Anti-Inflammatory Activity in Colon Models Is Derived from Δ9-Tetrahydrocannabinolic Acid That Interacts with Additional Compounds in Cannabis Extracts.

“Inflammatory bowel diseases (IBDs) include Crohn’s disease, and ulcerative colitis. Cannabis sativa preparations have beneficial effects for IBD patients. However, C. sativa extracts contain hundreds of compounds. Although there is much knowledge of the activity of different cannabinoids and their receptor agonists or antagonists, the cytotoxic and anti-inflammatory activity of whole C. sativa extracts has never been characterized in detail with in vitro and ex vivo colon models.

Material and Methods: The anti-inflammatory activity of C. sativa extracts was studied on three lines of epithelial cells and on colon tissue. C. sativa flowers were extracted with ethanol, enzyme-linked immunosorbent assay was used to determine the level of interleukin-8 in colon cells and tissue biopsies, chemical analysis was performed using high-performance liquid chromatography, mass spectrometry and nuclear magnetic resonance and gene expression was determined by quantitative real-time PCR.

Results: The anti-inflammatory activity of Cannabis extracts derives from D9-tetrahydrocannabinolic acid (THCA) present in fraction 7 (F7) of the extract. However, all fractions of C. sativa at a certain combination of concentrations have a significant increased cytotoxic activity. GPR55 receptor antagonist significantly reduces the anti-inflammatory activity of F7, whereas cannabinoid type 2 receptor antagonist significantly increases HCT116 cell proliferation. Also, cannabidiol (CBD) shows dose dependent cytotoxic activity, whereas anti-inflammatory activity was found only for the low concentration of CBD, and in a bell-shaped rather than dose-dependent manner. Activity of the extract and active fraction was verified on colon tissues taken from IBD patients, and was shown to suppress cyclooxygenase-2 (COX2) and metalloproteinase-9 (MMP9) gene expression in both cell culture and colon tissue.

Conclusions: It is suggested that the anti-inflammatory activity of Cannabis extracts on colon epithelial cells derives from a fraction of the extract that contains THCA, and is mediated, at least partially, via GPR55 receptor. The cytotoxic activity of the C. sativa extract was increased by combining all fractions at a certain combination of concentrations and was partially affected by CB2 receptor antagonist that increased cell proliferation. It is suggested that in a nonpsychoactive treatment for IBD, THCA should be used rather than CBD.”

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Cannabis in Inflammatory Bowel Diseases: from Anecdotal Use to Medicalization?

“Inflammatory bowel diseases (IBD) are disorders of chronic intestinal inflammation of unknown etiology. The basic pathophysiological process is that of immune mediated inflammation affecting the intestinal tract. This process is dependent on and governed by both genetic and environmental factors. There are two distinct forms of IBD – ulcerative colitis and Crohn’s disease.

There is no curative medical treatment. Furthermore, over 30% of patients, and over 70% with Crohn’s disease, will need surgical intervention for their disease. Thus, it comes as no surprise that many patients will turn to complementary or alternative medicine at some stage of their disease. Recent information reveals that between 16% and 50% of patients admit to having tried marijuana for their symptoms.

There is a long list of gastrointestinal symptoms that have been reported to be relieved by cannabis. These include anorexia, nausea, abdominal pain, diarrhea, gastroparesis – all of which can be part of IBD. These effects are related to the fact that the gastrointestinal tract is rich in cannabinoid (CB) receptors and their endogenous ligands, comprising together the endocannabinoid system (ECS).

In conclusion, use of cannabis is common in IBD, and it seems to be mostly safe. Accumulating preliminary data from human studies support a beneficial role of cannabinoids in IBD.”

https://www.ima.org.il/FilesUpload/IMAJ/0/228/114217.pdf

https://www.ima.org.il/imaj/ViewArticle.aspx?aId=4045

https://www.ncbi.nlm.nih.gov/pubmed/28457058

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Cannabinoid Receptor 2 Functional Variant Contributes to the Risk for Pediatric Inflammatory Bowel Disease.

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“We conducted a case-control association analysis to establish the role of a common CB2 functional variant, Q63R, in the susceptibility to inflammatory bowel disease (IBD).

Endocannabinoids may limit intestinal inflammation through cannabinoid receptor 1 and/or 2 (CB1, CB2).

The CB2-Q63R variant contributes to the risk for pediatric IBD, in particular CD. The R63 variant is associated with a more severe phenotype in both UC and CD.

Taken together, our data point toward the involvement of the CB2 receptor in the pathogenesis and clinical features of pediatric IBD.”

https://www.ncbi.nlm.nih.gov/pubmed/27875353

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Cannabidiol reduces intestinal inflammation through the control of neuroimmune axis.

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“Enteric glial cells (EGC) actively mediate acute and chronic inflammation in the gut; EGC proliferate and release neurotrophins, growth factors, and pro-inflammatory cytokines which, in turn, may amplify the immune response, representing a very important link between the nervous and immune systems in the intestine.

