Elena Maria Varoni

Marcello Iriti

Frontiers in Nutrition

Marcello eIriti

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Commentary: Oral bioavailability of dietary melatonin: more high-quality studies are needed

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January 2016 | Volume 3 | Article 21
General Commentary
published: 25 January 2016
doi: 10.3389/fnut.2016.00002
Frontiers in Nutrition | www.frontiersin.org
Edited by: 
Emmanouil Apostolidis, 
Framingham State University, USA
Reviewed by: 
Sunghoon Jo, 
University of Massachusetts, USA 
Nastaran Gerami-Moayed, 
Merrimack Pharmaceuticals, USA 
Michael Rychlik, 
Technische Universität München, 
Germany
*Correspondence:
Marcello Iriti  
marcello.iriti@unimi.it
Specialty section: 
This article was submitted to Food 
Chemistry, 
a section of the journal 
Frontiers in Nutrition
Received: 21 September 2015
Accepted: 11 January 2016
Published: 25 January 2016
Citation: 
Iriti M and Varoni EM (2016) 
Commentary: Are the proposed 
benefits of melatonin-rich foods too 
hard to swallow? 
Front. Nutr. 3:2. 
doi: 10.3389/fnut.2016.00002
Commentary: are the proposed 
benefits of melatonin-rich foods too 
hard to swallow?
Marcello Iriti1* and Elena Maria Varoni2
1 Department of Agricultural and Environmental Sciences, Milan State University, Milan, Italy, 2 Department of Biomedical, 
Surgical and Dental Sciences, Milan State University, Milan, Italy
Keywords: biokinetics, bioactive compounds, mediterranean diet, nutraceuticals, functional food
A commentary on
Are the proposed benefits of melatonin-rich foods too hard to swallow?
by Kennaway DJ. Crit Rev Food Sci Nutr (2015). doi: 10.1080/10408398.2014.962686
Even if the discovery of melatonin in plants dates back to 1995 (1, 2), in the past decade, the topic of 
melatonin in plant foods has been largely investigated (3–5). Certainly, the detection of melatonin 
in grapevine (6), an important food plant, promoted the studies in this new and exciting research 
field. Noteworthy, it was also suggested that dietary melatonin may be regarded as a bioactive 
phytochemical, similar to polyphenols, as well as a component of the traditional Mediterranean 
diet (7–9).
In this context, the recent article by Kennaway, entitled “Are the proposed benefits of melatonin-
rich foods too hard to swallow?” (10), appeared in Critical Reviews in Food Science and Nutrition, 
really astonished and disappointed us. In his review, the author criticized the studies investigating 
the measurement of blood and urine melatonin after the intake of foods containing this indoleamine. 
The author suggested that the claimed increases in circulating melatonin are not consistent with 
the amount of the dietary melatonin ingested, stating that “Studies reporting the appearance of 
melatonin in blood and its metabolites in urine following ingestion of melatonin-rich foods appear 
to be flawed.” We want to use this paper to highlight the urgency of high-quality studies on this topic, 
rather than to disapprove the currently available results.
Indeed, we think that some data and issues emphasized in this article can be, instead, discussed 
from a different perspective. Such perspective largely depends on the poor-quality of methodology 
applied to perform the existing studies on blood melatonin (11, 12). None of these clinical trials 
achieve the high standard of quality required by the evidence-based medicine approach, necessary 
for drug efficacy assessment as well as for phytochemical research (13). No randomized, placebo-
controlled, double-blinded clinical trial is available, so far, on dietary melatonin. The use of placebo, 
in particular, appears to be undoubtedly one of the major problems to overcome, being that food is 
a very complex matrix where a plethora of active ingredients can act in concert (as melatonin and 
polyphenols, another important group of bioactive phytochemicals) (8).
This paucity of studies on efficacy of foods rich in melatonin largely hinders the achievement 
of reliable conclusions in answering the Kennaway’s question: “Are the proposed benefits of 
melatonin-rich foods too hard to swallow?” However, the author, lapidary, concludes: “While 
there may be health benefits of ingestion of certain foods it is difficult to accept that they are 
due to their melatonin content.” The only data used in the review to support this sentence are 
based on criticism of (very few) biokinetics results on blood melatonin, rather than findings 
on the beneficial effects of dietary melatonin on health (as mentioned before, to date still miss-
