Melatonin: Born in the night, the correct way to use it is like this

Have you ever had a similar experience: after putting down your phone, you toss and turn and have trouble falling asleep?

I finally fell asleep, but my sleep was shallow and I woke up early;

Feeling sleepy during the day and energetic at night...

If the answer is yes, I'm afraid your sleep quality is not up to standard. The "2023 China National Healthy Sleep White Paper" shows that people generally have problems such as reduced sleep time, difficulty falling asleep, and insomnia. More than 60% of the respondents have sleep symptoms.

Sleep is the nourishment of life, and one-third of human life is spent in sleep. In today's fast-paced era, healthy work and rest has become one of the most concerned issues for young people.

The sleep-aid products on the market are dazzling, and people can easily pay the IQ tax. Auxiliary products such as white noise, sleep devices, sprays, steam eye masks, and aromatherapy have no direct effect. Sleeping pills have side effects and cannot be taken for a long time. Melatonin, a molecule that regulates the human body's "biological clock", quickly stood out from the many sleep-aid products and became a "net-famous" sleep-aid health product.

However, what exactly is melatonin? How does it control our sleep? How can we use it to improve our sleep? With these questions, let us unveil the mystery of melatonin.

1. “Born at night, dispersed at dawn”: the synthesis and secretion of melatonin in the human body

Melatonin is a hormone produced by the pineal gland in the brain of humans and mammals. It is a small molecule indole heterocyclic compound with a chemical formula of C13H16N2O2 and a chemical name of N-acetyl-5-methoxytryptamine[1].

Figure 1. Structure of melatonin

The secretion of melatonin is controlled by light. When night falls, the retina senses the brightness of blue light in the environment and transmits light and dark signals to the pineal gland. The pineal cells that receive the signal use L-tryptophan as a raw material, first generating 5-hydroxytryptophan under the action of tryptophan hydroxylase, which is then converted into 5-hydroxytryptamine (serotonin) through the action of decarboxylase; it is then converted into N-acetyl-5-hydroxytryptamine under the catalysis of N-acetyltransferase, and finally generates melatonin under the action of methyltransferase [2].

Figure 2. The synthesis mechanism of melatonin in the human body[3]

The secretion of melatonin has a clear circadian rhythm. Melatonin usually starts to be secreted at 9-10 pm, reaches a peak at 2-4 am, and gradually decreases to the lowest level at 7-9 am. The concentration of melatonin at night is 3-10 times higher than that during the day. In a person's life, melatonin secretion is vigorous during adolescence; with age, melatonin secretion gradually decreases.

Figure 3. Changes in melatonin secretion during the day and night [4]

2. “Small molecules, big effects”: the effects and mechanisms of melatonin on sleep In animals, melatonin can significantly shorten the time it takes to fall asleep, prolong sleep duration, and improve sleep quality, playing a role in stabilizing and strengthening circadian rhythms [5]. Oral melatonin can also help treat sleep disorders such as delayed sleep phases, and has a certain effect on relieving jet lag syndrome.

After seeing the true appearance of melatonin, we can't help but wonder: How can such a small substance as melatonin play such an important role?

It turns out that melatonin participates in regulating the sleep and wake cycles of the human body through interactions with the suprachiasmatic nucleus of the hypothalamus and the retina, promoting sleep and inhibiting wake-up signals through interactions with melatonin receptors. Melatonin receptors are mainly divided into two categories, MT1 (Mel1a) and MT2 (Mel1b), which belong to "G protein-coupled receptors" and are distributed on the cell surface.

Figure 4. The structure of the sleep-related melatonin receptor [6-7]

Melatonin receptors can act as inboxes, transmitting information to cells and triggering a series of activities. The functions of MT1 receptors include inhibiting neuronal discharge (suprachiasmatic nucleus), adjusting the phase changes at the beginning of the circadian rhythm, and regulating light cycle information; the functions of MT2 receptors include regulating the phase changes of the peak of the circadian rhythm of the suprachiasmatic nucleus discharge, inhibiting dopamine release (rabbit retina), etc. [8]. The MT1 and MT2 receptors of melatonin are very prone to "desensitization", that is, their activity decreases significantly after exposure to hormones with concentrations exceeding normal levels. Therefore, the chance of developing melatonin resistance will increase if melatonin is taken in large doses for a long time.

Figure 5. The mechanism of action of melatonin on receptors[8]

3. "Use it in a proper way": The correct way to use melatonin to help you sleep. The secretion of melatonin is affected by many factors, including light intensity, light wavelength, light exposure time, etc. Once you miss the peak of melatonin secretion, the depth and quality of sleep will be compromised.

So, how do we regulate melatonin levels in our bodies?

