Products containing bitter orange (Citrus aurantium) or synephrine are used for their claims of promoting weight loss.
However, these products are not authorized by Health Canada for this indication. Synephrine, the main active compound in
bitter orange, is claimed to increase metabolism and promote thermogenesis.1 Although their effectiveness remains unclear,1
many products containing bitter orange are being promoted as "Ephedra/ephedrine free," since the use of Ephedra has been
restricted in Canada2 and prohibited in dietary supplements in the United States3 owing to adverse cardiovascular and
cerebrovascular reactions.
Synephrine, a sympathetic a-adrenergic agonist, is structurally related to ephedrine; thus bitter orange extract may be associated with a spectrum of adverse reactions (ARs) similar to those associated with the use of Ephedra/ephedrine.4 In animals, synephrine use has been associated with dose-related cardiotoxicity, specifically ventricular arrhythmias.5 A case of myocardial infarction in a patient with no history of heart disease has been reported in association with synephrine-containing products.6 Health Canada issued an advisory on a natural health product containing synephrine and other stimulants, cautioning that synephrine may have cardiovascular effects similar to those of ephedrine.4 Synephrine's cardiovascular effects may be increased when combined with other stimulants such as caffeine.7 Previously, Health Canada warned consumers about using Ephedra products containing caffeine, for the same reasons,2 and other reviews have reiterated this safety concern.8
From Jan. 1, 1998, to Feb. 28, 2004, Health Canada received 16 reports in which products containing bitter orange or synephrine were suspected of being associated with cardiovascular ARs, including tachycardia, cardiac arrest, ventricular fibrillation, transient collapse and blackout. All cases were considered serious. One involved a suspect product containing bitter orange but no caffeine or Ephedra/ephedrine. In 7 cases the suspect product also contained caffeine, and in 8 cases the suspect product also contained both Ephedra/ephedrine and caffeine. Two of the 16 patients died, both of whom had taken products containing Ephedra/ephedrine and caffeine in addition to bitter orange. Evaluation of these reports is challenging because of many factors such as the lack of information on the ingested dose of synephrine, the contributory effects of other (multiple) ingredients such as Ephedra and caffeine, and the ambiguity of the reported information.
Consumers need to be aware of the potential serious ARs when using these products containing bitter orange or synephrine and may wish to consult their health care providers with regard to their use. Health care professionals are encouraged to ask their patients to list the natural health products they are taking and report to Health Canada any suspected ARs related to the use of such products, including those claiming to promote weight loss.
Scott Jordan, PhD, Mano Murty, MD, CCFP, FCFP, and Karen Pilon, RN, Health Canada
References
1 Blumenthal M, senior editor. Herbal medicine - expanded Commision E monographs. 1st ed. Austin (TX): American Botanical Council; 2000. p. 287-9.
2 Health Canada reminds Canadians of the dangers of Ephedra/ephedrine products. Ottawa: Health Canada; 2003 June 9. Available: http://www.hc-sc.gc.ca/english/protection/warnings/2003/2003_43.htm (accessed 2004 July 5).
3 FDA announces rule prohibiting sale of dietary supplements containing ephedrine alkaloids effective April 12 [FDA statement]. Rockville (MD): US Food and Drug Adminstration; 2004 Apr 12. Available: http://www.fda.gov/bbs/topics/NEWS/2004/NEW01050.html (accessed 2004 June 28).
4 Health Canada warns Canadians not to use "Thermonex." Ottawa: Health Canada; 2004 May 28. Available: http://www.hc-sc.gc.ca/english/protection/warnings/2004/2004_30.htm (accessed 2004 July 5). 5 Calapai G, Firenzuoli F, Saitta A, Squadrito F, Arlotta MR, Canstantino G, Inferrera G. Antiobesity and cardiovascular toxic effects of Citrus aurantium extracts in the rat: a preliminary report. Fitoterapia 1999;70:586-92.
6 Nykamp DL, Fackih MN, Compton AL. Possible association of acute lateral-wall myocardial infarction and bitter orange supplement. Ann Pharmacother 2004;38(5):812-6.
7 Bucci L, Shugarman AE, Feliciano J, Wright J. Acute metabolic responses to synephrine-caffeine compared to ephedrine-caffeine. Presented at the Conference on the Science and Policy of Performance-Enhancing Products. NIH Office of Dietary Supplements; Bethesda, Md; Jan. 8-9, 2002. Available: http://ods.od.nih.gov/news/conferences/BucciPEPCRN _Ephedra_Presentation_Jan02.pdf (accessed 2004 June 27).
