My personal testimonial if IBS/IBD

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

Main Category: Irritable-Bowel Syndrome
Article Date: 04 Aug 2005 - 0:00 PDT


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 today (Monday 1 August), could bring new hope for the UK's 90,000 - 180,000 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.

Both Crohn's and ulcerative colitis - often referred to under the umbrella term of IBD - cause patients' immune systems to go into overdrive, producing inflammation in different areas of the gastrointestinal tract.

This inflammation can cause pain, urgent diarrhoea, severe tiredness and loss of weight, and is most commonly diagnosed in young adults of both sexes between the ages of 15 and 25.

Patients with IBD who are also users of cannabis often report that their symptoms are alleviated following cannabis use, suggesting that the gut is able to respond to some of the molecules found in cannabis.

Investigating this phenomenon, researchers from the University of Bath worked with colleagues at the Royal United Hospital in Bath to look at the interaction of cannabis with specific molecules, known as receptors, found on the surface of cells in the gut.

Examining gut samples from healthy people and IBD patients, the researchers looked at two specific receptors, called CB1 and CB2, which are known to be activated by the presence of molecules found in cannabis.

They discovered that whilst CB1 is present in healthy people, the presence of CB2 increases in IBD patients as their disease progresses.

The researchers believe that the presence of CB2 receptor only during the disease-state may be linked to its known role in suppression of the immune system. In other words, it is part of the body's natural mechanisms that attempt to restore the normal healthy state of the gut.

If so, this makes it an ideal candidate for the development of new cannabis-derived drugs to help IBD patients. They also found that the CB1 receptor helps to promote wound healing in the lining of the gut.

"This gives us the first evidence that very selective cannabis-derived treatments may be useful as future therapeutic strategies in the treatment of Crohn's and ulcerative colitis," said Dr Karen Wright from the University's Department of Pharmacy and Pharmacology.

"This is because some extracts from cannabis, known as cannabinoids, closely resemble molecules that occur naturally in our body, and by developing treatments that target this system, we can help the body recover from some of the effects of these diseases."

Ordinarily, CB1 and CB2 have the task of recognising and binding to a family of substances called "endocannabinoids" that occur naturally in our bodies. Once these receptors have detected the presence of specific molecules in their surrounding environment, a chain of biochemical signals is activated which culminates in switching immune responses on or off - depending on what their function is.

"The normal job of the CB1 and CB2 receptors is to help moderate diverse responses throughout the body, but their presence in the gut means that they could be useful targets for the development of cannabis-derived drugs for controlling the progression of IBD," said Dr Wright.

"The research shows that whilst cannabis use may have some benefits for patients with IBD, the psychoactive effects and the legal implications associated with herbal cannabis use make it unsuitable as a treatment. Targeting drug development to components of the in-built cannabinoid system could be the way forward."

Cannabis-based medicines that help alleviate the pain endured by Multiple Sclerosis patients have already been given a licence for use in Canada, and Salisbury-based GW Pharmaceuticals is pioneering many of the advances in this field.

The research was funded by the Wellcome Trust and an NHS Research Grant.

Case studies of people with colitis or Crohn's are available from National Association for Colitis and Crohn's Disease on +44 (0)1727 830038.

1Figures from the National Association for Colitis and Crohn's Disease. There is no national database of people with Crohn's or Colitis - the figures are taken from estimates published by the British Society for Gastroenterology in 2004.

Inflammatory Bowel Disease

� Inflammatory Bowel Disease (IBD) is an umbrella term referring to two chronic diseases that cause inflammation of the intestines: ulcerative colitis (UC) and Crohn's disease (CD).

Crohn's disease

� Between 30,000 and 60,000 people in the UK live with CD. Between 3,000 and 6,000 new cases are diagnosed each year.

� In 1996, a study from South Glamorgan reported a doubling of the number of children diagnosed with CD between 1983 and 1993

� In 1999 a study of children in Scotland has reported a 50% increase over 10 years in the incidence of CD.

� CD can affect anywhere from the mouth to the rectum but most commonly affects the small intestine.

� It causes inflammation, deep ulcers and scarring to the wall of the intestine and often occurs in patches with healthy tissue in between. There is no cure for CD at present.

� The main symptoms are pain, urgent diarrhoea, severe tiredness and loss of weight.

� CD is quite often associated with other inflammatory conditions affecting the joints, skin and eyes. Most patients will be treated with drugs, including steroids, to reduce inflammation or by means of special liquid feeds to rest the bowel. Surgery may be required to remove narrowed or damaged parts of the intestine.

� The condition is named after Dr Burril Crohn, one of the three doctors who first identified the disease in 1932. � The cause of CD has not yet been identified.

Ulcerative Colitis

� Between 60,000 and 120,000 people in the United Kingdom live with UC

� Between 6,000 and 12,000 new cases are diagnosed each year.

� Ulcerative Colitis affects men and women equally.

� The number of new cases each year has not risen recently, but is not decreasing.

� Ulcerative Colitis affects the colon (large intestine) or rectum. Inflammation and ulcers develop on the inside lining of the colon resulting in pain, urgent and bloody diarrhoea, and continual tiredness.

� There is no cure for Ulcerative Colitis at present.

