Symptoms and Extraintestinal Manifestations in Active Cannabis Users with Inflammatory Bowel Disease

Abstract

Introduction:

Cannabis use is common in the setting of inflammatory bowel disease (IBD). Patients frequently use cannabis to treat IBD-associated symptoms, and there is evidence that cannabis and its derivatives are helpful for this purpose. However, it is unclear how the symptom profiles of active IBD cannabis users and nonusers compare and how these symptoms may relate to their underlying disease state and/or complications.

Materials and Methods:

We performed a retrospective cohort study using a consented IBD natural history registry from a single tertiary care referral center between January 1, 2015 and August 31, 2020. We asked patients about current cannabis use and frequency. We also abstracted demographic and clinical characteristic information, including endoscopic severity, and totals and subscores of surveys assessing IBD characteristics, presence of anxiety/depression, and IBD-associated symptoms. We compared clinical and demographic factors of cannabis users and nonusers and developed a logistic regression model to evaluate for independent associations with cannabis use.

Results:

Three hundred eighty-three IBD patients met the inclusion criteria (206 females, 177 males; 258 Crohn's disease [CD], 118 ulcerative colitis, and 7 indeterminate colitis). Thirty patients (7.8%) were active cannabis users, consuming it for an average of 2.7 times per week. Cannabis users were more likely to report abdominal pain (83.3% vs. 61.7%), gas (66.7% vs. 45.6%), tenesmus (70.0% vs. 47.6%), and arthralgias (53.3% vs. 20.3%) compared to those that did not use cannabis (p<0.05 for each). Incidence of moderate-severe endoscopic inflammation was similar between cannabis users and nonusers, while CD-associated complications were more common in nonusers (39.1% vs. 69.7%, p<0.05). The only factor that demonstrated a significant association with cannabis use on multivariable analysis was arthralgia (p<0.01).

Discussion:

Active IBD cannabis users were more likely to report a variety of symptoms, including abdominal pain, gas, tenesmus, and arthralgias. However, they did not demonstrate more frequent active disease or IBD-associated complications, suggesting that other nonluminal factors influence their symptoms and/or decision to use cannabis. These findings demonstrate the importance of evaluating for extraintestinal contributors to symptom burden in IBD cannabis users, as well as the ongoing need to develop safer and more effective methods for recognizing and managing abdominal pain and other symptoms in this setting.

Introduction

Cannabis use is common in patients with inflammatory bowel disease (IBD), including both Crohn's disease (CD) and ulcerative colitis (UC). Recent studies suggest that up to 12% of IBD patients utilize cannabis at least intermittently.^1–4 There has been widespread hope that cannabis and/or its derivatives can help treat IBD, as many animal studies utilizing enterocolitis models demonstrate improvement in inflammation after exposure to these agents.⁵ Human studies are yet to demonstrate a significant improvement in IBD-associated inflammation as a result of cannabis use. However, IBD patients who use cannabis frequently describe taking it specifically for the purpose of addressing symptoms, such as abdominal pain, that they perceive are related to their IBD.^1,4 Importantly, recent clinical studies have demonstrated quantifiable improvement in patient-reported symptoms, including abdominal pain, and overall quality of life in IBD patients who started cannabis or a cannabinoid derivative.^6–8

Symptoms experienced by cannabis users in this context can vary widely. Previous studies have demonstrated that IBD patients who use cannabis describe an array of gut-based symptoms, including abdominal pain, nausea, loss of appetite, weight loss, change in bowel habits, as well as extraintestinal issues, such as anxiety, depression, and fatigue.¹ Unfortunately, it is not always clear how these symptoms specifically relate to IBD activity status, related complications (e.g., strictures, fistulae, abscesses), extraintestinal manifestations (EIMs; e.g., dermatopathies, arthralgias, and so on), or other factors. Very few of the studies undertaken to date have used direct assessments of disease activity, such as endoscopy, while simultaneously assessing symptomatic status. Thus, it has been challenging to determine whether the symptoms experienced by this population are driven by active inflammation or other factors unrelated to inflammation. Considering how common cannabis use is in the IBD population, even in a state where its recreational use remains illegal, it is critical that we develop a more objective understanding of how the factors above relate to patient symptoms so that providers can more effectively counsel patients and manage these issues.

