Elsevier

Food and Chemical Toxicology

Volume 42, Issue 9, September 2004, Pages 1513-1529
Food and Chemical Toxicology

Review
Safety assessment of (−)-hydroxycitric acid and Super CitriMax®, a novel calcium/potassium salt

https://doi.org/10.1016/j.fct.2004.04.014Get rights and content

Abstract

(−)-Hydroxycitric acid (HCA) is a principle constituent (10–30%) of the dried fruit rind of Garcinia cambogia, a plant native to Southeastern Asia. The dried rind has been used for centuries throughout Southeast Asia as a food preservative, flavoring agent and carminative. Extensive experimental studies show that HCA inhibits fat synthesis and reduces food intake. The objective of this review is to systematically review the available safety/toxicity literature on HCA to determine its safety in-use. The primary mechanism of action of HCA appears to be related to its ability to act as a competitive inhibitor of the enzyme ATP-citrate lyase, which catalyzes the conversion of citrate and coenzyme A to oxaloacetate and acetyl coenzyme A (acetyl-CoA), primary building blocks of fatty acid and cholesterol synthesis. Super CitriMax®, a novel calcium/potassium–HCA extract (HCA-SX), is considerably more soluble and bioavailable than calcium-based HCA ingredients. Acute oral toxicity studies in animals demonstrate that CitriMax (50% HCA as calcium salt) has a low acute oral toxicity. In a subchronic study in rats, the gavage administration of HCA-SX at doses up to 2500 mg/kg/day for a period of 90 days caused a significant decrease in body weight and reduction in feed consumption without any adverse effects. The structure, mechanism of action, long history of use of HCA and other toxicity studies indicate that HCA-SX is unlikely to cause reproductive or developmental effects. HCA-SX was not mutagenic in the presence or absence of metabolic activation in Ames genotoxicity assays in strains TA98 and TA102. HCA-SX-induced increases in number of revertants in other strains (TA100 and TA1535 in the absence of metabolic activation and in strain TA1537 in the presence of metabolic activation) but these were not considered as biologically indicative of a mutagenic effect. In several, placebo-controlled, double-blind trials employing up to 2800 mg/day HCA, no treatment-related adverse effects were reported. There is sufficient qualitative and quantitative scientific evidence, including animal and human data suggesting that intake of HCA at levels up to 2800 mg/day is safe for human consumption.

Introduction

Super CitriMax® (HCA-SX), a popular dietary supplement, is derived from the dried fruit rind of a small pumpkin-shaped fruit (5-cm diameter) from the plant Garcinia cambogia (family Guttiferae), a tree that is native to Southeast Asia. HCA-SX consist of a calcium/potassium salt of (−)-hydroxycitric acid (HCA). HCA is also reportedly found in several other species of Garcinia genus. The dried fruit rind of G. cambogia, also known as Malabar tamarind, is commonly used in Southeast Asia (particularly southern India) as a food preservative, flavoring agent and carminative. Thus, HCA, the primary constituent of HCA-SX, has a long history of consumption through its use in foods. As stated in Boll et al. (1969), the natural occurrence of HCA was reported as early as 1883 by Lippman. Structurally, HCA is chemically nearly identical to citric acid, the agent that gives citrus fruits their characteristic tart flavor. Citric acid is present in practically all plants and in many animal tissues and fluids, and is a common food additive.

In recent years, HCA has received considerable attention because of its putative weight reduction effects in animal and human studies. Several independent animal and human studies on the safety and efficacy of HCA have appeared in the published literature. However, no systematic review on the safety of HCA based on the published reports has appeared. In the present review, the available information on the mechanism of action of HCA and a novel calcium/potassium–HCA complex (HCA-SX; Super CitriMax®) from pre-clinical and clinical studies, along with adverse events from the clinical trials, were critically evaluated to determine the safety of HCA-SX and HCA. No attempt was made to review or comment on findings related to the potential benefits of HCA, or any risk versus benefit considerations.

