GASTROINTESTINAL DISORDERS - LUCKY 13 MARIJUANA RESEARCH PAPERS

GI Disorders - Medical Marijuana Research Papers Worldwide - 2000- 2017

GI Disorders - Medical Marijuana Research Papers Worldwide - 2000- 2017

 

RESEARCH HIGHLIGHTS

  • Complete remission was achieved by 5 of 11 subjects in the marijuana group.

  • Of the 30 patients 21 improved notably after treatment with marijuana.

  • Subjects receiving marijuana reported improved appetite and sleep, with no notable negative side effects.

  • Animal research indicates that cannabinoids work well to control gastro-esophageal reflux disease, where gastric acids attack the esophagus.  

  • Medications prescribed for this condition such as atropine, have serious adverse negative side effects, while marijuana based medicines are well tolerated.

  • Phyto-cannabinoids THC and CBD affect an improvement in the integrity of the lining of the gastrointestinal tract in animal-rodent studies.

  • THC-rich marijuana produced notable clinical, steroid-free benefits to 10 of 11 patients with active Crohn's disease-CD, compared with placebo, without negative side effects.  

 


PATIENT COMMENTARY

  • A terrific reliever of Crohn’s symptoms.

  • A more easily controlled medication than offered by pills.

  • Alcohol has been a big problem for me that I don’t have with marijuana.

  • Only positive effects, no negative effects.

  • Best appetite stimulant, very good calming effect.

  • Marijuana provides relief without knocking me out or other bad side effects that I had with steroids.

  • I’ve committed myself to this form of treatment, and my quality of life has improved by leaps and bounds.

  • I’ve struggled for years with opiate addiction from chronic pancreatitis —marijuana lets me control my pain without being a slave to opiates.

  • Marinol bothered my stomach —I don’t get sick, constipated, or vomit with marijuana.


 

1 MARIJUANA USE IN CROHN'S 90% REPORT IMPROVEMENT- NEARLY 50% IN FULL REMISSION

 

1 Marijuana induces a clinical response in patients with Crohn's disease-CD: a prospective placebo-controlled study. Naftali et.al. 2013.  Clinical Gastroenterology & Hepatology 11: 1276 to 1280. Massa & Monory. 2006. op. cit.

1 We examined 21 patients with Crohn's disease-CD Activity Index -CDAI scores greater than 200 who did not respond to treatment with steroids, immunomodulators, or anti-tumor necrosis factor-α agents. Patients were assigned randomly to groups given marijuana, two times daily, in the form of cigarettes containing 115 milligrams of d9THC  or placebo containing marijuana  bud from which the THC was extracted. Disease activity and laboratory tests were assessed during 8 weeks of treatment and 2 weeks thereafter.

1 Complete remission was achieved by 5 of 11 subjects in the marijuana group and 1 of 10 in the placebo group. A clinical response was observed in 10 of 11 subjects in the marijuana group and 4 of 10 in the placebo group. Three patients in the marijuana group were weaned from steroid dependency. Subjects receiving marijuana reported improved appetite and sleep, with no notable negative side effects.

1 THC-rich marijuana produced notable clinical, steroid-free benefits to 10 of 11 patients with active Crohn's disease-CD, compared with placebo, without negative side effects. Further studies, with larger patient groups and a nonsmoking mode of intake, are warranted.


 

2 66% NOTICEABLE IMPROVEMENT IN GI DISEASE WITH CANNABIS - SURGERY DOWN 820%

 

2 Treatment of Crohn's disease-CD with marijuana: an observational study.Naftali et.al. 2011.   Journal of the Israeli Medical Association 13: 455 to 458.

2 The marijuana plant marijuana is known to have therapeutic effects, including improvement of inflammatory processes. However, no report of patients using marijuana for Crohn's disease -CD was ever published.

2 Of the 30 patients 21 improved notably after treatment with marijuana. The need for other medication was notably reduced. Fifteen of the patients had 19 invasive surgeries during an average period of 9 years before marijuana use, however, only 2 required surgery during an average period of 3 years of marijuana use.

2 This is the first report of marijuana use in Crohn's disease-CD in people. The findings indicate that marijuana may have a positive effect on disease activity, as reflected by a reduction in disease activity index and in the need for other drugs and surgery. Prospective placebo-controlled studies are warranted to fully evaluate the efficacy and negative side effects of marijuana in Crohn's.


