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Hydroxycitrate [(-)hydroxycitric acid, HCA], is a popular component of over-the-counter weight-loss formulations, where it is marketed under the names Citrin (Sabinsa Corp.) and CitriMax (InterHealth Co.) and appears in products such as the No-Diet Diet , Bio-Max 3000, PhytriMax, Lite Bites , Garcinia Trim-Plus, Garcinia-Max Diet System, Citrilite, Citrichrome, Lipotrol, MicroSlim, Body Busters, and Super Prolean Mega Fat Burner. Hydroxycitrate is found in high concentrations in Garcinia cambogia (a plant from India), as well as two other plants of the genus Garcinia, and these plants are used for commercial preparations of the compound. Other names applied to these plants include "brindall berry" and "Malabar Tamarind" (though strictly the latter refers to a much different species).
The reputed effects of hydroxycitrate are based on its action as a potent inhibitor of the enzyme ATP citrate lyase (also known as citrate cleavage enzyme), which is required for the synthesis of fatty acids. The enzyme takes citrate, which has been exported from the mitochondria to the cytoplasm, and forms acetyl CoA and oxaloacetate from it. Coincidentally, this inhibitory effect was discovered in the laboratory of my Ph.D. mentor, Dr. John M. Lowenstein of Brandeis University . (Although my own research project did not involve hydroxycitrate, I can remember it being used in other ongoing studies in the Lowenstein laboratory while I was there in the 1970's.) Lowenstein has followed recent developments in the use of his discovery with great interest, and has shared his observations with me; some of his conclusions are presented in this article.
In the preparation of this article I am also indebted to Larry S. Hobbs, who devoted a chapter of his book The New Diet Pills (Pragmatic Press, 1994) to hydroxycitrate . Hobbs has corresponded extensively with the major researchers and promoters of hydroxycitrate, and has provided me with a considerable amount of information on the subject.
In mid-1995, I performed a search of the medical literature (Medline, National Library of Medicine) covering the period 1983 through May 1995, looking at the key words "hydroxycitrate," "hydroxycitric," "garcinia," and "cambogia." There were no articles found for "cambogia," and those obtained for "garcinia" all dealt with species other than cambogia and with compounds other than hydroxycitrate. References obtained for the keywords "hydroxycitrate" and "hydroxycitric" were nearly all to papers in which the compound was used as a research tool to manipulate metabolism in experimental animals or cell preparations. The only clinical study was a Russian-language article whose translated title was "Treatment of Patients with Food Toxinfection in Middle and Old Age." Thus, there were no studies in the regular medical literature documenting the usefulness of the compound for weight loss in humans.
Of the other papers identified in the search, two [3, 4] were review articles coauthored by Ann C. Sullivan of Hoffman-LaRoche, Inc., who was involved in many of the early animal studies. (Hoffman-LaRoche began studying the compound in the 1970's and held several related patents.) These articles, dealing with the general topic of appetite regulation by drugs and other compounds, summarized the results obtained with hydroxycitrate in animals (rats, mice, chickens). The authors proposed that hydroxycitrate acted primarily through its effects on the appetite, possibly involving increases in glycogen levels (see below).
The other two articles were published in the journal Medical Hypotheses. One of these  briefly discussed the animal studies and described the presence of HCA in fruits of Garcinia species. It also mentioned, with no documentation of methodology, the author's personal success in using the compound for weight loss (claimed to be "about one pound per day without any dieting" and accompanied by "sustained increase in energy"). The second of these  was a much longer article by Mark McCarty. He is vice-president of Nutrition 21, which manufactures chromium picolinate. The article reviewed theories of appetite control, as well as effects of hydroxycitrate and their possible mechanisms (see below). The author proposed that HCA might be combined with carnitine for a weight-loss program, the latter because of its alleged ability to promote fat oxidation - even though he acknowledged "a lack of clinical studies demonstrating its efficacy" in weight loss.
