September 2004

AHPA challenges FDA and journal
allegations on bitter orange

The number of alleged adverse reactions from the herb bitter orange has been over-exaggerated, according to the American Herbal Products Association (AHPA), the trade organization for the herbal industry. And a recent report published in Experimental Biology and Medicine claiming that bitter organize dietary supplements pose a risk to consumers is wrong, according to AHPA.

INACCURATE FDA REPORTS
Three news stories in different media reported different numbers of adverse incidents of the herb, with information allegedly given by Food and Drug Administration (FDA) officials. AHPA said an April 11, 2004, New York Times article indicated 85 adverse reactions and 7 deaths; a July 5, 2004, Food Chemical News article pointed to 169 bitter orange AERs (July 5, 2004); and a July 19, 2004 Los Angeles Times, said 169 adverse incidents had been linked to bitter orange.

Following the publication of the first of these cited articles AHPA filed a Freedom of Information Act (FOIA) request with FDA to obtain copies of any AERs regarding dietary supplements containing bitter orange.

The FDA subsequently provided AHPA with 147 such reports, which the association analyzed to find:

• 52 of the 147 reports received from FDA were either apparent duplicates or did not provide any information to confirm that bitter orange was listed as an ingredient in the product;

• 70 of the received reports were associated with products that contained both bitter orange and ephedra. In its recent ban on ephedra the government branded any amount of ephedrine in a dietary supplement as presenting an unreasonable risk of illness or injury.

FDA has therefore already assigned ephedrine as the “associated” ingredient for each of these 70 cases and utilized that information as part of the basis on which it has banned ephedrine alkaloids from dietary supplements, but apparently now considers these cases to be “associated” with bitter orange.

• All but one of the remaining reports involved products that contained both bitter orange and a source of caffeine. Thus, only a single adverse event report, received more than five years ago, was associated with a product that contained bitter orange but did not contain either caffeine or ephedrine.

The case involved a 74-year-old woman who had taken three separate herbal formulas, one of which contained “immature bitter orange” as one of its six listed ingredients. The woman’s prior medical history included osteoarthritis, hypertension, and diabetes and she was taking five prescription drugs. Her adverse experience was recorded as: “Felt very unwell, weak,” and later “lower extremity swelling (2+ edema).”

AHPA President Michael McGuffin has contacted FDA to discuss the apparent misrepresentation of these reports by the agency. “It was apparent in my conversation with the agency that FDA officials knew that many of these reported adverse reactions were associated with products that also contained ephedrine alkaloids when they provided numbers to the media but did not consider it to be important to disclose that information. That information is material, and FDA’s failure to disclose it makes their unqualified statements misleading in the extreme.”

NOT A RISK
The association is also challenging the conclusions of a publication that warns bitter orange dietary supplements pose a risk to consumers. The study, “Citrus aurantium, an ingredient of dietary supplements marketed for weight loss: current status of clinical and basic research,” by Adriane Fugh-Berman and Adam Myers of Georgetown University, was published in the September 2004 issue of the journal Experimental Biology and Medicine.

“This review mistakenly implies that bitter orange supplements are likely to affect drug metabolism,” said Steven Dentali, PhD, AHPA vice president of scientific and technical affairs. “The authors cite references for this effect from bitter orange juice, which is not relevant to the plant parts used in dietary supplements. The fact is that while the juice may have this property, there is no reason to believe that bitter orange extracts, made from the dried fruit or peel, have any such effect. And in fact, one scientific study of 12 human volunteers taking a supplement containing bitter orange found no effect on drug metabolism.”(1)

The authors also discuss the potential effect of bitter orange on blood pressure. They report that synephrine, a constituent found in bitter orange, raises blood pressure in humans, but their evidence consisted only of one study where the pure chemical was administered by continuous intravenous infusion at the rate of 4 mg/minute.

“Research on intravenous administration of purified synephrine is not directly applicable to oral consumption of bitter orange extracts in dietary supplements,” added Dentali. “The authors do cite one study on the effect on blood pressure of a dietary supplement containing bitter orange, but this research found no effect on blood pressure after six weeks of use.”

A press release generated by Georgetown University blurred the distinction between synephrine and bitter orange extract and quoted one of the authors as stating, “C[itrus] aurantium has many of the same potential deleterious cardiovascular effects as ephedra,” in spite of the fact that there is no such conclusion in the article itself.

“There is one point on which we may all agree,” said Dentali, “and that is that more research on this herb would be welcome. But critical interdisciplinary thinking — espoused by these authors— should begin with consideration of the ingredient that consumers are actually taking.”

(1) Gurley et al. Assessment of Botanical Supplementation on Human Cytochrome P450 Phenotype: Citrus aurantium, Echinacea, Milk Thistle, Saw Palmetto. Clinical Pharmacology and Therapeutics 2004;75(2):P35.<!--[endif]-->

Source: American Herbal Products Association, http://www.ahpa.org

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