Cannabinoids and the GI Tract

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“The synthesis and degradation of endocannabinoids, location of cannabinoid (CB) receptors, and cannabinoid mechanisms of action on immune/inflammatory, neuromuscular, and sensory functions in digestive organs are well documented. CB2 mechanisms are particularly relevant in immune and sensory functions. Increasing use of cannabinoids in the USA is impacted by social determinants of health including racial discrimination which is associated with tobacco and cannabis co-use, and combined use disorders. Several conditions associated with emesis are related to cannabinoid use, including cannabinoid hyperemesis or withdrawal, cyclic vomiting syndrome, nausea and vomiting of pregnancy. Cannabinoids generally inhibit gastrointestinal motor function; yet they relieve symptoms in patients with gastroparesis and diverse nausea syndromes. Cannabinoid effects on inflammatory mechanisms have shown promise in relatively small placebo-controlled studies in reducing disease activity and abdominal pain in patients with inflammatory bowel disease (IBD). Cannabinoids have been studied in disorders of motility, pain, and disorders of gut brain interaction. The CB2 receptor agonist, cannabidiol, reduced total Gastroparesis Cardinal Symptom Index and increased ability to tolerate a meal in patients with gastroparesis appraised over 4 weeks of treatment. In contrast, predominant-pain endpoints in functional dyspepsia with normal gastric emptying were not significantly improved with cannabidiol. The CB2 agonist, olorinab, reduced abdominal pain in IBD in an open-label trial and in constipation-predominant irritable bowel syndrome in a placebo-controlled trial. Cannabinoid mechanisms alter inflammation in pancreatic and liver diseases. In conclusion, cannabinoids, particularly agents affecting CB2 mechanisms, have potential for inflammatory, gastroparesis, and pain disorders; however, the trials require replication and further understanding of risk-benefit to enhance use of cannabinoids in gastrointestinal diseases.”


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“Background: Cannabis (Δ9THC), a non-selective cannabinoid receptor (CBR) agonist relieves nausea and pain. Cannabidiol (CBD), a CBR2 inverse agonist with central effects, also reduces gut sensation and inflammation.

Aims: To compare effects of 4 weeks’ treatment with pharmaceutical CBD vs. placebo in patients with idiopathic (IG) or diabetic (DM) gastroparesis.

Methods: We performed a randomized, double-blinded, placebo-controlled study of CBD b.i.d. (Epidiolex® escalated to 20mg/kg/day) in patients with nonsurgical gastroparesis with delayed gastric emptying of solids (GES). Symptoms were assessed by Gastroparesis Cardinal Symptom Index Daily Diary (GCSI-DD). After 4 weeks’ treatment, we measured GES, gastric volumes, and Ensure® satiation test (1kcal/mL, 30mL/min) to assess volume to comfortable fullness (VTF) and maximum tolerance (MTV). Patients underwent specific FAAH and CNR1 genotyping. Statistical analysis compared 2 treatments using ANOVA including baseline measurements and BMI as covariates.

Results: Among 44 patients (32 IG, 6 DM1, and 6 DM2), 5 patients did not tolerate full dose escalation; 3 withdrew before completing 4 weeks’ treatment (2 placebo, 1 CBD); 95% completed 4 weeks’ treatment and diaries. Compared to placebo, CBD reduced total GCSI score (P=0.008), inability to finish a normal-sized meal (P=0.029), number of vomiting episodes/24 hours (P=0.006), and overall symptom severity (P=0.034). Patients treated with CBD had higher VTF and MTV and slower GES. FAAH rs34420 genotype significantly impacted nutrient drink ingestion. The most common adverse events reported were diarrhea (14), fatigue (8), headache (8), and nausea (7).

Conclusions: CBD provides symptom relief in patients with gastroparesis and improves the tolerance of liquid nutrient intake, despite slowing of GES.”

