Despite our best efforts, the human mind can sometimes be fickle with memory storage. What’s more, human physiology works against us as we age. As the Alzheimer’s Association notes, 15% to 20% of people age 65 or older experience mild cognitive impairment (MCI), which can negatively impact both memory and thinking skills and is linked to increased risk of developing dementia.

But when it comes to murky memory, it’s not all bad news. Recent research from Tokyo Medical and Dental University (TMDU) suggests that melatonin may show promise as a mega memory booster.

Hello Darkness, My Old Friend

What is melatonin, anyway? And how does melatonin affect the brain?

This naturally occurring hormone is produced by your brain’s pineal gland. According to the National Center for Complementary and Integrative Health, it’s released into your bloodstream in response to darkness and “helps with the timing of your circadian rhythms and with sleep.” Artificial iterations of this hormone are widely available as tablet or capsule supplements to help address sleep-related issues, such as delayed sleep phases, insomnia, jet lag and some sleep disorders in children.

According to the Cleveland Clinic, typical dosages for adults range from 0.5 to 3 milligrams. And while minor side effects such as daytime drowsiness, headache and dizziness are possible, there are no negative side effects connected to reducing or eliminating melatonin use. Recent pandemic pressures have also prompted significant market growth for this over-the-counter supplement. Business Insider reports that, in 2020 alone, U.S. consumers spent more than $825 million on melatonin — a 42.6% increase from the year before.

Mice to Meet You

But what if melatonin could do more than help you get a good night’s sleep? That’s what TMDU researchers hoped to find out, as a paper published in the Journal of Pineal Research outlines. According to lead study author Atsuhiko Hattori, the work was inspired by speculation that specific metabolites that are created by melatonin when it’s broken down by the body might promote improved cognition. To test their theory, Hattori and his team turned to mice.

Assessing the potential impact of melatonin required the TMDU team to manipulate a manageable memory framework. The mental structure of mice fit the bill nicely since they’re predisposed to spend more time examining unfamiliar objects than familiar ones. In young mice, exposure to an object three times in the same day is enough for them to “remember” it the next day and focus their attention elsewhere when they encounter it again. Older mice, meanwhile, display cognitive declines similar to that of aging humans — even after being exposed to a new object in the same way as their younger counterparts, these elder mice behaved as if the “familiar” object was new when they saw it again the next day.

However, when older mice were given a dose of melatonin 15 minutes after a single object exposure, Hattori found that they were able to “remember” the object again the next day, and the effect lasted up to four days after the first dose. Younger and middle-aged mice also saw their cognitive performance improve from saline control evaluations across both 1- and 4-day tests.

Metabolizing Mega Memory

While initial mice memory results showcased melatonin’s potential to improve cognition, they also prompted a new question: How does melatonin affect the brain? Is melatonin itself the cause of increased object familiarity, or are there other processes at work?

As it turns out, positive memory movement was tied to two melatonin metabolites — N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK). Both of these metabolites are produced when melatonin is broken down by the brain. The TMDU data suggested that melatonin itself along with these two metabolites began accumulating in the hippocampal region of the brain after being administered. This is notable because this cognitive component plays a critical role in converting lived experience into stored memories.

To test the impact of melatonin metabolites on improved memory, the TMDU team blocked its conversion into AFMK and AMK. The result? Mice were unable to benefit from the memory-boosting power of this hormone, suggesting that melatonin itself isn’t enough to enhance long-term memory formation. Measurable impacts depend on the conversion of melatonin into AFMK and AMK, with AMK outperforming its metabolic partner.

“We have shown that melatonin’s metabolite AMK can facilitate memory formation in all ages of mice,” Hattori explained in a EurekAlert press release.

Forward Progress for Thinking Back

While memory-maxing mice may help to stave off their cognitive decline, what does this research mean for humans?

“We are hopeful that future studies will show similar effects in older people,” Hattori said in the press release. “If this happens, AMK therapy could eventually be used to reduce the severity of Mild Cognitive Impairment and its potential conversion to Alzheimer’s disease.” But this is no small feat, because any efforts to single out melatonin as a scientifically vetted memory booster in a crowded market of supposed recall supplements would require both substantive testing and statistically significant results.

As PNAS notes, there’s good reason to believe that human trials will mostly mimic work with mice. For example, a 1999 investigation of Rett syndrome — which can cause slowed growth, loss of coordination and breathing problems in children — found that a specific mutation of gene MECP2 was the primary cause. Removing this gene in mice caused them to display symptoms similar to those of affected humans.

However, LiveScience points out that drug treatments that produce remarkable results in mice often deliver lackluster results in humans. This is because brain cells in mice may activate genes that either aren’t present or are in different places in human brains. While this doesn’t mean that AMK metabolites are doomed to fall into the realm of functional inter-species failure, it does point to the need for rigorous testing of melatonin in humans to determine if results match up.

If AMK applications do live up to expectations, there’s potential for this melatonin metabolite to become part of the standard treatment model for MCI and other age-related cognitive concerns. Even if results in humans aren’t as substantive as those in mice, the ability to reduce familiar object confusion and improve day-to-day life could be significant. It also suggests a massive market opportunity for synthetic melatonin producers and distributors.

Given the established safety of this hormone for human use and the built-in supplement distribution channels available, high-quality melatonin products could command a significant price as total recall remedies and could change the hormone market scale. Instead of competing on packaging or price, producers could focus on creating the highest-quality hormones available to facilitate metabolic breakdown and streamline the production of AMK.

Of Mice and Mental Health

Mice remain a reliable analogue for the human mind. And while there’s no guarantee that memory booster metabolites in rodent recipients will have the exact same effects in people, there’s enough evidence to warrant a melatonin investigation to assess the cognitive impact of this already helpful hormone on overall human cognition.

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