrow defined schizophrenia, 10 schizophrenia spectrum disorder (schizoaffective disorder and delusional disorder), 12 bipolar disorder with psychotic episodes, 19 major depression with psychotic features, 54 other psychosis (brief reactive psychosis, psychosis NAS, other psychotic disorder). Of these, 57 out of 124 (46.0%) were female. Attrition In the attrition analysis, subjects from non-intact families were less likely to participate in the study than subjects from intact families (60% vs. 70%) when the participants were 15-16 years old. Also, participation rate in subjects from non-urban (72%) was higher than in subjects from urban areas (64%) (13). Not participating in the follow-up study was associated with greater risk for psychosis (HR = 1.52, 95%CI 1.13-2.04). Associations between adolescent cannabis use and subsequent psychosis The frequencies and hazard ratios (HR) for risk of psychosis in relation to cannabis use are presented in Table 2. Of the cannabis users, 18 out of 375 (4.8%) received a psychosis diagnosis during the 15-year follow-up (4 narrow defined schizophrenia, 4 schizophrenia spectrum disorder, 0 bipolar disorder with psychotic features, 7 major depression with psychotic features, 3 other psychosis). Among those without adolescent cannabis use, the incidence of psychosis was 1.7% (n=106; 25 narrow defined schizophrenia, 6 schizophrenia spectrum disorder, 12 major depression with psychotic features, 12 bipolar disorder with psychotic features, 51 other psychosis. Use of cannabis at the age 15-16 years was associated with psychosis (unadjusted HR= 2.85; 95%CI=1.73-4.67). When studied by category, using cannabis less than five times had no statistically significant association with psychosis. The proportion of psychoses in each cannabis use category were following: once 2.6% (5/190), 2-4 times 5.0% (6/119) and for 5 times or more 10.6% (7/66). A dose-response was seen with the trend test (OR=1.83; 95%CI=1.45-2.31). More frequent use of cannabis, i.e. using at least five times, was associated with subsequent psychosis (HR=6.47; 3.01-13.91), and this was also evident when the data was adjusted for prodromal symptoms of psychosis (see Table 2). When further adjusted for daily tobacco smoking, frequent alcohol use, other substance use and parental psychosis, the association between frequent cannabis use in this sample and subsequent psychosis attenuated but remained statistically significant (see Table 2). When the psychosis diagnoses were analyzed separately, diagnosis of psychotic depression (HR = 9.74; 3.83-24.73) and schizophrenia spectrum disorder (HR = 11.18; 3.16-39.62) were associated with cannabis use. No statistical significance was reached for schizophrenia, bipolar disorder with psychotic episodes and other psychosis in cannabis users vs. controls. Figure 2 presents cumulative incidences of psychosis and hazard curves for psychosis risk by cannabis use and prodromal symptoms in four groups. As can be seen in this descriptive figure, adolescents with prodromal symptoms (cut off ≥ 3) and cannabis use had approx. twofold higher incidence of psychosis by age 30 years compared to adolescents with prodromal symptoms but no cannabis use. **Insert Table 2 and Fig 2 here** DISCUSSION Cannabis use at the age of 15-16 years was associated with subsequent psychosis diagnosis, and this was evident in the group with heaviest cannabis use even after controlling for baseline prodromal symptoms, daily smoking, frequent alcohol use, other substance use and parental psychosis. We found a dose-response effect suggesting that more frequent cannabis use is associated with a greater risk for psychosis. Our results further confirm the previous results of meta-analyses (1-4) indicating that adolescent cannabis use is associated with increased risk for psychosis. In our study, this was evident even when adjusted with multiple covariates. Further, in line with previous studies (1,3), cannabis use was associated with subsequent psychosis diagnosis in a dose-response manner. As stated earlier, several studies have examined the impact of psychotic baseline severity in relation to cannabis-psychosis association (e.g. 8-11), but to our knowledge there is only one prospective study (Dunedin) examining cannabis use and psychosis diagnosis that has adjusted for psychotic baseline severity (8). In our study, the association between the use of cannabis 5 times or more in adolescence and subsequent psychosis remained statistically significant after adding the prodromal symptoms in the multivariable model. However, inclusion of the prodromal symptoms decreased the hazard ratio of the cannabis-psychosis association approximately by 30%. There might be a sub-sample of subjects that are self-medicating, but it is unlikely that the whole decrease in the strength of association would be due to self-medicating since the study population was only 15-16 year-olds during the field study. Some studies have revealed certain schizophrenia risk alleles are associated with increased use of cannabis (18). In addition, recent study revealed that symptoms of cannabis use disorder and psychotic-like experiences in young adults could be partly explained by shared genetic factors (19). Therefore, the decrease in the strength of the association might rather be due to high correlation between these two variables (Prod-screen > 3 and cannabis use). However, shared genetic factors are likely explain only part of the association and we are still missing the data from adolescent samples. In our previous report those who had tried cannabis had a higher mean number of prodromal symptoms than the controls (3.11 vs. 1.88; t-test 8.68, p<0.001) (13). Experiencing prodromal symptoms in adolescence is common (20) and in our study 30.5% of adolescents reported frequency of 3 more items in PROD-screen. It should be noted that as this is a population based study, individuals having self-reported prodromal symptoms differ from clinical or other high risk samples (21) since no interview assessing symptoms was performed. It is likely that the current estimate of frequency of prodromal symptoms would have been much lower in the interview. For example in the ALSPAC study, 38.9% of children self-reported experiencing prodromal symptoms in the previous 6 months, however observer-rated assessments identified only 13.7% of children as experiencing these symptoms (22). In our current study, subjects with prodromal symptoms and cannabis use in adolescence had double the incidence of psychosis compared to controls with prodromal symptoms but no cannabis use (see Figure 2). Current evidence indicates that early-onset cannabis use predates the onset of psychosis, especially among those with pre-existing vulnerability and heavier cannabis use (23). Subjects with prodromal symptoms in adolescence might be more prone to adverse effects of cannabis, experiencing more severe prodromal and psychotic symptoms compared to those without cannabis use. In line with previous strong evidence (24), parental psychosis was a significant risk factor for offspring psychosis. However, frequent cannabis use in adolescence increased the risk for psychotic illness independently of parental psychosis in our sample. Subjects with both parental psychosis and cannabis use have been shown to have a greater risk for psychotic outcomes (24). It has been speculated that there might be a shared genetic etiology between cannabis dependence and schizophrenia (25), which may in part explain the associations between adolescent cannabis use, parental psychosis, and onset of offspring psychotic illness. Unfortunately, due to the relatively low number of psychosis cases among the cannabis users, we could not reliably study interaction of these risk factors (parental psychosis and adolescent cannabis use). Cannabis use disorder has been associated with greater psychosis conversion, independently of other forms of substance use (12). In order to study the cannabis-specific association with psychotic illness, we added daily smoking, frequent drunkenness, or illicit drug use other than cannabis to the multivariable models with parental psychosis history. In these analyses, an association between frequent cannabis use and psychosis was shown independent of other substance use. However, statistical significance between frequent cannabis use and subsequent psychotic illness was attenuated by 28% when substance use other than cannabis, i.e. daily smoking, frequent drunkenness or other forms of substance use, was included in the multivariate model with baseline prodromal symptoms. This may mostly be explained by over-adjustment, because polysubstance use was very common