Most of us think of melatonin as the hormone that is required for optimal sleep. While this is true, melatonin also has a variety of other beneficial effects beyond sleep. Melatonin is known to affect the immune system, bone health, fertility, mitochondrial function, and more.1 Since melatonin does have a profound impact on many different organs and tissues, it is important to test your natural melatonin levels and be mindful of them when thinking about supplementing with this fascinating hormone.
What is melatonin and what does melatonin do?
Melatonin (N-acetyl-5-methoxytryptamine) is produced from the neurotransmitter serotonin. Yes - that serotonin! The serotonin that is often low in those who have depression or a methylene-tetrahydrofolate reductase (MTHFR) gene mutation.2,3,4 If your serotonin level is low, your melatonin level could be low as well.5
The conversion from serotonin to melatonin (MLT) requires the activity of two enzymes – N-acetyltransferase (NAT) and N-acetylserotonin O-methyltransferase (ASMT). Optimal methylation is critically important for both serotonin and MLT production.6
Unlike serotonin, MLT is not a neurotransmitter; it is a neurohormone.7 MLT is also known as the “hormone of darkness” or the “dark hormone” since it is primarily produced by the pineal gland in the brain in response to the absence of light.1,7
When light enters or does not enter your eye, the cells in your retina send this information to the suprachiasmatic nucleus (SCN) in your brain. The SCN processes and delivers the darkness signals to your pineal gland, which then produces the MLT that induces sleep.8 Exposure to light, including artificial light, suppresses the darkness signals from the retina and reduces the MLT secretion from the pineal gland.1,8 Thus, MLT production tends to be highest at night, around midnight, and at its’ lowest during daylight hours.8
The MLT produced by the pineal gland is released into the blood and cerebrospinal fluid to affect tissues throughout the body. The pineal gland is the source of most of the MLT present in saliva when melatonin levels are tested with a saliva hormone test. MLT is also produced in the gastrointestinal tract, liver, kidney, adrenal glands, placenta, heart, platelets, thymus, uterus, and many immune system cells, including natural killer cells, for purposes beyond sleep.8
The MLT that is synthesized outside the pineal gland, though, primarily exerts a local effect, and only small amounts, if any, diffuse into the blood and saliva. For example, we know the amount of MLT in liver cells changes during the day, but there is no association with the MLT levels in the blood.8
Those who supplement with MLT often begin taking it as a sleep aid because they have insomnia or trouble sleeping. But MLT has many other beneficial effects on the body beyond sleep.
Beyond Sleep and Insomnia - Melatonin as an Antioxidant
Melatonin (MLT) is not only a neurohormone but also a potent antioxidant. It is an especially powerful antioxidant because it is both water-soluble and fat-soluble, or amphiphilic. Due to its amphiphilic nature, MLT can efficiently cross the blood-brain barrier and enter most cells to affect the nucleus and the expression of many genes.1
Research shows one molecule of MLT can scavenge and neutralize up to TEN reactive oxygen species (ROS) and reactive nitrogen species (RNS). Most antioxidants, such as vitamin C, can only quench a few ROS per molecule. MLT is now seen as a prominent guardian against oxidative stress and free radicals at the cellular and tissue levels.1
In addition to lowering the number of free radicals in the body, MLT also favorably interacts with non-radical oxidants, including hydrogen peroxide (H2O2), singlet oxygen (1O2), and peroxynitrite (HNOO). MLT is also effective in blocking metal-induced oxidation. It inhibits oxidation by the redox-generating metal copper and is known to chelate iron, lead, and aluminum.9
MLT reduces oxidative stress by many different mechanisms. In addition to directly targeting free radicals and chelating oxidative metals, MLT also inhibits pro-oxidative enzymes, such as xanthine oxidase, and enhances the activity of the antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase, and catalase.9
Melatonin and Fertility
Melatonin (MLT) receptors are widely distributed throughout the reproductive system in humans. MLT plays a significant role in the production and function of human gonadotropins, such as FSH and LH, and steroid hormones. MLT also influences the onset of puberty, sexual maturation, follicular development, ovulation, pregnancy, and menopause.9
Unfortunately, most of the studies that have looked at the effects of MLT on fertility disorders are either animal studies or human studies with small sample sizes. Thus, melatonin’s beneficial effects on fertility still need to be confirmed in large randomized trials.10
In general, oxidative stress appears to negatively impact fertility in both men and women. Since MLT is a strong scavenger of free radicals, it is reasonable to suggest that it could improve the quality of sperm and oocytes (eggs), resulting in improved fertility.1
