Assessing evidence for a causal link between cannabis and psychosis: A review of cohort studies

International Journal of Drug Policy 21 (2010) 10–19

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International Journal of Drug Policy journal homepage: www.elsevier.com/locate/drugpo

Review

Assessing evidence for a causal link between cannabis and psychosis: A review of cohort studies Jennifer A. McLaren a , Edmund Silins a,∗ , Delyse Hutchinson a , Richard P. Mattick a , Wayne Hall b a b

National Drug and Alcohol Research Centre, University of New South Wales, NSW 2052, Australia School of Population Health, University of Queensland, QLD 4006, Australia

a r t i c l e

i n f o

Article history: Received 6 May 2009 Received in revised form 17 August 2009 Accepted 8 September 2009

Keywords: Cannabis Psychosis Schizophrenia Cohort Methodology Causal relation

a b s t r a c t Over the past five years, the release of cohort studies assessing the link between cannabis and psychosis has increased attention on this relationship. Existing reviews generally conclude that these cohort studies show cannabis has a causal relationship to psychosis, or at least that one cannot be excluded. Few studies have evaluated the relative strengths and limitations of these methodologically heterogeneous cohort studies, and how their relative merits and weaknesses might influence the way the link between cannabis use and psychosis is interpreted. This paper reviews the methodological strengths and limitations of major cohort studies which have looked at the link between cannabis and psychosis, and considers research findings against criteria for causal inference. Cohort studies that assessed the link between cannabis and psychosis were identified through literature searches using relevant search terms and MEDline, PsycINFO and EMBASE. Reference lists of reviews and key studies were hand searched. Only prospective studies of general population cohorts were included. Findings were synthesised narratively. A total of 10 key studies from seven general population cohorts were identified by the search. Limitations were evident in the measurement of psychosis, consideration of the short-term effects of cannabis intoxication, control of potential confounders and the measurement of drug use during the follow-up period. Pre-existing vulnerability to psychosis emerged as an important factor that influences the link between cannabis use and psychosis. Whilst the criteria for causal association between cannabis and psychosis are supported by the studies reviewed, the contentious issue of whether cannabis use can cause serious psychotic disorders that would not otherwise have occurred cannot be answered from the existing data. Further methodologically robust cohort research is proposed and the implications of how evidence informs policy in the case of uncertainty is discussed. © 2009 Elsevier B.V. All rights reserved.

Introduction Over the past five years, the publication of cohort studies assessing the relationship between cannabis and psychosis has attracted considerable attention in the research literature, popular media, and the community generally (Andreasson, Allebeck, Engstrom, & Rydberg, 1987; Arseneault et al., 2002; Caspi et al., 2005; Fergusson, Horwood, & Ridder, 2005; Henquet, Krabbendam, et al., 2005; van Os et al., 2002; Zammit, Allebeck, Andreasson, Lundberg, & Lewis, 2002). These studies have often been interpreted as demonstrating that cannabis use is causally related to psychotic disorders, such as schizophrenia (Smit, Bolier, & Cuijpers, 2004). Existing reviews have concluded that evidence from these cohort studies show

∗ Corresponding author. Tel.: +61 02 9385 0141; fax: +61 02 9385 0222. E-mail address: [email protected] (E. Silins). 0955-3959/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.drugpo.2009.09.001

that cannabis has a causal relationship to psychosis (Arseneault, Cannon, Witton, & Murray, 2004; Henquet, Murray, Linszen, & van Os, 2005; Moore et al., 2007; Semple, McIntosh, & Lawrie, 2005; Smit et al., 2004), or that the possibility of such a relationship cannot be excluded (Macleod et al., 2004a, 2004b). However, a number of methodological limitations of these cohort studies raise uncertainties about whether cannabis use is causally related to psychotic disorders. Whilst a number of reviews of these cohort studies have been published (Arseneault et al., 2004; Hall, 2006a, 2006b; Macleod et al., 2004a, 2004b; Moore et al., 2007), few have evaluated the relative strengths and limitations of these methodologically heterogeneous cohort studies (e.g., Moore et al., 2007), and how their relative merits and weaknesses might influence the way in which the link between cannabis use and psychosis is interpreted. Psychosis describes a mental state characterised by the following symptoms: delusions, which involve having beliefs that are not true; hallucinations, which involve sensing things that are not there

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such as hearing voices; and gross disorganisation of speech and/or behaviour such that the sufferer’s speech and actions do not make sense (American Psychiatric Association, 2000). Psychosis is usually thought of in association with schizophrenia, but is also present to varying degrees in over ten additional mental disorders (American Psychiatric Association, 2000). It should be noted that discrete psychotic symptoms can be experienced without necessarily being part of a psychotic disorder; such symptoms are not necessarily clinically significant, especially if they are transient or short lived. If the symptoms are severe enough, or there are multiple symptoms co-occurring for a sufficient time period, then a psychotic disorder, such as schizophrenia, may be diagnosed. To diagnose schizophrenia the following criteria need to be met: (a) experience of two or more characteristic symptoms (delusions, hallucinations, disorganised speech, grossly disorganised or catatonic behaviour, in addition to ‘negative symptoms’, which refer to a set of symptoms including lack of emotional expression, lack of speech, and/or lack of motivation) for a significant part of a one-month period of time; (b) social or occupational dysfunction; and (c) continuous signs of disturbance for at least six months (American Psychiatric Association, 2000). This paper aims to review the methodological strengths and limitations of cohort studies which have looked at the link between cannabis and psychosis, and consider research findings against criteria for causal inference.

