Abstract
Background
Marijuana may be used by some patients with gastroparesis (Gp) for its potential antiemetic, orexigenic and pain-relieving effects.
Aims
The aim of this study was to describe the use of marijuana by patients for symptoms of Gp, assessing prevalence of use, patient characteristics, and patients’ perceived benefit on their symptoms of Gp.
Methods
Patients with symptoms of Gp underwent history and physical examination, gastric emptying scintigraphy, and questionnaires assessing symptoms. Patients were asked about current use of medications and alternative medications including marijuana.
Results
59 of 506 (11.7%) patients with symptoms of Gp reported current marijuana use; being similar among patients with delayed and normal gastric emptying and similar in idiopathic and diabetic patients. Patients using marijuana were younger, more often current tobacco smokers, less likely to be a college graduate, married or have income >$50,000. Patients using marijuana had higher nausea/vomiting subscore (2.7 vs 2.1; p=0.002), higher upper abdominal pain subscore (3.5 vs 2.9; p=0.003), more likely to be using promethazine (37 vs 25%; p=0.05) and dronabinol (17 vs 3%; p<0.0001). Of patients using marijuana, 51% had been using it for more than 2 years, 47% were using this once or more per day, and 81% of marijuana users rated their benefit from marijuana as better or much better.
Conclusions
A subset of patients (12%) with symptoms of Gp use marijuana. Patients with severe nausea and abdominal pain were more likely to use marijuana and perceive it to be beneficial for their symptoms.
Keywords: marijuana, cannabis, cannabinoids, dronabinol, gastroparesis
Introduction
Gastroparesis (Gp) patients have symptoms of nausea and vomiting along with early satiety, postprandial fullness, loss of appetite, and in some patients, abdominal pain (1). reatment often consists of dietary modifications, prokinetic agents, and antiemetic agents (2). Many of these symptoms can be hard to treat with many patients having persistent symptoms.
Healthcare providers should be aware of the use of different modalities that patients may be using to control their symptoms. Some patients with refractory nausea and vomiting resort to the use of marijuana (Cannibis Sativa) to treat their symptoms, particularly nausea, vomiting, and anorexia (3). Marijuana use for medical and recreational use is becoming increasingly common. Its potential orexigenic, antinauseant and pain-relieving properties attract many patients with chronic GI symptoms such as Gp. There are no published clinical trials on marijuana in Gp (3), only single center reports estimating the frequency of use (4). The use and effectiveness of marijuana in patients with Gp is of particular importance now that states are legalizing marijuana, as well as allowing the use of medical marijuana for a variety of conditions.
The main pharmacologically active chemicals in cannabis are tetrahydrocannabinol (THC) and cannabidiol (CBD). Current understanding is that the actions of cannabis are mediated by receptors that are part of an endogenous cannabinoid system (5), a widely distributed transmitter system that controls gut functions peripherally and centrally which appears to be an important physiologic regulator of gastrointestinal motility and visceral sensation (5). The endocannabinoid system (ECS) consists of the naturally occurring ligands N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), their biosynthetic and degradative enzymes, and the cannabinoid receptors CB1 and CB2. THC works by binding to and activating the cannabinoid (CB) receptors - CB1 and CB2 receptors. Cannabinoids are thought to mediate their antiemetic effects via CB1 receptors in the dorsal vagal complex of the brainstem (6). Cannabinoid receptor agonists such as dronabinol, a synthetic form of THC, are approved for nausea, vomiting, loss of appetite and weight loss in other conditions.
The aim of this study was to describe the use of marijuana by patients for symptoms of Gp – prevalence, duration, frequency of use, and the patient’s perceived benefit of marijuana on their symptoms of gastroparesis. The use of marijuana was compared to use of other medications for Gp including dronabinol.
Methods
Overview
The National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) sponsored Gastroparesis Clinical Research Consortium (GpCRC) Gastroparesis Registry (GpR2) cohort study (ClinicalTrials.gov Identifier: NCT01696747) provides assessment of a large number of well-documented patients followed at 7 sites (7). For this study, we used the baseline visit to study patients enrolled in GpR2 to help understand if these patients may be using alternate approaches other than medically prescribed medications to control their symptoms. Patients with symptoms of Gp from diabetic, idiopathic, or post-Nissen fundoplication etiologies and negative endoscopy (without ulceration or signs of obstruction) were invited to enroll in GpR2 between September 2012 and March 2018 and underwent history and physical examination, gastric emptying scintigraphy (GES), and questionnaires assessing symptoms of Gp. The medical history review included specific questions on current marijuana use and the frequency and duration of use, if the use was for Gp symptoms, and the patient’s perceived benefit of marijuana on their symptoms of gastroparesis. Other medications used for Gp symptoms were queried including antiemetic agents such as ondansetron, promethazine as well as dronabinol (Marinol).
All studies were approved by the Institutional Review Board at each Clinical Center and the Data Coordinating Center. All authors had access to the study data and also reviewed and approved the final manuscript.
