The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases

ijms-logo“The Endocannabinoid System (ECS) is primarily responsible for maintaining homeostasis, a balance in internal environment (temperature, mood, and immune system) and energy input and output in living, biological systems.

In addition to regulating physiological processes, the ECS directly influences anxiety, feeding behaviour/appetite, emotional behaviour, depression, nervous functions, neurogenesis, neuroprotection, reward, cognition, learning, memory, pain sensation, fertility, pregnancy, and pre-and post-natal development.

The ECS is also involved in several pathophysiological diseases such as cancer, cardiovascular diseases, and neurodegenerative diseases. In recent years, genetic and pharmacological manipulation of the ECS has gained significant interest in medicine, research, and drug discovery and development.

The distribution of the components of the ECS system throughout the body, and the physiological/pathophysiological role of the ECS-signalling pathways in many diseases, all offer promising opportunities for the development of novel cannabinergic, cannabimimetic, and cannabinoid-based therapeutic drugs that genetically or pharmacologically modulate the ECS via inhibition of metabolic pathways and/or agonism or antagonism of the receptors of the ECS. This modulation results in the differential expression/activity of the components of the ECS that may be beneficial in the treatment of a number of diseases.

This manuscript in-depth review will investigate the potential of the ECS in the treatment of various diseases, and to put forth the suggestion that many of these secondary metabolites of Cannabis sativa L. (hereafter referred to as “C. sativa L.” or “medical cannabis”), may also have potential as lead compounds in the development of cannabinoid-based pharmaceuticals for a variety of diseases.”

https://pubmed.ncbi.nlm.nih.gov/34502379/

https://www.mdpi.com/1422-0067/22/17/9472

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Cannabis sativa L. as a Natural Drug Meeting the Criteria of a Multitarget Approach to Treatment

ijms-logo“Cannabis sativa L. turned out to be a valuable source of chemical compounds of various structures, showing pharmacological activity. The most important groups of compounds include phytocannabinoids and terpenes.

The pharmacological activity of Cannabis (in epilepsy, sclerosis multiplex (SM), vomiting and nausea, pain, appetite loss, inflammatory bowel diseases (IBDs), Parkinson’s disease, Tourette’s syndrome, schizophrenia, glaucoma, and coronavirus disease 2019 (COVID-19)), which has been proven so far, results from the affinity of these compounds predominantly for the receptors of the endocannabinoid system (the cannabinoid receptor type 1 (CB1), type two (CB2), and the G protein-coupled receptor 55 (GPR55)) but, also, for peroxisome proliferator-activated receptor (PPAR), glycine receptors, serotonin receptors (5-HT), transient receptor potential channels (TRP), and GPR, opioid receptors.

The synergism of action of phytochemicals present in Cannabis sp. raw material is also expressed in their increased bioavailability and penetration through the blood-brain barrier. This review provides an overview of phytochemistry and pharmacology of compounds present in Cannabis extracts in the context of the current knowledge about their synergistic actions and the implications of clinical use in the treatment of selected diseases.”

https://pubmed.ncbi.nlm.nih.gov/33466734/

https://www.mdpi.com/1422-0067/22/2/778

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Cannabidiol Isolated From Cannabis sativa L. Protects Intestinal Barrier From In Vitro Inflammation and Oxidative Stress

Frontiers in Pharmacology (@FrontPharmacol) | Twitter“The relevance and incidence of intestinal bowel diseases (IBD) have been increasing over the last 50 years and the current therapies are characterized by severe side effects, making essential the development of new strategies that combine efficacy and safety in the management of human IBD. Herbal products are highly considered in research aimed at discovering new approaches for IBD therapy and, among others, 

Cannabis sativa L. has been traditionally used for centuries as an analgesic and anti-inflammatory remedy also in different gastrointestinal disorders. This study aims to investigate the effects of different C. sativa isolated compounds in an in vitro model of intestinal epithelium. The ability of treatments to modulate markers of intestinal dysfunctions was tested on Caco-2 intestinal cell monolayers.

