FDA concluded in 2004 that a substance known as isopropyloctopamine—also called deterenol—did not qualify as a dietary ingredient in supplements.

Yet several studies have identified the presence of deterenol in over-the-counter supplements, and the ingredient was among the substances contained in a food supplement linked to such serious adverse events as agitation, chest pain and cardiac arrest in The Netherlands.

In an article published Tuesday in a peer-reviewed medical journal, researchers disclosed many brands available for sale in the U.S. and labeled as containing deterenol or one of its synonyms also contained other prohibited stimulants—including substances flagged by FDA in warning letters and other regulatory actions.

Most of the products analyzed by the researchers and purchased online in April 2018 were marketed as either weight loss or sports/energy supplements.

The amount of deterenol identified in the products ranged from 2.7 milligrams (mg) to 17 mg per serving. When following recommended serving sizes appearing on the label, consumers could be taking up to 69 mg of deterenol per day, the study disclosed.

"We're urging clinicians to remain alert to the possibility that patients may be inadvertently exposed to experimental stimulants when consuming weight loss and sports supplements," said Dr. Pieter Cohen, associate professor of medicine at Harvard Medical School, internist at Cambridge Health Alliance and a co-author of the study, in a press release. "We're talking about active pharmaceutical stimulants that have not been approved by the U.S. FDA for oral use as either prescription medications or dietary supplements. These ingredients have no place in dietary supplements."

The article, published in Clinical Toxicology, described deterenol as a “pharmaceutical beta-agonist that has never been approved for use in the U.S.” Cohen and his colleagues said they were only aware of one study published in 1949 that examined the effects of orally administered deterenol in humans.

The study of 16 human subjects revealed taking 2 to 3 mg per kilogram (kg) of deterenol led to such effects as anxiety, decreased diastolic blood pressure, increased heart rate and tingling of the extremities and face. Taking 5 mg/kg of deterenol brought on such effects as blurred vision, hypotension, palpitations and respiratory distress.

Deterenol was the subject of a new dietary ingredient (NDI) notification to FDA in 2004—a 75-day premarket notification requirement in the law intended to ensure a novel ingredient in a supplement is reasonably expected to be safe.

In 2004, Syntech International Inc. notified FDA that it planned to market “Betaphrine,” an NDI. In a letter to the company, FDA’s Division of Dietary Supplement Programs responded the ingredient—also known as isopropyloctopamine or deterenol—appeared to be a chemically synthesized substance and did not qualify as a dietary ingredient. FDA did not assess the safety of the NDI.

“In sum, the ingredient for which you have submitted a new dietary ingredient notification is not a dietary ingredient under the Federal Food, Drug and Cosmetic Act,” FDA’s letter stated. “Moreover, the product to which you refer in your submission appears to be a drug under the Act and thus subject to the regulatory requirements of drugs.”

Multiple stimulants

The new study found that as recently as 2018, several supplements available on the internet contained multiple stimulants, including deterenol. In an analysis of 17 brands of supplements labeled as containing deterenol or one of its synonyms, researchers discovered eight brands contained more than one prohibited stimulant. In nearly half of the brands—or eight of 17 brands—deterenol was the only stimulant present, while four of the brands analyzed did not detect deterenol, the researchers said. FDA has targeted many stimulants identified in the tested products.

“Seven stimulants (i.e., 1,3-DMAA, 1,4-DMAA, 1,3-DMBA, BMPEA, higenamine, oxilofrine and octodrine) have previously been subject to FDA regulatory actions, including product seizures, warning letters and public notices,” Cohen and his colleagues wrote. “To our knowledge, [two] of the stimulants detected, deterenol and phenpromethamine, have not been subject to any FDA enforcement actions or consumer warnings.”

Four brands combined two stimulants and two brands tested positive for three stimulants, while two other brands combined four stimulants.

“Edge of Insanity”—a brand marketed for pre-workouts by Psycho Pharma—was among those containing deterenol based on test results, according to the researchers. In an email to Natural Products Insider, Darren Householder, who is affiliated with Psycho Pharma, described the listing as a “mistake” when asked about the researchers’ findings in Clinical Toxicology.

Several other companies whose products were identified in the study either declined comment or did not immediately respond to requests for comment, while a few firms could not be immediately reached.

"These hidden stimulant cocktails have never been tested in humans and their safety is unknown," said John Travis, senior researcher at NSF International and a co-author of the study, in the press release. "You never want to find unlabeled ingredients in supplements, but it is especially concerning to find these strange brews of experimental stimulants in products that are readily available in the United States."

FDA under fire

FDA has long faced criticism for failing to swiftly enforce against illegal stimulants sold in products labeled as dietary supplements. “Our study provides further evidence that the FDA may fail to act even when the agency’s own scientists identify adulterated supplements, as appears to be the case for deterenol,” the researchers concluded.

