A Systematic Review of the Effect of Licorice on Head and Neck Chemotherapy- and Radiotherapy-Induced Mucositis

Abstract

Head and neck cancers are among the most common cancers in the world. The main treatments for these cancers are radiotherapy and chemotherapy, which will cause many side effects, the most important of that is called mucositis. This study was aimed to evaluate the effect of licorice on oral mucositis. The research question was designed according to the Patient/Population, Intervention, Comparison, and Outcomes (PICO) framework, and data were obtained from PubMed, Scopus, Embase, Google Scholar, Science Direct, Springer, Web of Science, Cochrane Science Direct, and ProQuest databases. The search strategies, inclusion and exclusion criteria, validation of selected studies, extraction of the results of each study, impartial interpretation of results, summarizing, discussion, and conclusion of the results were also determined. In the initial search based on the search line and limitations, 143 articles were obtained, 85 of which were excluded because they were irrelevant and their full text was not available. The, 42 articles were excluded because they did not have enough information and were duplicates or reviews. Finally, 16 articles remained, from which nine articles examined the effect of licorice on mucositis. Licorice and its compounds are effective in reducing the duration and severity of chemotherapy- and radiotherapy-induced pain and inflammation. Further, its topical or systemic application can alter its efficacy.

INTRODUCTION

Head and neck cancers are among the most common cancers around the world. Radiotherapy and chemotherapy are the main treatments for these cancers, which will cause many side effects, the most important, of which is mucositis. Oral mucositis is the most common type of mucositis in these patients and is often debilitating during the treatment of cancer. Head and neck cancers account for 35% of all cancers.

In this complication, which is a painful inflammation of the mucosal membranes, patients are unable to eat, and their quality of life and treatment change drastically. It is also too costly for the health systems. There are several treatments to prevent and treat this complication, but none of them can completely improve the mucosa, and they are mainly sedative treatments. Recently, studies have focused on natural products such as honey and its compounds and plant compounds to improve mucositis, which has yielded promising results. One of these products is a plant called licorice. Licorice is used for the treatment of gastric ulcers, dental caries, candidiasis, and gingival diseases owing to its anti-inflammatory, antioxidant, antimicrobial, and antiviral properties.[1,2,3,4]

Over the past few years, the use of complementary and alternative medicine has become popular.[5] One of the treatments in complementary medicine is the use of herbal medicine, which has received general public acceptance due to the lower side effects.[6] One of these medicinal herbs is licorice, which is considered by pharmaceutical and food industries due to a large number of flavonoids.[7] The natural form of this substance is useful in the treatment of mouth and digestive tract ulcers.[8] A study conducted by Das et al.[18] in 2011 found that licorice was effective in preventing and treating oral mucositis caused by radiotherapy in patients with cancer in the head and neck without any interruption in treatment. According to these studies and the use of complementary medicine in mucositis by patients undergoing chemotherapy, licorice can be applied to reduce the complications of chemotherapy due to its prominent anti-inflammatory symptoms.

Studies have shown that licorice and its compounds may play a role in the treatment of radiotherapy- and chemotherapy-induced mucositis symptoms in patients with head and neck cancers. Due to the extensive therapeutic properties of this plant in inflammatory and oral diseases, the present systematic review was conducted to investigate the effect of licorice on the improvement of radiotherapy- and chemotherapy-induced mucositis in patients with head and neck cancer and compare it with other therapeutic methods.

MATERIALS AND METHODS

A total of 16 studies were reviewed. The inclusion criteria were Persian and English full-text articles on the effect of licorice on mucositis based on the topic and Population, Intervention, Comparison, and Outcomes (PICO) framework from 1970 to date. The exclusion criteria consisted of duplicate and irrelevant articles, articles whose full texts were not available, reviews that used the articles we reviewed separately. Two reviewers independently extracted data on study design, sample size, intervention details, outcomes, and adverse events. Quality was assessed using Cochrane risk-of-bias tools and Newcastle-Ottawa Scale.

The research question formulated based on the PICO model was “Can licorice improve radiotherapy- and chemotherapy-induced mucositis in patients with head and neck cancer?” According to the designed research question, the intended PICO was the samples of oral mucositis caused by the head and neck chemotherapy or radiotherapy, animal models with induced oral mucositis, and cell lines that received licorice.

