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Keywords:

  • accommodation;
  • colon;
  • dronabinol;
  • motility;
  • stomach;
  • transit

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Abstract  Cannabinoid receptor (CBR) stimulation inhibits motility and increases food intake in rodents. Effects of CBR stimulation in human gastrointestinal (GI) tract are unclear. We compared effects of dronabinol (DRO) and placebo (PLA) on GI transit, gastric volume and satiation in humans. In a double-blind, randomized study, 30 healthy volunteers were randomly assigned to DRO 5 mg b.i.d. or PLA for three doses. We measured GI functions noninvasively: day 0, Ensure® satiation test to measure maximum tolerated volume (MTV) and 30-min post-Ensure® symptoms; day 1, scintigraphic transit (111In-egg meal) and fasting and postprandial gastric volume (99Tcm-SPECT); day 2, 24-h colonic transit and repeat satiation test. ancova was used to compare treatment groups with gender, age, and, for the satiation test, the baseline MTV, as covariates. A log-rank test was used to assess treatment effects on gastric emptying. Planned sample size had 80% power to detect 25–30% differences in primary end points. There was an overall retardation of gastric emptying with DRO (P = 0.018); this was more pronounced in females (P = 0.011), than in males (P = 0.184). No significant treatment differences were detected for gastric volumes, MTV, post-Ensure® symptoms, small bowel and colonic transit. Fasting gastric volume was greater in males receiving DRO compared with PLA (238 ± 17 vs 185 ± 16, P = 0.04). DRO retards gastric emptying in humans; effects are gender-related. Dronabinol also increases fasting gastric volumes in males.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Cannabinoids are medications approved for relief of vomiting and for stimulating appetite in patients with cancer. The effects of cannabinoids are mediated primarily by cannabinoid receptors (CBR), which are located on cells in the central and enteric nervous systems, and on immune cells. Two types of G protein-coupled CBRs, named CB1 and CB2, have been identified and cloned.1–3 Recent data suggest the presence of a third, as yet uncloned, CBR.4 The endocannabinoid system consists of anandamide, 2-arachidonyl glycerol (2-AG), their receptors and the inactivating enzymes monoacylglyceride lipase and fatty acid amide hydrolase (FAAH).5–8

CB1 immunoreactivity is present in enteric neurones of human colon and ileum; activation of these receptors results in inhibition of excitatory cholinergic input to smooth muscles. CB2 immunoreactivity is also found in human colon.9–12 There is great variability in the activity of the endocannabinoid system between species, and in different regions of the gastrointestinal (GI) tract of the same species. CB1 immunoreactivity is detected in myenteric cholinergic neurones of rodents and pigs.13,14 In rodent models, activation of enteric cannabinoid CB1 receptors inhibits gastric and small intestinal transit without altering intraluminal pressure and basal tone.15,16 In mice, endocannabinoids acting on myenteric CB1 receptors, tonically inhibit colonic propulsion.17

Thus, while much is known about the effects of cannabinoid modulation on GI motor function in animals, the effects in human GI tract are unclear; specifically, reports of effects on GI transit and sensation in humans in vivo are sparse, and the role of stomach function in the appetite-stimulating effects of cannabinoid agonists is unclear. Conversely, CBR1 antagonists such as rimonabant are being tested as agents to reduce appetite and weight and a proportion of patients develop nausea, and postprandial glycaemic levels and insulin responses that are all consistent with an effect on gastric emptying.18

The aims of the present study were to characterize the effects of a non-selective cannabinoid agonist, dronabinol (DRO), on gastric emptying, small bowel and colonic transit, gastric volume, satiation and postprandial symptoms in healthy volunteers.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

This was a double-blind, randomized, placebo-controlled, parallel-group study of the pharmacodynamic effects of DRO on GI transit, gastric volume, satiation and postprandial symptoms. The study was approved by Mayo Clinic Institutional Review Board (IRB) and a data safety monitoring (DSM) plan was established prior to starting the study. The trial consisted of an initial screening visit, to evaluate if the subjects qualify for randomization to study medication. All participants underwent a baseline satiation test prior to treatment.

