Summary
Cannabis use is becoming increasingly common, both for recreational and medical purposes. However, there is a paucity of data regarding cannabis use in the context of eosinophilic esophagitis (EoE). We aimed to determine the impact of cannabis use on presentation and treatment response in EoE. To this end, we conducted a retrospective cohort study at a large academic medical center of newly diagnosed EoE patients age ≥ 12 years. Self-reported cannabis use status, baseline characteristics, and treatment response to topical corticosteroids and dietary therapy data were extracted. Bivariate and multivariable analyses were used to compare cannabis users and non-users at time of EoE diagnosis and to assess treatment response. Of 983 EoE patients, 80 reported using cannabis, with the majority reporting daily use and administration by inhalation. Baseline symptoms and peak eosinophil count were similar between cannabis users and non-users; cannabis users were less likely to have baseline endoscopic findings of exudates, edema, and stricture, and lower total Endoscopic Reference Score. On multivariable analysis, younger age, male sex, non-White race, and psychiatric diagnosis were independently associated with history of cannabis use at EoE presentation and stricture was independently associated with cannabis non-use. Post-treatment symptom and histologic responses were similar between cannabis users and non-users though there was a higher odds of post-treatment endoscopic inflammatory features with cannabis use. In conclusion, despite presenting with milder initial endoscopic findings, cannabis users exhibited greater inflammatory findings after treatment, highlighting a potential negative influence of cannabis use on EoE management.
Keywords: cannabis, eosinophilic esophagitis, outcome, treatment
INTRODUCTION
Eosinophilic esophagitis (EoE) is a chronic, progressive inflammatory disease of the esophagus characterized by symptoms of dysphagia and reduced quality of life.1,2 The incidence and prevalence of EoE have increased significantly over the past two decades, making it a significant cause of chronic gastrointestinal morbidity.3–5 Current treatment options for EoE primarily focus on medications, such as proton pump inhibitors, topical corticosteroids, and biologics, as well as dietary therapy to manage inflammation and prevent complications.6
There is a growing interest in the potential therapeutic effects of cannabis for various conditions, including many gastrointestinal disorders.7 From 2002 to 2019, cannabis use increased from 10.4% to 18.0% in the United States.8 Cannabinoid receptors are widely distributed in the gastrointestinal tract and regulate many physiological processes, including inflammation, immune activation, pain perception, and gastrointestinal motility.7,9 Given these properties, cannabis use has been explored for managing gastrointestinal conditions such as inflammatory bowel disease, irritable bowel syndrome, and gastroparesis.10,11 However, despite the common use of cannabis, little is known about cannabis use in EoE.
In this study, we aimed to determine the impact of cannabis use on presentation and treatment response in EoE.
MATERIALS AND METHODS
We conducted a retrospective cohort study utilizing the UNC EoE Clinicopathologic Database. This database has been previously described in other publications.12–15 In brief, the database contains baseline demographics, clinical, endoscopic, and histologic information about patients over the last two decades with a new diagnosis of EoE per consensus guidelines.1,16 Using this data source, we identified all newly diagnosed EoE adults and adolescents age 12 years or older. Medical records were reviewed, patients who self-reported cannabis use were identified, and details regarding cannabis use were extracted. Using standardized data collection forms, data were extracted from the medical record, including treatment response to topical corticosteroid and diet elimination therapy.
Treatment response was assessed to topical corticosteroid and dietary therapy. Treatment response included symptom, endoscopic, and histologic outcome measures. Global symptomatic response was defined as yes/no per patient description of disease activity at follow-up clinic visit or endoscopy. Endoscopic response was determined by global endoscopic response (yes/no per general endoscopist assessment), EoE Endoscopic Reference Score (EREFS) (score range, 0–9, based on presence of esophageal edema, rings, exudates, furrows, and strictures),17 and Endoscopic Severity Score (ESS) (score range, 0–5, based on the sum of the presence of the 5 EREFS features).18 EREFS was not available for all patients because the database was established before its development. Histologic response was defined as fewer than 15 eosinophils per high-power field (eos/hpf) with additional assessment for thresholds of 6 or fewer eos/hpf and fewer than 1 eos/hpf.19,20
Patients with and without reported cannabis use at EoE diagnosis were compared using bivariate analyses with the chi-squared test for categorical variables and the 2-sample t test for continuous variables. Multivariable logistic regression was utilized to assess whether any baseline variables were independently associated with cannabis use at EoE presentation. We also used bivariate analyses to assess EoE treatment response between cannabis users and non-users. All statistical analyses were performed using Stata version 17 (College Station, TX). The University of North Carolina Institutional Review Board approved this study.
