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

Cathy Davies; Matthijs G Bossong; Daniel Martins; Robin Wilson; Elizabeth Appiah-Kusi; Grace Blest-Hopley; Paul Allen; Fernando Zelaya; David J Lythgoe; Michael Brammer; Jesus Perez; Philip McGuire; Sagnik Bhattacharyya

doi:10.1093/schizbullopen/sgad022

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

Cathy Davies, Matthijs G Bossong, Daniel Martins, Robin Wilson, Elizabeth Appiah-Kusi, Grace Blest-Hopley, Paul Allen, Fernando Zelaya, David J Lythgoe, Michael Brammer, Jesus Perez, Philip McGuire, Sagnik Bhattacharyya

Research output: Contribution to journal › Article › peer-review

Abstract

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 ( P FWE =.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 language	English
Pages (from-to)	gad022
Journal	Schizophrenia Bulletin Open
Volume	4
Issue number	1
DOIs	https://doi.org/10.1093/schizbullopen/sgad022
Publication status	Published - Jan 2023

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Davies, C., Bossong, M. G., Martins, D., Wilson, R., Appiah-Kusi, E., Blest-Hopley, G., Allen, P., Zelaya, F., Lythgoe, D. J., Brammer, M., Perez, J., McGuire, P., & Bhattacharyya, S. (2023). Hippocampal Glutamate, Resting Perfusion and the Effects of Cannabidiol in Psychosis Risk. Schizophrenia Bulletin Open, 4(1), gad022. https://doi.org/10.1093/schizbullopen/sgad022

@article{4f4dabdf50af49ed808b3f7b828298cf,

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

abstract = "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 ( P FWE =.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.",

author = "Cathy Davies and Bossong, {Matthijs G} and Daniel Martins and Robin Wilson and Elizabeth Appiah-Kusi and Grace Blest-Hopley and Paul Allen and Fernando Zelaya and Lythgoe, {David J} and Michael Brammer and Jesus Perez and Philip McGuire and Sagnik Bhattacharyya",

note = "{\textcopyright} The Author(s) 2023. Published by Oxford University Press on behalf of the University of Maryland's school of medicine, Maryland Psychiatric Research Center.",

year = "2023",

month = jan,

doi = "10.1093/schizbullopen/sgad022",

language = "English",

volume = "4",

pages = "gad022",

journal = "Schizophrenia Bulletin Open",

issn = "2632-7899",

publisher = "Oxford University Press (OUP)",

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TY - JOUR

T1 - Hippocampal Glutamate, Resting Perfusion and the Effects of Cannabidiol in Psychosis Risk

AU - Davies, Cathy

AU - Bossong, Matthijs G

AU - Martins, Daniel

AU - Wilson, Robin

AU - Appiah-Kusi, Elizabeth

AU - Blest-Hopley, Grace

AU - Allen, Paul

AU - Zelaya, Fernando

AU - Lythgoe, David J

AU - Brammer, Michael

AU - Perez, Jesus

AU - McGuire, Philip

AU - Bhattacharyya, Sagnik

N1 - © The Author(s) 2023. Published by Oxford University Press on behalf of the University of Maryland's school of medicine, Maryland Psychiatric Research Center.

PY - 2023/1

Y1 - 2023/1

N2 - 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 ( P FWE =.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.

AB - 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 ( P FWE =.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.

U2 - 10.1093/schizbullopen/sgad022

DO - 10.1093/schizbullopen/sgad022

M3 - Article

C2 - 39145348

SN - 2632-7899

VL - 4

SP - gad022

JO - Schizophrenia Bulletin Open

JF - Schizophrenia Bulletin Open

IS - 1

ER -

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

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