Synthetic Melatonin vs. Phytomelatonin: The Scientific Difference – Vitamin Retailer Magazine

Are natural source nutraceuticals better than the synthetic version? The honest answer is sometimes yes, sometimes no. It really depends on whether the science on that nutraceutical can show a demonstrable difference. For most of the time melatonin has been on the market there has really been no opportunity to answer this question since synthetic melatonin was the exclusive source of this nutraceutical. This has changed, however, since the introduction of natural phytomelatonin. Before jumping into a discussion of phytomelatonin, however, letโ€™s begin with a brief review of melatonin.

About Melatonin

Melatonin is a hormone with a wide array of biological activities in plants, animals, unicellular organisms and fungi. In humans and other mammals, it is produced by the tiny pineal gland, located behind the third ventricle of the brain. Melatonin plays important regulatory roles in sleep, body temperature balance, locomotory activities, circadian rhythms, immune system and retinal physiology.1,2

Melatonin supplementation is best known for its role in helping people fall asleep.3 In adults with difficulty sleeping, short-term use of melatonin modestly reduces the time it takes to fall asleep (sleep latency).4 In addition, some patients report minor improvement in subjective feelings of sleep quality.5-7 Furthermore, research has shown that melatonin supplementation is effective in adults with difficulty sleeping, secondary to other causes.8

In addition, both human and laboratory research has shown that melatonin decreases the upregulation of or suppresses levels of inflammatory chemicals in the body.9-16 Interestingly, this additional benefit also has a relationship to sleep.

Inflammation and Sleep

Poor sleep is associated with higher levels of inflammatory markers. One study17 found that a significant association between the sleep inconsistency and inflammation (p = 0.021), suggesting inconsistent sleep is associated with higher levels of inflammatory biomarkers. Another study18 found that self-reported insomnia symptoms were associated with higher values of inflammatory markers, while higher amounts of rapid eye movement (REM) sleep were associated with lower inflammatory markers. Sleep disturbances, specifically difficulties maintaining sleep and early morning awakenings were associated with higher inflammatory markers.

About Phytomelatonin

As with animals, melatonin is also produced in all plant species. In this case it is called phytomelatonin, and it aids plants in terms of root growth, leaf morphology, chlorophyll preservation and fruit development.19 Although its presence in plants is relatively ubiquitous, there are only some plants from which the extraction of melatonin is commercially viable. These include St. Johnโ€™s wort and tomatoes, as discussed below. Meanwhile, letโ€™s look at how phytomelatonin generally compares to synthetic melatonin.

To begin with, the scope of the impact of phytomelatonin in humans is broad, with roles having been demonstrated in mood swings, body temperature, sleep, cardiac rhythms and immunological regulation modulators, as well as antioxidant property.20

An in-vitro study21 was conducted, comparing the effects of phytomelatonin and synthetic melatonin, with or without vitamin C, in HaCaT keratinocytes (i.e., a type of skin cell) using a COX-2 enzyme inhibitory test (COX-2 is an inflammatory marker). Results were that COX-2 inhibitory activity was found to be about 6.5 times stronger with phytomelatonin than with synthetic melatonin. The reason for this is unknown but may be associated with other naturally occurring compounds in phytomelatonin.

In any case, additional research has also shown that phytomelatonin is capable of decreasing plasma levels of other inflammatory makers, including interleukin-6 (IL-6), tumor necrosis factor-a (TNF-a), and C-reactive protein (CRP), heat shock protein 70 extracellular (Hsp70e), and vascular endothelial growth factor (VEGF).22

It is also worth noting that, in animal research,23 phytomelatonin was shown to have impressive bioavailability. Furthermore, the elevated level of melatonin in the blood was associated with a rise in total antioxidant capacity of the blood with an ability to resist free radical damage.

Phytomelatonin Derived From St. Johnโ€™s Wort

As previously mentioned, St. Johnโ€™s wort serves as a plant source for extracting phytomelatonin. Laboratory analysis of St. Johnโ€™s wort derived phytomelatonin (Somnatural, Nutraland USA) reveals that in addition to its natural phytomelatonin content, it also contains 2-hydroxymelatonin and N-acetylserotonin.


Laboratory research24 found that there is a synergistic stimulating effect of 2-hydroxymelatonin and a specific bone protein (bone morphogenetic protein (BMP)-4). Together, they were found beneficial for anabolic effects on bone.

