Supplements Commonly Used for Weight Loss: What's the Skinny?

By David Kiefer, MD, Dr. Kiefer recently completed a fellowship at the Program in Integrative Medicine, College of Medicine, University of Arizona in Tucson; he reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study.

There are many reasons why people consider trying to lose weight. It may be yet another attempt after the New Year as the energy to stick to a resolution is still fresh, or the upcoming beach vacation during the summer swimsuit season. Certainly, all of the press surrounding the rising obesity epidemic brings the issue to the forefront of discussions, from the medical clinic to people's homes.

The weight-loss plan may include fad diets, new exercise regimens, pharmaceutical interventions, surgery, or a myriad of dietary supplements, or a combination of all of the above, to achieve ideal body weight. With respect to weight-loss supplements, there are many claims of efficacy that may be difficult for consumers and health care practitioners to interpret. This evidence-based review will explore the research and proven efficacy for some of the most common products for sale on the shelves of pharmacies and health food and supplement stores.


The weight-loss supplement industry is huge. Sales for approximately 50 individual supplements and 125 combination products totaled over $1.3 billion in 2001.1 Some demographic groups may be more likely to purchase weight-loss products; for example, in 1999, almost one-third of young, obese women used over-the-counter supplements for weight loss.1 Until ephedra was banned, approximately 12 million people in the United States were using it.2

Weight-loss supplements are found in grocery stores, pharmacies, supplement shops, and health food stores. A recent survey of seven such establishments in the Seattle metropolitan area found six to 103 different products for sale over the counter for weight loss, with a mean of 46 products per store; health food stores stocked more weight-loss products, as did the health food stores and pharmacies with a section dedicated specifically to weight-loss products (unpublished data, study conducted by author). Some of the products that you or your patients may see for sale are listed in the Table. The rest of this article will review six of the most common supplements for weight loss, examining their mechanism of action, adverse effects, and evidence for efficacy.

Individual Supplement Mechanisms of Action and Clinical Evidence

Ephedra. Ephedra refers to a genus of plants that contains 40 different species.2 The ones that were most commonly used medicinally in the United States are from three Asian species (Ephedra sinica, E. intermedia, E. equisentina) that are particularly high in physiologically active alkaloids. These alkaloids (40-90% of which is ephedrine) act as alpha- and beta-adrenergic agonists, leading to bronchodilation, decongestion, vasopressant activity, and a variety of cardiovascular effects such as increased blood pressure and increased heart rate.2

Clinical trials have demonstrated approximately 1 kg/month of weight loss when ephedra or ephedrine is used in adequate doses,3 though such doses are associated with a two- to fourfold increase in the incidence of adverse effects, including such severe conditions as myocardial infarction and stroke.3-6

Despite some difficulty in establishing a direct cause-and-effect relationship between the documented adverse effects and ephedra use,3 and the safe use of ephedra in traditional Chinese medicine in low doses,7 the decision was made in 2004 by the FDA to ban the sale of ephedra products.

Bitter orange. Bitter, or sour, orange weight-loss products refer to extracts from the fruit or rind of Citrus aurantium, one of the many orange species. The active compounds in bitter orange are a family of adrenergic amines, including synephrine (with a structure similar to ephedrine) and octopamine (with a structure similar to norepinephrine);8 basic science supports a sympatho-mimetic effect of these compounds, with synephrine more specifically having an alpha-1-adrenergic effect.9 A beta-adrenergic effect of these compounds may cause some lipolysis, in animals more than humans, and with octopamine more than synephrine.8 Synephrine has very poor oral absorption that is improved significantly by coadministration with caffeine.9

One randomized, double-blind clinical trial in 23 individuals on an 1,800 calorie/d diet compared placebo to a combination product that contained 975 mg of bitter orange, 528 mg caffeine, and 900 mg of St. John's wort for six weeks.10 The study participants were able to exercise three times a week, and, after six weeks, lost 1.4 kg of weight and 2.9% of their body fat. There was no documented change in mood or cardiovascular parameters, but there were three dropouts who were not included in the final analysis on an intention-to-treat basis.

