Plant Profiler

Bitter orange (Citrus aurantium)


Synonyms / Common Names / Related Terms
Aurantii pericarpium, auraptene, bergamot aromatherapy oil, bergamot orange, bergapten, beta-daucosterol(XI), beta-sitosterol, bigaradier, chisil, Citri aurantii fructus (CAF), Citri grandis pericarpium (CGP), Citrus amara, Citrus aurantium, Citrus aurantium dulcis, Citrus aurantium extract (CAE), Citrus aurantium L., Citrus aurantium L. var. amara, Citrus aurantium sinensis (CAS), Citrus aurantium ssp bergamia, Citrus aurantium var. amara, Citrus aurantium var. dulcis (sweet orange), Citrus bigarradia, citrus essential oils (EOs), citrus extract, Citrus L. Rutaceae, citrus peel extract, Citrus silension (CS), Citrus vulgaris, Citrus xaurantium, corteza de, Cyathifera Y. Tanaka, Daidai, Fructus aurantii, Goutou orange, Goutou sour orange, green orange, hesperidin, Kijitsu, limonene, marmalade, marmin, m-synephrine, naranja amarga, naringin, N-methyltyramine, neohesperidin, neroli oil, nobiretin, non-volatile fraction, octopamine, oil of bergamot, oxedrine, oxypeucedanin, oxy-psoralen (5-[(6',7'-dihydroxy-3',7'-dimethyl-2-octenyl)], pericarps of Citrus grandis, phenylephrine, pomeranze, Poncirus trifoliate x C. aurantiumsour orange, Rutaceae (family), Seville orange, Shangzhou Zhiqiao, sour orange, sour orange flower, sour orange leaf, sweet orange, synephrine, tangeretin, volatile oil, Xiangcheng, Xiucheng, Zhiqino, Zhi Qiao, Zhi Shi.


Mechanism of Action

Pharmacology:

  • Constituents: Bitter orange extract comes from the Citrus aurantium plant. Citrus aurantium contains synephrine alkaloids and para-octopamine6,16,17 these molecules are usually cited on product labels as "active ingredients."
  • Flavonoids, including limonene, hesperidin, neohesperidin, naringin, and tangaretin, are present in bitter orange peel, flowers, and leaves.11 The flavonoid content of bitter orange is noted as being higher in the flowers than the leaves.18 Bitter orange also contains the furocoumarins bergapten and oxypeucedanin.15,13,14
  • Adrenergic effects: Similar to ephedra, Citrus aurantium contains alkaloids that may have adrenergic agonist effects, and is often incorporated into supplements claimed to aid in weight loss.7 These alkaloids are believed to primarily be alpha-adrenergic agonists, but may also have some beta-adrenergic agonist properties.
  • Para-synephrine, often referred to as simply synephrine, has been shown to be an alpha-adrenergic agonist19 that may also have beta-adrenergic properties8. Para-synephrine occurs naturally in the human body in small quantities and may act as a neurotransmitter.9 Para-synephrine is usually indicated under the name oxedrine. Oxedrine is thought to be the primary ingredient in Citrus aurantium that produces weight loss, although it has not been firmly established.
  • Antibacterial effects: Bitter orange preparations are reported to have a variety of antimicrobial properties. Based on laboratory study, bitter orange peel oil may have insecticidal activity.3
  • Anti-inflammatory effects: Bitter orange peel may have anti-inflammatory activity, which might be due to the flavonoids naringin and nobiletin.12 Nobiletin suppressed the interleukin 1 (IL-1) induced production of proMMP-9/progelatinase B in synovial cells and most effectively suppressed proMMP-9 production along with the decrease in its mRNA. Nobiletin also reduced IL-1 induced production of PGE2 in the synovial cells, but did not modify the synthesis of total protein.
  • Antitumor effects: Preliminary research indicates that bitter orange constituents auraptene, marmin, tangeretin, nobiretin, and a psoralen compound, might have antitumor effects.1
  • Antiviral effects: Two flavonoids of the bitter orange fruit, neohesperidin and hesperidin, are reported to have antiviral activity against rotavirus infection4
  • Cardiovascular effects: In animal models, bitter orange caused vasoconstriction and increased mean arterial pressure (MAP), but reduced portal pressure.2 Synephrine given intravenously in men increases systolic blood pressure, but did not increase diastolic blood pressure or heart rate.11
  • In a randomized, double-blind, placebo controlled trial, systolic blood pressure, diastolic blood pressure, and heart rate were higher for up to five hours after a single dose (900mg dietary supplement extract standardized to 6% synephrine) of bitter orange versus placebo in young, healthy adults.5 Systolic blood pressure increased from baseline after bitter orange, but not placebo, at all time periods. Systolic blood pressure after bitter orange was significantly increased versus placebo at hours 1-5 (p<0.0001); the peak difference was 7.3 ± 4.6mmHg at three hours after administration. Diastolic blood pressure decreased for all time periods after baseline for both bitter orange and placebo. This decrease in diastolic blood pressure appeared to be a systematic effect observed in both the bitter orange and placebo groups. However, the placebo group had a decrease of 2.3-5.7mmHg, while the bitter orange group had a smaller decrease of 0.9-2.0mmHg. Notwithstanding, diastolic blood pressure was significantly increased after administration of bitter orange versus placebo at hours four and five (p≤0.02). The peak difference in diastolic blood pressure between bitter orange and placebo was 2.6 ± 3.8mmHg at five hours after administration. Similar to systolic blood pressure, heart rate increased from baseline after bitter orange, but not placebo, for all time periods. Heart rate was significantly increased after bitter orange versus placebo for hours 2-5 (p<0.01).
  • Metabolic effects: Citrus aurantium has been shown to increase the thermic effect of food, especially in women, by adrenergic amines extracted from Citrus aurantium.20
  • Neurologic effects: Preliminary research suggests that synephrine might have antidepressant effects, possibly by promoting norepinephrine release.9,10

Pharmacodynamics/Kinetics:

  • With respect to administration, meta-synephrine is readily absorbed after oral administration.21 About 80% of oral doses are excreted in the urine within 24 hours. After single oral doses, peak plasma concentrations are typically reached in one to two hours. Plasma half-life is approximately two to three hours.

