Because thermogenesis and fat oxidation are to a large extent under the control of the SNS, approaches that mimic or interfere with the SNS and its neurotransmitter noradrenaline offer a rational approach for obesity management. Current interest in the nutrititional/nutraceutical arenas has focused on plant ingredients capable of enhancing the release of noradrena-
line from presynaptic neurons (ephedrine), prolonging the half-life of noradrenaline in the synaptic cleft (catechin polyphenols), potentiating the actions of noradrenaline in postsynaptic cells (caffeine and other methyl-xanthines), or having adrenergic agonist activity (ephedrine, synephrine).
Caffeine (and other methylxanthines, abundant in coffee and teas) inhibits cAMP phosphodiesterases, thus prolonging the half-life of cAMP, which is a critical intracellular mediator for the lipolytic and thermogenic effects of catecholamines. Ephedrine, the principle alkaloid found in shrubs of plants of the genus Ephedra, and other Ephedra alkaloids, promote the release of noradrenaline from SNS terminals and possess adrenoceptor agonist activity, thus favoring thermogenesis, vasoconstriction and increased blood pressure; in addition, Ephedra alkaloids have amphetamine-like effects in the central nervous system, promoting appetite suppression, mood elevation and resistance to fatigue (reviewed in reference 162). Combinations of ephedrine and caffeine are marketed both as pure compounds in capsular form and as herbal preparations sold under the category of dietary supplements.
Ephedrine and Ephedra alkaloids, alone and especially when combined with caffeine or caffeine-containing herbs, have been repeatedly demonstrated to promote a modest but significant short-term weight loss (approximately 0.9 kg/month more than placebo, without caloric restriction) in human trials, as concluded in a recent meta-analysis.163 This meta-analysis also concluded, however, that the intake is associated with a 2.2- to 3.6-fold increase in the likelihood of psychiatric, autonomic or gastrointestinal symptoms, and heart palpitations.163 Some authors consider that the benefits of mixtures of ephedrine and caffeine in treating obesity may outweigh the associated risks, because side effects, when the products are used under controlled conditions, are usually mild and transient.164 1 65 However, individual susceptibility to adverse effects associated with the consumption of combinations of ephedrine and caffeine cannot be ignored; similarly, it is essential not to ignore the fact that the side effects may be particularly inappropriate for obese individuals, who often already have hypertension and other cardiovascular risk factors. Moreover, there have been case reports of serious adverse effects (such as death, myocardial infarction, hypertension and stroke) attributed to the consumption of ephedrine and Ephedra.162'166 Because of safety concerns, the US Food and Drug Administration (FDA) banned Ephedra and ephedrine-containing drugs and dietary supplements in April 2004.
Bitter orange (Citrus aurantium)
Following the withdrawal of ephedrine from the dietary supplement marketplace, sales of products containing Citrus aurantium (bitter orange or Seville orange) for weight loss are believed to have increased dramatically. Citrus aurantium contains a number of constituents speculated to lead to weight loss, of which the most frequently cited constituents are synephrine and octopamine, which are structural analogs of adrenaline and noradrena-line, respectively, that can act as adrenoceptor agonists.
An increase in the thermic effect of food in women by adrenergic amines extracted from Citrus aurantium has been described, but this acute response may not translate into a chronic effect or a clinically significant weight loss over time.167 Synephrine has lipolytic effects in human fat cells only at high doses, and octopamine does not have lipolytic effects in human adipocytes.168 The only randomized placebo-controlled clinical trial of Citrus aurantium for weight loss conducted so far tested a combination product with high levels of caffeine (in addition to energy restriction and physical exercise over 6 weeks) and did not find an effect superior to placebo on body weight loss; reduction of body fat mass was higher in the treated group, but this effect cannot be attributed to Citrus aurantium alone (see references 169 and 170). In addition, concerns have been raised about the safety of products containing synephrine, since this compound increases blood pressure in humans and other species, and has the potential to increase the incidence of adverse cardiovascular events (see references 169 and 170).
Catechin polyphenols inhibit the enzyme catechol-O-methyl-transferase, which normally degrades noradrenaline at the synaptic junctions. Catechin polyphenols are found in large quantities in non-fermented teas, which also contain caffeine, and considerable interest has focused on the potential use of these teas, green tea and oolong tea (or extracts of them), in assisting in weight management. Acutely, oral administration of green tea extract was shown to increase 24 h energy expenditure and fat oxidation in humans,171 and administration of green tea extract over 12 weeks, as part of a regular self-selected diet, was claimed to result in a 4.6% reduction of body weight and a 4.5% reduction of body circumference.172 The few studies examining the effects of oolong and green tea as a beverage did find modest effects on energy expenditure and fat oxidation, but were studies of very short duration.173174 Therefore, whether these slight increases in energy expenditure and fat oxidation persist over a long period, or are subject to dietary compensation to offset the slight energy imbalance, remains to be established. In addition, the quantity of tea (as a beverage) that must be consumed to obtain an effect has not been established, and may be disproportionately high.108 Thus, the potential of green tea and oolong tea as functional foods for weight management remains to be established.
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