Ephedra (Ephedra sinica, E. equisentina, E. intermedia)

Ephedra, also known as ma-huang, was widely sold as a dietary supplement for weight loss and to enhance athletic performance in the United States until February 2004. Before its introduction in the West, Asian populations had used ephedra as an herbal remedy for asthma, cough, headache, fever, allergies, and congestion for more than 5000 years. Ephedra is the common name for three principal species: Ephedra sinica, E. equisentina, and E. intermedia. Asian species of ephedra contain varying amounts of pharmacologically active ephedrine alkaloids, mainly ephedrine and pseudoephedrine, whereas North American species (commonly referred to as Mormon tea) contain small amounts or are devoid of these alkaloids.¹ Ephedrine was first isolated from ephedra in 1887 by Japanese chemist N. Nagai but did not gain popularity in the West until K.K. Chen and Carl F. Schmidt published a series of studies on the pharmacological properties of ephedrine in the 1920s.² Research has shown that ephedrine stimulates heart rate, resulting in increased cardiac output, while constricting peripheral blood vessels, which leads to increased peripheral resistance and blood pressure.³ Ephedrine relaxes bronchial smooth muscle, which explains its long history of use in the treatment of asthma.³

Bitter Orange (Citrus aurantium)

Citrus aurantium (also known as bitter, sour, or Seville orange) originated in China and seems to have entered the written record there by 300 BC. By about 100 BC, C. aurantium seeds appear to have reached Rome. The dried orange peel was traditionally used as a digestive tonic and flavoring agent. The German Commission E recognizes the use of dried C. aurantium peel for dyspeptic complaints and loss of appetite.⁹ Many companies are substituting C. aurantium for ephedra in their weight loss formulations as a result of the unfavorable publicity of ephedra in the media. The use of C. aurantium will likely grow now that the ephedra ban is in place. C. aurantium is made from the dried outer part of the pericarp of the ripe or nearly ripe fruit.¹⁰ It contains synephrine and octopamine, among other compounds, and has been reported in two studies to aid weight loss and in three to increase thermogenesis, at least to some extent.¹¹ Synephrine and octopamine are phenolamines found in sympathetic nerve fibers. Synephrine is similar to adrenaline, and octopamine is similar to noradrenaline (differing only in the number of hydroxyl groups on the aromatic ring).¹² Synephrine activates both α-adrenoreceptors and β₃-adrenoreceptors; both synephrine and octopamine inhibit production of cyclic adenosine monophosphate. β₃-Adrenoreceptor agonists are full lipolytic agents in rats, hamsters, and dogs but are less active in human beings.⁷

A double-blind, randomized, placebo-controlled, three-armed study of 23 subjects with BMIs of more than 25 kg/m² compared treatment, placebo, and no intervention as an adjunct to a 1800-calorie American Heart Association step I diet and a weight circuit training exercise program 3 days a week under the direction of an exercise physiologist.¹³ The treatment product tested contained a daily dosage of 975 mg of C. aurantium extract (6% synephrine alkaloids), 528 mg of caffeine, and 900 mg of St. John’s wort (3% hypericum) and was administered for 6 weeks. Outcome measures included weight, fat loss, and mood. Twenty subjects completed the study. Treated subjects lost a significant amount of weight (mean 1.4 kg) compared with the placebo group (mean 0.9 kg) and control group (mean 0.04 kg). However, the table in the article appears to indicate that the differences are significant compared with the baseline but not between groups. The amount of caffeine in this product is the rough equivalent of four cups of coffee or 10 cups of tea. The treatment group lost 2.9% body fat; no significant change was noted in the placebo and control groups. The researchers detected no significant changes in any group in a questionnaire profiling the subjects’ mood states or in blood lipid levels, blood pressure, heart rate, electrocardiographic findings, serum chemistry values, or urinalysis. The treated group demonstrated a significant increase in basal metabolic rate, whereas the placebo group showed a significant decrease in basal metabolic rate; no change was noted in the no-treatment group. No side effects were reported. (NOTE: Although the trial lists the St. John’s wort as containing 3% hypericum, it likely means the product was standardized to 0.3% hypericin. Assuming that the 3% hypericum reported in the study actually means 0.3% hypericin, the dose of St. John’s wort in this product would be a therapeutic antidepressant dose.)

Small amounts of synephrine occur naturally in many citrus products. Human populations consume Seville, or sour-orange, juice without adverse effects. A crossover open-label safety study in 12 normotensive subjects ranging from 20 to 27 years of age was conducted to evaluate the cardiovascular effects of two doses of C. aurantium juice (8 oz, 8 hours apart). The test was repeated with water a week later. Blood pressure was measured every hour for 5 hours after the second dose of juice; systolic and diastolic blood pressure, mean arterial pressure, and heart rate were not significantly altered. It was estimated that the subjects consumed 13 or 14 mg of synephrine, comparable to a dose of phenylephrine in a decongestant-containing cold preparation.¹⁴

Pharmacokinetic data and safety studies have not been published on the high potency of synephrine-containing products. Any sympathomimetic agent in sufficient amounts can increase thermogenesis and cannot be presumed to be safe, especially in individuals with cardiovascular disease. C. aurantium extract has caused cardiac disturbances in animals.¹⁴ Extracts available on the Internet contain between 4% and 50% synephrine, far greater than the amount that occurs naturally in the fruit and rind (0.25% to 2%). The extracts sold in weight loss products do not represent the traditional uses or doses of the crude herb. C. aurantium, known as zhishi or chih-shih in traditional Chinese medicine, has been used safely in the treatment of epigastric pain, constipation, and other digestive disorders for centuries. The safety accorded to crude preparations of bitter-orange peel cannot be extrapolated to weight loss products containing highly concentrated levels of adrenergic compounds.