We undertook this study to (1) compare clinical characteristics and symptomatic experiences of IBD patients who do and do not actively use cannabis; and (2) to determine which patient factors are most likely to be associated with active cannabis use in IBD. To more carefully evaluate the relationships between disease activity, symptoms, and cannabis use, we only included patients who had completed contemporaneous surveys on substance use, clinical experience, as well as endoscopic assessments of their disease. Utilizing this approach, we sought to reexamine the symptom profile associated with cannabis use in IBD and to clarify whether particular patient characteristics predicted cannabis use in this population.

Materials and Methods

Study population

We performed a retrospective cohort study utilizing consecutively enrolled patients in the Intestinal Diseases Natural History Database at Pennsylvania State University Hershey Medical Center (PSHMC) between January 1, 2015 and August 31, 2020. This database includes clinical and research information related to all health care encounters for over 6000 patients treated within the dedicated IBD center at PSHMC, a tertiary care referral hospital. This work was performed in accordance with the internal rules and regulations of the Pennsylvania State University College of Medicine Institutional Review Board and carried out under protocol STUDY00013788.

All participants in this study were >17 years old and had an established diagnosis of CD, UC, or IBD colitis of indeterminate nature, based upon standard clinical criteria routinely used to identify IBD.⁹ In addition, all participants had undergone an ileocolonoscopy and completed contemporaneous surveys on substance use and IBD-related symptoms, including the Harvey-Bradshaw Index (HBI), Simple Clinical Colitis Activity Index (SCCAI), Hospital Anxiety and Depression Scale (HADS), and Short Inflammatory Bowel Disease Questionnaire (SIBDQ).

Definitions and data abstraction

Cannabis (a.k.a. marijuana) use was defined as any active utilization, either through purposeful routes of oral consumption or respiratory inhalation, based upon patient responses to the following questions: (1) “Do you currently use marijuana?,” and (2) “If yes, how many times per week?.” Survey administration was performed at the time of individual clinic visits. Of note, recreational use of cannabis is currently illegal in the state of Pennsylvania, and this fact may have altered study participant responses. We did not ask respondents to describe individual reason(s) for use of cannabis or the exact method/mode of its consumption.

Disease activity was based upon ileocolonoscopic evaluation. In CD, disease activity was assessed with the Simple Endoscopic Score for CD (SES-CD), which ranges from 0 to 2 (remission), 3 to 6 (mild endoscopic activity), 7 to 15 (moderate endoscopic activity), and greater than 15 (severe endoscopic activity). Thus, moderate-to-severe disease activity in CD was defined as a SES-CD greater than or equal to 7. Disease activity was assessed in UC with the Mayo endoscopy subscore, which ranges from 0 (no disease) to 3 (severe disease). Utilizing this approach, moderate-to-severe disease activity in UC was defined as a Mayo endoscopy subscore of 2 or 3.

