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Background: Preclinical and human data suggest that psychosis onset involves hippocampal glutamatergic dysfunction, driving hyperactivity and 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 perfusion remains unknown. Methods: Using a double-blind, parallel-group design, 33 CHR patients were randomized to a single 600 mg dose of 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 × glutamate × cerebral perfusion (measured using Arterial Spin Labeling) 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 CHR-CBD (P =.031). Moreover, there was a significant interaction between group (controls vs CHR-placebo), hippocampal glutamate, and perfusion in the putamen and insula (PFWE =.012), with a strong positive correlation in CHR-placebo vs a negative correlation in controls. Conclusions: Our findings suggest that hippocampal glutamate is lower in CHR patients and may be partially normalized by a single dose of CBD. Furthermore, we provide the first in vivo evidence of an abnormal relationship between hippocampal glutamate and perfusion in the striatum and insula in CHR.

Original languageEnglish
Article numbersgad022
JournalSchizophrenia Bulletin Open
Issue number1
Early online date26 Sept 2023
Publication statusPublished - 2023


  • Glutamate
  • Psychosis Risk


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