Other research has shown that 2-hydroxymelatonin could contribute to plant stress resistance,25 promoting resistance to physical stresses.26 In fact, research has shown that 2-hydroxymelatonin alleviated the effects of simultaneous physical stressors (e.g. a combination of cold and drought) in plants.27 Interestingly, 2-hydroxymelatonin also has greater immune benefits than melatonin.28


Laboratory research found that N-acetylserotonin inhibited hydrogen peroxide from causing oxidative damage to cells.29,30 Laboratory research has also shown that N-acetylserotonin has neuroprotective and anti-inflammatory properties, and can exert neuroprotective effects by inhibiting oxidative stress, anti-apoptosis and regulating autophagy dysfunction.31

Brain-derived neurotrophic factor (BDNF) is a key molecule in the body that plays an important role in nerve survival and growth, serves as a neurotransmitter modulator, and participates in neuronal plasticity (i.e., adaptability to changes in environment), which is essential for learning and memory.32 BDNF itself is important for long-term memory.33 In multiple studies, N-acetylserotonin has been shown to promote the production of BDNF.34-36

Likewise, research37 has shown that N-acetylserotonin may play an important role in mood regulation, as well as stimulate proliferation of neuroprogenitor cells (i.e., cells that give rise to many different nerve cells) and prevent some of the negative effects of sleep deprivation. It may also turn out to play a role in mitigating common, age-related cognitive decline.38

Phytomelatonin Derived From Tomatoes

Tomatoes likewise serve as a whole-food plant source for extracting phytomelatonin. In fact, human research has shown that consumption of tomatoes prior to bedtime increased circulating melatonin and improved sleep quality,39 and that tomato capsules before bedtime also had sleep-inducing effects.40 These benefits were likely due to the phytomelatonin content, but other naturally occurring compounds may have played a role as well. Laboratory analysis of tomato derived phytomelatonin (Somato, Nutraland USA) reveals that in addition to its natural phytomelatonin content, it also contains 2-hydroxymelatonin and N-acetylserotonin, as well as lycopene and GABA.


Research suggests that the natural carotenoid lycopene may have a positive impact on heart health41,42 and offer valuable antioxidant properties.43 In addition, research has also demonstrated that lower intakes of lycopene are associated with lower levels of sleep (<5 hours)44 and sleeping problems.45 In fact, a review article in the journal Oxidative Medicine and Cellular Longevity46 stated, โ€œIndeed, the association between sleep duration and plasma total carotenoids and lycopene supports the positive impact of a lycopene-rich diet on sleep parameters.โ€


The neurotransmitter gamma-aminobutyric acid (GABA) has a calming effect, reducing specific signals in the central nervous system (brain and spinal cord) which can facilitate restfulness.47 It is well established that activation of GABA receptors in the brain favors sleep.48 In addition, GABA has been successfully used as a nutraceutical for facilitating relaxation.49

About Synthetic Melatonin

Just as natural plant sources provide their own naturally occurring compounds in addition to phytomelatonin, a common commercial process of creating synthetic melatonin likewise results in about 13 different residual chemical compounds which occur at concentrations below 0.5 percent.50 One of those compounds is 1,1โ€™-ethylidenebis-(tryptophan), otherwise known as peak E. A few other compounds include formaldehyde-melatonin condensation products and hydroxymelatonin isomers, which are structural analogues of peak E. The significance of this is that high levels of peak E from a contaminated batch of tryptophan were previously implicated in eosinophilia-myalgia syndrome (EMS), an inflammatory disease that occurred in epidemic proportions in the United States during 1989 (resulting in some deaths).

Let me be clear, though. The tiny amounts of peak E present in synthetic melatonin are wholly insufficient to present any health riskโ€”particularly when synthetic melatonin is used in doses up to 10 mg/day. I would also add that some synthetic melatonin producers include a quality control procedure to assure that no peak E is present in their material. Unfortunately, it is not always clear which synthetic melatonin sources contain peak E and which do not. That being the case, consider that there is some cancer research in which synthetic melatonin is used under doctorโ€™s supervision at doses of 100 mg/day. At that level, I might personally have some concern about the amount of peak E present. A medical journal similarly indicated that phytomelatonin is preferred over synthetic melatonin in cancer treatments to avoid these โ€œunwanted by productsโ€ and to โ€œlead to substantial improvement in the results.โ€51


Phytomelatonin seems to offer some meaningful advantages over synthetic melatonin (the predominant form of melatonin in dietary supplements). Aside from the obvious advantage of being a natural, plant-based sourceโ€”which is certainly a plus in the natural products industryโ€”its other naturally occurring compounds (2-hydroxymelatonin and N-acetylserotonin from St. Johnโ€™s wort derived phytomelatonin; and these same compounds plus lycopene and GABA from tomato derived phytomelatonin) may offer additional benefits for sleep and other health/wellness considerations. Furthermore, the phytomelatonin sources discussed are free of the range of chemical compounds found in synthetic melatonin.VR


1 Carrillo-Vico A, Lardone PJ, Alvarez-ลšnchez N, et al. Melatonin: buffering the immune system. Int J Mol Sci. 2013;14: 8638e83.