� The condition varies as to how much of the colon is affected and the severity of the symptoms also fluctuates unpredictably over time. Patients are likely to experience flare-ups in between intervals of reduced symptoms or remission.

� Most patients will be treated with drugs, including steroids, to control or reduce the inflammation. Some people need surgery to remove the affected part of the colon, if their symptoms do not respond to treatment with drugs.

� The cause of UC has not yet been identified. The University of Bath is one of the UK's leading universities, with an international reputation for quality research and teaching. In 17 subject areas the University of Bath is rated in the top ten in the country.
source: http://www.medicalnewstoday.com/articles/28584.php

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Cannabis may soothe inflamed bowels


Cannabis-based drugs could offer treatment hope to sufferers of inflammatory bowel disease, UK researchers report.

Cannabis smokers with inflammatory bowel disease (IBD) have often claimed that smoking a joint seems to lessen their symptoms. So a group of researchers from Bath University and Bristol University, both in the UK, decided to explore the clinical basis for the claims. "There is quite a lot of anecdotal evidence that using cannabis seems to reduce the pain and frequency of Crohn’s disease and ulcerative colitis, so we decided to see if we could find out what was going on there," says Karen Wright, a pharmacologist at Bath University. "Historically, it was smoked in India and China centuries ago for its gastrointestinal properties". The chronic conditions, known collectively as IBD, are caused by an over-active immune system which produces severe inflammation in areas of the gastrointestinal tract. Up to 180,000 people in the UK are thought to have colitis or Crohn’s disease and suffer symptoms of pain, urgent diarrhoea, severe tiredness and loss of weight. Repeated attacks can lead to scarring of the colon and fibrosis to the extent that the bowel narrows to form a stricture, for which a colonectomy - the surgical removal of the bowel - is the only cure.

Repair trigger

Reports that cannabis eased IBD symptoms indicated the possible existence of cannabinoid receptors in the intestinal lining, which respond to molecules in the plant-derived chemicals. Wright and colleagues grew sections of human colon and examined them in vitro. To their surprise, the team discovered CB1 cannabinoid receptors - which are known to be present in the brain - in the endothelial cells which line the gut. "I think they must be involved in repairing the lining of the gut when it is damaged," Wright says. She deliberately damaged the cells to cause inflammation of the gut lining and then added synthetically produced cannabinoids."The gut started to heal: the broken cells were repaired and brought back closer together to mend the tears," she told New Scientist. Wright believes that in a healthy gut, natural endogenous cannabinoids are released from endothelial cells when they are injured, which then bind to the CB1 receptors. The process appears to set off a wound-healing reaction. "When people use cannabis, the cannabinoids bind to these receptors in the same way," she said.

Excess cells

Previous studies have shown that CB1 receptors located on the nerve cells in the gut respond to cannabinoids by slowing gut motility, therefore reducing the painful muscle contractions associated with diarrhoea. But Wright and her team also discovered another cannabinoid receptor, CB2, in the guts of IBD sufferers, which was not present in healthy guts. These receptors, which also respond to chemicals in cannabis, appear to be associated with apoptosis - programmed cell death - and may have a role in suppressing the overactive immune system and reducing inflammation by moping up excess cells, she suggests. "Ideally we would want to be able to stimulate the body’s own endogenous cannabinoid system, which might become dysregulated during long-term inflammation. Knowing more about how this system actually works will help us to look for therapeutic targets," Wright says. "We are not advocating cannabis use, particularly as smoking tobacco exacerbates Crohn’s disease and many smokers of cannabis use tobacco as well." "Anything that offers hope is good news for sufferers of IBD," says a spokesperson from the National Association for Colitis and Crohn’s Disease, commenting on the research.

Source: http://www.chanvre-info.ch/info/en/Cannabi...e-inflamed.html

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Bowel Study Backs Cannabis Drugs
BBCi, 1st August 2005

Patients with inflammatory bowel disease may benefit from cannabis-based drugs, UK scientists believe. The Bath University team found people with the gut disorder had an abundant number of a type of cannabinoid receptors in their body.

They believe this is part of the body's attempt to dampen down the inflammation and that giving a drug that binds to these receptors could boost this. Their findings appear in the journal Gastroenterology.

Cannabinoids
When people have Crohn's disease or ulcerative colitis - collectively known as inflammatory bowel disease or IBD - their immune system goes into overdrive, producing inflammation in different areas of the digestive tract.

This causes symptoms such as pain and urgent diarrhoea.

Anecdotally, people with IBD who have been users of cannabis have reported that their symptoms get better when they use the drug.

" These initial results look extremely promising and exciting." - Dr Derek Scott from Aberdeen University

Dr Karen Wright and colleagues examined gut samples from healthy people and IBD patients and looked for the presence of two receptors known to react to natural cannabis-like compounds produced by the body.

Both the patients and the healthy people had similar numbers of CB1 receptors in their gut. However, the IBD patients had far greater numbers of CB2 receptors.

The normal job of CB1 and CB2 receptors is to switch immune responses on or off. CB1 receptors also help to promote wound healing in the lining of the gut.

Potential Therapy
Dr Wright said: "This gives us the first evidence that very selective cannabis-derived treatments may be useful as future therapeutic strategies in the treatment of Crohn's and ulcerative colitis.

