Development Over Time of the Population-Attributable Risk Fraction for Cannabis Use Disorder in Schizophrenia in Denmark

Research

JAMA Psychiatry | Original Investigation Development Over Time of the Population-Attributable Risk Fraction for Cannabis Use Disorder in Schizophrenia in Denmark

Carsten Hjorthøj, PhD; Christine Merrild Posselt, MSc; Merete Nordentoft, DrMedSc

Editorial

IMPORTANCE Cannabis use and potency of cannabis have increased during the past 2 Multimedia decades. If the association between cannabis use and schizophrenia is causal, this should be reflected in an increase in the proportion of cases of schizophrenia being attributable to Supplemental content cannabis, the population-attributable risk fraction (PARF).

OBJECTIVE To determine whether the PARF for cannabis use disorder in schizophrenia has increased over time.

DESIGN, SETTING, AND PARTICIPANTS This nationwide, register-based historical prospective cohort study included all people in Denmark born before December 31, 2000, who were alive and 16 years or older at some point from January 1, 1972, to December 31, 2016. Data analysis was performed from August 2020 to April 2021.

EXPOSURE Diagnosis of cannabis use disorder.

MAIN OUTCOMES AND MEASURES Diagnosis of schizophrenia, with estimated PARF of cannabis use disorder in schizophrenia from 1972 to 2016.

RESULTS A total of 7 186 834 individuals were included in the analysis, including 3 595 910 women (50.0%) and 3 590 924 men (50.0%). The adjusted hazard ratio for schizophrenia Author Affiliations: Copenhagen fluctuated at approximately 4 (with 95% CIs ranging from approximately 3 to 6) throughout Research Center for Mental Health– most of the study period when people diagnosed with cannabis use disorder were compared CORE, Mental Health Center with those without cannabis use disorder. The PARF of cannabis use disorder in schizophrenia Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark also fluctuated, but with clear evidence of an increase from 1995 (when the PARF was (Hjorthøj, Posselt, Nordentoft); relatively stable around 2.0%, with a 95% CI of approximately 0.3% to either side) until Section of Epidemiology, Department reaching some stability around 6.0% to 8.0% (with a 95% CI of approximately 0.5% of Public Health, University of to either side) since 2010. Copenhagen, Copenhagen, Denmark (Hjorthøj); The Lundbeck Foundation CONCLUSIONS AND RELEVANCE The results from these longitudinal analyses show the Initiative for Integrative Psychiatric Research, iPsych, Copenhagen and proportion of cases of schizophrenia associated with cannabis use disorder has increased Aarhus, Denmark (Hjorthøj, 3- to 4-fold during the past 2 decades, which is expected given previously described increases Nordentoft). in the use and potency of cannabis. This finding has important ramifications regarding Corresponding Author: Carsten legalization and control of use of cannabis. Hjorthøj, PhD, Copenhagen Research Center for Mental Health–CORE, Mental Health Center Copenhagen, JAMA Psychiatry. doi:10.1001/jamapsychiatry.2021.1471 Gentofte Hospitalsvej 15, Fourth Published online July 21, 2021. Floor, DK-2900 Hellerup, Denmark ([email protected]).

everal studies and meta-analyses1,2 have indicated that Despite this, some debate persists regarding whether the the risk of schizophrenia and related psychoses is in- association between cannabis use and schizophrenia is truly S creased for people who use cannabis. The association causal. Epidemiological studies, although able to provide appears to be particularly driven by heavy and frequent can- strong evidence, can never completely exclude the possibility nabis use.2,3 This has led to a persisting hypothesis that can- of residual confounding. One argument against the causal hy- nabis may be a component cause of schizophrenia, at least in pothesis has been that, with increasing use and potency of can- some people. This hypothesis is strengthened by several fac- nabis in the population, one should have observed an increase tors, such as strong attempts to control for reverse causation in the incidence of schizophrenia, which has been postulated to (eg, people self-medicating prodromal symptoms of schizo- be absent.10-12 A long-standing dogma states that the incidence phrenia). Similarly,cannabis-induced psychosis has been found of schizophrenia has remained stable over time, but Kühl et al13 to be associated with later onset of schizophrenia.4-6 Further- recently showed that the incidence of schizophrenia has steadily more, experimental evidence strongly suggests that canna- increased in Denmark from 2000 to 2012, especially in younger bis, even in relatively low doses, causes psychoticlike symp- groups. This study did not, however, make any claims that this toms in healthy individuals.7-9 should have been due to increasing use or potency of cannabis.13