Before each ileocolonoscopy, patients completed surveys that included questions relating to IBD-related symptoms. Specifically, a comprehensive review of these symptoms was derived from the patient-reported subscores of the Likert-scale-based HBI, SCCAI, and SIBDQ surveys. The symptoms specifically evaluated in these surveys were: fatigue (based upon the first question in the SIBDQ [“How often has the feeling of fatigue or of being tired and worn out been a problem for you during the last 2 weeks?”], using an answer of 6 or less as present), abdominal pain (based upon the fourth question in the SIBDQ [“How often over the past 2 weeks have you experienced abdominal pain?”], using an answer of 6 or less as present), tenesmus (based upon the SIBDQ question, “How much of the time during the last 2 weeks have you been troubled by a feeling of having to go to the bathroom even though your bowels are empty?,” using an answer of 6 or less as present), gas (based upon the SIBDQ question, “Overall, in the last 2 weeks, how much of a problem have you had with passing large amounts of gas?,” using 6 or less as present), diarrhea (defined as >3 bowel movements per day based on the HBI/SCCAI question, “How many stools did you have the previous day”), rectal bleeding (any rectal bleeding reported based upon the HBI/SCCAI question, “Is there blood in your stool?”), fecal urgency (based upon the HBI/SCCAI question, “How much urgency do you usually feel with each stool?”), and current presence of known EIMs, including IBD-attributed arthritides/arthralgias [i.e., joint pain(s)], dermatopathies (e.g., pyoderma gangrenosum, erythema nodosum), uveitis, episcleritis, and primary sclerosing cholangitis. In addition, the presence of anxiety or depression symptoms was determined based upon responses to the HADS completed at the time of the clinical encounter, which ranges from 0 to 7 (normal), 8 to 10 (borderline abnormal), and 11 to 21 (abnormal). HADS anxiety or depression subscores of 8 or greater were described as clinically significant presence of anxiety or depression.

Additional demographic and clinical characteristics were abstracted from the medical record, including patient age, sex, IBD duration, IBD extent/location (e.g., organ involvement, using the Montreal classification system), disease complications (including previous or current gastrointestinal stricture, intra-abdominal fistula, abscess, and cancer development), surgical history, laboratory values (platelet count, white blood cell count [WBC], sedimentation rate [ESR], C-reactive protein [CRP]), current medications (including mesalamine, immunomodulator, biologic, antidepressant/anxiolytic, corticosteroid, opioid, and non-steroidal anti-inflammatory drug [NSAID] usage), and tobacco use.

Statistical analysis

Data were extracted and analyzed using GraphPad Prism version 8 (San Diego, CA) or R (v3.6.3; R Core Team [2020]. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org). The primary outcome evaluated for was cannabis use (as defined above). We completed descriptive statistics and univariate analyses (e.g., Student's t-test for continuous variables and chi-square or Fisher's exact test for categorical variables as appropriate) comparing demographic and clinical factors (including the presence of each symptom described above) in two cohorts: (1) cannabis users and (2) cannabis nonusers. A multivariable logistic regression model was then created that incorporated several key clinical factors found to be significantly (p<0.05) or near significantly (p=0.5–0.1) associated with cannabis use in our univariate analysis. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were reported from the model. Similar univariate and multivariable analyses (using the same inclusion criteria for the latter) were also separately completed for the CD cohort. p-Values of <0.05 were considered to be statistically significant.

Results

Study participants

Three hundred eighty-three IBD patients met the inclusion criteria described above. Two hundred six study participants (53.8%) identified as female. Two hundred fifty-eight individuals had CD (67.4%), 118 had UC (30.8%), and 7 indeterminate colitis (1.2%). A total of 30 patients (7.8%) were active cannabis users. Cannabis users consumed it on average 2.7 times per week.

There were a few differences between IBD patients who consumed cannabis and IBD patients who did not use cannabis. Specifically, cannabis users had a lower mean age (36.7 years vs. 44.6 years, p=0.01) and were more likely to have current EIMs of IBD (50.0% vs. 29.7%, p<0.05). CD patients who used cannabis had a lower incidence of complications [i.e., strictures and/or intra-abdominal fistula(e)] compared to CD patients who did not use cannabis (39.1% vs. 61.7%, p<0.05) (Table 1). Cannabis users and nonusers had similar sex and IBD type distribution, as well as incidence of moderate-severe inflammation on endoscopic examination. They also had similar mean inflammatory marker levels (i.e., WBC, platelet count, CRP, and ESR). Finally, their IBD medications (i.e., active mesalamine, immunomodulator, biologic, and corticosteroid use), as well as NSAID, opioid, and tobacco usage, were also statistically similar (Table 1).

Table 1.

