Cannabinoids Treat Gastrointestinal Disorders

Peptic Ulcer

A peptic ulcer is erosion in the lining of the stomach or the first part of the small intestine, an area called the duodenum.
If the peptic ulcer is located in the stomach, it is called a gastric ulcer.
A peptic ulcer, also known as PUD or peptic ulcer disease,  is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful.  It is defined as mucosal erosions equal to or greater than 0.5 cm.  As many as seventy to ninety percent of such ulcers are associated with Helicobacter pylori, a spiral-shaped bacterium that lives in the acidic environment of the stomach; however, only forty percent  of those cases go to a doctor.  Ulcers can also be caused or worsened by drugs such as aspirin, Plavix (clopidogrel), ibuprofen, and other NSAIDs.

Contrary to general belief, four times as many peptic ulcers arise in the duodenum—the first part of the small intestine, just after the stomach—rather than in the stomach itself.  About four percent  of stomach ulcers are caused by a malignant tumor, so multiple biopsies are needed to exclude cancer.  Duodenal ulcers are generally benign.

Causes

A major causative factor (60% of gastric and up to 90% of duodenal ulcers) is chronic inflammation due to Helicobacter pylori that colonizes the antral mucosa.  The immune system is unable to clear the infection, despite the appearance of antibodies.  Thus, the bacterium can cause a chronic active gastritis (type B gastritis), resulting in a defect in the regulation of gastrin production by that part of the stomach, and gastrin secretion can either be increased, or as in most cases, decreased, resulting in hypo- or achlorhydria.  Gastrin stimulates the production of gastric acid by parietal cells and, in H. pylori colonization responses that increase gastrin, the increase in acid can contribute to the erosion of the mucosa and therefore ulcer formation.

Another major cause is the use of NSAIDs .  The gastric mucosa protects itself from gastric acid with a layer of mucus, the secretion of which is stimulated by certain prostaglandins.  NSAIDs block the function of cyclooxygenase 1 (cox-1), which is essential for the production of these prostaglandins.  COX-2 selective anti-inflammatories (such as celecoxib or the since withdrawn rofecoxib) preferentially inhibit cox-2, which is less essential in the gastric mucosa, and roughly halve the risk of NSAID-related gastric ulceration.  As the prevalence of H. pylori-caused ulceration declines in the Western world due to increased medical treatment, a greater proportion of ulcers will be due to increasing NSAID use among individuals with pain syndromes as well as the growth of aging populations that develop arthritis.

The incidence of duodenal ulcers has dropped significantly during the last 30 years, while the incidence of gastric ulcers has shown a small increase, mainly caused by the widespread use of NSAIDs.  The drop in incidence is considered to be a cohort-phenomenon independent of the progress in treatment of the disease.  The cohort-phenomenon is probably explained by improved standards of living which has lowered the incidence of H. pylori infections.

Although some studies have found correlations between smoking and ulcer formation,  others have been more specific in exploring the risks involved and have found that smoking by itself may not be much of a risk factor unless associated with H. pylori infection.  Some suggested risk factors such as diet, spice consumption and blood type, were hypothesized as ulcerogens (helping cause ulcers) until late in the 20th century, but have been shown to be of relatively minor importance in the development of peptic ulcers.  Similarly, while studies have found that alcohol consumption increases risk when associated with H. pylori infection, it does not seem to independently increase risk, and even when coupled with H. pylori infection, the increase is modest in comparison to the primary risk factor.

Gastrinomas (Zollinger Ellison syndrome), rare gastrin-secreting tumors, also cause multiple and difficult-to-heal ulcers.
Most ulcers occur in the first layer of the inner lining.  A hole that goes all the way through the stomach or duodenum is called a perforation. A perforation is a medical emergency.The following also raise your risk for peptic ulcers:

• Drinking too much alcohol
• Regular use of aspirin, ibuprofen, naproxen, or other nonsteroidal anti-inflammatory drugs (NSAIDs).  Taking aspirin or NSAIDs once in awhile is safe for most people.
• Smoking cigarettes or chewing tobacco
• Being very ill, such as being on a breathing machine
• Radiation treatments

Many people believe that stress  causes ulcers.  It is not clear if this is true, at least for everyday stress at home.
The diagnosis is mainly established based on the characteristic symptoms.  Stomach pain is usually the first signal of a peptic ulcer.  In some cases, doctors may treat ulcers without diagnosing them with specific tests and observe whether the symptoms resolve, this indicating that their primary diagnosis was accurate.

Symptoms

Small ulcers may not cause any symptoms.  Some ulcers can cause serious bleeding.

