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It is well documented that exposure to pollutants (both high and low doses) contribute to a multitude of acute and chronic diseases. Of interest, even exposure to low dose chemical pollutants can interfere with the “synthesis, secretion, transport, binding or elimination of natural blood-borne hormones.”(1), keeping in mind that melatonin in a hormone.


Synthetic melatonin, the most common, economical form used in dietary supplements, is produced through at least four chemical pathways using starter compounds like the following (2):

  • 5-methoxy-3-indolylacetonitrile

  • 5-methoxy-3-(2-nitroethyl)-indole

  • 5-methoxytryptamine

  • Phthalimide (1,3-dihydro-1,3-dioxoisonidole)
















Image Credit: Arnao, M.B.; Giraldo-Acosta, M.; Castejón-Castillejo, A.; Losada-Lorán, M.; Sánchez-Herrerías, P.; El Mihyaoui, A.; Cano, A.; Hernández-Ruiz, J. Melatonin from Microorganisms, Algae, and Plants as Possible Alternatives to Synthetic Melatonin. Metabolites 2023, 13, 72.

Based on the method used, synthetic melatonin can produce yields of 80–98%; however, there is the theoretical possibility that unwanted solvents and substrates could be present depending on the raw material sourced and the specifications, although the final product is often the pure substance with the other agents burned off through reactions or heat (2). The industrial process outlined by various patents typically indicates the use of toxic solvents or petrochemical-derived substrates (3). Since commercial or synthetic melatonin is produced via chemical processes, which are considered highly polluting, there are also concerns about yielding pollution and these processes’ overall negative environmental impact (4). Because various manufacturers are aware of these constraints, different research groups are seriously attempting to streamline the steps involved. For instance, one method developed by a team in China used microwave irradiation to reduce solvent, time, cost, and pollution (3). Another area of development includes microbial fermentation processes (1).


Thus, the purity of a melatonin dietary supplement available to most consumers on the retail store shelf may be debatable or simply unknown without greater diligence to investigate the source, which is often cumbersome and time-consuming. Moreover, with the indole structure of melatonin closely resembling that of tryptophan, there could be theoretical safety concerns related to the Eosinophilia-Myalgia Syndrome (EMS) outbreak in 1989 from the intake of at least six contaminants in an L-tryptophan dietary supplement (5–7), although the dose of melatonin tends to be about 1000 times lower than that of tryptophan. Common contaminants of synthetically produced melatonin, which may or may not be in the final product, include the following compounds (2):

  • 1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid;

  • 3-(phenylamino)-alanine;

  • 1,1’-ethylidene bis-(tryptophan) (‘peak E’, one of the contaminants related to EMS);

  • 2-(3-indolylmethyl)-tryptophan;

  • Formaldehyde-melatonin;

  • Formaldehyde-melatonin condensation products;

  • Hydroxymelatonin isomers;

  • 5-hydroxy-tryptamine derivatives;

  • 5-methoxy-tryptamine derivatives;

  • N-acetyl-and diacetyl-indole derivatives;

  • 1,3-diphthalimidopropane;

  • Hydroxy-bromo-propylphthalimide;

  • Chloropropylphthalimde.


Arnao & Hernandez-Ruiz state, “...there is a very small degree of risk involved in taking chemically synthesized melatonin supplements. In the case of phytomelatonin, its a priori natural origin should rule out any possibility of contamination due to chemical synthesis.” (1) 





































Authors: Deanna Minich, Ph.D., Melanie Henning, ND, Catherine Darley, ND, Mona Fahoum, ND, Corey B. Schuler, DC, James Frame

Reviewer: Peer-review in Nutrients Journal

Last updated: January 26, 2022




1. Naidu R, Biswas B, Willett IR, Cribb J, Kumar Singh B, Paul Nathanail C, et al. Chemical pollution: A growing peril and potential catastrophic risk to humanity. Vol. 156, Environment International. 2021.

2. Arnao MB, Hernández-Ruiz J. The potential of phytomelatonin as a nutraceutical. Molecules. 2018.

3. He L, Li JL, Zhang JJ, Su P, Zheng SL. Microwave assisted synthesis of melatonin. Synth Commun. 2003;33(5).

4. Xie X, Ding D, Bai D, Zhu Y, Sun W, Sun Y, et al. Melatonin biosynthesis pathways in nature and its production in engineered microorganisms. Vol. 7, Synthetic and Systems Biotechnology. 2022.

5. Williamson BL, Tomlinson AJ, Mishra PK, Gleich GJ, Naylor S. Structural characterization of contaminants found in commercial preparations of melatonin: Similarities to case-related compounds from L- tryptophan associated with eosinophilia-myalgia syndrome. Chem Res Toxicol. 1998;11(3).

6. Allen JA, Peterson A, Sufit R, Hinchcliff ME, Mahoney JM, Wood TA, et al. Post-epidemic eosinophilia-myalgia syndrome associated with L-tryptophan. Arthritis Rheum. 2011;63(11).

7. Williamson BL, Tomlinson AJ, Naylor S, Gleich GJ. Contaminants in commercial preparations of melatonin. Vol. 72, Mayo Clinic Proceedings. 1997.

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