Using public advertisement at a medical centre, we recruited 30 healthy subjects with no history of GI symptoms, particularly no evidence of irritable bowel syndrome, anxiety or depression,19,20 and no exposure to cannabinoids for at least 3 months. Participants were randomized to placebo (PLA), or DRO. The initial DRO dose of 7.5 mg b.i.d. (taken with water, 1 h before meal) for three doses was decreased to 5 mg b.i.d. for three doses after the first six participants were randomized. This was in response to the required dose reduction according to the prespecified DSM plan after side effects were experienced by three of these first six participants. The adverse events were reported to the IRB and in accordance with the plan, the dose was reduced in all subsequent participants (n = 24). Allocation was concealed throughout the study, and investigators were blinded to all treatment assignments until study blind was communicated to the study statistician by the research pharmacist.

One hour after the first dose of study medication, participants underwent a combined scintigraphic transit test and gastric volume measurement using a previously validated method.21 Participants took a second dose of study medication in the evening of this first study day. Colonic transit images at 24 h22 and a satiation test were performed 1 h after the third and last dose of study medication23 (Fig. 1).

image

Figure 1.  Experimental protocol. Each participant received three doses of study medication and physiological tests were started 1 h after the first and third doses.

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Participants and eligibility criteria

Thirty healthy participants were recruited by public advertisement. Each participant completed a validated bowel disease questionnaire (abridged Bowel Disease Questionnaire19), the Hospital Anxiety and Depression Scale (HADS20) and was screened for any chronic GI symptoms. Inclusion criteria were: adults 18–65 years of age, free of chronic GI illness and body mass index (BMI) between 18 and 32 kg m−2.24 All females of child-bearing potential had to have negative pregnancy test within 48 h of study.

Exclusion criteria included: abdominal surgery other than appendectomy or hernia repair (at least 3 months prior to study); positive GI symptoms on bowel disease questionnaire; use of medications that may alter GI motility or sensation (including over-the-counter medication within 7 days of start of the study); symptoms of a significant clinical illness in the preceding 2 weeks; alcoholic or known substance abusers (screened specifically by questionnaire); history of cannabinoid use in the past 3 months and history of allergy to sesame seed oil.

Pharmacology of dronabinol

Dronabinol is synthetic delta-9-tetrahydrocannabinol (Δ9-THC).25 It is a non-selective cannabinoid agonist, 90–95% of the dose is absorbed after a single oral dose. Due to the combined effects of first pass hepatic metabolism and high lipid solubility, only 10–20% of the administered oral dose reaches the systemic circulation. After oral administration, onset of action is approximately after 0.5–1 h and peak effect at 2–4 h. The elimination phase follows a two-compartment model, with an initial half-life of about 4 h and a terminal half-life of 25–36 h. Dronabinol undergoes extensive first-pass hepatic metabolism, primarily by microsomal hydroxylation, yielding both active and inactive metabolites. Biliary excretion is the major route of elimination.

Simultaneous GI transit and gastric volume measurement

A detailed description of our established and validated scintigraphic method of simultaneous measurement of GI transit and gastric volume measurement has been published.26 One hour after ingestion of the first dose of study medication, participants received 99Tcm-pertechnetate (10 mCi) i.v. This is taken up by the gastric mucosa. Ten minutes later, dynamic tomographic acquisition of the gastric wall was captured using a Single Photon Emission Computed Tomography (SPECT) camera (time acquisition approximately 15 min). At the end of recording fasting gastric volume, the participants ingested a standard solid and liquid egg meal containing 100 μCi of 111InCl3. The meal consisted of two eggs to which 111InCl3 was added during the scrambling, cooking process. The eggs were served on one slice of buttered bread with one eight-ounce glass of 1% milk (total calories: 296 kcal, 32% protein, 35% fat, 33% carbohydrate). Postprandial images of the gastric wall were obtained while patients lay horizontally on the SPECT camera table. Further, static anterior and posterior gamma camera images were obtained immediately after completing meal ingestion (H0) and 1, 2, 3, 4 and 6 h thereafter to determine the stomach and orocecal transit. A standardized meal (550 kcal, chicken, potato and pudding) was ingested 4 h after the radiolabelled meal. Images were also obtained to estimate colonic transit, 1 h after the third (last) dose of study medication, at 24 h from the time of ingestion of the radiolabelled meal.

