Introduction

The extract of the fruit or peel of bitter orange (Citrus aurantium, Rutaceae) and its primary protoalkaloidal constituent, p-synephrine, are widely used in weight management as well as sports performance products, with many millions of doses having been consumed by possibly millions of individuals.¹ However, bitter orange has been listed by Consumer Reports² as being possibly unsafe and a dietary supplement “to avoid.” The editors of Consumer Reports note that bitter orange has been “linked by clinical research or case reports to serious side effects,” having arrived at this verdict based on conclusions found in the Natural Medicines Comprehensive Database. The article further states that bitter orange “contains synephrine, which is similar to ephedrine, banned by the FDA [US Food and Drug Administration] in 2004.” No detailed information was provided to support these conclusions. The following information summarizes current research and knowledge regarding bitter orange extract and p-synephrine.

Chemistry

Like all botanical products, bitter orange peel contains a variety of naturally occurring compounds. In Traditional Chinese Medicine (TCM), the peel and/or whole, dried, immature fruit is used for a variety of clinical applications, including indigestion, diarrhea and dysentery, constipation, and as an expectorant.^3-5 According to TCM, zhi shi (immature bitter orange) “is one of the best herbs to treat gastrointestinal disorders characterized by stagnation and accumulation,” and “is one of the best herbs to relieve distention and hardness of the epigastric area caused by cholecystitis.”⁵ Pharmacologically, this compendium⁵ reports that zhi shi does not affect respiration or heart rate and has minimal toxicity. Bitter orange has also been used in South American folk medicine to treat insomnia, anxiety, and epilepsy.⁴

The primary pharmacologically active protoalkaloid (biogenic amine) in bitter orange peel and its extracts is para-synephrine.^6-13 p-Synephrine is a phenylethanolamine derivative with the hydroxy group in the para position on the benzene ring of the molecule (Figure 1). This is the form found in most bitter orange products (e.g., the patented bitter orange extract, Advantra Z^® [Nutratech, Inc.,West Caldwell, NJ]). p-Synephrine comprises greater than 85% of the total protoalkaloids in bitter orange extract. Other minor protoalkaloidal constituents include octopamine, hordenine, tyramine, and N-methyltyramine.^6,7,12,13 Much confusion exists in both scientific and lay literature because there is also meta-synephrine, known as phenylephrine (hydroxyl group in the meta-position on the benzene ring; Figure 2). The latter is an FDA-approved over-the-counter (OTC) drug ingredient typically found in nasal decongestants and sprays.

Contrary to some commentaries,^14,15 m-synephrine does not appear to be naturally occurring in bitter orange^6-13 and has not been shown to be present in some of the leading bitter orange extract products, such as Advantra Z.¹⁶ No evidence exists that m-synephrine is a natural product. Furthermore, m-synephrine is not a constituent of—nor has it been identified in—standardized bitter orange reference materials prepared by the National Institute of Standards and Technology (NIST).¹⁷ When m-synephrine has been reported in weight-loss products,¹⁸ it is believed to be due to addition of the synthetic ingredient.¹⁹ Trace amounts of m-synephrine have been reported in human plasma, although the source of this material is not known.²⁰

Animal and Human Pharmacology

p-Synephrine is believed to act primarily as a beta-3 adrenergic receptor agonist, which results in increased thermogenesis and lipolysis (breakdown of fats).^11,21-24 Ligand binding to alpha- as well as beta-1 and beta-2 adrenoreceptors results in cardiovascular effects including increased blood pressure and heart rate.^25,26,27 In general, binding to α-adrenergic receptors results in vasoconstriction, while increased cardiovascular contractility and heart rate occur in response to β1-adrenergic receptor binding, and bronchodilation occurs in response to β2-adrenergic receptor binding.28 m-Synephrine is 100-fold and p-synephrine 40,000-fold less potent than nor-epinephrine with respect to binding to beta-1 and beta-2 adrenoreceptors in guinea pig atria and trachea.²⁵ p-Synephrine is approximately 50-fold less potent than m-synephrine in activating human alpha-1a adrenoreceptors, and has even lower binding affinity for human alpha-2a- and alpha-2c adrenoreceptor subtypes.²⁶