Type of participant

Cancer patients treated with chemotherapy or radiation therapy.

Type of intervention

Participants in the intervention groups were treated with licorice or licorice-related medicine combined with chemotherapeutic drugs. There was no concern about the forms of interventions (e.g., decoction, capsule, acupoint patch gel, and granule), the dosage, or the treatment duration. The control groups used chemotherapy alone, chemotherapeutic drugs plus a placebo, or chemotherapeutic drugs plus western medicine. The control groups used chemotherapy alone, chemotherapeutic drugs plus a placebo, or chemotherapeutic drugs plus western medicine.

Type of outcome measure

Mainly focusing on chemotherapy-induced side effects, such as fatigue, oral mucositis, anorexia, anemia, constipation, etc.

Oral mucositis samples that received licorice were compared to the other groups that received treatments other than licorice or were not being treated for their mucositis. The results comprised the effect of licorice on improving the symptoms of oral mucositis such as oral, gingival, and tongue ulcers, pain and burning sensation in the throat and mouth, difficulty swallowing and chewing food, increased mucosal secretion in mucus-secreting areas, etc., in the study population.

The selected search line using MeSH included (stomatitis or oral mucositis) AND (glycyrrhiza or licorice or licorice or glycyrrhiza glabra) AND ((chemotherapy or antineoplastic agents) OR (head and neck radiation therapy). PubMed, Google Scholar, Scopus, Embase, Cochrane, Science Direct, Database of Abstracts of Reviews of Effects (DARE), Clinical Data Repository (CDR), Springer link, Magiran, Magiran, and Iran Medex databases were searched to retrieve the published articles. Other unpublished resources such as books, theses, conferences, etc., from 1970 to 2021 were also used to gather the required data.

Quality assessment

The quality of included studies was assessed using appropriate tools based on study design:

• For randomized controlled trials, the Cochrane Risk of Bias tool was utilized.

• For observational studies, the Newcastle-Ottawa Scale was applied.

• Qualitative studies were assessed using the Critical Appraisal Skills Programmed (CASP) qualitative checklist.

• This assessment was carried out by two independent reviewers, and any disagreements were resolved through consensus.

Inclusion and exclusion criteria

First, the titles of the articles obtained from the search strategy were reviewed. Topics related to the research question were selected. If the title of the article was too far from the research question, the article was excluded, and if the title was far away but could partially cover the objectives of the study, the summary of the article was reviewed and a decision was made about it. Next, the summary of the articles selected for inclusion in the current systematic review was reviewed. We tried to include as many as possible. As the number of licorice-related studies, the study size is small-scale.

For example, some of the criteria that were set for the inclusion of articles were:

• Patients with head or neck cancers undergoing radiotherapy or chemotherapy, who suffered from mucositis not being treated.

• Patients with head or neck cancers undergoing radiotherapy or chemotherapy, who suffered from mucositis (population) and were not under treatment with therapeutic methods (comparison) other than licorice (intervention).

• Patients with head or neck cancers undergoing radiotherapy, who suffered from mucositis under treatment with licorice.

• Patients with various types of cancer undergoing radiotherapy or chemotherapy, who suffered from mucositis and were under treatment with various interventions.

• Patients with various types of cancer undergoing radiotherapy or chemotherapy, who suffered from mucositis and were under treatment with licorice or other interventions.

Patients with mucositis under treatment with licorice or other treatments compared to licorice.

RESULTS

In the initial search based on the search line and limitations, 143 articles were obtained, from which 85 were excluded because they were irrelevant and were not full-text articles. Of the remaining 58 articles, 42 were excluded because they did not have enough information and were duplicates or reviews. Finally, 16 articles were left, nine of which examined the effect of licorice on mucositis [Figure 1].

Figure 1.

Study flowchart

The pharmacological and therapeutic effects of licorice in medicine and dentistry were studied in six selected articles, including four reviews and two animal studies. Licorice has anti-inflammatory, antimicrobial, antiviral, antioxidant, stimulating, and anti-caries properties, affects the immune systems, reduces candidiasis and aphthous, and increases active cortisol.

