Melatonin in Food and Wine

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Does wine contain melatonin? And does this partly explain why so many people can relax with a glass of wine?  It’s plausible that the melatonin content in wine could help regulate the circadian rhythm. Researchers have suggested that that hormone can be found in small quantities in wine.

Italian researchers found melatonin in extracts from different wine grapes, including Nebbiolo, Croatina, Sangiovese, Merlot, Marzemino, Cabernet Franc, Cabernet Sauvignon and Barbera.  Melatonin appears to form as the grapes ripen. The anti-mold fungicide benzothiadiazole, which wineries spay on their plants to protect the grapes, seems to increase the concentration of melatonin.

It has long been known that grape juice and wine have health benefits. The chemicals in the grapes that provide these benefits include resveratrol, anthocyanins and proanthocyanidins. It now appears possible that melatonin is another phytochemical in grapes that people can benefit from.

Melatonin is present in foods like tomatoes and potatoes at very low levels, and such foods do not form a viable source of dietary melatonin. Consumption of walnuts has been shown to raise melatonin levels in the blood and nuts such as almonds may also have enough melatonin to affect serum levels.  Some Italian researchers have speculated that the heart-healthy “Mediterranean diet” may derive its power partly from melatonin content in plants, although they have no hard proof.  Despite what you might read on some websites about foods rich in melatonin, we could find no evidence that diet is a significant source of melatonin in the body.  The levels naturally occurring in foods, even in nuts, is not high enough that an individual can change his or her melatonin level just from diet.

Melatonin supplements, which are high levels of the hormone, are a different story. They can affect serum melatonin levels and influence sleep patterns.

Melatonin scavenges free radicals in the body and acts as an antioxidant, which is why so many are interested in it for fighting aging.  The chemical activity of melatonin against common bodily oxidants as the peroxynitrite anion, peroxynitrous acid, and hypochlorous acid has been shown in lab conditions.  While lab results do not necessarily mean the same reactions occur in the body, such activity is consistent with observations of melatonin fed to or injected into animals.

Naturepublished a blurb about a study that suggested melatonin supplements could slow testicular damage caused by a high-fat diet.

The oddly named Journal of Pineal Research has lots of studies on the benefits of melatonin, including its protective properties in nonalcoholic fatter liver disease, how “chronic” melatonin can help mitigate the downsides of obesity, and how experiments where scientists fed high-fructose corn syrup to rats to make them obese, supplemental melatonin helped mitigate metabolic syndrome.

So if melatonin is such a great antioxidant and fights aging (maybe), why don’t the vitamin companies include it in their multi-vitamins? Maybe some do.  Melatonin is not a vitamin, however, and unlike vitamins there is no recommended daily allowance.  And the timing of melatonin ingestion matters, while vitamins are often consumed in the morning.

Functional Foods Enriched With Melatonin – the Controversy

Entrepreneurs have developed products with melatonin in them to take advantage of the hype about melatonin.

The Innovative Beverage Group made a product called Drank which they advertised to help customers relax.  It included Valerian Root, Rose Hips, and Melatonin.  The FDA sent a letter in 2010 saying Drank was “adultered..because it bears or contains melatonin, which is an unapproved food additive”.

A number of baked goods incorporate melatonin. Lazy Cakes are “supplement squares” that look like brownies.  The contain chocolate and melatonin. Kush Cakes promotes itself as a “premium relaxation brownie” and lists melatonin as a key active ingredient.

The FDA warned the makers of Lazy Cakes in 2011 that melatonin is not an approved food additive and that the product faced possible seizure from store shelves.  This followed reports of children becoming ill after eating the product.

Although the FDA does not regulate dietary supplements such as melatonin, it does have authority over food and beverage products. The makers of Lazy Cakes, also called Lazy Larry’s brownies, apparently responded by removing the word “cakes” from the name and explicitly promoting the product as a supplement.

