Liquorice and herbal medicine

Liquorice (licorice is the American spelling) is extracted from the root, or more correctly, the stolon of the low growing bushes of the Glycyrrhiza family of which G. glabra is the most widespread in the Middle East, although in China G. urelesis is more common. There are many other varieties which we could cite, but these two are germane to this chapter. The name, given by no less a person than Dioscorides, is derived from the Greek glukur (sweet) and rhiza (root). In Chinese it is called gancao 甘草, meaning ‘sweet grass’. G. glabra (Figure 50.1) grows naturally in the Mediterranean region, central and southern Russia, Asia Minor and parts of Iran. Presumably its medicinal value was discovered in these regions and that knowledge spread, over many years, westwards to Europe and eastwards to China.

Figure 50.1   Glycyrrhiza glabra Wellcome Collection: Glycyrrhiza glabra (Liquorice or Licorice). Credit: Rowan McOnegal. Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)

It is said that a specimen of the bush was brought back to Britain by soldiers returning from the Crusades and grown, initially, around Godalming and Pontefract. It flourished particularly well in the soil around Pontefract and was grown in fields or ‘garths’ and harvested in the autumn. Pontefract became the principal source of liquorice in the UK and there is a liquorice museum there. Because of its Mediterranean origin, liquorice was known locally as ‘Spanish’ and cultivation flourished until the demand of the confectionery business became so great that cheaper and more plenteous supplies imported from the Near East made it uneconomic to grow it locally.

Although today we associate liquorice with children’s sweets, it has been used in medicine far longer than in confectionery. The transition from medicine to sweets appears to date from 1760 when George Dunhill of Pontefract made a cake by adding sugar to liquorice. These were marketed as Pontefract cakes and have the shape of a medicinal lozenge, reflecting the older use of liquoric (Lee 2018: 378–82). For detailed information on all aspects of liquorice, including botany, phytochemistry, pharmacy and the economics of cultivation, a specialist publication in the series ‘Springer Briefs in Plant Science’ should be consulted (Ӧztürk 2017). Although there was widespread use of liquorice in European herbal medicine, even greater use of it was made by the Chinese. It was a component of around 50% of all prescriptions and credited with many wondrous cures. To understand why it was a component of so many prescriptions, it is necessary to examine a little of the chemistry of the components of the liquorice bush.

The components of raw liquorice

The crude material, extracted from the stolons with hot water, is a complex mixture of over 400 triterpenes, flavones, isoflavones, chalcone and related compounds. For a full account, the text by Tang and Eisenbrand (1992) should be consulted. The dominant compound is glycyrrhizin (or glycyrrhetinic acid but the first name is preferred), a triterpene and a saponin (soap-like substance). The name is difficult to spell and problematic to pronounce. It is glycyrrhizin that gives liquorice its distinctive sweet taste and some of its curative properties. Glycyrrhizin was first isolated in pure form by the German chemist Paul Karrer (Karrer, Karrer and Chao 1923) in the 1920s and its chemical structure (Figure 50.2) established by Basil Lythgoe in the 1940s (Lythgoe and Trippett 1950). Readers can also consult the data aggregation websites, SuperTCM, developed by the Charite – University Medicine Berlin, and Symmap.org (Wu, Zhang, Yang et al. 2018) for an analysis of its chemical components and their molecular targets in the human body.

Chemical structure of glycyrrhizin. The left part of the molecule is hydrophilic while that on the right is hydrophobic (Drawn by Hazel Nicholson)

The natural colour of liquorice is yellow, due to the presence of flavonoids, and the black colour we normally associate with liquorice sweets is an added vegetable dye. The flavour of liquorice is not due to glycyrrhizin but to anethole, an aromatic, unsaturated ether, found alongside glycyrrhizin. A more plenteous and much used source of this flavour is aniseed oil from Pimpinella anisum and Liquorice Allsorts may not contain any liquorice at all. There are at least twenty-five other triterpene components in liquorice and it would be almost certainly incorrect to credit all its curative properties to glycyrrhizin alone. As if over 400 components were not enough, ten new ones were reported in a paper published as recently as 2018 (Schmid, Dawid, Peters and Hofmann 2018). The more sensitive the analytical instrument used, the more components are found.

