A review of the effects of cannabis on gastrointestinal disorders

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RESEARCH SUPPLEMENT A review of the effects of cannabis on gastrointestinal disorders Yuki Lai, HBSc1, Lawrence B. Cohen, MD, MSc, FRCP1* 1. DIVISION OF GASTROENTEROLOGY, SUNNYBROOK HEALTH SCIENCES CENTRE, TORONTO, ON * CORRESPONDING AUTHOR

Keywords: Cannabis, gastrointestinal disorder, review, hepatology, gastrointestinal symptoms ABSTRACT Cannabis operates on the endocannabinoid system to influence various gastrointestinal disorders and symptoms. Despite growing enthusiasm surrounding medical cannabis, a lack of high quality clinical trials investigating the effects of cannabis on gastrointestinal diseases prevents its approval as a primary treatment. Our review examines the efficacy of cannabis in treating gastrointestinal disorders. Studies suggest that cannabis reduces issues associated with irritable bowel syndrome and inflammatory bowel disease. Manipulation of cannabinoid receptors also protects against hepatological diseases; however, effects of cannabis on the pancreas are controversial. Furthermore, cannabis helps to manage nausea, vomiting, anorexia, and weight loss, but benefits come with a risk of developing conditions associated with chronic cannabis use. Although there are promising uses for cannabis in the treatment of gastrointestinal disorders, more rigorous clinical trials must be performed to determine safe and effective indications for medical cannabis. INTRODUCTION annabis sativa and Cannabis indica are two main subspecies of the Cannabis plant. They contain approximately 60 aromatic hydrocarbon compounds known as cannabinoids. These cannabinoids include: delta-9-tetrahydrocannabinol (THC), which is primarily psychotropic; cannabidiol (CBD), known to be efficacious in inflammation, motility, and analgesia; and cannabigerol (CBG), with its effect still largely undetermined.1,2 Cannabis has been used to ameliorate a variety of gastrointestinal disorders, including abdominal pain, nausea, vomiting, diarrhea, constipation, manifestations of inflammation, and dysmotility.3,4 However, clinical trials investigating the effects of medical cannabis on gastrointestinal, hepatic, and pancreatic function and diseases typically produce low quality results due to lack of standardization in cannabinoid products, variability of strains studied, variability in routes of administration, influence of confounding bioactive compounds contained in the natural product, and the variable endpoints being measured. As a result, the reliability and reproducibility of these findings are limited. The pharmacodynamics and pharmacokinetics of inhaled and ingested cannabis have been well studied. Psychotropic effects of cannabis begin within minutes of inhalation, peak at approximately 30 minutes, and taper with metabolism over two to three hours. The onset of physiological effects following oral ingestion occurs at approximately 30 to 90 minutes, peaks at two


Printed with permission from: Yuki Lai, HBSc and Lawrence B. Cohen, MD, MSc, FRCP Division of Gastroenterology, Sunnybrook Health Sciences Centre, Toronto, ON Content has been edited to conform with the Canadian Press Publication Style Guide


to three hours, and diminishes over the subsequent four to 12 hours.5 Cannabinoids’ range of action include influence on gastrointestinal motility, intestinal secretions, inhibition of inflammatory mediators, promotion of fibrosis, along with control over CNS mood, pain, and appetite.3 Therapeutic gastrointestinal cannabis acts on the endocannabinoid system. This system consists of cannabinoid receptor types, endogenous ligands, such as anandamide and 2-arachidonoylglycerol (2-AG) that bind active drugs to the receptors, and enzymes that are involved in cannabinoid metabolism.2 The two recognized types of cannabinoid receptors in the gastrointestinal tract are CB1 and CB2. CB1 receptors regulate neurotransmitter release and are located in the enteric nervous system, including the epithelium of the gastrointestinal tract, and sensory terminals of vagal and spinal neurons. Meanwhile, CB2 receptors are mostly distributed throughout the immune system and produce a host of defined yet unknown immunotherapeutic responses, such as the modification of inflammatory expression by macrophages, neutrophils, and B- and T-cell subtypes.6 The pharmacological challenge is that both types of receptors influence the immune system in a challenging fashion, producing either agonistic or antagonistic effects. Despite the enthusiasm to prescribe medical cannabis for gastrointestinal disorders, at the present time, “medical cannabis should not replace Health Canada-approved medical therapy for treatment of any gastroenterologic or hepatologic disease if the approved therapy is

