{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T20:02:21Z","timestamp":1789675341521,"version":"4.0.1"},"reference-count":70,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T00:00:00Z","timestamp":1737590400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"LITTLE GREEN PHARMA LTD."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Current inflammatory bowel disease (IBD) treatments focus on symptomatic relief, highlighting the need for innovative approaches. Dysregulation of the cannabinoid 1 (CB1) receptor, part of the endocannabinoid system, is linked to colitis. While tetrahydrocannabinol (THC) alleviates colitis via CB1 activation, its psychotropic effects limit clinical use. ZCZ011, a CB1R allosteric modulator, and cannabidiol (CBD), a non-psychoactive cannabinoid, offer alternatives. This study investigated combining sub-therapeutic THC doses with ZCZ011 or CBD in a murine model of dextran sodium sulphate (DSS)-induced colitis. Methods: Acute colitis was induced with 4% DSS for 7 days, followed by 3 days of water. Chronic colitis was modelled over 24 days with alternating DSS concentrations. The combination of 2.5 mg\/kg THC with 20 mg\/kg ZCZ011 or 10 mg\/kg CBD was evaluated. Key markers were assessed to determine efficacy and safety, including disease activity index (DAI), inflammation, cytokine levels, GLP-1, and organ health. Results: DSS-induced colitis resulted in increased DAI scores, cytokines, organ inflammation and dysregulation of GLP-1 and ammonia. THC at 10 mg\/kg significantly improved colitis markers but was ineffective at 2.5 and 5 mg\/kg. ZCZ011 alone showed transient effects. However, combining 2.5 mg\/kg THC with either 20 mg\/kg ZCZ011 or 10 mg\/kg CBD significantly alleviated colitis markers, restored colon integrity and reestablished GLP-1 homeostasis. This combination also maintained favourable haematological and biochemical profiles, including a notable reduction in colitis-induced elevated ammonia levels. Conclusions: This study demonstrates the synergistic potential of low-dose THC combined with CBD or ZCZ011 as a novel, effective and safer therapeutic strategy for ulcerative colitis.<\/jats:p>","DOI":"10.3390\/ph18020148","type":"journal-article","created":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T05:49:54Z","timestamp":1737611394000},"page":"148","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Enhancing Tetrahydrocannabinol\u2019s Therapeutic Efficacy in Inflammatory Bowel Disease: The Roles of Cannabidiol and the Cannabinoid 1 Receptor Allosteric Modulator ZCZ011"],"prefix":"10.3390","volume":"18","author":[{"given":"Dinesh","family":"Thapa","sequence":"first","affiliation":[{"name":"Curtin Medical Research Institute, Curtin University, Perth, WA 6102, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohan","family":"Patil","sequence":"additional","affiliation":[{"name":"Curtin Medical Research Institute, Curtin University, Perth, WA 6102, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6369-0219","authenticated-orcid":false,"given":"Leon N","family":"Warne","sequence":"additional","affiliation":[{"name":"Curtin Medical Research Institute, Curtin University, Perth, WA 6102, Australia"},{"name":"College of Science, Health, Engineering and Education, Murdoch University, Perth, WA 6150, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0038-7391","authenticated-orcid":false,"given":"Rodrigo","family":"Carlessi","sequence":"additional","affiliation":[{"name":"Curtin Medical Research Institute, Curtin University, Perth, WA 6102, Australia"},{"name":"Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6009, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9801-7235","authenticated-orcid":false,"given":"Marco","family":"Falasca","sequence":"additional","affiliation":[{"name":"College of Science, Health, Engineering and Education, Murdoch University, Perth, WA 6150, Australia"},{"name":"Department of Medicine and Surgery, University of Parma, 43125 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,23]]},"reference":[{"key":"ref_1","first-page":"33","article-title":"Inflammatory Bowel Disease: An Expanding Global Health Problem","volume":"6","year":"2013","journal-title":"Clin. 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