According to the current data, MLT appears to support male fertility by affecting the function of Leydig and Sertoli cells via its influence on cell proliferation and energy metabolism. Research shows supplementation with MLT alone or a combination of MLT and myoinositol may improve the quality of male semen. Supplementation of MLT for 45 days enhances antioxidant capacity and reduces oxidative damage to protect sperm DNA.10
Continuous treatment with MLT also improves the cellular response in those with erectile dysfunction by increasing vasodilatory cytokines. Furthermore, research suggests MLT improves the penetration capacity of human spermatozoa impaired by mitochondrial dysfunction to improve fertilization.10
In women, the research that has been completed to date shows MLT supplementation is promising for effectively supporting those with advanced-age infertility and improving the outcome of in vitro fertilization.1
And according to recent groundbreaking research, MLT is now acknowledged as a key signaling molecule between mother and fetus during pregnancy. MLT levels significantly increase during the second and third trimesters of pregnancy, and MLT receptors are present in the fetus, suggesting MLT is required for optimal fetal development. Research also shows MLT might prevent complications during pregnancy, including neonatal encephalopathy and maternal preeclampsia.9
Melatonin and Mitochondria Function
Mitochondria are the organelles in the cell that produce adenosine triphosphate (ATP), which is cellular energy. Mitochondria could be considered cellular batteries. Mitochondrial membranes are sensitive and can be damaged by many factors, especially oxidative stress.9
MLT acts directly at the mitochondrial level within cells, where it supports the continuity of the electron transport chain, protects ATP synthesis, and significantly reduces free radical formation. MLT also protects mitochondrial DNA. MLT levels in the mitochondria are known to be much higher, even 100-fold higher, than the levels present in the blood.9
The mitochondria produce their own MLT to protect themselves based on intracellular needs. Mitochondrial membranes are also able to selectively take up MLT, which is a function not shared by other antioxidants. MLT supports overall mitochondrial homeostasis and health at all ages.1,9
Mitochondrial dysfunction and declining MLT levels are both associated with aging and the diseases of aging. Animal and human studies document a reduction in the aging process and physiological regeneration with supplemental MLT, which could occur because of reduced oxidative stress in the mitochondria.1
Research shows MLT administration can lower the cell mortality rate and mitochondrial dysfunction in a neuron (brain cell) and cardiac myocytes (heart cells) after injury.9
Melatonin and the Immune System
Many of us learned all about the dangerous “cytokine storm” associated with the SARS-COV2 virus during the COVID-19 pandemic. A cytokine storm occurs when overwhelming amounts of reactive oxygen species (ROS), including superoxide, hydrogen peroxide, hydroxyl radical, and peroxynitrite, are produced.11
Excessive activation of the immune cells known as neutrophils generates myeloperoxidase (MPO) during a cytokine storm. Neutrophil MPO substantially contributes to oxidative stress and the underlying pathophysiology of COVID-19.11 Melatonin is now known to be a potent MPO inhibitor. Media and researchers significantly increased their interest in MLT during the pandemic due to its beneficial effects in treating COVID-19.1,11
Yes, in addition to all the other benefits it offers, MLT also regulates the immune response. MLT is not consistently directly anti-inflammatory; rather, it modulates the immune system in a much more complex manner. Initially, MLT supports a robust immune defense but then prevents harmful chronic inflammatory activity.12
Most of the evidence of direct anti-inflammatory activity has been obtained from animal studies, while clinical studies have had inconsistent results. According to the available research, MLT appears to reduce the pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) and increase the anti-inflammatory cytokine IL-4.9
MLT also appears to inhibit the expression of cyclooxygenase (COX) and inducible nitric oxide synthase (iNOS) while reducing the production of high concentrations of prostanoids and leukotrienes, as well as other mediators of the inflammatory process, such as chemokines and adhesion molecules.9
Since melatonin can act as an antioxidant, anti-inflammatory, and immune-regulatory agent, it offers a unique opportunity for its use in a variety of therapeutic approaches. Because of its profound effect on the immune system, MLT has shown promising benefits for infectious and inflammatory diseases. MLT provides an accessible, relatively inexpensive, and safe treatment option that might buffer the cytokine storm and overactive immune response associated with COVID-19 and other infections.11
It is also important to support the natural endogenous production of MLT in your body for optimal immune function, particularly if your MLT levels are low.