(1) Intake of tryptophan and melatonin from natural foods

Tryptophan is an important raw material for synthesizing melatonin. Eating foods rich in tryptophan can increase the levels of serotonin and melatonin, thereby reducing sleep problems[9]. Foods such as sour cherries, kiwis, bananas, and milk are rich in serotonin or tryptophan and have a sleep-inducing effect[10]. In addition, tomatoes, onions, cucumbers, oats, corn, sesame seeds, pumpkin seeds, almonds, black walnuts, and ginger all contain melatonin.

(2) Control the light

Exposure to more natural light during the day promotes the secretion of serotonin, an intermediate in the synthesis of melatonin[11]. At night, exposure to blue light should be reduced. This is because when the eyes receive a large amount of blue light, the body determines that the outside world is daytime, and the secretion of melatonin will be greatly inhibited[12]. This is also the reason why it is easy to stay awake when browsing the phone before going to bed.

(3) Taking melatonin

In my country, the recommended daily dose of melatonin is 1 to 3 mg[13]. Exogenous melatonin is suitable for people who need to adjust to jet lag, middle-aged and elderly people who suffer from insomnia due to pineal gland atrophy, and people with sleep disorders.

Oral melatonin is "exogenous melatonin" and cannot replace the "endogenous melatonin" synthesized by the body. Melatonin is only approved for sale as a health food and cannot replace drugs to treat insomnia. In addition, melatonin has side effects such as causing hypothermia and inhibiting gonadal development, so it is not suitable for long-term and large-scale use [14]. Therefore, when taking melatonin, you must consult a doctor and strictly follow the doctor's advice.

Finally, I hope everyone can have a good sleep every day.

References:

[1] Liu Jianzhong, Zhu Yanjun, Zhou Lifang. Research progress on the physiological and pharmacological effects of melatonin[J]. Journal of Wuhan University of Science and Technology (Natural Science Edition), 2004(02), 198-201.

[2] Mannino G, Pernici C, Serio G, Gentile C, Bertea CM. Melatonin and Phytomelatonin: Chemistry, Biosynthesis, Metabolism, Distribution and Bioactivity in Plants and Animals-An Overview. Int J Mol Sci. 2021 Sep 16;22(18):9996.

[3] Kvetnoy, I.; Ivanov, D.; Mironova, E.; Evsyukova, I.; Nasyrov, R.; Kvetnaia, T.; Polyakova, V. Melatonin as the Cornerstone of Neuroimmunoendocrinology. Int. J. Mol. Sci. 2022, 23, 1835.

[4] Choi, K., Shin, C., Kim, T. et al. Awakening effects of blue-enriched morning light exposure on university students' physiological and subjective responses. Sci Rep 9, 345 (2019).

[5] Jing Yingli, Wu Qingbin, Yuan Xiaochen, Xiu Ruijuan. Effects of melatonin on human sleep and blood pressure[J]. Progress in Modern Biomedicine, 2013, 13(11), 2165-2167.

[6] Stauch, B., Johansson, LC, McCorvy, JD et al. Structural basis of ligand recognition at the human MT1 melatonin receptor. Nature 569, 284–288 (2019).

[7] Johansson, LC, Stauch, B., McCorvy, JD et al. XFEL structures of the human MT2 melatonin receptor reveal the basis of subtype selectivity. Nature 569, 289–292 (2019).

[8] Shivakumar S. Ladde, & Bhusnure OG (2020). REVIEW ON MELATONIN IS A NOVEL MOLECULE FOR MANAGEMENT OF VARIOUS DISORDERS. Journal of Biomedical and Pharmaceutical Research, 9(3).

[9] Cubero, J.; Valero, V.; Sánchez, J.; Rivero, M.; Párvez, H.; Rodríguez, AB; Barriga, C. 2005. The circadian rhythm of trypto-phan in breast milk affects the rhythms of 6-sultatoxymelatonin and sleep in newborn. Neuroendocrinology Letter, 26(6): 657-661.

[10] Fan Zhihong. What can help you sleep well? Recommended sleep-promoting foods [EB/OL]. (2023-05-02). [2023-12-09]. http://kpzg.people.com.cn/n1/2023/0502/c404214-32677226.html.

[11] Young SN. How to increase serotonin in the human brain without drugs. J Psychiatry Neurosci. 2007 Nov;32(6):394-9. PMID: 18043762; PMCID: PMC2077351.

[12] Gabel, V., Reichert, CF, Maire, M. et al. Differential impact in young and older individuals of blue-enriched white light on circadian physiology and alertness during sustained wakefulness. Sci Rep 7, 7620 (2017).

[13] State Administration for Market Regulation. List of Health Food Ingredients: Melatonin [S/OL]. [2023-12-09]. https://www.cfe-samr.org.cn/zcfg/bjsp_134/gsgg/ba/202208/t20220802_4411.html.

[14] Man Yuhong. Take melatonin when you have insomnia? Here’s what you need to know about melatonin [EB/OL]. (2022-08-16). [2023-12-09]. http://kpzg.people.com.cn/n1/2022/0816/c404214-32503312.html.