The receptor binding activities of the meta and para isomers of synephrine as well as octopamine to rat aorta alpha-1 and rabbit saphenous vein alpha-2 adrenoreceptors have been studied.²⁷ The binding of m-synephrine was 6-fold less than nor-epinephrine to alpha-1 adrenoreceptors and 150-fold less to alpha-2-adrenoreceptors. Moreover, p-synephrine was 1000-fold less active than nor-epinephrine in binding to alpha-1 and alpha-2 adrenoreceptors. Finally, studies involving interactions for alpha-1 adrenoreceptor binding and activation have demonstrated that it is the meta-hydroxy of m-synephrine and not the para-hydroxy of p-synephrine that preferentially binds to the receptor, allowing receptor activation.²⁹ As a consequence, p-synephrine would be expected to have little or no effect on blood pressure relative to m-synephrine or nor-epinephrine.

The above receptor binding studies are in agreement with several human studies where p-synephrine exhibited little or no effect on blood pressure,^15,30-37 although an increase in heart rate was reported³³ that has not been observed or substantiated in various other human studies.^15,30,34-37 These receptor binding results are also in agreement with animal studies that have shown no adverse cardiovascular effects following oral administration of bitter orange extract or p-synephrine.^38,39 The assumption that the 2 forms of synephrine have similar if not identical effects has lead to serious inaccuracies, and the inappropriate attribution of potentially adverse effects produced by m-synephrine to p-synephrine, which occurs in bitter orange.

Chemically, p-synephrine is structurally related to ephedrine (Figure 3). However, ephedrine is a phenylpropanolamine derivative, having a methyl group on the alpha carbon of the sidechain and no para-substituted hydroxy group, as compared to p-synephrine which is a phenylethanolamine derivative. These 2 chemical differences greatly impact the stereochemistry and alter the pharmacokinetic properties, particularly the ability of p-synephrine to cross the blood-brain barrier. The addition of the para hydroxy group on the p-synephrine molecule, as well as the lack of the additional methyl group, greatly decreases the lipid solubility of p-synephrine as compared to ephedrine, resulting in little transport into the central nervous system (CNS) as compared to ephedrine.^3,21,22 As a consequence, p-synephrine exhibits little or no CNS and cardiovascular stimulation. However, p-synephrine may act locally on the cardiovascular system. The existence of alpha- and beta-1 and beta-2 adrenoreceptors within the cardiovascular system is well known, while beta-3 adrenoreceptors have been recently identified in cardiovascular tissues,⁴⁰ and evidence suggests that their activation modulates sympathetic overstimulation through regulation of nitric oxide.⁴¹ These observations may further explain the lack of cardiovascular stimulation by p-synephrine in addition to its low level of binding to alpha- as well as beta-1 and beta-2 adrenoreceptors.

Safety

A series of review articles regarding the safety and activity of bitter orange has been published over the past 8 years.^3,4,14,42-44 None of these reviews has reported any serious or significant adverse events that are directly attributable to bitter orange, nor does the research literature support the development of adverse cardiovascular or neurological events in humans or animals when administered orally.

During the past several years, a number of case studies have been reported for products containing bitter orange that involved adverse cardiovascular or other events where the authors suggested that the causative agent was synephrine or bitter orange.^45-54 However, in each case, the product in question contained 5 to 12 alkaloidal and protoalkaloidal ingredients, including bitter orange. It is not possible to ascribe the effects specifically to one of these constituents, and the effects may have been due to a combination of ingredients. High caffeine intake has been proposed as the most likely culprit responsible for cardiovascular adverse events when consuming dietary supplements containing multiple herbal ingredients.⁵⁵ In the majority of cases, other confounding factors were also noted. A number of the cases involved body builders or serious athletes,^{4,46,50,52,54} and dehydration was involved in at least 2 of the cases.^46,50 There are questions as to whether individuals had also been using steroids, anabolic agents or other ergogenic or thermogenic agents, or various prescription and non-prescription drugs. Other factors may have contributed, including pre-existing conditions such as previously undetected heart disease⁴⁵ or hypertriglyceridemia,⁴⁸ sickle cell trait,⁵⁰ extensive use of tobacco products,^45,47,54 consumption of large amounts of caffeine daily,^45,53 or a history of substance abuse.⁴⁷ In addition, there is a high probability that the events were concurrent but random and unrelated, based on the fact that cardiovascular events occur in millions of people annually.

