• psychoses;
  • trauma;
  • cannabis;
  • genetics


  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Declaration of interest
  9. References


To test whether the association between childhood abuse, cannabis use and psychotic experiences (PEs) was moderated by the COMT (catechol-O-methyltransferase) gene.


Psychotic experiences (PEs), childhood abuse, cannabis use and COMT Val158Met genotypes were assessed in 533 individuals from the general population. Data were analysed hierarchically by means of multiple linear regression models.


Childhood abuse showed a significant main effect on both positive (β = 0.09; SE = 0.04; P = 0.047) and negative PEs (β = 0.11; SE = 0.05; P = 0.038). A significant three-way interaction effect was found among childhood abuse, cannabis use and the COMT gene on positive PEs (β = −0.30; SE = 0.11; P = 0.006). This result suggests that COMT genotypes and cannabis use only influenced PE scores among individuals exposed to childhood abuse. Furthermore, exposure to childhood abuse and cannabis use increased PE scores in Val carriers. However, in individuals exposed to childhood abuse but who did not use cannabis, PEs increased as a function of the Met allele copies of the COMT gene.


Cannabis use after exposure to childhood abuse may have opposite effects on the risk of PEs, depending on the COMT genotypes providing evidence for a qualitative interaction. Val carriers exposed to childhood abuse are vulnerable to the psychosis-inducing effects of cannabis.

Significant outcomes

  • The psychosis-inducing effect of cannabis use is related to exposure to childhood abuse and genetic variability in COMT gene.
  • Cannabis use increased the likelihood to report positive psychotic experiences in Val carriers only when they were exposed to childhood abuse.
  • Sensitization processes involving dopaminergic signalling may be underlying this gene–environment–environment interaction.


  • The sample size was modest.
  • Childhood abuse was measured retrospectively.
  • Age of onset, potency or duration of cannabis use were not assessed in the current sample.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Declaration of interest
  9. References

It is well established that attenuated psychotic symptoms occur in some individuals from the general population [1-3]. In the absence of illness or the need for treatment, these milder forms of psychotic symptoms are referred to as psychotic experiences (PEs) [4]. It has been suggested that clinical and subclinical expression of psychosis share genetic and/or environmental factors in their aetiology [4]. Therefore, the study of the risk factors for PEs would ultimately contribute to the understanding of the aetiology of psychotic disorders.

In this context, both cannabis use [5-7] and childhood adversity [8-10] have been associated with an increased risk of developing psychosis in clinical and non-clinical samples. However, not everyone exposed to childhood adversity develops psychotic symptoms later in life. Similarly, only a minority of cannabis users develop psychotic symptoms suggesting the implication of other factors in this association [11].

In this regard, several studies have shown that the joint exposure to these two environmental factors, cannabis use and childhood adversity, may increase the likelihood of developing psychotic symptoms to a greater extent than the risk expected for each factor working independently [12-15].

These results are neurobiologically plausible, as both stressful experiences and delta-9-tetrahydrocannabinol (THC), the main psycho-active constituent of cannabis, have been found to increase dopaminergic signalling in the mesolimbic system [16], which is hypothesized to result in an increased risk of delusions and hallucinations [17]. However, a recent study of a large sample drawn from the general population failed to replicate the interaction effect reported between cannabis and childhood trauma on the risk of developing psychotic symptoms [18]. Individual differences in neurobiological susceptibility to the impact of childhood abuse and cannabis use might help to explain this failure to replicate. Indeed, recent evidence suggest that differential sensitivity to environmental stress occasioned by the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene, probably in interaction with other factors, might be underlying psychosis risk [19-21].

The COMT gene encodes the enzyme catechol-O-methyltransferase, which plays an important role in the degradation of dopamine in the brain, and contains a functional polymorphism (COMT-Val158Met) that results in two common variants of the enzyme (Val and Met) [22]. The Val variant is associated with increased COMT activity, which results in a combination of reduced dopamine neurotransmission in the prefrontal cortex and increased levels of dopamine in mesolimbic areas [23]. Individuals carrying the Met/Met genotype have the lowest COMT activity and heterozygotes are considered to be of intermediate activity, as the two alleles are codominant [24].

In this regard, gene–environment interaction studies have shown that the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene moderates i) the association between cannabis use and psychosis [25-27], although some studies failed to replicate the original findings from Caspi and colleagues [For review see: [28] and [11]] and ii) the association between childhood trauma and schizotypal traits [29]. However, to our knowledge, no study to date has investigated whether the impact of the joint effect of exposure to childhood adversity and cannabis use on the subsequent development of PEs might be influenced by the COMT-Val158Met polymorphism.

Aims of the study

This study aimed to investigate whether the impact of the childhood adversity and cannabis effects on the development of psychotic experiences varies according to COMT-Val158Met polymorphism genotypes.