Adverse effects from bitter orange could be surmised from its phytochemical constituents. Animal research has shown a hypertensive effect of the adrenergic compounds in bitter orange, and some human trials show increased blood pressure from isolated synephrine (which may not occur from the complete bitter orange extract).8 Bitter orange, with 46.9 mg of synephrine, also led to an increased heart rate in 10 individuals.9 Compared to ephedrine, synephrine appears to be less lipophilic and less able to cross the blood-brain barrier, though there have still been isolated case reports of stroke, myocardial infarction, and exercise-induced syncope with synephrine; the myocardial infarction appeared to be the result of synephrine tablet abuse.8,9

Chitosan. Chitosan is a positively charged compound derived from chitin, which makes up the shells of crustaceans. The theory is that in the lumen of the intestine chitosan binds fat particles because they are negatively charged. Animal research has found decreases in cholesterol absorption, serum cholesterol, liver cholesterol, and atherosclerosis, but one human trial investigating the proposed mechanism of action demonstrated only a clinically negligible increase in fecal fat excretion in 15 men taking 4.5 g of chitosan daily for four days.11

With respect to weight loss in humans, there have been two meta-analyses. One review of 14 trials found a 1.7 kg weight loss with chitosan when compared to placebo, and decreases in serum cholesterol and systolic and diastolic blood pressure.12 The meta-analysis found a similar effect on fecal fat excretion and side effect profile for chitosan when compared to placebo. The authors commented on the poor quality of the research available for this meta-analysis, and a wide variance in research results. Another meta-analysis on the use of chitosan for 1-6 months also found a 1.7 kg weight loss when compared to placebo.13 The effective dose remains to be determined definitively, but one study using 1 g of chitosan twice daily failed to demonstrate any changes in body mass index or lipid parameters;14 the thought was that this study was probably under-dosed.

The primary adverse effects of chitosan are flatulence and constipation.15

Conjugated Linoleic Acid. Conjugated linoleic acid (CLA) is a collection of isomers of linoleic acid, one of the omega-6 fatty acids. CLA is created by mixing cis/trans isomers at several double-bond positions; some experts classify it, therefore, as a trans-fatty acid.16 There is approximately 200 mg of CLA (especially the cis9-trans11 form) naturally in our diet, primarily occurring in dairy and meat. In contrast, the dose for weight-loss purposes is generally 3-4 g daily.16 In animals, especially murine trials, there is convincing evidence that CLA supplementation leads to a variety of physiological effects such as inhibition of adipogenesis, loss of fat mass, increase in lean tissue mass, attenuation of fat cell differentiation, and overall weight loss, possibly through feeding aversion versus increased energy expenditure.16,17 Of note, approximately 130 g of CLA daily would have to be used in humans to match the amount used in some of these animal trials.

One review of 13 human clinical trials using 1-8 g daily of CLA for 4-13 weeks found no effect on lean body mass nor weight.16 However, one recent double-blind, randomized, controlled trial compared 3.4 g of CLA daily to placebo in 157 overweight, otherwise healthy adults for 24 months.18 For the 125 people who completed the trial, results showed a 1.5-2.4 kg decrease in body weight and a 6-8% decrease in body fat mass in the CLA group. No intention-to-treat analysis was done for the study dropouts.

Numerous adverse effects have been documented with the use of CLA, some of which could have been predicted from what is known regarding trans-fatty acids. Human trials have shown liver hypertrophy and insulin resistance16 and increased lipoprotein A.18 Further adverse effects surfaced with another randomized, controlled trial that compared 3.4 g of CLA (trans10-cis12 form) to placebo for 12 weeks in 60 men with metabolic syndrome.17 The results showed a 110% increase in CRP and a 578% increase in PGE2-alpha, measures of inflammation and lipid peroxidation, respectively.

Hoodia. Ethnobotanical research continues to add plants to our modern medical treatment repertoire. One plant early in the continuum from traditional medicine to basic science research to clinical trials is hoodia, a plant from southern Africa that is one of either two species (Hoodia gordonii or H. lugardii) in the milkweed family, Asclepediaceae. The sap from this cactus-like plant has the reputation in traditional medicine to curb appetite, leading researchers to consider its use in humans.19

A steroidal glycoside P57AS3 has been isolated from H. gordonii and tested in rats; for rats fed a low-calorie diet, P57AS3 seems to have a central nervous system effect, by inhibiting the decreases in hypothalamic ATP that normally occur with starvation.19 Though P57AS3 has a similar structure to cardiac glycosides, it appears to have a different mechanism, perhaps, as per the above study, acting centrally on hypothalamic control of nutrient sensing. Other research by pharmaceutical and supplement companies is alluded to on various web sites, but remains unpublished and inaccessible.

Green tea. Green tea (Camellia sinensis) is a common addition to weight-loss supplements. It is used for this purpose not only for its caffeine content (a cup of green tea may have 40-50 mg caffeine), but because of procyanidin flavonoid compounds, also called polyphenols, such as epigallocatechin gallate (EGCG). Caffeine is well known as a central nervous system stimulant and causes increases in systolic blood pressure, probably through adenosine inhibition. Also, as mentioned above, caffeine can enhance other sympathomimetics such as bitter orange, leading to some changes in cardiovascular parameters including increased diastolic blood pressure and increased heart rate.

