- Email: [email protected]
Assessment of the adverse event reports associated with Citrus aurantium (bitter orange) from April 2004 to October 2009
JOURNAL OF FUNCTIONAL FOODS
2 (2 0 1 0) 2 3 5–23 8
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/jff
Assessment of the adverse event reports associated with Citrus aurantium (bitter orange) from April 2004 to October 2009 Sidney J. Stohs* School of Pharmacy and Health Professions, Creighton University Medical Center, Omaha, NE 68178, USA
A R T I C L E I N F O
A B S T R A C T
Article history:
From April 2004 through October 2009, the FDA received 22 adverse event reports (AERs)
Received 22 May 2010
involving products that were reported to contain Citrus aurantium (bitter orange) extract
Accepted 26 October 2010
(BOE). During this same time, 10 clinical cases reports were published involving adverse
Available online 18 November 2010
events associated with products that contained BOE (C. aurantium) or its predominant alkaloid p-synephrine. A review and assessment of these reports was made. All products
Keywords:
involved in these reports were poly-herbal and poly-alkaloidal in composition. The conclu-
Citrus aurantium
sion that BOE and p-synephrine are responsible for adverse events presented in these
Bitter orange
reports is unjustified, based on the presence of confounding factors, the paucity of detailed
p-Synephrine
information in many reports, current knowledge of the pharmacokinetic and adrenorecep-
Adverse event reports Clinical case reports
tor binding properties of p-synephrine, the high probability of concurrent but independent events, knowledge of dose–response relationships, and the widespread use of BOE containing supplements and p-synephrine containing juice and food products. Ó 2010 Elsevier Ltd. All rights reserved.
Contents References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
In response to a request for adverse event reports (AERs) associated with Citrus aurantium (bitter orange, BOE) submitted to the Center for Food Safety and Applied Nutrition (CFSAN) of the US Food and Drug Administration (FDA) for the time frame April 2004 through October 2009, a total of 22 reports were received from that agency. This time frame represents the interval after the receipt of information in 2004 by the American Herbal Products Association regarding purported AERs associated with BOE containing products (McGuffin, 2006). As was noted in the information provided
by CFSAN, the AER reports submitted to the FDA vary markedly in quality of the information provided, in part based on the information available to the person making the report and the knowledge base and biases of that individual. In addition to the AERs received by the FDA, from May 2004 to December 2009, a total of 10 clinical case reports involving adverse events presumably associated with products containing BOE were published in a wide range of medical and scientific journals. A majority of these articles suggest or imply that the causative agent for the adverse events in question
* Address: 4967 Stillwater Trail, Frisco, TX 75034, USA. Tel.: +1 214 215 6655. E-mail address: [email protected] 1756-4646/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.jff.2010.10.003
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was synephrine, the predominant alkaloid in BOE. The information associated with the 22 FDA AERs and 10 clinical reports is summarized. Of the 22 AER reports received by the FDA, 20 involved use of a product in solid (capsule or tablet) dosage form with one report (in duplicate) involving a lotion. One report involved use of two products while a second report consisted of three different products. Twenty-one different products were represented in the 22 case reports, with one product involved in three reports and a second product named twice. No report involved BOE as a single ingredient. Ten of the AERs listed BOE as the first ingredient in spite of the fact that it was not present in the greatest amount relative to other ingredients. All products were complex poly-herbal and poly-alkaloidal mixtures. The smallest number of botanical ingredients in any one product was five, while three products contained 36–37 distinct herbal ingredients. The majority of products contained six to eight herbal ingredients. Two products were reported to contain ephedra, while one product was noted to contain ‘‘caffeine derivatives of epinephrine.’’ Three products contained yohimbine. In one case, the very high dose of yohimbine was believed to be responsible for the adverse event. Twelve of the products contained caffeine, with one product containing as much as 400 mg caffeine per dose. Three of the products are no longer being marketed, while four products that were reported to contain BOE no longer contain this ingredient or the original AER report was in error with respect to the presence of BOE. The report regarding a body lotion was duplicated since the lotion was applied to two children who both developed hives. This product contains more than 40 ingredients with at least 12 of them being botanical in nature. This lotion contains sweet orange oil, orange flower oil and lemon oil, all of which are used widely in the food and cosmetics industries as flavoring agents and for their aroma. All three oils are derived from Citrus species. However, none of the three ingredients are bitter orange derivatives and none contain alkaloids as found in BOE. Thus, one can not ascribe the dermatological reaction associated with this lotion to BOE. Only four AERs, which had