RESULTS
Of 983 EoE patients age 12 years and above within the UNC EoE Clinicopathologic Database, 80 (8%) reported using cannabis. The most common methods of administration were inhalation (76%) and oral ingestion (27%). Most (53%) used cannabis daily, 26% used it weekly, and 19% used it monthly. 79% reported using cannabis for 3 or more years at the time of EoE diagnosis.
Cannabis users were younger (32.4 ± 14.3 years vs. 38.8 ± 16.1 years; P = 0.07), more commonly male sex (79% vs. 63%; P = 0.005), less frequently identified as White race (83% vs. 91%; P = 0.003), and had a lower history of food allergy (14% vs. 23%; P = 0.09) at EoE diagnosis as compared to non-cannabis users (Table 1). There was a higher prevalence of psychiatric diagnoses (49% vs. 34%; P = 0.03) among cannabis users, including anxiety (39% vs. 27%; P = 0.07), bipolar disorder (6% vs. 2%; P = 0.05), and post-traumatic stress disorder (8% vs. 2%; P = 0.002). Similar frequency of baseline EoE symptoms, including dysphagia, food impaction, heartburn, chest pain, abdominal pain, nausea, and vomiting, were reported between cannabis users and non-users. At baseline endoscopy, cannabis users were less likely to have endoscopic findings of exudates (33% vs. 44%; P = 0.05), edema (35% vs. 45%; P = 0.08), and stricture (26% vs. 38%; P = 0.04) and had a lower total EREFS (3.3 ± 1.8 vs. 3.6 ± 1.9; P = 0.04) and ESS (2.2 ± 1.3 vs. 2.6 ± 1.5; P = 0.03). Baseline peak eosinophil count was comparable between the groups.
Table 1.
Comparison of baseline characteristics between non-cannabis and cannabis using EoE patients
| No cannabis (n = 903) | Cannabis (n = 80) | P | |
|---|---|---|---|
| Age at diagnosis (mean years ± SD) | 35.8 ± 16.1 | 32.4 ± 14.3 | 0.07 |
| Children, 12–18 years (n, %) | 172 (19) | 17 (21) | 0.63 |
| Male (n, %) | 568 (63) | 63 (79) | 0.005 |
| White (n, %) | 821 (91) | 66 (83) | 0.003 |
| Insurance (n, %) | 753 (83) | 72 (90) | 0.14 |
| BMI (mean kg/m2 ± SD) | 26.6 ± 6.2 | 27.0 ± 7.1 | 0.67 |
| Any atopic condition (n, %) | 499 (55) | 34 (43) | 0.09 |
| Allergic rhinitis | 374 (41) | 26 (33) | 0.12 |
| Asthma | 220 (24) | 18 (23) | 0.71 |
| Eczema | 94 (10) | 8 (10) | 0.92 |
| Food allergy | 209 (23) | 11 (14) | 0.09 |
| Any psychiatric diagnosis (n, %) | 300 (34) | 24 (49) | 0.03 |
| Anxiety | 240 (27) | 19 (39) | 0.07 |
| Bipolar | 17 (2) | 3 (6) | 0.05 |
| Depression | 188 (21) | 14 (29) | 0.22 |
| Post-traumatic stress disorder | 15 (2) | 4 (8) | 0.002 |
| Schizophrenia | 0 (0) | 1 (2) | 0.11 |
| Symptom length prior to diagnosis (mean years ± SD) | 8.5 ± 9.0 | 7.2 ± 7.3 | 0.23 |
| Symptoms (n, %) | |||
| Dysphagia | 782 (87) | 69 (86) | 0.83 |
| Food impaction | 364 (40) | 33 (41) | 0.92 |
| Heartburn | 314 (35) | 30 (38) | 0.67 |
| Chest pain | 113 (13) | 9 (11) | 0.72 |
| Abdominal pain | 131 (15) | 12 (15) | 0.93 |
| Nausea | 79 (9) | 6 (8) | 0.68 |
| Vomiting | 146 (16) | 13 (16) | 0.98 |
| Endoscopic findings (n, %) | |||
| Exudates | 396 (44) | 26 (33) | 0.05 |
| Rings | 563 (62) | 46 (58) | 0.43 |
| Edema | 405 (45) | 28 (35) | 0.08 |
| Furrows | 644 (71) | 55 (69) | 0.57 |
| Stricture | 340 (38) | 21 (26) | 0.04 |
| Narrowing | 177 (20) | 10 (13) | 0.12 |
| Crepe-paper mucosa | 31 (3) | 5 (6) | 0.20 |
| Erosive esophagitis | 212 (23) | 19 (24) | 0.98 |
| Hiatal hernia | 118 (13) | 6 (8) | 0.15 |
| Dilation | 342 (38) | 26 (33) | 0.31 |
| Total EREFS (mean ± SD)* | 3.9 ± 1.9 | 3.3 ± 1.8 | 0.04 |
| Total ESS (mean ± SD)* | 2.6 ± 1.5 | 2.2 ± 1.3 | 0.03 |
