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Dietary Supplements: A Framework for Evaluating Safety Appendix F Melatonin: Prototype Monograph Summary1 V. SUMMARY AND CONCLUSIONS A. Summary Melatonin, a substance normally produced in the human body, is a dietary supplement available in the United States in a synthetic form. Upon stimulation by norepinephrine, pinealocytes synthesize melatonin from serotonin. In humans, under normal circumstances, the synthesis of melatonin has a circadian rhythm. The levels of endogenous melatonin can be decreased due to various disease states or physiological conditions. It is common to find decreased levels of melatonin in people with insomnia. 1 This is a summary of a prototype monograph, prepared for the purpose of illustrating how a safety review of a dietary supplement ingredient might be prepared following the format described in this report. While it was prepared as a prototype using the processes described in the report, it was not conducted under the auspices of the Food and Drug Administration utilizing all the resources available to the agency. Thus some pertinent information not available to the Committee could be of importance in evaluating safety to determine if use of this dietary supplement ingredient would present an unreasonable risk of illness or injury. Also, the development and review of this prototype was conducted by individuals whose backgrounds are in general aspects of evaluating science and whose expertise is not necessarily focused specifically on this dietary ingredient, although significant additional assistance was provided by consultants with relevant expertise. Therefore, this prototype monograph, while extensive, does not represent an authoritative statement regarding the safety of this dietary supplement ingredient. The full prototype monograph and its data tables on melatonin may be accessed at http://www.iom.edu/fnb.
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Dietary Supplements: A Framework for Evaluating Safety The literature on melatonin includes reports of adverse effects reported with human melatonin use at 10 mg/day or less to include central nervous system effects (e.g., somnolence, headaches, increased frequency of seizures, nightmares), cardiovascular effects (e.g., hypotension or hypertension), gastrointestinal effects (e.g., diarrhea, abdominal pain), and dermatological effects. In addition, melatonin use at higher doses (240–1,000 mg/ day) in a small number of subjects was associated with hormonal changes that were inconsistent among the different reports. This summary explores the quality and other factors that may have contributed to serious adverse events. The available data on melatonin safety in humans are based mostly on reports of studies with small numbers of participants that were not designed to evaluate the safety of melatonin. This monograph is based on 48 studies and reports of melatonin use in humans that included over 1,000 subjects (in the melatonin arms). The range of melatonin doses used in these studies is wide, 0.1 to 1,000 mg. These studies vary from one-time ingestion of melatonin to 6 months of daily ingestion. Many studies omit statements about adverse effects or state that no adverse effects were observed without describing the safety parameters monitored. Moreover, there is insufficient information on interactions of melatonin with drugs or other dietary supplements. Most available studies were conducted with adults, and little information is available for infants and young children regarding adverse effects, specifically concerning possible melatonin-induced alterations of pubertal development. Likewise, there is no information on safety of melatonin use by pregnant or lactating women. The LD50 of melatonin in animal models (1–3 g/kg body weight for oral doses in rats and mice) far exceeded the typical doses used as a dietary supplement in humans (0.5–10 mg/d). At a dose of 20 mg/L in drinking water, melatonin was associated with an increased rate of spontaneous tumors in one strain (CBA) of female mice. However, more recent studies by the same group showed the same amount of melatonin administered to another strain (SHR) of female mice had no effect on tumor rate. Thus the data on the effect of melatonin on tumor incidence in mice is inconclusive and this area of investigation should continue to be monitored. (This monograph focus is on understanding and interpreting these data, as limited resources were instead focused on human data.) In addition, it has been well established that melatonin has significant effects on the reproductive axis in animals (Reiter, 1991; Rivest et al., 1986). These effects might be undesirable if they occured in humans.
