Author: Jacob Schor, ND, FABNO
ABSTRACT
Significant quantities of melatonin are produced in the human digestive tract. Melatonin has multiple effects on digestion and is important in maintaining normal digestive function. It may have clinical use in treating a range of gastrointestinal disorders, including gastroesophageal reflux disease, gastric ulceration, pancreatitis, liver fibrosis, irritable bowel syndrome, and ulcerative colitis. Clinicians are encouraged to consider using melatonin as an adjunct in treating these conditions.
Many of the therapeutic options available to the naturopathic physician today are far from the simple cures of our professional forefathers. Although the basic premise of our practices should be centered on stimulating the vis medicatrix naturae, I find myself turning increasingly to supplementing or replacing biologic elements that are rendered in short supply as a result of our modern lifestyle. An excellent example is the hormone cholecalciferol, or vitamin D3. Living where we do and spending as much time indoors as we do, taking supplemental vitamin D3 makes sense. Of late, I have begun to wonder if we should not see melatonin in a similar light as vitamin D3 as a hormone required for health but of which deficiency is common because of lifestyle. At this point, we have little clinical experience in using melatonin except as a sleep aid and as an adjunctive treatment for cancer. This article focuses on the therapeutic potential of using melatonin to treat diseases of the digestive tract.
Melatonin has a significant role in regulating the digestive tract, and this should come as no surprise. Most individuals report a clear circadian rhythm to their bowel habits, and melatonin is the clock that controls circadian rhythms. Levels of melatonin increase with darkness and decrease again with light; this is how our bodies know it is night or day.
The brain is not the only source of melatonin in the body; the digestive tract also produces melatonin. Lerner and coworkers discovered melatonin in the bovine pineal gland in 1958, more than half a century ago.1 Sixteen years later, Raĭkhlin and Kvetnoĭ2 isolated melatonin from the human appendix. In 1976, Bubenik and Brown3 at the University of Guelph, Guelph, Ontario, Canada, reported detection of melatonin in the mucous membrane of the gastrointestinal tract (GIT). Melatonin is produced in the GIT by the enteroendocrine cells that line the digestive tract. The gut does not need or depend on the brain for melatonin; it makes its own. If you cut out the pineal gland of a rat, blood melatonin levels are drastically decreased, yet the melatonin levels in the gut remain unchanged.4 We will assume the same holds true among people: nobody is volunteering to play the rat in a similar human trial.
Oral doses of l-tryptophan increase blood levels of melatonin.5 This occurs even in animals that have had their pineal glands removed.6 l-tryptophan is converted into melatonin in the GIT rather than in the brain. We should acknowledge that the commonly held belief that l-tryptophan is converted to serotonin may be inaccurate. Serotonin is an intermediary on the pathway between l-tryptophan and melatonin and is not the end of the road.
A diagram of l-tryptophan conversion pathways is available at http://upload.wikimedia.org/wikipedia/en/0/0b/Tryptophan_metabolism.png. l-tryptophan can take 1 of 2 pathways in the body: one path leads to production of niacin, and the other path leads to production of serotonin first and then melatonin.
The factors that control which pathway l-tryptophan takes are only recently being explored. Stress, disease, malignancy, active immune activity, and pesticides cause changes in the rate of conversion. Chronic immune activation pushes tryptophan toward niacin production, such that low l-tryptophan serum levels are found in certain conditions such as cancer. As noted by Schröcksnadel et al, “Low serum/plasma tryptophan concentration is observed in infectious, autoimmune, and malignant diseases and disorders that involve cellular (Th1-type) immune activation as well as during pregnancy due to accelerated tryptophan conversion.”7(p)
In these chronic states in which flow is directed toward making niacin, low tryptophan may lead to low serotonin levels and presumably low melatonin levels. This supports the use of melatonin in patients with cancer and suggests that we should consider melatonin treatment in other conditions besides cancer.
