FWD 2 Botanical Adulterants Monitor: BAM20 - Science Update - US FDA Scientists Publish Results on Bitter Orange Peel
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Botanical Adulterants Monitor: Issue 20, September 2020

US FDA Scientists Publish Results of the Analysis of 59 Commercial Products Claiming to Contain Bitter Orange Peel or its Amines

Reviewed: Pawar RS, Sagi S, Leontyev D. Analysis of bitter orange dietary supplements for natural and synthetic phenethylamines by LC-MS/MS. Drug Test Anal. 2020. [epub ahead of print]

Keywords: Adulteration, bitter orange, Citrus x aurantium, synephrine, UHPLC-MS

Dietary supplements containing extracts of bitter orange (Citrus × aurantium, Rutaceae) peel have been popular in the weight management and sports nutrition categories. The benefits are believed to be due to the presence of phenethylamine derivatives, most prominently synephrine and N-methyltyramine.

Minor amines in bitter orange peel include hordenine, octopamine, and tyramine. Hordenine, N-methyltyramine, and octopamine are on US FDA’s Dietary Supplement Ingredient Advisory List,1 which is a compilation of ingredients that do not appear to be lawfully included as dietary ingredients in products marketed as dietary supplements according to the agency.

Fifty-nine commercial products (tablets, capsules, soft gels, or powders) were purchased online for the investigation. The products were selected based on their label claiming bitter orange fruit powder (n = 6), bitter orange extract (n = 33), or any bitter orange phenethylamine derivatives (e.g., para-synephrine, aka p-synephrine) as an ingredient (n = 15). Five claimed both, bitter orange extract and one or several of the phenethylamines. After extraction with 80% aqueous methanol containing 1% HCl and appropriate dilution, the samples were analyzed by a validated ultrahigh-performance liquid chromatography coupled to a triple quadrupole mass spectrometer (UHPLC-QqQ-MS). In addition to the naturally occurring phenethylamine derivatives, four synthetic amines (phenylephrine [syn: m-synephrine], methylsynephrine, etilefrine, and isopropyloctopamine) were also measured as part of the investigation.

All the 44 products claiming to have bitter orange peel, or bitter orange extract, contained p-synephrine, 42 contained N-methyltyramine, and 38 had measurable amounts of tyramine. Dietary supplements listing orange peel powder all contained between 90-96% p-synephrine (with respect to the total amine content), consistent with the naturally occurring ratio of p-synephrine and other phenethylamine derivatives. However, six products claiming to contain extracts had higher than expected contents of N-methyltyramine compared to p-synephrine. Out of the 23 products that listed synephrine concentrations on their label, eight contained less (0-77%) and ten more (122-306%) than the stated amount. The researchers also found methylsynephrine in six products, isopropyloctopamine in one dietary supplement, one product providing up to 240 mg methylsynephrine per day, and another delivering a daily dosage of 110 mg methylsynephrine and 76 mg isopropyloctopamine.

Comment: Dietary supplements sold for weight loss and in the sports nutrition category are known to be among those most frequently adulterated. Of particular concern is the illegal sale of undeclared conventional drugs inappropriately marketed as dietary supplements. Therefore, it is reasonable to expect that the US FDA would keep a close eye on products marketed in these two categories. Synephrine and other phenethylamines are known to have mild stimulant effects and to activate metabolism. However, when combined with other stimulants and strenuous exercise, high intake of phenethylamines is known to cause serious adverse effects.2

This investigation suggests that those dietary supplements that claim to be made from bitter orange peel without added pure compounds are generally authentic, although the contents in p-synephrine are highly variable and may not reflect the label contents. Purchasing “dietary supplements” that list synephrine, hordenine, octopamine, or any other phenethylamine as an ingredient are best avoided since they do not appear to be considered lawful by the FDA and have a high risk of containing synthetic adulterants. Manufacturers of bitter orange supplements should be aware of these risks and take the necessary steps to check for undeclared synthetic amines.


  1. FDA’s Dietary Supplement Ingredient Advisory List. College Park, MD: US Food and Drug Administration, Office of Dietary Supplement Programs. 2019. https://www.fda.gov/food/dietary-supplement-products-ingredients/dietary-supplement-ingredient-advisory-list. Accessed August 5, 2020.
  2. Blascheck W, Frohne D, Loew D. Aurantii amari epicarpium et mesocarpium. In: Blaschek W. (ed). Wichtl – Teedrogen und Phytopharmaka. 6th ed. Stuttgart, Germany: Wissenschaftliche Verlagsgesellschaft mbH; 2016:99-101.