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Change in cannabis use in the general population: A longitudinal study on the impact on psychotic experiences
Schizophrenia Research 157 (2014) 266–270
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Change in cannabis use in the general population: A longitudinal study on the impact on psychotic experiences W.A. van Gastel a,b,c,1, A. Vreeker a,⁎,1, C.D. Schubart a,d, J.H. MacCabe e, R.S. Kahn a, M.P.M. Boks a a
Brain Center Rudolf Magnus, University Medical Center Utrecht, Department of Psychiatry, HP. B01.206, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands Department of Psychiatry, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands Department of Sexology & Psychosomatic Obstetrics and Gynaecology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands d Department of Psychiatry, Tergooi Hospital, Hilversum, The Netherlands e Department of Psychosis Studies, Institute of Psychiatry, King's College, London, UK b c
a r t i c l e
i n f o
Article history: Received 10 January 2014 Received in revised form 17 March 2014 Accepted 24 April 2014 Available online 12 June 2014 Keywords: Cannabis Risk Psychotic experience Psychosis
a b s t r a c t Objective: To prospectively assess the relationship between cannabis use and psychotic experiences over time. Method: In a longitudinal design, young adults aged 18–27 years (N = 705) gave online information on cannabis use and completed the Community Assessment of Psychic Experiences (CAPE). These measures were repeated after an interval ranging from six months to five years. Results: A decrease in cannabis use was associated with a decrease in total psychotic experiences (β = −0.096, p = 0.01) after adjustment for a range of potential confounders. An increase in cannabis use was associated with increased positive symptoms at follow-up (β = 0.07, p = 0.02), but was not significantly associated with increases in Negative and Depression symptom scores, nor with the total number of psychotic experiences. Conclusion: In the first study to the association of change in cannabis use and psychotic experiences over time in the general population, we found an association between changes in cannabis use and changes in the frequency of psychotic experiences. While this does not prove a causal relationship between cannabis use and psychosis, our findings are consistent with studies suggesting that cessation of cannabis use may be beneficial in terms of reducing psychotic experiences. © 2014 Elsevier B.V. All rights reserved.
1. Introduction The association between cannabis use and psychotic symptoms is now firmly established (Arseneault et al., 2002; Henquet et al., 2005; Moore et al., 2007; Kuepper et al., 2011). Recent findings suggest that cessation of cannabis use alleviates symptoms and burden of disease in psychotic patients (Mullin et al., 2012). The association of cannabis use and psychotic symptoms is not restricted to clinically significant psychotic symptoms, since cannabis use is also related to psychotic experiences in the general population (Verdoux et al., 2003; Stefanis et al., 2004; Schubart et al., 2011; van Gastel et al., 2012). Prior studies particularly focused on the relationship between (early) cannabis use and psychotic experiences in cross-sectional designs (Schubart et al., 2011). Furthermore, the only longitudinal study to the relationship of cannabis use and psychotic experiences to date specifically focused on heavy cannabis use and found that cannabis dependence at a young age was associated with an increased risk of psychotic experiences (Fergusson et al., 2003). However, it has not yet been investigated Abbreviations: CAPE, Community Assessment of Psychic Experiences. ⁎ Corresponding author. Tel.: +31 88 755 6370; fax: +31 88 755 5487. E-mail address: [email protected] (A. Vreeker). 1 Equal contribution.
http://dx.doi.org/10.1016/j.schres.2014.04.023 0920-9964/© 2014 Elsevier B.V. All rights reserved.
whether a change in cannabis use (either irregular use, regular use or heavy use) over time is associated with a change in psychotic experiences in the general population. The nature of the association between cannabis use and psychotic experiences remains subject to debate (Murray et al., 2007). The most probable explanations for this association are: (1) that cannabis use is a risk factor for the development or persistence of psychotic symptoms (Caspi et al., 2005; Henquet et al., 2005; Cougnard et al., 2007; Bossong and Niesink, 2010; Costas et al., 2011; Kuepper et al., 2011), (2) reverse causality, whereby psychosis-prone individuals start using cannabis in an attempt to self-medicate (Henquet et al., 2005; Macleod et al., 2007) or (3) confounding by other risk factors (Macleod and Hickman, 2006; Macleod et al., 2006; Macleod, 2007) such as smoking (van Gastel et al., 2013). The longitudinal relationship of changes in cannabis use with psychotic experiences can inform this debate. From a public health perspective it is relevant to understand the cannabis–psychosis relationship, as intervention strategies in young people often focus on reducing cannabis use, with the ultimate goal of reducing the risk of mental health problems. We set out to investigate whether a longitudinal relationship of change in cannabis use and psychotic experiences exists in both directions: whether an increase of cannabis use coincides with an increase in psychotic experiences, as well as a decrease in cannabis
W.A. van Gastel et al. / Schizophrenia Research 157 (2014) 266–270
use with a decrease of psychotic experiences. We investigated this in a sample of young adult respondents to an internet survey assessing frequency of cannabis use and psychotic experiences at two points in time with a variable interval. 2. Methods 2.1. Participants Data were collected over the period of June 2006 until April 2011 using a research website designed for this purpose (Schubart et al., 2011). Participants were recruited via advertisements on websites, chat messenger applications, college intranets and in ‘coffeeshops’ (Dutch shops that are allowed to sell small quantities of cannabis). As an incentive, participants had a chance of winning a prize, ranging from a Hawaiian garland and credit for online shopping to an Apple iPod™ or a Nintendo Wii™. In order to detect random answering and automated answers by internet robots, verification items were included as a measure of quality control. All participants gave online informed consent and the study was approved by the ethics committee of the University Medical Center, Utrecht. After completing a baseline online questionnaire on psychotic experiences and cannabis use, participants were invited to join in the second part of the study: a more extensive online assessment of mental health and social environment. Participants were free to choose when to participate in this second part, resulting in a variable time interval in between measurements. Of the total 20,295 participants who joined in the first measurement, 1034 filled out the cannabis inventory twice. For the current analysis, a selection was made so that the minimum period between measurements was six months (the maximum being five years). This resulted in a follow-up sample of 705 male and female participants from the general population, aged 18–27 years. 