MELATONIN IS NOT THE SLEEP HORMONE
Melatonin’s function in the brain
Melatonin, originally thought to be purely a pineal gland hormone, could be called a vitamin, since it is present in vegetables, fruit, rice, wheat and herbs. However it is found in all organisms including bacteria, algae, fungi, plants, insects, and vertebrates including humans. Therefore it must have been evolutionarily conserved, which indicates that it is of great value to life, generally.
Anyway, in humans, melatonin’s major production site is the bowel, not the pineal gland. It probably did evolve as an antioxidant vitamin, but eventually acquired autocoid (intracellular), paracoid (local tissue) and multiple hormonal properties [1].
Although it is called a hormone, it actually has both hormonal and nonhormonal functions: it is known
for its hypnotic, chronobiotic, antidepressant, pro-cognitive, anxiolytic and analgesic effects and is referred to as the sleep hormone, because its diurnal spike coincides with our preferred sleep patterns. However, when you look at
the scientific evidence, it is clear that MELATONIN IS NOT THE SLEEP HORMONE!
It does reduce onset-of-sleep time by 6 minutes (or less!), but this isn’t a prime effect (maybe a side effect?): the main hormone which puts us to sleep is Allopregnanolone. So while the pineal gland’s melatonin production does spike at sleep time, fitting in with our circadian rhythm, the pineal’s melatonin output is probably for the benefit of the brain only, not the rest of the body.
Melatonin is a multifunctional hormone, which scavenges reactive oxygen and nitrogen species, increases antioxidant defenses, prevents tissue damage and blocks pro-inflammatory cytokines. It reduces free radical damage to DNA and prevents degenerative changes in the central nervous system, as has been shown in models of Alzheimer’s and Parkinson’s disease. It works during sleep, with Allopregnanolone, to keep brain cells and nerve cells healthy; but it does many other jobs for the body.
How melatonin is made, and where
Melatonin, N-acetyl-5-methoxytryptamine, is made from Tryptophan, an essential amino acid, in humans and other
vertebrates. It is made by the pineal gland and released in circadian rhythm, with maximum secretion from the pineal at night, in the abscence of blue light. However this is probably just a supply for the Brain.
Melatonin is produced by many other organs, such as the gastrointestinal tract, which secretes it mostly after meals: there is huge secretion from the bowel: melatonin’s concentration in gastrointestinal tissues surpasses blood levels by a factor of 10–100 and the gut is said to contain more than 400 times more than the pineal. The peripheral tissues of the body, like the bowel, can secrete melatonin on their own, but the suprachiasmatic nucleus (SCN) directs them, to achieve “optimal overall output” [3,4,5].
Circadian rhythm and chronobiology
Chronobiology is the study of circadian rhythms.
Circadian rhythms are physical, mental, and behavioral changes that follow a 24-hour cycle. These natural processes respond primarily to light and dark and affect most living things, including animals, plants, and microbes.
One example of a light-related circadian rhythm is sleeping at night and being awake during the day.
Melatonin and blue light
The retinal photoreceptor cells of mammals* contain melanopsin, a blue-light-sensitive pigment. The axons of
these cells do not carry visual images and do not connect to the visual cortex of the brain: they transmit information about ambient blue light directly to the biological clock, the suprachiasmatic nucleus (“SCN”) in the anterior hypothalamus, which stimulates the pineal gland via norepinephrine-releasing, “sympathetic”** neurons, to control intracerebral melatonin production. [7] So the SCN, not the pineal, is the main driver of circadian rhythms, synchronising endocrine and neuronal pathways, including melatonin secretion by the pineal gland, and not the other way around.
What Melatonin does
Melatonin has hormonal and nonhormonal functions: it is a free radical scavenger****, it is a powerful direct antioxidant in its own right and it also regulates antioxidant enzymes. It is a tissue factor and a protective agent which prevents macromolecule damage, protects membrane lipids and nuclear DNA from oxidative damage, boosts the immune system and has anti-cancer properties [2].
Melatonin receptors
(MR) have been found in many species and many human organs. In humans, MRs are found in the brain, the retina,
the pituitary, the cardiovascular system, liver, gallbladder, colon, skin, fat, kidneys, immune system, placenta, spleen, breast, testes, ovary, testis, pancreas, adrenal cortex and other organs.
Melatonin regulates the expression of several genes and it also influences antioxidant enzyme activity and cellular “messenger RNA” levels for the enzymes involved. It assists Allopregnanolone to promote sleep and with brain maintenance and repair, it supports the immune system, it reduces blood pressure and it is useful as a treatment in heart failure.
It reduces the toxicity and increases the efficacy of a large number of drugs (considering this, its use in combination with these agents should be investigated). [6]
Melatonin protects against radiation-induced cellular damage and inhibits the growth of several types of cancer cells, for example human prostate cancer cells, by a mechanism which involves the regulation of androgen receptor function; but it is not clear whether other mechanisms may be involved.
