ABSTRACT
Melatonin is primarily synthesized and released from the pineal gland and is known for its multiple neurohormonal functions, exerting its action centrally within the nervous system, as well as peripherally, in many tissues.1-3 Melatonin exhibits both receptor-dependent and receptor-independent effects. In the gastrointestinal tract, melatonin is released from the serotonin-rich enteroendocrine cells and is reported to exert endocrine, autocrine, paracrine, as well as luminal functions.4-6 Concentration of melatonin in the gastrointestinal tract, which is derived from both the pineal gland and local de novo synthesis, is reported to be as much as 100 times that found in blood and 400 times that found in the pineal gland.5-7 While melatonin’s central role on the maintenance of the circadian rhythm and sleep-wake cycle is well known, its roles in the modulation of gastrointestinal functions are less well characterized, and the associated regulatory pathways remain largely unclear. Gastrointestinal motility follows a circadian rhythm with reduced nocturnal activity, but circadian rhythms are frequently found disrupted in patients with gastrointestinal motility disorders such as irritable bowel syndrome (IBS), and subjects with upset day/night cycle such as those working on night shifts and subjects traveling over time zones. These subjects often experience exacerbations of abdominal symptoms as well as episodes of diarrhea or constipation.8-15
In the early 2000s, we conducted a double-blind cross-over study to determine the effect of melatonin on IBS patients and healthy subjects. In the study, we showed that, compared with controls (n = 17), colonic transit time (mean ± SD) in constipation-predominant IBS patients (n = 7) was prolonged (65.2 ± 33.3 vs. 25.2 ± 7.7 hours in controls; p < 0.01). In healthy control patients, treatment with 3 mg/day melatonin at bedtime for 8 weeks signi£cantly increased the colonic transit time from 27.4 ± 10.5 to 37.4 ± 23.8 hours (p = 0.04). However, melatonin treatment did not signi£cantly change the colonic transit time of IBS patients.15 The £ndings pointed to the possibility of melatonin’s inhibitory role on normal human gut transit. In another similar study we conducted on 17 female IBS patients, we demonstrated that an 8-week course of oral melatonin at a dose of 3 mg/day was effective in improving bowel symptoms in these patients.16 Using validated questionnairesthe GI symptom, the sleep questionnaires, and the Hospital Anxiety and Depression Scale-to assess symptom severity and to compute the IBS, sleep, and anxiety/depression scores, respectively, we showed that improvements in mean IBS scores were signi£cantly greater after treatment with
11.1 Introduction ..........................................................................................................................205 11.2 Clinical Studies .....................................................................................................................205 11.3 Summary ..............................................................................................................................207 References ......................................................................................................................................207