Material and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Declaration of interest
  9. References


The sample consisted of 533 individuals who were recruited from the campus of the Jaume I University in Castelló (Spain), as well as from university offices and community technical schools in the metropolitan area of Barcelona (Spain). Recruiting was conducted mainly through advertisements in the university offices and schools. All the participants were adults (mean age: 22.9 years; SD = 5.4) and 45.4% were males. At assessment, 77% of the participants were students. Further details of this sample can be found elsewhere [30, 31].

Exclusion criteria were the presence of any major medical illness affecting brain function, neurological conditions, current substance abuse (alcohol or any illicit drug), neurological conditions, history of head injury and personal history of psychiatric medical treatment. These areas were screened by means of a short interview designed ad hoc for this study. The design of the short interview was based on selected items from structured scales such as the Structural Clinical Interview for DSM-IV disorders [SCID-I; [32]] and Family Interview for Genetic Studies [FIGS; [33]]. Specific questions about psychiatric assistance, psychotropic medication, hospital admissions and suicide attempts were asked to the participants.

All participants were of Spanish (Caucasian) ancestry, thereby reducing the possibility of confounding genetic differences by population stratification.

Ethical approval was obtained from local research ethics committees. All participants provided written informed consent before inclusion in the study. All procedures were carried out according to the Helsinki Declaration.


The Community Assessment of Psychic Experiences [CAPE; [34]] was used to assess positive and negative PEs in the sample. This self-report questionnaire measures the lifetime prevalence of PEs on a frequency scale ranging from ‘never’ to ‘nearly always’. The positive dimension of the CAPE includes items mainly referring to subclinical expressions of positive psychotic symptoms (hallucinations and delusions) such as ‘do you ever feel as if things in magazines or TV were written especially for you?’. Similarly, the negative dimension of CAPE includes items assessing subclinical expressions of negative psychotic symptoms such as alogia, avolition, anhedonia and lack of interest in social relationships. An example of item is ‘do you ever feel that you experience few or no emotions at important events?’. The CAPE provides a total continuous score per dimension ranging from 20 to 80 in the positive dimension and from 14 to 56 in the negative dimension. To obtain the prevalence of PEs, CAPE scores were recoded as 0 (never, sometimes) and 1 (often, almost always). Self-report dimensions of psychotic experiences assessed by means of the CAPE have shown to be stable, reliable and valid [35]; furthermore, this instrument has been validated in Spanish population [36].

Childhood abuse was assessed by the shortened version of the Childhood Trauma Questionnaire [CTQ; [37, 38]]. This questionnaire consists of 28 items that measure five types of childhood trauma: emotional abuse, physical abuse, sexual abuse, emotional neglect and physical neglect. In the current study, the subscales that assess abuse were combined to yield a total score of childhood abuse. Neglectful events were discarded, as only abusive events were shown to be associated with PEs in a previous study conducted in this sample [1]. An example of an item on childhood abuse is ‘people in my family hit me so hard that it left me with bruises or marks’. The score for each item ranges from 1 to 5 (‘never true’ – ‘very often true’), depending on the extent to which individuals agree with the statement. The reliability and validity of the CTQ have been demonstrated [38]. Childhood abuse was recoded as 0 (never true) and 1 (rarely true, sometimes true, often true and very often true) to calculate the prevalence. Reliability and validity of the CTQ have both been demonstrated [38].

Cannabis use was assessed with one question regarding the frequency of consumption: ‘never’, ‘once’, ‘monthly’, ‘weekly’ or ‘daily’ (this variable was then dichotomized into two categories: ‘not exposed to cannabis’: never, once; and ‘exposed to cannabis’: monthly, weekly, daily).

All analyses were corrected by gender, age, schizotypal personality and anxiety levels as in a previous study conducted in this sample [1]. Schizotypal personality was measured with the Schizotypy Personality Questionnaire-Brief [SPQ-B; [39]]. Anxiety as a behavioural trait was assessed using the State-Trait Anxiety Inventory [STAI-T; [40]].

Laboratory methods

Genomic DNA was extracted from saliva samples using the Collection Kit BuccalAmp DNA extraction kit (Epicentre, ECOGEN, Barcelona, Spain). The SNP rs4680 (Val158Met) of the COMT gene was genotyped using Applied Byosystems (AB) TaqMan technology. The AB assay-on-demand service was used to order the probes. Genotype determinations were performed blind to the clinical condition. Randomized individuals were retested for their genotypes to confirm the pattern reproducibility.

