The endogenous cannabinoid system in the gastrointestinal (GI) tract is a widespread collection of cannabinoid agents and their receptors, mediating various physiological bowel activities including motility, inflammation, healing, and fibrosis (1,2). Acting via the endogenous cannabinoid system, cannabinoid compounds from recreational cannabis use could modulate the activities of the GI system. Unlike the well-reported opposing actions of the predominant cannabinoid receptors (CB1R and CB2R) on hepatic inflammation, fibrosis, and various hepatic diseases (3), contemporary reports on the effect of these receptors on bowel motility (constipation and diarrhea) are conflicting. Current evidence suggests that cannabinoids slow colonic transit through actions on the CB1 receptor (1,4). However, a recent clinical trial reported that hemp seed pills (HSPs) improved constipation symptoms among patients with functional constipation, suggesting that the summative effect of the separate cannabinoids in the marijuana (MJ) plant might have a unique effect on bowel motility (5).
Constipation and diarrhea are prevalent bowel function disorders commonly encountered by general medical practitioners and responsible for 50% of outpatient gastroenterology care in the United States (6). Globally, constipation affects 14% of community dwellers, translating to a significant financial burden with implications for quality of life (7–10). Likewise, noninfectious chronic watery diarrhea afflicts about 5% of the population and is associated with adverse medical consequences and mental health, including loss of self-confidence (11–13).
With the increasing use of recreational MJ and widespread liberalization of US cannabis regulation, population-based studies can fill the gap between our understanding of the physiologic effects of cannabis on bowel function and the real-world implications of regular MJ use. Herein, we investigate the effect of MJ use on bowel function among community dwellers across the United States using a large, population-based survey.
We selected adult subjects (aged 20–59 years) from the continuous National Health and Nutrition Survey (NHANES) 2005–2010 (Figure 1). Conducted by the National Center for Health Statistics of the Centers for Disease Control, the NHANESs are biannual cross-sectional surveys of nationally representative noninstitutionalized members of the United States. A complex multistaged stratified clustered probability-based methodology was used to select study participants, with oversampling of some demographic groups to prevent their underrepresentation. Sample weights in the NHANES allow results to be extrapolated to the population of the United States as a whole with accommodations for the dissimilarities in participant selection, complex sample design, survey nonresponse, and poststratification.
We included all subjects who responded to both the bowel health questionnaires and drug use questionnaire (N = 9,645). Although both questionnaires were completed with a Computer-Assisted Personal Interview System at the Mobile Examination Centers, the drug use questionnaires were conducted in a private room and were limited to those younger than 60 years.
Assessment of bowel motility function
Bowel function (constipation, diarrhea, and normal function) was assessed using both the Bristol Stool Form Scale (BSFS) and the frequency criteria, which were both derived from the bowel health questionnaire, a standardized set of questions pertaining to bowel movement perception, frequency, and consistency. Both methods have been extensively used in other NHANES publications (14–17). Subjects were categorized as either having diarrhea or constipation if they met any of the 2 classification criteria.
The BSFS was administered with color picture cards containing pictures and written descriptors of the 7 stool types, and subjects were asked the following written questions: “Please look at this card and tell me the number that corresponds with your usual or most common stool type.” Constipation was defined as type 1 (separate hard lumps, like nuts) and type 2 (sausage-like, but lumpy). Normal function was defined as type 3 (like a sausage but with cracks in the surface), type 4 (like a sausage or snake, smooth and soft), or type 5 (soft blobs with clear-cut edges). Diarrhea was defined as type 6 (fluffy pieces with ragged edges, a mushy stool) or type 7 (watery, no solid pieces).
Bowel function was also measured using weekly stool frequency with the following question, “How many times per week do you usually have a bowel movement?” Responses were trichotomized into less than 3 bowel movements per week (constipated), 3 to 21 bowel movements per week (normal), and more than 21 bowel movements per week (diarrhea) in line with previous NHANES data (15).