1. Strength of association: the association between the risk factor and outcome occurs more often than would be expected by chance. 2. Consistency: the relationship between the risk factor and outcome is shown in multiple studies using different methods and different populations. 3. Temporality: the risk factor must occur before the outcome. This is the only absolutely essential criterion for causality. 4. Biological gradient: an increase in exposure to the risk factor increases the risk of the outcome. Similarly, the risk of the outcome should decrease when exposure to the risk factor is reduced. This is also known as a dose–response effect. 5. Coherence: the causal relationship fits with what is known about trends in the prevalence of the outcome and the risk factor. 6. Specificity: most people who are exposed to the risk factor will suffer from the outcome, and most people who suffer from the outcome will have been exposed to the risk factor. 7. Plausibility: there is a plausible mechanism (e.g., biological) that potentially underlies the relationship between the risk factor and the outcome. 8. Analogy: that the risk factor is similar to another factor that is known to increase risk. In other words, how does cannabis compare to other risk factors which potentially contribute to the aetiology of psychosis (e.g., family history of schizophrenia, other drug use)?

Approach

Results

Search strategy and inclusion criteria

The literature search returned 270 studies after duplicate studies were removed. On the basis of abstracts, 75 studies were judged as potentially relevant. Of these, 65 were excluded as not relevant after reading the whole paper and after expert advice. A total of 10 studies (from seven general population cohorts) were identified as relevant to the review (Table 1). The following major cohort studies were identified.

Cohort studies published from 1950 to 2008 that have assessed the link between cannabis and psychosis were identified in English language sources through literature searches using MEDline, PsycINFO and EMBASE. Standardised search terms used included combinations of: cannabis, marihuana, cannabinoid, hemp, ganja, bhang, THC, psychosis, psychotic, psychoses, schizo$ (‘$’ indicates truncation), cohort studies, and prospective studies. Relevant subject headings were ‘exploded’, so that subheadings were also included. Additionally, reference lists of reviews and key studies were hand searched. Full details of the search strategy are available on request. Only prospective studies of general population cohorts which had assessed psychotic symptoms or psychotic disorders were included. The review focused on prospective cohort studies as such studies provide the best methodology for assessing causal relationships. Findings from studies were synthesised narratively. Framework for critical appraisal The methodological strengths and limitations of the cohort studies selected were appraised in relation to the measurement of psychosis outcome, short-term effect of cannabis intoxication, control of potential confounding factors, measurement of cannabis and other drug use during the follow-up period and psychosis vulnerability. Additionally, research findings were considered against criteria for causal inference. The guidelines for assessing causation according to Hill (Hill & Hill, 1991) are commonly used and well-respected in clinical and medical research (Daly & Bourke, 2000; Tugwell & Haynes, 2006). These guidelines provide a framework for the analysis of whether cannabis use is causally associated with psychosis. The more principles that are fulfiled, the greater the weight of the evidence for causality (Tugwell & Haynes, 2006). For conclusions to be drawn about whether a particular association is causal, it is desirable for evidence to show:

Swedish Conscript Study The first cohort study to find that cannabis use predicts subsequent development of psychosis was based on a sample of 45,570 male Swedish conscripts. Conscripts were assessed at age 18 for substance use and psychiatric diagnosis and then followed up during a 15-year period for inpatient admission for schizophrenia (Andreasson et al., 1987). Although most participants who were treated for schizophrenia during the follow-up period did not use cannabis, those who did report using cannabis more than 50 times by age 18 were six times more likely to be hospitalised for schizophrenia by the age of 33 than those who had not used cannabis. Moreover, those who had used cannabis more than 10 times (but less than 50 times) were three times more likely to be hospitalised for schizophrenia. Once psychiatric factors, social and family background, and other substance use were controlled for, the relative risk associated with being hospitalised for schizophrenia amongst those who had used cannabis at least 10 times was reduced to 2.3 (95% CI: 1.0–5.3) and was no longer statistically significant. The adjusted odds ratio for those who had used cannabis more than 50 times was not reported. The variable that best predicted schizophrenia was psychiatric diagnosis at baseline (relative risk: 3.1, 95% CI: 2.1–4.7), followed by having parents that were divorced (relative risk: 1.8, 95% CI: 1.2–2.8), followed by cannabis consumption 1–10 times (relative risk: 1.5, 95% CI: 0.6–3.3). The data from this study did not provide information about the duration of cannabis use, although cannabis use at conscription was strongly associated with later treatment for cannabis use and other substance use during the follow-up period

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Table 1 Cohort studies on cannabis use and psychotic disorders and symptoms. Authors (year)

Symptoms Tien and Anthony (1990)

van Os et al. (2002)

Sample

Cannabis use measure

Outcome (measure)

Frequencies (cases/cannabis; cases/no cannabis)

Controls

Adjusted odds ratio (95% CI)

2295 American adults, aged 18–49 (ECA)

Daily use of cannabis at baseline

Experienced at least one psychotic symptom one year later (DIS)

51/235; 456/4759

2.0 (1.2–3.1) (relative risk)

4104 Dutch males and females from population sample, aged 18–64 (NEMESIS)

Used cannabis at baseline

(a) Low-level psychotic symptoms (BPRS) three years later

(a) 8/312; 30/3652

(b) Pathological-level symptoms (BPRS) Psychotic symptoms in past month at age 18, 21 and 25 (SCL-90) Any psychotic symptoms four years later (M-CIDI)

(b) 7/312; 3/3652

Psychiatric diagnosis at baseline, age, gender, education, marital status, employment, alcohol use disorder, daily cocaine use, psychotic symptoms at baseline. Age, gender, ethnic group, marital status, education, urban dwelling, discrimination, other drug use. Those with psychotic symptoms at baseline excluded. Other drug dependence, gender, IQ, parental criminality. Baseline use of other drugs, predisposition to psychosis, age, gender, socioeconomic status, urban dwelling, childhood trauma. Age, gender, area of residence, social support, adverse life events, alcohol and tobacco use, marital status, IQ. Individuals with a psychotic disorder or psychotic symptoms at baseline were excluded.

