Abstract
Introduction:
The antiemetic properties of cannabis have motivated its use in the management of chemotherapy-induced nausea and vomiting. Conversely, case reports of intractable vomiting among heavy cannabis users have increasingly appeared in the literature. Studies on cannabis and gastrointestinal tract (GIT) health are scare. Here, we use data for the National Health and Nutrition Examination Surveys (NHANES, 2005–2018) to estimate the association between cannabis use and GIT illness.
Methods:
The study sample included non-pregnant adult NHANES participants (20–59 years) without history of cancer or HIV (n = 18753). Cannabis use was categorised into never, former (0 days in the past 30 days), infrequent (1–2 days), occasional (3–19 days) and frequent (20–30 days) use. Recent GIT illness was defined as experiencing GIT illness with vomiting or diarrhea that started in the 30 days prior to NHANES. Logistic regression was used to regress GIT illness on cannabis use, adjusting for potential confounders.
Results:
Compared to never use, frequent cannabis use was associated with higher odds of GIT illness (OR = 1.4; 95% CI 1.04, 1.9). There were no associations between former, infrequent or occasional cannabis use and GIT illness.
Discussion and Conclusions:
Frequent cannabis use is associated with GIT illnesses in a large cross-sectional study of US residents. It is possible that frequent cannabis use adversely affects GIT health, consistent with clinical case reports. Alternatively, patients with GIT illness might self-medicate with cannabis given its antiemetic properties. Prospective studies are needed to understand the effects of cannabis use on GIT health.
Keywords: cannabis, emesis, GIT, NHANES
Introduction
The prevalence of cannabis use among United States (US) adults has increased, concurrent with cannabis legalisation in many states [1]. Despite the rise in its use, evidence regarding the health effects of cannabis, including on the gastrointestinal tract (GIT), remains unclear.
Delta-9-tetrahydrocannabinol (THC), cannabis main psychoactive constituent, has been long used as an antiemetic and THC-based medications are FDA-approved for managing chemotherapy-induced nausea and vomiting (NV) and HIV-induced anorexia [2]. Pre-clinical studies implicated the endocannabinoid system, which consists of the cannabinoid-1 (CB1) and cannabinoid-2 (CB2) receptors, in mediating the antiemetic properties of THC [3]. Functional CB1 and CB2 receptors are expressed in several brain regions involved in the control of NV [4]. Both receptors are also expressed and functional in the GIT [5]. Genetic deletion of CB1 receptors in rodents promoted gastric emptying, whereas human use of CB1 antagonists (i.e., Rimonabant) promoted diarrhea [5, 6]. Modulation of CB2 receptor signaling also affected gastric motility, but only in inflammatory disease states [7].
Despite its antiemetic properties, the clinical literature now includes several reports of cannabinoid hyperemesis syndrome (CHS), a condition characterised by intractable NV in heavy cannabis users that resolves with abstinence [8]. Although the exact mechanism is unknown, CB1 receptor downregulation, altered thermoregulation and gastric motility changes have been suggested as potential pathways via which cannabis use induces CHS [9]. Because CHS was recently identified, the majority of literature is comprised of case reports and emergency department record analyses [10, 11]. To date, there is no epidemiological investigation on cannabis use and GIT health. Therefore, the aim of this study is to estimate the association between cannabis use and recent GIT illness in a large sample of US adults recruited for the National Health and Nutrition Examination Survey (NHANES).
Methods
The NHANES is designed to be nationally representative of the US non-institutionalised population. Each year, NHANES uses a stratified multistage probability sampling approach to recruit participants [12]. Participants first take part in a household interview followed by physical exams in NHANES mobile examination center (MEC). Analysis of the publicly-available NHANES data was approved by Michigan State University Institutional Review Board as non-human subject research.
This study includes adults (20–59-years) who attended NHANES MEC between 2005–2018 (n = 25348). Participants were excluded if they were pregnant (n = 697), had a history of cancer (n = 993), had a positive HIV antibody test (n = 114) or had missing data on GIT illness (n = 2502), cannabis use (n = 617) or other covariates included in the analysis (n = 1672). The final analytic sample size included 18753 participants.