2.2. Measures 2.2.1. Psychotic experiences The Community Assessment of Psychic Experiences (CAPE) was used to assess psychotic experiences (Stefanis et al., 2002; Konings et al., 2006). The CAPE is a 42-item, self-rating questionnaire partly based on the Peters et al., Delusional Inventory (Peters et al., 1999) and has discriminative validity in subjects from the general population (Stefanis et al., 2002; Konings et al., 2006). In the CAPE participants are asked to rate the frequency of lifetime positive, negative and depressive experiences on a four-point scale of ‘Never’, ‘Sometimes’, ‘Often’ and ‘Nearly Always’. The total frequency score is the main outcome measure. Subsequently, we performed a post-hoc analysis for the Positive, Negative and Depressive subscales. CAPE scores at baseline were included as indicator for longitudinal analyses. 2.2.2. Cannabis use Cannabis use was measured by asking the monetary value of cannabis consumed per week: incidentally or less than €3 per week (1); between €3 and €10 (2); between €10 and €25 (3); and more than €25 (4). Except for the first category, all categories applied to the last month or longer. Since in the Netherlands, the THC concentration and market value of cannabis are correlated (r = 0.37 (p b 0.001) in marijuana and r = 0.72 (p b 0.001) in hashish) (Niesink et al., 2009) this is used as a proxy for the level of THC consumption. For reference, 1 g of Dutch marijuana (‘Nederwiet’) costs €8.13 and has an average THC content of 17.8% (van Laar, 2011). Dummy variables were constructed for change in cannabis use, based on a shift between use categories (increase, decrease and unchanged use). Unchanged use was set as the reference category. Participants were also asked at what age they started using cannabis. For analyses, baseline cannabis use was dichotomised into never versus €3 or more per week, based on a median split and evidence for a significant association with psychotic
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experiences from previous studies (Schubart et al., 2011; Vreeker et al., 2013). This dichotomized measure of baseline cannabis use, instead of a categorical variable of cannabis use, effectively accounted for the effect of baseline cannabis use without compromising the power of the analysis as much as modelling 4 potential baseline levels of cannabis use. 2.2.3. Confounders Potential confounders were assessed at follow-up. Alcohol use was defined as at least 12 alcoholic consumptions during the past year. Cigarette smoking was defined as daily smoking for at least one month during the past year. Use of any other illicit substance (e.g. amphetamine, khat, opiates, cocaine, GHB and psychedelics) was defined as ever use. Since not all participants had reached the age of graduation, education was coded as educational track. Dutch secondary schools broadly offer three levels of education: preparatory vocational, preparatory polytechnic and preparatory university education. These levels were combined in categories with the corresponding levels of tertiary education. Furthermore, treatment of one or both parents for a mental disorder, covering addiction, psychotic and affective symptoms, was included. Time between the two measurements was also considered a possible confounder. Last, since cannabis intake and psychosis risk both depend on ethnic background (Van Gastel et al., 2013; Wu et al., 2014), we considered ethnicity as a possible confounder. Ethnicity was based on the country of birth of the grandparents; participants with two or more grandparents born outside the Netherlands were defined as Non-Dutch. 2.3. Data analysis The analyses were carried out with the statistical package for the social sciences (SPSS 20.0) and R software (R Development Core Team, 2008). Listwise exclusion was applied for missing values. A quality check was applied for cannabis use: participants who stated never to have used at follow-up, while they indicated use at baseline, were removed. Linear regressions were carried out, with the CAPE total frequency score at follow-up as the outcome measure and change in cannabis use as predictor (in the form of dummy variables for increased use and decreased use, compared to unchanged use as reference category). Statistical assumptions were verified using scatterplots of the residuals. We first investigated a model correcting for baseline CAPE score, baseline cannabis use (dichotomized), age and gender. In a second model, other potential confounders were added if they were significantly associated with change in cannabis use and CAPE score at follow-up (at p b 0.05) or if they changed the predictive value (β) of change in cannabis use by 10% or more (Greenland, 1989; Chaves et al., 2007). Leaving out potential confounders that do not meet these criteria reduces the chance of loss of power and over-fitting the model. Post-hoc analyses were performed with the frequency scores of the Positive, Negative and Depressive subscales as outcome variables. 2.3.1. Attrition To investigate whether bias due to the large attrition was likely, the follow-up group was compared with the initial baseline group (n = 20,295) on available baseline information. We conducted Χ2-tests for gender, ethnicity, level of education, age at onset of cannabis use and cannabis use and performed t-tests for age, CAPE total frequency score and CAPE Positive, Depressive and Negative frequency subscores. 3. Results In the total sample of 753 participants with follow-up information with a minimum timelag of 6 months, there was 1 missing value for ethnicity, 24 for educational track and 23 participants with inconsistency in cannabis use (stating to have used at baseline but stating
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‘never’ to have used at follow-up). Listwise exclusion of these subjects resulted in a sample of 705 young adults aged 18–27 years, 375 (53.2%) male. Table 1 shows sample characteristics, stratified by change in cannabis use. The majority of participants did not change their cannabis use (56.7%), about a third reduced their cannabis use (35.3%) and 7.9% increased their cannabis use. At baseline, 41.8% indicated no cannabis use; this had risen to 70.5% at follow-up. Participants who used cannabis most frequently spent between €10 and €25 per week on the substance; 22.1% of the total sample at baseline and 12.6% at follow-up. Based on the selection criteria for inclusion in the model, alcohol use was not included for any of the models. Also other alcohol thresholds (heavy use: N21 units per week for males and N 14 units per week for females; daily use) did not meet the selection criteria. Time between measurements and Ethnicity (Non-Dutch) were not included in models predicting the Depressive subscale. Furthermore, low level of education was not included in the adjusted model with the Negative subscale as outcome.