Our results, obtained by evaluation of ROS production, TEER and paracellular permeability measurements and tight junctions evaluation show Cannabidiol as the most promising compound against intestinal inflammatory condition. Cannabidiol is able to inhibit ROS production and restore epithelial permeability during inflammatory and oxidative stress conditions, suggesting its possible application as adjuvant in IBD management.”

https://pubmed.ncbi.nlm.nih.gov/33995048/

https://www.frontiersin.org/articles/10.3389/fphar.2021.641210/full

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Endocannabinoids Inhibit the Induction of Virulence in Enteric Pathogens

Cell | Publons
“Endocannabinoids are host-derived lipid hormones that fundamentally impact gastrointestinal (GI) biology. The use of cannabis and other exocannabinoids as anecdotal treatments for various GI disorders inspired the search for mechanisms by which these compounds mediate their effects, which led to the discovery of the mammalian endocannabinoid system. Dysregulated endocannabinoid signaling was linked to inflammation and the gut microbiota. However, the effects of endocannabinoids on host susceptibility to infection has not been explored. Here, we show that mice with elevated levels of the endocannabinoid 2-arachidonoyl glycerol (2-AG) are protected from enteric infection by Enterobacteriaceae pathogens. 2-AG directly modulates pathogen function by inhibiting virulence programs essential for successful infection. Furthermore, 2-AG antagonizes the bacterial receptor QseC, a histidine kinase encoded within the core Enterobacteriaceae genome that promotes the activation of pathogen-associated type three secretion systems. Taken together, our findings establish that endocannabinoids are directly sensed by bacteria and can modulate bacterial function.”
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“Fighting intestinal infections with the body’s own endocannabinoids. By harnessing the power of natural compounds produced in the body and in plants, we may eventually treat infections in a whole new way.”  https://www.sciencedaily.com/releases/2020/10/201007123119.htm

“Study may explain why cannabis plant can reduce symptoms of various bowel conditions” https://www.news-medical.net/news/20201007/Study-could-help-explain-why-cannabis-plant-can-reduce-symptoms-of-various-bowel-conditions.aspx

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Efficacy of combined therapy with fish oil and phytocannabinoids in murine intestinal inflammation

Phytotherapy Research“Fish oil (FO) and phytocannabinoids have received considerable attention for their intestinal anti-inflammatory effects.

We investigated whether the combination of FO with cannabigerol (CBG) and cannabidiol (CBD) or a combination of all three treatments results in a more pronounced intestinal antiinflammatory action compared to the effects achieved separately.

Colitis was induced in mice by 2,4-dinitrobenzenesulfonic acid (DNBS). CBD and CBG levels were detected and quantified by liquid chromatography coupled with time of flight mass spectrometry and ion trap mass spectrometry (LC-MS-IT-TOF). Endocannabinoids and related mediators were assessed by LC-MS. DNBS increased colon weight/colon length ratio, myeloperoxidase activity, interleukin-1β, and intestinal permeability.

CBG, but not CBD, given by oral gavage, ameliorated DNBS-induced colonic inflammation. FO pretreatment (at the inactive dose) increased the antiinflammatory action of CBG and rendered oral CBD effective while reducing endocannabinoid levels. Furthermore, the combination of FO, CBD, and a per se inactive dose of CBG resulted in intestinal anti-inflammatory effects. Finally, FO did not alter phytocannabinoid levels in the serum and in the colon.

By highlighting the apparent additivity between phytocannabinoids and FO, our preclinical data support a novel strategy of combining these substances for the potential development of a treatment of inflammatory bowel disease.”

https://pubmed.ncbi.nlm.nih.gov/32996187/

https://onlinelibrary.wiley.com/doi/10.1002/ptr.6831

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Cannabis and the Gastrointestinal Tract

“Cannabis has been used for its medicinal purposes since ancient times. Its consumption leads to the activation of Cannabis receptors CB1 and CB2 that, through specific mechanisms can lead to modulation and progression of inflammation or repair. The novel findings are linked to the medical use of Cannabis in gastrointestinal (GI) system.

