Sean Moloughney, Editor04.08.16
Days after FDA issued seven warning letters dated Mar. 31 to companies selling products that contain methylsynephrine (also known as oxilofrine), a study published online in Drug Testing and Analysis on Apr. 7 indicated that 14 over-the-counter dietary supplement products (out of 27 brands tested) contained this unapproved pharmaceutical stimulant, presenting a potentially serious risk to consumers.
Oxilofrine, 4-[1-hydroxy-2-(methylamino)propyl]phenol (also known as methylsynephrine, p-hydroxyephedrine, oxyephedrine, 4-HMP and suprifen), is a pharmaceutical drug developed in Europe in the 1930s to stimulate the heart, increase blood pressure and improve oxygen exchange, according to researchers. However, it has never been approved in the U.S. for use as a medication or as a dietary supplement.
Several professional athletes also have been disqualified from sports due to testing positive for oxilofrine, which is banned by the World Anti-Doping Agency (WADA) and most major sports organizations including Major League Baseball (MLB) and the National Football League (NFL).
Consumption of supplements containing oxilofrine may also pose serious health risks. For example, one brand of supplements containing oxilofrine has been linked to serious adverse events including vomiting, agitation, and cardiac arrest.
According to the FDA, oxilofrine is an illegal dietary ingredient, which means products containing oxilofrine are considered misbranded under the law. Warning Letters were delivered to the following companies (for their respective products): Chaotic Labz (Malice), Line One Nutrition, Inc (Fat Burning Lean Pills), m4 Nutrition Companies LLC (iBurn 2, which contains methylsynephrine and picamilon—another ingredient FDA has said is an unapproved New Dietary Ingredient), NutraClipse, Inc. (Thermobombs), Swagger Supps (Miami Lean), and Xcel Sports Nutrition, LLC (Leaner You). The companies have 15 days from receipt of the warning letters to respond to FDA with specific, corrective actions.
Steve Mister, president and CEO of the Council for Responsible Nutrition (CRN), Washington, D.C., applauded FDA for taking action against companies breaking the law and potentially putting consumers at risk.
“Selling products that list methylsynephrine as a dietary ingredient is illegal because the ingredient, also known as oxilofrine, has not been subjected to the New Dietary Ingredient (NDI) notification process, a requirement under the law,” he said. “Responsible marketers and manufacturers of supplements who compose the mainstream dietary supplement industry are in lockstep with FDA when it comes to enforcing the law and protecting the safety of their consumers, and we strongly urge the companies that received these warning letters—and any others that may be selling this illegal ingredient—to heed the agency’s warning immediately.
Study Details
For the study published in Drug Testing and Analysis, researchers from Harvard Medical School (including lead author Dr. Pieter Cohen), NSF International, the National Center for Natural Products Research (NCNPR) at the University of Mississippi and the National Institute for Public Health and the Environment in the Netherlands (RIVM) designed their study to determine the presence and quantity of oxilofrine in dietary supplements sold in the U.S. A validated ultra-high performance liquid chromatography-quadrupole time of flight-mass spectrometry method was developed for the identification and quantification of oxilofrine.
The separation was achieved using a reversed phase column, mass spectrometry detection, and a water/acetonitrile gradient as the mobile phase. The presence of oxilofrine was confirmed using a reference standard. They analyzed 27 brands of supplements labeled as containing a synonym of oxilofrine (methylsynephrine) and found that oxilofrine was present in 14 different brands (52%) at dosages ranging from 0.0003 to 75 mg per individual serving. Of the supplements containing oxilofrine, 43% (6 of 14) contained pharmaceutical or greater dosages of oxilofrine. Following instructions on the label, consumers could ingest as much as 250 mg of oxilofrine per day. This dosage is twice the typical adult dosage prescribed by physicians in other countries where the drug is approved for use during anesthesia and for treating a variety of medical conditions.