been submitted by physicians’ offices, provided detailed patient assessment information including medical histories. A total of 10 AERs provided some medical history information such as morbid obesity, asthma, diabetes, hypertension, hyperlipidemia, heart attack, stroke, pneumonia, alcoholism, drug abuse, depression, anxiety, and nicotine use. The extent to which any of these factors may have been involved in the adverse event was only discussed in a single report. Of the 10 clinical case reports, only one (Gange, Madias, Felix-Gretzik, Weintraub, & Estes, 2006) was also reported as an AER and is included in the 22 FDA reports. As was the case for the FDA AERs, all clinical case reports involved the purported use of products containing multiple herbal ingredients with multiple alkaloids. These reports all included confounding factors that may have contributed to or been responsible for the resulting adverse event, or involved potentially causative factors that were not eliminated. Three of the clinical case reports involve products present among the 22 FDA AERs. In one case, the product was not named but the pri-
2 ( 2 0 1 0 ) 2 3 5 –2 3 8
mary ingredients were discussed, although it was not clear that these constituted all the ingredients in the product. The adverse events associated with the FDA AERs represented a wide range of effects including chest pain, anxiety, pain in the lower right side, interstitial nephritis resulting in vomiting and lower back pain, shortness of breath and diaphoresis, angina, headache, loss of appetite, nausea, muscle cramps, diarrhea, acute delirium, depression, suicidal and violent behavior, heart palpitations, tightness in the neck, inflammatory liver disease, stomach pain, tachycardia, chest pain, hives, dizziness and hallucinations. Three deaths were reported among the 22 AERs. The frequency and extent of the use of the products in question with respect to these three cases were not reported, and as a consequence no cause-and-effect relationship can be determined. The cause of death for one was listed as morbid obesity. A second individual who died on the football practice field had a history of asthma attacks, and ‘‘10 other players struggled or collapsed during the drill.’’ The third case involved a report by a family friend of the death of an obese man from a massive heart attack with no history of product use provided. All three cases involved probable causes and plausible explanations other than the use of a multi-herb, multi-alkaloid-containing product. The adverse events associated with the published clinical case studies included acute lateral-wall myocardial infarction (Nykamp, Fackih, & Compton, 2004), exercise induced syncope associated with QT prolongation (Nasir, Durning, Ferguson, Barold, & Haigney, 2004), ischemic stroke (Bouchard, Howland, Greller, Hoffman, & Nelson, 2005), variant angina (Gange et al., 2006), ischemic colitis (Sultan, Spector, & Mitchell, 2006), coronary spasm and thrombosis (Smedema & Muller, 2008), vasospasm and stroke (Holmes & Tavee, 2008), ST segment-elevation myocardial infarction (Thomas, Munir, McIntyre, & Ferguson, 2009), and ventricular fibrillation (Stephensen & Sarlay, 2009). Furthermore, in one case report it was suggested that a bitter orange-containing dietary supplement may have masked bradycardia and hypotension while exacerbating weight loss in an individual with anorexia nervosa (Gray & Woolf, 2005), although no evidence was provided that an actual adverse event had occurred. A wide range of confounding factors existed among the 10 published case reports including a history of smoking, physical inactivity, obesity, heart murmur, pre-existing heart disease, dehydration, pneumonia, possible use of anabolic steroids and other performance enhancing drugs, hypertriglyceridemia, gastroesophageal disease, high alcohol consumption, amount of product actually taken, and use of other un-reported supplements and drugs. In each AER and clinical case report, the product in question contained multiple herbal ingredients with a minimum of five alkaloidal constituents including synephrine. As a consequence, it is not possible to ascribe the effects to one of the constituents. Furthermore, in approximately half of the FDA AERs and all of the clinical reports, confounding factors were reported which may or may not have caused or contributed to the adverse events. Noteworthy is that the title of each of the 10 case reports specifically refers to C. aurantium, bitter orange, synephrine or ephedra-free product rather than denoting a multi-herb, multi-alkaloid-containing supplement. One
JOURNAL OF FUNCTIONAL FOODS
of the other ingredients or the combination of ingredients may have contributed to an adverse event, although based on the information provided this determination cannot be made. Discussion centered on adrenergic receptor agonist and cardiovascular effects of ephedrine in all of the clinical case reports, with emphasis on structural similarities between ephedrine and p-synephrine. The authors were apparently unaware of the structural differences which result in vastly different pharmacokinetic and receptor binding properties between ephedrine and p-synephrine, and therefore the dissimilar pharmacological activities (Haaz et al., 2006; Stohs & Shara, 2007). p-Synephrine contains a para-hydroxy group in the aromatic (benzene) ring and the absence of a methyl group on the ethylamino side chain relative to ephedrine. As evidence of cardiovascular and intestinal effects, several of the reports cited studies with