Melatonin From Microorganisms, Algae, And Plants As Possible Alternatives To Synthetic Melatonin Part 2

4.2. Melatonin from Plants

Obtaining melatonin from plants was, apparently, one of the most successful strategies. Phytomelatonin has been detected in all photosynthetic species (plants, algae, and some bacteria) analyzed so far. In algae and plants, endogenous levels of phytomelatonin are very low, between picograms and nanograms per gram of tissue [110,130]. On the other hand,  phytomelatonin-rich extracts can have several advantages in addition to being natural,  such as the presence of biologically healthy compounds, such as antioxidants, vitamins, etc. However, obtaining phytomelatonin-rich extracts in sufficient concentrations to meet the expectations of the natural supplement industry has not been an easy task due to contrary factors, such as low and variable content in phytomelatonin. Some of the plant products currently on the market or that have future possibilities are shown in Table 1.

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a. Phytomelatonin from cherries 

Phytomelatonin obtained from freeze-dried Montmorency tart cherry skin extracts was possibly the first phytomelatonin commercialized product (Sleep Support®, New Zealand) (Table 1, product #5). This product contains around 14 µg of phytomelatonin per pill, a very low amount to improve sleep quality but quite an achievement considering the very low amounts of phytomelatonin contained in the original plant material (~14 ng·g −1  fruit [121]. However, some studies suggest that cherry-rich products may have some effect on improving antioxidative status and sleep health [131,132].

b. Phytomelatonin from rice seeds

Based on studies of phytomelatonin extraction methodology in different varieties of rice seeds (Table 1, product #6), the authors aim to develop healthy products that are phytomelatoninrich from rice, obtaining richness in extracts of up to 216 ng·g DW−1 [122–124].

c. Phytomelatonin from mustard seeds 

Two mustard varieties (Brassica campestris) were studied to check the possibilities of this plant material as a supplier of extracts rich in phytomelatonin. Yellow mustard seeds contained up to 660 ng·g DW−1, around three-fold more than black mustard seeds (Table 1, product #7). According to the authors, oily extracts are safe to be used as antioxidants in food supplements with interesting hypocholesterolemic and hypoglycemic activities [125,126].

d. Phytomelatonin from medicinal aromatic plants (MAPs) 

d.1. Phytomelatonin from St. John’s Wort (Hypericum perforatum) 

Interestingly, a new plant source of phytomelatonin has recently been commercialized. In this case, although we do not know the supplier or the details, the phytomelatoninrich extracts of St. John’s wort (Hypericum perforatum) that show a richness of around 1%  are promising if the minimum levels of characteristic components of this plant such as naphthodianthrones (hypericin and others) can be guaranteed (Table 1, product #8).

d.2. Phytomelatonin from Valerian roots 

The effectiveness of valerian (Valeriana officinalis) roots as a mild tranquilizer in cases of generalized nervousness, insomnia, restlessness, and moderate anxiety states is well known [133]. Recently, we measured the phytomelatonin content in natural roots and commercial valerian samples to study the possible contribution of phytomelatonin as a  sedative and sleep improvement agent [127]. Phytomelatonin-rich extracts from valerian roots can be obtained, but the high variability in the phytomelatonin content of raw sources (Table 2) and their limited richness will be a major disadvantage for commercial purposes (Table 1, product #9).

d.3. Other PAMs

To obtain plant extracts rich in phytomelatonin, we tested hundreds of plants of different origins and varieties. One of the patterns that are repeated is the great variability in the phytomelatonin contents in plant samples, influencing their origin, variety, mode of cultivation, and preservation. Table 2 shows some of the phytomelatonin contents in multiple samples of the same species and of different origins or conditioning. There is great variability in the phytomelatonin contents, which makes it extremely difficult to obtain a  raw material with guarantees for commercial purposes. Likewise, our quantification data for phytomelatonin content in different plants, although they are usually within the ranges given by the literature, tend to differ considerably, being much lower than those measured by other authors (Table 2).

Since the estimated natural phytomelatonin contents in plants were not very high,  we opted to produce medicinal aromatic plants (MAPs) previously elicited to increase their phytomelatonin content [129]. In this way, we have been able to obtain extracts rich in phytomelatonin with increases in the content of around 60/80 times concerning their basal endogenous content, which makes them interesting from a commercial point of view (Table 1, product #10). Thus, our plants and extracts (Bioriex product) have been characterized as containing several natural antioxidants such as phenolics, flavonoids, and carotenoids and as showing melatonin activity in vivo in a melatonin-specific bioassay that determined the ability of phytomelatonin-rich extracts to aggregate melanophores in fish were positively verified [129].

