Is cannabis a panacea for digestive diseases? (PART II)


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Expert Pharmacologist
Jul 6, 2021
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Effect of cannabis on nausea and vomiting
Cannabinoid receptors are found along gagging pathways in the peripheral system and the CNS, including areas associated with the generation of nausea and vomiting (particularly the postrema and dorsal vagal complex areas). Cannabinoid agonists probably inhibit the gag reflex. Animal studies have shown that activation of the ECS suppresses serotonin release from enterochromaffin cells and inhibits neurokinin pathways induced by Substance P, thereby exerting an antiemetic effect. Enzymes that regulate ECS, such as FAAH, diacylglycerollipase, and N-acyl-phosphatidylethanolamine-specific phospholipase D, may also affect CNS processes, although relevant data have so far only been obtained in experiment. The use of cannabis and cannabinoids as antiemetics has mainly been studied in patients receiving chemotherapy inducing nausea and vomiting. In a meta-analysis of 28 studies, including nabilone, dronabinol and levonantradol, nabiximols cannabis extract, and THC, cannabinoid use was more effective than placebo and comparison drugs such as alizapride, hydroxyzine, metoclopramide and ondansetron, although the results were not statistically significant. Importantly, the pharmacodynamics and pharmacokinetics of these compounds may influence their effectiveness, as newer drugs show better results. Recent oncology guidelines recommend dronabinol as a "rescue therapy" for chemotherapy-induced nausea and vomiting.

Emetic syndrome (reflex) is a complex of symptoms including nausea, urge to vomit and vomiting itself. High prevalence of symptoms of nausea and vomiting determines the frequent referral of patients to physicians of all specialties, both in the hospital and in the outpatient network.
Fewer studies have been conducted on cannabis as an antiemetic during pregnancy. Cannabis use during pregnancy is not recommended because evidence of its benefits and safety is lacking. However, a recent telephone survey indicates that many health care providers in some states in the United States (e.g., Colorado) still recommend cannabis for pregnant patients to reduce nausea and prevent vomiting.

Excessive cannabinoid vomiting syndrome
Cases of cannabis hyperemesis syndrome (CHS) have increased since the legalization of medicinal cannabis. This syndrome is now seen as a potential side effect in some patients. CHS is more common in people who have been taking marijuana for a long time and fairly frequently (daily for 1 year or more), as well as in adolescents and young men. The mechanisms of CHS are still unclear. Chronic cannabis use may reduce CB1 expression in people with certain genetic variants, which lowers the gag threshold. The different composition of cannabis products (THC/CBD ratio) may be important.

Patients with CHS present with symptoms similar to cyclic vomiting syndrome (CVS), and it is possible that CHS may also be a subtype of CVS. However, unlike CHS, CVS is more common in women and is usually associated with psychological comorbidities such as anxiety and dysphoria, migraines, and headaches. Importantly, some patients with CVS show improvement after self-medicating with cannabis.

In patients with CHS, symptoms are episodic and typically disappear after taking a hot shower. The disappearance of symptoms after stopping cannabis use indicates a diagnosis of CHS, so the first line of therapy is withdrawal of the drug. The most commonly prescribed drugs for long-term treatment are the tricyclic antidepressants - benzodiazepines, haloperidol and capsaicin - which can be used in acute emergencies. Clinicians should remember to inquire about the history of cannabis use when evaluating patients with episodic vomiting and evaluate the effects of various treatments.

Endocannabinoid system in obesity
ECS regulates energy intake and appetite by affecting central and peripheral metabolic pathways. Activation of ECS accelerates anabolic processes, promotes positive energy balance and energy conservation. In the CNS there is a strict control of metabolism through the production of endocannabinoids "on demand" when energy requirements increase, an increase and decrease in endocannabinoid levels during fasting and food consumption states, respectively. The effects of ECS on metabolism can be regulated by retrograde neuromodulation of presynaptic CB1 in excitatory and inhibitory pathways in response to energy demands. ECS also affects homeostatic pathways in the hypothalamus and brainstem by modifying anorexigenic (such as leptin) and orexigenic hormones (such as ghrelin). In overweight people, leptin production is reduced, resulting in decreased inhibition of endocannabinoid levels, which contributes to insulin resistance.