Animal research shows that caffeine and the polyphenols may synergize to cause thermogenesis and weight loss through a combination of decreased food intake and decreased fat tissue accumulation; one biochemical mechanism that may be involved is polyphenolic inhibition of catechol-o-methyltransferase, an enzyme that degrades norepinephrine.20 Further research demonstrates the importance of the polyphenol component to possible weight-loss effects, as an injection of pure EGCG (the equivalent of 6-12 cups of tea daily for humans) in rats for one week led to reduced food intake, decreased body weight, and decreased cholesterol and triglyceride.21

A human clinical trial tested a green tea extract (50 mg caffeine, 90 mg EGCG), caffeine (50 mg), or placebo three times daily on the 24-hour energy expenditure in 10 healthy men.22 The green tea extract caused a 4% increase in energy expenditure, a decrease in respiratory quotient (used in calculations of basal metabolic rate), and a 40% decrease in urinary norepinephrine relative to placebo, with a fat oxidation contribution to energy expenditure of 41.5% (vs. 31.6% for placebo); the caffeine treatment did not have any significant effects. There was no change in urinary nitrogen excretion, which when combined with the above results, led the researchers to conclude that the green tea extract did not affect protein oxidation, but did increase fat oxidation and lower carbohydrate oxidation; they did not believe this to be the result of caffeine's effects alone.

Caffeine. Many weight-loss supplements contain either purified caffeine and/or plants that naturally contain caffeine and related compounds. Caffeine has been shown in human clinical trials on both healthy and overweight individuals to have a variety of effects that may contribute to weight loss, such as increasing thermogenesis and energy expenditure, and increasing oxygen consumption and serum free fatty acids, which could indicate enhanced lipolysis.23 There are numerous botanicals that are added to weight-loss supplements as a caffeine source. For example, guarana (Paullinia cupana and P. sorbilis) contains 3-5% caffeine by dry weight, compared to 1-2% for dry coffee beans.24 Other herbs that provide "hidden" caffeine include yerba mate (Ilex paraguariensis) and kola nut (Cola nitida). The side effects of excess caffeine intake, or even minimal caffeine intake in people not used to it, include tremor, insomnia, anxiety, and gastrointestinal upset.


Numerous supplements are being marketed for their weight-loss effects. For some of them, there are both basic science and clinical trial data that permit adequate risk-benefit analyses to be conducted. For others, such as hoodia, there is a paucity of published literature to guide clinical decision-making.

Ephedra is effective in weight loss (about 1 kg per month), but it is associated with unacceptable, though rare, side effects such as myocardial infarction and stroke. These side effects ultimately led the FDA to take ephedra products off the market.

Two supplements, chitosan and green tea, have some positive efficacy data. Meta-analyses show a 1.7 kg weight loss with chitosan but the dose used and time periods studied were variable; it appears that 1 g twice daily is not an adequate dose. Green tea has one small human trial exploring physiological effects of an extract that appears promising; there needs to be more clinical research focused on weight loss in humans.

Accumulating data suggest that bitter orange and CLA may be unsafe. Bitter orange contains synephrine, an adrenergic agonist, which may have some of the same adverse effects as ephedra, and CLA appears to increase inflammation and have adverse effects on the liver, as well as on insulin resistance.

Caffeine, primarily through an increase in energy expenditure, may contribute to weight loss, though this needs to be balanced against the well-known side effects associated with excessive caffeine intake.

There are still many unknowns about these and other weight-loss supplements, such as the clinical efficacy of hoodia, the exact mechanism of action of CLA or green tea and its polyphenols, and the best dosing for almost all of these products.


There is no substitute for a healthy diet and lifestyle that contains adequate amounts of activity to facilitate weight loss. For people looking for an extra edge, the medical literature provides some clues about weight-loss supplements but no firm answers at this point.

Avoid bitter orange and CLA, due to potentially serious side effects combined with unconvincing efficacy data. A green tea extract could be useful for weight loss, but more data are needed before a detailed recommendation can be made about whether the EGCG component or the caffeine, or both, is the most important part. A person not overly sensitive to caffeine could incorporate a green tea extract into their weight-loss program that notes percentage and amount of EGCG.

Chitosan seems to be reasonably safe and may have some effect. Until more data accumulate, chitosan can be used on a trial basis in doses of at least 2 g twice daily as adjunctive therapy for weight loss.


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