Sleep is the most essential and fundamental process to maintain physical, mental and general well-being of an individual. Sleep plays a major role in the restoration of body and brain to process the information acquired during wake period and to facilitate learning, memory functioning and general development.1 In humans, a central circadian clock is located in the higher centers of brain that tunes the normal functioning of the body in relation to the 24-hour light-dark cycle. Melatonin, a hormone produced by brain plays a central role in the regulation of circadian rhythm and sleep.
This article focuses on sleep inducing hormone melatonin, its types, its role in regulation of circadian rhythm and sleep and use of supplemental melatonin in various sleep disorders.
What is melatonin?
First identified by Lerner and co-workers, melatonin is a neurobehavioral hormone. Structurally, a methylindole synthesized from tryptophan, (an essential amino acid) and secreted by the pineal gland situated in the brain at night in response to dark-light cycles. The higher centers in the hypothalamus in brain chiefly regulate the secretion of melatonin.
The dark-light cycle is the main synchronizer for the regulating system of melatonin secretion from brain. The melatonin rhythm is entrained with the dark cycle of the day regulating the circadian rhythm to follow the natural sleep pattern.2
Types of melatonin: Melatonin is a natural hormone of the body, it helps in regulating the circadian rhythm and synchronizes our sleep, and wake cycles with day and night. Melatonin created inside the body, regulating the normal physiological functions is known as the endogenous melatonin. On the other hand, melatonin produced synthetically as a dietary supplement and hormonal therapy and as a drug for the management of insomnia, and other sleeping disorder is known as exogenous melatonin.3
What affects the secretion of melatonin: The dark/light cycles are the main regulators for the secretion of melatonin. Once formed melatonin is not stored inside the pineal gland, it is released into the circulation and maximum levels are observed around 3.00-4.00 am in the morning varying with the sleep schedule, environmental and behavioral factors. The advancing technologies and increased use of screens at night have highly affected the circadian rhythm. Exposure to artificial light at high intensities for longer hours at night highly suppresses the endogenous melatonin production. However, escape of inhibition has also been observed after exposure to light for several consecutive nights, progressively shifting melatonin release (phase-delay) to the mornings.2A number of factors have been associated with decline in melatonin production with the advancing age such as decrease in the size of pineal gland, variation in ocular lens, use of drugs, and co-morbidities.4
Melatonin and sleep
Melatonin has been identified as an important hormone in the regulation of physiological sleep. The endogenous production of melatonin increases the sleep propensity at night generally 2 hours after the release. Sleep is divided into alternating cycles of neural activity, which are controlled by internal homeostatic and circadian systems of body. These two processes work interactively as well independently in regulating the mechanism of sleep. Slow wave sleep or non-rapid eye movement (NREM) phase of sleep is mainly controlled by the homeostatic mechanisms whereas the timing of sleep onset and offset, as well as the distribution of REM sleep are controlled by the circadian rhythm.5
The sleep and wake cycles represent a complex behavior generated by various parts of brain and the daily variations in sleep and wakefulness are connected to the various external factors such as light and dark cycles. The circadian rhythm generated in brain generally promotes wakefulness. During the night time, close to the timing of human sleep, it signals the brain to start the production of melatonin to initiate the physiological cycle of sleep.5 The circadian release of melatonin is highly synchronized with the habitual sleeping hours. The onset of melatonin production is in coordination with the onset of the nocturnal sleepiness.6
Besides the well-known effects of melatonin on the regulation of sleep-wake rhythms, melatonin also acts as an internal synchronizer and a chronobiotic molecule, that reinforces oscillations or adjusts the timing of the central biological clock located in the higher centers of the brain to stabilize bodily rhythms.7Another important function played by melatonin is to act as a synchronizer for the seasonal variations. The duration of melatonin profile varies with the change in the daily direction of the day with the changing season i.e. variations with the increase and decrease in night duration resulting in changes in melatonin secretion.8
Other than regulating the physiology of sleep, melatonin has also been associated with the regulation of blood pressure, cardiovascular system, immune system as well as physiologic functions such as retinal opacity, free radical detoxification and antioxidant actions.7
Melatonin supplements and sleep disorders:
Sleep disturbances are one of the most common disorders of modern world, affecting more than one-third of Western populations. Treatment of various sleep disorders, whether acute or chronic requires complex management, involving both pharmacological and behavioral interventions. Over the past few years, multiples studies have been conducted investigating the effects of exogenous or supplemental melatonin on sleep. Most of the studies favored the observations that melatonin reduces the sleep onset latency and increases total sleep time, which may result in overall improvement of sleep quality. With its multiple benefits and uses and over the counter availability in US, melatonin is misused more frequently and in an irregular manner for several primary and secondary sleep disorders.4
