REVIEW Toxicological Effects of Glycyrrhiza glabra (Licorice): A Review Somayeh Nazari, 1 Maryam Rameshrad 2 and Hossein Hosseinzadeh 2 * 1 Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran 2 Pharmaceutical Research Center, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran Licorice (Glycyrrhiza glabra) has been considered as an herbal drug since ancient time. Nowadays, it is a well- known spice that possesses worth pharmacological effects. However, some relevant articles have revealed nega- tive impacts of licorice in health. By considering the great wishes in using herbal medicine, it is important to show adverse effects of herbal medicine in health. At present, there are misunderstandings toward the safety of herbal medicines. Herein, we gathered scientific research projects on the toxicity effects of licorice and glycyrrhizin to highlight their safety. In this regards, we categorized our findings about the toxicity effects of licorice and glycyrrhizin in acute, sub-acute, sub-chronic, and chronic states. Besides, we discussed on the cytotoxicity, genotoxicity, mutagenicity, and carcinogenicity of licorice and glycyrrhizin as well as their developmental toxicity. This review disclosed that G. glabra and glycyrrhizin salts are moderately toxic. They need to be used with cau- tion during pregnancy. G. glabra and glycyrrhizin possess selective cytotoxic effects on cancerous cells. The most important side effects of licorice and glycyrrhizin are hypertension and hypokalemic-induced secondary disor- ders. Licorice side effects are increased by hypokalemia, prolonged gastrointestinal transient time, decreased type 2 11-beta-hydroxysteroid dehydrogenase activities, hypertension, anorexia nervosa, old age, and female sex. Copyright © 2017 John Wiley & Sons, Ltd. Keywords: Glycyrrhiza glabra; liquorice; glycyrrhizin; acute toxicity; developmental toxicity; cancer cell. INTRODUCTION Liquorice or licorice is an important medicinal herb with nutritional and therapeutic values. It is mainly obtained from the root of Glycyrrhiza glabra (Fabaceae) that is widely cultivated in numerous temperate or semitropi- cal parts of Europe and Asia (Federation of American Societies for Experimental and United, 1974). There are several critical ingredients in licorice in- cluding saponins, flavonoids (Isbrucker and Burdock, 2006), and coumarins (Kinoshita et al., 2005). Special yellow color and sweet taste of this spice are resulted from flavonoids and glycyrrhizin, respectively. Glycyrrhizin (Fig. 1), a triterpenoid saponin, is the most important constituent of licorice and is found in the form of potassium and calcium salts of 18β-glycyrrhizic acid (also known as glycyrrhizic or glycyrrhizinic acid and a glycoside of glycyrrhetinic acid) in licorice root and ammonium salt in the commercial preparations (Isbrucker and Burdock, 2006). Licorice root glycyrrhizin concentration is ranging up to 15% that the presence of this saponin could be changed by the ex- traction method and the root source (Fugh-Berman and Ernst, 2001). Licorice has a long history of use around the world, which could be called as ‘the grandfather of plants’. The application of licorice goes back to ancient Assyr- ian, Egyptian, Chinese, and Indian culture. Tradition- ally, it has been used for treating asthma, hoarseness of voice, cough, and lung diseases. It was a remedy for mouth ulcerations, diseases of liver, and heart burning. It has been prescribed for artery diseases, heart palpita- tion, and angina. Besides, it has been suggested to treat bladder and kidney pain, kidney stones, fever, neural- gia, skin, and eye diseases (Fiore et al., 2005). Nowa- days, it is a well-known spice for its taste and worth pharmacological properties. Licorice extract and glycyrrhizin derivatives are used for treating inflamma- tion, allergy, and peptic ulcer and applied to cosmetic preparation because of their antisensitizing and skin- whitening effects (Hayashi and Sudo, 2009). The phar- macology of licorice and its constituents has been reviewed extensively by Nassiri Asl and Hosseinzadeh (2007, 2008, 2015). G. glabra and its bioactive com- pounds have antioxidant (Sil and Chakraborti, 2016), antiviral (Nassiri Asl and Hosseinzadeh, 2007), antimi- crobial, antiprotozoal, antiinflammatory, and immuno- modulatory activities (Nassiri Asl and Hosseinzadeh, 2008). They could reverse drug resistance of methicillin-resistant Staphylococcus aureus infections (Gaur et al., 2016) and evoke hepatoprotective (Chigurupati et al., 2016; Nassiri Asl and Hosseinzadeh, 2008) and antitumor effects (Nassiri Asl and Hosseinzadeh, 2008). Besides, they could be used as a remedy in cardiovascular diseases and diabetes owing to their antiplatelet aggregation activity, thrombin inhib- itory effects, vasorelaxant effects, antiangiogenic * Correspondence to: Hossein Hosseinzadeh, Pharmaceutical Research Center, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. E-mail: hosseinzadehh@mums.ac.ir PHYTOTHERAPY RESEARCH Phytother. Res. (2017) Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ptr.5893 Copyright © 2017 John Wiley & Sons, Ltd. Received 30 May 2017 Revised 22 July 2017 Accepted 24 July 2017