Probably most of my readers think they know the essentials about melatonin, the hormone produced in the brain’s pineal gland that helps regulate the body’s sleep-wake cycle, aka its circadian rhythm. Chances are, you’ve probably taken it from time to time when struggling with sleep or crisscrossing time zones. For those who imbibe, the idea is that as evening falls, your primary energy hormone cortisol drops and melatonin goes up, cueing the body for sleep, which is why some have dubbed melatonin “the hormone of darkness.” 

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Well, guess what? Melatonin has come into the light. The latest research has revealed that it’s produced in the mitochondria, the cell powerplants, in a number of your organs, and that it’s involved a wide range of important physiological processes, some of which have nothing directly to do with sleep – we’ve got melatonin receptors distributed throughout the body. 

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And melatonin, like most of our hormones, declines with age, along with the rest of us. That raises the tantalizing possibility that if we can supplement it back up to the levels we enjoyed in our twenties (remember how well we used to sleep back then), we’ll derive an all systems-go physiological lift and protection from the insidious “diseases of aging,” especially neurodegenerative diseases like Alzheimer’s and Parkinson’s that so often compromise our longevity and our healthspan. It’s pretty exciting idea and it makes melatonin and brain health one of the most intriguing research frontiers in longevity medicine. What kind of brain health support can we expect? Here’s a look at what you need to know about it and it’s potential to stack the deck in your brain’s favor:      

Melatonin’s been around for ages, so why’s it a big deal now? 

The idea that supplemental melatonin might be something more than a sleep aide isn’t brand new. Some of you may be old enough to remember a best-seller from the mid-‘90s, The Melatonin Miracle. But since then, the research has only gotten stronger. The real shot across the bow was an academic review paper that came out last year, “Melatonin: A potential nighttime guardian against Alzheimer’s,” which summarized decades of investigation looking at the possible health benefits of supplemental melatonin. While the research is still relatively early days, what’s so exciting is that the basic science has given us a theoretical framework to explain the positive benefits we’ve measured in humans.   

Melatonin and the ‘Hallmarks.”  

Our best understanding of aging is that isn’t caused by just one thing, but instead it’s driven by a number of interlocking processes, the so-called “hallmarks of aging.” And melatonin is in the thick of the hallmark mix. The hormone is a powerful antioxidant, that is, it neutralizes cell and DNA-damaging “free radical” compounds, and unlike other well-known antioxidants like vitamin C and E, it doesn’t generate any pro-oxidant molecules in the process. Think of it as cleaning out the cellular “rust” so the whole human system can operate more smoothly, with less inflammation. And it attacks inflammation directly, by helping to suppress the body’s production of inflammatory molecules. That’s exactly what you want when it comes to protection from neuro-degenerative diseases like Alzheimer’s which we now think of, at least in part, as a disease of the inflamed brain. 

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And last, but not least, the science has shown us that not only is melatonin produced in the cell mitochondria in different organs – the brain, the gut, the liver, the kidney – the hormone itself actually helps protect the mitochondria from damage. That’s super-valuable since generating energy in the body is a dirty business and the decline and decay of those mitochondria is one of the Hallmarks of Aging we want to resist. 

What’s going on with melatonin in the brain, specifically? 

Quite a bit actually. Probably by now, many of us are familiar with the idea that proteins in the brain can clump together to form the plaques and tangles so often found in the damaged brains of people with Alzheimer’s. Whether these (amyloid protein) plaques and (tau protein) tangles are actually causing the cognitive disruption in Alzheimer’s patients is still debated but often, it does seem to be a relevant part of the disease process. 

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The lab work has shown us that melatonin can help these proteins maintain their proper shape so they’re less prone to misfolding into clumps and tangles.  (Interestingly, melatonin also seems to do something similar in the cardiovascular system, helping to prevent LDL cholesterol particles from clumping into atherosclerotic plaque inside the coronary arteries.) 

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We also have evidence that melatonin helps reinforce the blood brain barrier, protecting our sensitive brains from toxins that circulate in the rest of the body’s bloodstream. And, finally, it looks to shield neurons directly. Likely working through particular melatonin receptors in the brain, it helps protect them from deterioration and even cell death. 

Melatonin outside the lab. 