Oxilofrine could be disguised or unlisted on the label and poses serious health risks to consumers, according to the researchers. Oxilofrine has been studied in animals and humans and found to cause effects on the heart similar to ephedrine, a compound banned by FDA in 2004 due to serious side effects. Since then, scientists at NSF International have discovered several unapproved and potentially dangerous replacement stimulants such as DEPEA, DMAA, DMBA and now oxilofrine in dietary supplements.
According to the analysis, 26 adverse events have been reported in the Netherlands linked to supplements containing oxilofrine. These supplements led to nausea and vomiting, tachycardia, chest pain and cardiac arrest. Additionally, oxilofrine is often disguised on labels as “methylsynephrine” or “extract of Acacia rigidula.”
Researcher Reactions
“Adolescents who use these products might be placing themselves at risk of serious harm. The larger-than-adult doses we found might overstimulate their smaller, growing bodies,” said Dr. Cohen, an assistant professor of medicine at Harvard Medical School who has conducted extensive research on supplements. “In countries where oxilofrine is prescribed by doctors, the usual amount of the drug for adolescents is 24 mg or less. We found amounts in supplements of oxilofrine more than three times higher than the usual pediatric dose. Combined with physical activity and other stimulants commonly found in supplements, the consequences could be catastrophic.”
This is the fourth time in three years that the research team has found unapproved stimulants disguised in supplements as botanical ingredients. “This compound was found in 14 supplements which are used as either dieting aides or pre-workout supplements,” said John Travis, NSF International research scientist. “As a public health organization we want to warn consumers about these compounds that may harm instead of improve their health.”
“The presence of potentially harmful compounds such as oxilofrine, disguised as ‘methylsynephrine’ or ‘extract of Acacia rigidula,’ in over-the-counter supplements is illegal, and consumers should be aware of and avoid products containing these compounds. NSF International developed a testing and certification program that verifies supplement labels are accurate and the product itself is free from harmful levels of contaminants such as oxilofrine. We urge consumers to seek NSF certified dietary supplements to avoid unintentionally consuming harmful compounds,” Mr. Travis added.
NSF International helped develop the only accredited American National Standard for dietary supplements (NSF/ANSI 173). NSF’s accredited dietary supplement certification program is based on this standard. The program includes a label and formulation review, testing to verify the supplement does not contain harmful levels of contaminants and two facility audits annually to confirm compliance to Good Manufacturing Practices (GMPs). Products certified to the stringent NSF Certified for Sport program include additional steps to screen supplements for more than 230 athletic banned substances, which is why the program is used by the NFL, NHL, MLB, PGA, LPGA, the Canadian Centre for Ethics in Sport (CCES) and the New York City Police Department.
“NSF International’s dietary supplement and Certified for Sport certification programs help retailers, consumers and athletes to make more educated decisions knowing that what is on the label matches what is in the container, and that they are not consuming any unintended substances like oxilofrine,” added Mr. Travis.
Scientists at the NCNPR conducted analyses on the products. “We are pleased to be a part of this research team, which is working to understand the risks and ensure the safety of botanical supplements for consumers,” said Dr. Larry Walker, Director of the NCNPR.
Isolating Offenders
CRN’s Mr. Mister said the study findings “are particularly troubling to responsible marketers of dietary supplements because they demonstrate once again that rogue companies will ignore the laws designed to protect consumers.”
Oxilofrine is not a legitimate dietary ingredient, and its marketers have not complied with the legal requirements for bringing an NDI to market, he noted. “Oxilofrine, also referred to as methylsynephrine, has not met the legal requirements for demonstrating a reasonable expectation of safety, and thus it raises questions about the potential health risks to consumers who might use these products.”
CRN appreciates the work that Dr. Cohen and the co-authors have done, he added, and hopes it will result in “isolating fringe players that recklessly break the law.”
Urging FDA to use all the resources at its disposal to take action against these companies and to remove the products from the marketplace, Mr. Mister said, “This type of blatant illegal activity is not only disturbing, but also disruptive, to companies in the dietary supplement industry who sell reputable products. When rogue companies use the supplement space to peddle illegal products, like we have in this situation, the legitimate companies have their reputations damaged—and worst of all, consumers are put at risk.”