Four prior studies identified deterenol in over-the-counter supplements, including one conducted by FDA’s analytic chemists, the researchers wrote. But they noted they were unaware of any enforcement by FDA to remove the stimulant from supplements or warn consumers of the presence of deterenol in such products.

“FDA is dedicated to advancing our strategic priorities for dietary supplements: safety, product integrity and informed decision-making,” said Lindsay Haake, an FDA spokeswoman, in an emailed statement. “We appreciate studies like this for raising awareness and bringing needed attention to these matters.”

FDA needs to be doing more to remove products from the market containing illegal ingredients, several industry leaders concurred.

“This is where [Dr.] Cohen is right,” said Dan Fabricant, Ph.D., president and CEO of the Natural Products Association (NPA), in an interview. “It just shows the agency’s lazy. If they’re not actively doing searches for ingredients of interest, or if these aren’t ingredients of interest, then what are they doing?”

The Council for Responsible Nutrition (CRN) agrees “with the report’s conclusion that stronger, more proactive enforcement action is needed to protect the public from adulterated products in the market,” assured Steve Mister, president and CEO of CRN, in an emailed statement. “When illicit products are brought to the agency’s attention, FDA must act more quickly and decisively, both to establish a deterrent and to protect consumers.”

John Troup, Ph.D., vice president of scientific affairs and dietary supplements with the Consumer Healthcare Products Association (CHPA), said his organization supports increased efforts by FDA to hold accountable “those who violate the law and jeopardize public health.”

CHPA and its members supports efforts to modernize the Dietary Supplement Health and Education Act of 1994 (DSHEA) “to help continue to protect public health,” he added in an emailed statement, “including ridding the market of illegal products that pose a danger to consumers and tarnish the reputation of established, credible supplement industry leaders.”

FDA response

Haake, the FDA spokesperson, said her agency “is committed to doing everything within its resources and authorities to identify and remove unsafe and illegal products from the market.

“We monitor the compliance of dietary supplement firms through a variety of surveillance activities and carefully review product complaints and adverse event reports,” she said. “If FDA determines that a product labeled as a dietary supplement violates the law, the agency takes regulatory action as appropriate, based on public health priorities and available resources, such as issuing warning letters or taking enforcement action.”

But FDA has reiterated it has no regular way of keeping track of supplements on the market and the ingredients contained in those products, including when new supplements are introduced. In budget requests to Congress in recent years, through the administration of former President Donald Trump, FDA advocated for a new requirement in the law, which would require the listing of dietary supplement products with the agency.

“With mandatory listing, the FDA would know as soon as a new product containing an unlawful ingredient is introduced, so we could more quickly act against those products,” Haake explained. “And because products would be required to bear a listing number, consumers could easily check to see if a product has complied with the basic requirement of identifying itself to the FDA.”

She added, “Fraudulent and deceptive behavior will persist no matter what the legal framework, but mandatory listing would make it harder for these products to blend in and afford FDA with additional tools to better protect public health.”

‘Reputable’ firms

Fabricant said the names of products marketed as supplements but containing undeclared drugs should be reported to FDA for action, and the information—including where the products are sold—should be publicized. Over the years, NPA and other industry trade groups have written to FDA about substances of concern in products labeled as dietary supplements.

But Fabricant doesn’t think mandatory product listing is going to help solve the adulteration problem because he expressed doubt that scofflaws would list their products with FDA. “They’re already selling illegal products,” observed Fabricant, who previously oversaw FDA’s Division of Dietary Supplement Programs.

Industry leaders also attempted to distinguish their members from companies whose products were flagged in the study.

Companies identified in the study “aren’t the industry,” Fabricant said. “That’s the bigger problem. [The researchers are] trying to address a problem that’s not industry-related. These people are never going to join a trade association.”

The new “study is an example of companies that aren’t established and reputable leaders in the dietary supplement industry selling dangerous, fraudulent products that pose significant public health risk,” according to Troup.

DSHEA “continues to provide a strong regulatory framework for dietary supplements, including [current] good manufacturing practice (cGMP) requirements for manufacturing, packaging, labeling and other quality system procedures,” Troup said. “Consumers should know that this behavior is a very minor part of the industry, with responsible supplement manufacturers following the law by adhering to these rigorous quality control standards. It’s these reputable manufacturers who provide important health and wellness products that are not adulterated and allow consumer confidence in product safety and quality.”

Mister shared similar observations. According to him, products identified in the study are not representative of “the mainstream sports nutrition and weight management categories,” are peddled by “unscrupulous online sellers” and are “unlikely to be found on store shelves of reputable retailers or mainstream online platforms.”

“The products identified in the analysis are not legal dietary supplements but illegal products that masquerade as supplements, hoping to evade detection,” he stated. “Legitimate dietary supplements in the sports nutrition and weight management categories—the ones most consumers would encounter in local stores or on mainstream shopping platforms—are safe, beneficial and help consumers meet their fitness and weight goals. As with other dietary supplements, these products are meant to complement smart lifestyle choices, such as eating a healthy diet, exercising regularly and getting enough sleep.”