The drug use questionnaire was self-administered in the MEC using the Audio Computer-Assisted Self-Interview system. Participants were asked if they ever used cannabis. An answer of ‘NO’ was used to identify never users. Participants who answered ‘Yes’ were asked how long it had been since they last used cannabis. Former use was defined as lifetime cannabis use but not in the 30 days prior to attending MEC, whereas use at least once in the past 30 days defined recent use. Frequency of recent use was determined by creating tertiles for the number of days of cannabis use and categorised into infrequent (1–2), occasional (3–19) and frequent use (20–30). Recent GIT illness was defined as having a stomach or intestinal illness with vomiting or diarrhea that started in the 30 days prior to attending the MEC.
Analysis of variance for continuous variables and Rao-Scott X2 test for categorical variables were used to determine differences in sociodemographic characteristics between cannabis users and never users (e.g., frequent vs. never use). Logistic regression was then used to regress recent GIT illness on cannabis use status. Crude odds ratios (OR) were generated, adjusting for NHANES complex survey design (i.e., MEC weights, clustering and stratification) using SAS v.9.4. Multivariable ORs were additionally adjusted for potential confounding variables including age, sex, race/ethnicity, education, ratio of family income to poverty, body mass index, tobacco smoking and alcohol drinking. In separate models, we added interaction terms for cannabis and each potential confounder to test for effect modification.
Results
The majority of participants were either never (n = 8556; 39.8%) or former cannabis users (7431; 45.7%). Of recent cannabis users (n = 2766), 815 were infrequent (4.3%), 976 were occasional (5.1%) and 975 were frequent users (5.1%). Approximately 7.7% of the sample had GIT illness in the past 30 days (n =1444). Table 1 displays the characteristics of participants stratified by cannabis use status. Compared to never users, frequent cannabis users were more likely to be younger, male, active tobacco smokers, frequent alcohol drinkers and have higher prevalence of GIT illness (p <0.01). Similar findings were observed when comparing infrequent or occasional cannabis users vs. never users.
Table 1.
Characteristics of study participants by cannabis use status. Data for NHANES 2005–2018 (n = 18753)
| Cannabis Use Status | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Never User n = 8556 |
Former User n = 7431 |
Recent User n = 2766 |
||||||||
| Infrequent1 n = 815 |
Occasional2 n = 976 |
Frequent3 n = 975 |
||||||||
| n (weighted column %)† or mean (SE) | ||||||||||
| Age, years (SE) | 39.8 | (0.2) | 40.2 | (0.2) | 34.2 | (0.5) | 35.1 | (0.5) | 34.4 | (0.5) |
| Female | 4782 | (54.8) | 3450 | (47.1) | 375 | (44.6) | 332 | (35.5) | 320 | (31.5) |
| Race/Ethnicity | ||||||||||
| Non-Hispanic White | 2496 | (54.5) | 3852 | (74.3) | 350 | (63.5) | 438 | (65.4) | 469 | (68.1) |
| Non-Hispanic Black | 1623 | (11.7) | 1581 | (9.9) | 235 | (16.5) | 303 | (17.4) | 281 | (15.6) |
| Hispanic | 3028 | (22.7) | 1386 | (10.4) | 155 | (13.9) | 145 | (10.7) | 136 | (9.9) |
| Other | 1409 | (11.1) | 612 | (5.4) | 75 | (6.1) | 90 | (6.5) | 89 | (6.4) |
| Education | ||||||||||
| <High school | 2033 | (16.2) | 1087 | (10.2) | 159 | (14.8) | 209 | (18.1) | 219 | (18.4) |
| High school/GED | 1757 | (21.2) | 1710 | (22.2) | 203 | (24.7) | 283 | (28.5) | 288 | (29.4) |
| >High school | 4766 | (62.6) | 4634 | (67.6) | 453 | (60.5) | 484 | (53.4) | 468 | (52.2) |
| BMI, Kg/m2 (SE) | 29.4 | (0.1) | 29.3 | (0.1) | 27.5 | (0.3) | 27.6 | (0.3) | 27.6 | (0.2) |
| Income to poverty ratio (SE) | 2.9 | (0.04) | 3.3 | (0.04) | 2.7 | (0.1) | 2.5 | (0.1) | 2.5 | (0.1) |
| Active tobacco smoking | 963 | (10.0) | 2180 | (26.0) | 358 | (40.6) | 548 | (53.0) | 557 | (55.9) |
| Past 12-month alcohol drinking | ||||||||||
| Infrequenta | 5916 | (64.7) | 3349 | (41.1) | 250 | (27.6) | 284 | (25.6) | 374 | (36.0) |
| Occasionalb | 1572 | (20.1) | 1878 | (25.5) | 232 | (28.0) | 239 | (23.8) | 219 | (21.0) |
| Frequentc | 1068 | (15.2) | 2204 | (33.4) | 333 | (44.4) | 453 | (50.6) | 382 | (43.0) |
| Recent GIT illness | 570 | (7.0) | 606 | (7.4) | 69 | (7.5) | 93 | (8.3) | 106 | (10.6) |
Used cannabis 1–2 days in the 30 days prior to NHANES MEC.