Patient Enrollment
The enrollment criteria for GpR2 includes: 18 years or older with symptoms of at least 12 weeks duration, a GES test within 6 months of enrollment, and no structural abnormality as seen by upper endoscopy within one year of enrollment or any other reason by physician judgment that may explain symptoms.
Study Protocol
During interviews with each subject, study physicians or coordinators at each Clinical Center completed case report forms capturing gastroparesis disease onset, symptoms, associated medical and surgical conditions, including diabetes mellitus, and medication and supplemental therapies. Clinical severity of gastroparesis was graded on a scale (8); grade 1: mild gastroparesis (symptoms relatively easily controlled and able to maintain weight and nutrition on a regular diet); grade 2: compensated gastroparesis (moderate symptoms with only partial control with use of daily medications, able to maintain nutrition with dietary adjustments); grade 3: gastroparesis with gastric failure (refractory symptoms that are not controlled as shown by the patient having ER visits, frequent doctor visits or hospitalizations and/or inability to maintain nutrition via an oral route).
Patients filled out the Patient Assessment of Upper GI Symptoms (PAGI-SYM) questionnaire which assesses symptoms of gastroparesis, dyspepsia, and gastroesophageal reflux disease (9); it includes the nine symptoms of the Gastroparesis Cardinal Symptom Index (GCSI) (10). Patients are asked to assess the severity of their symptoms during the previous two weeks using a 0 to 5 scale where no symptoms=0, very mild=1, mild=2, moderate=3, severe=4, and very severe=5. Total GCSI score equals mean of the nausea/vomiting subscore, postprandial fullness/early satiety subscore, and bloating subscore where: Nausea/vomiting subscore=mean of scores for nausea, retching, and vomiting; Postprandial fullness/early satiety sub-score=mean of scores for stomach fullness, inability to finish meal, excessive fullness, and loss of appetite; and Bloating subscore=mean of scores for bloating (feeling like you need to loosen your clothes) and stomach or belly visibly larger. Upper abdominal pain subscore was average of upper abdominal pain and upper abdominal discomfort.
Disease-specific quality of life was assessed by the Patient Assessment of Upper Gastrointestinal Disorders Quality of Life (PAGI-QOL) survey (11) which assesses the impact of Gp symptoms on QOL over the previous 2 weeks. The Medical Outcomes Study 36-Item Short-Form Health Survey version 2 (SF-36v2) was used to assess the patients’ views of overall physical and mental health in the past 4 weeks (scale 0–100) (12). Higher scores on both QOL questionnaires indicate higher quality of life. Depression was assessed with the Beck Depression Index (BDI) (scale 0–30) (13) and anxiety with the State-Trait Anxiety Inventory (STAI) (scale 0–80) (14) where higher scores indicate more severe depression or anxiety. Patient Health Questionnaire (PHQ–15) is a questionnaire that is useful in screening for somatization and in monitoring somatic symptom severity (15). From this, the PHQ-12 was calculated, removing the three GI symptoms (16).
Gastric emptying scintigraphy was performed using a low-fat, egg white meal with imaging at 0, 1, 2, 4 hours after meal ingestion (17,18). This protocol ensures standardized information about gastric emptying across sites.
Statistical Methods
Baseline patient characteristics were compared between those who use marijuana vs. those who do not use it. Data are presented as means±SD or N (%) and p-values determined by Pearson chi-square or Fisher’s exact test for categorical measures and by two-sample t-test for continuous measures (19). The candidate set of 37 baseline characteristics used for the multiple logistic regression models included age (years), sex (female vs male), ethnicity (Hispanic or not), white race, smoking (never, former, current), alcohol use (vs no), college educated (vs no), income (≥$50,000 vs <$50,000), marital status (vs not), BMI (kg/m2), diabetes status, psychiatric diagnosis, gastroparesis etiology (Idiopathic, Diabetic, Post-Nissen), acute vs. insidious symptom onset, presence of initial infectious prodrome, nature and severity of Gp symptoms (mild/compensated/severe), hospitalization for gastroparesis in past year, gastric emptying status (not delayed vs delayed), use of alternative medications (vs no), Rome III identified cyclic vomiting syndrome (CVS) (vs no), 6 PAGI-SYM subscores, which includes upper and lower abdominal pain severity, and Gastroesophageal Reflux Disease (GERD) severity, Somatic Symptom category, Patient Health Questionnaire (PHQ-15) score, 5 PAGI-QOL subscores, SF-36 physical and mental scores, BDI total score, STAI total score (both State and Trait). Multivariable logistic regression was used to assess independent relationships of selected clinical factors associated with use of marijuana. Twenty-nine patients of the 506 total (N=477) were dropped from the final multivariable model due to either having post-Nissen etiology (n=24) or due to missing data (n=5). The selected model had the lowest Akaike Information Criteria (AIC) indicating the “best” ability to discriminate marijuana use from the 37 candidate variables (20). The final model was determined using backward stepwise logistic and minimum AIC of all models determined by all possible combinations of the candidate variables remaining after each selection step. Associations were considered significant if p<0.05 using nominal 2-sided p-values. Analyses were performed using SAS version 9.4 (SAS institute, Cary, NC) or Stata (Release 15.1, Stata Corporation, College Station, TX) (21).