Finally, some comments should be made about the costs and prices of products containing chemical/synthetic melatonin or phytomelatonin. Melatonin from chemical synthesis is currently very cheap, with the possibility of obtaining an acceptable quality at 95% purity for around EUR 0.25–0.3 per gram (or even cheaper). On the other hand, phytomelatonin requires the use of considerable amounts of raw material, plants, or algae,  thus, having to process several kg of raw material to obtain a few mg. For example, if raw plants contain 5 µg of phytomelatonin·g DW−1 (a considerable amount, see Table 2) from 1 kg of plants, we can obtain five pills of 1 mg of phytomelatonin. Assuming a price of about EUR 3 per kg of dried plant, the cost of 1 mg of phytomelatonin would be EUR 0.6,  about 2000 times more expensive than chemical melatonin, all without taking into account the costs of handling plants and the extraction and concentration processes necessary to obtain appropriate richness in the extracts. To give a similar example with cultured algae would be impossible to understand, considering the minimal phytomelatonin content in microalgae (see above). Surprisingly, we can find cheaper phytomelatonin pills on the market than chemical melatonin pills. In this regard, some brands are honest with their customers when they are asked about phytomelatonin, answering: “ . . . while waiting for science to find a reliable, validated but also affordable source (of phytomelatonin), we offer you this synthetic alternative which is just as effective, but above all much cheaper!”. Knowing whether the melatonin contained in dietary supplements is synthetic or natural would clear up many reasonable doubts about the products currently on the market. For this, accurate methods of detection and the identification of by-products that originated from the chemical synthesis of melatonin should be applied, thus, clarifying the possible adulteration and not proposing eccentric isotopic approximations to discern between natural and chemical melatonin, as we have received. The lack of control by the competent authority does not facilitate transparency in the dietary supplement sector.

5. Conclusions and Future Directions

Synthetic melatonin is targeted at an important market with very relevant amounts of production, consumption, and sales. Motivated mainly by the desire of the population to consume more natural dietary supplements, the possibility of obtaining melatonin from natural sources arose a few years ago. The first investigations were aimed at obtaining phytomelatonin from plants, although obtaining it from microalgae was the first product to be marketed. One of the permanent doubts about phytomelatonin, in addition to its origin, points to its possible adulteration or enrichment with melatonin and/or precursors of chemical synthesis, thus, not obtaining 100% natural products. Currently, the studies and development of technologies for obtaining melatonin from microorganism biofactories are receiving a great boost from pharmaceutical multinational companies. Of the two published approaches, the transgenic model of E. coli achieved better results in terms of natural melatonin production capacity than the transgenic S. cerevisiae model. Consumers’  acceptance of future dietary supplements containing melatonin obtained by GMOs presents a challenge for marketers. On the other hand, phytomelatonin-rich extracts from plants, even from organically grown plants, have and will have better acceptance than melatonin from GMOs. However, obtaining 100% natural phytomelatonin-rich extracts to meet market demand is currently a challenge to be won. The problems to be solved are the low levels and high variability in the natural contents of phytomelatonin in the studied plants, the expensive concentration protocols to be applied, and the possible presence of undesirable metabolites such as alkaloids, saponins, and many others. Finally, one of the most determining aspects might be that the sale of phytomelatonin (100% natural)  at the same or similar price as chemical melatonin does not currently convince the most discerning consumer.

Author Contributions: Conceptualization, M.B.A. and J.H.-R.; methodology, M.G.-A. and A.E.M.;  software, A.C.; validation, A.C. and J.H.-R.; formal analysis, M.G.-A., A.C.-C., M.L.-L., P.S.-H. and A.E.M.; investigation, M.G.-A., A.E.M. and A.C.; data curation, M.B.A., A.C. and J.H.-R.; writing—  original draft preparation, M.B.A.; writing—review and editing, M.B.A., A.C. and J.H.-R.; visualization, M.B.A. and J.H.-R.; funding acquisition, M.B.A. All authors have read and agreed to the published version of the manuscript.

Funding: This research received no external funding.

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