Melatonin in insomnia: Studies have reported, approximately 30-35% of the adult population experience occasional or intermittent sleep disturbances. Insomnia is the most common sleep disorder characterized by poor quality of sleep usually presenting as difficulty in sleep onset, frequent awakening while sleeping or early morning awakenings. Insomnia is most often a symptom of most of the psychological or physiological problems. Because of its low toxicity and fewer side effects, melatonin is considered as an ideal hypnotic agent, and safer in elderly for insomnia. Studies have suggested, supplementing with 1 and 5mg of melatonin is found to be useful in the treatment of insomnia in elderly. Another controlled-release melatonin formulation i.e. 2mg/day for 1 week has also been associated with increased sleep efficiency and reduced episodes of night-time awakenings after sleep onset. Secondary insomnia is a common medical situation, administrating an average daily dose of 5.4mg for a period of 8 to 16 days associated with significant improvement in sleep onset, quality as well as total sleep time. Considering the short-half life of melatonin, various synthetic analogues of melatonin are used in the treatment of insomnia including Ramelteon, a tricyclic synthetic analogue approved by US FDA for the treatment of insomnia.5 These newer melatonin agonists are proven to reduce sleep latency onset and improve quality of sleep. Effects on duration of sleep and maintaining quality sleep whole night are yet under study.4
Melatonin in sleep breathing disorders (SBDs)
SBDs are the breathing disorders of sleep, characterized by difficulty in respiration while sleeping. These disorders are further divided into obstructive sleep apnea (OSA) disorders, central sleep apnea disorders, sleep-related hypoventilation disorders and sleep-related hypoxemia disorders. SBD’s are usually considered as risk factors for the development of cognitive impairment, heart problems, kidney issues, diabetes mellitus and many more. Continuous positive airway pressure (CPAP) is used as the most common treatment for SBD. However, CPAP has several disadvantages such as postoperative recurrence, dental injuries with oral appliances, poor tolerance, difficulty to use, poor and uncomfortable sleep, and weight loss. In recent trials and studies, melatonin has shown to improve the complications in patients with SBDs. Melatonin helps in improving the quality of sleep at night and reducing the symptoms of daytime fatigue as well. It also prevents the increase in glucose levels caused due to intermittent episodes of breathlessness.9
Melatonin on circadian rhythm sleep-wake disorders:
Circadian rhythm sleep-wake disorders are broadly classified into intrinsic circadian rhythm disorders and extrinsic circadian rhythm disorders.
Intrinsic circadian rhythm disorders includes, advanced sleep phase syndrome, delayed sleep phase syndrome (DSPS), non-24-h circadian rhythm disorder and irregular sleep phase syndrome. Intrinsic circadian rhythm disorder most commonly presents as delayed sleep phase syndrome (DSPS) specially in adolescent and young adults. The patients of DSPS present a hallmark picture of delayed habitual bedtime and delayed wake up time, roughly 3-6 hours past the conventional sleep time. This results in significant irregularity in the individual’s sleep requirements and also the conventional 24-hour sleep wake cycle disturbing the natural circadian regulation of the body.9
Extrinsic circadian rhythm disorders: Jet-lag and shift work disorder represent the classic examples of extrinsic disorders of circadian rhythmicity. Studies have reported the significant role of melatonin in the dose of 0.5 to 5 mg for the regulation of sleep in patients suffering from jet lag due to frequent travels across 5 or more time zones. It has been observed that slow release 2mg preparation were not that effective, on the other hand short-lived higher peak concentration were found to be highly effective in regulating sleep. Along with the appropriate concentration, timing of the melatonin dose also plays a powerful role. Supplemental melatonin while travelling has proven to be beneficial in regulating the symptoms of jet lag afterwards. 9
Another common presentation of extrinsic circadian rhythm disorder is shift work disorder. Exogenous use of melatonin has great significance in the treatment of day time sleep irregularities in patients working in the night shifts.9
Melatonin on hypersomnolence
Hypersomnolence or narcolepsy is the central disorder characterized by episodes of excessive need for daytime sleep in spite of normal quality and quantity of sleep at night. According to ICSD 3rd edition, disorder of hypersomnolence or narcolepsy is classified into three distinguish subtypes: narcolepsy type 1, narcolepsy type 2 and idiopathic hypersomnia. The amount of sleep is variable and seen more in conditions which are less engaging like in unexciting, sedentary and boring situations. Most of the current treatments focus on managing the consequences daytime sleepiness. Two major classes of drugs approved by the Food and Drug Administration for the treatment of hypersomnia include methylphenidate and modafinil. According to recent research, melatonin provides a decent option in improving narcolepsy and consequences of daytime sleepiness. Exogenous use of melatonin helps in narcolepsy by altering the sleep architecture and improving the quantity of rapid eye movement (REM) sleep, and disorder of circadian rhythm. Melatonin has been shown to relieve sleepiness in shift workers by regulating circadian rhythm and quality of sleep.9
Melatonin on parasomnias