Results
Patients
In GpR2, the total number of patients enrolled was 506 patients with symptoms of gastroparesis: 324 (64.0%) were idiopathic, 158 (31.2%) were diabetic, and 24 (4.7%) were post-Nissen fundoplication (Table 1). Overall, 366 patients (72.3%) had delayed gastric emptying whereas 140 patients (27.7%) had normal gastric emptying. There were 86.0% female and average age was 44.1 years.
Table 1:
Characteristics of patients with gastroparesis by marijuana use
| Current Marijuana Use* |
||||
|---|---|---|---|---|
| Characteristic | No (N=447) | Yes (N=59) | Total (N=506) | P value† |
| Reason for Gastroparesis | 0.97 | |||
| Idiopathic | 287 (64.2%) | 37 (62.7 %) | 324 (64.0%) | |
| Diabetic | 139 (31.1%) | 19 (32.2%) | 158 (31.2%) | |
| Post- Nissen | 21 (4.7%) | 3 (5.1%) | 24 (4.7%) | |
| Gastric Emptying: | 0.83 | |||
| Delayed | 324 (72.5%) | 42 (71.2%) | 366 (72.3%) | |
| Normal | 123 (27.5%) | 17 (28.8%) | 140 (27.7%) | |
| Demographic, lifestyle: | ||||
| Gender (Females) | 388 (86.8%) | 47 (79.7%) | 435 (86.0%) | 0.14 |
| Age (years) | 45.2 ± 13.7 | 36.1 ± 12.7 | 44.1 ± 13.9 | <0.0001 |
| Hispanic | 82 (18.3%) | 4 (6.8%) | 86 (17.0%) | 0.03 |
| Race: White | 398 (89.4%) | 51 (86.4%) | 449 (89.1%) | 0.49 |
| Body Mass Index Category : | 0.22 | |||
| Underweight (<18 kg/m2) | 22 (4.9%) | 2 (3.4%) | 24 (4.7%) | |
| Normal (18–24 kg/m2) | 157 (35.2%) | 29 (49.1%) | 186 (36.8%) | |
| Overweight (25–30 kg/m2) | 112 (25.1%) | 11 (18.6%) | 123 (24.4%) | |
| Obese (>30 kg/m2) | 155 (34.7%) | 17 (28.8%) | 172 (34.1%) | |
| Body mass index (kg/m2) | 28.4 ± 8.3 | 27.4 ± 7.7 | 28.3 ± 8.3 | 0.38 |
| Smoking (Tobacco): | ||||
| Current smoker | 42 (9.4%) | 22 (37.3%) | 64 (12.6%) | <0.0001 |
| Ever smoker | 131 (29.3%) | 38 (64.4%) | 169 (33.4%) | <0.0001 |
| Alcohol consumption | 226 (50.6%) | 37 (62.7%) | 263 (52.0%) | 0.08 |
| Education: College | 181 (40.5%) | 14 (23.7%) | 195 (38.5%) | 0.01 |
| Marriage status: married | 257 (57.6%) | 19 (32.2%) | 276 (54.6%) | 0.0002 |
| Income: $50,000 and greater | 230 (51.4%) | 18 (30.5%) | 248 (49.0%) | 0.003 |
| Medical History: | ||||
| History of psychiatric conditions | ||||
| Eating disorders | 10 (2.2%) | 2 (3.4%) | 12 (2.4%) | 0.58 |
| Major depression | 133 (29.7%) | 22 (37.3%) | 155 (30.6%) | 0.24 |
| Schizophrenia | 0 | 0 | 0 | |
| Bipolar disorder | 33 (7.4%) | 9 (15.2%) | 42 (8.3%) | 0.04 |
| Obsessive compulsive disorder | 21 (4.7%) | 5 (8.5%) | 26 (5.1%) | 0.22 |
| Severe anxiety disorder | 120 (26.8%) | 22 (37.3%) | 142 (28.1%) | 0.09 |
| Personality disorder | 5 (1.1%) | 1 (1.7%) | 6 (1.2%) | 0.70 |
| Hospitalizations (any in past year) | 127 (28.4%) | 26 (44.1%) | 153 (30.2%) | 0.01 |
| Number of hospitalizations in past year | 1.2 ± 4.1 | 2.8 ± 7.5 | 1.4 ± 4.6 | 0.13 |
| Initial infectious prodrome | 82 (18.3%) | 18 (30.5%) | 100 (19.8%) | 0.03 |
| Type of symptom onset: | 0.38 | |||
| Acute | 162 (36.5%) | 25 (42.4%) | 187 (37.2%) | |
| Insidious | 282 (63.2%) | 34 (57.6%) | 316 (62.6%) | |
