**5. Concluding Remarks**

The reported scientific literature shows that nutritional supplements based on Garcinia extracts are effective in just over half of the reported studies. In these cases, the supplements should not constitute a treatment per se but, they should represent complementary tools to the conventional treatment of excess body fat. Moreover, due to their positive effects on lipid and glycemic profile, these supplements could be useful for the managemen<sup>t</sup> of the co-morbidities associated with obesity.

Garcinia-based supplements have been shown to be safe in numerous human experiments, but the growing number of cases that report significant adverse effects, mainly associated with liver damage, and to a lesser extent with serotonin toxicity and mania, may lead to reconsideration of the safety of them. Although very often HCA has been signaled as the main element responsible for the toxic effects of Garcinia supplements, it should be noted that the fruit of *Garcinia cambogia*, an important source of HCA, has been consumed for centuries in Southeast Asia and has been generally recognized as safe

(GRAS) [69]. On the other hand, as explained before in this review, in many cases Garcinia supplements contain a grea<sup>t</sup> number of components. Consequently, the toxicity cannot be reliably attributable to Garcinia, and it is difficult to make conclusions without giving rise to doubts or objections. Furthermore, potential negative effects due to the combination of the Garcinia supplement with other dietary supplements included in the consumer diet, or even with several drugs, cannot be discarded.

Importantly, adverse effect case reports usually reflect the associations between the observed toxicity and the intake of the dietary supplement, rather than causality. These associations need to be rigorously examined and, if finally, the supplements are found to be the causative factors for the alterations observed, the true agents need to be firmly identified, along with the dose at which the negative effects are induced [69]. In this regard, an important problem in diagnosing the cause that produces the adverse effects, is that many people perceive these type of products as not harmful or as "natural" products, thus, they tend to forget to mention them when they are asked about the foods, beverages and medications that they have consumed. It is therefore likely, that there are more cases than those diagnosed, and consequently, the magnitude of the problem may be underestimated. When the dose administered or the exact content of HCA are not specified, it is not possible to identify whether the dose exceeds the value established as NOAEL. Another important aspect, is that the issue of obesity-related liver co-morbidities as a cause of liver alterations, has been poorly handled in toxic effect reports. Much more attention should be paid to obesity-associated liver diseases in the causality assessment of dietary supplements used for weight reduction [70].

In this scenario, more studies are needed to evaluate the efficacy and safety of these products, using larger sample sizes and longer follow-up periods. Finally, it should be pointed out that there are certain population groups in which the use of these supplements should be discouraged. This is the case for pregnan<sup>t</sup> and lactating women. HCA can affect the production of fatty acids and cholesterol, and can directly influence the production of sterols and steroid hormones. Pregnancy is a time of extreme sensitivity to steroid hormones, therefore, these products are not recommended. In the case of children— although it has not been possible to prove that they are dangerous—the advice is not to consume them in large doses and for long periods of time. On the other hand, the evolution of patients with mild depression or with occasional episodes of hypomania who consume Garcinia should be monitored, since their situation may worsen.

**Author Contributions:** Conceptualization, M.P.P., Writing-Original Draft Preparation, N.A.; Writing-Review & Editing, M.P.P. and R.M.G.; Funding Acquisition, M.P.P. All authors have read and agreed to the published version of the manuscript.

**Funding:** This study was funded by Instituto de Salud Carlos III (CIBERobn) under Grant CB12/03/30007 and University of the Basque Country under Grant GIU18-173.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.