Garcinia is a large genus of approximately 180 species of polygamous trees or shrubs, distributed in tropical Asia, Africa and Polynesia. Approximately 30 species of Garcinia are found in India. One of the species, G. cambogia, found commonly in the evergreen forests of southwest India, is a small or medium-sized tree with a rounded crown and horizontal or drooping branches. The leaves are dark green and shiny, elliptic obovate, 5–12 cm long and 2–7 cm broad. The tree flowers during the hot season, and fruits ripen during the rainy season. The fruit, which is the source of HCA, is ovoid, 5 cm in diameter, yellow, orange or red when ripe, with six to eight grooves. The fruit has six to eight seeds surrounded by a succulent aril. The G. cambogia fruit is included in the USDA's inventory of perennial edible fruits of the tropics (Martin et al., 1987).

The fruit contains approximately 10–30% acid calculated as citric acid on a dry weight basis (Lewis et al., 1964). In some early studies, the organic acids present in the fruits were mistakenly identified as tartaric and citric acids. In subsequent studies, the major acid in the fruit of G. cambogia was identified as HCA (Lewis and Neelakantan, 1965; Lewis, 1969). HCA-SX, derived from the dried fruit rind of G. cambogia, contains approximately 95% calcium/potassium salt of (−)-hydroxycitric acid. The calcium/potassium salt contains approximately 60% HCA, calculated as the acid. General descriptive parameters and properties of HCA-SX are summarized in Table 1.

HCA (1,2-dihydroxypropane-1,2,3-tricarboxylic acid) has two asymmetric centers; hence two pairs of distereoisomers or four different isomers are possible (Fig. 1). All four isomers, (−)-HCA, (+)-HCA, (−)-allo-HCA and (+)-allo-HCA, have been chemically synthesized starting from trans-aconitic acid (Martius and Maue, 1941). One of these isomers, the principal constituent of HCA-SX, occurs in Garcinia (Fig. 1A) and another in Hibiscus species (Fig. 1B) (Lewis, 1969). (−)-HCA is the principal acid in the highly acidic fruit of G. cambogia. The absolute configuration of (−)-HCA was determined from Hudson's lactone rule, optical rotatory dispersion curves, circular dichromism curves and calculation of partial molar rotations (Boll et al., 1969). By employing X-ray crystallography, Glusker et al., 1969, Glusker et al., 1971 reported the structure and absolute configuration of the calcium hydroxycitrate and (−)-HCA lactone.

The acid is present at a level of 10–30% in the dried fruit rinds of G. cambogia. The acid can be isolated in the free form, as a mineral salt (i.e., calcium–HCA, potassium–HCA, calcium/potassium–HCA, etc. formed post extraction) or as the lactone by various methods. Lowenstein and Brunengraber (1981) have estimated the hydroxycitrate content of the fruit of G. cambogia by gas chromatography (GC). During concentration and evaporation, free HCA leads to the formation of HCA lactone. Based on the information submitted to the US Patent office, several investigators have reported the preparation of HCA concentrate from Garcinia rinds with 23–54% HCA and 6–20% lactone (Guthrie and Kierstead, 1977; Moffett et al., 1977). Recently, Jayaprakasha and Sakariah, 1998, Jayaprakasha and Sakariah, 2000 developed high-performance liquid chromatography (HPLC) methods for the estimation of organic acids in the fruits of G. cambogia and commercial samples of G. cambogia extracts. Using these methods, dilute extracts can be quantified without concentration, drying or derivatization. An additional advantage of these methods is that the HCA and its lactone can be quantified separately. Loe et al. (2001) reported a gas-chromatography/mass spectrophotometry method for quantitative determination of blood hydroxycitrate levels.

Lewis and Neelakantan (1965) reported a method on isolation of large scale HCA from the dried rinds of G. cambogia. In this method, the acid is extracted by heating the raw material with water under pressure. Subsequently, the extract was concentrated and pectin was removed by precipitation with alcohol. The clear filtrate was neutralized and the acid was recovered after passing through cation exchange resin. The recovered acid was concentrated, dried and recrystalized to small needle shaped crystals of lactone. In another method, Lewis (1969) reported isolation of HCA from dried rinds using acetone. The acetone extract was concentrated and the acid was extracted in water. The water extract was evaporated to yield lactone. In yet another process, aqueous extract of HCA was passed through anion exchange column for adsorption of HCA. The adsorbed HCA was eluted with sodium/potassium hydroxide. The free acid was prepared by passing through a cation exchange column. In recent years, several manufacturers have employed different procedures (patented) to prepare salts of HCA with improved bioavailability.

