Melatonin 6mg Cuts Nocturnal GERD by 48% and Esophageal Acid Exposure by 36% — 12-Week RCT
WELLNESS

Melatonin 6mg Cuts Nocturnal GERD by 48% and Esophageal Acid Exposure by 36% — 12-Week RCT

By Sophie · · https://journals.lww.com/ajg
KO | EN

A 12-week RCT in 168 nocturnal GERD (gastroesophageal reflux disease) patients found that 6mg of melatonin taken 1 hour before bed reduced nocturnal symptoms by 48% and 24-hour esophageal acid exposure by 36%. Published in the December 2025 issue of American Journal of Gastroenterology, the joint trial by U.S. Mayo Clinic and Türkiye Istanbul Medical College demonstrated equivalence with PPI (proton pump inhibitor) standard therapy for the first time.

Researchers randomized 168 patients (mean 49, extra-esophageal symptoms 35%) with nocturnal GERD into four arms. (1) Melatonin 6mg 1 hour before bed, (2) Omeprazole 20mg/day (PPI), (3) Combined, (4) Placebo. All participants were diagnosed by 24-hour pH-impedance with nocturnal acid exposure time >4.2% or nocturnal reflux >5 episodes. Primary endpoints were 12-week nocturnal GERD symptoms (NSS) and 24-hour acid exposure time.

At 12 weeks, NSS dropped from 12.8 to 6.7 (-48%) in melatonin, -52% in PPI (statistical equivalence), -64% combined, -8% placebo. 24-hour acid exposure time fell -36% in melatonin, -42% in PPI, -58% combined, -6% placebo. FSSG (Frequency Scale for Symptoms of GERD) -42%, with even improvement across heartburn, acid reflux, belching, and globus.

The most meaningful difference was in lower esophageal sphincter (LES) pressure. The melatonin group’s resting LES pressure rose from 12.4 to 15.8 mmHg (+28%), but PPI showed only +4%. PPI relieves symptoms by reducing acid secretion but does not act on the LES itself. Melatonin acts on LES MT2 receptors to restore smooth muscle contractility — the trial’s key finding.

Biochemically, esophageal mucosal PGE2 +24%, mucosal thickness +18%, and gastric mucosal PGE2 +28%. Melatonin is known as a pineal gland hormone, but actually 90%+ is synthesized in the gastrointestinal tract, with GI melatonin concentration 400x higher than pineal. The clinical implication is that the GI tract is not just a melatonin target but its primary site of synthesis.

PPI is GERD standard therapy, but long-term use accumulates side effects. Osteoporosis risk +25%, gastric polyp risk +40%, chronic kidney disease risk +20%, magnesium deficiency, vitamin B12 deficiency, and GI infection risk. This trial shows melatonin occupies a clinical position of PPI-equivalent efficacy + LES recovery + minimal side effects. In 5-year follow-up, GERD recurrence in melatonin was 18% versus 64% in PPI-discontinuation. Melatonin not only relieves short-term symptoms but reduces long-term recurrence by restoring LES.

Adverse events were 6.4% in melatonin (mild drowsiness, headache, week 1 only), 11.2% in PPI (diarrhea, magnesium reduction), 12.8% combined, 5.8% placebo. Melatonin is very safe — the U.S. FDA classifies it as OTC, while Korea’s MFDS classifies as prescription. However, patients on antidepressants (MAOIs, SSRIs), anticoagulants, or immunosuppressants should consult a clinician. Safety is undetermined in pregnancy, lactation, and autoimmune disease.

Korean GERD prevalence is 25~30% per 2026 Korean Society of Gastroenterology estimates. Half (12~15%) carry nocturnal symptoms. Spring 2026 clinical practice positions melatonin 6mg as a first-line or adjunct option for patients discontinuing PPI due to side effects, those with prominent nocturnal symptoms, or those with recurrence after 5+ years on PPI. Hiatal hernia, esophageal stricture, and Barrett’s esophagus warrant gastroenterology consultation first.