2 Paredes SD, Korkmaz A, Manchester LC, Tan DX, Reiter RJ. Phytomelatonin: a review. J Exp Bot. 2009; 60:57e69.

3 Buscemi N, Vandermeer B, Hooton N, et al. The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis. J Gen Intern Med 2005;20:1151-8.

4 Buscemi N, Vandermeer B, Hooton N, et al. The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis. J Gen Intern Med 2005;20:1151-8.

5 Ellis CM, Lemmens G, Parkes JD. Melatonin and insomnia. J Sleep Res 1996;5:61-5.

6 James SP, Sack DA, Rosenthal NE, Mendelson WB. Melatonin administration in insomnia. Neuropsychopharmacol 1990;3:19-23.

7 Buscemi N, Vandermeer B, Pandya R, et al. Melatonin for treatment of sleep disorders. Summary, Evidence Report/Technology Assessment #108. (Prepared by the Univ of Alberta Evidence-based Practice Center, under Contract#290-02-0023.) AHRQ Publ #05-E002-2. Rockville, MD: Agency for Healthcare Research & Quality. November 2004.

8 Buscemi N, Vandermeer B, Hooton N, et al. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis. BMJ 2006;332:385-93.

9 Reiter, R. J., Calvo, J. R., Karbownik, M., Qi, W., and Tan, D. X. Melatonin and its relation to the immune system and inflammation. Ann N.Y.Acad Sci 2000;917:376-386.

10 Lahiri, S., Singh, P., Singh, S., Rasheed, N., Palit, G., and Pant, K. K. Melatonin protects against experimental reflux esophagitis. J.Pineal Res. 2009;46(2):207-213.

11 Makay, B., Makay, O., Yenisey, C., Icoz, G., Ozgen, G., Unsal, E., Akyildiz, M., and Yetkin, E. The interaction of oxidative stress response with cytokines in the thyrotoxic rat: is there a link? Mediators.Inflamm. 2009;2009:391682.

12 Tahan, V., Atug, O., Akin, H., Eren, F., Tahan, G., Tarcin, O., Uzun, H., Ozdogan, O., Tarcin, O., Imeryuz, N., Ozguner, F., Celikel, C., Avsar, E., and Tozun, N. Melatonin ameliorates methionine- and choline-deficient diet-induced nonalcoholic steatohepatitis in rats. J.Pineal Res. 2009;46(4):401-407.

13 Kim, T. H., Jung, J. A., Kim, G. D., Jang, A. H., Ahn, H. J., Park, Y. S., and Park, C. S. Melatonin inhibits the development of 2,4-dinitrofluorobenzene-induced atopic dermatitis-like skin lesions in NC/Nga mice. J.Pineal Res. 2009;47(4):324-329.

14 Yang, F. L., Subeq, Y. M., Lee, C. J., Lee, R. P., Peng, T. C., and Hsu, B. G. Melatonin ameliorates hemorrhagic shock-induced organ damage in rats. J.Surg.Res. 5-15-2011;167(2):e315-e321.

15 Fang, Q., Chen, G., Zhu, W., Dong, W., and Wang, Z. Influence of melatonin on cerebrovascular proinflammatory mediators expression and oxidative stress following subarachnoid hemorrhage in rabbits. Mediators.Inflamm. 2009;426346.

16 Cichoz-Lach, H., Celinski, K., Konturek, P. C., Konturek, S. J., and Slomka, M. The effects of L-tryptophan and melatonin on selected biochemical parameters in patients with steatohepatitis. J.Physiol Pharmacol. 2010;61(5):577-580.

17 Dzierzewski JM, Donovan EK, Kay DB, Sannes TS, Bradbrook KE. Sleep Inconsistency and Markers of Inflammation. Front Neurol. 2020 Sep 16;11:1042.

18 Ghilotti F, Bellocco R, Trolle Lagerros Y, Thorson A, Theorell-Haglรถw J, ร…kerstedt T, Lindberg E. Relationship between sleep characteristics and markers of inflammation in Swedish women from the general population. J Sleep Res. 2021 Apr;30(2):e13093.