1.7 (1.1–2.5)

Psychiatric diagnosis at age 18, social and family background, school adjustment, tobacco, alcohol and solvent use. Psychiatric diagnosis at age 18, IQ, social integration, disturbed behaviour, tobacco use, place of upbringing, other drug use. Age, gender, ethnic group, marital status, education, urban dwelling, discrimination, other drug use. Those with psychotic symptoms at baseline excluded. Gender, socioeconomic status, psychotic symptoms prior to cannabis use. Use of other drugs, childhood psychotic symptoms, IQ, conduct disorder.

No significant effect after adjustment

Daily cannabis use in year prior to ages 18, 21, and 25

1795 British males and females from the general population (NPM)

Used cannabis in the year prior to baseline, or dependence on cannabis

Incident psychotic symptoms during the 18 month follow-up period (Psychosis Screening Questionnaire)

Not available

45,570 Swedish male conscripts, aged 18 (SC)

Used cannabis more than 10 times by age 18

Hospital admission for schizophrenia 15 years later at age 33 (hospital records)

49/4290; 197/41,280

Zammit et al. (2002)

50,053 Swedish male conscripts, aged 18 (SC)

Used cannabis more than 50 times by age 18

Hospital admission for schizophrenia 27 years later at age 45 (hospital records)

73/5391; 215/36,429

van Os et al. (2002)

4104 Dutch males and females from population sample, aged 18–64 (NEMISIS)

Used cannabis at baseline

Need for treatment (judged by clinicians)

4/312; 3/3652

Arseneault et al. (2002)

759 New Zealander males and females from Dunedin birth cohort (DMHDS) 803 New Zealander males and females from Dunedin birth cohort (DMHDS)

Used cannabis at age 15, continued use at age 18

DSM-IV diagnosis of schizophreniform disorder at age 26 (DIS) DSM-IV diagnosis of schizophreniform disorder at age 26 (DIS)

3/29; 22/730

Henquet, Krabbendam, et al. (2005), Henquet, Murray, Linszen, and van Os (2005)

Wiles et al. (2006)

Disorders Andreasson et al. (1987)

Caspi et al. (2005)

Used cannabis at least five times at baseline

Used cannabis by age 15 or used regularly at age 18

82/320; 342/2117

14/193; 15/610

(b) 16.9 (3.3–86.1) 1.6 (1.2–2.0) (incidence rate ratio)

No significant effect

3.1 (1.7–5.5)

10.5 (1.8–63.2)

No significant effect

10.9 (2.2–54.1) with genetic vulnerability, no association for those without such vulnerability

Abbreviations: DIS: Diagnostic Interview Schedule; BPRS: Brief Psychiatric Rating Scale; SCL-90: Symptom Checklist 90; M-CIDI: Munich Version of the Composite International Diagnostic Interview; ECA: Epidemiological Catchment Area Study; NEMISIS: Netherlands Mental Health Survey and Incidence Study; CHDS: Christchurch Health and Development Study; EDSP: Early Developmental Stages of Psychopathology Study; NPM: National Psychiatric Morbidity Survey; SC: Swedish Conscript Study; DMHDS: Dunedin Multidisciplinary Health and Development Study.

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Not available

1055 New Zealander males and females from Christchurch birth cohort (CHDS) 2437 German males and females from population sample, aged 14–24 (EDSP)

Fergusson et al. (2005)

(a) No significant effect

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(Andreasson et al., 1987). The study did not measure existing psychotic or other psychiatric symptoms at baseline (only diagnosis), so it is not possible to determine whether cannabis use preceded psychiatric symptoms. It is also not possible to determine whether premorbid personality traits were responsible for both cannabis use and the development of schizophrenia. In addition, the study did not control for the use of other potentially psychotogenic substances such as amphetamines. A re-analysis, which encompassed a longer follow-up period (27 years as opposed to 15 years), found that cannabis use remained predictive of schizophrenia in a dose-dependent manner even after stimulant and other substance use (including alcohol) were controlled for (Zammit et al., 2002). Those who had used cannabis at least 50 times by the age of 18 were about three times (OR: 3.1, 95% CI: 1.7–5.5) more likely to be hospitalised for schizophrenia than those who had not used cannabis. All subjects were screened for schizophrenia at conscription, and the re-analysis adjusted for other psychiatric problems recorded at that time. This study also included a more comprehensive measure of premorbid social integration, adjustment for which did not affect the relationship between cannabis use and schizophrenia. Epidemiological Catchment Area (ECA) Study In the United States, a multi-site survey of the population was undertaken between 1980 and 1984 (Tien & Anthony, 1990). The Diagnostic Interview Schedule (DIS) was used to measure the presence of psychiatric disorders. This was administered at baseline and at follow-up one year later. Substance use and social and demographic characteristics were also measured. To assess the risk associated with substance use and psychotic symptoms one year later, those with baseline psychotic symptoms (one or more positive responses to psychotic symptoms on the DIS) were excluded, and ‘cases’ (i.e., those who experienced at least one psychotic symptom at follow-up) were matched with ‘controls’ (i.e., those who did not report psychotic experiences at follow-up) on age. The age of the sample ranged between 18 and 49 years. A total of 477 cases were matched with 1818 controls. Once social and demographic factors (e.g., gender, education, marital status, employment), baseline psychiatric disorders and other substance use (daily cocaine use, alcohol disorder) were controlled, cannabis use was associated with a two-fold risk of experiencing psychotic symptoms one year later. Netherlands Mental Health Survey and Incidence Study (NEMESIS) In the Netherlands, a population cohort of 4045 males and females aged between 18 and 64 years found that those who reported any cannabis use at baseline were not more likely to experience mild psychotic symptoms at follow-up (three years later, OR: 2.11, 95% CI: 0.78–5.71, not significant). However, they were almost 17 times more likely to report clinically significant psychotic symptoms three years later (OR: 16.93, 95% CI: 3.33–86.13); and over 10 times more likely to be judged to be in need of psychiatric care as a result of psychotic symptoms than those who had not used cannabis at baseline (OR: 10.51, 95% CI: 1.75–63.21) (van Os et al., 2002). These results were found after controlling for age, sex, socio-economic status and other drug use. Additionally, the relationship between cannabis use and a diagnosis of psychosis was dose-dependent. Importantly, none of those included in the NEMESIS sample had psychotic symptoms at baseline. Those who did show evidence of a psychotic disorder at baseline were studied separately (n = 59), and the predictive effect of cannabis on subsequent psychotic symptoms was stronger for these participants than for those who were symptom-free at baseline. Baseline cannabis use was more predic-

