A review of the human clinical studies involving citrus aurantium (bitter orange) extract and its primary protoalkaloid p-synephrine

International Journal of Medical Sciences

Volumn 9, Issue 7, 2012, Pages 527-538

  Stohs, Sidney J ^a   Preuss, Harry G ^b   Shara, Mohd ^c  

^a CREIGHTON UNIVERSITY MEDICAL CENTER   (United States)

^b GEORGETOWN UNIVERSITY MEDICAL CENTER   (United States)

^c JORDAN UNIVERSITY OF SCIENCE AND TECHNOLOGY   (Jordan)

Author keywords

Bitter orange; Caffeine; Citrus aurantium; Efficacy; Human subjects; Obesity overweight; P synephrine; Safety

Indexed keywords

4 OXEDRINE; ANTIOBESITY AGENT; CAFFEINE; EPHEDRINE; HYDROXYCITRIC ACID; JAVAFIT; LEAN SOURCE; LEAN SYSTEM 7; MELTDOWN; OCTOPAMINE; OXEDRINE; PHENETHYLAMINE; PLACEBO; RIPPED FUEL EXTREME CUT; SEVILLE; SOUR ORANGE EXTRACT; ULTRA SLIM DOWN; UNCLASSIFIED DRUG; XENADRINE EFX; XENADRINE RFA 1; PLANT EXTRACT; 3 SYNEPHRINE; 4 SYNEPHRINE; ADVANTRA Z; AGENTS AFFECTING METABOLISM; HERBACEOUS AGENT; XENADRINE;

ABSENCE OF SIDE EFFECTS; BLOOD CELL COUNT; BLOOD CHEMISTRY; BLOOD PRESSURE; BRADYCARDIA; BRAIN ISCHEMIA; CARDIOVASCULAR EFFECT; CARDIOVASCULAR RESPONSE; CONTROLLED CLINICAL TRIAL (TOPIC); CORONARY ARTERY SPASM; DIET SUPPLEMENTATION; DIET THERAPY; DRUG BLOOD LEVEL; DRUG CONTRAINDICATION; DRUG DOSE COMPARISON; DRUG EFFICACY; DRUG HALF LIFE; DRUG MECHANISM; DRUG SAFETY; DRUG STRUCTURE; ECG ABNORMALITY; ENERGY EXPENDITURE; HEALTH HAZARD; HEART INFARCTION; HEART RATE; HEART VENTRICLE FIBRILLATION; HUMAN; HYPOTENSION; ISCHEMIC COLITIS; KINESIOTHERAPY; METABOLIC RATE; NONHUMAN; OBESITY; ORANGE JUICE; QT INTERVAL; QT PROLONGATION; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; RHABDOMYOLYSIS; SIDE EFFECT; SINGLE DRUG DOSE; SLEEP DISORDER; ST SEGMENT ELEVATION MYOCARDIAL INFARCTION; STROKE; SYNCOPE; THROMBOSIS; TREATMENT DURATION; UNSPECIFIED SIDE EFFECT; URINALYSIS; VARIANT ANGINA PECTORIS; VASOSPASM; WEIGHT CONTROL; WEIGHT REDUCTION; XEROSTOMIA; CHEMISTRY; CITRUS; ISOLATION AND PURIFICATION; BLOOD PRESSURE MEASUREMENT; CEREBROVASCULAR ACCIDENT; CLINICAL EFFECTIVENESS; DISEASE ASSOCIATION; DOSE RESPONSE; DRUG EFFECT; DRUG TOLERABILITY; ELECTROCARDIOGRAPH; ELECTROCARDIOGRAPHY; EXERCISE; HYPERTENSION; MONOTHERAPY; OUTCOME ASSESSMENT; PATIENT MONITORING; PATIENT SAFETY; STRUCTURAL HOMOLOGY;

CITRUS; HUMANS; OBESITY; OVERWEIGHT; PLANT EXTRACTS; SYNEPHRINE;

