The endocannabinoid system in the gastrointestinal tract plays a role in the peripheral regulation of energy balance and has been implicated in the control of intestinal barrier function. Previous studies have shown that high-fat diet (HFD) increases endocannabinoid tone and changes in endocannabinoid tone have been associated with a disruption in gut barrier function. Whether the cannabinoid 1 (CB1) receptor is expressed on the intestinal epithelium and is involved in the acute regulation of intestinal barrier function has not been determined. Therefore, the research presented in this thesis sought to test the hypothesis that CB1 receptor activation acutely regulates intestinal barrier function. The expression and function of the CB1 receptor was examined in the small intestine of mice fed standard chow or HFD (45% kcal) for 2, 6 and 12 weeks. We used immunohistochemistry and quantitative polymerase chain reaction (qPCR) to assess the expression and localization of the CB1 receptor on the gastrointestinal epithelium and Ussing chambers to assess intestinal barrier function using 4kDa fluorescein isothiocyanate-dextran (FD4) as a marker of paracellular permeability. Two structurally distinct CB1 agonists (AM841 [1μM] and CP55,940 [100nm]), an inverse agonist/antagonist (AM251 [1μM]) and a neutral antagonist (AM6545 [1μM]) were used. We found that the CB1 receptor is expressed on the small intestinal epithelium and its protein expression is upregulated in response to 2 weeks of HFD feeding. Acute application of CB1 agonists and antagonists following 2 weeks of HFD feeding reduces intestinal permeability, although these drugs have no effect in tissues from animals fed a chow diet or on tissues from animals fed HFD for a longer duration. The CB1 antagonists block the effect of the agonists and the effects of CB1 agonists and antagonists are absent in CB1 knock-out (KO) mice fed a 2-week HFD. Taken together, this study demonstrates that the CB1 receptor is involved in the acute regulation of small intestinal permeability in conditions where baseline intestinal permeability is perturbed such as in initial exposure to HFD. Further studies are required to elucidate the mechanism by which agonists and antagonists of the CB1 receptor give rise to similar responses in the small intestine.