Cannabis, cannabinoids and the endocannabinoid system – is there therapeutic potential for inflammatory bowel disease?

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“Cannabis sativa and its extracts have been used for centuries both medicinally and recreationally. There is accumulating evidence that exogenous cannabis and related cannabinoids improve symptoms associated with inflammatory bowel disease such as pain, loss of appetite, and diarrhoea. In vivo, exocannabinoids have been demonstrated to improve colitis, mainly in chemical models. Exocannabinoids signal through the endocannabinoid system, an increasingly understood network of endogenous lipid ligands and their receptors, together with a number of synthetic and degradative enzymes and the resulting products. Modulating the endocannabinoid system using pharmacological receptor agonists, genetic knockout models, or inhibition of degradative enzymes have largely shown improvements in colitis in vivo. Despite these promising experimental results, this has not translated into meaningful benefits for human IBD in the few clinical trials which have been conducted to date. The largest study to date being limited by poor medication tolerance due to the Δ9-tetrahydrocannabinol component. This review article synthesises the current literature surrounding the modulation of the endocannabinoid system and administration of exocannabinoids in experimental and human IBD. Findings of clinical surveys and studies of cannabis use in IBD are summarised. Discrepancies in the literature are highlighted together with identifying novel areas of interest.”

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The Role of Cannabis in the Management of Inflammatory Bowel Disease: A Review of Clinical, Scientific, and Regulatory Information: Commissioned by the Crohn’s and Colitis Foundation.

Oxford University Press

“There is significant interest among patients and providers in using cannabis (marijuana) and its derivatives to treat a number of chronic illnesses, including inflammatory bowel disease. Despite the Schedule I classification of cannabis by the federal government, state governments have sought ways to make cannabis available for specific medical conditions, and some states have legalized cannabis outright. This white paper summarizes the preclinical data, clinical data, safety data, and the regulatory landscape as they apply to medical cannabis use in inflammatory bowel disease. Animal models of cannabinoid chemistry and physiology give evidence of anti-inflammatory, antidiarrheal, and nociceptive-limiting properties. Human studies have found benefit in controlling symptoms and improving quality of life, but no studies have established true disease modification given the absent improvement in biomarker profiles or endoscopic healing. Finally, this review describes the legal, regulatory, and practical hurdles to studying the risks and benefits of medical cannabis in the United States.”

https://www.ncbi.nlm.nih.gov/pubmed/30358848

https://academic.oup.com/ibdjournal/advance-article-abstract/doi/10.1093/ibd/izy319/5144402?redirectedFrom=fulltext

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The Use of Cannabinoids in Colitis: A Systematic Review and Meta-Analysis.

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“Clinical trials investigating the use of cannabinoid drugs for the treatment of intestinal inflammation are anticipated secondary to preclinical literature demonstrating efficacy in reducing inflammation.

We systematically reviewed publications on the benefit of drugs targeting the endo-cannabinoid system in intestinal inflammation.

 

CONCLUSIONS:

There is abundant preclinical literature demonstrating the anti-inflammatory effects of cannabinoid drugs in inflammation of the gut.”

https://www.ncbi.nlm.nih.gov/pubmed/29562280

https://academic.oup.com/ibdjournal/article-abstract/24/4/680/4944355?redirectedFrom=fulltext

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A Randomized, Double-blind, Placebo-controlled, Parallel-group, Pilot Study of Cannabidiol-rich Botanical Extract in the Symptomatic Treatment of Ulcerative Colitis.

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“Cannabidiol (CBD) exhibits anti-inflammatory properties that could improve disease activity in inflammatory bowel disease.

This proof-of-concept study assessed efficacy, safety and tolerability of CBD-rich botanical extract in ulcerative colitis (UC) patients.

Although the primary endpoint was not reached, several signals suggest CBD-rich botanical extract may be beneficial for symptomatic treatment of UC.”

https://www.ncbi.nlm.nih.gov/pubmed/29538683

“Cannabinoid administration is associated with a number of beneficial effects in the gut including decreasing emesis, gastric acid secretion, inflammation and intestinal motility. Cannabis has been reported to produce symptom improvement in people with IBD and some patients self-medicate with cannabis.”

https://academic.oup.com/ibdjournal/advance-article/doi/10.1093/ibd/izy002/4925788

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Cannabidiol restores intestinal barrier dysfunction and inhibits the apoptotic process induced by Clostridium difficile toxin A in Caco-2 cells.

 SAGE Journals

“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.

RESULTS:

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.

CONCLUSIONS:

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.”

https://www.ncbi.nlm.nih.gov/pubmed/29238589

“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

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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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Manipulation of the Endocannabinoid System in Colitis: A Comprehensive Review.

