Liquorice, Seniors and Blood Pressure by Dr. Louis Z G Touyz. BDS, MSc(Dent), MDent(OralMed&Perio), FADI, FICD, FPFA, FACD, Associate Professor, Periodontics: McGill Faculty of Dentistry, Montreal, Québec, Canada.

Liquorice is enjoyed by many seniors, but may contribute to hypertension.  Liquorice is an organic substance named glycyrrhizin and is derived from plants, mainly Glycyrrhiza glabra.  It is 50 times sweeter than sucrose, and is a flavorant in many foods and medicines.  On hydrolysis glycyrrhizin transforms to a structure that partially resembles that common to steroids.  Glycyrrhizin inhibits the conversion of the precursor cortisol to cortisone by inhibiting the enzyme 11-betahydroxysteroid dehydrogenase, and excess intake leads to hypertension. Because of inhibition of 11-beta hydroxysteroid dehydrogenase by liquorice, cortisol levels are high within the collecting duct of the kidney, potassium is excreted, sodium is retained and hypertension obtains.  Liquorice chewing may cause staining of the oral mucosae, tongue and teeth.

OUTLINE

Introduction
Aim

LIQUORICE

Botany
Active ingredient
Properties and Pharmacology
Posology and Dosage
Liquorice Toxicity
Consumption products

Medical impact
Oral and Dental effects
Discussion
Conclusion
References

Introduction:

Liquorice, or licorice, is a uniquely tasting herb derived from the plant Glycyrrhiza glabra and has been used in medicines for thousands of years.  Liquorice is used as a flavorant in a variety of edibles, medicines and tobaccos, and is often innocently consumed in vast amounts without any regard or only with vague concepts of side effects liquorice may produce.  Liquorice is a favoured flavour of treats among seniors.

 Aim:

This paper appraises liquorice, it’s properties, use and possible toxic effects.  Botanical sources, chemical structure, active liquorice ingredients, pharmacological properties, common liquorice containing consumables, and the systemic impact on physiology are summarised.  Medical and oro-dental effects are described, and some important clinical management principles to constrain liquorice use are suggested.

Botany:

The roots (rhizomes) and stolons of Glycyrrhiza glabra (also known as Sweet Root, Spanish or Italian Liquorice) are the commonest variety source of liquorice.  G.g lepidota is American wild liquorice, while G.g violacea and G.g glandulifera are Persian/Turkish and Russian varieties respectively.  Glycyrrhiza uralensis (a.k.a. Manchurian liquorice) is the species favoured for traditional Chinese Eastern Medicines.  Liquorice flavours are also found in the plants like Fennel, (Foeniculum vulgare), and Anise seeds (from Pimpinella anisum) as well as other plants. (1)

Active ingredient:

The active chemical ingredients imparting the unique liquorice taste are glycyrrhizic acid and it’s glucoside, glycyrrhizin (C42H62016 ).  These molecules are regarded as nearly synonymous, are powerful organoleptic flavorants and impart characteristic liquorice taste and aroma to mixtures in small concentrations. (2)

Properties and Pharmacology:

Glycyrrhizin is 50 times sweeter than sucrose.  It retains, when sapid, a singular liquorice flavour.  The liquorice sweetness has a slower onset than sugar and lingers.  Unlike artificial sweeteners like aspartame, saccharine and cyclamates, it contains no sulfur molecule, (3) and retains its sweetness when heated.(2)  One hydrolysis glycyrrhizin yields 2 mols of glucuronic acid and 1 of glycyrrhetenic acid, a pentacyclic, tri-terpene which structure partially resembles that common to steroids, with a moiety attached.

Glycyrrhizin inhibits the conversion of the precursor cortisol to cortisone by inhibiting the enzyme 11-betahydroxysteroid dehydrogenase. (4)  Hydrolysis of slowly absorbing glycyrrhizin into the more rapidly absorbed glycyrrhetenic acid is performed by intestinal microbiota.  Consequently antibiotics affecting gut flora, adversely affects absorption of liquorice.  Liquorice boosts cellular formation of endogenous interferon, and has a positive long-term healing effect on Hepatitis-C infected patients. (5, 6, 7,8,9)

Posology and Dosage:

Liquorice is marketed in various forms, and because it’s often sold as the natural grown product, concentrations in the plant varies.  Solid extract 250-500mg, three times daily is suggested for medicinal purposes.  Dried root is dispensed at 1-4 grams, three times daily to a maximum of 12 Grams (2).  At 75 mgm daily of glycyrrhetenic acid (derived from 50G/day liquorice), a raising effect on blood pressure is noted after 2 weeks.  More than this daily dose increases blood pressure proportional to increased liquorice intake. (24)

Liquorice Toxicity:

This on its own is rare, yet not infrequent when encountered clinically and usually occurs in diuretic medicated patients unwittingly combining consumption of commercial products containing high amounts of liquorice extract like chewing tobacco, laxatives, or confections with concentrated liquorice extracts. (9,10,11)

Consumption of glycyrrhizin is considered safe at 200 milligrams per day, a dose accepted as recommendation to Japanese.  In the United States of America, glycyrrhizin is classified “as generally recognised as safe” as a flavouring agent, although not as a sweetener. (2)
Commercially licorice flavoured sweets rarely have any serious medicinal side effects, especially if consumed irregularly, in moderate amounts, of less than 25 grams of liquorice per day.

Consumption products:

Liquorice used as a flavorant in candies adds much gustatory joy to the variety of living pleasures.  The flavour is so positive and pleasant, it is also used for flavouring other foods like ice-cream, biscuits, cakes and drinks.  It is a very popular flavour for sweet treats as “Liquorice All Sorts” (see figure 1 and 2), and also in Salty Liquorice in Holland.  Liquorice is added to baked confectionery, toffees, chocolates and sucking sweets.  Black and Red varieties are made using food dyes (figure 2) with colorings.

Figure 1:
Ubiquitous Licorice All sorts. A tasty carbohydrate and licorice confection.
(by Maynards-Bassetts. Cadbury Adams, Toronto On M2N 7E9.) These sweets are delicious, well balanced and a popular health treat.

Figure 2:
Licorice All-Sorts with Red and Black Licorice Twirls (Allan Candy, Toronto Ontario M6J 3L9 ), and black Panda Licorice Tubes (Elco Fine Foods, Richmond Hill, Ontario L4B 1G5).  These sweets are delicious, well balanced and a popular health treat.

Liquorice is also part of spice mixes constituting curry, and liquorice is also used in breath fresheners.
It is also used in medications, in many syrups, lozenges, capsules, laxatives, cough-lozenges and mixtures to mask bitterness and foul-flavours of other drugs. Liquorice is included in commercial over-the-counter tobacco products like pipe and chewing tobacco and snuffs. (see figure 4, 5 and 6).

Liquorice concentrate-flavour is popular in alcoholic drinks too like Absinthe (thujole containing) and Pernod in France, Anise in Europe and Ouzo in Greece

Medical impact:

Liquorice has many positive and negative health modulating physiological effects, which explain a variety of its medical effects.  The most widely renowned negative action derives from liquorice’s association with hypertension.  Because of the inhibition of 11-beta hydroxysteroid dehydrogenase, by liquorice, cortisol levels are high within the collecting duct of the kidney, and potassium is excreted while sodium is retained. (4) See Figure 7  Cortisol has high mineralo-corticoid properties, i.e. it acts like aldosterone and increases sodium re-absorption from the glomerular filtration in the proximal tubules of the kidney in ENaC channels (3, 4).  Sodium retention leads to higher osmotic intravascular pressure, which in turns retains more water, which increases circulating blood volume with consequent increased blood pressure leading to hypertension. (4, 24).

Figure 7:
Effects of glycyrrhizin. 11βHSD2  reduces formation of cortisone.  Cortisol has a mineralocorticoid effect leading to hypokalamia, hypernatremia, and hypertension.[2] 

Liquorice has a variety of positive healthy effects on the body. For example it is known that Liquorice has anti-viral properties and has some inhibitory effects on HIV, encephalitis and SARS-corona viruses. (11,12, 13, 14)

Also, Glycyrrhetenic acid itself has a retardant effect on peptic ulcers, possibly due to the fact that it has anti-bacterial properties and retards the growth of Helicobacter pylori.(15)
Other medicinal claims are that liquorice is anti-ulcer (peptic, duodenal and aspirin (16,17).  Liquorice induced hypokalemic myopathy may explain why GIT spasms relax, but also why liquorice containing alcohols are said not to induce emesis. (18)  With gastric smooth muscle paralysis, the irritating effect of ethanol is reduced and gastric contraction is temporarily weakened.  Liquorice, among others, is claimed to also be anti-inflammatory, an immune-stimulant, a demulcent, an expectorant, anti-catarrhal, hepato-protective, a GIT spasmolytic, a mild laxative, and an antioxidant. (18,19, 20,21)