Used cannabis 3–19 days in the 30 days prior to NHANES MEC.
Used cannabis 20–30 days in the 30 days prior to NHANES MEC.
≤12 drinks in the past 12 months.
>12 drinks in the past 12 months to ≤1 drink/week in the past 12 months.
>1 drink/week in the past 12 months.
BMI, body mass index
Table 2 depicts results from multiple logistic regression models estimating the association between cannabis use and recent GIT illness. Compared to never use, frequent cannabis use was associated with higher odds of GIT illness (OR = 1.6; 95% confidence interval [CI] 1.2, 2.0). Estimates were attenuated, but remained statistically significant, after adjustment for potential confounding variables (OR= 1.4; 95% CI 1.04, 1.9). We observed no association between former, infrequent or occasional cannabis use and GIT illness. An alternative categorisation of past 30-day cannabis use frequency based on McCartney et al. suggested that findings did not differ from the main analysis based on tertiles [13].
Table 2.
Results from multiple logistic regression models estimating the association between cannabis use and recent GIT illness.* Data for NHANES 2005–2018 (n = 18753)
| Model | Cannabis Use Status | |||||
|---|---|---|---|---|---|---|
| Never | Former | Infrequent1 | Occasional2 | Frequent3 | p-trend | |
| Odds ratios (95% CI) | ||||||
| Model 1a | 1.0 (reference) | 1.1 (0.9, 1.2) | 1.1 (0.8, 1.5) | 1.2 (0.9, 1.6) | 1.6 (1.2, 2.0) | 0.02 |
| Model 2b | 1.0 (reference) | 1.1 (0.9, 1.3) | 1.1 (0.8, 1.6) | 1.3 (1.0, 1.8) | 1.8 (1.3, 2.3) | 0.003 |
| Model 3c | 1.0 (reference) | 1.0 (0.8, 1.2) | 1.0 (0.7, 1.4) | 1.1 (0.8, 1.5) | 1.4 (1.04, 1.9) | 0.2 |
Recent GIT illness defined as having a stomach or intestinal illness in the 30 days prior to MEC.
Used cannabis 1–2 days in the 30 days prior to NHANES MEC.
Used cannabis 3–19 days in the 30 days prior to NHANES MEC.
Used cannabis 20–30 days in the 30 days prior to NHANES MEC.
Model 1 is adjusted for NHANES complex survey design.
Model 2 is additionally adjusted for age (years) and sex (male/female).
Model 3 is additionally adjusted for race/ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic and all others).
Education (<high school, high school and >high school), ratio of family income to poverty ratio, body mass index (Kg/m2), active tobacco smoking (yes/no), and alcohol drinking (infrequent, occasional and frequent).
Statistically significant interactions (p <0.1) were observed for education, tobacco smoking and alcohol drinking. Compared to never use, the association between frequent cannabis use and GIT illness was stronger among participants with high school education (OR = 1.6; 95% CI 1.02, 2.6) or more than high school education (OR = 1.5; 95% CI 1.03, 2.1) than participants with less than high school education (OR = 0.9; 95% CI 0.5, 1.8). The association between frequent cannabis use and GIT illness was stronger among participants who did not actively smoke tobacco (OR = 1.9; 95% CI 1.3, 2.8) than participants who were active smokers (OR = 0.9; 95% CI 0.6, 1.6). The association between frequent cannabis use and GIT illness was also stronger among infrequent (OR = 1.9; 95% CI 1.3, 3.0) and occasional alcohol drinkers (OR = 1.5; 95% CI 0.8, 3.0), than participants who frequently drank alcohol (OR = 0.9; 95% CI 0.5, 1.6). Comparing the ORs of GIT illnesses for frequent cannabis users across different subgroups of education, tobacco smoking or alcohol use, however, was not statistically significant (p >0.05).
