Abstract
Objectives
To establish whether the risk of psychotic disorders in cannabis users changes with time following cannabis cessation using data from the European Network of National Networks studying Gene–Environment Interactions in Schizophrenia (EU-GEI) case–control study.
Methods
The EU-GEI case–control study collected data from first episode psychosis patients and population controls across sites in Europe and Brazil between May 2010 and April 2015. Adjusted logistic regressions were applied to examine whether the odd of psychosis case status changed: (1) with time following cannabis cessation and (2) across different cannabis use groups.
Results
Psychosis risk declined following cessation of cannabis use (β = −0.002; 95% CI −0.004 to 0.000; P = 0.067). When accounting for duration of use, this effect remained (β = −0.003; 95% CI −0.005 to −0.001; P = 0.013). However, in models adjusting for frequency and potency of use the result was not significant. Analysis of different cannabis use groups indicated that ex-users who stopped 1 to 4 weeks previously had the highest risk for psychotic disorder compared to never users (OR = 6.89; 95% CI 3.91–12.14; P < 0.001); risk declined for those who stopped 5 to 12 weeks previously (OR = 2.70; 95% CI 1.73–4.21; P < 0.001) and 13 to 36 weeks previously (OR = 1.53; 95% CI 1.00–2.33; P = 0.050). Ex-users who stopped 37 to 96 weeks (OR = 1.01; 95% CI 0.66–1.57; P = 0.949), 97 to 180 weeks (OR = 0.73; 95% CI 0.45–1.19; P = 0.204), and 181 weeks previously or more (OR = 1.18; 95% CI 0.76–1.83; P = 0.456) had similar psychosis risk to those who had never-used cannabis.
Conclusion
Risk of psychotic disorder appears to decline with time following cannabis cessation, receding to that of those who have never used cannabis after 37 weeks or more of abstinence. Although, preliminary results suggest that frequent users of high potency types of cannabis might maintain an elevated risk compared to never users even when abstaining for longer than 181 weeks.
Keywords: cannabis use, psychotic disorder, cessation, risk, cannabis potency
Résumé
Objectif
Déterminer si le risque de troubles psychotiques chez les utilisateurs de cannabis change au fil du temps après l’arrêt de l’utilisation du cannabis en puisant dans les données issues de l’étude cas-témoins EU-GEI (European Network of National Networks studying Gene-Environment Interactions in Schizophrenia).
Méthodologie
Les chercheurs de l’étude cas-témoins EU-GEI ont recueilli des données auprès de patients présentant leur premier épisode de psychose et auprès de sujets témoins en Europe et au Brésil entre mai 2010 et avril 2015. La méthode des régressions logistiques corrigées a été appliquée pour déterminer si la probabilité d’un état psychotique changeait: (1) au fil du temps après l’arrêt de l’utilisation du cannabis et (2) dans les divers groupes d’utilisateurs de cannabis.
Résultats
Le risque de psychose baissait après l’arrêt de l’utilisation du cannabis (β = −0,002; IC à 95%: −0,004 à 0,000; \P = 0,067). Si on tenait compte de la durée de l’utilisation, cet effet persistait (β = −0,003; IC à 95%: −0,005 à −0,001; P = 0,013). Toutefois, selon les modèles corrigés pour tenir compte de la fréquence et de la puissance des prises, le résultat n’était pas significatif. L’analyse des divers groupes d’utilisateurs de cannabis a révélé que le risque de survenue d’un trouble psychotique était le plus élevé chez les sujets ayant cessé d’utiliser le cannabis au cours des quatre semaines précédentes par rapport aux sujets n’ayant jamais utilisé le cannabis (RC = 6,89; IC à 95%: 3,91 à 12,14; P < 0,001); le risque était moindre chez les sujets ayant cessé au cours des cinq à 12 semaines précédentes (RC = 2,70; IC à 95%: 1,73 à 4,21; P < 0,001) et chez ceux où la cessation remontait à 13 à 36 semaines (RC = 1,53; IC à 95%: 1,00 à 2,33; P = 0,050). Quand l’arrêt de l’utilisation du cannabis remontait à 37 à 96 semaines (RC = 1,01; IC à 95%: 0,66 à 1,57; P = 0,949), à 97 à 180 semaines (RC = 0,73; IC à 95%: 0,45 à 1,19; P = 0,204), et à 181 semaines ou plus (RC = 1,18; IC à 95%: 0,76 à 1,83; P = 0,456), le risque de psychose était semblable à celui observé chez les sujets n’ayant jamais utilisé le cannabis.
Conclusion
Le risque d’apparition d’un trouble psychotique semble décroître au fil du temps après l’arrêt de l’utilisation du cannabis, devenant aussi faible que chez des sujets n’ayant jamais utilisé le cannabis après 37 semaines d’abstinence ou plus. Par contre, d’après les résultats provisoires, l’utilisation fréquente de formes puissantes de cannabis donnerait lieu au maintien d’un risque élevé comparativement à des sujets n’ayant jamais utilisé le cannabis, même si le début de l’abstinence remonte à plus de 181 semaines.