Cannabidiol (CBD) is an interesting compound because of its ability to control reactive gliosis in the CNS, without any unwanted psychotropic effects.

Therefore the rationale of our study was to investigate the effect of CBD on intestinal biopsies from patients with ulcerative colitis (UC) and from intestinal segments of mice with LPS-induced intestinal inflammation.

Our results therefore indicate that CBD indeed unravels a new therapeutic strategy to treat inflammatory bowel diseases.

The results of the present study correlate and expand the findings suggesting CBD as a potent compound that is able to modulate experimental gut inflammation.

In this study we demonstrate that during intestinal inflammation, CBD is able to control the inflammatory scenario and the subsequent intestinal apoptosis through the restoration of the altered glia-immune homeostasis.

CBD is therefore regarded as a promising therapeutic agent that modulates the neuro-immune axis, which can be recognised as a new target in the treatment of inflammatory bowel disorders.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3232190/

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ENDOCANNABINOID SYSTEM: A multi-facet therapeutic target.

Image result for Curr Clin Pharmacol.

“Cannabis sativa is also popularly known as marijuana. It is being cultivated and used by man for recreational and medicinal purposes from many centuries.

Study of cannabinoids was at bay for very long time and its therapeutic value could not be adequately harnessed due to its legal status as proscribed drug in most of the countries.

The research of drugs acting on endocannabinoid system has seen many ups and down in recent past. Presently, it is known that endocannabinoids has role in pathology of many disorders and they also serve “protective role” in many medical conditions.

Several diseases like emesis, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia, cardiovascular disorders, cancer, obesity, metabolic syndrome related diseases, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and Tourette’s syndrome could possibly be treated by drugs modulating endocannabinoid system.

Presently, cannabinoid receptor agonists like nabilone and dronabinol are used for reducing the chemotherapy induced vomiting. Sativex (cannabidiol and THC combination) is approved in the UK, Spain and New Zealand to treat spasticity due to multiple sclerosis. In US it is under investigation for cancer pain, another drug Epidiolex (cannabidiol) is also under investigation in US for childhood seizures. Rimonabant, CB1 receptor antagonist appeared as a promising anti-obesity drug during clinical trials but it also exhibited remarkable psychiatric side effect profile. Due to which the US Food and Drug Administration did not approve Rimonabant in US. It sale was also suspended across the EU in 2008.

Recent discontinuation of clinical trial related to FAAH inhibitor due to occurrence of serious adverse events in the participating subjects could be discouraging for the research fraternity. Despite of some mishaps in clinical trials related to drugs acting on endocannabinoid system, still lot of research is being carried out to explore and establish the therapeutic targets for both cannabinoid receptor agonists and antagonists.

One challenge is to develop drugs that target only cannabinoid receptors in a particular tissue and another is to invent drugs that acts selectively on cannabinoid receptors located outside the blood brain barrier. Besides this, development of the suitable dosage forms with maximum efficacy and minimum adverse effects is also warranted.

Another angle to be introspected for therapeutic abilities of this group of drugs is non-CB1 and non-CB2 receptor targets for cannabinoids.

In order to successfully exploit the therapeutic potential of endocannabinoid system, it is imperative to further characterize the endocannabinoid system in terms of identification of the exact cellular location of cannabinoid receptors and their role as “protective” and “disease inducing substance”, time-dependent changes in the expression of cannabinoid receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/27086601

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Dietary Supplement Therapies for Inflammatory Bowel Disease: Crohn’s Disease and Ulcerative Colitis.

“Inflammatory bowel disease (IBD) including ulcerative colitis and Crohn’s disease are chronic relapsing and remitting chronic diseases for which there is no cure.

The treatment of IBD frequently requires immunosuppressive and biologic therapies which carry an increased risk of infections and possible malignancy.

There is a continued search for safer and more natural therapies in the treatment of IBD.

This review aims to summarize the most current literature on the use of dietary supplements for the treatment of IBD. Specifically, the efficacy and adverse effects of vitamin D, fish oil, probiotics, prebiotics, curcumin, Boswellia serrata, aloe vera and cannabis sativa are reviewed.”

http://www.ncbi.nlm.nih.gov/pubmed/26561079

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Therapeutic potential of cannabinoid medicines.

Drug Testing and Analysis

“Cannabis was extensively used as a medicine throughout the developed world in the nineteenth century but went into decline early in the twentieth century ahead of its emergence as the most widely used illicit recreational drug later that century. Recent advances in cannabinoid pharmacology alongside the discovery of the endocannabinoid system (ECS) have re-ignited interest in cannabis-based medicines.

The ECS has emerged as an important physiological system and plausible target for new medicines. Its receptors and endogenous ligands play a vital modulatory role in diverse functions including immune response, food intake, cognition, emotion, perception, behavioural reinforcement, motor co-ordination, body temperature, wake/sleep cycle, bone formation and resorption, and various aspects of hormonal control. In disease it may act as part of the physiological response or as a component of the underlying pathology.

