Pharmacogenetic trial of a cannabinoid agonist shows reduced fasting colonic motility in patients with nonconstipated irritable bowel syndrome

Abstract

Background & aims: Cannabinoid receptors are located on cholinergic neurons. Genetic variants that affect endocannabinoid metabolism are associated with colonic transit in patients with irritable bowel syndrome (IBS) with diarrhea. We compared the effects of dronabinol, a nonselective agonist of the cannabinoid receptor, with those of placebo on colonic motility and sensation in patients with IBS, and examined the effects of IBS subtype and specific genetic variants in cannabinoid mechanisms.

Methods: Seventy-five individuals with IBS (35 with IBS with constipation, 35 with IBS with diarrhea, and with 5 IBS alternating) were randomly assigned to groups that were given 1 dose of placebo or 2.5 mg or 5.0 mg dronabinol. We assessed left colonic compliance, motility index (MI), tone, and sensation during fasting and after a meal. We analyzed the single nucleotide polymorphisms CNR1 rs806378, fatty acid amide hydrolase (FAAH) rs324420, and MGLL rs4881.

Results: In all patients, dronabinol decreased fasting proximal left colonic MI compared with placebo (overall P = .05; for 5 mg dronabinol, P = .046), decreased fasting distal left colonic MI (overall P = .08; for 5 mg, P = .13), and increased colonic compliance (P = .058). The effects of dronabinol were greatest in patients with IBS with diarrhea or IBS alternating (proximal colonic MI, overall P = .022; compliance, overall P = .03). Dronabinol did not alter sensation or tone. CNR1 rs806378 (CC vs CT/TT) appeared to affect fasting proximal MI in all patients with IBS (P = .075). Dronabinol affected fasting distal MI in patients, regardless of FAAH rs324420 variant (CA/AA vs CC) (P = .046); the greatest effects were observed among IBS with constipation patients with the FAAH CC variant (P = .045). Dronabinol affected fasting proximal MI in patients with IBS with diarrhea or alternating with the variant FAAH CA/AA (P = .013).

Conclusions: In patients with IBS with diarrhea or alternating, dronabinol reduces fasting colonic motility; FAAH and CNR1 variants could influence the effects of this drug on colonic motility.

Trial registration: ClinicalTrials.gov NCT01253408.

Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Trial flow chart and baseline characteristics of study participants (Mean ± SEM, unless otherwise noted).

Figure 2

Effect of dronabinol on colonic compliance. Data reported are least squares (LS) means and standard errors (SEM). The error bars are based on the square root of the ratio: pooled estimate of residual error variance (across all subgroups from the ANCOVA) divided by the subgroup sample size.

Figure 3

Effect of dronabinol on colonic phasic pressure activity. Data reported are least squares (LS) means and standard errors (SEM). The error bars are based on the square root of the ratio: pooled estimate of residual error variance (across all subgroups from the ANCOVA) divided by the subgroup sample size.

Figure 4

Pharmacogenetics of CNR1 rs806378 and colonic motility index. Treatment effects were most prominently suggested in IBS-D/A and the CNR1 rs806378 genotype CC for proximal left colon MI (p=0.075). Data reported are least squares (LS) means and standard errors (SEM). The error bars are based on the square root of the ratio: pooled estimate of residual error variance (across all subgroups from the ANCOVA) divided by the subgroup sample size.

Figure 5

Pharmacogenetics of FAAH and colonic motility index. Differential treatment effects among FAAH rs324420 genotypes (CC vs. CA/AA) and IBS subtypes were observed for proximal left colon MI, (p=0.09), and were most pronounced in IBS-D/A and CA/AA (p=0.013). Differential treatment effects were also observed for distal left colon MI (p=0.046), and were most pronounced in IBS-C and CC (p=0.045). Data reported are least squares (LS) means and standard errors (SEM). The error bars are based on the square root of the ratio: pooled estimate of residual error variance (across all subgroups from the ANCOVA) divided by the subgroup sample size.