Keywords: consommation de cannabis, trouble psychotique, cessation, risque, puissance du cannabis
Introduction
Epidemiological and experimental research has shown that cannabis use is associated with increased risk of psychotic disorders in a dose-dependent manner.1–6 Moreover, individuals who develop psychosis in the context of daily and high potency cannabis use experience earlier illness onset and more severe positive symptoms than patients who do not use cannabis.5,7,8 Recent studies have also demonstrated that differences in the frequency and potency of cannabis use can account for variation in psychosis incidence between demographic regions.3,9,10
More recently, studies taking advantage of genetic data have re-addressed the question of direction of the causal association between cannabis use and psychotic disorders. Indeed, some evidence has suggested that underlying genetic risk for schizophrenia is associated with patterns of cannabis use to some extent, although some of this might be explained by the underlying risk for cannabis use disorder, which is known to be genetically correlated.11,12 Moreover, the most recent Mendelian randomization study supports a bi-directional association, indicative of this complex relationship, but with a larger effect size for cannabis use causing psychosis. 11
In their commentary, 13 Gillespie and Kendler appraise the evidence from epidemiological and genetics studies and suggest that the association between cannabis use and psychosis phenotypes is partially causal and partially confounded by familial factors as well as reverse causality. They discuss new data from studies investigating incidence rates of psychotic disorders in countries where rates of cannabis use have changed because of its legalization. Such studies are now also adding evidence to the causal link between cannabis use and psychotic disorders.14–16
There is evidence of improvements in anxiety, depression, and sleep following reduction or cessation of cannabis use among the general population, as well as some limited evidence of improvements in quality of life.17–19 In people with serious mental illness, however, the negative impact of heavy cannabis use is more extreme, 20 and evidence shows that people who cease cannabis use after developing a psychotic disorder have better clinical and functional outcomes compared to those who continue use,21–23 regardless of medication adherence. 24 However, it remains unclear whether the risk of developing psychosis can be lowered through stopping cannabis use prior to psychosis onset.25,26 This relationship is clear for other substances of abuse and their harm, e.g., lung and pharyngeal cancer risk declines following cessation of tobacco and alcohol respectively.27–29
Recent findings from multiple localities in the United States suggest that liberalization of cannabis legislation has been followed by higher rates of cannabis use, cannabis use disorder, and psychosis.10,30,31 Given these findings and the global trend to more permissive cannabis laws, a greater understanding of the effects of cannabis cessation prior to psychosis onset can contribute to better informed public health policies, clinical care, and personal decision-making. Consequently, we aimed to establish whether the risk of psychotic disorders in cannabis users changes with time since cannabis cessation using data from the European Network of National Networks studying Gene–Environment Interactions in Schizophrenia (EU-GEI) study.
Methods
Study Design and Participants
The EU-GEI case–control study is a multi-centre study of first episode psychosis (FEP) patients and population controls recruited between May 2010 and April 2015 across 17 catchment areas in England, France, the Netherlands, Italy, Spain, and Brazil. 32 Ethical approval was provided by the relevant committees at each of the study sites, and all participants provided written informed consent. For our analysis, we only included the 11 EU-GEI study sites with complete data on cannabis use (Supplementary Figure 1). 3
Patients presenting with FEP were identified by trained researchers who carried out regular checks across each catchment area's mental health services. Patients were included if they: (1) were aged between 18 and 64 years; (2) resided within the catchment areas at FEP presentation; (3) and received an International Classification of Diseases, 10th Revision (ICD-10 F20-29, F30-33) diagnosis of psychosis. The Operational Criteria Checklist algorithm was used to ensure that a research-based diagnosis was received by every FEP patient. 33 Exclusion occurred if an individual: (1) had previously been treated for psychosis; (2) met criteria for organic psychosis (ICD-10: F09); or (3) was diagnosed with transient psychotic symptoms resulting from acute intoxication (ICD-10: F1X.5). For a more detailed breakdown of diagnostic sub-categories see Rodriguez et al., 2021. 34 FEP patients were assessed within 6 weeks of first contact with psychiatric services both in community and in patients’ settings. If the first presentation to Mental Health Services for FEP coincided with admission to hospital, patients were asked about their cannabis use up to the point of admission (e.g., where you a current user before coming to hospital?).
Control subjects were recruited using random and quota sampling strategies at each of the sites. The quotas were set based on local census data, ensuring that the controls were representative of each catchment area's population at risk. Exclusion of controls occurred if they had received a diagnosis of, and/or treatment for, a psychotic disorder. 32
Measures
Sociodemographic data was collected by administering the Medical Research Council Sociodemographic Schedule. 35 Data pertaining to patterns of cannabis use was collected using the modified Cannabis Experience Questionnaire. 3 To minimize recall bias, neither cannabis nor its role as a psychosis risk factor was referred to in any of the materials used for recruitment. Participants were initially asked if they had ever used cannabis. Those answering yes were then asked about their pattern of use, including the type of cannabis. This enabled participants to report the colloquial name.
We used the following measures of cannabis use in our analysis: (1) lifetime cannabis use, (2) current cannabis use, (3) age first tried cannabis, (4) duration of cannabis use, (5) frequency of cannabis use, (6) potency of cannabis use, and (7) time since cessation.
The variable estimating time since cannabis cessation was continuous (in weeks). Participants reporting both current cannabis use and a time since cessation value were excluded from our analysis. As this variable was only available for lifetime cannabis users, we created a separate variable termed “cannabis use groups” which categorized participants according to their lifetime cannabis use and duration of cessation. This was done to establish the approximate duration taken for the psychosis risk among those who ceased use (“ex-users”) to become equivalent to those who never used cannabis (“never users”). Due to the novel nature of this analysis, we had no indication of the appropriate groupings for ex-users. We first divided the controls into quartile groups and used these as thresholds for the overall sample. Based on the existing evidence reporting cannabis withdrawal symptoms that can precipitate psychosis and observation of the data distribution (Figure 1), we further divided the lowest quartile (most recent cannabis cessation) into 3 groups: ex-users who stopped 1 to 4 weeks ago, 5 to 12 weeks ago, and 13 to 16 weeks ago. Our cannabis use groups were as follows: never users = 0 (reference category); ex-users who stopped 181 weeks or longer previously = 1; ex-users who stopped 97 to 180 weeks previously = 2; ex-users who stopped 37 to 96 weeks previously = 3; ex-users who stopped 13 to 36 weeks previously = 4; ex-users who stopped 5 to 12 weeks previously = 5; ex-users who stopped 1 to 4 weeks previously = 6; and those who currently use cannabis (“current users”) = 7.
Figure 1.
The distribution of time since cessation in FEP cases and population controls in our EU-GEI sample.
The duration of cannabis use was a continuous measurement, measuring the years of cannabis use. This was derived through the following steps for non-current cannabis users:
Dividing weeks since cannabis cessation by 52.143 to establish the number of years since cannabis cessation;
Establishing the age cannabis use was ceased by subtracting a participant's years since cannabis cessation value from their age at the time of the study;
Subtracting a participant's age at cessation from the age they tried cannabis.