Statistical analysis

Multiple linear regressions were conducted using stata 10.0 for Windows. Separate models were tested for positive and negative PEs (continuous variables) as dependent variables. The independent variables for main and interaction effects were childhood abuse, cannabis use and the Val158Met polymorphism of the COMT gene (continuous childhood abuse, dichotomous cannabis use and three categories in the COMT gene: Val/Val, Val/Met and Met/Met). Data were analysed hierarchically. In the first step, the main effects of childhood abuse, cannabis use and the Val158Met polymorphism of the COMT gene on positive PEs were tested in the same model on positive and negative PEs separately. Two-way interaction terms (childhood abuse*cannabis use; childhood abuse*COMT gene and COMT gene*cannabis use) were added in a second step. In the third step, a three-way interaction term (childhood abuse*cannabis use*COMT gene) was entered.

Age, gender, schizotypy and trait anxiety were included as covariates in all analyses.

Additional analyses were carried out using logistic regression analysis to investigate whether childhood abuse increased the risk of cannabis use and whether the COMT-Val158Met polymorphism was associated with cannabis use.

The log-likelihood ratio test was used to assess the difference between nested models. In our case, if a significant interaction effect was detected, the log-likelihood ratio test was used to examine whether the addition of the interaction term (either two-way or three-way) significantly improved the model fit compared to the main effects model.

A power analysis was performed using the QUANTO V.1.2 program [41]. The sample of 419 individuals had 0.85 power to detect a gene–environment interaction effect, accounting for at least 2% of the variance of the studied outcome at an α level of 0.05. If a gene–environment interaction was detected, the effect size was calculated using eta squared (η2). This parameter can be used to estimate the proportion of variance in the outcome that is accounted for by the predictor.

In addition, P < 0.05 was considered to indicate statistical significance, but we used a more stringent P-value, based on the Bonferroni correction, for the interactions tested. We conducted three tests (main effects, two-way interaction effects and three-way interaction effects) for two outcomes (positive and negative PEs). Therefore, for a Bonferroni correction on the P-values for interactions, we used P = 0.05/6 = 0.0083 as a threshold for significance.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Declaration of interest
  9. References

In the current sample, 40.7% of the individuals reported that often or almost always experienced at least one positive PE. For the negative dimension, 47.6% of the sample often or almost always experienced at least one negative PE. Of note, prevalences for some items addressing more severe psychotic experiences were lower. For example, 4.8% of the sample often or almost always felt that they were ‘under the control of some force or power other than themselves’; similarly, 1.8% of the sample often or almost always ‘heard voices talking to each other’ [CAPE; [34]].

With regard to childhood abuse, 25.5% of the individuals were exposed to at least one abusive event during childhood. Nevertheless, regarding to specific and severe forms of childhood abuse and neglect, only the 9.2% and 10.3% of the sample reported being exposed to sexual abuse and physical neglect respectively.

For cannabis use, 29.1% of the sample used cannabis monthly, weekly or daily.

All the variables included in the model were available for 419 individuals from the total sample. In this final sample, the genotype frequencies for the Val158Met polymorphism of the COMT gene were as follows: Val/Val: 30.3% (n = 127); Val/Met: 48.0% (n = 201); and Met/Met: 21.7% (n = 91). These frequencies did not differ from others described in Caucasian individuals [25]. The Hardy–Weinberg equilibrium was verified for the present population (χ2 = 0.47; df = 2; P = 0.49).

A main effect of childhood abuse was found in both positive (β = 0.09; SE = 0.04; 95% CI .01–0.17; P = 0.047) and negative PEs (β = 0.11; SE = 0.05; 95% CI .01–0.21; P = 0.038). Cannabis use showed a main effect on negative PEs (β = 0.88; SE = 0.44; 95% CI .01–1.75; P = 0.047) but not on positive PEs. However, these main effects did not remain significant after correcting for multiple testing. No main effect was found for the Val158Met polymorphism of the COMT gene on either dimension of PEs.

None of the two-way interactions tested (childhood abuse*cannabis use; childhood abuse*COMT gene or cannabis use*COMT gene) were significant.

However, a significant three-way interaction among childhood abuse, cannabis use and the COMT gene was found in positive PEs [β = −0.30; SE = 0.11; 95% CI (−0.51)–(−0.09); P = 0.006] (Table 1; Fig. 1). This result was significant even after correction for multiple testing. It accounted for 2% of the variance of positive PEs (η2 = 0.2).


Figure 1. Graphic representation of the interaction effect among childhood abuse, cannabis use and the Val158Met polymorphism of the COMT gene on positive psychotic experiences (PEs) corrected for age, gender, schizotypal personality and trait anxiety. Cannabis use and the Val158Met polymorphism of the COMT gene have a negligible effect on positive PEs when individuals are not exposed to childhood abuse or exposed to low rates of such events (red and blue lines). The use of cannabis in individuals exposed to childhood abuse has opposite effects depending on their genotype (purple and green lines). Positive PEs score increases as a function of the number of copies of the Met allele of the COMT gene in those individuals exposed to childhood abuse who do not use cannabis (green line). Thus, Met carriers seem to be especially vulnerable to the effect of childhood abuse on their later development of PEs and cannabis use may have a protective effect. However, in individuals exposed to childhood abuse who use cannabis, a positive PEs score increases as a function of the Val allele copies of the COMT gene (purple line).