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Denmark has the benefit of having unselected nationwide Danish registers that allow for large-scale studies using Key Points the entire population. Using these registers, Nielson et al14 Question Has the population-attributable risk fraction for showed that cannabis use disorder, an indicator of regular use cannabis use disorder in schizophrenia increased over time, as of cannabis, is associated with schizophrenia. Both cannabis would be expected with increasing use and potency of cannabis? use and cannabis use disorder have indeed been increasing Findings In this Danish nationwide, register-based cohort study, over time in many countries, such as Denmark.12 The same is the population-attributable risk fraction for cannabis use disorder true for the potency of cannabis products available on the in schizophrenia increased from approximately 2% in the period to market.10,11 If all other risk factors for schizophrenia re- 1995 to approximately 6% to 8% since 2010. mained stable in the same period, this should then lead to an Meaning These findings may indicate that cannabis use disorders increase in the population-attributable risk fraction (PARF) of are associated with an increase in the proportion of cases of cannabis use disorder in schizophrenia. The PARF estimates schizophrenia. the proportion of cases with schizophrenia that would have been prevented if nobody had cannabis use disorder. We thus aimed to investigate whether the PARF for cannabis use dis- K86.0, O35.4, Y57.3, Z50.2, Z71.4, and Z72.1) and other sub- order in schizophrenia has increased over time in the Danish stance use disorder (ICD-8 codes 304.x except 304.5; ICD-10 population. codes F1X.X except F10.X, F12.X, and F17.X), both as time- varying covariates identified in the Psychiatric Central Re- search Register and the National Patient Register; sex; and other Methods psychiatric diagnoses except those pertaining to substance use disorder or schizophrenia (ICD-8 codes 290-315; ICD-10 codes We used the nationwide Danish registers, full linkage of which FX, except those previously used) as time-varying covariates is made possible through the personal identification number identified in the Psychiatric Central Research Register. We also issued to all people born in Denmark or obtaining legal resi- included parental psychiatric history and parental history of dence in Denmark since 1968.15 We included all people born alcohol, cannabis, and substance use disorder, using the same before December 31, 2000, who were alive and 16 years or older diagnostic codes as described previously. Analyses were fur- at some point from January 1, 1972, to December 31, 2016, en- ther adjusted for sex, age at the beginning of each year, whether suring that all people would be able to turn at least 16 years of a person was born outside of Denmark, and the parents’ high- age during follow-up. Purely register-based studies do not re- est level of education. In cases of missing data, we included a quire ethics approval under Danish law. This study was ap- unique value in the analyses indicating missingness. proved by the Danish Data Protection Agency, and analyses were conducted on servers at Statistics Denmark using en- Statistical Analysis crypted personal identification numbers, making identifica- The data analysis was performed from August 2020 to April tion of single individuals impossible. This study followed the 2021. The PARF is calculated by the following formula: Strengthening the Reporting of Observational Studies in Epi- PARF = pd([RR − 1]/RR), where pd refers to the proportion of demiology (STROBE) reporting guideline. exposed participants among cases (ie, the proportion of those who develop schizophrenia who were diagnosed with canna- Cannabis Use Disorder and Schizophrenia bis use disorder), and RR is the rate ratio, which in this study Information on both cannabis use disorder and schizophre- was estimated using the hazard ratio following a Cox propor- nia was obtained from the Psychiatric Central Research Reg- tional hazards regression model with time-varying covari- ister, in which all inpatient treatment at psychiatric depart- ates. We applied this formula for the PARF because it is inter- ments has been registered since 1969, as well as outpatient nally valid when confounding exists and adjusted rate ratios treatment at psychiatric departments since 1995.16 In the case must be used.18 We used the Greenland method for estimat- of cannabis use disorder, this was supplemented with data from ing 95% CIs of the PARF.19 the National Patient Register, which contains data on inpa- We estimated the PARF for each year from 1972 to 2016 tient treatment at general (nonpsychiatric) departments since by using delayed entry into the Cox proportional hazards 1977 and outpatient treatment since 1995.17 Cannabis use dis- regression model on January 1 of a given year, and censoring order was defined as International Classification of Diseases, individuals on December 31 of the same year if they had not Eighth Revision (ICD-8) diagnostic code 304.5 and Interna- either developed incident schizophrenia or been censored ow- tional Statistical Classification of Diseases and Related Health ing to death or emigration. People were entered into the analy- Problems, Tenth Revision (ICD-10) diagnostic code F12.X. ses no earlier than their 16th birthday. For each year under in- Schizophrenia was defined as ICD-8 diagnostic code 295.X vestigation, we considered a person positive for cannabis use (except 295.7) and ICD-10 diagnostic code F20.X. disorder only if at least 1 diagnosis thereof had been given no more than 3 years before the start of that year. The propor- Potential Confounders tion of individuals with diagnosed cannabis use disorder in a The following potential confounders were included in the given year was evaluated using this time-varying covariate. Age analyses: alcohol use disorder (ICD-8 codes 291, 303, and 571.0; of the individual was used as the underlying timescale, en- ICD-10 codes F10.x, E24.4, E52, G31.2, G62.1, G72.1, K29.2, K70, suring that analyses were adjusted for age.

