http://www.iom.edu/O...onograph.v2.pdf
A. Summary
Melatonin, a substance normally produced in the human body, is a dietary supplement
available in the U.S. 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.
The literature on melatonin includes reports of adverse effects reported with human
melatonin use at 10 mg/day or less include central nervous system effects (somnolence,
headaches, increased frequency of seizures, nightmares), cardiovascular effects (hypotension or
hypertension), gastrointestinal effects (diarrhea, abdominal pain) and dermatologic 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 the adverse events
of a serious nature.
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. The
monograph is based on 48 studies and reports of melatonin use in humans that included over one
thousand subjects (in the melatonin arms). The range of melatonin doses used in these studies is
wide, 0.1-1000 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 in infants
and young children regarding adverse effects, specifically concerning possible melatonininduced
alterations of pubertal development. Likewise, there is no information on safety of
melatonin use in 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 the drinking water, melatonin was associated with an increased rate of
spontaneous tumors in female CBA mice. However, more recent studies by the same group
showed the same amount of melatonin administered to female SHR mice had no effect on tumor
rate. Thus, the effect of melatonin on tumor incidence in mice has not be shown conclusively and
this area of investigation should continue to be monitored (this report did not focus on
understanding and interpreting these data, as limited resourses 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, 1986). If similar effects occur in humans these
effects may be undesirable.
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 of harm because use of
melatonin 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
amounts of melatonin above 10 mg per day increases the level of concern because there are few
clinical studies using amounts in excess of 10 mg and serious adverse effects were observed in
some of these studies. 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 pre-existing 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 at al., 2001; Okatani et al., 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 at al., 2001; Okatani et al., 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:
• 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 vary
greatly in duration of treatment, from single dose to a few weeks or months.
• Only 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.