The CNS also affects energy intake by influencing the behavioral regulation pathways in the mesolimbic system. For example, endocannabinoid levels are elevated after the consumption of palatable food. It is thought that ECS inhibits GABAergic neurons, which results in disinhibition of dopamine production and activates the need for further food intake. Associated orosensory stimulation activates CB1-mediated olfaction and taste, thereby increasing food intake, especially sweet food.

ECS also modulates peripheral metabolism and insulin sensitivity by affecting the digestive organs and skeletal muscles. ECS stimulation increases insulin resistance, promotes dyslipidemia, and increases body weight. Additional activation of ECS from aberrant plasma and intestinal endocannabinoid signals is noted in obese patients, which is accompanied by inhibition of intestinal brain satiety signaling and ultimately contributes to hyperphagia and weight gain.

Cannabinoid therapy for obesity
CB1 may be one of the targets in the treatment of disorders associated with changes in body weight. Dronabinol has been found to increase BMI values in patients with cachexia associated with cancer or acquired immunodeficiency syndrome, probably by stimulating appetite. Although cannabis benefits these patients, its effects vary because of unreliable dosing and pharmacokinetics.

CB1 antagonists have been found to promote weight loss in obese people, but are accompanied by negative side effects. A meta-analysis of randomized trials of rimonabant showed that patients lost an average of 4.7 kg compared to placebo after 1 year of use (95% confidence interval). Unfortunately, patients receiving rimonabant had high levels of depression and anxiety, and there was a 1.4-fold increased risk of serious adverse events, including suicidal ideation. Because of this, rimonabant has now been withdrawn from the pharmaceutical market. Taranabant had similar effects regarding changes in body weight; the highest dose (2 mg once daily) resulted in a loss of 6.7 kg after 52 weeks. However, similar concerns about side effects led to the discontinuation of studies. Peripheral CB1 antagonists were synthesized to reduce the risk of side effects. Compared with rimonabant, the second-generation CB1 antagonist TM-38837 has a reduced ability to penetrate the CNS, although its peripheral activity is also lower.

Cannabis use in obese patients
Epidemiological studies have shown a reduced incidence of obesity among chronic cannabis users. This seems to be related to low CB1 expression due to long-term cannabis use or to differences in phenotypic manifestations in different populations. Despite evidence that CB1 contributes to energy metabolism, other yet unexplored components of ECS, such as CB2, may also affect metabolic processes leading to weight loss. Further research into these pathways could lead to new therapies.

Cannabis and liver disease
Irritation of CB1 can affect lipid metabolism, insulin sensitivity, and the development of hepatic steatosis. In mice, CB1 activation in hepatocytes increases de novo fatty acid synthesis and increases the expression of lipogenic enzymes such as fatty acid synthase, leading to lipid accumulation and steatosis. This was confirmed in studies with CB1 deactivation in mice, which did not develop hepatic steatosis after following a high-fat diet. Studies involving humans have also shown a role for CB1 in the development of NAFLD. For example, in a randomized trial, patients who received rimonabant for 48 weeks had decreased liver steatosis. Unfortunately, rimonabant has been discontinued because of its psychotropic side effects.


It has been found that chronic cannabis use can lead to decreased body weight and severity of hepatic steatosis. In a study of heavy cannabis users who were treated for drug addiction, normal levels of liver enzymes were found that did not correlate with levels of THC or its metabolites. In another population-based study, cannabis users were found to have a lower prevalence of NAFLD compared to controls. Among chronic cannabis users, the prevalence of NAFLD in dependent patients was 43% lower compared with episodic users. In principle, these findings are contrary to the physiological effects of endocannabinoids and their action on cannabinoid receptors. One potential reason suggested by Dibba et al. suggests that long-term cannabis use decreases THC tolerance as well as CB1 density, accompanied by a subsequent lower CB1 activity overall. Another potential mechanism involves the so-called "surround effect," whereby other constituents of cannabis, such as THC and tetrahydrocannabivarin, reduce CB1 activation, contributing to reduced liver steatosis and inflammation. This theory is supported by the fact that CBD and tetrahydrocannabivarin (in high doses) are CB1 and CB2 antagonists.

Interestingly, exocannabinoids have anti-inflammatory effects and can prevent the development of NAFLD by inhibiting cytokines. This is probably due to the antagonistic effects of CBD on CB2. Unfortunately, a study of the effects of rimonabant in patients with nonalcoholic steatohepatitis has been discontinued because of safety concerns. Namacizumab, which is a negative allosteric antibody against CB1 designed to suppress it, is the first peripherally restricted biological agent designed to treat NAFLD by acting on ECS. Its clinical trials are currently ongoing.

