Atheroprotective Effects of Glycyrrhiza glabra L: A Critical Analysis of the 2022 Molecules Review

This review, published in Molecules in July 2022, examined the atheroprotective potential of Glycyrrhiza glabra L (licorice) and its bioactive compounds. The authors — from the Petrovsky National Research Center of Surgery and the Chazov National Medical Research Center of Cardiology in Moscow — synthesized evidence from in vitro studies, animal experiments, and available clinical data to assess licorice's potential role in cardiovascular disease prevention.

Why this review matters: Cardiovascular diseases associated with atherosclerosis remain the leading cause of death worldwide. Natural products with potential anti-atherogenic properties continue to attract research interest. Licorice is one of the most widely used medicinal plants globally, both in traditional medicine systems and as a food additive. In TCM, Zhi Gan Cao (honey-fried licorice, 炙甘草) is a key ingredient in cardiovascular-related formulas such as Zhi Gan Cao Tang (炙甘草汤), one of the most celebrated classical formulas for palpitations and arrhythmia in the Shang Han Lun.

Scope of the review: The authors reviewed the anti-inflammatory, anti-cytokine, antioxidant, anti-atherogenic, and anti-platelet properties of licorice and its major bioactive compounds, including glabridin, glycyrrhizin, liquiritigenin, and liquiritin. They included both in vitro and in vivo (animal model) evidence and summarized available clinical data on cardiovascular risk factor modification.

Anti-Inflammatory and Anti-Cytokine Effects

The review identified that licorice extracts and their constituent compounds — particularly glabridin and glycyrrhizin — may suppress the production of pro-inflammatory cytokines (TNF-alpha, IL-1beta, IL-6) through inhibition of the NF-kB and MAPK signaling pathways. In experimental atherosclerosis models, this anti-inflammatory activity was associated with reduced plaque formation and stabilization of existing plaques. These findings are based primarily on cell culture and animal models.

Antioxidant Activity and LDL Modification

One of the most consistently discussed mechanisms in the review is the inhibition of LDL oxidation. Oxidized LDL (oxLDL) is a critical driver of foam cell formation in atherosclerotic plaques. Glabridin, in particular, has been shown to protect LDL from oxidative modification in multiple in vitro studies. The review also cited evidence that licorice compounds may activate endogenous antioxidant defense systems, including upregulation of paraoxonase 2 (PON2) and modulation of NADPH oxidase activity. Again, these are primarily preclinical findings.

Anti-Atherogenic Effects

The review described studies in which licorice extracts reduced intracellular cholesterol accumulation in macrophages — a key step in foam cell formation. The authors presented data from their own in vitro study demonstrating that blood serum from subjects receiving licorice showed an enhanced ability to reduce intracellular cholesterol accumulation in cultured macrophages. In animal models of atherosclerosis, licorice administration was associated with reduced aortic plaque area and improved plaque stability.

Clinical Evidence

The clinical data cited in the review is limited. The authors referenced studies suggesting that licorice consumption may be associated with improvements in lipid profiles (reduced LDL cholesterol, increased HDL cholesterol) and reductions in inflammatory markers. However, these clinical studies were generally small, short-term, and had methodological limitations. No large-scale, long-term clinical trials of licorice for cardiovascular disease prevention were identified.

While this review provides a thorough synthesis of the preclinical literature, there are critical limitations that must be acknowledged:

Predominantly Preclinical Evidence

The vast majority of evidence summarized in this review comes from in vitro cell culture studies and animal models (primarily ApoE-deficient mice and rabbit models of atherosclerosis). These models do not fully replicate the complexity of human atherosclerosis, which develops over decades and involves a complex interplay of genetic, metabolic, environmental, and lifestyle factors. The leap from mouse aortic plaque reduction to cardiovascular event reduction in humans is enormous and has not been demonstrated.

The Dual Nature of Licorice: Benefit vs. Risk

This is perhaps the most important limitation. The review focuses on the atheroprotective potential of licorice but does not adequately address the well-documented cardiovascular risks. Glycyrrhizin, a major constituent of licorice, inhibits 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), the enzyme that converts active cortisol to inactive cortisone in the kidney. The resulting cortisol excess acts on mineralocorticoid receptors, causing sodium retention, potassium loss, and hypertension. This effect is dose-dependent and can occur with as little as 100 mg of glycyrrhizin per day. The European Medicines Agency recommends that consumers not exceed 100 mg/day of glycyrrhizin. For cardiovascular patients — the very population that might theoretically benefit from licorice's atheroprotective effects — this risk is particularly concerning.

Narrative Review Without Systematic Methodology

This is a narrative review, not a systematic review. The authors did not follow PRISMA guidelines, did not perform a comprehensive literature search with predefined inclusion criteria, and did not assess the quality of included studies using standardized tools. This means the review is subject to selection bias — the authors may have preferentially cited studies with positive findings.

Lack of Standardization

Different studies used different licorice preparations — whole extract, individual compounds (glabridin, glycyrrhizin, liquiritigenin), different extraction methods, and different doses. This heterogeneity makes it impossible to determine the optimal preparation, dose, or compound for cardiovascular protection.

Relevance to Zhi Gan Cao (Honey-Fried Licorice)

The review examines Glycyrrhiza glabra (European licorice), while TCM primarily uses Glycyrrhiza uralensis (Chinese licorice). The honey-frying process used to prepare Zhi Gan Cao may alter the chemical composition — potentially reducing glycyrrhizin content and modifying the flavonoid profile. However, the extent of these changes and their impact on cardiovascular effects has not been well characterized. The review does not address the honey-fried preparation specifically.

The claims made in this review are characterized by varying levels of verification:

• Anti-inflammatory effects of licorice compounds in cell culture: Well-replicated across multiple studies. Verified at the in vitro level.
• Antioxidant and LDL-protective effects of glabridin: Consistently demonstrated in vitro. Verified at the in vitro level.
• Anti-atherogenic effects in animal models: Shown in multiple animal studies. Suggestive but not directly applicable to humans.
• Cardiovascular risk factor modification in humans: Limited clinical data, small studies, inconsistent results. Not verified for clinical recommendations.
• Cardiovascular event reduction in humans: No clinical trial data. Unverified.
• Safety for cardiovascular patients: Significant concerns documented. Glycyrrhizin-induced hypertension and hypokalemia are well-established risks.

Despite the interesting preclinical findings, the clinical implications are limited:

• Not ready for clinical use: Licorice should not be recommended as a cardiovascular protective agent. The gap between preclinical promise and clinical evidence is too large, and the cardiovascular risks of glycyrrhizin are well documented.
• Research tool: Licorice compounds, particularly glabridin, remain valuable research tools for understanding atherosclerosis pathophysiology and developing new therapeutic approaches. Isolated, purified compounds without glycyrrhizin may eventually have clinical relevance.
• TCM context: Zhi Gan Cao has been used in classical formulas for centuries. Its role in TCM is primarily as a harmonizing herb that moderates the effects of other ingredients in a formula, not as a standalone cardiovascular agent. The traditional use in formulas like Zhi Gan Cao Tang for palpitations should be understood in its historical and theoretical context, not as evidence for cardiovascular protection.
• Patient counseling: Cardiovascular patients who express interest in licorice products should be counseled about the risks of hypertension and hypokalemia, the lack of clinical trial evidence for cardiovascular benefit, and the importance of continuing evidence-based treatments.