Discussion and Conclusions
Results indicate a modest association between frequent cannabis use and recent GIT illness, that was more pronounced among participants at a relatively lower risk for GIT illness including non-smokers, infrequent alcohol drinkers and participants with higher educational attainment [14–16]. Strengths of this study include the large, nationally representative sample of US adults and the assessment of cannabis use and GIT illness within the same 30-day period. The NHANES also assess the frequency of recent cannabis use to differentiate between infrequent, occasional and frequent use.
Limitations of the study include the inability to establish causality due to the observational nature of NHANES. It was not possible to analyse vomiting and diarrhea separately, as the question on GIT illness combines both conditions. Cannabis use data were collected via self-report and thus cannabis use prevalence might be underestimated owing to social desirability [17]. The cross-sectional nature of NHANES made it impossible to ascertain whether cannabis use precedes GIT illness or vice versa. It is possible that cannabis use adversely affects GIT health based on precedent reports of CHS, defined as episodic vomiting after excessive heavy cannabis use [18]. Conventional antiemetics are usually ineffective in managing CHS, yet abstinence alleviates symptoms, suggesting a causal link [19]. The increase in cannabis potency makes it imperative to investigate the mechanisms underlying CHS, as only heavy use has been linked to CHS in clinical reports and not infrequent or occasional use, similar to our observations [20].
Alternatively, patients with GIT illnesses might self-medicate using cannabis given its antiemetic properties. In a study of 27169 participants, 21% of cannabis users attributed their consumption to the management of NV and/or chemotherapy [21]. The NHANES do not collect data on motives for cannabis use. We excluded patients with history of HIV or cancer for whom cannabis can be recommended to alleviate NV. We further excluded participants with a history of diabetes mellitus (to account for gastroparesis) or liver conditions, and our conclusion did not change (data are not shown). However, data on other possible causes of NV or diarrhea (e.g., irritable bowel syndrome or Crohn’s disease) are not available in NHANES, and we cannot ascertain if participants were using cannabis to alleviate these conditions.
In summary, this epidemiological investigation suggests an association between frequent cannabis use and GIT illness. It remains unclear if cannabis use affects GIT health or if adults with poor GIT health are self-medicating with cannabis. Adequately powered prospective studies are warranted to better understand the effects of cannabis use on GIT health.
Key Point Summary.
Cannabis and its synthetic analogues are used as antiemetic agents for cancer and HIV/AIDS patients.
Conversely, case reports of intractable vomiting among heavy cannabis users have increasingly appeared in the literature.
In this epidemiological study, frequent cannabis use was associated with recent GIT illness.
Future prospective studies are needed to understand the effects of cannabis use on GIT health.
Acknowledgments
Declarations of competing interests:
This work was supported by Michigan State University, the United States National Center for Complementary and Integrative Health [AT009156] and the United States National Institute on Drug Abuse [DA054487]. The funding organisations had no role in the design and conduct of the study.
Role of Funding Source:
This work was supported by Michigan State University, the National Institutes of Health/National Center for Complementary and Integrative Health [AT009156 to OA] and the National Institutes of Health/National Institute on Drug Abuse [DA054487 to AV].
Footnotes
Conflict of Interest: None to declare.
