**1. Introduction**

Obesity is one of the most common nutritional problems worldwide, currently reaching epidemic proportions. This pathology was previously considered typical in developed countries, but nowadays it also shows a high prevalence in underdeveloped countries. According to figures from the World Health Organization (WHO), in 2019 more than 1.9 billion adults aged ≥18 years were overweight, and of them more than 650 million were obese [1]. Since 1975 the worldwide prevalence of obesity has tripled, thus leading to a major public health problem. Obesity is associated with a large number of comorbidities, such as type 2 diabetes mellitus, hypertension, dyslipidemia, non-alcoholic fatty liver disease and cardiovascular diseases, among others. Furthermore, according to the WHO, people with obesity have a 50 to 150% increased risk of death from any cause compared to individuals with normal weight [2].

Hypocaloric diets and physical activity based treatments for overweight and obesity represent the first line of therapy. Due to the difficulty in achieving and maintaining an adequate adherence to this treatment, many people often turn to nutritional supplements that promise to help them lose weight in the short run or at least, to maintain it. For many people it is an easy solution, which enables them not to modify their lifestyle too much. In

**Citation:** Andueza, N.; Giner, R.M.; Portillo, M.P. Risks Associated with the Use of Garcinia as a Nutritional Complement to Lose Weight. *Nutrients* **2021**, *13*, 450. https:// doi.org/10.3390/nu13020450

Academic Editor: Antonella Amato Received: 4 December 2020 Accepted: 24 January 2021 Published: 29 January 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

many instances, the motivation for the use of these supplements is due to aesthetic reasons, since the beauty standards that mark our society today encompass being slim.

These supplements work through five basic mechanisms, these being stimulation of thermogenesis, reduction in lipogenesis, increase in lipolysis, suppression of appetite, and decrease in lipid absorption. Among these nutritional supplements we find those based on plant extracts, which have been used for many centuries in the Eastern world. Nowadays, their use has become more and more prevalent throughout the world. Among them, *Garcinia cambogia* is one of the most promoted as a potential anti-obesity agen<sup>t</sup> and has received a lot of attention in the media [3].

Although the current consumption of herbs and dietary supplements is unknown, in a study carried out in six European countries, it was estimated that 18.8% of the 2358 consumers selected for the study consumed one or more dietary supplements, not taking into account herbal products. The percentages of plant food supplement consumers were 9.6% in Finland, 16.9% in Germany, 22.7% in Italy, 17.9% in Romania, 18.0% in Spain and 19.1% in the United Kingdom [4].

The aim of this review is to gather the reported information concerning both the effectiveness and the side-effects of nutritional supplements based on *Garcinia cambogia* to promote weight loss. In addition, the efficacy of other *Garcinia* species is also presented. For this purpose, a selective literature search in PubMed and Cochrane databases was performed. To search for the effects on body weight loss, the terms Garcinia, HCA, weight loss, fat mass and obesity were introduced, adding "and", "or", "not" to improve the classification. In addition, the filters "clinical trial" and "meta-analysis" were used. To search for toxic effects, the terms Garcinia, HCA and toxic effects were used. In the Cochrane Library database we sought the term "Garcinia" in the title or the abstract in meta-analyses and clinical trials. The search was extended to a total of 25 years (Figure 1).

**Figure 1.** Flow chart showing the process for the inclusions of articles.

#### **2. Active Principle and Mechanisms of Action**

The genus *Garcinia,* native to Asia and Africa, belongs to the *Clusiaceae* family and includes more than 300 species, such as *Garcinia cambogia* (Figure 2)*, Garcinia mangostana* and *Garcinia atroviridis* [5]. Potential therapeutic effects, such as anti-obesity, anti-ulcerogenic, antioxidant, anti-diabetes, anti-fungal, anti-inflammatory and anti-neoplasic [6], have been attributed to this genus. This has led to multiple investigations by pharmaceutical companies [5]. Some of the bioactive compounds isolated from Garcinia are garcinol, isogarcin, ( −)-hydroxycitric acid (HCA), mangostin, and xanthoquimol [6]. It should be noted that out of the species mentioned above, *Garcina cambogia* is the most used as a nutritional supplement for weight loss or maintenance. The anti-obesity properties have been attributed to HCA, which is present in the rind or epicarp of the fruit and represents 20–30% of the dry weight [7]. Many food supplements containing HCA are currently marketed for weight reduction.