| Peak eosinophil count (mean eos/hpf ± SD) | 65.0 ± 47.1 | 68.0 ± 44.7 | 0.60 |
* EREFS data available for n = 529; ESS, endoscopic severity score, for which all data available
On multivariable analysis (Table 2), younger age (aOR: 0.98, 95% CI: 0.96–1.00), male sex (aOR: 2.64, 95% CI: 1.43–4.84), non-White race (aOR: 2.56, 95% CI: 1.27–5.17), and psychiatric diagnosis (aOR: 2.89; 95% CI: 1.70–4.91) were independently associated with history of cannabis use at EoE presentation and stricture (aOR: 0.41, 95% CI 0.21–0.79) was independently associated with cannabis non-user status. There was no difference in the odds of food allergy or exudates.
Table 2.
Multivariable logistic regression model of cannabis use at EoE presentation
| Adjusted odds ratio | 95% confidence interval | |
|---|---|---|
| Age at EoE diagnosis | 0.98 | 0.96–1.00 |
| Male sex | 2.64 | 1.43–4.84 |
| Non-White race | 2.56 | 1.27–5.17 |
| Any psychiatric diagnosis | 2.89 | 1.70–4.91 |
| Food allergy | 0.52 | 0.26–1.04 |
| Exudates | 0.82 | 0.48–1.38 |
| Stricture | 0.41 | 0.21–0.79 |
Topical corticosteroid treatment and response was available for 23 cannabis users and 376 cannabis non-users (Table 3). Post-treatment symptom response (75% vs. 78%; P = 0.83) was similar between cannabis users and non-users as was endoscopic response as determined by general endoscopist assessment (65% vs. 72%; P = 0.49), EREFS (2.4 ± 2.0 vs. 2.5 ± 2.0; P = 0.85), and ESS (2.0 ± 1.7 vs. 2.0 ± 1.5; P = 0.95) (Fig. 1A). When considering individual endoscopic findings, furrows were common in cannabis users (70% vs. 47%; P = 0.05). Histologic response was numerically but not statistically lower in cannabis users at <15 eos/hpf (43% vs. 56%; P = 0.23), ≤6 eos/hpf (39% vs. 49%; P = 0.34), and < 1 eos/hpf (13% vs. 30%; P = 0.09). Additionally, amongst cannabis users, there was no statistically significant difference in histologic response rate at <15 eos/hpf by frequency of cannabis use (p = 0.18).
Table 3.
Topical steroid treatment and response between EoE patients without and with cannabis use
| No cannabis (n = 376) | Cannabis (n = 23) | P | |
|---|---|---|---|
| Type of steroid used (n, %) | 0.97 | ||
| Fluticasone | 130 (35) | 8 (35) | |
| Budesonide | 246 (65) | 15 (65) | |
| Mean steroid dose (mcg ± SD) | 1842 ± 675 | 1805 ± 687 | 0.80 |
| Symptom response (n, %)* | 112 (78) | 6 (75) | 0.83 |
| Post-treatment peak eosinophil count (mean eos/hpf ± SD) | 24.1 ± 35.7 | 31.3 ± 32.8 | 0.35 |
| P value vs. baseline | < 0.001 | 0.006 | |
| Histologic response (n, %) | |||
| < 15 eos/hpf | 212 (56) | 10 (43) | 0.23 |
| ≤ 6 eos/hpf | 186 (49) | 9 (39) | 0.34 |
| < 1 eos/hpf | 111 (30) | 3 (13) | 0.09 |
| Post-treatment endoscopic findings (n, %) | |||
| Normal | 57 (15) | 4 (17) | 0.77 |
| Exudates | 95 (25) | 8 (35) | 0.36 |
| Rings | 210 (56) | 9 (39) | 0.09 |
| Edema | 108 (29) | 5 (22) | 0.42 |
| Furrows | 178 (47) | 16 (70) | 0.05 |
| Stricture | 150 (40) | 9 (39) | 0.87 |
| Narrowing | 80 (21) | 3 (13) | 0.31 |
| Crepe-paper mucosa | 4 (1) | 0 (0) | 0.61 |
| Dilation | 146 (39) | 8 (35) | 0.63 |
| Candida | 32 (9) | 0 (0) | 0.14 |
| Endoscopic response (n, %) | 269 (72) | 15 (65) | 0.49 |
| Post-treatment endoscopic severity (mean scores ± SD) | |||
| EREFS** | 2.5 ± 2.0 | 2.4 ± 2.0 | 0.85 |
| P value vs. baseline | < 0.001 | 0.001 | |
| ESS | 2.0 ± 1.5 | 2.0 ± 1.7 | 0.95 |
| P value vs. baseline | < 0.001 | 0.09 |
* Available for n = 187 and n = 8 subjects, respectively
** Available for n = 225 and n = 16 subjects, respectively
Fig. 1.