Mild stress also increases melatonin production. A 2009 study8 reports that 2 hours of restraint, used to trigger a mild stress response, increase melatonin production. The stress was classified as mild because the subjects did not develop bleeding ulcers.
Several insecticides, including parathion, carbaryl, and lindane, have been shown to increase melatonin production.9-11 However, it would be inappropriate to suggest these chemicals as a treatment for insomnia.
The rate of conversion from serotonin to melatonin is variable, so typically we choose to use melatonin itself rather than l-tryptophan to increase gut melatonin levels. l-tryptophan has a reputation as being useful to treat insomnia, and the obvious explanation would be that it increases serum melatonin levels.
Eating food triggers melatonin production by the GIT, and some of this melatonin enters the bloodstream. Fasting also increases gut melatonin production. Eating after a period of fasting will create a surge in melatonin.12 The postprandial drowsiness that many of us were taught was the result of an “alkaline wave” in the blood secondary to stomach acid neutralization in the gut might after all just be a spike in blood melatonin levels.
The pineal gland produces a spike in melatonin levels at night in the dark, but during the day the gut maintains the baseline levels. There is much more melatonin in the GIT than in the blood. Melatonin concentrations in GIT tissues are 10 to 100 times higher than those in blood. According to 1994 calculations by Huether, the GIT contains 400 to 500 times more melatonin than the pineal gland.13
In the lower GIT, melatonin helps regulate peristalsis. It cancels out the spasmodic effect of serotonin on the intestine and restores peristalsis. Pretreatment with melatonin prevents serotonin-induced spasm. This is observed when measuring bowel transit times (BTTs). Serotonin speeds things up, shortening BTT. Adding melatonin slows things back down, lengthening BTT. Small doses of melatonin also aid motility by relaxing serotonin spasms.14 Melatonin slows processes down if they move too quickly and speeds them up if they move too slowly. Melatonin could be called a peristaltic modulator. These properties render melatonin a possible treatment for irritable bowel syndrome (IBS).15
de Souza Pereira brought to our attention the idea of using melatonin to treat reflux disease in a letter to the editor published in the Journal of Pineal Research in May 2006.16 He described a 64-year-old woman whose gastroesophageal reflux disease (GERD) symptoms responded favorably to a formula containing melatonin (6 mg) plus several amino acids and vitamins. In October 2006, the same journal published an article by de Souza Pereira17 comparing the action of this melatonin formula with that of omeprazole. de Souza Pereira administered melatonin containing supplement to 176 patients and omeprazole (20 mg) to another 175 patients. All 176 patients who received melatonin supplements “reported a complete regression of symptoms after 40 days of treatment.”17(p195) Only 115 patients receiving omeprazole (65.7%) reported similar improvement. These results are almost too good to be believable. The formula for the mixture used in the research is no secret; de Souza Pereira lists it in the text of his article. It is surprising that some enterprising supplement manufacturer is not selling it.
Melatonin inhibits nitric oxide production, and this prevents relaxation of the lower esophageal sphincter (LES). This may explain how melatonin prevents reflux.
A 2006 article18 reported on nighttime melatonin levels among individuals with upper digestive tract disorders. Blood melatonin levels were measured in 24 patients with nonerosive esophageal reflux disease (NERD), in 25 patients with GERD, in 34 patients with duodenal ulcer disease (DUD), in 36 patients with functional dyspepsia (FD), and in 30 healthy control subjects. Patients with GERD and DUD produced less melatonin than the control subjects (27.2 and 25.5 pg/mL, respectively, vs 34.7 pg/mL). Patients with the nonerosive diseases, NERD and FD, had the highest levels of melatonin (43.2 and 42.4 pg/mL, respectively). High melatonin seems to be protective of the mucosal tissues of the upper digestive tract.18
In a 2007 study,19 60 individuals diagnosed as having epigastric pain syndrome (EPS) or postprandial disorders syndrome (PDS) were administered melatonin (5 mg nightly) for 6 weeks. The concentration of nitric oxide metabolites in gastric juice was measured in the test subjects and in 25 healthy control subjects. Nitric oxide levels were lower in the control subjects (6.8 µm vs 11.0 and 9.3 µm in patients with EPS and PDS, respectively); after treatment with melatonin, nitric oxide levels dropped to 8.2 and 6.9 µm, respectively.
