Receptor-Enriched Analysis of Connectivity by Targets for mapping cannabinoid psychopharmacology
Poster No:
1764
Submission Type:
Abstract Submission
Authors:
Ekaterina Shatalina1, Natalie Ertl2, Kat Petrilli3, Shelan Ofori4, Anna Borissova4, H Valerie Curran5, Claire Mokrysz4, Will Lawn1, Tom Freeman3, Oliver Howes1, Matthew Wall2
Institutions:
1King's College London, London, London, 2Invicro, London, London, 3University of Bath, Bath, Somerset, 4University College London, London, London, 5Clinical Psychopharmacology Unit, University College London, London, United Kingdom
First Author:
Co-Author(s):
Introduction:
Cannabis contains cannabinoids, notably tetrahydrocannabinol (THC) and cannabidiol (CBD), which have distinct pharmacological actions and complex interactions when co-administered. THC primarily exerts psychotropic effects via CB1 receptors, while CBD's effects are less understood. Receptor-Enriched Analysis of Functional Connectivity by Targets (REACT) identifies changes in functional connectivity linked to pharmacological effects on specific receptor systems [1]. We investigated the effects of THC on CB1 and CB2 receptor-enriched functional connectivity, and if the addition of CBD modulated these effects.
Methods:
A randomized, double-blind, placebo-controlled, crossover study included 48 semi-regular cannabis users (24 adolescents, 17.2 ± 0.44 years; 24 adults, 27.8 ± 1.04 years; 12 females per group). Participants received vaporized THC, THC+CBD, or placebo cannabis 50 minutes before undergoing an 8-minute resting-state fMRI scan [2].
A dual regression approach was used to estimate receptor-enriched connectivity using CB1 maps derived from [¹¹C]OMAR PET and CB2 maps from the Allen Human Brain Atlas (AHBA), both normalised to MNI space and smoothed to match the fMRI data (6 mm FWHM). CB1 maps from the AHBA were included to validate AHBA data use in REACT analyses. The receptor maps served as spatial regressors to extract receptor-specific BOLD time series, then these time series were entered into the second step of the dual regression to generate spatial maps of receptor-enriched connectivity for each condition. Group-level contrasts (THC+CBD>Placebo, THC-only>Placebo) were analyzed with Randomise (5000 permutations, threshold-free cluster enhancement [TFCE] correction applied). Dice coefficients compared CB1 PET and AHBA maps for validation of the method. Exploratory voxel-wise correlations (using AFNI's 3dTcorr1D) examined associations between connectivity changes, THC/CBD plasma levels, and subjective "feel drug effect" scores. R-coefficients were transformed to Z-scores, and significant correlations were identified using TFCE (E=0.5, H=2, Hmin=2.3). Additional analyses tested age-group differences and drug-by-age interactions.
A dual regression approach was used to estimate receptor-enriched connectivity using CB1 maps derived from [¹¹C]OMAR PET and CB2 maps from the Allen Human Brain Atlas (AHBA), both normalised to MNI space and smoothed to match the fMRI data (6 mm FWHM). CB1 maps from the AHBA were included to validate AHBA data use in REACT analyses. The receptor maps served as spatial regressors to extract receptor-specific BOLD time series, then these time series were entered into the second step of the dual regression to generate spatial maps of receptor-enriched connectivity for each condition. Group-level contrasts (THC+CBD>Placebo, THC-only>Placebo) were analyzed with Randomise (5000 permutations, threshold-free cluster enhancement [TFCE] correction applied). Dice coefficients compared CB1 PET and AHBA maps for validation of the method. Exploratory voxel-wise correlations (using AFNI's 3dTcorr1D) examined associations between connectivity changes, THC/CBD plasma levels, and subjective "feel drug effect" scores. R-coefficients were transformed to Z-scores, and significant correlations were identified using TFCE (E=0.5, H=2, Hmin=2.3). Additional analyses tested age-group differences and drug-by-age interactions.
Results:
Both THC-only and THC+CBD cannabis significantly decreased CB1 and CB2 receptor-enriched connectivity compared to placebo (Figure 1). THC+CBD caused more extensive reductions, affecting the dorsolateral prefrontal cortex, cingulate cortex, insula, hippocampus, amygdala, and putamen. THC plasma levels were higher in the THC+CBD condition (27.86 ± 14.20 ng/ml) than in THC-only (14.88 ± 7.15 ng/ml, t(44) = -7.30, p < 0.0001), correlating with greater connectivity decreases. Subjective effects were negatively correlated with CB2-enriched connectivity in the frontal pole and temporal regions. No significant age-group differences or drug×age interactions were identified. CB1 connectivity maps from PET and AHBA showed high spatial overlap in the THC+CBD condition (Dice coefficient = 0.81)
·Figure 1
Conclusions:
Cannabinoids decreased resting-state connectivity in CB1 and CB2 receptor networks. Co-administering CBD with THC enhanced these effects, likely due to increased THC plasma levels from metabolic interactions. REACT mapping revealed connectivity decreases in regions critical for executive function, salience processing, and affective regulation. Greater subjective drug effects correlated with smaller CB2-enriched connectivity decreases in the frontal pole and temporal regions, suggesting CB2-mediated effects may counteract CB1-driven psychoactive effects. This study is the first to demonstrate the feasibility of using AHBA-derived receptor maps in REACT analyses, showing strong spatial correspondence with PET-derived maps. These findings advance our understanding of how cannabinoids modulate brain networks and highlight the importance of considering cannabinoid interactions in research and clinical practice.
Modeling and Analysis Methods:
fMRI Connectivity and Network Modeling
Other Methods
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Transmitter Receptors 1
Novel Imaging Acquisition Methods:
BOLD fMRI 2
Physiology, Metabolism and Neurotransmission:
Pharmacology and Neurotransmission
Keywords:
Other - pharmaco-fMRI; cannabinoid receptors; cannabis
1|2Indicates the priority used for review
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Provide references using APA citation style.
2. Ertl, N., et al., Acute effects of different types of cannabis on young adult and adolescent resting-state brain networks. Neuropsychopharmacology, 2024: p. 1-12.