Purpose: The objective of the present paper is to elucidate the role of Cannabis consumption in GI system. An additional aim is to review the information on the function of Cannabis in non-alcoholic fatty liver disease (NAFLD).

Methods and results: This review summarizes the recent findings on the role of cannabinoid receptors, their synthetic or natural ligands, as well as their metabolizing enzymes in normal GI function and its disorders, including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) and possible adverse events. The synergism or antagonism between Cannabis’ active ingredients and the “entourage” plays a role in the efficacy of various strains. Some elements of Cannabis may alter disease severity as over-activation of Cannabis receptors CB1 and CB2 can lead to changes of the commensal gut flora. The endocannabinoid system (ECS) contributes to gut homeostasis. The ability of ECS to modulate inflammatory responses demonstrates the capacity of ECS to preserve gastrointestinal (GI) function. Alterations of the ECS may predispose patients to pathologic disorders, including IBD. Clinical studies in IBD demonstrate that subjects benefit from Cannabis consumption as seen through a reduction of the IBD-inflammation, as well as through a decreased need for other medication. NAFLD is characterized by fat accumulation in the liver. The occurrence of inflammation in NAFLD leads to non-alcoholic-steatohepatitis (NASH). The use of Cannabis might reduce liver inflammation.

Conclusions: With limited evidence of efficacy and safety of Cannabis in IBD, IBS, and NAFLD, randomized controlled studies are required to examine its therapeutic efficacy.”

https://pubmed.ncbi.nlm.nih.gov/32762830/

https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/31242

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Association Between Cannabis Use and Healthcare Utilization in Patients With Irritable Bowel Syndrome: A Retrospective Cohort Study

Cureus | LinkedIn“Irritable bowel syndrome (IBS) is a frequent cause of abdominal pain and altered bowel habits, which is associated with significant healthcare utilization.

The effects of the active compound of cannabis, Δ9-tetrahydrocannabinol (THC), on gut motility and tone have been studied in several experimental models. It is unknown whether these effects correlate with improved healthcare utilization among cannabis users.

The purpose of this study is to evaluate the impact of cannabis use on inpatient length of stay and resource utilization for patients with a primary discharge diagnosis of IBS.

Cannabis users were less likely to have the following: upper gastrointestinal endoscopy (17.9% vs. 26.1%; adjusted odds ratio [aOR]: 0.51 [0.36 to 0.73]; p<0.001) and lower gastrointestinal endoscopy (21.1% vs. 28.7%; aOR: 0.54 [0.39 to 0.75]; p<0.001). Additionally, cannabis users had shorter length of stay (2.8 days vs. 3.6 days; p=0.004) and less total charges (US$20,388 vs. US$23,624). There was no difference in the frequency of CT abdomen performed.

Cannabis use may decrease inpatient healthcare utilization in IBS patients. These effects could possibly be through the effect of cannabis on the endocannabinoid system.”

https://pubmed.ncbi.nlm.nih.gov/32528750/

“Our study provides evidence to suggest that cannabis use may decrease healthcare utilization and costs among hospitalized patients with IBS. These findings are likely attributable to the effects of cannabis’ active compound, THC, on gastrointestinal motility and colonic compliance. The role of cannabis in the treatment for IBS has potential for significant impact at the individual and population level given the burden of IBS on individual quality of life and healthcare expenditures.”

https://www.cureus.com/articles/30417-association-between-cannabis-use-and-healthcare-utilization-in-patients-with-irritable-bowel-syndrome-a-retrospective-cohort-study

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Cannabinoid agonists possibly mediate interaction between cholinergic and cannabinoid systems in regulating intestinal inflammation.