In the studies that were reviewed, licorice showed complications and drug interactions such as hypokalemia, and muscle paralysis, hypertension, contact allergies, and cardiovascular disorders and interfered with cortisone, prednisolone, contraceptives, verapamil, warfarin, alprazolam, and hydrochlorothiazide.

Among the nine studies in which licorice was used to treat and control mucositis, there were six human studies, one cellular study, and two animal studies. The drug forms used were mouthwash, oral suspension, topical application, cell coating, and paste and mucosal adhesive added to the apical part of the cells.

A total of six studies evaluating the effects of licorice on mucositis across different models and patient populations were analyzed. These included animal studies, cell-based assays, and clinical trials, each demonstrating various degrees of efficacy of licorice in reducing inflammation, promoting healing, and alleviating symptoms of mucositis [Tables 1 and 2].

Table 1.

The included studies

Author name	Year	Place of study	Title	Type of study	Results
Hoseinzadeh[3]	2015	Qazvin, Iran	Pharmacologic effects of licorice	Review	Anti-inflammatory, antimicrobial, antiviral, antioxidant, and hepatic protective properties, effect on diabetes, anti-tumor effect, effect on CNS and GABAergic system, effect on the dopaminergic system, effect on beta-amyloid, cardiovascular effect, effects on the immune system, antitussive properties, effect on RAS, effects on sore throat after extubating and skin problems.
Hendricks[9]	2012	USA	Oral derivatives of licorice, 18 betas glycyrrhizin acid, cause the maturation of lymphatic follicles in the intestinal mucosa and reduces rotavirus shedding.	Animal study	Expression of chemical receptor genes and ligands in the intestine, effect on immune cell population, effect on CD19, and reduction of rotavirus antigen shedding.
Messier[10]	2011	Canada	Licorice and its possible effects and beneficial properties in common oral diseases	Review	Anti-caries properties, effect on periodontal bacteria and diseases, effect on candidiasis and its reduction, and effect on RAS
Cirillo[11]	2017	Australia	The role of tissue steroid metabolism in oral diseases	Review	Inhibiting 11 β-HSD, increasing active cortisol, and decreasing oral inflammation
Lee[12]	2013	South Korea	Pharmacokinetics of licorice derivatives and their metabolites in mice	Animal study	Low bioavailability of licorice due to the hepatic and intestinal metabolism
Sidhu[4]	2017	Malaysia	Therapeutic benefits of licorice in dentistry	Review	Therapeutic properties and benefits on Candidiasis, gingivitis, periodontal disease, oral cancer, canal rinsing agent, anti-inflammatory, anti-microbial, and anti-microbial properties
Yasue[13]	2007	Japan	Severe hypokalemia rhabdomyolysis, muscle paralysis, and respiratory and blood pressure problems in a patient consuming licorice	Case report
Mamgain[1]	2020	India	Effect of licorice on radiotherapy-induced mucositis
Hoseinzadeh[3]	2015	Qazvin, Iran	Pharmacological effects of licorice	Review

CNS= central nervous system, RAS= Renin-Angiotensin System, β-HSD= β-hydroxylase

Table 2.