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available and has not been used”.7 IRRITABLE BOWEL SYNDROME (IBS) Cannabinoids reduce intestinal motility and secretions through CB1 agonist activity. Anecdotal and clinical studies report outcome data professing amelioration of a spectrum of gastrointestinal issues, including irritable bowel syndrome (IBS) associated constipation,4 diarrhea, anorexia, nausea, and abdominal pain, providing impetus for use in motility disorders like IBS.9 The abdominal visceral pain of IBS is attributed to enhanced perception of colonic distention in about 70 per cent of patients,10 and that visceral sensation is partially mediated through the cannabinoid receptors. The potential therapeutic role for cannabis in diarrheaor pain-dominant forms of IBS is supported by a small number of clinical trials.11,12,13 Arguable efficacy was reported on abdominal pain perception and changes in intestinal motility.57 Another component of this CB1 mediated activity causes decreased motility and prolonged gastric emptying. The inhibition of gastric emptying leads to early satiety and may serve as a mechanism of action in a weight loss strategy, contrary to the well-known CNS-mediated appetite stimulation and modification of nausea.14,15 INFLAMMATORY BOWEL DISEASE (IBD) The gastrointestinal tract has an extensive network of CB2 receptors that may promote the integrity of intestinal epithelium16 and mediate significant mucosal anti-inflammatory effects.17 CBD receptor agonists have been demonstrated to significantly affect the gastrointestinal mucosal immune inflammatory cascade in vitro17 and in vivo.18

Inflammatory signs and symptoms of inflammatory bowel disease (IBD) have been shown to improve with CBD treatment. CBD purportedly exerts an anti-inflammatory effect by stimulating the peroxisome proliferator activate receptor gamma (PPAR-gamma).19 In a prospective cohort survey study, Allegretto, et al20 reported that the majority of their IBD patients found that cannabis helped to completely relieve abdominal pain, nausea, and diarrhea, when taken in conjunction with their prescription anti-inflammatory medications. Objective parameters of clinical, laboratory, and endoscopic improvement in patients with IBD, specifically Crohn’s Disease, have been described and demonstrated.21,22,58 Interestingly, there may be a difference in response to cannabis between patients with ulcerative colitis (UC) and Crohn’s Disease. Storr, et al18 reported a worse outcome regarding risk of surgery in Crohn’s Disease patients receiving CBD compared to the UC group. Meanwhile, Kafil, et al23 reviewed available publications on cannabis safety and efficacy in adults with active UC and found a non-statistical trend for efficacy without signals of adverse clinical outcomes. To date, there is still insufficient data to deem cannabis effective enough to alter the course of treatment for patients with IBD. More well-designed studies are needed to establish the beneficial or deleterious effects of cannabis on the natural history of IBD through measurement of clinical and biochemical inflammatory markers, mucosal healing, and impact on complications, hospitalization rates, and surgical outcomes. Cannabis therapy may be considered an alternative adjunct to

conventional therapeutics in the management of the signs and symptoms of active IBD, but not as a primary anti-inflammatory therapy.59 HEPATOLOGY Evidence is emerging that cannabinoids influence a variety of liver disorders, including hepatic steatosis and fibrosis, portosystemic encephalopathy, and alcohol liver disease. Stimulation of CB1 receptors in the liver may promote steatosis by increasing lipogenesis, decreasing fatty acid oxidation, and inducing hyperphagia. On the contrary, CB1 antagonists suppress hepatic steatosis.25 Furthermore, hepatic CB1 receptors may stimulate fibrogenesis especially in alcohol hepatitis, while in-vitro studies show that CB1 antagonists may protect against development of alcohol-induced liver fibrosis.26 Daily cannabis use in viral hepatitis patients is controversial. Ishida, et al27 found daily cannabis use to be strongly associated with moderate to severe fibrosis in hepatitis C patients; however, Brunet, et al28 and Liu, et al29 discovered no adverse effects of cannabis use on the natural history of hepatitis C. Currently, there are no reported data on the impact of cannabis on the natural history of hepatitis B infection. In patients co-infected with human immunodeficiency virus (HIV) and hepatitis C, cannabis use may reduce the rate of steatosis30 and insulin resistance.31 The impact of fibrogenesis in the co-infected group is controversial. Stimulation of CB2 receptors, which may be upregulated in chronic liver disease,32 has also been reported to protect against hepatic fibrosis.33 Curiously, in alcoholic liver disease, the balance of cannabinoids may have a potential