| Nature of gastroparesis symptoms: | 0.36 | |||
| Chronic, but stable | 97 (21.9%) | 10 (16.9%) | 107 (21.3%) | |
| Chronic, but progressive worsening | 107 (24.1%) | 12 (20.3%) | 119 (23.7%) | |
| Chronic, but some improvement | 44 (9.9%) | 3 (5.1%) | 47 (9.4%) | |
| Chronic with some periodic exacerbations | 123 (27.8%) | 22 (37.4%) | 145 (28.9%) | |
| Cyclic pattern | 72 (16.2%) | 12 (20.34%) | 84 (16.73%) | |
| Gastroparesis severity: | 0.13 | |||
| Mild (Grade 1) | 95 (21.3%) | 6 (10.2%) | 101 (20.0%) | |
| Compensated (Grade 2) | 296 (66.5%) | 45 (76.3%) | 341 (67.7%) | |
| Severe (Grade 3) | 54 (12.1%) | 8 (13.6%) | 62 (12.3%) | |
| Medication History: | ||||
| Current use of dronabinol (Marinol) | 13 (2.9%) | 10 (16.9%) | 23 (4.5%) | <0.0001 |
| Current use of narcotic pain medication | 145 (32.4%) | 20 (33.9%) | 165 (32.6%) | 0.82 |
| Current use of benzodiazepines | 100 (22.4%) | 19 (32.2%) | 119 (23.5%) | 0.09 |
| Current use of alternative medicines | 199 (44.5%) | 31 (52.5%) | 230 (45.4%) | 0.24 |
| Current use of antidepressant medication | 154 (34.4%) | 20 (33.9%) | 174 (34.4%) | 0.93 |
| Current use of metoclopramide (Reglan) | 52 (11.6%) | 12 (20.3%) | 64 (12.6%) | 0.06 |
| Current use of domperidone | 60 (13.4%) | 10 (16.9%) | 70 (13.8%) | 0.46 |
| Current use of erythromycin | 16 (3.6%) | 5 (8.5%) | 21 (4.1%) | 0.08 |
| Current use of ondansetron (Zofran) | 180 (40.3%) | 27 (45.8%) | 207 (40.9%) | 0.42 |
| Current use of prochlorperazine (Compazine) | 24 (5.4%) | 2 (3.4%) | 26 (5.1%) | 0.52 |
| Current use of promethazine (Phenergan) | 112 (24.9%) | 22 (37.3%) | 134 (26.5%) | 0.05 |
| PAGI-SYM symptom severity (0–5): | ||||
| Nausea sub-score | 2.1 ± 1.4 | 2.7 ± 1.4 | 2.2 ± 1.4 | 0.002 |
| Nausea item | 3.1 ± 1.5 | 3.5 ± 1.2 | 3.2 ± 1.5 | 0.02 |
| Retching item | 1.6 ± 1.7 | 2.2 ± 1.8 | 1.7 ± 1.7 | 0.006 |
| Vomiting item | 1.5 ± 1.8 | 2.3 ± 1.8 | 1.6 ± 1.8 | 0.003 |
| Appetite sub-score | 3.3 ± 1.2 | 3.5 ± 1.1 | 3.4 ± 1.2 | 0.43 |
| Bloating sub-score | 3.1 ± 1.6 | 3.0 ± 1.5 | 3.1 ± 1.6 | 0.65 |
| Cardinal symptom index (GCSI) | 2.8 ± 1.1 | 3.1 ± 1.0 | 2.9 ± 1.1 | 0.17 |
| Upper Abdominal pain sub-score | 2.9 ± 1.5 | 3.5 ± 1.2 | 3.0 ± 1.5 | 0.003 |
| Upper abdominal pain item | 2.8 ± 1.6 | 3.5 ± 1.3 | 2.9 ± 1.6 | 0.0001 |
| Upper abdominal discomfort item | 3.0 ± 1.6 | 3.5 ± 1.3 | 3.0 ± 1.5 | 0.02 |
| Lower abdominal pain sub-score | 2.0 ± 1.5 | 2.2 ± 1.6 | 2.0 ± 1.5 | 0.33 |
| GERD sub-score | 1.9 ± 1.4 | 1.9 ± 1.3 | 1.9 ± 1.4 | 0.77 |
| PAGI-QOL (0–5): | ||||
| Activity sub-score | 2.6 ± 1.2 | 2.2 ± 1.2 | 2.6 ± 1.2 | 0.03 |
| Clothing sub-score | 3.0 ± 1.8 | 2.7 ± 1.7 | 2.9 ± 1.8 | 0.35 |
| Diet sub-score | 1.8 ± 1.4 | 1.4 ± 1.1 | 1.8 ± 1.3 | 0.03 |
| Relationship sub-score | 3.3 ± 1.4 | 3.2 ± 1.3 | 3.3 ± 1.4 | 0.37 |
| Psychological sub-score | 3.2 ± 1.4 | 2.9 ± 1.2 | 3.1 ± 1.3 | 0.10 |
| Total Score | 2.8 ± 1.1 | 2.5 ± 1.0 | 2.8 ± 1.1 | 0.06 |
| SF-36v2 Health Survey: | ||||
| Physical health summary measure | 33.8 ± 11.0 | 30.8 ± 9.8 | 33.5 ± 10.9 | 0.05 |
