“The endocannabinoid system (ECS) plays a crucial role in numerous physiological processes in the central and peripheral nervous systems. In the gastrointestinal (GI) tract, selective cannabinoid (CB) receptor agonists exert potent inhibitory actions on motility and pain signalling. In the present study, we used mouse models of diarrhea, hypermotility, and abdominal pain to examine whether a novel synthetic CB1 receptor agonist AM9405 [(2-(2,6-dihydroxy-4-(2-methyloctan-2-yl)phenyl)-1,3-dimethyl-1H-benzo[d]imidazol-3-ium bromide); also known as GAT379] exhibits effects of potential therapeutic relevance. AM9405 significantly slowed mouse intestinal motility in physiological conditions. Moreover, AM9405 reversed hypermotility and reduced pain in mouse models mimicking symptoms of functional GI disorders, such as stress-induced diarrhoea and writhing test. Interestingly, some of the effects of AM9405 were blocked by a 5-HT3 antagonist suggesting interaction with 5-HT3 receptors. In our study we show that combining CB1 agonism with 5-HT3 agonism may alter physiological functions and experimental pathophysiologies in a manner that make such compounds promising drugs for the future treatment of functional GI disorders.”
“Cannabis sp and their products (marijuana, hashish…), in addition to their recreational, industrial and other uses, have a long history for their use as a remedy for symptoms related with gastrointestinal diseases.
After many reports suggesting these beneficial effects, it was not surprising to discover that the gastrointestinal tract expresses endogenous cannabinoids, their receptors, and enzymes for their synthesis and degradation, comprising the so-called endocannabinoid system.
This system participates in the control of tissue homeostasis and important intestinal functions like motor and sensory activity, nausea, emesis, the maintenance of the epithelial barrier integrity, and the correct cellular microenvironment. Thus, different cannabinoid-related pharmacological agents may be useful to treat the main digestive pathologies.
To name a few examples, in irritable bowel syndrome they may normalize dysmotility and reduce pain, in inflammatory bowel disease they may decrease inflammation, and in colorectal cancer, apart from alleviating some symptoms, they may play a role in the regulation of the cell niche.
This review summarizes the main recent findings on the role of cannabinoid receptors, their synthetic or natural ligands and their metabolizing enzymes in normal gastrointestinal function and in disorders including irritable bowel syndrome, inflammatory bowel disease, colon cancer and gastrointestinal chemotherapy-induced adverse effects (nausea/vomiting, constipation, diarrhea).”
“Clostridium difficile toxin A is responsible for colonic damage observed in infected patients.
Drugs able to restore Clostridium difficile toxin A-induced toxicity have the potential to improve the recovery of infected patients. Cannabidiol is a non-psychotropic component of Cannabis sativa, which has been demonstrated to protect enterocytes against chemical and/or inflammatory damage and to restore intestinal mucosa integrity.
The purpose of this study was to evaluate (a) the anti-apoptotic effect and (b) the mechanisms by which cannabidiol protects mucosal integrity in Caco-2 cells exposed to Clostridium difficile toxin A.
Clostridium difficile toxin A significantly decreased Caco-2 cells’ viability and reduced transepithelial electrical resistence values and RhoA guanosine triphosphate (GTP), bax, zonula occludens-1 and occludin protein expression, respectively. All these effects were significantly and concentration-dependently inhibited by cannabidiol, whose effects were completely abolished in the presence of the cannabinoid receptor type 1 (CB1) antagonist, AM251.
Cannabidiol improved Clostridium difficile toxin A-induced damage in Caco-2 cells, by inhibiting the apoptotic process and restoring the intestinal barrier integrity, through the involvement of the CB1 receptor.”
“In the last decade, cannabinoids extracted from the marijuana plant (Cannabis sativa) and synthetic cannabinoids have shown numerous beneficial effects on gastrointestinal (GI) functions. Non-psychotropic phytocannabinoid cannabidiol (CBD) is one of the most interesting compounds, since it exerts a wide range of beneficial pharmacological actions on GI functions, ranging from antioxidant to antinflammatory activities. CBD has been shown to act as a non-competitive negative allosteric modulator of CB1 receptors. Notably, CBD is able to restore in vitro intestinal permeability increased by ethylenediaminetetraacetic acid (EDTA) or pro-inflammatory stimuli.
Clostridium difficile infection is the leading cause of hospital-acquired diarrhoea and pseudomembranous colitis. Clostridium difficile-Toxin A significantly affects enterocytes permeability leading to apoptosis and colonic mucosal damage.
In the present study, we showed that Cannabidiol, a non-psychotropic component of Cannabis sativa significantly inhibit the apoptosis rate in TcdA-exposed cells and restores barrier function by a significant RhoA GTP rescue.
We also provide evidence that the effects of Cannabidiol are mediated by CB-1 receptor.
Given the absence of any significant toxic effect in humans, cannabidiol may ideally represent an effective adjuvant treatment for Clostridium difficile-associated colitis.” http://journals.sagepub.com/doi/10.1177/2050640617698622
“Fifty years after the discovery of Δ9-tetrahydrocannabinol (THC) as the psychoactive component of Cannabis, we are assessing the possibility of translating this herb into clinical treatment of inflammatory bowel diseases (IBDs).