Table 2 Standardized regression coefficients (β) and p-values for the association between change in cannabis use (reference: no change) and psychotic experiences (total CAPE-score) at follow-up for crude and adjusted models. For the adjusted models, associations between all factors and CAPE-scores are also displayed. βs with a p-value below 0.05 are shown in italic. Model
Variable
Crude
Decrease in cannabis use Increase in cannabis use Female gender Age CAPE baseline CU baseline Decrease in cannabis use Increase in cannabis use Female gender Age CAPE baseline CU baseline Non-Dutch Low education Smoker Other illicit substances (ever) Age at onset of cannabis use b15 years Parent(s) psychiatrically treated
Adjusted
3.1. Association between change in cannabis use and psychotic experiences at follow-up The results of the analysis of the association of change in cannabis use with psychotic experiences, as measured by CAPE total frequency score, are shown in Table 2. A decrease in cannabis use predicted a lower CAPE total score at follow-up, in both a crude (β = − 0.096, p = 0.01) as well as a fully adjusted model (β = − 0.096, p = 0.01). An increase however, was not significantly associated with the number of psychotic experiences at follow-up. 3.2. Association between cannabis use and CAPE Positive, Negative and Depressive subscales The results for the association between the change in cannabis use and the Positive, Negative and Depressive subscales of the CAPE are shown in Table 3. A decrease in cannabis use was associated with fewer Positive symptoms at follow-up in the unadjusted model (β = − 0.12, p = 0.002), but not in the fully adjusted model (β = − 0.06, p = 0.06). An increase in cannabis use was associated with a higher score of the CAPE Positive subscale at follow-up in a fully adjusted model (β = 0.07, p = 0.02). There was no significant association between change in cannabis use and the Negative subscale. For the Depressive subscale, a decrease in cannabis use was predictive of a lower score at follow-up, but only in the unadjusted model (β = − 0.10, p = 0.01). 3.3. Assessment of attrition bias We compared baseline characteristics of the follow-up group with the entire group of which we had baseline measures. We found no significant differences between gender, level of education and age at onset
Association to psychotic experiences Beta
p-Value
−0.096 0.04 0.04 −0.02 0.70 0.12 −0.096 0.04 0.04 −0.02 0.69 0.11 0.07 −0.02 −0.01 0.01 0.02 0.03
0.01 0.17 0.16 0.37 b0.001 0.002 0.01 0.19 0.16 0.40 b0.001 0.04 0.01 0.44 0.82 0.80 0.62 0.28
of cannabis use. Furthermore, the groups did not differ on CAPE total frequency score and scores on the Positive, Negative and Depressive subscales. However, significant differences were found for age, ethnicity and cannabis use across groups: the follow-up group consisted of more moderate to severe cannabis users. Details can be found in Table 4. 4. Discussion In this longitudinal study in 705 subjects from the general population we found that a reduction in cannabis use was associated with a reduced frequency of psychotic experiences at follow-up. This suggests that, since psychotic experiences are a risk factor for later psychotic disorders and mental health problems in general (Johns and van, 2001; Hanssen et al., 2005; Yung et al., 2009), cessation of cannabis may be beneficial in reducing the risk of clinical psychosis in the long run. Alternatively, the association may reflect reverse causality whereby those whose psychotic symptoms decline become less inclined to use cannabis. To our knowledge, this is the first study to investigate the association of change in cannabis use over time with psychotic experiences in a population sample. Our findings largely parallel those for clinically significant psychosis: a recent review (Mullin et al., 2012) summed the evidence that cessation of cannabis use resulted in an alleviation of psychotic symptoms in patients.
Table 1 Sample characteristics of total study sample (n = 705), stratified by change in cannabis use between measurements: decrease, no change or increase. Characteristic
Decreased (n = 249)
Unchanged (n = 400)
Increased (n = 56)
Total (n = 705)
Age in years (Mean, SD)⁎ Age at onset of cannabis use (Mean, SD)⁎ Male gender (n,%)⁎ Non-Dutch (n,%)⁎ Low level of education (n,%)⁎ Parent(s) treated for mental health problem (n, %) Cigarette smoking (n,%)⁎ Alcohol use (n,%)⁎ Other illicit substance use ever (n,%)⁎
21.4 (2.4)⁎ 15.6 (2.2) 150 (60.2%) 32 (12.9%) 82 (32.9%) 70 (28.1%) 146 (58.6%) 231 (92.8%) 156 (62.7%) 16.4 (7.2)
20.8 (2.1) 15.8 (2.9) 184 (46.0%) 30 (7.5%) 128 (32%) 98 (24.5%) 107 (26.8%) 344 (86.0%) 93 (23.3%) 18.1 (8.0)
20.5 (2.5) 14.8 (2.0) 41 (73.2%) 10 (17.9%) 30 (53.6%) 18 (32.2%) 46 (82.1%) 54 (96.4%) 37 (66.1%) 17.6 (7.3)
21.0 (2.2) 15.6 (2.4) 375 (53.2%) 72 (10.2%) 240 (34.0%) 186 (26.4%) 299 (42.4%) 629 (89.2%) 286 (40.6%) 17.5 (7.7)
Time between measurements in months (Mean, SD)⁎
⁎ Significant difference between cannabis user groups at p b 0.05, applying a one-way ANOVA for age, age at onset and time to follow-up and a two-sided Chi-square test for the other variables.