References

  1. Satoh, Y., Tashiro, S., Satoh, M., Fujimoto, Y., Xu, J. Y., and Ikekawa, T. [Studies on the bioactive constituents of Aurantii Fructus Immaturus]. Yakugaku Zasshi 1996;116(3):244-250. 8721353
  2. Huang, Y. T., Wang, G. F., Chen, C. F., Chen, C. C., Hong, C. Y., and Yang, M. C. Fructus aurantii reduced portal pressure in portal hypertensive rats. Life Sci 1995;57(22):2011-2020. 7475952
  3. Mwaiko, G. L. Citrus peel oil extracts as mosquito larvae insecticides. East Afr Med J 1992;69(4):223-226. 1644035
  4. Kim, D. H., Song, M. J., Bae, E. A., and Han, M. J. Inhibitory effect of herbal medicines on rotavirus infectivity. Biol Pharm Bull 2000;23(3):356-358. 10726895
  5. Bui, L. T., Nguyen, D. T., and Ambrose, P. J. Blood pressure and heart rate effects following a single dose of bitter orange. Ann Pharmacother 2006;40(1):53-57. 16317106
  6. Pellati, F., Benvenuti, S., Melegari, M., and Firenzuoli, F. Determination of adrenergic agonists from extracts and herbal products of Citrus aurantium L. var. amara by LC. J Pharm Biomed Anal 8-1-2002;29(6):1113-1119. 12110397
  7. Preuss, H. G., DiFerdinando, D., Bagchi, M., and Bagchi, D. Citrus aurantium as a thermogenic, weight-reduction replacement for ephedra: an overview. J Med 2002;33(1-4):247-264. 12939122
  8. Jordan, R., Midgley, J. M., Thonoor, C. M., and Williams, C. M. Beta-adrenergic activities of octopamine and synephrine stereoisomers on guinea-pig atria and trachea. J Pharm Pharmacol 1987;39:752-754. 2890747
  9. Kim, K. W., Kim, H. D., Jung, J. S., Woo, R. S., Kim, H. S., Suh, H. W., Kim, Y. H., and Song, D. K. Characterization of antidepressant-like effects of p-synephrine stereoisomers. Naunyn Schmiedebergs Arch Pharmacol 2001;364(1):21-26. 11485034
  10. Song, D. K., Suh, H. W., Jung, J. S., Wie, M. B., Son, K. H., and Kim, Y. H. Antidepressant-like effects of p-synephrine in mouse models of immobility tests. Neurosci Lett 8-23-1996;214(2-3):107-110. 8878095
  11. Fugh-Berman, A. and Myers, A. Citrus aurantium, an ingredient of dietary supplements marketed for weight loss: current status of clinical and basic research. Exp Biol Med (Maywood) 2004;229(8):698-704. 15337824
  12. Ishiwa, J., Sato, T., Mimaki, Y., Sashida, Y., Yano, M., and Ito, A. A citrus flavonoid, nobiletin, suppresses production and gene expression of matrix metalloproteinase 9/gelatinase B in rabbit synovial fibroblasts. J Rheumatol 2000;27(1):20-25. 10648013
  13. Malhotra, S., Bailey, D. G., Paine, M. F., and Watkins, P. B. Seville orange juice-felodipine interaction: comparison with dilute grapefruit juice and involvement of furocoumarins. Clin Pharmacol Ther 2001;69(1):14-23. 11180034
  14. Penzak, S. R., Acosta, E. P., Turner, M., Edwards, D. J., Hon, Y. Y., Desai, H. D., and Jann, M. W. Effect of Seville orange juice and grapefruit juice on indinavir pharmacokinetics. J Clin Pharmacol 2002;42(10):1165-1170. 12362932
  15. Naganuma, M., Hirose, S., Nakayama, Y., Nakajima, K., and Someya, T. A study of the phototoxicity of lemon oil. Arch Dermatol Res 1985;278(1):31-36. 4096528
  16. Blumenthal, M., Goldberg, A., and Brinckmann, J. Herbal Medicine Expanded Commission E Monographs. 2000;
  17. Hu, J. F. [Inhibitory effects of Phyllanthus emblica juice on formation of N-nitrosomorpholine in vitro and N-nitrosoproline in rat and human]. Zhonghua Yu Fang Yi Xue Za Zhi 1990;24(3):132-135. 2253517
  18. Carnat, A., Carnat, A. P., Fraisse, D., and Lamaison, J. L. [Standardization of the sour orange flower and leaf]. Ann Pharm Fr 1999;57(5):410-414. 10520514
  19. Brown, C. M., McGrath, J. C., Midgley, J. M., Muir, A. G., O'Brien, J. W., Thonoor, C. M., Williams, C. M., and Wilson, V. G. Activities of octopamine and synephrine stereoisomers on alpha-adrenoceptors. Br J Pharmacol 1988;93(2):417-429. 2833972
  20. Gougeon, R., Harrigan, K., Tremblay, J. F., Hedrei, P., Lamarche, M., and Morais, J. A. Increase in the thermic effect of food in women by adrenergic amines extracted from citrus aurantium. Obes Res 2005;13(7):1187-1194. 16076988
  21. Phenylephrine. 2004;(London, UK)




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