biostudies-literatureDamstra-Oddy JLIrish Research Council for Science, Engineering and TechnologyMedical Research CouncilBiotechnology and Biological Sciences Research Council1149-1163https://www.ebi.ac.uk/biostudies/studies/S-EPMC9328663biostudies-literatureUnknown178(5)<h4>Background and purpose</h4>Cannabidiol (CBD) has been shown to differentially regulate the mechanistic target of rapamycin complex 1 (mTORC1) in preclinical models of disease, where it reduces activity in models of epilepsies and cancer and increases it in models of multiple sclerosis (MS) and psychosis. Here, we investigate the effects of phytocannabinoids on mTORC1 and define a molecular mechanism.<h4>Experimental approach</h4>A novel mechanism for phytocannabinoids was identified using the tractable model system, Dictyostelium discoideum. Using mouse embryonic fibroblasts, we further validate this new mechanism of action. We demonstrate clinical relevance using cells derived from healthy individuals and from people with MS (pwMS).<h4>Key results</h4>Both CBD and the more abundant caBritish journal of pharmacologyPhytocannabinoid-dependent mTORC1 regulation is dependent upon inositol polyphosphate multikinase activity.PMC9328663DTP studentshipMR/T028904/1MC_UU_12018/4EPSPG/2015/131Damstra-Oddy JLWilliams RSBCostelloe LFitzpatrick JKHind WDowner EJSaiardi APerry CJDesfougeres YSchaf JWarren ECfalsePhytocannabinoid-dependent mTORC1 regulation is dependent upon inositol polyphosphate multikinase activity.<h4>Background and purpose</h4>Cannabidiol (CBD) has been shown to differentially regulate the mechanistic target of rapamycin complex 1 (mTORC1) in preclinical models of disease, where it reduces activity in models of epilepsies and cancer and increases it in models of multiple sclerosis (MS) and psychosis. Here, we investigate the effects of phytocannabinoids on mTORC1 and define a molecular mechanism.<h4>Experimental approach</h4>A novel mechanism for phytocannabinoids was identified using the tractable model system, Dictyostelium discoideum. Using mouse embryonic fibroblasts, we further validate this new mechanism of action. We demonstrate clinical relevance using cells derived from healthy individuals and from people with MS (pwMS).<h4>Key results</h4>Both CBD and the more abundant ca2021-01-01T00:00:00Z2021 Mar2026-05-09T14:16:03.437Z2025-04-05T18:48:19.286ZS-EPMC93286633334760410.1111/bph.15351