 

3 MARIJUANA IMPROVES MOOD, APPETITE, WEIGHT GAIN IN GI PATIENTS

3 Gastrointestinal illness & marijuana use in a rural Canadian community. Gahlinger, Paul M. 1984. Journal of Psychoactive Drugs 16: 263 to 265.

3 Marijuana and new cannabinoid drugs are attractive for Gastrointestinal-GI treatment because they can address a number of symptoms at once with minimal negative side effects.  Phyto-cannabinoids alter how the gut feels, affect the signals the brain sends back and forth to the gut and modulate the actions of the Gastrointestinal-GI tract itself.  Beginning in the 1970s, a series of human clinical trials established marijuana' ability to stimulate food intake and weight gain in healthy volunteers.  In a randomized trial, THC notably improved appetite and nausea in comparison with placebo.  

3 There were also trends towards improved mood and weight gain. Unwanted effects were mostly mild or moderate in severity.  Marijuana helps combat the painful and often debilitating cramping that accompanies many Gastrointestinal-GI conditions because phyto-cannabinoids relax contractions of the smooth muscle of the intestines.  In fact, smooth-muscle relaxant properties of phyto-cannabinoids are so well established that preparations of guinea-pig intestine are commonly used as an in vitro screening tool to test the potency and function of synthetic cannabinoids.

3 Research on different kinds of rodents has shown that endogenous (body's own) cannabinoids play crucial neuromodulatory roles in controlling the operation of the gastrointestinal system, with synthetic and natural phyto-cannabinoids acting powerfully to control gastrointestinal motility (move simultaneously) and inflammation.  Cannabinoid receptors comprise G-protein coupled receptors that are predominantly in enteric and central neurons and immune cells.  

3 The digestive tract contains endogenous (body's own) cannabinoids and cannabinoid CB1 receptors can be found on myenteric and submucosal nerves. Activating cannabinoid receptors has been demonstrated to inhibit gastrointestinal fluid secretion and inflammation in animal-rodent models.

3 In the last decade, evidence obtained from the use of selective agonists (dials-up) and inverse agonists/antagonists indicates that manipulation of CB1R can have notable findings.  Research has also shown that in the case of intestinal inflammation, the body will increase the number of cannabinoid receptors in the area in an attempt to regulate the inflammation by processing more cannabinoids.

 

3 Phyto-cannabinoids have a demonstrated ability to block spinal, peripheral and gastrointestinal mechanisms that promote pain in IBS and related conditions.   Animal  research also indicates that cannabinoids work well in controlling gastroesophageal reflux disease, a condition in which gastric acids attack the esophagus and for which commonly prescribed medications, such as atropine, have serious adverse negative side effects.

 

4 CANNABIS IMPROVES GUT LINING - AND SYMPTOMS IN GI

4 Marijuana alleviates symptoms of Crohn's disease-CD. Jeff Hergenrather. 2005. O’Shaughnessy’s 2: 3.

4 A pilot study of the effect of marijuana on Crohn’s disease was conducted in California this summer by physicians in the Society of Cannabis Clinicians. Crohn’s is an inflammatory bowel disease which is disabling and difficult to treat.

4 Our findings are supported the concept that phyto-cannabinoids activate the CB1 and CB2 receptors in the gut lining, promoting it to heal the inflamed lining of the gastrointestinal tract

 

 

5 MARIJUANA REPLACES BODY'S OWN CANNABINOIDS - THUMBS UP ON PAIN RELIEF

5 Cannabis use among patients with inflammatory bowel disease. Lal et.al. 2011.  European Journal of Gastroenterology & Hepatology 23: 891 to 896.

5 Experimental evidence suggests the endogenous (body's own) cannabinoid system may protect against colonic inflammation, leading to the possibility that activation of this system may have a therapeutic role in inflammatory bowel disease -IBD. Medicinal use of marijuana for chronic pain and other symptoms has been reported in a number of medical conditions. We aimed to evaluate marijuana use in patients with IBD.

5 Cannabis use is common amongst patients with IBD for symptom relief, particularly amongst those with a history of abdominal surgery, chronic abdominal pain and/or a low quality of life index. The therapeutic benefits of cannabinoid derivatives in IBD may warrant further exploration.