among cannabis users. For example, 45% of the cannabis users were also daily smokers and 66% of cannabis users were frequent alcohol users. Furthermore, assessing the true significance of cannabis use or cigarette smoking may also be challenging because cannabis users usually smoke cannabis mixed with tobacco (26). We reported that individuals from non-intact families (60% vs. 70%) and urban areas (64% vs. 72%) were less likely to participate in the NFBC field study in 2001-2002. As these individuals were more likely to have ever used cannabis, it is likely that our proportion of individuals using cannabis is underestimated, but as the participation rates are still very good it is unlikely that this affected the overall conclusions of the study. Although boys report cannabis use more often in general (27), here girls reported more cannabis use than boys (6.3% vs. 5.1%). However, this was mostly due more sporadic use than of boys. It can be speculated that girls of this age (15-16 years) might be more prone to single experiments with cannabis in general because of earlier puberty. Finally, although there were more cannabis users among girls, gender did not reach statistical significance for psychosis in the crude analyses. Unfortunately, we were unable to analyze psychosis risks separately by gender due to the low amount of cannabis users. We reported also that specifically diagnoses of psychotic depression and schizophrenia spectrum disorder were associated with cannabis use. Interestingly, no significance was found for narrow schizophrenia. Due to small number of cases strong conclusions cannot be drawn, since we could not analyze the effect of frequent use of cannabis on separate diagnoses. However, this has not been reported in previous prospective samples to our knowledge and should be noted in further studies. Strengths and limitations There are notable strengths in our study: 1) This is one of the largest birth cohort studies with high genetic and ethnic homogeneity with relatively low attrition. 2) We were able to use several nationwide registers, and only a very small proportion (3.2%) of cohort members deceased or emigrated during the follow-up. Therefore, the coverage of clinically significant psychosis diagnoses within this population during the 15-year-follow-up can be considered to be high. 3) We made substantial effort to minimize the possibility of residual confounding. 4) Furthermore, adjusting for prodromal symptoms indicated a possible temporal or even causal link between cannabis use and subsequent psychosis that is in line with previous research. However, following limitations should be taken into account when interpreting our results: 1) The number of cannabis users with psychosis diagnosis was relatively low. Also, no prospective data on cannabis use before or after the age of 15-16 years was available. 2) Information on substance use was collected using self-report, which may give rise to a bias of underreporting and possible underestimation of the true association (7). 3) Cannabinoid levels of cannabis may vary considerably, and different strains may have different psychotropic potentials (28). The THC/CBD concentration of different strains has also increased considerably over years (29) and may alter the generalizability of our results. This should be noted in future studies. 4) Unfortunately, we did not have any data on other family/relative psychosis and this should be noted in order to account for genetic vulnerability more comprehensively. 5) The subjects from non-intact families and urban areas were less likely to participate in the NFBC field study in 2001-2002, which may introduce bias. Further, adolescents with prodromal symptoms may also be less likely to answer on self-report questionnaires, as the risk of psychosis was higher among the non-participants compared to those who participated. Conclusions Our study provides further evidence on the temporal order of adolescent cannabis use and psychosis. According to our results, cannabis use increases the risk for subsequent psychosis even after prodromal symptoms of psychosis, parental psychosis and other substance use have been taken into account. However, it is still controversial whether cannabis use alone is a sufficient risk factor for psychosis or rather a component cause in the pathogenesis. The