m-synephrine (phenylephrine, hydroxyl group in the meta position on the benzene ring) (Stephensen & Sarlay, 2009) and pseudoephedrine (Sultan et al., 2006) which are not identical with p-synephrine (hydroxyl group in the para position on the benzene ring). Both m-synephrine and pseudoehedrine are used as nasal decongestants and both may increase heart rate and blood pressure. No reference was made to a study (Jordan, Thonoor, & Williams, 1987) which has shown that m-synephrine is 100-fold and p-synephrine 40,000-fold less potent that norepinephrine with respect to binding to beta-1 and beta-2 adrenoreceptors, evidence clearly indicating why the two forms of synephrine do not have equivalent or even similar actions. Furthermore, p-synephrine is approximately 50-fold less potent than m-synephrine in activating alpha-1a-adrenoreceptors, and p-synephrine has even lower binding affinity for alpha-2a- and alpha-2c-adrenoreceptor subtypes (Ma, Bavadekar, Schaneberg, Khan, & Feller, 2010). All of these receptors are involved in local and systemic vasoconstriction. The putative binding of p-synephrine to the beta-3-adrenoreceptor that modulates lipolysis was not reported or considered (Carpene et al., 1999; Hamilton & Doods, 2010). Unverified and non-adjudicated AER information released by the FDA in April 2004 (McGuffin, 2006) regarding C. aurantium (bitter orange) and its primary alkaloid p-synephrine has continued to be reiterated in the AERs being reported and the clinical case studies that have been published. The analysis by McGuffin (2006) of the FDA reports demonstrated that no adverse events or deaths could be attributable to bitter orange. Unfortunately, the FDA has not adequately acknowledged this gross error either in scientific publications or mainstream news media, and as a consequence, misinformation regarding BOE continues to be perpetuated. The belief that p-synephrine exerts serious cardiovascular and other events continues to be believed by the lay public as well as healthcare professionals, in spite of the lack of clearly defined supportive evidence for this supposition, as well as extensive evidence to the contrary (Haaz et al., 2006; Haller, Benowitz, & Jacob, 2005; Min, Cios, Kluger, & White, 2005; Stohs & Shara, 2007). Furthermore, there is a broad lack of understanding regarding the structural differences between ephedrine and p-synephrine which result in markedly different receptor binding characteristics and therefore significant
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237
differences in pharmacological properties, particularly with respect to cardiovascular and central nervous system effects. For example, p-synephrine in the form of the patented BOE Advantra Z was shown to have no effect on blood pressure at a dose of 46.9 mg orally in healthy human subjects (Haller et al., 2005). Advantra Z, through independent analysis, has been shown to contain only p-synephrine and no m-synephrine (Nutratech Inc., 2005). The historical and traditional use of BOE in Chinese medicine as well as the fact that more than 100 million doses of products containing BOE (p-synephrine) has been consumed in this country over the past 12–15 years without the occurrence of clearly attributable adverse events is significant (Haaz et al., 2006; Stohs & Shara, 2007). No serious adverse events have been directly attributable to BOE or p-synephrine, including any of the diverse effects reported in the current and past FDA AERs and the published clinical case reports. A total of only 169 AERs have been reported to the FDA between 1969 and October 2009, and in all of these cases no evidence was provided directly linking BOE to the adverse event. The consumption of p-synephrine may be much more common than generally recognized (Arbo et al., 2008; Dragull, Breksa, & Cain, 2008; Mattoli et al., 2005; Mercolini et al., 2010; Pellati, Benvenuti, & Melegari, 2004; Penzak et al., 2001). According to the US Department of Agriculture, a widely consumed juice from mandarin oranges grown in California contains as much as 35 mg p-synephrine per eight oz. glass (Dragull et al., 2008). In only one product associated with the reports discussed above was there evidence that this amount of p-synephrine was present in a single dose. Several products appeared to contain 6 mg or less of p-synephrine per dose. The amount of p-synephrine in a typical sweet orange has been reported to be about 6 mg (Mattoli et al., 2005). From April 2004 until October 2009, the FDA received 22 reports of adverse events associated with multi-component products in which C. aurantium (bitter orange) was presumed or stated to be an ingredient. During this time frame, 10 clinical case reports were published or submitted for publication involving adverse events associated with multi-ingredient products containing BOE. In each clinical case report, an accusatory finger was pointed at BOE and its primary alkaloid synephrine as the most probable cause. The conclusion that BOE and p-synephrine are responsible for adverse events presented in these reports is unwarranted and unjustified, based on the poly-herbal, poly-alkaloidal composition of the products involved, the numerous confounding factors present, the high probability of independent but concurrent events, the paucity of information provided in some cases, the major differences in pharmacokinetic and receptor binding properties between p-synephrine and phenylpropanolamine derivatives as ephedrine, and the widespread and uneventful use of bitter orange-containing fruit and juice products.