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We also calculated the E-value for the estimate and the Table. Characteristics of Individuals Included in at Least 1 Analysis lower limit of the 95% CI each year in the same period. The E- of Yearly PARF value is a measure of the strength of unmeasured confound- No. (%) of participants ers on both cannabis use disorder and schizophrenia that would Characteristic (N = 7 186 834)a need to exist to completely explain the observed association.20 Sex We conducted sensitivity analyses in which we censored Male 3 590 924 (50.0) individuals as they turned 50 years of age, to better reflect the Female 3 595 910 (50.0) population most at risk of both cannabis use disorder and in- Decade of birth cident schizophrenia. We conducted further sensitivity analy- 1939 or earlier 2 195 395 (30.5) ses, expanding the time frame for positive cannabis use dis- 1940s 828 617 (11.5) order to 7 years and 1 sensitivity analysis without a time limit 1950s 837 048 (11.6) of exposure. In a final set of sensitivity analyses, we did not 1960s 945 783 (13.2) adjust for other psychiatric disorders, which may be a case of 1970s 860 459 (12.0) overadjustment, for instance because other psychiatric disor- 1980s 757 927 (10.5) ders might rather be considered mediators. All analyses were 1990s or 2000 761 605 (10.6) conducted in Stata/MP, version 16.1 (StataCorp LLC). Not born in Denmark 656 739 (9.1) Developed schizophrenia during follow-up 42 611 (0.6) Positive for cannabis use disorder in ≥1 analysis 23 809 (0.3) Results Positive for alcohol use disorder in ≥1 analysis 169 571 (2.4) Positive for other substance use disorder 135 066 (1.9) We included 7 186 834 individuals in at least 1 of the yearly in ≥1 analysis PARF analyses (3 595 910 women [50.0%] and 3 590 924 men Positive for other psychiatric disorders 726 991 (10.1) [50.0%]). Additional characteristics of the study population in ≥1 analysis Died during follow-upb 2 075 920 (28.9) are provided in the Table. Parental history The association between cannabis use disorder and schizo- Schizophrenia 23 889 (0.3) phrenia over time is depicted in Figure 1. Figure 1A and B show the hazard ratios, which, unadjusted, decreased from more Alcohol or substance use disorder 340 092 (4.7) than 100 to reaching some stability at approximately 50 or even Other psychiatric disorder 643 562 (9.0) c 30. The adjusted hazard ratio fluctuated over time, but with Highest level of parental education attained no clear trend, and generally centered around an adjusted haz- Primary/lower secondary 762 319 (10.6) ard ratio of approximately 4 (with 95% CIs ranging from ap- Upper secondary (high school equivalent) 1 357 350 (18.9) proximately 3 to 6). The association remained statistically sig- Short-cycle tertiary 147 817 (2.1) nificant throughout the period, as indicated by the 95% CIs. Bachelor’s degree or equivalent 590 162 (8.2) The 95% CIs tended to narrow after 1995. This substantial de- Master’s degree or equivalent or higher 257 325 (3.6) crease in the hazard ratios is likely a case of overadjustment, Not available in registers 4 071 861 (56.7) because most of the reduction occurred when adjusting for a Percentages have been rounded and may not total 100. other psychiatric disorders. This would indicate that the fully b Includes deaths occurring while at risk of schizophrenia. Consequently, adjusted hazard ratios may actually be artificially low. How- deaths occurring after incident schizophrenia or after emigration are not ever, we opted to use these because conservative results, bi- counted here. c ased toward the null hypothesis, are preferable owing to our Uses International Standard Classification of Education definitions. desire to avoid false-positive findings. Figure 1C and D show the development over the period of incident schizophrenia 10, beyond the other variables already included in the ad- and of recently diagnosed (within 3 years) cannabis use dis- justed analyses. order. The latter increased almost linearly throughout the pe- Figure 4 shows results from the 4 sensitivity analyses. riod, whereas the incidence of schizophrenia showed a gen- The results were largely the same, with the same apparent in- erally increasing tendency, albeit with some fluctuations. crease being evident, albeit with slightly higher PARFs. Parameter estimates for all variables are shown in the eTable in the Supplement for the years 1972, 2000, and 2016. The development of the PARF over time is depicted in Discussion Figure 2. Despite some fluctuation, a general increase over time is evident, starting first around 1995 (when the PARF was rela- An increase in the PARF over time for cannabis use disorder tively stable at approximately 2.0% with a 95% CI of approxi- in schizophrenia was clearly observed. The PARF increased mately 0.3% to either side) until reaching some stability around from approximately 4.0% around the turn of the millennium 6.0% to 8.0% (with a 95% CI of approximately 0.5% to either to 8.0% since 2010, albeit with some fluctuations, especially side) since 2010. Figure 3 shows the E-value over time, indi- in 2006, which appears to be an unexplained anomaly, be- cating that an unmeasured confounder would need to be as- cause ignoring 2006 would yield a regular linear trend. A fur- sociated with both cannabis use disorder and schizophrenia ther increase was observed beginning already in the mid- at a relative risk of well above 5, and sometimes even above 1990s, until which point it had been relatively stable at around

