A single dose of cannabidiol modulates the coupling between hippocampal glutamate and learning-related prefrontal activation in individuals at Clinical High Risk of Psychosis

BackgroundCannabidiol (CBD) is being studied as a potential intervention for the people at clinical high risk for psychosis (CHR), though the mechanisms underlying its effects are not fully understood. Previous studies indicate that a single dose of CBD can normalize alterations in memory-related brain activation and modulate hippocampal glutamate levels in the early stages of psychosis. This study aimed to examine the acute effects of CBD on the coupling between hippocampal glutamate levels and brain activation during verbal memory in individuals at CHR. Methods33 participants at CHR participants were randomly assigned to receive either a single dose of 600 mg CBD (CHR-CBD) or an identical placebo capsule (CHR-PLB). 19 age-matched healthy controls (HC) received no study drugs. Participants underwent MRI scanning while performing a verbal learning task, and proton magnetic resonance spectroscopy to measure hippocampal glutamate levels. Group x hippocampal glutamate x brain activation interactions were tested. ResultsCHR-PLB showed positive correlation between hippocampal glutamate levels and dorsolateral prefrontal cortex (dlPFC) (Pcorr. = 0.0039) activation compared to HC during both verbal encoding and recall. Under a single dose of CBD, the glutamate-dlPFC activation coupling was negative and significantly different compared to placebo in CHR individuals (Pcorr. = 0.0001). The reversed correlation in CBD group also observed in the parahippocampal gyrus (Pcorr. = 0.0022) and amygdala (Pcorr. = 0.0019). ConclusionsThese findings suggest that the mechanism underlying the effect of CBD in CHR may involve reversing of altered coupling between hippocampal glutamate levels and prefrontal and mediotemporal activation.