Clinical and Demographic Characteristics of Study Population

	Total (n=383)	Cannabis use (n=30)	No cannabis use (n=353)	p
Sex, female, n (%)	206 (53.8)	13 (43.3)	193 (54.7)	0.256
Age, years, mean±SEM	44.0±0.8	36.7±2.4	44.6±0.9	0.010
IBD subtype (CD/UC/IC)	258/118/7	23/6/1	235/112/6	0.358
Moderate-to-severe inflammation (on endoscopic evaluation), n (%)	144 (37.6)	10 (33.3)	134 (38.0)	0.700
Complications of CD patients, n (%)	154 (67.4)	9 (39.1)	145 (61.7)	0.045
Any current active EIM, n (%)	120 (31.3)	15 (50.0)	105 (29.7)	0.038
White blood cell count, 109 cells/L	8.2±0.2	8.5±0.7	8.2±0.2	0.666
Platelet count, 109 cells/L	295.2±6.3	315.3±28.7	293.3±6.4	0.331
ESR, mm/h	19.0±1.2	15.4±5.0	19.4±1.2	0.324
CRP, mg/dL	1.4±0.1	0.7±0.2	1.5±0.1	0.104
Mesalamine use, n (%)	89 (23.2)	4 (13.3)	85 (24.1)	0.259
Immunomodulator use, n (%)	84 (21.9)	6 (20.0)	78 (22.1)	0.999
Biologic use, n (%)	213 (55.6)	19 (63.3)	194 (55.0)	0.446
Corticosteroid use, n (%)	52 (13.6)	3 (10.0)	49 (13.9)	0.782
Opioid use, n (%)	44 (11.5)	5 (16.7)	39 (11.0)	0.368
NSAID use, n (%)	68 (17.8)	3 (10.0)	65 (18.4)	0.324
Tobacco use, n (%)	44 (11.4)	4 (13.3)	40 (11.3)	0.764

Bold values were statistically significantly different from one another (p<0.05).

CD, Crohn's disease; CRP, C-reactive protein; EIM, extraintestinal manifestation; ESR, sedimentation rate; IBD, inflammatory bowel disease; IC, indeterminate colitis; NSAID, non-steroidal anti-inflammatory drug; SEM, standard error of the mean; UC, ulcerative colitis.

Symptom profiles and EIMs

Individuals who consumed cannabis were more likely to report abdominal pain (83.3% vs. 61.7%, p<0.05), gas (66.7% vs. 45.6%, p<0.05), tenesmus (70.0% vs. 47.6%, p<0.05), and arthralgias (53.3% vs. 20.3%, p=0.0001) compared to those that did not use cannabis (Table 2). These cohorts had similar incidences of fatigue, diarrhea, fecal urgency, rectal bleeding, dermatopathies, primary sclerosing cholangitis, and uveitis. They also had similar incidences of anxiety and/or depression.

Table 2.

Symptoms and/or Extraintestinal Manifestations of Inflammatory Bowel Disease

	Total (n=383), n (%)	Cannabis use (n=30), n (%)	No cannabis use (n=353), n (%)	p
Fatigue	320 (83.6)	26 (86.7)	294 (83.3)	0.800
Abdominal pain	244 (63.7)	215 (83.3)	219 (62.0)	0.018
Gas	181 (47.3)	20 (66.7)	161 (45.6)	0.035
Tenesmus	189 (49.3)	21 (70.0)	168 (47.6)	0.022
Diarrhea	141 (36.8)	9 (30.0)	132 (37.4)	0.555
Fecal urgency	265 (69.2)	21 (70.0)	244 (69.1)	0.999
Rectal bleeding	137 (35.8)	9 (30.0)	128 (36.3)	0.557
Any current EIM(s)	120 (31.3)	15 (50.0)	105 (29.7)	0.038
Arthralgia	88 (23.0)	16 (53.3)	72 (20.4)	0.0001
Dermatopathies	42 (11.0)	4 (13.3)	38 (10.8)	0.556
Erythema nodosum	5 (1.3)	0 (0.0)	5 (1.4)	0.999
Primary sclerosing cholangitis	6 (1.6)	2 (6.7)	4 (1.1)	0.073
Uveitis	21 (5.5)	3 (10.0)	18 (5.1)	0.221
Anxiety and/or depression	180 (47.0)	17 (56.7)	163 (46.2)	0.341

Bold values were statistically significantly different from one another (p<0.05).

