Bitter orange concerns ‘unwarranted and unjustified’: Review

By Stephen Daniells

- Last updated on GMT

An 8 oz glass of Californian mandarin orange juice may contain up to 35 mg p-synephrine (USDA). A sweet orange typically contains about 6 mg p-synephrine
An 8 oz glass of Californian mandarin orange juice may contain up to 35 mg p-synephrine (USDA). A sweet orange typically contains about 6 mg p-synephrine

Related tags Bitter orange

Safety concerns and adverse events associated with bitter orange, and the p-synephrine compound it contains, are ‘unwarranted and unjustified’, according to a review of FDA’s reports.

Writing in the Journal of Functional Foods​, Sidney J. Stohs, dean emeritus of the Creighton University School of Pharmacy and Health Professions, presents a review of the 22 reports submitted to the Center for Food Safety and Applied Nutrition (CFSAN) of the US Food and Drug Administration (FDA). A total of 10 clinical cases reports were also published between 2004 and 2009 relating to products reportedly containing C. aurantium​ or p-synephrine, its predominant alkaloid.

“The conclusion that bitter orange and p-synephrine are responsible for adverse events presented in these reports is unwarranted and unjustified, based on the poly-herbal, poly-alkaloidal composition of the products involved, the numerous confounding factors present, the high probability of independent but concurrent events, the paucity of information provided in some cases, the major differences in pharmacokinetic and receptor binding properties between p-synephrine and phenylpropanolamine derivatives as ephedrine, and the widespread and uneventful use of bitter orange-containing fruit and juice products,”​ writes Professor Stohs.


Products reportedly containing bitter orange (Citrus aurantium)​ or p-synephrine, its predominant alkaloid, are typically positioned in the weight loss segment, and reports also suggest efficacy in the relief of heartburn, loss of appetite and nasal congestion as well as skin infections such as ringworm and athlete's foot.

The ingredient’s profile has increased since ephedra was banned by the US Food and Drug Administration (FDA) in 2004 as it contains similar compounds and has been favored by dietary supplements manufacturers as an ephedra substitute. It is most often consumed in pill-form but can also be applied to the skin.

However, in his review, Prof Stohs states: “The belief that p-synephrine exerts serious cardiovascular and other events continues to be believed by the lay public as well as healthcare professionals, in spite of the lack of clearly defined supportive evidence for this supposition, as well as extensive evidence to the contrary.”

“Furthermore, there is a broad lack of understanding regarding the structural differences between ephedrine and p-synephrine which result in markedly different receptor binding characteristics and therefore significant differences in pharmacological properties, particularly with respect to cardiovascular and central nervous system effects,”​ he added.

“As evidence of cardiovascular and intestinal effects, several of the reports cited studies with m-synephrine (phenylephrine, hydroxyl group in the meta position on the benzene ring) and pseudoephedrine which are not identical with p-synephrine (hydroxyl group in the para position on the benzene ring). Both m-synephrine and pseudoehedrine are used as nasal decongestants and both may increase heart rate and blood pressure,”​ stated the Nebraska-based scientist.

“A total of only 169 AERs have been reported to the FDA between 1969 and October 2009, and in all of these cases no evidence was provided directly linking BOE to the adverse event,”​ he added.


Commenting on the review, Steven Dentali, PhD, Chief Science Officer for the America Herbal Products Association (AHPA) said: “AHPA is pleased to see this critical review of FDA Adverse Event Reports (AERs) on bitter orange. Serious AERs should always be examined carefully. Standing alone, they show only that a product was somehow associated with a reported adverse event. Determining whether there is a causal connection between ingestion of a botanical ingredient and the reported adverse event requires much more.

"In this particular instance, Dr. Stohs, after careful review of the reports and current pharmacological understanding about bitter orange’s bioactive constituents, was not able to conclude that bitter orange extract was the cause of the adverse events reported to the FDA.”

Source: Journal of Functional Foods
Published online ahead of print, doi: 10.1016/j.jff.2010.10.003
“Assessment of the adverse event reports associated with Citrus aurantium (bitter orange) from April 2004 to October 2009”
Author: S.J. Stohs

This article has been updated from its original form to include the comment by Dr Dentali.

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Disclosure warranted?

Posted by Doug Kalman PhD, RD,

If advocare sells or ever sold Citrus Aurantium Sidney (IMO) should have disclosed his sitting on their board and if he receives any form on payment or benefit from sitting on their board). That type of disclosure helps with the naysayers and for transparency in growing the science and validity in the industry

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Posted by Stephen Daniells,

Hi Doug,
No disclosure or potential conflicts of interest were listed in the Journal article. According to Advocare, Prof Stohs is indeed a member of the company's Scientific & Medical Advisory Board. Many thanks for asking the question.

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Posted by Doug Kalman,

Does Professor Stohs still work with Advocare?

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