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Table 3 Standardized regression coefficients (β) and p-values for the association between change in cannabis use (reference: no change) and CAPE-score at follow-up for crude and adjusted models. For the adjusted models, associations between all factors and CAPE-scores are also displayed. βs with a p-value below 0.05 are shown in italic. Model
Variable
Positive symptoms Beta (p-value)
Negative symptoms Beta (p-value)
Depressive symptoms Beta (p-value)
Crude
Decrease in cannabis use Increase in cannabis use Female Gender Age CAPE baselinea CU baseline Decrease in cannabis use Increase in cannabis use Female gender Age CAPE baselinea CU baseline Time between measurements Non-Dutch Low education Smoker Other illicit substances (ever) Age at onset of cannabis use b15 years
−0.12 (0.002) 0.04 (0.18) 0.04 (0.19) −0.01 (0.83) 0.71 (b0.001) 0.14 (b0.001) −0.06 (0.06) 0.07 (0.02) 0.02 (0.39) 0.00 (0.99) 0.70 (b0.001) 0.02 (0.69) −0.06 (0.03) 0.08 (0.002) 0.01 (0.85) 0.01 (0.89) 0.02 (0.62) 0.03 (0.43)
−0.04 (0.30) 0.05 (0.12) 0.003 (0.92) −0.03 (0.33) 0.66 (b0.001) 0.06 (0.16) −0.01 (0.72) 0.06 (0.06) 0.004 (0.91) −0.02 (0.50) 0.66 (b0.001) −0.02 (0.74) 0.07 (0.01) 0.06 (0.03) Not included 0.02 (0.58) 0.02 (0.65) 0.01 (0.78)
−0.10 (0.01) −0.002 (0.95) 0.09 (0.002) −0.03 (0.38) 0.65 (b0.001) 0.14 (0.001) −0.05 (0.10) 0.02 (0.58) 0.09 (0.003) −0.02 (0.44) 0.65 (b0.001) 0.003 (0.95) Not included Not included 0.000 (0.998) −0.01 (0.82) 0.08 (0.07) 0.05 (0.15)
Adjusted
a
Baseline score on the subscale of interest.
We did not find evidence that increasing cannabis use coincides with increasing frequency of psychotic experiences in general; increased cannabis use was only associated with an increase in positive symptoms. Previous studies also suggest that cannabis is most strongly associated with positive symptoms compared with other symptom dimensions (Chapman et al., 1994; Welham et al., 2009; Schubart et al., 2011). A similar selective association for positive symptoms was reported previously by Schubart et al. (2011) for the association with early cannabis use. However, as we only found an association of general psychotic experiences and decreased cannabis use, and not with an increase, the current study does not show definitive evidence for a causal relationship between cannabis use and psychotic experiences in the general population.
4.1. Limitations The major limitation of this study is that selective drop-out or attrition may have occurred due to the limited number of participants from the online screening that consented to the assessment at follow-up. Particularly, fewer people with increased cannabis use consented to follow-up (n = 56). This indicates that we had less power to detect an effect of increased cannabis use on psychotic experiences. Analysis of the attrition suggests that our findings may be restricted to a population of high users of cannabis of non-Dutch origin and may not extend to the general population. The fact that our data were gathered by self-report via the internet, possibly leading to either over- or underreporting of undesirable behaviour such as cannabis use, poses a minor limitation as recent studies
have shown that the internet is a suitable instrument for scientific research (Meyerson and Tryon, 2003; Vleeschouwer et al., 2014) and potential bias is unlikely to be systematic. Another potential limitation may be that the CAPE questionnaire inquires after psychotic experiences that may be hard to distinguish from the acute intoxication effects of cannabis. There is however some evidence that high CAPE scores associated with acute cannabis intoxication are a reflection of psychosis proneness as well (Genetic Risk and Outcome in Psychosis (GROUP) investigators, 2011). Finally, unknown sources of confounding may remain: although measures of demographic factors and substance use were available, residual confounding by extensive behavioural and psychopathological factors such as attention-deficit hyperactivity disorder, externalising behaviour and conduct disorder (Monshouwer et al., 2006; Lee et al., 2011; Malcolm et al., 2011) cannot be ruled out. Factors that may play a role, but that were not measured, include urbanicity, socio-economic status, social support and household composition (van Gastel et al., 2012).
4.2. Conclusion Overall we found an association between changes in cannabis use and changes in the frequency of psychotic experiences. Our results do not demonstrate a causal relationship between cannabis use and psychotic experiences, but our findings do suggest that cessation of cannabis use is associated with a reduction of psychotic experiences. Cessation of cannabis use might be effective in terms of reducing psychotic experiences or alternatively may be a good indicator of improved mental health. Since psychotic experiences are predictive of later
Table 4 Comparison of the baseline and follow-up groups by t-tests and Χ2 tests. p-Values below 0.05 are shown in italic.
Age, Mean (SD) Gender (M) % Non-Dutch % Level of education (low) % Age at onset cannabis use (before 15)% CAPE total, Mean (SD) CAPE positive, Mean (SD) CAPE negative, Mean (SD) CAPE depressive, Mean (SD) Cannabis use (0–3 euros per week)
Baseline group (n = 20.295)
Follow-up group (n = 705)
t-Value or Χ2
p-Value
23.4 (12.4) 49.1% 18% 35% 32% 65.6 (12.0) 28.2 (5.6) 23.7 (5.5) 13.7 (3.1) 68%
21.0 (2.20) 53% 10% 34% 33% 66.2 (14.0) 28.3 (6.3) 24.1 (6.5) 13.8 (3.6) 58%
T Χ2 Χ2 Χ2 Χ2 T T T T Χ2
b0.001 0.24 b0.001 0.48 0.49 0.31 0.72 0.15 0.49 b0.001
= = = = = = = = = =
19.7 1.4 29.6 0.49 0.48 −1.01 −0.37 −1.43 −0.69 26.84
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psychotic disorders (Johns, 2001; Hanssen, 2005), our results are compatible with the possibility that cessation of cannabis use may reduce the risk of clinical psychosis in the long run. Considering the potential implication for public mental health, a longitudinal experimental study would be very worthwhile. Role of funding source This study was financially supported by a Grant of the NWO (Netherlands Organization for Scientific Research), Grant number: 91207039. The NWO had no role in the design of the study, in the collection, analysis, interpretation of data and writing the report. Contributors Willemijn van Gastel was involved in the conceptualization and design of the study, collecting and analysing the data and drafting the paper. Annabel Vreeker was involved in collecting and analysing the data and drafting the paper. Christian Schubart was involved in the conceptualization and design of the study and critical revision after the draft. James MacCabe was involved in the interpretation of the data and revision of the draft. René Kahn was involved in the design of the study, interpretation of the data, revision of the draft and supervision of the project. Marco Boks was involved in the design of the study, interpretation of the data, revision of the draft and supervision of the project. Conflict of interest None of the authors has any conflict of interest. Acknowledgement This study was financially supported by a Grant of the NWO (Netherlands Organization for Scientific Research), Grant number: 91207039.