 

 

6 ORTHODOX MEDICINE NEEDS TO GET UP TO SPEED ON CANNABIS BASED MEDICINES

6 Marijuana use patterns among patients with inflammatory bowel disease. Ravikoff et.al. 2013.  Inflammatory Bowel Diseases 19: 2809 to 2814.

6 The prevalence and perceived effectiveness of marijuana consumption has not been well examined in inflammatory bowel disease -IBD despite increasing legal permission for its use in Crohn's disease-CD. Health care providers have little guidance about the IBD symptoms that may improve with marijuana use. The aim of this study was to assess the prevalence, sociodemographic (regional-type of people) characteristics, and perceived benefits of marijuana use among patients with IBD.

6 A notable number of patients with IBD currently use marijuana. Most patients find it very helpful for symptom control, including patients with ulcerative colitis, who are currently excluded from medical marijuana laws. Clinical trials are needed to determine marijuana's potential as an  Inflammatory bowel disease - IBD treatment and to guide prescribing decisions.

 

 

7 CELL RECEPTORS - CB1 & CB2 - HOLD THE SECRET TO INFLAMMATION

7 Endocannabinoids & the gastrointestinal tract. Massa & Monory. 2006. Journal of Endocrinological Investigation 29 -Suppl: 47 to 57.

7 In the past centuries, different preparations of marijuana have been used for the treatment of gastrointestinal -GI conditions, such as Gastrointestinal-GI pain, gastroenteritis and diarrhea. d9-THC; the active component of marijuana, as well as endogenous (body's own) and synthetic cannabinoids, exert their biological functions on the gastrointestinal tract by activating two types of cannabinoid receptors, cannabinoid type 1 receptor (CB1 receptor) and cannabinoid type 2 receptor (CB2 receptor).

7 While CB1 receptors are located in the enteric nervous system and in sensory terminals of vagal and spinal neurons and regulate neurotransmitter release, CB2 receptors are mostly distributed in the immune system, with a role presently still difficult to establish.

7 Under pathophysiological (physical observation in GI patient) conditions, the endocannabinoid system conveys protection to the Gastrointestinal-GI tract, eg from inflammation and abnormally high gastric and enteric secretion. For such protective activities, the endocannabinoid system may represent a new high-potential therapeutic target against different Gastrointestinal-GI conditions, including frankly inflammatory bowel diseases - Crohn's disease-CD, functional bowel diseases like irritable bowel syndrome - IBS, and secretion- and motility (move simultaneously)-related conditions.

 

8 CANNABIS DIALS DOWN RECEPTORS THAT CAUSE OVER CONTRACTION OF GI

8 Phyto-cannabinoids & the gastrointestinal tract. Roger Pertwee. 2001. Gut 48: 859 to 867.

8 The enteric nervous system of several species, including the mouse, rat, guinea pig and people, contains cannabinoid CB1 receptors that depress gastrointestinal motility (move simultaneously), mainly by inhibiting ongoing contractile transmitter release.

8 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 nonadrenergic 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 or in non pretreated tissue.

8 The inhibitory effects of cannabinoid receptor agonists (dials-up) on gastric emptying and intestinal transit are modulated 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.

8 Cannabinoid receptor agonists (dials-up) delay gastric emptying in people 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 (dials-up) on gastrointestinal motility (move simultaneously).

8 Findings that the CB1 selective antagonist/inverse agonist (dials-up)SR141716A (anti-obesity drug) produces in vivo and in vitro signs of increased motility (move simultaneously) of the rodent small intestine probably reflect the presence in the enteric nervous system of a population of CB1 receptors that are pre coupled 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.

8 Further research is required to investigate the role both of endogenous (body's own) cannabinoid receptor agonists (dials-up) and of non-CB1 cannabinoid receptors in the gastrointestinal tract. The extent to which the effects on gastrointestinal function of cannabinoid receptor agonists (dials-up) 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.

 

9 MANIPULATION OF BODY - INFLAMMATION - PAIN - CLEARLY POSSIBLE WITH NATURAL AND SYNTHETIC CANNABINOIDS

9 Phyto-cannabinoids for gastrointestinal diseases: potential therapeutic applications. DiCarlo & Izzo. 2003.  Expert Opinion on Investigational Drugs 12: 39 to 49.

