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

Phase 2

Completed

Conditions: Irritable Bowel Syndrome

Interventions: Drug: Placebo
Drug: Dronabinol

Registration Number: NCT01253408

Lead Sponsor: Mayo Clinic

Brief Summary: Irritable bowel syndrome (IBS) affects about 15% of the U.S. population. There are still no effective and safe medications approved for the treatment of abdominal pain associated with bowel symptoms in IBS. This study will investigate the effects of an approved medication, Dronabinol, on the movement of food through the stomach and colon in subjects with a history of diarrhea-predominant Irritable Bowel Syndrome (D-IBS).

Dronabinol is a synthetic medication (a medication made in a laboratory) related to the active ingredient of "cannabinoid or marijuana". Dronabinol is approved by the Food and Drug Administration (FDA) for preventing nausea and vomiting in patients with cancers undergoing chemotherapy. It is also used in AIDS patients with excessive weight loss for improvement in appetite and weight gain.

The hypothesis in this study is that dronabinol will slow down the movement of food through the colon, and that this effect is regulated by the genes controlling the body messengers (receptors) that respond to medicinal marijuana or synthetic medicines that work on the same messengers that are present in the gastrointestinal tract and pain nerves.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 36

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo will be taken orally with water twice per day for two days.
Dronabinol 2.5 mg bid	Dronabinol	Dronabinol 2.5 mg will be taken orally with water twice per day for two days.
Dronabinol 5 mg bid	Dronabinol	Dronabinol 5 mg will be taken orally with water twice per day for two days.

Primary Outcome Measures

Name	Time	Method
Colonic Transit Geometric Center at 24 Hours	24 hours	The scintigraphic method is used to measure colonic transit. An isotope is adsorbed on activated charcoal particles and delivered to the colon in a delayed release capsule. Anterior and posterior gamma images are taken hourly. The geometric center (GC) is the weighted average of counts in the different colonic regions. The scale ranges from 1 to 5; a high GC implies faster colonic transit, a GC of 1 implies all isotope is in the ascending colon, and a GC of 5 implies all isotope is in the stool.

Secondary Outcome Measures

Name	Time	Method
Gastric Emptying Half-Time (t1/2)	Approximately 2 hours after radiolabel meal is ingested	The time for half of the ingested solids or liquids to leave the stomach.
Colonic Transit Geometric Center	28, 32, and 48 hours	The scintigraphic method is used to measure colonic transit. An isotope is adsorbed on activated charcoal particles and delivered to the colon in a delayed release capsule. Anterior and posterior gamma images are taken hourly. The geometric center (GC) is the weighted average of counts in the different colonic regions. The scale ranges from 1 to 5; a high GC implies faster colonic transit, a GC of 1 implies all isotope is in the ascending colon, and a GC of 5 implies all isotope is in the stool.
Colonic Filling at 6 Hours	6 hours after radiolabeled meal was ingested	Percent of the radio-labeled meal that reached the colon at 6 hours, indirectly reflecting small bowel transit time.
Ascending Colon Emptying T 1/2	48 hours after radiolabeled meal was ingested	Ascending colon emptying t1/2 will be estimated by power exponential analysis of the proportionate emptying over time of counts from the colon. The primary data for this analysis will be the proportion of decay and depth-corrected counts in the ascending colon on the hourly scans on the first day of transit measurement and the 48 hour data.
Gastric Emptying at 2 and 4 Hours	2, 4 hours	Proportion of stomach contents emptied at a 2 and 4 hours.