Cannabinoids and the Gastrointestinal Tract

Abstract

The synthesis and degradation of endocannabinoids, location of cannabinoid (CB) receptors, and cannabinoid mechanisms of action on immune/inflammatory, neuromuscular, and sensory functions in digestive organs are well documented. CB₂ mechanisms are particularly relevant in immune and sensory functions. Increasing use of cannabinoids in the United States is impacted by social determinants of health including racial discrimination, which is associated with tobacco and cannabis co-use, and combined use disorders. Several conditions associated with emesis are related to cannabinoid use, including cannabinoid hyperemesis or withdrawal, cyclic vomiting syndrome, and nausea and vomiting of pregnancy. Cannabinoids generally inhibit gastrointestinal motor function; yet they relieve symptoms in patients with gastroparesis and diverse nausea syndromes. Cannabinoid effects on inflammatory mechanisms have shown promise in relatively small placebo-controlled studies in reducing disease activity and abdominal pain in patients with inflammatory bowel disease. Cannabinoids have been studied in disorders of motility, pain, and disorders of gut-brain interaction. The CB₂-receptor agonist, cannabidiol, reduced the total Gastroparesis Cardinal Symptom Index and increases the ability to tolerate a meal in patients with gastroparesis appraised over 4 weeks of treatment. In contrast, predominant-pain end points in functional dyspepsia with normal gastric emptying were not improved significantly with cannabidiol. The CB₂ agonist, olorinab, reduced abdominal pain in inflammatory bowel disease in an open-label trial and in constipation-predominant irritable bowel syndrome in a placebo-controlled trial. Cannabinoid mechanisms alter inflammation in pancreatic and liver diseases. In conclusion, cannabinoids, particularly agents affecting CB₂ mechanisms, have potential for inflammatory, gastroparesis, and pain disorders; however, the trials require replication and further understanding of risk-benefit to enhance use of cannabinoids in gastrointestinal diseases.

Keywords: Cannabis; Gastroparesis; Inflammatory Bowel Diseases; Nausea; Pain Disorders; Vomiting.

Figure 1.. The biosynthesis of endocannabinoids is derived from membrane phospholipids and occurs ‘on demand’ and is followed by immediate release extracellularly, e.g., into a synapse. The endocannabinoids [anandamide (AEA) and 2-arachidonoyl glyceral (2-AG)] are synthesized in postsynaptic neurons. The synthesis results from the action of synthetic enzymes specifically N-arachidonoyl phosphatidyl ethanolamine-preferring phospholipase D (NAPE-PLD) for AEA and diacyl glycerol lipase-α (DAGLα) for 2-AG.

Reprinted from ref. , Maselli DB, Camilleri M. Pharmacology, clinical effects, and therapeutic potential of cannabinoids for gastrointestinal and liver diseases. Clin Gastroenterol Hepatol 2021;19:1748–1758.e2.

Figure 2.. Summary of the multitude of effects of cannabis and its derivatives in gastrointestinal organs and effects on the liver, metabolism, and pancreas.

Adapted from ref. , Gotfried J, Naftali T, Schey R. Role of cannabis and its derivatives in gastrointestinal and hepatic disease. Gastroenterology 2020;159:62–80.