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Figure 1. Association Between Cannabis Use Disorder and Schizophrenia Over Time

A Crude hazard ratio B Adjusted hazard ratio

300 10 8 100 6 50 4

2 Association between cannabis use Association between cannabis use disorder and schizophrenia, HR (95% CI) disorder and schizophrenia, HR (95% CI) 1 1 1972 1976 1980 1984 1988 1992 1996 2000 2004 2008 2012 2016 1972 1976 1980 1984 1988 1992 1996 2000 2004 2008 2012 2016 Study year Study year

C Incident schizophrenia D Recent cannabis use disorder

40 0.20

0.15 30

0.10

per 100000 population 0.05 Incidence of schizophrenia Proportion with cannabis use disorder, % Proportion with cannabis use disorder, 10 0 1972 1976 1980 1984 1988 1992 1996 2000 2004 2008 2012 2016 1972 1976 1980 1984 1988 1992 1996 2000 2004 2008 2012 2016 Study year Study year

Development of the crude (A) (adjusted for age) and adjusted (B) (adjusted for alcohol use disorder, other psychiatric disorders, parental schizophrenia, parental other psychiatric disorder, parental alcohol or substance use disorder, parental educational attainment, sex, and age) hazard ratios (HRs) between cannabis use disorder and schizophrenia in Denmark and of the incidence of schizophrenia (C) and cannabis use disorder (D) in the same period. Shaded areas indicate 95% CIs.