| Mental health summary measure | 42.3 ± 12.9 | 39.8 ± 11.9 | 42.0 ± 12.8 | 0.17 |
| PHQ-15: | ||||
| PHQ-15 total score | 14.1 ± 5.0 | 15.3 ± 4.6 | 14.3 ± 5.0 | 0.08 |
| PHQ-12 total score | 9.3 ± 4.3 | 10.2 ± 4.0 | 9.4 ± 4.3 | 0.13 |
| Beck Depression Inventory: | ||||
| Severe depression indicated (yes) | 83 (18.6%) | 17 (28.8%) | 100 (19.8%) | 0.06 |
| BDI total score | 16.9 ± 11.2 | 19.5 ± 12.0 | 17.2 ± 11.3 | 0.09 |
| State-Trait Anxiety Inventory (STAI): | ||||
| State anxiety score ≥ 50 (severe) | 132 (29.5%) | 21 (35.6%) | 153 (30.2%) | 0.34 |
| Trait anxiety score ≥ 50 (severe) | 118 (26.4%) | 28 (47.5%) | 146 (28.9%) | 0.0008 |
| State anxiety score | 41.8 ± 13.6 | 44.9 ± 12.8 | 42.1 ± 13.6 | 0.09 |
| Trait anxiety score | 41.8 ± 13.0 | 46.0 ± 12.1 | 42.3 ± 12.9 | 0.02 |
No. (%) presented for categorical or binary variables and means ± 95% confidence intervals for continuous data are reported.
P-values (2-sided) determined using Pearson’s chi-square test or Fisher’s exact text for categorical or binary variables and two-sided t-tests for continuous variables. Bolded p’s denote P<0.05.
Marijuana
As shown in Table 1, 59 of 506 (11.7%) patients with symptoms of Gp reported they use marijuana. The use was similar among patients with delayed and normal gastric emptying (11.5% and 12.1%; p=0.83) and similar among idiopathic, diabetic, and postfundoplication patients (11.4, 12.0, 12.5%; p=0.97). This registry study enrolled patients over a 5 year period. An increase in marijuana use was seen in our enrolled patients ages 18–25 years from the year 2013 (6.7% use) to 2017 (50% use).
Patients using marijuana compared to those that did not were younger (36 vs 45 years; p<0.0001), more often current tobacco smokers (37 vs 9%; p<0.0001), less likely college graduate (24 vs 40%; p=0.01), less likely married (32 vs 58%; p=0.0002), and less likely income >$50,000 (31 vs 51%; p=0.003) (Table 1). Most patients using marijuana had chronic symptoms (80%) with a minority having episodic symptoms (20%).
Patients using marijuana had a higher nausea/vomiting subscore (2.7 vs 2.1; p=0.002), higher upper abdominal pain subscore (3.5 vs 2.9; p=0.003). Patients using marijuana had decreased QOL as assessed with SF-36v2 physical component (p=0.05) and PAGI-QOL total score (p=0.06) (Table 1). Users of marijuana more often reported having bipolar disorder (15 vs 7%; p=0.04) and anxiety disorder (37 vs 27%; p=0.09). Users of marijuana had increased trait anxiety score (46 vs 42; p=0.02) and tended to have a higher Beck Depression Inventory score (20 vs 17; p=0.09).
Table 2 shows information on patients using marijuana. Of patients using marijuana, 51% had been using this for more than 2 years, 47% of patients using this once or more per day. 81.4% of patients rated their benefit from marijuana for their symptoms of gastroparesis as better or much better.
Table 2.
Duration of use, perceived benefit, and frequency of use for marijuana, dronabinol, ondansetron, and promethazine.