Cannabinoids Lead to Significant Improvement in Gastroparesis—Related Abdominal Pain

“Neuropathy plays a large role in the pathogenesis of gastroparesis. Neuropathic pain in gastroparesis is an often difficult—to—treat symptom of the disease, despite 80—90% of patients with gastroparesis reporting abdominal pain as a symptom. Treatment for gastroparesis—related pain is especially limited. Neuromodulators are used for this purpose despite a lack of evidence supporting their effectiveness.

Cannabinoids, primarily delta—9—tetrahydrocannabinol (THC) and cannabidiol (CBD), are increasingly utilized for medicinal purposes. In New York medical marijuana is approved for the treatment of neuropathy with severe pain. Similarly, Dronabinol (a synthetic THC analogue) has been used for nausea vomiting and anorexia for years.

We showed that cannabinoids are effective in the treatment of gastroparesis—related abdominal pain.”

“Conclusion: Our study shows that cannabinoids may play an important role in the management of gastroparesis—related abdominal pain. There are currently no treatments shown to be effective for gastroparetic pain in clinical trials, and cannabinoids may serve a niche for this under—treated symptom.”

Plasma endocannabinoids and cannabimimetic fatty acid derivatives are altered in gastroparesis: A sex- and subtype-dependent observation

“Background: Gastroparesis (GP) is a motility disorder of the stomach presenting with upper gastrointestinal symptoms in the setting of delayed gastric emptying. Endocannabinoids are involved in the regulation of GI function including motility. However, their role in the pathophysiology of GP has not been sufficiently investigated. Our goal was to compare the circulating levels of endocannabinoids and cannabimimetic fatty acid derivatives in GP versus control subjects.

Methods: The study compared plasma concentrations of endocannabinoids and their lipoamine and 2-acyl glycerol congeners, measured by high-pressure liquid chromatography/tandem mass spectrometry (HPLC-MS-MS), in adult patients with diabetic gastroparesis (DM-GP; n = 24; n = 16 female), idiopathic gastroparesis (ID-GP; n = 19; n = 11 female), diabetic patients without GP (DM; n = 19; n = 10 female), and healthy controls (HC; n = 18; n = 10 female). Data, presented as mean ± SEM, were analyzed with ANOVA (Sidak post hoc).

Key results: Endocannabinoids anandamide (AEA: 0.5 ± 0.1 nMol/L) and 2-arachidonoyl glycerol (2-AG: 2.6 ± 0.7 nMol/L) were significantly lower in female DM-GP patients vs. DM females (AEA: 2.5 ± 0.7 nMol/L and 2-AG: 9.4 ± 3.3 nMol/L). Other monoacylglycerols including 2-palmitoyl glycerol and 2-oleoyl glycerol were also lower in female DM-GP patients compared to DM females. No changes were observed in men.

Conclusions & inferences: Endocannabinoids and other fatty acid derivatives with cannabimimetic properties are reduced in female DM-GP patients. Since GP, particularly with diabetic etiology, is more prevalent among women and since cannabinoids are antiemetic, this decrease in levels may contribute to symptom development in these subjects. Targeting the endocannabinoid system may be a future therapeutic option in DM-GP patients.”

“Targeting the endocannabinoid system may be a future therapeutic option in DM-GP patients.”

Gastroparesis with Cannabis Use: A Retrospective Study from the Nationwide Inpatient Sample

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“Background: With increasing utilization of cannabis in the United States (US), clinicians may encounter more cases of Gastroparesis (GP) in coming years.

Objective: The primary outcome was inpatient mortality for GP with cannabis use. Secondary outcomes included system-based complications and the burden of the disease on the US healthcare system.

Methods: From the Nationwide Inpatient Sample (NIS), we identified adult hospitalizations with a primary discharge diagnosis of GP for 2016 and 2017. Individuals ≤18 years of age were excluded. The study population was subdivided based on a secondary diagnosis of cannabis use. The outcomes included biodemographic characteristics, mortality, complications, and burden of disease on the US healthcare system.

