Introduction

Melatonin isn’t just the “sleep hormone”—it regulates over 500 genes and plays a key role in the body’s antioxidant defenses.

As we age, melatonin production declines significantly. By the time a person reaches 50 years old, melatonin levels are 50% of what they were at age 20. By age 80, melatonin production can be ten times lower than in teenagers. This reduction in melatonin is linked to changes in sleep patterns, circadian rhythm disruption, and overall health as we age.

Melatonin supplementation isn’t just beneficial for sleep, it also increases antioxidant enzymes like glutathione and superoxide dismutase, decreases biomarkers of oxidative stress, reduces systolic and diastolic blood pressure, and improves clinical outcomes in cancer, surgical patients, and pregnant women.

Because of its potent antioxidant effects, melatonin’s benefits extend to cardiovascular protection and cellular health. Its wide-reaching effects make it critical for much more than just a good night’s sleep.

In fact, this hormone could protect against neurodegenerative conditions like Alzheimer’s disease and other forms of dementia.

Melatonin and sleep

Melatonin is produced not only by the pineal gland but also in various tissues throughout the body like the gut.

Melatonin production follows a ~24 hour rhythm (a circadian rhythm) that’s synchronized to the light-dark cycle—melatonin levels rise in the afternoon, peak around midnight, and then fall to undetectable levels during the day.

When melatonin binds to receptors in the brain (MT1 and MT2), it synchronizes the body’s internal clock to promote feelings of sleepiness, reduces core body temperature (a signal for sleep onset), decreases the activity of wake-promoting neurons, and enhances the release of inhibitory neurotransmitters (i.e., GABA). Melatonin doesn’t necessarily force sleep, but rather, it promotes conditions conducive to it.

Does melatonin improve sleep?

Several meta-analyses have investigated the effects of melatonin supplementation in adults with a variety of sleep-related conditions, and overall, it appears to improve sleep duration, sleep quality, and sleep onset latency (it reduces the time to fall asleep). However, these effects are somewhat small—some outcomes like sleep onset latency and total sleep time may only improve by a few minutes depending on the population studied. And while melatonin may also improve subjective sleep quality, the clinical significance isn’t firmly established.

Here’s a summary of some of the latest evidence:

• In adults with respiratory conditions, metabolic diseases, and sleep disorders, melatonin improves overall sleep quality, as measured by the Pittsburgh Sleep Quality Index (PSQI); it also enhances PSQI scores (indicating improved sleep quality) in neurodegenerative conditions such as Alzheimer’s and Parkinson’s disease.
• In healthy adults without underlying conditions, melatonin modestly increases total sleep time by 14–20 minutes, improves sleep onset latency by 4–9 minutes, and enhances sleep efficiency by 2.2%.
• For adults with diagnosed insomnia, melatonin appears less effective, with little to no improvement in sleep duration, sleep onset latency, or sleep efficiency. However, for children and adolescents with insomnia, melatonin improves both sleep onset latency and total sleep duration.
• In children and adolescents with sleep and neurodevelopmental disorders (along with insomnia), melatonin significantly improves sleep onset latency (by 20–25 minutes) and total sleep time (by 25–41 minutes). In contrast, melatonin has minor effects on sleep onset latency and no effect on total sleep time for adults with insomnia or other sleep disorders—although adults with delayed sleep phase disorder (a condition characterized by the delaying of a person’s circadian rhythm) seem to improve their total sleep time when taking melatonin.

This suggests that melatonin's effectiveness is more pronounced in children and individuals with specific diseases than in healthy adults or those with insomnia. As with most supplements, your mileage may vary—some people report major improvements in their sleep when taking melatonin, while others notice little to no effect. Don’t expect miracles from melatonin, but don’t disregard its potential benefits either.

Melatonin dose and timing for sleep

The optimal dose and timing of melatonin will depend on your unique circumstances.

Melatonin dose

• The most effective dose for reducing sleep onset latency and increasing total sleep time ranges from 2 to 4 mg, but 3 mg/day appears to provide the greatest benefit, significantly outperforming the common 2 mg/day dose​.

Timing of administration

• Melatonin is most effective when taken 1 to 3 hours before bedtime or your desired sleep time.
• Administering it 2-3 hours before bed maximizes its sleep-promoting effects, reducing sleep onset latency by ~20 minutes—taking melatonin closer to bedtime (within an hour) is less effective for improving sleep​.

