What's Really in Those Dietary Supplements? Fair Warning for Patients

Be prepared to caution patients of the undesirable health consequences possible from banned, potentially dangerous pharmaceuticals, and other undisclosed ingredients in so-called natural, nutritional supplements.

With Madhur Kumar, MS, PhD, Pieter Cohen, MD, Mitchell Katz, MD, Lindsay Haake (FDA)

One of every two patients is likely to take at least one dietary supplement, although they may not tell you that. Many take nutritional supplements with the intent of improving their overall health, but others take them to lose weight, build muscle, perform better sexually, or improve their memory.

Given the growing use of prescription medications to manage chronic diseases, including diabetes, cardiovascular disease, gastrointestinal reflux, depression and anxiety, arthritis, osteoporosis, the potential for harm is growing.

"The drug ingredients have the potential to cause serious adverse health effects," Madhur Kumar, MS, PhD, an investigator with the California Department of Public Health told EndocrineWeb. “This could be due to misuse, overuse, or their interaction with other medicines. It could also be due to a patient's own underlying health issues or to the presence of other pharmaceutical drugs in the supplement.”

Buyer beware—Dietary supplements may contain toxic, banned, or unapproved substances.Potentially harmful substances are added to popular nutritional supplements but not declared on the label, according to 2 recent studies. Phots: 123RF

Prescription Drugs and Unapproved Ingredients Added, Not Disclosed

These two reports,1,2 both just published, suggest these patients may be risking more than benefitting from their good intentions.

Researchers found banned, or even experimental and potentially dangerous pharmaceutical grade ingredients, in dietary supplements—sometimes even after the companies had been warned about the problem and specific ingredients by the FDA.1,2

In the first study,1 published in JAMA Network Open, a team of California researchers led by Dr. Kumar reviewed the Tainted Products Marketed as Dietary Supplements database maintained by the Food and Drug Administration (FDA) Center for Drug Evaluation and Research. This research team looked at records between 2007 and 2016.1

Over those nine years, 776 adulterated supplements were identified by the FDA, implicating 146 different companies. Despite FDA warning letters and public announcements, the suspect ingredients were rarely removed from the nutritional products.

"Overall, the analysis found that active pharmaceutical ingredients continue to be identified in dietary supplements, especially those marketed for sexual enhancement or weight loss, even after prior public FDA warnings," Dr. Kumar said. 

In the second report,2 published in JAMA Internal Medicine, a team led by Pieter Cohen, MD, associate professor of medicine at Harvard Medical School and a general internist at Cambridge Health Alliance, in Boston, Massachusetts, also found that public notices issued by the FDA to supplement makers, warning them that stimulants found in their supplements were prohibited, had little effect.

When the Harvard team analyzed 12 brands of supplements sold for weight loss, sports performance, or cognitive functioning—in 2014 and again in 2017—the banned stimulants were often still present.2

Examining Trends in Ingredient Patterns in Popular Nutritional Supplements

In the California Health Department study,1 Dr. Kumar's team analyzed the information for trends detected with regard to adulterated dietary supplements for which manufacturers had been issued a warning notice from the FDA.

They found that 20% of the 776 products were adulterated, often containing more than one unapproved or banned ingredient.More illicit substances—not declared on the ingredient label—were found in the following “natural” dietary supplement categories:

  • Sexual performance supplements, containing sildenafil (Viagra), were identified in 166 of 353 analyzed supplements.
  • Weight loss supplements most often had added sibutramine (formerly Meridia, banned in 2010), involving 269 of 317 products. 
  • In muscle-building supplements, 82 out of 92 adulterated products included synthetic steroids or steroid-like ingredients.

Twenty-eight products got more than one warning by the FDA, 6 months apart. Of these supplements, 19, or nearly 70% were found to contain suspect and potentially harmful substances in these so-called natural supplements even after a second or third warning,1 suggesting a clear defiance of FDA warnings.

Popular Supplements Tainted with Prescription Grade Drugs

The researchers broke their findings down this way:1

  • Products touted for Sexual enhancement: 353 products, or about 45% of this category
  • Weight loss supplements: 317 products, or nearly 41% of this supplement group
  • Muscle building products: 92, or nearly 12% of these pills and powders
  • Other tainted supplements were marketed for joint or muscle pain, sleep issues, gout, osteoporosis, and other health concerns, involving 14 products, or about 2%

Typically, one hidden ingredient was found but at least six hidden ingredients were found in two of the products,1 said Dr. Kumar.

During the time period examined, public notifications were issued by the FDA for 342 tainted products. In other cases, a news release was sent out or a warning letter was sent to the offending manufacturer. As for actions taken, nearly half of the products had been voluntarily recalled, leaving the rest on the shelves.

Elicit Substances Added to OTC Supplements

In the Harvard-led study,2 Dr. Cohen and his colleagues analyzed 12 supplements bought in 2014 and purchased again in 2017. The researchers analyzed these dietary supplements for the presence of prohibited stimulants before and after FDA issued public notices.

Between 2013 to 2016, the FDA issued notices regarding four prohibited sympathomimetic stimulants: 1,3-dimethylamylamine (1,3-DMAA), 1,3-dimethylbutylamine (DMBA), β-methylphenylethylamine (BMPEA), and methylsynephrine (4-HMP, oxilofrine).3

The researchers used liquid chromatography-quadrupole time-of-flight mass spectrometry to analyze the supplements. The presence of each of these adulterated ingredients was confirmed by accurate mass, retention time, isotope patterns, and at least one fragment ion from mass spectra assessment.2

Only 12 of the 21 brands analyzed in 2014 were still available for purchase in 2017, so the researchers compared the remaining 12 over-the-counter supplements.2 Of the supplements purchased in 2017, 75% (nine) still contained at least one of the four stimulants for which the FDA had issued warnings, and 50% of these products contained 2 or more illicit drugs. One substance, DMBA, not found in any supplements bought in 2014, and for which the FDA issued a warning in 2015, was found in four  dietary supplements bought in 2017.2

Dr. Cohen said, given the small study size,2 and sampling just one of each supplement, there is clearly a need for a broader analysis.