Physical characteristics and specifications of HCA-SX are presented in Table 2. Analysis reveals a highly water-soluble, calcium/potassium salt of HCA extracted from G. cambogia, commercially known as Super CitriMax® (HCA-SX). Quantitative estimations show that HCA-SX consists of 95% calcium/potassium–HCA providing 60% hydroxycitric acid. HCA-SX was characterized by HPLC, UV–VIS and IR, 1H-NMR, 13C-NMR spectral data and mass spectra. The stability data suggest that HCA-SX is stable over three years at temperature of 30° C and relative humidity of 65%. HCA-SX is reported to provide approximately 150 calories per 100 g.

The fruits of G. cambogia are valued for their dried rinds, which are used extensively in Southern India for culinary purposes and particularly as a condiment, in place of tamarind or lemon, for flavoring curries, meat and seafood dishes. The fruit extract also serves as a unique flavor enhancer for beverages, gourmet spice and as a post-prandial carminative. The fruit has also been used for centuries to make meals more `filling' (Sergio, 1988; Mattes and Bormann, 2000). Dried rind of G. cambogia, which contains HCA, is also used in pickling fish (Sreenivasan and Venkataraman, 1959; Clouatre and Rosenbaum, 1994); the commercial pickling of fish is called “Colombo curing” (Sreenivasan and Venkataraman, 1959; Lewis et al., 1964). The organic acids present in the fruit are responsible for the bacteriostatic effect of the pickling medium by a simple lowering of the pH. In addition to flavoring and preservative effects of the fruit extract, in the traditional system of herbal medicine in India (Ayurveda), Garcinia is considered to be one of the prime herbs that are beneficial for health. A decoction of the fruit rind is given for rheumatism and bowel complaints. In veterinary medicine, the extract is employed as a rinse for some diseases of the mouth in cattle (Jena et al., 2002). HCA, the organoleptically characterizing ingredient of G. cambogia, is a popular component of several dietary supplements marketed under various trade names. It has been reported that calcium salts of HCA, which are typically less than 50% soluble, are less bioavailable compared to readily soluble calcium/potassium salts of HCA. As a dietary supplement in the US, HCA is regulated under the Dietary Supplement Health and Education Act (DSHEA) of 1994 (DSHEA, 1994).

Section snippets

Biological data

In the published literature, several studies have appeared on the biological and toxicological effects of HCA. In a number of these studies, the investigators have not identified the specific stereoisomer of hydroxycitric acid employed. Although not identified as such, in a majority of these studies, the stereoisomer used was most likely HCA for the following reasons: first, the HCA or extract used in majority of the studies was isolated from G. cambogia; secondly, in several mechanistic

Summary and conclusion

Super CitriMax® (HCA-SX) is a novel extract from the dried fruit rind of the plant Garcinia cambogia, a tree native to Southeast Asia and grown widely in India. The primary constituent of HCA-SX is (−)-hydroxycitric acid (HCA), which is structurally similar to citric acid, a common food additive. The dried fruit rind of G. cambogia, is commonly used in Southeast Asia as a food preservative, flavoring agent and carminative. In recent years, HCA-SX and other products containing HCA have been

References (82)

  • M.F. McCarty

    Promotion of hepatic lipid oxidation and gluconeogenesis as a strategy for appetite control

    Medical Hypotheses

    (1994)
  • J. Panksepp et al.

    (−)-Hydroxycitrate and conditioned aversions

    Pharmacology Biochemistry Behavior

    (1977)
  • H.G. Preuss et al.

    Effects of natural extract of (−)-hydroxycitric acid (HCA-SX) and a combination of HCA-SX plus niacine-bound chromium and Gymnema sylvestre extract in weight loss

    Diabetes, Obesity and Metabolism

    (2004)
  • R. Rao et al.

    Lipid lowering and antiobesity effect of (−)hydroxycitric acid

    Nutrition Research

    (1988)
  • W. Sergio

    A natural food, the Malabar Tamarind, may be effective in the treatment of obesity

    Medical Hypotheses

    (1988)
  • W. Stallings et al.