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Dietary Supplements: A Framework for Evaluating Safety B. Conclusions and Recommendations About the Safety of the Ingredient Based on the Strength of the Scientific Evidence Based on the available data, it appears that short-term use of melatonin in a daily amount of 10 mg or less does not raise concern of harm for healthy adults who are not taking concurrent medications or other dietary supplements. The basis for each of these qualifications is explained below. Long-term use of melatonin increases the level of concern because use for periods longer than a few weeks has not been documented except in a small number of subjects or for therapeutic uses (e.g., entrainment of blind individuals). Use of melatonin in amounts above 10 mg per day increases the level of concern because there are only a few clinical studies using these amounts and, in some, serious adverse effects were observed. Use of melatonin in populations other than healthy adults increases the level of concern based in part on the observation that serious adverse effects reported at 10 mg or less of melatonin per day generally occurred in humans with preexisting medical or psychological conditions that may have contributed to the ill effects. Specifically, concern of harm exists for individuals with one or more of the following: (1) past or current depression; (2) cardiovascular problems; (3) seizure disorders; (4) immune system disorders; (5) chronic liver disease; (6) chronic kidney disease; (7) predisposition to headaches; especially migraine headaches; and (8) concurrent use of anticonvulsant, sedative, hypnotic, or psychotropic medications. One exception to the lack of concern of harm in healthy adults is that women attempting to become pregnant should be aware that melatonin may affect reproductive function, including possible effects on hormone levels (Forsling et al., 1999; Ninomiya et al., 2001; Okatani and Sagara, 1993; Pawlikowski et al., 2002). Use of melatonin by children cannot be recommended without supervision by a physician due to the lack of data available for individuals below the age of 18 years and possible effects on hormone levels (Forsling et al., 1999; Luboshitzky et al., 2002; Ninomiya et al., 2001; Okatani and Sagara, 1993; Pawlikowski et al., 2002; Valcavi et al., 1987). Even among healthy adults, caution about use of melatonin should be considered for (1) individuals participating in functions that require alertness (e.g., operating a motor vehicle or machinery), (2) lactating women, and (3) individuals ingesting medications or other dietary supplements. C. Unresolved Issues and Uncertainties in the Available Data Uncertainty about potential for harm with the use of melatonin remains because of the following factors:
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Dietary Supplements: A Framework for Evaluating Safety Human data are from very short-term and relatively short-term treatment studies that were not designed to examine safety. Few studies included children. Many of the available studies in humans included small numbers of participants and varied greatly in duration of treatment, from a single dose to dosing for a few weeks or months. Few investigators described systematic collection of adverse effects in clinical trials. There is uncertainty in the dose-response relationship for adverse effects. The risk of harm from doses greater than 10 mg/day is unknown. D. Data Gaps and Future Research Recommended All future clinical trials should include systematic collection and evaluation of adverse effects. Dose-dependent safety studies in adults and children are needed. These studies should include investigations of the potential for harm in individuals taking more than 10 mg of melatonin per day. The literature should continue to be monitored for signs of melatonin effects on tumors and testes. The long-term safety of melatonin use in adults and children needs further study. These studies should include close monitoring of individuals with cardiovascular disease, specifically hypotension. More information is needed concerning possible interactions between melatonin and drugs, particularly various cardiovascular, psychotropic, and anticonvulsant drugs. REFERENCES Forsling ML, Wheeler MJ, Williams AJ. 1999. The effect of melatonin administration on pituitary hormone secretion in man. Clin Endocrinol (Oxf) 51:637–642. Luboshitzky R, Shen-Orr Z, Nave R, Lavi S, Lavie P. 2002. Melatonin administration alters semen quality in healthy men. J Androl 23:572–578. Ninomiya T, Iwatani N, Tomoda A, Miike T. 2001. Effects of exogenous melatonin on pituitary hormones in humans. Clin Physiol 21:292–299. Okatani Y, Sagara Y. 1993. Role of melatonin in nocturnal prolactin secretion in women with normoprolactinemia and mild hyperprolactnemia. Am J Obstet Gynecol 168:854–861. Pawlikowski M, Kolomecka M, Wojtczak A, Karasek M. 2002. Effects of six months melatonin treatment on sleep quality and serum concentrations of estradiol, cortisol, dehydroepiandrosterone sulfate, and somatomedin C in elderly women. Neuroendocrinol Lett 23:17–19. Reiter RJ. 1991. Pineal gland: Interface between the photoperiodic environment and the endocrine system. Trends Endocrinol Metab 2:13–19.
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Dietary Supplements: A Framework for Evaluating Safety Rivest RW, Aubert ML, Lang U, Sizonenko PC. 1986. Puberty in the rat: Modulation by melatonin and light. J Neural Transm Suppl 21:81–108. Valcavi R, Dieguez C, Azzarito C, Edwards CA, Dotti C, Page MD, Portioli I, Scanlon MF. 1987. Effect of oral administration of melatonin on GH responses to GRF 1-44 in normal subjects. Clin Endocrinol (Oxf) 26:453–458.
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