The purpose of this report is to determine the effects of synthetic melatonin on the brain and the effect it has on the circadian rhythm and sleep cycles. While many people may know that melatonin is a hormone, not all will know that it is also a drug that can be taken to help regulate sleep cycles. The circadian rhythm is the body’s biological clock and controls when a person sleeps or when they wake, which has to do with melatonin. This report will explain melatonin as a hormone versus man-made melatonin, then expand on how synthetic melatonin is made. The chemical qualities of melatonin will be explored as well as the administration and effects of taking melatonin supplements. The relation of melatonin to the circadian rhythm will be discussed and how taking melatonin as a drug can affect sleep in an individual.
Melatonin is made into a medication in two ways. It can be extracted from the pineal gland of animals or man made through chemical reactions. It is not recommended to take melatonin extracted from animals because there is risk of contamination of viral material. Synthetic melatonin does not have this danger.
The most simple and sustainable reaction pathway for melatonin starts by reducing 100 mg of 5-methoxyindole-3-acetonitrile with 160 mg of sodium and 2 ml of ethanol. This is then acetylated for 1 minute at 100℃ with 4 ml of glacial acetic acid and 4 ml of acetic anhydride. This pathway (figure 1) produces 40mg of melatonin.
Taking melatonin as a medication should be directed by a doctor or pharmacist. Melatonin is taken when getting ready to sleep, before bed. It is not an addictive drug. Some side effects that are common of melatonin supplements are:
Synthetic melatonin is taken orally, usually as a capsule or disintegrating tablet. When taken in capsule form, melatonin is absorbed through the average gastrointestinal tract whereas disintegrating tablets are dissolved under the tongue (absorbed sublingually).
Melatonin’s interactions with the brain are quite complicated. In the brain, melatonin binds to melatonin receptors on neurons and when it reaches its threshold for melatonin it activates an action potential. As the action potential moves down the axon, sodium and potassium channels open and it becomes positive inside the neuron. When the action potential reaches the axon terminal, neurotransmitters are released at the synapse. If enough neurotransmitters reach the dendrites of the next neuron, the signal will continue. This signal is what stimulates the depression of the nervous system and sends the body to sleep.
Circadian rhythm refers to the body’s biological clock. It is controlled by the Suprachiasmatic Nucleus (SCN), which is located in the hypothalamus. Light travels to the SCN from the optic nerve of the eye, signalling when it is time to sleep or wake. When it is light the SCN delays the production of melatonin and when it’s dark the SCN releases melatonin from the pineal gland, triggering the onset of sleep.
The effect of melatonin supplements on sleep cycles has been backed up with studies done on blind individuals. If a person had no vision or light perception at all, their sleep cycle was very irregular. However, if they took melatonin tablets at the appropriate bedtime then their sleep had a regular pattern.
In this study, someone with absolutely no light perception made a sleep diary (figure 4). The grey indicates sleep at night, the black indicates naps taken and the red stars represent the peak of melatonin in their body.
Background
Melatonin is a hormone produced naturally in the brain, triggered by darkness and inhibited by exposure to light. It is secreted from the pineal gland, just above the the centre of the brain. Melatonin levels can be ten times higher at night than the levels they are during the day, which are barely detectable. Melatonin is generally produced from around 9pm and it’s levels in the bloodstream stay high for about 12 hours.Melatonin is made into a medication in two ways. It can be extracted from the pineal gland of animals or man made through chemical reactions. It is not recommended to take melatonin extracted from animals because there is risk of contamination of viral material. Synthetic melatonin does not have this danger.
The most simple and sustainable reaction pathway for melatonin starts by reducing 100 mg of 5-methoxyindole-3-acetonitrile with 160 mg of sodium and 2 ml of ethanol. This is then acetylated for 1 minute at 100℃ with 4 ml of glacial acetic acid and 4 ml of acetic anhydride. This pathway (figure 1) produces 40mg of melatonin.
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| Figure 1- synthetic melatonin reaction pathway 1- retrieved from http://www.ch.ic.ac.uk/local/projects/s_thipayang/synth.html |
Melatonin can also be made by dissolving 1g, of 5-Methoxytryptamine hydrochloride in 10 ml of pyridine and 10 ml of acetic anhydride. This is kept overnight at 20 oC then poured onto iced. It is neutralised with hydrochloric acid and extracted with 2x25 ml of chloroform. The combined extracts are washed in water then dried in magnesium sulfate. It is then evaporated to afford a liquid of N,N diacetyltryptamine derivative which is poured into 50 ml of water. Once again it is extracted with 2x25 ml of chloroform, washed in water and dried in magnesium sulfate. Once the product is evaporated to dryness it is dissolved in benzene and recrystallised to produce melatonin at an 80% yield.
Melatonin has a molecular weight of 232.283 g/mol and is a solid at room temperature. Melatonin has the melting point of 116-118 ℃. Its solubility in water at 20 degrees is 2 grams per litre, the solubility increases as the temperature increases.
Melatonin’s molecular formula is C13H16N2O2. It has three functional groups, a secondary amine, an amide and an ether group.
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| Figure 2- melatonin synthesis pathway 2- retrieved from http://www.ch.ic.ac.uk/local/projects/s_thipayang/synth.html |
Melatonin has a molecular weight of 232.283 g/mol and is a solid at room temperature. Melatonin has the melting point of 116-118 ℃. Its solubility in water at 20 degrees is 2 grams per litre, the solubility increases as the temperature increases.
