Biology subjects

Freeman, T. P.

Publications and source records attributed to Freeman, T. P..

7 recordsLinked to original sources

bioRxiv2026

Longitudinal fMRI reveals altered developmental trajectories of functional network organisation associated with adolescent cannabis use

Adolescence is a critical period of brain development during which the endocannabinoid system continues to mature. These developmental changes may contribute to age-related differences in the association between cannabis use and large-scale functional network organisation, yet this association remains incompletely characterised. We hypothesised that regular cannabis use would be associated with differential one-year changes in resting-state functional connectivity between adolescents and adults. Resting-state fMRI data at two time points, one year apart, were analysed from 66 participants (31 aged 16-17 years; 35 aged 26-29 years) including 29 with regular cannabis use and 37 age-matched cannabis-naive controls. Seed-to-voxel analyses examined longitudinal changes in functional connectivity across age and cannabis-use groups. Year change, age by user-group interactions were identified in salience and default mode network connectivity, including divergent changes in anticorrelations with medial prefrontal, thalamic, cerebellar and juxtapositional regions. Directionality of effects differed by network and region. Additional main effects of user group were observed for executive control and associative striatal connectivity, with the cannabis-use group showing decreased positive connectivity and reduced anticorrelation, respectively. Changes in functional connectivity were developmentally dissociable and predominantly observed in regions contributing to attentional and transmodal processing. These findings suggest that cannabis may be associated with alterations in the maturational refinement of higher-order neural systems, potentially reflecting age-related differences in neurobiological sensitivity to cannabis exposure. Considering developmental stage may therefore be important for characterising cannabis-related neurobiological differences and may have implications for understanding age-dependent vulnerability to cannabis-related psychiatric outcomes.

neuroscience↗

bioRxiv2026

Epigenetic and brain age across development: Performance and associations in the MIND consortium

Understanding how biological age measures perform across development lays the groundwork for investigations into lifespan trajectories of healthy aging. We provide the most comprehensive assessment of epigenetic and brain age models across development (birth to 24 years; [≤]20,917 observations across 15 cohorts), evaluating how these models associate with chronological age and with each other, and how these associations change across development. Chronological age-prediction accuracy of epigenetic and brain age models was modest and varied substantially. Accuracy improved with age and stabilized by middle childhood. Few brain and fewer epigenetic clocks performed stably and well across all developmental stages. Performance was better when age range and tissue corresponded between training and testing data. Associations between epigenetic-brain age residuals were small, and changed little across development, tissues or clock generation. Given this developmentally dynamic system of epigenetic-brain age performances and associations, we give key recommendations to improve developmental research in this field.

neuroscience↗

bioRxiv2025

Receptor-enriched analysis of functional connectivity (REACT) for understanding cannabinoid neuropsychopharmacology

BackgroundCannabis is one of the most widely used psychoactive substances in the world and is increasingly investigated as a treatment for neuropsychiatric conditions. Cannabis contains delta-9-tetrahydrocannabinol (THC), which is thought to underlie its main psychoactive effects, and cannabidiol (CBD), which has been proposed to modulate the effects of THC on the brain. Both have activity at CB1 receptors, whilst THC also binds to CB2 receptors. However, it is unclear how THCs effects on brain function are related to cannabinoid receptors, or how CBD co-administration affects this. We aimed to investigate the effects of vaporised THC and the moderating effects of CBD on CB1 and CB2 receptor- enriched functional connectivity. MethodsForty-eight participants (24 adolescents and 24 adults) who used cannabis 0.5-3 days/week (mean=1.5 days/week) participated in a randomised, crossover, placebo- controlled, double-blind experiment where they inhaled vaporised cannabis containing either THC-only (8mg/75kg person), THC+CBD (8 mg THC + 24 mg CBD/75 kg person) or no psychoactive compounds (placebo). Resting-state functional MRI data were collected approximately 50 minutes post-administration. Receptor distribution maps were derived from positron emission tomography (PET) imaging for CB1 receptors and the Allen Human Brain Atlas (AHBA) for CB2 receptors. Receptor-Enriched Analysis of Connectivity by Targets (REACT) analytical methodology was used to investigate changes in functional connectivity related to specific receptor targets. ResultsInhalation of both THC-only and THC+CBD cannabis induced significant decreases in CB1 and CB2 receptor-enriched functional connectivity compared to placebo. The THC+CBD condition showed more extensive reductions than THC-only cannabis for both CB1- and CB2- enriched functional connectivity, affecting regions including the dorsolateral prefrontal cortex, cingulate cortex, insula, hippocampus, amygdala, and putamen. Higher THC plasma levels were associated with greater decreases in functional connectivity in the THC+CBD condition. Exploratory analyses identified significant positive and negative relationships between subjective drug effects and receptor-enriched functional connectivity in a region- dependent manner. ConclusionsCannabis with and without CBD decreased resting-state functional connectivity in networks associated with CB1 and CB2 receptor distribution. Co-administration of CBD with THC appears to enhance these effects. The REACT analytical methodology identified changes in CB1- and CB2-enriched functional connectivity are related to THC and CBD plasma levels as well as subjective drug effects across a range of regions.

neuroscience↗

bioRxiv2020

The acute effects of cannabidiol on emotional processing and anxiety: a neurocognitive imaging study

