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An experimental study of catechol-o-methyltransferase Val158Met moderation of delta-9-tetrahydrocannabinol-induced effects on psychosis and cognition.

Abstract

Observational studies have suggested that psychometric psychosis liability and a functional polymorphism in the catechol-O-methyltransferase (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=30), relatives of patients with a psychotic disorder (n=12), and healthy controls (n=32) were exposed to Delta-9-tetrahydrocannabinol (Delta-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 Delta-9-THC-induced psychotic experiences, but this was conditional on prior evidence of psychometric psychosis liability. Delta-9-THC impacted negatively on cognitive measures. Carriers of the Val allele were also more sensitive to Delta-9-THC-induced memory and attention impairments compared to carriers of the Met allele. Experimental effects of Delta-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.

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  • FREE Publisher Full Text
  • Authors

    Henquet C, Rosa A, Krabbendam L, Papiol S, Fananás L, Drukker M, Ramaekers JG, van Os J

    Source

    MeSH

    Adolescent
    Adult
    Amino Acid Sequence
    Amino Acid Substitution
    Brain
    Catechol O-Methyltransferase
    Cognition Disorders
    Cross-Over Studies
    DNA Mutational Analysis
    Dopamine
    Double-Blind Method
    Dronabinol
    Environmental Exposure
    Female
    Genetic Predisposition to Disease
    Genetic Testing
    Genotype
    Humans
    Male
    Middle Aged
    Placebos
    Polymorphism, Single Nucleotide
    Psychoses, Substance-Induced
    Psychotic Disorders

    Pub Type(s)

    Journal Article
    Randomized Controlled Trial
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    16936704