In 2000, an estimated 30.5 percent of adults were obese (i.e., had a body mass index [BMI] greater than 30 kg per [m.sup.2]) (1) and 15.5 percent of adolescents were overweight (BMI of 25 to 30 kg per [m.sup.2]). (2) Given the medical and psychosocial impact of being overweight, as well as the difficulty in making sustained improvements in diet and physical activity, it is not surprising that patients often turn to over-the-counter (OTC) proprietary weight-loss products containing single or multiple dietary supplements (e.g., herbs, vitamins, minerals, amino acids).

A multi-state survey (3) in 1998 found that 7 percent of adults used OTC weight-loss supplements, with the greatest use noted among young obese women (28 percent). Retail sales of weight-loss supplements were estimated to be more than $1.3 billion in 2001. (4) Metabolife 356, an ephedra-containing combination supplement, was the top-selling diet supplement with $70 million in sales, representing a 127 percent increase from sales in 2000. (4)

Possible reasons that patients use dietary supplements for weight loss are summarized in Table 1. These supplements appeal to the desire for a "magic bullet" that is less demanding than special diets and increased physical activity. They are available without a prescription and often advertise remarkable benefits. Patients also may be attracted to them because they are marketed as "natural," which may be interpreted by some (albeit inaccurately) as an assurance of safety and efficacy.

To help identify patients using these supplements, physicians should ask their overweight and obese patients in a nonjudgmental manner questions such as, "Have you tried, or considered trying, special diets, exercise programs, diet pills, herbs, or vitamins for weight loss?" If the ingredients of a patient's weight-loss product are not evident, an Internet search can rapidly yield a product's Web site and its labeled components.

To counsel patients appropriately, physicians must be knowledgeable about the efficacy, safety, and quality of common weight-loss supplements. Given that supplement users also may be taking prescription medications, (3) the potential for drug/supplement interactions should be considered. Because of the Dietary Supplement Health and Education Act of 1994, manufacturers are not required to provide the U.S. Food and Drug Administration (FDA) with proof of safety and efficacy before marketing supplements. Furthermore, adoption of good manufacturing practices by supplement makers is not currently mandatory. Therefore, product quality (e.g., absence of contamination, accuracy of labeling) is variable and uncertain.

More than 50 individual dietary supplements and 125 proprietary products are listed in the Natural Medicines Comprehensive Database as commonly being used for weight loss. (5) Individual supplements found in at least five commercial products (Table 25,6) are discussed in this review, according to their purported mechanism of action. Of note, approximately one half of the most common individual supplements used in weight-loss products listed in Table 2 have not been studied in randomized controlled trials (RCTs) in humans.

Supplements Purported to Increase Energy Expenditure

EPHEDRA ALKALOIDS AND CAFFEINE COMPOUNDS

Ephedra sinica (or Ma huang in Chinese) is a shrub native to China and Mongolia that contains sympathomimetic compounds referred to as ephedra alkaloids. Bitter orange and country mallow contain related chemicals. Ephedra alkaloids commonly are combined with caffeine or botanical sources of caffeine (e.g., guarana, yerba mate) for weight loss. (7) A recent meta-analysis (8) of RCTs showed a weight loss of 0.9 kg (2 lb) more per month for ephedra-containing supplements compared with placebo. However, no long-term data (i.e., greater than six months) on efficacy were available.

Using adverse event data from 50 trials of ephedra, a 2.2- to 3.6-fold increase in the odds of psychiatric, autonomic, cardiovascular, and gastrointestinal symptoms was estimated. (8) Another review (9) of adverse events possibly associated with ephedra use included 87 reports to the FDA MedWatch program between June 1997 and March 1999. These reports included episodes of hypertension, arrhythmias, myocardial infarction, stroke, and seizures. Ten events led to death and 13 yielded permanent disability. Of these 23 reports, nine occurred at recommended dosages of ephedra in persons without significant preexisting cardiovascular risk factors. (9)

