Date Published: February 14, 2018
Publisher: Public Library of Science
Author(s): Thomas Stephanus Johannes Vaessen, Lea de Jong, Annika Theresia Schäfer, Thomas Damen, Aniek Uittenboogaard, Pauline Krolinski, Chinyere Vicky Nwosu, Florentina Maria Egidius Pinckaers, Iris Leah Marije Rotee, Antonius Petrus Wilhelmus Smeets, Ayşegül Ermiş, James L. Kennedy, Dorien H. Nieman, Arun Tiwari, Jim van Os, Marjan Drukker, Weihua YUE.
Neither environmental nor genetic factors are sufficient to predict the transdiagnostic expression of psychosis. Therefore, analysis of gene-environment interactions may be productive.
A meta-analysis was performed using papers investigating the interaction between cannabis use and catechol-O-methyl transferase (COMT) polymorphism Val158Met (COMTVal158Met).
PubMed, Embase, PsychInfo.
All observational studies assessing the interaction between COMTVal158Met and cannabis with any psychosis or psychotic symptoms measure as an outcome.
A meta-analysis was performed using the Meta-analysis of Observational Studies in Epidemiology guidelines and forest plots were generated. Thirteen articles met the selection criteria: 7 clinical studies using a case-only design, 3 clinical studies with a dichotomous outcome, and 3 studies analysing a continuous outcome of psychotic symptoms below the threshold of psychotic disorder. The three study types were analysed separately. Validity of the included studies was assessed using “A Cochrane Risk of Bias Assessment Tool: for Non-Randomized Studies of Interventions”.
For case-only studies, a significant interaction was found between cannabis use and COMTVal158Met, with an OR of 1.45 (95% Confidence Interval = 1.05–2.00; Met/Met as the risk genotype). However, there was no evidence for interaction in either the studies including dichotomous outcomes (B = -0.51, 95% Confidence Interval -1.72, 0.70) or the studies including continuous outcomes (B = -0.04 95% Confidence Interval -0.16–0.08).
A substantial part of the included studies used the case-only design, which has lower validity and tends to overestimate true effects.
The interaction term between cannabis use and COMTVal158Met was only statistically significant in the case-only studies, but not in studies using other clinical or non-clinical psychosis outcomes. Future additional high quality studies might change current perspectives, yet currently evidence for the interaction remains unconvincing.
Interaction between genes and environment may increase the risk to develop outcomes in the psychosis spectrum [1, 2]. Although the causes of the transdiagnostic expression of psychosis remain unknown , several risk factors have been identified. First, the transdiagnostic expression of psychosis, however defined, clusters in families [4, 5]. Second, environmental factors such as cannabis consumption also increase the risk of developing psychotic disorder or symptoms [6–8]. Genes and environment may reinforce each other’s effects; thus, it has been suggested that genetic variation may render an individual more sensitive to the psychotogenic effects of cannabis . One example of gene-cannabis interaction is the hypothesized moderating effect of the catechol-O-methyl transferase (COMT) polymorphism Val158Met (COMTVal158Met) in the association between cannabis use and the emergence of the psychosis phenotype [10, 11]. The prevalence of cannabis consumption among patients with a diagnosis of psychosis is significantly higher than in the general population (42.1% lifetime use vs 22.5% lifetime misuse ). However, causal inference is difficult. For example, some patients use cannabis as a form of self-medication or to reduce the side effects of anti-psychotic medication . On the other hand, causality may be plausible. The plant produces several compounds classified as cannabinoids, Δ9-tetrahydrocannabinol (THC) being the major psychoactive component. Animal studies have reported cannabis-associated alterations in dopaminergic neurotransmission both in the prefrontal cortex [14, 15] and in the mesolimbic pathway (reward system) .
A total of 41 articles were selected based on the inclusion of the three search terms (Table 2, Fig 1). After searching PubMed, searching Psychinfo and Embase didn’t provide any extra studies. After the initial search, backward citation tracking was utilised in order to ensure that all relevant studies were identified. However, no further research articles were found. After applying the aforementioned exclusion criteria, 13 articles were included in the final selection (7 case-only studies [22, 28, 31, 36–39], 2 studies analysing dichotomous outcomes [10, 40] and 3 analysing continuous outcomes [35, 41, 42]). A third study analysing dichotomous outcomes  was excluded from the meta-analysis because the data needed for extraction were not provided and the authors did not respond to requests for additional data. Authors of all articles checked for Hardy Weinberg equilibrium in order to ensure that the genotyping was done correctly.
A significant cannabis X COMTVal158Met interaction was found in the case-only studies (OR = 1.43, 95% CI = 1.01; 2.04; Met/Met as the risk genotype), but not in the dichotomous outcomes (B = 0.51; CI -0.70; 1.72) or the continuous outcomes (B = -0.04; CI -0.16; 0.08).
In conclusion, the present meta-analysis did not show evidence for an interaction between cannabis and COMTVal158Met when studying psychotic symptoms or psychotic disorder. For future studies, multiple other factors should be taken into account. The analysis of gene-environment interplay may provide useful information about the development and treatment of psychotic disorders.