How Cannabis Causes Paranoia: Using the Intravenous Administration of ∆ 9 -Tetrahydrocannabinol (THC) to Identify Key Cognitive Mechanisms Leading to Paranoia

Daniel Freeman,Artemis Igoumenou,Rachel Lister,Rudolf Brenneisen,Angus Antley,Catherine J Harmer,Graham Dunn,Philip Cowen,Paul D Morrison,Robin M Murray,Elizabeth M Tunbridge,Mel Slater,Martina Di Simplicio,Nicole Evans,Beata Godlewska,Robert Cornish,Paul J Harrison,Jonathan Williams

doi:10.1093/schbul/sbu098

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.

Highlights

Paranoia—unfounded fears that others intend harm to the individual—is a central experience of psychotic disorders such as schizophrenia
There were 3 hypotheses: (a) THC increases the occurrence of paranoia, (b) the occurrence of anomalous experiences and negative affect explains the increase in paranoia, and (c) that paranoid interpretations can be partially blocked by cognitive awareness
The binary dummy variables THC and Cognitive Awareness were entered together to test the effects of the randomization conditions, and the initial visual analogue scales for paranoia and for anxiety were used as baseline covariates

Summary

Introduction

Paranoia—unfounded fears that others intend harm to the individual—is a central experience of psychotic disorders such as schizophrenia. Factor analytic studies indicate that it is an independent experience that requires explanation in its own right.[1] Many people have a few paranoid ideas, and a few people have many.[2] Paranoia is associated with youth, poverty, poor physical health, suicidal ideation, and the use of cannabis.[3] We took this latter association to carry out a unique experimental investigation into the causes of paranoia. We set out to establish that cannabis causes paranoia, using the most comprehensive battery ever used to assess such fears. Cannabis was used as a probe to identify the key cognitive mechanisms causing paranoid fears. Determination of the immediate causes can be used to advance the treatment of delusions.[4]

A Cognitive Account of Paranoia

Participants

Design

Results

Discussion