Dietary supplements combining bitter orange with herbal ingredients that include caffeine significantly increase blood pressure, a small study published in the September American Journal of Medicine finds.

"These findings indicate that reformulated weight-loss supplements have similar acute cardiovascular stimulant actions as banned ephedra products and could cause adverse health effects in some individuals," Christine Haller, MD, Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, et al., state.

While "results apply only for synephrine/caffeine products," these kind of ephedra-free supplements make up "the majority of the market products," Haller elaborates.

Bitter orange (Citrus aurantium) taken on its own, however, did not raise blood pressure, the authors report.

In fact, neither bitter orange - a botanical source of synephrine and octopamine - nor caffeine alone can account for the observed rise in both systolic and diastolic blood pressure, the researchers say, since caffeine has been shown to "modestly increase systolic but not diastolic blood pressure."

"Potentially," the cumulative rise in blood pressure is "related to the actions or interactions of other [non-caffeine] constituents in the multi-ingredient product," Haller et al. propose.

The results of the randomized, double-blind, placebo-controlled, three-arm crossover study were presented earlier this year at the American Society for Clinical Pharmacology & Therapeutics annual meeting (¹ Also see "ASCPT In Brief" - Pink Sheet, 7 March, 2005., p. 12).

The study included five male and five female healthy adult nonsmokers aged 18-49 years.

A minimum one-week washout period was instituted between three study visits in which participants received either placebo, three tablets of Nutratech's single-ingredient Advantra Z (46.9 mg synephrine) or two tablets of Cytodyne Technologies' multi-ingredient Xenadrine EFX (5.5 mg synephrine, 5.7 mg octopamine).

The administered dose of Xenadrine EFX purportedly included such ingredients as ginger root, yerba mate and green tea extract and contained almost 240 mg of caffeine.

Both supplements significantly increased heart rate. However, Advantra Z increased neither systolic nor diastolic blood pressure.

"Our study suggests that [bitter orange], when ingested alone in modest doses, is unlikely to have significant pharmacological activity," Haller et al. conclude.

"The finding that ingestion of Advantra Z, containing an eight-fold higher dose of synephrine than Xenadrine EFX, had no effect on blood pressure supports this hypothesis," researchers say. "Although the synephrine alone product did not raise BP, it did increase heart rate - so this merits further study too," Haller adds.

Xenadrine EFX increased both systolic and diastolic blood pressure a peak mean of more than 9 mm Hg. The maximal increase in blood pressure was observed two hours after participants ingested the supplement.

The authors discourage use of ephedra-free weight-loss dietary supplements in individuals with hypertension, heart disease and other pre-existing conditions that could be exacerbated by the cardiovascular-stimulating actions.

"Chronic dosing studies are needed to determine if the acute hemodynamic effects seen with Xenadrine EFX persist or diminish with repeated use," Haller et al. continue. Until such data are available, the researchers recommend physicians closely monitor patients taking bitter orange/caffeine weight loss supplements.

Haller et al. hope to conduct a chronic dose study in normal weight and overweight adults later this year. The researchers have institutional review board approval but are in need of funding.

The researchers also note that the efficacy of the weight-loss products was not evaluated in their study, adding, "as with any drug, a risk-benefit analysis is needed to determine if any potential advantage for weight loss outweighs the possible adverse effects of the product."

FDA's use of a risk-benefit analysis to support their ban of ephedra is defended by the agency in a recent brief appealing a Utah court decision that found risk-benefit analyses erroneously placed the burden of proof on supplement companies (² Also see "FDA Appeals Utah Ephedra Court Ruling, Defends Use Of Risk/Benefit Analysis" - Pink Sheet, 12 September, 2005., p. 10).

Bitter Orange/Caffeine Combinations Could Cause Adverse Events – Study

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