The sweetness of glycyrrhizin has attracted attention as a low calorie sweetener. It is fifty times sweeter than sucrose. Minor chemical modification of the molecule gives rise to extremely sweet substances (Iijchi and Tamagaki 2005). Without doubt, one of the roles of liquorice in Chinese medicine was that of disguising the unpleasant flavour of herbs with its natural sweetness. In particular this would make the remedy more acceptable to children. Thus, liquorice in a prescription can act as an adjunct or zuo herb in Tao Hongjing’s rubrics, in that it moderates harshness.

Metabolism

Glycyrrhizin is a molecule of two parts (Figure 50.2). One half is a disaccharide (a sugar) and the other half has a steroid-like structure. The disaccharide is water soluble while the steroid is lipid soluble and this combination gives the molecule special properties, which may be of medicinal value, a matter that will be discussed later. Once ingested, glycyrrhizin may undergo a number of chemical changes. It is first hydrolysed by intestinal bacteria into 18β-glycyrrhetinic acid (Figure 50.3) and a disaccharide. After complete absorption of the former into the blood stream, it is metabolised into 3β-monoglucuronyl-18β-glycyrrhetinic acid in the liver (Kim et al. 1999).

Chemical structure of glycyrrhetinic acid, a hydrolytic product of glycyrrhizin metabolism (Drawn by Hazel Nicholson)

Addition of a glucuronyl group keeps the molecule soluble enough to circulate in the blood stream but it readily releases 18β-glycyrrhetinic acid and it is this molecule that may give glycyrrhizin its biological activity. The Greek letter β merely indicates the stereochemistry of the hydrogen atom at position 18 on the molecule and 18β is the naturally occurring form of the molecule.

Later Chinese remedy literature

Throughout subsequent centuries many compendia of materia medica and remedies were assembled but, rather than being de novo works, they were largely additions to and revisions of the Shennong bencao jing. For example, a number of scholars revised the work sometime between 200 and 250 CE to produce Lei Gong jizhu Shennong bencao 雷公集注神農本草 (Shen Nong’s Materia Medica, Compiled and Annotated by Lei Gong). There were probably other revisions, now lost. The polymath Tao Hongjing, introduced above, made significant revisions to produce Bencao jing jizhu 本草經集注 (Materia Medica Canon Variorum Edition) and this work, in particular, marked the beginning of a vast bencao literature. It included a revision ordered by Emperor Taizu (927–976 CE) to produce Kaibao chongding bencao 開寶重訂本草 (Materia Medica, Newly Examined and Determined during the Kaibao Period) (Chapters 8 and 9 in this volume). This revision listed 983 simples and was published in 977 CE.

In general, Chinese scholars added to what had been written before, with only a few deletions, and the consequence was that the bencao literature became a succession of poorly arranged encyclopaedias filled with repetitions and contradictions (Unschuld 1986). The situation with regard to herbal and mineral medicine in China was completely changed by the work of the scholar Li Shizhen 李時珍 (1518–93 CE), who produced an entirely new work entitled Bencao gangmu 本草綱目 (Materia Medica Arranged according to Drug Description and Technical Aspects) which, although based on what had been written before, adopted a far more critical approach (Chapters 8, 9 and 21 in this volume). He removed many of the repetitions and discussed the contradictions and did what he could to resolve them. It took him a life-time to complete and was not published until after his death in 1596 CE. It remains, to this day, the definitive account of the herbs and minerals used in Chinese medicine and is rated as one of the great works of Chinese scholarship. Although most of the entries concern herbs, there is some mention of animal and mineral materials used in Chinese medicine. The complete work has been translated into English and annotated by Luo Xiwen (2003).

