{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T11:48:03Z","timestamp":1785671283627,"version":"3.56.0"},"reference-count":56,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,1,18]],"date-time":"2021-01-18T00:00:00Z","timestamp":1610928000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["DTP studentship"],"award-info":[{"award-number":["DTP studentship"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001596","name":"Irish Research Council for Science, Engineering and Technology","doi-asserted-by":"publisher","award":["EPSPG\/2015\/131"],"award-info":[{"award-number":["EPSPG\/2015\/131"]}],"id":[{"id":"10.13039\/501100001596","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>A novel mechanism for phytocannabinoids was identified using the tractable model system, <jats:italic>Dictyostelium discoideum<\/jats:italic>. 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).<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Both CBD and the more abundant cannabigerol (CBG) enhance mTORC1 activity in <jats:italic>D. discoideum<\/jats:italic>. We identify a mechanism for this effect involving inositol polyphosphate multikinase (IPMK), where elevated IPMK expression reverses the response to phytocannabinoids, decreasing mTORC1 activity upon treatment, providing new insight on phytocannabinoids' actions. We further validated this mechanism using mouse embryonic fibroblasts. Clinical relevance of this effect was shown in primary human peripheral blood mononuclear cells, where CBD and CBG treatment increased mTORC1 activity in cells derived from healthy individuals and decreased mTORC1 activity in cells derived from pwMS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Our findings suggest that both CBD and the abundant CBG differentially regulate mTORC1 signalling through a mechanism dependent on the activity of the upstream IPMK signalling pathway, with potential relevance to the treatment of mTOR\u2010related disorders, including MS.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15351","type":"journal-article","created":{"date-parts":[[2020,12,22]],"date-time":"2020-12-22T02:39:21Z","timestamp":1608604761000},"page":"1149-1163","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Phytocannabinoid\u2010dependent mTORC1 regulation is dependent upon inositol polyphosphate multikinase activity"],"prefix":"10.1111","volume":"178","author":[{"given":"Joseph L.","family":"Damstra\u2010Oddy","sequence":"first","affiliation":[{"name":"Centre for Biomedical Sciences, School of Biological Sciences Royal Holloway University of London  Egham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleanor C.","family":"Warren","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Sciences, School of Biological Sciences Royal Holloway University of London  Egham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Perry","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Sciences, School of Biological Sciences Royal Holloway University of London  Egham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yann","family":"Desfoug\u00e8res","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Cell Biology University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John\u2010Mark K.","family":"Fitzpatrick","sequence":"additional","affiliation":[{"name":"Discipline of Physiology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin University of Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Schaf","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Sciences, School of Biological Sciences Royal Holloway University of London  Egham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Costelloe","sequence":"additional","affiliation":[{"name":"Department of Neurology Beaumont Hospital  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Hind","sequence":"additional","affiliation":[{"name":"GW Research Ltd  Histon UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric J.","family":"Downer","sequence":"additional","affiliation":[{"name":"Discipline of Physiology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin University of Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adolfo","family":"Saiardi","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Cell Biology University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9826-6020","authenticated-orcid":false,"given":"Robin S.B.","family":"Williams","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Sciences, School of Biological Sciences Royal Holloway University of London  Egham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,1,18]]},"reference":[{"issue":"1","key":"e_1_2_11_2_1","first-page":"S1","article-title":"The Concise Guide to PHARMACOLOGY 2019\/20: Introduction and other protein targets","volume":"176","author":"Alexander S. 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