19 Reiter RJ, Tan DX, Zhou Z, Cruz MH, Fuentes-Broto L, Galano A. Phytomelatonin: assisting plants to survive and thrive. Molecules. 2015 Apr 22;20(4):7396-437.

20 Arnao MB, Hern_andez-Ruiz J. The potential of phytomelatonin as a nutraceutical. Molecules 2018;23:1e19.

21 Kukula-Koch W, Szwajgier D, Gaweล‚-Bฤ™ben K, Strzฤ™pek-Gomรณล‚ka M, Gล‚owniak K, Meissner HO. Is Phytomelatonin Complex Better Than Synthetic Melatonin? The Assessment of the Antiradical and Anti-Inflammatory Properties. Molecules. 2021 Oct 8;26(19):6087.

22 Al-Rasheed NM, Fadda L, Attia HA, Sharaf IA, Mohamed AM, Al-Rasheed NM. Pulmonary prophylactic impact of melatonin and/or quercetin: a novel therapy for inflammatory hypoxic stress in rats. Acta Pharm. 2017;67:125e35.

23 Reiter RJ, Tan DX, Manchester LC, Simopoulos AP, Maldonado MD, Flores LJ, Terron MP. Melatonin in edible plants (phytomelatonin): Identification, concentrations, bioavailability, and proposed functions. World Rev Nutr Diet. 2007;97:211-230.

24 Lee SH, Hwang JW, Han Y, Lee KY. Synergistic stimulating effect of 2-hydroxymelatonin and BMP-4 on osteogenic differentiation in vitro. Biochem Biophys Res Commun. 2020 Jul 5;527(4):941-946.

25 Yu Y, Lv Y, Shi Y, Li T, Chen Y, Zhao D, Zhao Z. The Role of Phyto-Melatonin and Related Metabolites in Response to Stress. Molecules. 2018 Jul 28;23(8):1887.

26 Hy-Jung L, Kyoungwhan B. 2-Hydroxymelatonin promotes the resistance of rice plant to multiple simultaneous abiotic stresses (combined cold and drought). J Pineal Res. 2016; 61(3):303-16.

27 Lee HJ, Back K. 2-Hydroxymelatonin promotes the resistance of rice plant to multiple simultaneous abiotic stresses
(combined cold and drought). J Pineal Res. 2016 Oct;61(3):303-16.

28 Yang Y, Zhou R, Park SY, Back K, Bae WK, Kim KK, Kim H. 2-Hydroxymelatonin, a Predominant Hydroxylated Melatonin Metabolite in Plants, Shows Antitumor Activity against Human Colorectal Cancer Cells. Molecules. 2017 Mar 14;22(3):453.

29 Yidian W, Jihe K, Xudong G, Daxue Z, Mingqiang L, Xuewen K. N-Acetylserotonin Protects Rat Nucleus Pulposus Cells Against Oxidative Stress Injury by Activating the PI3K/AKT Signaling Pathway. World Neurosurg. 2023 May 9:S1878-8750(23)00621-6.

30 Kang J, Wang Y, Guo X, He X, Liu W, Chen H, Wang Z, Lin A, Kang X. N-acetylserotonin protects PC12 cells from hydrogen peroxide induced damage through ROS mediated PI3K / AKT pathway. Cell Cycle. 2022 Nov;21(21):2268-2282. doi: 10.1080/15384101.2022.2092817.

31 Kang JH, Guo XD, Wang YD, Kang XW. Neuroprotective Effects of N-acetylserotonin and Its Derivative. Neuroscience. 2023 May 1;517:18-25.

32 Bathina S, Das UN. Brain-derived neurotrophic factor and its clinical implications. Arch Med Sci. 2015 Dec 10;11(6):1164-78.

33 Bekinschtein P, Cammarota M, Katche C, Slipczuk L, Rossato JI, Goldin A, Izquierdo I, Medina JH. BDNF is essential to promote persistence of long-term memory storage. Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2711-6.

34 Yoo JM, Lee BD, Sok DE, Ma JY, Kim MR. Neuroprotective action of N-acetyl serotonin in oxidative stress-induced apoptosis through the activation of both TrkB/CREB/BDNF pathway and Akt/Nrf2/Antioxidant enzyme in neuronal cells. Redox Biol. 2017 Apr;11:592-599.