EID: 84866538896     PISSN: 14491907     EISSN: None     Source Type: Journal    
DOI: 10.7150/ijms.4446     Document Type: Review

References (56)

1. Chen JK, Chen TT. Zhi Shi (Fructus Aurantii Immaturus). Chinese Medical Herbology and Pharmacology. City of Industry, CA USA: Art of Medicine Press. 2004: 485-487.
2. Stohs SJ, Shara M. A review of the safety and efficacy of Citrus aurantium in weight management. In: Bagchi D, Preuss HG, editors. Obesity: Epidemiology, Pathophysiology, and Prevention. Boca Raton, FL, USA: CRC Press. 2007: 371-382.
3. Pellati F, Benvenuti S. Chromatographic and electrophoretic methods for the analysis of phenethylamine alkaloids in Citrus aurantium. J Chromatog A. 2007; 1171: 71-88.
4. Sander LC, Putzbach K, Nelson BC, et al. Certification of standard reference materials containing bitter orange. Analyt Bioanalyt Chem 2008; 391: 2023-2034.
5. Evans RL, Pho AN, Roman MC, Betz JM. Certification of standard reference materials containing bitter orange. Analyt Bioanalyt Chem 2008; 391: 2023-2034.
6. Penzak SR, Jann MW, Cold JA, et al. Seville (sour) orange juice: synephrine content and cardiovascular effects in normotensive adults. J Clin Pharmacol 2001; 41: 1059-1063.
7. Bent S, Padula A, Neuhaus J. Safety and efficacy of Citrus aurantium for weight loss. Amer J Cardiol 2004; 94: 1359-1361.
8. Nasir JM, Durning SJ, et al. Exercise-induced syncope associated with QT prolongation and ephedra-free Xenadrine. Mayo Clinic Proceed 2004; 79: 1059-1062.
9. Stephensen TA, Sarlay Jr R. Ventricular fibrillation associated with use of a synephrine containing dietary supplement. Military Med 2009; 174: 1313-1319.
10. Stohs SJ, Preuss HG, Shara M. A review of the receptor-binding properties of p-synephrine as related to its pharmacological effects. Oxid Med Cell Long 2011; doi:10.1155/2011/482873.
11. Stohs SJ, Preuss HG. Stereochemical and pharmacological differences between naturally occurring p-synephrine and synthetic p-synephrine. J Funct Foods 2011; doi:10.1016/j.jff.2011.09.004.
12. McGuffin M. Media spins numbers on bitter orange AERs based on erroneous information from FDA. HerbalGram 2006; 69: 52-55.
13. Stohs SJ, Preuss HG. The Safety of bitter orange (Citrus aurantium) and its primary protoalkaloid ^-synephrine. HerbalGram 2011; 89: 34-39.
14. Stohs SJ, Preuss HG, Shara M. The safety of Citrus aurantium (bitter orange) and its primary protoalkaloid p-synephrine. Phytother Res 2011; doi: 10.1002/ptr.3490.
15. 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 overweight healthy adults. Curr Therap Res 1999; 60: 145-153.
16. Dulloo AG, Duret C, Rohrer D, et al. Efficacy of a green tea extract rich in catechin polyphenols and caffeine in increasing 24-h energy expenditure and fat oxidation in humans. Amer J ClinNutr 1999; 70: 1040-1045.
17. [Internet] Kendall-Reed P. Study on the effectiveness of Ultra Slim Down® for the reduction of body weight. Unpublished report. 2000. http://www.nutratechinc.com/advz/advz.php?p=2.
18. Kalman DS, Oxford S, Schwartz HI, Krieger DR. A double blind clinical evaluation of the metabolic effects of Xenadrine EFX™ compared to two ephedra-containing products in normal healthy volunteers. Presented at the annual meeting of the American College of Nutrition, Abstract No. 101. J Amer Coll Nutr 2002; 21: 488.
