Licorice Towards Safe Use

LICORICE TOWARDS SAFE USE A.Abouelnour

University of Westminster, London, United Kingdom

Table of Contents:

1.Introduction: .................................................................................................................................. 1

2. Research Design: .................................................................................................................... 2

3. Licorice Background: ............................................................................................................... 3

3.1. Botanical Origin: ...................................................................................................................... 3

3.2. Historical Uses: ........................................................................................................................ 3

3.3. Modern Uses: .......................................................................................................................... 3

3.4. Active Constituents: ................................................................................................................. 4

3.5. Pharmacological Activity .......................................................................................................... 5

4. Evidenced Risks for Adverse Effects: ...................................................................................... 6

4.1. Glycyrrhizin Metabolism: .......................................................................................................... 6

4.2. Genitourinary System .............................................................................................................. 7

4.3. Electrolyte Balance and Hypertension ..................................................................................... 8

5. Growing Evidence of Risk for Adverse Effects: ........................................................................ 8

5.1. Central Nervous System interactions ....................................................................................... 8

5.2. Genetic Variations: .................................................................................................................. 9

11-ß-Hhydroxysteroid dehydrogenase II: ....................................................................................... 9

UDP-glucuronosyltransferase ........................................................................................................ 9

5-ß reductase ................................................................................................................................. 9

5.3. Interactions with other drugs: ................................................................................................. 10

5.4. Maximum Tolerated Dose ...................................................................................................... 10

6. Regulatory Situation .............................................................................................................. 11

7. Marketed products overview .................................................................................................. 12

8. Discussion and Conclusion .................................................................................................... 13

9. Attachments .......................................................................................................................... 15

9.1. Bibliography ........................................................................................................................... 15

9.2. Case Reports: ........................................................................................................................ 15

LICORICE TOWARDS SAFE USE

1

1. Introduction:

The interest in the herbal medicinal preparations is not only attracting scientific research

but expands to cover the pharmaceutical market and consumers too. For researchers,

intensive studies are being designed and done studding the efficacy and safety of several

preparations assuring either evidence of specific indication or a new indication(s) for certain

herbal preparation or possible short term or long term side effects in either as randomized

clinical trials, in-vitro studies, observational studies or review of these studies finding

comparing finding and analyzing results comparing with the historical inherited folkloric

uses. For Pharmaceutical companies, especially intermediate and small size companies,

looking for licensing their products and marketing them with limited regulatory restrictions,

process and cost of approvals compared with other orthodox medicines have found their

interest in that market segment however the severe competition between similar products

using the recent communication tools for accessing their consumer via internet and social

media advertisements. For patients who are suffering from getting orthodox medicines for

chronic diseases without relief and even getting side effects of these medicines are being

growing their interest to herbal medicines in either the form of visiting herbal practitioners

rather than physicians or getting herbal medicines rather than their chronic prescribed

medications. For consumers who are just getting into acute symptoms of either cold, flu,

cough, fatigue, headache are growing use of herbal medicines specially with their busy life

schedule and long waiting patients queues in clinics considering that these products may

be more safe or effective than other over the counter products((Ong et al., 2005;Studdert,

1998). For both consumers and patients herbal medicines would be more effective than

other orthodox medicines that they used to use taking into that orthodox medicines are

either activating or blocking certain receptors within certain organ or tissue and the simple

concept of down regulation mechanism of certain receptor associated with prolonged

activation or blockage of this receptor resulting in limitation of that drug efficacy with

prolonged use so these herbal medicines would be ,for sure, trustful for those groups of

patients (Dickenson et al., 2012) .Other factors promoting the patient and consumers

access for herbal medicines are the availability of these herbal medicinal products as over

the counter products and online marketing tools used by pharmaceutical companies

facilitating the access to these products where figures show that 80% of world population is


2

getting these herbal preparations (Ekor, 2014). Both the herbal medicines positive

response and the percept thinking that those products are generally safe may potentiate

the risk of repeated administration of certain drugs preparations whose long term safety is

still unclear, not evaluated, under research, or associated with risk either if administered

alone or in case of interaction with other co administered drugs or in cases associated with

certain risk factors or diseases either diagnosed or silent.

licorice is considered as one of the most common used herbal medicines either alone or in

combinations with other herbs in different over the counter products in many countries for

several indications and in different forms either in children (Taylor et al., 2015) or adults .In

USA it is one of the top 40 sales herbal medicines of around 60 million USD sales in 2012

and positive 15% growth (Lindstrom et al., 2013).