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Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Change in cannabis use in the general population: A longitudinal study on the impact on psychotic experiences W.A. van Gastel a,b,c,1, A. Vreeker a,⁎,1, C.D. Schubart a,d, J.H. MacCabe e, R.S. Kahn a, M.P.M. Boks a a
Brain Center Rudolf Magnus, University Medical Center Utrecht, Department of Psychiatry, HP. B01.206, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands Department of Psychiatry, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands Department of Sexology & Psychosomatic Obstetrics and Gynaecology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands d Department of Psychiatry, Tergooi Hospital, Hilversum, The Netherlands e Department of Psychosis Studies, Institute of Psychiatry, King's College, London, UK b c
a r t i c l e
i n f o
Article history: Received 10 January 2014 Received in revised form 17 March 2014 Accepted 24 April 2014 Available online 12 June 2014 Keywords: Cannabis Risk Psychotic experience Psychosis
a b s t r a c t Objective: To prospectively assess the relationship between cannabis use and psychotic experiences over time. Method: In a longitudinal design, young adults aged 18–27 years (N = 705) gave online information on cannabis use and completed the Community Assessment of Psychic Experiences (CAPE). These measures were repeated after an interval ranging from six months to five years. Results: A decrease in cannabis use was associated with a decrease in total psychotic experiences (β = −0.096, p = 0.01) after adjustment for a range of potential confounders. An increase in cannabis use was associated with increased positive symptoms at follow-up (β = 0.07, p = 0.02), but was not significantly associated with increases in Negative and Depression symptom scores, nor with the total number of psychotic experiences. Conclusion: In the first study to the association of change in cannabis use and psychotic experiences over time in the general population, we found an association between changes in cannabis use and changes in the frequency of psychotic experiences. While this does not prove a causal relationship between cannabis use and psychosis, our findings are consistent with studies suggesting that cessation of cannabis use may be beneficial in terms of reducing psychotic experiences. © 2014 Elsevier B.V. All rights reserved.
1. Introduction The association between cannabis use and psychotic symptoms is now firmly established (Arseneault et al., 2002; Henquet et al., 2005; Moore et al., 2007; Kuepper et al., 2011). Recent findings suggest that cessation of cannabis use alleviates symptoms and burden of disease in psychotic patients (Mullin et al., 2012). The association of cannabis use and psychotic symptoms is not restricted to clinically significant psychotic symptoms, since cannabis use is also related to psychotic experiences in the general population (Verdoux et al., 2003; Stefanis et al., 2004; Schubart et al., 2011; van Gastel et al., 2012). Prior studies particularly focused on the relationship between (early) cannabis use and psychotic experiences in cross-sectional designs (Schubart et al., 2011). Furthermore, the only longitudinal study to the relationship of cannabis use and psychotic experiences to date specifically focused on heavy cannabis use and found that cannabis dependence at a young age was associated with an increased risk of psychotic experiences (Fergusson et al., 2003). However, it has not yet been investigated Abbreviations: CAPE, Community Assessment of Psychic Experiences. ⁎ Corresponding author. Tel.: +31 88 755 6370; fax: +31 88 755 5487. E-mail address: [email protected] (A. Vreeker). 1 Equal contribution.
http://dx.doi.org/10.1016/j.schres.2014.04.023 0920-9964/© 2014 Elsevier B.V. All rights reserved.
whether a change in cannabis use (either irregular use, regular use or heavy use) over time is associated with a change in psychotic experiences in the general population. The nature of the association between cannabis use and psychotic experiences remains subject to debate (Murray et al., 2007). The most probable explanations for this association are: (1) that cannabis use is a risk factor for the development or persistence of psychotic symptoms (Caspi et al., 2005; Henquet et al., 2005; Cougnard et al., 2007; Bossong and Niesink, 2010; Costas et al., 2011; Kuepper et al., 2011), (2) reverse causality, whereby psychosis-prone individuals start using cannabis in an attempt to self-medicate (Henquet et al., 2005; Macleod et al., 2007) or (3) confounding by other risk factors (Macleod and Hickman, 2006; Macleod et al., 2006; Macleod, 2007) such as smoking (van Gastel et al., 2013). The longitudinal relationship of changes in cannabis use with psychotic experiences can inform this debate. From a public health perspective it is relevant to understand the cannabis–psychosis relationship, as intervention strategies in young people often focus on reducing cannabis use, with the ultimate goal of reducing the risk of mental health problems. We set out to investigate whether a longitudinal relationship of change in cannabis use and psychotic experiences exists in both directions: whether an increase of cannabis use coincides with an increase in psychotic experiences, as well as a decrease in cannabis
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use with a decrease of psychotic experiences. We investigated this in a sample of young adult respondents to an internet survey assessing frequency of cannabis use and psychotic experiences at two points in time with a variable interval. 2. Methods 2.1. Participants Data were collected over the period of June 2006 until April 2011 using a research website designed for this purpose (Schubart et al., 2011). Participants were recruited via advertisements on websites, chat messenger applications, college intranets and in ‘coffeeshops’ (Dutch shops that are allowed to sell small quantities of cannabis). As an incentive, participants had a chance of winning a prize, ranging from a Hawaiian garland and credit for online shopping to an Apple iPod™ or a Nintendo Wii™. In order to detect random answering and automated answers by internet robots, verification items were included as a measure of quality control. All participants gave online informed consent and the study was approved by the ethics committee of the University Medical Center, Utrecht. After completing a baseline online questionnaire on psychotic experiences and cannabis use, participants were invited to join in the second part of the study: a more extensive online assessment of mental health and social environment. Participants were free to choose when to participate in this second part, resulting in a variable time interval in between measurements. Of the total 20,295 participants who joined in the first measurement, 1034 filled out the cannabis inventory twice. For the current analysis, a selection was made so that the minimum period between measurements was six months (the maximum being five years). This resulted in a follow-up sample of 705 male and female participants from the general population, aged 18–27 years. 