Satiation test

An adaptation of the method of Tack et al. was used.26 This is a meal-induced challenge test that provides information on the maximum tolerated volume (MTV) and the symptoms 30 min post-Ensure® challenge.23 Subjects were asked to ingest a nutrient drink (ENSURE® Ross Laboratories, Abbott Park, IL, USA; 0.95 kcal mL−1) from a cup through a straw, at a rate of 120 mL per 4 min. The cup was refilled and the subjects were instructed to maintain intake at the required rate. At 5-min intervals, participants scored their fullness using a graphic rating scale that combined verbal descriptors on a scale graded 0–5 [0 = no symptoms; 1 = first sensation of fullness (threshold); 2 = mild; 3 = moderate; 4 = severe; 5 = maximum (unbearable fullness)].19,23 Participants were told to stop meal intake when a fullness score of 5 was obtained, at which point the MTV was recorded.

Postprandial symptoms (bloating, fullness, nausea and pain) were measured 30 min after completing the test using a visual analogue scale (VAS) with 100 mm lines anchored with the words ‘none’ (0 mm) and ‘worst ever’ (100 mm) at each end.11 The aggregate symptom score was calculated as the sum of the four 100-mm VAS for each symptom (i.e. maximum 400).

Data analysis

The analyses of all imaging measurements were performed by a single technologist who was blinded to the information on the randomization or any adverse effects experienced by the participants.

Gastrointestinal transit  A variable region of interest programme was used to quantitate the counts in the stomach and each of four colonic regions: ascending (AC), transverse (TC), descending (DC), and combined sigmoid and rectum. These counts were corrected for isotope decay, and tissue attenuation.27,28 Primary outcomes for GI transit were the gastric emptying t1/2 (calculated by linear interpolation of gastric emptying at 1, 2, 3, 4 and 6 h), colonic filling at 6 h (a surrogate for the small bowel transit time)27 and the colonic geometric center (GC) at 24 h. The GC is the weighted average of counts in the different colonic regions: AC, TC, DC, rectosigmoid (RS) and stool. At any time, the portion of colonic counts in each colonic region is multiplied by its weighting factors as follows:

  • image

Thus, a high GC implies faster colonic transit. A GC of 1 implies that all isotope is in the AC, and a GC of 5 implies that all isotope is in the stool.

Gastric volumes during fasting and in response to feeding  The primary end point to assess the effect of DRO on gastric volume was the postprandial change in gastric volume.

Satiation volume and postprandial symptoms  We recorded the volume ingested to reach MTV, and the VAS scores for each postprandial symptom 30 min post-Ensure® challenge. The primary end points were the MTV and the aggregate postprandial symptom score. In previous studies, these have been shown to be the robust end points measured by the nutrient drink test.23,26

Power assessment and statistical analysis

The study was powered for the primary end points based on published data from our laboratory using the same methodology as in the present study.29–31Post hoc analyses evaluated gender effects of DRO. The planned sample size (n = 12 per group) had 80% power to detect 25–30% differences in primary end points between two groups, using a two-sided α of 0.05. The total sample size was increased to 30 after the occurrence of adverse events in three of the first six participants, which led to a decrease in the initial, proposed dose (from 7.5 to 5 mg). An ancova was used to assess overall treatment effects. Age, gender, BMI and pretreatment response values for the satiation test (MTV) were considered as potential covariates underwent to adjust for potential baseline differences among groups. Since two subjects had censored gastric emptying t1/2 values (>240 min) a log-rank test, overall and by gender, was used to assess treatment effects on gastric emptying. All statistical tests used a two-sided α of 0.05. No adjustment in α-level for multiple (types of) end points was planned. Data are reported as adjusted mean ± SEM unless otherwise noted. Treatment effects were assessed based on using an intention-to-treat (ITT) paradigm. Missing values in a few subjects were imputed using the overall mean value in subjects with non-missing values for each specific end point. A corresponding adjustment in the error degrees of freedom was used to compensate by subtracting one degree of freedom for each missing value imputed.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Participants and compliance with medication