Melatonin for jet lag

Melatonin can help alleviate jet lag by adjusting the body's internal clock to match the destination's time zone. It is most effective when taken in the evening according to the local time of the destination.

• Dosage: The recommended dose is 3 mg when traveling eastward, though doses as low as 0.5 mg and up to 10 mg have been shown to be effective depending on individual response.
• Timing: Take melatonin in the evening of your destination’s local time for up to 5 days upon arrival. Eastward travel (crossing time zones in that direction) tends to require melatonin more frequently; westward travel spanning more than 12 time zones may also benefit from melatonin, but travel spanning fewer than 12 time zones often does not require it.

Melatonin for shift workers

For people working night shifts or rotating schedules, melatonin can help realign their sleep-wake cycle after a shift change. However, the evidence is not entirely conclusive, so its effectiveness may vary between individuals.

• Dosage: Typically, 1–3 mg of melatonin can be effective for shift workers, though exact recommendations vary.
• Timing: Melatonin should be taken in the evening, before the desired sleep time in the shift schedule, to help reset the sleep cycle.

Both for jet lag and shift work (and everyone for that matter) melatonin’s efficacy can be enhanced by controlling light exposure and maintaining consistent sleep routines.

Does melatonin supplementation affect endogenous production?

Despite the well-known benefits and high safety profile of melatonin, some people are concerned that supplementing with it will impair our body’s natural production. This doesn’t appear to be the case, at least when using a low but effective dose at the right time of day. Studies on melatonin administration have found that doses of 0.5 mg, 5 mg, and even 50 mg per day do not reduce the body’s natural melatonin production—for people with insomnia, it may even enhance it.

After all, we consume foods that contain tryptophan (and some that contain melatonin), an amino acid that gets metabolized and eventually converted into melatonin. Admittedly, the amount of melatonin we derive from these sources is incredibly small (nanogram and picogram amounts)—we’d need to consume large amounts of them to achieve the melatonin content of a supplement.

Age-related declines in melatonin and neurodegeneration

People with sleep problems, older adults who may be dealing with a disrupted sleep-wake cycle, and people with cognitive complaints may want to consider supplementing with Melatonin. Adults aged 50 and older should take melatonin (around 0.3 mg per night) to offset the age-related reduction in melatonin; levels are about half as much at age 50 compared to age 20 and ten-fold lower at age 80 compared to teenage years.

Could these age-related declines in melatonin also be contributing to neurodegeneration? We know that sleep is one of the most important factors for maintaining cognitive health and resilience. Melatonin is intricately involved in our ability to sleep well.

If you’re someone who’s worried about cognitive decline or who suffers from sleep-related issues, melatonin should be on your radar.

That’s because melatonin may have direct and indirect neuroprotective effects, and it may help reduce the burden of one of the most debilitating cognitive conditions of them all—Alzheimer’s disease.

What is Alzheimer’s Disease?

Alzheimer’s disease is a neurodegenerative condition characterized by the accumulation of amyloid-beta plaques, neurofibrillary tangles, and neurodegeneration.

Genetics play an important role in Alzheimer’s disease. A variant of the APOE gene called APOE4 is the primary genetic risk factor for late-onset Alzheimer's disease. Carrying one copy of APOE4 increases a person's Alzheimer's disease risk two- to threefold while carrying two copies increases it as much as 15-fold. The health of the blood vessels that comprise the blood-brain barrier may also be a critical and early pathological feature of Alzheimer's disease and other dementias.

Environment and lifestyle also contribute to Alzheimer’s disease risk, and sleep is one of the most well-recognized modifiable lifestyle factors.

When we sleep, the brain clears out metabolic waste and protein fragments via the glymphatic system. Sleep also strengthens the blood-brain barrier, bolsters synaptic integrity, and regulates neuroinflammatory processes, all of which are crucial for promoting a healthy brain.

Improving sleep reduces Alzheimer’s disease risk, and it therefore seems reasonable to establish a relationship between melatonin and Alzheimer’s disease. And that’s just what we see: Studies have observed lower levels of melatonin in the CSF of people with Alzheimer’s disease and higher risks of Alzheimer’s disease in people working the night shift who have impaired melatonin production and release. On the other hand, older adults with higher melatonin levels have less cognitive impairment and depressed mood, both of which are early warning signs of Alzheimer’s disease.