Melatonin and Bone Health
Melatonin (MLT) receptors are widely distributed throughout the body, including bone tissue.13 There is an association between aging and a decrease in nocturnal MLT production, weakening of the bone structure, and an increased risk of bone fractures. Recent clinical studies suggest that supplementation with MLT may reverse bone loss and support optimal bone health.10
So far, research shows MLT may be supportive during bone-grafting procedures, in counteracting bone loss due to osteopenia and osteoporosis, and in the management of periodontal disease.1,10 A composite adhesive hydrogel system known as “GelMA-DOPA@MT” releases MLT in a sustained way and has been shown to increase bone mass around bone implants.10
Women aged 56–73 years were supplemented with 1 mg or 3 mg of melatonin nightly for one year in a randomized controlled trial. The results demonstrated that melatonin significantly increased bone mineral density (BMD) in the femoral neck in a dose-dependent manner. The BMD increased by 0.5% in women taking 1 mg of MLT and by 2.3% in women taking 3 mg of MLT for one year.10
Animal studies suggest MLT preserves the extracellular matrix (ECM) content of collagen II in joints, ameliorates intervertebral disc degeneration, and beneficially affects bone health via numerous other indirect and direct pathways.10,13
What is the Best Melatonin Dosage from a Supplement?
Melatonin (MLT) has become more popular in recent years, with consumers more than doubling the sales of MLT dietary supplements in the U.S. from 2017 to 2020. In 2020, consumers in the U.S. spent 821 million USD on MLT supplements.1
The MLT doses available in supplement form vary significantly. Research studies on MLT have also used a large range of doses, including high doses. With MLT, more is not always better, and the dose depends on the condition being treated. In general, when supplementing with hormones, a good guideline is to take the smallest dose that is effective and always consult with your trusted healthcare provider for guidance.14
While most MLT supplements offer a dose between 1 – 20 milligrams (mg), many find a lower dose of 0.3 mg of MLT before bed effectively supports healthy sleep.14 On average, the natural endogenous production of MLT by the pineal gland is between 0.1 and 0.9 mg of MLT per day; thus, 0.3 mg is a very reasonable “physiologic dose” of MLT.1
Since approximately 99% of all MLT supplements are synthetic, it might also be beneficial to support the natural production of MLT by supplementing with magnesium, vitamin B6, and other nutrients.14,15,16 Fortunately, supplements with natural “phytomelatonin,” which is derived from plants, are also available, but not as common as supplements with synthetic MLT.14
Is a Melatonin Test Available and Should I Test My Melatonin Levels?
Yes, you can test your melatonin (MLT) levels. As discussed in a previous blog post, the most convenient and accurate testing option is a saliva test panel. To assess the highest level of MLT produced by your pineal gland, ideally, a specimen will be collected in a dark room at night while in bed. You can easily collect saliva in the comfort of your home in this manner, while an overnight blood draw is nearly impossible unless admitted to the hospital.
In general, it is also beneficial to assess MLT levels at 4-5 different times throughout the day and night to get insight into the overall circadian rhythm and screen for the presence of a circadian rhythm disorder. Saliva can conveniently be collected while at home or work at any time.
Saliva testing is also ideal because approximately 70% of MLT in the blood is bound to blood proteins and, therefore, inactive. The other 30% in the blood is free MLT, and it is the free MLT that is present in the saliva. The free MLT moves from the blood into the saliva by passive diffusion.17
Salivary MLT represents roughly 24-33% of the MLT in the blood, and blood and saliva levels of MLT directly correlate. Clinical trials confirm salivary and blood levels change simultaneously after the administration of supplemental MLT.17
While urine specimens can also be collected at home, saliva MLT testing is preferred over urine MLT testing. Testing the MLT level in a saliva specimen will show the MLT concentration at the exact time of saliva collection, while urine measurements only show the total accumulated amount of MLT metabolites produced since the last urination.17
Saliva testing allows you to see your peak MLT level and the timing of the peak. The more frequent the saliva sampling, the more accurate the results will be, so when thinking about testing your MLT levels, consider choosing a test panel that requires the collection of at least 4 or 5 saliva specimens to clarify your circadian rhythm.17
Vitamin B6 and Magnesium support the optimal production of melatonin. Highly bioavailable magnesium fumarate and vitamin B6 are available in Fura-Mag:*
Vitamin B6, magnesiusm citrate malate, and other ingredients that support healthy sleep, such as organic Ashwagandha root, are available as a synersistic blend in B-KalmPlexus:*
* This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.
