Licorice belongs to the genus Glycyrrhiza, and radix glycyrrhizae (RG) is the dried roots and rhizomes of licorice. Licorice is commonly used as a natural sweetener and in herbal medicine. It mainly acts as a supplement in Western countries, for products such as herbal teas, soft drinks, and tobacco products. However, it is regarded as a medicine in Asia. Licorice is utilized to relieve pain, phlegm, spasms, cough, and dyspnea. The abundant active ingredients in licorice demonstrate efficacy in many different biological and physiological functions. To date, more than 300 bioactive compounds have been identified in licorice, including ~100 types of triterpenoid saponins and sapogenins, and ~300 kinds of phenolic compounds [17]. However, it has been found that the cultivated geographical area, the state of plant maturity, environmental conditions (including the pH of the soil, temperature, and weather), harvesting, and processing all affect the content of the bioactive compounds in licorice [18]. For example, the triterpenoid saponins in licorice, especially glycyrrhizic acid (GL; approximately 1.84% to 9.82% of licorice, depending on the sources and methods of extraction), are the major constituents and bioactive ingredients of licorice [19,20,21]. Flavonoids (approximately 1.78% to 4.82% of licorice, depending on the sources and methods of extraction) are the other main bioactive compound found in licorice, including isoliquiritigenin (ISL), isoliquiritin, and liquiritigenin, etc. [19,22]. In the 2010 edition of the Chinese Pharmacopoeia, GL and isoliquiritigenin were selected as the biomarkers for licorice, and it is stated that their content should exceed 2% and 0.5%, respectively [23]. Interestingly, we found that these two major compounds (GL and ISL) appear in many studies related to chemotherapy, which will be discussed further in a later section.

Licorice can be simply categorized into three Glycyrrhiza species: Glycyrrhiza uralensis Fisch., Glycyrrhiza glabra L., and Glycyrrhiza inflata Bat. [24]. In China, G. uralensis, G. glabra, and G. inflata are considered equivalent, and are combined and utilized as licorice without discrimination in the 2015 edition of the Chinese Pharmacopoeia. However, the morphological characteristics of the three Glycyrrhiza species show differences in the root, rhizome, seed, fruit, and inflorescence, as well as in the leaf and stem height. It is difficult to identify these licorice species accurately based only on their root or rhizome morphology [25].

There are significant differences between the species, which were established by the analytical methods of numerous studies aimed at separating and quantifying the active ingredients in licorice samples. These studies report that different licorice species have species-specific markers (Table 1); for example, the content of major flavonoids (liquiritin, liquiritigenin, and isoliquiritin) in G. uralensis is higher than that in G. glabra, and glycycoumarin only exists in G. uralensis [26,27,28,29,30]. Glycyrrhizin, 50 times sweeter than sugar and especially suitable for children, is evenly distributed in the three species [29]. The amount of isoliquiritigenin (2′,4′,4-trihydroxychalcone, ISL), one of the major bioactive compounds in licorice, is higher in G. uralensis than in G. glabra and G. inflata. [31,32].

Glycyrrhiza Species	Region	Specific Content	Ref
Glycyrrhiza uralensis (Glycyrrhiza radix)	China Northeastern Far east Russia	Owning the highest content of flavonoids (liquiritin, liquiritigenin, and isoliquiritin). Glycycoumarin only represented in G. uralensis.	[26,27,28,29,30,43]
		Isotrifloliol, licoricone, neoglycyrol, glycyrin, and licorisoflavan A in G. uralensis are higher.	[26]
		Glyinflanin D/G and licoflavone B are absent.	[44]
Glycyrrhiza glabra	Italy Spain China Russia Iran Central Asia	Owning the highest content of 18α-glycyrrhizic acid and 18β-glycyrrhizic acid.	[45]
		Higher content of saponins–licorice saponin K2/H2, licorice saponin B2, and licorice saponin G2/yunganoside K2. Quercetin absent in G. glabra.	[44,46,47]
		The highest content of apiosides (liquiritin apioside, isoliquiritin apioside, licuraside).	[30]
		Abundant 8-cyclized isoprenyl isoflavanes (e.g., glabridin and 4′-O-methylglabridin).	[29]
		Polysaccharide content in G. glabra is the highest.	[48,49]
Glycyrrhiza	China, Asia	Highest content of triterpene saponins.	[25,29]
inflata		Chalcone derivatives such as licochalcone (A, B, C, E), kanzonol C, and echinatin in G. inflata are higher.	[29,44,50]
		The content of quercetin is higher than that in G. uralensis.	[44,46,47]
		Highest content of prenylated chalcones.	[44]

Licorice and its derivatives exert anti-inflammatory and antioxidant effects, suggesting their potential as chemopreventive or therapeutic agents. For example, licorice can be used for reducing inflammation and allergic responses, as well as preventing liver damage [24,33,34]. Licorice extract also acts as a moderate hypocholesterolemic nutrient, and a potent antioxidant agent, to prevent cardiovascular disease [35]. Clinical data suggest that licorice, or its bioactive components, prevent dyspepsia and hyperlipidemia [36,37]. When taken concurrently with a glycyrrhizin-containing product, licorice is shown to afford hepatoprotection during alcohol consumption [38]. Three randomized clinical trials claim that Glycyrrhiza acts as a mucoadhesive film, improving oral mucositis during radiotherapy [39,40,41]. Moreover, preoperative gargling with a licorice solution reduces postoperative sore throat, thus, revealing its analgesic properties [42]. The clinical trials of licorice are summarized in Table 2.

Name	Disease/Disorder	Dose/Duration	Trial				Location/ Identifier No.	Ref
			Patient (n)	Experiment Group	Control Group	Outcome
Extract of G. glabra	Radiotherapy Head or neck	Oral 100 c.c/Bid 2 weeks	n = 37	Extract of G. glabra	Placebo (radiotherapy)	Prevent oral mucositis	IRCT201203012464N4 Iran Tehran University of medical science	[39]
G. glabra (yashtimadhu)	Radiotherapy Head or neck	Oral 5 g/Bid 6 weeks	n = 127	G. glabra	Placebo (radiotherapy)	Prevent oral mucositis	Himalayan Institute of Medical Sciences, Dehradun, India	[40]
Licorice	Radiotherapy Head or neck	Mouth wash	n = 60	Licorice mucoadhesive film	Placebo mucoadhesive film	Prevent oral mucositis	Isfahan University of Medical Sciences, Isfahan, Iran	[41]
Licorice extract	Randomized Double-blind	Oral 1 g/Tid	n = 236	+licorice extract	Sugar water	Pain relieving	NCT02968823	[42]
Licorice	Dyspepsia	380 mg/Bid 4 weeks	n = 120	+licorice	N.A.	Improved H. pylori eradication	IRCT2014061718124N	[36,37]
Glycyrrhizin	Alcohol consuming	Oral 0.1–0.3% 12 days	n = 24	+Licorice	Placebo (alcohol)	Hepato-protection	N.A.	[38]

2. Bioactive Components of Licorice