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Nov 24, 2023

Melatonin gummies deemed "unsafe"—but are they really?

Todd Runestad | May 01, 2023 A crusading supplements critic strikes again.

Todd Runestad | May 01, 2023

A crusading supplements critic strikes again.

Harvard Medical School associate professor Pieter Cohen, M.D., has been tilting against supplements windmills for some 15 years. He has become a leading stakeholder to rewrite the governing legislation around supplements, the Dietary Supplement Health and Education Act of 1994 (DSHEA).

Related: CRN Issues Guidelines for Melatonin Products

Last week, he published a paper in the well-known (if supplements-averse) medical publication, the Journal of the American Medical Association. In it, he went after melatonin gummies. His reason was a report that calls to poison control centers for melatonin overconsumption by children jumped more than 500% in the last decade. He also noted dosage levels in the gummies far exceeded the label claims. The report mentioned a 10 percent overage threshold for pharmaceutical drugs, and it noted none of the supplements came within 10 percent of stated label claim for melatonin quantity.

All the major mainstream media outlets covered the report, from the New York Times ("22 out of 25 melatonin products were mislabeled, study finds") to the Wall Street Journal ("Those melatonin gummies may have more than you bargained for") and CNN ("Potentially dangerous doses of melatonin and CBD found in gummies sold for sleep").

The heart of the research was correct. Poison control reports on children's melatonin consumption is on the rise, and the amount found in gummies exceeded label claim in all but two products—but the raison d’etre was misguided.

Cohen is well aware of the regulations around supplements. He has correctly noted, for example, that supplements are regulated as foods, not drugs, and they are extensively regulated at that.

So one must assume the information the media received was duplicitous on purpose.

It's the wrong argument, twice. One, the 10 percent rule is a drug rule, not a supplements rule. Two, melatonin is not unsafe. Health Canada advises melatonin under 10 mg is perfectly safe, and none of the products in the report exceeded this amount, with most coming in under half that.

"When you look at the safety data, it's mostly unintended ingestion," said Steve Mister, president and CEO of the Council for Responsible Nutrition trade group. "It's the mother who turns her back and the kid got into an adult version of a product, and in an overabundance of caution, she calls the poison control center. About 85 percent of the reports are asymptomatic."

The likelihood that a child got into a bottle of gummies and popped a handful like candy is also all too real.

"That's the concern with gummies in general," said Tara Couch, Ph.D., owner of TLC Regulatory and Laboratory Consulting, an organic chemist with 35 years’ experience in laboratory and regulatory environments and quality control. "Child-resistant caps should be used for any gummy for that reason."

The other notable point, that the dosage quantity exceeded label claims, is not just the law—but it's a good idea. Here's why.

"Dietary supplements are not drugs," said Couch. "If a supplement product is tested and does not meet 100 percent of label claim, it's misbranded. Dietary ingredients degrade rapidly in the body, that's what a vitamin does. If you formulate to 100 percent, there's no way a product would meet that in two years or even less. So the dietary supplement industry has to formulate with overages to accommodate test method variability and any potential degradation."

And the ER visits by children were, by and large, because of overdosing on too many gummies, not because melatonin is inherently a cause of safety concerns.

"It's true that there has been an increase in the number of reported exposures [but] that is not uncommon for products that experience significant market penetration," said Rick Kingston, Pharm.D., co-founder and president of regulatory and scientiic affairs with SafetyCall International, which operates a 24/7 adverse event call center. "As regards the number of reported melatonin exposures, it's not uncommon for younger children [under age 5] to ingest a variety of substances that are inherently safe. Parents may take them to emergency clinics out of an abundance of caution. This is especially true when there are reports of exposures for a given substance and isolated incidents where more serious effects have been reported."

Yes, there can be select problems with ingredient quality by brands that do not do a good enough job of qualifying vendors and testing ingredients at every step along the value chain, as well as brands that do not have a robust stability program to ensure dosage levels will remain above 100 percent by the end of shelf life. But by and large, supplements remain a safe class of consumer products.

But to Cohen, supplements are an "unsafe marketplace."

In 2015, Cohen created quite a stir in the supplements industry by going after a few brands using a compound known as BMPEA, allegedly derived from a shrub, Acacia rigidula, which is chemically similar to amphetamines, in weight-loss formulations. In his paper, Cohen named the names of the supplements companies using this ingredient. The paper compelled FDA to order the products off store shelves. The letter compelled the lead supplement company named to sue Cohen for defamation (Cohen won). The suit compelled Cohen, doubtlessly, in the current melatonin study, to not mention any specific supplement companies—he listed the 25 only as Supplement A through Y.

In 2021, Cohen explained to the American Medical Association that his overarching complaint is supplements should be regulated much closer to pharmaceuticals than foods as is currently the case.

"Because the FDA isn't vetting these products before they show up on store shelves or on the internet, what happens is that they can pose unpredictable risks. So we need to work on reform," he said in that 2021 interview. "We need to work on ways to strengthen the FDA's ability to limit what comes on to the market, to have a safety gauge, to make sure that dangerous, potentially dangerous, products don't appear in store shelves. And when they do that, they can rapidly be taken off the market. So we're really going to need to see a lot of changes in order to deal with this very actively evolving health care products [marketplace]."