2.0%. This was consistent with our hypothesis. Because the increase in either the proportion using cannabis or in the po- PARF was estimated under the assumption of potential cau- tency of cannabis would be expected if the association was in- sality, maintaining this assumption and increasing potency deed causal. Previous data suggest an increase in the use and and frequency of use of cannabis use in recent years should problematic use of cannabis in Denmark.12 Moreover, canna- yield a corresponding increase in PARF.10-12 Ours is, to our bis on the Danish market is noted to be among the most po- knowledge, the first study to demonstrate such an increase. tent variants in Europe and has increased from approxi- Although not actual proof of a causal link, our results from lon- mately 13% Δ9-tetrahydrocannabinol in 2006 to nearly 30% gitudinal analyses of the associations over time between can- in 2016.10 The fact that the hazard ratio did not increase over nabis use disorder and schizophrenia provide evidence that time was unexpected, because this would have been ex- some of this association may be causal.21 This evidence might pected if the association between cannabis use disorder and also help explain the general increase in the incidence of schizo- schizophrenia was primarily driven by high-potency canna- phrenia that has been observed in recent years.13 In total, our bis, as has previously been suggested.2 This could either in- study thus provides some support for a potential causal infer- dicate that potency of cannabis in Denmark has long been ence that the long-observed association between cannabis and above the threshold for psychotogenic effects, or that canna- schizophrenia is likely partially causal in nature.1,2 bis use disorder is itself an indicator of severe exposure. Fur- The PARF is an estimate of the proportion of cases of thermore, we estimated the E-value over time, which is a mea- schizophrenia that would have been prevented if no individu- sure of how strong an unmeasured confounding effect would als had been exposed (in this case to cannabis use disorder), be required to conclude that cannabis use disorder was not under the assumption that the association between cannabis causally associated with schizophrenia. With some fluctua- and schizophrenia may be causal. In light of this assumption, tions, a requirement for such an unmeasured confounder the PARF cannot confirm whether an association is truly causal. would be association with both cannabis use disorder at a rela- However, an increase in the PARF co-occurring alongside an tive risk of above 5, often approximately 10, and with schizo-

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Figure 2. Development of the Population-Attributable Risk Fraction Figure 3. Development of the E-Value for the Estimate (PARF) of Cannabis Use Disorder in Schizophrenia in Denmark Between Cannabis Use Disorder and Schizophrenia in Denmark

10 15

10 6

4 5 Estimate, E-value Estimate,

2 Population-attributable risk fraction, % Population-attributable risk fraction,

0 0 1972 1976 1980 1984 1988 1992 1996 2000 2004 2008 2012 2016 1972 1976 1980 1984 1988 1992 1996 2000 2004 2008 2012 2016 Study year Study year

Shaded areas indicate 95% CIs. The lower bound of the shaded area is the E-value for the lower bound of the 95% CI for the hazard ratio used to estimate the E-value.

