At the top of my supplement list is melatonin, and it has nothing to do with how well I sleep! Instead, the benefits of this ‘sleep hormone’ are many and varied, including boosting immune function, preventing Alzheimer’s disease, and staving off osteoporosis.
What is melatonin?
Melatonin is a hormone synthesized by the pineal gland at night. The pineal gland releases it and it circulates throughout the body. As a hormone, melatonin has various functions including synchronizing the day-night cycle.
Biosynthesis of melatonin:
Tryptophan is the precursor amino acid needed for the production of melatonin. Most foods containing protein usually contain tryptophan, and it is readily available in most people’s diets.
Tryptophan converts to serotonin and then into melatonin in a multistep process. Along the way, several cofactors needed in this process, including folate, B6, B12, and possibly zinc and magnesium.[ref][ref]
The pineal gland produces melatonin at night:
The pineal gland is a tiny endocrine gland in the brain, and pretty much all it does is produce melatonin. Rene Descartes, the 17th-century scientist and philosopher, described the pineal gland as “the principal seat of the soul and the place in which all our thoughts are formed.”[ref]
Melatonin can be created inside of cells in other organs as well, and it can act as an intracellular antioxidant.[ref] But the majority of melatonin production happens at night and is released by the pineal gland into circulation.
The ‘at night’ part is important. There are two things controlling melatonin production: the circadian clock and light from the environment. The suppression of melatonin synthesis in the pineal gland occurs when light hits the retina of the eye. Specifically, light in the blue wavelengths (around 480nm) activates a non-image-forming photoreceptor called melanopsin, which sends a signal to reduce melatonin production. The lack of 480nm light allows melatonin production to happen in large amounts in the pineal gland.[ref]
The pineal gland, aging, and melatonin production:
As we age, the pineal gland begins to calcify and produce less melatonin at night. This is a downhill slope from adolescence onward. The amount of uncalcified pineal gland volume predicts the amount of melatonin produced at night.[ref]
What is supplemental melatonin useful for?
If we all are destined to produce less melatonin with aging, the question becomes whether or not supplemental melatonin is beneficial.
Melatonin for sleep: regulating circadian rhythm:
Let’s get “sleep” out of the way first, as a topic, since this is what most people think of in regards to melatonin.
Melatonin is often promoted as a supplement to take when you can’t sleep — advertised as the sleep hormone. A review of 35 randomized controlled trials showed that melatonin helps a little with sleep-onset insomnia, but that it isn’t a huge effect.[ref]
The exception to the ‘not a huge effect’ is for people who have delayed-sleep phase disorder. For this minority of people, supplemental melatonin can have a significant effect on shifting the timing of sleep and decrease sleep latency significantly.[ref]
Additionally, melatonin has shown to help sleep quality and insomnia in elderly people.[ref]
Alzheimer’s Prevention with Melatonin:
Melatonin is linked to Alzheimer’s disease in several important ways:
- Pineal calcification is greater in Alzheimer’s patients than age-matched controls without dementia.[ref]
- There are decreased melatonin receptors (MT1 and MT2) in brain regions of people with Alzheimer’s disease.[ref]
- Decreased melatonin production is found in Alzheimer’s patients in comparison to age-matched controls.[ref]
- A melatonin receptor (MT1) variant is linked both to fewer melatonin receptors in the brain and to an increased risk of Alzheimer’s disease.[ref]
Using supplemental melatonin as part of an Alzheimer’s prevention strategy has emerging research to back it up. For instance, melatonin as a free radical scavenger reduces amyloid-beta production. Additionally, circadian rhythm impacts amyloid-beta production, so melatonin acting to set circadian rhythm is also important.[ref]
In a clinical trial of people already in the early stages of Alzheimer’s disease, supplemental melatonin (timed-release, 2mg) slowed the cognitive decline.[ref]
Immune system support depends on melatonin:
When it comes to an immune response, balance is key. You want the body to strongly fight off a pathogen, killing off nasty bacteria or viruses. But… you don’t want too strong of an immune response (or too long of a response), resulting in damage to your own cells. Melatonin modulates the immune system response.