Experimentally, treatment of prostate cancer cells with melatonin slows the growth of both androgen‐sensitive and androgen‐insensitive cancer cells and encourages morphing (“differentiation”) of cancer cells into noncancerous cell types. These effects should be evaluated thoroughly, since melatonin levels are diminished in the aged individuals in whom prostate cancer typically occurs. [11]
On the other hand, Melatonin inhibits apoptosis*** in immune cells and opposes demyelination of neurons:******* (exactly the opposite of its role in facilitating the apoptotic death of cancer cells). [3]
Melatonin recognises no obstacle, even passing through the blood-brain barrier and the placenta, to exercise its
antioxidant properties inside all, including foetal, cells, in the body. [10]
Since brain regions, the retina, peripheral tissues, white blood cells, fibroblasts, adipose tissue, pancreatic islets, animal tissue explants and even cultures of immortalized cells have been observed to possess circadian rhythm, it is no wonder that rhythm disturbances have been found to affect overall health, performance and well-being. Melatonin disruptions have been observed in sleep disorders, type 2 diabetes, cancer, jet lag, insomnia and immune system issues, although as noted above, the SCN is the overall director of diurnal variations.
The importance of melatonin in apoptosis, immunodeficiency, neurodegeneration and cancer is summarised in
reference # [9].
Melatonin production falls, with age: as production gradually declines *-*-*, those parts of the individual’s body which are most sensitive to lowered melatonin availability, especially those which are most prone to oxidative stress, begin to fail. **** In aging, Parkinson’s, Alzheimer’s, epilepsy, sepsis and injury to the brain, inflammation produces oxidative stress, with mitochondrial damage which leads to further increase in free radicals, then apoptosis. *****
SO: what can we do to increase our supply of melatonin? ****** ……………………. *******
FLAGS:
* Non-mammalian species produce Melanopsin elsewhere: the brain, other organs and in some, even in skin.
**The autonomic (non-voluntary) nerve supply is divided into 2 separate systems. The “sympathetic” system controls fast involuntary responses by releasing noradrenaline at the ends of the nerve fibres.
The “parasympathetic” system controls slower, involuntary responses by releasing Acetylcholine at the nerve endings. The sympathetic system is said to be “adrenergic” and the parasympathetic, “cholinergic”.
*** Apoptotic cell death is a physiological phenomenon necessary for homeostasis and proper functioning of organs, to remove cells which are no longer working. It is only infrequently employed.
**** This is not surprising: production of almost all of our hormones declines as we age (most starting at
age 26-30) and many of our systems deteriorate due to loss of hormonal support. Thus most of our disabilities take root in the gradual disappearance of our hormones, with Melatonin, DHEA, Testosterone, Progesterone, Oestradiol and Thyroid 3 deficiencies becoming progressively worse as time passes.
***** In inflammatory conditions, melatonin directly scavenges toxic oxygen and nitrogen-based reactants, activates antioxidative enzymes and increases the efficiency of the electron transport chain, limiting free radical generation and promoting (energy boosting) ATP synthesis, thus preserving the mitochondria and helping to maintain cell function. [8] This has been demonstrated in experimental Multiple Sclerosis and Parkinson’s disease.
****** The easy answer to promoting healthy melatonin levels and circadian rhythm health is, take melatonin. However the questions are,
– How do we know who needs supplementation (tests for it are not easily available),
– How much melatonin should we take, and what about shift workers?
– The argument is rendered even more difficult because the GI tract produces the hormone after eating, in much greater quantity than the Pineal does in the dark. Also, the half-life of Melatonin is only 40 minutes in the dark, and is lower in blue light, SO WHO KNOWS? (??) (!!).
On a practical basis, it is safe to say that Melatonin supplementation should not be necessary before the age of 60 years, that supplementing after that age “can’t do anything but good” and that before 60 years, it is
extremely unlikely to cause harm.
******* A quotation from Dr. Richard Wurtman, re. prescribing melatonin for MS: “Perhaps it is time for systematic studies to be initiated to examine possibly useful effects of melatonin, or melatonin analogs, in preventing or treating MS flare-ups. If positive, the data would open a new chapter in melatonin physiology, in which the hormone would probably be administered not in the very small doses given as a “replacement therapy” to older people, but in the larger doses required to enable it to act as a drug” [14].
*-*-* Melatonin production peaks at age 2 – 5 years and thereafter, reduces continuously. The pineal gland
calcifies in about 70% of people and the calcification can be complete by age 20.
THE
MELATONIN CONTROVERSY
Some aspects of Melatonin’s production, reduction with age, half-life, action as “the sleep hormone”, dosage protocol and adverse side effects are controversial. I considered adding a paragraph regarding that, to this page, but explaining that argument would balloon this paper unconscionably.
Therefore to keep things simple, I have collated my thoughts on the subject, as follows ……
My view is:
– Melatonin reduces sleep-onset time by just a few minutes (3-6) But Allopregnanolone, not melatonin,
is the sleep hormone. So for sleep, Progesterone, to boost Allopregnanolone, is a better idea. (In menopausal women, 100-300mg of Progesterone cures insomnia).
– Older men should take Melatonin, 10mg and Progesterone, 100 mg, for sleep, memory and brain maintenance, every night.
