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, letโs 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. Johnโs wort and tomatoes, as discussed below. Meanwhile, letโs 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. Johnโs Wort
As previously mentioned, St. Johnโs wort serves as a plant source for extracting phytomelatonin. Laboratory analysis of St. Johnโs wort derived phytomelatonin (Somnatural, Nutraland USA) reveals that in addition to its natural phytomelatonin content, it also contains 2-hydroxymelatonin and N-acetylserotonin.
2-hydroxymelatonin
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
N-Acetylserotonin
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.
Lycopene
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, โIndeed, the association between sleep duration and plasma total carotenoids and lycopene supports the positive impact of a lycopene-rich diet on sleep parameters.โ
GABA
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 riskโparticularly 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 doctorโs 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 โunwanted by productsโ and to โlead to substantial improvement in the results.โ51
Conclusion
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 sourceโwhich is certainly a plus in the natural products industryโits other naturally occurring compounds (2-hydroxymelatonin and N-acetylserotonin from St. Johnโs 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
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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 eugenejbruno@gmail.com.