Letter to the editor

Nutratech: BfR report is ‘clearly at odds with the scientific literature on safety of bitter orange-caffeine combinations’

Nutratech: BfR report is ‘clearly at odds with the scientific literature on safety of bitter orange-caffeine combinations’

Related tags Bitter orange science

Leading bitter orange/ p-synephrine supplier Nutratech has countered a report from the German Federal Institute for Risk Assessment (BfR) over concerns about the ingredient’s safety, noting it is at odds with the scientific literature.

As reported by our European site​ yesterday, the BfR warned that sports supplements and weight loss products containing a combination of caffeine and synephrine from bitter orange may not comply with current regulations and could be classified as unsafe.

In response to the German report, Bob Green, President, Nutratech, Inc., the exclusive worldwide distributor of bitter orange-derived ingredient Advantra Z, told NutraIngredients-USA that these conclusions are “in direct opposition to the conclusions drawn by highly regarded government and scientific organizations, as well as peer-reviewed scientific journals – which have consistently recognized the safety of bitter orange and its dominant amine, p synephrine, even when combined with caffeine.”


Mr Green submitted a long and detailed rebuttal of the BfR report, and here we publish his response in its entirety:

“To properly evaluate the BfR position statement, I consulted Dr. Sidney Stohs, who is one of the leading researchers of diet, fitness, and energy ingredients (S.J. Stohs, Ph.D., R.Ph., FACN, CNS, ATS,  FASAHP, Dean Emeritus, School of Pharmacy and Health Professions, Creighton University, Omaha, Nebraska). 

Dr. Stohs’ assessment matches my own: The conclusions drawn by the BfR statement often contradict those in the papers they’ve cited.

For example, the paper references “Physiological effects following administration of ​Citrus aurantium for 28 days in rats,”​ Hansen et al. (Toxicology and Applied Pharmacology​, 2012) as proof that synephrine causes negative cardiovascular side effects.

In this study, lab rats were given very large amounts (10-50 mg p synephrine/kg) of bitter orange / p synephrine – which are 13 to 43 times the typical human dosage used in dietary supplements (on a weight to weight basis). Doses were given in the presence (25 mg/kg) and absence of caffeine.  Heart rate and blood pressure increased only 4% to 11.5%. 

These numbers may be statistically significant, but they are clinically insignificant increases for humans.  As you may know, heart rate and blood pressure can increase 10% to 20% simply walking up a flight of stairs or doing household choirs.  

In fact, these results clearly indicate that p-synephrine would not have any effect on heart rate and blood pressure at the doses typically used in dietary supplements even in the presence of caffeine.

Health Canada

Moreover, after reviewing the scientific literature on p-synephrine and caffeine – which is almost identical to that cited in the BfR statement – another government agency, Health Canada, drew precisely the opposite conclusion, relaxing and redefining its guidelines. (Report attached.)

In October 2011, Health Canada’s 49-page “Synephrine, Octopamine and Caffeine Health Risk Assessment Report” ​concluded that although p synephrine-containing products have been implicated in adverse event case reports, “causality is not likely due to the p-synephrine content on its own, but rather due to other ingredients.”​  The report also addressed misconceptions and misinformation concerning the safety of p-synephrine and established new dosing guidelines: 

-          1 to 50 mg of p-synephrine per day for healthy adults is now classified as a Type III health risk:  “a situation in which the use of, or exposure to, a product is not likely to cause any adverse health consequences.” 

-          Products providing up to 40 mg of p-synephrine in combination with a maximum of 320 mg of caffeine per day also have Type III classifications.

-          Products containing greater amounts of these ingredients are now classified as Type II:  “a situation in which use of, or exposure to, a product may cause temporary adverse consequences or where the possibility of serious adverse health consequences is remote.”

Another authoritative assessment of safety of bitter orange/ p synephrine-caffeine combination formulas was issued February 13, 2013 by Intertek Cantox (formerly Cantox Health Sciences International), a global leader in scientific, toxicology, and regulatory services that is highly respected for its cautious and conservative approach to ingredient usage. 

Their “Review of the Safety Data Available on p-Synephrine, Caffeine, and p-Synephrine-Caffeine Containing Combination Products”​ states, “Although p-synephrine and caffeine have been assumed to produce similar clinical effects, but through different mechanisms, recent data regarding the isoform of synephrine present in ​C. aurantium [bitter orange] extracts and from receptor binding studies indicates that p-synephrine is unlikely to have significant effects on inotropy, vasoconstriction, or blood pressure.” 

The report concludes that the following dosages are “not likely to cause adverse effects:

-          Up to 70 mg p-synephrine alone or 40 mg in combination with 320 mg of caffeine

-          If taken as divided doses spaced out over the course of the day, 100 mg of p synephrine alone (e.g., 50 mg twice a day or 33 mg three times daily) or 70 mg p-synephrine in combination with 320 mg caffeine

To prepare this report, Intertek Cantox evaluated scientific information and data obtained from literature searches, regarding the safety of p synephrine and caffeine, and of the use of these ingredients in combination products, citing 71 references – including most of those cited in the BfR report.

In addition, close to 20 studies supporting the safety of p synephrine have been published in highly respected peer-reviewed scientific journals.  Most recently:  Food and Chemistry Toxicology​ (May 2013, available online February 2013), International Journal of Medical Sciences​ (September 2012), Phytotherapy Research​ (April 2011), American Botanical Council’s HerbalGram​ (February 2011), and Journal of Functional Foods​ (November 2010).


The conclusions of the BfR report are clearly at odds with the wealth of scientific literature on the safety of bitter orange/p-synephrine-caffeine combination formulas – most of which is posted on the Nutratech website (www.nutratechinc.com/advz/advz.php?p=2).   And while I cannot speak authoritatively about generic bitter orange extracts, the facts unmistakably indicate that Advantra Z – Nutratech’s branded bitter orange extract – is extremely safe when used as directed. 

This statement is not only supported by science, but also by the fact that millions of people have used tens of millions of doses of products containing Advantra Z in the almost 20 years this ingredient has been on the market.”

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