Melatonin (N-acetyl-5-methoxy tryptamine) carries out a vast array of tasks; it also has the potential to be medically useful in a number of conditions, including radiation exposure, Alzheimer's disease and tinnitus.
Melatonin has been lovingly conserved by evolution and can be found in animals, plants, fungi and bacteria. In animals, it is described as a hormone and plays a number of important roles, the most well-known of which is the maintenance of circadian (daily) rhythms.
In this article, we will look at melatonin's role in the human body and how it is used medically.
Contents of this article:
Here are some key points about melatonin. More detail and supporting information is in the main article.
- Melatonin was first discovered in 1958
- Initially, melatonin was extracted from cow pineal glands
- Melatonin is most famous for regulating the body's internal clock
- Melatonin is involved in many processes, including the regulation of certain immune responses
- Melatonin supplements cause very few side effects but they can interact with other drugs
- Some evidence suggests melatonin might relieve certain symptoms of Alzheimer's disease
- Melatonin has strong antioxidant capabilities
- The primary medical use of melatonin is to treat sleep disorders
- Melatonin might help ward off damage caused by radioactivity.
What is melatonin?
Melatonin's chemical structure allows it to travel through the systems of the body with ease.
Although melatonin is most commonly called a hormone, it could just as easily be referred to as an autacoid (a biological factor that acts like a local hormone), a chronobiotic (an agent that causes changes to the body clock), a hypnotic (a sleep inducer), an immunomodulator or a biological modifier. Such is the scope and variety of this all-pervasive substance.
Melatonin is amphiphilic, meaning that it has hydrophilic (water-loving) and lipophilic (fat-loving) properties. These properties enable melatonin to pass easily into any cell, fluid or compartment within the body.
Melatonin was initially discovered in 1958 by Lerner, Case and Takahashi. They extracted it from the pineal glands of cows and gave it the name we use today. They identified melatonin's skin-lightening capabilities in frogs and fish and hoped that it might be useful in the treatment of skin conditions.1
In the 1970s, Lynch and colleagues found that melatonin was released from the pineal gland in a circadian rhythm.2 Over the years, the secrets of melatonin's role in regulating the sleep/wake cycle have slowly been revealed. Later, in the 1990s, melatonin's antioxidant properties were discovered.3
The role of melatonin in circadian rhythms
Circadian rhythms are generated within the hypothalamus.
Of melatonin's many roles, the most well understood is the part it plays in maintaining circadian rhythms. From the third month after birth, levels of melatonin enter a cyclical pattern that will continue for the rest of an individual's life.
In mammals, the circadian "clock" resides in two groups of cells within the hypothalamus, referred to as the suprachiasmatic nucleus (SCN). Using the daily cycle of light and dark, the SCN creates and maintains a daily cycle.
Certain hormones are released preferentially at specific times of the day. In the late afternoon and early evening, the body gets ready for sleep. During the early hours of the morning, the body starts to prepare for waking and activity.
Information regarding light levels reaches the SCN from a set of special light receptors in the retina (separate to the rods and cones most people are familiar with). This light information is relayed to the brain even when the eyelids are closed. The timing of light and dark phases is passed from the SCN on to the pineal gland.
The pineal gland, deep in the center of the brain, responds and releases melatonin at night. Conversely, the release of melatonin is suppressed during daylight.
Even when a human is kept away from all external light sources and time references, the body maintains a near perfect rhythm, typically relaxing into a natural rhythm of 24 hours and 11 minutes. Previous estimates put the natural circadian rhythm at 25 or even 28 hours, but the most recent and accurate results suggest it is astonishingly close to the length of a natural solar day.4
Other roles of melatonin
Although the maintenance of circadian cycles appears to be melatonin's primary function, it also carries out other roles.
Some of the other functions of melatonin are:
Free radicals are a natural byproduct of biological processes. They are necessary for the body to maintain normal physiological functions, but if the body loses control over their production, they can damage DNA, protein and lipids, as well as trigger diseases.5
Melatonin works as a potent antioxidant. Its ability to traverse cell membranes and the blood-brain barrier allows it to carry out its free radical scavenging across the entire organism.
Melatonin has not only been shown to remove free radicals on its own but also to assist other antioxidants in their work. Another characteristic that sets melatonin apart from other antioxidants is that its metabolites (the chemicals that it breaks down into) are also antioxidants.6
In vitro, melatonin has been found to form complexes with metals including cadmium, aluminum and copper. The in vivo importance of this is not yet known, but it is theorized that melatonin might help detoxify metals.7
Melatonin plays a role in mediating the immune system, although the details of the process are not fully understood.
Melatonin is known to have a role within the immune system but the exact processes are not yet known. The best-understood activity is its anti-inflammatory action. Melatonin may also enhance cytokine production.