One of the problems about using the bencao literature in a search for new drugs to treat diseases as they are now described and understood is that, in the bencao era, diagnoses were made according to very different criteria, such that it is often difficult to identify the disease under discussion. However, there are an increasing number of tools available for those interested but do not read Chinese. Apart from Luo’s translation there is a dictionary of the same by Paul Unschuld. ² Even with these aids, caution must be exercised, especially where illness and substance identification are concerned.

There have been few additions to the bencao literature published since the appearance of the encyclopaedic Bencao gangmu. In 1666 CE Guo Peilan 郭佩蘭 published Bencao hui 本草匯 (Collected Pharmaceutical Knowledge) which, he claims, deals with matters neglected by Li Shizhen (Chapter 48 in this volume). In more recent years the Chinese government has published a pharmacopoeia which gives details of not only modern synthetic drugs used in China but also traditional remedies ( Pharmacopoeia of the People’s Republic of China: 2000). There are also compendia of Chinese remedies written in European languages, or by Chinese doctors practising in the West. One of the most comprehensive is that by Bensky and Gamble (1993).

Throughout all the publications mentioned above liquorice is frequently mentioned as a medicinal herb and also as a component of prescriptions used to treat a wide range of diseases. Whether liquorice is the ‘sovereign’ drug, providing the therapeutic thrust, or an ‘envoy’ drug directing the ‘sovereign’ to the appropriate organ, is not always stated and we must consider both possibilities. How far these prescriptions live up to the claims made for them when tested using modern pharmacological and clinical procedures is one of the concerns of this article.

Testing the therapeutic value of liquorice and glycyrrhizin

Over the last twenty or so years there have been hundreds of reports of investigations into the therapeutic value of both liquorice extract and glycyrrhizin in the treatment of diseases, some of which are mentioned in the bencao literature. The reports are of variable quality and some appear in journals with low impact factors. Most are positive, but we must accept these conclusions with caution. The use of liquorice extract is problematic as its composition may vary according to the species, the manner of cultivation and the time of harvest. This makes confirmation or denial of results difficult and so emphasis will be given to studies using purified glycyrrhizin, but if some other component of liquorice is the main chemical agent that drives the efficacy of what we might think of as the sovereign drug then the results of these tests are valueless. Much of the work reported describes in vitro studies and all those involved in drug discovery know how frequently successful in vitro results disappear when in vivo studies are undertaken. Mention has been made already of the metabolism undergone once liquorice is ingested.

Studies, using modern pharmacological methods, have been reviewed by a number of researchers three of whose findings are referenced (Damle 2013: 132–6; Ming and Yin 2013; Mamedov and Egamberdieva 2019). The reviews would have been of greater value had they been more critical of the results. However, Mamedov and Egamberdieva conveniently list the conditions where, according to the bencao literature and other studies, liquorice has a beneficial effect. They include antimicrobial, antiviral, anti-inflammatory, anti-ulcer and hepatoprotective activity, as well as dermatological effects. It would be remarkable if they were all correct. We will briefly consider each of these, in turn.

Liquorice is so frequently mentioned in Chinese and European herbal manuals as a treatment for coughing that it has been little studied as its success is well established. However, the value of liquorice in the treatment of other inflammatory conditions has been the subject of much research. This has been reviewed by Yang et al (2017) and the data tabulated there are impressive, although in some studies the doses were rather high. A recent paper by Liu et al (2018) suggests that glycyrrhizin appears to suppress the production of a number of substances that cause inflammation, such as nitric oxide, PGE2, TFN-α and IL-1β. This applies to both liquorice extract and pure glycyrrhizin, so glycyrrhizin must be the active ingredient, or acting as the sovereign drug by analogy. It would not be unreasonable to suggest that glycyrrhizin is ready for clinical trials as an anti-inflammatory drug. It is interesting to note that a liquorice drink is sometimes given to patients recovering from anaesthesia who have excessive dryness of the mouth (xerostomia) (Kuniyama and Maeda 2019).

