title: How cannabis causes paranoia: using the intravenous administration of ∆9-tetrahydrocannabinol (THC) to identify key cognitive mechanisms leading to paranoia.
abstract: Paranoia is receiving increasing attention in its own right, since it is a central experience of psychotic disorders and a marker of the health of a society. Paranoia is associated with use of the most commonly taken illicit drug, cannabis. The objective was to determine whether the principal psychoactive ingredient of cannabis-∆(9)-tetrahydrocannabinol (THC)-causes paranoia and to use the drug as a probe to identify key cognitive mechanisms underlying paranoia. A randomized, placebo-controlled, between-groups test of the effects of intravenous THC was conducted. A total of 121 individuals with paranoid ideation were randomized to receive placebo, THC, or THC preceded by a cognitive awareness condition. Paranoia was assessed extensively via a real social situation, an immersive virtual reality experiment, and standard self-report and interviewer measures. Putative causal factors were assessed. Principal components analysis was used to create a composite paranoia score and composite causal variables to be tested in a mediation analysis. THC significantly increased paranoia, negative affect (anxiety, worry, depression, negative thoughts about the self), and a range of anomalous experiences, and reduced working memory capacity. The increase in negative affect and in anomalous experiences fully accounted for the increase in paranoia. Working memory changes did not lead to paranoia. Making participants aware of the effects of THC had little impact. In this largest study of intravenous THC, it was definitively demonstrated that the drug triggers paranoid thoughts in vulnerable individuals. The most likely mechanism of action causing paranoia was the generation of negative affect and anomalous experiences.
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, UK; daniel.freeman@psych.ox.ac.uk.
authors.forename: Daniel
authors.initials: D
authors.lastname: Freeman
authors.affiliation: Centre for Biostatistics, Institute of Population Health, University of Manchester, Manchester, UK;
authors.forename: Graham
authors.initials: G
authors.lastname: Dunn
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King's College London, London, UK;
authors.forename: Robin M
authors.initials: RM
authors.lastname: Murray
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, UK;
authors.forename: Nicole
authors.initials: N
authors.lastname: Evans
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, UK;
authors.forename: Rachel
authors.initials: R
authors.lastname: Lister
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, UK;
authors.forename: Angus
authors.initials: A
authors.lastname: Antley
authors.affiliation: Department of Computer Science, University College London, London, UK; Institució Catalana de Recerca i Estudis Avançats (ICREA), University of Barcelona, Barcelona, Spain;
authors.forename: Mel
authors.initials: M
authors.lastname: Slater
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, UK;
authors.forename: Beata
authors.initials: B
authors.lastname: Godlewska
authors.affiliation: Oxford Health NHS Foundation Trust, Oxford, UK;
authors.forename: Robert
authors.initials: R
authors.lastname: Cornish
authors.affiliation: Waikato Hospital, Hamilton, New Zealand;
authors.forename: Jonathan
authors.initials: J
authors.lastname: Williams
authors.affiliation: MRC Cognition and Brain Sciences Unit, Cambridge, UK;
authors.forename: Martina
authors.initials: M
authors.lastname: Di Simplicio
authors.affiliation: Queen Mary University of London, Violence Prevention Research Unit, Barts and the London School of Medicine and Dentistry, Wolfson Institute of Preventive Medicine, London, UK;
authors.forename: Artemis
authors.initials: A
authors.lastname: Igoumenou
authors.affiliation: Department Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Brenneisen
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, UK;
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Tunbridge
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, UK;
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Harrison
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, UK;
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Harmer
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, UK;
authors.forename: Philip
authors.initials: P
authors.lastname: Cowen
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King's College London, London, UK;
authors.forename: Paul D
authors.initials: PD
authors.lastname: Morrison
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000339:Affect / Q000187:drug effects*; D063386:Cannabinoid Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects*; D013759:Dronabinol / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010259:Paranoid Disorders / Q000139:chemically induced* / Q000503:physiopathology; D055815:Young Adult
chemical_list: D063386:Cannabinoid Receptor Agonists; D013759:Dronabinol
keywords: THC; cannabis; cognitive; delusions; paranoia