Experts say that other issues pertaining to poor sleep quality, such as light exposure and certain behaviors, should be tackled ahead of resorting to use of the hormone melatonin to regulate sleep. But if it is used, an individual's daily onset of natural melatonin production should be taken into account before deciding on an appropriate dose to supplement, they say.
Melatonin, which is available over-the-counter in the United States but restricted in other developed countries, is typically recommended acutely for sleep schedules thrown off by, for example, jet lag or chronically for certain circadian rhythm disorders. It has also been touted as something close to a panacea, with some even suggesting it can treat cancer, cognitive dysfunction, and obesity. However, it is the explosion in the use of melatonin to regulate general sleep in otherwise healthy individuals that has led to US consumers reportedly spending more than $400 million on melatonin supplements in 2018.
This has raised concerns over its safety among healthcare professionals and led to questions as to whether the hormone should be taken for jet lag at all and whether its use should be restricted in children. This ongoing debate led the American Chemical Society to recently produce a video produce a video that debunks many of the myths around melatonin and its effects, including the magnitude of its benefits in improving sleep.
Now, José Cipolla-Neto, MD, PhD, Institute of Biomedical Sciences, University of São Paulo, and Fernanda Gaspar do Amaral, PhD, a professor at the Federal University of São Paulo, Brazil, have conducted an in-depth review of the literature on melatonin and its uses. Moreover, they have produced a series of recommendations, published in the December issue of Endocrine Reviews, that set out how best to use the hormone, including advice on the most effective dosage and timing.
But others question whether people should look to melatonin to regulate sleep at all, suggesting that, instead, individuals should be looking at controlling night-time light exposure and even regulating light levels in shops. The sheer amount of research that has been conducted into melatonin in recent years is staggering. Cipolla-Neto and Amaral point out more than 4000 studies have been published in the last 20 years, of which 200 were randomized controlled trials and 195 systematic reviews.
Melatonin has been shown to affect a number of physiological processes, including downstream effects on the cardiovascular, reproductive, immune, respiratory, and endocrine systems, alongside energy metabolism. Melatonin synchronizes our organism's temporal order both daily and on the seasonal time scale. Consequently, multiple modes of action should be taken into account both when performing laboratory experiments and conducting clinical studies into melatonin's use as a treatment.
Melatonin's effects depend not just on the route of administration and concentration but also on the time of administration, among other factors. Additionally, the daily variation in melatonin levels varies between individuals. For example, those who prefer to get up early start daily melatonin production earlier than those who prefer to stay up later, while long sleepers tend to produce the hormone for longer periods than those who sleep less.
A given dose of melatonin may, moreover, result in different plasma levels between individuals, owing to pharmacokinetic differences in the way that it is absorbed, distributed, metabolized, and eliminated. These processes can themselves be affected by an individual's age and clinical condition, the presence of pathological conditions, and the physiological performance of the gastrointestinal tract, liver, and kidneys. If these factors are not adequately considered, they say that the clinical efficacy of melatonin will be altered.
How Should Melatonin Be Best Used?
The first recommendation is to determine the start of melatonin production, known as the dim light melatonin onset (DLMO), and its duration in each patient, and use that to guide prescribing. This is because, without using the DLMO as an indicator of the timing of administration, melatonin could advance, delay, or even have no effect on the timing of endogenous circadian rhythms.
However, is not typically feasible to determine the DLMO in everyday clinical practice. A more practical surrogate is to take the time at which the patient usually goes to sleep at night. Because of bioavaiability, melatonin should be taken around an hour before the usual bedtime at exactly the same time every day.
In terms of the dose, there is no consensus in the literature. What is known is that young people who take approximately 0.1 to 0.3 mg of melatonin will have a plasma concentration in the range of 100 to 200 pg/mL, which is considered to be within the physiological range.
A dose of 1.0 mg would result in a plasma concentration of approximately 500 to 600 pg/mL, which is far higher than the physiological concentration. For example, if the outcome is an acute phase displacing, as it is desired for jet lag treatment, a fast-release pulse correctly timed is perfectly adequate. However, if the desired effect is a sustained phase displacement as, for example, in non-24-hour sleep disorder or circadian dysfunction in totally blind people, the synchronizing effect requires chronic continuous daily intake of melatonin. For this purpose, a slow-release or dual-release formulation is the most appropriate."
Should Melatonin Be Taken at All?
A question nevertheless remains as to whether melatonin should be taken at all by individuals who do not have a recognized clinical condition, or indeed whether it is the most appropriate treatment in those who do.
Satchidananda Panda, PhD, and his colleagues at the Salk Institute for Biological Studies, La Jolla, California, published a study in mice showing how the protein melanopsin in retinal cells continually responds to light. Melanopsin, which is tuned to blue light, is essentially checking whether it's daylight still out there and, if there is daylight, then it will tell the brain to avoid sleeping and stay awake. It does that by two ways, one is increasing the circadian clock, telling that it's still daytime, and the second is it tells the pineal gland to slow down production of melatonin. Melatonin, threfore, has a big impact on sleep and it should not be seen as a panacea, and should be heavily regulated, which it's not. At the present time melatonin is the only hormone produced in the human body that's not heavily regulated.
Not Harmful, But Not That Effective
That said, currently, there isn't any hard evidence to say that taking melatonin on a daily basis is harmful; there aren't large-scale multicenter clinical trials to really test that. Most of the ongoing research is now being focused on reduction of light exposure in the hours prior to bedtime.
