Randomized Pharmacodynamic and Pharmacogenetic Trial of Dronabinol Effects on Colon Transit in Irritable Bowel Syndrome-Diarrhea

Neurogastroenterol Motil. 2012 Apr;24(4):358-e169. doi: 10.1111/j.1365-2982.2011.01874.x. Epub 2012 Jan 30.

Abstract

Background: Genetic variation in endocannabinoid metabolism is associated with colonic transit in irritable bowel syndrome (IBS) with diarrhea (IBS-D). The nonselective cannabinoid (CB) receptor agonist, dronabinol (DRO), reduced fasting colonic motility in nonconstipated IBS. FAAH and CNR1 variants influenced DRO's effects on colonic motility. Our aims were: (i) to compare dose-related effects of DRO to placebo (PLA) on gut transit in IBS-D, and (ii) to examine influence of genetic variations in CB mechanisms on DRO’s transit effects.

Methods: Thirty-six IBS-D volunteers were randomized (double-blind, concealed allocation) to twice per day PLA (n = 13), DRO 2.5 mg (n = 10), or DRO 5 mg (n = 13) for 2 days. We assessed gastric, small bowel, and colonic transit by validated radioscintigraphy and genotyped the single nucleotide polymorphisms CNR1 rs806378 and FAAH rs324420. Data analysis utilized a dominant genetic model.

Key results: Overall treatment effects of DRO on gastric, small bowel, or colonic transit were not detected. CNR1 rs806378 CT/TT was associated with a modest delay in colonic transit at 24 h compared with CC (P = 0.13 for differential treatment effects on postminus pretreatment changes in colonic transit by genotype). No significant interaction of treatment with FAAH rs324420 was detected.

Conclusions & inferences: Overall, DRO 2.5 or 5 mg twice per day for 2 days had no effect on gut transit in IBS-D. There appears to be a treatment-by-genotype effect, whereby DRO preferentially delays colonic transit in those with the CNR1 rs806378 CT/TT genotypes. Further study of CB pharmacogenetics may help identify a subset of IBS-D patients most likely to benefit from CB agonist therapy.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / genetics
  • Analgesics, Non-Narcotic / administration & dosage*
  • Analgesics, Non-Narcotic / pharmacokinetics
  • Diarrhea / drug therapy*
  • Diarrhea / etiology
  • Diarrhea / genetics
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Dronabinol / administration & dosage*
  • Dronabinol / pharmacokinetics
  • Gastrointestinal Transit / drug effects*
  • Gastrointestinal Transit / genetics
  • Genomics
  • Genotype
  • Humans
  • Irritable Bowel Syndrome / complications
  • Irritable Bowel Syndrome / drug therapy*
  • Irritable Bowel Syndrome / genetics*
  • Polymorphism, Single Nucleotide
  • Receptor, Cannabinoid, CB1 / genetics

Substances

  • Analgesics, Non-Narcotic
  • CNR1 protein, human
  • Receptor, Cannabinoid, CB1
  • Dronabinol
  • Amidohydrolases
  • fatty-acid amide hydrolase