Safety of melatonin
Can all these findings on antioxidant and radical-avoiding actions of melatonin justify its intake as a food additive or as a medication? The idea of substitution therapy may seem especially attractive for the elderly who have more or less lost the nocturnal peak of circulating melatonin. Nevertheless, the use as a food additive is still a matter of controversy. The argument for a naturally occurring compound, which is a normal food constituent, cannot suffice alone, since commerical preparations would always lead to at least transient pharmacological concentrations in the blood, and the immunomodulatory actions of melatonin may not be desired in every case. Therefore, experience will have to answer the question of its usefulness. Without any doubt, melatonin is remarkably well tolerated. Of course, one can find in any large statistical sample of melatonin users some individuals who complain about side effects, scientifically understandable or not. In a currently running study on ALS, patients receiving daily very high doses of melatonin (30 or even 60 mg per day), we did not see any harmful side effects [14] and have not to date. In patients with rheumatoid arthritis, some symptoms were suspected to be associated with immunomodulatory actions of melatonin [159], so that caution is due in this group of individuals. More research will be required on melatonin in different diseases and disorders, but there is no good reason to assume that melatonin, at moderate or even at high doses, is dangerous to a healthy person or to patients with types of oxidative stress phenomena not caused by (auto-)-immune responses. One might also suspect that melatonin could exert unfavorable effects by increasing the blood pressure, due to downregulation of nitric oxide synthase and nitric oxide scavenging by the indoleamine itself or by AMK. Melatonin was tested in clinical trials on hypertension and was reported to decrease blood pressure in one study [160], but to interfere with nifedipine [161], whereas a combination of lacidipine with melatonin was recommended in another investigation [162]. Therefore, interaction with other medication has to be considered.
Problems of dosage and side effects may also arise from impurities in the melatonin preparations sold over the counter. Contaminants have repeatedly been detected in such material, including our own experience of that kind. As long as the contaminant is only AFMK, this may be less serious, but one should be aware that the pharmacology of kynuramines is only partially known. Moreover, manufacturers must consider that an easily oxidizable compound like melatonin can undergo reactions under air exposure. On large surfaces, such as silica gels, we see this every day in the laboratory.
Another important aspect for the use of melatonin as a food additive is timing. As soon as the substance is given as a pill or as a preparation from a medicinal plant causing relatively high pharmacological blood levels, the situation is entirely different from the uptake with normal food or from the postprandial gastrointestinal release. Since circulating melatonin peaks at night, pharmaceutical preparations should be strictly given at the same time of day in the evening. The usual recommendation "at bed time" may be insufficient since this could mean in practice different hours of the day. Here, one has to consider the chronobiological functions of melatonin. When given during the day, a high dose of melatonin would cause mild narcotic effects, drowsiness etc. and the practice is not recommended for this reason. It would not shift the circadian oscillator much, because of the silent zone of the phase response curve for melatonin, in which phase shifts are negligibly small. This is the same reason that a postprandial release of gastrointestinal melatonin does not shift the circadian oscillator. Advance shifts of the endogenous clock by melatonin are much larger at late afternoon and early night [157,158]. Therefore, melatonin should be given relatively precisely at the same hour, to avoid phase shifts differing in extent and pushing of the circadian oscillator back and forth. As mentioned above, pertubations of the internal time structure can also cause oxidative stress [77].
Conclusion
In terms of nutrition, melatonin is interesting both as a natural constituent of food, and as a food additive. Its use for the latter purpose can be recommended only with some caution, given the present state of our knowledge, although the risks by melatonin appear remarkably low, compared to other medications and food additives. Melatonin's antioxidant capacity is based not only on direct radical detoxification, but comprises manifold effects. Some of the most promising areas, modulation of mitochondrial metabolism by melatonin and actions of its kynuric metabolites, deserve particular attention in the future and may change our view of the value of these compounds profoundly.