In the forefront of clinical research are the cannabinoids delta-9-tetrahydrocannabinol and cannabidiol, and their contrasting pharmacology will be briefly outlined. The therapeutic potential and possible risks of drugs that inhibit the ECS will also be considered. This paper will then go on to review clinical research exploring the potential of cannabinoid medicines in the following indications: symptomatic relief in multiple sclerosis, chronic neuropathic pain, intractable nausea and vomiting, loss of appetite and weight in the context of cancer or AIDS, psychosis, epilepsy, addiction, and metabolic disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/24006213

http://onlinelibrary.wiley.com/doi/10.1002/dta.1529/abstract

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The endocannabinoid system and its therapeutic exploitation.

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“The term ‘endocannabinoid’ – originally coined in the mid-1990s after the discovery of membrane receptors for the psychoactive principle in Cannabis, Delta9-tetrahydrocannabinol and their endogenous ligands – now indicates a whole signalling system that comprises cannabinoid receptors, endogenous ligands and enzymes for ligand biosynthesis and inactivation. This system seems to be involved in an ever-increasing number of pathological conditions. With novel products already being aimed at the pharmaceutical market little more than a decade since the discovery of cannabinoid receptors, the endocannabinoid system seems to hold even more promise for the future development of therapeutic drugs. We explore the conditions under which the potential of targeting the endocannabinoid system might be realized in the years to come.”  http://www.ncbi.nlm.nih.gov/pubmed/15340387

http://www.nature.com/nrd/journal/v3/n9/full/nrd1495.html

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Cannabis-based drugs could offer new hope for inflammatory bowel disease patients

“Researchers investigating anecdotal evidence that cannabis relieves some of the symptoms of inflammatory bowel disease (IBD) have discovered a potential new target for cannabis-derived drugs for treatment of the disease.

This finding, published in the journal Gastroenterology… could bring new hope for… sufferers of diseases like Crohn’s and ulcerative colitis1 with the possibility that cannabis-derived drugs may help to heal the gut lining, which is damaged during the course of disease. ”

Read more: http://www.medicalnewstoday.com/releases/28584.php

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Cannabis for Ulcerative Colitis and Crohn’s Disease treatment

“Chemicals found in cannabis could prove an effective treatment for the inflammatory bowel diseases Ulcerative Colitis and Crohn’s Disease, say scientists.

Laboratory tests have shown that two compounds found in the cannabis plant – the cannabinoids THC and cannabidiol – interact with the body’s system that controls gut function.

Crohn’s Disease and Ulcerative Colitis, which affect about one in every 250 people in Northern Europe, are caused by both genetic and environmental factors. The researchers believe that a genetic susceptibility coupled with other triggers, such as diet, stress or bacterial imbalance, leads to a defective immune response.

Dr Karen Wright, Peel Trust Lecturer in Biomedicine at Lancaster University, will be presenting her soon-to-be published work at The British Pharmacological Society’s Winter Meeting in London today (Thursday).

She said: “The lining of the intestines provides a barrier against the contents of the gut but in people with Crohn’s Disease this barrier leaks and bacteria can escape into the intestinal tissue leading to an inappropriate immune response.

“If we could find a way to restore barrier integrity in patients we may be able to curb the inflammatory immune response that causes these chronic conditions.”

Dr Wright, working with colleagues at the School of Graduate Entry Medicine and Health in Derby, has shown that cells that react to cannabinoid compounds play an important role in normal gut function as well as the immune system’s inflammatory response.

“The body produces its own cannabinoid molecules, called endocannabinoids, which we have shown increase the permeability of the epithelium during inflammation, implying that overproduction may be detrimental,” said Dr Wright.

“However, we were able to reverse this process using plant-derived cannabinoids, which appeared to allow the epithelial cells to form tighter bonds with each other and restore the membrane barrier.”

The research was carried out using cell cultures in a dish but, interestingly, when the team attempted to mimic the conditions of the gut by reducing the amount of oxygen in the cells’ environment, much lower concentrations of cannabinoid were needed to produce the same effect.

Dr Wright added: “What is also encouraging is that while THC has psychoactive properties and is responsible for the ‘high’ people experience when using cannabis, cannabidiol, which has also proved effective in restoring membrane integrity, does not possess such properties.”

The British Pharmacological Society (BPS) – the primary UK learned society concerned with research into drugs and the way they work – is hosting its annual Winter Meeting in London, attracting experts from across the world.

The three-day conference, running from 15 to 17 December 2009, will hear presentations on the latest pharmacological developments to tackle a range of conditions and diseases.”

http://www.news-medical.net/news/20091217/Cannabis-for-Ulcerative-Colitis-and-Crohns-Disease-treatment.aspx

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