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tive of psychotic symptoms three years later than cannabis use at the follow-ups. The authors interpret this as evidence that the acute effects of cannabis cannot fully explain the association between cannabis use and psychosis, and that the effect of cannabis use on the risk of psychotic symptoms was a long-term effect. Dunedin Multidisciplinary Health and Development Study The Dunedin Multidisciplinary Health and Development Study is a birth cohort study that has been running in New Zealand since the 1970s. This study assessed childhood psychotic symptoms prior to cannabis use (age 11), cannabis use at age 15 and 18, and schizophrenia symptoms and diagnosis of schizophreniform disorder at age 26, amongst 759 males and females born between 1972 and 1973 (Arseneault et al., 2002). Schizophreniform disorder is similar to schizophrenia in terms of symptoms and signs but lasts for a shorter duration (one month) and does not necessarily lead to occupational or social problems (American Psychiatric Association, 2000). The investigators used a conservative set of diagnostic criteria for schizophreniform disorder that required evidence of social and occupational problems, in addition to delusions, hallucinations and/or thought disorder for at least one month. Those who had used cannabis by age 15 had more symptoms of schizophrenia at the age of 26 than those who had not used cannabis, even after other drug use and childhood psychotic symptoms were statistically controlled for. Cannabis use at age 15, but not 18, was associated with schizophreniform diagnosis. However, this association did not remain significant once childhood psychotic symptoms were controlled for in the analyses (Arseneault et al., 2002). A recently published study of the Dunedin birth cohort data suggested that a genetic predisposition moderated the effect of cannabis on psychosis risk. Adolescent cannabis users with a functional polymorphism of a gene (catechol-O-methyltransferase, or COMT) involved in the dopamine system (the neurotransmitter system implicated in schizophrenia) were at 10-fold higher risk of developing schizophreniform disorder by the age of 26 whereas cannabis users who did not have this genetic polymorphism (i.e., who were not homozygous Val allele carriers) were not at increased risk (Caspi et al., 2005). No main effect was found for the genotype. The authors argued that this indicated that the increased risk of psychosis amongst those with the particular polymorphism was conditional on the presence of an environmental risk factor (in this case, adolescent cannabis use). Participants with the Val/Val allele who did not start using cannabis until adulthood were not at an increased risk of schizophreniform disorder. A large case–control study by Zammit et al. (2007) has failed to replicate this result. Christchurch Health and Development Study The Christchurch Health and Development Study, another New Zealand birth cohort started in the 1970s, has recently reported evidence for a causal link between cannabis and psychotic symptoms (Fergusson et al., 2005). Ten items from the Symptom Checklist 90 (SCL-90) were chosen to represent psychotic symptoms (Fergusson, Horwood, & Swain-Campbell, 2003). These items were administered to the 1055 participants at age 18, 21 and 25 years to determine psychotic symptoms experienced during the month preceding the interview, although it is unclear how the items were scored. This study controlled for a wide variety of possible confounding factors, including prior history of psychotic symptoms and cannabis use, other psychiatric diagnosis, other substance use disorders, adverse life events, deviant peer affiliations, family socio-economic status, family functioning, child abuse, IQ and individual personality characteristics. Fixed unmeasured factors – such

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as genetic factors – were controlled through statistical modelling using fixed effects regression. Generally, increasing rates of cannabis use were associated with increasing rates of psychotic symptoms at ages 18, 21 and 25 years. Daily cannabis users in the past year had past month rates of psychotic symptoms that were between 1.6 (incidence rate ratio: 1.55, 95% CI: 1.21–1.99) and 1.8 (incidence rate ratio: 1.77, 95% CI: 1.28–2.44) times higher than non-users of cannabis, after covariate adjustment. Structural equation modelling indicated that cannabis use increased the risk for psychotic symptoms, rather than the other way around. However, the study only measured past year cannabis use with past month psychotic symptoms, so any long-term effects of cannabis use on psychotic symptoms were not assessed.

the association often showed a dose–response relationship. These results, combined with the cross-sectional evidence for association, provide evidence that cannabis use, particularly early and frequent cannabis use, is associated with later ‘psychosis’. However, in a number of studies the associations between cannabis use and psychosis do not remain significant once factors such as psychosis vulnerability are controlled for (see Table 1). Moreover, only one study has actually assessed the relationship between cannabis and schizophrenia (Swedish Conscript Study). These and other methodological issues raise obstacles to definitive statements that cannabis is causally related to psychotic disorders. Methodological strengths and limitations of cohort studies reviewed

