Glycyrrhiza glabra, commonly known as licorice or mulethi, has been a cornerstone of traditional medicine in Ayurveda, Traditional Chinese Medicine (TCM), and other systems for centuries. Its primary bioactive compound, glycyrrhizin (and its metabolite glycyrrhizic acid), has garnered significant attention for its antiviral, anti-inflammatory, and immunomodulatory properties. With the emergence of SARS-CoV in 2003 and SARS-CoV-2 (COVID-19) in 2019, researchers, particularly in China, have explored licorice’s potential as a therapeutic agent. This discussion delves into the clinical findings, mechanisms of action, and research on licorice’s effectiveness against COVID-19, building on its historical use against SARS and subsequent dedicated studies.
Historical Context: Licorice and SARS-CoV
The severe acute respiratory syndrome (SARS) outbreak in 2003 prompted early investigations into licorice’s antiviral potential. A pivotal study conducted in Germany tested glycyrrhizin against two clinical isolates of SARS-CoV (FFM-1 and FFM-2) from patients. Glycyrrhizin was found to be the most effective among tested compounds (including ribavirin and mycophenolic acid), significantly inhibiting viral replication in Vero cells with a selectivity index of 67. This meant it was highly effective at non-toxic concentrations. The study suggested glycyrrhizin interfered with viral attachment, penetration, and replication, likely by targeting the viral envelope or host cell receptors like angiotensin-converting enzyme 2 (ACE2). These findings laid the groundwork for licorice’s consideration in future coronavirus outbreaks, including COVID-19.
In China, where TCM is widely integrated into healthcare, licorice (known as Gan Cao) was a common component in herbal formulas during the SARS epidemic. Its role in modulating inflammation and boosting immunity was noted anecdotally, though rigorous clinical trials were limited at the time. These early observations fueled interest when COVID-19 emerged, given the genetic similarities between SARS-CoV and SARS-CoV-2 (sharing 79.5% genetic sequence and using ACE2 as the entry receptor).
Mechanisms of Action Against SARS-CoV-2
Licorice’s potential against COVID-19 stems from its multifaceted mechanisms, which target viral replication, host immune response, and inflammatory pathways. Clinical and in vitro studies, particularly from China and globally, have elucidated the following mechanisms:
Antiviral Activity
Inhibition of Viral Replication: Glycyrrhizin and glycyrrhizic acid inhibit SARS-CoV-2 replication by targeting the viral main protease (Mpro or 3CLpro), an enzyme critical for viral protein processing. A 2021 German study demonstrated that glycyrrhizin potently blocked Mpro activity in vitro, reducing viral replication in Vero E6 cells at subtoxic concentrations (2 mg/mL). Molecular docking studies further confirmed glycyrrhizin’s high binding affinity to Mpro, forming stable interactions with key amino acids like Cys145 and His41.
Blocking Viral Entry: Glycyrrhizin interacts with the ACE2 receptor, the primary entry point for SARS-CoV-2. In silico studies from India and China showed glycyrrhizin binds to ACE2, potentially reducing viral attachment. A 2020 study from Huazhong University of Science and Technology, China, highlighted glycyrrhizin’s ability to alter ACE2 conformation, hindering viral spike protein binding.
Spike Protein Inhibition: Compounds like glycyrrhizic acid and glyasperin A (another licorice phytochemical) bind to the SARS-CoV-2 spike glycoprotein, preventing viral entry into host cells. A 2020 study published in Research Square found glycyrrhizic acid exhibited high affinity for the spike protein’s receptor-binding domain, offering a dual mechanism of entry blockade.
Anti-inflammatory Effects
COVID-19 is characterized by a cytokine storm, where excessive inflammatory cytokines (e.g., IL-6, TNF-α, IL-1β) cause acute respiratory distress syndrome (ARDS) and multi-organ damage. Glycyrrhizin’s anti-inflammatory properties suppress pro-inflammatory pathways, including NF-kB and HMGB1 (high-mobility group box 1), which are elevated in severe COVID-19 cases. A 2020 Chinese study funded by the National Natural Science Foundation of China showed glycyrrhizic acid reduced HMGB1 levels, mitigating lung inflammation in animal models.
Licorice also modulates T-helper cell responses, reducing Th2 and Th17 cytokine production (e.g., IL-4, IL-17A) while promoting regulatory T-cell activity. A 2022 study using a hamster model of SARS-CoV-2 infection found prophylactic licorice treatment lowered mRNA expression of pro-inflammatory cytokines and plasminogen activator inhibitor-1 (PAI-1), reducing lung pathology.