importance of psychoeducation and prevention of adolescent cannabis use is emphasized as adolescents using cannabis and having prodromal symptoms were at two-fold risk for subsequent psychosis. Figure 1. Data flow from the current study in the Northern Finland Birth Cohort 1986 4 Table 1 Family characteristics, smoking, alcohol use and other drug use by cannabis use categories in the 15-16 -Year Follow-Up Study of the Northern Finland 1986 Birth Cohort Have you ever tried or used marihuana or hashish? Statistical test Occurrence of psychosis during the follow-up Statistical test Never Ever (at least once) Never vs. ever No   Yes   No vs. Yes n % n % OR (95% CI)1 n % n % OR (95% CI)1 Total sample (n=6534) 6159 94.3 375 5.7 - 6410 98.1 124 1.9 - Gender - Boys (n=3209) 3044 94.9 165 5.1 [Reference] 3142 97.9 67 2.1 [Reference] - Girls (n=3325) 3115 93.7 210 6.3 1.24 (1.01-1.53) 3268 98.3 57 1.7 0.82 (0.57-1.17) Place of residence at age 15-16 years - Non-urban (n=4277) 4084 95.5 193 4.5 [Reference] 4195 98.1 82 1.9 [Reference] - Urban (n=2257) 2075 91.9 182 8.1 1.86 (1.51-2.29) 2215 98.1 42 1.9 0.87 (0.67-1.41) Family background Family structure - Intact (n=4043) 3856 95.4 187 4.6 [Reference] 3972 98.2 71 1.8 [Reference] - Non-Intact (n=2491) 2303 92.5 188 7.5 1.68 (1.37-2.07) 2438 97.9 53 2.1 1.21 (0.85-1.74) Social status of the family - Non-professionals (n=1194) 1129 94.6 65 5.4 [Reference] 1172 98.2 22 1.8 [Reference] - Professionals (n=4448) 4194 94.3 254 5.7 1.05 (0.80-1.39) 4362 98.1 86 1.9 1.05 (0.66-1.69) Parental psychosis - No (n=6244) 5890 94.3 354 5.7 [Reference] 6131 98.2 113 1.8 [Reference] - Yes (n=290) 269 92.8 21 7.2 1.30 (0.82-2.05) 279 96.2 11 3.8 2.13 (1.14-4.02) Adolescent substance use 10 or more times during the past 12 months - No (n=5188) 5066 97.6 122 2.4 [Reference] 5102 98.3 77 1.7 [Reference] - Yes (n=1183) 935 79.0 248 21.0 11.01 (8.77-13.83) 1147 97.0 30 3.0 1.86 (1.26-2.76) Daily smoking - No (n=5277) 5103 96.7 174 3.3 [Reference] 5195 98.4 82 1.6 [Reference] - Yes (n=756) 588 77.8 168 22.2 8.38 (6.67-10.53) 731 96.7 25 3.3 2.17 (1.38-3.41) Other drug use - No (n=6471) 6125 94.7 346 5.3 [Reference] 6351 98.1 120 1.9 [Reference] - Yes (n=35) 7 20.0 28 80.0 70.81 (30.71-163.25) 31 88.6 4 11.4 6.83 (2.37-19.65) 1 Odds Ratio (95% Confidence Interval). Statistically significant (p<0.05) differences are in bold. Table 2. The hazard ratios (HR) for the risk of psychosis in Northern Finland Birth Cohort 1986 in different groups of cannabis use Cannabis use n HR (95% CI) Crude (N=6534) Never 6159 Ref. Ever 375 2.85 (1.73-4.67) Crude (N=6534) Never 6159 Ref. Once 190 1.53 (0.63-3.76) 2-4 times 119 3.03 (1.33-6.90) 5 times or more 66 6.47 (3.01-13.91) Model 1 (N=6534) Never 6159 Ref. Once 190 1.21 (0.49-2.98) 2-4 times 119 2.25 (0.98-5.18) 5 times or more 66 4.38 (2.00-9.59) Model 2 (N=5872) Never 5534 Ref. Once 171 1.13 (0.44-2.90) 2-4 times 108 1.43 (0.50-4.07) 5 times or more 59 3.16 (1.21-8.29) Model 3 (N=5872) Never 5534 Ref. Once 171 1.15 (0.46-2.95) 2-4 times 108 1.46 (0.51-4.16) 5 times or more 59 3.02 (1.14-7.98) Statistically significant (p<0.05) differences are in bold. Covariates: Model 1: PROD; Model 2: PROD, Other substance use HR = 2.19 (0.67-7.17), frequent alcohol use HR = 1.27 (0.78-2.07), daily tobacco smoking HR = 1.42 (0.84-2.39); Model 3: Model 2, parental psychosis HR = 1.83 (0.91-3.64) 22 Figure 2. Cumulative incidences of psychosis in four groups with and without cannabis use and prodromal symptoms in the Northern Finland Birth Cohort 1986 Declaration of interest: This study was funded by EU QLG1-CT-2000-01643 (EUROBLCS) Grant no. E51560, NorFA Grant no. 731, 20056, 30167, USA / NIHH 2000 G DF682 Grant no. 50945, the Academy of Finland (#268336), Jalmari and Rauha Ahokas Foundation, the Northern Finland Health Care Support Foundation, NARSAD: the Brain and Behavior Research Fund, the Signe and Ane Gyllenberg Foundation, Finland, the Sigrid Jusélius Foundation, Finland, Thule Institute, University of Oulu, Finland and Finnish Cultural Foundation, The Olvi Foundation, Juho Vainio Foundation and Oulun Lääketieteellinen tutkimussäätiö. 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Traditional marijuana, high‐potency cannabis and synthetic cannabinoids: increasing risk for psychosis. World Psychiatry 2016; 15: 195–204.   