Early Developmental Stages of Psychopathology Study The Early Developmental Stages of Psychopathology (EDSP) Study assessed a population-based sample of 2437 German adolescents and young adults (aged 14–24 years) at baseline, and four years later (Henquet, Krabbendam, et al., 2005). Predisposition to psychosis was measured using the SCL-90-R, and a psychosis outcome was defined as endorsing at least one or two of fifteen core psychosis items in the composite international diagnostic interview (CIDI). The CIDI was also used to measure depression and substance use. At baseline 13.1% reported use of cannabis at least five times and 14.8% did so at follow-up, suggesting most use had occurred prior to baseline. After controlling for age, sex, socio-economic status, childhood trauma, other drug use and predisposition to psychosis, those who used cannabis at least five times at baseline were more likely to suffer from any psychotic symptom four years later than those who had not used cannabis (OR: 1.53, 95% CI: 1.13–2.07). There was a dose–response relation between cannabis use and psychosis risk. The effect was stronger for those who were predisposed to psychosis at baseline than those who lacked such a predisposition. Importantly, predisposition to psychosis did not predict cannabis use four years later, suggesting that cannabis use leads to psychotic symptoms, rather than the other way around. National Psychiatric Morbidity Survey In Great Britain, a representative sample of the general population was interviewed for symptoms of psychiatric disorders using the Clinical Interview Schedule-Revised (CIS-R). Participants who had a mental disorder or neurotic symptoms at baseline, as well as a random sample of 20% of participants who did not have a mental disorder were followed up 18 months later (Wiles et al., 2006). At baseline and follow-up, the Psychosis Screening Questionnaire (PSQ) was used to measure psychotic symptoms. Individuals with a psychotic disorder at baseline were excluded, leaving a sample of 1795. Cannabis dependence at baseline was related to psychotic symptoms at follow-up. However, after sociodemographic variables, drug use and psychiatric morbidity were controlled for, neither of the cannabis use variables (used cannabis in the year prior to baseline and baseline dependence on cannabis) were related to psychotic symptoms. Four other variables were related to an elevated risk for psychotic symptoms: living in a rural area (OR: 3.45, 95% CI: 1.52–7.80), lack of social support (OR: 3.43, 95% CI: 1.10–10.70), adverse life events (OR ranged from 3.57 to 11.80 depending on the number of adverse life events experienced), and CIS-R score (OR: 1.07, 95% CI: 1.04–1.09). Discussion All but one of the cohort studies reviewed here reported associations between cannabis use and subsequent ‘psychosis’, and

Measurement of the psychosis outcome A number of important limitations were evident in the measurement of psychosis. In the Christchurch study, for example, psychotic symptoms were measured using ten items from the SCL90 that contribute to the ‘psychoticism’ and ‘paranoid ideation’ scales. Research on the specificity and sensitivity of the SCL-90 suggest that the psychosis and paranoid scales of the instrument do not identify psychotic patients in clinical samples, and that participants who are not psychotic may have elevated scores on this scale (Wetzler & Marlowe, 1993). It has also been argued that this instrument should be used as a global measure of psychological distress rather than as a measure of symptoms of particular disorders (Brophy, Norvell, & Kiluk, 1988; Elliot et al., 2006). In the Christchurch study, the average number of symptoms endorsed by daily cannabis users was less than two, and it was unclear whether the particular items endorsed by participants on the SCL-90 were the cardinal symptoms of serious psychotic disorders (e.g., ‘Hearing voices that other people do not hear’), or other symptoms of schizophrenia that are not specific to DSM-IV diagnosis of schizophrenia (e.g., ‘Feeling that other people cannot be trusted’, ‘The idea that something serious is wrong with your body’) (American Psychiatric Association, 2000; Mattick & McLaren, 2006). The clinical significance of endorsing one or two symptoms is unclear, particularly if the symptoms endorsed were not cardinal symptoms of schizophrenia. Even then the clinical significance is still unclear because items may have been endorsed at the lowest level (i.e., the symptom has bothered or distressed the participant ‘a little bit’). Two other studies, EDSP and the British Psychiatric Morbidity study, only measured psychotic symptoms; similar limitations apply in terms of determining the clinical significance of these symptoms. One of the major strengths of the Swedish and Dunedin studies was that the outcome measures – hospital admissions for schizophrenia, and diagnosis of schizophreniform disorder, respectively – were clear and quantifiable in terms of clinical and public health significance. Although the Dutch NEMESIS study measured psychotic symptoms associated with the need for psychiatric care (judged by a panel of professionals), the number of participants who experienced psychosis that warranted treatment was very small (n = 7), leading to wide confidence intervals around odds ratios. The short-term effect of cannabis intoxication In two of the cohort studies it was unclear whether the psychotic symptoms reported by cannabis users occurred only whilst intoxicated, or whether they persisted. The Christchurch study assessed the relationship between psychotic symptoms in the past month with cannabis use in the past year. It remains possible that the psychotic symptoms endorsed may have occurred only when intoxicated. The British survey also did not take intoxication effects into account when measuring the psychosis outcome.

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The instruments used to measure the psychotic outcome in the Dunedin, NEMESIS and EDSP studies contain instructions not to include psychotic symptoms that only occur in the context of intoxication. The authors of the Swedish Conscript Study maintained that it is unlikely that substance-induced intoxication would have been misdiagnosed as schizophrenia (Zammit et al., 2002). Taking intoxication effects in to account is important as the administration of high doses of cannabis has been reported to cause short-term psychotic symptoms in those without a psychotic disorder. These symptoms are transient and generally disappear when cannabis use ceases (American Psychiatric Association, 2000). Some studies have reported cases of psychosis or psychotic symptoms immediately following the use of cannabis (Chopra & Smith, 1974; Favrat et al., 2005; Solomons, Neppe, & Kuyl, 1990; Wylie, Scott, & Burnett, 1995). However, these studies have been criticised for failing to investigate whether the cases have a family history of psychotic disorder, or whether cannabis use occurred up to symptom onset (Thornicroft, 1990).

