Gastrointestinal Adverse Events of Cannabinoid 1 Receptor Inverse Agonists suggest their Potential Use in Irritable Bowel Syndrome with Constipation: A Systematic Review and Meta-Analysis

J Gastrointestin Liver Dis. 2019 Dec 9;28(4):473-481. doi: 10.15403/jgld-265.

Abstract

Background and aims: Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal (GI) disorders characterized by pain and impaired bowel movements. Currently available drugs show limited efficacy. Cannabinoid 1 receptor (CB1) inverse agonists (CB1-RAN) cause diarrhea and may be candidates for the treatment of constipation-predominant IBS (IBS-C). We evaluated the effects of CB1-RAN in clinical trials for their potential use in IBS-C.

Methods: Database search identified all clinical trials published up to May 2018 that reported rimonabant and taranabant treatment for at least one month and detailed the GI adverse events (AEs). Categorical outcomes (subgroups of AEs) were analyzed using the odds ratio (OR).

Results: Eighteen trials met the inclusion criteria. Rimonabant 20 mg produced significantly more overall AEs (OR=1.35, CI: 1.19-1.52, p<0.0001), psychiatric events (OR=1.79, CI: 1.46-2.21, p<0.001) and GI AEs (OR=2.05, CI: 1.65-2.55, p<0.001) compared to placebo. Taranabant at doses ranging from 0.5 to 8 mg produced significantly more overall AEs (OR=1.36, CI: 1.13-1.64, p<0.002), psychiatric AEs (1.82, CI: 1.54-2.16, p<0.001) and GI AEs (OR=1.75, CI: 1.29-2.37, p<0.001) compared to placebo.

Conclusions: The approach to target CB1 in the gut for the treatment of IBS-C or chronic constipation seems a promising therapeutic option. Prospective clinical trials on the possible targeting of CB1 and the endocannabinoid system are warranted.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Amides / adverse effects
  • Amides / therapeutic use
  • Cannabinoid Receptor Antagonists / adverse effects
  • Cannabinoid Receptor Antagonists / therapeutic use*
  • Constipation / drug therapy*
  • Gastrointestinal Agents / adverse effects
  • Gastrointestinal Agents / therapeutic use*
  • Gastrointestinal Diseases / chemically induced
  • Humans
  • Irritable Bowel Syndrome / drug therapy*
  • Mental Disorders / chemically induced
  • Pyridines / adverse effects
  • Pyridines / therapeutic use
  • Rimonabant / adverse effects
  • Rimonabant / therapeutic use

Substances

  • Amides
  • Cannabinoid Receptor Antagonists
  • Gastrointestinal Agents
  • Pyridines
  • Rimonabant
  • N-(3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl)-2-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)propanamide