ANTTI MUSTONEN1,2, MD, SOLJA NIEMELÄ3,4, , MD, PhD, TANJA NORDSTRÖM1,2, PhD, GRAHAM K. MURRAY5, MRCPSych, PIRJO MÄKI2,3,6,7, MD, PhD, ERIKA JÄÄSKELÄINEN1,2, MD, PhD, JOUKO MIETTUNEN1,2, PhD 1) Center for Life Course Health Research, University of Oulu, Oulu, Finland 2) Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland 3) Department of Psychiatry, Research Unit of Clinical Neuroscience, University of Oulu, Oulu, Finland 4) Department of Psychiatry, Lapland Hospital District, Rovaniemi, Finland 5) Department of Psychiatry, University of Cambridge, Cambridge, U.K. 6) Department of Psychiatry, Oulu University Hospital, the Northern Ostrobothnia Hospital District, Oulu, Finland 7) Department of Psychiatry, Länsi-Pohja healthcare district; Department of Psychiatry, the Middle Ostrobothnia Central Hospital, Soite; Mental health services, Joint Municipal Authority of Wellbeing in Raahe District; Mental health services and Basic Health Care District of Kallio Correspondence: Antti Mustonen, Center for Life Course Health Research, University of Oulu, P.O. Box 5000, 90014 UNIVERSITY OF OULU, Finland Phone +358 400437618, Fax +358 8 5315037, Email: antti.mustonen@student.oulu.fi Contribution: Antti Mustonen - conception and design, analysis, interpretation of data and drafting the article, revising the article critically for important intellectual content and final approval of the version to be published Solja Niemelä - conception and design, analysis, interpretation of data and drafting the article, revising the article critically for important intellectual content and final approval of the version to be published Jouko Miettunen - conception and design, analysis, interpretation of data and drafting the article, revising the article critically for important intellectual content and final approval of the version to be published Tanja Nordström - conception and design, analysis, interpretation of data Graham K. Murray - revising the article critically for important intellectual content and final approval of the version to be published Pirjo Mäki - revising the article critically for important intellectual content and final approval of the version to be published Erika Jääskeläinen - revising the article critically for important intellectual content and final approval of the version to be published Cannabis use + & Prodromal symptoms of psychosis + (n=13/134) 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 0 0 0 0 0 5.2083333333333296E-3 5.2083333333333296E-3 1.5625E-2 2.0833333333333301E-2 2.0833333333333301E-2 2.6041666666666699E-2 4.1666666666666699E-2 4.1666666666666699E-2 4.1666666666666699E-2 4.6875E-2 4.6875E-2 5.7291666666666699E-2 5.7291666666666699E-2 6.25E-2 6.7708333333333301E-2 6.7708333333333301E-2 Cannabis use + & Prodromal symptoms of psychosis - (n=5/134) 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 0 0 0 0 0 0 6.0606060606060597E-3 6.0606060606060597E-3 6.0606060606060597E-3 6.0606060606060597E-3 6.0606060606060597E-3 6.0606060606060597E-3 6.0606060606060597E-3 6.0606060606060597E-3 1.21212121212121E-2 2.4242424242424201E-2 2.4242424242424201E-2 2.4242424242424201E-2 3.03030303030303E-2 3.03030303030303E-2 3.03030303030303E-2 Cannabis use - & Prodromal symptoms of psychosis + (n=54/134) 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 0 0 5.7504312823461695E-4 5.7504312823461695E-4 2.30017251293847E-3 2.8752156411730899E-3 3.4502587694077002E-3 6.3254744105807901E-3 6.9005175388154099E-3 9.7757331799884998E-3 1.1500862564692399E-2 1.6101207590569301E-2 1.8976423231742399E-2 2.0701552616446201E-2 2.2426682001150101E-2 2.3001725129384702E-2 2.5876940770557799E-2 2.64519838987924E-2 2.7602070155261602E-2 2.9902242668200098E-2 3.10523289246693E-2 Cannabis use - & Prodromal symptoms of psychosis - (n=62/134) 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 2.31803430690774E-4 2.31803430690774E-4 2.31803430690774E-4 6.9541029207232199E-4 6.9541029207232199E-4 1.1590171534538701E-3 1.85442744552619E-3 1.85442744552619E-3 2.5498377375985201E-3 3.2452480296708401E-3 4.1724617524339404E-3 5.0996754751970299E-3 5.7950857672693498E-3 6.4904960593416801E-3 7.185906351414E-3 9.0403337969401903E-3 1.0662957811775601E-2 1.2053778395920299E-2 1.29809921186834E-2 1.3908205841446499E-2 1.4371812702828E-2 Age (years) at psychosis onset Cumulative incidence (%) of psychosis image1.tiff