Control of potential confounding factors Control of potential confounding factors is of great importance when assessing the relationship between cannabis and psychosis, given that both cannabis use and psychosis share an association with certain social and family factors. Cannabis use may simply be a marker for a factor occurring earlier in life that plays a causal role in developing a psychotic disorder. A major strength of both the Christchurch and Dunedin studies is the birth cohort design, which allows for a wide range of early childhood and family risk factors to be measured and controlled for in the analysis. The Dunedin study was the first study to measure and control for psychotic symptoms in late childhood, before the onset of cannabis use. Importantly, the predictive association between adolescent cannabis use and schizophreniform disorder was no longer significant once early psychotic symptoms were controlled for, suggesting that the association between cannabis use and schizophreniform disorder could be explained by preexisting psychosis vulnerability. Alternatively, failure to identify a significant relationship may have been due to low power arising from the small number of participants who were diagnosed with a schizophreniform disorder (n = 25). The British survey and the NEMESIS and ECA studies, did not measure early childhood and family risk factors as rigorously as the New Zealand studies. As a result, factors that may be related to both cannabis use and psychosis – such as adverse events in childhood – could not be controlled for. It has been argued that failing to measure a potential confounding factor, or measuring such a factor imprecisely could mean that significant effects are reported which are in fact representing spurious associations (Macleod et al., 2004a, 2004b; Smith & Ebrahim, 2002). In other areas of health research, it has been found that significant associations found in observational studies of population cohorts are not replicated in randomised controlled trials (for example, see Smith & Ebrahim, 2002). Another important variable that was controlled in most, but not all studies, was baseline psychotic symptoms. Although the Swedish Conscript Studies controlled for psychiatric disorder at baseline, they did not control for psychotic symptoms. Most of the sample would not have developed schizophrenia at conscription (when aged 18–20 years), since the modal age of onset of schizophrenia for males is between 18 and 25 years (American Psychiatric Association, 2000). It therefore remains possible that participants with early psychotic symptoms were more likely to have used cannabis producing a spurious relationship between cannabis use at age 18 and later hospitalisation for schizophrenia.

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Measurement of cannabis and other drug use during the follow-up period A major limitation of the Swedish study was that there was no measure of cannabis use (or other drug use) during the 27year follow-up period. It remains possible that those who used cannabis at age 18 were also more likely to use substances such as amphetamines (known to be psychotogenic) in their 20s. It has been found that cannabis use usually precedes the use of other illicit drugs (Fergusson, Boden, & Horwood, 2006), such as amphetamines, and that heavy cannabis users are much more likely to move on to other illicit drug use than people who had not used cannabis (Fergusson & Horwood, 2000). Data from the Christchurch cohort show that, by the age of 25, 26.9% of the sample had used amphetamines (Boden, Fergusson, & Horwood, 2006). The link between cannabis and psychosis may, therefore, be overstated if amphetamine induced psychosis at least partly explained the association between cannabis use and schizophrenia. Findings from a study of a large epidemiological sample with DSM-III-Rdiagnosed psychoses found a more severe course of illness was linked to alcohol but not cannabis misuse (Kavanagh et al., 2004), further underscoring the importance of controlling for alcohol and other drug use. The importance of psychosis vulnerability Pre-existing vulnerability to psychosis appears to be an important factor that influences the link between cannabis use and psychotic disorders in the studies reviewed here. The Dunedin data showed that once childhood psychotic symptoms were controlled for, cannabis use no longer predicted development of schizophreniform disorder, although the association between cannabis and psychotic symptoms persisted (Arseneault et al., 2002). The Dunedin cohort data are also suggestive of a potential genetic vulnerability to the psychotogenic effect of cannabis (Caspi et al., 2005). Unmeasured vulnerability to psychosis or other unmeasured psychiatric problems may play a role in later cannabis use. This should be assessed or controlled for in studies on the relationship between cannabis and psychosis (Macleod et al., 2004a, 2004b). If it is not, authors and readers need to be very cautious in interpreting results. Does the evidence fit in with the Hill guidelines for assessing causation? Using established criteria for causal inference there is considerable weight of evidence to suggest the link between cannabis and psychosis is causally related. Evidence from cross-sectional research consistently shows that cannabis and psychosis occur together more often than would be expected by chance (Agosti, Nunes, & Levin, 2002; Degenhardt & Hall, 2001; Thomas, 1996). The causal link between cannabis use and psychosis is consistent with other biological knowledge and is biologically plausible (D’Souza et al., 2004; Hall, Degenhardt, & Teesson, 2004; Linszen, Peters, & de Haan, 2004), although further research is needed to elucidate the mechanism. One of the major weaknesses of cross-sectional studies is that the temporal order of cannabis and psychosis cannot be determined. Temporality is considered an essential criterion for causality (Hill, 1977). The two factors may be associated because those who develop a psychotic disorder use cannabis in an attempt to alleviate their symptoms; in other words, they use cannabis to ‘self-medicate’. The cohort studies reviewed here do not support this possibility. The prospective design of these studies enabled the temporal order of cannabis and psychosis to be investigated. Specific methods used to rule out the self-medication hypotheses were: (a) statistical modelling (Fergusson et al., 2005) that excluded individuals with any history of psychotic experiences in the follow-up