Immunomodulation
Glycyrrhizin enhances interferon-gamma (IFN-γ) production by T cells, bolstering antiviral immunity. A 1997 in vivo study showed glycyrrhizin protected mice from lethal influenza doses via IFN-γ-mediated pathways, a mechanism relevant to COVID-19. Chinese researchers noted that glycyrrhizic acid’s immunomodulatory effects could counteract the weak IFN response observed in severe COVID-19 cases, as reported in a 2020 study in Frontiers in Immunology.
Licorice’s polysaccharides stimulate immune cell proliferation (e.g., spleen lymphocytes), enhancing systemic immunity. A 2023 study in Molecules suggested licorice’s low toxicity at high doses (2 g/kg in animals) makes it a safe candidate for immune support.
Antioxidant Protection
SARS-CoV-2 infection induces oxidative stress, exacerbating tissue damage. Licorice’s flavonoids (e.g., liquiritin, glabridin) and glycyrrhizin scavenge reactive oxygen species (ROS) and mitochondrial ROS (mtROS), protecting lung and other tissues. The 2022 hamster study demonstrated licorice’s ability to suppress ROS and neutrophil extracellular trap (NET) formation, reducing vascular damage in COVID-19 models.
ACE2 Expression Modulation
A 2021 study in Nutrients found that licorice extract reduced ACE2 mRNA and protein expression in the small intestine of rats, potentially limiting SARS-CoV-2 entry points. This effect was linked to glycyrrhizin’s interaction with the mineralocorticoid receptor (MR) and 11-beta-hydroxysteroid dehydrogenase type 2 (11βHSD2), which regulate ACE2 expression in tissues like the lung and intestine. While promising, this mechanism requires further validation in lung tissue.
Clinical Findings on COVID-19
While in vitro and animal studies provide strong evidence, clinical trials on licorice’s efficacy against COVID-19 are limited but growing. Below are key findings from dedicated studies, with a focus on Chinese research and global efforts:
Chinese Clinical Observations
During the early COVID-19 outbreak in Wuhan, TCM was used in over 85% of cases, with licorice as a core component in formulas like Qing-Fei-Pai-Du decoction, recommended by China’s National Health Commission. Retrospective studies reported reduced hospitalization rates and symptom severity (e.g., fever, cough) in patients receiving TCM, though licorice’s specific contribution was not isolated.
A 2020 study from Guangzhou University of Chinese Medicine highlighted glycyrrhizic acid’s role in TCM formulations, noting its anti-inflammatory and antiviral effects in moderate COVID-19 cases. Patients showed improved inflammatory markers (e.g., C-reactive protein) and faster symptom resolution, though these were observational findings lacking placebo controls.
Randomized Controlled Trial (RCT)
A 2023 RCT in Inflammopharmacology evaluated licorice extract (760 mg glycyrrhizin, three times daily for seven days) in 60 patients with moderate COVID-19. The study found no significant improvement in primary outcomes (SpO2, body temperature, respiratory rate) compared to the control group. However, secondary outcomes like C-reactive protein (CRP) and alanine aminotransferase (ALT) levels improved, suggesting anti-inflammatory and hepatoprotective effects. The trial concluded licorice was safe, with no increase in adverse events, but its clinical benefits were modest, warranting larger, multi-center trials.
Animal Model Studies
A 2022 study in Frontiers in Immunology used a hamster model to assess prophylactic licorice treatment against SARS-CoV-2. Licorice reduced lung pathology, splenomegaly, and pro-inflammatory cytokine expression, demonstrating immunomodulatory and antiviral efficacy. The study provided proof-of-concept for licorice’s potential, advocating for clinical trials to identify active ingredients.
In vitro studies, such as a 2021 German study in Viruses, confirmed glycyrrhizin’s ability to inhibit SARS-CoV-2 replication at concentrations achievable in licorice tea (12.5 mg/mL), supporting its use as a complementary therapy.
Global Research
A 2020 Indian study in Research Square used molecular docking to show licorice phytochemicals (glycyrrhizin, glyasperin A) inhibited SARS-CoV-2 spike protein and non-structural protein-15 (Nsp15), suggesting a role in preventing viral entry and replication. These findings aligned with Chinese in silico studies, reinforcing licorice’s multi-target approach.
A 2023 study in Molecules from Kazakhstan tested licorice extract against SARS-CoV-2 in cell cultures but found low antiviral activity compared to drugs like Cridanimod. However, its low toxicity (2 g/kg in animals) supported its potential as a safe adjunctive therapy.