Cannabis and pancreatic diseases
CB1 and CB2 have also been found to be expressed in the pancreas, drawing increased attention to the role of cannabis in acute pancreatitis and chronic pancreatitis. Acute pancreatitis has been found to be characterized by inflammation in which cannabis use may play a role, although it is not yet clear whether cannabis is a contributing or debilitating factor. A recent systematic review has shown that cannabis may act as one cause of so-called idiopathic pancreatitis. A cohort study of 460 patients with a first episode of acute pancreatitis showed a high prevalence of cannabis use in acute pancreatitis of any etiology (10%), including cases designated as idiopathic.

In mice with acute cerulein-induced pancreatitis, infusion of the CB1 agonist anandamide increased the severity of pancreatitis. It is thought that CB1 may activate the inflammatory response in the pancreas by enhancing TNF-a production, in contrast to its anti-TNF effects in other parts of the gastrointestinal tract. In contrast, some studies have shown that cannabis can protect against the development of acute pancreatitis. According to the largest database of hospitalized patients to date, patients who used cannabis had a milder course of acute pancreatitis and fewer deaths and fewer serious complications compared to patients who did not use cannabis.

The visceral inflammatory process in pancreatitis is thought to be likely associated with ECS activation. These data provide a basis for testing the therapeutic value of cannabinoids as adjunctive therapies as analgesics and anti-inflammatory agents. The inconsistency in the available data may be the result of differences in the dosing or delivery method of cannabis, and further research is needed.

Cannabis and inflammatory bowel disease (IBD)
ECS can modulate the pathogenesis of IBD, as evidenced by the correlation between cannabinoid receptor genotypes and the nature of IBD. Thus, the CB2 polymorphism 188-189 GG/GG complementary DNA was associated with a twofold decrease in endocannabinoid-induced inhibition of T-cell proliferation. The CB2 R63 variant was significantly associated with the presence of IBD, especially Crohn's disease. The CB1 p.Thr453Thr polymorphism appears to modulate susceptibility to ulcerative colitis and Crohn's disease. Patients with Crohn's disease who are homozygous for the FAAH p.Pro129Th polymorphism were more likely to have severe disease associated with fistulas and extraintestinal manifestations, and patients with ulcerative colitis who were homozygous for this mutation had earlier disease onset. Despite significant progress in IBD therapy, many patients do not respond to treatment, and some turn to alternative therapies, including cannabis, as evidenced by survey data.

Despite ample preclinical evidence that cannabinoid drugs can reduce intestinal inflammation, not many clinical trials have yet been conducted. Two Cochrane reviews of randomized studies of patients with Crohn's disease (3 studies) and ulcerative colitis (2 studies) are known. In a study of 21 patients with a Crohn's disease activity index >200, they were randomly assigned to groups receiving either cannabis containing THC or placebo. Complete remission was achieved in 5 of 11 patients in the cannabis group (45%) and in 1 of 10 subjects in the placebo group who did not reach the primary endpoints of the study. However, clinical response was observed in 10 of 11 subjects in the cannabis group. Patients also reported improved appetite and sleep quality without significant side effects. Thus, these studies confirmed previous experimental data and concluded that cannabis preparations may be of interest in the treatment of Crohn's disease.

ECS plays an essential role in maintaining GI homeostasis. There is now ample evidence for the anti-inflammatory and anti-nociceptive effects of cannabis and cannabinoids, so many patients with gastrointestinal pathology may benefit from their use. Several studies support the usefulness of cannabis or cannabinoids in patients with functional gastrointestinal pathology, including gastroparesis and irritable bowel syndrome, as well as inflammatory bowel disease, NAFLD, and obesity. Current studies often give contradictory results, which once again emphasizes the complexity and diversity of pathways of ECS interaction with GI and other organs and systems. Future studies evaluating not only cannabinoid receptors, but also the synthesis and degradation of various endocannabinoid-related enzymes, as well as new peripherally restricted therapeutic agents, may lead to new therapeutic strategies that use cannabis and its derivatives to treat gastrointestinal diseases. Of course, despite the many encouraging treatment results, cannabinoids should not be considered a new panacea - more research is needed to clarify their efficacy and potential harmful effects.
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