• Abdominal pain is a common symptom but it doesn't always occur.  The pain can differ a lot from person to person.
• Feeling of fullness unable to drink as much fluid
• Hunger and an empty feeling in the stomach, often 1 - 3 hours after a meal
• Mild nausea (vomiting may relieve symptom)
• Pain or discomfort in the upper abdomen
• Upper abdominal pain that wakes you up at night
• Other possible symptoms include:
• Bloody or dark tarry stools
• Chest pain
• Fatigue
• Vomiting, possibly bloody
• Weight loss

Treatment

The best way to stop any further growth of a stomach ulcer is to follow a healthy diet.  It must contain non-acidic meals along with liquid meals.  Sour agents like lemon should be strictly avoided in the diet.  Younger patients with ulcer-like symptoms are often treated with antacids or H2 antagonists before EGD is undertaken.  Bismuth compounds may actually reduce or even clear organisms, though the warning labels of some bismuth subsalicylate products indicate that the product should not be used by someone with an ulcer.

Patients who are taking nonsteroidal anti-inflammatories (NSAIDs) may also be prescribed a prostaglandin analogue (Misoprostol) in order to help prevent peptic ulcers, which may be a side-effect of the NSAIDs.
When H. pylori infection is present, the most effective treatments are combinations of two  antibiotics (e.g. Clarithromycin, Amoxicillin, Tetracycline, Metronidazole) and one  proton pump inhibitor (PPI), sometimes together with a bismuth compound.  In complicated, treatment-resistant cases, three antibiotics (e.g. amoxicillin + clarithromycin + metronidazole) may be used together with a PPI and sometimes with bismuth compound.  An effective first-line therapy  for uncomplicated cases would be Amoxicillin + Metronidazole + Pantoprazole (a PPI).  In the absence of H. pylori, long-term higher dose PPIs are often used.

Treatment of H. pylori usually leads to clearing of infection, relief of symptoms and eventual healing of ulcers.  Recurrence of infection can occur and retreatment may be required, if necessary with other antibiotics.  Since the widespread use of PPI's in the 1990s, surgical procedures (like "highly selective vagotomy") for uncomplicated peptic ulcers  became obsolete.
Perforated peptic ulcer is a surgical emergency and requires surgical repair of the perforation.  Most bleeding ulcers require endoscopy urgently to stop bleeding with cautery, injection, or clipping.

Ranitidine provides relief of peptic ulcers, heartburn, indigestion and excess stomach acid and prevention of these symptoms associated with excessive consumption of food and drink.  Ranitidine is available over the counter from a pharmacy and works by decreasing the amount of acid the stomach produces allowing healing of ulcers.  Zantac tablets contain Ranitidine ( 150 mg)  as the active ingredient which can also be bought generically.

Sucralfate, (Carafate) has also been a successful treatment of peptic ulcers.

Complications

Gastrointestinal bleeding is the most common complication.  Sudden large bleeding can be life-threatening.  It occurs when the ulcer erodes  one of the blood vessels, such as the gastroduodenal artery.
Perforation (a hole in the wall) often leads to catastrophic consequences.  Erosion of the gastro-intestinal wall by the ulcer leads to spillage of stomach or intestinal content into the abdominal cavity.  Perforation at the anterior surface of the stomach leads to acute  peritonitis, initially chemical and later bacterial peritonitis.  The first sign is often sudden intense abdominal pain.

• Bleeding inside the body (internal bleeding)
• Gastric outlet obstruction
• Inflammation of the tissue that lines the wall of the abdomen (peritonitis)
• Perforation of the stomach and intestines

Posterior wall perforation leads to bleeding due to involvement of gastroduodenal  artery that lies posterior to the first  part of duodenum.
Penetration is when the ulcer continues into adjacent organs such as the liver and pancreas.
Scarring and swelling due to ulcers causes narrowing in the duodenum and gastric outlet obstruction. Patient often presents with severe  vomiting.
Cancer is included in the differential diagnosis (elucidated by biopsy), Helicobacter pylori as the etiological factor making it three to six times more likely to develop stomach cancer from the ulcer.
Peptic ulcers tend to come back if untreated.  If you follow your doctor's treatment instructions and take all of your medications as directed,  the H. pylori infection will be cured and you will be much less likely to get another ulcer.

Prevention

Avoid aspirin, ibuprofen, naproxen, and other NSAIDs.  Try acetaminophen instead.  If you must take such medicines, talk to your doctor first.  Your doctor may:

• Test you for H. pylori first
• Have you take proton pump inhibitors (PPIs) or an acid blocker
• Have you take a drug called misoprostol
• The following lifestyle changes may help prevent peptic ulcers:
• Do not smoke or chew tobacco.
• Limit alcohol to no more than two drinks per day.