Response to (A) topical corticosteroid therapy and (B) dietary therapy in eosinophilic esophagitis by cannabis use.
Dietary therapy treatment and response was available for 9 cannabis users and 198 cannabis non-users (Table 4). No difference was found between cannabis users and non-users for post-treatment symptom response (88% vs. 63%; P = 0.15), endoscopic response as determined by general endoscopist assessment (56% vs. 53%; P = 0.91) and EREFS (3.1 ± 2.1 vs. 2.8 ± 2.4; P = 0.68), and histologic response at <15 eos/hpf (33% vs. 37%; P = 0.71), ≤ 6 eos/hpf (33% vs. 28%; P = 0.74), and < 1 eos/hpf (11% vs. 13%; P = 0.89) (Fig. 1B). Post-treatment endoscopic inflammatory features of exudates (67% vs. 36%; P = 0.07) and furrows (78% vs. 55%; P = 0.17) were numerically higher in cannabis users than non-users.
Table 4.
Dietary therapy treatment response between EoE patients without and with cannabis use
| No cannabis (n = 198) | Cannabis (n = 9) | P | |
|---|---|---|---|
| Diet type (n, %)* | |||
| Elemental | 2 (1) | 0 (0) | 0.73 |
| Targeted elimination | 51 (28) | 2 (22) | 0.54 |
| Six-food elimination | 68 (37) | 4 (44) | 0.48 |
| Four-food elimination | 19 (10) | 3 (33) | 0.07 |
| Two-food elimination | 28 (15) | 0 (0) | 0.62 |
| One-food elimination | 17 (9) | 0 (0) | 0.31 |
| Symptom response (n, %)** | 117 (63) | 7 (88) | 0.15 |
| Post-treatment peak eosinophil count (mean eos/hpf ± SD) | 44.3 ± 51.4 | 36.7 ± 67.5 | 0.66 |
| P value vs. baseline | < 0.001 | 0.03 | |
| Histologic response (n, %) | |||
| < 15 eos/hpf | 74 (37) | 3 (33) | 0.71 |
| ≤ 6 eos/hpf | 56 (28) | 3 (33) | 0.74 |
| < 1 eos/hpf | 25 (13) | 1 (11) | 0.89 |
| Post-treatment endoscopic findings (n, %) | |||
| Normal | 35 (18) | 0 (0) | 0.17 |
| Exudates | 72 (36) | 6 (67) | 0.07 |
| Rings | 1 (1) | 0 (0) | 0.90 |
| Edema | 50 (25) | 3 (33) | 0.59 |
| Furrows | 108 (55) | 7 (78) | 0.17 |
| Stricture | 1 (1) | 0 (0) | 0.41 |
| Narrowing | 57 (29) | 2 (22) | 0.67 |
| Crepe-paper mucosa | 3 (2) | 0 (0) | 0.71 |
| Dilation | 87 (44) | 3 (33) | 0.53 |
| Endoscopic response (n, %) | 87 (53) | 5 (56) | 0.91 |
| Post-treatment endoscopic severity (mean scores ± SD) | |||
| EREFS*** | 2.8 ± 2.4 | 3.1 ± 2.1 | 0.68 |
| P value vs. baseline | < 0.001 | 0.48 |
* Diet type in the listed categories for n = 185 and n = 9 subjects, respectively
** Available for n = 187 and n = 7 subjects, respectively
*** Available for n = 178 and n = 9 subjects, respectively
DISCUSSION
Cannabis use has gained popularity for its potential therapeutic effects in gastrointestinal diseases, but its impact on EoE remains unknown. In this study, we assessed the effect of cannabis use on EoE presentation and evaluated how cannabis use may influence treatment response.