Measurement of MJ use
We assessed MJ use among those who completed the drug use questionnaire, which was limited to participants aged 20–59 years. Participants completed 2 questions related to MJ use: “Have you ever, even once, used marijuana or hashish?” and “During the past 30 days, on how many days did you use marijuana or hashish?” We coded MJ use in 2 variables based on responses to both questions: a binary variable of recent users vs past/never users (individuals who have used MJ at least once within the past 30 days vs all others) and a trinomial variable comprising of recent users in 1 group and the 2 other groups derived from splitting of past/never users: past users (those who have used MJ in the past but not in the recent 30 days) and never users (those who have never used MJ before). Similar methods have been used to study MJ use in the NHANES previously (18,19).
Demographic, comorbid medical, lifestyle, and dietary factors were identified from the NHANES as covariables. Demographic factors included sex, age (grouped into decades: 20–29, 30–39, 40–49, and 50–59 years), race/ethnicity (Hispanic, non-Hispanic whites, non-Hispanic blacks, and others), education (below, completed, and above high school/general education), and poverty income ratio (<2 and ≥2 times the poverty threshold), and the body mass index was calculated and categorized (normal: <25 kg/m2, overweight: 25–29.9 kg/m2, and obese: ≥30 kg/m2).
Comorbid medical diagnoses included many diseases that were identified by self-reported diagnosis with the question “Has a doctor or other health professional ever told you that you had (name of disease)?” Diseases included thyroid disorders, chronic lung diseases (asthma, emphysema, or chronic bronchitis), chronic heart failure, coronary artery disease, stroke, cancer, hypertension, and chronic liver disease. The number of the chronic diseases was grouped into 5 categories: none, 1, 2, 3, or 4 or more. Depression was assessed with the validated Patient Health Questionnaire (PHQ) (20). We identified diabetes as self-report of being informed by a health professional of having diabetes or taking diabetic medications or insulin or hemoglobin A1c of ≥6.5. General health status was measured as a binary variable from a question where respondents reply how they feel about their health condition. Responses with “Excellent or very good or good” was one category, whereas “Fair or poor” was the second category. Alcohol, cigarette, heroin, and cocaine use were all coded in binary form as recent users vs past/never users, similar to MJ use. Medications that could result in constipation were captured from a list of daily medications taken by the respondents (see Table S1, Supplementary Digital Content 1, http://links.lww.com/AJG/B314). Vigorous physical activity was captured by questions on participation in any vigorous activity causing heavy sweating, large increase in breathing, or increased heart rate either at work or during leisure time. Finally, given that MJ has been reported to be an anxiolytic, we collected data on emotional disturbances, which were captured as having ever had any sort of emotional problems including depression and anxiety for more than 3 days.
Dietary factors were assessed using a 24-hour dietary recall methodology comprising of questionnaires on the details of the type and quantity of food, water, beverages, and nutrients consumed during the preceding 24-hour period. Two interviews were conducted. The first was during an in-person visit, and the second was by telephone 3–10 days after the initial, in-person visit. Over 60 food items/nutrients were estimated from the responses on the questionnaires. The funding, collection, coding, processing, analyses, and validation of this method are by the US Department of Agriculture and US Department of Health and Human Services (21). For this study, we averaged the values of 8 food items (protein, carbohydrate, kcal, fat, sugar, caffeine, fiber, and liquid) of both 2-day dietary recalls. These food items were divided and analyzed in quartiles, as done in similar NHANES studies (14).
All statistical analyses were performed with SAS 9.4 and accounted for the complex survey design of the NHANES. A P value of 0.05 was chosen a priori. Effects measures with their 95% confidence intervals and P values were reported.
Categorical variables were presented as frequencies (with percentages) and compared with χ2 tests. Skewed numeric variables were categorized into quartiles. Because the outcome (bowel motility function) was trinomial (constipation, diarrhea, and normal), multinomial logistic regressions (with a generalized logit function) were used to estimate the odds ratio (OR) of having constipation or diarrhea with normal bowel function as the reference. The initial univariate model estimated the crude OR of constipation (or diarrhea) with MJ use (model 1). The model was stepwise adjusted, by including confounding factors as covariates. Model 2 included age alone as a covariate. Model 3 included demographic factors as covariate: age, sex, race/ethnicity, education level, poverty index ratio, and body mass index. Model 4 included all variables in model 3 and comorbidities, constipating medications, substance use (alcohol, tobacco, heroin, and cocaine), general health condition, rigorous physical activity, and emotional disturbances. Finally, model 5 included model 4 and 24-hour dietary composition: protein, sugar, carbohydrate, calorie, fat, caffeine, fiber, and liquid. All the above models were repeated using either the BSFS or bowel frequency as a measure of bowel function.
