Oregon Medical Marijuana Program
Cannabis May Offer Relief from Bowel Disorders
WEDNESDAY, Aug. 3 (HealthDay News) -- Cannabis-based drugs could prove effective for treating inflammatory bowel disease (IBD), a British study has found.
Researchers at the University of Bath were investigating whether cannabis -- marijuana -- can help relieve some IBD symptoms. They identified a potential new target for cannabis-based drugs to treat IBD, which includes Crohn's disease and ulcerative colitis. Some IBD patients report that their symptoms are reduced after they use cannabis.
The team examined gut samples from healthy people and IBD patients and looked at two specific receptors -- CB1 and CB2 -- that are found on the surface of cells in the gut and are known to be activated by certain molecules found in cannabis.
The investigators found that the presence of CB2 increases in IBD patients as their disease progresses. The researchers suggest that CB2 may be part of the body's natural mechanisms attempting to restore the gut to a normal, healthy state. If this is true, CB2 would be an ideal target for the development of new cannabis-based drugs to treat IBD, according to the report in the current issue of the journal Gastroenterology.
"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," researcher Dr. Karen Wright, from the department of pharmacy and pharmacology, said in a prepared statement.
"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," Wright said.
Cannabinoids Offer Novel Therapy For GI Disorders
June 15, 2006 - Mainz, Germany
Mainz, Germany: Cannabinoids protect the gastrointestinal (GI) tract from inflammation and abnormally high gastric secretions, and could potentially treat numerous GI-related disorders such as Crohn's disease and irritable bowl syndrome, according to review data published in the Journal of Endocrinological Investigation.
Investigators at Germany's Johannes Gutenberg University report that activation of the body's cannabinoid receptors protect the gastrointestinal tract from inflammation and modulate gastric secretions and intestinal motility. "For such protective activities, the endocannabinoid system may represent a new promising therapeutic target against different GI disorders, including inflammatory bowel diseases, functional bowel diseases, and secretion and motility disorders," they conclude.
Though the use of cannabis to treat symptoms of GI disorders has been reported anecdotally for several decades, virtually no clinical trials on the subject have been conducted. Survey data reported last fall in O'Shaughnessy's: The Journal of Cannabis in Clinical Practice, found that Crohn's patients experienced subjective benefits from cannabis, including pain relief and increased appetite. German investigators at the University Hospital in Munich are now assessing the efficacy of cannabis extracts for the treatment of Crohn's.
Researchers in the United Kingdom also reported last year that cannabinoids promote healing in the gastrointestinal membrane, and may provide therapeutic relief to patients with irritable bowel syndrome.
For more information, please contact Paul Armentano, NORML Senior Policy Analyst, at (202) 483-5500. Full text of the study, "Endocannabinoids and the gastrointestinal tract," appears in the current issue of the Journal of Endocrinological Investigation.
Mayo Study: Marijuana's THC Reduces Stomach Cramping
Sunday, October 29 2006 @ 09:10 PM EST
Edited by: Michael Hess
Science: THC reduces stomach cramping after eating according to a clinical study by the Mayo Clinic
IACM via BBSNews 2006-10-29 -- THC may relax the colon and reduce stomach cramping after eating, according to a study presented at the 71st Annual Scientific Meeting of the American College of Gastroenterology. The study compared the effects of dronabinol (THC) and placebo on colonic motility and sensation in healthy adults.
Doctors at the Mayo Clinic in Rochester, USA, conducted a double-blind, parallel-group study of 52 volunteers who were randomly assigned placebo or a single dose of dronabinol. The researchers found that THC relaxes the colon and reduces post- eating contractions and cramping. Further, the effects were most pronounced in females. "The potential for cannabinoids to modulate colonic motor function in disease deserves a further look," said study leader Dr. Tuba Esfandyari.
Cannabinoids and the gastrointestinal tract.
Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen Foresterhill, Aberdeen AB25 2ZD, UK. email@example.com
The enteric nervous system of several species, including the mouse, rat, guinea pig and humans, contains cannabinoid CB1 receptors that depress gastrointestinal motility, mainly by inhibiting ongoing contractile transmitter release. Signs of this depressant effect are, in the whole organism, delayed gastric emptying and inhibition of the transit of non-absorbable markers through the small intestine and, in isolated strips of ileal tissue, inhibition of evoked acetylcholine release, peristalsis, and cholinergic and non-adrenergic non-cholinergic (NANC) contractions of longitudinal or circular smooth muscle. These are contractions evoked electrically or by agents that are thought to stimulate contractile transmitter release either in tissue taken from morphine pretreated animals (naloxone) or in unpretreated tissue (gamma-aminobutyric acid and 5-hydroxytryptamine). The inhibitory effects of cannabinoid receptor agonists on gastric emptying and intestinal transit are mediated to some extent by CB1 receptors in the brain as well as by enteric CB1 receptors. Gastric acid secretion is also inhibited in response to CB1 receptor activation, although the detailed underlying mechanism has yet to be elucidated. Cannabinoid receptor agonists delay gastric emptying in humans as well as in rodents and probably also inhibit human gastric acid secretion. Cannabinoid pretreatment induces tolerance to the inhibitory effects of cannabinoid receptor agonists on gastrointestinal motility. Findings that the CB1 selective antagonist/inverse agonist SR141716A produces in vivo and in vitro signs of increased motility of rodent small intestine probably reflect the presence in the enteric nervous system of a population of CB1 receptors that are precoupled to their effector mechanisms. SR141716A has been reported not to behave in this manner in the myenteric plexus-longitudinal muscle preparation (MPLM) of human ileum unless this has first been rendered cannabinoid tolerant. Nor has it been found to induce "withdrawal" contractions in cannabinoid tolerant guinea pig ileal MPLM. Further research is required to investigate the role both of endogenous cannabinoid receptor agonists and of non-CB1 cannabinoid receptors in the gastrointestinal tract. The extent to which the effects on gastrointestinal function of cannabinoid receptor agonists or antagonists/inverse agonists can be exploited therapeutically has yet to be investigated as has the extent to which these drugs can provoke unwanted effects in the gastrointestinal tract when used for other therapeutic purposes.
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.