CRN is part of a coalition that lobbies for FDA to receive additional resources in order to fully enforce the law. “We are committed to doing what we can to help to support both the agency’s and industry’s efforts to protect consumers,” Mr. Mister said.
Oxilofrine, 4-[1-hydroxy-2-(methylamino)propyl]phenol (also known as methylsynephrine, p-hydroxyephedrine, oxyephedrine, 4-HMP and suprifen), is a pharmaceutical drug developed in Europe in the 1930s to stimulate the heart, increase blood pressure and improve oxygen exchange, according to researchers. However, it has never been approved in the U.S. for use as a medication or as a dietary supplement.
Several professional athletes also have been disqualified from sports due to testing positive for oxilofrine, which is banned by the World Anti-Doping Agency (WADA) and most major sports organizations including Major League Baseball (MLB) and the National Football League (NFL).
Consumption of supplements containing oxilofrine may also pose serious health risks. For example, one brand of supplements containing oxilofrine has been linked to serious adverse events including vomiting, agitation, and cardiac arrest.
According to the FDA, oxilofrine is an illegal dietary ingredient, which means products containing oxilofrine are considered misbranded under the law. Warning Letters were delivered to the following companies (for their respective products): Chaotic Labz (Malice), Line One Nutrition, Inc (Fat Burning Lean Pills), m4 Nutrition Companies LLC (iBurn 2, which contains methylsynephrine and picamilon—another ingredient FDA has said is an unapproved New Dietary Ingredient), NutraClipse, Inc. (Thermobombs), Swagger Supps (Miami Lean), and Xcel Sports Nutrition, LLC (Leaner You). The companies have 15 days from receipt of the warning letters to respond to FDA with specific, corrective actions.
Steve Mister, president and CEO of the Council for Responsible Nutrition (CRN), Washington, D.C., applauded FDA for taking action against companies breaking the law and potentially putting consumers at risk.
“Selling products that list methylsynephrine as a dietary ingredient is illegal because the ingredient, also known as oxilofrine, has not been subjected to the New Dietary Ingredient (NDI) notification process, a requirement under the law,” he said. “Responsible marketers and manufacturers of supplements who compose the mainstream dietary supplement industry are in lockstep with FDA when it comes to enforcing the law and protecting the safety of their consumers, and we strongly urge the companies that received these warning letters—and any others that may be selling this illegal ingredient—to heed the agency’s warning immediately.
Study Details
For the study published in Drug Testing and Analysis, researchers from Harvard Medical School (including lead author Dr. Pieter Cohen), NSF International, the National Center for Natural Products Research (NCNPR) at the University of Mississippi and the National Institute for Public Health and the Environment in the Netherlands (RIVM) designed their study to determine the presence and quantity of oxilofrine in dietary supplements sold in the U.S. A validated ultra-high performance liquid chromatography-quadrupole time of flight-mass spectrometry method was developed for the identification and quantification of oxilofrine.
The separation was achieved using a reversed phase column, mass spectrometry detection, and a water/acetonitrile gradient as the mobile phase. The presence of oxilofrine was confirmed using a reference standard. They analyzed 27 brands of supplements labeled as containing a synonym of oxilofrine (methylsynephrine) and found that oxilofrine was present in 14 different brands (52%) at dosages ranging from 0.0003 to 75 mg per individual serving. Of the supplements containing oxilofrine, 43% (6 of 14) contained pharmaceutical or greater dosages of oxilofrine. Following instructions on the label, consumers could ingest as much as 250 mg of oxilofrine per day. This dosage is twice the typical adult dosage prescribed by physicians in other countries where the drug is approved for use during anesthesia and for treating a variety of medical conditions.
Oxilofrine could be disguised or unlisted on the label and poses serious health risks to consumers, according to the researchers. Oxilofrine has been studied in animals and humans and found to cause effects on the heart similar to ephedrine, a compound banned by FDA in 2004 due to serious side effects. Since then, scientists at NSF International have discovered several unapproved and potentially dangerous replacement stimulants such as DEPEA, DMAA, DMBA and now oxilofrine in dietary supplements.