He further proposed that the addition of chromium picolinate to a hydroxycitrate/carnitine mixture would be even better. A review of this popular "health food" item is beyond the scope of this article, but a recent critical review  gave reasons to be skeptical of the value of chromium supplements. For one thing, it is difficult to determine whether anyone is chromium deficient, and people who aren't deficient will not benefit from supplements. Also, clinical results supporting the use of chromium in reducing fat have not been replicated. In November, 1996, the Federal Trade Commission announced consent agreements with Nutrition 21 and two other marketers of chromium picolinate. The companies had been charged with making unsupported claims about the benefits of chromium.
During final preparation of this article (December, 1996) I updated my literature search. The only new articles relevant to HCA supplements were three more by McCarty in Medical Hypotheses [8-10]. These develop further the ideas that HCA may be useful in promoting fat oxidation and gluconeogenesis (see below).
Possible Modes of Action
While the ability of hydroxycitrate to block ATP citrate lyase, and therefore fatty acid synthesis, has been established in experimental animals, this alone would not be expected to produce weight loss. First, calories consumed in one form (say, carbohydrates) would not simply disappear because they couldn't be converted to fat; they would be directed to other metabolic pathways (for example, storage as glycogen). Secondly, the major problem in obesity is not that too much fat is synthesized; rather, too much is consumed in the diet.
Nevertheless, studies with rats and mice indicate that hydroxycitrate decreases weight gain. (It should be noted that unlike the adult humans for whom the compound is being promoted, these animals continue to grow throughout their life spans. Thus, it was a decrease in weight gain, rather than a loss of weight, which was measured. This difference in growth patterns emphasizes the need for human studies to confirm the effectiveness of the compound.) The most likely mechanism for the decreased weight gain seems to be a decrease in appetite (and animals consuming the compound do eat less), but the mechanism by which hydroxycitrate produces such an effect is unclear. One suggestion is that hydroxycitrate would divert calories toward the synthesis of liver glycogen (a polymer of glucose). Animal studies support increased gluconeogenesis (synthesis of glucose from compounds such as lactate and amino acids) and glycogen synthesis in response to HCA. The resulting increased glycogen, or possibly glucose itself, might then be involved in the satiety signal. However, there is no general agreement on how appetite is controlled, and some experts in the field reject the idea that glycogen is involved. (Related to glycogen, it has been suggested  that the increased glycogen could help maintain blood sugar, leading to an increased feeling of "energy," "for those with glycogen storage problems." Since the synthesis and breakdown of glycogen, as well as other pathways controlling the level of blood glucose, are highly regulated processes, there would appear to be no advantage in this respect for normal individuals.)
A second suggested mode of action is that hydroxycitrate somehow increases thermogenesis (metabolism of fat or other compounds to produce heat rather than metabolic energy in the form of ATP). Normally, cells only consume fuels when needed to produce ATP; otherwise, the fuels are converted to stored energy in the form of fat or glycogen. However, in brown adipose tissue (brown fat), there is a type of fat consumption in which calories are converted to heat without producing ATP. I am unaware of any reason to think that hydroxycitrate would regulate this process. However, McCarty [6)]advances the thermogenesis hypothesis based on comparisons of reduced weight gain in experimental animals to the reduced food intake, which suggests that extra calories were being disposed of in some way.
McCarty also suggests that other metabolic effects could contribute to wasting of ATP, and therefore extra consumption of calories in the presence of hydroxycitrate. For example, gluconeogenesis consumes ATP energy, and if molecules are converted to glucose (and glycogen) rather than to fat, this would consume ATP. This seems unlikely to me. First, there is only a limited capacity for taking up extra carbohydrate in glycogen, so this would not produce much long-term effect on weight. Second, this pathway is also limited by the body's natural regulatory mechanisms; a rise in blood glucose would trigger release of insulin, and this in turn should inhibit gluconeogenesis. Third, converting the pyruvate to glucose would consume less ATP than converting it to fat (the process blocked by hydroxycitrate). (Clouatre and Rosenbaum  assert that the inhibition of ATP citrate lyase by HCA "uses up a significant amount of energy," but provide no rationale for this claim.)
