Inherent Safety of HCA Salts


Transition Metal Chelating Toxicity of (–)-Hydroxycitric Acid as Free Acid and Lactone

HCA Generally Safe

(–)-Hydroxycitric Acid obtained directly from fruit sources as used in traditional foods and in the form of fully reacted salts is extremely safe. A large number of peer-reviewed published studies based upon research performed at Roche and elsewhere using a pure trisodium (–)-hydroxycitrate indicated great safety with this fully reacted salt, even when ingested at extremely high dosages. More recently, studies employing a potassium-calcium salt of HCA likewise found no indications of toxicity even at elevated levels of intake. The following journal articles review the general safety of HCA and results found with high levels of intake under controlled circumstances in male and female rats:

Jena BS, Jayaprakasha GK, Singh RP, Sakariah KK. Chemistry and biochemistry of (–)-hydroxycitric acid from Garcinia. J Agric Food Chem. 2002 Jan 2;50(1):10-22. Review.

Shara M, Ohia SE, Schmidt RE, Yasmin T, Zardetto-Smith A, Kincaid A, Bagchi M, Chatterjee A, Bagchi D, Stohs SJ. Physico-chemical properties of a novel (–)-hydroxycitric acid extract and its effect on body weight, selected organ weights, hepatic lipid peroxidation and DNA fragmentation, hematology and clinical chemistry, and histopathological changes over a period of 90 days. Mol Cell Biochem. 2004 May;260(1-2):171-86.

Shara M, Ohia SE, Yasmin T, Zardetto-Smith A, Kincaid A, Bagchi M, Chatterjee A, Bagchi D, Stohs SJ. Dose- and time-dependent effects of a novel (–)-hydroxycitric acid extract on body weight, hepatic and testicular lipid peroxidation, DNA fragmentation and histopathological data over a period of 90 days. Mol Cell Biochem. 2003 Dec;254(1-2):339-46.

Ohia SE, Opere CA, LeDay AM, Bagchi M, Bagchi D, Stohs SJ. Safety and mechanism of appetite suppression by a novel hydroxycitric acid extract (HCA-SX). Mol Cell Biochem. 2002 Sep;238(1-2):89-103.

One or more fully reacted HCA salts have been granted Generally Regarded As Safe (GRAS) status in the United States. However, Roche did find an issue of testicular atrophy (shrinkage or non-development) with a specific form of HCA, to wit, the ethylenediamine salt of HCA. Ethylenediamine is a chelator of metals and removes various minerals, including the transition metals iron and zinc, from the body if taken in any quantity or chronically. When used to create ethylenediamine (–)-hydroxycitrate [(–-)-threo-hydroxycitric-acid-ethylenediamine-salt], the problem may be compounded. At any rate, ethylenediamine releases HCA in an unbound form when ethylenediamine (–)-hydroxycitrate reaches the relatively high pH of the small intestine. HCA as either free acid / lactone (the material is labile between these two forms and therefore is not purely one or the other under normal circumstances) acts as a chelating agent. For instance, it has been tested as a chelator of aluminum and shown even in very short term tests also to increase the excretion of iron significantly.

Graff L, Muller G, Burnel D. In vitro and in vivo evaluation of potential aluminum chelators. Veterinary and Human Toxicology. 1995;37(5):455-461.

Freed via ingestion of ethylenediamine (–)-hydroxycitrate, unbound HCA in an unpublished Roche trial appears to have sequestered enough zinc (or possibly iron or copper) from the systems of male animals to prevent proper testicular development and maintenance. Researchers have demonstrated repeatedly that a zinc deficiency will have an adverse effect upon testicular health and functions. In an animal model, the same is true of iron deficiency.

Behne D, Kyriakopoulos A, Gessner H, Vormann J, Gunther T. Sex-related effects of zinc deficiency on the selenium metabolism in rats. J Trace Elem Electrolytes Health Dis. 1992 Mar;6(1):21-5.

Fukuoka M, Kobayashi T, Hayakawa T. Mechanism of testicular atrophy induced by di-n-butyl phthalate in rats. Part 5. Testicular iron depletion and levels of ferritin, haemoglobin and transferrin in the bone marrow, liver and spleen. J Appl Toxicol 1995 Sep-Oct;15(5):379-86

Citric acid from fruit, by the way, is not a significant chelator of minerals because when ingested, most citric acid is cleaved to bicarbonates early in the small intestine.

Before the big launch of HCA products into the US health foods industry in 1994, Roche’s experience with the HCA ethylenediamine salt and the likely sequestering of one or more transition metals was extensively discussed by an number of consultants on the project who had been in contact with individuals at Roche with experience with HCA. Hence, it has long been known that the chronic ingestion of HCA free acid and/or lactone was not advisable. More recent tests apparently have confirmed the dangers.

Safety Concerns Arising from Tests Conducted in Japan

Quite a number of studies have been conducted in the United States and Europe using HCA products from at least two different companies without any findings of testicular toxicity. However, in January 2005 the following study was published. Its title is self-explanatory:

Saito M, Ueno M, Ogino S, Kubo K, Nagata J, Takeuchi M. High dose of Garcinia cambogia is effective in suppressing fat accumulation in developing male Zucker obese rats, but highly toxic to the testis. Food Chem Toxicol. 2005 Mar;43(3):411-9.