| Medication |
||||
|---|---|---|---|---|
| Marijuana (N=59) | Dronabinol (N=23) | Ondansetron (N=207) | Promethazine (N=134) | |
| Duration | ||||
| Less than 1 month | 5 (8.5%) | 1 (4.3%) | 7 (3.4%) | 11 (8.2%) |
| 1–6 months | 5 (8.5%) | 13 (56.5%) | 34 (16.4%) | 31 (23.1%) |
| 6–11 months | 3 (5.1%) | 3 (13.0%) | 37 (17.9%) | 10 (7.5%) |
| 1–2 years | 16 (27.1%) | 3 (13.0%) | 59 (28.5%) | 28 (20.9%) |
| More than 2 years | 30 (50.8%) | 3 (13.0%) | 70 (33.8%) | 54 (40.3%) |
| Benefit | ||||
| Not taking for gastroparesis | 1 (1.7%) | 0 (0%) | 3 (1.4%) | 2 (1.5%) |
| No or minimal | 4 (6.8%) | 6 (26.1%) | 34 (16.4%) | 20 (14.9%) |
| Better | 11 (18.6%) | 6 (26.1%) | 105 (50.7%) | 74 (55.2%) |
| Much Better | 37 (62.7%) | 11 (47.8%) | 63 (30.4%) | 36 (26.9%) |
| Worse | 1 (1.7%) | 0 (0%) | 1 (0.5%) | 1 (0.7%) |
| Much Worse | 5 (8.5%) | 0 (0%) | 1 (0.5%) | 1 (0.7%) |
| Frequency | ||||
| Rarely | 7 (11.9%) | |||
| About once per month | 2 (3.4%) | |||
| Several times per month | 9 (15.2%) | |||
| About once per week | 1 (1.7%) | |||
| Several times per week | 12 (20.3%) | |||
| About once per day | 7 (11.9%) | |||
| More than once per day | 21 (35.6%) | |||
The patients using marijuana for more than 2 years (30 patients) were compared to those using marijuana for less than 2 years (29 patients). Chronic use (>2 years) was associated more often with delayed gastric emptying (83 vs 59%; p=0.04), current smoker (57 versus 17%; p=0.002), and more likely to have cyclic pattern of symptoms (23 vs 17%).
The patients using marijuana at least once per day (28 patients) were compared to those using marijuana less than daily (31 patients). At least once per day marijuana use was associated with severe anxiety disorder (50 vs 26%; p=0.06), higher SF-36 mental health score (43 vs 37; p=0.05), and less BDI total score (16 vs 23; p=0.04).
Multivariable logistic regression analysis was performed for independent factors related to marijuana use in patients (Table 3). Significant independent factors included current and former smoker, lower age at enrollment, non-married, non-Hispanic, use of alternative medicines, higher upper abdominal pain PAGI-SYM sub-score, and diabetic rather than idiopathic gastroparesis.
Table 3.
Multivariable Logistic Regression Analysis of Independent Factors Related to Marijuana Use in Patients with Symptoms of Gastroparesis (N=477)* †
| Marijuana Use |
|||
|---|---|---|---|
| Clinical Factors | Odds ratioǂ | 95% Confidence Interval | P‡ |
| Smoking: Former smoker vs. non-smoker | 4.90 | 2.15 – 11.18 | <0.001 |
| Current smoker vs. non-smoker | 14.24 | 5.91 – 34.28 | <0.001 |
| Age at enrollment (/years) | 0.94 | 0.91 – 0.97 | <0.001 |
| PAGI-SYM: Upper abdominal pain sub-score (/score) | 1.35 | 1.05 – 1.75 | 0.02 |
| Non-married vs. married | 2.41 | 1.17 – 5.00 | 0.02 |
| Etiology: Diabetic vs. Idiopathic gastroparesis | 2.25 | 1.04 – 4.87 | 0.04 |
| Non-Latino/Hispanic vs. Latino or Hispanic | 3.41 | 1.07 – 10.83 | 0.04 |
| Use of alternative medicine (yes vs. no) | 2.00 | 1.00 – 3.99 | 0.05 |
| Initial infectious prodrome (yes vs. no) | 1.76 | 0.84 – 3.68 | 0.14 |
| Alcohol use (yes vs. no) | 1.73 | 0.87 – 3.43 | 0.08 |
Model variables selected from a candidate set of 37 baseline variables using Akaike Information criteria (AIC) with backward selection using logistic regression. The candidate set of baseline variables included: gastric emptying (normal vs. delayed), etiology of gastroparesis (idiopathic vs. diabetic), gender (female vs. male), ethnicity (Hispanic vs. non-Hispanic), race (white vs. non-white), age, BMI, smoking status (non-smoker/ former smoker/ current smoker), alcohol use (yes vs. no), Rome III identified cyclic vomiting syndrome (yes vs. no), married vs. non-married, acute symptom onset vs. insidious onset, college (yes vs. no), income above $50,000 (yes vs. no), infectious prodrome (yes vs. no), hospitalizations in past year (yes vs. no), nature of gastroparesis symptoms, severity of gastroparesis (mild/ compensated/ severe), use of alternative medicine (yes vs. no), psychiatric diagnoses (anxiety, bipolar, eating disorders, major depression, obsessive compulsive disorder, personality disorder), STAI state score, STAI trait score, Beck Depression Inventory score, PAGI-SYM sub-scores, PAGI-QOL sub-scores, SF36 Physical and Mental components, Somatic Symptom category, and PHQ-15 score.
Post-Nissen gastroparesis subjects (N=24) excluded due to low number. 5 additional subjects excluded due to one or more missing variables.
Odds of marijuana use vs. no marijuana use. Prevalence of marijuana use: N=59 (12.4%)
P-values determined from multiple regression (2-sided). Bolded p’s denote <0.05.