Comparison with SARS Research
The SARS-CoV studies provided a stronger foundation for glycyrrhizin’s antiviral efficacy, with clear in vitro inhibition of viral replication. COVID-19 research, while promising, shows mixed results:
Similarities: Both viruses rely on ACE2 for entry, and glycyrrhizin’s ability to bind ACE2 and inhibit proteases (Mpro in SARS-CoV-2, similar enzymes in SARS-CoV) is consistent. Its anti-inflammatory effects are relevant to both diseases, given their shared cytokine storm pathology.
Differences: SARS-CoV-2’s higher transmissibility and varied clinical presentation (e.g., asymptomatic cases, long COVID) complicate therapeutic strategies. Clinical trials for COVID-19 have been more rigorous but less conclusive, partly due to the complexity of isolating licorice’s effects in multi-herb TCM formulas.
Limitations and Challenges
Despite promising findings, several challenges limit licorice’s adoption as a COVID-19 therapeutic:
Limited Clinical Evidence: Most studies are in vitro, in silico, or animal-based, with few high-quality RCTs. The 2023 RCT’s modest results highlight the need for larger trials to confirm efficacy.
Dose-Dependent Toxicity: Glycyrrhizin’s cortisol-mimicking effects can cause hypertension, hypokalemia, and fluid retention at high doses (>100 mg/day chronically). COVID-19 patients with comorbidities (e.g., hypertension, kidney disease) are at higher risk, necessitating careful monitoring.
Variable Formulations: Licorice’s efficacy varies by preparation (e.g., extract, DGL, tea). Standardized dosing and quality control are critical but often lacking in TCM and Ayurvedic products.
Drug Interactions: Licorice may interact with corticosteroids, antivirals, or ACE inhibitors, complicating its use in COVID-19 treatment protocols.
Heterogeneous Study Designs: Chinese studies often combine licorice with other herbs, making it hard to isolate its effects. Global studies vary in methodology, hindering meta-analyses.
Future Directions
The research on licorice for COVID-19 is encouraging but incomplete. Key steps forward include:
Large-Scale RCTs: Multi-center trials with standardized licorice extracts (e.g., glycyrrhizin or DGL) are needed to assess efficacy in diverse COVID-19 populations, focusing on mild-to-moderate cases where anti-inflammatory effects may be most beneficial.
Active Ingredient Identification: Studies like the 2022 hamster model suggest licorice’s multi-component nature (glycyrrhizin, glyasperin A, liquiritin) contributes to its effects. Isolating and testing these compounds could lead to targeted therapies.
Combination Therapies: Licorice’s complementary role in TCM suggests it could enhance standard treatments (e.g., remdesivir, dexamethasone). Trials combining licorice with antivirals or immune modulators are warranted.
Long COVID Exploration: Licorice’s anti-inflammatory and immunomodulatory effects may benefit long COVID symptoms (e.g., fatigue, brain fog), an area ripe for investigation.
Safety Optimization: Deglycyrrhizinated licorice (DGL) or low-glycyrrhizin extracts could minimize side effects, making licorice safer for broader use.
Practical Considerations for Use
For those considering licorice as a complementary approach:
Dosage: Stick to low doses (e.g., 5-15 g root/day, equivalent to 200-600 mg glycyrrhizin, as per German Commission E guidelines). Licorice tea (1-2 cups daily) or DGL supplements (500-1000 mg/day) are safer options.
Monitoring: Regular checks for blood pressure, potassium levels, and liver function are essential, especially in prolonged use.
Consultation: Always consult a healthcare provider, particularly for COVID-19 patients on other medications or with comorbidities.
Quality: Choose third-party-tested products to ensure purity and avoid contaminants.
Conclusion
Glycyrrhiza glabra holds significant promise as a complementary therapy for COVID-19, building on its established efficacy against SARS-CoV. Its antiviral, anti-inflammatory, immunomodulatory, and antioxidant properties target key aspects of SARS-CoV-2 pathology, from viral entry to cytokine storm. Chinese research, rooted in TCM, has been instrumental in highlighting licorice’s role, supported by global studies showing glycyrrhizin’s inhibition of Mpro, ACE2, and inflammatory pathways. However, clinical evidence remains limited, with modest benefits in RCTs and stronger support from preclinical studies. Licorice’s potential is tempered by dose-dependent toxicity and the need for standardized formulations. As research progresses, licorice could emerge as a safe, accessible adjunct to conventional COVID-19 treatments, particularly in resource-limited settings. For now, its use should be cautious, guided by medical advice, and informed by ongoing trials to unlock its full therapeutic potential.
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