Whether Chinese physicians realised that liquorice had antibacterial and antiviral activity is not a question that can be addressed as both concepts (bacteria and viruses) were unknown to them. Instead the infection would have been described in terms of wind invasion and of the Five Agents or the disturbed flow of qi (Chapters 1, 4 and 9 in this volume). Yet 300 years before the Five Agents were systematically applied to pharmacological knowledge, liquorice was suggested in the second century BCE remedy manuscript Wushier bingfang (Treatment for Fifty-two Ailments) as an aid to wound healing, perhaps because it inhibited bacterial infections. Liquorice was to become a common ingredient in Chinese tonics, a term still used in traditional Chinese medical circles. The Shennong bencao jing, which dates to around the first century CE, recommends that it should be consumed regularly to promote long life and prolong sexual activity. In an age when hygiene was little understood, a herb that acted as a mild antibiotic might have given beneficial results. Some modern research (Kowalska and Kalinowska-Lis 2019) suggests that liquorice can be a treatment for certain dermatological conditions such as atopic dermatitis, puritis and acne vulgaris. Its role here could be employing both its antibacterial and anti-inflammatory properties. However, this use of liquorice in the treatment of skin conditions does not appear with any frequency in the bencao literature.

Rather surprisingly, clear descriptions of peptic and gastric ulcers are also not common in the bencao literature. It could be that they are described in a way that is so different from that of Western medical literature that they are difficult to recognise. Chinese herbal medicine describes its primary target as the spleen, which in traditional medicine is paired with the stomach, and governs digestion. However, liquorice has long been used to ease the discomfort of duodenal and gastric ulcers. In the 1970s Larkworthy showed by an endoscopic study that deglycyrrhizinated liquorice (liquorice from which all the glycyrrhizin had been removed) brought about healing of chronic duodenal ulcers (Larkworthy and Holgate 1975). Clearly glycyrrhizin is not providing the main therapeutic thrust, or acting as the sovereign drug in our analogy. Later (Bennett, Clark-Wibberley, Stamford and Wright 1980) discovered that in the healing of aspirin-induced gastric mucosal damage in rats, a mixture of cimetidine and deglycyrrhizinated liquorice given together was more successful than a dose of either drug alone. This observation gives us a hint of what may be a significant role of glycyrrhizin in herbal medicine. The matter will be discussed in more detail shortly. In the treatment of ulcers, it is possible that glycyrrhizin displays antibacterial properties against Helicobacter pylori (Hajaghamohammadi, Zargar,Oveisi et al. 2019).

The use of liquorice in the treatment of liver disease is well authenticated in modern Westernised Asian medicine but in the West is seen as an ‘alternative’ or ‘complementary’ therapy. The subject has been summarised at some length by (Li, Sun and Liu 2019). Their conclusion is that the natural ingredients in liquorice relieve liver disease and prevent drug-induced liver injury through targeting a number of therapeutic mechanisms. They claim that further toxicological studies and clinical trials offer an ‘alluring prospect’ for the use of liquorice in this area of medicine. Time will tell.

An unexpected and recent article on the use of liquorice in dentistry is worthy of special mention. A number of components of liquorice show activity against some common bacteria responsible for dental caries (Sidhu, Shankargouda, Rath et al. 2020). Based on these observations, Hu, He, Eckert et al. (2011) devised a sugar free, orange-flavoured lollipop containing glycyrrizol A, a compound related to glycyrrhizin. Its use over a three week period among pre-school children led to a substantial reduction in the number of Streptococcus mutans in the mouths of the children. Other infections in the mouth, as well as inflammatory conditions, are said to benefit from treatment with liquorice. In canal root treatment one of the more difficult bacteria to remove completely by irrigation is Enterococcus faecalis against which liquorice is claimed to be particularly effective (Badr, Omar and Badria 2011). One of the thrusts of the above article is that, for dental practitioners in emerging nations, local herbal remedies are often just as effective as expensive modern drugs.

The special nature of liquorice

Although liquorice does have therapeutic properties, particularly as a remedy for coughing and other inflammatory conditions, its role is widely described as ‘harmonising’ the other components of the prescription. Although an attractive term, with a clear meaning when applied to, say, music, this is not so when applied to pharmacy at a molecular level. The liquorice molecule has some unusual properties, as mentioned previously, and these may be a reason for liquorice having been attributed a ‘harmonising role’ historically. Let us first examine what the Bencao gangmu has to say about liquorice. In this instance, there is no difficulty in identifying the plant.