Oral and Dental effects:

Glycyrrhyzin by itself does not stain teeth, but when combined with dark food dyes, tobacco and/or curries, liquorice is associated with stains.  Frequently, liquorice is mixed with dark caramel and food colorings which leave a temporary tongue stain (figure 3).

Figure 3
Short lived staining of the tongue after sucking black Licorice confection.  This stain is water-soluble and usually disappears after a few hours.

It contributes to increased tobacco staining, especially when included in aromatic pipe tobaccos; the dental stain is directly proportional to the amount and frequency of the pipe smoking.  Not only is the palatal and lingual side of teeth prone to accumulating dark tobacco stain, but also the mucosa undergoes specific changes. (figure 4)

Figure 4:
Heavy tobacco staining from pipe smoking with Licorice as an additive.  Gingival recession and periodontal pockets result from the deleterious effect of the tobacco smoke.

A common habit among many seniors is to indulge in sucking or chewing flavoured tobacco.  This is most undesirable and unfortunate as this habit produces many deleterious side effects. 
Combined with chewing tobacco, licorice additives enhances and prolongs the flavour of the chewing tobacco experience, and consequently damage from longer contact time onto the gingiva, seems to derive more from tobacco contents rather than just liquorice. Adjacent recession, cervical dentinal staining and thickening with hyperkeratosis of mucosa is seen.

Liquorice, a favourite aroma and taste for women

Among the many fragrances enjoyed by mature women, the smell of liquorice, along with the smell of banana bread, is ranked among their top favourites.  This may also explain why so many seniors (mostly women) have a preference for liquorice flavoured sweets, and why the flavour preferred for many orally administered medicine is liquorice. [40]

Discussion:

Liquorice effects on the body are not widely acknowledged or understood by the public. This is because it is generally safe to eat licorice-flavoured candies, and it is rare for someone to gormandise on them to reach toxic levels.

Hypertension (as high Blood pressure) is presumed to obtain when a measure of 130/90 mm mercury (Systolic/Diastolic pressure) or more is measured, normal being 120/70 mm Mercury.  Hypertension is among the major causes of morbidity and mortality in the world today, and because it is mainly symptomless and painless, hypertension has been labelled “the silent killer.”  Atherosclerosis, myocardial infarction and stroke can all result from chronic undetected hypertension. (22,23,24,25,26)

A linear dose-related rise in blood pressure has been reported with liquorice consumption in various doses of [20-200 Grams a day for 4-2 weeks], corresponding to a daily intake of  75-540mgm glycerrhetinic acid. (27)  This is an inordinate amount of daily liquorice consumption and would be regarded as a “Fad-diet” and not to be sustained for health.
An acceptable daily intake of 0.015- 0.229mg glycyrrhizin/kg body weight/day has been proposed. (28)

Most problems derive from people on diuretic medications in combination with other sources of Licorice.  Hypo-kalemia partially paralyses smooth muscle contraction, and excess imbibing of liquorice flavoured alcohols contributes to gastric paralysis, prevents emesis, and indirectly contributes to the development of alcoholism.  Excess consumption affects blood pressure, kidney function and gastro intestinal tract.  Other than the proven aldosterone effect of liquorice, other medical claims seem inconclusive with regard to cause and effect.  Liquorice contributes in part positively to all these claims, but does not cure or totally prevent severe conditions presenting with these symptoms.
The measured effects are from liquorice-with-drug or alcohol abuse, or experimental observations derived from very high doses given to volunteers or animals in vivo.  More scientifically sound research (double blind, cross over, placebo controlled experiments) to secure cause-and-effect evidence is needed for most of these claims.

