Stepping up use of melatonin as sleep aid raises safety concerns: JAMA

USA: A recent article published in the Journal of the American Medical Association (JAMA) has shed light on the increasing use of melatonin for insomnia and the related safety concerns.  

Melatonin is a hormone secreted by the pineal gland that helps to synchronize the body's daily circadian rhythms with the light-dark cycle. Melatonin levels slowly increase a few hours before bedtime that setting the stage for the body to switch gears for rest and other nighttime physiological activities. It can be very effective in resetting the clock and changing sleep timing by advancing or delaying it but is often misused to help with insomnia. 

Judith Owens, MD, MPH, in recent years has seen increasing numbers of her pediatric patients taking over-the-counter (OTC) melatonin supplements as a sleep aid. In some cases, parents decide on their own to give it to their children having trouble sleeping; others gave it on the recommendation of a pediatrician. Owens is the director of the Center for Pediatric Sleep Disorders at Boston Children's Hospital and a professor of neurology at Harvard Medical School. 

National Health Interview Survey data from interviews with 17 321 adults caring for children and teens aged 4 to 17 years found a 7-fold increase in melatonin use, to 0.7% of the youths in 2012, up from 0.1% in 2007. 

According to the article, increasing use is not limited to children and adolescents. More recent data from a total of 55 021 participants in 10 cycles of the National Health and Nutrition Examination Survey (NHANES) showed that melatonin use increased by 5-fold, to 2.1% of 5563 participants in the 2017-2018 cycle compared with 0.4% of 4865 participants in the 1999-2000 cycle.

The data also revealed that more adults are using greater than 5 mg, which boosts serum melatonin levels far beyond typical nighttime peak concentrations before declining after 4 to 8 hours. 

Sales data indicate the trend may be accelerating, with melatonin sales more than doubling to $821 million in 2020 from $339 million in 2017, according to data from Statista. Market research company Technavio predicts continued growth in melatonin sales through 2026 due to an aging population that's at greater risk of sleep problems and increasingly hectic lifestyles that can result in anxiety and disordered sleep.

"It's a crazy situation that has gotten out of hand," said Owens, who also is president of the International Pediatric Sleep Association.

She and other sleep experts are concerned about the potential harm melatonin use without physician oversight may cause, particularly at higher doses and over the long term. And US poison centers have reported a startling increase in the past decade of calls about children who have ingested melatonin.

"It's a bit alarming; just because the product is available over the counter doesn't mean it is totally harmless and doesn't have important physiological effects," senior author of the NHANES analysis, Naima Covassin, PhD, an assistant professor at the Mayo Clinic College of Medicine and Science in Rochester, Minnesota, said in an interview.

Risks involved with melatonin use 

Generally, melatonin supplements are safe and well-tolerated but are not completely free of risks. The adverse effects may include headache, fatigue, dizziness, or daytime sleepiness. Small studies have also documented potentially more severe consequences, including impaired glucose tolerance and increased blood pressure and heart rate in patients concurrently taking melatonin and antihypertensive medication.

"Not much is known about long-term safety," Covassin said. For example, a recent analysis concluded that long-term studies are needed to assess melatonin's effects on puberty based on research on how it influences other hormones and sexual behavior in animals.

High doses may increase the risk of adverse effects. The pineal gland releases melatonin in picograms and that doses used to treat circadian shift disorders are typically small—about half a milligram, which is far lower than what is offered in many OTC products.

The dose of melatonin and when it's taken also affect how the user will feel. Owens explained that a 3- to 5-mg dose taken a half hour before bed will induce drowsiness. A much lower dose of about 0.5 mg taken earlier in the evening will shift bedtime earlier. A high dose of melatonin taken in the middle of the night could lead to morning drowsiness, Zee noted.

"If given at the wrong time of day, it can shift your clock in the wrong direction," Phyllis Zee, director of the Center for Circadian and Sleep Medicine and professor of neurology at Northwestern University's Feinberg School of Medicine, said. "Given at the right time of day, it can help you maintain a healthier clock. It goes both ways."

The same as with prescription drugs, inappropriate use or carelessness can have dire consequences. Between 2012 and 2021, US poison control centers fielded 260 435 calls about children who had ingested melatonin—a 530% increase during the period. Most of the children were asymptomatic and recovered at home. But 4097 were hospitalized, 287 needed intensive care, 5 required mechanical ventilation, and 2 died.

Owens said she hopes the CDC report gives pause to clinicians and parents who use melatonin. Many products are fruit-flavored or sold as gummies or chewables and lack childproof packaging. She noted that parents calling melatonin "candy" or "vitamins" to get their child to take it might also send the wrong message.

"It's a drug," Owens said. "Like any other drug, you don't leave it on the kitchen counter for your toddler to get into."

Reference:

Kuehn BM. Climbing Melatonin Use for Insomnia Raises Safety Concerns. JAMA. Published online July 27, 2022. doi:10.1001/jama.2022.11506