R E F E R E N C E S
Arbo, M. D., Larentis, E. R., Linck, V. M., Aboy, A. L., Pimentel, A. L., Henriques, A. T., et al. (2008). Concentrations of p-synephrine in fruits and leaves of Citrus species (Rutaceae) and the acute
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toxicity testing of Citrus aurantium extract and p-synephrine. Food and Chemical Toxicology, 46, 2770–2775. Bouchard, N. C., Howland, M. A., Greller, H. A., Hoffman, R. S., & Nelson, L. S. (2005). Ischemic stroke associated with use of an ephedra-free dietary supplement containing synephrine. Mayo Clinic Proceedings, 80, 541–545. Carpene, C., Galitzky, J., Fontana, E., Algie, C., Lafontan, M., & Berlan, M. (1999). Selective activation of beta 3adrenoreceptors by octopamine: Comparative studies in mammalian fat cells. Naunyn Schmiedebergs Archives Pharmacology, 359, 310–321. Dragull, K., Breksa, A. P., & Cain, B. (2008). Synephrine content of juice from Satsuma mandarins (Citrus unshiu Marcovitch). Journal of Agricultural and Food Chemistry, 56, 8874–8878. Gange, C. A., Madias, C., Felix-Gretzik, E. M., Weintraub, A. R., & Estes, N. A. M. III, (2006). Variant angina associated with bitter orange in a dietary supplement. Mayo Clinic Proceedings, 81, 545–548. Gray, S., & Woolf, A. D. (2005). Citrus aurantium used for weight loss by an adolescent with anorexia nervosa. Journal of Adolescent Health, 37, 415–416. Haaz, S., Fontaine, K. R., Cutter, G., Limdi, N., Perumean-Chaney, S., & Allison, D. B. (2006). Citrus aurantium and synephrine alkaloids in the treatment of overweight and obesity: An update. Obesity Review, 7, 79–88. Haller, C. A., Benowitz, N. L., & Jacob, P. III, (2005). Hemodynamic effects of ephedra-free weight-loss supplements in humans. American Journal of Medicine, 118, 998–1003. Hamilton, B. S., & Doods, H. N. (2010). Identification of potential agonists acting at an endogenous atypical b3-adrenoreceptor state that modulate lipolysis in rodent fat cells. European Journal of Pharmacology, 580, 55–62. Holmes, R. O., Jr., & Tavee, J. (2008). Vasospasm and stroke attributable to ephedra-free Xenadrine: Case study. Military Medicine, 173, 708–710. Jordan, R., Thonoor, C. M., & Williams, C. M. (1987). Betaadrenergic activities of octopamine and synephrine stereoisomers on guinea-pig atria and trachea. Journal of Pharmacy and Pharmacology, 39, 752–754. Ma, G., Bavadekar, S. A., Schaneberg, B. T., Khan, I. A., & Feller, D. R. (2010). Effects of synephrine and beta-phenylephrine on human alpha-adrenoceptor subtypes. Planta Medica, 76, 981–986. Mattoli, L., Cangi, F., Maidecchi, A., Ghiara, C., Stubaro, M., & Tralda, P. (2005). A rapid liquid electrospray ionization mass spectroscopy method for evaluation of synephrine in Citrus aurantium L. samples. Journal of Agricultural Food Chemistry., 53, 9860–9866.
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McGuffin, M. (2006). Media spins numbers on bitter orange AERs based on erroneous information from FDA. HerbalGram, 69, 52–55. Mercolini, L., Mandrioli, R., Trere, T., Bugamelli, F., Ferranti, A., & Raggi, M. A. (2010). Fast CE analysis of adrenergic amines in different parts of Citrus aurantium fruit and dietary supplements. Journal of Separation Science, 32, 1–8. Min, B., Cios, D., Kluger, J., & White, C. M. (2005). Absence of QTcinterval-prolonging or hemodynamic effects of a single dose of bitter orange extract in healthy subjects. Pharmacotherapy, 25, 1719–1724. Nasir, J. M., Durning, S. J., Ferguson, M., Barold, H. J. S., & Haigney, M. C. (2004). Exercise-induced syncope associated with QT prolongation and ephedra-free Xenadrine. Mayo Clinic Proceedings, 79, 1059–1062. Nutratech Inc. (2005). Advantra Zâ. The next generation weight loss ad fitness ingredient. Applications/dosage guidelines.. Nykamp, D. L., Fackih, M. N., & Compton, A. L. (2004). Possible association of acute lateral-wall myocardial infarction and bitter orange supplement. Annals of Pharmacotherapy, 38, 812–816. Pellati, F., Benvenuti, S., & Melegari, M. (2004). High-pressure liquid chromatography methods for the analysis of adrenergic amines and flavanones in Citrus aurantium L. var. amara. Phytochemical Analysis, 15, 220–225. Penzak, S. R., Jann, M. W., Cold, J. A., Hon, Y. Y., Desai, H. D., & Gurley, B. J. (2001). Seville (sour) orange juice: Synephrine content and cardiovascular effects in normotensive adults. Journal of Clinical Pharmacology, 41, 1059–1063. Smedema, J. P., & Muller, G. J. (2008). Coronary spasm and thrombosis in a bodybuilder using a nutritional supplement containing synephrine, octopamine, tyramine and caffeine. South African Medical Journal, 98, 372–373. Stephensen, T. A., & Sarlay, R. Jr., (2009). Ventricular fibrillation associated with use of synephrine containing dietary supplement. Military Medicine, 174, 1313–1319. Stohs, S. J., & Shara, M. (2007). A review of the safety and efficacy of Citrus aurantium in weight management. In D. Bagchi & H. G. Preuss (Eds.), Obesity: Epidemiology, pathophysiology, and prevention (pp. 371–382). Boca Raton (FL): CRC Press. Sultan, S., Spector, J., & Mitchell, R. M. (2006). Ischemic colitis associated with use of a bitter orange-containing dietary weight-loss supplement. Mayo Clinic Proceedings, 81, 1630–1631. Thomas, J. E., Munir, J. A., McIntyre, P. Z., & Ferguson, M. A. (2009). STEMI in a 24-year-old man after use of a synephrinecontaining dietary supplement. A case report and review of the literature. Texas Heart Institute Journal, 36, 586–590.