Independent associations with cannabis use

We included all of the factors found to be significantly (p<0.05) or near significantly (p=0.5–0.10) different between all IBD cannabis users and nonusers in a multivariable logistic regression model. The only factor that demonstrated a significant independent association with cannabis use was the presence of arthralgia. Age was inversely associated with cannabis use (although with a relatively small effect size) (Table 3).

Table 3.

Multivariable Logistic Regression Model, Associations with Cannabis Use in Inflammatory Bowel Disease

Variable	Odds ratio	95% Confidence limits	p
Age	0.96	0.93–0.99	0.007
Abdominal pain	1.144	0.30–4.32	0.843
Gas	3.55	0.98–12.84	0.053
Tenesmus	0.86	0.33–2.27	0.766
Arthralgia	4.00	1.79–8.96	0.007

Bold values were statistically significantly different from one another (p<0.05).

As the CD contingent composed the largest percentage of the study cohort, had unique clinical considerations (e.g., the presence of CD-related complications such as strictures and intra-abdominal fistulae), and had been previously reported on in similar studies, we decided to evaluate the CD cohort alone in a similar manner. Using the same inclusion criteria (i.e., variables demonstrating statistical significance (p≤0.05) or near significance (p=0.05–0.1) in the univariate analysis), while including CD-associated complications (i.e., strictures and/or intra-abdominal fistulae), we identified four variables to include into a separate multivariable logistic regression model for the CD cohort: presence of fecal urgency (p=0.09), presence of arthralgia (p=0.0002), female sex (p=0.08), and presence of anxiety and/or depression (p=0.002). Based upon this analysis, we found that the presence of arthralgia (OR=4.19, CI: 1.61–10.89; p=0.002) and presence of anxiety and/or depression (OR=3.99, CI: 1.22–13.10; p=0.03) were each independently associated with cannabis use, while female sex (OR=0.37, CI: 0.14–0.92; p=0.04) was inversely associated with cannabis use in CD (Supplementary Table S1).

Discussion

In this study, we demonstrated that IBD cannabis users are more likely to report a variety of symptoms, including abdominal pain, gas, tenesmus, and arthralgias. Interestingly, they did not demonstrate more frequent moderate-to-severe disease activity or CD-associated complications or higher inflammatory marker levels. This suggests that other nonluminal factors influence their symptoms and/or decision to use cannabis. This concept was also supported by the fact that the only clinical factor to be independently associated with cannabis use in our cohort was the presence of arthralgias.

As cannabis has become increasingly available and familiar throughout the United States (both medically and recreationally), IBD patients have expressed growing interest in its therapeutic potential and demonstrated an increased willingness to consume it compared to the general population.¹⁰ As a result, health care providers are increasingly asked to provide advice about cannabis and its promise as a treatment for IBD. Currently, there is confusion about how best to counsel IBD patients in this regard, particularly given gaps in knowledge about its effects in this context and evidence to suggest it may be harmful under certain circumstances (including being associated with an increased risk for surgery in CD).^7,11 A few studies have attempted to directly measure the impacts of cannabis and cannabinoid compounds on IBD and its associated symptoms. To date, no human study has demonstrated that cannabis has a definitive impact on gastrointestinal inflammation in IBD. However, some investigations have demonstrated that patients perceive that cannabis helps to address several symptoms, including reduced appetite, nausea, diarrhea, abdominal pain, and joint pain.^3,4,7,12

