Hit or miss: the use of melatonin supplements

Citation:

Goldstein CA, Burgess HJ. Hit or miss: the use of melatonin supplements. J Clin Sleep Med. 2020;16(suppl_1):29S–30S.

Supplemental melatonin is one of the most widely used hypnotics, in part because it is available over the counter in the United States.¹ Although melatonin supplements are generally considered safe,¹ individuals who take melatonin for self-management of sleep problems and providers who recommend melatonin to patients rarely consider the nuances of dosing and the potential for untoward effects.

In 2017, Erland and Saxena² tested 30 different commercially available melatonin supplements in a variety of formulations. The actual melatonin content varied from the labeled content by more than 10% in most of the supplements.² Serotonin, a precursor of melatonin that was not included on product labels, was present in 26% of the supplements.² The majority of supplements that contained serotonin included herbal extracts in addition to melatonin.² The authors found greater melatonin variability in lower doses (1 and 1.5 mg) and certain formulations (chewable tablets).² Furthermore, the same manufacturer’s products varied in melatonin content from lot to lot.² Three years later, not much more is known about melatonin supplements.

Beyond the variability in content reported by Erland and Saxena,² there are other aspects of supplemental melatonin that contribute to imprecision in dosing. First, there are high interindividual differences in the bioavailability of melatonin—the resulting melatonin concentration in the circulation after taking a fixed dose can vary markedly between individuals.³ Second, the peak nocturnal concentration of endogenous melatonin in the circulation has more than a 10-fold variation among healthy adults.⁴ Therefore, a 0.5 mg dose may lead to supraphysiological levels in one individual but may closely approximate another individual’s normal nocturnal levels.

Finally, the dose and timing of melatonin vary according to the intended treatment outcome: sleep promotion or circadian phase shifting. Melatonin can cause a phase advance when dosed 3–5 hours before an individual’s natural sleep onset and a phase delay when dosed late in the habitual sleep period or just after natural sleep offset.^5,6 Phase advances are typically required from a clinical standpoint, and accordingly, low doses (≤ 0.5 mg) are usually recommended to avoid any resultant sleepiness from melatonin taken in the afternoon. Because of its soporific properties, supplemental melatonin is more commonly used as a sleep aid at bedtime, and meta-analyses indicate that supplemental melatonin can reduce sleep onset latency by 5–22 minutes.^7–9 The sleep-inducing capabilities of melatonin seem even more pronounced when melatonin is administered when endogenous secretion is minimal (biological daytime).¹⁰

When using melatonin, one should also consider the formulation (immediate or sustained release) and route of administration (most commonly oral, but intranasal, transdermal, and transmucosal methods are available). Both of these factors will impact the time to peak and duration of action. Not surprisingly, given the complexity of dosing, although melatonin is recommended for the treatment of individuals with delayed sleep-wake phase disorder, blind adults with non-24-hour sleep-wake rhythm disorder, and children and adolescents with irregular sleep-wake rhythm disorder, the precise timing, dose, and formulation are not specified.¹¹ Erland and Saxena’s findings,² in the context of existing uncertainty surrounding melatonin, suggest barriers to achieving the desired therapeutic outcome, and in patients taking very high doses, the possibility of next-day drowsiness.

The media’s attention to sleep has grown exponentially and resulted in an increasing awareness of disordered sleep among the lay public. Although we welcome the availability of therapies marketed directly to consumers for self-management, greater quality control and transparency among supplement manufacturers is required for successful and safe melatonin use.

DISCLOSURE STATEMENT

All authors have seen and approved this manuscript. Dr. Burgess is a consultant for Natrol, LLC. Dr. Goldstein reports no conflicts of interest.