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A new clinical trial published in the Journal of Pineal Research found that a high nightly dose of melatonin was safe and well-tolerated in older adults with mild cognitive impairment, but did not produce significant improvements in brain function, mood, or sleep over a 12-week period. The findings suggest that future studies should use larger samples and longer durations to determine whether melatonin might help prevent dementia-related decline.
Melatonin is a hormone that regulates sleep and is also known for its antioxidant and anti-inflammatory properties. Some researchers believe it might offer protective benefits for the aging brain by reducing oxidative stress, which is a build-up of damaging molecules that has been linked to the early stages of dementia. This study aimed to evaluate whether taking 25 milligrams of melatonin each night is a practical and acceptable intervention for people with mild cognitive impairment—a condition that often precedes dementia.
The trial was conducted in Sydney, Australia by a team from the University of Sydney, the Woolcock Institute of Medical Research, and other affiliated institutions. The researchers recruited 40 adults aged 60 to 80 years who met the clinical definition for mild cognitive impairment. These individuals had subjective memory concerns but were still functioning in daily life. They were randomly assigned to receive either melatonin or a placebo for 12 weeks. The study was conducted during periods of pandemic-related restrictions, with most assessments carried out remotely through video calls and online platforms.
The main purpose of the study was not to test whether melatonin works, but to see whether running this kind of trial is practical. The researchers evaluated three things: feasibility (how many people qualified for the study), acceptability (how many were willing to participate), and tolerability (whether participants could stick to the treatment and complete the required assessments).
Out of nearly 400 people screened, only about 11 percent met the study’s inclusion criteria . Still, of those who qualified, over 90 percent agreed to participate, and nearly all completed the trial as intended. Participants adhered well to the daily melatonin or placebo capsules, and most were able to complete complex assessments such as sleep tracking, cognitive testing, and magnetic resonance spectroscopy brain scans.
Although the study wasn’t designed to measure treatment effects, the researchers did collect data on brain chemistry, sleep patterns, mood, and cognitive performance. One of their key measures was the concentration of glutathione, a powerful antioxidant found in the brain. Lower levels of glutathione have been linked to neurodegeneration, and melatonin has been proposed as a way to boost these levels.
There was a small, statistically non-significant increase in glutathione in one brain region among participants taking melatonin, but the effect appeared to be due to differences between the groups at the start of the study rather than a result of the treatment. The same was true for other measures, including sleep quality and depressive symptoms—there were some changes, but none were large or consistent enough to draw conclusions.
The researchers reported no major safety issues. Adverse events occurred at similar rates in both the melatonin and placebo groups, and no serious problems were clearly linked to the study medication. In fact, all participants met the threshold for medication adherence, and most reported that participating in the trial, even remotely, was manageable.
The trial’s success in implementing a remote-friendly protocol is an important outcome in itself. Despite common concerns about older adults’ ability to use technology, most participants were able to complete assessments online, including neuropsychological testing and sleep tracking. This suggests that future clinical trials in similar populations may be able to rely more on remote methods, which could reduce costs and increase access.
Still, there were limitations. Because of the small sample size and relatively short duration, the study was not powered to detect subtle effects of melatonin on cognition or brain health. The sample was also not very diverse, with most participants having relatively high education levels, which may limit how broadly the findings can be applied. The COVID-19 pandemic also interrupted recruitment and may have influenced participant experiences during the trial.
Despite these limitations, the study provides a strong foundation for future research. The protocol was feasible, the treatment was well-tolerated, and the participants were able to complete a wide range of assessments even under challenging circumstances. The authors suggest that larger and longer-term trials are needed—ideally with around 200 participants per group and follow-up periods of at least six months to a year. These future studies could also target subgroups of people with both cognitive impairment and sleep disturbances, who may benefit the most from melatonin’s sleep-promoting effects.
In the meantime, while melatonin continues to be widely used for sleep, this study adds to a growing body of research aimed at understanding whether it could also play a role in protecting the aging brain. The current findings suggest that it’s safe to use in higher doses over the short term, but more data is needed to determine whether it can meaningfully slow the progression of cognitive decline.
The study, “3‐Month Melatonin Supplementation to Reduce Brain Oxidative Stress and Improve Sleep in Mild Cognitive Impairment: A Randomised Controlled Feasibility Trial,” was authored by Zoe Menczel Schrire, Craig L. Phillips, Shantel L. Duffy, Nathaniel S. Marshall, Loren Mowszowski, Haley M. La Monica, Lachlan Stranks, Christopher J. Gordon, Julia L. Chapman, Bandana Saini, Sharon L. Naismith, Ronald R. Grunstein, and Camilla M. Hoyos.