Thirty healthy volunteers meeting the entry criteria were screened and participated in the study. Three subjects did not take the third dose of their medication due to headache, nausea and lightheadedness and did not participate in the satiation test on visit 3 of the study (one in the PLA group and two in the active drug group). Two of the same three participants did not undergo measurement of colonic transit study at 24 h (one in each treatment group). However, these individuals were included in the analysis with their missing data imputed (see Materials and Methods) to maintain an ITT analysis. Participants and investigators remained blinded to the randomization. Compliance with the study treatment assigned was complete after decreasing the DRO dose to 5 mg. Table 1 summarizes patients’ demographics (age, BMI) and baseline satiation parameters by treatment group. No BMI association was detected nor treatment by BMI interaction effects on gastric emptying or gastric volume responses.

Table 1.   Participants’ baseline characteristics (mean ± SEM)
 Dronabinol (n = 15)Placebo (n = 15)
Age (years)26 ± 229 ± 1
Number of males (mean age) : number of females (mean age)7 (22) : 8 (29)7 (29) : 8 (29)
BMI (kg m−2)25.4 ± 0.825.4 ± 1.0
Baseline maximum tolerated volume (mL)1197 ± 781138 ± 107
Baseline aggregate symptom score (maximum 400 mm)140 ± 12147 ± 20

Gastric emptying

Dronabinol resulted in significant delay of gastric emptying (P = 0.018, Table 2). Post hoc analysis showed that the overall drug effect on gastric emptying was due to a significant effect observed in females (P = 0.011), with no statistically significant difference (P = 0.184) in males (Table 2 and Fig. 2). There was a borderline gender interaction effect (increase in female and no change in males) detected for gastric emptying using ancova (P = 0.082).

Table 2.   Effect of dronabinol on gastric emptying (mean† ± SEM)
 DronabinolPlacebo
  1. *P < 0.05, based on log-rank test.

  2. †Mean values (±SEM) ignoring the censoring (two values >240 min).

GE t50, min (n = 15; median)175 ± 11 (165)150 ± 6 (145)*
GE t50, min, male (n = 7; median)146 ± 11 (157)140 ± 5 (140)
GE t50, min, female (n = 8; median)200 ± 13 (200)158 ± 10 (158)*
image

Figure 2.  Effect of dronabinol and placebo on gastric emptying t1/2 (min) in males and females; note the significant effect of dronabinol is essentially due to a significant effect in females.

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Small bowel and colonic transit

Colonic filling at 6 h, a surrogate of small bowel transit, and colonic transit at 24 h (GC 24 h) were not significantly different in response to DRO vs PLA (Table 3). The overall effect of DRO on small bowel and colonic transit was not gender-dependent (Table 3).

Table 3.   Effect of dronabinol on small bowel transit (CF at 6 h) and colonic transit at 24 h [geometric center, GC at 24 h (mean* ± SEM)]
 DronabinolPlacebo
  1. *Least-squares mean (±SEM) values adjusted for age and gender from ancova (includes imputed values for missing GC24 values in two subjects).