19. [Internet] Kalman DS, Rubin S, Martinez T, Schwartz HI. Efficacy of a commercial green tea extract/caffeine based product to increase basal metabolism in healthy adults. Presented at a meeting of NIH-National Institute of Diabetes and Digestive and Kidney Diseases. Unpublished report. 2002. http://www.nutratechinc.com/advz/advz.php?p=2.
20. [Internet] Kalman DS, Rubin S, Schwartz HI. An acute clinical trial to evaluate the safety and efficacy of a popular commercial weight loss supplement when used with exercise. Presented at Federation of American Societies of Experimental Biology. Unpublished report. 2003. http://www.nutratechinc.com/advz/Studies2011/Efficacy/E11%20Kalman%202003.pdf.
21. Kalman DS, Colker CM, Shi Q, Swain MA. Effects of a weight-loss aid in healthy overweight adults: double-blind, placebo-controlled clinical study. Curr Ther Res 2000; 61: 199-205.
22. Kalman DS, Incledon T, Gaunaurd I, et al. An acute clinical trial evaluating the cardiovascular effects of an herbal ephedra-caffeine weight loss product in healthy overweight adults. Int J Obes 2002; 26: 1363-1366.
23. Kalman DS. Comment on: An acute clinical trial evaluating the cardiovascular effects of an herbal ephedra-caffeine weight loss product in healthy overweight adults. Int J Obes Relat metab Disord 2004; 28: 1355-1356.
24. Gurley BJ, Gardner SF, Hubbard MA, et al. In vivo assessment of botanical supplementation on human cytochrome P450 phenotypes: Citrus aurantium, Echinacea purpurea, milk thistle, and saw palmetto. Clin Pharmacol Therap 2004; 76: 428-440.
25. [Internet] Zenk JL, Kuskowski MA. A prospective, randomized, double blind study to evaluate the effect of Lean Source™ on body composition in overweight adult men and women. Unpublished report. 2005. http://www.nutratechinc.com/advz/advz.php?p=2.
26. Zenk JL, Leikam SA, Kassen LJ, Kuskowski MA. Effect of Lean System 7 on metabolic rate and body composition. Nutrition 2005; 21: 179-185.
27. 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.
28. Haller CA, Benowitz N, Peyton J III. Hemodynamic effects of ephedra-free weight loss supplements in humans. Amer J Med 2005; 118: 998-1003.
29. Bui LT, Nguyen DT, Ambrose PJ. Blood pressure and heart rate affects following a single dose of bitter orange. Ann Pharmacodyn 2006; 40: 53-57.
30. 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.
31. Gougeon R, Harrigan K, Tremblay JF, et al. Increase in the thermic effect of food in women by adrenergic amines extracted from Citrus aurantium. Obesity Res 2006; 13: 1187-1194.
32. Hoffman JR, Kang J, Ratamess A, et al. Thermogenic effect from nutritionally enriched coffee consumption. J Int Soc Sports Nutr 2006; 3: 35-41.
33. [Internet] Talbott SM, Christopulos AM, Richards E. Citrus aurantium extract has no effect on blood pressure or heart rate in healthy adults. Unpublished report 2007. www.nutratechinc.com/adz/UploadFile/Talbott%2020907.pdf.
34. Haller CA, Duan M, Peyton J III, Benowitz N. Human pharmacology of a performance-enhancing dietary supplement under resting and exercise conditions. Brit J Clin Pharmacol 2008; 65: 833-840.
35. Seifert JG, Nelson A, Devonish J, et al. Effect of acute administration of an herbal preparation on blood pressure and heart rate in humans. International J Med Sci 2011; 8: 192-197.
36. Stohs SJ, Preuss HG, Keith SC, et al. Effects of p-synephrine alone and in combination with selected bioflavonoids on resting metabolism, blood pressure, heart rate and self-reported mood changes. Int J Med Sci 2011; 8: 295-301.
