Trial Information

Study of the Effect of Cannabinoid Agonist on Gastrointestinal and Colonic Motor and Sensory Functions in Patients With Irritable Bowel Syndrome

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:

1. 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."

2. Baseline colonic transit measurement (Geometric Center 24-h and 48-h), off treatment.

3. 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.

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