Finally, we performed a subgroup analysis on respondents with recent 30-day MJ use (n = 1,180). We trichotomized them into 3 groups based on frequency (number of days within the past month) of MJ usage (1–3-days, 4–19-days, and 20–30-days) and estimated the frequency of bowel function (constipation, diarrhea, and normal) in each category. We performed a series of sensitivity analyses. The first was to exclude respondents with colon cancer (n = 16), inflammatory bowel disease (n = 38), and celiac disease (n = 22). The second was to exclude respondents with laxative use (n = 262), which was only captured in the 2009–2010 NHANES cycle.
Because NHANES data are deidentified and publicly available, no institution review board approval was considered necessary, but all participants provide written informed consent before completing the surveys.
Table 1 shows the distribution of bowel function with MJ use. Using the BSFS as a measure of bowel function, recent MJ users had reduced frequency of constipation compared with past or never users (recent users: 5.2% vs past users: 6.7% and never users: 8.1%) (Figure 2). Recent MJ users also had a higher frequency of normal bowel function compared with past or never users (88.2% vs 87.2% and 86.2%). There was no significant difference when bowel function was assessed according to bowel movement frequency. However, when both BSFS and bowel movement frequency were used as a composite measure of bowel function, recent MJ users also had lower frequencies of constipation (7.4% vs 9.4% and 11.2%) and diarrhea (6.9% vs 6.8% and 6.2%), and a higher frequency of normal bowel function (85.7% vs 83.7% and 82.6%) compared with past and never users.
Recent MJ users were more likely to be male, younger (between ages 20 and 29 years), and black compared with never or past users (Table 2). Similarly, they were also more likely to skew toward higher and lower levels of education, have increased levels of poverty, and were less likely to be overweight and/or obese. Compared with past/never users, recent MJ users were more likely to consume alcohol, tobacco, heroin, and cocaine and be depressed (by PHQ data), but were also more likely to have fewer medical comorbidities, diabetes, fewer emotional disturbances (including depression/anxiety), and be engaged in regular, vigorous health activity.
Compared with past and never users, recent MJ users were more likely to be in the highest quartile of daily protein, carbohydrate, calorie, fat, sugar, and liquid intake (see Table S2, Supplementary Digital Content 1, http://links.lww.com/AJG/B314). However, they had a lower frequency of high daily fiber intake (30.1%, 22.5%, and 22.0% in the lowest quartile of fiber intake among recent, past, and never MJ users, respectively).
Multivariate analysis of constipation and MJ use
Recent MJ use was associated with a 30% decreased odds of constipation (crude OR 0.71 [0.56–0.89], P = 0.005) compared with past and never users (Table 3). After stratifying past/never users into 2 groups (past users and never users), recent and past MJ use were associated with 35% and 17% decreased odds of constipation, respectively (crude ORs 0.64 [0.48–0.86] and 0.83 [0.69–0.99]).
Compared with past/never users, recent MJ use was associated with 36% reduced odds of constipation (adjusted odds ratio [AOR] 0.64 [0.51–0.82], P = 0.0005) after adjusting for age alone (model 2, Table 3). The relationship between MJ use and constipation persisted during stepwise adjustment (models 2, 3, 4, and 5, Table 3). After full adjustment for demographic, comorbidities, and diet (model 5), recent MJ use was associated with a 32% decreased odds of constipation (AOR 0.68 [0.52–0.89], P = 0.006). After subgrouping past/never users into 2 (past and never users), recent MJ use was associated with 32% decreased odds of constipation compared with never users (AOR 0.68 [0.478–0.995], P = 0.02), whereas there was no difference between past users compared with never users (AOR 1.00 [0.81–1.23], P = 0.99).