One of the crucial parts of the entry on liquorice in the Bencao gangmu is where Li Shizhen quotes from the writings of Tao Hongjing, a quotation that includes the phrase:

此草最為眾藥之主

The translation given in the 2003 English language version of the Bencao gangmu by Luo Xinwen, who gives this synopsis:

Gancao (liquorice) is the principal drug among the drugs. Most of the classical prescriptions have this drug as an important ingredient… It is also called guolao 國老 or ‘the principal instructor’… It can bring harmony among all drugs in a prescription and can neutralise the toxins of herbs and stone drugs.

The term ‘stone drugs’ means minerals, which were often used in Chinese prescriptions. The above is just one possible translation and others could legitimately suggest more strongly some property of liquorice that makes its use so widespread.

John Moffett (private comm.) offers the following, including some clauses which Luo left out:

This herb makes the best master of the multitude of materia medica. It is rarely absent from classic formulae, in the same way as incense contains agarwood.

Valerie Pallett (private comm.) translates the whole passage as follows:

The herb is one of the most important drugs and there are very few classical remedies which do not use it, just like agalloch eaglewood among the fragrant herbs. Liquorice is known as the emperor of herbs for, although it is not a sovereign drug, it is revered as such. It can be used to harmonise with other drugs and detoxify.

All three translations emphasise its widespread use and that it can harmonise the drugs in a prescription, an effect that is well-known to practitioners of Chinese medicine. The term ‘harmonise’ is difficult as it does not correspond to any commonly used term in modern pharmacology. However, it is a term used frequently in Chinese administrative language and, perhaps, in this instance it should be understood as bringing about a co-operative effect between components of the prescription. At least this description suggests that there is something special about liquorice. It may not provide the ‘therapeutic thrust’ but its presence makes the prescription more potent and much of Chinese pharmacy is concerned with enhancing potency.

Another indication of the value ascribed to liquorice is that the great Tang dynasty physician Sun Simiao in his compendium of prescriptions, charmingly entitled Qianjin yaofang 千金要方 (Thousand Ducat Prescriptions), gives details of what should be in a first-aid kit. It includes liquorice.

Liquorice as an aid to drug delivery

The special place given to liquorice may possibly be explained by an examination of the chemistry of the glycyrrhizin molecule. As mentioned previously, one half of the molecule (the sugar half) is hydrophilic, while the other half (the steroid part) is hydrophobic. Molecules of this type are known as amphiphilic. An aqueous environment causes glycyrrhizin molecules to aggregate rather than dissolve, probably in the form of a sphere (although cylindrical aggregates are possible) (Zhang, Wang, Wang and Yu 2006) with the hydrophobic part of the molecules pointing in, and the sugar part on the outside hydrogen bonding to water molecules in the solvent. There is good physical evidence to support this view. A mass spectroscopic study with glycyrrhetinic acid revealed that, in the spectrometer, aggregates of up to eight molecules form readily (Borisenko, Lekar, Vetova et al. 2016).

This result was confirmed by extensive studies using nuclear magnetic resonance spectroscopy (Petrova, Schlotgauer, Kruppa and Leshina 2017). Such aggregates are known as micelles. In very dilute solutions of amphiphilic substances, micelles do not form but at the critical micelle concentration (cmc) aggregation commences and is the dominant state of the molecules (Figure 50.4).

Figure 50.4   Cross section of a micelle. A drug may be contained within the micelle (Drawn by Hazel Nicholson)

The significance of micelles to drug therapy is that, as a biochemical analogue to the harmonising function as described by Tao Hongjing and taught still today in Chinese medical schools, micelles can enhance the solubility of a drug and thus make it easier to deliver a therapeutic dose (Ahmad, Shah, Siddiq and Kraatz 2014).

