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

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.

[1]  B. Rozec,et al.  beta3-adrenoceptors in the cardiovascular system: putative roles in human pathologies. , 2006, Pharmacology & therapeutics.

[2]  R. Gougeon,et al.  Increase in the thermic effect of food in women by adrenergic amines extracted from citrus aurantium. , 2005, Obesity research.

[3]  P. Smits,et al.  The cardiovascular effects of methylxanthines. , 2011, Handbook of experimental pharmacology.

[4]  M. Jann,et al.  Seville (sour) Orange Juice: Synephrine Content and Cardiovascular Effects in Normotensive Adults , 2001, Journal of clinical pharmacology.

[5]  Vera Marisa Costa,et al.  Synephrine: from trace concentrations to massive consumption in weight-loss. , 2011, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[6]  S. Benvenuti,et al.  Chromatographic and electrophoretic methods for the analysis of phenetylamine alkaloids in Citrus aurantium , 2007 .

[7]  S. Stohs,et al.  Effects of p-Synephrine alone and in Combination with Selected Bioflavonoids on Resting Metabolism, Blood Pressure, Heart Rate and Self-Reported Mood Changes , 2011, International journal of medical sciences.

[8]  P. Ambrose,et al.  Blood Pressure and Heart Rate Effects Following a Single Dose of Bitter Orange , 2006, The Annals of pharmacotherapy.

[9]  J. M. Midgley,et al.  β‐Adrenergic activities of octopamine and synephrine stereoisomers on guinea‐pig atria and trachea , 1987, The Journal of pharmacy and pharmacology.

[10]  Dangerous supplements: what you don't know about these 12 ingredients could hurt you. , 2010, Consumer reports.

[11]  B. Patil,et al.  Rapid simultaneous determination of amines and organic acids in citrus using high-performance liquid chromatography. , 2011, Talanta.

[12]  B. Cain,et al.  Synephrine content of juice from Satsuma mandarins (Citrus unshiu Marcovitch). , 2008, Journal of agricultural and food chemistry.

[13]  S. Stohs,et al.  A Review of the Receptor-Binding Properties of p-Synephrine as Related to Its Pharmacological Effects , 2011, Oxidative medicine and cellular longevity.

[14]  J. Neuhaus,et al.  Safety and efficacy of citrus aurantium for weight loss. , 2004, The American journal of cardiology.

[15]  S. Stohs.  Assessment of the adverse event reports associated with Citrus aurantium (bitter orange) from April 2004 to October 2009 , 2010 .

[16]  N. Benowitz,et al.  Human pharmacology of a performance-enhancing dietary supplement under resting and exercise conditions. , 2008, British journal of clinical pharmacology.

[17]  N. Benowitz,et al.  Hemodynamic effects of ephedra-free weight-loss supplements in humans. , 2005, The American journal of medicine.

[18]  M. Shara,et al.  A Review of the Safety and Efficacy of Citrus aurantium in Weight Management , 2007 .

[19]  S. Wise,et al.  Certification of standard reference materials containing bitter orange , 2008, Analytical and bioanalytical chemistry.

[20]  C. White,et al.  Absence of QTc‐Interval–Prolonging or Hemodynamic Effects of a Single Dose of Bitter‐Orange Extract in Healthy Subjects , 2005, Pharmacotherapy.

[21]  I. Khan,et al.  Simultaneous quantification of adrenergic amines and flavonoids in C. aurantium, various Citrus species, and dietary supplements by liquid chromatography. , 2005, Journal of AOAC International.

[22]  S. Benvenuti,et al.  High-performance liquid chromatography methods for the analysis of adrenergic amines and flavanones in Citrus aurantium L. var. amara. , 2004, Phytochemical analysis : PCA.

[23]  Scott Sawler.  Synephrine , Octopamine and Caffeine Health Risk Assessment ( HRA ) Report , 2011 .

[24]  I. Khan,et al.  Effects of synephrine and beta-phenethylamine on human alpha-adrenoceptor subtypes. , 2010, Planta medica.

[25]  Harriet de Wit,et al.  Genetics of caffeine consumption and responses to caffeine , 2010, Psychopharmacology.

[26]  M. Inchiosa.  Experience (Mostly Negative) with the Use of Sympathomimetic Agents for Weight Loss , 2010, Journal of obesity.

[27]  J. Arch.  β3-Adrenoceptor agonists: potential, pitfalls and progress , 2002 .

[28]  S. Stohs,et al.  A Review of the Human Clinical Studies Involving Citrus aurantium (Bitter Orange) Extract and its Primary Protoalkaloid p-Synephrine , 2012, International journal of medical sciences.

[29]  J. Hengstmann,et al.  [Pharmacokinetics and metabolism of 3H-synephrine (author's transl)]. , 1978, Arzneimittel-Forschung.

[30]  E. Burke,et al.  Effect of Acute Administration of an Herbal Preparation on Blood Pressure and Heart Rate in Humans , 2011, International journal of medical sciences.

[31]  J. McGrath,et al.  Activities of octopamine and synephrine stereoisomers on α‐adrenoceptors , 1988 .

[32]  D. Perez,et al.  The Unique Nature of the Serine Interactions for -Adrenergic Receptor Agonist Binding and Activation (*) , 1996, The Journal of Biological Chemistry.

[33]  S. Stohs,et al.  The Safety of Citrus aurantium (Bitter Orange) and its Primary Protoalkaloid p‐Synephrine , 2011, Phytotherapy research : PTR.

[34]  S. Stohs,et al.  A 60day double-blind, placebo-controlled safety study involving Citrus aurantium (bitter orange) extract. , 2013, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[35]  A. Fugh-Berman,et al.  Citrus aurantium, an Ingredient of Dietary Supplements Marketed for Weight Loss: Current Status of Clinical and Basic Research , 2004, Experimental biology and medicine.