2. Research Design:

The aim of this research is to study the herbal medicinal pharmaceutical over the counter

products containing Licorice, short term safety consideration , prolonged term safety

consideration and risks associated with these products in cases associated with other

diseases either diagnosed or still and co-administered medicines trying to explore gaps and

point the regulatory and research questions needs an answer to avoid any risk avoiding the

reoccurrence such events associated with some other herbal medicines like Kava Kava

(USA FDA, 2002) or st john’s wort (Rey and Walter, 1999).We will highlight an over view on

licorice botanical characters ,constituents, pharmacology of constituents, recorded

interactions of (Clinical trials and case reports) , other possible pharmacological

interactions of risk of occurrence ,regulatory status of over the counter sold products and

labeling of these products in different countries to put conclusion and recommendations ,if

applicable, for appreciate use of these products to avoid any risk. Although there are more

than twenty species identified within the genus Glycyrrhiza but This research will include

only published literature covering the Glycyrrhiza glabra L species only which is the mainly

used species in western herbal medicine (Kew Royal Botanic Garden, 2016) in the search

terms of Licorice, Liquorice or. Glycyrrhiza glabra. Researches published on other species


3

will be only used if outcomes are only validated by parallel control experiment using

standard or standardized glycyrrhizin or glycyrrhetinic acid.

3. Licorice Background:

3.1. Botanical Origin:

Licorice is herbaceous perennial plant belonging to family Fabacaea and genus

Glycyrrhiza.with scientific name of Glycyrrhiza glabra L and other 22 scientific names

considered to be synonyms where the most common is Glycyrrhiza glandulifera (Kew

Royal Botanic Garden, 2016). Licorice is native to North Africa, China, Magnolia, Siberia,

Western Asia and Eastern, Southwestern and southeastern Europe and cultivated widely in

different countries (U.S. National Plant Germplasm System, 2007).

3.2. Historical Uses:

Historical data shows it was used in prehistoric era by ancient Greek, Egyptians, Chinese

for either sweetening and or medicinal uses for treatment of several indication like cough,

heart burn, kidney stones, skin ulcers, fever and pain (Fiore et al., 2005).recently

Licorice is used as an additive sweetener for food and drinks due to the presence of

glycyrrhizin which is 50 times more sweetener than sugar, added to tobacco products and

as an ingredient on many cosmetic products or additive in pharmaceutical industry specially

as a masking agent to overcome the bitter taste in liquid preparations (Obolentseva et al.,

1999)

3.3. Modern Uses:

Medicinally it’s root is used widely either as tincture or fluid extract or ingredient in over the

counter pharmaceutical products for cough, antitussive, expectorant, asthma, peptic ulcers

and hepatic-protective products due to its, anti-inflammatory, anti-ulcerative demulcent,

antimicrobial and hepatic-protective activities (Peng et al., 2015).In Japan, Intravenously,

licorice components are used for treating hepatitis B and C (National Center for

Complementary and Integrative Health, 2016). Other indications still under research like

https://en.wikipedia.org/wiki/Glycyrrhiza


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different cancer conditions (Colon, Breast, Hepatic and Prostate), ant diabetic,

antiangiogenic, neuro-protective, rheumatoid arthritis and cardio-protective (Peng et al.,

2015).