The above are by no means the entirety of melatonin's repertoire; it also appears to play a protective role in neurodegenerative diseases and acute pancreatitis. In addition, it can regulate fat cells, giving it a potential role in managing obesity.8
Melatonin-specific receptors are to be found in the brain, cardiovascular system, liver, intestine and kidneys, inferring roles in those locations that are as yet unknown.9
Medical uses of melatonin
To match melatonin's impressive physiological roles, the medical community has attempted to find as many uses for it as possible. Because melatonin appears to have limited side effects, is naturally occurring and relatively easy to synthesize, it makes good sense to test out all possible applications.
Below are some of the current conditions being investigated for their reaction to melatonin.
A variety of sleep problems have been treated with melatonin with varying success rates. The strongest evidence for melatonin's use in sleep problems is for people whose issues with sleep are behavioral, developmental or as a result of a mental disorder.
Children with autism can have abnormal melatonin pathways and lower than normal melatonin levels. Some studies have shown that melatonin helps improve sleep duration, reduce the time taken to drift off to sleep and reduce the number of night-time awakenings in these children. However, much of the research has been conducted using self-reported levels of improvement; more investigation in this area needs to be done.11
Despite the importance of melatonin in natural sleep cycles, taking melatonin as a supplement without an underlying condition does not seem to extend or deepen sleep. Even its evidence for advancing the onset of sleep is scant in healthy individuals.12
Melatonin might ease headaches because of its anti-inflammatory effects, its promotion of cytokines, the removal of antioxidants or another mechanism entirely. Evidence is still lacking, though.
Some evidence suggests that melatonin might be beneficial in conjunction with other cancer treatments.
A literature review and meta-analysis carried out in 2005 found that the "substantial reduction in risk of death, low adverse events reported and low costs related to this intervention suggest great potential for melatonin in treating cancer."15
However, all of the trials in the analysis were unblinded; the authors suggest the need for larger, blinded trials before melatonin can be rolled out more widely as a supplement to cancer treatment.
Melatonin levels decrease with age across the population, but this reduction is more pronounced in patients with Alzheimer's disease.
Research has shown that melatonin appears to slow the cognitive decline associated with Alzheimer's. It also appears to arrest the production of amyloid plaques that are a feature of the brains of people with Alzheimer's.16
Melatonin also decreases "sundowning," a worsening of confusion and agitation in the late afternoon and early evening.17
There is some evidence that the effects of tinnitus could be slightly improved by melatonin. The hypothesized method of action might be improved sleep or due to its antioxidant properties.18
One tinnitus study in 2011 found that:
"Melatonin is most effective in men, those without a history of depression, those who have not undergone prior tinnitus treatments, those with more severe and bilateral tinnitus, and those with a history of noise exposure."19
Free radical damage is known to increase the chances of gallstone development. Melatonin's antioxidant properties are considered to be beneficial.23
Protection from radioactivity
Much of the damage inflicted by contact with radioactive substances is caused by free radicals. In this respect, melatonin might be useful for patients undergoing radiation therapy or for those who work in high-radiation areas.24
Melatonin in fertility
In animals other than humans, melatonin plays a part in circadian rhythms but also has a role in annual seasonal changes. Because many species of mammal only breed at certain times of the year, it is no surprise that melatonin is also involved in the reproductive cycle.
So far, research into the role of melatonin in human fertility has been inconclusive.20 One study showed that melatonin consumption during IVF increased the chance of pregnancy.21
One literature review concluded that melatonin improves sperm quality and affects hormone levels in males while other researchers have found no effect.22 For a time, melatonin was even trialed as a prophylactic.
Side effects of melatonin
Melatonin might cause blood clots in certain patients.
Melatonin, by all accounts, has very few side effects. A number of clinical trials have investigated short-term, low-dose and up to 3-month usage and found no adverse events.
Another study found that adverse effects such as headaches, nausea, dizziness and drowsiness were reported equally for melatonin and a placebo.
Other work has found that side effects can include grogginess and irritability the day after use.25 There is also evidence that melatonin lowers follicle-stimulating hormones and might interfere with reproduction.26
Some studies on older people noted side effects including restless legs, skin pigmentation and thrombosis (blood clots).
As with any chemical, there can be interactions with other drugs. Patients who are taking medication to lessen bleeding, prevent blood clotting or to moderate blood pressure or blood sugar levels are advised to avoid melatonin.
Individuals who are using ACE inhibitors are also recommended to avoid melatonin.
Melatonin might increase any drowsiness that occurs as a side effect of other drugs, such as benzodiazepines, codeine, alcohol and barbiturates.27
Melatonin clearly has many functions within the human body. It also seems that it might, at the very least, ameliorate some illnesses. No doubt in time, its full potential within the pharmaceutical world will become clear.
It is well known that drinking coffee at night can keep people awake, but scientists from the Medical Research Council Laboratory of Molecular Biology in the UK and the University of Colorado have made a discovery that may hold the key to how caffeine consumption affects the underlying body clock.
Circadian rhythms enable all living beings to coordinate with the daily cycle, but how the body clock keeps accurate time, or how its malfunction affects people with sleep disorders, is not fully understood. Now, scientists say that a molecular "phosphoswitch" may provide the key.