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Table 1. 1) Main effects, 2) two-way interaction effects and 3) three-way interaction effects of childhood abuse, cannabis use and the COMT Val158Met polymorphism are presented for positive psychotic experiences (PEs) and negative PEs. All the models were corrected by age, gender, schizotypal personality and trait anxiety. Adjusted R2 values (Adj-R2) are presented for each step for positive and negative PEs. Significant results are indicated in bold
 Positive PEsNegative PEs
  1. Positive PEs: i) Adj-R2 = 0.29, ii) Adj-R2 = 0.29 and iii) Adj-R2 = 0.30.

  2. Negative PEs: i) Adj-R2 = 0.33, ii) Adj-R2 = 0.33 and iii) Adj-R2 = 0.33.

  3. β, regression coefficient; SE, standard error.

  4. a

    P < 0.05.

1) Main Effects
Childhood abuse 0.088 0.044 0.047 a 0.107 0.051 0.038 a
Cannabis use0.3780.3840.325 0.883 0.443 0.047 a
COMT 0.1480.2410.541−0.1570.2780.573
2) Two-way interaction effects
Childhood abuseaCannabis use0.0580.0890.516−0.0630.1030.539
Childhood abuseaCOMT0.0980.0530.0650.0680.0610.269
Cannabis useaCOMT−0.4520.5190.384−0.2310.6020.702
3) Three-way interaction effects
Childhood abuseaCannabis useaCOMT0.303 0.110 0.006 a −0.1560.1290.228

In individuals exposed to childhood abuse who used cannabis, positive PEs score increased as a function of the Val allele dose of the COMT gene. However, among individuals exposed to childhood abuse who did not use cannabis, the positive PEs score increased as a function of the Met allele copies of the COMT gene. When individuals were exposed to low rates of childhood abuse, cannabis use and the Val158Met polymorphism of the COMT gene had a negligible effect on the presence of positive PEs scores.

The log-likelihood ratio test indicated that addition of the three-way interaction term in the third step resulted in a statistically significant improvement in model fit compared to the main effects (χ2 = 12.7; df = 2; P = 0.013).

Additional logistic regression analyses revealed that neither childhood abuse (OR = 1.01; 95% CI .96–1.07; P = 0.671) nor the COMT-Val158Met polymorphism (OR = 1.19; 95% CI .71–1.98; P = 0.513) was associated with cannabis use.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Declaration of interest
  9. References

Rates for PEs and childhood trauma in the current sample were consistent with previous reports in European and North American samples [4, 37, 42] [further details can be found elsewhere [1, 30]]. Also, the rate of individuals using cannabis (monthly, weekly or daily) was 29.1%, which is similar to the rates reported in other European countries [43].

As previously shown in this sample, childhood abuse was associated with both positive and negative PEs [1]. These findings support the role of childhood abuse in the development of PEs in the general population, as reported in previous research [8-10]. Furthermore, the fact that cannabis use did not show a main effect on positive PEs in the current study may be related to the inclusion of childhood abuse in the model [in univariate analyses cannabis was significantly associated with positive PEs (β = 1.20; SE = 0.44; P = 0.007)]. As previous studies have suggested, explorations of the association between cannabis and psychosis need to consider the effects of childhood trauma as an important potential effect modifier [12, 14]. Nevertheless, both childhood abuse and cannabis use were associated independently with negative PEs. The association between cannabis and negative PEs has been reported previously [7, 44].

The term gene–environment correlation refers to the fact that exposure to an environmental risk factor is not random but is influenced by the individual's genotype. Similarly, environment–environment correlation occurs when the exposure to a given environmental factor is influenced by the previous exposure to another environmental factor [45, 46]. With regard to these mechanisms, additional analyses enabled us to rule out the possibility that childhood abuse increased the likelihood of using cannabis (environment–environment correlation). A gene–environment correlation can also be discarded, as COMT genotypes were not associated with cannabis use.

In accordance with recent evidence, we did not find an interaction between the effect of childhood abuse and cannabis use on PEs [18]. However, we believe that this may be related to the inclusion of COMT genotypes in the analyses, as a significant gene–environment–environment interaction effect was detected. This finding is consistent with previous studies indicating that environmental exposures, in interaction with genetic factors, may induce psychological or physiological alterations that can be traced to a final common pathway of altered dopamine neurotransmission. This pathway facilitates the onset and persistence of psychotic symptoms [47].

Therefore, our main findings suggest that the psychosis-inducing effects of childhood abuse and cannabis use are moderated by the Val158Met polymorphism of the COMT gene, which supports a gene–environment–environment interaction effect.