3.4. Active Constituents:

The main active component of Glycyrrhiza glabra is Glycyrrhizin (known also as 18β-

glycyrrhizic acid or glycyrrhizinic acid) which is a triterpenoid saponin glycoside responsible

for the sweetening taste of Licorice present in a mixture of calcium, potassium and

magnesium salts in range of 4% to 20% in root .The molecule is composed of two parts

which are the sugar part composed of two molecules of D-glucuronic acid and the aglycone

part known as 18β-glycyrrhetic acid or enoxolone (Sabbioni et al., 2005).(figure 1)

Figure 1: Structure of Glycyrrhizin (A) and 18β-glycyrrhetic acid (Sabbioni et al., 2005)

Many other flavonoids are identified in Glycyrrhiza glabra roots but the most important are

liquiritin, isoliquiritin and their single aglycones which are giving the roots the characteristic

yellow color and representing around 1 to 1.5% of the liquid extract. Other ingredients are

Carbohydrates (Sugars and Starch), amino acids, proteins and Lipids (Isbrucker and

Burdock, 2006).


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3.5. Pharmacological Activity

Glycyrrhizin had an antiviral activity against human immunodeficiency virus, herpes simplex

virus, hepatitis B and hepatitis C viruses however the mechanism still not known. It may be

attributed to inhibition of viral adherence to host cell , replication , other transduction

mechanism , stimulation of immune system or a complex mechanism involving one or more

of the previous(Fiore et al., 2007).In Japan , intravenous glycyrrhizin improved liver function

and serum hepatic transaminases (Coon and Ernst, 2004).

Hepatoprotective effect of glycyrrhizin was examined in different animal and in-vitro models

suggesting showing reduction in induced liver toxicity with carbon tetrachloride speculating

the possible mechanism to be related with inhibition of hepatic cytochrome P450 2E1

activation of tetrachloride (JEONG et al., 2002).other studies showed reduction in induced

liver cells inflammation on induced by tumor necrosis factor alpha by glycyrrhizin (Chen et

al., 2014 ) which needs more confirmation with other different hepatic induced injuries or

other transgenic or knock-out animals.

Recent studies shown the positive effect of alcoholic root extract of Glycyrrhiza glabra on

induction of autophagy-related cell death in cancerous prostatic cell lines and down

regulated the cell division in breast cancerous cell induced by endocrine disturbing

chemicals but still these finding need more validation by further research efforts.

In modulating and enhancing immune response ,experiments results showed some

contradiction where glycyrrhizin had an up-regulating effect over dendritic cells and

immune responses via T helper 1 response (Bordbar et al., 2012) while on other

experiment 18β-Glycyrrhetinic acid impaired that up-regulation (Kim et al., 2013) which still

remain a research question.

The antitussive effect of water extract of Glycyrrhiza glabra on guinea pigs was more

effective than codeine (Saha et al., 2011). glycyrrhizic acid recovered the interleukin (IL)-4,

IL-5, IL-13 levels in ovalbumin-induced asthma animal model (Ma et al., 2013).

Glycyrrhizin also enhanced the activity of both epoxide hydrolase and thioredoxin

reductase enzymes restoring the NF-κB (Qamar et al., 2012).


6

For gastrointestinal activities, It was found that the liquid extract has an effect against

peptic ulcers by increasing the level of local mucosal prostaglandins and nitric oxide ,by

inhibiting the enzyme responsible for the breakdown and metabolism of Prostaglandin E2,

thus resulting in increase in gastric mucus secretion and healing and of ulcers(Jalilzadeh-

Amin et al., 2015).It was interesting that the glycyrrhizic acid-free extracts produce the

same effect which may attribute the gastric healing mechanism to other flavonoids content

of the extract. More researches showed that isolated flavonoids from different species of

Glycerrihzia had an antimicrobial activity against Helicobacter pylori which may be also a

synergetic effect beside the first mechanism acting by inhibiting Prostaglandin E2

metabolism however it is limited in glabra Species ( Fukai et al., 2002).The first mechanism

needs more researches for confirmation where experiments and trials are done since more

than 30 years missing many quality aspects of blinding ,randomization and control where

structure activities studies can at least now serve as adjunctive tool for potentiating or

declining the hypothesis of this theory.

