Cannabis and its derivatives can have beneficial but also detrimental effects on gastrointestinal and hepatic function, via the endocannabinoid system (ECS). These are discussed in a review article in the July issue of Gastroenterology.
Cannabis and its derivatives affect many gastrointestinal processes via the ECS and has reported anti-inflammatory, anti-nociceptive, and anti-secretory effects. Some gastrointestinal disorders might therefore be treated with cannabinoids. Despite numerous studies in cell lines and animals, few human studies have evaluated the therapeutic effects of cannabinoids.
Jonathan Gotfried et al review the effects of cannabinoids on chemotherapy-induced nausea and emesis, chronic pain, metabolism, obesity, and nonalcoholic fatty liver disease, and inflammatory bowel diseases. Cannabis use can have undesired or even detrimental effects that can limit its use, such as cannabinoid hyperemesis syndrome.
Cannabis contains numerous chemically active compounds, including cannabinoids, terpenoids, flavonoids, and alkaloids. The best characterized are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). There are, however, more than 100 active cannabinoids, each with capacity to modulate the ECS—a network of cannabinoid receptors, ligands, and regulating synthesizing and degrading enzymes.
Cannabinoid receptors and their ligands are distributed throughout the human gastrointestinal tract with regional variations in expression. Cannabinoid receptor 1 (CB1) is expressed in the enteric nervous system in epithelial cells and myenteric and submucosal plexuses, and is found adjacent to motoneurons, interneurons, and primary afferent neurons. CB2 is expressed by immune cells and the peripheral nervous system. Activation of the ECS leads to increased food intake and other metabolic processes that affect energy balance, including lipolysis and glucose metabolism
Gotfried et al explain the effects of these compounds on gastrointestinal motility, esophageal function, gastric emptying and gastroparesis, colon transit, pancreatic diseases, and irritable bowel syndrome (IBS). The authors state that although cannabinoids could have beneficial effects, they are not used in management of dysmotility-associated conditions. Results from studies of functional gastrointestinal disorders are listed in a table.
Use of cannabis and cannabinoids as anti-emetics has been mostly studied in patients with chemotherapy-induced nausea and vomiting. The review discusses the formulations and delivery methods have been used in treatment, sometimes with other anti-emetics, with varying results.
Gotfried et al cover cannabinoid hyperemesis syndrome (CHS), which has been reported to increase in states after legalization of medicinal and recreational cannabis, highlighting potential side effects in some users. The authors state that CHS likely occurs in long-term users (near daily use for 1 year), most often in adolescent males or young adults. Chronic use might down-regulate CB1 in persons with specific genetic variants, lowering emetic pathway thresholds. Other theories attribute relative potency or formulation differences of cannabis products (ratio of THC:CBD). Tricyclic antidepressants are the most commonly prescribed long-term treatment in patients requiring medical therapy.
The authors discuss how cannabis might modify the intestinal microbiome, and studies for treatment of obesity or nonalcoholic liver disease (NAFLD). In obese individuals, CB1 antagonists appeared to promote weight loss, but with negative side effects. CB2 is expressed in tissues with high levels of metabolism, such as liver, pancreas, and adipose tissue, so it might be involved in development of obesity or metabolic disorders. A CB2 agonist was reported to promote white adipose tissue browning, converting it to beige adipose (functions similar to brown adipose tissue), which can stimulate thermogenesis and caloric expenditure.
The review covers alterations in the ECS in patients with inflammatory bowel diseases (IBD) and correlations between cannabinoid receptor genotypes and IBD characteristics. The authors explain the potential treatment of IBD with cannabis and list the results of trials of cannabis in patients with IBD.
Gotfried et al conclude that the ECS helps maintain gastrointestinal homeostasis and might be manipulated therapeutically. There is evidence for anti-inflammatory and anti-nociceptive effects of cannabinoids, and findings from small studies support use of cannabis or cannabinoids in patients with IBD. However, results from epidemiology studies contradict results from animal and human studies of cannabis and cannabinoids—especially their effects on obesity and fatty liver, relief from symptoms of gastroparesis, and IBS.
These discordant results indicate the complicated pathways and interactions of the ECS with other organ systems. Cannabinoids are far from a panacea—additional studies are needed to increase our understanding of their sometimes detrimental effects.