History

John Lykoudis,  a general practitioner in Greece, treated patients for peptic ulcer disease with antibiotics, beginning in 1958, long before it was commonly recognized that bacteria were a dominant cause for the disease.
Helicobacter pylori was rediscovered in 1982 by two Australian scientists, Robin Warren and Barry J. Marshall as a causative factor for ulcers.  In their original paper, Warren and Marshall contended that most stomach ulcers and gastritis were caused by colonization with this bacterium, not by stress or spicy food as had been assumed before.

The H. pylori hypothesis was poorly received, so in an act of self-experimentation Marshall drank a Petri dish containing a culture of organisms extracted from a patient and five days later developed gastritis.  His symptoms disappeared after two weeks, but he took antibiotics to kill the remaining bacteria at the urging of his wife, since halitosis is one of the symptoms of infection.  This experiment was published in 1984 in the Australian Medical Journal and is among the most cited articles from the journal.

In 1997, the Centers for Disease Control and Prevention, with other government agencies, academic institutions, and industry, launched a national education campaign to inform health care providers and consumers about the link between H. pylori and ulcers.  This campaign reinforced the news that ulcers are a curable infection, and that health can be greatly improved and money saved by disseminating information about H. pylori.
In 2005, the Karolinska Institute in Stockholm awarded the Nobel Prize in Physiology or Medicine to Dr. Marshall and his long-time collaborator Dr. Warren "for their discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease."  Professor Marshall continues research related to H. pylori and runs a molecular biology lab at UWA in Perth, Western Australia.

It was a previously widely accepted misunderstanding that the use of chewing gum resulted in gastric ulcers.  The medical profession believed that mastication stimulated production of hydrochloric acid in the stomach and that hyperchlorhydria in the absence of food would erode the stomach lining.

On the other hand, in the recent past, some believed that mastic gum, a tree resin extract, actively eliminates the H. pylori bacteria.  However, multiple subsequent studies have found no effect of using mastic gum on reducing H. pylori levels.

Medical Marijuana and Peptic Ulcers

Medical benefits of marijuana for people with gastrointestinal disorders were backed up by the United States Institute of Medicine medical marijuana study. According to the Institute, “For patients who suffer simultaneously from severe pain, nausea, and appetite loss, cannabinoid drugs might offer broad-spectrum relief not found in any other single medication."
Medical marijuana can be used to treat a variety of diseases and symptoms related to the gastrointestinal system. Cannabis helps combat cramping that accompanies many GI disorders because cannabinoids relax contractions of the smooth muscle of the intestines.  Research shows that the body’s own cannabinoids, known as anandamides, affect neurological systems that control the gastrointestinal system.  External and internal cannabinoids strongly control gastrointestinal motility and inflammation. They also have the ability to decrease gastrointestinal fluid secretion and inflammation.  This means that cannabis can be useful to stop ulcers and other syndromes.
Studies indicate that cannabinoids in marijuana bind with cannabinoid receptors in the digestive tract, especially the small and large intestine, causing muscle relaxation, reduction of inflammation, analgesia, increased nerve-muscle coordination, anti-emesis, and relief of spasms such as those that cause nausea.

The overall opinion of enlightened people in the medical community is that medical cannabis can interact with the endogenous cannabinoid system to reduce problems associated with nausea, vomiting, gastric ulcers, irritable bowel syndrome, Crohn's disease, secretory diarrhea, paralytic ileus and gastroesophageal reflux disease.
There are no clinical studies with cannabinoids in gastric ulcers. However, THC and other substances that bind to the cannabinoid-1-receptor (CB1 receptor agonists) inhibited the gastric acid production in humans and the formation of ulcers in animals.
The nervous system of the bowel of several species, including the mouse, rat, guinea pig and humans, contains cannabinoid CB1 receptors that depress motility of stomach and intestine.
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.

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.

Modified according to: Pertwee RG. Cannabinoids and the gastrointestinal tract. Gut 2001;48(6):859-867

In anaesthetized rats the non selective CB-receptor agonist WIN 55,212-2 and the selective CB(1)-receptor agonist HU-210 dose-dependently decreased the acid secretion. Our results indicate that the antisecretory effects of cannabinoids on the rat stomach are mediated by suppression of the activity of the vagus nerve on the stomach through activation of CB1 receptors.
Modified according to: Adami M, et al. Gastric antisecretory role and immunohistochemical localization of cannabinoid receptors in the rat stomach. Br J Pharmacol 2002;135(7):1598-1606.