Your immune response varies according to your circadian rhythm. In general, your body is primed for an immune system response during the day, with fewer immune system cells produced at night.[ref]
Research shows that melatonin stimulates the production of several types of immune system cells including natural killer cells and CD4+ cells. Both of these decline with age (along with melatonin.) Supplemental melatonin, therefore, may help to enhance immune function in older people.[ref]
Importantly, though, melatonin also acts to modulate the immune response. When the immune response is overactive, melatonin reduces inflammatory mediators and neutrophil infiltration.[ref]
A recent study showed that supplemental melatonin use reduced the likelihood of a positive COVID-19 test by 28%.[ref] Other studies point to the benefits of supplemental melatonin in viral infections as well.[ref][ref]
Bone mass and melatonin:
Melatonin is also important for healthy bone mass. Animal studies show that reduced pineal gland production of melatonin causes low bone mass and that a deficiency of the MT2 melatonin receptor also causes low bone mass. The decrease in bone mass is due to decreased osteoblasts, which form new bone.[ref]
Animal studies show that supplemental melatonin decreases the normal ‘post-menopausal’ bone loss.[ref]
The effects from melatonin, though, may be more long term rather than a quick turn around. A six-month-long study of perimenopausal women showed that 3mg of melatonin nightly did not statistically affect bone density scores.[ref]
A year-long clinical trial in postmenopausal women with osteopenia found that melatonin did increase bone mineral density (BMD). Interestingly, the increase seemed dependent on the dose. Women taking 3mg of melatonin per night increased femoral BMD by 2.3%, which was greater than the 0.5% increase in the 1mg/day group. Both supplement groups, though, outperformed the placebo group.[ref]
Melatonin acts both in bone health for the jaw and as an anti-inflammatory to decrease periodontal inflammation.
In periodontal disease (inflammation of the gums), there is an inverse correlation between melatonin levels in the saliva and the degree of inflammation. Additionally, salivary melatonin levels are higher (on average) in people without gum disease, as compared to people with periodontitis or gingivitis.[ref][ref]
Melatonin is also important in jaw bone health. Numerous animal studies clearly show that melatonin supplementation helps to increase bone growth around implants. [ref]
A clinical trial found that 6mg of supplemental melatonin decreased inflammation (IL-6) and decreased gum bleeding in type 2 diabetics with periodontal disease.[ref]
Migraine prevention: melatonin is as good as prescription drugs?
A placebo-controlled clinical trial compared melatonin to amitriptyline (prescription migraine med) for migraine prevention. The study participants took 3mg of melatonin nightly for 4-weeks. Results showed melatonin reduced migraine frequency by 50% performing slightly better than amitriptyline with fewer side effects.[ref] Similar results were found when comparing melatonin to valproate, as well.[ref]
Depression, circadian rhythm, melatonin:
Circadian rhythm disruption can be at the root of depression, and many circadian rhythm genetic variants increase the risk of depression and bipolar disorder. (Read more here). But how does melatonin impact depression?