Other antiemetics
Patients using marijuana were more likely to be using promethazine (37 vs 25%; p=0.05), metoclopramide (20 vs 12%; p=0.06), benzodiazepines (32 vs 22%; p=0.09), erythromycin (8 vs 4%; p=0.08), and dronabinol (17 vs 3%; p<0.0001) (Table 1). There were no differences of the prevalence of opiate use in patients using and not using marijuana.
Comparatively, 23 of the 506 (4.5%) patients were using dronabinol. Of dronabinol users, 26% had been using this for one or more years, with 74% rating their benefit from dronabinol as better or much better (Table 2). Ondansetron was used by 207 patients (40.9%) with 62% using this for one or more years, and 81.1% rating their benefit favorably (better or much better). Promethazine was used by 134 patients (26.5%) with 61% using this one or more years, and 82.0% rating their benefit as better or much better.
Discussion
For this study, we systematically assessed the use of marijuana among patients enrolled in our NIH Gastroparesis Registry. The results show that a significant minority (12%) of patients with symptoms of Gp use marijuana. Patients using marijuana compared to those that did not were younger, more often current tobacco smokers, less likely college graduate, less likely married, and had a lower income. Patients with severe nausea and abdominal pain were more likely to use marijuana, consistent with its perceived benefits.
Our study showed that 12% patients with symptoms of Gp reported they use marijuana. The use was similar among patients with delayed and normal gastric emptying and in idiopathic and diabetic patients. The reported use in patients with symptoms of gastroparesis in our cohort (12% prevalence) is slightly lower than that reported in the general US population (15.3% in 2017) (22). Of note, an increase in marijuana use was seen in our enrolled patients ages 18–25 years from the year 2013 (6.7% use) to 2017 (50% use). Prevalence of marijuana use may differ depending on the legalization status in the particular state as well as the development of medical marijuana programs. Our centers were in a variety of states including Maryland, Pennsylvania, North Carolina, California, Michigan, Kentucky, and Massachusetts. The study design used self-reported data provided by the patients. Patients reported the use of marijuana on a questionnaire; patients using marijuana might have reported “no” to use of marijuana due to fear of repercussions; this would lower the true prevalence rate. Urine drug screens are often performed in clinical trials to detect use of cannabis often to exclude these patients; in this type of study, they could be used to capture additional users. There is an increasing body of evidence that self-reported patient information is an accepted method to assess healthcare utilization (23).
Our study found that patients using marijuana compared to those that did not were younger, more often current tobacco smokers, less likely college graduate, less likely married, and having a lower income. Studies in chronic functional nausea and vomiting have shown similar results (24). Our study looked at patients with symptoms of gastroparesis, both delayed and normal gastric emptying, suggesting the disorders gastroparesis and chronic unexplained nausea and vomiting (CUNV). There was no difference in the use of marijuana in patients with delayed or normal gastric emptying. Many of our patients meet the criteria for functional dyspepsia (25). CUNV patients could be classified as chronic nausea and vomiting syndrome according to the Rome IV criteria (26,27).
Of patients using marijuana, 51% had been using marijuana for more than 2 years, 47% of patients using this once or more per day. Most patients in our study using marijuana had chronic symptoms of gastroparesis (80%) with only a minority having cyclic symptoms (20%). Chronic cannabis use has been linked to the disorder of Cannabinoid Hyperemesis Syndrome (CHS). In CHS, patients using chronic marijuana (frequency and duration) have intermittent episodes of nausea and vomiting, similar to cyclic vomiting syndrome (CVS); they are also reported to have the propensity to take hot showers/baths to help try to relieve their symptoms (28,29). In cyclic vomiting syndrome, gastric emptying is often rapid or normal, in contrast to the delayed gastric emptying seen in gastroparesis (30). Similar to the beneficial results we report here in patients with symptoms of gastroparesis, some patients with CVS use marijuana to suppress their symptoms when they occur. We did not specifically ask about presence of cyclic vomiting syndrome (CVS) or cannabinoid hyperemesis syndrome; most patients had chronic, daily symptoms of Gp. However, some patients did describe their symptoms as cyclic in nature. Thus, a small proportion of the patients (particularly the idiopathics, or those with normal gastric emptying) might actually have CHS rather than Gp. CHS is poorly understood and under-reported; whether CHS also causes chronic symptoms similar to Gp is not known.
Patients using marijuana had a higher nausea/vomiting subscore and higher upper abdominal pain subscore. These symptoms are probably the ones leading these patients to use marijuana. Consistent with the high nausea/vomiting subscore, patients were also more likely to be using medications for nausea such as promethazine and dronabinol. Do these patients using marijuana represent those with the worse symptoms who use marijuana for their severe symptoms, or are the higher nausea/vomiting scores a consequence of marijuana use? This study does not provide a definitive answer to this question. A prospective, interventional study would help address this. Further studies are needed to address this as the use of cannabinoids (including cannabidiol) is rapidly growing. Given our findings and the literature (31), we cannot rule out that marijuana use is worsening symptoms in this condition and may have a deleterious effect, that is, marijuana might be worsening their symptoms.
