Cardiovascular Safety of Oral p-Synephrine (Bitter Orange) in Healthy Subjects: A Randomized Placebo-Controlled Cross-over Clinical Trial

Phytother Res. 2016 May;30(5):842-7. doi: 10.1002/ptr.5590. Epub 2016 Mar 7.


Bitter orange (Citrus aurantium) extract and its primary protoalkaloid p-synephrine are widely consumed in combination with multiple herbal ingredients for weight management and sports performance. p-Synephrine is also present in juices and foods derived from a variety of Citrus species. Questions exist regarding the safety of p-synephrine because of structural similarities with other biogenic amines. This study assessed the cardiovascular (stimulatory) effects of bitter orange extract (49-mg p-synephrine) given to 18 healthy subjects (nine men and nine women) in a double-blinded, placebo-controlled cross-over study. Heart rates, blood pressures, and electrocardiograms were determined at baseline, 30, 60, 90 min, 2, 4 , 6, and 8 h. Blood samples were drawn at baseline, 2 h and 8 h for serum chemistries, blood cell counts, and p-synephrine and caffeine levels. No significant changes occurred in electrocardiograms, heart rates, systolic blood pressure, blood chemistries, or blood cell counts at any time point in either control or p-synephrine treated group. A small (4.5 mmHg) decrease in diastolic blood pressure occurred in the p-synephrine treated group at 60 min. No adverse effects were reported. Caffeine ingestion varied markedly among the participants. p-Synephrine does not act as a stimulant at the dose used. Copyright © 2016 John Wiley & Sons, Ltd.

Keywords: Citrus aurantium; ECG; bitter orange; blood chemistry; blood pressure; heart rate; hemodynamic effects; p-synephrine.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Blood Pressure / drug effects*
  • Citrus / chemistry*
  • Cross-Over Studies
  • Double-Blind Method
  • Female
  • Healthy Volunteers
  • Heart Rate / drug effects*
  • Humans
  • Male
  • Plant Extracts / chemistry*
  • Plant Extracts / pharmacology
  • Prospective Studies
  • Synephrine / chemistry*
  • Synephrine / pharmacology
  • Young Adult


  • Plant Extracts
  • Synephrine