Use of licorice for the treatment of mucositis

Author name	Year	Place of study	Title	Type of study	Number of samples	Results	Index used
H-S Kwon[14]	2007	South Korea	Reduction of colon inflammation by licorice in DSS-induced colitis in rats	Animal study		Reduce mortality rate and inflammation and weight loss	Clinical scoring system Biopsy Measurement of cytokine by RT-PCR IHC
Najafi[15]	2017	Tehran, Iran	Inhibitory effect of licorice extract on oral mucosa in patients undergoing head and neck radiotherapy	RCT	37	Reduced oral mucositis	WHO
Ching Wei[16]	2016	Taiwan	Effect of licorice on LPS-induced intestinal mucositis in Caco-2 cells	Cellular		Reduced mucositis	Cell survival MTT assay, Inflammatory response, cytokine mRNA expression
Miyano[2]	2020	Japan	Licorice causes the migration of oral keratinocytes to increase the healing of chemotherapy-induced oral mucositis	Cellular		Increased tissue repair in mucositis	Visual oral mucositis score modified for radiation-induced OUM model
Sattari[17]	2019	Ahvaz, Iran	Comparative study of the effect of licorice mouthwash and combined mouthwash on the incidence and severity of chemotherapy-induced mucositis symptoms	Clinical trial	72	Reduced amount and severity of mucositis, better patient tolerance	WHO
Das[18]	2011	India	Protective effect of licorice against the side effects of radiotherapy/chemotherapy in head and neck malignancies	75	Case-control	Great reduction in the severity of radiotherapy- and chemotherapy-induced mucositis using licorice	RTOG grading system
Ghalayani[19]	2017	Isfahan, Iran	Comparison of triamcinolone acetonide adhesive with licorice adhesive in radiotherapy-induced oral mucositis	60	Clinical trial	T and L being similar in reducing pain, less discomfort observed in group L, but not statistically significant. Both effective in mucositis, but L being more effective in reducing the degree of mucositis. No statistically significant difference in reducing pain and anti-inflammatory effects.	WHO VAS
Mamgain[1]	2020	India	The effect of licorice on radiation-induced mucositis in patients with head and neck cancer	30	Intervention	A clinically significant mucosal reduction in the group consuming licorice	RTOG grading system
Pakravan[20]	2021	Iran	Comparative Study of the Effect of Licorice Muco-adhesive Film on Radiotherapy Induced Oral Mucositis	60	Clinical trial	significant difference in decreasing the degree of pain and the amount of mucositis in the licorice group	WHO
Das[18]	2011	India	Protective effect of licorice against the side effects of radiotherapy/chemotherapy in head and neck malignancies	75	Case-control	Great reduction in the severity of radiotherapy- and chemotherapy-induced mucositis using licorice	RTOG grading system
Ghalayani[19]	2017	Isfahan, Iran	Comparison of triamcinolone acetonide adhesive with licorice adhesive in radiotherapy-induced oral mucositis	60	Clinical trial	T and L being similar in reducing pain, less discomfort observed in group L, but not statistically significant. Both effective in mucositis, but L being more effective in reducing the degree of mucositis. No statistically significant difference in reducing pain and anti-inflammatory effects.	WHO VAS
Mamgain[1]	2020	India	The effect of licorice on radiation-induced mucositis in patients with head and neck cancer	30	Intervention	A clinically significant mucosal reduction in the group consuming licorice	RTOG grading system

RCT= Randomized controlled trial, RT- PCR= Real-Time- Polymerase Chain Reaction, WHO = World Health Organization, DSS= Dextran Sulfate Sodium, IHC= Immunohistochemistry, MTT= Mean Transit Time, mRNA= Messenger ribonucleic acid, OUM= Oral ulcerative mucositis, RTOG= Radiation therapy oncology group, VAS= Visual Analogue Scale

Animal study

Kwon et al. (2007)[14] conducted an animal experiment in South Korea, where licorice administration in rats with Dextran Sulfate Sodium (DSS)-induced colitis resulted in a significant reduction in mortality, inflammation, and weight loss. The study used clinical scoring systems, cytokine measurement via real-time- polymerase chain reaction (RT- PCR), biopsies, and immunohistochemistry (IHC), confirming the anti-inflammatory effects of licorice.

Clinical trial

Najafi et al. (2017)[15] performed a randomized controlled trial in Tehran, Iran, involving 37 patients undergoing head and neck radiotherapy. The use of licorice extract mouthwash significantly reduced the incidence and severity of oral mucositis, as assessed by the World Health Organization (WHO) grading system, improving patient tolerance.

Cellular studies

Ching Wei (2016)[16] from Taiwan investigated the effect of licorice on Lipopolysaccharide (LPS)-induced intestinal mucositis in Caco-2 cells. The results showed a reduction in inflammatory cytokine messenger ribonucleic acid (mRNA) expression and inflammatory response, leading to decreased mucositis severity. Cell viability was assessed through Mean Transit Time (MTT) assays, indicating enhanced cell survival.

In vitro healing model

Miyano et al. (2020)[2] in Japan demonstrated that licorice promotes healing by increasing the migration of oral keratinocytes, leading to improved tissue repair in models of chemotherapy-induced oral mucositis. Tissue repair was assessed through a modified visual oral mucositis scoring system, evidencing increased repairing activity with licorice application.