In 90 volunteers participating in a vaccine-development programme consumption of beer more than 3 days a week was linked with high stomach acid output, and smoking of cannabis greater than 2 days a week was linked with low acid output. in one word less protection againt helico and pepsin.

Source: Nalin DR, et al. Cannabis, hypochlorhydria, and cholera. Lancet 1978;2(8095):859-862.

Increasing number of evidence suggest that gastric mucosal protection can be induced also centrally.  Several neuropeptides, such as TRH, amylin, adrenomedullin, enkephalin, β-endorphin, nociceptin, nocistatin, ghrelin or orexin given centrally induce gastroprotection and the dorsal vagal complex and vagal nerve may play prominent role in this centrally initiated effect.  Since also cannabinoid receptors are present in the dorsal vagal complex, we aimed to study whether activation of central cannabinoid receptors result in gastric mucosal defense and whether there is an interaction between cannabinoids and endogenous opioids. Gastric mucosal damage was induced by 100% ethanol in rats.  The cannabinoids were given intravenously (i.v.) or intracerebroventricularly (i.c.v.), while the antagonists were given i.c.v or intracisternally (i.c.).  Gastric lesions were evaluated macroscopically 60 min later. Anandamide, methanandamide and WIN55,212-2 reduced ethanol-induced mucosal lesions after both peripheral (0.28-5.6 µmol/kg, 0.7-5.6 µmol/kg and 0.05-0.2 µmol/kg i.v., respectively) and central (2.9-115 nmol/rat, 0.27-70 nmol/rat and 1.9-38 nmol/rat i.c.v., respectively) administration.  The gastroprotective effect of anandamide and methanandamide given i.c.v. or i.v.was reversed by the CB1 receptor antagonist SR141716A (2.16 nmol i.c.v.). Naloxone (27.5 nmol i.c.v.) also antagonized the effect of i.c.v. or i.v. injected anandamide
and WIN55,212-2, but less affected that of methanandamide.  The gastroprotective effect of anandamide was diminished also by endomorphin-2 antiserum.  In conclusion it was first demonstrated that activation of central CB1 receptors results in gastroprotective effect. The effect is mediated at least partly by endogenous opioids.

Can cannabis be helpful in gastric ulcers?

Answers:

• Franjo Grotenhermen
  There are no clinical studies with cannabinoids in gastric ulcers. However, THC and other substances that bind to the cannabinoid-1-receptor (CB1 receptor agonists) inhibited the gastric acid production in humans and the formation of ulcers in animals.
• Roger Pertwee
  The nervous system of the bowel of several species, including the mouse, rat, guinea pig and humans, contains cannabinoid CB1 receptors that depress motility of stomach and intestine. (...)
  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. (...)
  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.
  Modified according to: Pertwee RG. Cannabinoids and the gastrointestinal tract. Gut 2001;48(6):859-867.
• Adami et al.
  In anaesthetized rats the non selective CB-receptor agonist WIN 55,212-2 and the selective CB(1)-receptor agonist HU-210 dose-dependently decreased the acid secretion. (...) Our results indicate that the antisecretory effects of cannabinoids on the rat stomach are mediated by suppression of the activity of the vagus nerve on the stomach through activation of CB1 receptors.

Modified according to: Adami M, et al. Gastric antisecretory role and immunohistochemical localization of cannabinoid receptors in the rat stomach. Br J Pharmacol 2002;135(7):1598-1606.
Sofia et al.
Delta-9-tetrahydrocannabinol (THC) inhibited ulcer formation in the rat. However, this antiulcer activity of THC was substantially less than for tridihexethyl chloride.
Modified according to: Sofia RD, et al. Evaluation of antiulcer activity of delta9-tetrahydrocannabinol in the Shay rat test.  Pharmacology 1978;17(3):173-177.

Nalin et al.
In 90 volunteers participating in a vaccine-development programme consumption of beer more than 3 days a week was linked with high stomach acid output, and smoking of cannabis greater than 2 days a week was linked with low acid output.
Source: Nalin DR, et al. Cannabis, hypochlorhydria, and cholera. Lancet 1978;2(8095):859-862.

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[i] reports anecdotal use of cannabis to control bowel movements in multiple sclerosis, and relief from the symptoms of Crohn"s disease. Mikuriya[ii] 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. Consroe et al[iii], in an anonymous survey of 112 MS patients, found a large proportion reported improvements in bowel and bladder dysfunction from smoked cannabis.  There are no clinical trials currently published, although I understand GW trials of cannabis extracts on patients with bowel disorders are either under way or at an advanced stage of planning.