This three-way interaction effect indicated that positive PEs showed almost no variation for individuals exposed to low rates of childhood abuse, regardless of their cannabis use frequency or their genotype for the Val158Met polymorphism of the COMT gene. However, among individuals exposed to childhood abuse, cannabis use only increased the likelihood of reporting positive PEs if individuals were carriers of the Val allele of the COMT gene. Furthermore, Met carriers exposed to childhood abuse were more likely to report positive PEs without cannabis use. Thus, our findings suggest that use of cannabis after exposure to childhood abuse may have opposite effects on the development of positive PEs depending on the COMT genotypes.

Although the effect size of this finding is modest (2% of the variance of positive PEs) and requires replication, these results may partially account for previous discrepancies found when examining the possible moderator role of COMT genotypes in the association between cannabis and clinical and non-clinical expression of psychosis. For example, as abovementioned, Kuepper [18] and colleagues failed to replicate the interaction shown between childhood trauma and cannabis use [12-15]. This discrepancy could be owing to sampling variation or different time of follow-up [11] but it might be also possible that COMT genotypes play a role in this association considering our results. With regard to the interaction between cannabis and COMT-Val158Met polymorphism, several studies examining different aspects of the psychosis phenotype (psychotic symptoms, psychotic disorders, age of onset or duration of untreated psychosis) have yielded inconsistent results [11, 25-27]. Also, a failure to find such interaction effect has been reported [48]. As our findings suggest that psychosis-inducing effects of cannabis have opposite effects depending on the COMT genotypes but only among those exposed to childhood abuse; future studies testing this gene–environment interaction effect may consider including childhood trauma in this association if the measure is available.

The fact that exposure to both childhood abuse and cannabis was associated with higher scores of positive PEs in Val carriers may be explained by sensitization involving dopaminergic signalling. Evidence from animal studies suggests a possible interaction (exposure to one factor increases sensibility to the effects of the other factor) between stress and THC. Rats living under normal conditions (i.e. access to water and food), that were exposed to THC, showed only minor behavioural changes and no change in dopaminergic transmission [49]. In contrast, under stressful conditions (i.e. isolation and food deprivation), THC administration had marked behavioural consequences and was associated with a significant increase in dopamine uptake [49]. Similarly, it has been shown in humans that the psychosis-inducing effect of cannabis may be stronger in subjects exposed to early stress [15]. Our results indicate that variability in the COMT gene confers different neurobiological vulnerability to cannabis use in the risk of developing PEs. In accordance with previous studies, Val carriers are more vulnerable to the psychosis-inducing effects of cannabis than Met/Met individuals [25-27], but only when exposed to childhood abuse. Consistent with previous studies indicating that Met carriers were more vulnerable to stress than carriers of the Val/Val genotype [21], Met carriers were vulnerable to the psychosis-inducing effects of childhood abuse, but only when they did not use cannabis. Previous evidence indicates that the risk of psychosis did not increase in Met carriers of the COMT gene who used cannabis [25]. However, in the current study, individuals exposed to childhood abuse who are homozygous for the Met allele appeared to be able to use cannabis without any increase in risk of developing PEs. It might be possible that cannabis may exert some benefit effect in certain individuals. Indeed, it has been suggested that cannabis use alleviate the stress associated with childhood traumatic events and the experience of PEs [50]. However, such conclusions cannot be drawn from our results, thus this result needs replication and must be interpreted with caution.

In this regard, although the findings of gene–environment interaction studies have been exciting, there is increasing concern about the reliability and contribution of such results to the understanding of complex traits such as PEs [51]. Dismissal of gene–environment interaction studies arises mainly as a result of the failure to replicate [52, 53]. As there are powerful reasons to expect that gene–environment interaction effects are involved in the aetiology of complex traits and psychiatric disorders [54], the debate is more focused on the reliability and clinical relevance of such findings [51]. To prevent false positive results or statistically significant results that may not represent true insights, the current study was developed with an a priori hypothesis that guided the choice of the gene, the polymorphism and the environmental risk factors that were explored. Moreover, as abovementioned, power analyses are specified and correction for multiple testing was applied. Furthermore, the use of cannabis after exposure to childhood abuse had opposite effects on positive PEs depending on the COMT genotypes. This pattern of results coincides with the epidemiological definition of qualitative interaction. A qualitative interaction refers to an inverse or crossover effect from a given variable (e.g. cannabis exposure) according to differences in another variable (e.g. COMT genotypes) [51, 55]. Although these type of interactions have only rarely been observed in medicine, the implications of qualitative or crossover interactions are believed to have a clear biological meaning and be more helpful than the ones derived from quantitative or non-crossover interactions [51].