Older literature suggested that THC does not affect gastric emptying (32), more recent studies suggest cannabinoid agonists may slow GI motility and inhibit gastric acid secretion. THC at a dose used for preventing chemotherapy-induced nausea and vomiting was found to delay gastric emptying of solid food in normal human subjects (33). Drobinolol also delays gastric emptying and slows colonic transit (34). Thus, chronic marijuana use may worsen gastroparesis because of effects on gastric emptying. Caution should also be used in the interpretation of gastric emptying in chronic users of marijuana. In addition, by increasing appetite and sometimes provoking binge eating, marijuana can make symptoms worse as well.
Interestingly, when asking the patients, 81% of the users of marijuana perceived benefit (better or much better) on their symptoms of gastroparesis from its use. We did not ask the patients what specific symptoms improved. Thus, cannabinoids may have a potential therapeutic effect on nausea and vomiting in patients with Gp. In addition, patients with abdominal pain use marijuana. Cannabinoids have been suggested as an alternative to the use of opiates. In our cohort, there were no differences of the prevalence of opiate use in our patients using and not using marijuana. One wonders if marijuana may acutely reduce symptoms of nausea and vomiting leading to patients perceived benefit, but chronically worsen the condition and symptoms as assessed by the PAGI-SYM questionnaire. To address this, symptom severity scores prior to their use of marijuana would be of interest.
The effects of marijuana on reducing nausea/vomiting, reducing abdominal pain, and improving appetite have been reported to be favorable in other disorders (4,31). THC may help chronic neuropathic or cancer pain and cannabinoids may help nausea and vomiting secondary to chemotherapy (31). There are two cannabinoid derivatives approved by the FDA (dronabinol and nabilione) for chemotherapy-induced nausea and vomiting. Dronabinol was shown to be as efficacious as the 5HT3 antagonist, ondansetron, in preventing delayed chemotherapy-induced nausea and vomiting (CINV) in humans (35). Dronabinol is occasionally used in patients with Gp, particularly for loss of appetite and chronic nausea. In our study, 23 of the 506 (4.5%) patients were using dronabinol. Of dronabinol users, 57% had been using this for 1–6 months, with 74% rating their benefit from dronabinol as better or much better. Similar ratings of perceived benefit were recorded with the use of promethazine. Although the synthetic analog, dronabinol, was used by a small minority, it appeared to be comparable in efficacy to marijuana and may be an effective alternative.
We did not specifically ask about side effects of using marijuana. Although marijuana use has been viewed in the public as benign, this is often not the opinion of many health care providers (37). In our study, patients that were using marijuana had increased prevalence of anxiety and bipolar disorders; although, it is not clear if this association is cause or effect. Patients using marijuana scored higher on anxiety and depression measures. Long term marijuana users have been shown to have an increase in anxiety, depressive, and psychotic symptoms (38). Frequent use of high-strength cannabis may increase the risk of mental health problems, particularly psychotic symptoms (39).
This is one of the first manuscripts reporting the characteristics of marijuana users among patients with suspected gastroparesis. This study capitalized on the information we obtained in our NIH registry comprising a large number of patients from different centers with symptoms of gastroparesis. This manuscript adds to the literature in a number of areas: this is a multicenter study rather than previous single center reports of smaller number of patients questioned about marijuana use (4), utilization of multivariable analysis to look at independent factors with marijuana use, and looking at the relationship between marijuana use and possible side effects of marijuana. We did not ask about route of marijuana/cannabis use: smoke, vapor (higher bioavailability, quicker onset of action), or edibles like pills (lower bioavailability due to metabolism through first-pass effect, late onset of action, but effects can last longer) (36). We also did not have symptom scores of the patients that used marijuana prior to their use of marijuana.
In summary, this study describes the use and type of patients using marijuana for symptoms of gastroparesis, showing that a significant minority (12%) of patients with symptoms of Gp use marijuana. Patients with severe nausea/vomiting and abdominal pain were more likely to use marijuana, consistent with its perceived benefits. Marijuana use will likely increase, as more states are starting medical marijuana programs and legalizing marijuana. From a clinical care perspective, physicians taking care of patients with symptoms of gastroparesis should inquire about use of marijuana and other cannabinoids by their patients, as they may be using these substances for treatment; perhaps with a beneficial response or possibly with side effects.
Acknowledgments
Funding: The NIH/NIDDK Gastroparesis Clinical Research Consortium (GpCRC) is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (grants U01DK073975 [Parkman], U01DK073983 [Pasricha], U01DK074007 [Abell], U01DK073974 [Koch], U01DK074035 [McCallum], U01DK112193 [Kuo], U01DK074008 [Tonascia]).
Footnotes
No conflicts of interest exist.
Publisher's Disclaimer: This Author Accepted Manuscript is a PDF file of an unedited peer-reviewed manuscript that has been accepted for publication but has not been copyedited or corrected. The official version of record that is published in the journal is kept up to date and so may therefore differ from this version.
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