  2. CF, colonic filling.

CF at 6 h,% (n = 15)31.4 ± 5.729.3 ± 5.7
 CF at 6 h%, male (n = 7)49.5 ± 9.051.8 ± 8.2
 CF at 6 h%, female (n = 8)13.2 ± 7.76.9 ± 7.7
Colonic GC at 24 h (n = 15)2.0 ± 0.22.4 ± 0.2
 GC 24 h, male (n = 7)2.2 ± 0.32.9 ± 0.3
 GC 24 h, female (n = 8)1.9 ± 0.31.8 ± 0.3

Gastric volume and postprandial symptoms

The effects of DRO on fasting gastric volume, postmeal gastric volume, MTV, postprandial aggregate symptom score and postprandial fullness score are shown in Table 4. Overall, no significant differences due to treatment were detected, though a gender by treatment interaction effect was observed for fasting gastric volumes (P = 0.047). Dronabinol resulted in a larger fasting gastric volume in males (238 ± 17 vs 185 ± 16 on PLA, P = 0.040), but a slightly smaller fasting gastric volume in females (216 ± 15 vs 230 ± 15 on PLA, P = 0.50).

Table 4.   Effect of dronabinol on gastric volumes, MTV and postprandial symptoms (mean* ± SEM)
 Dronabinol (n = 15)Placebo (n = 15)
  1. *Least-squares adjusted mean (±SEM) values adjusted for age and gender from the ancova (includes imputed values for subjects missing data on satiation test measurements).

  2. P = 0.069.

  3. MTV, maximum tolerated volume.

Fasting gastric volume (mL)227 ± 11208 ± 11
Postmeal gastric volume (mL)800 ± 27736 ± 26
Postmeal change in gastric volume (mL)574 ± 27529 ± 270
MTV (mL)1242 ± 651178 ± 64
Aggregate symptom score (maximum 400)143 ± 16159 ± 16
Fullness score (maximum 100)59 ± 470 ± 4†

Adverse effects

As previously stated, three of the first six participants in the study (who were in the phase where they were randomized to PLA or DRO 7.5 mg b.i.d.) experienced vasovagal episodes with lightheadedness and dizziness.

After the DRO dose was reduced to 5 mg b.i.d, 14 of the 24 participants who were randomized to treatment with DRO or PLA experienced symptoms, such as drowsiness, dry mouth, lightheadedness, difficulty to concentrate, mild confusion and nausea (Table 5). It is worth noting that six participants randomized to PLA experienced lightheadedness or drowsiness, though more participants on DRO were nauseated. Information on adverse effects was not provided to the technologist performing any of the data analyses.

Table 5.   Adverse events
 Dronabinol (n = 15)Placebo (n = 15)
Dizziness/lightheadedness102
Drowsiness56
Dry mouth40
Disturbed mental concentration31
Excitement20
Euphoria/relaxed20
Flushing10
Headache22
Numbness01
Nausea70
Vasovagal21

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

In vitro studies suggest that cannabinoids enhance delay transit in human colon and ileum.11,17 The present double-blind, randomized trial is the first study to evaluate the effect of administration of an exogenous cannabinoid agonist, DRO, on the physiology of the human GI tract, including gastric and colonic transit, gastric volumes and satiation in healthy human subjects.

Prior to this study, limited and conflicting data were available regarding the effects of the cannabinoid system and GI motility in healthy human subjects. In a randomized double blind trial, McCallum et al. showed that Δ9-THC (10 mg m−2) administered 1 h before the meal, delayed gastric emptying of a radiolabelled solid meal in nine male and four female healthy subjects, who were experienced cannabis users.32 In contrast, Bateman found that gastric emptying of liquid, measured by real time ultrasound, was unaffected by Δ9-THC (0.5 and 1 mg i.v.) in seven fasted cannabis-naive male volunteers.33 The different conclusions derived from these studies might be due to the methodology or to differences in prior exposure to cannabis. McCallum et al.32 studied the gastric emptying of a radiolabelled solid meal, whereas Bateman33 studied gastric emptying of liquid measured by ultrasound. McCallum et al.32 assessed people with prior experience with cannabinoids, while Bateman33 studied cannabis-naive subjects. Bateman33 studied only male volunteers. This is relevant given the potential for gender-related differences in the effects of cannabinoids on gastric emptying.