However, there does appear to be some scientific support for 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.  Cannabinoids relax smooth muscles.
Intestinal Motility and Irritable Bowel Syndrome:
The CB1 cannabinoid receptor has specifically been found to inhibit motility of the intestine in a variety of laboratory and farm animals.  The effect is specific, indicating that endogenous cannabinoids to be responsible for regulating smooth muscle tone in the intesting, and the rate of peristalsis.

Summary - Cannabinoids and the GI Tract:

While I am not aware of any published results from controlled human studies of medical use of cannabis in the treatment of conditions such as gastric ulcers or irritable bowel syndrome, there appears to be sufficient animal evidence of the potential efficacy of cannabis in reducing intestinal spasms, ulceration and gastric acid secretion to merit further research into this and related indications.

Recommendation:  Indica x Sativa hybrid.  Whole plant extracts.  Vaporizer, Tinctures (under the tongue), Suppositories, Edibles (maybe), CannaButter.
Get the medicine into the system as quickly as possible.

References

Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary;  HAS Institute of Experimental Medicine, Budapest, Hungary;
Department of Pathophysiology, Faculty of Medicine,
Semmelweis University, Budapest, HungaryReferences
[i] Grinspoon L & Bakalar JB (1997) Marijuana - The Forbidden Medicine (2nd Ed) Yale University Press
[ii] Mikuriya TH (1998) International Classification of Diseases 9-CM 1996 - Conditions treated with cannabis, encountered 1994-1998.
[iii] Consroe P, Musty R, Rein J, Tillery W, Pertwee R. [1997] The perceived effects of smoked cannabis on patients with multiple sclerosis. Eur Neurol 38(1):44-8
[iv] Rosell S, Agurell S & Martin B (1976) Effects of cannabinoids on isolated smooth muscle preparations. Ch in Nahas (Ed) Marijuana, Chemistry, Biochemistry & Cellular Effects. pp 397-406. Springer-Verlag
[v] Pertwee RG, Fernando SR, Nash JE, Coutts AA. (1996). Further evidence for the presence of cannabinoid CB1 receptors in guinea pig small intestine. Br. J. Pharmacol. 118:2199•205
[vi] Kazuhisa K, Natsuo U, Yuko K, Hiroshi S, Shozo Y, Itsuo K (1997) Distribution of anandamide amidohydrolase in rat tissues with special reference to small intestine, BBA - Lipids And Lipid Metabolism (1347) 2-3 pp. 212-218
[vii] Katayama K, Ueda N, Kurahashi Y, Suzuki H, Yamamoto S, Kato I. [1997] Distribution of anandamide amidohydrolase in rat tissues with special reference to small intestine. Biochim Biophys Acta 1347(2-3):212-8
[viii] Martin BR, Thomas BF & Razdan K (1995) Structural requirements for cannabinoid receptor probes. Ch in Pertwee RG (Ed) Cannabinoid Receptors. London: Academic Press
[ix] Lan R, Liu Q, Fan P, Lin S, Fernando SR, McCallion D, Pertwee R, Makriyannis A. [1999] Structure-activity relationships of pyrazole derivatives as cannabinoid receptor antagonists. J Med Chem 42(4):769-76
[x] Shook JE, and Burks TF (1989) Psychoactive cannabinoids reduce gastrointestinal propulsion and motility in rodents J Pharmacol Exp Ther 249 (2): 444-449.
[xi] Cadas H, Gaillet S, Beltramo M, Venance L, and Piomelli D (1996) Biosynthesis of an Endogenous Cannabinoid Precursor in Neurons and its Control by Calcium and cAMP J Neurosci 16 (12) pp. 3934-3942
[xii] Coutts AA, Irving AJ, Mackie K, Pertwee RG, Anavi-Goffer S [2002] Localisation of cannabinoid CB(1) receptor immunoreactivity in the guinea pig and rat myenteric plexus. J Comp Neurol 448(4):410-22