ing). It is also interesting to note as the biokinetics data on blood melatonin provided by the 
January 2016 | Volume 3 | Article 22
Iriti and Varoni Oral Bioavailability of Dietary Melatonin
Frontiers in Nutrition | www.frontiersin.org
author as “reference” are based on studies where melatonin was 
administered as pure compound. It is well known, instead, how 
phytochemical bioavailability strictly depends on the complex-
ity of food matrix, consisting of plant cell-wall polysaccharides, 
hydrosoluble and non-hydrosoluble fibers, and other inert 
components.
In addition, the paradigm of dietary melatonin is somewhat 
limiting while our knowledge on food tryptophan derivatives 
and indoleamines is now more and more increasing. In the last 
decade, our experience mainly focused on grape and wine. We 
demonstrated that a number of melatonin isomers are present 
in red wine and, probably, in other plant foods, as well as a high 
amount of tryptophan and tryptophan ethylester, a putative 
tryptophan donor (14–17). In this view, melatonin can also be 
produced from tryptophan locally by the gastrointestinal tract 
and, then, released in the bloodstream, thus confounding the 
levels of the food melatonin really absorbed. In fact, enteroen-
docrine (or enterochromaffin) cells can synthesize serotonin 
and melatonin from tryptophan and/or its derivatives, which 
are contained in the plant foods (18). Nonetheless, serotonin is 
abundantly contained in these foods (19) and may be directly 
converted into melatonin within the gut. Noteworthy, melatonin 
produced in the gastrointestinal tract represents a major pool of 
extrapineal melatonin, reaching much higher levels than in the 
pineal gland (20).
With regard to methodology, another hypothesis, as also 
suggested by the author, is that indoleamines different from 
melatonin, mainly its isomers, may generate misinterpreta-
tion of the results because of their cross-reactivity during the 
analysis. The latter has been mainly based on the enzyme-linked 
immunosorbent assay (ELISA), which is the sole technique, so 
far, used to determine blood melatonin after food intake (11, 12). 
We strongly encourage, in the future, the use of more reliable 
techniques, such as liquid chromatography coupled to mass 
spectroscopy (LC–MS), to assess unequivocally the amount of 
melatonin.
Furthermore, the production of microbial melatonin by the 
colonic microbiota represents another fascinating perspective 
to further comprehend the measured levels of melatonin after 
food intake. Even if no study is now available on this topic, the 
gut microflora may embody an alternative source of melatonin, 
possibly synthesized by some types of bacteria, which deserves 
to be investigated (20). The development of a specific LC–MS/
MS method could shed significantly more light on the origin: if 
stable-isotope-labeled precursors are applied, the labeling pattern 
of melatonin and its sulfate could indicate the contribution of the 
different biosynthetic pathways.
We think that more scientific in human evidences should be 
collected before any judgment is expressed, similarly to what 
occurred and is still ongoing about the health-promoting effects 
of dietary polyphenols. We recommend more high-level studies, 
rather than considering “flawed” currently available data. These 
latter, although preliminary, can be considered a good starting 
point to grow knowledge on this relatively novel food component 
and ascertain, besides its real concentrations in blood, the effects 
of such levels on health.
aUtHor ContrIBUtIonS
MI and EV conceived the commentary and wrote the manuscript.
reFerenCeS
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January 2016 | Volume 3 | Article 23
Iriti and Varoni Oral Bioavailability of Dietary Melatonin
Frontiers in Nutrition | www.frontiersin.org
potential functions. Cell Mol Life Sci (2014) 71:2997–3025. doi:10.1007/
s00018-014-1579-2 
Conflict of Interest Statement: The authors declare that the research was con-
ducted in the absence of any commercial or financial relationships that could be 
construed as a potential conflict of interest.
Copyright © 2016 Iriti and Varoni. This is an open-access article distributed under the 
terms of the Creative Commons Attribution License (CC BY). The use, distribution or 
reproduction in other forums is permitted, provided the original author(s) or licensor 
are credited and that the original publication in this journal is cited, in accordance 
with accepted academic practice. No use, distribution or reproduction is permitted 
which does not comply with these terms.


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