"This is because some extracts from cannabis, known as cannabinoids, closely resemble molecules that occur naturally in our body, and by developing treatments that target this system, we can help the body recover from some of the effects of these diseases."

She said that the psychoactive effects and the legal implications associated with herbal cannabis use made it unsuitable as a treatment.

However, it might be possible to make a synthetic cannabis-like drug that has all of the therapeutic benefits and none of the other actions of cannabis.

"Targeting drug development to components of the in-built cannabinoid system could be the way forward," she said.

Dr Derek Scott, a researcher in Biomedical Sciences at Aberdeen University, said: "These initial results look extremely promising and exciting.

More Trials
"However, further work is required so that we can better understand exactly how the signalling pathways controlled by cannabinoid receptors might be targeted in IBD patients, and whether there might be any side-effects."

Cannabis-based medicines are already used for multiple sclerosis in some countries.

Dr John Zycheck, from the Peninsula Medical School in Plymouth, which has been granted £2 million to study these drugs for MS, said: "There is no reason why clinical studies could not be undertaken at a fairly early stage because we are already testing cannabinoids for a variety of different conditions.

"Cannabinoids do have an effect on the gut. It slows gut transit. We see it in our MS patients."

He said more work was needed to check whether these drugs would reduce inflammation and to work out a dose that was strong enough but not toxic.

Dr George Kunos from the US National Institutes of Health said an alternative approach could involve testing compounds that amplify the action of the body's natural cannabinoids by blocking their normal destruction in the gut.

He said animal studies suggested compounds that block the enzyme fatty acid amidohydrolase (FAAH) do this.

Dr John Bennett, Chairman of Core, a national gut and liver disorders charity, said: "I would not want any patient to think that a cannabis-based treatment for IBD is around the corner. Much more work is needed."

source: http://www.thehempire.com/index.php/cannab..._cannabis_drugs

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Cannabidiol, extracted from Cannabis sativa, selectively inhibits inflammatory hypermotility in mice.
Capasso R, Borrelli F, Aviello G, Romano B, Scalisi C, Capasso F, Izzo AA

1Department of Experimental Pharmacology, University of Naples Federico II and Endocannabinoid Research Group, Naples, Italy.


Background and purpose:Cannabidiol is a Cannabis-derived non-psychotropic compound that exerts a plethora of pharmacological actions, including anti-inflammatory, neuroprotective and antitumour effects, with potential therapeutic interest. However, the actions of cannabidiol in the digestive tract are largely unexplored. In the present study, we investigated the effect of cannabidiol on intestinal motility in normal (control) mice and in mice with intestinal inflammation.Experimental approach:Motility in vivo was measured by evaluating the distribution of an orally administered fluorescent marker along the small intestine; intestinal inflammation was induced by the irritant croton oil; contractility in vitro was evaluated by stimulating the isolated ileum, in an organ bath, with ACh.Key results:In vivo, cannabidiol did not affect motility in control mice, but normalized croton oil-induced hypermotility. The inhibitory effect of cannabidiol was counteracted by the cannabinoid CB(1) receptor antagonist rimonabant, but not by the cannabinoid CB(2) receptor antagonist SR144528 (N-[-1S-endo-1,3,3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide), by the opioid receptor antagonist naloxone or by the alpha(2)-adrenergic antagonist yohimbine. Cannabidiol did not reduce motility in animals treated with the fatty acid amide hydrolase (FAAH) inhibitor N-arachidonoyl-5-hydroxytryptamine, whereas loperamide was still effective. In vitro, cannabidiol inhibited ACh-induced contractions in the isolated ileum from both control and croton oil-treated mice.Conclusions and implications:Cannabidiol selectively reduces croton oil-induced hypermotility in mice in vivo and this effect involves cannabinoid CB(1) receptors and FAAH. In view of its low toxicity in humans, cannabidiol may represent a good candidate to normalize motility in patients with inflammatory bowel disease.British Journal of Pharmacology (2008) 154, 1001-1008; doi:10.1038/bjp.2008.177; published online 12 May 2008.

Published 30 June 2008 in Br J Pharmacol, 154(5): 1001-8.

source: http://marijuana.researchtoday.net/archive/5/6/1797.htm

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Cannabinoids and the gut

The plant Cannabis sativa produces a variety of cannabinoid compounds of which 9-tetrahydrocannabinol (9-THC) is the main psychotropic constituent. The effects of 9-THC are thought to be mediated primarily by the mammalian cannabinoid receptors CB1 and CB2 which are G protein-coupled receptors. CB1 receptors are expressed mainly by neurons in the brain, spinal cord, peripheral nervous system, and enteric nervous system. CB2 receptors appear to be expressed mainly by cells of the immune system.

Endogenous ligands for the cannabinoid receptors have been identified; the best known include anandamide (arachidonoyl ethanolamide) and 2-arachidonoyl glycerol (2-AG). When released, anandamide and 2-AG appear to be removed from extracellular compartments by a carrier mediated uptake process, and once within the cell, both endocannabinoids are hydrolyzed by the enzyme fatty acid amide hydrolase (FAAH), which appears to be a major determinant of physiological levels of both molecules.1 In addition to the 2 cannabinoid receptors, it has recently been shown that anandamide and 2-AG are also agonists for the TRPV1 receptor (transient receptor potential vanilloid subtype 1; also called VR1), the cognate receptor for the pungent plant compound, capsaicin.2 Therefore, some effects of anandamide and 2-AG may be mediated by TRPV1 receptors instead of CB1 or CB2 receptors.

