The most award winning
healthcare information source.
TRUSTED FOR FOUR DECADES.
May 2001; Volume 4; 52-55
By Michael D. Cirigliano, MD, FACP, and Philippe O. Szapary, MD
Obesity has been and continues to increase as a significant health problem in the United States. According to data from the National Health and Nutrition Examination Surveys (NHANES III), the prevalence of overweight individuals in the U.S. population has increased by 8% from 25% to 33% over the past 10 years.1 Given this epidemic, numerous attempts have been made to address this problem including fad diets, prescription medications, surgery, and behavior modification. Many obesity therapies have been found to be ineffective over the long term and in some cases have even led to harm.2 This has led many to look for "natural" diet aids thought to be safer and not having the same risks as surgery and/or pharmaceutical agents. These natural substances have included guarana, ephedra, chromium, carnitine, psyllium, chitosan, conjugated linolenic acid, DHEA, and dandelion to name a few. Garcinia cambogia has become one of the most popular and highly marketed natural products utilized for the treatment of obesity.Background: Overweight and Obesity
An estimated 97 million U.S. adults are overweight or obese, a condition that substantially raises their risk of morbidity from hypertension, dyslipidemia, type 2 diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, sleep apnea, and endometrial, breast, prostate, and colon cancers.3
Obesity is defined as having a body mass index (BMI) of ³ 30 kg/m2. Recent data indicate that the prevalence of obesity has increased from 12% in 1991 to 17.9% in 1998.4 Obesity is a multifactorial chronic disease that develops from an interaction of genetics and environment. In 1996, the Food and Drug Administration for the first time approved a medication, dexfenfluramine, for long-term treatment of obesity. However, in 1997, valvular heart disease appeared in a significant number of persons who took dexfenfluramine, the d-isomer of fenfluramine, especially in combination with phentermine.5 This experience has raised concern over the long-term use of any anti-obesity medications. Even newer and apparently safer medications, including sibutramine and orlistat, promise only modest weight loss. Because of their prescription status and high cost, these medications may have a minimal effect on the general population. The limited success and potential complications of these pharmacologic weight loss aids has led to a large and growing market for alternative therapies such as herbal products.6 Garcinia is one such agent that has been the subject of significant clinical interest and scientific study.Source and Identification
Garcinia is found and grown primarily in Southeast Asia. The dried and cured pericarp, or rind, of the fruit of this species contains up to 30% by weight of (-)-hydroxycitric acid (HCA)7 and is considered the active compound for weight loss. A member of the Clusiaceae family, it is also commonly known as brindle berry. Rinds of the fruit traditionally are used in regional cooking practices and are noted to make meals more filling.8 Historically, garcinia has been used for dysentery, as a purgative, and for treatment of worms and parasites, in addition to its use for weight loss.9 Garcinia has a sour taste and is used extensively as a "souring agent" in traditional Indian cuisine.
Mechanism of Action
Garcinia is believed to have a multifactorial effect on promoting weight loss. This is thought to occur through suppression of de novo fatty acid synthesis, increased lipid oxidation, and reduced food intake.10 The effect of enhanced satiety may account for the decrease in food consumption.6 Early satiety effects may be caused by inhibition of ATP citrate lyase, which limits the availability of acetyl coenzyme A (acetyl CoA) for lipid synthesis during carbohydrate feeding. Carbon then is diverted to glycogen synthesis. It is thought that glycogen levels serve as a primary signal for energy regulation.11 However, this concept is controversial.12
The anorectic effects of garcinia may be caused by reductions in acetyl CoA; malonyl CoA levels also are depressed reducing negative feedback on carnitine acyltransferase.13 This results in increased lipid transport into the mitochondria and inefficient oxidation with ketone body formation.6 Ketones are appetite suppressants. This mechanism also is controversial as an association between hunger levels and ketosis has not been observed.14 Some have also theorized an effect on the hypothalamic satiety center.Animal Studies
In one study, garcinia’s effects on the metabolic rate of mice was studied in a placebo-controlled trial.15 In this study, mice were placed into metabolic chambers and administered 10 mg of garcinia or water orally. Serum-free fatty acid levels were significantly higher 100 min after administration in the garcinia-treated group, but the respiratory exchange ratio was not different between the groups. The concentration of glycogen in the gastrocnemius muscle was higher in the treated group 16 hours after administration. Maximum swimming time until fatigue was slightly longer in the treatment group. Results suggested that chronic administration of garcinia promotes lipid oxidation and spares carbohydrate utilization in mice at rest and during running.
In another animal study, several animal models were used to observe changes in obesity with use of garcinia.16 In this study, the mature rat, the gold thioglucose-induced obese mouse, and the ventromedial hypothalamic lesioned obese rat had reduced food intake and body weight gain when given a chronic nontoxic dose of garcinia. Body composition analyses of mature rats treated with garcinia demonstrated a significant depression of body lipid levels and an unaltered body protein content. However, the authors did not find any statistically significant effects on weight gain, food intake, or body lipid or protein levels when compared to controls.