**Figure 2.** Tree, branch, and fruit of *Garcinia cambogia*.

The effects of HCA are associated with a reduction in food intake via serotonin level regulation and metabolic modifications, such as an increase in fat oxidation, a decrease in de novo lipogenesis and the stimulation of hepatic glycogenesis, thus promoting energy expenditure. HCA is a competitive inhibitor of adenosine triphosphate (ATP)-citrate lyase, an enzyme that catalyzes the extramitochondrial breakdown of citrate into oxalacetate and acetyl-CoA, thus limiting the availability of acetyl-CoA, a compound that plays a key role in the synthesis of fatty acids in diets rich in carbohydrates (Figure 3).

**Figure 3.** Mechanisms of action of hydroxycitric acid (HCA). CPT: Carnitine palmitoyltransferase.

#### **3. Effectiveness of Garcinia to Lose and Maintain Body Weight**

In in vitro studies, HCA has been shown to inhibit fatty acid synthesis [8]. Specifically, in isolated hepatocytes, HCA inhibits the synthesis of fatty acids from glucose, but not from acetate. Therefore, HCA is an inhibitor of lipogenesis only if cytoplasmic acetyl-CoA is produced by ATP-citrate lyase. Nevertheless, fatty acid synthesis is able to continue as long as acetate, another acetyl-CoA precursor, is available. As the synthesis of acetyl-CoA is reduced, that of malonyl-CoA is reduced too, thus decreasing the negative feedback of carnitine acyltransferase. This produces an increase in lipid transport in the mitochondria and inefficient oxidation, that promotes the formation of ketone bodies. These molecules can pass into the bloodstream and reach the brain, where they constitute an energy reserve in the event of fasting [8].

In preclinical studies using animal models, chronic oral administration of HCA to rats significantly reduces food intake in the first hour after administration, together with body weight and concentrations of cholesterol, triglycerides and fatty acids. When evaluating the acute and chronic effects of HCA on energy metabolism in mice, it was observed that

oral administration of 10 mg increased serum concentration of free fatty acids and glycogen concentration in skeletal muscle [9].

Leonhardt et al. (2002) studied the long-term effect of HCA in male Sprague–Dawley rats after a notable body weight loss in two different experiments. Each experiment had 23 or 24 rats, respectively [10]. The rats were fed a 1% fat diet or a 12% fat diet, depending on the experiment. Both diets were supplemented with 3% HCA. HCA produced a long-term reduction in body weight recovery in both groups (in both rats fed 1% fat or 12% fat diets). However, only HCA produced a long-term suppressive effect in the case of the group of rats fed the 12% fat diet. No effect on plasma β-hydroxybutyrate levels was observed, so the hypothesis that increased fatty acid oxidation in the liver is involved in suppressing food intake by HCA was not supported by these results [11]. In another study, young lean and obese female Zucker rats were fed a diet (70% glucose, 1% corn oil) supplemented with HCA (52.6 mmol/kg diet) for 39 days. Amongst the lean rats, HCA decreased food intake, body weight, the percent of body fat, and fat cell size. Amongst the obese rats, food intake and body weight were lowered, but body fat percentage remained unchanged [10].

In other studies, instead of isolated HCA, extracts of Garcinia were used for supplementation. Saito et al. (2005) studied the ability of a *Garcinia cambogia* extract, containing HCA, to suppress the accumulation of body fat in growing male obese Zucker rats (6 weeks) [12]. They were given diets containing different amounts of the extract, which provided 10, 51, 102 or 154 mmol of HCA/kg of diet, respectively, for 92–93 days. Rats fed the highest amount of extract, and therefore receiving the highest dose of HCA (154 mmol HCA/kg diet), significantly decreased epididymal fat accumulation, compared to the other groups.

