Melatonin: Magic Potion or Unregulated Danger?

Melatonin: Magic Potion or Unregulated Danger?

"The most magical sleep supportive potion I'm aware of is melatonin," says Rubin Naiman, PhD, sleep specialist, psychologist, and clinical assistant professor at the University of Arizona in Tucson. Although major sleep societies don't recommend it for the treatment of insomnia, Naiman compares melatonin to Nyx, the Greek mythological goddess of the night who mothered Hypnos, the god of sleep — calling it "Nyx in a bottle."

And indeed, millions of North Americans seem to agree. In 2012, an estimated 3.1 million Americans were taking melatonin, a number that has likely skyrocketed given that the global melatonin market, which was valued at $700 million in 2018, is projected to reach $2790 million by the end of 2025.

In much of the world, it's only available by prescription, but in Canada and the United States, it's freely available as a dietary supplement.

Ironically, although most people take melatonin for sleep, its best-kept secret may be its other reported benefits as an anti-inflammatory, antioxidant, and oncostatic agent.

Melatonin is a "multitasking molecule" whose "bewildering array of functions...has exceeded the expectations of the most ardent melatonin devotees," according to Russel J. Reiter, PhD, from UT Health San Antonio, a top authority on the molecule and one such devotee.

Reiter has published hundreds of papers on melatonin, with his most recent ones outlining its benefits or possible uses in cancer, diabetes, hypertension, intestinal diseases, neurodegenerative diseases, and even aging.

So why are the major sleep societies hesitant to endorse melatonin for run-of-the-mill insomnia? The American Sleep Association and National Sleep Foundation cite conflicting evidence about efficacy while cautiously suggesting that it might help some people. The American Academy of Sleep Medicine (AASM) actually advises clinicians against recommending melatonin, weighing the overall evidence as "weakly against" its efficacy.

A review of randomized, double-blind, placebo-controlled studies of melatonin for insomnia without significant comorbidities "suggests a modest reduction in time to fall asleep of not better than around 10 minutes, which by our definition was not clinically significant," said Michael J. Sateia, MD, lead author of the AASM recommendation. The review found that melatonin also failed to show robust improvement in other sleep outcomes.

However, melatonin is approved in Europe to treat primary insomnia in older adults and has been shown to help insomnia in children with autism spectrum disorders, adolescents with depression, women with premenstrual dysphoric disorder, patients with hypertension taking beta-blockers, and children with attention deficit hyperactivity disorder.

"AASM's recommendation against melatonin does not mean that it is proven ineffective or unsafe," stressed Sateia. "It simply means that based on the rigorous standards we applied, there was insufficient evidence demonstrating its effectiveness. Moreover, our recommendation was based on the entire adult population; we were not able to conduct separate meta-analyses for the elderly population."

"That said, there are certainly studies out there that suggest melatonin may be helpful for insomnia in older individuals, perhaps especially those who have significant declines in endogenous melatonin levels associated with aging," he said. "Those data, however, also show conflicting results."

And he added, "The use of melatonin in children with developmental or psychiatric disabilities is an entirely different matter that we did not address whatsoever."

Minor Risks, Relationships Unclear

Despite the caution from sleep societies, "the data we have clearly support its role in regulating circadian rhythms, which is critical for healthy sleep," said Naiman.

So if melatonin might help some people sleep, what's the harm in patients trying it? Is there any evidence of risk?

Melatonin generally has a favorable safety profile, with minor adverse events such as fatigue and sluggishness being short-lived and associated with dose timing. Although there is some evidence of adverse blood pressure and heart rate effects in people with cardiovascular conditions and concurrent antihypertensive medications, it is unclear whether they are because of melatonin or drug interactions.

Because melatonin has immune-enhancing properties, there is also some debate about its safety in patients with autoimmune diseases. Although recent discussion has largely sided with its safety in this context, there are still a few cautionary voices.

Rüdiger Hardeland, PhD, from the University of Göttingen, who has studied melatonin and is now a retired zoologist, is one of them. "Melatonin can stimulate the release of proinflammatory cytokines and other mediators," he said, explaining that studies linking endogenous melatonin levels to symptoms of rheumatoid arthritis (RA) have convinced some clinicians that melatonin supplementation may not be advisable in patients with RA. "For me, this finding has to be seen as a caveat concerning all autoimmune diseases," he cautioned.

Indeed, the Arthritis Foundation advises against melatonin for patients with autoimmune disease.

But this remains highly controversial. Other researchers, including Reiter, believe melatonin may actually alleviate the symptoms of RA and other autoimmune diseases.

"The majority of studies related to melatonin and autoimmune diseases suggest that the use of melatonin would not be an issue," said Reiter. "Considering the tens of thousands of people who use melatonin daily, there have been few indications that it is [contraindicated] for autoimmunity or anything else."

So Why the Worry?

Researchers in most fields of medicine have repeatedly called for more studies on the effects of melatonin supplementation because many questions remain. But it's doubtful that there will be a glut of new studies.

"There is little financial incentive for studying melatonin more thoroughly, primarily because it can't be patented and competes with the lucrative hypnotics market," said Naiman.

In addition, most health professionals are hesitant to recommend melatonin supplements because of uncertainties about product quality, dose, and timing, he said.

"The standard 3-mg tablet is significantly more than we need for sleep. In recent years, we're seeing products dosed at 5 mg and even 10 mg. More is not better, and could theoretically downregulate our endogenous melatonin," Naiman said.

Timing is also very important and too frequently disregarded, he added.

"Given that one of its primary functions is to regulate circadian rhythms, it's striking how little regard is given to the timing of melatonin use. There is virtually no discussion in the literature about attempting to replicate the natural release curve seen in the brain," said Naiman.

"Natural melatonin levels are low early in the evening, rise steadily through the night, and peak in the last third of sleep. Because melatonin has a short half-life (about 30-45 minutes), taking a standard-release tablet around bedtime results in a peak early in the night and a tail toward morning — precisely the opposite of the natural pattern."

He suggests taking time-released tablets around bedtime or sublingual regular-release products in the middle of the night.

Finally, in North America, where melatonin supplements are not regulated, product quality is a serious concern. The melatonin content in products sold in Canada did not measure up in more than 71% of those tested, with melatonin content ranging from −83% to +478% of the labeled claim, and as much as 465% variation between lots of the same product.

"There are a handful of companies producing 'pharmaceutical grade' (pure) melatonin, which is a must, that is available to consumers," said Naiman.

Whether worshipped as the goddess Nyx or the body's "God particle," melatonin has avid disciples — and mostly tepid detractors. Although enthusiasm for its potential is rooted in a growing body of research, concerns remain, centered mostly on the need for more evidence.