Our study suggests that DRO was associated with a significant delay in gastric emptying of a standard solid and liquid meal, and there is a suggestion of a gender effect influencing the response to the cannabinoid agonist, as indicated by the borderline gender interaction effect (increase in female and no change in males) detected for gastric emptying using ancova (P = 0.082) and the post hoc analysis showing a significant slowing in gastric emptying in females (P = 0.01). Dronabinol did not significantly change gastric emptying in males.

Data from our laboratory has shown that there is no consistent age- or gender-related differences in GI transit among healthy volunteers up to 65 years old, using the same methodology used in this study.28 The lack of effect of DRO on gastric emptying in males is consistent with the observations in Bateman's33 study which included only healthy male volunteers. The retardation in gastric emptying by the cannabinoid DRO is of interest given the reports that the CB1 antagonist rimonabant reduces appetite and weight in obesity.18 The role of cannabinoid-induced modulation of gastric emptying on satiation, appetite and weight loss deserves further study. Thus, if a cannabinoid antagonist results in accelerated gastric emptying, there may be increased postprandial satiation. This is supported by the observation that reduction of gastric volume or acceleration of gastric emptying at 1 h with pharmacological agents induced symptoms of satiation in obesity.34

The antiemetic effects of cannabinoids are shown in clinical trials of the use of cannabinoids for medicinal purposes.35,36 Our study did not assess the potential antiemetic property of DRO. It is, however, useful to note whether the increase in fasting gastric volume observed in male participants might have an antiemetic effect, though this needs to be tested formally in future studies.

Previous study suggests that higher fasting gastric volume is associated with reduced postprandial symptoms and reduced satiation after a meal, which may facilitate greater food intake.30,34 This may contribute to the orexigenic properties of cannabinoids. Interestingly, the fullness score after the meal challenge was somewhat lower with DRO (P = 0.08). However, the DRO dose used in this study was at the lower end of the 2.5–40 mg day−1 range of doses typically used for countering emesis or inducing appetite, and may therefore have been too low to induce a reduction in symptoms, such as nausea after the challenge test with Ensure®. Dronabinol did not change postprandial gastric volume, MTV or sensation at the dose tested. Our data suggest that the antiemetic effect of cannabinoids is not due to a direct effect on gastric accommodation or sensation, but to a central effect. The change in fasting gastric volume without alteration of gastric emptying observed in males is at present of unclear significance and requires further study.

In contrast to animal models and in vitro functional studies in human colonic and ileal smooth muscle, our study did not show a significant delay in small bowel or colonic transit in response to the cannabinoid agonist, DRO. The discrepancy could be due to species differences in the population of the neurones that contain CBRs. In animals, there is co-localization of CBRs with cholinergic neurones in the enteric nervous system.13,14,17 This was proposed as a potential modulator of colonic motor function, as in vitro CBR activation inhibits cholinergic excitation to human colonic and ileal smooth muscle.10,11 Localization of CBRs on myenteric neurones of human GI tract is unknown.

The significance of the gender-related differences in effects of DRO on human gastric emptying is unclear. The literature does not provide other examples of gender-related differences in the effects of cannabinoids in humans. However, gender-related differences in biological effects of cannabinoids have been reported in animal models.37,38 Chronic exposure to Δ9-THC produces activation of corticotrophin-releasing hormone (CRH) and pro-opiomelanocortin (POMC) gene expression in the rat hypothalamus. Cochero et al. showed that POMC and CRH gene expression induced by Δ9-THC is gender-related.37,38

In conclusion, the ‘endocannabinoid system’ in the human stomach can be stimulated by a non-selective CBR agonist, DRO, to delay gastric emptying. Further studies with selective and non-selective cannabinoid antagonists are indicated. Given the suggestion of gender-related changes in gastric emptying and fasting gastric volume observed with acute DRO treatment, future studies with cannabinoids should stratify subjects by gender to formally appraise the effect of gender.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

This study was supported, in part, by Mayo General Clinical Research Center Grant RR00585 and by grants R01-DK54681, R01-DK 67071 and K24-DK02638 (MC) from National Institutes of Health.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
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