Excess liquorice consumption may contribute not only to deteriorating general health through potassium loss and sodium retention, but also to oro-dental compromise with use of chewing tobacco, and chronic habitual frequent swallowing of high content liquorice medications.  Tooth staining from black liquorice is known, but severe staining is mainly from added dyes and tobacco containing licorice.[29]  This allows for a tacky gummy surface of muco-polysaccharides to form, which sticks to stagnant areas on teeth.  With adherent chromogenic bacteria, and tobacco products, teeth discolour and accelerate adjacent gingival breakdown.  Safe removal through scaling and polishing from teeth is feasible.

With regular dental maintenance, regular medical history updates are essential; some dental practices measure blood pressure before any surgery.  Some patients may even volunteer information about raised blood pressure.  Health care professionals should check the diets of all hypertensive patients and besides giving advice about eschewing liquorice products, could refer affected people for early diagnosis and treatment for hypertension.

Conclusion:

Licorice sweets are generally health promoting, pleasant to eat, and on their own rarely stain teeth.  Health care workers, including all in the dental team, discovering new hypertension patients, or noting a history of taking diuretics, should always enquire about consumption or use of any liquorice-containing product.
Unduly stained teeth, or other oro-dental signs of intra-oral chewing tobacco abuse combined with elevated blood pressures, should alert dentists to the possibility of morbidity arising from liquorice toxicity or abuse.

References:

1. Brown D. In ‘Encyclopaedia of Herbs and their Uses.’ 1995. pp 283-4, 289. RD Press Montreal.

2. Sontia B; Mooney J; Gaudet L; Touyz RM, Pseudoaldoseronism Liquorice and hypertension.. Jnl Hypertension. 2008. 10(2); 1-5.

3. The Merck Index. Budavari S Editor. Published data. 12th Edition. 1996. Chemical Formulations. Glycyrrhizin-4515. Cyclamate-2770; Saccharin-8463. Merck & Co. NJ-USA.

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6. Acharya SK, Dasaraathy S, Tandon A, Joshi YK, Tandon BK. A preliminary open trial on interferon stimulator (SNMC) derived from Glycyrrhiza glabra in the treatment of subacute hepatic failure. Indian J Med Res 1993;98 :69-74.

7. Arase Y, Ikeda K, Murashima N, Chayam K, Tsubota A, Koida I, Suzuki Y, Saitoh S, Kobayashi M, Kumada H. The long term effect of glycyrrhizin in chronic hepatitis-C patients. Cancer. 1997.Apr 15: 79(8); 1494-500.

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9. Van Rossum TG, Vulto AG, Hop WC, Schalm SW. Glycyrrhizin induced reduction of ALT in European Patients with chronic hepatitis c. Am J Gastroenterol, 2001. 96(8): 2432-2437.

10. Farese RVJr, Biglieri EG, Shackleton CH, Irony I Gomez-Fontes R. Licorice induced hyper mineralocorticoidism . Potassium depleting diuretics potentiates effects of glycyrrhizin. New Eng Jnl Med 1991; Oct 24.325 (17) 1223-1227.

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14. Hattori T, Ikematsu S, Koito A, Matsushita S, Maeda Y, Hada M, Fujimaki M, Takatsuki K. Preliminary evidence for inhibitory effect of glycyrrhizin on HIV replication in patients with AIDS. Antiviral Res. 1989; II:255-262.

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29. Touyz LZG. Liquorice, hypertension and the dentist. J Can Dent Assoc 2007; 73(6): 467-468.

30. Hirsch Alan(L2004) Tasty Kisses. Chicago Psychiatrist; Conference Association for Chemoreceptive Sciences, Sarasota Florida. April 2004

Declaration: The author has no conflict of interest to declare.

About the author:

Dr. Louis Z.G. Touyz, BDS, MSc(Dent), MDent(OralMed& Perio), FADI, FICD, FPFA, FACD, was born in Johannesburg, South Africa in 1939. Trained originally as a teacher, Dr. Touyz qualified as a dentist in 1962 at the University of the Witwatersrand in Johannesburg, South Africa following which he worked in private general practice for sixteen years. He then specialized in Oral Medicine and Periodontics, receiving a MDent in 1983 from the University of the Witwatersrand.

In 1991, Dr. Touyz was recruited to the McGill University Faculty of Dentistry in Montréal, Québec, Canada as a full time professor in Periodontics, and licensed Periodontist specialist. Today, as Director and Associate Professor in the Dept. of Periodontics, Dr. Touyz teaches and does research in periodontics as well as research in beverages, pain, HIV/AIDS and other subjects.