Results: For 2016 and 2017, we identified 99,695 hospitalizations with GP. Of these hospitalizations, 8,870 had a secondary diagnosis of cannabis use while 90,825 served as controls. The prevalence of GP with cannabis use was 8.9%. For GP with cannabis use, the patients were younger (38.5 vs 48.1 years, p < 0.001) with a Black predominance (Table 1) and lower proportion of females (52.3 vs 68.3%, p < 0.001) compared to the non-cannabis use cohort. Additionally, the cannabis use cohort had higher percentage of patients with co-morbidities like hypertension, diabetes mellitus and a history of smoking. The inpatient mortality for GP with cannabis use was noted to be 0.27%. Furthermore, we noted shorter mean length of stay (LOS) (3.4 vs 4.4 days, aMD: -0.7, 95%CI: -0.9 – [-0.5], p < 0.001), lower mean total hospital charge (THC) ($30,400 vs $38,100, aMD: -5100, 95%CI: -6900 – [-3200], p < 0.001), and lower rates of sepsis (0.11 vs 0.60%, aOR: 0.22, 95% CI: 0.05-0.91, p = 0.036) for GP hospitalizations with cannabis use compared to the non-cannabis use cohort.

Conclusion: Inpatient mortality for GP hospitalizations with cannabis use was 0.27%. Additionally, these patients had shorter LOS, lower THC, and lower sepsis rates.”

Trends and Socioeconomic Health Outcomes of Cannabis Use Among Patients With Gastroparesis: A United States Nationwide Inpatient Sample Analysis

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“Background: Although cannabis may worsen nausea and vomiting for patients with gastroparesis, it may also be an effective treatment for gastroparesis-related abdominal pain. Given conflicting data and a lack of current epidemiological evidence, we aimed to investigate the association of cannabis use on relevant clinical outcomes among hospitalized patients with gastroparesis.

Materials and methods: Patients with a diagnosis of gastroparesis were reviewed from the National Inpatient Sample (NIS) database between 2008 and 2014. Gastroparesis was identified by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes with patients classified based on a diagnosis of cannabis use disorder. Demographics, comorbidities, socioeconomic status, and outcomes were compared between cohorts using χ2 and analysis of variance. Logistic regression was then performed and annual trends also evaluated.

Results: A total of 1,473,363 patients with gastroparesis were analyzed [n=33,085 (2.25%) of patients with concomitant cannabis use disorder]. Patients with gastroparesis and cannabis use disorder were more likely to be younger and male gender compared with nonusers (36.7±18.8 vs. 51.9±16.8; P<0.001 and 52.9% vs. 33.5%; P<0.001, respectively). Race/ethnicity was different between groups (P<0.001). Cannabis users had a lower median household income and were more likely to have Medicaid payor status (all P<0.001). Controlling for confounders, length of stay, and mortality were significantly decreased for patients with gastroparesis and cannabis use (all P<0.001).

Conclusion: While patients with gastroparesis and cannabis use disorder were younger, with a lower socioeconomic status, and disproportionately affected by psychiatric diagnoses, these patients had better hospitalization outcomes, including decreased length of stay and improved in-hospital mortality.”

“Cannabis Use Disorder in Patients With Gastroparesis Associated With Better Hospitalization Outcomes”

Marijuana, Ondansetron, and Promethazine Are Perceived as Most Effective Treatments for Gastrointestinal Nausea.

 SpringerLink“Many anti-nausea treatments are available for chronic gastrointestinal syndromes, but data on efficacy and comparative effectiveness are sparse.


To conduct a sectional survey study of patients with chronic nausea to assess comparative effectiveness of commonly used anti-nausea treatments.


One hundred and fifty-three patients completed the survey. The mean efficacy score of all anti-nausea treatments evaluated was 1.73. After adjustment, three treatments had scores statically higher than the mean, including marijuana (2.75, p < 0.0001), ondansetron (2.64, p < 0.0001), and promethazine (2.46, p < 0.0001). Several treatments, including many neuromodulators, complementary and alternative treatments, erythromycin, and diphenhydramine had scores statistically below average. Patients with more severe nausea responded better to marijuana (p = 0.036) and diphenhydramine (p < 0.001) and less so to metoclopramide (p = 0.020). There was otherwise no significant differential response by age, gender, nausea localization, underlying gastrointestinal cause of nausea, and GCSI.


