Research: Stimulants remain in supplements years after FDA warning letters
Research published in the Journal of the American Medical Association sparked criticism of the Food and Drug Administration concerning its lack of follow-up enforcement against dietary supplement products containing illicit ingredients.
Many weight loss and sports supplement products subject to an FDA warning letter due to the presence of a prohibited stimulant remained available for sale several years later and contained at least one FDA-prohibited ingredient, according to the results of a study published Tuesday.
Researchers from Harvard and the University of Mississippi analyzed 31 dietary supplement products subject to an FDA warning letter due to the presence of BMPEA (2015 warning letters), methylsynephrine (2016) or DMHA (2019), also known as 1,5-DMHA and octodrine.
In the study, products that remained available for sale using the Google search engine in January 2022 were purchased online. Nine of 31 products remained available to purchase online an average (“mean”) of six years after FDA issued the warning letters, and of the nine products, five (56%) contained at least one FDA-prohibited ingredient, according to the research published in the peer-reviewed Journal of the American Medical Association (JAMA).
Other findings included:
- Of the 31 products, only one (3%) was recalled by the manufacturer.
- Four of the nine products still available to purchase online (44%) identified the presence of at least one prohibited ingredient on the label.
- One product label listed the same prohibited ingredient that incited the FDA warning letter, and three product labels declared other ingredients prohibited by FDA.
- One dietary supplement product subject to a 2015 warning letter concerning BMPEA contained three illicit ingredients: methylsynephrine, also known as oxilofrine; DMHA; and 1,4-DMAA.
According to FDA, 1,4-DMAA does not appear to be a lawful ingredient in dietary supplements, and researchers said it is an analogue of 1,3-dimethylamylamine (DMAA), which FDA has described as “an amphetamine derivative” found to be unlawful in supplements by a U.S. District Court and affirmed on appeal.
- In their analysis of powder from dietary supplement products reconstituted in methanol and examined for the presence and amount of FDA-prohibited ingredients, researchers identified ingredient-per-serving sizes ranging from 0.7 to nearly 146 mg (milligrams).
Many of the serving sizes of the prohibited ingredients found in supplements are similar to dosages found in drugs, according to one of the researchers.
A chemical analysis of a product subject to a 2019 warning letter concerning DMHA revealed the presence of the same ingredient at a per serving size of 145.5 mg—far higher than amounts used in Germany as a drug as part of a multicomponent oral medication (8.2, 16.5 and 33 mg).
- The study also revealed the presence of an ingredient (omberacetam) that researchers said was developed in Russia, marketed as Noopept and has a typical pharmaceutical dose of 10 mg, but has never been approved for use in the U.S.
The ingredient found in the supplement contained a per serving size of 28.3 mg.
“The FDA is dedicated to advancing our strategic priorities for dietary supplements: safety, product integrity, and informed decision-making,” an FDA spokeswoman said in response to the study. “We appreciate studies like this for raising awareness and bringing needed attention to these matters. However, 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.”
‘No credible explanation’
Dr. Pieter Cohen, associate professor of medicine at Harvard Medical School who oversaw the research, said the “study highlights a fundamental problem that the FDA’s not doing its job.”
“The FDA is spending a lot of time and energy here in these cases … identifying products that are clearly in violation of the law and that the agency is concerned might pose a risk to consumers, and I certainly agree with them,” Cohen said in an interview. But FDA officials “are not following up to the point where they actually remove the products from the store shelf, and they have the authority to do that.”
If consumers are susceptible to these prohibited drug ingredients and if taken in high enough dosages, the products could cause such harm as “increasing blood pressure, bleeding into the brain, or even in a worst-case scenario, one’s heart stopping,” warned Cohen, who conducted the study in collaboration with researchers from the University of Mississippi, including Bharathi Avula, Ph.D., principal research scientist in the National Center for Natural Products Research.
Michael McGuffin, president of the American Herbal Products Association (AHPA), said his organization “strongly encourages FDA to act assertively to remove these products from the marketplace.”
“There is no credible explanation for why the products identified in this article have such market shelf life after coming to the attention of FDA,” he said in an email. “We agree with the authors that FDA should consider ways to ensure products that are falsely identified as supplements and contain prohibited drugs are removed from the market.”
This is not the first time Cohen has identified dietary supplement products that remain on the market after being flagged by FDA.
For example:
- His research examined products that were recalled due to the presence of a pharmaceutical ingredient between Jan. 1, 2009, and Dec. 31, 2012, and remained available for purchase in July or August 2013 directly from the websites of supplement manufacturers or retailers.
The study, described in an October 2014 research letter published in JAMA, identified one or more pharmaceutical adulterants in 66.7% of recalled supplements still available to purchase.
- A December 2018 research letter in JAMA examined the effectiveness of FDA’s public notices issued between 2013 and 2016 targeting certain prohibited stimulants in supplements, including 1,3-DMAA, DMBA, BMPEA and methylsynephrine.
Of 12 supplements purchased in 2017, nine (75%) contained at least one of the four stimulants subject to FDA notices, and six (50%) contained two or more.
FDA officials have “a lot of tools in their toolbox and they’re simply not using them,” Cohen said in the interview.
Absence of FDA ‘willpower’
His latest research drew a strong reaction from the Council for Responsible Nutrition (CRN), a trade association representing dietary supplement and functional food manufacturers and ingredient suppliers.
“It is unfortunately the case that the agency is not doing its job when one can find the same rogue ingredients in the same bad products six years after warning letters have been issued,” said Megan Olsen, senior vice president and general counsel of CRN, which praised Cohen for holding FDA accountable.
The study shows “warning letters alone are not viewed as sufficient threats by bad actors and outliers,” Olsen said in a written statement. “FDA should stop assuming that everyone in the market wants to do the right thing. Unfortunately, it is reality that there are bad guys out there who simply don’t.”
FDA also was critiqued recently for sending warning letters to dietary supplement companies about ingredients that were already subject to previous warning letters, including higenamine and hordenine, rather than following up with such enforcement action as a seizure of products.
“FDA’s enforcement must have consequences,” Olsen said. “The perceived risk to bad actors must be greater than the gains possible by flouting the law.”
Natural Products Association (NPA) President and CEO Dan Fabricant, Ph.D., who directed FDA’s Division of Dietary Supplement Programs from 2011 to 2014, cited a lack of “willpower” at his former employer.