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“Inflammatory bowel disease (IBD) is a lifelong disease of the gastrointestinal tract whose annual incidence and prevalence is on the rise. Current immunosuppressive therapies available for treatment of IBD offer limited benefits and lose effectiveness, exposing a significant need for the development of novel therapies. In the clinical setting, cannabis has been shown to provide patients with IBD symptomatic relief, although the underlying mechanisms of their anti-inflammatory effects remain unclear.

RESULTS:

Cannabinoid receptors 1 and 2, endogenous cannabinoids, and atypical cannabinoids are upregulated in inflammation, and their presence and stimulation attenuate murine colitis, whereas cannabinoid receptor antagonism and cannabinoid receptor deficient models reverse these anti-inflammatory effects. In addition, inhibition of endocannabinoid degradation through monoacylglycerol lipase and fatty acid amide hydrolase blockade can also attenuate colitis development, and is closely linked to cannabinoid receptor expression.

CONCLUSIONS:

Although manipulation of the endocannabinoid system in murine colitis has proven to be largely beneficial in attenuating inflammation, there is a paucity of human study data. Further research is essential to clearly elucidate the specific mechanisms driving this anti-inflammatory effect for the development of therapeutics to target inflammatory disease such as IBD.”

https://www.ncbi.nlm.nih.gov/pubmed/28079617

“Plant cannabinoids THC and CBD proved beneficial in DNBS-induced colitis in a bell-shaped dose-related response, but more importantly, the effects of the phytocannabinoids were additive, as CBD increased an ineffective THC dose to the level of an effective one.” https://academic.oup.com/ibdjournal/article/23/2/192/4347176

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Anti-inflammatory effect of cannabinoid agonist WIN55, 212 on mouse experimental colitis is related to inhibition of p38MAPK.

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“To investigate the anti-inflammatory effect and the possible mechanisms of an agonist of cannabinoid (CB) receptors, WIN55-212-2 (WIN55), in mice with experimental colitis, so as to supply experimental evidence for its clinical use in future.

These results confirmed the anti-inflammatory effect and protective role of WIN55 on the mice with experimental colitis, and revealed that this agent exercises its action at least partially by inhibiting p38MAPK.

Furthermore, the results showed that SB203580, affected the expression of CB1 and CB2 receptors in the mouse colon, suggesting a close linkage and cross-talk between the p38MAPK signaling pathway and the endogenous CB system.”

https://www.ncbi.nlm.nih.gov/pubmed/27920472

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Application of carbon nanotubes as the carriers of the cannabinoid, 2-arachidonoylglycerol: Towards a novel treatment strategy in colitis.

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“Treatment of colitis has remained a major clinical challenge.

The cannabinoid, 2-arachidonoyglycerol (2-AG), has shown beneficial effects in colitis, however, poor solubility or rapid hydrolysis may limit its efficiency. According to the high biocompatibility of carbon nanotubes (CNTs) and their ability for controlled drug delivery, we aimed to prepare multi-walled CNTs-2-AG (MWCNTs-2-AG) complex in order to improve the pharmacological profile of 2-AG and evaluate the therapeutic potential of this nanocomplex in a rat model of colitis.

Aminated MWCNTs and MWCNTs-2-AG complex exhibited significantly lower cytotoxicity than acidified MWCNTs. Once daily intrarectal application of MWCNTs-2-AG complex (containing 2mg/kg of 2-AG) 2days before and 8days after the induction of colitis effectively reduced the macroscopic and microscopic injuries, malondialdehyde, tumour necrosis factor-α, and interlukin-1β concentrations, and myeloperoxidase activity. While, free 2-AG (2mg/kg), and acidified or aminated MWCNTs showed no beneficial effects.

SIGNIFICANCE:

Amino-functionalized MWCNTs appear as the suitable carriers for 2-AG which provide a sustained concentration for this cannabinoid leading to the promising therapeutic effects in the experimental colitis.”

https://www.ncbi.nlm.nih.gov/pubmed/27888115

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Activation of Cannabinoid Receptor 2 Ameliorates DSS-Induced Colitis through Inhibiting NLRP3 Inflammasome in Macrophages.

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“Activation of cannabinoid receptor 2 (CB2R) ameliorates inflammation, but the underlying mechanism remains unclear.

In the present study, we examined whether activation of CB2R could suppress the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome.

We conclude that activation of CB2R ameliorates DSS-induced colitis through enhancing autophagy that may inhibit NLRP3 inflammasome activation in macrophages.”

http://www.ncbi.nlm.nih.gov/pubmed/27611972

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