For those currently using cannabis, duration of use was established by subtracting the age they first tried cannabis from their age at the time of the study. Individuals with negative duration of use values whose current age matched the age they tried cannabis had their values recoded to 0 as we were unable to establish the exact difference between the age they tried cannabis and their current age. Individuals with negative duration of use variables that were greater than −1 were excluded entirely from our analysis due to the incorrect reporting of either their time since cessation, age tried cannabis, or current age variables. Individuals who had never used cannabis were assigned 0 as their duration of use value.
Statistical Analysis
Analyses were conducted using RStudio version 4.3.1. Descriptive analyses were conducted using t-tests and chi-squared tests. Adjusted linear and logistic regression models established if time since cessation predicted psychosis risk and whether psychosis risk differed across our cannabis use groups. Our regression models were adjusted for key sociodemographic variables (age, site, sex, and ethnicity) and lifetime tobacco use (0 = never smoked or ≤10 cigarettes per day; 1 = 11 cigarettes or more per day 3) as most cannabis users consumed cannabis with tobacco. The addition of each covariate led to an improvement of our models as assessed by Akaike information criterion (Supplementary Table 1). Additional models were adjusted for duration of cannabis use, frequency of cannabis use, and potency of cannabis use, which were added in a stepwise fashion to consider other cannabis use patterns known to impact case status.1,3
Table 1.
Sample Sociodemographic Characteristics and Measures of Cannabis Use.
FEP (N = 875) | Controls (N = 1,230) | Test-statistic (df) | P | ||
---|---|---|---|---|---|
Age | Mean (SD) | 30.89 (10.59) | 36.20 (13.39) | t = −10.15 (2079) | <0.001 |
Sex | Male (%) | 539 (61.60) | 576 (46.83) | χ2(1) = 43.95 | <0.001 |
Site | Amsterdam | 96 | 100 | χ2(10) = 47.24 | <0.001 |
Barcelona | 31 | 36 | |||
Bologne | 66 | 65 | |||
Cambridgeshire | 43 | 106 | |||
Gouda and Voorhout | 97 | 108 | |||
Madrid | 39 | 38 | |||
Palermo | 55 | 99 | |||
Paris | 45 | 100 | |||
Puy de Dome | 15 | 47 | |||
Ribeirao Preto | 189 | 302 | |||
Southeast London | 199 | 229 | |||
Ethnicity | White | 516 | 923 | χ2(5) = 70.63 | <0.001 |
Black | 166 | 117 | |||
Mixed | 101 | 113 | |||
Asian | 31 | 33 | |||
North African | 38 | 23 | |||
Other | 22 | 19 | |||
Highest educational attainment | School, no qualifications | 157 | 65 | χ2(5) = 236.44 | <0.001 |
School, with qualifications | 227 | 159 | |||
Tertiary | 194 | 333 | |||
Vocational | 150 | 175 | |||
Higher (undergraduate) | 101 | 313 | |||
Higher (postgraduate) | 36 | 177 | |||
Current employment status | Unemployed | 353 | 708 | χ2(1) = 22.77 | <0.001 |
Employed | 399 | 511 | |||
Lifetime tobacco use | Lifetime users (%) | 251 (28.69) | 133 (10.81) | χ2(1) = 113.89 | <0.001 |
Lifetime cannabis use | Lifetime users (%) | 559 (63.89) | 569 (46.26) | χ2(1) = 65.84 | <0.001 |
Current cannabis use | Current users (%) | 169 (19.31) | 126 (10.24) | χ2(1) = 35.13 | <0.001 |
Frequency of cannabis use | Rare | 171 | 346 | χ2(3) = 206.98 | <0.001 |
Weekly | 99 | 86 | |||
Daily | 238 | 81 | |||
Potency of cannabis use | Low <10% THC | 226 | 293 | χ2(2) = 81.95 | <0.001 |
High ≥10% THC | 283 | 221 | |||
Weeks since cessation | Mean (SD) | 64.75 (106.12) | 129.14 (125.88) | t = −7.50 (721.07) | <0.001 |
Duration of cannabis use (years) | Mean (SD) | 6.69 (7.56) | 6.18 (9.53) | t = 1.33 (1931.80) | 0.185 |
df = degrees of freedom; SD = standard deviation.
Results
Participant Characteristics
A summary of demographic characteristics and cannabis use measures across our sample is presented in Table 1. The working sample for our analysis consisted of 875 FEP patients and 1,230 population-based controls. In comparison to controls, FEP patients were more likely to be current cannabis users (χ2(1) = 35.13; P < 0.001) and have had fewer weeks of cannabis cessation: FEP mean = 64.75, SD = 106.12; controls mean = 129.14, SD = 125.88 (t = −7.50 (721.07); P < 0.001). FEP patients were also more likely to use cannabis frequently (χ2(3) = 206.98; P < 0.001) and higher potency forms (χ2(2) = 81.95; P < 0.001). There was no significant difference in the duration of cannabis use between groups: FEP mean = 6.69, SD = 7.56; controls mean = 6.18, SD = 9.53 (t = 1.33 (1931.80); P = 0.185).
Does the Risk of Psychosis Change With Time Following Cannabis Cessation?
Linear regression adjusted for age, site, sex, ethnicity, country, and lifetime tobacco use showed a trend of declining psychosis risk each week following the cessation of cannabis use (Model 1: β = −0.002, 95% CI −0.004 to 0.000, P = 0.067). This effect remained similar when additionally adjusting in a stepwise manner for the duration of cannabis use (Model 2: β = −0.003, 95% CI −0.005 to −0.001, P = 0.013), frequency of cannabis use (Model 3: β = −0.002, 95% CI −0.005 to 0.001, P = 0.129), and potency of cannabis use (Model 4: β = −0.002, 95% CI −0.005 to 0.001, P = 0.133). The full results of each of our adjusted linear regression models are displayed in Table 2 and Supplementary Table 2. Figure 2 plots the decrease in psychosis risk over time for users based on the frequency and potency of their cannabis use, demonstrating that risk is highest and takes the longest time to decline for regular, high potency users.