In clinical trials both extract and Glycyrrhiza glabra and pure glycyrrhetinic acid had an

improving outcomes for Helicobacter pylori (Puram et al., 2013), nonerosive reflux (Di

Pierro et al., 2013) however the later study included other interventions beside the

glycyrrhetinic acid which may had an effect beside.

Other activities studied and shown positive findings were anti-oxidant activity (Malekinejad

et al., 2010), Anti diabetic (Kuroda et al., 2010), Hypnotic (Cho et al., 2012), Anticonvulsant

(Chowdhury et al., 2013), anti-Parkinson’s (Teng et al., 2014) anti-Alzheimer (Zhu et al.,

2010), Cardio protective (Ojha et al., 2013)

4. Evidenced Risks for Adverse Effects:

4.1. Glycyrrhizin Metabolism:

Metabolism of Glycyrrhiza glabra is a complex process which involves different interaction

with human body affecting the physiological balance on different levels. Although it was

considered that the structural similarity of glycyrrhizin and its metabolite 18β-glycyrrhetic

acid with some endogenous steroidal hormones may be the main reason for that


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interference, some more recent studies showed that the flavonoid content of the extract

may also play a role in that interference. It is essential to study the metabolic cycle of

components of Glycyrrhiza glabra for better understanding of risk interference points that

may affect body functions causing adverse effect and other benefits that may be beneficial

therapeutically either for certain patients or healthy populations. Focusing over the main

constituent glycyrrhizin, Studies showed that it is has poor oral bioavailability where it

hydrolyzed after oral administration into the aglycone(18β-glycyrrhetic acid or enoxolone)

by the effect of intestinal flora hydrolytic enzyme ß-glucuronidase where 18β-glycyrrhetic

was found to inhibit both forms of enzyme hydroxysteroid dehydrogenase which are

responsible for regulation the body balance of both Cortisol and Cortisone where the first

isoform (hydroxysteroid dehydrogenase I) is responsible for reduction of cortisone to the

active cortisol that activates glucocorticoid receptors while the second isoform is

responsible for the oxidation or cortisol to cortisone. The balance produced by the both

enzyme isoforms is a key factor for prevention of extra activation of mineralocorticoid

receptor (originally activated by Aldosterone) that may result by Cortisol due to its structure

similarity with Aldosterone (Ploeger et al., 2001).

In liver, Absorbed Glycyrrhetic acid is then conjugated with glucuronide or sulfate which

then pass into entero-hepatic circulation where these conjugates undergo further hydrolysis

by intestinal flora (Ploeger et al., 2001), however some recent studies shown that

glycyrrhetinic undergo metabolism via CYP3A4 (Zhao et al., 2012). The intestinal motility is

a key factor for the later hydrolysis reaction where in populations of poor motility may

increase the level of the metabolites .more recent studies showed that glucuronidated

glycyrrhetinic acid inhibited selectively the second isoform of the 11-ß-Hhydroxysteroid

dehydrogenase enzyme by its action on hepatic transporters which depends on the

situation of liver function (Makino et al., 2012b).

4.2. Genitourinary System

The alcoholic extract of Glycyrrhiza glabra reduced the prostate weight in male

immature rats in doses of 150 and 300 mg /kg. However the mechanism is not known but

still highlights the antiandrogenic activity of Glycyrrhiza glabra (Zamansoltani et al., 2009)


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However the estrogenic activity of Glycyrrhiza glabra was demonstrated before in an

animal study and was attributed to estrogenic receptor subtype α(Simons et al., 2011) ,still

glabra species is the least species activating the estrogen receptors in animal models

(Hajirahimkhan et al., 2013).However ,these data early to depend on but it highlight the

importance of more docking studies for the estrogenic receptors with the active

components of Glycyrrhiza glabra to elucidate the possible activity parallel with some

observational studies for the populations getting different extracts of Glycyrrhiza glabra or

even preparations with glycyrrhizin alone.