Comparative clinical study

Sattari et al. (2019)[17] in Ahvaz, Iran, compared the effects of licorice mouthwash versus combined mouthwash on chemotherapy-induced mucositis in 72 patients. Both groups showed a significant reduction in the incidence and severity of mucositis, with licorice mouthwash demonstrating better patient tolerance and less severe symptoms, as measured by WHO grading.

Across these varied models and clinical settings, licorice consistently demonstrated anti-inflammatory, healing, and protective effects against mucositis. The evidence suggests licorice not only reduces inflammation and cytokine expression but also accelerates mucosal healing and enhances cell migration, ultimately leading to decreased severity and improved patient comfort.

DISCUSSION

Nine articles on the effect of licorice on mucositis were included in the study. Due to the lack of similarity of the type of mucosal evaluation indices in these articles, meta-analysis was not possible. In three studies by H-Skwon, Ching Wei, and Miyano, which were performed as cellular or animal studies, biopsy, measurement of inflammatory cytokines by PCR, and clinical evaluation were used to evaluate mucositis. In all three studies, licorice reduced mucositis and enhanced tissue repair.

To assess mucositis and inflammation, in addition to clinical evaluations, the level of inflammatory cytokines was measured by PCR, which is more scientific and accurate. Therefore, it can be argued that cellular and animal studies may have been more accurate, but the results of these studies cannot be generalized to human studies because the human body is highly complex and dynamic and constantly changing. Even the differing moods of patients can affect the results, and the immune system and response to drugs and treatments vary in various people. Further, evaluation of pain by some indices can be defective because the pain has a fluid nature, and patients who are more anxious, feel worse about themselves and their disease, and do not receive adequate psychological support from family and others feel more pain.[2,14,16]

In the cellular and animal study of Miyano et al., a Japanese plant compound was used, one of its main active compounds was licorice.[2] However, since the combined licorice was used, it cannot be said that these favorable effects are due to licorice. Because the article reported that licorice is one of the main active ingredients, it was used in the present study.

This compound with multiple pharmacological effects, including antioxidant, anti-inflammatory, antibacterial, and analgesic effects, improves oral mucositis. This compound, one of whose main active components is licorice, reduces inflammatory mediators such as 1L-1B, which produces Prostaglandin E2 (PGE2) and reduces COX2. In this study, licorice did not cause the growth or migration of cancer cells, rather it reduced the growth of some cancers such as tongue SCC.[2]

In the animal and cellular study of H-Skwon et al.,[14] licorice inhibited septic shock due to the production of nitric oxide (NO), PGE2 and tumor necrosis factor (TNF). Licorice has also strong anti-inflammatory properties.[14]

In the cellular study of Ching Wei et al.,[16] the effect of high and low concentrations of licorice was evaluated. Licorice had anti-inflammatory effects at low concentrations and reduced Interleukin 6 (IL-6), Interleukin 8 (IL-8), Transforming Growth Factor beta(TGF-β) and TNF but in high concentration these effects were not seen.[16] Licorice also regulated the function and reduced the inflammation of intestinal cells at low concentrations. The concentration of licorice solution seems to be highly important and can reverse the therapeutic effect. Ching Wei used LPS to induce mucositis and evaluate its effect, but H-Skwon used DSS.[14,16] Some clinical trial studies used the WHO index to assess mucositis[15,17,19,20], while others used the RTOG index.[1,18] Among these studies, only Mamgain’s study evaluated the side effects and drug interactions of licorice. Licorice reduced plasma clearance and increased the plasma concentration and effect of certain drugs such as prednisolone. It also increased blood pressure, edema, and hypokalemia when used with oral contraceptives. Oral contraceptives increase the sensitivity to licorice. Women are more prone to the side effects of licorice, so licorice should not be used for long periods with thiazide and loop diuretics because it increases potassium loss. Licorice reduces the duration of hospitalization due to severe mucositis and reduces the severity of mucositis.[1]