The historical and traditional use of extracts of bitter orange in TCM, as well as the extensive use of products containing bitter orange extract and p-synephrine aid in putting the safety issue into context. Two percent of respondents in a survey reported taking a dietary supplement containing bitter orange,¹ which, if extrapolated nationwide, would entail several million individuals. No serious adverse events have been directly attributable to bitter orange or p-synephrine.^3,4,14,42-44

Furthermore, millions of people daily consume, without ill effect, various juices and food products such as marmalade from Citrus species including Seville orange, grapefruit, mandarin, and other orange-related species that contain p-synephrine.^3,7-10,56 A typical sweet orange contains about 6 mg p-synephrine.¹⁰ A wide variety of citrus juices contain approximately 5 mg p-synephrine per 8-ounce glass,^3,7 while juice from mandarin oranges may contain more than 20 mg p-synephrine per 8-ounce glass.^3,56 These amounts of p-synephrine are similar to the amounts found in a vast range of dietary supplements. A US Department of Agriculture study of the p-synephrine content of mandarin orange juice from 10 different groves in California found that the p-synephrine content ranged from 73 to 158 mg per liter, with an overall mean of 93 mg per liter.⁵⁶

A major contributor to the concerns regarding the safety of bitter orange and p-synephrine has been the US federal government. In 2004, the FDA supplied information to a major newspaper indicating that 85 adverse reactions and 7 deaths had been associated with bitter orange-containing dietary supplements. Subsequently, the purported number of adverse events increased to 169. A dissection of the FDA information by McGuffin,⁵⁷ obtained through the Freedom of Information Act and on which the reports were based, clearly indicated that no credible adverse events could be attributed to bitter orange. A recent review of FDA adverse events reports and published clinical case reports over the past 5 years has again concluded that no serious adverse events can be directly attributed to bitter orange or p-synephrine.⁵⁸ The FDA has acknowledged some “misstatements” about bitter orange.

The possible dangers of bitter orange (fainting, heart-rhythm disorders, heart attack, stroke, death) listed in the Consumer Reports article² are clearly not supported by scientific and clinical literature. None of these adverse effects have been directly linked with bitter orange extract or p-synephrine. Unfortunately, this reality has not prevented many individuals from making statements that are not based on scientific fact or clinical data.

Summary

In summary, based on current research as well as the extensive ingestion of bitter orange and p-synephrine in the form of dietary supplements as well as fruits, juices, and other citrus food products, the data demonstrate that bitter orange extract is safe for human consumption. No credible adverse events have been directly attributed to bitter orange, or its primary protoalkaloid, p-synephrine, in association with oral ingestion.

Conflict of Interest Disclosure

The authors have served as consultants for Nutratech, Inc., a company that markets bitter orange extracts.