In clinical trials data, glycyrrhetinic acid increased the levels of deoxycorticosterone,

testosterone and Dehydroepiandrosterone in saliva (Al-Dujaili et al., 2011)

Moreover, The dose of 1140 mg/day of Glycyrrhiza glabra extract reduced the durations of

hot flushes which may be associated with estrogenic activity. These findings potentiate the

estrogenic activity however it was not clear the standardization of the intervention used in

the trial which may attribute the activity to other components beside the glycyrrhizin.

4.3. Electrolyte Balance and Hypertension

Glycyrrhetinic acid in dose of 1000 mg daily for 6 months reduced serum levels of

potassium in dialysis patients (Farese et al., 2009).This may be of potential considerations

in patients administering licorice and already having electrolyte imbalance .It is worth

mentioned that all the above findings contraindicate the concurrent use of both licorice

(either crude or as glycyrrhizin) with corticosteroids due to the potential risk of hypertension

and other related resulting complications.

5. Growing Evidence of Risk for Adverse Effects:

5.1. Central Nervous System interactions

Studies shown the possible effect of alcoholic extract of Glycyrrhiza glabra on gamma-

amino-benzoic-acid receptors and benzodiazepines in cell line experiment, although the


9

study neglects the blood brain barrier effect for the body system but still matches with

findings of anxiolytic effect of licorice (Cho et al., 2012).

5.2. Genetic Variations:

The concept of genetic variation is growing rapidly in recent days where discovery of

human genetic map and other running projects like HapMap is providing a tool for scientists

to predict sources of different drug responses between different genetic structure

individuals to limit adverse effects and get the optimum efficacy (Dickenson et al., 2012)

.Here bellow some possible sources of risk may be associated with licorice based on

individual genetic variations.

11-ß-Hhydroxysteroid dehydrogenase II:

For the risk of lower 11-ß-Hhydroxysteroid dehydrogenase II activity which is mainly may

be due to a genetic variation of certain alleles, only one study found to highlight this effect.

However the author suggested that genetic variation within 11-ß-Hhydroxysteroid

dehydrogenase II is not the reason for licorice associated hypertension and predisposed

that to genetic variations in epithelial sodium channel gamma subunit, it is still limited by

only 2 11-ß-Hhydroxysteroid dehydrogenase II variants covered by the research and

neglecting of other outcomes may be monitored to get full profile of those variant. More

studies should be done on that area to cover the different alleles and different related

outcomes like aldosterone activity, rennin, Cortisol and Cortisone (Miettinen et al., 2010).

UDP-glucuronosyltransferase

Both glycyrrhizic acid and glycyrrhetinic acid caused inhibition for some tested isoforms of

UDP-glucuronosyltransferase enzyme (UGT1A1, UGT1A3, UGT1A9, and UGT2B7)

(Huang et al., 2012) which may be a highlighting a caution with different genetic variants of

the enzyme isoforms specifically if co-administered with other drugs inhibiting these

enzymes too which may lead to toxicity.

5-ß reductase

It was shown that glycyrrhetinic acid had an inhibitory effect on 5-ß reductase activity in

male rats which may result in elevated Aldosterone levels. (Latif et al.1990). It is important


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factor to be considered in inherited poor 5-ß reductase activity.Combining thes data with

the previous effect of Glycyrrhiza on the 11-ß- hydroxysteroid dehydrogenase II may

highlight the potential effect of licorice on enhancing Pseudo-hyperaldosteronism or

exaggerating the case in populations with genetic variation in encoding genes of the 11-ß-

hydroxysteroid dehydrogenase II with either enzyme reduced expression, altered activity or

complete defect.