Note that the GERD clinical trial18 was 40 days in length, and the aforementioned trial19 was 6 weeks in length. It is useful to point this out to patients and to inform them not to expect results for 6 weeks.20,21
The common assumption that individuals experience heartburn at night because they are horizontally oriented and gravity no longer holds the food down may need to be rethought. Nighttime lighting may lower melatonin secretion and allow the LES sphincter to relax inappropriately. This may partly explain why reflux worsens at night.
It is not just gut smooth muscles that are affected by melatonin. Perhaps we should be administering melatonin during labor. Research dating back to the 1960s and 1970s indicates that melatonin relaxes smooth muscles in the reproductive tract.22 Melatonin has a synergistic effect with oxytocin in triggering more coordinated and more forceful uterine contractions, so it may be of use in labor and delivery.23 Melatonin also seems to moderate placental function for the better.24 Although some anecdotal sources suggest that melatonin is contraindicated during pregnancy, I have been unable to ascertain the reason. In contrast, recent evidence suggests that it may be beneficial.25
Melatonin is often referred to as an antioxidant.26 It is reported to be twice as effective as vitamin E.27 Melatonin prevents the damage caused by ischemia-reperfusion of gut mucosa.28
Melatonin may be useful in treating a range of diseases of the digestive tract. It may be of therapeutic benefit in treating bacterial, fungal, or viral oral infections and may be useful for healing tooth extractions, periodontal diseases, and oral cancers.29 An option might be to add melatonin to the toothpaste that one uses at bedtime.
Melatonin may be of use in treating gastric ulcers. If a restrained rat is stressed by water immersion, the rat rapidly develops gastric ulcerations.30-32 These ulcers bleed more during the day and start to heal at night. If the pineal gland of the rat is destroyed so that it cannot produce nighttime melatonin, the ulcers rapidly worsen and do not heal even at night. A possible explanation for this action is that melatonin relaxes smooth muscles in the intestinal tract and increases mucosal blood flow.33
Melatonin may be useful for treating pancreatitis. It stimulates amylase secretion by the pancreas and protects the pancreas from damage. These “…beneficial effects of melatonin…on acute pancreatitis could be related to the ability of melatonin to scavenge the free radicals, to activate antioxidative enzymes and to modulate the cytokine production.”34(p65) In animal models of pancreatitis, melatonin not only protects against damage but also moderates the effects of the disease. In a rat study,35 melatonin reduced pancreatic damage by decreasing tumor necrosis factor levels.
Melatonin moderates BTT, so it may be useful for treating IBS.15 In a clinical trial36 of 18 patients published in 2007, each patient received melatonin (3 mg) or placebo at bedtime for 8 weeks. Those receiving melatonin significantly improved their overall IBS scores (45.00% vs 16.66%). The improvement in quality-of-life scores was 43.63% in the melatonin group and 14.64% in the placebo group. Although the study sample was small, the improvements are significant.
We should cautiously consider melatonin for the treatment of ulcerative colitis (UC) and Crohn disease. A 2003 article37 in the American Journal of Gastroenterology raised the question of whether melatonin might be a useful treatment for UC. A 2007 study38 measured the urine metabolites of melatonin in 24 individuals with UC. Data showed that the metabolites were significantly higher in the group with UC than in healthy control subjects. Higher levels of the metabolites were correlated with milder disease. This led the researchers to conclude that “melatonin seems to be a part of anti-inflammatory response and its high level may appease the course of UC.”38(p) A 2008 study39 using a rat model of UC reported that melatonin treatment prevented the translocation of bacteria from the gut into the circulation. With this in mind, it is no surprise that the authors of a review article40 published in January 2009 suggested the use of melatonin in treating UC. As of this writing, Emory University, Atlanta, Georgia, is recruiting participants with UC for a 12-week study to test the effect of the daily use of melatonin (5 mg) (http://clinicaltrials.gov/ct2/show/NCT00790478 [clinicaltrials.gov identifier: NCT00790478]).