[xiii] Lopez-Redondo F, Lees GM, Pertwee RG. [1997] Effects of cannabinoid receptor ligands on electrophysiological properties of myenteric neurones of the guinea-pig ileum. Br J Pharmacol 122(2):330-4
[xiv] Pinto L, Izzo AA, Cascio MG, Bisogno T, Hospodar-Scott K, Brown DR, Mascolo N, Di Marzo V, Capasso F. [2002] Endocannabinoids as physiological regulators of colonic propulsion in mice. Gastroenterology 123(1):227-34
[xv] Izzo AA, Fezza F, Capasso R, Bisogno T, Pinto L, Iuvone T, Esposito G, Mascolo N, Di Marzo V, Capasso F. [2001] Cannabinoid CB1-receptor mediated regulation of gastrointestinal motility in mice in a model of intestinal inflammation. Br J Pharmacol 134(3):563-70
[xvi] Izzo AA, Mascolo N, Tonini M, Capasso F. [2000] Modulation of peristalsis by cannabinoid CB(1) ligands in the isolated guinea-pig ileum. Br J Pharmacol 129(5):984-90
[xvii] Mancinelli R, Fabrizi A, Del Monaco S, Azzena GB, Vargiu R, Colombo GC, Gessa GL. [2001] Inhibition of peristaltic activity by cannabinoids in the isolated distal colon of mouse. Life Sci 69(1):101-11
[xviii] Ueda N, Goparaju SK, Katayama K, Kurahashi Y, Suzuki H, Yamamoto S. [1998] A hydrolase enzyme inactivating endogenous ligands for cannabinoid receptors. J Med Invest 45(1-4):27-36
[xix] Croci T, Manara L, Aureggi G, Guagnini F, Rinaldi-Carmona M, Maffrand JP, Le Fur G, Mukenge S, Ferla G. [1998] In vitro functional evidence of neuronal cannabinoid CB1 receptors in human ileum. Br J Pharmacol 125(7):1393-5
[xx] Tyler K, Hillard CJ, Greenwood-Van Meerveld B [2000] Inhibition of small intestinal secretion by cannabinoids is CB1 receptor-mediated in rats. Eur J Pharmacol 409(2):207-11
[xxi] Nalin DR, Levine MM, Rhead J, Bergquist E, Rennels M, Hughes T, O'Donnel S, Hornick RB. [1978] Cannabis, hypochlorhydria, and cholera. Lancet 2(8095):859-62
[xxii] Izzo AA, Mascolo N, Borrelli F, Capasso F. [1999] Defaecation, intestinal fluid accumulation and motility in rodents: implications of cannabinoid CB1 receptors. Naunyn Schmiedebergs Arch Pharmacol 359(1):65-70
[xxiii] Winn M, Arendsen D, Dodge P, Dren A, Dunnigan D, Hallas R, Hwang K, Kyncl J, Lee YH, Plotnikoff N, Young P, Zaugg H. [1976] Drugs derived from cannabinoids. 5. delta6a,10a-Tetrahydrocannabinol and heterocyclic analogs containing aromatic side chains. J Med Chem 19(4):461-71
[xxiv] Turker RK, Kaymakcalan S, Ercan ZS. [1975] Antihistaminic action of (--)-trans-delta 9-tetrahydrocannabinol. Arch Int Pharmacodyn Ther 214(2):254-62
[xxv] Kulkarni-Narla A, Brown DR. [2000] Localization of CB1-cannabinoid receptor immunoreactivity in the porcine enteric nervous system. Cell Tissue Res 302(1):73-80
[xxvi] Pertwee RG [2001] Cannabinoids and the gastrointestinal tract. Gut 48(6):859-67
[xxvii] Landi M, Croci T, Rinaldi-Carmona M, Maffrand J, Le Fur G, Manara L. [2002] Modulation of gastric emptying and gastrointestinal transit in rats through intestinal cannabinoid CB(1) receptors. Eur J Pharmacol 450(1):77
[xxviii] Izzo AA, Mascolo N, Capasso R, Germano MP, De Pasquale R, Capasso F. [1999] Inhibitory effect of cannabinoid agonists on gastric emptying in the rat. Naunyn Schmiedebergs Arch Pharmacol 360(2):221-3
[xxix] Krowicki ZK, Moerschbaecher JM, Winsauer PJ, Digavalli SV, Hornby PJ. [1999] Delta-9-tetrahydrocannabinol inhibits gastric motility in the rat through cannabinoid CB1 receptors. Eur J Pharmacol 371(2-3):187-96
[xxx] Bateman DN. [1983] Delta-9-tetrahydrocannabinol and gastric emptying. Br J Clin Pharmacol 15(6):749-51
[xxxi] Adami M, Frati P, Bertini S, Kulkarni-Narla A, Brown DR, de Caro G, Coruzzi G, Soldani G. [2002] Gastric antisecretory role and immunohistochemical localization of cannabinoid receptors in the rat stomach. Br J Pharmacol 135(7):1598-606