Exposure to light at night, even dim levels of light when sleeping, can reduce melatonin production. Dim light at night significantly increases the risk of depression in older adults.[ref]
A prescription antidepressant that binds to the melatonin receptor, agomelatine (Valdoxan), is an approved depression and anxiety medication in Europe and Australia. [ref]
What about using melatonin supplements to treat depression? The clinical trial results are all over the place, with some showing it to be effective and others showing no difference from placebo.[ref]
Mitochondrial function depends on melatonin:
Mitochondria produce the energy, stored as ATP, that drive cellular function. The mitochondria can produce melatonin for use within the cell. Melatonin acts as a free-radical scavenger, regulating free radical generation in the mitochondria.[ref]
Cell studies show that melatonin stops mitochondrial fission while enhancing mitophagy (clearance of damaged mitochondria) in liver cells.[ref] In brain cells, “melatonin supplementation reduces cell death and restores mitochondrial function through the regulation of autophagy.”[ref] When challenged with viral-induced liver failure, melatonin modulates mitophagy, preserving mitochondrial function when needed.[ref][ref]
Additional clinical trials of supplemental melatonin:
- Atopic dermatitis: A clinical trial in kids with atopic dermatitis (eczema) found that 3mg of melatonin per night reduced the rash significantly. It also helped the kids fall asleep 21 minutes faster.[ref]
- Blood glucose levels: A recent meta-analysis shows that supplemental melatonin reduces fasting blood glucose levels. Additionally, it increases insulin sensitivity, but it doesn’t influence overall insulin levels.[ref]
- Blood pressure: Another meta-analysis pooled the data from clinical trials on blood pressure and melatonin supplementation. The results showed that melatonin supplements reduce blood pressure (a little) in people who have high blood pressure.[ref]
- DNA damage: A trial of 20mg/day of melatonin in high-intensity interval training athletes decreased DNA damage.[ref]
Cancer and melatonin:
Common sense note: If you have questions about cancer, talk with your doctor. While there are likely cancer prevention benefits from melatonin, it is not going to cure cancer (even if you read that it would on the Facebook).
Breast cancer: Numerous studies have looked at the link between higher melatonin levels and decreased breast cancer risk. These studies show several different mechanisms through which higher melatonin levels protect against the risk of breast cancer. For example, exposure to light at night, which reduces endogenous melatonin production, is a well-studied risk factor for breast cancer. Additionally, studies show that women with ER+ breast cancers have lower nocturnal plasma melatonin concentrations on average. One more way that melatonin protects against breast cancer is through protecting against the harmful effects of cadmium, which acts as a metalloestrogen to increase the risk of breast cancer.[ref][ref]
Lung cancer: Exogenous melatonin is being studied as a combination treatment with chemotherapy for lung cancer. The benefits may stem from melatonin’s ability to inhibit metastasis as well as slow tumor growth.[ref]
Cancer in general: Melatonin acts as a free radical scavenger, decreasing oxidative stress and preventing damage to DNA. DNA damage in the wrong place can cause cancer. Thus, in general, melatonin could decrease the initiation of cancer-causing mutations. Additionally, melatonin acts through the MT1 receptor at night to protect against double-stranded DNA breaks. Here is a great overview of all of the research on melatonin reducing DNA damage from radiation, reactive oxygen species, and other free radicals.
The World Health Organization lists light at night as a probable carcinogen. The increase in cancer due to light at night is, in part, due to the reduction in melatonin.
Melatonin supplements: getting into the details
In the US and Canada, melatonin is considered a dietary supplement and available over the counter. In other countries, such as the UK, it is considered a drug and you may need a prescription.
More is not always better:
When you look for melatonin supplements, you are going to find a wide range of products. Supplements come in 0.3mg (300 mcg) to 10 mg ranges. Most studies seem to use 1 – 3 mg doses, but the overall range is from 0.1mg to 50mg.[ref]
Since your need for melatonin increases with age, there is no one-size-fits-all answer here… Instead, let’s look at how quickly metabolization occurs and the different formulations available, and you can experiment to find out what works best for you.
The half-life of supplemental melatonin:
A study in young adult males looked at the pharmacokinetics of a 10 mg oral dose of supplemental melatonin. The results showed that the absorption of oral melatonin is pretty quick, with melatonin levels rising after 6 minutes. Maximum absorption was reached at 40 minutes, and the half-life for elimination was 53 minutes.[ref]
Here is a graph of how quickly melatonin is metabolized:[CC license ref]
Timed-release vs. immediate-release melatonin:
With the half-life of oral melatonin being less than an hour, you may want to consider a timed-release (sustained-release) melatonin supplement instead. This should better mimic normal, overnight melatonin production.
Timed-release melatonin (2mg dose) has shown in a double-blind, placebo-controlled clinical trial to decrease sleep latency (the time it takes to get to sleep) in people age 55+. Additionally, timed-release melatonin improved sleep quality for all age groups (18-80).[ref]
Metabolism of melatonin:
The CYP family of enzymes break down or metabolize drugs (medications, supplements) as well as substances produced in the body. In metabolizing melatonin, the enzymes CYP1A1, CYP1A2, and CYP1B1 can all be used. Additionally, CYP2C19 plays a minor role in metabolism.[ref] While variants that slow the function are common in all of those CYP genes, it is less likely that a variant in any single gene will cause issues with melatonin due to the ubiquity of all three CYP enzymes.
