Medical Marijuana for Digestive Disorders: Time to Prescribe?
Medical Marijuana for Digestive Disorders: Time to Prescribe?
Marijuana is the common name for the Cannabis plant, from which nearly 500 different chemical compounds have been isolated. Among these, the most clinically relevant are the phytocannabinoids that are concentrated in the plant's flowering buds that are harvested for consumption. The vast majority of interest has focused on Δ9-tetrahydrocannabinol (THC), which is primarily responsible for the psychoactive effects of marijuana. Marijuana also contains ~70 other phytocannabinoids, such as cannabidiol (CBD), that are present in varying ratios when compared with THC content and seem to have minimal psychotropic effects. There are two main subspecies of the Cannabis plant: Cannabis sativa and Cannabis indica. Sativa-dominant strains have higher THC content than indica strains, in which the CBD content is higher.
Scientific interest in the medical application of marijuana-based compounds heightened in the early 1990s with the discovery of an endogenous cannabinoid signaling system, termed the endocannabinoid system, through which phytocannabinoids appear to signal. The endocannabinoid system has since been implicated in diverse physiologic processes. It includes two G protein-coupled cannabinoid receptors, CB1 and CB2, as well as two endogenous ligands or endocannabinoids: anandamide and 2-arachidonylglycerol. Generally, CB1 is found in greatest abundance in central and peripheral neurons, whereas CB2 is expressed predominantly in immune cells. In the gastrointestinal tract, CB1 receptors are expressed principally in the enteric nervous system with high concentration within cholinergic neurons of the myenteric and submucosal plexus where receptors are thought to promote an inhibitory effect on motility and secretory function via reduced acetylcholine release. CB1 receptors have also been identified in normal human colonic epithelium and smooth muscle, and CB1 receptor activation has been shown to enhance epithelial wound healing. CB2 receptor expression appears to be more pronounced in inflamed colonic epithelium and lamina propria immune cells, and there is in vitro evidence to suggest that activation of epithelial CB2 receptors by cannabinoids inhibits tumor necrosis factor-α-induced interleukin-8 release. Expression of cannabinoid receptors is very limited in the normal liver but is increased in experimental liver injury and cirrhosis. CB1 and CB2 receptor activation have been shown to induce pro- and anti-fibrogenic effects, respectively. In the normal pancreas, there is weak expression of CB1 and CB2 that increases in the setting of inflammation; however, there have been conflicting studies on the impact of cannabinoid receptor activation on experimental pancreatitis. There is also evidence that cannabinoid agonists have apoptotic, antiproliferative, and antimetastatic effects in several gastrointestinal cancer cell lines and animal models.
THC is a partial agonist of both CB1 and CB2 but has higher affinity for CB1, which appears to mediate its psychoactive properties. CBD has much weaker affinity for cannabinoid receptors but has demonstrated anti-inflammatory properties that may occur through CB2 inverse agonism or independently of cannabinoid receptors altogether. Several synthetic cannabinoid compounds have been developed to try to modulate the endocannabinoid system for therapeutic purposes. Two have been approved by the Food and Drug Administration (FDA). Dronabinol (Marinol) is a synthetic THC that is indicated for chemotherapy-induced nausea and vomiting as well as AIDS anorexia. Another THC analog, known as nabilone (Cesamet), was approved for nausea and vomiting after cancer chemotherapy unresponsive to typical antiemetics. A third commercial medication, nabiximols (Sativex), is an oromucosal spray with relatively equal amounts of THC and CBD. It is approved in 13 countries, including Canada and the United Kingdom, for use in patients with cancer pain, neuropathic pain, or spasticity due to multiple sclerosis. Rimonabant (Acomplia) is a selective CB1 antagonist that was marketed for weight loss and used for smoking cessation but has been withdrawn because of adverse psychiatric effects—primarily depression. Numerous other CB1 and CB2 agonists and antagonists are currently undergoing investigation, including a phase II study in Europe of an oral therapy for ulcerative colitis that contains CBD and THC in a ratio of 20:1
Phytocannabinoids and the Endocannabinoid System
Marijuana is the common name for the Cannabis plant, from which nearly 500 different chemical compounds have been isolated. Among these, the most clinically relevant are the phytocannabinoids that are concentrated in the plant's flowering buds that are harvested for consumption. The vast majority of interest has focused on Δ9-tetrahydrocannabinol (THC), which is primarily responsible for the psychoactive effects of marijuana. Marijuana also contains ~70 other phytocannabinoids, such as cannabidiol (CBD), that are present in varying ratios when compared with THC content and seem to have minimal psychotropic effects. There are two main subspecies of the Cannabis plant: Cannabis sativa and Cannabis indica. Sativa-dominant strains have higher THC content than indica strains, in which the CBD content is higher.
