Melatonin is the pineal hormone that is the master regulator of the sleep-wake cycle — it is synthesised from the tryptophan in the pineal gland in the darkness, it is secreted into the blood and the cerebrospinal fluid at night, and it acts on the MT1 and MT2 receptors in the suprachiasmatic nucleus (SCN) of the hypothalamus to signal the brain that it is night and that it is time to sleep. The melatonin is often called the “hormone of darkness” because its secretion is suppressed by the light — particularly by the blue light at 460-480nm, which is detected by the intrinsically photosensitive retinal ganglion cells and transmitted to the pineal gland via the retinohypothalamic tract. This light-detection pathway is the primary mechanism by which the external light-dark cycle entrains (synchronises) the endogenous circadian clock to the 24-hour day, and it is the reason why the artificial light at night, the shift work, and the jet lag all disrupt the melatonin secretion and produce the circadian rhythm disorders. The melatonin is therefore the hormonal signal that coordinates the endogenous circadian clock with the external light-dark cycle, and it is essential for the maintenance of the circadian rhythm, the regulation of the sleep-wake cycle, and the coordination of the peripheral clocks in all tissues with the central clock in the SCN. Without adequate melatonin and its circadian regulatory effects, the sleep is fragmented, the circadian rhythm is disrupted, and the metabolic, the immune, and the endocrine functions are all impaired — producing the insomnia, the jet lag, the shift work disorder, and the accelerated ageing that are the hallmark of the melatonin deficiency. The typical endogenous melatonin secretion in adults is 0.1-0.3mg per night, and the therapeutic doses for the sleep and the circadian regulation are 0.5-5mg of the oral melatonin supplement, taken 30-60 minutes before the bedtime. The dietary melatonin is found in small amounts in the tart cherries, the walnuts, the rice, and the barley — but the dietary intake is negligible compared to the endogenous production, and the supplementation is the only practical way to raise the blood melatonin levels significantly.
Melatonin and the Sleep Initiation
Melatonin acts on the MT1 and MT2 receptors in the SCN to reduce the neuronal activity of the SCN, to promote the sleep onset, and to consolidate the sleep throughout the night. The MT1 receptor mediates the suppression of the neuronal activity in the SCN (which is the primary mechanism of the sleep-promoting effect of the melatonin — by reducing the SCN activity, the melatonin removes the arousal signal that the SCN normally provides during the day and enables the transition to sleep). The MT2 receptor mediates the phase shifting of the circadian clock (which is the mechanism by which the melatonin corrects the jet lag and the shift work disorder — by resetting the circadian clock to the new time zone or to the new work schedule, the melatonin enables the rapid resynchronisation of the sleep-wake cycle to the external environment). The melatonin also acts on the peripheral tissues (the liver, the gut, the immune cells, the adrenal gland) to coordinate the phase of the peripheral clocks with the central clock in the SCN — this coordination is essential for the metabolic health, because each tissue has its own circadian clock that must be synchronised with the central clock to maintain the normal metabolic function. The misalignment of the peripheral clocks with the central clock (which occurs in the shift work, in the jet lag, and in the chronic melatonin deficiency) is associated with the metabolic syndrome, the obesity, the cardiovascular disease, and the cognitive impairment — all of which are consequences of the circadian disruption that is caused by the melatonin deficiency.
The clinical importance of the melatonin for the sleep and the circadian regulation is underscored by the observation that the melatonin supplementation improves the sleep onset, the sleep quality, and the circadian alignment in people with the insomnia and in people with the circadian rhythm disorders. A meta-analysis of 19 RCTs in over 1600 participants found that the melatonin supplementation at 0.5-5mg daily significantly reduced the sleep onset latency (by 8-12 minutes), increased the total sleep time (by 20-30 minutes), and improved the sleep quality (as measured by the Pittsburgh Sleep Quality Index) — making the melatonin one of the most effective and safest interventions for the insomnia and for the circadian rhythm disorders. The melatonin is particularly effective for the circadian rhythm disorders — the jet lag, the shift work disorder, and the delayed sleep phase syndrome — because it can reset the circadian clock when taken at the appropriate time (which is typically 30-60 minutes before the desired bedtime for the sleep advancement, or in the morning for the sleep delay).
Practical Application
For general melatonin supplementation for the sleep support and for the circadian regulation, the evidence-based approach is to supplement with 0.5-5mg of melatonin daily, taken 30-60 minutes before the bedtime. The melatonin should be taken at the same time each night (to establish a consistent sleep schedule and to reinforce the circadian rhythm of the melatonin secretion), and it should be taken in the darkness (with the lights dimmed) to avoid the suppression of the endogenous melatonin secretion by the blue light. The melatonin is generally well-tolerated with no significant adverse effects at doses up to 10mg daily, though it may cause the next-day drowsiness, the vivid dreams, the morning grogginess, and the mild depression in some individuals. For comprehensive sleep and circadian support, melatonin pairs well with the magnesium (which has complementary sedative and muscle-relaxant effects — approximately 50% of the population is magnesium deficient, and the magnesium deficiency is associated with the insomnia and the restless leg syndrome), with the L-theanine (which has complementary anxiolytic and sleep-promoting effects by increasing the GABA and the serotonin levels in the brain), with the valerian root (which has complementary sedative and anxiolytic effects through the GABA system), and with the blue-light filtering glasses (which should be worn in the evening to avoid the suppression of the endogenous melatonin secretion by the artificial light from the screens).
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