It has also been suggested  that HCA, since it inhibits the formation of acetyl CoA in the cytoplasm, would also inhibit the formation of the next compound in the pathway of fatty acid synthesis, malonyl CoA. Malonyl CoA is in turn an inhibitor of the enzyme carnitine acyltransferase, which is needed for oxidation of fat. Therefore, reducing malonyl CoA formation with HCA might stimulate fat metabolism (along this same line of reasoning, provision of carnitine is also proposed to enhance fat metabolism, so that McCarty  advocates joint administration of HCA and carnitine). However, as noted above, cells normally only metabolize fuels when they need to produce energy, so if more calories in the form of fat are being consumed, fewer carbohydrate calories will be disposed of. The shift in the relative use of carbohydrate and fat would not by itself result in weight loss unless the resulting increased carbohydrate levels cause a decrease in appetite, as discussed above.
In reading McCarty's article (6), I noticed reference to one "controlled clinical study" of HCA by Anthony Conte, M.D. , published in The Bariatrician (cited by McCarty as "Am. J. Bariatric Med.") This is a specialty publication of professionals dealing with obesity and its associated diseases. Not only is this journal not part of the mainstream medical literature (otherwise it would have showed up in my Medline search), but the article was not a regular peer-reviewed research article. Rather, it appeared as a more informal item under the heading "How I Do It In My Bariatric Practice," a regular feature of the journal. The article describes a double-blind study of 50 obese volunteers, who took Lipodex-2 (containing hydroxycitrate and chromium) or a placebo, along with a special low-fat diet. In the 8-week study period the treatment group lost about three times as much weight as the control group.
Hobbs has criticized this study on several grounds. Among his points in Ref. 2 are:
In unpublished correspondence, Hobbs provided additional criticisms:
Additional points of my own are:
In defense of the Conte article, it does not purport to be a fully-detailed, regular research paper. Informal communications such as this article can be useful stimuli to further research. However, it is reasonable to ask for better doumentation of the methods and results, as well as replication by other investigators, before we can conclude that HCA is an effective agent in weight control.
In addition to Conte's study, Hobbs and Lowenstein informed me that other controlled clinical studies have been performed (but not published in full) or are in progress. Two of these have been presented in abstract form. In one , a study of 200 subjects, the treatment group received 1500 mg HCA daily, in addition to carnitine and chromium. These subjects lost twice as much weight as controls (all subjects had a low-fat diet and increased exercise). In the second , involving 60 subjects, the treatment group received 1320 mg HCA daily. Again, all subjects were on a low-fat diet with increased exercise, and the HCA group lost nearly twice as much weight.
In summary, while at least three investigators have obtained clinical data supporting the use of hydroxycitrate for weight control, their results have yet to be documented in regular peer-reviewed publications. It will be important that such studies document the long-term utility of the compound, since many dieters are successful in losing weight initially, only to regain the weight at a later time.
In addition to the question of whether hydroxycitrate is effective in weight loss, it is important to ask whether it is safe. Animal studies indicate that the compound is no more toxic than citric acid itself, which is present in many foods in addition to being a normal intracellular compound. Also, HCA is a component of a natural product which has long been used in Indian cooking, as well as for medicinal purposes. Thus, marketers of "health food" products using the natural form of the compound need not demonstrate its safety as would be the case for a new pharmaceutical. Nevertheless, it seems wise to ask for data showing that the compound is safe in humans when consumed at the levels being advocated for weight loss. Investigators performing the clinical studies discussed above have, of course, been monitoring their subjects for adverse side effects. But, as noted, none of these has yet to appear as a regular publication in the medical literature.