Table 1 presents a summary of the results obtained in 20 reported intervention studies in humans [13–32]. In 12 studies, statistically significant reductions in body weight were observed [14,15,18–22,26–28,30,31]. Conversely, the supplementation turned out to be ineffective in the remaining studies [13,16,17,23–25,29,32]. In the studies where significant weight loss was observed, the average value was between 2 and 6 kg in 2–4 months, with the exception of one where a loss of 14 kg was induced in 6 months [31]. Interestingly, in 11 studies [19–21,23,24,26,27,29–32], significant reductions in other parameters, such as waist and hip circumference, triglycerides, cholesterol and glucose were also observed regardless of body weight loss. It was specified in the vast majority of the studies that the supplement should be consumed approximately half an hour before meals. Splitting the doses of HCA has also been shown to be more effective than utilizing the same amount given as a single dose.

**Table 1.** Characteristics and results of published intervention studies in humans.



**Table1.***Cont*.


**Table 1.** *Cont*.


**Table 1.** *Cont*.

BMI: body mass index; HCA: hydroxycitric acid; HOMA-IR: insulin resistance index, MCT: medium chain triglyceride; TG: triglycerides; IWQOL: impact of weight on quality of life—lite.

> Of note, important differences in the experimental design can be observed among the reported studies. The number of participants ranged from 11 to 214. The fact that the majority of the studies had a small sample size limits the reliability of the results. In addition, in some cases there is a lack of proportion between men and women. The inclusion of both genders is important in order to determine whether there is sexual dimorphism in the effectiveness of the nutritional supplement. Conversely, in all the selected studies, the participants were overweight or obese (based on body mass index) and the duration of treatments ranged from 2 to 4 months in the majority studies, with the exception of two longer ones, in which the duration was 6 or 6.5 months.

> The variability is also observed in the type of supplement administered. Upon that, *Garcinia cambogia*/HCA was used in 15 studies, *Garcinia mangostana* in four studies and *Garcinia artroviridis* in one study. Lastly, in some cases HCA or Garcinia appeared to be combined with other ingredients, such as glucomannan (fiber), *Sphaeranthus indicus* or *Coffea arabica*. Consequently, it is not possible to determine whether the effect produced was due to the HCA content, to other ingredients, or to a combination of the effects of the different ingredients. The dose administered is another differential aspect among the studies. Last of all, the presentation of the supplement is different (pills, capsules or sachets). It is indicated in all cases that the supplement should be consumed before the meal (approximately half an hour before).

> Differences in other aspects of the experimental design, such as diet and physical activity can also be found. In some studies, the participants were instructed to continue with their usual diet and physical activity, while in others they were given specific instructions. Lastly, in others they were prescribed a hypocaloric diet along with specific practice of regular physical activity.

Some of these differential aspects could explain the lack of effect observed in several studies, for instance, the lowest sample size in the studies reported by Kovacs et al. (2001) [16], Kovacs et al. (2001) [17] and Watanabe et al. (2018) [32] In the study reported by Heymsfield et al. (1998) [13], *Garcinia cambogia* was not effective since the diet was low in energy and high in fiber. The amount of fiber could have inhibited the gastrointestinal absorption of HCA (active compound in *Garcinia cambogia*) and the low energy supplied (approximately 1200 Kcal) could have affected the usefulness of HCA. In addition, the dose of HCA was lower than that used in other studies. Another parameter that could have an influence was the excess of calcium used to stabilize HCA, that could have reduced the solubility of this bioactive compound, and therefore its bioavailability [8]. In a similar way, the lack of effect in the studies carried out by Roongpisuthipong et al. (2007) [21] and Vasques et al. (2014) [29] could be related to the low amount of energy provided by the diet (1000 Kcal/d and 1500 Kcal/d, respectively). In the study conducted by Vasques et al. (2008) [23], the only apparent potential reason could be that neither dieting, nor practicing physical activity were recommended. In contrast, in all the studies in which positive results were obtained, a healthy lifestyle was either prescribed or recommended. Last of all, in the studies conducted by Kim et al. (2011) [24] and Hayamizu et al. (2003) [18], in an Asian population, it is believed that the fact that the fruit of the Garcinia is of common use as part of the traditional diet, could have led to a reduced susceptibility to its effects.