Melatonin

Melatonin is a hormone produced by the pineal gland, a small gland in the brain, that plays a part in the body’s sleep cycles. The brain makes this neurohormone from the amino acid tryptophan. Like other hormones, melatonin is a key in kicking off a series of biochemical reactions and bodily events. The melatonin comes out of the pineal gland inside the head and binds to receptors in the SCN. The master-clock SCN slows its firing frequency, reducing the arousal levels in the body and signaling the onset of a sleep period. In a body with typical sleep patterns the melatonin levels start to rise 14 to 16 hours after awakening,

In humans and other diurnal animal species, melatonin secretion happens during normal sleep hours, in contrast to nocturnal animals which are at the peak of their activity while producing melatonin. Melatonin is sometimes called “the hormone of the night.” The melatonin cycle is roughly the opposite of the body temperature cycle. At 4 am, the temperature is at its lowest and the melatonin level is at its highest.

Melatonin is ubiquitous through the living world and can be found in most animals and plants. Its role in the circadian cycle extends through many species; it even appears to play a part in swimming behavior of the marine worm Platynereis dumerilii . Scientist believe the role of melatonin in the circadian control mechanism goes back 700 million years.

Very small amounts of melatonin are found in foods although how much diet contributes to melatonin levels in the body is not clear. How it actually causes sleepiness is unknown as are the details of its metabolism and excretion from the body.

Melatonin has been used to adjust the circadian system in people with jetlag, shiftwork, delayed sleep phase syndrome, and some sleep problems of the elderly. No long-term safety data exist, and the optimum dose and formulation for any application remains to be clarified.

An American Academy of Sleep Medicine task force issued a guideline in 2007 for doctors treating blind patients with sleep disorders, and recommended consideration of timed melatonin administration for people with is indicated for shift-work disorder, jet lag, delayed sleep phase disorder, and free-running disorder. This is because blind people do not respond to the zeitgebers of daylight that sighted people can see.

Even in sighted people melatonin has been used in treatment of jet lag, shift work sleep disorder, DSPS, ASPS, free-running sleep disorder, and ISWRD.

Melatonin was discovered as a neurohormone in 1958.  (It was known as a chemical decades earlier.) Melatonin is now sold in pill form (like vitamin supplements) in retail stores. As with vitamins, the manufacture and sales marketing of melatonin is not regulated by the FDA or by the regulatory agencies of the various states. Melatonin itself has few side effects, but you don’t really know what else is in the pill. Further dosages may be different from what is printed on the label (a common problem with nutritional supplements) Most doctors do not prescribe or recommend melatonin supplements.

Incredible as this sounds, there is no consensus agreement on the half-life of melatonin in the body.  (Believe us, if you know anything about pharmacology, that is incredible.)  The government’s Agency for Healthcare Research and Quality quotes a half-life between 30 minutes and 2 hours and further says “the time required to reach peak values ranged from 0.25h to 13h”.  This is an astonishingly wide range, based probably on the different formulations of the melatonin supplements.

This is another example of how the prescription drugs approval process generates useful data for everyone – data that can be used even after the developer loses patent protection.  It is difficult to gauge the quality and efficacy of melatonin on the market.

High melatonin levels (either natural or from taking melatonin tablets) are associated with the type of physiological activity seen before bedtime – sleepiness, lower core temperature, and loss of body heat. This suggests that melatonin pills can make people sleep better or longer. They are not as strong as prescription sleep aids, however, and the US Food and Drug Administration has never actually approved melatonin for circadian rhythm sleep disorders.

A 2005 meta-analysis (an analysis of other studies on melatonin) concluded that melatonin treatment reduces sleep onset latency, increased sleep efficiency, and increased total sleep duration. However, the average increase in sleep duration was only 13 minutes. The Agency for Healthcare Research and Quality conduced a meta-analysis and said there was a “substantial amount of heterogeneity across studies of melatonin.” Substantial amount of heterogeneity meaning there are no clear answers.

Doubts about melatonin

Another meta-analysis showed that only a small dose of melatonin (about 0.3 milligrams) is necessary for a restful effect. However, that commercially available melatonin pills contain 10 times the effective amount.

The government’s Medline says melatonin “supplements appear to be relatively safe for short-term use”.

Melatonin agonists – chemicals that more or less mimic melatonin in the body – are under development for treatment for insomnia. Melatonin has also been found to be connected to brown adipose tissue. It may elevate the metabolic activity of adipocytes, which is of interest to obesity researchers.