Here, a discussion on the problems associated with a potential treatment is given.
From first surveys and small clinical studies in patients with IBD we have learned that Cannabis is frequently used to alleviate diarrhea, abdominal pain, and loss of appetite.
Single ingredients from Cannabis, such as THC and cannabidiol, commonly described as cannabinoids, are responsible for these effects. Synthetic cannabinoid receptor agonists are also termed cannabinoids, some of which, like dronabinol and nabilone, are already available with a narcotic prescription.
Recent data on the effects of Cannabis/cannabinoids in experimental models of IBD and in clinical trials with IBD patients have been reviewed using a PubMed database search. A short background on the endocannabinoid system is also provided.
Expert commentary: Cannabinoids could be helpful for certain symptoms of IBD, but there is still a lack of clinical studies to prove efficacy, tolerability and safety of cannabinoid-based medication for IBD patients, leaving medical professionals without evidence and guidelines.”
“In this mini-review, we focus on the potential of the endocannabinoid system as a target for novel therapies to treat gastrointestinal (GI) inflammation. We discuss the organization of the endocannabinoid signaling and present possible pharmacological sites in the endocannabinoid system. We also refer to recent clinical findings in the field. Finally, we point at the potential use of cannabinoids at low, non-psychoactive doses to counteract non-inflammatory pathological events in the GI tract, like chemotherapy-induced diarrhea, as evidenced by Abalo et al. in the rat model.”
“Cannabis sativa, a subspecies of the Cannabis plant, contains aromatic hydrocarbon compounds called cannabinoids.
Tetrahydrocannabinol is the most abundant cannabinoid and is the main psychotropic constituent.
Cannabinoids activate two types of G-protein-coupled cannabinoid receptors: cannabinoid type 1 receptor and cannabinoid type 2 receptor.
There has been ongoing interest and development in research to explore the therapeutic potential of cannabis. Tetrahydrocannabinol exerts biological functions on the gastrointestinal (GI) tract.
Cannabis has been used for the treatment of GI disorders such as abdominal pain and diarrhea.
The endocannabinoid system (i.e. endogenous circulating cannabinoids) performs protective activities in the GI tract and presents a promising therapeutic target against various GI conditions such as inflammatory bowel disease (especially Crohn’s disease), irritable bowel syndrome, and secretion and motility-related disorders.
The present review sheds light on the role of cannabis in the gut, liver, and pancreas and also on other GI symptoms, such as nausea and vomiting, cannabinoid hyperemesis syndrome, anorexia, weight loss, and chronic abdominal pain.
Although the current literature supports the use of marijuana for the treatment of digestive disorders, the clinical efficacy of cannabis and its constituents for various GI disorders remains unclear.”
“The antineoplastic drug 5-fluoruracil (5-FU) is a pirimidine analog, which frequently induces potentially fatal diarrhea and mucositis.
Cannabinoids reduce gastrointestinal motility and secretion and might prevent 5-FU-induced gut adverse effects.
Here, we asked whether cannabinoids may prevent diarrhea and mucositis induced by 5-FU in the rat.
CONCLUSIONS AND INFERENCES:
5-FU-induced diarrhea, but not mucositis, was partly prevented by WIN at a low dose.
Cannabinoids might be useful to prevent chemotherapy-induced diarrhea.”
“Inflammatory bowel diseases (IBDs) such as ulcerative colitis and Crohn’s disease affects over a million people in the United States, with an estimated indirect cost from work loss of $3.6 billion annually. Many of these individuals suffer from pain, diarrhea and poor ability to digest their food, and in up to half of those with IBD, the disease is so severe that it ultimately requires surgery to remove the affected bowel segment.
Historically, marijuana has been used to treat diarrhea and has been advocated for the treatment of a variety of other gastrointestinal problems, including Crohn’s disease.
More recent pharmacological studies have clearly established that cannabinoids inhibit gastrointestinal motility and secretion by acting on CB1 receptors located on the terminals of both intrinsic and extrinsic submucosal neurons.
When administered to mice with chemically induced enteritis, cannabinoids also reduce inflammation and fluid accumulation in the gut.
Cannabinoids inhibit motility and secretion in the intestine.
They are now assigned the additional task of curbing excessive inflammation, suggesting that drugs targeting the endogenous cannabinoid system could be exploited for inflammatory bowel disease.
These findings may offer a new therapeutic approach to IBD.”
“The cannabis plant has been known to humanity for centuries as a remedy for pain, diarrhea and inflammation.
Current research is inspecting the use of cannabis for many diseases, including multiple sclerosis, epilepsy, dystonia, and chronic pain.
In inflammatory conditions cannabinoids improve pain in rheumatoid arthritis and: pain and diarrhea in Crohn’s disease.
Despite their therapeutic potential, cannabinoids are not free of side effects including psychosis, anxiety, paranoia, dependence and abuse.
Controlled clinical studies investigating the therapeutic potential of cannabis are few and small, whereas pressure for expanding cannabis use is increasing.
Currently, as long as cannabis is classified as an illicit drug and until further controlled studies are performed, the use of medical cannabis should be limited to patients who failed conventional better established treatment.”