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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