Other factors significantly associated with increased odds of constipation (see Table S2, Supplementary Digital Content 1, http://links.lww.com/AJG/B314) were female sex, black race, lower education levels, increased poverty, depression (by PHQ), and emotional disturbances. Alternatively, decreasing age, obesity, recent cigarette use, excellent/very good/good health condition, and higher dietary fiber and liquid intakes were all associated with decreased odds of constipation. These latter findings are consistent with other NHANES studies examining odds factors for constipation (14).
When only the BSFS was used as a measure of bowel function, recent MJ use was associated with decreased odds of constipation compared with past/never users for the crude and adjusted models except the final model including diet (see Table S3, Supplementary Digital Content 1, http://links.lww.com/AJG/B314). However, when bowel function was measured with weekly stool frequency, recent MJ use was only associated with bowel function in the fourth model (see Table S4, Supplementary Digital Content 1, http://links.lww.com/AJG/B314).
Multivariate analysis of diarrhea and MJ use
There was no relationship between MJ use and diarrhea either in univariate or multivariate analyses (Table 4).
Frequency of bowel function among recent MJ users
There was no significant difference in odds of constipation among MJ users with use in the past 20–30 days vs 4–19 days vs 1–3 days (6.5% vs 7.4% vs 8.3%) (see Table S5, Supplementary Digital Content 1, http://links.lww.com/AJG/B314). Similarly, there was no significant difference in the frequency of diarrhea based on the timing of use (20–30 days, 9.7%; vs 4–19 days, 4.9%; vs 1–3 days, 6.1%).
Exclusion of respondents with colon cancer, inflammatory bowel disease, and celiac disease did not change the relationship between recent MJ use and bowel function. Similarly, after exclusion of laxative users and performing a subgroup analysis only among respondents in the 2009–2010 NHANES cycle, there was no difference in the relationship between recent MJ use and bowel function.
In this representative sample of US adults, recent MJ use was associated with decreased odds of constipation, but not diarrhea. Specifically, we demonstrate that recent MJ use was inversely associated with hard stool form as defined by the BSFS (a surrogate for colonic transit), but not bowel movement frequency.
The ingestion of the MJ plant seed—Fructus cannabis—has a long record of use in constipation dating back centuries (22). Indeed, a recent clinical trial evaluating the effect of an HSP, a prepared combination with 37.5% of its components derived Fructus cannabis, on constipation revealed that patients with constipation who were administered HSP had decreased constipation during and after treatment compared with patients who received placebo (5). A follow-up study demonstrated resolution of constipation in 68% of patients compared with 57.7% and 33% among those receiving senna and placebo, respectively, at 8 weeks (23). In addition, 8 weeks after stopping the initial 8-week treatment, the laxative effects were sustained on more patients taking HSP (47.4%) than senna (20.6%) or placebo (17.5%). Other constipation symptoms were also decreased among patients receiving HSP. Although the directionality of our findings was similar, the magnitude of the absolute difference in constipation between MJ users and nonusers was modest (2%–4%). The difference may have been more pronounced if the prevalence of constipation was higher in our population, which may have been artificially decreased by the exclusion of individuals aged 60 years and older, who typically suffer disproportionately from the disease. Moreover, constipation affects a median of 16% of the population worldwide and 33.5% of the elderly, so even small changes in the percentage of affected individuals may have significantly larger economic and disease burden implications (24).
Importantly, the current data are unable to distinguish between subjects using inhaled vs ingested cannabis, although other population-based samples would suggest that inhalation/smoking is the primary means of consuming cannabis products among the US population (25). Thus, we presume that our results reflect primarily users of inhaled cannabis products, for which there are little available data on GI physiology.
