2025
Pharmaceuticals (Basel) . 2025 Jan 23;18(2):148. doi: 10.3390/ph18020148.
Enhancing Tetrahydrocannabinol's Therapeutic Efficacy in Inflammatory Bowel Disease: The Roles of Cannabidiol and the Cannabinoid 1 Receptor Allosteric Modulator ZCZ011
Curtin Medical Research Institute, Curtin University, Perth, WA 6102, Australia. College of Science, Health, Engineering and Education, Murdoch University, Perth, WA 6150, Australia. Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6009, Australia. Department of Medicine and Surgery, University of Parma, 43125 Parma, Italy.
Service type: Stock strains
Abstract
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. Keywords: CB1R allosteric modulator; DSS-induced ulcerative colitis; ZCZ011; ammonia; cannabidiol (CBD); cannabinoid 1 receptor (CB1R); glucagon-like peptide 1 (GLP-1); inflammatory bowel disease; tetrahydrocannabinol (THC).
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