All that basic science looking at what melatonin can do in the body (admittedly, mostly in human cell lines in a petri dish and in animal models) is well and good, but it’s even better when it can serve as a theoretical model to explain the connections we see in the real world, between melatonin levels and health and longevity. Observational studies have shown us that older people with higher hormone levels tend to be healthier than those with lower levels. On average, they have sharper memories and a hippocampus – the brain’s memory center – that’s larger. Not surprisingly, people with Alzheimer’s have melatonin levels seven times lower than their counterparts who don’t have AD. By themselves, these associations don’t mean that high melatonin levels are promoting healthy brain aging and lower levels the opposite. But it’s a good sign that we’re barking up the right tree. Given that levels of the hormone can be roughly three to four times lower in an 80-year-old than in a teenager, it may be the case, admittedly not yet proven, that if we can supplement ourselves back to those robust teenage levels, our aging brains will thank us.    

‍Melatonin and getting that often-elusive good night’s sleep.

Let’s not forget about sleep. Just because we now know that melatonin does more than help ensure a good night’s sleep doesn’t mean sleep isn’t a big part of the brain aging/Alzheimer’s puzzle. It’s during the deepest phases of a night’s sleep that the brain goes about the business of cleaning out the day’s accumulated gunk and preparing itself for the next day. We call it the glymphatic system – the nightly rinse cycle – and it’s essential for brain resiliency. So, when our melatonin levels decline with age, we have a more challenging time getting that good night’s sleep and our brains do a not-so-good job of housecleaning. It’s a viscous circle. A pattern of poor sleep in our middle or elder years steers us toward the Alzheimer’s track and then (making matters worse) Alzheimer’s makes sleep that much more difficult. In fact, we do have observational studies that suggest a strong connection between sleep and Alzheimer’s disease. Two years ago, researchers in the UK crunched data from 276,000 people and found that people involved in night shift work, which depresses melatonin levels, had a 1.5 times higher risk of AD.   

The clinical trials offer even more clues to melatonin’s positive powers.

No question that mice are the stars of melatonin research. A number of studies have shown that pumping up their hormone levels yields improvements in memory and learning ability – just what we want for our aging human brains. The results of the clinical trials (that is, on humans) are somewhat more mixed but still encouraging. One large “meta-analysis” of 22 randomized controlled trials (the evidentiary gold standard) showed that AD patients who’d received more than 12 weeks of melatonin supplementation showed improvement on a standardized cognitive test. The results were more impressive in the subjects who had only mild Alzheimer’s, certainly positive news.  The less great news though is that once the disease process is well underway, combatting the decline becomes a far more formidable challenge, one that modern medicine – or, for that matter, melatonin – has yet to meet, to stop it or slow it in a big way. However, the additional good news is that we also have preliminary evidence from these studies indicating that melatonin may have an anti-depression effect as well. 

The rules for the dosing game are still being written.

One likely reason why the human melatonin trials haven’t returned consistently positive results is that proper dosing is still all over map. Many of the Alzheimer trials for instance have used large doses that I tend not to recommend to my patients – particularly elderly patients more prone to morning grogginess and at risk for falling – until further research has established what can be safely tolerated and what can’t. 

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People who currently take melatonin supplements for sleep are usually in the 1-5 milligram range. I suspect that melatonin will in time come into its own as an everyday brain-protective supplement, possibly even at much smaller doses, like less than 1mg, or roughly about what a healthy young person’s system might produce. As for using it therapeutically at much higher doses for patients suffering from neurodegenerative diseases like Alzheimer’s, Parkinson’s and Huntington’s, we’ll have to see where the science takes us. 

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For now, if you are taking melatonin regularly, probably best to cycle off it periodically, and always work with an integrative health care practitioner to keep an eye on effects and interactions. Also check with your doc before taking melatonin if you take blood thinners, immunosuppressants, diabetes meds, or have epilepsy, as melatonin can interact with certain drugs.

Mind your melatonin (with a caveat emptor).

Keep in mind, when shopping for melatonin, supplements are only lightly regulated, so the onus is on you to be a smart shopper. Look for the most reputable brands which have been tested by independent labs, third party testing and/or USP verification to ensure consistent dosing, as the actual amount of melatonin found in run-of-the-mill supplements can vary wildly. While almost all the product on the market is synthesized melatonin, at least one brand, Herbatonin, is a plant extract (yes, small amounts of the hormone are found in the plant world) and there is some evidence that it may deliver a more efficacious dose.