35 Iuvone PM, Boatright JH, Tosini G, Ye K. N-acetylserotonin: circadian activation of the BDNF receptor and neuroprotection in the retina and brain. Adv Exp Med Biol. 2014;801:765-71.

36 Yoo DY, Nam SM, Kim W, Lee CH, Won MH, Hwang IK, Yoon YS. N-acetylserotonin increases cell proliferation and differentiating neuroblasts with tertiary dendrites through upregulation of brain-derived neurotrophic factor in the mouse dentate gyrus. J Vet Med Sci. 2011 Nov;73(11):1411-6.

37 Tosini G, Ye K, Iuvone PM. N-acetylserotonin: neuroprotection, neurogenesis, and the sleepy brain. Neuroscientist. 2012 Dec;18(6):645-53.

38 Oxenkrug G, Ratner R. N-acetylserotonin and aging-associated cognitive impairment and depression. Aging and Disease. 2012; 3(4):330-8.

39 Yang TH, Chen YC, Ou TH, Chien YW. Dietary supplement of tomato can accelerate urinary aMT6s level and improve sleep quality in obese postmenopausal women. Clin Nutr. 2020 Jan;39(1):291-297.

40 Dehnavi P, Rakhshandeh H, Bakhtiari E, Asadpour H, Moshirian Farahi SM, Forouzanfar F. Effect of Tomato (Solanum lycopersicum) Extract in Patients with Primary Insomnia: A Double-blind Randomized Study. Cent Nerv Syst Agents Med Chem. 2023;23(2):137-143.

41 Biddle MJ, Lennie TA, Bricker GV, et al. Lycopene dietary intervention: a pilot study in patients with heart failure. J Cardiovasc Nurs 2015;30(3):205-12.

42 Karimian B, Soleimani A, Mohammadsharifi G, et al. Effect of lycopene supplementation on some cardiovascular risk factors and markers of endothelial function in Iranian patients with ischemic heart failure: A Randomized Clinical Trial. Cardiol Res Pract 2022;2022:2610145.

43 Wei RR, Lin QY, Adu M, Huang HL, Yan ZH, Shao F, Zhong GY, Zhang ZL, Sang ZP, Cao L, Ma QG. The sources, properties, extraction, biosynthesis, pharmacology, and application of lycopene. Food Funct. 2023 Nov 2. doi: 10.1039/d3fo03327a.

44 Grandner MA, Jackson N, Gerstner JR, Knutson KL. Dietary nutrients associated with short and long sleep duration. Data from a nationally representative sample. Appetite. 2013 May;64:71-80.

45 Chen Z, Yu L, Li W, Zhang H, Huang X, Chen W, Wang D. Association of vitamins with hearing loss, vision disorder and sleep problem in the US general population. Environ Sci Pollut Res Int. 2023 Apr;30(18):53876-53886.

46 Khan UM, Sevindik M, Zarrabi A, Nami M, Ozdemir B, Kaplan DN, Selamoglu Z, Hasan M, Kumar M, Alshehri MM, Sharifi-Rad J. Lycopene: Food Sources, Biological Activities, and Human Health Benefits. Oxid Med Cell Longev. 2021 Nov 19;2021:2713511.

47 Jewett BE, Sharma S. Physiology, GABA. [Updated 2023 Jul 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from:

48 Gottesmann C. GABA mechanisms and sleep. Neuroscience. 2002;111(2):231-239. doi:10.1016/s0306-4522(02)00034-9.

49 Abdou AM, Higashiguchi S, Horie K, Kim M, Hatta H, Yokogoshi H. Relaxation and immunity enhancement effects of gamma-aminobutyric acid (GABA) administration in humans. Biofactors. 2006;26(3):201-8.

50 Arnao MB, Hernรกndez-Ruiz J. The Potential of Phytomelatonin as a Nutraceutical. Molecules. 2018 Jan 22;23(1):238.

51 Arnao MB, Hernรกndez-Ruiz J. The Potential of Phytomelatonin as a Nutraceutical. Molecules. 2018 Jan 22;23(1):238.

Gene Bruno, MS, MHS, Professor Emeritus of Nutraceutical Science, is a nutritionist, herbalist, writer and educator. For more than 40 years he has educated and trained natural product retailers and health care professionals, has researched and formulated natural products for dozens of dietary supplement companies, and has written articles on nutrition, herbal medicine, nutraceuticals and integrative health issues for trade, consumer magazines and peer-reviewed publications. He can be reached at

Source link


Leave a Reply

Your email address will not be published. Required fields are marked *