FDA Identifies Unlawful Ingredient, Methylsynephrine, in Sports Supplements

In recent years, FDA has identified a number of sports products that are marketed as dietary supplements but contain substances that don’t qualify as dietary ingredients and may pose health risks to consumers.

Methylsynephrine, which is also known as oxilofrine or p-hydroxyephedrine, has joined the list of substances that are the subject of FDA warning letters to marketers of sports products.

In letters issued on March 31 to seven companies marketing methylsynephrine in their dietary supplements, FDA noted the substance doesn’t meet the legal definition of a dietary ingredient. Dietary supplements that declare the substance as a dietary ingredient are “misbranded," FDA explained on a webpage linking to the warning letters.

"Additionally, methylsynephrine is not approved as a food additive or prior sanctioned for use in dietary supplements," FDA stated in the warning letters. "Further, FDA's review of this substance does not identify a basis to conclude that the substance is GRAS [generally recognized as safe] for use in food."

FDA warned that failure to cease distribution of the products could result in enforcement action without further notice, and the agency gave the companies 15 days to identify measures to correct the alleged violations.

“These letters were prompted by FDA’s increased focus on ensuring the integrity of dietary supplements—doing our part to safeguard the public from unknown or untested ingredients that show up in products marketed as dietary supplements," FDA spokeswoman Marianna Naum said in an emailed statement. “Through our research, we determined that methyl synephrine does not fit the definition of a dietary ingredient, although a number of products were labeled to contain it as a dietary ingredient."

Steve Mister, president and CEO of the Council for Responsible Nutrition (CRN), expressed support for FDA’s action.

“As disappointed as we are to find out that we are now going through this with yet another synthetic stimulant, we are very pleased to see FDA acting on this," Mister said in a phone interview. “And this is one area where we are lockstep with the agency. If these kinds of products are in the marketplace, then we applaud FDA for cracking down on them. We hope that it won’t stop with a warning letter."

Pieter Cohen, M.D., an assistant professor of medicine at Harvard Medical School whose research on tainted ingredients in sports products has been widely cited in the mainstream press, said methylsynephrine or oxilofrine can only be obtained by synthesizing it in a chemistry lab or factory.

“I’m not aware of a single study that even suggests that oxilofrine might be found in nature," he said in an email to INSIDER. “Certainly, no one has ever extracted oxilofrine from a plant."

In the warning letters, FDA didn’t cite any specific risks associated with the ingredient. Asked about potential health risks, Cohen said it would depend on how much oxilofrine was contained in a product.

“If a bottle contained a trace amount of oxilofrine, then the oxilofrine would be unlikely to pose a serious health risk," he explained. “However, if supplements contained prescription-doses of oxilofrine, then I would be extremely worried about the health effects. We would worry that high doses of oxilofrine would over-stimulate the heart, increase blood pressure and possibly lead to much more serious health problems."

Daniel Fabricant, Ph.D., executive director and CEO of the Natural Products Association, said the issues surrounding methylsynephrine are not cut and dried.

He raised the question whether the ingredient derives from bitter orange. According to the National Center for Complementary and Integrative Health, the bitter orange tree is native to eastern Africa and tropical Asia and grown today in California and Florida.

“I think that the question is, ‘does it exist in bitter orange,’” Fabricant said in a phone interview. “Obviously FDA doesn’t believe that it does based on a literature search … we are doing our own searches to see if it’s correct or not.”

“Also, there is nothing addressing whether or not the compound occurs in other plant species,” he added. “I think there is some literature that may suggest that it does.”

FDA issued warning letters to Nutraclipse Inc., Swagger Supps, Total Body Nutrition LLC, Xcel Sports Nutrition LLC, M4 Nutrition Companies LLC, Line One Nutrition Inc. and Chaotic Labz. None of the recipients of the letters immediately responded Monday to requests for comment.

The letters are representative of a number of ingredients that FDA has identified as being unlawfully marketed in sports supplements. Other ingredients flagged by FDA in recent years have included BMPEA, DMAA and DMBA.

Asked by INSIDER whether the ingredients in sports products flagged by FDA reflect just the “tip of the iceberg," Mister responded, “I think it’s more aptly a game of whack-a-mole because you are going to hit down one and then these same kinds of companies are going to come along and find some other kind of synthetic stimulant … but it’s not like this is representative of a much larger problem in the industry. It’s these same kinds of fringe companies that they put one product out there on the market, and when FDA cracks down on that, then they move on to the next one, and then on to the next one."

In an email to STAT, a new national publication reporting on health, medicine and scientific discovery, Sen. Claire McCaskill (D-Missouri) criticized FDA for acting too slowly to target methylsynephrine.

“Today’s action can be filed squarely in the ‘better late than never’ category,” McCaskill told the publication. “For the past seven years athletes have been prohibited from using this substance, but the FDA waited until today to act. We have a system in which tainted and adulterated dietary supplements routinely make their way to consumers because Congress and the FDA refuse to take even the smallest steps to stop them, or as is the case with this substance, for the FDA to inform consumers of the existence of potentially dangerous ingredients.”

Fabricant, a former director of FDA’s Division of Dietary Supplement Programs, disagreed with McCaskill’s assertions that FDA has been slow to take action.  He also pointed out McCaskill sits on a special aging committee, not the committee that has jurisdiction over FDA: the Senate Committee on Health, Education Labor & Pensions (HELP). He said the lawmakers responsible for jurisdiction over the agency “don’t seem to have a challenge with FDA’s speed to get to these things.”

“I think the agency certainly has to dot their I’s and cross their T’s whenever they move against any ingredient,” Fabricant said. “They are a science-based agency. Science when it comes to building cases doesn’t happen overnight.”