The results of this study should be interpreted in the context of its limitations. First, we used a relatively small sample size to detect a three-way interaction, replication in larger samples with higher statistical power are needed to confirm these findings. Second, the characteristics of the sample – young age, educational level, no history of psychiatric treatment – need to be considered when generalizing the present findings. Also, as substance abuse constituted an exclusion criterion, heavy cannabis users, who experience problems in their daily life because of their cannabis consumption, were not included in the study. Therefore, although the sample is drawn from the general population, the representativeness of the sample is limited by these characteristics. Third, no main genetic effects for COMT-Val156Met polymorphism on PEs were found in the current study. As the power to detect interactions is typically lower than the power to detect main effects [56], well-powered studies should be able to detect statistically significant main genetic effects unless a qualitative interaction effect is detected as is the case for this study. In qualitative interactions, main effects are cancelled out; therefore, the lack of significant main genetic effects in this study should not compromise the reliability of the reported results. Fourth, the cross-sectional nature of the design does not allow causal inference. Fifth, childhood abuse was measured retrospectively, which may constitute an inherent source of bias. Furthermore, this instrument has not been yet validated in Spanish population. That said, the Childhood Trauma Questionnaire has been validated in several European countries including Dutch and Swedish populations [57, 58] and is considered a reliable measure of childhood adversity [38]. Finally, frequency of cannabis use was dichotomously defined in this study, and other parameters that have been related to the expression of psychotic symptoms such as onset, duration or potency of cannabis consumed [7, 34, 59, 60], were not specified. Furthermore, biological samples for confirming drug use by means of laboratory techniques were not available in this study.

Of note, we would like to stress the fact that consistent evidence indicates that cannabis may induce psychosis and/or worse psychotic symptoms [5-7]. Therefore, public health message about the potential risk of cannabis use should not be modified by results indicating that its use may not be harmful for a subgroup of the population.

To conclude, our findings suggest that the psychosis-inducing effects of childhood abuse and cannabis use are moderated by the Val158Met polymorphism of the COMT gene, which supports a gene–environment–environment interaction effect. Cannabis use after exposure to childhood abuse may have opposite effects on the risk of PEs development, depending on the COMT genotypes.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Declaration of interest
  9. References

We thank all participants of the study. This work was supported by research projects funded by the Ministry of Science and Innovation (grant numbers SAF2008-05674-C03-00 and 03; PNSD2008-I090; PNSD2009-I019), the Institute of Health Carlos III, CIBER of Mental Health (CIBERSAM), the Comissionat per a Universitats i Recerca, DIUE, Generalitat de Catalunya (grant number 2009SGR827) and Fundació Caixa Castelló-Bancaixa (grant numbers P1·1B2010-40 and P1·1B2011-47). Silvia Alemany would like to thank the Institute of Health Carlos III for her PhD grant (FI00272).