References
- 1.Anthony JC, Lopez-Quintero C, Alshaarawy O. Cannabis epidemiology: A selective review. Curr Pharm Des. 2016;22:6340–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.National Academies of Sciences, Engineering, and Medicine. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. 2017, Washington, DC: The National Academies Press. [PubMed] [Google Scholar]
- 3.Pertwee RG, Howlett AC, Abood ME, Alexander SPH, Di Marzo V, Elphick MR, Greasley PJ et al. International union of basic and clinical pharmacology. LXXIX. Cannabinoid receptors and their ligands: Beyond CB1and CB2. Pharmacol Rev. 2010;62:588–631. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Sharkey KA, Darmani NA, Parker LA. Regulation of nausea and vomiting by cannabinoids and the endocannabinoid system. Eur J Pharmacol. 2014;722:134–46. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Izzo AA, Camilleri M. Emerging role of cannabinoids in gastrointestinal and liver diseases: basic and clinical aspects. Gut. 2008;57:1140–55. [DOI] [PubMed] [Google Scholar]
- 6.Fabisiak A, Włodarczyk M, Fabisiak N, Storr M, Fichna J. Gastrointestinal adverse events of cannabinoid 1 receptor inverse agonists suggest their potential use in irritable bowel syndrome with constipation: A systematic review and meta-analysis. J Gastrointestin Liver Dis. 2019;28:473–81. [DOI] [PubMed] [Google Scholar]
- 7.Tartakover Matalon S, Ringel Y, Konikoff F, Drucker L, Pery S, Naftali T. Cannabinoid receptor 2 agonist promotes parameters implicated in mucosal healing in patients with inflammatory bowel disease. United European Gastroenterol J. 2020;8:271–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Pergolizzi JV Jr, LeQuang JA, Bisney JF. Cannabinoid hyperemesis. Med Cannabis Cannabinoids. 2018;1:73–95. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.DeVuono MV, Parker LA. Cannabinoid hyperemesis syndrome: A review of potential mechanisms. Cannabis Cannabinoid Res. 2020;5:132–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Hernandez JM, Paty J, Price IM. Cannabinoid hyperemesis syndrome presentation to the emergency department: A two-year multicentre retrospective chart review in a major urban area. CJEM. 2018;20:550–5. [DOI] [PubMed] [Google Scholar]
- 11.Venkatesan T, Levinthal DJ, Li BUK, Tarbell SE, Adams KA, Issenman RM et al. Role of chronic cannabis use: Cyclic vomiting syndrome vs cannabinoid hyperemesis syndrome. Neurogastroenterol Motil. 2019;31 (Suppl 2):e13606. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.United States Centers for Disease Control and Prevention. National Center for Health Statistics (NCHS). National Health and Nutrition Examination Survey Data.: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention,. 2010. [cited 2013 11/1]. Available from: http://wwwn.cdc.gov/nchs/nhanes/search/nhanes09_10.aspx. [Google Scholar]
- 13.McCartney D, Arkell TR, Irwin C, McGregor IS. Determining the magnitude and duration of acute Δ(9)-tetrahydrocannabinol (Δ(9)-THC)-induced driving and cognitive impairment: A systematic and meta-analytic review. Neurosci Biobehav Rev. 2021;126:175–93. [DOI] [PubMed] [Google Scholar]
- 14.Berkowitz L, Schultz BM, Salazar GA, Pardo-Roa C, Sebastián VP, Álvarez-Lobos MM, Bueno SM. Impact of cigarette smoking on the gastrointestinal tract inflammation: Opposing effects in Crohn’s Disease and ulcerative colitis. Front Immunol. 2018;9:74. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Bishehsari F, Magno E, Swanson G, Desai V, Voigt RM, Forsyth CB, Keshavarzian A. Alcohol and Gut-Derived Inflammation. Alcohol Res. 2017;38:163–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Herd P, Schaeffer NC, DiLoreto K, Jacques K, Stevenson J, Rey F, Roan C. The influence of social conditions across the life course on the human gut microbiota: A pilot project with the Wisconsin Longitudinal Study. J Gerontol B Psychol Sci Soc Sci. 2017;73:124–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Johnson T, Fendrich M. Modeling sources of self-report bias in a survey of drug use epidemiology. Ann Epidemiol. 2005;15:381–9. [DOI] [PubMed] [Google Scholar]
- 18.Rome Foundation. Rome IV Criteria 2016. Available from: https://theromefoundation.org/rome-iv/romeiv-criteria/.
- 19.Senderovich H, Patel P, Jimenez Lopez B, Waicus S. A systematic review on cannabis hyperemesis syndrome and its management options. Med Princ Pract. 2022;31:29–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.ElSohly MA, Chandra S, Radwan M, Majumdar CG, Church JC. A comprehensive review of cannabis potency in the United States in the last decade. Biol Psychiatry Cogn Neurosci Neuroimaging. 2021;6:603–6. [DOI] [PubMed] [Google Scholar]
- 21.Leung J, Chan G, Stjepanović D, Chung JYC, Hall W, Hammond D. Prevalence and self-reported reasons of cannabis use for medical purposes in USA and Canada. Psychopharmacology (Berl) 2022;239:1509–19. [DOI] [PMC free article] [PubMed] [Google Scholar]