Melatonin may not prevent MS relapses or disability, new review study finds

A systematic review of clinical studies found no clear evidence that melatonin supplements reduce relapses, disability progression, or new MRI-detected disease activity in people with multiple sclerosis (MS).

Some small studies suggested melatonin may improve sleep, fatigue, pain, physical and cognitive function, and mood, but the findings were inconsistent. Daily doses of 0.5 to 25 mg appeared reasonably well tolerated in small studies, while a separate small trial raised liver safety concerns at 300 mg per day.

Future trials testing whether melatonin can slow MS disease activity “would need substantially larger samples, longer follow-up, and prespecified relapse, disability, and magnetic resonance imaging endpoints,” the researchers wrote.

The study, “Melatonin supplementation in multiple sclerosis: a systematic review of clinical, imaging, biomarker, and safety outcomes,” was published in the journal Frontiers in Neurology.

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In MS, the immune system mistakenly attacks the myelin sheath, the protective layer around nerve fibers that helps nerve signals travel quickly. This damage can cause a wide range of symptoms, including problems with thinking, balance, movement, and vision, as well as fatigue, pain, and mood disturbances.

Melatonin is a hormone produced naturally in the brain that helps regulate the sleep-wake cycle. Its antioxidant and anti-inflammatory properties, along with its effects on the immune system and potential to protect nerve cells, have raised interest in whether it could help people with MS beyond improving sleep.

Laboratory and animal studies suggest melatonin may affect immune responses and help protect cells that produce myelin. However, clinical trials involving people with MS have shown mixed results, leaving questions about the best dose, how long treatment should last, and its safety.

To better understand melatonin’s potential benefits and risks, researchers systematically reviewed studies published through Aug. 15, 2026, that examined the safety and effectiveness of oral melatonin supplements in adults with MS. A total of 10 independent studies involving 435 people with MS met the eligibility criteria and were included in the final analysis.

The studies were conducted in the U.S., U.K., Mexico, Spain, Poland, Iran, and Tunisia. Nine were randomized clinical trials. Melatonin doses ranged from 0.5 to 300 mg per day, and treatment lasted from two weeks to 14 months.

No clear benefit seen for MS relapses or disability progression

Across the studies, melatonin did not appear to reduce relapse activity, disability progression, or new MRI activity. In one yearlong, placebo-controlled trial, taking 3 mg of melatonin each night showed no statistically significant benefit for relapse numbers, disability scores, or new or active brain lesions.

The findings were more mixed when researchers looked at melatonin’s effects on MS symptoms. Some studies reported less fatigue and pain, along with improvements in sleep, walking, balance, thinking abilities, or mood. However, most of these findings came from individual small trials and had not been confirmed by other studies.

For example, one crossover study found that melatonin significantly increased objectively measured sleep time by about 18 minutes compared with placebo. Sleep was measured using a wearable device, and participants received melatonin and placebo at different times, allowing researchers to compare the results within the same people.

However, the 18-minute increase fell short of the 20-minute threshold researchers had set for a clinically meaningful improvement. Other measures of sleep, fatigue, mood, and walking showed no statistically significant differences between treatments.

Melatonin’s effects on biomarkers, or measurable signs of inflammation, cell damage, and metabolism, were also inconsistent. Changes in these markers “did not consistently come with improvements in relapses, disability, imaging, or patient-reported outcomes,” the researchers wrote.

“Future mechanistic studies should prespecify a limited number of biomarkers and test whether changes correlate with clinically meaningful outcomes, rather than reporting isolated laboratory differences,” they added.

High-dose melatonin raises liver safety concerns

Melatonin appeared reasonably well tolerated at daily doses of 0.5 to 25 mg. However, the studies were small, and researchers did not consistently report adverse events.

By contrast, a much higher dose of 300 mg per day raised concerns about liver safety in a small Phase 1/2 trial called MELATOMS-1 (NCT03540485). The trial involved people with primary progressive MS who were receiving Ocrevus (ocrelizumab).

Three of the four patients given high-dose melatonin (ages 38–57; 75% women) had elevated liver enzymes, which can be a sign of liver injury. None of the four patients given a placebo had this problem. The liver enzyme levels improved after melatonin was stopped but rose again in one patient when treatment restarted.

Because of these safety concerns, “people with MS should not use high-dose melatonin outside monitored trials,” the researchers wrote.

Overall, “current evidence does not support a disease-modifying effect of melatonin in MS,” the researchers concluded. “Any symptomatic or biomarker benefits need confirmation in larger, well-designed trials, and high-dose melatonin may carry meaningful [liver] risk.”