Another study examined the effects of administration of garcinia on the accumulation of lipid in the meal-fed rat by examining the rates of lipogenesis after acute and chronic treatment.17 Oral HCA administration significantly depressed the in vivo lipogenic rates in a dose-dependent manner in the liver, adipose tissue, and small intestine over an eight-hour period. Control animals demonstrated elevated rates of lipid synthesis. Rats receiving garcinia consumed less food than the untreated controls.Clinical Studies
A number of clinical trials have attempted to identify the safety and efficacy of garcinia for weight loss. Although there have been intriguing, scientifically sound animal studies and theoretical findings, studies in humans have been limited and results have been contradictory. Most studies showing a positive effect have been limited by small sample sizes, utilized combination products, lacked placebo control, and used inaccurate measures of body lipid change.18
In one placebo-controlled trial, the effect of garcinia on suppression of hunger was evaluated in 89 mildly overweight females.6 These subjects were prescribed 5,020-kJ diets for 12 weeks as part of a double-blind, placebo-controlled study. Forty-two participants ingested 400 mg caplets of garcinia 30-60 minutes prior to meals for a total dose of 2.4 g/d (1.2 g/d HCA). Forty-seven participants ingested matched placebos. Weight and body composition were assessed at baseline and every other week for 12 weeks. Food intake and appetitive variables were assessed at baseline and monthly for 12 weeks. Both groups lost weight with the treatment group achieving a significantly greater reduction (3.7 ± 3.1 kg vs. 2.4 ± 2.9 kg). Hunger and garcinia ingestion, however, were unrelated. The authors concluded that garcinia does not work through a satiety mechanism.
In the largest and most rigorously conducted trial, 135 overweight men and women subjects were randomized to receive either active herbal compound (1,500 mg/d HCA) or placebo, and both groups were prescribed a high-fiber, low-energy diet for 12 weeks.19 Body weight was evaluated every other week and fat mass was measured at weeks 0 and 12. Patients in both groups lost a significant amount of weight during the 12-week treatment period (P < 0.001); however, between-group weight loss differences were not statistically significant (mean SD, 3.2 ± 3.3 kg vs. 4.1 ± 3.9 kg; P = 0.14). There were no significant differences in estimated percentage of body fat mass loss between treatment groups. The fraction of subject weight loss as fat was not influenced by the treatment group. Garcinia failed to produce significant weight loss and fat mass loss beyond that observed with placebo.
This study and its conclusions have been criticized for a variety of reasons.20 It has been noted that for garcinia to be effective it must be coadministered with a simple carbohydrate-rich (lipogenic) diet. This study utilized a high-fiber diet with 20%, 50%, and 30% of energy as fat, carbohydrate, and protein, respectively. A high-fiber diet may, in fact, reduce gastrointestinal absorption of HCA. This is important because HCA must be present inside the target cell to inhibit the intracellular enzyme adenosine triphosphate (ATP)-citrate-lyase.
Additional criticisms have been made of the low-energy diet, which may have limited HCA’s conversion of citrate to acetyl-CoA by ATP-citrate-lyase.21 This conversion occurs only when the rate of glycolysis exceeds the body’s energy requirements. If the body’s energy needs are not met, the Krebs cycle converts carbohydrate calories into ATP for energy rather than citrate for fatty acid synthesis. This, therefore, would limit the ability of HCA to be effective.
In another clinical trial, 10 sedentary adult males aged 22-38 with BMIs of 22.4-37.6 kg/m2 were enrolled in a randomized, double-blind, placebo-controlled, crossover study involving three days of HCA (3 g/d) or placebo supplementation.22 Protocol A involved treatment and placebo arms with no exercise and Protocol B involved treatment and placebo arms with moderately intense exercise. Energy expenditure and respiratory quotient were measured for 150 minutes following overnight fast. Blood samples were collected for the determination of glucose, insulin, glucagons, lactate, and beta-hydroxybutyrate concentrations.
In a fasted state and following three days of HCA treatment, respiratory quotient was not significantly lowered during rest or during exercise when compared to placebo. Energy expenditure was not affected. Blood substrates measured were not different between treatment groups. The authors concluded that this study did not support the hypothesis that HCA alters the short-term rate of fat oxidation in the fasting state during rest or moderate exercise.Adverse Effects and Drug Interactions
No reported adverse effects or drug interactions have been reported in the literature. Given a lack of safety data, garcinia’s use during pregnancy and lactation is contraindicated.Formulation and Dosage
At least 14 over-the-counter garcinia products are available to consumers. Many preparations are combination products containing other agents including chromium, ephedra, guarana, and Iris versicolor. Typical dosages are 1,000 mg tid with extracts containing 50% HCA.23 Calcium, common in many HCA products, can further reduce solubility and also may hinder bioavailability.24
In many herbal weight loss preparations, combinations of herbal agents, such as guarana and ma huang, are utilized regularly. These have documented serious side effects, have the potential for exacerbating hypertension and arrhythmias, and have been shown to have minimal efficacy.Conclusion
The limited placebo-controlled, scientifically sound research assessing garcinia’s effectiveness as a weight loss agent fails to provide positive evidence. Fortunately, garcinia appears to be safe over the short term. However, randomized controlled trials in obese patients on high carbohydrate diets with larger doses of garcinia are needed to further assess the therapeutic potential of this ayurvedic herb.Recommendation
Based on the present data, the use of garcinia for weight loss cannot be recommended. It is important to advise patients to avoid combination products that might contain stimulants, such as ma huang and guarana, which have been associated with serious adverse cardiovascular outcomes. Patients should be referred to a medically sound weight management program for assistance with the skills needed to change eating and fitness habits.
