**4.3 Licorice in heart disease**

Cases of hypokalemia and hypertension have been reported after daily ingestion of licorice tea or after short-term high dose [52–54]. In one case patient was combining licorice with the glucocorticoid medication fludrocortisone [55]. The active components of licorice, glycyrrhizinates, inhibit the enzyme responsible for inactivating cortisol and bind to mineralocorticoid receptors resulting in reversible hyper-mineralocorticoid effects [56]. A meta-analysis with 18 clinical trials found that chronic daily intake of 100 mg glycyrrhizin increases systolic and diastolic blood pressure [57]. In another meta-analysis including 26 clinical trials and 985 subjects, mainly healthy and overweight but some with hypercholesterolemia, found licorice to reduce body weight and BMI but increase diastolic blood pressure. Licorice was given as licorice flavonoid oil with a dose range of 300 mg to 1.8 g/day for 2–16 weeks [58]. In a dose–response relationship investigation in healthy men and women, licorice root with 108 or 217 mg of glycyrrhizin per day for 4 weeks caused no adverse events. However, licorice with 380 and 814 mg glycyrrhizin caused headache, arterial hypertension, hyperkalemia, and peripheral edema. One individual had a family history of hypertension [59]. Lastly, a similar study compared adverse events in patients with hypertension versus normotensive individuals during 100 g licorice containing 150 mg glycyrrhetinic acid per day for 4 weeks. Systolic and diastolic blood pressure were slightly increased in normotensive (3.5 and 3.6 mmHg) but significantly greater increase in hypertensive patients (15.3 and 9.3 mmHg). Increase in urinary cortisol correlated with the rise in blood pressure [60]. These data suggest that glycyrrhizin at dose >200 mg/day short-term and > 100 mg/day long-term in patients or healthy individuals can cause reversible hyperkalemia and hypertension.

#### **4.4 Licorice toxicity**

Despite licorice being a substance generally recognized as safe (GRAS) in the United States [61] and regarded as having a high safety profile because it is consumed as food [32], licorice can cause hypertension and hypokalemia in a dose-dependent manner [57]. However, safe dose will vary depending on licorice's composition and the underlying medical conditions. Those with hypertension, heart or kidney disease are more sensitive to licorice toxicity [40]. In a study involving 360 subjects, no clinically significant change in renal function (potassium, blood urea nitrogen, and creatinine levels) were found in 98.3% of the subjects after ~19 days of ~8 g licorice per day taken as dietary supplements that contained other ingredients. The remaining 1.7% of subjects developed hyperkalemia [62]. In a safety and toxicity study with 39 healthy female and male volunteers aged 19–40 years old, glycyrrhizic acid was administered at 1, 2, and 4 mg/kg body weight daily for 8 weeks. A no-effect level of 2 mg/kg was found and applying a 100-safety factor, the acceptable daily intake of 0.2 mg/kg body weight was proposed. This is equivalent to 12 mg glycyrrhizic acid/day for a 60-kg person [63]. Similarly, based on review of in vivo and clinical evidence, an acceptable daily intake has been proposed to be 0.015–0.229 mg glycyrrhizin/kg body weight [64]. The acceptable daily intake without a safety factor is equivalent to 120 mg glycyrrhizic acid. This dose could be considered safe if used short-term in a situation of high benefit versus risk.

#### **4.5 Licorice pharmacokinetics**

*Glycyrrhiza glabra* has shown weak inhibition of CYP3A4 and moderate inhibition of CYP2B6, 2C8, 2C9, and 2C19. *Glycyrrhiza uralensis* showed strong inhibition *Safety Review of Herbs and Supplements in Heart Disease, Diabetes, and COVID-19 DOI: http://dx.doi.org/10.5772/intechopen.96811*

of CYP2B6, moderate inhibition of CYP2C8, 2C9, and 2C19, and no inhibition of CYP3A4 and 2D6. *Glycyrrhiza inflata* strongly inhibited CYP2C enzymes and moderately inhibited of CYP3A4, 1A2, 2B6, and 2D6. None of the three species inhibited CYP2E1 and 2A6. Glycyrrhizin content was highest in *G. uralensis* suggesting that glycyrrhizin is a weak inhibitor of the major enzymes CYP3A4 and 2D6 [65]. Weak inhibition of CYP3A4 and 2D6 by glycyrrhizin and *G. glabra* were also found in a different study [66].

#### **4.6 Licorice safety summary**

A safe daily dose for short-term use consists of licorice with less than 100 mg glycyrrhizin. For daily long-term use a dose of 12 mg glycyrrhizin has been proposed. COVID-19 studies are using short-term doses of <100 mg glycyrrhizin per day. Caution should be taken when combining licorice with medications. Licorice inhibits several cytochrome P450 enzymes including CYP1A2, 2B6, 2C8, 2C9, and 2C19. Only *G. inflata* inhibits CYP3A4 and 2D6.