The authors of the study write that safety at the level of intake of 15–30 mg HCA/kg BW/d [that is, an upper limit of a mere 2,100 mg/day for a 150 pound human] “is not essentially ruled out” and then go on to recommend against the use of the product. Significantly, one major US purveyor of HCA products already is suggesting an intake of just under 3 grams per day, which is above the intake that the Japanese authors consider to be proven safe.

This article would have been noteworthy even had it been the first such finding using a particular HCA diet product being sold to the public. However, this is at least the second finding of toxicity with a product supplied by Nippon Shinyaku of Japan and produced by Renaissance Herbs/Dhanvantari Botanicals. If one visits the home page of the Japanese Ministry of Health and Labor Welfare (JMHLW), one will find the first official announcement from the JMHLW (dated March 7th, 2002) describing toxicity findings based upon an HCA product supplied by Nippon Shinyaku of Japan. Not commonly known is the fact that Renaissance Herbs, Inc., via its subsidiary Dhanvantari Botanicals of Bangalore, India, is the manufacturer of Garcinia cambogia extracts for Nippon Shinyaku. The March 2002 announcement is an interim report of a technical study dated February 4th, 2002 and can be found at this web site (in Japanese): http://www.mhlw.go.jp/topics/2002/03/tp0307-1.html

The findings of this initial Japanese government 26-week safety study actually performed in 2001 showed some anomalies. The primary oddity was that rats in all groups receiving the Nippon Shinyaku HCA salt showed signs of testicular atrophy. This lack of a dose response curve is consistent with contamination, for example, di(2-ethylhexyl)phthalate from plastics, and not with the product itself being toxic. Therefore the study was followed by a second study continuing twice as long (52 weeks) and using far more animals.

The second and full finding of toxicity using a fresh batch of product manufactured by Renaissance Herbs for Nippon Shinyaku was published in January 2005 in the article given above, although this data was available probably at least a year earlier in Japan: Saito M, Ueno M, Ogino S, Kubo K, Nagata J, Takeuchi M. High dose of Garcinia cambogia is effective in suppressing fat accumulation in developing male Zucker obese rats, but highly toxic to the testis. Food Chem Toxicol. 2005 Mar;43(3):411-9. Inasmuch as the authors of the study are from Japan’s National Institute of Health and Nutrition, it would have been translated from a Japanese draft. The article was received by the journal on 15 July 2004. Therefore, the animal data likely was known and disseminated for discussion by early to mid-2003.

Regarding the 2005 paper, we already have a response from other researchers. In a letter published June 30, 2005, researchers associated with InterHealth Nutraceuticals indicated that findings of toxicity with a (–)-hydroxycitric acid product tested in Japan were due to the high amount of HCA lactone in the Japanese item. Here see:

Burdock G, Bagchi M, Bagchi D. Garcinia cambogia toxicity is misleading. Food Chem Toxicol. 2005 Nov;43(11):1683-4.

Normal HCA salts produced by Roche and others have not shown any effect upon testicular functioning. Therefore, it would seem to be clear that something about the Nippon Shinyaku / Renaissance Herbs salt tested was at fault. At the very least, a high lactone content in any HCA salt remains highly suspect. The material used in the published Japanese findings of toxicity appears to be a salt variously called “Hi-Sol” HCA calcium salt or “Ca60” or Garcitric Gold Ca60. The HCA content of this item is almost sixty percent HCA lactone, as indicated not only by Saito et al., but also by Nippon Shinyaku itself. Here see:

Sawada H., Tamura K, Tomi H. Effects of Liquid Garcinia Extract and Soluble Garcinia Powder on Body Weight Change. Journal of Japan Oil and Chemicals. 1997.

Effects of Garcinia on Endurance. Society of Agricultural Chemistry. 1997.

The Applications of Garcinia Extract. Japanese Spice Studies. 1997.

Other work using Nippon Shinyaku materials found that animals given the HCA free acid / lactone product showed signs of agitation and poor tolerance for the material.

Ishihara K, Oyaizu S, Onuki K, Lim K, Fushiki T. Chronic (-)-hydroxycitrate administration spares carbohydrate utilization and promotes lipid oxidation during exercise in mice. J Nutr. 2000 Dec;130(12):2990-5.

(More information, including Japanese language materials, is available here.)

A number of companies are now placing HCA salts in beverages. It is unclear how beverages with either low pH or undergoing pasteurization can be produced in which a substantial percentage of the HCA is not gradually released as either free acid or lactone. Prudence would suggest that all such beverages should be tested over their expected range of shelf life for lactone content.


Properly Made HCA Products Are Safe

To date, there has been no public response from the makers of the products that failed the Japanese safety tests. By way of comparison, at least one salt produced by different methods for another company has GRAS status in the US and no safety concerns have ever been raised regarding the pure synthesized trisodium (–)-hydroxycitrate studied by Roche. Moreover, tests both by Roche and Glykon with fully reacted HCA salts have shown increases in body mineral stores, not losses. (See US Patent 6,441,041.) Our conclusion is that the free acid and lactone forms of HCA should not be ingested chronically, but that fully reacted salts are safe.