Evidence has accumulated in recent years that endocannabinoids and their receptors may play a role in inhibiting gastric emptying and intestinal peristalsis (reviewed in Pertwee3). These effects on gastrointestinal motility appear to be mediated primarily by peripheral CB1 receptors that inhibit excitatory transmitter release in the enteric nervous system. Gastric acid secretion is also inhibited by cannabinoid receptor agonists in animals and humans although the mechanisms involved are not yet clear. The cannabinoid receptor antagonists/inverse agonists SR141716A (selective for CB1 receptors) and SR144528 (selective for CB2 receptors) have proven to be very useful tools in the analysis of the actions of the endocannabinoids. The observation that SR141716A administered alone has effects on motility in intestinal preparations in vitro suggests that the endocannabinoid system is active tonically and may affect gut function physiologically. Since SR141716A is both a CB1 receptor antagonist and an inverse agonist, the tonic endocannabinoid activity in the intestine may be due to the presence of a population of CB1 receptors that are precoupled to their effector mechanisms rather than from the endogenous release of endocannabinoids.

The list of potential roles for the endocannabinoid system in the gut is expanded by 2 new reports appearing in this issue of GASTROENTEROLOGY. In the first, evidence is presented that the endogenous cannabinoid, anandamide, exerts an antidiarrheal action in mice treated with oral cholera toxin (CT) to induce secretory diarrhea.4 Selective CB1 receptor agonists produced a dose-dependent and significant inhibition of CT-induced fluid accumulation in the small intestine; this effect, in turn, was inhibited by pretreatment of the mice with the selective CB1 receptor antagonist/inverse agonist, SR141716A but not by the selective CB2 receptor antagonist/inverse agonist, SR144528. When given to CT-treated animals without CB1 receptor agonists, SR141716A but not SR144528 produced dose-dependent and significant increases in intraluminal fluid accumulation, suggesting that the secretory effects of CT are normally counteracted by endocannabinoid release. In addition, a selective anandamide re-uptake inhibitor, VDM11, significantly prevented CT-induced intraluminal fluid accumulation, providing further evidence in favor of the concept that endogenous cannabinoids inhibit CT-induced secretory diarrhea.

In addition to these pharmacological results, the authors also demonstrated that CT caused increased intestinal levels of anandamide but not 2-AG and that this was not due to a change in the enzymatic hydrolysis of anandamide because CT did not affect the rate of hydrolysis of 14C-anandamide added to small intestinal homogenates. Immunohistochemistry was used to demonstrate CB1 receptor expression in myenteric and submucous neurons that co-expressed choline acetyltransferase, a marker of cholinergic neurons, and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to show that CB1 transcripts are present in the mouse small intestine and that CB1 transcripts are significantly increased in CT-treated mice compared with controls.

The authors conclude that their data indicate that endogenous anandamide exerts an inhibitory influence on CT-stimulated fluid accumulation in the mouse intestine via activation of up-regulated CB1 receptors on enteric cholinergic nerves. This interpretation is consistent with previous demonstrations that activated CB1 receptors mediate inhibition of evoked acetylcholine release in myenteric neurons3 and suggests that cannabinoid administration to patients may be a way to inhibit selectively cholinergic neurons in the intestine that may be involved in the secretory pathway in diarrhea. The authors suggest that their findings indicate 2 possible novel strategies for pharmacological inhibition of secretory diarrhea without provoking unacceptable side effects such as psychotropic actions. First, development of selective CB1 receptor agonists that do not cross the blood-brain barrier may be expected to inhibit intestinal secretion without concomitant psychotropic effects. Second, administration of inhibitors of endocannabinoid inactivation (such as inhibitors of FAAH or the cellular re-uptake mechanism) might be expected to result in increasing local intestinal concentrations of anandamide to inhibit secretion. It is fascinating to note that this is not a totally new concept—there are several accounts of the effective use of Cannabis to treat dysentery and cholera in the 18th and 19th centuries.5

Another article appearing in this issue describes a potential role of endocannabinoids in colorectal cancer growth inhibition.6 In their introduction, the authors point out that the endocannabinoids and their receptors have previously been reported to inhibit the proliferation of breast cancer cells, prostate cancer cells, and rat thyroid cancer cells. In the current study, colonic mucosal biopsies were obtained from healthy and cancer tissue in patients with left-sided colon carcinoma and from healthy tissue and adenomatous polyps in patients with colonic adenomas. A small piece of tissue was taken from the head of each polyp by snare polypectomy. All tissues were found to contain anandamide, 2-AG, CB1 and CB2 receptors, and FAAH. The levels of anandamide and 2-AG were increased relative to controls in the adenomatous polyps and carcinomas, but there appeared to be no differences in levels of CB1 and CB2 receptors or FAAH among the tissues.

