The Potential Use of Stevia (Stevia rebaudiana) in Coronavirus Diseases (COVID-19)
The objective of this report is to assess the currently available evidence on the potential of stevia (Stevia rebaudiana) extract and its main chemical constituents (steviol glycosides and steviol) in COVID-19 management based on the following:
- Efficacy: Focus on 1: antiviral properties of stevia extract and 2: the steviol glycosides potential in the modulation of immune response including anti-inflammatory, and role as other supportive therapy or management of COVID-19; and their respective potential mechanism(s) of actions.
- Safety on stevia extract, steviol and steviol glycosides (stevioside and rebaudioside A).
Electronic databases were searched using pre-determined terminologies such as ‘stevia rebaudiana’, ‘stevia’, ‘steviol glycosides’, ‘antiviral’, immunomodulatory’, ‘immune response’, ‘inflammation’, ‘mechanism of action’, and ‘safety’. Any peer-reviewed journals found were included, which covers PubMed, Ovid Medline®, EBM Reviews-Cochrane Central Register of Controlled Trials, EBM Reviews-Cochrane database of systematic reviews. The articles included in the search strategy were limited to those which were published within the year 1991 to November 2019. All clinical and preclinical studies (both in vitro and in vivo) related to the safety and efficacy or effectiveness of S. rebaudiana extract and its main chemical constituents were included.
Results and discussion:
- There is no documented evidence of the antiviral effects of Stevia rebaudiana and steviol glycosides for treatment of COVID-19 or any viral and respiratory infection.
- One preliminary study highlighted the antiviral activities of purified stevia extracts against coronavirus, bovine herpes virus and porcine teschovirus. Nevertheless, the effective concentration of the extract used was exceedingly high. This study is lacking in cytotoxicity data and the purity of the steviol glycosides purified from the extract was also not mentioned.
- Stevia leaf extracts have also been reported to inhibit the growth of human rotavirus and herpes simplex virus type 1. In these studies, the polysaccharides are reported to inhibit the virus entry into the host cells.
- Although limited literature is available, anti-inflammatory roles of stevioside have been observed using in vitro and in vivo models.
- Cytotoxicity study on various cell lines indicated no toxicity for up to ~2,000 µM of stevioside and rebaudiosides A, and 100 µM of steviol.
- Based on the safety documents, high purity stevia extracts (at least 95% steviol glycosides) are generally considered to be safe for human consumption at a human equivalent dose of 4 mg/kg body weight/day. The findings of toxicity studies showed that steviol glycosides (stevioside and reb A) are not genotoxic, carcinogenic or associated with any toxicity for reproduction/developmental and are unlikely to produce adverse effects when tested on animal models and cell (in vitro and in vivo) in short and long term administration. On the other hand, although steviol and some of its oxidative derivatives have been shown in one study to produce in-vitro genotoxicity, this was not expressed in vivo. Indeed, the Joint Expert Committee for Food Additives (JECFA) report concluded that this issue is addressed by the fact that steviol is present if any at a negligible level in the systemic circulation in humans.
Considering the present safety profile of stevia (Stevia rebaudiana) extract, their potential as antiviral in the treatment of COVID-19 may be explored in future investigations. However, this should also include the polysaccharides (usually obtained from water or ethanolic extract) and not only limited to the steviol glycosides. The steviol glycosides (stevioside, steviol and Reb A) were reported non-toxic on several cells, which ranged from 100 to 2,000 µM. However, the current data do not indicate the efficacious dose. Therefore, it is suggested that a pilot study is performed to determine the half maximal cytotoxic concentration (CC50) and half maximal effective concentration (EC50) of these compounds against the normal cell line and the virus, respectively. These values are needed for determination of selectivity index (SI) or specificity level of compound activity against the viral growth. From this pilot study, further studies will only be recommended if the anti-SARS-CoV-2 activity of a compound is greater than the cytotoxic activity on normal healthy cells or host cells (SI ≥ 10).