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. 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—we’d need to consume large amounts of them to achieve the melatonin content of a supplement. But even if you aren't supplementing with melatonin, there's a good chance you're getting some through dietary sources.

Age-related declines in melatonin and neurodegeneration

While I don’t think that everyone should be taking melatonin, there’s a compelling argument that 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 it. In fact, I’ve spoken before about how people 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. No wonder so many adults have sleep complaints!
 

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, and 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. Even if you aren’t someone who’s worried about either of these, after reading this email, you still might be inspired to explore melatonin supplementation due to its other cellular benefits.
 

That’s because, as we’ll discuss, 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.

The role of APOE4

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.

The role of sleep 

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.
 

Melatonin levels are lower in Alzheimer's disease

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 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.” Well, 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 amyloid-beta 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 (i.e., donepezil, galantamine, and memantine).

Final thoughts

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. Plus, there may be other benefits unrelated to sleep or brain health. For example, exogenous melatonin is 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 against cognitive decline.
 

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

To learn more about my thoughts on melatonin, watch Q&A Episode #54:

Relevant timestamps related to melatonin:

• 00:06:11 - Can melatonin function as an antioxidant?
• 00:07:18 - How melatonin might protect against radiation
• 00:08:15 - Are there adverse effects of high-dose melatonin?
• 00:08:45 - Does taking melatonin affect the body's natural melatonin production?
• 00:11:02 - Melatonin's activity on antioxidant and stress-response genes
• 00:13:30 - Could too much melatonin lead to reductive stress?
• 00:17:05 - Does melatonin lower blood pressure?
• 00:21:15 - What happens to melatonin levels with age?
• 00:23:38 - Does Rhonda supplement with melatonin?