References

1. Klonz KC, Timbo BB, Street D. Consumption of Dietary Supplements Containing Citrus aurantium (bitter orange)—2004 California behavioral risk factor surveillance survey (BRFSS). Ann. Pharmacother. 2006; 40:1747-1751.
2. Anon. Dangerous supplements. What you don’t know about these 12 ingredients could hurt you. Consumer Reports 2010; Sept.:16-20.
3. Blumenthal M. Bitter orange peel and synephrine. Part 1. Whole Foods 2004; March:77-79, 97.
4. Stohs SJ, Shara M. A review of the safety and efficacy of Citrus aurantium in weight management. In: Bagchi D. and Preuss H. G. (eds). Obesity: epidemiology, pathophysiology, and prevention. Boca Raton, FL: CRC Press; 2007:371-382.
5. Chen, JK, Chen, TT. Zhi Shi (Fructus Aurantii Immaturus), Chinese Medical Herbology and Pharmacology. CA: Art of Medicine Press;2004:485-486.
6. Pellati F, Benvenuti S, Melegari M. High-pressure liquid chromatography methods for the analysis of adrenergic amines and flavanones in Citrus aurantium L. var. amara. Phytochem Anal. 2004;15:220-225.
7. Pellati F, Benvenuti S, Melegari M, Firenzuoli F. Determination of adrenergic agonists from extracts and herbal products of Citrus aurantium L. var. amara by LC. J Pharmaceut Biomed Anal. 2002;29:1113-1119.
8. Pellati F, Benvenuti S, Melegari M. Enantioselective LC analysis of synephrine in natural products on a protein-based chiral stationary phase. J Pharmaceut Biomed. Anal. 2005;37:839-849.
9. Arbo M D, Larentis ER, Linck VM, Aboy AL, Pimentel AL, Henriques AT, Dallegrave E, Garcia SC, Leal MB, Limberger RP. Concentrations of p-synephrine in fruits and leaves of Citrus species (Rutaceae) and the acute toxicity testing of Citrus aurantium extract and p-synephrine. Food Chem Toxicol. 2008;46:2770-2775.
10. Mattoli L, Cangi F, Maidecchi A, Ghiara C, Stubaro M, Tralda P. A rapid liquid electrospray ionization mass spectroscopy method for evaluation aurantium L. samples. J Agric Food Chem.2005;53:9860-9866.
11. TsujitaT, Takaku T. Lipolysis induced by segment wall extract from Satsuma mandarin orange (Citrus unshu Mark). J Nutr Sci Vitaminol. 2007;53:547-551.
12. Roman MC, Betz JM, Hildreth J. Determination of synephrine in bitter orange raw materials, extracts, and dietary supplements by liquid chromatography with ultraviolet detection: single laboratory validation. J. Amer. Org. Anal. Chemists Int. 2007;90:68-81.
13. Mercolini L, Mandrioli R, Trere T, Bugamelli F, Ferranti A, Raggi MA. Fast CE analysis of adrenergic amines in different parts of Citrus aurantium fruit and dietary supplements. J Sep Sci. 2010;32:1-8.
14. Bent S, Padula A, Neuhaus J. Safety and efficacy of Citrus aurantium for weight loss. Amer J Cardiol. 2004;94:1359-1361.
15. Penzak SR, Jann MW, Cold J A, Hon YY, Desai HD, Gurley BJ. Seville (sour) orange juice: synephrine content and cardiovascular effects in normotensive adults. J Clin Pharmacol. 2001;41:1059-1063.
16. Independent analysis of protoalkaloidal content of Advantra ZTM. http://www.nutratechinc.com/advz/Uploaded Files/Advantra%20Z%20 Found%20to%20Contain%20Only%20P-Synephrine%20Isomer.pdf. (Communication with H. Miller, March 2010).
17. Sander LC, Putzbach K, Nelson BC, Rimmer CA, Bedner M, Thomas JB, Porter BJ, Wood LJ, Schrantz MM, Murphy KE, Sharpless KE, Wise SA, Yen JH, Siitonen PH, Evans RL, Pho AN, Roman MC, Betz JM. Certification of standard reference materials containing bitter orange. Anal Bioanal Chem. 2008;391:2023-2034
18. Allison DB, Cutter G, Poehlman ET, Moore DR, Barnes S. Exactly which synephrine alkaloids does Citrus aurantium (bitter orange) contain? Int J Obesity, 2005;29:443.