In the study of Ghalalyani et al.,[19] licorice mucoadhesive was used in the intervention group and triamcinolone acetonide mucoadhesive was used in the control group. Licorice in the intervention group reduced the degree of mucositis and discomfort, but they were similar in pain relief. However, in the study of Najafi et al.,[15] licorice mouthwash was used in the intervention group, and the control group received a placebo. Licorice in the intervention group reduced the inflammation and size of mucosal wounds compared to the control group. Ghalalyani, Pakravan, et al.[19,20] used licorice mucoadhesive, which releases the drug in the site for a longer time and spends more time in contact with the inflamed mucosa, so it can have more therapeutic effects than the licorice mouthwash used in the study of Sattari and Najafi because mouthwash is in contact with the mucosa for a shorter time and its effects are gradually reduced by the flow of saliva.[15,17]

In the study of Sattari et al.,[17] the intervention group received licorice mouthwash and the control group received conventional combined mouthwash. Both groups were similar in terms of reducing the amount and severity of mucositis, and licorice mouthwash alone had the same effect as the combined mouthwash.

The drugs used in the control groups were also different.[20] Ghalalyani et al.[19] used triamcinolone acetonide mucoadhesive, and Sattari et al.[17] used a conventional combined mouthwash. In the studies of Najafi, Pakravan, et al.,[15,20] the control group received a placebo, and because the effects of licorice were compared with different control groups, it could affects the results of the study. However, because licorice was compared with both corticosteroids and placebo and conventional mouthwash and had a positive effect, it can be argued that licorice has a positive effect on mucositis. In their clinical trials, Das, and Mamgain et al. divided patients to different groups. used oral licorice capsules in Mamgain’s study, licorice solution in Das’s study, a mixture of licorice powder and honey as topical paste, and conventional treatment. They compared the effect of licorice with different control groups, the results of which can be more valid in this regard.[1,18]

Najafi investigated the size of oral ulcers to evaluate the effect of licorice on mucositis, which was not evaluated in other studies.[15] Gholyani, Pakravan, et al.[19,20] studied the effect of licorice on mucositis only in patients, who underwent head and neck radiotherapy but in, Sattari study patients with colon cancer, who underwent chemotherapy, but the head and neck were not in the radiation field,[17] but in the studies of Ghalalyani, Pakravan, et al.,[19,20] patients undergoing chemotherapy were considered an exclusion criterion. According to the both studies, licorice reduced the intensity and amount of mucositis. The results of Das’s study showed higher and earlier therapeutic effects for oral and systemic licorice. In Das’s study, honey was studied only topically with honey in form of paste,[18] but in Mamgain’s study the effects of licorice were not evaluated topically.[1] In Das’s study, licorice was studied topically with honey in paste form, but in Mamgain’s study, the effect of topical licorice was not evaluated. The results of das’s study showed that licorice reduced the rate of hospitalization due to severe mucositis and reduced mucositis severity.[18]

Given the promising results, licorice could be integrated into supportive care protocols; however, evidence remains insufficient for widespread recommendation without further validation. Licorice shows potential as a supportive agent in managing chemotherapy- and radiotherapy-induced mucositis in head and neck cancer patients. Its anti-inflammatory and healing properties may improve patient comfort and reduce treatment interruptions. Nevertheless, more rigorous studies are needed to establish definitive clinical guidelines.

CONCLUSION

Licorice and its compounds are effective in reducing the duration and severity of chemotherapy- and radiotherapy-induced pain and inflammation due to mucositis. It should be noted that licorice can cause side effects when used in large quantities, so it must be used according to pharmacological standards and a lethal dose. It is suggested to be used according to a clinical pharmacologist’s recommendation. Moreover, its topical or systemic application can alter its efficacy, its effect can be increased or decreased and in combination with other drugs. In addition, the patient’s physical and mental conditions and the drugs consumed by the patient can reduce or increase the effects of licorice. Licorice’s constituents may modulate inflammatory responses, enhance mucosal regeneration, and exert antioxidant effects. Glycyrrhizin inhibits pro-inflammatory cytokine production and promotes tissue repair.

Suggestions

To accurately determine the effect of licorice on chemotherapy- and radiotherapy-induced mucositis, it is necessary to conduct more controlled studies with more samples to identify the exact mechanism and molecular pathways of licorice and to use different concentrations of licorice to evaluate the effectiveness and determine its side effects at different doses.

Ethics approval and consent to participate

The present study was a systematic review, with the code of ethics IR.MUI.RESEARCH.REC.1399.514, approved by Isfahan University of Medical Sciences.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.