  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Declaration of interest
  9. References
  • 1
    Alemany S, Arias B, Aguilera M et al. Childhood abuse, the BDNF-Val66Met polymorphism and adult psychotic-like experiences. Br J Psychiatry 2011;199:3842.
  • 2
    Kelleher I, Connor D, Clarke MC, Devlin N, Harley M, Cannon M. Prevalence of psychotic symptoms in childhood and adolescence: a systematic review and meta-analysis of population-based studies. Psychol Med 2012;9:17.
  • 3
    Van Os J, Linscott RJ, Myin-Germeys I, Delespaul P, Krabbendam L. A systematic review and meta-analysis of the psychosis continuum: evidence for a psychosis proneness-persistence-impairment model of psychotic disorder. Psychol Med 2009;39:17995.
  • 4
    Johns LC, Van Os J. The continuity of psychotic experiences in the general population. Clin Psychol Rev 2001;21:112541.
  • 5
    Henquet C, Murray R, Linszen D, Van Os J. The environment and schizophrenia: the role of cannabis use. Schizophr Bull 2005;31:60812.
  • 6
    Manrique-Garcia E, Zammit S, Dalman C, Hemmingsson T, Andreasson S, Allebeck P. Cannabis, schizophrenia and other non-affective psychoses: 35 years of follow-up of a population-based cohort. Psychol Med 2012;42:13218.
  • 7
    Skinner R, Conlon L, Gibbons D, Mcdonald C. Cannabis use and non-clinical dimensions of psychosis in university students presenting to primary care. Acta Psychiatr Scand 2011;123:217.
  • 8
    Janssen I, Krabbendam L, Bak M et al. Childhood abuse as a risk factor for psychotic experiences. Acta Psychiatr Scand 2004;109:3845.
  • 9
    Read J, Van Os J, Morrison AP, Ross CA. Childhood trauma, psychosis and schizophrenia: a literature review with theoretical and clinical implications. Acta Psychiatr Scand 2005;112:33050.
  • 10
    Varese F, Smeets F, Drukker M et al. Childhood adversities increase the risk of psychosis: a meta-analysis of patient-control, prospective- and cross-sectional cohort studies. Schizophr Bull 2012;38:6617.
  • 11
    Pelayo-Teran JM, Suarez-Pinilla P, Chadi N, Crespo-Facorro B. Gene-environment interactions underlying the effect of cannabis in first episode psychosis. Curr Pharm Des 2012;18:502435.
  • 12
    Harley M, Kelleher I, Clarke M et al. Cannabis use and childhood trauma interact additively to increase the risk of psychotic symptoms in adolescence. Psychol Med 2010;40:162734.
  • 13
    Houston JE, Murphy J, Adamson G, Stringer M, Shevlin M. Childhood sexual abuse, early cannabis use, and psychosis: testing an interaction model based on the National Comorbidity Survey. Schizophr Bull 2008;34:5805.
  • 14
    Houston JE, Murphy J, Shevlin M, Adamson G. Cannabis use and psychosis: re-visiting the role of childhood trauma. Psychol Med 2011;18:110.
  • 15
    Konings M, Stefanis N, Kuepper R et al. Replication in two independent population-based samples that childhood maltreatment and cannabis use synergistically impact on psychosis risk. Psychol Med 2012;42:14959.
  • 16
    Gessa GL, Melis M, Muntoni AL, Diana M. Cannabinoids activate mesolimbic dopamine neurons by an action on cannabinoid CB1 receptors. Eur J Pharmacol 1998;341:3944.
  • 17
    Kapur S. Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry 2003;160:1323.
  • 18
    Kuepper R, Henquet C, Lieb R, Wittchen HU, Van Os J. Non-replication of interaction between cannabis use and trauma in predicting psychosis. Schizophr Res 2011;131:2623.
  • 19
    Collip D, Van Winkel R, Peerbooms O et al. COMT Val158Met-stress interaction in psychosis: role of background psychosis risk. CNS Neurosci Ther 2011;17:61219.
  • 20
    Peerbooms O, Rutten BP, Collip D et al. Evidence that interactive effects of COMT and MTHFR moderate psychotic response to environmental stress. Acta Psychiatr Scand 2012;125:24756.
  • 21
    Van Winkel R, Henquet C, Rosa A et al. Evidence that the COMT(Val158Met) polymorphism moderates sensitivity to stress in psychosis: an experience-sampling study. Am J Med Genet B Neuropsychiatr Genet 2008;147B:1017.
  • 22
    Chen J, Lipska BK, Halim N et al. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet 2004;75:80721.
  • 23
    Meyer-Lindenberg A, Kohn PD, Kolachana B et al. Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype. Nat Neurosci 2005;8:5946.
  • 24
    Mannisto PT, Kaakkola S. Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Pharmacol Rev 1999;51:593628.
  • 25
    Caspi A, Moffitt TE, Cannon M et al. Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biol Psychiatry 2005;57:111727.
  • 26
    Estrada G, Fatjo-Vilas M, Munoz MJ et al. Cannabis use and age at onset of psychosis: further evidence of interaction with COMT Val158Met polymorphism. Acta Psychiatr Scand 2011;123:48592.
  • 27
    Henquet C, Rosa A, Delespaul P et al. COMT ValMet moderation of cannabis-induced psychosis: a momentary assessment study of ‘switching on’ hallucinations in the flow of daily life. Acta Psychiatr Scand 2009;119:15660.
  • 28
    Decoster J, Van Os J, Myin-Germeys I, De Hert M, Van Winkel R. Genetic variation underlying psychosis-inducing effects of cannabis: critical review and future directions. Curr Pharm Des 2012;18:501523.
  • 29
    Savitz J, Van Der Merwe L, Newman TK, Stein DJ, Ramesar R. Catechol-o-methyltransferase genotype and childhood trauma may interact to impact schizotypal personality traits. Behav Genet 2010;40:41523.