Promotional material for commercial preparations has pointed out some possible concerns. One booklet [11) suggests that since hydroxycitrate can inhibit production of cholesterol and consequently of steroid hormones, its use should be avoided in young children, as well as during pregnancy and lactation. Another booklet  points out that increased gluconeogenesis and ketone formation can be deleterious in diabetics (some obese individuals suffer from non-insulin-dependent diabetes), although it was thought that this would be outweighed by the benefits of the putative anti-obesity effects.
In general, promotional literature for weight-loss products containing hydroxycitrate suffers from two major flaws. First, statements are made concerning the effectiveness of the product even though these claims have not been established for humans; rather, they are based on animal or preliminary human studies. For example, we are told that HCA "inhibits fat production and forces the body to burn fat," helps "prevent excess calories from being synthesized into fat and cholesterol," "gives you more energy while lowering the appetite," "prevents the carbohydrate you consume...from being converted to fat," boosts "the rate the body burns calories and stores fat, and actually controls appetite cravings"; that "within 10-15 days you will begin to notice that you have more energy and that your appetite has decreased by 50%"; and that "HCA's effects last considerably longer than other diet aids."
Second, there is inadequate or misleading documentation. The materials often refer to scientific studies (with or without citations) without informing the consumer that these were almost entirely done with animals. An advertisement for Bio-Max 3000 refers extensively to the Conte study, saying it was "published in a prestigious American medical journal," while only in next paragraph noting that the study "may be preliminary."
Unlike some products being marketed in the area of "health foods" and diet remedies, hydroxycitrate has a respectable history of scientific investigation. Its use in weight loss is supported by animal studies, where it appears to act (by a mechanism which is not yet clear) by reducing food intake. Some preliminary data support the effectiveness of HCA in humans, but this has not yet been demonstrated in regular peer-reviewed publications. Dr. John Lowenstein, who pioneered the biochemical studies of the compound, feels that it may be useful in humans, but he is not convinced by the data presented to date. However, in a recent (December, 1996) phone conversation he noted that results of a new clinical trial should be forthcoming soon.
Despite the lack of solid data supporting the use of the compound, it is being heavily promoted in the "health food" industry, which does not convey the tentative nature of the scientific findings. Consumers should be wary of spending large amounts of money on this product until more conclusive results have been published.
In 1998, the Journal of the American Medical Association published athe results of a large randomized, controlled clinical trial in which 135 overweight men and women received either hydroxycitrate or placebo along with a high-fiber, low-energy diet (5040 kJ/day (1210 kcal/day), 20% as fat) . Hydroxycitrate was taken three times per day, 30 minutes before meals, for a total daily dose of 1500 mg. The subjects were followed for 12 weeks (compared to 4 to 8 weeks in previous studies). Both groups lost weight (4.1 +/- 3.9 kg (mean +/- S.D.) for placebo and 3.2 +/- 3.3 kg for HCA) (9.0 and 7.0 lb, respectively) and had a reduction in body fat mass (2.16 +/- 2.06% for placebo vs. 1.44 +/- 2.15% for HCA). While the mean losses were actually greater for placebo than for HCA, the differences between groups were not statistically significant at the P < 0.05 level. Using the observed distribution of weight changes, the authors estimated the power of their study. This analysis indicated an 89% probability of predicting differences as small as 2 kg (4.4 lb). Some earlier studies have reported benefits of about this size or greater.
In discussing possible reasons why HCA might not have been effective, the authors noted that they tested the compound under conditions in which the subjects were already losing weight. This was because they "intended to mimic diets commonly prescribed as a component of weight control programs." They went on to suggest "The possibility exists that the lipid synthesis-inhibiting properties of hydroxycitric acid may be more evident in subjects relapsing following a failed diet attempt, particularly if high-carbohydrate foods are ingested."
Consistent with the previous indications that HCA is relatively safe, there were no differences between treatment and control groups in reported adverse effects.