When treating nausea in patients with chronic gastrointestinal syndromes, clinicians may consider trying higher performing treatments first, and forgoing lower performing treatments. Further prospective research is needed, particularly with respect to highly effective treatments.”

Impact of Cannabinoids on Symptoms of Refractory Gastroparesis: A Single-center Experience.

“Cannabinoids are increasingly used for medicinal purposes, including neuropathy.

Gastroparesis is a neuromuscular disorder and neuropathy plays a large role in its pathogenesis. It is thus reasonable that cannabinoids can serve a beneficial role in the management of gastroparesis.

Our study evaluates the effect of cannabinoids on gastroparesis symptoms.

A significant improvement in the GCSI total symptom composite score was seen with either cannabinoid treatment (mean score difference of 12.8, 95% confidence interval 10.4-15.2; p-value < 0. 001). Patients prescribed marijuana experienced a statistically significant improvement in every GCSI symptom subgroup. Significant improvement in abdominal pain score was also seen with either cannabinoid treatment (mean score difference of 1.6; p-value <0.001).

Conclusions: Cannabinoids dramatically improve the symptoms of gastroparesis. Furthermore, an improvement in abdominal pain with cannabinoids represents a breakthrough for gastroparesis-associated abdominal pain treatment, for which there are currently no validated therapies.”

“In conclusion, cannabinoids dramatically improve refractory gastroparesis symptoms, including abdominal pain. Marijuana may be superior to dronabinol in improving these symptoms, though both cannabinoids seem to be promising as novel therapeutic options in gastroparesis.”

Marijuana Use in Patients with Symptoms of Gastroparesis: Prevalence, Patient Characteristics, and Perceived Benefit.

“Marijuana may be used by some patients with gastroparesis (Gp) for its potential antiemetic, orexigenic, and pain-relieving effects.

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.


Fifty-nine 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.


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.”

“Marijuana, Ondansetron, and Promethazine Are Perceived as Most Effective Treatments for Gastrointestinal Nausea”

Cannabinoid Use in Patients With Gastroparesis and Related Disorders: Prevalence and Benefit.


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“Gastroparesis (Gp) can be a challenging disorder to manage due to the paucity of treatment options. We do not know how frequently patients with Gp symptoms resort to cannabinoids to address their symptoms. This study (i) determines the prevalence of cannabinoid use in patients with Gp symptoms, (ii) describes the patients with Gp symptoms using cannabinoids, and (iii) assesses the patients’ perceived benefit of cannabinoids for Gp symptoms.


Consecutive outpatients with symptoms suggestive of Gp seen on follow-up at our academic center from June 2018 to September 2018 filled out questionnaires on their symptoms and the current treatments.


Of 197 patients, nearly half (n = 92, 46.7%) reported current (35.5%) or past (11.2%) use of cannabinoids, including tetrahydrocannabinol (n = 63), dronabinol (n = 36), and/or cannabidiol (n = 16). Of these, most perceived improvement in Gp symptoms from cannabinoids (93.5% with tetrahydrocannabinol, 81.3% with cannabidiol, and 47.2% with dronabinol). Cannabinoids were used most commonly via smoking (n = 46). Patients taking cannabinoids were younger (41.0 ± 15.4 vs 48.0 ± 15.9 years; P < 0.01) and had a higher Gastroparesis Cardinal Symptom Index total score (3.4 ± 1.0 vs 2.8 ± 1.3; P < 0.01) compared with patients with no history of cannabinoid use.


A third of patients with Gp symptoms actively use cannabinoids for their chronic symptoms. Most of these patients perceive improvement in their symptoms with cannabinoids. Patients taking cannabinoids were younger and more symptomatic than those not taking cannabinoids. Further studies on the efficacy and safety of cannabinoids in Gp will be useful.”