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Research Supplement: A review of the effects of cannabis on gastrointestinal disorders

protective effect against inflammation and steatosis through reducing oxidative stress,34 and thereby lower rates of alcohol seato-hepatitis, cirrhosis, and hepatocellular carcinoma.35 With respect to non-alcoholic liver conditions, epidemiological studies also suggest that cannabis use is associated with a lower prevalence of non-alcoholic fatty liver disease.36 Achebe, et al37 reported that in obese patients, cannabis use was associated with a decrease in the prevalence and progression of steatohepatitis. Cannabis hepatotoxicity is arguable, but cannabinoids may have a defined role in management of chronic liver disease as more studies emerge.60 PANCREAS The pancreas contains both types of cannabinoid receptors. As in the liver, activation of CB1 pancreatic receptors promotes fibrogenesis, which is opposed by CB2 receptor agonists.2 Cannabis has also been reported to induce pancreatitis,38 but this outcome may be dependent on dose and duration of use.39 Undoubtedly, the effects of cannabis on the pancreas must be further studied to determine whether cannabis is a suitable treatment for gastroenterological conditions. CANNABIS USE IN GASTROINTESTINAL SYMPTOMS Some evidence suggests that cannabis can be used to alleviate common gastrointestinal symptoms, such as nausea, vomiting, anorexia, and weight loss, but not without risk. Longterm effectiveness and safety of cannabis for chronic gastrointestinal symptoms remain largely unknown and therefore, should be avoided until further studies of cannabis in the management of non-specific GI symptoms exist. CANNABIS USE DISORDER (CUD) With respect to cannabis use disorder (CUD), Kondo, et al40 reported that “although data on pharmacologic interventions for CUD are scarce, evidence exists that several drug classes, including cannabinoids and SSRIs, are ineffective. Due to increased access and use of cannabis in the general population, along with

a high prevalence of CUD among current cannabis users, an urgent need exists for more research to identify effective pharmacologic treatments.” NAUSEA AND VOMITING For management of refractory nausea and vomiting associated with chemotherapy as well as abdominal pain in both benign and malignant disease states, cannabis and related cannabinoids may be considered as a primary or adjunctive therapy for limited prescription periods, especially where conventional therapeutics have been ineffective.41 In fact, a metaanalysis by Smith, et al42 concluded that cannabinoids yielded significant efficacy in the treatment of chemotherapy induced nausea and vomiting (CINV). The mechanism of action may involve CB1 receptors located in the dorsal vagal complex of the brain stem (area postrema), which plays a role in the pathogenesis of vomiting.43 Despite these data, American and European oncology guidelines state that cannabinoids should be prescribed for CINV after conventional medical therapy has been deemed ineffective, and not as first-line intervention.44,45 ANOREXIA AND WEIGHT LOSS Studies on the efficacy of exogenous cannabinoids in modifying appetite and weight gain are controversial and may reflect differences in study design, disease state being evaluated, and outcome parameters. A study by Strasser, et al46 reported no benefit from synthetic cannabinoids in malignant anorexia-cachexia compared to placebo controls. On the contrary, Brisbois, et al47 demonstrated significant improvement in appetite, enhancement of taste, and increased protein-calorie intake in cannabinoid-treated cancer patients compared to the placebo-treated control group. Some evidence indicates that marijuana use in patients with AIDS-associated anorexia and weight loss causes significant improvement in weight gain and quality of life;48 however, Whiting, et al41 could not reproduce these data and suggest that there is limited evidence of an association between cannabinoid use and weight gain, enhanced appetite, and increase