2 (2 0 1 0) 2 3 5–23 8
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/jff
Assessment of the adverse event reports associated with Citrus aurantium (bitter orange) from April 2004 to October 2009 Sidney J. Stohs* School of Pharmacy and Health Professions, Creighton University Medical Center, Omaha, NE 68178, USA
A R T I C L E I N F O
A B S T R A C T
Article history:
From April 2004 through October 2009, the FDA received 22 adverse event reports (AERs)
Received 22 May 2010
involving products that were reported to contain Citrus aurantium (bitter orange) extract
Accepted 26 October 2010
(BOE). During this same time, 10 clinical cases reports were published involving adverse
Available online 18 November 2010
events associated with products that contained BOE (C. aurantium) or its predominant alkaloid p-synephrine. A review and assessment of these reports was made. All products
Keywords:
involved in these reports were poly-herbal and poly-alkaloidal in composition. The conclu-
Citrus aurantium
sion that BOE and p-synephrine are responsible for adverse events presented in these
Bitter orange
reports is unjustified, based on the presence of confounding factors, the paucity of detailed
p-Synephrine
information in many reports, current knowledge of the pharmacokinetic and adrenorecep-
Adverse event reports Clinical case reports
tor binding properties of p-synephrine, the high probability of concurrent but independent events, knowledge of dose–response relationships, and the widespread use of BOE containing supplements and p-synephrine containing juice and food products. Ó 2010 Elsevier Ltd. All rights reserved.
Contents References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
In response to a request for adverse event reports (AERs) associated with Citrus aurantium (bitter orange, BOE) submitted to the Center for Food Safety and Applied Nutrition (CFSAN) of the US Food and Drug Administration (FDA) for the time frame April 2004 through October 2009, a total of 22 reports were received from that agency. This time frame represents the interval after the receipt of information in 2004 by the American Herbal Products Association regarding purported AERs associated with BOE containing products (McGuffin, 2006). As was noted in the information provided
by CFSAN, the AER reports submitted to the FDA vary markedly in quality of the information provided, in part based on the information available to the person making the report and the knowledge base and biases of that individual. In addition to the AERs received by the FDA, from May 2004 to December 2009, a total of 10 clinical case reports involving adverse events presumably associated with products containing BOE were published in a wide range of medical and scientific journals. A majority of these articles suggest or imply that the causative agent for the adverse events in question
* Address: 4967 Stillwater Trail, Frisco, TX 75034, USA. Tel.: +1 214 215 6655. E-mail address: [email protected] 1756-4646/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.jff.2010.10.003
236
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was synephrine, the predominant alkaloid in BOE. The information associated with the 22 FDA AERs and 10 clinical reports is summarized. Of the 22 AER reports received by the FDA, 20 involved use of a product in solid (capsule or tablet) dosage form with one report (in duplicate) involving a lotion. One report involved use of two products while a second report consisted of three different products. Twenty-one different products were represented in the 22 case reports, with one product involved in three reports and a second product named twice. No report involved BOE as a single ingredient. Ten of the AERs listed BOE as the first ingredient in spite of the fact that it was not present in the greatest amount relative to other ingredients. All products were complex poly-herbal and poly-alkaloidal mixtures. The smallest number of botanical ingredients in any one product was five, while three products contained 36–37 distinct herbal ingredients. The majority of products contained six to eight herbal ingredients. Two products were reported to contain ephedra, while one product was noted to contain ‘‘caffeine derivatives of epinephrine.’’ Three products contained yohimbine. In one case, the very high dose of yohimbine was believed to be responsible for the adverse event. Twelve of the products contained caffeine, with one product containing as much as 400 mg caffeine per dose. Three of the products are no longer being marketed, while four products that were reported to contain BOE no longer contain this ingredient or the original AER report was in error with respect to the presence of BOE. The report regarding a body lotion was duplicated since the lotion was applied to two children who both developed hives. This product contains more than 40 ingredients with at least 12 of them being botanical in nature. This lotion contains sweet orange oil, orange flower oil and lemon oil, all of which are used widely in the food and cosmetics industries as flavoring agents and for their aroma. All three oils are derived from Citrus species. However, none of the three ingredients are bitter orange derivatives and none contain alkaloids as found in BOE. Thus, one can not ascribe the dermatological reaction associated with this lotion to BOE. Only four AERs, which had been submitted by physicians’ offices, provided detailed patient assessment information including medical histories. A total