5.3. Interactions with other drugs:

Researches in on human liver microsomes showed the inhibitory effect of glycyrrhetinic

acid CYP2C9, CYP2C19 (Zhao et al., 2012).Further animal experiment showed that

glycyrrhizin increased the serum level of Cyclosporine which was attributed by author to

excitatory effect of glycyrrhizin on CYP3A4 and P-glycoprotein (Hou et al., 2012) which

may be confirmed by the effect of aqueous extract of Glycyrrhiza glabra on reducing

Verapamil serum level which is a substrate for CYP3A4 (D. Al-Deeb et al., 2010

;DrugBank: Verapamil). However these results needs more in-vivo experiments for

confirmation but still highlights the importance of monitoring the effect of the co-

administered drugs metabolized by those enzymes specially those of narrow therapeutic

index due to potential risk of toxicity or loss of efficacy in either case respectively.

Glycyrrhizin had an increased the serum level co-administrated Methotrexate in rats (Lin et

al., 2009 ) which highlight a caution in patients getting Methotrexate to be advised to avoid

getting either licorice or glycyrrhizin containing products .

Due to the hypokalemic effect of licorice, It should not be concurrently used with diuretics

generally and potassium non-sparing diuretics specifically. This was confirmed also through

a clinical trial combining daily doses 25 mg hydrochlorothiazide and 32 g of licorice

(Hukkanen et al., 2009).Although these doses may seems to be high but it is logic and

matching all the above studies.

5.4. Maximum Tolerated Dose

It is not easy to determine a specific dose of licorice due to the complexity of active

ingredients in licorice and also it’s’ complex effects on different body function. Also the


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variability of different grades and sources of licorice itself and extraction methods plays a

role beside the variable populations getting these preparations for variable reasons. Clinical

studies shown that a daily dose of 200 mg of glycyrrhizin was tolerated without observed

adverse effects (Bernardi et al., 1994).Although this study gave a dose the tolerated dose

,it covered only small group of healthy volunteers for short period of 2 weeks and only

evaluated limited markers of adverse effects .More studies of more wide representative

population groups (age ,sex, ethnic origin) ,longer exposure and more markers of adverse

effects will be needed for better understanding.

6. Regulatory Situation

In US Food and Drug Administration FDA, licorice and licorice derivatives are regulated as

food supplements and the code of federal register 184.1408 (21 CFR 184.1408) is

highlighting the maximum allowed glycyrrhizin content in different formulations. It neglects

the frequency of administration and the duration of use (FDA, 2015). Within Over the

Counter OTC monographs, licorice is included within three categories of OTC products for

either smoking prevention , orally administered menstrual drug products and aphrodisiac

products (FDA, 2015b)

In the European Medicines Agency EMA, Glycyrrhiza glabra L. and/or Glycyrrhiza inflata

Bat. and/or Glycyrrhiza uralensis are combined within one approved monograph on

2012.The monograph did not include any well-established use data were all data included

was only under traditional use sections. Indications approved were burning sensation,

dyspepsia, expectorant in cough associated with cold. However the monograph stated the

dose allowed for each indication but the mentioned dose did not consider the

standardization of the used extract or dry herb with either glycyrrhizin or other marker

compound which did not count for the variability of active components levels within different

species within monograph or even different sources within same species. The monograph

limited the duration of use for maximum of 4 weeks for gastric indications and for one week

for respiratory indications. The monograph used the term of “not recommended” in special

warning section for patients having hypokalemia, hypertension and cardiac rhythm

disorders but this term seems to be weak regarding the possible adverse effects related to


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these conditions which may better to be “must not use “instead. The monograph highlighted

the warning of concurrent use of diuretics, cardiac glycosides, corticosteroids, stimulant

laxatives or other medications which may aggravate electrolyte imbalance with licorice

preparations (Committee on Herbal Medicinal Products HMPC, 2012). It is worth for EMA

to revise precautions to add warning for males with Testosterone imbalance and benign

prostatic hyperplasia and females of estrogenic imbalance too (Hajirahimkhan et al., 2013;

Zamansoltani et al., 2009).

