Effect of delta9-tetrahydrocannabinol, a cannabinoid receptor agonist, on the triggering of transient lower oesophageal sphincter relaxations in dogs and humans.
OBJECTIVE
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 CB(1)/CB(2) 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.


METHODS
In dogs, manometry was used to evaluate the effect of delta(9)-THC in the presence and absence of the CB(1) 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.


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
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.
Beaumont
H
H
Academic Medical Centre, Department of Gastroenterology and Hepatology, Amsterdam, The Netherlands.
Jensen
J
J
Carlsson
A
A
Ruth
M
M
Lehmann
A
A
Boeckxstaens
Ge
G
D000328:Adult; D000818:Animals; D063386:Cannabinoid Receptor Agonists; D003679:Deglutition / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D013759:Dronabinol / Q000009:adverse effects / Q000494:pharmacology*; D049630:Esophageal Sphincter, Lower / Q000187:drug effects* / Q000502:physiology; D005260:Female; D005764:Gastroesophageal Reflux / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008875:Middle Aged; D009126:Muscle Relaxation; D010880:Piperidines / Q000494:pharmacology; D019518:Postprandial Period; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors; D000077285:Rimonabant; D013045:Species Specificity; D055815:Young Adult
D063386:Cannabinoid Receptor Agonists; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D013759:Dronabinol; D000077285:Rimonabant