Melatonin can also be used and broken down in reactions involving neutralizing reactive oxygen species (ROS), and it can be metabolized in the mitochondria using cytochrome C. In the brain, the metabolism of melatonin uses IDO, also important in the kynurenine pathway. Interestingly, some of the metabolites of melatonin also are important as antioxidants that interact with ROS.[ref]
Side effects reported for melatonin supplements:
Anecdotal side effects include grogginess in the morning after larger doses of melatonin and a general hangover-type feeling.
The majority of clinical trials report no adverse effects from melatonin, but this likely refers to significant effects. The trials that do include minor, short-lived adverse events show melatonin supplements may be linked to fatigue, mood, or ‘neurocognitive performance’ for some people. These events were linked to dosage and timing.[ref] In other words, if you take too much melatonin or take it too late at night, the next morning you could be foggy and grumpy.
Will you stop producing melatonin if you take supplemental melatonin?
The answer here seems to be ‘no’. Studies show no rebound effects or withdrawal symptoms from stopping supplemental melatonin.
- One study that looked at 6-months of supplemental timed-release melatonin found no withdrawal symptoms and no rebound insomnia when melatonin was stopped.[ref]
- Other studies on longer-term (10+years) of melatonin supplement also found no adverse effects on sleep when stopping melatonin.[ref]
Quality of melatonin supplements:
Not all supplements contain the amount that they state on the label. Labdoor is a company that tests supplements off the shelf to see if they contain what is on the label and whether there are any impurities in the product. Check out Labdoor’s ranking for melatonin supplements. (I have no affiliation with this company – I just like what they are doing.)
Medication interactions and pregnancy:
Medication interactions with epilepsy.
Melatonin may decrease blood pressure in people with hypertension, so it is possible that you could have an interaction with blood pressure lowering medications.[ref]
If you are pregnant or breastfeeding — talk to your doctor, of course, but in general, melatonin supplements are not recommended. Melatonin does cross the placenta, and it is important for the baby. Instead, you may be better off blocking blue light at night to increase your natural melatonin levels, rather than supplementing with higher amounts than are normal for your body.[ref]
Genetics and Melatonin:
Below is an overview of some of the studies associated with melatonin-related genetic variants that are available in 23andMe or AncestryDNA data.
Variants related to the production of melatonin:
AANAT gene: The alkylamine N-acetyltransferase (AANAT) gene controls the rhythmic production of melatonin by the pineal gland.
Check your genetic data for rs28936679 (23andMe v4 only):
- A/A: rare, linked to delayed sleep phase disorder[ref]
- A/G: rare, may cause delayed phase sleep disorder
- G/G: typical
Members: Your genotype for rs28936679 is —.
Check your genetic data for rs3760138 (AncestryDNA):
- G/G: decreased melatonin; increased risk of breast cancer[ref], increased risk of lupus[ref], possibly increased risk of depression[ref]
- G/T: typical risk
- T/T: typical
Members: Your genotype for rs3760138 is —.
TPH2 Gene: The TPH2 gene codes for the rate-limiting enzyme involved in the conversion of tryptophan to serotonin, which can then be converted to melatonin. The link between TPH2 and melatonin levels is indirect, but I’ve included it here to illustrate the connection between melatonin precursors and disrupted circadian rhythm.[ref][ref]
Check your genetic data for rs4290270 (23andMe v4; AncestryDNA):
- T/T: increased risk of waking early, increased risk of depression[ref][ref]
- A/T: probably a slightly increased risk of waking early, depression (this is the most common genotype)
- A/A: typical
Members: Your genotype for rs4290270 is —.