Despite these encouraging suggestions, we should be cautious. Two case reports, one presenting a patient with Crohn disease41 and the other presenting a patient with UC,42 describe significant aggravation of disease when the patients took melatonin. Both patients were taking the same combination of drugs (salicylazosulfapyridine, corticosteroids, and melatonin). Although these drugs may be useful when administered separately, their combined administration may provoke unwanted aggravation. For these reasons, we should not administer melatonin in combination with these other drugs.
Only 1 article41 addressed whether melatonin might be useful for treating Crohn disease. No abstract is available, but the title (“Melatonin Triggers Crohn’s Disease Symptoms”) is not encouraging. For now, practitioners should avoid administering melatonin to patients with Crohn disease.
Melatonin may be of use in the treatment of diseases that cause liver fibrosis, including primary biliary cirrhosis. Researchers discussed this possibility in a 1979 study.43 Removing the pineal gland from a laboratory animal precipitates the formation of fibrosis in the intestinal cavity, especially the liver. The authors went so far as to suggest that “[p]rimary biliary cirrhosis may be a pineal deficiency disease.”43(p403) Although an older article, its message may be relevant, especially in light of more recent articles44,45 stating that melatonin protects against liver fibrosis and cirrhosis caused by carbon tetrachloride poisoning or from fatty liver.
Melatonin may be useful for patients undergoing abdominal surgery. It promotes faster healing of surgical incisions and prevents formation of abdominal adhesions.46,47
Melatonin may be useful during pregnancy. Various anecdotal sources state that it is contraindicated during pregnancy, but no rationale is given. As previously mentioned, authors of several recent review articles48-50 suggest that melatonin may be beneficial during pregnancy and prevents postpartum depression. Given the unwanted effects of the current medications used to treat pregnancy-related reflux disease, melatonin may someday be judged preferable.
If melatonin is beneficial for these conditions, is there evidence to suggest that their incidence correlates with melatonin levels? A major factor in melatonin suppression is nighttime exposure to light. For example, an Israeli study51 correlated breast cancer incidence with nighttime outdoor light intensity. The study judged exposure to light at night by examining nighttime satellite photographs taken by the US National Aeronautics and Space Administration.
Evidence suggests that the symptoms of gastrointestinal disease fluctuate with nighttime light exposure and with melatonin levels. Women who work night shifts produce less melatonin.52 Individuals experiencing shift work sleep disorder, the diagnostic name for complaints that stem from working night shifts or swing shifts, have a higher than average incidence of gastrointestinal disorders.53 The strongest correlation is the association of shift work with peptic ulcer disease.54
Considering that night-shift workers produce less melatonin, a 2003 study55 analyzed data from the Nurses’ Health Study and evaluated the risk of colon cancer relative to the frequency of working night shifts. The authors concluded that “…working a rotating night shift at least three nights per month for 15 or more years may increase the risk of colorectal cancer in women.”55(p825)
This information should probably alter our treatment of several conditions. We should consider prescribing melatonin for gastrointestinal conditions with the possible exception of Crohn disease. Because it is a precursor to melatonin, l-tryptophan may also be useful to treat these conditions. Our experience in questioning patients with digestive complaints is that many will also report sleep disorders. It is this group of patients with both digestive disorders and sleep complaints who may benefit from melatonin. Moderate doses of melatonin (6 mg in the GERD studies and 3 mg in the UC studies) seem adequate for treating these conditions.
It would seem that our modern illuminated lifestyle has inadvertently caused a hormone deficiency that has long-term health implications. This knowledge opens the possibility of correcting a wide range of conditions.
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