[xxxii] Izzo AA, Mascolo N, Capasso F [2001] The gastrointestinal pharmacology of cannabinoids. Curr Opin Pharmacol 1(6):597-603
[xxxiii] Coruzzi G, Adami M, Coppelli G, Frati P, Soldani G. [1999] Inhibitory effect of the cannabinoid receptor agonist WIN 55,212-2 on pentagastrin-induced gastric acid secretion in the anaesthetized rat. Naunyn Schmiedebergs Arch Pharmacol 360(6):715-8
[xxxiv] Nalin DR, Levine MM, Rhead J, Bergquist E, Rennels M, Hughes T, O'Donnel S, Hornick RB. [1978] Cannabis, hypochlorhydria, and cholera. Lancet 2(8095):859-62
[xxxv] Germano MP, D'Angelo V, Mondello MR, Pergolizzi S, Capasso F, Capasso R, Izzo AA, Mascolo N, De Pasquale R. [2001] Cannabinoid CB1-mediated inhibition of stress-induced gastric ulcers in rats. Naunyn Schmiedebergs Arch Pharmacol 363(2):241-4
[xxxvi] De Souza H, Trajano E, de Carvalho FV, Palermo Neto J. [1978] Effects of acute and long-term cannabis treatment of restraint-induced gastric ulceration in rats. Jpn J Pharmacol 28(3):507-10
a b "GI Consult: Perforated Peptic Ulcer". Retrieved 2007-08-26.
a b "Peptic Ulcer". Retrieved 2010-06-18.
"Peptic ulcer". Retrieved 2010-06-18.
"Ulcer Disease Facts and Myths". Retrieved 2010-06-18.
Cullen DJ, Hawkey GM, Greenwood DC, et al. (1997). "Peptic ulcer bleeding in theelderly: relative roles of Helicobacter pylori and non-steroidal anti-inflammatory drugs". Gut 41 (4): 459–62. doi:10.1136/gut.41.4.459. PMC 1891536. PMID 9391242.
"Peptic Ulcer: Peptic Disorders: Merck Manual Home Edition". Retrieved 2007-10-10.
http://www.merck.com/mmhe/sec09/ch121/ch121c.html
Johannessen T. "Peptic ulcer disease". Pasienthandboka.
Kato, Ikuko; Abraham M. Y. Nomura, Grant N. Stemmermann and Po-Huang Chyou (1992). "A Prospective Study of Gastric and Duodenal Ulcer and Its Relation to Smoking, Alcohol, and Diet". American Journal of Epidemiology 135 (5): 521–530. PMID 1570818. Retrieved 2010-03-18.
a b Salih, Barik; M Fatih Abasiyanik, Nizamettin Bayyurt, Ersan Sander (June 2007). "H pylori infection and other risk factors associated with peptic ulcers in Turkish patients: A retrospective study". World Journal of Gastroenterology 13 (23): 3245–3248. PMID 17589905.
Martin, U.S.A.F.M.C. (Major), David F.; Captain Elizabeth Montgomery, U.S.A. M.C., Arthus S, Dobek, Ph.D., Geoffrey A, Patrissi, M.A., Colonel David A, Peura, U.S.A. M.C., F.A.C.G. (28 June 2008). "Campylobacter pylori, NSAIDS, and Smoking: Risk Factors for Peptic Ulcer Disease". American Journal of Gastroenterology 84 (10): 1268–1272. doi:10.1111/j.1572-0241.1989.tb06166.x. PMID 2801677. Retrieved 2010-03-18.[dead link]
Kurata Ph.D., M.P.H., John H.; Nogawa, Aki N. M.S. (Jan 1997). "Meta-analysis of Risk Factors for Peptic Ulcer: Nonsteroidal Antiinflammatory Drugs, Helicobacter pylori, and Smoking". Journal of Clinical Gastroenterology 24 (1): 2–17. doi:10.1097/00004836-199701000-00002.PMID 9013343. Retrieved 2010-03-18.
For nearly 100 years, scientists and doctors thought that ulcers were caused by stress, spicy food, and alcohol. Treatment involved bed rest and a bland diet. Later, researchers added stomach acid to the list of causes and began treating ulcers with antacids. National Digestive Diseases Information Clearinghouse
A, Sonnenberg; Müller-Lissner SA, Vogel E, Schmid P, Gonvers JJ, Peter P, Strohmeyer G, Blum AL (1981). "Predictors of duodenal ulcer healing and relapse.". Journal of Gastroenterology 81 (6): 1061–1067. PMID 7026344. Retrieved 2010-03-18.