  • 30
    Aguilera M, Arias B, Wichers M et al. Early adversity and 5-HTT/BDNF genes: new evidence of gene-environment interactions on depressive symptoms in a general population. Psychol Med 2009;39:142532.
  • 31
    Arias B, Aguilera M, Moya J et al. The role of genetic variability in the SLC6A4, BDNF and GABRA6 genes in anxiety-related traits. Acta Psychiatr Scand 2012;125:194202.
  • 32
    First MB, Spitzer RL, Williams JBW, Gibbon M. Structured clinical interview of DSM-IV disorders-Research Version (SCID-RV). Washington, DC: American Psychiatric Association, 1997.
  • 33
    Maxwell M. Family interview for genetic studies (FIGS): manual for FIGS. Bethesda, MD: Clinical Neurogenetics Branch, Intramural Research Program, National Institutde of Mental Health, 1992.
  • 34
    Stefanis NC, Hanssen M, Smirnis NK et al. Evidence that three dimensions of psychosis have a distribution in the general population. Psychol Med 2002;32:34758.
  • 35
    Konings M, Bak M, Hanssen M, Van Os J, Krabbendam L. Validity and reliability of the CAPE: a self-report instrument for the measurement of psychotic experiences in the general population. Acta Psychiatr Scand 2006;114:5561.
  • 36
    Ros-Morente A, Vilagra-Ruiz R, Rodriguez-Hansen G, Wigman JH, Barrantes-Vidal N. Process of adaptation to Spanish of the Community Assessment of Psychic Experiences (CAPE). Actas Esp Psiquiatr 2011;39:95105.
  • 37
    Bernstein DPFL. Childhood Trauma Questionnaire: a Retrospective Self-report. San Antonio: The Psychological Corporation, 1998.
  • 38
    Bernstein DP, Stein JA, Newcomb MD et al. Development and validation of a brief screening version of the Childhood Trauma Questionnaire. Child Abuse Negl 2003;27:16990.
  • 39
    Raine A, Benishay D. The SPQ-B: a brief screening instrument for schyzotypal personality disorder. J Personal Disord 1995;9:34655.
  • 40
    Spielberg CG, Gorsuch RL, Lushene RE. Manual for the State-Trait Anxiety Inventory. Palo Alto, CA: Consulting Psychologists Press, 1970.
  • 41
    Gauderman W, Morrison J. QUANTO 1.1: a computer program for power and sample size calculations for genetic-epidemiology studies. http:/ 2006.
  • 42
    Nuevo R, Chatterji S, Verdes E, Naidoo N, Arango C, Ayuso-Mateos JL. The continuum of psychotic symptoms in the general population: a cross-national study. Schizophr Bull 2012;38:47585.
  • 43
    Kokkevi A, Nic Gabhainn S, Spyropoulou M. Early initiation of cannabis use: a cross-national European perspective. J Adolesc Health 2006;39:71219.
  • 44
    Stefanis NC, Delespaul P, Henquet C, Bakoula C, Stefanis CN, Van Os J. Early adolescent cannabis exposure and positive and negative dimensions of psychosis. Addiction 2004;99:133341.
  • 45
    Compton MT, Furman AC, Kaslow NJ. Preliminary evidence of an association between childhood abuse and cannabis dependence among African American first-episode schizophrenia-spectrum disorder patients. Drug Alcohol Depend 2004;76:31116.
  • 46
    Henquet C, Di Forti M, Morrison P, Kuepper R, Murray RM. Gene-environment interplay between cannabis and psychosis. Schizophr Bull 2008;34:111121.
  • 47
    Collip D, Myin-Germeys I, Van Os J. Does the concept of “sensitization” provide a plausible mechanism for the putative link between the environment and schizophrenia? Schizophr Bull 2008;34:2205.
  • 48
    Zammit S, Owen MJ, Evans J, Heron J, Lewis G. Cannabis, COMT and psychotic experiences. Br J Psychiatry 2011;199:3805.
  • 49
    Maclean KI, Littleton JM. Environmental stress as a factor in the response of rat brain catecholamine metabolism to delta8-tetrahydrocannabinol. Eur J Pharmacol 1977;41:17182.
  • 50
    Di Forti M. Why do psychotic patients take cannabis? Psychol Med 2008;38:10712.
  • 51
    Zammit S, Wiles N, Lewis G. The study of gene-environment interactions in psychiatry: limited gains at a substantial cost? Psychol Med 2010;40:71116.
  • 52
    Munafo MR, Flint J. Replication and heterogeneity in gene x environment interaction studies. Int J Neuropsychopharmacol 2009;12:7279.
  • 53
    Duncan LE, Keller MC. A critical review of the first 10 years of candidate gene-by-environment interaction research in psychiatry. Am J Psychiatry 2011;168:10419.
  • 54
    Rutter M, Moffitt TE, Caspi A. Gene-environment interplay and psychopathology: multiple varieties but real effects. J Child Psychol Psychiatry 2006;47:22661.
  • 55
    Gail M, Simon R. Testing for qualitative interactions between treatment effects and patient subsets. Biometrics 1985;41:36172.
  • 56
    McClelland GH, Judd CM. Statistical difficulties of detecting interactions and moderator effects. Psychol Bull 1993;114:37690.
  • 57
    Gerdner A, Allgulander C. Psychometric properties of the Swedish version of the Childhood Trauma Questionnaire-Short Form (CTQ-SF). Nord J Psychiatry 2009;63:16070.
  • 58
    Thombs BD, Bernstein DP, Lobbestael J, Arntz A. A validation study of the Dutch Childhood Trauma Questionnaire-Short Form: factor structure, reliability, and known-groups validity. Child Abuse Negl 2009;33:51823.
  • 59
    Di Forti M, Morgan C, Dazzan P et al. High-potency cannabis and the risk of psychosis. Br J Psychiatry 2009;195:48891.
  • 60
    Dragt S, Nieman DH, Schultze-Lutter F et al. Cannabis use and age at onset of symptoms in subjects at clinical high risk for psychosis. Acta Psychiatr Scand 2012;125:4553.