    Structural studies of hydroxycitrate and their relevance to certain enzymatic mechanisms

    Archives of Biochemistry and Biophysics

    (1979)
  • A.C. Sullivan et al.

    Reactivity and inhibitor potential of hydroxycitrate isomers with citrate synthase, citrate lyases and ATP citrate lyases

    Journal of Biological Chemistry

    (1977)
  • J.A. Watson et al.

    Citrate and the conversion of carbohydrate into fat. Fatty acid synthesis by a combination of cytoplasm and mitochondria

    Journal of Biological Chemistry

    (1970)
  • J. Watson et al.

    Tricarballylate and hydroxycitrate: substrate and inhibitor of ATP: citrate oxaloacetate lyase

    Archives of Biochemistry and Biophysics

    (1969)
  • Z.X. Xu et al.

    Glucocorticoid induction of fatty acid synthase mediates the stimulatory effect of the hormone on cholinephosphate cytidylyltransferase activity on fetal rat lung

    Biochimica Biophysica Acta

    (1990)
  • Aujoulat, M., 2003. Super CitriMax HCA-600-SXS––Bacterial reverse mutation test (Plate incorporation and preincubation...
  • Badmaev, V., Majeed, M., 1995. Open field, physician controlled, clinical evaluation of botanical weight loss formula...
  • V. Badmaev et al.

    Garcinia cambogia for weight loss

    JAMA

    (1999)
  • Bagchi, D., Preuss, H.G., Ohia, S.E., Rao, C.V.S., Bagchi, M., 2002a. Weight management and mechanisms of action of a...
  • M. Bagchi et al.

    Efficacy of a novel (−)-hydroxycitric acid extract in weight management

    Journal of the American College of Nutrition

    (2002)
  • P.M. Boll et al.

    Naturally occurring lactones and lactames. The absolute configuration of the hydroxycitric acid lactones: hibiscus acid and garcinia acid

    Acta Chemica Scandinavia

    (1969)
  • S. Cheema-Dhadli et al.

    Inhibition of enzymes which interact with citrate by (−)-hydroxycitrate and 1,2,3-tricarboxybenzene

    European Journal of Biochemistry

    (1973)
  • D. Clouatre et al.

    The Diet and Health Benefits of HCA (Hydroxycitric Acid)

    (1994)
  • A.A. Conte

    A non-prescription alternative in weight reduction therapy

    American Journal of Bariatric Medicine

    (1993)
  • A.A. Conte

    The effects of (−)-hydroxycitrate and chromium (GTF) on obesity

    Journal of the American College of Nutrition

    (1994)
  • DSHEA, 1994. Dietary Supplements Health and Education Act of 1994. US Food and Drug Administration, Center for Food...
  • EPA, 2001. U.S. High Production Volume (HPV) Chemcial Challenge Program Assessment Plan For Acetic Acid and Salts...
  • FDA, 1982. Toxicological principles for the safety assessment of direct food additives and color additives used in food...
  • FDA, 1993. Toxicological principles for the safety assessment of direct food additives and color additives used in food...
  • F. Firenzuoli et al.

    Garcinia cambogia for weight loss

    JAMA

    (1999)
  • M. Ginanneschi et al.

    Propolis allergy: Synthesis and patch testing of gamma,gamma-dimethylallyl caffeic acid ester and its o-methyl derivatives

    Contact Dermatitis

    (1989)
  • M. Girola et al.

    Dose effect in lipid-lowering activity of a new dietary integrator (Chitosan, Garcinia cambogia extract, and Chrome)

    Acta Toxicologica et Therapeutica

    (1996)
  • J.P. Glusker et al.

    Absolute configuration of the naturally occurring hydroxycitric acids

    Archives of Biochemistry and Biophysics

    (1969)
  • J.P. Glusker et al.

    The structure and absolute configuration of the calcium salt of garcinia acid, the lactone of (−)-hydroxycitric acid

    Acta Crystallography B

    (1971)
  • M.R. Greenwood et al.

    Effect of (−)-hydroxycitrate on development of obesity in the Zucker obese rat

    American Journal of Physiology

    (1981)
  • Guthrie, R.W., Kierstead, R.W., 1977. Hydroxycitric acid derivatives. US Patent 4005086 and US Patent...
  • Cited by (0)

    View full text