Effect of Cannabinoid Agonist on Gastrointestinal and Colonic Motor Functions in Patients With Irritable Bowel Syndrome (IBS)
Condition: Irritable Bowel Syndrome
MeSH terms: Irritable Bowel Syndrome; Syndrome
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): Dronabinol; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Dronabinol is a synthetic delta-9-tetrahydrocannabinol, a nonselective cannabinoid agonist. Subjects will receive either 2.5 mg bid, or 5 mg bid, taken orally with water for 2 days.; Placebo will match study drug; taken orally with water twice per day for two days.
Other intervention name(s): Marinol
Intervention MeSH terms: Dronabinol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Keywords: anandamide; cannabinoid; fatty acid amide hydrolase; gastric; motility; small bowel