Check your genetic data for rs4570625 (23andMe v4, v5; AncestryDNA):
- G/G: less TPH2 function[ref], more likely to achieve depression remission with escitalopram*[ref]
- G/T: higher TPH2
- T/T: higher TPH2, less depression[ref]
Members: Your genotype for rs4570625 is —.
*Escitalopram (Lexapro) is an antidepressant that acts on the circadian system.[ref]
Melatonin receptor variants:
MTNR1B gene: This gene codes for the MT2 melatonin receptor.
Check your genetic data for rs10830963 ( 23andMe v4, v5 ; AncestryDNA):
- G/G: linked to a higher risk of diabetes, gestational diabetes[ref][ref][ref][ref] increased fasting glucose – don’t eat dinner late[ref]
- C/G: linked to a higher risk of diabetes, increased fasting glucose – don’t eat dinner late
- C/C: typical
Members: Your genotype for rs10830963 is —.
Check your genetic data for rs1387153 (23andMe v4, v5, AncestryDNA):
- T/T: increased fasting glucose, increased risk of gestational diabetes[ref]
- C/T: somewhat increased fasting glucose
- C/C: typical
Members: Your genotype for rs1387153 is —.
MTNR1A gene: This gene codes for the MT1 melatonin receptor.
Check your genetic data for rs2375801 (23andMe v4)
- C/C: increased risk of cancer metastasis (liver)[ref]
- C/T: increased risk of cancer metastasis (liver)
- T/T: typical
Members: Your genotype for rs2375801 is —.
Check your genetic data for rs6553010 (23andMe v4, AncestryDNA):
- A/A: increased risk of cancer metastasis (liver)[ref]
- A/G: increased risk of cancer metastasis (liver)
- G/G: typical
Members: Your genotype for rs6553010 is —.
Check your genetic data for rs12506228 (23andMe v4, v5; AncestryDNA):
- A/A: likely fewer melatonin receptors in the brain, a greater impact from working the night shift, increased risk of Alzheimer’s[ref][ref]
- A/C: somewhat fewer melatonin receptors, somewhat impacted from light at night, increased risk of Alzheimer’s
- C/C: typical MTNR1A variant
Members: Your genotype for rs12506228 is —.
Note: As far as I can find, no research exists showing the CYP enzymes involved in melatonin metabolism have an effect on supplement melatonin.
Lifehacks for increasing your melatonin production:
While supplements are a nice option, you may also want to consider ways to raise your own natural production of melatonin. Producing melatonin endogenously is likely a better option since it rises and falls at the right time in sync with your circadian rhythm.
What can you do to increase production at night?
Block blue light at night:
Light in the blue wavelengths at night suppresses melatonin when it is supposed to rise. The ubiquitous exposure to light at night relates to the changes in our modern world – from your cellphone, TV, bright LED lightbulbs, to your laptop, or tablet.
If you aren’t willing to turn off everything with a screen and switch to old-fashioned, dim, yellowish bulbs for several hours before bed, you may want to wear blue-blocking glasses. You can find lenses that block 100% of blue light (amber or orange-colored lenses) in many different styles. Studies on 100% blue-blocking glasses show that wearing the glasses for a couple of hours prior to bedtime raises night-time melatonin production by about 50% in two weeks.[ref]
A recent study found that, on average, home lighting in the evening suppresses melatonin production significantly. By home lighting, the study was looking at the amount of light people are normally subjected to after dark – from turning on the overhead lights in your living room to the additive light from electronics. The interesting thing about the study was that the range of melatonin suppression is huge: At the low end, there were a few people that were barely affected by light in the evening hours, but at the high end, some people had up to an 86% suppression of melatonin production just from normal household lights.[ref]
Increasing tryptophan to increase melatonin:
Tryptophan is an amino acid that is converted by the body into serotonin and then into melatonin. A diet that restricts tryptophan causes decreased serotonin and melatonin production.