Medical Hypotheses“Inflammatory Bowel Disease (IBD) is idiopathic, chronic and affects the gastrointestinal tract. It results from the association of genetic, environmental and immune deregulation, which culminates in the development and progression of the inflammatory process. In an attempt to reverse colonic inflammation, endogenous systems involved in intestinal physiology are studied and the cholinergic system is fundamental for this process. In addition, this system has anti-inflammatory action in experimental models of IBD. Another important endogenous system in regulating the exacerbated inflammatory response in the gut is mediated by endocannabinoids, which play an important role in restoring bowel functionality after the onset of the inflammatory process. There are several reports in the literature showing the interconnection between the cannabinoid and cholinergic systems in different tissues. Considering that the activation of the cholinergic system stimulates the production of cannabinoid agonists in the intestine, our hypothesis is that the interaction between the muscarinic system and the cannabinoid in the control of intestinal inflammation is mediated by endogenous cannabinoids, since they are stimulated by the activation of muscarinic receptors.”

https://www.ncbi.nlm.nih.gov/pubmed/32085982

https://www.sciencedirect.com/science/article/abs/pii/S030698771931429X?via%3Dihub

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Endocannabinoid system in irritable bowel syndrome and cannabis as a therapy.

Complementary Therapies in Medicine“Irritable bowel syndrome (IBS) global burden is underestimated despite its high prevalence. It’s a gastrointestinal disease having obscure pathophysiology with multiple therapies yet unsatisfactory remedies.

The Endocannabinoid system (ECS) of our body plays a key role in maintaining normal physiology of the gastrointestinal tract as well as involves abnormalities including functional diseases like IBS. This review highlights the importance of the Endocannabinoid system, its connections with the normal gastrointestinal functions and abnormalities like IBS.

It also discusses the role of cannabis as medical therapy in IBS patients.

A literature search for articles related to endocannabinoids in IBS and medical cannabis in PubMed and Google Scholar was conducted. The studies highlighted the significant participation of ECS in IBS. However, the breach in obtaining the promising therapeutic model for IBS needed further investigation in ECS and uncover other treatments for IBS.

This review summarizes ECS, highlights the relationship of ECS with IBS and explores cannabis as a potential therapy to treat IBS.”

https://www.ncbi.nlm.nih.gov/pubmed/31987224

https://www.sciencedirect.com/science/article/pii/S0965229919310179?via%3Dihub

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Gastrointestinal Adverse Events of Cannabinoid 1 Receptor Inverse Agonists suggest their Potential Use in Irritable Bowel Syndrome with Constipation: A Systematic Review and Meta-Analysis.

 Image result for J Gastrointestin Liver Dis“Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal (GI) disorders characterized by pain and impaired bowel movements. Currently available drugs show limited efficacy.

Cannabinoid 1 receptor (CB1) inverse agonists (CB1-RAN) cause diarrhea and may be candidates for the treatment of constipation-predominant IBS (IBS-C). We evaluated the effects of CB1-RAN in clinical trials for their potential use in IBS-C.

METHODS:

Database search identified all clinical trials published up to May 2018 that reported rimonabant and taranabant treatment for at least one month and detailed the GI adverse events (AEs). Categorical outcomes (subgroups of AEs) were analyzed using the odds ratio (OR).

RESULTS:

Eighteen trials met the inclusion criteria. Rimonabant 20 mg produced significantly more overall AEs (OR=1.35, CI: 1.19-1.52, p<0.0001), psychiatric events (OR=1.79, CI: 1.46-2.21, p<0.001) and GI AEs (OR=2.05, CI: 1.65-2.55, p<0.001) compared to placebo. Taranabant at doses ranging from 0.5 to 8 mg produced significantly more overall AEs (OR=1.36, CI: 1.13-1.64, p<0.002), psychiatric AEs (1.82, CI: 1.54-2.16, p<0.001) and GI AEs (OR=1.75, CI: 1.29-2.37, p<0.001) compared to placebo.

CONCLUSIONS:

The approach to target CB1 in the gut for the treatment of IBS-C or chronic constipation seems a promising therapeutic option. Prospective clinical trials on the possible targeting of CB1 and the endocannabinoid system are warranted.”

https://www.ncbi.nlm.nih.gov/pubmed/31826058

https://www.jgld.ro/jgld/index.php/jgld/article/view/265

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