Table 2.
Adjusted Logistic Regression Models Examining Whether Psychosis Risk Declines with Time Following Cessation and Across Different Cannabis Use Groups.
Model 1: adjusted for age, sex, site, ethnicity, tobacco use | Model 2: adjusted for age, sex, site, ethnicity, tobacco use, and duration of cannabis use | Model 3: adjusted for age, sex, site, ethnicity, tobacco use, duration of cannabis use, and frequency of cannabis use | Model 4: adjusted for age, sex, site, ethnicity, tobacco use, duration of cannabis use, frequency of cannabis use, and potency of cannabis use | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Predictors | β | CI | P | β | CI | P | β | CI | P | β | CI | P |
Weeks since cessation | −0.002 | −0.004 to 0.000 | 0.067 | −0.003 | −0.005 to −0.001 | 0.013 | −0.002 | −0.005 to 0.001 | 0.129 | −0.002 | −0.005 to 0.001 | 0.133 |
Observations | 720 | Observations | 719 | Observations | 652 | Observations | 652 | |||||
R2 Tjur | 0.239 | R2 Tjur | 0.245 | R2 Tjur | 0.322 | R2 Tjur | 0.324 |
Figure 2.
Fully adjusted logistic regression model showing the probability of developing psychosis as a function of time for 6 different categories of ex-users.
Predictors | OR | CI | P | OR | CI | P | OR | CI | P | OR | CI | P |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Current-users | 1.60 | 1.16–2.20 | 0.005 | 1.94 | 1.26–2.97 | 0.003 | 2.42 | 1.42–4.11 | 0.001 | 2.03 | 1.17–3.52 | 0.012 |
Ex-users 1–4 weeks | 6.89 | 3.91–12.14 | <0.001 | 8.34 | 4.49–15.47 | <0.001 | 10.10 | 4.87–20.96 | <0.001 | 8.61 | 4.09–18.11 | <0.001 |
Ex-users 5–12 weeks | 2.70 | 1.73–4.21 | <0.001 | 3.22 | 1.95–5.30 | <0.001 | 4.46 | 2.35–8.44 | <0.001 | 3.71 | 1.92–7.17 | <0.001 |
Ex-users 13–36 weeks | 1.53 | 1.00–2.33 | 0.050 | 1.86 | 1.14–3.04 | 0.014 | 3.05 | 1.61–5.78 | 0.001 | 2.61 | 1.36–5.03 | 0.004 |
Ex-users 37–96 weeks | 1.01 | 0.66–1.57 | 0.949 | 1.25 | 0.75–2.08 | 0.392 | 2.02 | 1.05–3.91 | 0.036 | 1.72 | 0.87–3.38 | 0.117 |
Ex-users 97–180 weeks | 0.73 | 0.45–1.19 | 0.204 | 0.91 | 0.52–1.59 | 0.742 | 1.90 | 0.95–3.77 | 0.068 | 1.70 | 0.84–3.41 | 0.138 |
Ex-users 181+ weeks | 1.18 | 0.76–1.83 | 0.456 | 1.60 | 0.87–2.92 | 0.130 | 3.35 | 1.54–7.28 | 0.002 | 2.88 | 1.31–6.35 | 0.009 |
Observations | 1,914 | Observations | 1,909 | Observations | 1,838 | Observations | 1,838 | |||||
R2 Tjur | 0.185 | R2 Tjur | 0.185 | R2 Tjur | 0.216 | R2 Tjur | 0.218 |
OR = odds ratio; CI = 95% confidence interval.
Does the Risk of Psychosis Differ Across Cannabis Use Groups?
Logistic regression adjusted for age, site, sex, ethnicity, and lifetime tobacco use indicated that current cannabis users had elevated psychosis risk compared to never-users (OR = 1.60, 95% CI 1.16–2.20, P = 0.005). In comparison to never users, those with the greatest psychosis risk were ex-users who stopped 1 to 4 weeks previously (OR = 6.89, 95% CI 3.91–12.14, P < 0.001); risk declined for ex-users who had stopped 5 to 12 weeks previously (OR = 2.70, 95% CI 1.73–4.21, P < 0.001), and declined further for ex-users who had stopped for 13 to 36 weeks (OR = 1.53, 95% CI 1.00–2.33, P = 0.062). Ex-users who stopped for 37 to 96 weeks were no different in their psychosis risk to never users, (OR = 1.01, 95% CI 0.66–1.57, P = 0.949), as were ex-users who stopped for 97 to 180 weeks (OR = 0.73; 95% CI 0.45–1.19, P = 0.204) and 181 or more weeks (OR = 1.18; 95% CI 0.76–1.83; P = 0.456).
These effects increased slightly across all use groups when additionally adjusting in a stepwise manner for duration of cannabis use (Model 2), frequency of cannabis use (Model 3), and potency of cannabis use (Model 4). Furthermore, in Model 3, which included frequency of use and Model 4, which also included potency of cannabis use, ex-users who stopped using cannabis 181 weeks or longer previously had an elevated risk of psychosis compared to never-users (Model 3: OR = 3.35; 95% CI 1.54–7.28; P = 0.002; Model 4: OR = 2.88; 95% CI 1.31–6.35; P = 0.009), although the wide confidence intervals for this group indicate that this result should be interpreted with caution.
The full results of each of our adjusted logistic regression models are displayed in Table 2 and Supplementary Table 3. Figure 3 provides a visual representation of the differences in the odds ratios and 95% confidence intervals of our cannabis use groups in Model 1.
Figure 3.
Forest plot displaying the odds ratio and 95% confidence intervals of the cannabis use groups in our adjusted logistic regression models.