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study (van Os et al., 2002), and (b) assessment of whether predisposition to psychosis predicted later cannabis use (Henquet, Krabbendam, et al., 2005). It should be noted that it is still possible that individuals who develop psychotic disorders use cannabis to alleviate some of the symptoms they experience; however, these studies show that the self-medication hypothesis is not the most plausible explanation for the relationship between cannabis and psychosis (Smit et al., 2004). Indeed, a recent Australian study of a group of patients with psychotic disorders found a bidirectional relationship with cannabis use: cannabis use predicted psychotic symptom relapse, and psychotic symptoms predicted cannabis use relapse, independent of medication and other drug use (Hides, Dawe, Kavanagh, & Young, 2006). Despite a rise in the prevalence of cannabis use in the population internationally over the last three decades, there has been little change in the incidence of schizophrenia or other psychotic disorders during that time (Degenhardt et al., 2001; Hall et al., 2004; Macleod, Smith, & Hickman, 2006; Rey & Tennant, 2002). Similarly, a recent study found cannabis use did not impact on trends in diagnosed schizophrenia in the United Kingdom from 1996 to 2005 (Frisher, Crome, Martino, & Croft, 2009). This incongruity is often used as an argument to refute the possibility of a causal link (Degenhardt, Hall, & Lynskey, 2003). Whilst coherence with other information about trends in cannabis use and psychosis is desirable, it is not, however, regarded as absolutely necessary because the information with which it is inconsistent may itself be erroneous. One possible manifestation of the increase of cannabis use is that the age of onset of psychosis may be lower than in the past (Caspi et al., 2005). This is of clinical importance as earlier age of onset of schizophrenia is associated with poorer prognosis (Veen et al., 2004). Age of onset in schizophrenia has lowered over the last three decades (Di Maggio, Martinez, Menard, Petit, & Thibaut, 2001), and cannabis users have been found to have a younger age of onset of the first psychotic episode than those who have not used cannabis (Veen et al., 2004). Di Maggio et al. (2001) found a progressive decline of about five years in age at first appearance of psychotic symptoms (24.5, 22 and 20 years) and age at first hospitalisation (26, 24 and 21 years) in three successive birth cohorts spanning 1905–1984. The authors cautiously suggested that this might be partly explained by higher rates of drug use amongst the younger cohort. Similarly, Kendell, Malcolm, and Adams (1993) found the mean age at first hospitalisation for schizophrenia decreased by four years between the 1970s and 1980s. However, only hospital admission rates were investigated. The observed cohort effect in hospitalisation may also reflect increased emphasis on diagnosing the early symptoms of psychosis in order to reduce morbidity and improve quality of life (McGorry, 2001). Likewise, specificity is a desirable but not a necessary condition. It would exist, for example, if cannabis use was strongly associated with psychosis that was rare in the absence of cannabis use. Specificity is not seen as such an important factor in assessing causality, given that many diseases or disorders have multiple causes. A risk factor (e.g., smoking) may be causally related to the outcome (e.g., heart disease), and not be the only causal factor (Daly & Bourke, 2000). With regard to the criterion of analogy, numerous risk factors, such as drug use (McKetin, McLaren, Lubman, & Hides, 2006; Moore et al., 2007), environment (Mortensen et al., 1999), and family history of schizophrenia (Mortensen et al., 1999), potentially contribute to the aetiology of psychotic disorders. How do they compare with one another? Some studies have attempted to place a figure on the proportion of cases of psychotic disorders which can be attributed to cannabis by reporting the population attributable risk (PAR). The PAR refers to the proportion of cases of psychotic disorder, as opposed to psychotic symptoms, that could be prevented if cannabis use was eliminated

from the population (assuming that the relationship is causal and all other factors remain unchanged). According to the Dunedin study, the PAR was 8% (Arseneault et al., 2004). Zammit et al. (2002) reported a PAR of 13% in the Swedish conscript cohort. It is unclear in these two studies whether the authors calculated this risk whilst taking into account other risk factors. This is one of three conditions that need to be met if attributable risk is to be meaningful (Benichou, 1998). In the NEMESIS study, where the contribution of measured confounders was taken in to account, clinically significant outcomes (such as pathologic psychotic symptoms and diagnosis of a psychotic disorder) were associated with a PAR of over 50% (van Os et al., 2002). The amount of variation in the PAR between studies is considerable, raising questions about the meaningfulness and accuracy of the reported figures. In comparison, Mortensen et al. (1999) calculated the PAR for various risk factors for schizophrenia, and found that the factor with the highest PAR was place of birth (34.6%), and that season of birth was the second most significant risk factor, accounting for 10.5% of hospitalisations for schizophrenia. Family history of schizophrenia was associated with a relatively low PAR (one or both parents with schizophrenia, 3.8%; one or more siblings with schizophrenia, 1.9%) because far fewer people have parents who have been diagnosed with schizophrenia than are exposed to place of birth and season of birth. In terms of PAR, the lower range of 8–13% for PAR of cannabis as a risk factor for schizophrenia suggests it is more important than family history and similar in significance to season of birth. Possible explanations for the association between schizophrenia and place/season of birth include selective migration to urban areas, increased exposure to infections during pregnancy and childhood in densely populated areas, and differences in the availability of psychiatric services (Mortensen et al., 1999). Questions remain to be answered, therefore, about the relative importance of genetic and environmental risk factors for psychosis. The use of other illicit substances such as methamphetamine, and to a lesser extent cocaine, is also a known risk factor for psychosis (Curran, Byrappa, & McBride, 2004; McKetin et al., 2006). Like amphetamines and cocaine, the administration of large doses of cannabis and chronic heavy use have been reported to cause psychotic symptoms lasting several hours in those without an existing psychotic disorder (Ames, 1958; Nunez & Gurpegui, 2002). Overall, the evidence for a transient cannabis psychosis is not as strong as for other substances like amphetamines (Hall & Degenhardt, 2006). However, the lower prevalence of use of amphetamines makes it difficult to compare the extent to which that use contributes to psychosis compared to cannabis. The association between alcohol and psychosis has been widely established (Johns et al., 2004; Teesson, Hall, Lynskey, & Degenhardt, 2000), and underlines the importance of controlling for alcohol use when assessing the link between cannabis and psychosis (e.g., Andreasson et al., 1987; Tien & Anthony, 1990; Wiles et al., 2006). A number of alternative explanations might account for the observed link between cannabis and psychosis. It could be that those prone to psychosis are more likely to be predisposed to risk-taking behaviours which may lead to the use of substances, including cannabis. Additionally, cannabis use may simply be a marker for a factor occurring earlier in life (e.g., predisposition to poor health) that plays a causal role in developing a psychotic disorder.