The current understanding of the physiological actions of cannabinoids and their receptors on intestinal motility (1) seems to challenge our findings that MJ use was associated with decreased constipation. Our observed effect might be explained by many factors. First, the motility activities of the ingredients in MJ are not completely understood. The MJ plant consists of several agents such as tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol, each with diverse activities on the GI tract (26). Acting primarily through the cannabinoid 1 and 2 receptors (CB1R and CB2R), which are abundant within the GI tract, cannabinoids can directly and indirectly modulate GI motility through regulation of smooth muscle activities and secretion, respectively (1,4,27,28). Most available research has focused on the effects of CB1R agonism specifically. By inhibiting leiomyocyte motility, CB1R agonism at the myenteric plexus results in gastric emptying suppression, colonic tone and phasic pressure inhibition, and increased colonic compliance (29,30). Thus, the effects of pure CB1R activation, such as seen with the synthetic agonist dronabinol (a THC mimetic), are expected to increase the odds of constipation (1) by slowing down the bowel, increasing colonic transit time, facilitating more fecal water reabsorption, and resulting in generation of hard, lumpy feces, as measured by the BSFS (31). However, our results show just the opposite effect, with decreased frequency of hard stools by the BSFS. MJ, as opposed to dronabinol/THC, contains hundreds of different agents, with varying activities on CB1R and CB2Rs; thus, some of the other agents in MJ might augment colonic motility, decreasing colonic transit time, and result in decreased constipation.
A second explanation for our findings may be that the motility effects of THC are modified by the presence of other cannabinoids. For example, unlike THC—a partial agonist at both CB1R and CB2Rs—CBD is an antagonist at CB1R and a full agonist at CB2R, potentially attenuating the CB1R-mediated activities of THC. Interestingly, THC monotherapy via dronabinol has been shown to be less efficacious, with more adverse effect from excessive CB1R agonism than dual therapies of THC: CBD in trials involving multiple sclerosis and neuropathic pain (32,33). The cannabinoids in MJ also exert synergistic effects, which are not observed with individual agents. Indeed, the observed effect of MJ use comprises the different activities of its hundreds of components, acting synergistically, termed the “entourage effect.” (33,34) Therefore, the summative actions of the MJ plant are likely very different from those of dronabinol, the agent most extensively studied in trials—but a mimetic of just one of the hundreds of substances in MJ.
A third reason may be that the cannabinoids in MJ exert other motility modulatory activities on noncannabinoid receptors. Recent analysis of the activities of HSP on suppressing constipation suggests that multiple receptor signaling pathways are involved, including acetylcholine, estrogen, prostaglandin, cannabinoid, and purine receptors (35). Fourth, regular MJ use may also modify the intestinal microbiota, a factor that is known to impact a variety of colonic disorders, including slow transit constipation (36,37). Patients with constipation have increased quantities of several species in the Firmicutes phyla (37), which have been shown to be suppressed by MJ use in murine models (38). Furthermore, a trial of fecal microbiota transplantation demonstrated temporary relief of constipation (39), affirming the role of the microbiota in constipation and suggesting a mechanism by which recent MJ use might impact constipation.
Alternative to the preceding explanations, the observed relation between MJ and bowel function in the study may be the result of reverse causation. Constipated subjects may decrease their MJ intake because they may have noticed worsening of their symptoms after MJ use. In addition, individuals consuming MJ strains with high THC content or synthetic cannabinoids with highly potent pro-CB1R agonism may have worsening constipation, given that CB1R activity has been associated with slowing of colonic motility.
Our results on other predisposing factors for constipation were generally consistent with previous literature on constipation using the NHANES database. Similar to other studies, we found that female sex, black race, lower education status, higher poverty levels, and higher comorbidity burden were all predisposing factors to constipation (7,14,40,41). Alternatively, obesity, alcohol use, excellent general health condition, high dietary fiber intake, and high liquid intake were protective factors against constipation (14,41–43).
