Hemodynamic and Electrocardiographic Effects of Bitter Orange Extract in Healthy Subjects

  • Bitter Orange (Citrus x aurantium)
  • Blood Pressure
  • Cardiovascular Activity
  • FasTrak
  • Date: February 15, 2006 HC# 010161-298

    Re: Hemodynamic and Electrocardiographic Effects of Bitter Orange Extract in Healthy Subjects

    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(12):1719-1724.

    This evaluation includes a study of the effects of an herbal ingredient on blood pressure and on the QT interval (the interval from the beginning of the QRS complex to the end of the T wave on an electrocardiogram that represents the time during which contraction of the cardiac ventricles occurs).

    Bitter orange (Citrus x aurantium) is a relatively popular herbal ingredient in weight-loss products. The popularity of bitter orange has increased in the past few years since previous weight-loss products containing the controversial herb ephedra (Ephedra sinica) were associated with adverse side effects and were banned by the Food and Drug Administration in 2004, although a federal judge in Utah has lifted the ban to the extent that dietary supplements containing a daily dose of up to 10 mg ephedrine alkaloids are now allowed (FDA is challenging this ruling in court).

    The authors appear to err regarding the chemistry of bitter orange and its extracts. They state that the "main constituent" in bitter orange is m-synephrine (a.k.a. phenylephrine or neosynephrine), an alkaloid which is an alpha1-selective adrenergic receptor agonist; however, most research that has been reviewed by the American Botanical Council has shown that the main alkaloid in bitter orange is p-synephrine, which, although it has the same chemical formula, is chemically different and thus has some different pharmacological activity than m-synephrine. The authors cite a previous study that showed that an ephedra-containing product (Metabolife 356®, Metabolife International, San Diego, CA), which also contains added caffeine, elevated the rate-corrected QT (QTc) interval.1 Therefore, the objective of this study was to evaluate the effect of bitter orange extract on hemodynamic (e.g., blood pressure) and electrocardiographic variables in healthy men and women.

    This randomized, double-blind, placebo-controlled crossover study was conducted at the University of Connecticut, Storrs campus. Eighteen healthy men (n = 9) and women (n = 9) aged 18 years or older were randomly assigned to receive 1 capsule (450 mg standardized to 27 mg m- or p-synephrine from bitter orange dried fruit extract) (Nature's Way, Springville, UT) or placebo in phase 1 of the study. During phase 2 of the study, after a 7-day washout period, the subjects received the treatment opposite of that received in phase 1. At least 12 hours before and during both phases of the study, the subjects abstained from herbal products, caffeine, and other stimulants. QTc intervals and systolic and diastolic blood pressure were measured immediately before the capsules were ingested (baseline) and then 1, 3, 5, and 8 hours after ingestion. All subjects were questioned about the experience of any adverse events.

    No significant differences in QTc intervals or blood pressure were observed between groups at baseline or after ingestion. QTc intervals during bitter orange extract and placebo ingestion were 402 plus/minus 29 and 403 plus/minus 24 msec, respectively (P = 0.653). Systolic blood pressure values during bitter orange extract and placebo ingestion were 114 plus/minus 10 and 115 plus/minus 8 mm Hg, respectively (P = 0.686). Diastolic blood pressure values during bitter orange extract and placebo ingestion were 68 plus/minus 9 and 68 plus/minus 8 mm hg, respectively (P = 0.879). No major adverse events were reported.

    A single dose of bitter orange extract had no significant effect on the hemodynamic and electrocardiographic variables measured. This result was not surprising given that the main active ingredient of bitter orange extract—p-synephrine—stimulates primarily the alpha1-adrenergic receptor. The results of previous studies have suggested that beta-adrenergic receptor stimulation causes prolonged ventricular polarization. The authors note, however, that the ingestion of greater amounts of bitter orange extract than used in this study and for a longer duration "may not have the same benign hemodynamic and electrocardiographic result" observed in the present study. The authors suggest additional studies to determine the safety of this herbal product when multiple doses are ingested.

    —Brenda Milot, ELS

    [Note: So far as the pharmacovigilance evidence shows, there appears to be few adverse effects reported on dietary supplement products containing bitter orange only. A guest editorial in HerbalGram 69 suggests that many of the adverse events classified by the FDA as pertaining to bitter orange are in fact related to adverse effects of dietary supplements containing ephedra plus bitter orange, or bitter orange and caffeine combinations, and that thus some of the media reports on bitter orange safety, using FDA data, are misleading and based on erroneous data.2 – Ed.]

    1. McBride BF, Karapanos AK, Krudys A, Kluger J, Coleman CI, White CM. Electrocardiographic and hemodynamic effects of a multicomponent dietary supplement containing ephedra and caffeine: a randomized controlled trial. JAMA 2004;291:216–221.
    2. McGuffin M. Media spins Numbers on Bitter Orange AERs Based on Erroneous Information from FDA Review Finds All But One "Report" Associated with Ephedrine or Caffeine. HerbalGram 2006; 69:52-55.

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