9 There is anecdotal (user testimony) evidence for the therapeutic benefit of phyto-cannabinoids in different kinds of human disease conditions, that spans over many centuries. Recently, however, in-depth research efforts have begun to document the biological mechanism involved. In addition, it is becoming clear that a pharmacological manipulation of the endogenous (body's own) cannabinoid system could have important therapeutic applications, including for the pathologies of the digestive system.  

9 The future should involve the study of strategies for reducing or abolishing the adverse effect of cannabinoid agonists (dials-up) without attenuating their beneficial clinical effects.  The unwanted central effects of cannabinoid agonists (dials-up) are probably modulated largely by CB1 receptors in the brain. These include sedation, cognitive dysfunction, ataxia and immunosuppressant effects, as well as psychotropic effects. The side-effect profile of cannabinoid antagonists (dials-up) is less understood. There are different possible strategies for minimising the unwanted negative side effects.
 

9 The first being the design of selective CB1 receptor agonists (dials-up) that do not readily cross the blood barrier , as a drug of this kind might be able to reduce intestinal motility (move simultaneously) and secretion by acting on the CB1 receptors located on enteric nerves. The second strategy would be to adopt the approach often used for the management of depression: drugs that block endocannabinoids (body's own) inactivation should magnify their physical effects in the same way as serotonin re-uptake or monoamine oxidase - MAO inhibitors heighten the mood-regulating actions of endogenous (body's own) biogenic amines.

9 Indirect activation of cannabinoid receptors is expected to be more advantageous than direct-acting cannabinoid receptor drugs, because inhibitors of anandamide inactivation are unlikely to affect endocannabinoid levels at one time, producing instead effects only at sites where ongoing production of endocannabinoids (body's own) is taking place. If the released endocannabinoids (body's own) participate in the modulation of specific gut disease, it is likely that this strategy will be successful.  This approach would also abolish the peripheral negative side effects associated with activation of peripheral CB1 receptors.
 

9 A third strategy would be to focus on non- CB1-modulated effects, as there is evidence from in vitro studies that anandamide and WIN-552122 exert inhibitory effects on intestinal and gastric motility (move simultaneously), respectively, via activation of non- CB1, non-CB2 receptors. This strategy is more hi-potential because it is likely devoid of psychotropic effects. However, to validate such an approach, this mechanism needs to be fully elucidated.
 

9 Finally, animal-rodent studies suggest that the cannabimimetic substance palmitoylethanolamide (a fatty acid released with a body produced cannabinoid) possesses anti inflammatory and anti motility (move simultaneously) actions which are not modulated by cannabinoid receptor activation. These effects open up the possibility that this compound, which, unlike anandamide, has weak psychotropic effects, can be used as a possible therapeutic drug for the treatment of intestinal hypermotility (move simultaneously) during inflammatory bowel diseases.

 

10 CANNABIS RECEPTORS CONTROL ALL - FILL, HOLD, MOVE AND EMPTY INTESTINES

10 The endocannabinoid system in the physiology and pathophysiology of the gastrointestinal tract. Massa et.al. 2005. Journal of Molecular Medicine 12: 944 to 954.

10 Numerous investigations have recently demonstrated the important roles of the endocannabinoid system in the gastrointestinal-GI tract under physical and pathophysiological (physical observation in GI patient) conditions. In the Gastrointestinal-GI tract, cannabinoid type 1 - CB1 receptors are present in neurons of the enteric nervous system and in sensory terminals of vagal and spinal neurons, while cannabinoid type 2 receptors are located in immune cells. Activation of CB1 receptors was shown to modulate several functions in the Gastrointestinal-GI tract, including gastric secretion, gastric emptying and intestinal motility (move simultaneously).

10 Under pathophysiological conditions caused experimentally in rodents, the endocannabinoid system conveys protection to the Gastrointestinal-GI tract. Such protective activities are largely in agreement with anecdotal (user testimony) reports from folk medicine on the use of Cannabis sativa extracts by subjects suffering from various Gastrointestinal-GI conditions.

10 Thus, the endocannabinoid system may serve as a high-potential therapeutic target against different Gastrointestinal-GI conditions, including frankly inflammatory bowel diseases like Crohn's disease-CD; functional bowel diseases like irritable bowel syndrome - IBS and secretion- and motility (move simultaneously)-related conditions.

