ACUTE NEURAL EFFECTS OF THE MAIN INGREDIENTS OF CANNABIS: IMPLICATIONS FOR PSYCHOSIS

Abstract

Background: Delta-9-tetrahydrocannabinol (THC) and Cannabidiol (CBD), the two main ingredients of the cannabis sativa plant have distinct symptomatic and behavioural effects. THC can induce psychotic symptoms and anxiety, impair memory and psychomotor control in healthy individuals, exacerbate existing psychotic symptoms, anxiety and memory impairments in patients with schizophrenia and is thought to be the ingredient responsible for the increased risk of developing schizophrenia following regular cannabis use. In contrast, CBD has anxiolytic and possibly antipsychotic properties and does not impair memory or other cognitive functions. The neural basis for these distinct effects of THC and CBD on psychiatric symptoms and cognitive function is unclear. We combined functional magnetic resonance imaging (fMRI) in healthy volunteers and pharmacological challenge with oral THC and CBD to examine the neural correlates of the various symptomatic and cognitive effects of cannabis. We also examined whether THC and CBD had opposite effects on regional brain function. Methods: Fifteen healthy men with minimal previous exposure to cannabis were scanned while performing an oddball novelty processing task, a verbal learning task, a response inhibition task, a sensory processing task and when viewing fearful faces. Subjects were scanned on three occasions, each preceded by oral administration of 10 mg of THC, 600 mg of CBD or placebo. BOLD responses were measured using fMRI. Results: During the oddball novelty processing task, while responding to emotionally neutral target stimuli that were salient because of their deviance/frequency, participants found the ‘baseline’ stimuli inappropriately salient compared to the 'oddball' stimuli while under the influence of THC. This was accompanied by attenuation of activation in the striatum and hippocampus by THC, while CBD augmented activation in these regions relative to placebo. The effect of THC on striatum was inversely correlated with the psychotic symptoms it concurrently induced. During the verbal learning task, THC augmented activation in the parahippocampal gyrus during the encoding condition such that the normal linear decrement in activation across repeated encoding blocks was no longer evident. THC also attenuated the normal time-dependent change in ventrostriatal activation during the retrieval condition, which was directly correlated with concomitantly induced psychotic symptoms. THC and CBD also had opposite effects on activation relative to placebo in the striatum during verbal recall, in the hippocampus during the response inhibition task, in the amygdala when subjects viewed fearful faces, in the superior temporal cortex when subjects listened to speech, and in the occipital cortex during visual processing. Discussion: The modulation of medial temporal and striatal function by THC may underlie the effects of cannabis on verbal learning, stimulus salience and psychotic symptoms. Evidence that THC influences function in these regions, particularly in the context of altered processing of salience, provides a plausible mechanism for the increased risk of schizophrenia in regular cannabis users. THC and CBD can have opposite effects on regional brain function, which may underlie their different symptomatic and behavioural effects, and is consistent with a potential therapeutic role for CBD in various neuropsychiatric conditions.