|Date: February 15, 2006||HC# 010361-298|
Re: Effects of Bitter Orange on Blood Pressure and Heart Rate
Bui L, Nguyen D, Ambrose P. Blood pressure and heart rate effects following a single dose of bitter orange. Ann Pharmacother. 2006;40(1):53-57.
Since the 2004 ban on ephedra by the Food and Drug Administration due to its association with myocardial infarctions, hypertension, strokes, and psychiatric problems, the number of ephedra-free herbal weight-loss products has increased.1,2 Bitter orange (Citrus x aurantium; also known as Zhi shi, and Seville orange) has been added as an ingredient in many "ephedra free" dietary supplements as a substitute for ephedra.3 The authors report on their study to assess the effects of a single dose of bitter orange on blood pressure and heart rate in healthy adults.
Bitter orange is usually derived from unripe dried fruits and fruit peels of C. aurantium. Bitter orange extract products available commercially in the United States usually contain 1.5% to 6% synephrine (usually as the isomer p-synephrine, not m-synephrine [aka neosynephrine).3 The authors report that sympathomimetic effects of synephrine may increase systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR).
The authors, from the University of California in San Francisco, conducted a prospective, randomized, double-blinded, placebo-controlled crossover trial between February and March 2005, consisting of 2 study days conducted 1 week apart. With flyers, they recruited 15 healthy subjects (10 males; 5 females) aged 22 to 29 years from pharmacy and graduate schools. Thirteen subjects completed both study days. To be included, the subjects had to have 3 BP readings of an SBP less than 140 mm Hg and DBP less than 90 mm Hg, and HR between 60 and 100 beats per minute before enrollment.
All subjects were randomized to receive either 2 capsules of Nature's Way Bitter Orange (Natures' Way, Springville, Utah), consisting of a total dose of 900 mg dietary supplement extract standardized to 6% synephrine, or 2 matching placebo capsules containing lactose (HUMCO, Texarkana, Texas). Subjects were then crossed over to receive the alternative treatment 1 week later. The subjects abstained from citrus-containing products for 3 days before each study day and throughout each 6-hour study period. They fasted for at least 10 hours overnight before each study day.
On both study days, 3 baseline BP and HR measurements were taken before the administration of bitter orange or placebo. About 1 hour after receiving bitter orange or placebo, the subjects ate a light breakfast. BP and HR were measured every hour for a total of 6 hours after administration.
To address the statistical importance of a bitter orange treatment effect in the experimental setting of a crossover, repeated-measure study design, a multivariable mixed model ANCOVA was performed using SAS statistical software (version 9.1, SAS Institute, Carey, N.C.).
Results revealed that SBP increased from baseline after bitter orange, but not placebo, at all time periods. SBP after bitter orange was significantly increased versus placebo at hours 1-5 (P < 0.0001); the peak difference was 7.3 ¡À 4.6 mm Hg. Although the baseline DPB was higher than after administration of both placebo and bitter orange, DBP after bitter orange was significantly increased versus placebo at hours 4 and 5 (P ¡Ü 0.02); the peak difference was 2.6 ¡À 3.8 mm Hg. HR was significantly increased after bitter orange versus placebo for hours 2-5 (P < 0.01); the peak difference was 4.2 ¡À 4.5 beats per minute.
The authors noted several limitations to their study: the subjects were young and healthy as opposed to actual consumers, who may be obese with comorbid conditions and seeking the potential weight-loss effects of bitter orange; and the study was not designed to evaluate the long-term potential for cardiovascular adverse effects of bitter orange. Finally, the purpose of the study was to assess the effects of a single dose of bitter orange alone without caffeine or St. John's wort (Hypericum perforatum); however, many consumers may use combination products currently marketed for weight loss that contain these other compounds.4
The authors conclude that caution may be warranted for those taking bitter orange supplements. However, this trial has produced a different result than a similar trial on the same bitter orange preparation which found that one dose did not increase in blood pressure or QT values as measured by EEG (electroencephalograph (see HerbClip # 010161-298).5
1Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. New England Journal of Medicine. 2000;343:1833-1838.
2Fugh-Berman A, Myers A. Citrus aurantium, an ingredient of dietary supplements marketed for weight loss: current status of clinical and basic research. Experimental Biology and Medicine. 2004;229:698-704.
3Bitter orange. Stockton, Calif.: Natural Medicines Comprehensive Database (copyright 1995-2000). Available at: www.naturaldatabase.com. Accessed Sept. 30, 2004.
4Colker 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. Current Therapeutic Research - Clinical and Experimental. 1999;60:145-153.
5. Min B, Cios D, Kluger J, White CM. Absence of QTc-interval¨Cprolonging or hemodynamic effects of a single dose of bitter-orange extract in healthy subjects. Pharmacotherapy. 2005;25(12):1719¨C1724.