To determine if the endocannabinoid system affects colorectal cancer cell growth, the authors tested the effects of cannabinoids on undifferentiated and differentiated CaCo-2 cells in vitro. Anandamide and 2-AG dose-dependently inhibited the growth of undifferentiated CaCo-2 cells as did selective CB1 receptor agonists; the cannabinoids had little effect on the proliferation of differentiated CaCo-2 cells. In addition, the antiproliferative effects of the cannabinoids were antagonized by SR141716A but not SR144528. CaCo-2 cells were also shown to express CB1 but not CB2 receptors by RT-PCR and Western blotting and contained anandamide, 2-AG, and FAAH. Pharmacological inhibition of the inactivation of endocannabinoids also inhibited proliferation of undifferentiated CaCo-2 cells and this effect was also antagonized by SR141716A.

As the authors point out, this article is apparently the first report that cannabinoid receptors are expressed in nonnervous mammalian intestinal tissue. Coupled with the demonstration of relatively high concentrations of anandamide and 2-AG in colonic polyps and tumors, the authors suggest that local concentrations of these endocannabinoids may be high enough to interact physiologically with CB1 receptors in the tissue resulting in endogenous inhibition of cancer growth. These observations in turn lead the authors to suggest that inhibitors of endocannabinoid inactivation might represent useful anticancer drugs. Whether this proves to be the case or not, this work shows that endocannabinoids can be regarded as potential endogenous tumor growth inhibitors, as well as possible markers for cancer cells. It will be interesting to see in future studies whether cannabinoids or inhibitors of endocannabinoid inactivation are able to affect the proliferation of human colorectal tumors. Perhaps this question could be examined in a nude mouse model, for example.

The potential roles of the endocannabinoid system in gastrointestinal disorders may extend even beyond secretory diarrhea and colorectal cancer. It has been reported in recent studies that endocannabinoids may be involved in intestinal inflammation. In a mouse model of intestinal inflammation induced by oral croton oil administration, cannabinoid receptor agonists were more active in delaying intestinal motility than in control mice and these effects were counteracted by the CB1 selective antagonist/inverse agonist, SR141716A.7 In addition, croton oil-induced intestinal inflammation was associated with an increased expression of the CB1 receptor. It was concluded in this study that gut inflammation increases the potency of cannabinoid agonists possibly by up-regulating CB1 receptor expression. In another model of acute intestinal inflammation induced by administration of toxin A from Clostridium difficile to isolated segments of the rat ileum, it was shown that toxin A treatment resulted in increased ileal concentrations of anandamide and 2-AG and that administration of either anandamide or 2-AG alone essentially duplicated the inflammatory effects of toxin A,8 suggesting that one or both of these endocannabinoids may mediate the inflammatory effects of toxin A. Unlike the findings in the mouse croton oil-induced enteritis model, however, pretreatment with cannabinoid receptor antagonists did not inhibit toxin A-, anandamide-, or 2-AG-induced ileitis. Instead, pretreatment of the rats with the TRPV1 antagonist, capsazepine, significantly inhibited the inflammatory responses to all 3 substances. This finding suggests that endocannabinoids in the gut may act via the vanilloid TRPV1 receptor, as well as the cannabinoid receptors in some cases. It remains for future studies to unravel the perhaps multiple roles of the endocannabinoid/endovanilloid system of the gut in health and disease.

Whether or not the novel gastrointestinal actions of endocannabinoids reported in this issue of GASTROENTEROLOGY and elsewhere stand up to future scrutiny, it seems clear that the influence of these agents on the gut extends beyond the realm of motility. As putative inhibitors of secretory diarrhea and colorectal cancer, the potential therapeutic value of the gut endocannabinoid system appears to be substantial.

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Bowel Study Backs Cannabis Drugs
July 31, 2005 © BBC News


United Kingdom -- Patients with inflammatory bowel disease may benefit from cannabis-based drugs, UK scientists believe. The Bath University team found people with the gut disorder had an abundant number of a type of Cannabinoid receptors in their body. They believe this is part of the body's attempt to dampen down the inflammation and that giving a drug that binds to these receptors could boost this. Their findings appear in the journal Gastroenterology.

Cannabinoids

When people have Crohn's disease or ulcerative colitis - collectively known as inflammatory bowel disease or IBD - their immune system goes into overdrive, producing inflammation in different areas of the digestive tract.

This causes symptoms such as pain and urgent diarrhea.

Anecdotally, people with IBD who have been users of cannabis have reported that their symptoms get better when they use the drug.

"These initial results look extremely promising and exciting." - Dr Derek Scott from Aberdeen University

Dr Karen Wright and colleagues examined gut samples from healthy people and IBD patients and looked for the presence of two receptors known to react to natural cannabis-like compounds produced by the body.

Both the patients and the healthy people had similar numbers of CB1 receptors in their gut. However, the IBD patients had far greater numbers of CB2 receptors.

The normal job of CB1 and CB2 receptors is to switch immune responses on or off. CB1 receptors also help to promote wound healing in the lining of the gut.

Potential Therapy

Dr Wright said: "This gives us the first evidence that very selective cannabis-derived treatments may be useful as future therapeutic strategies in the treatment of Crohn's and ulcerative colitis.

"This is because some extracts from cannabis, known as cannabinoids, closely resemble molecules that occur naturally in our body, and by developing treatments that target this system, we can help the body recover from some of the effects of these diseases."

She said that the psychoactive effects and the legal implications associated with herbal cannabis use made it unsuitable as a treatment.

However, it might be possible to make a synthetic cannabis-like drug that has all of the therapeutic benefits and none of the other actions of cannabis.