In the 2021 interview, Cohen shared there is no education around supplements in medical school, so as he was going through medical school, he just considered them "expensive placebos." Then he pivoted to give examples of sports supplements and their "health issues" and weight management supplements’ risks around panic attacks, hepatitis and strokes—and, of course, none of the efficacy.

Although Cohen's published paper does not explicitly list the companies he targeted (see above, about his legal issues the last time he tried that, courthouse victory notwithstanding), the paper makes clear the list came from the National Institutes of Health Office of Dietary Supplements dietary supplements label database, when filtered for on-market melatonin gummies. While the majority of brands are relatively unknown companies, there were seven products from Vitafusion, two from Nature Made, Nature's Way and Vicks, and one each from Bayer, Carlson, GNC, Nature's Answer and Vital Proteins. Quality brands.

The headlines blared one product contained 347 percent of the labeled quantity of melatonin and another product contained none at all. While true, all the others contained overages that were not too outlandishly over.

For instance, a 1-milligram (mg) product contained 1.3 mg. And a 5-mg product contained 5.9 mg while another product labeled with the same amount contained 5.4 mg. Some other 3-mg products contained 3.7 mg, 3.8 mg and 4 mg.

Not all exactly spot on, it is true—but that's not the legal expectation.

"FDA regulations require dietary supplements to contain a minimum of 100 percent of the amount claimed on the product label throughout its shelf life," said Duffy MacKay, the senior vice president of dietary supplements at trade group the Consumer Healthcare Products Association. "Intentional ingredient overage is permitted for nutrient longevity and safe for consumers when within known safety levels consistent with good manufacturing practices (GMPs)."

According to the National Center for Complimentary and Integrative Health at the National Institutes of Health, "…melatonin supplements at normal doses appear to be safe for most children…"

The Cohen paper raises unnecessary concern about these products and evidences a lack of understanding of the federal requirements for dietary supplements as well as the strong safety profile of melatonin among users of all ages.

"The 347 percent product is probably a bad player," said Couch. "The good part of the industry has robust stability programs to determine what these overage should be. That's what stability studies are designed to do—figure out what is that sweet spot. You don't want to put in too much; that's expensive. But this paper infers that people are just throwing stuff in. That's not true."

Almost all of the 25 products sampled contained adult servings and are expressly labeled for use in adults, yet Cohen conflates the findings with pediatric data.

"This report does a complete disservice to a safe product when it is used according to manufacturer's instructions," said Mister. "Parents know how to take care of their own kids, and, often in consultation with their health care providers, have been safely giving the pediatric versions of these melatonin products to their children for years."

CRN also noted no data was presented in the findings to suggest any children were harmed by pediatric levels of melatonin given as directed. Instead, the study authors conflate the issue by attempting to connect poison control center data capturing unintended ingestion of presumably "overdose" levels of melatonin by children, with the potential overage amount of an ingredient a child could hypothetically be given in a single recommended serving of the product being used as intended.

"Supplement companies go to great lengths to ensure their products contain safe and consistent levels of dietary ingredients, as labeled," added Mister. "And while there may be some variability in overages as companies adhere to the FDA's requirements regarding shelf life and potency, it does not mean there is a risk in taking these products as intended. It's a misleading comparison to look at scenarios where kids, for example, got their hands on an entire bottle of adult gummies and became ill after eating multiple servings, versus having slightly more of an ingredient in a single serving that, if taken as directed, would pose no harm."

When asked to comment on the melatonin study, FDA spokesperson Lindsay Haake noted the agency collects and tests supplements as part of its routing monitoring of the marketplace and investigations of suspected problems, but the onus is on brands to abide by GMPs and to verify product specs are met.

"The FDA takes product quality concerns, including under- or over-potent products, seriously. We appreciate when these issues are brought to our attention to inform our regulatory and compliance activities," said Haake. "In general, the FDA does not comment on specific studies, but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health. The FDA will review the findings of the paper."

She noted FDA also conducts routine inspections of facilities, and sends warning letters to scofflaws as appropriate.

"The agency also monitors complaints and adverse event reports from companies, consumers, and healthcare providers to help identify products that may be unsafe," she said.

Because the safety profile of melatonin—when taken according to label recommendations, hospital visits from overdosing notwithstanding—remains safe, this paper is likely to be just another tempest in a teapot.

"There's no denying there's a little of a PR issue here if people think they’re buying 3 mg and they’re getting 4," said Mister. "But I keep coming back to it's safe and it's legal. Consumers don't understand stability testing or labeling requirements. They’re certainly voting with their pocketbooks that they want gummies."

We predict melatonin—and gummies—will march on, despite the mainstream media headlines that call into question a blockbuster supplement. Headlines mostly do not change consumer sentiment, especially with a popular, experiential supplement that resonates with consumers.

Not for nothing, a similar melatonin market assessment was conducted by ConsumerLab, and that found 21 of 22 products actually passed a similar label test as conducted by Cohen, et al.

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