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- Minich DM, Henning M, Darley C, et al. Is Melatonin the "Next Vitamin D"?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements. Nutrients. 2022;14(19):3934. doi:10.3390/nu14193934
- Coppen AJ, Doogan DP. Serotonin and its place in the pathogenesis of depression. J Clin Psychiatry. 1988;49 Suppl:4-11.
- Halaris A, Sohl E, Whitham EA. Treatment-Resistant Depression Revisited: A Glimmer of Hope. J Pers Med. 2021;11(2):155. doi:10.3390/jpm11020155
- Sun H, Gusdon AM, Qu S. Effects of melatonin on cardiovascular diseases: progress in the past year. Curr Opin Lipidol. 2016;27(4):408-413. doi:10.1097/MOL.0000000000000314
- Miyamoto H, Nakamaru-Ogiso E, Hamada K, Hensch TK. Serotonergic integration of circadian clock and ultradian sleep-wake cycles. J Neurosci. 2012;32(42):14794-14803. doi:10.1523/JNEUROSCI.0793-12.2012
- Zhao D, Yu Y, Shen Y, et al. Melatonin Synthesis and Function: Evolutionary History in Animals and Plants. Front Endocrinol (Lausanne). 2019;10:249. doi:10.3389/fendo.2019.00249
- Hossain MF, Wang N, Chen R, et al. Exploring the multifunctional role of melatonin in regulating autophagy and sleep to mitigate Alzheimer's disease neuropathology. Ageing Res Rev. 2021;67:101304. doi:10.1016/j.arr.2021.101304
- Kvetnoy I, Ivanov D, Mironova E, et al. Melatonin as the Cornerstone of Neuroimmunoendocrinology. Int J Mol Sci. 2022;23(3):1835. doi:10.3390/ijms23031835
- Chitimus DM, Popescu MR, Voiculescu SE, et al. Melatonin's Impact on Antioxidative and Anti-Inflammatory Reprogramming in Homeostasis and Disease. Biomolecules. 2020;10(9):1211. doi:10.3390/biom10091211
- Ferlazzo N, Andolina G, Cannata A, et al. Is Melatonin the Cornucopia of the 21st Century?. Antioxidants (Basel). 2020;9(11):1088. doi:10.3390/antiox9111088
- Camp OG, Bai D, Gonullu DC, et al. Melatonin interferes with COVID-19 at several distinct ROS-related steps. J Inorg Biochem. 2021;223:111546. doi:10.1016/j.jinorgbio.2021.111546
- Bondy SC, Campbell A. Melatonin and Regulation of Immune Function: Impact on Numerous Diseases. Curr Aging Sci. 2020;13(2):92-101. doi:10.2174/1874609813666200711153223
- Munmun F, Witt-Enderby PA. Melatonin effects on bone: Implications for use as a therapy for managing bone loss. J Pineal Res. 2021;71(1):e12749. doi:10.1111/jpi.12749
- Minich, D. The Truth About Melatonin: Dosing, Quality, and Clinical Uses. Holistic Primary Care. https://holisticprimarycare.net/topics/functional-medicine/the-truth-about-melatonin-dosing-quality-and-clinical-uses/. Published November 11, 2022. Accessed March 28, 2023.
- Abbasi B, Kimiagar M, Sadeghniiat K, et al. The effect of magnesium supplementation on primary insomnia in elderly: A double-blind placebo-controlled clinical trial. J Res Med Sci. 2012;17(12):1161-1169.
- Pyridoxine (vitamin B6) influence on endogenic melatonin production during the experiment. Georgian Med News. 2007;(153):35-38.
- Rzepka-Migut B, Paprocka J. Melatonin-Measurement Methods and the Factors Modifying the Results. A Systematic Review of the Literature. Int J Environ Res Public Health. 2020;17(6):1916. doi:10.3390/ijerph17061916