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

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 Delta(9)-tetrahydrocannabinol (Delta(9)-THC) on TLESRs in dogs. Based on these findings, the effect of Delta(9)-THC was studied in healthy volunteers. Experimental approach: In dogs, manometry was used to evaluate the effect of Delta(9)-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 Delta(9)-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, Delta(9)-THC dose-dependently inhibited TLESRs and reduced acid reflux rate. SR141716A significantly reversed the effects of Delta(9)-THC on TLESRs. Similarly, in healthy volunteers, Delta(9)-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 Delta(9)-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: Delta(9)-THC significantly inhibited the increase in meal-induced TLESRs and reduced spontaneous swallowing in both dogs and humans. In humans, Delta(9)-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.