An Experimental Study of Catechol-O-Methyltransferase Val158Met Moderation of Δ-9-Tetrahydrocannabinol-Induced Effects on Psychosis and Cognition

Abstract

Observational studies have suggested that psychometric psychosis liability and a functional polymorphism in the catechol-Omethyltransferase (COMT Val 158 Met) gene moderate the psychosis-inducing effect of cannabis. To replicate and extend this finding, a double-blind, placebo-controlled cross-over design was used in which patients with a psychotic disorder (n ¼ 30), relatives of patients with a psychotic disorder (n ¼ 12), and healthy controls (n ¼ 32) were exposed to D-9-tetrahydrocannabinol (D-9-THC, the principal component of cannabis) or placebo, followed by cognitive assessment and assessment of current psychotic experiences. Previous expression of psychometric psychosis liability was also assessed. Models of current psychotic experiences and cognition were examined with multilevel random regression analyses to assess (i) main effects of genotype and condition, (ii) interactions between condition and genotype, and (iii) three-way interactions between condition, genotype, and psychometric psychosis liability. Carriers of the Val allele were most sensitive to D-9-THC-induced psychotic experiences, but this was conditional on prior evidence of psychometric psychosis liability. D-9-THC impacted negatively on cognitive measures. Carriers of the Val allele were also more sensitive to D-9-THC-induced memory and attention impairments compared to carriers of the Met allele. Experimental effects of D-9-THC on cognition and psychosis are moderated by COMT Val 158 Met genotype, but the effects may in part be conditional on the additional presence of pre-existing psychosis liability. The association between cannabis and psychosis may represent higher order gene-environment and gene-gene interactions.

AKT1 Moderation of Cannabis-Induced Cognitive Alterations in Psychotic Disorder

“…This is in keeping with the interpretation that in genetically vulnerable individuals, cannabis use may adversely impact on brain function and psychopathology (D'Souza et al, 2005; Genetic Risk and Outcome of Psychosis (GROUP) Investigators, 2011;Habets et al, 2011). The present findings are also in agreement with a previous study that the CPT is sensitive to genetic moderation of cognitive performance by cannabis in patients with schizophrenia (Henquet et al, 2006).…”

“…Since a previous study in patients with psychosis and healthy controls found genetic moderation of cannabisinduced cognitive impairments of verbal memory and especially sustained attention (Henquet et al, 2006), these were selected as the cognitive outcome measures. The standardized Dutch version of the visually presented Word Learning Task (WLT) was used to assess memory storage and retrieval of 15 monosyllabic nonrelated words from episodic memory (immediate recall, delayed recall and recognition after 20 min (Van Der Elst et al, 2005).…”

Cannabis and cognitive performance in psychosis: a cross-sectional study in patients with non-affective psychotic illness and their unaffected siblings

“…It seems essential to account for the recency of cannabis use in studies on the association between cannabis and cognitive functioning, since contradictory findings between acute administration and lifetime cannabis use have been found (D'Souza et al 2005 ;Henquet et al 2006 ;Coulston et al 2007a ;Potvin et al 2008 ;Loberg & Hugdahl, 2009 ;Yü cel et al 2010). In addition, the frequency of cannabis use should be taken into account in order to investigate dose-response relationships (Coulston et al 2007a).…”

Investigation of the COMT Val158Met variant association with age of onset of psychosis, adjusting for cannabis use

“…Other significant factors affecting AoP are gender (Mané et al., 2017) and family history of psychosis/schizophrenia (Byrne, Agerbo, & Mortensen, 2002; Kendler & MacLean, 1990). There have also been reports of associations between rs4680 and other relevant phenotypes, for example, healthy individuals of Val/Val genotype were at increased risk of experiencing hallucinations on cannabis consumption if they had high levels of psychosis vulnerability (Henquet et al., 2009), rs4680 moderating the effect of Δ‐9‐tetrahydrocannbinol on psychosis and cognition (Henquet et al., 2006) and those at risk of transitioning to psychosis showing an increased risk of positive symptoms in the case of Val/Val individuals with a history of cannabis use at least weekly, with a lesser degree of effect for those of Val/Met genotype (Nieman et al., 2016). …”