"Targeting drug development to components of the in-built cannabinoid system could be the way forward," she said.

Dr Derek Scott, a researcher in Biomedical Sciences at Aberdeen University, said: "These initial results look extremely promising and exciting.

More Trials

"However, further work is required so that we can better understand exactly how the signalling pathways controlled by cannabinoid receptors might be targeted in IBD patients, and whether there might be any side-effects."

Cannabis-based medicines are already used for multiple sclerosis in some countries.

Dr John Zycheck, from the Peninsula Medical School in Plymouth, which has been granted £2 million to study these drugs for MS, said: "There is no reason why clinical studies could not be undertaken at a fairly early stage because we are already testing cannabinoids for a variety of different conditions.

"Cannabinoids do have an effect on the gut. It slows gut transit. We see it in our MS patients."

He said more work was needed to check whether these drugs would reduce inflammation and to work out a dose that was strong enough but not toxic.

Dr George Kunos from the US National Institutes of Health said an alternative approach could involve testing compounds that amplify the action of the body's natural cannabinoids by blocking their normal destruction in the gut.

He said animal studies suggested compounds that block the enzyme fatty acid amidohydrolase (FAAH) do this.

Dr John Bennett, Chairman of Core, a national gut and liver disorders charity, said: "I would not want any patient to think that a cannabis-based treatment for IBD is around the corner. Much more work is needed."

source: http://hempworld.com/HempPharm/articles/bowel.html

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 Previously unknown immune cell may help those with Crohn's and Colitis

By Gwen Ericson


Nov. 3, 2008 -- The tonsils and lymphoid tissues in the intestinal tract that help protect the body from external pathogens are the home base of a rare immune cell newly identified by researchers at Washington University School of Medicine in St. Louis. The researchers indicate that the immune cells could have a therapeutic role in inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis.

Their report will appear in an upcoming issue of the journal Nature and is currently available through advanced online publication.

"These cells have an anti-inflammatory effect," says the article's lead author Marina Cella, M.D., research associate professor of pathology and immunology. "In the gut, we have beneficial bacteria, and it's important that the body does not recognize them as something detrimental and start an inflammatory reaction, which could ultimately promote tissue damage and inflammatory or autoimmune diseases such as IBD. The cells we've discovered are important for keeping such harmful inflammatory processes in check."

The cells are a type of natural killer (NK) cells, which are white blood cells classically known to eliminate tumor cells and cells infected by viruses. Because of their killer tendencies, NK cells are carefully controlled and don't act until they receive the right signal.

Some of the signals that activate the newly discovered cells are the same signals that turn on a different immune cell with strong inflammatory properties that can promote cell death and tissue damage if chronically active. But the anti-inflammatory cells, termed NK-22 cells, that the Washington University researchers discovered have the opposite effect — they promote cell proliferation and wound healing.

"That finding suggests that these cells play a role in maintaining a balance in the immune system between inflammatory processes and anti-inflammatory processes," says coauthor Jason Mills, M.D., Ph.D., assistant professor of pathology and immunology and of developmental biology. "They make sure that factors that turn up inflammation can be counteracted by the coordinated activation of anti-inflammatory effects."

The NK-22 cells are part of the innate immune system, which reacts quickly to invading pathogens. The researchers found that in response to immune signals warning of foreign invaders, the cells produce copious quantities of a compound called IL-22, which is why the researchers chose to name them NK-22 cells.

"NK-22 cells are already present in the mucosal tissue of the gastrointestinal tract, and as soon as they see a pathogen, they react," Cella says. "That is a great advantage to the body because it produces a protective response in the very first hours of pathogenic attack."

Now that immunologists know NK-22 cells exist and what immune factors influence them, they may be able to capitalize on them to treat a variety of inflammatory diseases, the researchers say.

"Diseases such as inflammatory bowel disease result from a defect in the intestine's protective barrier," says senior author Marco Colonna, M.D., professor of pathology and immunology. "If we can develop methods to culture NK-22 cells, we may be able to use them to promote healing and protect the gastrointestinal tract."



source: http://mednews.wustl.edu/news/page/normal/12892.html"]

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Cannabinoids and intestinal motility: welcome to CB2 receptors

Angelo A Izzo1

1Department of Experimental Pharmacology, University of Naples Federico II, via D Montesano 49, 80131 Naples, Italy

Correspondence: Angelo A. Izzo, Department of Experimental Pharmacology, University of Naples Federico II, via D Montesano 49, 80131 Naples, Italy. E-mail: aaizzo@unina.it

Received 16 April 2004; Accepted 21 May 2004; Published online 26 July 2004.
Top of page
Abstract

Delta9-Tetrahydrocannabinol (the active ingredient of marijuana), as well as endogenous and synthetic cannabinoids, exert many biological functions by activating two types of cannabinoid receptors, CB1 receptors (expressed by central and peripheral neurons) and CB2 receptors (that occur mainly in immune cells). Convincing evidence has accumulated in recent years that cannabinoids inhibit gastric and intestinal motility through activation of enteric CB1 receptors. However, a report in this issue of British Journal of Pharmacology has highlighted the possibility that CB2 receptors in the rat intestine could contribute to reducing the increase of intestinal motility induced by an endotoxic inflammation. By minimizing the adverse psychotropic effects associated with brain cannabinoid receptors, the CB2 receptor represents a new molecular target for the treatment of motility disorders associated with intestinal inflammation.
Keywords:

Cannabinoid receptors, cyclooxygenase, inflammation, intestine, intestinal motility, lipopolysaccharide (LPS)
Abbreviations:

2-AG, 2-arachidonylglycerol; Delta9-THC, tetrahydrocannabinol; LPS, lipopolysaccharide; NOS, nitric oxide synthase

Botanical preparations of Cannabis sativa (Indian hemp) have been widely used in the past to treat a variety of disorders including those affecting the digestive tract. In 1964, Delta9-tetrahydrocannabinol (Delta9-THC) was isolated, and was later shown to be responsible for many of the pharmacological actions of Cannabis preparations. The understanding of the mechanism by which marijuana exerts its pharmacological actions has seen considerable progress following the discovery in the early 1990s of specific membrane, G-protein-coupled receptors for Delta9-THC, namely CB1 receptors, expressed by central and peripheral nerves (including the enteric nervous system), and CB2 receptors, which occur mainly in immune cells. The discovery of these receptors has led to the demonstration that there are endogenous agonists for these receptors. The best known are anandamide, 2-arachidonylglycerol (2-AG) (nonselective cannabinoid receptor agonists), noladin ether (CB1 receptor agonist) and virodhamine (CB1 receptor antagonist/CB2 receptor agonist). When released, anandamide and 2-AG are removed from extracellular compartments by a carrier-mediated reuptake process, and once within the cell, both endocannabinoids are hydrolyzed by the enzyme fatty acid amide hydrolase (also named anandamide amidohydrolase). In addition to the two cannabinoid receptors, anandamide and 2-AG (both detected in the gut) can also activate vanilloid receptors, the molecular target for the pungent plant compound capsaicin (for a review, see De Petrocellis et al., 2004).

Several recent, independent investigations provide compelling evidence that cannabinoids reduce gastrointestinal motility through activation of enteric CB1 receptors. Cannabinoid receptor agonists affect motility of isolated intestinal segments in a manner that resembles the neuromodulatory response to prejunctional mu-opioid receptor or alpha2-adrenoceptor activation of cholinergic, postganglionic parasympathetic neurones. Thus, a number of cannabinoid receptor agonists (via CB1 activation) have been shown to reduce or inhibit excitatory transmission, neural acetylcholine release and peristalsis efficiency in isolated intestinal segments. A functional evidence for the presence of prejunctional CB1 in the human isolated ileum and colon, through which the cannabinoid receptor agonist WIN55,212-2 inhibited electrically evoked contractile responses, has also been demonstrated. Consistent with these in vitro studies, cannabinoid receptor agonists reduce gastric, small intestinal and colonic motility in rodents in vivo, an effect counteracted by the selective CB1 receptor antagonist SR141716A, but not by the selective CB2 receptor antagonist SR144528. Interestingly, a CB1-mediated reduction of intestinal motility has been observed also in some pathophysiological states in mice, including the experimental ileus induced by intraperitoneal administration of acetic acid and the model of intestinal inflammation induced by oral croton oil (for a review, see Di Carlo & Izzo, 2003).

In this issue of the British Journal of Pharmacology, Mathison et al. (2004) provide pharmacological evidence that the CB1-mediated reduction of gastrointestinal transit was absent in rats treated with an endotoxic inflammatory agent, being replaced by a CB2-mediated inhibition of stimulated transit. It is reported that the selective CB2 receptor agonist JWH-133 was without effect in control animals, but it reduced the increase in gastrointestinal transit induced by intraperitoneal administration of lipopolysaccharide (LPS). The effect of JWH-133 was dose dependent and it was prevented by the selective CB2 receptor antagonist AM-630. Perhaps surprisingly, the selective CB1 receptor agonist ACEA inhibited motility in control rats but it was without effect in mice treated with LPS. The authors hypothesised that the lack of effect of CB1 receptor on LPS-stimulated gastrointestinal transit might reflect an inactivation of this receptor by this inflammatory stimulus. It is very unlikely that CB2 receptors are tonically activated by endogenous cannabinoids in this model of intestinal inflammation, since the CB2 antagonist alone was without effect in the LPS-induced increase in transit. Notably, it has been recently reported that endogenous cannabinoid anandamide exerts a protective role on cholera toxin-induced fluid accumulation via activation of overexpressed CB1 receptors on enteric cholinergic nerves (Izzo et al., 2003).
To examine the role of putative mediators that might be involved in the inhibition of LPS-stimulated increase in gastrointestinal transit by CB2 receptors, the authors evaluated a number of antagonists/inhibitors in the absence and presence of the CB2 receptor agonist JWH-133. Based on these experiments, it was convincingly demonstrated that the CB2 agonist acted via cyclooxygenase metabolites and independently of inducible nitric oxide synthase (NOS) and platelet-activating factor (PAF). Indeed, indomethacin completely abrogated the inhibitory effect of JWH-133, while the PAF receptor antagonist PCA 4248 or the inducible NOS inhibitor SATU did not modify JWH-133-induced motility changes. Preliminary evidence for the possible involvement of interleukin-1beta or endothelial NOS was also provided. Based upon these results and the literature, it is hypothesized that cannabinoids act on CB2 receptors expressed by inflammatory/immune and/or epithelial cells to inhibit the release of inflammatory mediators, which are known to stimulate intestinal peristalsis. Consistent with this scenario, Ihenetu and colleagues have recently reported that TNF-alpha-induced interleukin-8 release was inhibited by cannabinoids through activation of CB2 receptors in human colonic epithelial cells, which are recognised to exert a major influence in the maintenance of intestinal immune homeostasis (Ihenetu et al., 2003).

