Study Objectives: Melatonin is an important neurohormone, which mediates circadian rhythms and the sleep cycle. As such, it is a popular and readily available supplement for the treatment and prevention of sleep-related disorders including insomnia and jet lag. This study quantified melatonin in 30 commercial supplements, comprising different brands and forms and screened supplements for the presence of serotonin. Methods: A total of 31 supplements were analyzed by ultraperformance liquid chromatography with electrochemical detection for quantification of melatonin and serotonin. Presence of serotonin was confirmed through analysis by ultraperformance liquid chromatography with mass spectrometry detection. Results: Melatonin content was found to range from −83% to +478% of the labelled content. Additionally, lot-to-lot variable within a particular product varied by as much as 465%. This variability did not appear to be correlated with manufacturer or product type. Furthermore, serotonin (5-hydroxytryptamine), a related indoleamine and controlled substance used in the treatment of several neurological disorders, was identified in eight of the supplements at levels of 1 to 75 µg. Conclusions: Melatonin content did not meet label within a 10% margin of the label claim in more than 71% of supplements and an additional 26% were found to contain serotonin. It is important that clinicians and patients have confidence in the quality of supplements used in the treatment of sleep disorders. To address this, manufacturers require increased controls to ensure melatonin supplements meet both their label claim, and also are free from contaminants, such as serotonin. Commentary: A commentary on this article appears in this issue on page 163. Keywords: contaminant, degradation, label claim, natural health product, stability Citation: Erland LA, Saxena PK. Melatonin natural health products and supplements: presence of serotonin and significant variability of melatonin content. J Clin Sleep Med. 2017;13(2):275-281. I NTRO DUCTI O NMelatonin (N-acetyl-5-methoxytryptamine) is an indoleamine, produced by the mammalian pineal gland as a neurohormone, but has since been found in almost all clades of life encompassing both vertebrate and invertebrate animals, bacteria, fungi, algae and plants. 1,2 In all kingdoms melatonin is produced from the aromatic amino acid tryptophan. In the mammalian system, biosynthesis then proceeds via hydroxylation to 5-hydroxytryptophan followed by decarboxylation to form serotonin (5-hydroxytryptamine).3 In the plant system the hydroxylation and decarboxylation steps are reversed and serotonin synthesis proceeds via the metabolic intermediate tryptamine. 4 Though several alternative routes have been identified, the primary biosynthetic pathway for melatonin then proceeds from serotonin to N-acetylserotonin to melatonin and involves addition of a methoxy and N-acetyl group to serotonin. [3][4][5] The primary role of melatonin in vertebrates is regulation of circadian rhythms, and for humans in particular t...

Melatonin and serotonin are important signaling and stress mitigating molecules that play important roles across growth and development in plants. Despite many well-documented responses, a systematic investigation of the entire metabolic pathway (tryptophan, tryptamine, and N-acetylserotonin) does not exist, leaving many open questions. The objective of this study was to determine the responses of Hypericum perforatum (L.) to melatonin, serotonin, and their metabolic precursors. Two well-characterized germplasm lines (#4 and 112) created by mutation and a haploid breeding program were compared to wild type to identify specific responses. Germplasm line 4 has lower regenerative and photosynthetic capacity than either wild type or line 112, and there are documented significant differences in the chemistry and physiology of lines 4 and 112. Supplementation of the culture media with tryptophan, tryptamine, N-acetylserotonin, serotonin, or melatonin partially reversed the regenerative recalcitrance and growth impairment of the germplasm lines. Quantification of phytohormones revealed crosstalk between the indoleamines and related phytohormones including cytokinin, salicylic acid, and abscisic acid. We hypothesize that melatonin and serotonin function in coordination with their metabolites in a cascade of phytochemical responses including multiple pathways and phytohormone networks to direct morphogenesis and protect photosynthesis in H. perforatum.

Melatonin and serotonin are indoleamines first identified as neurotransmitters in vertebrates; they have now been found to be ubiquitously present across all forms of life. Both melatonin and serotonin were discovered in plants several years after their discovery in mammals, but their presence has now been confirmed in almost all plant families. The mechanisms of action of melatonin and serotonin are still poorly defined. Melatonin and serotonin possess important roles in plant growth and development, including functions in chronoregulation and modulation of reproductive development, control of root and shoot organogenesis, maintenance of plant tissues, delay of senescence, and responses to biotic and abiotic stresses. This review focuses on the roles of melatonin and serotonin as a novel class of plant growth regulators. Their roles in reproductive and vegetative plant growth will be examined including an overview of current hypotheses and knowledge regarding their mechanisms of action in specific responses.

Melatonin and serotonin are important phytochemicals enabling plants to redirect growth in response to environmental stresses. Despite much research on their biosynthetic routes, localization of their biosynthetic enzymes and recent identification of a phytomelatonin receptor, localization of the molecules themselves has to date not been possible. Elucidation of their locations in living tissues can provide an effective tool to facilitate indolamine research across systems including both plants and animals. In this study, we employed a novel technique, quantum dot nanoparticles, to directly visualize melatonin and serotonin in axenic roots. Melatonin was absorbed through epidermal cells, travelled laterally, and accumulated in endodermal and rapidly dividing pericycle cells. Serotonin was absorbed by cells proximal to the crown with rapid polar movement toward the root tip. Thermal stress disrupted localizationand dispersed melatonin and serotonin across cells. These data demonstrate the natural movement of melatonin and serotonin in roots directing cell growth and suggest that plants have a mechanism to disperse the indolamines throughout tissues as antioxidants in response to environmental stresses. K E Y W O R D Sabiotic stress, indolamine, localization, melatonin, quantum dot, serotonin, transport 2 of 10 | ERLAND Et AL.

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