Physiological effects following administration of Citrus aurantium for 28 days in rats

Toxicol Appl Pharmacol. 2012 Jun 15;261(3):236-47. doi: 10.1016/j.taap.2012.04.006. Epub 2012 Apr 13.


Background: Since ephedra-containing dietary supplements were banned from the US market, manufacturers changed their formulations by eliminating ephedra and replacing with other botanicals, including Citrus aurantium, or bitter orange. Bitter orange contains, among other compounds, synephrine, a chemical that is chemically similar to ephedrine. Since ephedrine may have cardiovascular effects, the goal of this study was to investigate the cardiovascular effects of various doses of bitter orange extract and pure synephrine in rats.

Method: Female Sprague-Dawley rats were dosed daily by gavage for 28 days with synephrine from two different extracts. One extract contained 6% synephrine, and the other extract contained 95% synephrine. Doses were 10 or 50mg synephrine/kg body weight from each extract. Additionally, caffeine was added to these doses, since many dietary supplements also contain caffeine. Telemetry was utilized to monitor heart rate, blood pressure, body temperature and QT interval in all rats.

Results and conclusion: Synephrine, either as the bitter orange extract or as pure synephrine, increased heart rate and blood pressure. Animals treated with 95% synephrine showed minimal effects on heart rate and blood pressure; more significant effects were observed with the bitter orange extract suggesting that other components in the botanical can alter these physiological parameters. The increases in heart rate and blood pressure were more pronounced when caffeine was added. None of the treatments affected uncorrected QT interval in the absence of caffeine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blood Pressure / drug effects
  • Body Temperature / drug effects
  • Body Weight
  • Caffeine / pharmacology
  • Cardiovascular System / drug effects*
  • Central Nervous System Stimulants / pharmacology
  • Citrus / chemistry*
  • Citrus / toxicity*
  • Dose-Response Relationship, Drug
  • Electrocardiography / drug effects
  • Female
  • Heart Rate / drug effects
  • Plant Extracts / toxicity
  • Rats
  • Rats, Sprague-Dawley
  • Survival
  • Synephrine / toxicity
  • Telemetry
  • Time Factors
  • Vasoconstrictor Agents / toxicity


  • Central Nervous System Stimulants
  • Plant Extracts
  • Vasoconstrictor Agents
  • Caffeine
  • Synephrine