The potential therapeutic value of such findings seems to be relevant. Activation of CB2 receptors represents a novel mechanism for the re-establishment of normal gastrointestinal transit after an inflammatory stimulus. The strategy to use selective CB2 receptor agonists for the treatment of hypermotility during inflammatory bowel diseases is highly promising because it is likely to be devoid of the well-known Cannabis unwanted effects (e.g. Sedation, cognitive dysfunction, ataxia and psychotropic effects), which are due to activation of brain CB1 receptors. Also, it will be interesting to see in future studies whether a CB2 mechanism exists to protect the gut from the fluid hypersecretion and mucosal damage associated to endotoxic inflammation. Clearly, further exploration of the role of CB2 receptors in the gut is likely to produce worthwhile results.
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References

1. DE PETROCELLIS L., CASCIO M.G. & DI MARZO V. (2004) The endocannabinoid system: a general view and latest additions. Br. J. Pharmacol. 141: 765−774. | Article | PubMed | ChemPort |
2. DI CARLO G. & IZZO A.A. (2003) Cannabinoids for gastrointestinal diseases: potential therapeutic applications. Expert Opin. Investig. Drugs 12: 39−49. | Article | PubMed | ISI | ChemPort |
3. IHENETU K., MOLLEMAN A., PARSONS M.E. & WHELAN C.J. (2003) Inhibition of interleukin-8 release in the human colonic epithelial cell line HT-29 by cannabinoids. Eur. J. Pharmacol. 458: 207−215. | Article | PubMed | ChemPort |
4. IZZO A.A., CAPASSO F., COSTAGLIOLA A., BISOGNO T., MARSICANO G., LIGRESTI A., MATIAS I., CAPASSO R., PINTO L., BORRELLI F., CECIO A., LUTZ B., MASCOLO N. & DI MARZO V. (2003) An endogenous cannabinoid tone attenuates cholera toxin-induced fluid accumulation in mice. Gastroenterology 125: 765−774. | Article | PubMed | ISI | ChemPort |
5. MATHISON R., HO W., PITTMAN Q.J.M., DAVISON J.S. & SHARKEY K.A. (2004) Effects of cannabinoid receptor-2 activation on accelerated gastrointestinal transit in lipopolysaccharide-treated rats. Br J. Pharmacol. 142: 1247−1254. | Article | PubMed | ChemPort |

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Cannabis Helps - Crohn's/IBS

Although the use of cannabinoids as antiemetics (anti-nausea) is well-established, with Dronabinol available to stimulate appetite and counter effects of cancer chemotherapy, the effect of cannabinoids on disorders of the gut has not been extensively studied. However the current state of knowledge of the biochemistry of cannabinoids is increasing at an exponential rate and, with discoveries of cannabinoid receptors in unexpected areas of the body, new potential research/treatment avenues are appearing at an increasing rate.

Grinspoon reports anecdotal use of cannabis to control bowel movements in multiple sclerosis, and relief from the symptoms of Crohn’s disease. Mikuriya records irritable bowel syndrome, as well as other inflammatory gastrointestinal conditions (principally among AIDS patients), as one of a wide variety of conditions for which cannabis has been prescribed or recommended for therapeutic use in California.

There are no clinical trials currently published, and consequently use for the treatment of irritable bowel syndrome would represent at best an experimental therapy.

However, there does appear to be some scientific support for any claimed therapeutic benefits from the research literature concerning the actions and metabolism of cannabinoids and cannabinoid receptors. The wall of the intestine is composed of a type of muscle known as ‘smooth muscle’, also found lining the walls of arteries and in other involuntary functions.

Rosell et al first demonstrated that cannabinoids inhibit contractions of the small intestine in the rat. Pertwee et al established the presence of cannabinoid (CB1) receptors within the guinea-pig intestine and Kazuhisa et al established the presence of enzymes break down anandamide (the endogenous cannabinoid CB1-agonist) within the small intestine.

The smooth muscle-relaxant properties of cannabinoids are so well established that preparations of guinea-pig intestine are routinely used as an in vitro screening tool to test the potency and function of novel cannabinoids.

Shook & Burks found that THC reduced the frequency of intestinal contractions, and reduced the flow of food in the small intestine, without altering basal tone, and concluded that ‘delta 9-THC, delta 9,11-THC, cannabinol and nabilone (but not cannabidiol) exert an inhibitory effect on GI transit and motility in rats’.

Cadas et al reported that a gut enzyme (vasoactive intestinal peptide) may regulate the precursor chemical to anandamide (which activates cannabinoid CB1 receptors) and N-palmitoylethanolamine (which activates a CB2-like receptor subtype), suggesting that endogenous cannabinoids may play a role in regulating the activity of the gut.

source: http://www.budbuddies.com/cannabishelps/crohns_ibs.htm

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