19. Rossato LG, de Pinho PG, Silva R, Carmo H, Carvalho F, de Lourdes Bastos M, Costa VM, Remiao F. Development and validation of a GC/IT-MS method for simultaneous quantification of the para and meta-synephrine in biological samples. J Pharmaceut Biomed Anal. 2010;52:721-726
20. Andrew R, Best SA, Watson DG, Midgley JM, Reid JL, Squire IB. Analysis of biogenic amines in plasma of hypertensive patients and a control group. Neurochem Res. 1993;Nov.18:1179-1182.
21. Arch JR. β3-Adrenoceptor agonists: potential, pitfalls and progress, European J. Pharmacol. 2002;440:99-107.
22. Jones D. Citrus and Ephedra, Whole Foods, 2004;April:40-42.
23. Hamilton F, Doods, HN. Identification of potent agonists acting at an endogenous atypical β3-adrenoreceptor state that modulate lipolysis in rodent fat cells. European J Pharmacol. 2008;580:55-62.
24. Carpene C, Galitzky J, Fontana E, Algie C, Lafontan M, Berlan M. Selective activation of beta 3-adrenoreceptors by octopamine: comparative studies in mammalian fat cells. Naunyn Schmiedebergs Arch Pharmacol. 1999;359:310-321.
25. Jordan R, Midgley JM, Thonoor CM, Williams CM. Beta-adrenergic activities of octopamine and synephrine stereoisomers on guinea-pig atria and trachea. J Pharm Pharmacol. 1987;39:752-754.
26. Ma G, Bavadekar SA, Schaneberg BT, Khan IA, Feller DR. Effects of synephrine and beta-phenylephrine on human alpha-adrenoreceptor subtypes. Planta Med.2010;76:981-986.
27. Brown CM, McGrath JC, Midgley JM, Muir AG, O’Brien JW, Thonoor CM, Williams CM, Wilson VG. Activities of octapamine and synephrine stereoisomers on alpha-adrenoreceptors. Br J Pharmacol.1988;93:417-429.
28. Inchiosa MA. Evidence (mostly negative) with the use of sympathomimetic agents for weight loss. J Obesity 2011, Article ID 764584; doi:10.1155/2011/764584.
29. Hwa J, Perez DM. The unique nature of the serine interactions for alpha 1-adrenergic receptor agonist binding and activation. J Biol Chem. 1996;271:6322-6327.
30. Min B, Cios D, Kluger J, White CM. Absence of QTc-interval-prolonging or hemodynamic effects of a single dose of bitter orange extract in healthy subjects. Pharmacother. 2005;25:1719-1724.
31. Bui LT, Nguyen DT, Ambrose PJ. Blood pressure and heart rate effects following a single dose of bitter orange. Ann Pharmacodyn. 2006;40:53-57.
32. Haller CA, Benowitz NL, Peyton J III. Hemodynamic effects of ephedra-free weight-loss supplements in humans. Amer J Med. 2005;118:9981003.
33. Haller CA, Duan M, Peyton J III, Benowitz N. Human pharmacology of a performance-enhancing dietary supplement under resting and exercise conditions. Br J Clin Pharmacol. 2008;65:833-840.
34. Colker CM, Kalman DS, Torina GC, Perlis T, Street C. Effects of Citrus aurantium extract, caffeine and St. John’s wort on body fat loss, lipid levels and mood states in normal weight and obese individuals. Curr Ther Res. 1999;60:145-153.
35. Sale C, Harris RC, Delves S, Corbett J. Metabolic and physiological effects of ingesting extracts of bitter orange, green.tea and guarana at rest and during treadmill walking in overweight males. Int J Obesity 2006;30:764-773.
36. Gougeon R, Harrigan K, Tremblay JF, Hedrei P, Lamarche M, Morais JA. Increase in the thermic effect of food in women by adrenergic amines extracted from Citrus aurantium. Obesity Res. 2005;13;1187-1194.
37. Zenk JL, Leikam SA, Kassen LJ, Kushowski MA. Effect of Lean System 7 on metabolic rate and body composition. Nutrition 2005;21;179-185.
38. Calapai G, Firenzuoli F, Saitta A, Squadrito F, Arlotta MR, Constantino G, Inferrera G. Antiobesity and cardiovascular toxic effects of Citrus aurantium extracts in the rat: a preliminary report, Fitoterapia 1999;70: 586-592.