In Canada, Licorice is licensed as Natural Health Products where the official monograph of

Licorice is specific for Glycyrrhiza glabra and it specify the dose in either dried licorice root

or Glycyrrihzin as dose per day in minimum and maximum allowed amounts which is

maximum 100mg of Glycyrrihzin for children bellow 4 years and 600 mg for adults for

duration of 4 to 6 weeks (Health Canada, 2007).However contraindications are completely

matching with the EMA monograph but the only difference is that in Canadian monograph it

is stronger than that of the EMA monograph where the term “don’t use if” instead “not

recommended”.

In Australia, the Therapeutic Goods Administration TGA considered the species differences

also where Glycyrrhiza glabra is listed as Herbal Substance. Monographs did not specify

the dose or the precaution as they may depend on the specific electronic published

products’ characteristics which is published for each products (TGA eBusiness services,

2000)

7. Marketed products overview

To get a better understanding over the marketed products in the aspects of how labels of

these products are, forms, standardization and doses it was mandatory to search the

licensed products databases. Unfortunately the US FDA did not include an official data

base for marketed food supplements. In European Union, Traditional Herbal Registration

THR database within the Medicines and Health Regulatory Authority was examined

(MHRA, 2014) where 4 licensed products were found containing Glycyrrhiza glabra .Three

of these preparations were licensed for relief of chesty coughs, mucus coughs either as a

single component (1) or combined with other herbs (2).The main comments over the MHRA


13

published approved labels of these products that these products were allowed for use in

age over 12 years although the EMA monograph was only approving for age of over 18 and

neither labels not products characteristics included the amount of Glycyrrihzin any of these

products (Committee on Herbal Medicinal Products HMPC, 2012 ;MHRA, 2015).

In Australia, There are 193 products published on the TGA website containing Glycyrrhiza

glabra either single or combined with other ingredients. Main indications and forms were

either oral (Laxative, cough, dyspepsia, general wellbeing Including stress, brain and

memory functions, heart and vessels health, liver detox, women wellbeing and relief

menstrual symptoms) or topical (management of psoriasis, eczema and dermatitis).Labels

included the equivalent amount of the dry herb used in formulation which may be helpful for

patients and consumers to quantify their consumptions. In cough syrups, it was allowed for

children for over 2 years. In liver and gastric products, there were not any contraindications

or precautions in regarding hypertensive, hypokalemic, kidney patients although most of

these products are used by elderly populations who might be already in one of these

conditions regardless if even small quantity (TGA search)

In Canada, There are 94 licensed products as natural health products either in single form

or combinations and indications mainly for cough and gastric uses (Health Canada, 2014).

8. Discussion and Conclusion

It is clear on from the research the complexity of actions of licorice over many of body

functions, various organs (Digestive, Endocrine, Immune and g) and interference with many

physiological functions. However most of these effects were attributed to Glycyrrihzin or its

metabolites but still remain something related to complexity of ingredients in licorice which

may not been identified yet. Identified potential risks like hypokalemia, heart disease,

kidney diseases and hypertension are important but still there is a growing evidence of

interference with other body functions that may be a potential risk. These all requires a

great effort and collaboration between the researchers, regulatory authorities, industry and

consumers.


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In relation with researchers and science, there are many research questions still need to be

answered for both efficacy and safety considerations. For safety, this is the main core of

this research, still the growing evidence of relation of licorice with interference with sexual

hormonal balance (Hajirahimkhan et al., 2013; Zamansoltani et al., 2009) .Metabolic

pathways and possible interference with hepatic cytochrome metabolic enzymes in

excitatory or inhibitory effect and how that interference may be affecting other co-

administrated drugs. Genetic variations may be a potential risk also (Miettinen et al., 2010)