37. Shara M, Stohs SJ. Safety evaluation of bitter orange extract (p-synephrine) in healthy volunteers. Presented at the annual meeting of the American College of Nutrition. Abstract No. 16. J Amer Coll Nutr 2012; 30: 358.
38. Bloomer RJ, Canale RE, Blankenship MM, et al. Effects of the dietary supplement Meltdown on catecholamine secretion, markers of lipolysis, and metabolic rate in men and women: a randomized, placebo controlled, cross-over study. Lipids Health Disease 2009; 8: 32-40.
39. Bloomer R, Fisher-Wellman KH, Hammond KG, et al. Dietary supplement increases plasma norepinephrine, lipolysis, and metabolic rate in resistance trained men. J Int Soc Sports Nutr 2009; 6: 6-12.
40. Hoffman JR, Kang J, Ratamess NA et al. Thermogenic effect of an acute ingestion of a weight loss supplement. J Int Soc Sports Nutr 2009; 6: 1-5.
41. Stohs SJ. Assessment of the adverse event reports associated with Citrus aurantium (bitter orange) from April 2004 to October 2009. J Funct Foods 2010; 2: 235-238.
42. Dragull K, Breksa AP, Cain B. Synephrine content of juice from Satsuma mandarins (Citrus unshiu Marcovitch). J Agric Food Chem 2008; 56: 8874-8878.
43. Uckoo RM, Jayaprakasha GK, Nelson DS, Pati BS. Rapid simultaneous determinations of amines and organic acids in citrus using high-performance liquid chromatography. Talanta 2010; 83: 948-954.
44. Karch SB. Peer review and the process of publishing of adverse drug event reports. J Forensic Legal Med 2007; 14: 79-84.
45. Hengtmann JH, Aulepp H. Pharmacokinetics and metabolism of synephrinc. Arzneimittel Forschung 1978; 28: 2326-2331.
46. Hansen DK, George NI, White GE, et al. Physiological effects following administration of Citrus aurantium for 28 days in rats. Toxicol Appl Pharmacol 2012; doi: 10.1016/j.tap.2012.04.006.
47. Reagan-Shaw S, Nihal M, Ahmed N. Dose translation from animal to human studies revisited. FASEB J 2008; 22: 659-661.
48. Rozec B, Gauther C. β3-Adrenoreceptors in the cardiovascular system: Putative roles in human pathologies. Pharmacol Therap 2006; 111: 652-673
49. Moens AL, Yang R, Watts V, Barouch LA. Beta 3-adrenoreceptor regulation of nitric oxide in the cardiovascular system. J Molec Cell Cardiol 2010; 48: 1088-1095.
50. Yang A, Palmer AA, DeWit H. Genetics of caffeine consumption and responses to caffeine. Psychopharmacol 2010; 211: 245-257.
51. Riksen NP, Smits P, Rongen GA. The cardiovascular effects of methylxanthines. Handbook Exper Pharmacol 2011; 200: 413-437.
52. Avula B, Upparapalli SK, Navarrete A, Khan IA. Simultaneous quantification of adrenergic amines and flavonoids in C. aurantium, various Citrus species, and dietary supplements by liquid chromatography. J AOAC Int 2005; 88: 1592-1606.
53. Slezak T, Francis PS, Anastos N, Barnett NW. Determination of synephrine in weight-loss products using high performance liquid chromatography with acidic potassium permanganate chemiluminescence detection. Anal Chim Acta 2007; 593: 98-102.
54. Evans LE, Siitonen PH. Determination of caffeine and sympathomimetic alkaloids in weight loss supplements by high-performance liquid chromatography. J Chromatog Sci 2008; 46: 61-67.53.
55. Mercolini L, Mandrioli R, et al. Fast CE analysis of adrenergic amines in different parts of Citrus aurantium fruit and dietary supplements. J Sep Sci 2010; 33: 1-8.
56. Percy DW, Adcock JL, Conlan XA et al. Determination of Citrus au- rantium protoalkaloids using HPLC with potassium permanganate chemiluminescence detection. Talanta 2010; 80: 2191-2195.