– Older folk and people with insomnia should take 10mg nightly, for all of Melatonin’s “good works”, but not as a primary sleep aid: Melatonin has hormonal and nonhormonal functions and since Its levels fall as we get
older, we should take it as a matter of general principle.
– Perhaps young people should take it, for the same reasons: but if they are healthy, maybe they don’t need it.
– The best dose for sleep seems to be 1-3 mg and the best format is in combination with Tryptophan, or with 5-HTP and L-Theanine, but 10 mg does no harm, helps as an antioxidant, my retard cancer formation and is a better idea.
– The idea that Melatonin has side effects may seem reasonable to some people, but the list of possible side effects is unbelievable and I suspect that at least some of the reported effects are related to anxiety, rather than to taking this high-volume, natural, vital hormone.
REFERENCES: For the best treatise on Melatonin that I have seen, see reference reference #15.
[1] One molecule, many derivatives: A never‐ending interaction of melatonin with reactive oxygen and
nitrogen species? Dun‐Xian Tan, Lucien C. Manchester, Maria P. Terron, Luis J. Flores, Russel J. Reiter https://onlinelibrary.wiley.com/doi/full/10.1111/j.1600-079X.2006.00407.x
[2] V Kumar, Indian J Exp Biol, May 1996: https://pubmed.ncbi.nlm.nih.gov/9063071/
[3] Dr. David Brady, “The natural path to lifelong health”: July 10, 2019
[4] Melatonin as a broad spectrum antioxidant and free radical scavenger: DX Tan, Russel J Reiter, Lucien C Manchester, MT Yan, Mamdouh El-Sawi, Rosa M Sainz, Juan C Mayo, Ron Kohen, MC Allegra, Rudiger Hardeland, https://scholar.google.com/citations?user=pQU0FlMAAAAJ&hl=en#d=gs_md_cita-&u=%2Fcitations%3Fview_op%3Dview_citation%26hl%3Den%26user%3DpQU0FlMAAAAJ%26citation_for_view%3DpQU0FlMAAAAJ%3Au5HHmVD_uO8C%26tzom%3D300
[5] Russel J Reiter, Juan C Mayo, Dun‐Xian Tan, Rosa M Sainz, Moises Alatorre‐Jimenez, Lilan Qin, 2016/10
[6] Melatonin: reducing the toxicity and increasing the efficacy of drugs: Russel J. Reiter, Dun‐xian Tan, Rosa M. Sainz, Juan C. Mayo, Silvia Lopez‐Burillo: 18 February 2010, https://doi.org/10.1211/002235702760345374
[7] Melatonin and reproduction revisited: Russel J Reiter, Dun-Xian Tan, Lucien C Manchester, Sergio D Paredes, Juan C Mayo, Rosa M Sainz, 2009/9/1
[8] Melatonin and mitochondrial function: JosefaLeonaDarioAcuña-CastroviejobRosa MSainzaJuan
CMayoaDun-XianTanaRussel JReitera https://doi.org/10.1016/j.lfs.2004.03.003
[9], Melatonin and cell death: differential actions on apoptosis in normal and cancer cells: R. M. Sainz, J. C. Mayo, C.
Rodriguez, D. X. Tan, S. Lopez-Burillo & R. J. Reiter, Cellular and Molecular Life Sciences CMLS. https://link.springer.com/article/10.1007/s00018-003-2319-1
[10] The Oxidant/Antioxidant Network: Role of Melatonin Reiter R.J. · Tan D.-X. · Cabrera J. · D’Arpa D. · Sainz R.M. · Mayo J.C. · Ramos S. https://www.karger.com/Article/Abstract/14569
[11] Melatonin reduces prostate cancer cell growth leading to neuroendocrine differentiation via a receptor and PKA independent mechanism: Rosa M. Sainz Juan C. Mayo Dun‐xian Tan Josefa León Lucien Manchester Russel J. Reiter, First published: 17 September 2004, https://doi.org/10.1002/pros.20155
[12] Melatonin prevents apoptosis induced by 6‐hydroxydopamine in neuronal cells: Implications for
Parkinson’s disease: J C Mayo, R M Sainz, Higinio Uria, Isaac Antolin Manuel, M. Esteban Carmen Rodriguez,
30 January 2007. https://doi.org/10.1111/j.1600-079X.1998.tb00531.
[13] Melatonin, human aging, and age-related diseases: M Karasek https://pubmed.ncbi.nlm.nih.gov/1558228/#:~:text=Melatonin%20levels%20decline%20gradually%20over,an%20integral%20part%20of%20aging.
[14] Multiple Sclerosis, Melatonin, and Neurobehavioral Diseases: Richard Wurtman Front Endocrinol (Lausanne). 2017; 8: 280. Published online 2017 Oct 23. doi: 10.3389/fendo.2017.00280
PMCID: PMC5660121 PMID29109699
[15] “An Overview of Melatonin as an Antioxidant Molecule: A Biochemical Approach” …… An Open-access, peer-reviewed chapter by Aysun Hacışevki and Burcu Baba, November 5th, 2018, DOI:0.5772/intechopen.79421, https://www.int