2.2. Measures 2.2.1. Psychotic experiences The Community Assessment of Psychic Experiences (CAPE) was used to assess psychotic experiences (Stefanis et al., 2002; Konings et al., 2006). The CAPE is a 42-item, self-rating questionnaire partly based on the Peters et al., Delusional Inventory (Peters et al., 1999) and has discriminative validity in subjects from the general population (Stefanis et al., 2002; Konings et al., 2006). In the CAPE participants are asked to rate the frequency of lifetime positive, negative and depressive experiences on a four-point scale of ‘Never’, ‘Sometimes’, ‘Often’ and ‘Nearly Always’. The total frequency score is the main outcome measure. Subsequently, we performed a post-hoc analysis for the Positive, Negative and Depressive subscales. CAPE scores at baseline were included as indicator for longitudinal analyses. 2.2.2. Cannabis use Cannabis use was measured by asking the monetary value of cannabis consumed per week: incidentally or less than €3 per week (1); between €3 and €10 (2); between €10 and €25 (3); and more than €25 (4). Except for the first category, all categories applied to the last month or longer. Since in the Netherlands, the THC concentration and market value of cannabis are correlated (r = 0.37 (p b 0.001) in marijuana and r = 0.72 (p b 0.001) in hashish) (Niesink et al., 2009) this is used as a proxy for the level of THC consumption. For reference, 1 g of Dutch marijuana (‘Nederwiet’) costs €8.13 and has an average THC content of 17.8% (van Laar, 2011). Dummy variables were constructed for change in cannabis use, based on a shift between use categories (increase, decrease and unchanged use). Unchanged use was set as the reference category. Participants were also asked at what age they started using cannabis. For analyses, baseline cannabis use was dichotomised into never versus €3 or more per week, based on a median split and evidence for a significant association with psychotic
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experiences from previous studies (Schubart et al., 2011; Vreeker et al., 2013). This dichotomized measure of baseline cannabis use, instead of a categorical variable of cannabis use, effectively accounted for the effect of baseline cannabis use without compromising the power of the analysis as much as modelling 4 potential baseline levels of cannabis use. 2.2.3. Confounders Potential confounders were assessed at follow-up. Alcohol use was defined as at least 12 alcoholic consumptions during the past year. Cigarette smoking was defined as daily smoking for at least one month during the past year. Use of any other illicit substance (e.g. amphetamine, khat, opiates, cocaine, GHB and psychedelics) was defined as ever use. Since not all participants had reached the age of graduation, education was coded as educational track. Dutch secondary schools broadly offer three levels of education: preparatory vocational, preparatory polytechnic and preparatory university education. These levels were combined in categories with the corresponding levels of tertiary education. Furthermore, treatment of one or both parents for a mental disorder, covering addiction, psychotic and affective symptoms, was included. Time between the two measurements was also considered a possible confounder. Last, since cannabis intake and psychosis risk both depend on ethnic background (Van Gastel et al., 2013; Wu et al., 2014), we considered ethnicity as a possible confounder. Ethnicity was based on the country of birth of the grandparents; participants with two or more grandparents born outside the Netherlands were defined as Non-Dutch. 2.3. Data analysis The analyses were carried out with the statistical package for the social sciences (SPSS 20.0) and R software (R Development Core Team, 2008). Listwise exclusion was applied for missing values. A quality check was applied for cannabis use: participants who stated never to have used at follow-up, while they indicated use at baseline, were removed. Linear regressions were carried out, with the CAPE total frequency score at follow-up as the outcome measure and change in cannabis use as predictor (in the form of dummy variables for increased use and decreased use, compared to unchanged use as reference category). Statistical assumptions were verified using scatterplots of the residuals. We first investigated a model correcting for baseline CAPE score, baseline cannabis use (dichotomized), age and gender. In a second model, other potential confounders were added if they were significantly associated with change in cannabis use and CAPE score at follow-up (at p b 0.05) or if they changed the predictive value (β) of change in cannabis use by 10% or more (Greenland, 1989; Chaves et al., 2007). Leaving out potential confounders that do not meet these criteria reduces the chance of loss of power and over-fitting the model. Post-hoc analyses were performed with the frequency scores of the Positive, Negative and Depressive subscales as outcome variables. 2.3.1. Attrition To investigate whether bias due to the large attrition was likely, the follow-up group was compared with the initial baseline group (n = 20,295) on available baseline information. We conducted Χ2-tests for gender, ethnicity, level of education, age at onset of cannabis use and cannabis use and performed t-tests for age, CAPE total frequency score and CAPE Positive, Depressive and Negative frequency subscores. 3. Results In the total sample of 753 participants with follow-up information with a minimum timelag of 6 months, there was 1 missing value for ethnicity, 24 for educational track and 23 participants with inconsistency in cannabis use (stating to have used at baseline but stating
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‘never’ to have used at follow-up). Listwise exclusion of these subjects resulted in a sample of 705 young adults aged 18–27 years, 375 (53.2%) male. Table 1 shows sample characteristics, stratified by change in cannabis use. The majority of participants did not change their cannabis use (56.7%), about a third reduced their cannabis use (35.3%) and 7.9% increased their cannabis use. At baseline, 41.8% indicated no cannabis use; this had risen to 70.5% at follow-up. Participants who used cannabis most frequently spent between €10 and €25 per week on the substance; 22.1% of the total sample at baseline and 12.6% at follow-up. Based on the selection criteria for inclusion in the model, alcohol use was not included for any of the models. Also other alcohol thresholds (heavy use: N21 units per week for males and N 14 units per week for females; daily use) did not meet the selection criteria. Time between measurements and Ethnicity (Non-Dutch) were not included in models predicting the Depressive subscale. Furthermore, low level of education was not included in the adjusted model with the Negative subscale as outcome.