phrenia at the same magnitude of relative risk, after adjust- ment for all the covariates included in the present study In that study, researchers found that the theoretical removal (ie, alcohol or other substance use disorders, other psychiat- of high-potency cannabis would prevent 12% of cases of schizo- ric disorders, parental schizophrenia, parental other psychi- phrenia, and with PARFs as high as 30% in London and 50% atric disorders, parental alcohol or substance use disorder, pa- in Amsterdam. rental educational attainment, sex, and age). Although some unmeasured confounding may exist, it is unlikely to have such Implications strong associations as required by the E-value to explain the Although not in itself proof of causality, our study provides evi- associations we observed in the present study. Use of tobacco dence of the theory of cannabis being a component cause of has been suggested as such a potential risk factor for schizophrenia. Furthermore, our study challenges the often- schizophrenia22-24; first, some evidence actually suggests that cited argument against causality that an expected increase in cannabis use is the confounder of this association and not the cases of schizophrenia attributable to cannabis use has not been other way around23-25; and second, tobacco use is unlikely observed. Our study is particularly important with the increas- to yield relative risks from 5 to 10 with schizophrenia, al- ing legalization of cannabis for both medicinal and recre- though it may do so for cannabis use disorder.22 Another often- ational uses seeming to lead to an increase in the perception mentioned risk factor for schizophrenia is urbanicity24;wedid of cannabis as relatively harmless and possibly in the uptake not include urbanicity in our study because (1) urbanicity may of cannabis use, especially among youth.35,36 Although psy- be considered a mediator, in which people at risk of using chosis is not the only outcome of interest in terms of canna- cannabis and other substances gravitate toward urban cen- bis use, our study clearly indicates that cannabis should not ters, and (2) the variable was not available for the full study be considered harmless. Cannabis on the Danish market is period. We did not have information on childhood trauma, but among the strongest in the European market, which may com- the associations between childhood trauma and either can- pound the problem, because previous studies2,10,11 have shown nabis or schizophrenia are generally lower than our esti- that the cannabis-psychosis link may be most strongly rel- mated E-value, and previous studies have indicated at least par- evant for high-potency cannabis. An important implication of tial independence between the 2 risk factors.26-28 Other our study may thus be that both use of cannabis and the po- potential risk factors for schizophrenia, such as season of birth, tency of cannabis available should be reduced to achieve pri- vitamin D, and left-handedness, are likely not strongly asso- mary prevention of schizophrenia. ciated with cannabis use disorder.24,29-31 Genetic liability has been suggested as a partial confounder (ie, that the associa- Strengths and Limitations tion between cannabis use and schizophrenia is partly causal Our study holds both important strengths and limitations. and partly confounded by genes; eg, by risk genes for schizo- Regarding strengths, we were able to use the unselected na- phrenia increasing the risk of cannabis use).32,33 tionwide Danish registers to estimate annual associations be- To our knowledge, ours is the first study to investigate the tween cannabis use disorder and schizophrenia, without the contribution of time to the PARF of cannabis in schizophre- risk of selection biases related to, for instance, nonparticipa- nia. However, the multisite EU-GEI (European Network of Na- tion or dropouts. Furthermore, we were able to adjust for a tional Schizophrenia Networks Studying Gene-Environment range of potential confounders that may have changed their Interactions) study recently found that sites with high rates of effect with the association between cannabis use disorder and use of high-potency cannabis or high rates of daily use of can- schizophrenia over time. It is a further strength that we quan- nabis were associated with the incidence of schizophrenia.34 tified the risk of unmeasured confounding through the use of

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Figure 4. Results From 4 Sensitivity Analyses of the Development of the Population-Attributable Risk Fraction of Cannabis Use Disorder in Schizophrenia in Denmark

A 7-y Retrospective assessment of cannabis use disorder B No time limit regarding cannabis use disorder

10 10

8 8

6 6

4 4

2 2 Population-attributable risk fraction, % Population-attributable risk fraction, % Population-attributable risk fraction,

0 0 1972 1976 1980 1984 1988 1992 1996 2000 2004 2008 2012 2016 1972 1976 1980 1984 1988 1992 1996 2000 2004 2008 2012 2016 Study year Study year

C Censored at age 50 y D Not adjusted for other psychiatric disorders

10 10

8 8

6 6

4 4

2 2 Population-attributable risk fraction, % Population-attributable risk fraction, % Population-attributable risk fraction,

0 0 1972 1976 1980 1984 1988 1992 1996 2000 2004 2008 2012 2016 1972 1976 1980 1984 1988 1992 1996 2000 2004 2008 2012 2016 Study year Study year

Shaded areas indicate 95% CIs.