Dr. Cirigliano and Dr. Szapary are Assistant Professors of Medicine at the University of Pennsylvania School of Medicine in Philadelphia.References
1. Kuczmarski RJ, et al. Increasing prevalence of overweight among US adults. The National Health and Nutrition Examination Surveys, 1960 to 1991. JAMA 1994;272:205-211.
2. Douketis JD, et al. Periodic health examination, 1999 update: 1. Detection, prevention and treatment of obesity. Canadian Task Force on Preventive Health Care. CMAJ 1999;160:513-525.
3. National Heart, Lung and Blood Institute. Clinical Guidelines on the Identification, Evaluation and Treatment of Overweight and Obesity in Adults-The Evidence Report. Bethesda, MD: National Institutes of Health; 1998. NIH Publication 98-4083.
4. Mokdad AH, et al. The spread of the obesity epidemic in the United States, 1991-1998. JAMA 1999;282: 1519-1522.
5. Connolly HM, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997; 337:581-588.
6. Mattes RD, Bormann L. Effects of (-)-hydroxycitric acid on appetitive variables. Physiol Behav 2000;71: 87-94.
7. Lewis YS, Neelakantan S. (-)-Hydroxycitric acid-the principal acid in the fruits of Garcinia cambogia. Desr Psytochem 1965;4:619-625.
8. Cloutre D, Rosenbaum ME. The Diet and Health Benefits of HCA. New Canaan, CT: Keats Publishing; 1994.
9. Jellin JM, et al. Pharmacist’s Letter/Prescriber’s Letter. Natural Medicines Comprehensive Database. Stockton, CA: Therapeutic Research Faculty; 1999:344.
10. McCarty MF. Promotion of hepatic lipid oxidation and gluconeogenesis as a strategy for appetite control. Med Hypotheses 1994;42: 215-225.
11. Monello LF, et al. Hunger and satiety sensations in men, women, boys and girls: A preliminary report. Ann NY Acad Sci 1965;131:593-602.
12. Stubbs RJ, et al. Carbohydrate balance and the regulation of day-to-day food intake in humans. Am J Clin Nutr 1993;57:897-903.
13. McCarty M, Majeed M. The pharmacology of citrin. In: Majeed M, et al, eds. Citrin. A Revolutionary, Herbal Approach to Weight Management. Burlingame, CA: New Editions Publishing; 1994:34-52.
14. Silverstone JT, et al. Hunger during total starvation. Lancet 1966;1:343-344.
15. Ishihara K, et al. Chronic (-)-hydroxycitrate administration spares carbohydrate utilization and promotes lipid oxidation during exercise in mice. J Nutr 2000; 130:2990-2995.
16. Sullivan AC, Triscari J. Metabolic regulation as a control for lipid disorders. Influence of (-)-hydroxycitrate on experimentally induced obesity in the rodent. Am J Clin Nutr 1977;30:767-776.
17. Sullivan AC, et al. Effect of (-)-hydroxycitrate upon the accumulation of lipid in the rat: I. Lipogenesis. Lipids 1973;9:121-128.
18. Conte AA. A non-prescription alternative on weight reduction therapy. Am J Bariatr Med 1993;17-19.
19. Heymsfield SB, et al. Garcinia cambogia (hydroxycitric acid) as a potential antiobesity agent. JAMA 1998;280:1596-1600.
20. Badmaev V, et al. Garcinia cambogia for weight loss [letter]. JAMA 1999;282:233-234.
21. Schaller JL. Garcinia cambogia for weight loss [letter]. JAMA 1999;282:234.
22. Kriketos AD, et al. (-)-Hydroxycitric acid does not affect energy expenditure and substrate oxidation in adult males in a post-absorptive state. Int J Obes Relat Metab Disord 1999;23:867-873.
23. Jellin JM, et al. Pharmacist’s Letter/Prescriber’s Letter. Natural Medicines Comprehensive Database. Stockton, CA: Therapeutic Research Faculty;1999:365.
24. Sawada H, et al. Effects of liquid garcinia extract and soluble garcinia powder on body weight change: A possible material for suppressing fat accumulation. Nihon Yukagaku Kaishi 1997;46:1467-1474.