Effect of Cannabinoid Agonist on Gastrointestinal and Colonic Motor Functions in Patients With Irritable Bowel Syndrome (IBS)

Irritable bowel syndrome (IBS) affects about 15% of the U.S. population. Despite increasing understanding of the pathophysiology of IBS, there are unmet clinical needs and no effective medication approved for the treatment of abdominal pain associated with IBS. Cannabinoid receptors (CBR) are on cholinergic neurons in the brain stem, stomach and colon. A cannabinoid receptor type 1 (CB1) antagonist, rimonabant, is effective in induction of weight loss; however, the mechanism of this benefit is unclear. Human studies from this lab show that a CBR agonist, dronabinol, inhibits gastric and colonic motility, which may alter appetite or satiation in obesity, and may have potential in the treatment of IBS. The overall focus of the study is on the mechanisms involved in the modulation of gastric and colonic motor and sensory functions by cannabinoid receptors (CBR) in health and in IBS. CB1 receptors are also involved in nociception and in mediating inflammation which are increasingly recognized as being potential pathophysiological mechanisms in IBS. The aims of the study are to compare the effects of two doses of the cannabinoid agonist, dronabinol (5 and 10 mg/day) and placebo on gastrointestinal and colonic motor and sensory functions in IBS. Also, to determine whether variations in the fatty acid amide hydrolase (FAAH) gene and the monoacylglycerol lipase (MGLL) gene (for the rate limiting enzyme, monoacylglycerol lipase, for another endocannabinoid, 2-arachidonyl glycerol) influence the pharmacological effect of cannabinoid modulation on gastrointestinal motor and sensory functions.

All participants underwent the following procedures:

• Documentation of eligibility, screening questionnaires, and physical examination within the month prior to the study. The physical exam included standard rectal and pelvic floor examinations to exclude rectal evacuation disorder. This was necessary to ensure the diarrhea ws not secondary to "retention of stool with overflow."
• Baseline colonic transit measurement (Geometric Center 24-h and 48-h), off treatment.
• Treatment days corresponded to the scintigraphic transit testing days (days 1 and 2) with participants receiving the medication to which they were randomized. Scintigraphic measurements of gastric, small bowel, and colonic transit were conducted, using a previously validated method on days 1 and 2, and were completed with a fasting 48-h scan on day 3 when no medication was administered.

On days 1 and 2, the morning dose of medication was ingested in the research laboratory, with the participant fasting. On day 1, the morning dose of medication was administered together with the delayed release capsule containing an isotope labeled activated charcoal used to measure colonic transit. On day 2, the morning dose of medication was given after the 24-h scan. The evening doses on days 1 and 2 were ingested by participants at bed time in their homes.

• With appropriate consent, a venous blood sample was to be obtained from all participants for DNA extraction and pharmacogenomic studies.

Inclusion criteria

• Age 18-75 years
• Positive for IBS symptoms by Rome III criteria
• No prior abdominal surgery (except appendectomy or cholecystectomy)
• Baseline Geometric Center at 24 hours is greater/equal to 2.0
• Baseline Geometric Center at 48 hours is greater/equal to 3.9

Exclusion criteria

• Patients with significant depression (score of greater than 10 on Hospital and Anxiety Inventory)
• Patients with anxiety (score of greater than 10 on Hospital and Anxiety Inventory) will not be allowed to participate. However, patients on stable doses of selective serotonin re-uptake inhibitors (SSRIs) or low dose of tricyclic antidepressants will be eligible.