8 Bitter orange. Natural Medicines Comprehensive Database. Available: http://www.NaturalDatabase.com (accessed 2004 June 27). Jellin JM, Gregory PJ, Batz F, Hitchens K, et al. Pharmacist's letter/prescriber's letter. Natural Medicines Comprehensive Database. 6th ed. Stockton (CA): Therapeutic Research Faculty; 2004. p. 146-8.
Synephrine, a sympathetic a-adrenergic agonist, is structurally related to ephedrine; thus bitter orange extract may be associated with a spectrum of adverse reactions (ARs) similar to those associated with the use of Ephedra/ephedrine.4 In animals, synephrine use has been associated with dose-related cardiotoxicity, specifically ventricular arrhythmias.5 A case of myocardial infarction in a patient with no history of heart disease has been reported in association with synephrine-containing products.6 Health Canada issued an advisory on a natural health product containing synephrine and other stimulants, cautioning that synephrine may have cardiovascular effects similar to those of ephedrine.4 Synephrine's cardiovascular effects may be increased when combined with other stimulants such as caffeine.7 Previously, Health Canada warned consumers about using Ephedra products containing caffeine, for the same reasons,2 and other reviews have reiterated this safety concern.8
From Jan. 1, 1998, to Feb. 28, 2004, Health Canada received 16 reports in which products containing bitter orange or synephrine were suspected of being associated with cardiovascular ARs, including tachycardia, cardiac arrest, ventricular fibrillation, transient collapse and blackout. All cases were considered serious. One involved a suspect product containing bitter orange but no caffeine or Ephedra/ephedrine. In 7 cases the suspect product also contained caffeine, and in 8 cases the suspect product also contained both Ephedra/ephedrine and caffeine. Two of the 16 patients died, both of whom had taken products containing Ephedra/ephedrine and caffeine in addition to bitter orange. Evaluation of these reports is challenging because of many factors such as the lack of information on the ingested dose of synephrine, the contributory effects of other (multiple) ingredients such as Ephedra and caffeine, and the ambiguity of the reported information.
Consumers need to be aware of the potential serious ARs when using these products containing bitter orange or synephrine and may wish to consult their health care providers with regard to their use. Health care professionals are encouraged to ask their patients to list the natural health products they are taking and report to Health Canada any suspected ARs related to the use of such products, including those claiming to promote weight loss.
Scott Jordan, PhD, Mano Murty, MD, CCFP, FCFP, and Karen Pilon, RN, Health Canada
References
1 Blumenthal M, senior editor. Herbal medicine - expanded Commision E monographs. 1st ed. Austin (TX): American Botanical Council; 2000. p. 287-9.
2 Health Canada reminds Canadians of the dangers of Ephedra/ephedrine products. Ottawa: Health Canada; 2003 June 9. Available: http://www.hc-sc.gc.ca/english/protection/warnings/2003/2003_43.htm (accessed 2004 July 5).
3 FDA announces rule prohibiting sale of dietary supplements containing ephedrine alkaloids effective April 12 [FDA statement]. Rockville (MD): US Food and Drug Adminstration; 2004 Apr 12. Available: http://www.fda.gov/bbs/topics/NEWS/2004/NEW01050.html (accessed 2004 June 28).
4 Health Canada warns Canadians not to use "Thermonex." Ottawa: Health Canada; 2004 May 28. Available: http://www.hc-sc.gc.ca/english/protection/warnings/2004/2004_30.htm (accessed 2004 July 5). 5 Calapai G, Firenzuoli F, Saitta A, Squadrito F, Arlotta MR, Canstantino G, Inferrera G. Antiobesity and cardiovascular toxic effects of Citrus aurantium extracts in the rat: a preliminary report. Fitoterapia 1999;70:586-92.
6 Nykamp DL, Fackih MN, Compton AL. Possible association of acute lateral-wall myocardial infarction and bitter orange supplement. Ann Pharmacother 2004;38(5):812-6.
7 Bucci L, Shugarman AE, Feliciano J, Wright J. Acute metabolic responses to synephrine-caffeine compared to ephedrine-caffeine. Presented at the Conference on the Science and Policy of Performance-Enhancing Products. NIH Office of Dietary Supplements; Bethesda, Md; Jan. 8-9, 2002. Available: http://ods.od.nih.gov/news/conferences/BucciPEPCRN _Ephedra_Presentation_Jan02.pdf (accessed 2004 June 27).
8 Bitter orange. Natural Medicines Comprehensive Database. Available: http://www.NaturalDatabase.com (accessed 2004 June 27). Jellin JM, Gregory PJ, Batz F, Hitchens K, et al. Pharmacist's letter/prescriber's letter. Natural Medicines Comprehensive Database. 6th ed. Stockton (CA): Therapeutic Research Faculty; 2004. p. 146-8.
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