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Initial Review: Considering the Nature of the Evidence

The medical literature was searched to explore cardiovascular and psychiatric types of reports. Case reports indicated that melatonin might exacerbate psychiatric conditions, and it has been reported to cause seizures. Case reports included evidence that supported a causal relationship between melatonin and the occurrence of seizures, including challenge and rechallenge data. Animal data relevant to the issue were also examined. There was little animal data relevant to the behavioral effects, but data describing significant effects on the reproductive axis of animals added to the level of concern. Thus, at this step, multiple factors came together to suggest a higher level of concern regarding the use of melatonin, indicating the need for an integrative evaluation. In addition, there was concern that adverse events such as seizures and psychiatric problems worsened in persons particularly susceptible to these problems.

Integrative Evaluation

The integrative evaluation of melatonin began as a focused effort looking at the initial signal of seizure occurrence in an at-risk population, but the preliminary review to gather additional information yielded other areas of concern related to melatonin’s physiological role as a hormone. Once these data were identified, it did not seem appropriate to ignore them as they might also indicate that melatonin was a risk to public health.

Each of the various categories of data (human, animal, in vitro, and related substances data) was important to the development of the recommendations and conclusions of the working group. While there was a large amount of human data, it was collected following short-duration exposure to melatonin. Animal studies of some duration helped to put the human data in context. The in vitro data were useful for understanding the potential for melatonin to stimulate or inhibit the activity of other hormones. Evidence from human, animal, and in vitro studies in which doses far exceeded the usage of melatonin as a dietary supplement were also considered.

Saw Palmetto

Presumed Signals

Saw palmetto was selected for review because of two serious cardiac events reported to SN/AEMS. Other signals of concern could have been evidence that saw palmetto may have or has similar biological activity to a regulated drug (finasteride) and saw palmetto’s use as a drug in several

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