Search

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., Competing Interests: No 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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the University of Maryland's school of medicine, Maryland Psychiatric Research Center.)

High doses of delta-9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, have been shown to have anxiogenic effects. Additionally, THC effects have been shown to be modulated by genotype, including the single nucleotide polymorphism (SNP) rs1130233 at the protein kinase AKT1 gene, a key component of the dopamine signalling cascade. As such, it is likely that epigenetic methylation around this SNP may affect AKT gene expression, which may in turn impact on the acute effects of THC on brain function. We investigated the genetic ( AKT1 rs1130233) and epigenetic modulation of brain function during fear processing in a 2-session, double-blind, cross-over, randomized placebo-controlled THC administration, in 36 healthy males. Fear processing was assessed using an emotion (fear processing) paradigm, under functional magnetic resonance imaging (fMRI). Complete genetic and fMRI data were available for 34 participants. THC caused an increase in anxiety and transient psychotomimetic symptoms and para-hippocampal gyrus/amygdala activation. Number of A alleles at the AKT1 rs1130233 SNP, and percentage methylation at the CpG 11-12 site, were independently associated with a greater effect of THC on activation in a network of brain regions including left and right parahippocampal gyri, respectively. AKT1 rs1130233 moderation of the THC effect on left parahippocampal activation persisted after covarying for methylation percentage, and was partially mediated in sections of the left parahippocampal gyrus/hippocampus by methylation percentage. These results may offer an example of how genetic and epigenetic variations influence the psychotomimetic and neurofunctional effects of THC.

Emotional dysregulation and anxiety are common in people at clinical high risk for psychosis (CHR) and are associated with altered neural responses to emotional stimuli in the striatum and medial temporal lobe. Using a randomised, double-blind, parallel-group design, 33 CHR patients were randomised to a single oral dose of CBD (600 mg) or placebo. Healthy controls (n = 19) were studied under identical conditions but did not receive any drug. Participants were scanned with functional magnetic resonance imaging (fMRI) during a fearful face-processing paradigm. Activation related to the CHR state and to the effects of CBD was examined using a region-of-interest approach. During fear processing, CHR participants receiving placebo (n = 15) showed greater activation than controls (n = 19) in the parahippocampal gyrus but less activation in the striatum. Within these regions, activation in the CHR group that received CBD (n = 15) was intermediate between that of the CHR placebo and control groups. These findings suggest that in CHR patients, CBD modulates brain function in regions implicated in psychosis risk and emotion processing. These findings are similar to those previously evident using a memory paradigm, suggesting that the effects of CBD on medial temporal and striatal function may be task independent.

Cannabis use during the critical neurodevelopmental period of adolescence, may lead to brain structural, functional, and histological alterations that may underpin some of the longer-term behavioral and psychological harms associated with it. The endocannabinoid system performs a key regulatory and homeostatic role, that undergoes developmental changes during adolescence making it potentially more susceptible to the effects of exposure to cannabis during adolescence. Here, we synthesize evidence from human studies of adolescent cannabis users showing alterations in cognitive performance as well as in brain structure and function with relevant preclinical evidence to summarize the current state of knowledge. We also focus on the limited evidence that speaks to the hypothesis that cannabis use during adolescence, may pose a greater risk than use during adulthood, identify gaps in current evidence and suggest directions for new research. Existing literature is consistent with the association of cannabis use during adolescence and neurological changes. Adolescence cannabis users show altered functional connectivity within known functional circuits, that may underlie inefficient recruitment of brain regions, as largely increased functional activation has been observed compared to controls. This disruption in some cases may contribute to the development of adverse mental health conditions; increasing the chances or accelerating the onset, of their development. Preclinical evidence, further supports disruption from cannabis use being specific to the developmental period. Future studies are required to better investigate adolescent cannabis use with more accuracy using better defined groups or longitudinal studies and examine the permanency of these changes following caseation of use. Furthermore, research is required to identify heritable risk factors to cannabis use. There is a need for caution when considering the therapeutic potential of cannabis for adolescence and particularly in public discourse leading to potential trivialization of possible harm from cannabis use in adolescence. Current evidence indicates that adolescence is a sensitive period during which cannabis use may result in adverse neurocognitive effects that appear to show a level of permanency into adulthood., (Copyright © 2020 Blest-Hopley, Colizzi, Giampietro and Bhattacharyya.)

Cannabis has been associated with deficits in memory performance. However, the neural correlates that may underpin impairments remain unclear. We carried out a systematic review of functional magnetic resonance imaging (fMRI) studies investigating brain functional alterations in cannabis users (CU) compared to nonusing controls while performing memory tasks, complemented with focused narrative reviews of relevant preclinical and human studies. Twelve studies employing fMRI were identified finding functional brain activation during memory tasks altered in CU. Memory performance studies showed CU performed worse particularly during verbal memory tasks. Longitudinal studies suggest that cannabis use may have a causal role in memory deficits. Preclinical studies have not provided conclusive evidence of memory deficits following cannabinoid exposure, although they have shown evidence of cannabinoid-induced structural and histological alteration. Memory performance deficits may be related to cannabis use, with lower performance possibly underpinned by altered functional activation. Memory impairments may be associated with the level of cannabis exposure and use of cannabis during developmentally sensitive periods, with possible improvement following cessation of cannabis use.