Discussion
This is the first study to examine whether the risk for psychotic disorders associated with cannabis use changes following cessation of use in a sample of FEP patients and population controls from the EU-GEI study. Our findings suggest that psychosis risk declines following the cessation of cannabis but not independently of pattern of cannabis use. This is aligned with literature examining cessation of other substances of abuse and their harm.27–29
We investigated whether the risk of psychosis changed across different time-windows of cannabis abstinence. In this analysis, our models unadjusted for frequency and potency of cannabis use, showed that ex-users who had stopped between 1 and 4 weeks, had a 7-fold increase in the probability of psychosis compared to never-users. Interestingly, this effect persisted slightly after 5 to 12 weeks of abstinence, with these individuals having a 3-fold increase in the probability of psychosis compared to never-users, which was greater than current cannabis users. However, in those who had stopped cannabis for 37 weeks or more, the risk of psychosis was no different to never-users, suggestive of a reduction of the previously acquired cannabis-associated risk. Of note, the lung cancer risk associated with smoking reduces annually following cessation but never fully attenuates, 28 while other evidence suggests that the alcohol-associated pharyngeal cancer risk takes approximately 39 years of abstinence to reverse. 29 However, there is evidence that normalization of biomarkers and risk factors associated with vascular dysfunction and disease begins soon after tobacco abstinence.36–38
In models additionally adjusted for frequency and potency of cannabis use, we see a notable increase in the odds of psychosis across all groups, suggesting a modifying effect of patterns of cannabis use on the effect of cannabis cessation. These results follow the same overall pattern as the minimally adjusted models, where odds for psychosis declined until 181 weeks and then peaked slightly. This increase at 181 weeks is only significant when we adjust for cannabis frequency and potency. Although the wide confidence intervals for this group warrant a cautious interpretation and do not allow for formal interaction testing, it may be that the long-term risk for psychosis remains elevated compared to never users if we account for cannabis frequency and potency among former users. This further highlights the importance of considering cannabis potency and frequency of use, which have been previously shown to be highly relevant to clinical outcomes.21,39,40 The difference in the findings from the model using time since cessation as a continuous variable and the models looking at categorical time intervals since cessation, suggests that the association between time following cessation and risk of psychosis may not be linear. Additional studies using longitudinal design will be needed to fully understand the extent to which psychosis risk may decline over time following cannabis cessation.
It should be noted that FEP patients were recruited within 6 weeks of first contact with psychiatric services. Previous research has demonstrated that as many as 40% of FEP patients will cease cannabis use within 12 months of onset 41 ; therefore, it is possible that many ex-users who stopped 1 to 12 weeks ago had stopped using cannabis within the 6-week window post-initial contact with psychiatric services and recruitment to the study. This may partially explain the increase in odds ratio for this group compared to never users. Once again, prospectively designed longitudinal studies are required to understand this association. A recent case series suggests that some people who use cannabis experience psychosis when stopping cannabis as part of cannabis withdrawal syndrome (CWS). 42 CWS typically occurs in heavy cannabis users after abrupt cessation, with up to half of people describing the symptoms as severe.43,44 Heavy cannabis users are known to have a delayed onset due to the time-lag between abstinence and normalization of CB1 receptor expression.45,46 This could, partially, explain the increased odds ratio of ex-users who stopped between 1 and 12 weeks previously; the withdrawal symptoms which include disrupted sleep and increase anxiety might contribute to precipitate psychosis onset. Further studies are required to fully understand CWS and its potential role in precipitating psychosis.
Our research shows evidence that the time since cessation findings are not explained by duration of use, which, in our sample, does not differ between cases and controls. In contrast, adjusting for frequency and potency of use does impact the effect of cannabis cessation. This is in line with our previous evidence that shows that regular use of highly potent (THC concentrations > 10%) has a significant impact on psychotic disorder risk. 3 Indeed, stratifying users into groups based on pattern of use (combined frequency and potency) shows that risk of psychosis may remain elevated in daily users for several years.
Limitations
The main limitation of this study is the case–control design leading us to rely on retrospective data which is prone to bias. 47 Ideally longitudinal research should use prospective data to allow more accurate assessment of whether cessation of cannabis use leads to a decline in risk for psychotic disorders. Secondly, both our measures of cannabis use relied on self-report from our study participants, rendering responses liable to bias.48,49 However, it should be acknowledged that biological measures are also prone to error due to the time-lag between cannabis cessation and THC elimination, particularly from hair samples and in formerly heavy users.50–52 Therefore, thoughtful consideration of which metabolites and which sample type to examine should occur.
Implications
The findings of this study represent an important step in our understanding of the effects of cannabis cessation prior to the onset of psychotic disorder. Research in this area is of crucial importance for informing public health policy, clinical care, and personal decision-making, particularly given the recent global trend towards liberalization of cannabis legislation which appears to be increasing rates of cannabis use and CUD.30,31,53 It seems that individuals should not only be made aware that cannabis use will increase their psychosis risk but that this risk can be attenuated through cessation, the latter approached cautiously to prevent cannabis withdrawal which in turn might precipitate psychosis onset.
In primary care settings, interventions targeting cannabis use reduction should be routinely offered to help-seeking individuals who wish to reduce/stop their cannabis use. The current evidence-based provides some support for the use of psychosocial interventions to this end.54,55 More recent research has suggested that cannabinoids may effectively facilitate cannabis cessation and attenuate withdrawal symptoms.56,57
Conclusion
This is the first study to suggest that the psychosis risk acquired from cannabis use declines following use cessation, especially after 37 or more weeks. It remains unclear if such decline is independent of the frequency and potency of the cannabis used.
While further research addressing the limitations in this study design is essential to fully elucidate the potential impact of cannabis cessation on risk for psychotic disorder, our findings could have important implications for public health messaging, primary prevention and personal decision-making.