The authors also reviewed seven previous clinical trials of HCA, both published and unpublished. Concerning the studies described earlier in this article (12-14), they noted that Conte  had a small sample size and used HCA in combination with other potentially active agents, while Thom  had a small sample size and used an "inaccurate body composition method (near-infrared interactance)." The other four studies were also summarized:
Badmaev, V, and Majeed, M. (1995) "Open Field, Physician Controlled, Clinical Evaluation of Botanical Weight Loss Formula Citrin." Presented at: Nutracon 1995: Nutriceuticals, Dietary Supplements and Functional Foods; July 11-13; Las Vegas, Nev. This was an open label study of 77 subjects (55 completing the trial) in which 500 mg Garcinia cambogia extract (GCE) was given three times a day for eight weeks. About a 5% weight loss was observed. Limitations of the study include lack of blinding and controls; and use of another agent (chromium picolinate), as well as diet and exercise.
Ramos, R., Flores Saenz, J. and Alarcon, F. (1996), unpublished data. This was a randomized, double-blind, placebo-controlled trial of 40 obese subjects (35 completing the trial). GCE (500 mg) was given three times per day, along with a low fat diet, for eight weeks. The treatment group lost 4.1 +/- 1.8 kg (9.0 lb) vs. 1.3 +/- 0.9 kg (2.9 lb) for controls (P < 0.05).
Rothacker, D.Q. and Waitman, B.E. (1997) "Effectiveness of a Garcinia cambogia and Natural Caffeine Combination in Weight Loss: a Double-Blind Placebo-Controlled Pilot Study." Int. J. Obesity 21 (Supp. 2), 53. This was also a randomized, double-blind, placebo-controlled trial, with 50 obese subjects (48 completing the study) for six weeks. GCE (800 mg) was given three times per day, in addition to caffeine and chromium; the diet was limited to 5040 kJ per day. No significant effect of the treatment was seen, with the treatment group having a 4.0 +/- 3.5% fat loss compared to 3.0 +/- 3.1% for the control group (P = 0.30). This study was complicated by the use of two other agents besides HCA.
Girola, M., De Bernardi, M., Contos, S. et al. (1996) "Dose Effect in Lipid-Lowering Activity of a New Dietary Intetrator (Chitosan, Garcinia cambogia Extract, and Chrome)." Acta Toxicol. Ther. 17, 25-40. Another randomized, double-blind, placebo-controlled trial, with 150 subjects (the number completing the trial was not reported) for four weeks. Here the dose of GCE was much smaller, 55 mg once per day for one group and twice per day for another group. The treatment groups also received two other agents, chromium and chitosan (a treated form of chitin which binds intestinal fat, thus lowering its absorption), also once or twice per day, and all subjects were on a low-calorie diet. Data were expressed as "overweight reduction": 12.5 +/- 1.2% for two doses per day; 7.9 +/- 0.9% for one dose per day; and 4.3 +/- 1.0% for placebo.
The authors also note, among the limitations of the seven studies, "failure as of yet to publish study results in peer-reviewed literature in all but 2 of the 7 studes." The two exceptions are given as their references 13 and 14, Rothacker and Waitman, and Girola et al., respectively. However, this appears to be an error since Rothacker and Waitman is only an abstract. Conte and Girola et al. are listed as peer-reviewed publications in Table 2 of the paper, so perhaps the comment was supposed to refer to Conte rather than to Rothacker and Waitman. But, as described earlier in this article, Conte's paper does not seem to be a regular-reviewed article, but rather a more informal study. A Medline search (July 3, 1999) indicated that the Thom and Rothacker studies, published as abstracts in International Journal of Obesity, still have not been published as regular papers.
Thus, what appears to be the most thorough study of hydroxycitrate obtained negative results. In addition, one other recent study (Rothacker et al.) found results which were not statistically significant. The usefulness of this product remains to be demonstrated.