Melatonin’s molecular formula is C13H16N2O2. It has three functional groups, a secondary amine, an amide and an ether group.
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| Figure 3- chemical structure of melatonin- retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/Melatonin#section=3D-Conformer |
Taking melatonin as a medication should be directed by a doctor or pharmacist. Melatonin is taken when getting ready to sleep, before bed. It is not an addictive drug. Some side effects that are common of melatonin supplements are:
- daytime drowsiness
- depressed mood
- stomach pain
- headache
- dizziness
Synthetic melatonin is taken orally, usually as a capsule or disintegrating tablet. When taken in capsule form, melatonin is absorbed through the average gastrointestinal tract whereas disintegrating tablets are dissolved under the tongue (absorbed sublingually).
Melatonin’s interactions with the brain are quite complicated. In the brain, melatonin binds to melatonin receptors on neurons and when it reaches its threshold for melatonin it activates an action potential. As the action potential moves down the axon, sodium and potassium channels open and it becomes positive inside the neuron. When the action potential reaches the axon terminal, neurotransmitters are released at the synapse. If enough neurotransmitters reach the dendrites of the next neuron, the signal will continue. This signal is what stimulates the depression of the nervous system and sends the body to sleep.
Discussion
Medical melatonin is usually taken to help regulate sleep cycles. It is mainly used to treat insomnia or aid in improving sleep problems caused by shift work. It is also taken to treat sleep disorders in blind people. There are other possibilities for medical melatonin but they have not been backed up scientifically. These include treating jet lag, high blood pressure, tumours, anxiety, infertility, depression, bipolar disorder, attention deficit hyperactivity disorder, chronic fatigue syndrome and more. There is also the possibility of using melatonin to enhance sports performance and applying a topical form to prevent sunburn.Circadian rhythm refers to the body’s biological clock. It is controlled by the Suprachiasmatic Nucleus (SCN), which is located in the hypothalamus. Light travels to the SCN from the optic nerve of the eye, signalling when it is time to sleep or wake. When it is light the SCN delays the production of melatonin and when it’s dark the SCN releases melatonin from the pineal gland, triggering the onset of sleep.
The effect of melatonin supplements on sleep cycles has been backed up with studies done on blind individuals. If a person had no vision or light perception at all, their sleep cycle was very irregular. However, if they took melatonin tablets at the appropriate bedtime then their sleep had a regular pattern.
In this study, someone with absolutely no light perception made a sleep diary (figure 4). The grey indicates sleep at night, the black indicates naps taken and the red stars represent the peak of melatonin in their body.
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| Figure 4- sleep diary of a completely blind person- retrieved from https://www.youtube.com/watch?v=O0Uzy35uJzU |
As shown in figure 4, the subjects sleep was irregular and the peaks of melatonin were during the day. They had short and poor quality sleep at night and lots of time napping during the day. This indicates that their circadian rhythm was not synchronised with day and night time. However, when they started taking melatonin their sleep greatly improved. They had much better and longer sleep at night and less daytime napping. Their melatonin peaked at the right time- at around 4am- which meant that their circadian rhythm was synchronised to day and night time. From this study it is clear to see that melatonin is linked circadian rhythm and sleep.
Conclusion
This report provides an understanding of synthetic melatonin and its relation to circadian rhythms. The synthesis and chemical properties have been outlined and the body’s reaction to melatonin explored. After investigating the brain’s response to melatonin, the effect it has on sleep cycles has been explained. The hormone that is made naturally in the pineal gland has been synthesised artificially and is taken to regulate sleep cycles. This is proved by studies done on people who are absolutely blind, usually their sleep is irregular but when given melatonin they sleep better at night and nap less during the day. There have been proposals for many other uses of melatonin. Not all have been backed up scientifically, though further advances in research of this drug may uncover many other reasons to take melatonin.
Public education piece
For my public education piece I made a brochure to advise the general public on medical melatonin.
References
Drugs.com (2016). Melatonin. Retrieved from https://www.drugs.com/melatonin.html
National Sleep Foundation (2016). Melatonin and sleep. Retreived from https://sleepfoundation.org/sleep-topics/melatonin-and-sleep
ScienceLab.com (2013). Material Safety Data Sheet Melatonin MSDS. Retrieved from http://www.sciencelab.com/msds.php?msdsId=9924601
U.S. National Library of Education (2014). HSDB: Melatonin. Retrieved from https://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+hsdb:@term+@rn+@rel+73-31-4
Thipayang, S (1998). Chemical Synthesis of Melatonin. Retrieved from http://www.ch.ic.ac.uk/local/projects/s_thipayang/synth.html
PubChem (2016). Melatonin. Retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/Melatonin#section=3D-Conformer
Block, W (1998). Wake-up Call for Melatonin. Retrieved from http://www.life-enhancement.com/magazine/article/307-wake-up-call-for-melatonin
QIAGEN (2016). Melatonin Signaling. Retrieved from https://www.qiagen.com/au/shop/genes-and-pathways/pathway-details/?pwid=288
The Royal Institution (2016). The Science of Sleep: Melatonin to Neural Pathways [video file]. Retrieved from https://www.youtube.com/watch?v=O0Uzy35uJzU
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