Hippocampal Glutamate, Resting Perfusion and the Effects of Cannabidiol in Psychosis Risk

Background Preclinical and human data suggest that the onset of psychosis involves hippocampal glutamatergic dysfunction, driving hyperactivity/hyperperfusion in a hippocampal-midbrain-striatal circuit. Whether glutamatergic dysfunction is related to cerebral perfusion in patients at Clinical High Risk (CHR) for psychosis, and whether cannabidiol (CBD) has ameliorative effects on glutamate or its relationship with blood flow remains unknown. Methods Using a double-blind, parallel-group design, 33 CHR patients were randomised to 600mg CBD or placebo; 19 healthy controls did not receive any drug. Proton magnetic resonance spectroscopy was used to measure glutamate concentrations in left hippocampus. We examined differences relating to CHR status (controls vs placebo), effects of CBD (placebo vs CBD) and linear between-group effects, such that placebo>CBD>controls or controls>CBD>placebo. We also examined group x glutamate x cerebral perfusion (measured using arterial spin labelling) interactions. Results Compared to controls, CHR-placebo patients had significantly lower hippocampal glutamate (p=.015) and a significant linear relationship was observed across groups, such that glutamate was highest in controls, lowest in CHR-placebo and intermediate in patients under CBD (p=.031). There was also a significant interaction between group (controls vs CHR-placebo), hippocampal glutamate and perfusion in the putamen and insula (pFWE=.012), driven by a strong positive correlation in the CHR-placebo group vs a negative correlation in controls. Conclusions Our findings suggest that hippocampal glutamate is lower in CHR patients and may be partially normalised by CBD treatment. Furthermore, we provide the first in vivo evidence of an abnormal relationship between hippocampal glutamate and resting perfusion in the striatum and insula in these patients. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial ISRCTN46322781 ### Funding Statement This study was supported by grant MR/J012149/1 from the Medical Research Council (MRC). SB has also 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 King's Clinical Research Facility and NIHR Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, NIHR or the Department of Health and Social Care. 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. No other disclosures or any competing financial interests were reported and the authors declare that there are no conflicts of interest in relation to the subject of this study. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of Camberwell St Giles gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data produced in the present work are not openly available.