Scientific interest in the medical application of marijuana-based compounds heightened in the early 1990s with the discovery of an endogenous cannabinoid signaling system, termed the endocannabinoid system, through which phytocannabinoids appear to signal. The endocannabinoid system has since been implicated in diverse physiologic processes. It includes two G protein-coupled cannabinoid receptors, CB1 and CB2, as well as two endogenous ligands or endocannabinoids: anandamide and 2-arachidonylglycerol. Generally, CB1 is found in greatest abundance in central and peripheral neurons, whereas CB2 is expressed predominantly in immune cells. In the gastrointestinal tract, CB1 receptors are expressed principally in the enteric nervous system with high concentration within cholinergic neurons of the myenteric and submucosal plexus where receptors are thought to promote an inhibitory effect on motility and secretory function via reduced acetylcholine release. CB1 receptors have also been identified in normal human colonic epithelium and smooth muscle, and CB1 receptor activation has been shown to enhance epithelial wound healing. CB2 receptor expression appears to be more pronounced in inflamed colonic epithelium and lamina propria immune cells, and there is in vitro evidence to suggest that activation of epithelial CB2 receptors by cannabinoids inhibits tumor necrosis factor-α-induced interleukin-8 release. Expression of cannabinoid receptors is very limited in the normal liver but is increased in experimental liver injury and cirrhosis. CB1 and CB2 receptor activation have been shown to induce pro- and anti-fibrogenic effects, respectively. In the normal pancreas, there is weak expression of CB1 and CB2 that increases in the setting of inflammation; however, there have been conflicting studies on the impact of cannabinoid receptor activation on experimental pancreatitis. There is also evidence that cannabinoid agonists have apoptotic, antiproliferative, and antimetastatic effects in several gastrointestinal cancer cell lines and animal models.
THC is a partial agonist of both CB1 and CB2 but has higher affinity for CB1, which appears to mediate its psychoactive properties. CBD has much weaker affinity for cannabinoid receptors but has demonstrated anti-inflammatory properties that may occur through CB2 inverse agonism or independently of cannabinoid receptors altogether. Several synthetic cannabinoid compounds have been developed to try to modulate the endocannabinoid system for therapeutic purposes. Two have been approved by the Food and Drug Administration (FDA). Dronabinol (Marinol) is a synthetic THC that is indicated for chemotherapy-induced nausea and vomiting as well as AIDS anorexia. Another THC analog, known as nabilone (Cesamet), was approved for nausea and vomiting after cancer chemotherapy unresponsive to typical antiemetics. A third commercial medication, nabiximols (Sativex), is an oromucosal spray with relatively equal amounts of THC and CBD. It is approved in 13 countries, including Canada and the United Kingdom, for use in patients with cancer pain, neuropathic pain, or spasticity due to multiple sclerosis. Rimonabant (Acomplia) is a selective CB1 antagonist that was marketed for weight loss and used for smoking cessation but has been withdrawn because of adverse psychiatric effects—primarily depression. Numerous other CB1 and CB2 agonists and antagonists are currently undergoing investigation, including a phase II study in Europe of an oral therapy for ulcerative colitis that contains CBD and THC in a ratio of 20:1