Our findings support the results of these previous studies, as cannabis users in our cohort reported higher incidences of several symptoms, including abdominal pain and arthralgias. However, this study also demonstrated that those symptoms did not appear to be related to an increased degree or incidence of active inflammation or other IBD-related complications. In fact, there was an inverse association between cannabis use and IBD-related complications. In addition, the only symptom independently associated with cannabis use in the whole IBD cohort was an EIM of IBD, arthralgia. Similar findings were demonstrated in the CD cohort. Thus, it was the symptom(s), and not necessarily the underlying disease or its associated complications, that was most predictive of cannabis use. This is relevant because this is the first study to evaluate symptoms in IBD patients who simultaneously completed substance use surveys and underwent endoscopic assessments of disease activity. This was also one of the most comprehensive evaluations of IBD-associated gastrointestinal and extraintestinal symptoms undertaken in the context of cannabis use. Considering these factors, we believe that this investigation provides important new insights into the decision-making and clinical profiles of IBD patients who use cannabis.

Our study had several limitations. It relied upon a retrospective analysis and so is at increased risk of selection and surveillance bias (among other potential confounders). While this investigation was comparatively larger in size than several similar studies undertaken previously, the number of cannabis users was relatively small. This limited our ability to compare several potentially important variables and to effectively analyze subgroups within the study cohort (e.g., CD vs. UC). We were also not able to verify the amount, route of exposure, or type of cannabis consumed by our study participants. Nor did we have direct responses from the study participants to determine the exact reason for cannabis use. In addition, the designation of cannabis use was based upon survey responses and so there is potential for recall bias. We also note that our cannabis use rate (7.8%) was relatively smaller than other previous studies.^2–4 We evaluated the medical record of each patient to ensure that we were not missing other potential cannabis users but the possibility exists that we underestimated its use in this study population and/or that our study cohort was not necessarily representative of the IBD population (particularly because these data were derived from self-reported responses to questionnaires in a state that has not legalized recreational use of cannabis). Finally, we were unable to reliably assess for coexistent functional bowel disorders (e.g., irritable bowel syndrome [IBS]) in this particular study. While symptoms such as abdominal pain and altered bowel habits were not significantly associated with cannabis use in this analysis, it is possible that the symptoms of IBS and other related disorders could play a role in this regard.

Conclusion

The results of this study warrant further evaluation, in larger and more carefully phenotyped patient cohorts, as described above. Nonetheless, the findings reported here demonstrate the importance of evaluating for extraintestinal contributors to the symptom burden in IBD and in cannabis users in particular. This study also highlights the ongoing need to develop safer and more effective methods for recognizing and managing pain (both abdominal and extraintestinal) and other symptoms in IBD. As part of this effort, further investigation of the potential analgesic properties of cannabis and its derivatives should be made in the setting of IBD.

Abbreviations Used

CD

Crohn's disease

CIs

confidence intervals

CRP

C-reactive protein

EIM

extraintestinal manifestation

ESR

sedimentation rate

HADS

Hospital Anxiety and Depression Scale

HBI

Harvey-Bradshaw Index

IBD

inflammatory bowel disease

IBS

irritable bowel syndrome

NSAID

non-steroidal anti-inflammatory drug

ORs

odds ratios

PSHMC

Pennsylvania State University Hershey Medical Center

SCCAI

Simple Clinical Colitis Activity Index

SEM

standard error of the mean

SES-CD

Simple Endoscopic Score for CD

SIBDQ

Short Inflammatory Bowel Disease Questionnaire

UC

ulcerative colitis

WBC

white blood cell count

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This research was supported by the National Institutes of Health and National Institute of Diabetes and Digestive and Kidney Diseases (under Award No. R01DK122364), the Peter and Marsha Carlino Early Career Professorship in Inflammatory Bowel Disease (Matthew D. Coates), and the Margot E. Walrath Career Development Professorship in Gastroenterology (Matthew D. Coates).

Supplementary Material

Supplementary Table S1

Cite this article as: Coates MD, Dalessio S, Walter V, Stuart A, Bernasko N, Tinsley A, Razeghi S, Williams ED, Clarke K, Vrana K (2022) Symptoms and extraintestinal manifestations in active cannabis users with inflammatory bowel disease, Cannabis and Cannabinoid Research 7:4, 445–450, DOI: 10.1089/can.2020.0155.