10 As stimulation of this modulator system by CB1 receptor agonists (dials-up) can lead to unwanted psychotropic negative side effects, an alternative and hi-potential avenue for therapeutic applications resides in the treatment with CB1 receptor agonists (dials-up) that are unable to cross the blood-brain barrier, or with compounds that inhibit the degradation of endogenous (body's own) ligands -endocannabinoids (body's own) of CB1 receptors, hence prolonging the activity of the endocannabinoid system.

 

11 EXPOSED CELLS OF INTESTINAL TRACT HAVE RECEPTORS THAT CAN HAVE ACTIVITY NORMALIZED BY CANNABIS

11 Differential expression of cannabinoid receptors in the human colon: cannabinoids promote epithelial wound healing. Wright et.al. 2005.Gastroenterology 129: 437 to 453.

11 Aim: Two G-protein - coupled cannabinoid receptors, termed CB1 and CB2, have been identified and several mammalian enteric (surface cells) nervous systems express CB1 receptors and produce endocannabinoids (body's own). An immunomodulatory role for the endocannabinoid system in gastrointestinal inflammatory conditions has been proposed and this study sought to determine the location of both cannabinoid receptors in human colon and to investigate the epithelial receptor function.

11 Findings & data - The location of CB1 and CB2 receptors in human colonic tissue was determined by immunohistochemistry. Primary colonic epithelial cells were treated with both synthetic and endogenous (body's own) cannabinoids in vitro, and biochemical coupling of the receptors to known signaling events was determined by immunoblotting. Human colonic epithelial cell lines were used in cannabinoid-binding studies and as a model for in vitro wound-healing experiments.

11 CB1-receptor immunoreactivity was evident in normal colonic epithelium -cellular lining, smooth muscle, and the submucosal myenteric plexus. CB1- and CB2-receptor expression was present on plasma cells in the lamina propria, whereas only CB2 was present on macrophages. CB2 immunoreactivity was seen in the epithelium -cellular lining of the colonic tissue - characteristic of inflammatory bowel disease. Phyto-cannabinoids enhanced epithelial wound closure either alone or in combination with lysophosphatidic acid through a CB1- lysophosphatidic acid 1 heteromeric receptor complex.

11 CB1 receptors are expressed in normal human colon and colonic epithelium - cellular lining is responsive biochemically and functionally to cannabinoids. Increased epithelial CB2-receptor expression in human inflammatory bowel disease tissue implies an immunomodulatory role that may impact on mucosal immunity.

 

12 CANNABIS WORKS IN GI DISORDERS - WANT TO KNOW MORE ABOUT HOW

12 Cannabinoids & the digestive tract. Izzo & Coutts. 2005 Handbook of Experimental Pharmacology 168: 573 to 598.

12 Cannabinoid pretreatment induces tolerance to the inhibitory effects of cannabinoid receptor agonists (dials-up) on gastrointestinal motility (move simultaneously). Findings that the CB1 selective antagonist/inverse agonist (dials-up) SR141716A (anti-obesity drug)  produces in vivo (natural) and in vitro (artificial) signs of increased motility (move simultaneously) of the rodent small intestine.... probably reflect the presence in the enteric nervous system of a population of CB1 receptors that are pre coupled to their effector mechanisms. SR141716A (anti-obesity drug) 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.

12 Nor was cannabis found to induce "withdrawal" contractions in cannabinoid tolerant guinea pig ileal MPLM. Further research is required to investigate the role both of endogenous (body's own) cannabinoid receptor agonists (dials-up) 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.

 

 

13 ESTABLISHED MEDICAL RESEARCHERS GET INTERESTED IN THE WHOLE PLANT, NON-THC CANNABINOIDS

13 Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Izzo et.al. 2009. Trends in Pharmacological Sciences 30: 515 to 527.

13 d9-THC binds cannabinoid - CB1 and CB2 receptors, which are activated by endogenous (body's own) compounds -endocannabinoids (body's own) and are involved in a wide range of physiopathological processes affecting: neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions. The well-known psychotropic effects of d9-THC, which are modulated by activation of brain CB1 receptors, have greatly limited its clinical use.

13 However, the Cannabis plant contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more potent than d9-THC. Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids.

13 Special emphasis is given to cannabidiol, the possible applications, of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to d9-THCV, a novel CB1 antagonist (dials-up)which exerts potentially useful actions in the treatment of epilepsy and obesity.    

 

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Labels: crohn's GI gastrointestinal GI Disorder inflammation pain stomach ache IBD

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