According to the analysis, 26 adverse events have been reported in the Netherlands linked to supplements containing oxilofrine. These supplements led to nausea and vomiting, tachycardia, chest pain and cardiac arrest. Additionally, oxilofrine is often disguised on labels as “methylsynephrine” or “extract of Acacia rigidula.”
Researcher Reactions
“Adolescents who use these products might be placing themselves at risk of serious harm. The larger-than-adult doses we found might overstimulate their smaller, growing bodies,” said Dr. Cohen, an assistant professor of medicine at Harvard Medical School who has conducted extensive research on supplements. “In countries where oxilofrine is prescribed by doctors, the usual amount of the drug for adolescents is 24 mg or less. We found amounts in supplements of oxilofrine more than three times higher than the usual pediatric dose. Combined with physical activity and other stimulants commonly found in supplements, the consequences could be catastrophic.”
This is the fourth time in three years that the research team has found unapproved stimulants disguised in supplements as botanical ingredients. “This compound was found in 14 supplements which are used as either dieting aides or pre-workout supplements,” said John Travis, NSF International research scientist. “As a public health organization we want to warn consumers about these compounds that may harm instead of improve their health.”
“The presence of potentially harmful compounds such as oxilofrine, disguised as ‘methylsynephrine’ or ‘extract of Acacia rigidula,’ in over-the-counter supplements is illegal, and consumers should be aware of and avoid products containing these compounds. NSF International developed a testing and certification program that verifies supplement labels are accurate and the product itself is free from harmful levels of contaminants such as oxilofrine. We urge consumers to seek NSF certified dietary supplements to avoid unintentionally consuming harmful compounds,” Mr. Travis added.
NSF International helped develop the only accredited American National Standard for dietary supplements (NSF/ANSI 173). NSF’s accredited dietary supplement certification program is based on this standard. The program includes a label and formulation review, testing to verify the supplement does not contain harmful levels of contaminants and two facility audits annually to confirm compliance to Good Manufacturing Practices (GMPs). Products certified to the stringent NSF Certified for Sport program include additional steps to screen supplements for more than 230 athletic banned substances, which is why the program is used by the NFL, NHL, MLB, PGA, LPGA, the Canadian Centre for Ethics in Sport (CCES) and the New York City Police Department.
“NSF International’s dietary supplement and Certified for Sport certification programs help retailers, consumers and athletes to make more educated decisions knowing that what is on the label matches what is in the container, and that they are not consuming any unintended substances like oxilofrine,” added Mr. Travis.
Scientists at the NCNPR conducted analyses on the products. “We are pleased to be a part of this research team, which is working to understand the risks and ensure the safety of botanical supplements for consumers,” said Dr. Larry Walker, Director of the NCNPR.
Isolating Offenders
CRN’s Mr. Mister said the study findings “are particularly troubling to responsible marketers of dietary supplements because they demonstrate once again that rogue companies will ignore the laws designed to protect consumers.”
Oxilofrine is not a legitimate dietary ingredient, and its marketers have not complied with the legal requirements for bringing an NDI to market, he noted. “Oxilofrine, also referred to as methylsynephrine, has not met the legal requirements for demonstrating a reasonable expectation of safety, and thus it raises questions about the potential health risks to consumers who might use these products.”
CRN appreciates the work that Dr. Cohen and the co-authors have done, he added, and hopes it will result in “isolating fringe players that recklessly break the law.”
Urging FDA to use all the resources at its disposal to take action against these companies and to remove the products from the marketplace, Mr. Mister said, “This type of blatant illegal activity is not only disturbing, but also disruptive, to companies in the dietary supplement industry who sell reputable products. When rogue companies use the supplement space to peddle illegal products, like we have in this situation, the legitimate companies have their reputations damaged—and worst of all, consumers are put at risk.”
CRN is part of a coalition that lobbies for FDA to receive additional resources in order to fully enforce the law. “We are committed to doing what we can to help to support both the agency’s and industry’s efforts to protect consumers,” Mr. Mister said.
