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Melatonin

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Melatonin is a neurohormone secreted by the pineal gland in the brain. Melatonin levels are the gold standard for assessing the circadian rhythm, also known as your sleep-wake cycle. Melatonin supplementation is a powerful and safe way to modulate your biological clock: to consolidate your normal sleep cycle, to set your sleep cycle to a new timezone, and to enhance the efficiency of napping. Melatonin is tightly correlated with sleepiness – as melatonin levels rise, so does your drive to fall asleep (Figure 1).

Melatonin Circadian RhythmFigure 1. The top graph shows wakefulness, measured by video recording, and the bottom shows melatonin levels at these same times. Notice that melatonin peaks when wakefulness is at its lowest level.

Your circadian rhythm is the biological clock that resides in the suprachiasmatic nucleus of the brain and drives your sleep-wake cycle. The Howard Hughes Medical Institute has a wonderful animation describing how this important brain region regulates your internal clock. Melatonin is thought to weaken the circadian signal promoting wakefulness – specifically, it relies on; direct activity in the brain as well as on peripheral blood vessels to increase heat loss, which strongly promotes sleep.

Anatomy of the Pineal Gland and the Suprachiasmatic NucleusFigure 2. Anatomy of the brain, with the pineal gland (melatonin producing part of the brain) and the suprachiasmatic nucleus (brain’s sleep regulator) displayed.

Is it safe? Are there side effects?

Melatonin is classified as GRAS (generally regarded as safe) by the FDA. In a 2011 study, it was shown that “melatonin treatment in children can be sustained over a long period of time without substantial deviation of the development of children with respect to sleep quality, puberty development and mental health scores, as compared with the [general population].” This demonstrated that melatonin consumption is safe even during sensitive periods of neural and physical growth and development.

Effects on Cognition

Two important parameters of sleep ar modulated by melatonin: sleep efficiency, the effectiveness of the sleep you get, and sleep latency time required to fall asleep.

Melatonin affects sleep efficiency and latency, but the evidence suggests that it is most effective at improving sleep latency at night and sleep efficiency during the day. Essentially, nighttime melatonin acts more strongly to promote your desired sleep-wake cycle by reducing the time it takes to fall asleep. In contrast, daytime melatonin acts to promote sleepiness as well as improves the overall quality of sleep. Supplementing naturally-rising levels of melatonin right before bedtime will enhance and solidify your desired sleep-wkae cycle. During the day when melatonin is very low, it stands to reason that any increase in melatonin will enhance sleep, both latency and efficiency.

Another important use of melatonin is rescuing sleep-wake cycles that have been perturbed by light exposure. Many of us spend countless hours in front of a computer, and the blue light of the screen is particularly good at disrupting our normal circadian rhythm. Night-time melatonin may be particularly beneficial for both maintaining the desired sleep-wake cycle, and resuscitating it after environemental disruption.

Jet lag is the result of your body’s sleep-wake cycle setting itself to the new light-dark cycle as you cross through time zones. Melatonin supplementation has been shown to be a powerful method to pre-set your sleep wake-cycle. In a 2002 meta-analysis, it was shown that melatonin taken at or near bedtime at the target destination (10 pm – 12 am) significantly reduced jet lag.

Effects on Medical Conditions

There is great medical interest in applying melatonin to a host of sleep disorders, as well as disease-associated sleep disturbances (such as in mood disordered or Alzheimer’s patients).

Insomnia is difficulty in falling and/or staying asleep. Melatonin has been shown to improve sleep measures and psychomotor performance in elderly patients with insomnia. In another study, prolonged-release melatonin improved sleep quality and morning alertness in insomnia patients aged 55 years and older. No withdrawal effects were noted.

Melatonin has also been shown to reduce systolic and diastolic blood pressure in elderly individuals – particularly between 3 am – 8 am, when the risk for cardiovascular complications is highest.

There is limited evidence that melatonin may be beneficial in cancer treatment. While randomized control clinical trials have not shown melatonin to be effective in cancer treatment, a meta-analysis of smaller studies showed that “melatonin as an adjuvant therapy for cancer led to substantial improvements in tumor remission, 1-year survival, and alleviation of radiochemotherapy-related side effects.”7Melatonin has been implicated in reduced angiogenesis, or the formation of new blood vessels – a process critical for tumor survival. Additionally, melatonin has been shown to inhibit the metastasis of cancer cells. This lends support to possible anti-cancer effects of melatonin.2

Structure & Synthesis

The biosynthetic pathway of melatonin starts from the dietary amino acid L-tryptophan, which is converted to 5-hydroxytryptophan, or 5-HTP, by tryptophan-5-hydroxylase. 5-HTP is converted to the active hormone serotonin by the enzyme aromatic L-amino acid decarboxylase, further converted to N-acetylserotonin by the enzyme serotonin-N-acetyltransferase (sometimes called arylalkylamine-N-acetyltransferase), and finally converted to N-acetyl-5-methoxytryptamine (melatonin) by the enzyme hydroxyindole-O-methyltransferase (HIOMT).

Melatonin Biosynthesis PathwayFigure 3. Biosynthetic pathway of melatonin.

Other Interactions

Melatonin is also purported to play a variety of different roles in inflammation and immunity processes. Specifically, melatonin has been shown to reduce release of the pro-inflammatory signaling molecules interleukin-6, interleukin-8, and tumor necrosis factor. Melatonin signaling has been shown to reduce the migration of certain types of white blood cells. There is evidence that it could have powerful antioxidant effects. Melatonin levels also decrease with aging, concomitantly with reduced sleep quality in older individuals.

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