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The enterochromaffin cells of the gastrointestinal (GI) tract secrete 400 times as much melatonin as the pineal gland; therefore, it is not surprising that research is finding that this indole plays an important role in GI functioning. In animal studies, it protects against GI ulcerations, and randomized clinical trials suggest its efficacy in treating functional dyspepsia and irritable bowel syndrome. Melatonin administration has been shown to protect against esophageal lesions in animals. Moreover, in a randomized, single-blind clinical trial of subjects with gastroesophageal reflux disease (GERD), the combination of melatonin with other natural supplements was found to be superior to omeprazole, a proton pump inhibitor (PPI). Its administration as a single treatment for GERD has not been previously reported. A 64-year-old Caucasian female who required treatment with a PPI for symptoms of GERD wished to substitute a natural treatment because of the risk of worsening her osteoporosis. She experienced a return of symptoms following each of three 20-day trials of a proprietary blend of D-limonene when attempts were made to discontinue the PPI. She then underwent a trial of a natural formula consisting of melatonin 6 mg, 5-hydroxytryptophan 100 mg, D,L-methionine 500 mg, betaine 100 mg, L-taurine 50 mg, riboflavin 1.7 mg, vitamin B6 0.8 mg, folk acid 400 µg, and calcium 50 mg. After 40 days, the PPI was withdrawn without a return of symptoms. Subsequently, an attempt to reduce melatonin to 3 mg resulted in symptoms, while all other ingredients were withdrawn with minimal symptoms during 10 months of follow-up.

DISCUSSION

This appears to be the first published study to record the successful substitution of melatonin 6 mg at bedtime for the maximum recommended dosage of a PPI in a patient with GERD. The report suffers from 2 serious limitations. First, since it documents only a single case, it provides no indication of whether the findings can be generalized to other patients. Second, it fails to control for the placebo effect, so it is not possible to know whether the active treatment or a concurrent nonspecific factor is responsible for her response.

Perhaps the strongest indication that her response was unlikely to be due to the placebo effect was her discovery after the symptoms started that she had skipped taking melatonin the night before; thus her symptoms occurred even though she thought she was being protected by the pill. Further evidence suggesting that her response was not simply a placebo effect was her poor prior response to multiple trials of D-limonene, another natural agent that had been presented to the patient in a similar manner.

Asymptomatic on the combination supplement without the PPI, she was successfully weaned off of all of its ingredients except for melatonin, for which a 50% decrease in dosage led to the rapid return of symptoms. We cannot conclude, however, that the other ingredients were ineffective as it is possible that they had an initial role in repairing mucosal defenses so that melatonin alone would become adequate for treatment.

It appears that, through various mechanisms, melatonin protects the esophageal mucosa from injury due to the assault of acid reflux. Daily administration appears to be necessary, or symptoms immediately recur.

Despite its efficacy in preventing symptoms for almost a year, it is possible that symptoms may recur at a later date, perhaps due to worsening of the underlying disorder.

This report also addressed the question of whether 5-HTP, a melatonin precursor, could be substituted for melatonin in relieving the symptoms of GERD. The oral administration of L-tryptophan, the immediate precursor to 5-HTP, to chicks and rats has been found to cause a rapid, dose-dependent elevation of circulating melatonin, and the major source of the increase in circulating melatonin was not the pineal gland but the enterochromaffin cells of the GI tract.31 Other studies suggest that this increase may be roughly 4-fold compared to baseline levels.32,33

In the case presented here, an attempt was made to reduce the initial melatonin dosage by doubling and then by tripling the dosage of 5-HTP. However, 300 mg of 5-HTP, a dosage usually considered to be adequate for clinical applications, failed to permit melatonin to be reduced from 6 mg to 3 mg daily, and discontinuation of 5-HTP alone did not cause a return of symptoms. These findings suggest that the usual clinical dosages of 5-HTP are ineffective as a substitute for melatonin.

CONCLUSIONS

Findings of this single case study in addition to a review of the literature suggest that melatonin 6 mg at bedtime may be an effective treatment for GERD with fewer and less serious adverse effects than acid-reducing medications so long as anti-GERD medications are (1) continued during the first 40 days of treatment and (2) resumed for at least 1 dose whenever symptoms recur. Further studies, including randomized controlled trials, are needed to validate and extend these early findings.