of 10 AERs provided some medical history information such as morbid obesity, asthma, diabetes, hypertension, hyperlipidemia, heart attack, stroke, pneumonia, alcoholism, drug abuse, depression, anxiety, and nicotine use. The extent to which any of these factors may have been involved in the adverse event was only discussed in a single report. Of the 10 clinical case reports, only one (Gange, Madias, Felix-Gretzik, Weintraub, & Estes, 2006) was also reported as an AER and is included in the 22 FDA reports. As was the case for the FDA AERs, all clinical case reports involved the purported use of products containing multiple herbal ingredients with multiple alkaloids. These reports all included confounding factors that may have contributed to or been responsible for the resulting adverse event, or involved potentially causative factors that were not eliminated. Three of the clinical case reports involve products present among the 22 FDA AERs. In one case, the product was not named but the pri-
2 ( 2 0 1 0 ) 2 3 5 –2 3 8
mary ingredients were discussed, although it was not clear that these constituted all the ingredients in the product. The adverse events associated with the FDA AERs represented a wide range of effects including chest pain, anxiety, pain in the lower right side, interstitial nephritis resulting in vomiting and lower back pain, shortness of breath and diaphoresis, angina, headache, loss of appetite, nausea, muscle cramps, diarrhea, acute delirium, depression, suicidal and violent behavior, heart palpitations, tightness in the neck, inflammatory liver disease, stomach pain, tachycardia, chest pain, hives, dizziness and hallucinations. Three deaths were reported among the 22 AERs. The frequency and extent of the use of the products in question with respect to these three cases were not reported, and as a consequence no cause-and-effect relationship can be determined. The cause of death for one was listed as morbid obesity. A second individual who died on the football practice field had a history of asthma attacks, and ‘‘10 other players struggled or collapsed during the drill.’’ The third case involved a report by a family friend of the death of an obese man from a massive heart attack with no history of product use provided. All three cases involved probable causes and plausible explanations other than the use of a multi-herb, multi-alkaloid-containing product. The adverse events associated with the published clinical case studies included acute lateral-wall myocardial infarction (Nykamp, Fackih, & Compton, 2004), exercise induced syncope associated with QT prolongation (Nasir, Durning, Ferguson, Barold, & Haigney, 2004), ischemic stroke (Bouchard, Howland, Greller, Hoffman, & Nelson, 2005), variant angina (Gange et al., 2006), ischemic colitis (Sultan, Spector, & Mitchell, 2006), coronary spasm and thrombosis (Smedema & Muller, 2008), vasospasm and stroke (Holmes & Tavee, 2008), ST segment-elevation myocardial infarction (Thomas, Munir, McIntyre, & Ferguson, 2009), and ventricular fibrillation (Stephensen & Sarlay, 2009). Furthermore, in one case report it was suggested that a bitter orange-containing dietary supplement may have masked bradycardia and hypotension while exacerbating weight loss in an individual with anorexia nervosa (Gray & Woolf, 2005), although no evidence was provided that an actual adverse event had occurred. A wide range of confounding factors existed among the 10 published case reports including a history of smoking, physical inactivity, obesity, heart murmur, pre-existing heart disease, dehydration, pneumonia, possible use of anabolic steroids and other performance enhancing drugs, hypertriglyceridemia, gastroesophageal disease, high alcohol consumption, amount of product actually taken, and use of other un-reported supplements and drugs. In each AER and clinical case report, the product in question contained multiple herbal ingredients with a minimum of five alkaloidal constituents including synephrine. As a consequence, it is not possible to ascribe the effects to one of the constituents. Furthermore, in approximately half of the FDA AERs and all of the clinical reports, confounding factors were reported which may or may not have caused or contributed to the adverse events. Noteworthy is that the title of each of the 10 case reports specifically refers to C. aurantium, bitter orange, synephrine or ephedra-free product rather than denoting a multi-herb, multi-alkaloid-containing supplement. One
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of the other ingredients or the combination of ingredients may have contributed to an adverse event, although based on the information provided this determination cannot be made. Discussion centered on adrenergic receptor agonist and cardiovascular effects of ephedrine in all of the clinical case reports, with emphasis on structural similarities between ephedrine and p-synephrine. The authors were apparently unaware of the structural differences which result in vastly different pharmacokinetic and receptor binding properties between ephedrine and p-synephrine, and therefore the dissimilar pharmacological activities (Haaz et al., 2006; Stohs & Shara, 2007). p-Synephrine contains a para-hydroxy group in the aromatic (benzene) ring and the absence of a methyl group on the ethylamino side chain relative to ephedrine. As evidence of cardiovascular and intestinal effects, several of the reports cited studies with m-synephrine (phenylephrine, hydroxyl group in the