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 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 Sa~o 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.
A Multitude of Effects
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,” Cipolla-Neto commented in a press release from the São Paulo Research Foundation (FAPESP).
He and Amaral therefore argue that these 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.
“In this case, above all, it should be kept in mind that melatonin’s effects depend not just on the route of administration and concentration but also on the time of administration, among other factors,” argues Cipolla-Neto.
And crucially, the daily variation in melatonin levels varies between individuals, they say.
For example, so-called early birds, 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, Cipolla-Neto and Amaral point out.
If these factors are not adequately considered, they say that the clinical efficacy of melatonin will be altered.
Indeed, “proper chronic melatonin hormonal replacement therapy is only achieved when dosage and formulation are carefully chosen and individually tailored and controlled to accomplish the desired clinical effect,” Cipolla-Neto observes.
How Should Melatonin Be Best Used?
This led Cipolla-Neto and Amaral to set out a number of recommendations as to how melatonin should be used in clinical practice.
The first 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, they write.
However, is not typically feasible to determine the DLMO in everyday clinical practice.
Cipolla-Neto and Amaral therefore suggest that a more practical surrogate is to take the time at which the patient usually goes to sleep at night.
With the majority of melatonin formulations requiring approximately 45 minutes to become bioavailable, they recommend that they be taken around an hour before the usual bedtime at exactly the same time every day.
In terms of the dose, however, the authors say that 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 the authors say is “far higher than the physiological concentration.”
They note that, in reality, a wide range of doses are used, depending on the reason for taking melatonin and the formulation.
“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,” say Cipolla-Neto and Amaral.
“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, Salk Institute for Biological Studies, La Jolla, California, and colleagues recently 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,” Panda told Medscape Medical News.
“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.”
While Panda acknowledges that melatonin has a “huge impact” on sleep, he said that it should not be seen as a “panacea,” adding, “if it was, then it should be heavily regulated, which it’s not.”
He continued: “This is the only hormone produced in the human body that’s not heavily regulated, and that says something.”
“That says that the health benefits of melatonin are extremely hyped up beyond what…scientists accept or what is proven. And it’s easy for science writers and commentators to latch onto one hormone and amp up its significance.”
As to whether melatonin itself should be targeted to improve melatonin production or whether, for example, melanopsin would be more appropriate is also open to debate.
While Panda and colleagues were previously able to develop a drug that specifically targets melanopsin and induces a state similar to physiological darkness, he pointed out that “melanopsin has many other effects beyond melatonin.”
Kenneth P. Wright Jr, PhD, Director of the Sleep and Chronobiology Laboratory at the University of Colorado Boulder, agrees.
He notes that melatonin production continues to follow a circadian rhythm even in the absence of exposure to light, thus underlining the fact that there is not a direct relationship between the two proteins.
Not Harmful, But Not That Effective
Wright told Medscape Medical News, “Currently, we don’t have any evidence to say that taking melatonin on a daily basis in that sense is harmful, although there are no large-scale multicenter clinical trials to really test that.”
He added that it has nevertheless been shown in animal studies to be “very safe,” and that some individuals with 24-hour sleep-wake disorder, the majority of whom are blind, “have been taking this for decades, for example.”
However, Wright also points out that taking melatonin at night may help people fall asleep but “there is no evidence that it will help you sustain sleep for long periods of time if your body is already naturally producing it.”
He consequently believes that melatonin “is something that I wouldn’t say should be the first step if you’re trying to help someone improve their sleep.”
Instead, factors that may be disturbing sleep and behaviors around sleep should be examined, so that melatonin doesn’t have to be used “every night.”
Wright explained: “If you’re having a hard time falling asleep and having a hard time waking up in the morning, that could be just down to the fact that either you’re not getting enough sleep…or it could just be that your clock is just timed much later than is conducive to your school or work demands.”
“By using light, we can shift your clock earlier so, that way, your body is prepared to go to sleep earlier and wake up earlier, and that entails getting sunlight exposure in the morning and then reducing your exposure to light at night.”
How to Reduce Light Exposure
To achieve this, Panda says that there are a number of steps that individuals can take.
“Number one is, in the evening, people should switch on their night shift or nightlight features on their phones, laptops, etc, so that the screen becomes dimmer and switches to an orange hue, say around eight or nine o’clock.”
“That also acts as a nice nudge for people to prepare for sleep.”
However, visiting the shops at night could throw an individual’s light exposure, and consequently their sleep preparation, off-kilter.
“Many department stores these days have switched to blue LED light because that looks very bright and then the products look very appealing,” Panda explained.
“That light, at thousands lux of light in many department stores…will definitely reduce melatonin production and will reset the clock, and in some people it can also increase their anxiety levels, etc.”
In situations in which it is not possible to control light, “that’s where maybe having a pair of blue-filtering glasses is handy,” Panda added, saying that even wearing sunglasses could help, “although it sounds very weird.”
Alongside ensuring individuals use low lighting at home in the evenings, he believes that following these steps means “we don’t have to wait for a drug” to help regulate sleep.
“Any drug will have some side effects, and so it’s only in severe cases where people have migraine pain or some other photophobia where it may be better to wait for a drug.”
Wright agrees, noting: “For most people, I wouldn’t recommend using melatonin unless they’d tried other things and worked with the physician to see what might best be the strategy to improve their sleep, if that’s the goal.”
Although he added that, if all else fails, “things like melatonin or even more sophisticated behavioral treatments for sleep problems can be tried.”
Should Light Exposure Be Regulated?
Panda believes a better approach would be to introduce regulations on night-time light exposure, although the evidence on how light affects behavior, sleep, anxiety, and depression is currently not yet strong enough to develop specific guidelines.
He said that, for example, there is currently no advice that recommends stores “to cut down light…at night time, although we know that that amount of light has severe adverse neuroendocrine effects on the human brain and body, and it’s very close to an environmental toxin.”
Cipolla-Neto and Amaral agree, writing that “the present urban society and the industrial production processes as organized should be taken into account” when looking at sleep disturbances, “as both depend on the presence of indoor lights during the night.”
However, Panda notes: “Since we don’t have enough human studies, there is not enough [to] guide these department stores and drug stores on how much light they should have at night.”
“There is much basic science and translational research,” still to be done, he says.
Nevertheless, Panda believes that “in maybe 5 to 10 years we will have smart design in homes, factories, workplaces, shopping places, etc, that will nurture health instead of just lighting up the night.”
The guidelines were supported by Fundac¸a~o de Amparo à Pesquisa do Estado de Sa~o Paulo. The melanopsin study was supported by NIH grants to Panda; a Japan Society for the Promotion of Science fellowship to Megumi Hatori; and Fondation Fyssen and Catharina Foundation fellowships to Ludovic S. Mure. Funding from the Leona M. and Harry B. Helmsley Charitable Trust, Glenn Foundation for Medical Research, and NIH grants facilitated the generation of several viruses and their use in mouse behavioral studies. Panda is the author of The Circadian Code, for which he receives royalties. The authors have reported no other relevant financial relationships.
Endocrine Rev. 2018;39:990-1028. Abstract
Cell Reports. 2018;25:2497-2509. Abstract