Task-independent acute effects of delta-9-tetrahydrocannabinol on human brain function and its relationship with cannabinoid receptor gene expression: A neuroimaging meta-regression analysis
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Abstract
Abstract Background The neurobiological mechanisms underlying the effects of delta-9-tetrahydrocannabinol (THC) remain unclear. Here, we examined the spatial acute effect of THC on human on regional brain activation or blood flow (hereafter called ‘activation signal’) in a ‘core’ network of brain regions that subserve a multitude of processes. We also investigated whether the neuromodulatory effects of THC are related to the local expression of its key molecular target, cannabinoid-type-1 (CB1R) but not type-2 (CB2R) receptor. Methods A systematic search was conducted of acute THC-challenge studies using fMRI, PET, and arterial spin labelling in accordance with established guidelines. Using pooled summary data from 372 participants, tested using a within-subject repeated measures design under experimental conditions, we investigated the effects of a single dose (6-42mg) of THC, compared to placebo, on brain signal. Findings As predicted, THC augmented the activation signal, relative to placebo, in the anterior cingulate, superior frontal cortices, middle temporal and middle and inferior occipital gyri, striatum, amygdala, thalamus, and cerebellum crus II and attenuated it in the middle temporal gyrus (spatially distinct from the cluster with THC-induced increase in activation signal), superior temporal gyrus, angular gyrus, precuneus, cuneus, inferior parietal lobule, and the cerebellum lobule IV/V. Using post-mortem gene expression data from an independent cohort from the Allen Human Brain atlas, we found a direct relationship between the magnitude of THC-induced brain signal change, indexed using pooled effect-size estimates, and CB1R gene expression, a proxy measure of CB1R protein distribution, but not CB2R expression. A dose-response relationship was observed with THC dose in certain brain regions. Interpretation These meta-analytic findings shed new light on the localisation of the effects of THC in the human brain, suggesting that THC has neuromodulatory effects in regions central to many cognitive tasks and processes, with greater effects in regions with higher levels of CB1R expression.
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- Authors
- Gunasekera, B., Davies, C., Blest-Hopley, G., Veronese, M., Ramsey, N. F., Bossong, M. G., Radua, J., Bhattacharyya, S., Pretzsch, C., McAlonan, G., Walter, C., Lötsch, J., Freeman, T., Curran, V., Battistella, G., Fornari, E., Filho, G. B., Crippa, J. A., Duran, F., & Zuardi, A. W.
- Affiliations
- King's College London (GB)
- University of Padua (IT)
- Utrecht University (NL)
- Goethe University Frankfurt (DE)
- University College London (GB)
- University of California, San Francisco (US)
- Centre Hospitalier Universitaire Vaudois (CH)
- Corresponding author
- Bhattacharyya, Sagnik
- ORCID
- Venue
- Neuroscience & Biobehavioral Reviews
- Publisher
- Elsevier BV
- Published
- 2022-09
- Volume
- 140
- Pages
- 104801
- ISSN
- 0149-7634 (ISSN-L)
- OpenAlex
- W4288760192
- Cited by
- 10
- References
- 15
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 3 · 2022: 1
- FWCI
- 0.29
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neuroscience & Biobehavioral Reviews (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed (publishedVersion)
- SERVAL (Université de Lausanne) (publishedVersion, cc-by)
- IRIS (submittedVersion, cc-by)
- Research Portal (King's College London) (submittedVersion, cc-by)
- Fraunhofer-Publica (Fraunhofer-Gesellschaft) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (215747/Z/19/Z)
- GW Pharmaceuticals
- NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research
- National Institute for Health and Care Research (16/126/53)
- Parkinson's UK
- King's College London
- European Commission (215747)
- Dowager Countess Eleanor Peel Trust
- Rosetrees Trust
- Deutsche Forschungsgemeinschaft (DFG Lo612/10‐1, Lo 612/10-1, GRK757)
- Fundação de Amparo à Pesquisa do Estado de São Paulo (20/12110-9, 2014/)
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Universidade de São Paulo
- Instituto Nacional de Ciência e Tecnologia Translacional em Medicina
- Britannia Pharmaceuticals
- Greenwich Biosciences
- Medical Research Council (MR/J012149/1, MC_PC_14105)
- National Health and Medical Research Council
- Cilag
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- delta-9-tetrahydrocannabinol, acute cannabis effects, brain activation, regional cerebral blood flow, CB1 receptor, CB2 receptor, dose-response relationship, neuromodulation, cognitive tasks, human brain
- MeSH terms
- Brain, Humans, Regression Analysis, Dronabinol, Gene Expression, Receptors, Cannabinoid, Neuroimaging
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