meta position on the benzene ring) (Stephensen & Sarlay, 2009) and pseudoephedrine (Sultan et al., 2006) which are not identical with p-synephrine (hydroxyl group in the para position on the benzene ring). Both m-synephrine and pseudoehedrine are used as nasal decongestants and both may increase heart rate and blood pressure. No reference was made to a study (Jordan, Thonoor, & Williams, 1987) which has shown that m-synephrine is 100-fold and p-synephrine 40,000-fold less potent that norepinephrine with respect to binding to beta-1 and beta-2 adrenoreceptors, evidence clearly indicating why the two forms of synephrine do not have equivalent or even similar actions. Furthermore, p-synephrine is approximately 50-fold less potent than m-synephrine in activating alpha-1a-adrenoreceptors, and p-synephrine has even lower binding affinity for alpha-2a- and alpha-2c-adrenoreceptor subtypes (Ma, Bavadekar, Schaneberg, Khan, & Feller, 2010). All of these receptors are involved in local and systemic vasoconstriction. The putative binding of p-synephrine to the beta-3-adrenoreceptor that modulates lipolysis was not reported or considered (Carpene et al., 1999; Hamilton & Doods, 2010). Unverified and non-adjudicated AER information released by the FDA in April 2004 (McGuffin, 2006) regarding C. aurantium (bitter orange) and its primary alkaloid p-synephrine has continued to be reiterated in the AERs being reported and the clinical case studies that have been published. The analysis by McGuffin (2006) of the FDA reports demonstrated that no adverse events or deaths could be attributable to bitter orange. Unfortunately, the FDA has not adequately acknowledged this gross error either in scientific publications or mainstream news media, and as a consequence, misinformation regarding BOE continues to be perpetuated. The belief that p-synephrine exerts serious cardiovascular and other events continues to be believed by the lay public as well as healthcare professionals, in spite of the lack of clearly defined supportive evidence for this supposition, as well as extensive evidence to the contrary (Haaz et al., 2006; Haller, Benowitz, & Jacob, 2005; Min, Cios, Kluger, & White, 2005; Stohs & Shara, 2007). Furthermore, there is a broad lack of understanding regarding the structural differences between ephedrine and p-synephrine which result in markedly different receptor binding characteristics and therefore significant
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differences in pharmacological properties, particularly with respect to cardiovascular and central nervous system effects. For example, p-synephrine in the form of the patented BOE Advantra Z was shown to have no effect on blood pressure at a dose of 46.9 mg orally in healthy human subjects (Haller et al., 2005). Advantra Z, through independent analysis, has been shown to contain only p-synephrine and no m-synephrine (Nutratech Inc., 2005). The historical and traditional use of BOE in Chinese medicine as well as the fact that more than 100 million doses of products containing BOE (p-synephrine) has been consumed in this country over the past 12–15 years without the occurrence of clearly attributable adverse events is significant (Haaz et al., 2006; Stohs & Shara, 2007). No serious adverse events have been directly attributable to BOE or p-synephrine, including any of the diverse effects reported in the current and past FDA AERs and the published clinical case reports. A total of only 169 AERs have been reported to the FDA between 1969 and October 2009, and in all of these cases no evidence was provided directly linking BOE to the adverse event. The consumption of p-synephrine may be much more common than generally recognized (Arbo et al., 2008; Dragull, Breksa, & Cain, 2008; Mattoli et al., 2005; Mercolini et al., 2010; Pellati, Benvenuti, & Melegari, 2004; Penzak et al., 2001). According to the US Department of Agriculture, a widely consumed juice from mandarin oranges grown in California contains as much as 35 mg p-synephrine per eight oz. glass (Dragull et al., 2008). In only one product associated with the reports discussed above was there evidence that this amount of p-synephrine was present in a single dose. Several products appeared to contain 6 mg or less of p-synephrine per dose. The amount of p-synephrine in a typical sweet orange has been reported to be about 6 mg (Mattoli et al., 2005). From April 2004 until October 2009, the FDA received 22 reports of adverse events associated with multi-component products in which C. aurantium (bitter orange) was presumed or stated to be an ingredient. During this time frame, 10 clinical case reports were published or submitted for publication involving adverse events associated with multi-ingredient products containing BOE. In each clinical case report, an accusatory finger was pointed at BOE and its primary alkaloid synephrine as the most probable cause. The conclusion that BOE and p-synephrine are responsible for adverse events presented in these reports is unwarranted and unjustified, based on the poly-herbal, poly-alkaloidal composition of the products involved, the numerous confounding factors present, the high probability of independent but concurrent events, the paucity of information provided in some cases, the major differences in pharmacokinetic and receptor binding properties between p-synephrine and phenylpropanolamine derivatives as ephedrine, and the widespread and uneventful use of bitter orange-containing fruit and juice products.