However, ''it's not just pharmacological drugs'' found in supplements. "It's actually drugs in development or those only studies in small animals [not humans]," he told EndocrineWeb, emphasizing the importance that patients need to be warned now to avoid health consequences from drug-drug interactions and unrecognized side effects.

"Many new stimulants are bypassing the FDA's approval process by skipping the more burdensome drug approval process, and gaining shelf space as over-the-counter nutritional supplements," he said. "The FDA is aware that it is happening," he said. However, "The FDA's actions to remove those stimulants clearly is not working," partly due to the limitations inherent in the Dietary Supplement Health and Education Act of 1994 (DSHEA) that precludes sufficient oversight of these so-called natural products but more aggressive efforts are needed despite the barriers imposed by the law.

Despite Clinical Awareness, Patient Safety in Question

Dr. Cohen wrote an invited commentary on the Kumar study,5 calling these findings a wake-up call for physicians—who need to ask every patient about supplement use—and an urgent call to legislators to reform the Dietary Supplement Health and Education Act of 1994 to give the FDA more power to regulate supplements.

When it comes to supplements, Dr. Cohen says, physicians need to ''pay a lot more attention than we typically have been doing with regard to what over-the-counter dietary supplements our patients are using."

In an editorial,6 Mitchell H. Katz, MD, editor of JAMA Internal Medicine, pointed out the lack of evidence for benefit of supplements makes the wide, easy use problematic.

"In clinical trials, these [products] have rarely provided benefit compared with a healthful diet (with the possible exception of specific groups, such as pregnant women or those with nutritional deficiencies)," he wrote.

The lack of any certainty that a dietary supplement will contain only the ingredients listed on its label poses potentially significant harm to patients, he said, adding, an estimated 23,000 visits to emergency department each year have been linked to these “natural” nutritional supplements.6

The tainted nutritional supplement issue ''is a very serious problem that isn't going to go away soon," Dr. Cohen said, citing a ''fundamental flaw in the law" regulating dietary supplements as one driving force behind the problem.

Greater Clinical Vigilance Needed Given Prescription-Prone Aging Population

Under DSHEA,4 the manufacturers are responsible for evaluating the safety of their own products and assuring that their labeling is accurate—which may be likened to a rooster monitoring the hen house scenario. Once the product reaches the market, the FDA is responsible only for taking action against any supplement found to be tainted or misbranded;4 and given the thousands of products on the shelf and coming to market daily, that is too tall an order at present for this single federal agency.

"We have a law that is so permissive," Dr. Cohen said,  "that more than FDA action (when a problem is found in the supplement) will be required to ensure that all adulterated dietary supplements are effectively and swiftly removed from the market."

He added: it will take Congress finally moving to reform the DSHEA, to give the FDA better oversight, and he offers one fix that should be considered— Require supplement manufacturers to register all such nutritional supplements and dietary supplements with the FDA before they can be sold. In that way, if a “natural” supplement is found to be adulterated, the product registration could be revoked, and the product removed to avoid harmful consequences to consumers.

The FDA, meanwhile, should become more aggressive, he said. "They could issue a mandatory recall." Even after voluntary recalls, as the researchers found, the adulterated products show up again. The adulterations are not accidental, Dr. Cohen tells EndocrineWeb.

Food and Drug Administration Responds to Study Findings

In a statement shared with EndocrineWeb, FDA spokesperson Lindsay Haake said: "The FDA is aware of the [California Health Department] study and is in the process of reviewing and analyzing the findings;" and is also looking into the findings raised by the Harvard study.

She offered this comment in direct response to the Kumar-led study: ''The FDA is committed to doing everything within its resources and authorities to identify and remove unsafe products from the market, and we continue to work collaboratively with all of our stakeholders to help ensure that products marketed as dietary supplements are safe, well-manufactured, and accurately labeled."

When a product is found by the FDA to be adulterated or misbranded, including a supplement that contains potentially hazardous ingredients, the FDA's main objective is to inform consumers and then remove it from the market as soon as possible, Ms. Haake said.

However, the agency can face a number of challenges. She notes that even after one distributor's fraudulent product is recalled, other distributors may continue to sell it; or they may re-label a product to avoid detection. If products marketed as a nutritional or dietary supplement contain undeclared pharmaceuticals, they may then be subject to regulation as drugs, she said.

"The FDA does not have mandatory recall authority for drugs," although the public may think they do, Ms. Haake said. The FDA may request a recall if the drug is deemed risky or dangerous to health, or if it violates FDA labeling or manufacturing laws.

Steps for Clinicians to Take to Improve Patient Awareness and Safety   

Health providers should ''routinely ask about dietary and nutritional supplement use and encourage discontinued use when there is no evidence-based indication,"5 Dr. Katz said.

For patients who insist on taking supplements, including prenatal vitamins, vitamin D, fish oil, and other necessary dietary supplements: suggest that products be screened to include a logo/endorsement from a credible, nonprofit laboratory—such as USP Quality Supplements and ConsumerLab—to provide assurance that what is on the label is in the bottle.

Dr. Kumar and Dr. Katz offer no relevant financial disclosures. Dr. Cohen has collaborated in research with NSF International and received research support from Consumers Union. In addition, he was the subject of a civil suit brought by Hi-Tech Pharmaceuticals, a supplement company, regarding BMPEA; the jury found in Dr. Cohen's favor.

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