Onakpoya et al. (2011) published a systematic review and meta-analysis of randomized clinical trials devoted to evaluating the effectiveness of Garcinia extracts as weight reduction agents [33]. The authors concluded that these extracts generated short-term weight loss. However, the scale of this effect was small, since it was not statistically significant when only rigorous randomized clinical trials were considered. Therefore, the clinical relevance of these products appears to be questionable and they do not represent an altogether effective measure of the treatment of overweight and obesity.

#### **4. Negative Effects on Health**

#### *4.1. Animal Toxicity Studies*

Studies of acute, short-term, sub-chronic, and chronic toxicity, as well as studies of genotoxicity, cytotoxicity and toxicity in reproduction, have been conducted in different animal species, although mainly in rats and rabbits. These studies have shown that Garcinia/HCA have good safety profiles, so that they may be used as nutritional supplements for the treatment of obesity [34–36].

Ohia et al. (2002) evaluated the effects of Super Citri-Max ™, a novel calcium/potassium-HCA extract (HCA-SX), containing 60% HCA, administered for 14 days. This extract is considerably more soluble and bioavailable than calcium-based HCA ingredients [37]. The study was conducted in Albino rats (males and females) fed ad libitum, treated with a dose of 5000 mg/kg (through a gastric probe), which is equivalent to 350 g or 233 times the maximum dose of 1.5 g/day of HCA in humans. The authors did not report any death or significant clinical changes. Furthermore, no significant tissue injuries were observed during the necropsy, which led them to sugges<sup>t</sup> that the LD50 oral administration of HCA-SX in rats was over 5000 mg/kg. Similarly, in another study carried out by the Wil Research Laboratories, it was shown that 5000 mg HCA/kg of body weight did not produce visible symptoms of toxicity or death in animal models. In line with these studies, Clouatre et al. (2013) defended that HCA was extremely safe and this was corroborated by various reviews where it was claimed that HCA from *Garcinia cambogia* had a protective effect on the liver [38].

Shara et al. (2003) analyzed the effects of HCA intake on weight, testicular and liver lipid peroxidation, and DNA fragmentation, in addition to possible histopathological changes in Sprague–Dawley rats [39]. The animals received 0.2, 2.0, or 5.0% HCA (100–2500 mg/kg) in their diet, equivalent to approximately 100, 1000, and 2500 mg/kg/day, respectively, in humans. The lowest dose was equivalent to the daily recommended dosage in humans, but the doses of 2.0 and 5.0% are 10 to 25 times higher doses. The rats were

euthanized at 30, 60, and 90 days of treatment. After 90 days of HCA administration, rats showed decreased body weight, without changes in liver or testicular lipid peroxidation or in DNA fragmentation In a follow-up study, the same authors did not find differences in the weight of various organs. Moreover, no haematological or biochemical disorders or significant histopathological changes or mortality differences were found [40].

As an exception, Kim et al. (2013) in a study addressed in rats fed a high-fat diet (45% of total energy), it was shown that after 16 weeks of treatment with *Garcinia cambogia* (1%, *w/w*, 60% HCA) oxidative stress, inflammation and liver fibrosis were triggered [41]. Consequently, it appears that the form of HCA regarding its extraction process and the residual compounds, among other factors, may spur differences between study outcomes [42].

Toxicological studies have been also addressed with other Garcinia species. Farombi et al. (2013) carried out a study in adult male Wistar rats randomly assigned to four groups of 10 rats each group given *Garcinia kola* orally at different doses (0, 250, 500 and 1000 mg/kg) for 6 weeks [43]. After conducting the study, it was concluded that the administration of *Garcinia kola* increased the antioxidant status and did not produce adverse effects on the liver, testicles and sperm. Saiyed et al. (2015) performed various toxicological studies both in vitro and in animals to evaluate the safety of Meratrim™, a supplement that contains *Garcinia mangostana* [44]. Meratrim™ was determined to be non-irritating to the skin, mildly irritating to the eyes, not mutagenic, and the no-observed-adverse-effect level (NOAEL) for this supplement was 1000 mg/kg body weight/day (in Sprague–Dawley rats). The authors concluded that the safety of Meratrim was demonstrated given the results observed in this study, added to the clinical trials of tolerability already carried out.
