It’s summertime, and the living is easy. Forget the solstice. For most of North America, this week is the real start of summer – July 1 in Canada, and July 4 in the USA. Vacation time means breaking out of that those usual routines of work and school. I’m amazed after a few weeks of vacation how much sleep my body will accept if given the opportunity, where it will climb from six to nine hours a night within a week. I try not to change my kids’ habits too much, and one area I’m fairly disciplined with is maintaining a predictable sleep/wake cycle, even when they’re on vacation. I’ve learned, mainly through trial and error, that I suffer the consequences when my own kids don’t get enough sleep, or when their sleep cycle is thrown off. It wasn’t always like this. I remember a period of what felt like years when I had to crawl out of my child’s bedroom on my hands and knees so as to not disturb a child who simply would not fall asleep. And when it finally, mercifully, occurred, it would be a brief respite before the cycle began again. The sleepless nights left us all cranky and exhausted. Admittedly I was fortunate, either due to my successful parenting (but more likely mean reversion) and my kids are pretty good sleepers now. I’m reminded of my good fortune when I speak with exhausted and frustrated parents who have children that cannot sleep and are worried about the causes and consequences of persistent insomnia. As a pharmacist I’m regularly asked about insomnia for both kids and adults as there are a number of over-the-counter products available, and many consumers are understandably apprehensive about seeking out prescription products. Tell someone there’s “natural supplement” for sleep and there’s usually a lot of interest. That’s what I’ve seen with melatonin, a hormone that is sold without a prescription in Canada, the United States, and other countries. It is widely perceived as safe and alternative health purveyors like naturopaths, and even some health professionals, may recommend it for treating sleeping problems in both adults and children. Beyond sleeping, some believe melatonin is a wonder drug with efficacy for diseases ranging from chronic fatigue to cancer to irritable bowel.
I never take sleep questions lightly. While in many cases there may be no identifiable causes, insomnia and sleep disturbances can be symptoms of more serious medical conditions. I try to identify the main complaint (difficulty falling asleep, waking up during the night, waking up early, and daytime exhaustion) and identify any possible contributing factors, such as those with breathing disorders (e.g., asthma), on medication (e.g., ADHD drugs, anti-histamines, antidepressants, and some supplements), or developmental disorders (e.g., autism). (I could probably add blogging to that list.) Contributing factors require a detailed evaluation, and I generally advise against any self-medication in all but the most urgent or transient situations. Insomnia may not be the reason for a physician’s visit, but it should be, especially for children with persistent problems. One of the most foolish things health professionals can do is endorse drug treatment (natural or otherwise) before looking for underlying contributors, first.
I never recommend over-the-counter products to treat insomnia in children. Without a physician’s evaluation and recommendation, I strongly discourage parents from administering these products to children. It can be a difficult pitch because products like melatonin are just sitting on the shelf, and are backed by lots of advertising touting efficacy and safety. After all, if melatonin were unsafe, it wouldn’t be sold without a prescription, right?
My concern was partially reflected in a recent column in the Wall Street Journal, entitled “Melatonin: A ‘Magic’ Sleeping Pill for Children?”
Sales of melatonin have risen dramatically over the past five years, according to Nutrition Business Journal. Estimates for 2012 put sales at $260 million; in 2007, the market was just $90 million. Melatonin is available over the counter in the U.S., but in the U.K. and several European countries, the hormone supplement requires a doctor’s prescription.
A handful of companies market melatonin directly for children’s use, offering flavored, low-dose versions of the supplement. One melatonin manufacturer’s website even urges parents to “prepare your child for academic success” by getting him or her to sleep. It cites one study that found “students with C’s, D’s and F’s got about 25 fewer minutes of sleep and went to bed an average of 40 minutes later than A and B students.”
The column takes a fairly critical eye to the pediatric use of melatonin, citing a lack of data as well as what may be unwarranted parental enthusiasm for the product:
“I’ve never seen such widespread abuse of any drug or therapy in all my years of practice,” said Stuart Ditchek, clinical assistant professor of pediatrics at New York University School of Medicine. One mother told him that “she lines up her six healthy children nightly to give them their melatonin pill.” Dr. Ditchek believes the supplement should only be used for the most serious sleep and neurological disorders. The concern, he said, is the lack of long-term clinical studies to see how the hormone supplement interacts with other hormones in the body, potentially affecting fertility or sexual development.
Still, the natural=safe idea is hard to shake, especially for a product that is perceived as being safe enough to be sold in health food stores, without restrictions of any kind. Could melatonin be a supplement that actually works? It’s a hormone with an interesting but brief history – its function wasn’t understood until fairly recently and the gland that produces it (the pineal gland) was originally thought to be an evolutionary vestige without function. In the early 1900’s it was observed that the pineal gland did secrete a substance with physiologic effects, and the hormone itself was named in 1958. By the seventies, melatonin’s role in the circadian rhythm was beginning to be understood. Receptors for the hormone have been identified in the hypothalamus, the pituitary, and in other organs in the body. In humans and other mammals, melatonin secretion by the pineal gland follows the light cycle, being low during daylight hours, surging in the evening and peaking in the middle of the night. This secretion starts in infancy and continues through adulthood, followed by a decline as we age.