in body fat. Paradoxically, cannabinoids may have a therapeutic role in weight reduction strategies. Alshaarowy and Anthony49 recently showed an inverse relationship between cannabis use and obesity. One proposed mechanism for weight loss is that chronic cannabis use down-regulates CB1 receptors in the hypothalamus that contribute to the regulation of appetite and energy balance. Another theory involves the upregulation of CB2 receptors, which promotes antiinflammatory effects and leads to weight reduction. CANNABINOID HYPEREMESIS SYNDROME (CHS) Paradoxical pernicious protracted nausea and vomiting syndrome, previously called Cyclical Vomiting Syndrome and recently coined Cannabis Hyperemesis Syndrome, has emerged with increasing rates of regular cannabis use. This syndrome arises exclusively in patients who indulge in daily long-term cannabis smoking and not in patients who only indulge in oral cannabis ingestion.50 Although low dose CBD yields anti-emetic properties, higher doses produce a pro-emetic effect.51 Three phases have been defined in the clinical course of CHS: the prodromal phase, the hyper-emetic phase, and the recovery phase. The prodromal phase is characterized by early morning nausea, fear of vomiting, and non-specific abdominal discomfort that may last for months to years. Symptoms from the first phase intensify in the hyper-emetic phase. Patients typically develop intense nausea, pernicious vomiting, and diffuse abdominal pain, prompting them to seek assessment in the emergency department. There is a unique need in this phase for afflicted patients to take numerous, long, hot showers or baths in an attempt to alleviate this reaction. Cannabis causes a rise in core body temperature with a conflicting decrease in skin temperature; so, compulsive hot bathing helps to dissipate elevated core body heat by increasing blood flow to the skin.52 Patients may propagate the hyper-emetic phase by continuing to consume cannabis for the misbelief that they

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need the anti-emetic property of the substance. Treatments prescribed in the hyper-emetic phase in addition to cannabis withdrawal include haloperidol intravenous infusion, benzodiazepines, and topical capsaicin cream.53 Some patients also experience severe dehydration and acute renal failure, which are treated through intravenous hydration and anti-emetics. Use of narcotic pain medication is not recommended to treat CHS symptoms as it may increase bowel dysfunction as well as opioid dependence. Despite the availability of acute treatments, cannabis cessation still remains the only definitive solution for CHS.50 Finally, the recovery phase lasts weeks to months after cessation of cannabis consumption and is highlighted by the alleviation of symptoms and signs described in the first two phases. This improvement is followed by progressive weight regain as a result of a return to normal mood and eating patterns.54 As national policies regarding cannabis shift, defined recommendations have evolved to promote effective management of the psychological and physical effects associated with chronic cannabis use.40,55,56 Abstinence remains the most effective way to avoid cannabisrelated health risks; however, multiple guidelines exists for lower-risk use. Recommendations include avoiding cannabis use at an early age, choosing relatively low potency THC products, avoiding artificial cannabinoids, choosing non-smoking methods, and minimizing frequency of use.56 In addition, psychosocial interventions, mainly cognitive behavioural therapy and motivational enhancement therapy, can be used as primary treatments for cannabis use disorder55 to encourage informed behaviour. CONCLUSION The principles of pharmacotherapy apply to cannabis as they do to any drug. The efficacy and safety of therapeutics agents along with the risk to benefit ratio of medications and the disease for which medications are being prescribed must be well understood. Therefore, rigorous clinical trials need to be designed and undertaken to answer the clinical questions of appropriate indications for medical cannabis,

therapeutic dosing, and appropriate monitoring for effectiveness and adverse effects. Through a review of the literature, it is clear that these principles are currently being applied for promising use of cannabis in gastrointestinal and hepatico-pancreatic disorders and diseases. As more well designed clinical research trials are being conducted, rational prescribing profiles will be provided. The Canadian Association of Gastroenterology recommends “that physicians in Canada familiarize themselves with important aspects of medical cannabis before authorizing a patient for medical use. Moreover, with recreational use being so common, it also behooves physicians to understand the risks involved for patients and to be able to counsel them accordingly”.7 CONFLICT OF INTEREST STATEMENT The Authors declare that there is no conflict of interest. ETHICS STATEMENT The authors confirm that the ethical policies of the journal, as noted on the journal’s author guidelines page, have been adhered to. No ethical approval was required as this is a review article with no original research data. REFERENCES

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