Conclusion Although the studies reviewed here found a reasonably consistent relationship between cannabis and ‘psychosis’, only one

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study reported a significant relationship between cannabis use and the subsequent development of a psychotic disorder meeting diagnostic criteria, whilst controlling for confounding factors (Zammit et al., 2002). The population impact of experiencing one or two symptoms of psychosis – particularly when it is often unclear whether the symptoms occurred within the period of cannabis intoxication – is unclear. Nevertheless, some studies did find that psychotic symptoms predicted the development of a psychotic disorder later in life (e.g., Poulton et al., 2000). This is in line with research that has found that the experience of psychotic symptoms is related to an increased likelihood of developing a serious psychotic disorder in the future (Johns & van Os, 2001). The studies reviewed above have pointed to the importance of psychosis vulnerability in the cannabis and psychosis association. It seems most likely that cannabis produces psychotic disorders in individuals who possess an underlying vulnerability to psychosis. There are several plausible explanations for these data. First, it is possible that those who develop a psychotic disorder after using cannabis would have eventually developed the disorder, due to a pre-existing vulnerability. Second, it is also possible that the same factors that underlie cannabis use may underlie psychosis vulnerability. Thirdly, individuals with a vulnerability to psychosis may be more sensitive to the potential psychotogenic properties of cannabis than those who are not vulnerable to psychosis (Stefanis et al., 2004). The genetic study based on the Dunedin cohort provides support for the third explanation, since the only group that showed an increased risk of schizophreniform disorder were those with a particular variant of a gene thought to be involved in schizophrenia (Caspi et al., 2005). The interaction between cannabis use and vulnerability also helps to explain why the risk of psychosis in cannabis users is only two to three times; why the incidence of psychoses have not increased in line with the large rise in cannabis use (Degenhardt et al., 2003); and why the age of onset of schizophrenia might be earlier in cannabis users (Arendt, Rosenberg, Foldager, Perto, & Munk-Jorgensen, 2005; Veen et al., 2004). In considering Hill’s guidelines for assessing causation, overall, the criteria for causal association between cannabis and psychosis are supported by the general population cohort studies reviewed here—with the exception of the criteria that realistic alternative reasons for the association can be excluded. Importantly, there was consistent and robust evidence of an association between cannabis and psychosis; cannabis use was generally shown to precede psychotic symptoms; and a dose–response relationship was evident. Together, this evidence sheds further light on the link between cannabis and psychosis, and suggests that association may reflect a causal relationship. The contentious issue of whether cannabis use can cause serious psychotic disorders that would not otherwise have occurred cannot be answered based on the existing data. Further birth cohort studies which rigorously assess early psychotic symptoms and control for important environmental and biological confounding factors may help to resolve some of the uncertainty around the link between cannabis and psychosis. Measuring psychosis outcome in a way that provides information about the clinical significance is critical (e.g., measuring the diagnostic criteria for a psychotic disorder, and ensuring that the disorder occurs in the absence of intoxication). Adequate sample sizes are also important, given the low base rate of psychotic disorders in the population. Additionally, vulnerability to psychosis – that predates exposure to cannabis – needs to be measured using reliable and valid instruments. Data linkage and integration might also be another way to address the limitations of past studies. Mendelian randomization is the approach advocated by (Macleod & Davey Smith, 2003) using genomic information to better control for confounding.

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Evidence and policy: a public health case for prudence How strong does the evidence for a causal relationship between cannabis and psychosis need to be before we are justified in taking action? If we had similar evidence of an association between a pharmaceutical drug and an adverse effect it would either be withdrawn from the market, or it would only be allowed to be prescribed with clear warnings about the risk to patients and prescribers. This, for example, has been the response to what some argue is weaker evidence of increased suicide risk after the initiation of SSRI antidepressants (Klein, 2006), suggesting potential cannabis users should be informed of a link between cannabis and psychosis. There are of course important differences between the way that societies regulate pharmaceuticals and some recreational drugs. We appropriately err in the direction of prudence when responding to evidence of harm caused by therapeutic drugs. We are less concerned as a society about voluntarily assumed risks from using alcohol and tobacco; we generally allow adults to decide whether to take these risks or not whilst prohibiting the use of these drugs by minors. As critics of contemporary cannabis policy argue, cannabis is a conspicuous exception to this policy since in all developed countries adults are prohibited from using cannabis on penalty of imprisonment. Protecting people from the potentially adverse effects of cannabis use should be an important feature of cannabis law reform. In the case of uncertainty, we need to consider the possible costs and benefits of different policy actions. For example, the decision to advise parents to avoid putting infants to sleep in the prone position was advocated as a way of reducing SIDS on the grounds that: (1) this sleeping position was a strong risk factor for SIDS; (2) the proposed behaviour carried few risks; and (3) if incorrect, would not greatly inconvenience parents or their infants. Subsequent experience of a substantial reduction in SIDS deaths in countries that implemented this policy provided convincing proof of a causal relationship between sleeping position and SIDS (Dwyer, Ponsonby, Blizzard, Newman, & Cochrane, 1995). By the same sort of prudential reasoning, it would be arguably good social policy to encourage young people to avoid using cannabis or, at the least to delay their use into early adulthood (de Irala, Ruiz-Canela, & Martinez-Gonzalez, 2005). Suggesting cannabis use be discontinued is perhaps too simplistic an approach, especially given the failure of conventional ‘scare tactics’ and abstinencebased approaches to reducing cannabis use (Rosenbaum, 2000). Harm reduction campaigns may, therefore, have an important role (Rosenbaum, 2000). Assuming for the moment that we know how best to discourage cannabis use (e.g., interventions targeting adolescents (Diamond et al., 2002), harm reduction strategies (Rosenbaum, 2000), prohibition/decriminalization (Reinarman & Cohen, 2007; Reinarman, Cohen, & Kaal, 2004)), the public health gain if the relationship was causal (a possible 10% reduction in schizophrenia incidence), would arguably offset the foregone pleasure amongst those young people who did not use, or who delayed their cannabis use into young adulthood. A reduction in cannabis use amongst incident cases of psychosis would also provide some evidence for the effectiveness of this policy, although any reduction may be difficult to discern for the same reasons that it has been difficult to decide if the increasing prevalence of cannabis use has increased the incidence of schizophrenia (Degenhardt et al., 2003). This argument for prudence is supported by other evidence of the adverse effects of adolescent cannabis use, such as the development of dependence, impaired educational attainment, and possibly an increased risk of using other illicit drugs (Hall, 2006a, 2006b). For all these reasons it makes a good case to discourage cannabis use amongst young people, whilst there is room for disagreement about what the best means of achieving this goal are.

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