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

Abstract

BackgroundPreclinical 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.MethodsUsing 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.ResultsCompared 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.ConclusionsOur findings suggest that hippocampal glutamate is lower in CHR patients and may be partially normalised by CBD treatment. Furthermore, we provide the firstin vivoevidence of an abnormal relationship between hippocampal glutamate and resting perfusion in the striatum and insula in these patients.

Risk of psychosis in autism spectrum disorder individuals exposed to psychosocial stressors: A 9‐year chart review study

“…A role for psychological mechanisms was questioned, including insecure attachment styles, dysfunctional cognitive schemas, thinking errors, and non-psychotic symptoms (Appiah-Kusi et al, 2017;Bebbington, 2015;Rafiq et al, 2018). Moreover, a growing body of research has explored several potential biological underpinnings (Davies et al, 2022;Di Nicola et al, 2013;Egerton et al, 2016;Howes & Murray, 2014;Pruessner et al, 2017;Selten et al, 2013), accounting for the association between psychosocial stressors and psychosis, as well as the interacting or mediating role of other risk factors (e.g., cannabis use) (Arranz et al, 2018;Colizzi, Bortoletto et al, 2023). Interestingly, individuals with ASD were found to experience more psychosocial stressors over the course of their lives (e.g., family poverty, sexual abuse, parental illness, parental alcoholism, and parental divorce) compared with neurotypical individuals (Berg et al, 2016;Berg et al, 2018;Hoover & Kaufman, 2018;Schneider et al, 2019).…”