Table 2 Standardized regression coefficients (β) and p-values for the association between change in cannabis use (reference: no change) and psychotic experiences (total CAPE-score) at follow-up for crude and adjusted models. For the adjusted models, associations between all factors and CAPE-scores are also displayed. βs with a p-value below 0.05 are shown in italic. Model
Variable
Crude
Decrease in cannabis use Increase in cannabis use Female gender Age CAPE baseline CU baseline Decrease in cannabis use Increase in cannabis use Female gender Age CAPE baseline CU baseline Non-Dutch Low education Smoker Other illicit substances (ever) Age at onset of cannabis use b15 years Parent(s) psychiatrically treated
Adjusted
3.1. Association between change in cannabis use and psychotic experiences at follow-up The results of the analysis of the association of change in cannabis use with psychotic experiences, as measured by CAPE total frequency score, are shown in Table 2. A decrease in cannabis use predicted a lower CAPE total score at follow-up, in both a crude (β = − 0.096, p = 0.01) as well as a fully adjusted model (β = − 0.096, p = 0.01). An increase however, was not significantly associated with the number of psychotic experiences at follow-up. 3.2. Association between cannabis use and CAPE Positive, Negative and Depressive subscales The results for the association between the change in cannabis use and the Positive, Negative and Depressive subscales of the CAPE are shown in Table 3. A decrease in cannabis use was associated with fewer Positive symptoms at follow-up in the unadjusted model (β = − 0.12, p = 0.002), but not in the fully adjusted model (β = − 0.06, p = 0.06). An increase in cannabis use was associated with a higher score of the CAPE Positive subscale at follow-up in a fully adjusted model (β = 0.07, p = 0.02). There was no significant association between change in cannabis use and the Negative subscale. For the Depressive subscale, a decrease in cannabis use was predictive of a lower score at follow-up, but only in the unadjusted model (β = − 0.10, p = 0.01). 3.3. Assessment of attrition bias We compared baseline characteristics of the follow-up group with the entire group of which we had baseline measures. We found no significant differences between gender, level of education and age at onset
Association to psychotic experiences Beta
p-Value
−0.096 0.04 0.04 −0.02 0.70 0.12 −0.096 0.04 0.04 −0.02 0.69 0.11 0.07 −0.02 −0.01 0.01 0.02 0.03
0.01 0.17 0.16 0.37 b0.001 0.002 0.01 0.19 0.16 0.40 b0.001 0.04 0.01 0.44 0.82 0.80 0.62 0.28
of cannabis use. Furthermore, the groups did not differ on CAPE total frequency score and scores on the Positive, Negative and Depressive subscales. However, significant differences were found for age, ethnicity and cannabis use across groups: the follow-up group consisted of more moderate to severe cannabis users. Details can be found in Table 4. 4. Discussion In this longitudinal study in 705 subjects from the general population we found that a reduction in cannabis use was associated with a reduced frequency of psychotic experiences at follow-up. This suggests that, since psychotic experiences are a risk factor for later psychotic disorders and mental health problems in general (Johns and van, 2001; Hanssen et al., 2005; Yung et al., 2009), cessation of cannabis may be beneficial in reducing the risk of clinical psychosis in the long run. Alternatively, the association may reflect reverse causality whereby those whose psychotic symptoms decline become less inclined to use cannabis. To our knowledge, this is the first study to investigate the association of change in cannabis use over time with psychotic experiences in a population sample. Our findings largely parallel those for clinically significant psychosis: a recent review (Mullin et al., 2012) summed the evidence that cessation of cannabis use resulted in an alleviation of psychotic symptoms in patients.
Table 1 Sample characteristics of total study sample (n = 705), stratified by change in cannabis use between measurements: decrease, no change or increase. Characteristic
Decreased (n = 249)
Unchanged (n = 400)
Increased (n = 56)
Total (n = 705)
Age in years (Mean, SD)⁎ Age at onset of cannabis use (Mean, SD)⁎ Male gender (n,%)⁎ Non-Dutch (n,%)⁎ Low level of education (n,%)⁎ Parent(s) treated for mental health problem (n, %) Cigarette smoking (n,%)⁎ Alcohol use (n,%)⁎ Other illicit substance use ever (n,%)⁎
21.4 (2.4)⁎ 15.6 (2.2) 150 (60.2%) 32 (12.9%) 82 (32.9%) 70 (28.1%) 146 (58.6%) 231 (92.8%) 156 (62.7%) 16.4 (7.2)
20.8 (2.1) 15.8 (2.9) 184 (46.0%) 30 (7.5%) 128 (32%) 98 (24.5%) 107 (26.8%) 344 (86.0%) 93 (23.3%) 18.1 (8.0)
20.5 (2.5) 14.8 (2.0) 41 (73.2%) 10 (17.9%) 30 (53.6%) 18 (32.2%) 46 (82.1%) 54 (96.4%) 37 (66.1%) 17.6 (7.3)
21.0 (2.2) 15.6 (2.4) 375 (53.2%) 72 (10.2%) 240 (34.0%) 186 (26.4%) 299 (42.4%) 629 (89.2%) 286 (40.6%) 17.5 (7.7)
Time between measurements in months (Mean, SD)⁎
⁎ Significant difference between cannabis user groups at p b 0.05, applying a one-way ANOVA for age, age at onset and time to follow-up and a two-sided Chi-square test for the other variables.