Undesirable episodes and experiences that may occur during NREM, REM sleep or transitions to and from sleep are clubbed as parasomnias. Parasomnias are mainly classified on the basis of stage of sleep in which they may occur i.e. NREM or REM. Parasomnias are characterized as abnormal sleep-related complex movements, behaviors, emotions, perceptions, dreams and autonomic nervous system activity that result in physical injuries, disruption of sleep, adverse effects on physical and mental health. Clinically parasomnias have been seen to severely affect the patient as well as the bed partner or both. Studies have reported that patients treated with melatonin report significantly fewer episodes, less injuries and adverse effects. Parasomnias due to disturbances in rapid eye movement sleep (REM) i.e. REM behavior sleep disorder have shown to be benefitted by the use of melatonin and clonazepam. Melatonin has been found to be equally efficacious in improving symptoms and far less adverse effects. A dose of 3mg melatonin nightly produced a significant decrease in REM sleep without atonia, as well as subjective improvements in clinical symptoms of RBD. Due to less potential for addiction and fewer drug interactions melatonin has a favorable safety and tolerability, which is important in managing parasomnias, especially in elderly and patients with several other health problems.9
Side effects of melatonin supplements:
Available literature and studies indicate that melatonin is a well tolerated drug with few and mild side effects, which include drowsiness, nausea, headache or confusion. Right timed and dosage of melatonin plays an important part in treating disorders and minimizing adverse effects. Fatigue is reported only when melatonin is administrated in the morning at higher doses (>50mg). Most of the studies have reported insignificant side effects with no potential for addiction.5 Some studies have raised concerns about the interaction of melatonin with other drugs such as sleeping pills like zolpidem that may influence the memory and muscle performance.10 Melatonin is also not considered compatible in patients on anti coagulant therapy.11
Sleep is an important physiological process of human body to ensure proper functioning of body and mind. Preservation of regular physiological rhythms is essential to maintain a stabilized internal environment. Melatonin plays an important role in regulating the 24- hour circadian rhythm and sleep cycle with the variation of day and night. Melatonin is produced naturally in body in response to light and dark phases of the day, but a correctly timed administration of melatonin ensures quality and quantity of sleep in various sleep disorders and facilitates readjustment of disrupted circadian rhythm.
Q1. What is melatonin?
A1. Melatonin is chemically known as N-acetyl-5-methoxy tryptamine. It is a hormone produced by the pineal gland in hypothalamus. It is synthesized from essential amino acid tryptophan. Melatonin is naturally produced by body in response to darkness and helps in inducing sleep. It is referred to as sleep hormone because it informs body when to sleep and when to wake up.
Q2. When is melatonin secreted by pineal gland?
A2. Melatonin secretion follows a circadian rhythm i.e. secretion is low during daylight, starts increasing with the onset of darkness, peaking in the middle of the night between 11 PM and 3 AM, and then falling sharply before the time of light onset. The melatonin produced by the pineal gland diffuses into the cerebrospinal fluid (brain fluid) and the bloodstream. Melatonin is freely diffusible across cell membranes with high lipid solubility. It circulates in blood bound to the albumin protein.
Q3. Does melatonin help you fall asleep or keep you asleep?
A3. Melatonin is a sleep inducing hormone released from the pineal gland in response to dark and light variations. Melatonin does not make you fall sleep but it puts you in a quiet state of wakefulness that promotes sleep.
Q4. Can melatonin be used to prevent and treat jet lag?
A4. Melatonin is commonly studied as a treatment for jet lag. Melatonin helps in improving sleep to synchronize with sleep lack due to jet lag. Studies have proved melatonin as an effective agent in preventing or reducing the effects of jet lag. It should be recommended to travelers flying 5 or more different time zones experiencing jet lag on previous journeys. It is safe to recommend a daily dose between 0.5 to 5 mg before flight to improve the quality of sleep.
Q5. Can melatonin improve daytime sleep in night-shift workers?
A5. Sleeping disturbances are more commonly observed as a occupational hazard among night time shift workers. Melatonin is considered useful in regulating sleep in shift workers. It acts as an effective treatment for the night workers in day time sleep.
Q6. Is the production of melatonin affected by age?
A6. A marked variation has been observed in the production of melatonin by pineal gland with advancing age. The production of melatonin stats around the age of 3-4 months, increases rapidly with a peak around the age of 2 to 3 years and then starts declining slightly to achieve a plateau throughout the adulthood. With further increase in age, at around 70, nocturnal concentrations of melatonin decreases to only a quarter or less as compared to young adults.
Q7. Is there a seasonal variation in the concentration of melatonin?
A7. A seasonal variation has been observed in the production of melatonin. With the change in day length, with the changing seasons, the production of melatonin also varies.
Q8. What is the recommended dose of melatonin?
A8. A dose of 0.1 – 0.3 mg of melatonin before sleep is considered adequate. This dose helps in raising the plasma concentration of melatonin at night into the normal range observed in young adults. Consuming over the counter available formulations of melatonin, such as 10mg can raise the plasma concentration 60 times than their normal values. Exceedingly high levels of melatonin can cause hypothermia, tiredness and sleepiness in the daytime.
Q9. When is the best time to take melatonin?
A9. Melatonin helps best when taken 30 minutes to 2 hours before routine bed time. It is not advisable to take melatonin past your routine bedtime as it shifts your sleep cycle and does not help with onset of sleep.
Q10. What are the side effects of melatonin?
A10. Melatonin is usually considered as safe but all supplements come with risks. Short-term side effects of melatonin are usually mild including dizziness, nausea, vomiting, daytime fatigue and headache. On long-term use, no addictive potential has been observed.
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