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Arbo, M. D., Larentis, E. R., Linck, V. M., Aboy, A. L., Pimentel, A. L., Henriques, A. T., et al. (2008). Concentrations of p-synephrine in fruits and leaves of Citrus species (Rutaceae) and the acute
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toxicity testing of Citrus aurantium extract and p-synephrine. Food and Chemical Toxicology, 46, 2770–2775. Bouchard, N. C., Howland, M. A., Greller, H. A., Hoffman, R. S., & Nelson, L. S. (2005). Ischemic stroke associated with use of an ephedra-free dietary supplement containing synephrine. Mayo Clinic Proceedings, 80, 541–545. Carpene, C., Galitzky, J., Fontana, E., Algie, C., Lafontan, M., & Berlan, M. (1999). Selective activation of beta 3adrenoreceptors by octopamine: Comparative studies in mammalian fat cells. Naunyn Schmiedebergs Archives Pharmacology, 359, 310–321. Dragull, K., Breksa, A. P., & Cain, B. (2008). Synephrine content of juice from Satsuma mandarins (Citrus unshiu Marcovitch). Journal of Agricultural and Food Chemistry, 56, 8874–8878. Gange, C. A., Madias, C., Felix-Gretzik, E. M., Weintraub, A. R., & Estes, N. A. M. III, (2006). Variant angina associated with bitter orange in a dietary supplement. Mayo Clinic Proceedings, 81, 545–548. Gray, S., & Woolf, A. D. (2005). Citrus aurantium used for weight loss by an adolescent with anorexia nervosa. Journal of Adolescent Health, 37, 415–416. Haaz, S., Fontaine, K. R., Cutter, G., Limdi, N., Perumean-Chaney, S., & Allison, D. B. (2006). Citrus aurantium and synephrine alkaloids in the treatment of overweight and obesity: An update. Obesity Review, 7, 79–88. Haller, C. A., Benowitz, N. L., & Jacob, P. III, (2005). Hemodynamic effects of ephedra-free weight-loss supplements in humans. American Journal of Medicine, 118, 998–1003. Hamilton, B. S., & Doods, H. N. (2010). Identification of potential agonists acting at an endogenous atypical b3-adrenoreceptor state that modulate lipolysis in rodent fat cells. European Journal of Pharmacology, 580, 55–62. Holmes, R. O., Jr., & Tavee, J. (2008). Vasospasm and stroke attributable to ephedra-free Xenadrine: Case study. Military Medicine, 173, 708–710. Jordan, R., Thonoor, C. M., & Williams, C. M. (1987). Betaadrenergic activities of octopamine and synephrine stereoisomers on guinea-pig atria and trachea. Journal of Pharmacy and Pharmacology, 39, 752–754. Ma, G., Bavadekar, S. A., Schaneberg, B. T., Khan, I. A., & Feller, D. R. (2010). Effects of synephrine and beta-phenylephrine on human alpha-adrenoceptor subtypes. Planta Medica, 76, 981–986. Mattoli, L., Cangi, F., Maidecchi, A., Ghiara, C., Stubaro, M., & Tralda, P. (2005). A rapid liquid electrospray ionization mass spectroscopy method for evaluation of synephrine in Citrus aurantium L. samples. Journal of Agricultural Food Chemistry., 53, 9860–9866.
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McGuffin, M. (2006). Media spins numbers on bitter orange AERs based on erroneous information from FDA. HerbalGram, 69, 52–55. Mercolini, L., Mandrioli, R., Trere, T., Bugamelli, F., Ferranti, A., & Raggi, M. A. (2010). Fast CE analysis of adrenergic amines in different parts of Citrus aurantium fruit and dietary supplements. Journal of Separation Science, 32, 1–8. Min, B., Cios, D., Kluger, J., & White, C. M. (2005). Absence of QTcinterval-prolonging or hemodynamic effects of a single dose of bitter orange extract in healthy subjects. Pharmacotherapy, 25, 1719–1724. Nasir, J. M., Durning, S. J., Ferguson, M., Barold, H. J. S., & Haigney, M. C. (2004). Exercise-induced syncope associated with QT prolongation and ephedra-free Xenadrine. Mayo Clinic Proceedings, 79, 1059–1062. Nutratech Inc. (2005). Advantra Zâ. The next generation weight loss ad fitness ingredient. Applications/dosage guidelines.