the E-value. Finally, we conducted sensitivity analyses, re- conservative results, and without a clear effect on the devel- vealing that our results were robust to choices regarding the opment of the PARF. A third and related limitation is that we analytical procedure. do not have information on the types or potency of cannabis A few limitations also warrant mention, however. Use of use by the study population on an individual level. register-based information allowed us to assess only cannabis use disorder and not cannabis use per se. However, it has previously been suggested that the association between can- Conclusions nabis and schizophrenia is driven by high-potency cannabis and problematic use of cannabis.2 Consequently, this may not In this Danish, register-based cohort study, an increase in have a dramatic effect on our results. If anything, it would mean the proportion of cases of schizophrenia that may be attrib- that some cases of schizophrenia were erroneously classified utable to cannabis use disorder to a relatively stable level of as unexposed to cannabis, making our results slightly conser- 8.0% since 2010 was observed. This increase is in concor- vative. If the probability of being erroneously classified as not dance with what would be expected, given observed having a cannabis use disorder has decreased over time, this increases in use and potency of cannabis. These results from might explain a small part of the increase in the PARF. A simi- longitudinal analyses of the associations over time between lar limitation exists in that we were only able to assess canna- cannabis use disorder and schizophrenia lend further sup- bis use disorder in patients who had contact with the treat- port to the hypothesis that cannabis may be involved in the ment system. Again, this is likely to have yielded slightly etiology of schizophrenia.

ARTICLE INFORMATION Published Online: July 21, 2021. Author Contributions: Dr Hjorthøj had full access Accepted for Publication: April 15, 2021. doi:10.1001/jamapsychiatry.2021.1471 to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Concept and design: Hjorthøj, Posselt. potency and price of cannabis in Europe, 2006-16. 25. Menezes P, Busatto G, McGuire P, Murray R, Acquisition, analysis, or interpretation of data: Addiction. 2019;114(6):1015-1023. doi:10.1111/add. Scazufca M. Tobacco smoking and risk of first All authors. 14525 episode psychosis: a case-control study in Sao Drafting of the manuscript: Hjorthøj, Posselt. 11. Rømer Thomsen K, Lindholst C, Thylstrup B, Paulo, Brazil. Schizophrenia. 2016;(suppl):T126. Critical revision of the manuscript for important et al. Changes in the composition of cannabis from Published March 2016. Accessed June 14, 2021. intellectual content: Nordentoft. 2000-2017 in Denmark: analysis of confiscated https://www.nature.com/documents/ Statistical analysis: Hjorthøj, Posselt. samples of cannabis resin. Exp Clin Psychopharmacol. npjschz20167.pdf Obtained funding: Hjorthøj, Nordentoft. 2019;27(4):402-411. doi:10.1037/pha0000303 26. Popovic D, Schmitt A, Kaurani L, et al. Administrative, technical, or material support: 12. Sundhedsstyrelsen. The situation of narcotics in Childhood trauma in schizophrenia: current Posselt. findings and research perspectives. Front Neurosci. Supervision: Posselt, Nordentoft. Denmark 2017 [in Danish]. November 2017. Accessed September 6, 2020. https://www.sst.dk/ 2019;13:274. doi:10.3389/fnins.2019.00274 Conflict of Interest Disclosures: None reported. da/udgivelser/2017/narkotikasituationen-i- 27. Scheidell JD, Quinn K, McGorray SP, et al. Funding/Support: This study was supported by a danmark-2017 Childhood traumatic experiences and the grant from Lundbeckfonden. 13. Kühl JOG, Laursen TM, Thorup A, Nordentoft M. association with marijuana and cocaine use in Role of the Funder/Sponsor: The sponsor had no The incidence of schizophrenia and schizophrenia adolescence through adulthood. Addiction. 2018; role in the design and conduct of the study; spectrum disorders in Denmark in the period 113(1):44-56. doi:10.1111/add.13921 collection, management, analysis, and 2000-2012: a register-based study. Schizophr Res. 28. Sideli L, Fisher HL, Murray RM, et al. Interaction interpretation of the data; preparation, review, or 2016;176(2-3):533-539. doi:10.1016/j.schres.2016. between cannabis consumption and childhood approval of the manuscript; and decision to submit 06.023 abuse in psychotic disorders: preliminary findings the manuscript for publication. 14. Nielsen SM, Toftdahl NG, Nordentoft M, on the role of different patterns of cannabis use. Hjorthøj C. Association between alcohol, cannabis, Early Interv Psychiatry. 2018;12(2):135-142. doi:10. REFERENCES and other illicit substance abuse and risk of 1111/eip.12285 1. Moore THM, Zammit S, Lingford-Hughes A, et al. developing schizophrenia: a nationwide population 29. 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