Some blind people use melatonin to help them sleep on the same cycle as sighted people (who have visual sunlight cues to adjust their cycles). It seems to work in about half of people who try it. Blind teens are advised to not use melatonin because of concerns that it might affect puberty. Large amounts of melatonin are known to inhibit ovulation.

There is some recent interest in use of melatonin for treatment of tinnitus.

Taking melatonin

Like prescription and antihistamine sleeping pills, melatonin is taken shortly before the person wants to go to sleep.  The user does not feel an onslaught of sleepiness; it’s a subtle change.  Taking the pill about an hour before bedtime seems to work.  For instance, if you have flown three time zones East and now want to go to sleep three hours earlier than your body is used to, take the melatonin supplement an hour before bed.

Where does the melatonin come from?

The packaging might say where it comes from, but probably not.  Some melatonin is derived from animal sources, and it can also be synthesized.

The chemical name for melatonin is N-acetyl-5-methoxytryptamine. (CAS 73-31-4) Here’s the structure, for chemistry buffs:

chemical structure of melatonin

Sleeping with the lights on causes cancer!

No, but there was a headline a few years ago saying “Sleeping with lights on might trigger cancer through melatonin suppression.” Sleeping with the lights on lowers the amount of melatonin in the bloodstream. Melatonin is thought to have a mild chemopreventative function leading one researcher to speculate that uninterrupted darkness is a “mechanism for cancer prevention”. It also inhibits the growth of tumors. And there are overall health benefits to going through a full circadian cycle, which includes a period of darkness. So there might be some benefit to sleep without the lights on.

A bit of an exaggeration to say sleeping with the lights on “triggers” cancer. There has been concern that the shift work leads to higher rates of cancer. However an epidemiological study at Ohio State University found no link.

Dreams

There are user reports that melatonin causes vivid dreams. Actually, all sleep aids appear to some users to produce more vivid dreams. What is most likely happening is that the drug modifies the sleep cycle so the person emerges from REM sleep (when dreams are most vivid) to waking quickly – more quickly that when no drug is used. The user subjectively reports the drug as producing vivid dreams.

Melatonin and sleep in aging population.

Melatonin and Wine

Scientific Articles

Melatonin Doubts

The news on melatonin as a supplement is mixed. It can help some people, but experts warn against expecting too much.

Doctors and non-doctors alike have used melatonin for a host of disorders and “indications”: insomnia and jet lag, most notably, but also other sleep-related conditions including ADHD, anxiety, and weening patients off of benzodiazepines as well as non-sleep related conditions including sarcoidosis, thrombocytopeniam, and irritable bowel syndrome.

Unfortunately, scientific tests of the effect of melatonin are do not yield consistent results. Some patients experience an effect, but even those who do experience a modification of sleep architecture do not have the same change as everyone else. Melatonin has not been shown to change the amount of time spent in REM. This seems at odds at anecdotes that people experience more vivid dreams when they take melatonin. The apparent dream-inducing effect of melatonin is probably due to a more abrupt transition from REM to waking.

One good thing about melatonin, compared to most sleeping pills, is that users do not experience extra sleep inertia in the morning, provided they don’t take too much. Melatonin is also useful for blind people who cannot receive light cues to synchronize their circadian rhythms. It appears to be useful for about half of blind people who try it for this reason. Supplements also appear to be more useful for naturally light sleepers.

Despite what some marketers may claim, there is no evidence that melatonin slows the effects of aging in humans. The basis for this speculation was some results in laboratory mice that suggested the hormone had some protective effect.  But there is no real evidence that taking melatonin pills helps keep you young.

Melatonin appears relatively benign when used as a supplement with no pattern of side effects at normal dosages. At very high dosages, the blood levels of melatonin can exceed a thousand times the normal level, and result in symptoms including hypothermia and headache. Like other sleep aids, excessive use of this hormone can result in rebound insomnia through desensitization of receptors.

There are also marketing claims that melatonin is an antioxidant and has the benefits that other antioxidants are claimed to have – lowering risk of cancer and heart disease among others. This has never been proven in a clinical trial. Chemically melatonin is a demonstrated antioxidant in laboratory glassware (in vitro), at concentrations over 1000 times that normally found in the bloodstream. The animal work on melatonin found that vitamin E and vitamin C were more effective at typical concentrations found in the body. There is some evidence that melatonin can be an effective analgesic for endotracheal intubation given to premature babies.