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Table 3 Standardized regression coefficients (β) and p-values for the association between change in cannabis use (reference: no change) and CAPE-score at follow-up for crude and adjusted models. For the adjusted models, associations between all factors and CAPE-scores are also displayed. βs with a p-value below 0.05 are shown in italic. Model
Variable
Positive symptoms Beta (p-value)
Negative symptoms Beta (p-value)
Depressive symptoms Beta (p-value)
Crude
Decrease in cannabis use Increase in cannabis use Female Gender Age CAPE baselinea CU baseline Decrease in cannabis use Increase in cannabis use Female gender Age CAPE baselinea CU baseline Time between measurements Non-Dutch Low education Smoker Other illicit substances (ever) Age at onset of cannabis use b15 years
−0.12 (0.002) 0.04 (0.18) 0.04 (0.19) −0.01 (0.83) 0.71 (b0.001) 0.14 (b0.001) −0.06 (0.06) 0.07 (0.02) 0.02 (0.39) 0.00 (0.99) 0.70 (b0.001) 0.02 (0.69) −0.06 (0.03) 0.08 (0.002) 0.01 (0.85) 0.01 (0.89) 0.02 (0.62) 0.03 (0.43)
−0.04 (0.30) 0.05 (0.12) 0.003 (0.92) −0.03 (0.33) 0.66 (b0.001) 0.06 (0.16) −0.01 (0.72) 0.06 (0.06) 0.004 (0.91) −0.02 (0.50) 0.66 (b0.001) −0.02 (0.74) 0.07 (0.01) 0.06 (0.03) Not included 0.02 (0.58) 0.02 (0.65) 0.01 (0.78)
−0.10 (0.01) −0.002 (0.95) 0.09 (0.002) −0.03 (0.38) 0.65 (b0.001) 0.14 (0.001) −0.05 (0.10) 0.02 (0.58) 0.09 (0.003) −0.02 (0.44) 0.65 (b0.001) 0.003 (0.95) Not included Not included 0.000 (0.998) −0.01 (0.82) 0.08 (0.07) 0.05 (0.15)
Adjusted
a
Baseline score on the subscale of interest.
We did not find evidence that increasing cannabis use coincides with increasing frequency of psychotic experiences in general; increased cannabis use was only associated with an increase in positive symptoms. Previous studies also suggest that cannabis is most strongly associated with positive symptoms compared with other symptom dimensions (Chapman et al., 1994; Welham et al., 2009; Schubart et al., 2011). A similar selective association for positive symptoms was reported previously by Schubart et al. (2011) for the association with early cannabis use. However, as we only found an association of general psychotic experiences and decreased cannabis use, and not with an increase, the current study does not show definitive evidence for a causal relationship between cannabis use and psychotic experiences in the general population.
4.1. Limitations The major limitation of this study is that selective drop-out or attrition may have occurred due to the limited number of participants from the online screening that consented to the assessment at follow-up. Particularly, fewer people with increased cannabis use consented to follow-up (n = 56). This indicates that we had less power to detect an effect of increased cannabis use on psychotic experiences. Analysis of the attrition suggests that our findings may be restricted to a population of high users of cannabis of non-Dutch origin and may not extend to the general population. The fact that our data were gathered by self-report via the internet, possibly leading to either over- or underreporting of undesirable behaviour such as cannabis use, poses a minor limitation as recent studies
have shown that the internet is a suitable instrument for scientific research (Meyerson and Tryon, 2003; Vleeschouwer et al., 2014) and potential bias is unlikely to be systematic. Another potential limitation may be that the CAPE questionnaire inquires after psychotic experiences that may be hard to distinguish from the acute intoxication effects of cannabis. There is however some evidence that high CAPE scores associated with acute cannabis intoxication are a reflection of psychosis proneness as well (Genetic Risk and Outcome in Psychosis (GROUP) investigators, 2011). Finally, unknown sources of confounding may remain: although measures of demographic factors and substance use were available, residual confounding by extensive behavioural and psychopathological factors such as attention-deficit hyperactivity disorder, externalising behaviour and conduct disorder (Monshouwer et al., 2006; Lee et al., 2011; Malcolm et al., 2011) cannot be ruled out. Factors that may play a role, but that were not measured, include urbanicity, socio-economic status, social support and household composition (van Gastel et al., 2012).
4.2. Conclusion Overall we found an association between changes in cannabis use and changes in the frequency of psychotic experiences. Our results do not demonstrate a causal relationship between cannabis use and psychotic experiences, but our findings do suggest that cessation of cannabis use is associated with a reduction of psychotic experiences. Cessation of cannabis use might be effective in terms of reducing psychotic experiences or alternatively may be a good indicator of improved mental health. Since psychotic experiences are predictive of later
Table 4 Comparison of the baseline and follow-up groups by t-tests and Χ2 tests. p-Values below 0.05 are shown in italic.
Age, Mean (SD) Gender (M) % Non-Dutch % Level of education (low) % Age at onset cannabis use (before 15)% CAPE total, Mean (SD) CAPE positive, Mean (SD) CAPE negative, Mean (SD) CAPE depressive, Mean (SD) Cannabis use (0–3 euros per week)
Baseline group (n = 20.295)
Follow-up group (n = 705)
t-Value or Χ2
p-Value
23.4 (12.4) 49.1% 18% 35% 32% 65.6 (12.0) 28.2 (5.6) 23.7 (5.5) 13.7 (3.1) 68%
21.0 (2.20) 53% 10% 34% 33% 66.2 (14.0) 28.3 (6.3) 24.1 (6.5) 13.8 (3.6) 58%
T Χ2 Χ2 Χ2 Χ2 T T T T Χ2
b0.001 0.24 b0.001 0.48 0.49 0.31 0.72 0.15 0.49 b0.001
= = = = = = = = = =
19.7 1.4 29.6 0.49 0.48 −1.01 −0.37 −1.43 −0.69 26.84
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psychotic disorders (Johns, 2001; Hanssen, 2005), our results are compatible with the possibility that cessation of cannabis use may reduce the risk of clinical psychosis in the long run. Considering the potential implication for public mental health, a longitudinal experimental study would be very worthwhile. Role of funding source This study was financially supported by a Grant of the NWO (Netherlands Organization for Scientific Research), Grant number: 91207039. The NWO had no role in the design of the study, in the collection, analysis, interpretation of data and writing the report. Contributors Willemijn van Gastel was involved in the conceptualization and design of the study, collecting and analysing the data and drafting the paper. Annabel Vreeker was involved in collecting and analysing the data and drafting the paper. Christian Schubart was involved in the conceptualization and design of the study and critical revision after the draft. James MacCabe was involved in the interpretation of the data and revision of the draft. René Kahn was involved in the design of the study, interpretation of the data, revision of the draft and supervision of the project. Marco Boks was involved in the design of the study, interpretation of the data, revision of the draft and supervision of the project. Conflict of interest None of the authors has any conflict of interest. Acknowledgement This study was financially supported by a Grant of the NWO (Netherlands Organization for Scientific Research), Grant number: 91207039.
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