*4.2. Clinical Toxicity*

Based on toxicological studies, Soni et al. (2004) noted that there was sufficient quantitative and qualitative scientific evidence, from both animal and human data, to sugges<sup>t</sup> that HCA intake up to 2800 mg/day is safe for human consumption [35]. As a result, a NOAEL of 2800 mg/d was established [34,35].

Accordingly, none of the studies included in Table 1, devoted to analyzing the effects of Garcinia on body weight reductions at doses below this value have found serious adverse effects. Some of the minor side effects observed were leg cramps, heartburn, diarrhoea, increased gas, higher appetite, headaches, heartburn, rash, menstrual bleeding, and general weakness. In spite of this, other authors have reported toxic manifestations, including hepatotoxicity, acute pancreatitis, serotonin toxicity and psychosis after the consumption of Garcinia-containing products (either as an extract containing other components or pure). In 16 of the 21 cases described in Table 2 [45–60], these adverse effects have occurred after the intake of formulations which contained other ingredients besides Garcinia. One of these formulations is Hydroxycut™. Fourteen different products are marketed under this name, but only eight of them contain *Garcinia cambogia*. In addition, all of them are polyherbal products that can contain up to 20 different substances [34]. When toxic effects are induced by supplements that, in addition to Garcinia, contain other components, it has not been possible to confirm that Garcinia is the agen<sup>t</sup> responsible for the side-effects. In spite of this, the FDA (US Food and Drug Administration) issued a warning in 2009 on Hydroxycut™ products related to hepatotoxicity, which led to the recall of these products.

**Table 2.** Cases of liver damage associated with the consumption of *Garcinia cambogia* supplements in humans.



**Table 2.** *Cont*.


**Table2.***Cont*.


**Table 2.** *Cont*.


**Table 2.** *Cont*.

M: men; W: women; ALT: alanine aminotransferase; AST: aspartate aminotransferase; AF: alkaline phosphatase; GGT: gamma-glutamyl transferase; TB: total bilirrubin; DB: direct bilirrubin; INR: international normalized ratio; PT: prothrombin time; CRP: C-reactive protein; CT: computed tomography; MRCP: magnetic resonance cholangiopancreatography; MR: magnetic resonance; CIOMS/RUCAM: scale for diagnosing drug-induced liver damage; MELD: scale to measure the severity of chronic liver disease. In cases where information about dose is not provided, it is because it was not indicated in the article.

> The FDA warned consumers about the serious adverse effects associated with the consumption of Hydroxycut™. This recommendation was based on 23 cases of liver damage, including one death and a liver transplant. All this led to the withdrawal of the supplement from the market. Later on, García-Cortés et al. (2016) reported 29 cases of liver damage induced by this supplement [61].

> Taking this into account, as it can observed in Table 2, hepatotoxic effects have also been reported when using pure *Garcinia cambogia* extracts [49,50,54] or supplements that only contained *Garcinia cambogia* with minerals or vitamins [53,55,56]. The reason that justifies the occurrence of hepatotoxic effects in these cases, but not in all the studies gathered in Table 1, is not clear. Genetic interindividual variability leading to different susceptibility to the action of Garcinia cannot be ruled out. Nevertheless, it is important to emphasize that counting all the subjects that participated in the studies described in

Table 1, the lack of toxic effects refers to a quite big sample, whereas toxic effects have only been described in a reduced number of subjects.

The common pattern of symptoms, observed in all these cases, consisted of abdominal pain (predominantly in the right upper quadrant), vomiting, nausea, fatigue and alterations in liver parameters such as transaminases, alkaline phosphatase and bilirubin. Serological tests were performed to rule out other possible causes of liver damage and/or infection, such as hepatitis, Epstein–Barr virus, cytomegalovirus, etc. In eight cases the CIOMS/RUCAM scale was used. This scale is a scoring system used to establish the etiology of drug-induced liver damage, and depending on the score obtained, the substance is classified as a highly probable cause ( ≥9), probable cause (6–8), possible cause (3–5), unlike cause (1–2) or excluded cause (0) of liver injury. The scores obtained for the supplements in these studies ranged from 6 to 11 points; in other words, probable to highly probable cause. Importantly, after Garcinia supplement withdrawal, the symptoms subsided and all the altered parameters returned to normal levels, although in four cases the patient finally required liver transplantation.

Regarding acute pancreatitis, one case has been reported in an 82-year-old man with past medical history of obesity and two previous episodes of acute pancreatitis in the past. He denied any alcohol use and reported no recent changes in his medications, as well as the intake of *Garcinia cambogia* recently as an appetite suppressant. He was treated with bowel rest and intravenous fluid hydration, providing a significant improvement in his symptoms [62].

Other adverse effects associated with *Garcinia cambogia* ingestion are mania and psychosis, as shown in Table 3 [63–66]. Nevertheless, currently the existing scientific evidence is limited and a causal association has not ye<sup>t</sup> been established with certainty. In some cases, the participants had a previous psychiatric history and/or were treated with selective serotonin reuptake inhibitors (SSRI). HCA acts as a selective serotonin reuptake inhibitor, thus increasing serotonin levels and increasing the risk of toxicity due to this neurotransmitter [63,66]. The most relevant symptoms were irritability and agitation. After the withdrawal of the supplement, the symptoms remitted, and all the altered parameters returned to normal levels.

To conclude, another type of toxicity associated with the consumption of *Garcinia cambogia* can be observed in patients with pre-existing metabolic disorders. In this line, Bystrak et al. (2017) described the case of a 56-year-old insulin-dependent, hypertensive woman with chronic hepatitis C, who developed diabetic ketoacidosis, pancreatitis, and cardiomyopathic stress after consuming a *Garcinia cambogia* supplement (1400 mg HCA/day) to lose weight [67]. Applying the algorithm described by Naranjo et al. (1981) [68] to estimate the causality of an adverse drug reaction, a value of five was obtained, meaning a probable adverse reaction to the use of *Garcinia cambogia* [67].

**Table 3.** Cases of mania and serotonin toxicity associated with the intake of *Garcinia cambogia* supplements in humans.



**Table3.***Cont*.

M: men; W: women; SSRI: selective serotonin reuptake inhibitor.