The National Center for Compelementary and Integrative Health website says melatonin supplements can be “helpful” for sleep disorders in blind people.  It is also useful for jet lag and circadian disorders.

Melatonin lowers sperm count and reduces sperm motility.  It also appears to reduce libido. In women, large amounts of melatonin can affect changes in blood serum concentrations of reproductive system hormones:  estrogen, progesterone, and luteinizing hormone.  There are fears that melatonin consumption can stop ovulation and menstruation or induce miscarriages, although science on these questions appears to be sketchy.  Experiments on rats have shown the suppressive effect of melatonin, although the researchers used high doses.

Regulation

The biggest concern about melatonin supplements is not that melatonin is likely to have a harmful effect, but that the supplements are made and sold without the same safety and quality controls that drugs are. In most European countries melatonin is a prescription drug, but in the US it is sold as a supplement, as defined by the Dietary Supplement Health Education Act of 1994.  Supplements are not subjec to manufacturing purity regulations the way drugs are.  The other materials (not melatonin) in the supplement may vary considerably. The dosages are not consistent from supplement to supplement, sometimes even from the same seller.

Although melatonin sellers are not permitted to make unsubstantiated medical claims, they benefit from claims made by others. In a blistering blog post, the blogger and doctor Orac called the US regulation a “horrible, horrible, law.” Dietary supplements often contain this disclaimer: These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease. – a statement public health mavens have taken to calling the “Quack Miranda Warning”.

There is special concern about melatonin because it is a hormone.  You cannot buy estrogen or testosterone over-the-counter.  But if the melatonin is packaged as a “supplement” (not a food or a medicine), it can be sold to any adult.

Science

The pineal gland in the head makes melatonin from the amino acid tryptophan. (Small quantities of melatonin have been found elsewhere in the body, but those organs don’t seem to make most of the hormone that circulates throughout the body.)

The ancient spiritual idea of a mystical Third Eye was often thought to be in the same part of the head as the pineal gland turned out to be.  In the early days of anatomy science the pineal gland itself was sometimes called the third eye, although no serious scientist has
connected the gland to the spiritual third eye in centuries.

The pineal gland is outside the blood-brain barrier. It converts tryptophan to serotonin and keeps the serotonin during daylight hours. When it gets dark, the body releases norepinephrine onto the pineal gland cells, causing them to release the serotonin so that it can be metabolized by the enzymes SNAT and HIOMT. The resulting compound is melatonin which enters the cerebrospinal fluid and bloodstream and scientists have found the concentration of melatonin in blood plasma increases more than an order of magnitude at night (from about 2 to 10 pg/ml to 100 to 200 pg/ml).

Melatonin is lipid-soluble and attaches to albumin in the blood which is how it is transported around the body. The solubility in lipids helps it get through cellular membranes. The liver eventually breaks down melatonin; a small fraction is removed by the kidneys.

The pineal gland’s production of melatonin does not regulate the body’s circadian clock.  That is the function of the suprachiasmatic nucleus or nuclei (SCN) which is located elsewhere in the brain.  Sometimes called “the hormone of the night”, melatonin  does affect the SCN, however, and is part of the overall circadian system.  The melatonin cycle happens even in night workers working under bright lights, but light does suppress it.

The melatonin cycle operates roughly opposite of body temperature cycle.  In late afternoon and early evening, the body temperature is the lowest and the melatonin is the highest.  There is also evidence that the timing of melatonin is related to bodily growth.  In infant mammals high melatonin levels correspond with times of slow growth.
Low melatonin levels correspond with times of high growth.

Evolution may have given our ancestors an annual melatonin cycle to help handle environmental changes.  In the summer, when days are long, light is plentiful, and food is abundant, melatonin levels are low and the body is primed for growth in response to the available food.  In the winter, environmental cues raise the levels of melatonin, encouraging more sleep and less growth.  There is also less food available in the winter.  Thus humans do not have a wintertime hibernation the way bears do, but nature has given our bodies a system (including melatonin) to partially cope with the changing seasons.

The melatonin level in the body declines with age, and even more so in people with dementia. But supplements of melatonin do not appear to improve the cognitive abilities of with dementia patients.

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