Supplemental Material
Supplemental material, sj-docx-1-cpa-10.1177_07067437241290187 for Cannabis Use Cessation and the Risk of Psychotic Disorders: A Case–Control Analysis from the First Episode Case–Control EU-GEI WP2 Study: L’arrêt de l’utilisation du cannabis et le risque de troubles psychotiques: Une analyse cas-témoins tirée de l’étude cas-témoins EU-GEI WP2 centrée sur les premiers épisodes psychotiques by Benjamin W. Bond, Bea Duric, Edoardo Spinazzola, Giulia Trotta, Edward Chesney, Zhikun Li, Diego Quattrone, Giada Tripoli, Charlotte Gayer-Anderson, Victoria Rodriguez, Laura Ferraro, Caterina La Cascia, Ilaria Tarricone, Andrei Szöke, Celso Arango, Julio Bobes, Miquel Bernardo, Cristina Marta Del-Ben, Paulo Rossi Menezes, Jean-Paul Selten, Bart P. F. Rutten, Lieuwe de Haan, Simona Stilo, Franck Schürhoff, Baptiste Pignon, Tom P. Freeman, Evangelos Vassos, Robin M. Murray, Isabelle Austin-Zimmerman and Marta Di Forti in The Canadian Journal of Psychiatry
Acknowledgements
The EU-GEI WP2 Group (for a full list, see please see the online supplemental materials).
Footnotes
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MDF reports personal fees from Janssen, outside the submitted work. RMM reports personal fees from Janssen, Lundbeck, Sunovion, and Otsuka, outside of the submitted work. CA has been a consultant to or has received honoraria or grants from Acadia, Angelini, Biogen, Boehringer, Gedeon Richter, Janssen Cilag, Lundbeck, Medscape, Menarini, Minerva, Otsuka, Pfizer, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. The other authors have no conflicts of interest to declare.
Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The EU-GEI project was funded by the European Community's Seventh Framework Programme under grant agreement No. HEALTH-F2-2009-241909 (Project EU-GEI). The Brazilian study was funded by the São Paulo Research Foundation under grant number 2012/0417-0, Medical Research Council (MRC), National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at South London and Maudsley, NHS Foundation Trust and King's College London and the NIHR BRC at University College London. Wellcome Trust (grant 101272/Z/12/Z). MDF, IAZ, GT, and ES were supported by MRC SRF Fellowship (MRC MR/T007818/1). ES was also supported by Lord Leverhulme's Charitable Trust and the Velvet Foundation and by the Medical Research Council (MRC) [MR/T007818/1]. Dr. Arango receives support from the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (ISCIII), co-financed by the European Union, ERDF Funds from the European Commission, “A way of making Europe”, financed by the European Union – NextGenerationEU(PMP21/00051), PI19/01024. CIBERSAM, Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds, European Union Seventh Framework Program, European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking: Project PRISM-2 (Grant agreement No.101034377), Project AIMS-2-TRIALS (Grant agreement No 777394), Horizon Europe, the National Institute of Mental Health of the National Institutes of Health under Award Number 1U01MH124639-01 (Project ProNET) and Award Number 5P50MH115846-03 (project FEP-CAUSAL), Fundación Familia Alonso, and Fundación Alicia Koplowitz. Funders were not involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review or approval of the manuscript, and decision to submit the manuscript for publication.
ORCID iDs: Baptiste Pignon https://orcid.org/0000-0003-0526-3136
Isabelle Austin-Zimmerman https://orcid.org/0000-0002-3428-5070
Supplemental Material: Supplemental material for this article is available online.
References
- 1.Marconi A, Di Forti M, Lewis CM, Murray RM, Vassos E. Meta-analysis of the association between the level of cannabis use and risk of psychosis. Schizophr Bull. 2016;42:1262-1269. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Murray RM, Englund A, Abi-Dargham A, et al. Cannabis-associated psychosis: neural substrate and clinical impact. Neuropharmacology. 2017;124:89-104. [DOI] [PubMed] [Google Scholar]
- 3.Di Forti M, Quattrone D, Freeman TP, et al. The contribution of cannabis use to variation in the incidence of psychotic disorder across Europe (EU-GEI): a multicentre case-control study. Lancet Psychiatry. 2019;6:427-436. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.D’Souza DC, DiForti M, Ganesh S, et al. Consensus paper of the WFSBP task force on cannabis, cannabinoids and psychosis. World J Biol Psychiatry. 2022;23:719-742. [DOI] [PubMed] [Google Scholar]
- 5.Large M, Sharma S, Compton MT, Slade T, Nielssen O. Cannabis use and earlier onset of psychosis: a systematic meta-analysis. Arch Gen Psychiatry. 2011;68:555-561. [DOI] [PubMed] [Google Scholar]
- 6.Di Forti M, Sallis H, Allegri F, et al. Daily use, especially of high-potency cannabis, drives the earlier onset of psychosis in cannabis users. Schizophr Bull. 2014;40:1509-1517. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Budney, AJ, Roffman, R, Stephens, RS, Walker, D. Marijuana dependence and its treatment. Addict Sci Clin Pract. 2007;4(1):4-16. doi: 10.1151/ASCP07414. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Hines LA, Freeman TP, Gage SH, et al. Association of high-potency Cannabis use with mental health and substance use in adolescence. JAMA Psychiatry. 2020;77:1044-1051. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Lee Pow, J, Donald, C, di Forti, M, et al. Cannabis use and psychotic disorders in diverse settings in the Global South: findings from INTREPID II. Psychol Med. 2023;53(15):7062-7069. doi: 10.1017/S0033291723000399. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Moran, LV, Tsang, ES, Ongur, D, Hsu, J, Choi, MY. Geographical variation in hospitalization for psychosis associated with cannabis use and cannabis legalization in the United States. Psychiatry Res. 2022;308:114387-114387. doi: 10.1016/j.psychres.2022.114387. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Levey DF, Galimberti M, Deak JD, et al. Multi-ancestry genome-wide association study of cannabis use disorder yields insight into disease biology and public health implications. Nat Genet. 2023;55:2094-2103. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Verweij KJH, Abdellaoui A, Nivard MG, et al. Short communication: genetic association between schizophrenia and cannabis use. Drug Alcohol Depend. 2017;171:117-121. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Gillespie NA, Kendler KS. Use of genetically informed methods to clarify the nature of the association between Cannabis use and risk for schizophrenia. JAMA Psychiatry. 2021;78:467-468. [DOI] [PubMed] [Google Scholar]