For regulatory authorities whose main task is to ensure safety, efficacy and quality of health

products, It is still only focusing mainly on quality of herbal medicinal products where

regulatory requirements focusing on Good Manufacturing Practice GMP and Good

Agricultural and Collection Practice GACP which mainly focus on the quality of the herbs

used as a raw material with standardization (Anquez-Traxler, 2011) but still the safety area

needs more concern through various channels. It was clear from the case reports (Table1)

that the subjects are mainly over 40 years old with excessive use of licorice preparations

for prolonged time which may indicate that the precautions on labels on marketed products

may be not enough to protect consumers against those adverse effects either in acute

toxicity or with chronic toxicity. Presence of many other marketed products which still not

licensed is another source of risk which requires more strict legislations to stop any

potential hazards and ensure monitoring. However Pharmacovigilance concept is already

introduced in herbal medicinal products in the form of adverse effects reporting (Yellow

Cards) but in certain herbs like licorice is still not sufficient to ensure the consumer safety

where it may be better for regulatory authorities to think about adopting a higher level of

monitoring of such complex product by enforcement for companies to submit of periodic

safety update reports and risk management plans like in other pharmaceutical products

(European Medicines Agency, 2016).Regulation of internet advertisement campaigns and

better consumers and patients education about licorice may be an adjuvant beneficiary

measurements with continuous updates for monographs of licorice and products’ labels

one required beside continuous risk assessments for detecting the potential risk sources.


15

In conclusion, answering the research questions from researches with more appreciate

monitoring and continuous update by regulatory authorities may help to ensure an

appreciate use of licorice getting the most benefits and avoiding any adverse effects.

9. Attachments

9.1. Case Reports:

Summary of recorded case reports in last 10 years related to Glycyrrihzin or Glycyrrhiza

glabra.

No Case Origin Relation Reference

1

59 old man with chronic

hypertension with

palpitations, weakness,

and faintness

Getting 10-20 cups of

herbal tea containing

licorice (Concentration

not confirmed)

Hypokalemia

(Henderson et

al., 2010)

2 30 years male with

rhabdomyolysis 30 g daily of licorice

Hypokalemia

(Lapi et al.,

2008)


rhabdomyolysis

2 Tablets daily of


not confirmed

Hypokalemia

(Lapi et al.,

2008)


rhabdomyolysis

2-3 g of concentrated


not confirmed

Hypokalemia

(Lapi et al.,

2008)

5

49 years woman with

cerebral

vasoconstriction

1 / per day for 4 months Hypertension (Striano et al.,

2011)

6 49 years woman with

headache

Excessive (dose Not

Confirmed) Hypertension

(van Beers et

al., 2011)

7 49 year-old man with

headache

licorice 3 g/day for 3

years

Hypertension

hyperaldosteronis(Imtiaz, 2010)


16

m

8 44 year-old woman with

Carpal tunnel syndrome

licorice sticks in

excessive amount (dose

Not Confirmed)

Edema

hyperaldosteronis

m

(Taconi et al.,

2009)

9

71year s old woman

with hypotension and

bradycardia

large quantities

of licorice

(dose Not Confirmed)

hypokalemia

hyperaldosteronis

m

(Crean et al.,

2009

10 50 year old dead

woman Not confirmed

hypokalemia

arrhythmia

(Yorgun et al.,

2010)

11

49-year old woman with

peripheral edema and

hypertension

Not confirmed hypokalemia

hypertension (Johns, 2009)

12 51 year-old woman with

hypertension

5 years of daily 750–800

g Salty Norwegian

licorice

hypertension

(Ruiz-

Granados et

al., 2012)

13 A 47 years old woman

with Peripheral oedema

several sachets of raw

licorice candies for one

month

Peripheral edema

hypokalaemia

(Flores

Robles et al.,

2013)

14 A 47 years old man with

edema and weakness

500 mg glycyrrhizic acid

in form of beverage on

one day

Peripheral edema

hypokalaemia

(Celik et al.,

2012)

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Health & Medicine

Licorice Towards Safe Use