Important limitations to our study include the cross-sectional design, which makes it difficult to evaluate causal association. We mitigated this weakness by segregating MJ users into past and recent users, confirming that our measured effects were due to current MJ use. In addition, the NHANES data do not contain more detailed symptoms of constipation, akin to Rome IV, nor severity or duration of constipation. There may be a recall bias in regard to stool consistency or frequency. However, the BSFS is a common method for assessment of constipation, providing a robust assessment of slow transit constipation that has been confirmed in many studies to have a high correlation (correlation coefficient ∼0.7) with slow colonic transit with a sensitivity of 64% and specificity of 90% (31,44–46), and reliably excludes irritable bowel syndrome (47) and pseudodiarrhea (48). However, unlike these validations, the stool form questionnaires were not administered on 2 consecutive days in the NHANES, and the NHANES questionnaire did not specify the time scale of the Bristol stool form or whether respondents refrained from medications that may affect colonic motility. Also, our definition of constipation relies primarily on stool form and frequency, which does not capture every patient with constipation. In addition, some may dispute the clinical relevance of the BSFS over stool frequency. However, the BSFS has been shown to be relatively simple to use and has better concordance with colonic motility than stool frequency alone (46). We were also unable to determine which fraction of patients reporting constipation also had irritable bowel syndrome with constipation and may have benefited from putative actions of cannabis on visceral sensation (49,50). Despite these limitations, the NHANES has reliably been used to measure bowel function through the BSFS and stool frequency in many studies (14–17).
Importantly, the NHANES does not contain information on the strains of MJ, mode of consumption, or quantity of MJ. Different strains of MJ, such as sativa and indica, contain different THC: CBD ratios, which have differing potencies in activating cannabinoid receptors and could produce disparate effects on bowel function. Similarly, the mode of MJ consumption might result in different quantities of cannabinoid delivered to the GI tract and enteric nervous system. MJ ingestion is more likely to result in greater delivery of intact cannabinoid agents to the gut than vaping/inhaling, which results in modification of the cannabinoid contents through combustion. For example, intermittent vaping of MJ may be much less likely to modulate bowel function than ingestion of a large amount orally, which could impact bowel function for days. Furthermore, information on the quantity of MJ consumed each time may have facilitated a better dose-response analysis. Such uncertainties in strain, dose, and method of consumption may have impacted the precision of our effect estimates because some of the upper limits of the confidence intervals approach 1. Finally, the exclusion of patients aged ≥60 years from our analysis population represents a major limitation, given the substantial burden of constipation in this population.
Strengths of our study include the use of a large, nationally representative database (NHANES), which allows population-level assessments of common disease states (constipation) and behaviors (cannabis use) where relationships may not otherwise be apparent in smaller cohorts. With any observational study, there is always a risk of residual confounding. We were able to adjust for numerous established risk factors for constipation because of the comprehensive nature of the NHANES cohort. Moreover, our effect sizes remained stable despite these adjustments, suggesting that our observed results are unlikely to be due to residual confounding.
In conclusion, our study uses a nationally representative sample of noninstitutionalized community dwellers in the United States to demonstrate that recent MJ users had decreased odds of constipation. Our analysis is the first population-based human clinical study of MJ and bowel function providing important insights into the aggregate effects of the various components of the MJ plant on constipation. Owing to the high prevalence and burden of constipation in combination with the increasing availability of both recreational and medicinal cannabis, further studies are needed to identify how use of whole cannabis, different MJ strains, and frequency of MJ use exert their apparent effects on constipation.
CONFLICTS OF INTEREST
Guarantor of the article: Kyle Staller, MD, MPH.
Specific author contributions: A.C.A. and K.S. planned and designed the study and analyzed the data. A.C.A. drafted the manuscript. All authors interpreted the results and contributed to critical review of the manuscript. K.S. had full access to all the data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis. All authors approved the final manuscript.
Financial support: B.K. is supported by NIH 1U01DK112193. K.S. is supported by an American Gastroenterological Association (AGA) career development award.
Potential competing interests: A.C.A. and R.F. report no disclosures. B.K. has received research funding from AstraZeneca, Gelesis, and Medtronic and has served as a consultant to Medtronic and Ironwood. K.S. has received research support from AstraZeneca, Gelesis, and Takeda; has served as a speaker for Shire; and has served as a consultant to Bayer and Shire.
WHAT IS KNOWN
- ✓ MJ use and bowel motility disorders (constipation and diarrhea) are common.
- ✓ The impacts of MJ use on constipation and diarrhea are unclear.
WHAT IS NEW HERE
- ✓ MJ use is associated with a decreased odds of constipation.
- ✓ Recent MJ use is associated with decreased odds of constipation compared with past use.
- ✓ MJ use was not associated with a change in the frequency or odds of diarrhea.
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