- 14.Callaghan RC, Sanches M, Murray RM, et al. Associations between Canada’s Cannabis legalization and emergency department presentations for transient Cannabis-induced psychosis and schizophrenia conditions: Ontario and Alberta, 2015–2019. Can J Psychiatry. 2022;67:616-625. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Gonçalves-Pinho, M, Bragança, M, Freitas, A. Psychotic disorders hospitalizations associated with cannabis abuse or dependence: a nationwide big data analysis. Int J Methods Psychiatr Res. 2020;29(1):e1813. doi: 10.1002/mpr.1813. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Hjorthoj C, Uddin MJ, Wimberley T, et al. No evidence of associations between genetic liability for schizophrenia and development of cannabis use disorder. Psychol Med. 2021;51:479-484. [DOI] [PubMed] [Google Scholar]
- 17.Hser Y-I, Mooney LJ, Huang D, et al. Reductions in cannabis use are associated with improvements in anxiety, depression, and sleep quality, but not quality of life. J Subst Abuse Treat. 2017;81:53-58. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Brezing CA, Choi CJ, Pavlicova M, et al. Abstinence and reduced frequency of use are associated with improvements in quality of life among treatment-seekers with cannabis use disorder. Am J Addict. 2018;27:101-107. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Goldenberg M, IsHak WW, Danovitch I. Quality of life and recreational cannabis use. Am J Addict. 2017;26:8-25. [DOI] [PubMed] [Google Scholar]
- 20.Weye N, Santomauro DF, Agerbo E, et al. Register-based metrics of years lived with disability associated with mental and substance use disorders: a register-based cohort study in Denmark. Lancet Psychiatry. 2021;8:310-319. [DOI] [PubMed] [Google Scholar]
- 21.Schoeler T, Petros N, Di Forti M, et al. Association between continued Cannabis use and risk of relapse in first-episode psychosis: a quasi-experimental investigation within an observational study. JAMA Psychiatry. 2016;73:1173-1179. [DOI] [PubMed] [Google Scholar]
- 22.Waterreus A, Di Prinzio P, Ambrosi T, Morgan VA. Discontinuing cannabis use: symptomatic and functional outcomes in people with an established psychotic disorder. Schizophr Res. 2023;254:118-124. [DOI] [PubMed] [Google Scholar]
- 23.Schoeler, T, Monk, A, Sami, MB, et al. Continued versus discontinued cannabis use in patients with psychosis: a systematic review and meta-analysis. Lancet Psychiatry. 2016;3(3):215-225. doi: 10.1016/S2215-0366(15)00363-6. [DOI] [PubMed] [Google Scholar]
- 24.Levi L, Bar-Haim M, Winter-van Rossum I, et al. Cannabis use and symptomatic relapse in first episode schizophrenia: trigger or consequence? Data from the OPTIMISE study. Schizophr Bull. 2023;49:903-913. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Farris MS, Shakeel MK, Addington J. Cannabis use in individuals at clinical high-risk for psychosis: a comprehensive review. Soc Psychiatry Psychiatr Epidemiol. 2020;55:527-537. [DOI] [PubMed] [Google Scholar]
- 26.Chester LA, Valmaggia LR, Kempton MJ, et al. Influence of cannabis use on incidence of psychosis in people at clinical high risk. Psychiatry Clin Neurosci. 2023;77:469-477. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Reid A, De Klerk NH, Ambrosini GL, Berry G, Musk AW. The risk of lung cancer with increasing time since ceasing exposure to asbestos and quitting smoking. Occup Environ Med. 2006;63:509-512. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Tindle HA, Stevenson Duncan M, Greevy RA, et al. Lifetime smoking history and risk of lung cancer: results from the Framingham heart study. J Natl Cancer Inst. 2018;110:1201-1207. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Ahmad Kiadaliri, A, Jarl, J, Gavriilidis, G, Gerdtham, UG. Alcohol drinking cessation and the risk of laryngeal and pharyngeal cancers: a systematic review and meta-analysis. PLoS One. 2013;8(3):e58158. doi: 10.1371/journal.pone.0058158. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Aletraris L, Graves BD, Ndung’u JJ. Assessing the impact of recreational Cannabis legalization on Cannabis use disorder and admissions to treatment in the United States. Curr Addict Rep. 2023;10:198-209. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Gali K, Winter SJ, Ahuja NJ, Frank E, Prochaska JJ. Changes in cannabis use, exposure, and health perceptions following legalization of adult recreational cannabis use in California: a prospective observational study. Subst Abuse Treat Prev Policy. 2021;16:16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Gayer-Anderson C, Jongsma HE, Di Forti M, et al. The European network of national schizophrenia networks studying gene–environment interactions (EU-GEI): incidence and first-episode case–control programme. Soc Psychiatry Psychiatr Epidemiol. 2020;55:645-657. [DOI] [PubMed] [Google Scholar]
- 33.McGuffin P, Farmer A, Harvey I. A polydiagnostic application of operational criteria in studies of psychotic illness. Development and reliability of the OPCRIT system. Arch Gen Psychiatry. 1991;48:764-770. [DOI] [PubMed] [Google Scholar]
- 34.Rodriguez V, Alameda L, Quattrone D, et al. Use of multiple polygenic risk scores for distinguishing schizophrenia-spectrum disorder and affective psychosis categories in a first-episode sample; the EU-GEI study. Psychol Med. 2023;53:3396-3405. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Mallett R, Leff J, Bhugra D, Pang D, Zhao JH. Social environment, ethnicity and schizophrenia. A case-control study. Soc Psychiatry Psychiatr Epidemiol. 2002;37:329-335. [DOI] [PubMed] [Google Scholar]
