Review of Published Bitter Orange Extract and p-Synephrine Adverse Event Clinical Study Case Reports

Abstract

p-Synephrine is the primary active ingredient in bitter orange (Citrus aurantium) extract and is present in other citrus species. This review summarizes all known case reports that have been published regarding adverse events associated with multi-ingredient dietary supplements containing bitter orange extract. A common characteristic of all the case studies was the assumption that if bitter orange extract is listed on the label of the product it is the most likely cause of any adverse effect, although in no case was the presence of p-synephrine determined or a direct link demonstrated. No case study reviewed the existing published literature, and all failed to note that numerous clinical studies have not demonstrated adverse effects at commonly used doses. Most studies did not indicate the composition of the product involved, and no study analyzed the product in question. In no case was a direct correlation between the event and p-synephrine made. Although p-synephrine and ephedrine have some structural similarity, the structural differences result in markedly different pharmacokinetic, physiological, and pharmacological effects, and thus the effects produced by ephedrine cannot be extrapolated to p-synephrine.

Keywords:

• adverse event reports
• bitter orange extract
• case reports
• Citrus aurantium
• p-synephrine

Additional information

Notes on contributors

Sidney J. Stohs

Dr. Sidney J. Stohs is Dean Emeritus, School of Pharmacy and Health Professions, Creighton University Medical Center. He previously was a Professor in the College of Pharmacy and Eppley Cancer Institute at the University of Nebraska Medical Center. He also was the former Senior Vice President of Research and Development of AdvoCare International, a nutrition and wellness company. He received his PhD in Biochemistry from University of Wisconsin, BS in Pharmacy and MS in Pharmacognosy from the University of Nebraska. He conducted post-doctoral studies and research in the Department of Forensic Medicine at Karolinska Institute in Stockholm, Sweden, and the National Institute of Environmental Health, Research Triangle Park, NC, in nutrition, pharmacology and toxicology. He is a fellow of American College of Nutrition, the Association of Schools of Allied Health Professions, Academy of Toxicological Sciences, and the America Pharmacists Association, and a Certified Nutrition Specialist-Emeritus. He is the recent past President of the Board for Certification of Nutrition Specialists. He has authored more than 400 peer-reviewed articles. He is currently associated with Kitsto Consulting, LLC.

Sidhartha D. Ray

Dr. Sidhartha D. Ray is a Professor in the Department of Pharmaceutical and Biomedical Sciences, Touro College of Pharmacy and School of Osteopathic Medicine, Upper Manhattan, NY. He received his Ph.D. from the University of Indore, India (DAVV, Indore), and has conducted pharmacology/Toxicology research at Rutgers University, UC-Santa Cruz and Medical College of Virginia. He is known for his research on drug-induced cell death and anti-cancer/anti-toxic properties of phytochemicals/nutraceuticals., He received the Lifetime Award for Scholarly Achievement from Long Island University, two national awards from the Society of Toxicology, and an Outstanding Scholar of the Year award from Manchester University. He has over 120 peer-reviewed publications. He is the Editor-in-Chief of ‘Side Effects of Drugs-Annual’ (Elsevier), and serves on the editorial boards of several international journals.