39. Arbo MD, Schmitt GC, Limberger MF, Charao MF, Moro AM, Rigeiro GL, Dallegrave E, Garcia SC, Leal MB, Limberger RP. Subchronic toxicity of Citrus aurantium L. (Rutaceae) extract and p-synephrine in mice. Reg Toxicol Pharmacol. 2009;54:114-117.
40. Rozec B, Gauther C. β3-Adrenoreceptors in the cardiovascular system: Putative roles in human pathologies. Pharmacol Therap. 2006;111:652-673.
41. Moens AL,Yang R, Watts VL, Barouch LA. Beta 3-adrenoreceptor regulation of nitric oxide in the cardiovascular system. J Mol Cell Cardiol. 2010; 48:1088-1095.
42. Preuss HG, DiFerdinando D, Bagchi M, Bagchi D. Citrus aurantium as a thermogenic, weight-reduction replacement for Ephedra: an overview. J Med. 2002;33:247-264.
43. Fugh-Berman A, Myers A. Citrus aurantium, an ingredient of dietary supplements marketed for weight loss: current status of clinical and basic research. Exptl Biol Med. 2004;229:698-704.
44. Haaz S, Fontaine KR, Cutter G, Limdi N, Perumean-Chaney S, Allison DB. Citrus aurantium and synephrine alkaloids in the treatment of overweight and obesity: an update. Obes Res. 2006;7:79-88.
45. Nykamp DL, Fackih MN, Compton AL. Possible association of acute lateral-wall myocardial infarction and bitter orange supplement. Ann Pharmacother. 2004;38:812-816.
46. Nasir JM, Durning SJ, Ferguson M, Barold HJS, Haigney MC. Exercise-induced syncope associated with QT prolongation and ephedra-free Xenadrine. Mayo Clin Proc. 2004;79:1059-1062.
47. Bouchard NC, Howland MA, Greller HA, Hoffman RS, Nelson LS. Ischemic stroke associated with use of an ephedra-free dietary supplement containing synephrine. Mayo Clin Proc. 2005;80:541-545.
48. Gange CA, Madias C, Felix-Gretzik EM, Weintraub AR, Estes III N AM, Variant angina associated with bitter orange in a dietary supplement. Mayo Clin. Proc. 2006;81:545-548.
49. Sultan S, Spector J, Mitchell RM. Ischemic colitis associated with use of a bitter orange-containing dietary weight-loss supplement. Mayo Clin Proc. 2006;81:1630-1631.
50. Burke J, Seda G, Allen D, Knee TS. A case of severe exercise-induced rhabdomyolysis associated with a weight-loss dietary supplement. Military Med. 2007:172;656-658.
51. Smedema JP, Muller GJ. Coronary spasm and thrombosis in a bodybuilder using a nutritional supplement containing synephrine, octopamine, tyramine and caffeine. So African Med J. 2008;98:372-373.
52. Holmes Jr. RO, Tavee J. Vasospasm and Stroke attributable to ephedra-free Xenadrine: case study. Military Med. 2008;173:708-710.
53. Thomas JE, Munir JA, McIntyre PZ, Ferguson MA. STEMI in a 24-year-old man after use of a synephrine-containing dietary supplement. A case report and review of the literature. Texas Heart Inst J. 2009;36:586-590.
54. Stephensen TA, Sarlay Jr. R. Ventricular fibrillation associated with use of synephrine containing dietary supplement. Military Med. 2009;174:1313-1319.
55. Gurley BJ, Swain A, Barone GW, Williams DK, Breen P, Yates CR, et al. Hemodynamic and electrocardiographic effects of an “ephedra-free” dietary supplement (Metabolife Ultra^TM). Clin Pharmacol Therap. 2006:79(Suppl 1);2.
56. Dragull K, Breksa AP, Cain B. Synephrine content of juice from Satsuma mandarins (Citrus unshiu Marcovitch). J Agric Food Chem. 2008;56:8874-8878.
57. McGuffin M. Media spins numbers on bitter orange AERs based on erroneous information from FDA. HerbalGram. 2006;69:52-55.
58. Stohs SJ. Assessment of the adverse event reports associated with Citrus aurantium (bitter orange) from April 2004 to October 2009. J Funct Foods 2010. doi:10.1016/j.jff.2010.10.003.
59. Anon. CFSAN examines AER reporting following bitter orange miscalculation. The Tan Sheet 2004;12:11-12.