Background Cannabidiol (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.

Methods 33 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.

Results CHR-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).

Conclusions These 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.

The authors have declared no competing interest.

ISRCTN46322781

This work was supported by the grant MR/J012149/1 from the Medical Research Council. YS is supported by a Chinese Scholarship Council studentship with King's College London. SB received support from the National Institute for Health Research (NIHR) (NIHR Clinician Scientist Award; NIHR CS-11-001), the NIHR Mental Health Biomedical Research Centre at South London and Maudsley National Health Service (NHS) Foundation Trust and King's College London. This study represents independent research supported by the NIHR/Wellcome Trust Kings Clinical Research Facility and NIHR Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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