BackgroundThere is growing interest in the therapeutic potential of cannabidiol (CBD) across a range of psychiatric disorders. CBD has been found to reduce anxiety during experimentally-induced stress in anxious individuals and healthy controls. However, the mechanisms underlying the putative anxiolytic effects of CBD are unknown. We therefore sought to investigate the behavioural and neural effects of a single dose of CBD vs. placebo on a range of emotion-related measures to test cognitive-mechanistic models of its effects on anxiety. MethodsWe conducted a randomised, double-blind, placebo-controlled, crossover, acute oral challenge of 600 mg of CBD in 24 healthy participants on emotional processing, with neuroimaging (viewing emotional faces during fMRI) and cognitive (emotional appraisal) measures as well as subjective response to experimentally-induced anxiety. ResultsCBD did not produce effects on BOLD responses to emotional faces, cognitive measures of emotional processing, or modulate experimentally-induced anxiety, relative to placebo. ConclusionsGiven the rising popularity of CBD for its putative medical benefits, further research is warranted to investigate the clinical potential of CBD for the treatment of anxiety disorders.

neuroscience↗

bioRxiv2020

Individual and combined effects of Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) on striato-cortical connectivity in the human brain

Cannabidiol (CBD) and {Delta}9-tetrahydrocannabinol (THC) are two major constituents of cannabis with contrasting mechanisms of action. THC is the major psychoactive, addiction-promoting, and psychotomimetic compound, while CBD may have somewhat opposite effects. The brain effects of these drugs alone and in combination are poorly understood. In particular the striatum is implicated in the pathophysiology of several psychiatric disorders, but it is unclear how THC and CBD influence striato-cortical connectivity. Across two placebo-controlled, double-blind studies, we examine the effects of THC, CBD, and THC+CBD on the functional connectivity of striatal sub-divisions (associative, limbic, and sensorimotor) using resting-state functional Magnetic Resonance Imaging (fMRI) and seed-based functional connectivity analyses. Study 1 (N=17; inhaled 8mg THC, 8mg THC+10mg CBD, placebo) showed strong disruptive effects of both THC and THC+CBD conditions on connectivity in the associative and sensorimotor networks, but a specific effect of THC in the limbic striatum, which was alleviated in the THC+CBD condition such that it did not differ from placebo. In Study 2 (N=23, oral 600mg CBD, placebo) CBD increased connectivity in the associative network, but relatively minor decreases/disruptions were found in the limbic and sensorimotor. In conclusion, THC strongly disrupts striato-cortical networks, and this effect is selectively mitigated in the limbic striatum when co-administered with CBD. When administered alone, 600mg oral CBD has a more complex effect profile of relative increases and decreases in connectivity. The insula emerges as a key region affected by cannabinoid-induced changes in functional connectivity, with potential implications for understanding cannabis related disorders, and the development of cannabinoid therapeutics.

neuroscience↗

bioRxiv2019

The independent and combined influence of schizophrenia polygenic risk score and heavy cannabis use on risk for psychotic disorder: A case-control analysis from the EUGEI study.

Background: Some recent studies have challenged the direction of causality for the association between cannabis use and psychotic disorder, suggesting that cannabis use initiation is explained by common genetic variants associated with risk of schizophrenia. We used data from the European Union Gene-Environment Interaction consortium (EUGEI) case-control study to test for the independent and combined effect of heavy cannabis use, and of Schizophrenia Polygenic risk score (SZ PRS), on risk for psychotic disorder. Methods: Genome-wide data were obtained from 492 first episode psychosis patients (FEPp) and from 787 controls of European Ancestry, and used to generate SZ PRS from the summary results of an independent meta-analysis. Information on pattern of cannabis use was used to build a 7-level frequency-type composite cannabis use measure that we previously found was a strong predictor of psychotic disorder. Results: SZ PRS did not predict cannabis initiation (b=0.027; p=0.51) or how frequently controls (b=0.027; p=0.06) or FEPp (b=0.006; p=0.91) used it, or the type of cannabis they used (Controls: b = 0.032; p=0.31); FEPp: b= 0.005; p=0.89). The frequency-type composite cannabis use measure (OR=1.32; 95% CI 1.22-1.44) and SZ PRS (OR=2.29; 95%CI 1.71-3.05) showed independent effects from each other on the OR for psychotic disorder. Conclusion: SZ PRS does not predict an individual s propensity to try cannabis, frequency of use, or the potency of the cannabis used. Our findings provide the first evidence that SZ PRS and heavy cannabis use exert effects independent from each other on the risk for psychotic disorder.

genetics↗

bioRxiv2019

Cannabis-associated symptom profiles in patients with first episode psychosis and population controls

ObjectiveThe evidence is mixed on whether cannabis use is associated with a particular symptomatology in first episode psychosis (FEP) patients.\n\nThe authors set out to investigate a) patterns of association between cannabis use and transdiagnostic symptom dimensions; b) whether the extent of use of cannabis contributes to the variation in clinical and subclinical symptom profiles.\n\nMethodThe authors analysed data from 901 patients and 1235 controls recruited across six countries, as part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. Item response modelling was used to estimate two bifactor models, which included general and specific dimensions of psychotic symptoms in patients and psychotic experiences in controls. The associations between these dimensions and cannabis use was evaluated using linear mixed effects models analyses.\n\nResultsIn patients, there was a linear relationship between the positive symptom dimension and the extent of lifetime exposure to cannabis, with daily users of high potency cannabis having the highest score (B=0.35; 95%CI 0.14 to 0.56). Moreover, negative symptoms were more common among patients who never used cannabis compared with those with any pattern of use (B=-0.27; 95%CI -0.42 to -0.12).\n\nIn controls, psychotic experiences were associated with current use of cannabis but not with the extent of lifetime use.\n\nNeither patients nor controls presented differences in the depressive dimension related to cannabis use.\n\nConclusionsThe extent of use of cannabis explains part of the heterogeneous distribution of positive and negative symptoms of FEP patients.

neuroscience↗