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Randomized Controlled Trial
, 156 (1), 153-62

Effect of delta9-tetrahydrocannabinol, a Cannabinoid Receptor Agonist, on the Triggering of Transient Lower Oesophageal Sphincter Relaxations in Dogs and Humans

Affiliations
Randomized Controlled Trial

Effect of delta9-tetrahydrocannabinol, a Cannabinoid Receptor Agonist, on the Triggering of Transient Lower Oesophageal Sphincter Relaxations in Dogs and Humans

H Beaumont et al. Br J Pharmacol.

Abstract

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 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.

Experimental approach: 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.

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.

Figures

Figure 1
Figure 1
Mean Δ9-tetrahydrocannabinol (Δ9-THC) plasma concentration in dogs (A) and humans (B). Peak plasma concentrations occurred 40 and 60 min after drug administration in dogs and humans respectively, and declined rapidly with time. Note the difference in scaling of the axes.
Figure 2
Figure 2
Percentage of inhibition by different doses of Δ9-tetrahydrocannabinol in dog and human studies. Maximal inhibition of transient lower oesophageal sphincter relaxations (TLESRs) occurred up to 40% and 53% in dogs and humans respectively, with the selective CB1 receptor antagonist SR141716A reversing the inhibitory effect of Δ9-tetrahydrocannabinol.
Figure 3
Figure 3
(A) transient lower oesophageal sphincter relaxations (TLESRs) in dogs. Δ9-tetrahydrocannabinol (Δ9-THC) produced a dose-dependent inhibition of TLESRs. At the highest dose, the rate of TLESRs was significantly reduced from 10.2 ± 0.6 in control experiments to 6.0 ± 0.6 during Δ9-THC. SR141716A reversed the inhibitory effect of Δ9-THC. (B) The number of reflux episodes was significantly reduced by Δ9-THC at the two highest doses. *P < 0.05 compared with controls (Student's paired t-test).
Figure 4
Figure 4
(A) Swallowing rate in dogs was significantly reduced by Δ9-THC at 0.4 and 0.6 µmol kg−1. (B) No significant effect was seen on basal LES pressure in dogs. (C) Latency time to the first transient lower oesophageal sphincter relaxation (TLESR) was significantly increased at the dose of 0.4 µmol kg−1. *P < 0.05 compared with controls (Student's paired t-test). LESp, lower oesophageal sphincter pressure.
Figure 5
Figure 5
TLESRs in humans. (A) Meal induced increase in transient lower oesophageal sphincter relaxations (TLESRs) was most pronounced during the first postprandial hour. (B) Δ9-tetrahydrocannabinol (Δ9-THC) 20 mg, but not Δ9-THC 10 mg, significantly reduced the rate of TLESRs during the total three postprandial hours (mixed model using pairwise comparisons). (C) Δ9-THC dose-dependently decreased the rate of TLESRs during the first postprandial hour (placebo 7.7 ± 0.5; Δ9-THC 10 mg 5.5 ± 0.7; Δ9-THC 20 mg 3.7 ± 1.2) (mixed model using pairwise comparisons). No reduction in TLESRs was seen during the second and third postprandial hours *P < 0.05 compared with the preprandial period during placebo (Student's paired t-test).
Figure 6
Figure 6
(A) Latency time in humans was increased significantly from 5.1 ± 1.5 min during placebo to 37.7 ± 17.0 min during Δ9-THC 20 mg (P < 0.002). No significant effect was seen with Δ9-THC 10 mg compared with placebo. (B) Mean swallowing rate in humans. Δ9-THC 20 mg induced a significant inhibition of swallowing rate [placebo 251 ± 31.1; Δ9-THC 10 mg 208 ± 32.6 (ns); Δ9-THC 20 mg 135 ± 28.4 (P < 0.04)] (mixed model using pairwise comparisons). Δ9-THC, Δ9-tetrahydrocannabinol; TLESRs, transient lower oesophageal sphincter relaxations.
Figure 7
Figure 7
Acid reflux episodes in humans. If the total postprandial period is taken into account there is no difference in reflux episode rate. During the first postprandial hour the amount of reflux episodes was decreased from 1.83 ± 0.5 (placebo) to 0.67 ± 0.4 [Δ9-tetrahydrocannabinol (Δ9-THC) 20 mg]. This difference, however, was not significant, most likely due to the very few episodes detected.
Figure 8
Figure 8
Effect of Δ9-tetrahydrocannabinol (Δ9-THC) on basal LES pressure in humans. Both Δ9-THC 10 mg and 20 mg significantly decreased basal LES pressure starting around T = 60 min and this recovered slowly with time (P < 0.05) (mixed model using pairwise comparisons). LESp, lower oesophageal sphincter pressure.
Figure 9
Figure 9
The effect of the various treatments on mean heart rate in humans. During Δ9-tetrahydrocannabinol (Δ9-THC) there was a significant tachycardia starting at T = 45 min, with its maximum effect at T = 90 min (placebo 61 beats min−1, Δ9-THC 10 mg 74 beats min−1 and THC 20 mg 79 beats min−1); heart rate recovered slowly with time after administration of Δ9-THC. The tachycardia was most marked with Δ9-THC 20 mg (mixed model using pairwise comparisons).

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