For example, glycyrrhizin greatly enhances the solubility and the bioavailability of Atorvastatin (Kong, Zhu, Meleleva et al. 2018) and also shows promise as a carrier of anticancer therapy (Su, Wu, Hu et al. 2017). It does this by incorporating some molecules of the drug into the micelle. Why this happens is not completely clear but it is a well-established phenomenon, which is of great significance for the delivery of drugs in vivo. Solubility is a major problem with drugs and it is estimated that 80% of substance undergoing development as drugs have unacceptably low solubility. Hence the importance of drug delivery systems that enhance solubility. Not only does glycyrrhizin increase drug solubility but it may also aid its passage across the cell membrane so that it can enter the cell and reach the target for its therapeutic action (Seylutina et al. 2016). This may mean that, as drug delivery is more efficient, a lower dose can be given and a lower dose means fewer side effects. Experiments using a technique known as atomic force microscopy have shown that glycyrrhizin influences the permeability and elasticity of cell membranes (Seylutina and Polyakov 2019). Thus, the presence of glycyrrhizin constitutes a Drug Delivery System (DDS) and a DDS is just as important as the action of the drug itself in providing therapeutic thrust. This function, we might understand as analogous to the zuo shi functions of medieval Chinese medicine. The active drug which makes use of glycyrrhizin as a carrier could be from the jun herb or from any of the other herbs in the prescription.

Liquorice hazards

The ingestion of liquorice is not without its dangers. There is strong evidence that excessive intake leads to hypertension (van Uum 2005; Penninkilamp, Eslick and Eslick 2017). This effect is known by modern practitioners, who take nosebleeds as an indicative side-effect, and when they occur, will discontinue liquorice. Although the effect is so small that it is not a matter of significance for normal people, those with underlying cardiovascular conditions should take note. Rather more serious for pregnant women is the effect of taking excessive amounts of liquorice on the unborn child. In a carefully executed Scottish-Finnish study (Räikkönen, Pesonen, Heinonen et al. 2009) it was found that, because of the similarity of structure between cortisol and glycyrrhizin, mothers who consumed more than 500mg of glycyrrhizin per week gave birth to children with depressed verbal skills, as measured by the Beery Development Test. Although this work should not deter the occasional consumption of a liquorice sweet, pregnant women should be aware of the dangers of an excess.

Conclusion

Liquorice is special among the herbs used in Chinese herbal medicine. Whether or not we accept the rigid hierarchy of herbs in a Chinese prescription, it is not unreasonable to think that each component plays a different role. What is so special about liquorice is that it plays many parts. In some circumstances, as in the case of coughing, it does have a therapeutic role. Undoubtedly its sweetness makes the prescription more palatable, so it is an aid to consumption. Finally, it may, in some instances, provide a drug delivery system for other bioactive components of the prescription. That one herb should provide so much is impressive and valuable but what is even more impressive is that Chinese physicians, with no understanding of modern concepts of drug action, should have recognised that there could be value in adding liquorice to enhance the potency of a prescription.

Amphiphilic compounds like liquorice are used in drug delivery systems in biomedical pharmacy and so there is a sense in which nothing new has been revealed by this examination of the role of liquorice in traditional Chinese herbal medicine. However, it does enhance the reputation of Chinese physicians who developed the prescriptions that sustained the Chinese medical system for centuries. They had no understanding of modern concepts of drug delivery and drug action and yet noticed that the addition of liquorice enhanced the potency of the medicine.

When the Chinese government wanted a new treatment for malaria because there was resistance to chloroquine it recruited a team that included historians. The idea was that the bencao literature might offer some clues. But these were not easy to understand as malaria was not described in modern terms and the exact preparation of the drug for use was critically important. Nevertheless, they achieved extraordinary success and proved, despite the prejudices of historians, that one can leap across epistemological domains and map new pathways for scientific discovery. At its best, the prescriptions in the bencao literature are the results of clinical trials over thousands of years and with thousands of patients but, to maximise their value to modern pharmacy, they must be read collaboratively by those with historical understanding, not just by pharmacologists.