We found that over the past two decades, 8% of newly diagnosed EoE patients reported using cannabis. Cannabis use was more common in EoE patients who were younger, male, non-White, and had a history of psychiatric illness at the time of EoE diagnosis. These demographics align with nationally representative data on cannabis use.21,22 Our findings also revealed that cannabis use is associated with lower odds of esophageal stricture at EoE presentation, and this held after controlling for demographic factors including age. In the liver, cannabinoid receptor 2 receptors have anti-fibrogenic properties.23,24 More research is needed to evaluate the anti-fibrogenic potential on the esophagus, and whether this lower rate of strictures is seen in other populations.
We also assessed the impact of cannabis use on EoE treatment outcomes to topical corticosteroid therapy and dietary therapy. We found cannabis users and non-users had similar symptom response rates. However, cannabis users had higher odds of post-treatment endoscopic inflammatory features. Additionally, there was a numerically, but not statistically, lower histologic response with cannabis use as compared to no cannabis use. Previous studies have suggested that endocannabinoids are involved in eosinophil recruitment, and cannabis use may contribute to the development of health problems such as acute eosinophilic pneumonia.25–27 We hypothesize that a similar esophageal pathophysiology may occur, potentially contributing to the worse treatment response.
There are limitations to our study. Self-reported cannabis use in medical records is susceptible to underreporting, particularly in regions with restrictive cannabis laws. This study was conducted in North Carolina, where cannabis use remains illegal for both medical and recreational purposes, with decriminalization being the only legal allowance. Underreporting could mask associations between cannabis use and the study outcomes, potentially leading to an underestimation of any existing differences. Additionally, our sample size of cannabis users precluded a subanalysis by cannabis type. Despite this and other limitations inherent in the retrospective and single-center study design, data collection was standardized and granular patient-level data were available. As cannabis use becomes more common in the United States, healthcare providers are being asked about the effects of cannabis on EoE by their patients. This study is one of the first studies to investigate the relationship between cannabis use and EoE. While further research is needed, this study provides valuable initial data to address this knowledge gap.
In conclusion, our study suggests a potential negative association between cannabis use and EoE treatment outcomes. Cannabis users, despite presenting with fewer endoscopic features, had more inflammatory features on post-treatment endoscopy. It is unclear if the finding of fewer strictures at the time of diagnosis might counter this. Future larger studies with more rigorous methods for determining cannabis use status are needed to confirm these observations and explore the mechanisms by which cannabinoids might influence EoE.
Specific author contributions (all authors approved the final manuscript): Borinsky: Study design, data collection, analysis, and interpretation, manuscript drafting, critical revision. Weir, LaFata, Gee, Thel, Cameron, Xue, Kiran, Ocampo, McCallen, Lee, Redd, Barlowe, Kaakati, Cotton, Eluri, Reed: Data collection and interpretation, critical revision. Dellon: Project conception, study design, data collection, data analysis/interpretation, manuscript drafting, critical revision.
Financial support: This study was supported by NIH T32 HD094671, NIH T35 DK007386, T32 DK007634, and K23DK1221338.
Contributor Information
Stephanie A Borinsky, Pediatric Gastroenterology, Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Alexandra A Weir, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Sean S LaFata, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Timothy S Gee, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Hannah L Thel, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Brenderia A Cameron, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Angela Z Xue, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Akshatha Kiran, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Adolfo A Ocampo, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Justin McCallen, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Christopher J Lee, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Walker D Redd, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Trevor S Barlowe, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Rayan N Kaakati, Division of Allergy and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Cary C Cotton, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Swathi Eluri, Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA.
Craig C Reed, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Evan S Dellon, Center for Esophageal Diseases and Swallowing, University of North Carolina School of Medicine, Chapel Hill, NC, USA; Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Disclosures
Dr Dellon is a consultant for Abbott, Abbvie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Apollo, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Bryn, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Dr Falk Pharma, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, Upstream Bio; receives research funding from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Celldex, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, Shire/Takeda; and has received an educational grant from Allakos, Aqilion, Holoclara, Invea. None of the other authors report any potential conflicts of interest with this study.
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