Surprisingly, it might not be all about sleep—there appear to be several mechanisms by which supplementing with exogenous melatonin could protect against or slow the progression of Alzheimer’s disease, such as its antioxidant properties.

How melatonin protects against Alzheimer’s

Melatonin reduces the production and enhances the clearance of amyloid-beta plaques from the brain by blocking amyloid-beta-producing enzymes and increasing the uptake of amyloid-beta proteins into brain interstitial fluid for removal via the lymphatic system.

Melatonin also blocks tau hyperphosphorylation, a process that leads to the formation of detrimental neurofibrillary tangles. Together, neurofibrillary tangles and hyperphosphorylated tau proteins induce brain mitochondrial dysfunction and oxidative stress. Giving melatonin to older adults who have mild cognitive impairment reduces the levels of tau protein in their CSF.

And then there’s the role of insulin. Insulin resistance in the brain is implicated in Alzheimer’s disease and is one reason why some researchers refer to the condition as “Type 3 diabetes.” Melatonin has been shown to enhance beta-cell function (the beta-cells are insulin-producing cells in the pancreas) and reduce the burden of beta-amyloid plaques and tau hyperphosphorylation in the brain of diabetic rats.

As a brain antioxidant, melatonin can limit Alzheimer’s disease burden by reducing oxidative stress. Because of its unique chemical structure, melatonin can cross the blood-brain barrier and gain access to neurons and mitochondria, where it directly neutralizes reactive oxygen and reactive nitrogen species—free radicals that cause central nervous system oxidative stress and inflammation. Melatonin also detoxifies the brain of metals like iron and bolsters the activity of the Nrf2 pathway, which regulates the body’s antioxidant defense systems.

Adequate melatonin levels and proper melatonin timing also synchronizes our body and brain’s circadian rhythms. Melatonin release by the pineal gland is one of the most important signals that our body receives for circadian entrainment—when it’s out of whack, our health is compromised. As it turns out, people with Alzheimer’s disease have lower melatonin levels and disrupted sleep-wake rhythms. In a vicious cycle, these disrupted rhythms also contribute to many Alzheimer’s-disease-associated pathways. Supplementing with melatonin may act as a “circadian shield”—a way to maintain normal rhythms in hope of preventing cognitive decline and a way to restore rhythms to slow disease progression.

There’s also evidence that melatonin can enhance the integrity of the blood-brain barrier, not only by protecting it from damage, but by strengthening it directly.

Another mechanism involves waste clearance. Melatonin exerts indirect effects on the brain’s waste-removing system that happens during sleep (known as the glymphatic system) by promoting better quality sleep and by reducing blood pressure during sleep. Enhanced glymphatic clearance means that waste products like beta-amyloid get cleared out rather than accumulate.

Does melatonin improve Alzheimer’s disease symptoms?

These are all compelling mechanisms even if they don’t provide definitive proof of melatonin’s efficacy in combating cognitive decline.

The real question is whether supplementation helps or not, and we’ll need more studies to find out. The limited evidence that is available suggests that melatonin has cognition-enhancing effects in healthy older adults, and two meta-analyses suggest that melatonin administration improves cognitive function in adults with mild Alzheimer’s disease, an effect that’s strongest with low-dose and medium-term supplementation. In fact, melatonin outranked several pharmacological interventions (e.g., donepezil, galantamine, and memantine).

Conclusion

Will melatonin be the end to Alzheimer’s disease? Probably not.

The disease is widespread and afflicts tens of millions of people annually. But given the dismal performance of drugs developed to treat Alzheimer’s disease, it certainly can’t hurt to explore melatonin as an option, especially since it’s widely accessible, affordable, and carries very little risk. Exogenous melatonin is even being explored for its potential benefits for the cardiovascular system.

Addressing key factors such as diet, inflammation, insulin resistance, exercise, intermittent fasting, and sleep optimization seem to be most promising for preventing Alzheimer’s disease and slowing its progression. Lifestyle and environment are the first-line defense systems against cognitive decline.

But don’t sleep on melatonin. It might be the next big thing in neuroprotection.