- 36.Cheng YC, Ryan KA, Qadwai SA, et al. Cocaine use and risk of ischemic stroke in young adults. Stroke. 2016;47:918. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Maeda K, Noguchi Y, Fukui T. The effects of cessation from cigarette smoking on the lipid and lipoprotein profiles: a meta-analysis. Prev Med (Baltim). 2003;37:283-290. [DOI] [PubMed] [Google Scholar]
- 38.Kauss AR, Antunes M, de La Bourdonnaye G, et al. Smoking and apolipoprotein levels: a meta-analysis of published data. Toxicol Rep. 2022;9:1150. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Schoeler T, Petros N, Di Forti M, et al. Effect of continued cannabis use on medication adherence in the first two years following onset of psychosis. Psychiatry Res. 2017;255:36-41. [DOI] [PubMed] [Google Scholar]
- 40.Schoeler T, Petros N, Di Forti M, et al. Effects of continuation, frequency, and type of cannabis use on relapse in the first 2 years after onset of psychosis: an observational study. Lancet Psychiatry. 2016;3:947-953. [DOI] [PubMed] [Google Scholar]
- 41.Myles H, Myles N, Large M. Cannabis use in first episode psychosis: meta-analysis of prevalence, and the time course of initiation and continued use. Aust N Z J Psychiatry. 2016;50:208-219. [DOI] [PubMed] [Google Scholar]
- 42.Cohen, J, Petitjean, H, Blasco, MB, Mizrahi, R. Cannabis-induced psychotic disorder with onset during withdrawal: a brief report of emerging evidence. Acta Neuropsychiatr. 2024:1-5. doi: 10.1017/NEU.2023.60. [DOI] [PubMed] [Google Scholar]
- 43.Budney AJ, Novy PL, Hughes JR. Marijuana withdrawal among adults seeking treatment for marijuana dependence. Addiction. 1999;94:1311-1322. [DOI] [PubMed] [Google Scholar]
- 44.Bonnet U, Specka M, Stratmann U, Ochwadt R, Scherbaum N. Abstinence phenomena of chronic cannabis-addicts prospectively monitored during controlled inpatient detoxification: cannabis withdrawal syndrome and its correlation with delta-9-tetrahydrocannabinol and -metabolites in serum. Drug Alcohol Depend. 2014;143:189-197. [DOI] [PubMed] [Google Scholar]
- 45.Bonnet U, Preuss UW. The cannabis withdrawal syndrome: current insights. Subst Abuse Rehabil. 2017;8:9 . doi: 10.2147/SAR.S109576 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Kesner AJ, Lovinger DM. Cannabis use, abuse, and withdrawal: cannabinergic mechanisms, clinical, and preclinical findings. J Neurochem. 2021;157:1674. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Lewallen S, Courtright P. Epidemiology in practice: case-control studies. Community Eye Health. 1998;11:57. [PMC free article] [PubMed] [Google Scholar]
- 48.Althubaiti A. Information bias in health research: definition, pitfalls, and adjustment methods. J Multidiscip Healthc. 2016;9: 211. doi: 10.2147/JMDH.S104807 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Macleod J, Hickman M, Smith GD. Reporting bias and self-reported drug use. Addiction. 2005;100:562-563. [DOI] [PubMed] [Google Scholar]
- 50.Bergamaschi MM, Karschner EL, Goodwin RS, et al. Impact of prolonged cannabinoid excretion in chronic daily Cannabis smokers’ blood on per se drugged driving laws. Clin Chem. 2013;59:519. doi: 10.1373/clinchem.2012.195503 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.Hadland SE, Levy S. Objective testing – urine and other drug tests. Child Adolesc Psychiatr Clin N Am. 2016;25:549. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Moeller KE, Kissack JC, Atayee RS, Lee KC. Clinical interpretation of urine drug tests: what clinicians need to know about urine drug screens. Mayo Clin Proc. 2017;92:774-796. [DOI] [PubMed] [Google Scholar]
- 53.Farrelly, KN, Wardell, JD, Marsden, E, et al. The impact of recreational Cannabis legalization on cannabis use and associated outcomes: a systematic review. Subst Abuse. 2023;17(11782218231172054). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54.Cooper K, Chatters R, Kaltenthaler E, Wong R. Psychological and psychosocial interventions for cannabis cessation in adults: a systematic review short report. Health Technol Assess. 2015;19:1-129. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55.Walsh H, McNeill A, Purssell E, Duaso M. A systematic review and Bayesian meta-analysis of interventions which target or assess co-use of tobacco and cannabis in single- or multi-substance interventions. Addiction. 2020;115:1800-1814. [DOI] [PubMed] [Google Scholar]
- 56.Werneck MA, Kortas GT, de Andrade AG, Castaldelli-Maia JM. A systematic review of the efficacy of cannabinoid agonist replacement therapy for Cannabis withdrawal symptoms. CNS Drugs. 2018;32:1113-1129. [DOI] [PubMed] [Google Scholar]
- 57.Freeman TP, Hindocha C, Baio G, et al. Cannabidiol for the treatment of cannabis use disorder: a phase 2a, double-blind, placebo-controlled, randomised, adaptive Bayesian trial. Lancet Psychiatry. 2020;7:865-874. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental material, sj-docx-1-cpa-10.1177_07067437241290187 for Cannabis Use Cessation and the Risk of Psychotic Disorders: A Case–Control Analysis from the First Episode Case–Control EU-GEI WP2 Study: L’arrêt de l’utilisation du cannabis et le risque de troubles psychotiques: Une analyse cas-témoins tirée de l’étude cas-témoins EU-GEI WP2 centrée sur les premiers épisodes psychotiques by Benjamin W. Bond, Bea Duric, Edoardo Spinazzola, Giulia Trotta, Edward Chesney, Zhikun Li, Diego Quattrone, Giada Tripoli, Charlotte Gayer-Anderson, Victoria Rodriguez, Laura Ferraro, Caterina La Cascia, Ilaria Tarricone, Andrei Szöke, Celso Arango, Julio Bobes, Miquel Bernardo, Cristina Marta Del-Ben, Paulo Rossi Menezes, Jean-Paul Selten, Bart P. F. Rutten, Lieuwe de Haan, Simona Stilo, Franck Schürhoff, Baptiste Pignon, Tom P. Freeman, Evangelos Vassos, Robin M. Murray, Isabelle Austin-Zimmerman and Marta Di Forti in The Canadian Journal of Psychiatry