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.
References
- 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.
- 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.