Ephedra products comprised only 0.8 percent of all dietary supplement sales in 2001, yet they were responsible for 64 percent of all herb-related adverse events reported to U.S. Poison Control Centers during the same year. (10) Although ephedra-caffeine combinations may be effective for modest weight loss, safety issues motivated the FDA to ban their sale in April 2004. (11)

Supplements Purported to Modulate Carbohydrate Metabolism CHROMIUM AND GINSENG

Chromium deficiency is associated with hyperglycemia, hyperinsulinemia, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol. Chromium is thought to play a role in carbohydrate and lipid metabolism, potentially influencing weight and body composition. (12) However, data on healthy persons without diabetes do not support this theory, and data on patients with diabetes are inconclusive. (13)

Most weight-loss supplements use chromium picolinate in daily dosages of 200 to 400 mcg. The results of three RCTs (14-16) that studied the role of chromium in obesity did not show any differences in weight loss between the treatment and placebo groups. However, drawing conclusions from these studies is difficult because of their small size (n = 15 to 36). Although short-term trials using chromium picolinate did not report significant adverse effects, (17) there are theoretical concerns that this form of chromium could generate free-radical damage. (18) Rhabdomyolysis and renal failure, possibly related to ingestion of more than 1,000 mcg daily of chromium picolinate, have been reported. (19,20) Because of the lack of large, well-designed studies, the efficacy of chromium for weight loss and its long-term safety profile remain uncertain.

Although preliminary data suggest that ginseng (Panax ginseng) may improve glucose tolerance, (21) no RCTs in humans have shown greater weight loss with ginseng compared with placebo.

Supplements Purported to Increase Satiety

GLUCOMANNAN, PSYLLIUM, AND GUAR GUM Numerous weight-loss products contain sources of soluble fiber, which theoretically could absorb water within the gut, causing increased satiety and lower caloric intake. Fiber also may improve control of diabetes and hyperlipidemia, two common comorbidities in patients with obesity. Examples include guar gum (derived from the Indian cluster bean, Cyamopsis tetragonolobus), glucomannan (Amorphophallus konjac), and psyllium (derived from the seed husk of Plantago psyllium).

Although guar gum is relatively safe, a meta-analysis (22) of 11 RCTs of guar gum versus placebo for weight loss showed no benefit. Three RCTs (23-25) suggest that glucomannan in dosages of 3 to 4 g per day may be well tolerated and yield modest weight loss. However, these trials were small (n = 20 to 50) and had methodologic limitations. Although psyllium improved glucose and lipid parameters significantly more than placebo in 125 overweight patients with type 2 diabetes, there were no differences in weight loss. (26)

Supplements Purported to Increase Fat Oxidation or Reduce Fat Synthesis HYDROXYCITRIC ACID

Hydroxycitric acid (HCA) is derived from the Malabar tamarind tropical fruit (Garcinia cambogia) native to India. HCA has been found to inhibit mitochondrial citrate lyase, leading to decreased acetyl coenzyme A production and decreased fatty acid synthesis. 27 A 12-week RCT28 of mildly overweight women (n = 89; mean BMI of 28.6 kg per [m.sup.2]) reported a 1.3 kg (2 lb, 14 oz) greater weight loss in women who received 750 mg of HCA per day versus placebo. In contrast, an RCT29 comparing a different formulation of HCA at 1,500 mg per day and placebo in 135 men and women with a higher average BMI (31.2 kg per [m.sup.2]) showed no differences in BMI or adverse events. Although HCA appears to be well tolerated, the evidence for efficacy currently is contradictory.

CONJUGATED LINOLEIC ACID

Conjugated linoleic acid (CLA) refers to a family of trans-fatty acids that have been found to reduce fat deposition in obese mice, possibly through increased fat oxidation and decreased triglyceride uptake in adipose tissue. (30) A 12-week RCT (31) of 60 patients using 3.4 to 6.8 g per day of CLA reported no change in BMI. Persons taking CLA reported mild to moderate gastrointestinal symptoms. Currently, no human data support the efficacy of CLA in weightloss products.

GREEN TEA, LICORICE, PYRUVATE, VITAMIN B5, AND L-CARNITINE