Following a toxicological study on 17 dietary supplements marketed for sports nutrition or weight loss, which listed the illegal stimulant deterenol as an active ingredient, researchers from NSF, Harvard University, the Netherlands’ National Institute for Public Health and the Environment (RIVM), and Belgium’s Sciensano are urging consumers to avoid using weight loss products that list deterenol as an ingredient.
 
These products, currently available in the U.S., also contained the prohibited stimulants Vonedrine (last marketed as a WWII-era nasal inhaler designed to compete with amphetamines), oxilofrine, octodrine, BMPEA, 1,3-DMAA, 1,4-DMAA, 1,3-DMBA, and higenamine in various combinations. None of these stimulants have been tested, let alone clinically substantiated, for safety in the U.S. Each of these products are prohibited under section S6 of the WADA (World Anti-Doping Association) prohibited list, noted John Travis, senior researcher at NSF International.
 
 The research was published in the journal Clinical Toxicology.
 
“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 co-author of the study. “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.”

Stimulant Cocktails
In some cases, the tested supplements contained as many as four of the aforementioned experimental stimulants per product, the authors said. In the 17 brands of supplements tested, four brands included two stimulants, two combined three stimulants, and two combined four different stimulants. Understanding of how these stimulants work in combination is especially poor.
 
“These hidden stimulant cocktails have never been tested in humans and their safety is unknown,” said Travis. “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.”
 
Travis said that he and the team of researchers selected deterenol as an ingredient to investigate because it was one of the ingredients responsible for several adverse events in the Netherlands, and found products simply by googling the term “deterenol,” or one of its synonyms, such as “isopropyloctopamine” or “isopropylnorsynephrine.” All of the supplements listed one of these synonyms on label, some of which were misspelled, and of the four products which contained a different stimulant (phenpromethamine), only one disclosed that ingredient on the label.  
 
NSF independently tests and certifies dietary supplements, and has facilitated the development of the only American National Standard for dietary supplements (NSF/ANSI 173). To earn NSF certification, products are tested for formulation, label claims, and harmful levels of specific contaminants and potentially harmful ingredients; facilities must be inspected twice yearly to comply with the U.S. FDA’s GMP requirements. Products certified under the NSF Certified for Sport program must meet additional requirements, and are screened for 280 athletic banned substances.
 
“If consumers feel unwell after taking a food supplement, they should immediately stop taking it and seek medical advice,” Dr. Bastiaan Venhuis, senior researcher at RIVM and Celine Vanhee, senior researcher at Sciensano, said. “Clinicians can then send the food supplement to independent testing authorities in order to exactly pinpoint the cause of the adverse effect.”
 
According to the authors, a disproportionate number of the tens of thousands of dietary supplement-related emergency department visits are related to products marketed for weight loss and sports performance, and a similar mix of stimulants in one specific supplement has been linked to dozens of adverse events including nausea, vomiting, sweating, agitation, palpitations, chest pain, and cardiac arrest, the authors said. The implicated product, Dexaprine (marketed by iForce Nutrition at the time) was found to contain deterenol. Synonyms for deterenol that were included on the label included isopropylnorsynephrine, isopropylnorsynephrine HCI, N-isopropylnorsynephrine HCI, and isopropyloctopamine. 

“In the U.S., the FDA is responsible for removing adulterated supplements from the marketplace,” the authors of the study said. “The agency, however, does not always act accordingly. The FDA, for example, failed to recall more than half of 746 brands of supplements found to be adulterated with drugs. In another case, the FDA did not warn consumers after the agency’s scientists discovered a novel stimulant in sports and weight loss 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.”

Action and Approaches
On what near-term approaches sellers, anti-doping agencies, and the industry at large should take to combat the presence of these drugs in dietary supplement ingredients, “Each of these groups require a different approach,” Travis said. “Many athletic associations and sporting bodies are already taking steps to address the issue by recommending—and in some cases requiring—athletes to take only those supplements that have been Certified for Sport by NSF international. I also think sellers and retailers should require independent testing or certification of products in categories that are known to have a high risk of adulteration, such as the weight loss and pre-workout supplement categories.”
 
“These stimulants have found their way into supplements as a replacement for ephedra after its prohibition,” Travis continued. “They have used a tenuous link between peer reviewed literature which purports its presence in a botanical to that botanical as an old dietary ingredient, thus allowable under the statute. The scientific literature is old and has not been replicated in many cases and in others was very poorly done and would not withstand modern scrutiny. Brands engaging in the practice of using these stimulants are likely not collecting adverse events and even less likely to report them to the FDA. Emergency rooms and poison control centers may not collect information on brands and products when treating adverse events possibly attributed to a supplement.”
 
‘Unfortunate Truth About the Internet’
While the findings in the analysis were certainly revelatory for consumers in terms of ingredients to avoid, Steve Mister, president and CEO of the Council for Responsible Nutrition, said supplements that consumers would encounter in mainstream marketplaces are safe and beneficial for those with sports nutrition and weight management needs.
 
“This report continues to tell an unfortunate but unsurprising truth about the Internet: if researchers, like Dr. Pieter Cohen, specifically look online for products labeled to contain an illegal ingredient, they are not only likely to find them but other illegal ingredients as well. The small collection of products identified in the March 23 report certainly does not represent the mainstream sports nutrition and weight management categories. The products identified in the analysis are not legal dietary supplements but illegal products that masquerade as supplements, hoping to evade detection. 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.”

“This report serves as a reminder for consumers that it matters where one purchases dietary supplements. The illegal products identified in the report come from unscrupulous online sellers, unlikely to be found on store shelves of reputable retailers or mainstream online platforms. CRN reminds consumers to seek products from nationally recognized brands or store brands from trusted retailers. Avoid products that promise extreme results, research companies and supporting science, and always talk to a healthcare practitioner for advice on responsible supplement use.”

CRN agreed with the report’s conclusion that the FDA needs to take stronger, more proactive enforcement action on illegal products, Mister said. “FDA lacks a system to efficiently track products that come to market, so CRN continues to advocate for a mandatory product listing as a solution.”
 
CRN currently has a database called the Supplement OWL (Online Wellness Library) available to retailers and consumers, as a self-regulatory initiative serving as a model for mandatory product listing which showcases brands that choose to be accountable for their labels and ingredients.