Kim YH, Lee JH, Lee SS, et al. (2002). "Long-term stress and Helicobacter pylori infection independently induce gastric mucosal lesions in C57BL/6 mice". Scand. J. Gastroenterol. 37 (11): 1259–64. doi:10.1080/003655202761020515. PMID 12465722.
Wachirawat W, Hanucharurnkul S, Suriyawongpaisal P, et al. (2003). "Stress, but notHelicobacter pylori, is associated with peptic ulcer disease in a Thai population". J Med Assoc Thai 86 (7): 672–85. PMID 12948263.
"Peptic ulcer". Retrieved 2010-06-18.
"Tests and diagnosis". Retrieved 2010-06-18.
"ATLAS OF PATHOLOGY". Retrieved 2007-08-26.
Peptic Ulcer Symptoms. Retrieved on 2011-02-20
"Ranitidine in Peptic Ulcer".
"Sucralfate for Peptic Ulcer".
"WHO Disease and injury country estimates". World Health Organization. 2009. Retrieved Nov. 11, 2009.
Snowden FM (October 2008). "Emerging and reemerging diseases: a historical perspective". Immunol. Rev. 225 (1): 9–26. doi:10.1111/j.1600-065X.2008.00677.x. PMID 18837773.
Brown LM (2000). "Helicobacter pylori: epidemiology and routes of transmission.". Epidemiol. Rev. 22 (2): 283–97. PMID 11218379.
"Peptic ulcer disease". Retrieved 2010-06-18.
"Epidemiology of peptic ulcer disease". Retrieved 2010-06-18.
Marshall B.J., ed. (2002), "Helicobacter Pioneers: Firsthand accounts from the scientists who discovered helicobacters, 1892–1982", ISBN 0-86793-035-7. Basil Rigas, Efstathios D. Papavasassiliou. John Lykoudis. The general practitioner in Greece who in 1958 discovered the etiology of, and a treatment for, peptic ulcer disease.
Marshall B.J. (1983). "Unidentified curved bacillus on gastric epithelium in active chronic gastritis". Lancet 1 (8336): 1273–75. PMID 6134060.
Marshall B.J., Warren J.R. (1984). "Unidentified curved bacilli in the stomach patients with gastritis and peptic ulceration". Lancet 1 (8390): 1311–15. doi:10.1016/S0140-6736(84)91816-6. PMID 6145023.
Kathryn Schulz (2010-09-09). "Stress Doesn't Cause Ulcers! Or, How To Win a Nobel Prize in One Easy Lesson: Barry Marshall on Being ... Right". The Wrong Stuff. Slate. Retrieved 2011-07-17.
Van Der Weyden MB, Armstrong RM, Gregory AT (2005). "The 2005 Nobel Prize in physiology or medicine". Med. J. Aust. 183 (11–12): 612–4.PMID 16336147.
Ulcer, Diagnosis and Treatment - CDC Bacterial, Mycotic Diseases
Medicine for Nurses (Toohey, 1974)
Huwez FU, Thirlwell D, Cockayne A, Ala'Aldeen DA (December 1998). "Mastic gum kills Helicobacter pylori [Letter to the editor, not a peer-reviewed scientific article"]. N. Engl. J. Med. 339 (26): 1946. doi:10.1056/NEJM199812243392618. PMID 9874617. Retrieved 2008-09-06. See also their corrections in the next volume.
Loughlin MF, Ala'Aldeen DA, Jenks PJ (February 2003). "Monotherapy with mastic does not eradicate Helicobacter pylori infection from mice". J. Antimicrob. Chemother. 51 (2): 367–71. doi:10.1093/jac/dkg057. PMID 12562704.
Bebb JR, Bailey-Flitter N, Ala'Aldeen D, Atherton JC (September 2003). "Mastic gum has no effect on Helicobacter pylori load in vivo". J. Antimicrob. Chemother. 52 (3): 522–. doi:10.1093/jac/dkg366. PMID 12888582.
Ramakrishnan K, Salinas RC. Peptic ulcer disease. Am Fam Physician. 2007;76:1005-1012]
Chey WD, Wong BC. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol. Aug 2007;102:1808-1825]
Malagelada JR, Kuipers EJ, Blaser MJ. Acid peptic disease: clinical manifestations, diagnosis, treatment, and prognosis. In: Goldman L, Ausiello D, eds. Cecil Medicine. 23rd ed. Philadelphia, Pa: Saunders Elsevier; 2007:chap 142.
Lanza FL, Chan FK, Quigley EM; Practice Parameters Committee of the American College of Gastroenterology. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol. 2009;104:728-738.