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Bitter weight loss pill may be swallowed by regulatory net

The recent Food and Drug Administration ban on ephedrine and its sister alkaloids may blow dark clouds over other similar-acting natural bioactives. At the top of the list is synephrine, a phenolamine and sympathomimetic agent.

Synephrine is simply a ?monophenolic? version of ephedrine (a nonphenolic) by virtue of a hydroxyl group on the aromatic ring. Sympathomimetics, which include ephedrine, influence and mimic the actions of the sympathetic nervous system. Synephrine is found in abundance within certain species of the Citrus genus, especially C. aurantium (also known as bitter, Seville or sour orange); C. reticulata (mandarin orange); C. unshiu (Satsuma mandarin); and C. sinensis Cultivar Valencia (Valencia orange).1,2,3,4 Additionally, it is found in the unripe fruit of Tetradium ruticarpum (Evodia fruit).5

Because orange marmalade is made with C. aurantium, it, too, contains significant amounts of synephrine.4 Octopamine, bearing a prefix of ?eight? because of its initial isolation in the salivary glands of an octopus, is another sympathomimetic amine found in lesser amounts in C. aurantium, and in the juice and leaves of C. meyeri (Meyer lemon).1,6

Recent research suggests these phenolamines may indeed have biological relevance in humans, being found in plasma and inside blood platelets.7,8 Extracts of C. aurantium have been marketed for weight loss, purported to work in part by acting as a thermogenic agent.

One study orally delivered incremental doses of two commercially available C. aurantium extracts (claimed to contain 4 or 6 per cent synephrine) to adult male rats.9 Over the first seven days, significant dose-dependent drops in food intake and body weight were seen in the C. aurantium groups. No changes in blood pressure were noted but alterations in the electrocardiogram were observed. Notably, a dose-dependent pattern of death was also seen in these groups, with half of the group receiving the highest dose (20mg/kg body weight) of 6 per cent synephrine extract dying.

An acute human study had 12 subjects drink two servings of 240ml of Seville orange juice (analyzed to provide 12.9mg of synephrine per serving; no octopamine was detected), separated by eight hours, and two servings of water at a different time with a seven-day interval between beverages.10 The study was not designed for weight loss, and no difference in cardiovascular variables was seen.

To date there do not appear to be any published clinical studies showing a weight/fat loss-inducing effect of C. aurantium extracts. The only published full-length study that employed a C. aurantium extract in the absence of ephedrine alkaloids used a composition that also included caffeine and St. John?s wort (Hypericum perforatum) with 3 per cent hypericin.11 Twenty-three overweight subjects performed circuit-training exercise for 45 minutes, thrice weekly, and followed an 1,800-calorie diet. They were randomised to receive placebo capsules, an encapsulated product delivering a daily dose of 58.5mg synephrine (6 per cent C. aurantium extract), 528mg caffeine and 900mg of St. John?s wort, or nothing, for six weeks. The group receiving the synephrine-containing mixture did not show a statistically significant difference between groups in relation to weight loss but did in relation to per cent fatness (determined via bioelectric impedance).

Given the possible health risks of synephrine ingestion and the apparent lack of evidence-based benefits, this bioactive may also succumb to regulatory sanctions.

Anthony Almada is president and chief scientific officer of IMAGINutrition Inc.

1. Pellati F, et al. Determination of adrenergic agonists from extracts and herbal products of Citrus aurantium L. var. amara by LC. J Pharm Biomed Anal 2002;29:1113-9.
2. He X-G, et al. High-performance liquid chromatography?electrospray mass spectrometry in phytochemical analysis of sour orange (Citrus aurantium L.). J Chromatogr 1997;791:127-34.
3. Chen G, et al. Determination of hesperidin and synephrine in Pericarpium Citri Reticulatae by capillary electrophoresis with electrochemical detection. Anal Bioanal Chem 2002;373:169-73.
4. Kusu F, et al. Determination of synephrine enantiomers in food and conjugated synephrine in urine by high-performance liquid chromatography with electrochemical detection. Anal Biochem 1996;235:191-4.
5. Yu L-L, et al. Two 5-HT1A receptor-interactive tryptamine derivatives from the unripe fruit of Evodia rutaecarpa. J Nat Prod 1997;60:1196-8.
6. Stewart I and Wheaton TA. l-octopamine in citrus: isolation and identification. Science 1964;145:60-1.
7. Borowsky B, et al. Trace amines: identification of a family of mammalian G protein-coupled receptors. Proc Natl Acad Sci USA 2001;98:8966-71.
8. D?Andrea G, et al. HPLC electrochemical detection of trace amines in human plasma and platelets and expression of mRNA transcripts of trace amine receptors in circulating leukocytes. Neurosci Lett 2003;346:89-92.
9. Calapai G, et al. Antiobesity and cardiovascular toxic effects of Citrus aurantium in the rat: a preliminary report. Fitoterapia 1999;70:586-92.
10. Penzak SR, et al. Seville (sour) orange juice: synephrine content and cardiovascular effects in normotensive adults. J Clin Pharmacol 2001;41:1059-63.
11. Colker C, et al. Effect of Citrus aurantium extract, caffeine, and St. John?s wort on body fat loss, lipid levels and mood states in overweight healthy adults. Curr Ther Res 1999;60:145-53.

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