A clinical trial found that tryptophan-enriched breakfast porridge increased melatonin production at night in a group of elderly people.[ref]
Another trial found that for university students, a tryptophan-rich breakfast along with bright light during the daytime significantly increased melatonin at night. This study was interesting in that it looked at the interaction between tryptophan in the morning, the amount of light during the day, and melatonin at night. This four-way interaction showed that tryptophan + bright light was most effective, by far, at increasing melatonin at night. The second most effective, though, was simply bright light coupled with a low tryptophan breakfast.[ref]
Another study in younger children found that tryptophan, vitamin B6, and morning sunlight could increase serotonin and melatonin.[ref]
Not all studies, especially in younger individuals, show that tryptophan in the morning increases melatonin at night.[ref] One key here may be what else is eaten with the tryptophan supplement. An l-alpha, amino acid transporter (LAT1) needs to help tryptophan cross the blood-brain barrier.[ref] The addition of the tryptophan supplement to a carbohydrate-rich breakfast instead of a protein-rich breakfast may allow for more of the tryptophan to be transported to the brain due to the lack of competitive amino acids.
Cofactors needed for melatonin biosynthesis:
Can you just eat foods that contain melatonin?
Melatonin is a molecule created by all plants and animals. You’ll find articles online telling you about drinking cherry juice for melatonin. While cherry juice does have a relatively higher melatonin content than other juices, research shows that the amount is not high enough in any foods to impact sleep or give an antioxidant benefit.[ref] (Keep in mind how quickly the body metabolizes melatonin…)
Light during the daytime to increase melatonin:
Indoor lighting that is bright and contains the blue wavelengths is good during the day, as is exposure to sunlight. An animal study shows this perfectly: Rats kept in areas with blue-enriched light during the day have a 7-fold increase in nighttime melatonin compared to animals kept under fluorescent lighting.[ref]
Preventing pineal calcification in aging:
Animal studies show lifespan extension benefits when transplanting pineal glands from young animals… but that really isn’t a good option for people. (The studies transplanted pineal glands into the eye or the thymus… I’m not wanting a pineal gland in my eyeball).
There are environmental factors, though, that increase the calcification of the pineal gland. Stopping the calcification may be the first step here.
One thing that research shows increases calcification is fluoride, with the pineal gland having a higher fluoride to calcium ratio than bone.[ref] Fluoride is found in the water supply for most municipalities in the US to prevent cavities.
Cataract surgery, when needed:
Cataracts cloud the eyes as we get older. This yellow cross-linked layer decreases the amount of light that hits the retina during the day, thus reducing the amount of melatonin produced at night.
Cataract surgery, unsurprisingly, results in increased nightly melatonin production.[ref]
Exercise in the morning instead of the afternoon:
A study showed that exercising in the afternoon decreased melatonin production at night, compared to morning exercise.[ref] Note that this study was performed with 20-year-old men who regularly exercised.
Fasting decreases melatonin production:
You may notice that fasting can impact your sleep quality, and one reason for that could be the reduction in melatonin.
Research shows that fasting for 2-7 days reduces melatonin production by 20%. Giving the fasting people glucose returns melatonin concentrations to normal, so it’s actually not the restriction of tryptophan that is the culprit here.[ref]
Melatonin is a potent antioxidant, and excessive exposure to certain toxicants can cause a decrease in overall melatonin levels (using up melatonin in response to ROS). For example, dioxin is a persistent environmental pollutant that cuts circulating melatonin levels in half (animal study).[ref] Melatonin is also used in reaction to the toxicity of methamphetamines.[ref] And you may want to supplement with melatonin if exposed to mustard gas.[ref] One way of looking at it is that avoiding the toxicants that increase oxidative stress can spare melatonin. Alternatively, exposure to a higher toxicant burden, think about increasing your melatonin.
Related Articles and Genes:
Why light at night increases the risk for cancer
The World Health Organization listed ‘light at night’ as a possible carcinogen in 2007. Let’s let that sink in for a minute… On the same list of possible carcinogens that includes formaldehyde, aflatoxin, and the HPV virus is something as innocent as artificial light at night.
Serotonin: How your genes affect this neurotransmitter
There is a lot more to this molecule than most of us realize! This article covers the way that serotonin is made in the body, the transport of serotonin, and the receptors needed to complete the pathway.