Cannabis contains a number of chemically active compounds, including cannabinoids, terpenoids, flavonoids, and alkaloids. ²⁹ The most active constituent is the cannabinoid, THC, which is responsible for the well-characterized psychotropic effects associated with cannabis use. There are, however, over 100 other active cannabinoids that have been identified, each which modulates one or more components of the body’s ECS. ³⁰ A basic knowledge of the ECS is essential to understand how cannabis may be beneficial in patients with IBD.

The ECS consists of cannabinoid receptors, endogenous ligands for these receptors, and the enzymes for their synthesis and degradation.^17,30 The human body naturally produces endocannbinoids, which are lipid-mediators that bind to cannabinoid receptors, found throughout the body (Figure 1). This complex system is involved in regulating a number of cognitive and physiological processes in the central nervous system including pain, mood, appetite, stress, and memory.^17,31,32 In addition, the ECS regulates physiological processes outside of the brain, including those in the heart, gastrointestinal tract, reproductive system, and bone, to name a few.^{33bibr33-1756284819870977bibr34-1756284819870977bibr35-1756284819870977bibr36-1756284819870977–37} Physiological and pharmacological studies have demonstrated the ECS is widely distributed throughout the gastrointestinal tract, and is involved in regulation of food intake, emesis, gastric secretion, gastric and intestinal motility, visceral sensation, and intestinal inflammation. ³⁸ The cannabinoids found in cannabis (phytocannabinoids) act as exogenous ligands for several of the receptors of the ECS. ²⁹ Several synthetic cannabinoids structurally analogous to the endocannabinoids have also been developed, and these share a similar biological action.

The two primary endocannabinoid receptors that have been isolated are the G-protein coupled cannabinoid receptors CB₁ and CB₂. ⁴⁰ CB₁ receptors are located primarily on neural tissue including central and peripheral neurons as well as the enteric nervous system (Figure 1). ⁴¹ CB₂ receptors are also expressed in the central nervous system, although most are located in immune tissues, including neutrophils, macrophages, epithelial cells, and subsets of T and B cells.^41,42 In general, CB₁ signaling mediates neuromodulatory function, while CB₂ signaling mediates immunomodulatory activity.

CB₁ receptors are important in the control of gastrointestinal motility and gastric intestinal secretion.^37,43 CB₁ receptor agonists were shown to reduce gastrointestinal propulsion and transit in animal models.^44,45 Although the action on secretory function has been less studied, one study did demonstrate that gastric acid secretion was reduced with CB₁ activation. ⁴⁶ This suggests a therapeutic potential for the treatment of diarrhea in patients with IBD.

CB₁ receptor activation has also been demonstrated to increase appetite, and to promote food intake and energy conservation. ⁴⁷

Several in vitro studies have demonstrated the importance of both the CB₁ and CB₂ in modulating intestinal inflammation. CB₁ and CB₂ receptor agonists reduced experimentally induced intestinal inflammation in several murine studies, whereas antagonists were shown to exacerbate inflammation.^{48bibr49-1756284819870977–50} The ECS was physiologically involved in protecting against excessive colonic inflammation with activation of these receptors, dampening smooth muscle irritation and controlling cellular pathways involved in inflammatory responses. ⁵⁰ Activation of the CB₁ and CB₂ receptors was also demonstrated to reduce visceral sensitivity and pain associated with colonic distention in animal models.^{51bibr52-1756284819870977–53}

In addition to CB₁ and CB₂, other molecular targets for the cannabinoids have been identified, including the G-protein coupled receptors 18, 55, and 119 (GRP55 and GRP119); the peroxisome proliferator-activated receptor (PPAR); the serotonin-1A receptor (5-HT1A); and the transient receptor potential vanilloid 1 (TRPV1.)^{38,54bibr55-1756284819870977–56} The administration of cannabis, through its interaction with the various receptors of the ECS, modulates the gastrointestinal system by increasing appetite and reducing nausea, gastric secretions, intestinal contractility, peristalsis, visceral sensation as well as intestinal inflammation (Figure 1). ³⁸