Cannabinoid receptors (CBR) are located on cholinergic neurons in the brain stem, stomach and colon. CBR stimulation inhibits motility in rodents. Effects in humans are unclear. Hypothesis: Dronabinol (DRO), a non-selective CBR agonist, inhibits colonic motility and sensation. Aims: To compare effects of DRO and placebo (PLA) on colonic motility and sensation in healthy volunteers. Methods: 52 volunteers were randomly assigned (double-blind) to a single dose of DRO 7.5 mg or PLA p.o. with concealed allocation. A balloon-manometric assembly placed into descending colon allowed assessment of colonic compliance, motility, tone and sensation prior to and 1 hour after oral ingestion of medication, and during fasting, and for one hour after 1000 kcal meal. Results: There was an overall significant increase in colonic compliance (p=0.045), a borderline effect of relaxation in fasting colonic tone (p=0.096), inhibition of postprandial colonic tone (p=0.048), and inhibition of fasting and postprandial phasic pressure (p=0.008 and 0.030 respectively). While DRO did not significantly alter thresholds for first gas or pain sensation, there was an increase in sensory rating for pain during random phasic distensions at all pressures tested and in both genders (p=0.024). Conclusion: In humans, the non-selective CBR agonist, dronabinol, relaxes the colon and reduces postprandial colonic motility and tone. Increase in sensation ratings to distension in the presence of relaxation of the colon suggests central modulation of perception. The potential for CBR to modulate colonic motor function in diarrheal disease such as irritable bowel syndrome deserves further study.