Am Fam Physician. 1999 Jan 15;59(2):286-288.
to the editor: The use and efficacy of melatonin have been discussed in American Family Physician in an article by Dr. Cupp.1 This over-the-counter medication is widely used to treat a number of ailments.1,2 Numerous studies have been and continue to be conducted on the value of melatonin in such treatments.2 However, in a reply to a letter to the editor, Dr. Cupp commented that the compound has not been “objectively evaluated in clinical trials involving large numbers of patients.”3 This observation is also noteworthy and requires more consideration.
The use of “naturally occurring” alternative medications continues to strike a chord with the American public. The value and efficacy of alternative medications in the treatment of ailments and disease as compared with pharmaceutically derived therapeutics need to be carefully evaluated and tested. Hence, a healthy debate on the use of melatonin clearly must continue.
A separate and more immediate concern is the quality control exercised in the production of compounds such as melatonin. This was obliquely referred to by Dr. Cupp3 but not discussed or developed in any detail. With the advent of the Dietary Supplement Health and Education Act passed by Congress in 1994, the production and purity of such compounds are not directly regulated by the U.S. Food and Drug Administration.
The impact and effect of contaminants that are present in dietary supplements were dramatically highlighted by the outbreak of eosinophilia-myalgia syndrome that occurred in 1989. The outbreak was triggered by the consumption of contaminated L-tryptophan manufactured by Showa Denko K.K. of Japan. Subsequently, researchers at the Centers for Disease Control and Prevention demonstrated that at least six contaminants, namely peaks E, C, FF, UV-5 (also known as PAA), 200 and AAA, were case-implicated compounds.4
More recently, we have characterized the structure of a number of contaminants present in over-the-counter melatonin products.5 We used online high-performance liquid chromatography mass spectrometry to analyze three different samples of melatonin that were commercially available and purchased in the Rochester, Minn., area. Seven different contaminants were detected at the 0.1 to 0.5 percent level of parent melatonin and were presumably formed during the manufacturing process. The most significant finding was that five of the contaminants were melatonin structural analogs of case-implicated contaminants obtained from L-tryptophan made by Showa Denko K.K. In particular, four compounds were melatonin analogs of peak E and another was a mela-tonin analog of the indoline contaminants peaks C and FF.
It is disturbing that the contaminants found in melatonin are structurally very similar to case-implicated contaminants that were present in L-tryptophan manufactured by Showa Denko K.K. The fact that no cases of disease similar to eosinophilia-myalgia syndrome have been reported, to our knowledge, from patients ingesting melatonin may be due to differences in consumption. A typical daily intake of melatonin for jet lag is approximately 5 mg per day for an average of seven days. In contrast, the daily intake of L-tryptophan in patients who contracted eosinophilia-myalgia syndrome was approximately 500 mg—15 g per day over several months (3 g per day for patients using it as a health food supplement and 3 to 15 g per day for patients under medical supervision).
It is important to note that the efficacy of melatonin is still open to question, but to date there is no indication that the parent compound is, in itself, toxic. However, the presence of such impurities in commercially available melatonin raises serious questions about the possible consequences after long-term consumption, especially when used at doses higher than recommended.
1. Cupp MJ. Melatonin. Am Fam Physician. 1997;56:1421–8.
2. Sahelian R. Melatonin: nature's sleeping pill. Marina Del Rey, Calif.: Be Happier Press, 1995:143.
3. Sahelian R. Use of melatonin for insomnia [Letter]. Am Fam Physician. 1998;57:1783–7.
4. Hill RH Jr, Caudill SP, Philen RM, Bailey SL, Flanders WD, Driskell WJ, et al. Contaminants in L-tryptophan associated with eosinophilia myalgia syndrome. Arch Environ Contam Toxicol. 1993;25:134–42.
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;11:234–40.
in reply: I wish to thank Drs. Naylor and Gleich for their letter concerning the important new information on the purity of melatonin products.
In the article, I mentioned that “ . . . contamination of melatonin products by harmful substances is a possibility.”1 I also mentioned in the abstract and the patient information handout that the potency and purity of melatonin products cannot be assured. I did not elaborate on these points because at the time, there was no published information available. The potency and purity of melatonin products are certainly important considerations in the evaluation of data on safety and efficacy. Studies of melatonin products that contain either contaminants or more or less than their labeled content cannot be accurately evaluated.
I am unaware of studies that specifically address the potency of melatonin products, but such information from an objective, independent source would be welcomed by many clinicians.
1. Cupp MJ. Melatonin. Am Fam Physician. 1997;56:1421–8.
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