When consumed orally, melatonin is not consistently or extensively absorbed, so individual responses to doses can vary, which complicates dosing. Supplement doses can push blood levels much higher than any levels that can ever been reached naturally. Receptors are highly sensitive to high doses, and their activity decreases as a result, suggesting that long-term supplementation may have unanticipated consequences. It appears to have a good short term safety profile, however, and toxicity reports are rare. Supplement doses range from 0.1 – 10mg with most doses at the lower end of this scale.
How did a hormone come to be deemed a supplement? This is difficult to answer based on scientific principles, given melatonin is primarily synthesized in the pineal grand from the amino acid tryptophan, with serotonin produced in an intermediary step. There is no good evidence to suggest that dietary or supplementary tryptophan affects melatonin levels. Diet seems to have no effect on melatonin levels at all. Hormone pills don’t “supplement” any dietary source at all. Another challenge to the “supplement” and “natural” label is the fact that melatonin sold as a supplement is synthesized in a laboratory – there are no reliable natural sources. The consequence of being treated as a supplement (or in Canada as a “natural health product”), as has been described repeatedly at this blog, is a lowered regulatory bar for safety and efficacy. There is no evidence to show that the different forms of melatonin (e.g., extended-release) are well-absorbed or comparable to products studied in clinical trials. There is also no information to suggest that different brands are equivalent to each other. Given melatonin is inconsistently absorbed, switching brands may affect absorption, and ultimately, effect.
Melatonin supplementation does appear to have effects on sedation, fatigue, time to fall asleep and the total sleep duration. Studies are hard to synthesize, given they include big range of doses, a variety of dosing schedules, and a wide number of underlying conditions. The best evidence seems to be for circadian sleep disorders, where melatonin has FDA orphan drug status for this use. Based on the physiologic effects of melatonin, this makes some sense.
For general sleep disorders, the evidence is mixed. There is some tentative support for use in children, however the evidence base used to make this claim is based on an analysis of six small clinical trials, only one of which was in children with sleep disorders without other contributing cause or underlying medical issue (e.g., behavioral disturbances). This study, only four weeks in duration, noted a significant improvement in sleep onset (57 minutes) with 5mg of melatonin, but no change in total sleep time. Studies in children with secondary sleep disorders showed some improvements in sleep indicators as well, but whether these effects are meaningful isn’t clear. In all studies melatonin was well tolerated, though none of the studies looked at extended use of the drug. There is also some evidence to suggest that melatonin is effective at helping calibrate the sleep-wake cycle in children with developmental disabilities. But again, it had no effect on total sleep time. Overall the data are inconsistent and often unimpressive.
In adults, a 2005 meta-analysis suggested that melatonin would reduce the time to fall asleep by four minutes, while increasing total sleep duration by 13 minutes. Another 2005 meta-analysis drew a similar conclusion: melatonin was well tolerated but not very effective, improving the time to fall asleep by 12 minutes. A 2006 meta-analysis looked at secondary sleep disorders, like jet lag and shift work, and concluded that melatonin offered no meaningful benefits beyond placebo. It could be the short half-life of of the supplement that’s a factor. Show release versions or drug-based variants of melatonin (i.e., ramelteon) could plausibly have more meaningful effects.
Despite the array of doses used, melatonin is well tolerated. The most common side effects reported include daytime sleepiness, dizziness and headaches.
There are concerns about long-term use in children. Melatonin’s long-term effectiveness and safety are unclear. Given melatonin is a hormone, and receptors for this hormone are distributed throughout the body (including the sex organs), the safety, particularly during puberty, has not been established. For this reason there’s good cause for caution in children.
There are few comparisons between melatonin and other drugs like the infamous benzodiazepines, or newer agents like zolpidem. Reassuringly, there is no evidence of withdrawal effects caused by stopping melatonin, though there is admittedly a lack of long-term studies that have examined this potential risk thoroughly.
Melatonin is a hormone that is sold as a dietary supplement in some countries and as a prescription drug in others. Regardless of its regulatory status, evidence suggests that melatonin is only modestly effective, and many who use it will not show substantive improvements in their sleep quality. What is clear is while there’s nothing “natural” about taking huge doses of this hormone, it is well tolerated when used for short-term trials. Its safety in children, or with long-term use in adults, is less clear. Like other supplements, it’s a victim of a weak regulatory structure. In Canada and the United States, there’s little conclusive evidence to guide product selection and dosing. Buyer beware.