Effect of Δ9-tetrahydrocannabinol, a cannabinoid receptor agonist, on the triggering of transient lower oesophageal sphincter relaxations in dogs and humans


Professor Dr GE Boeckxstaens, Department of Gastroenterology, University Hospital Leuven, Catholic University of Leuven, Herestraat 45, 3000 Leuven, Belgium. E-mail: guy.boeckxstaens@med.kuleuven.be


Background and purpose:  Transient lower oesophageal sphincter relaxations (TLESRs) are the main mechanism underlying gastro-oesophageal reflux and are a potential pharmacological treatment target. We evaluated the effect of the CB1/CB2 receptor agonist Δ9-tetrahydrocannabinol (Δ9-THC) on TLESRs in dogs. Based on these findings, the effect of Δ9-THC was studied in healthy volunteers.

Experimental approach:  In dogs, manometry was used to evaluate the effect of Δ9-THC in the presence and absence of the CB1 receptor antagonist SR141716A on TLESRs induced by gastric distension. Secondly, the effect of 10 and 20 mg Δ9-THC was studied in 18 healthy volunteers in a placebo-controlled study. Manometry was performed before and for 3 h after meal ingestion on three occasions.

Key results:  In dogs, Δ9-THC dose-dependently inhibited TLESRs and reduced acid reflux rate. SR141716A significantly reversed the effects of Δ9-THC on TLESRs. Similarly, in healthy volunteers, Δ9-THC significantly reduced the number of TLESRs and caused a non-significant reduction of acid reflux episodes in the first postprandial hour. In addition, lower oesophageal sphincter pressure and swallowing were significantly reduced by Δ9-THC. After intake of 20 mg, half of the subjects experienced nausea and vomiting leading to premature termination of the study. Other side-effects were hypotension, tachycardia and central effects.

Conclusions and implications:  Δ9-THC significantly inhibited the increase in meal-induced TLESRs and reduced spontaneous swallowing in both dogs and humans. In humans, Δ9-THC significantly reduced basal lower oesophageal sphincter pressure. These findings confirm previous observations in dogs and indicate that cannabinoid receptors are also involved in the triggering of TLESRs in humans.