Natural licorice possesses both mineralocorticoid properties and glucocorticoid properties. Most licorice-flavored foods available in the United States do not contain GZA, and they do not produce the hypermineralocorticoid syndromes observed with the long-term consumption of moderate-to-significant amounts of natural licorice.

Consumption of large doses of GZA in licorice extract can lead to hypokalemia and serious hypertension, a syndrome known as hypermineralocorticoidism. [14, 15] Biochemical studies indicate that glycyrrhizinates inhibit 11-beta-hydroxysteroid dehydrogenase (type 2), the enzyme responsible for inactivating cortisol through conversion to cortisone. As a result, a continuous, high-level exposure to glycyrrhizin compounds can produce hypermineralocorticoid-like effects in both animals and humans. These effects are reversible upon withdrawal of licorice or glycyrrhizin. [1]

In the kidney, cortisol activation of mineralocorticoid receptors alters renal tubular exchange of sodium (retained), potassium (excreted), and hydrogen ions (excreted); producing an increased extracellular volume (hypertension, [16] edema), hypokalemia (weakness, muscle spasm), [17] and metabolic alkalosis. [18]

Pseudoprimary aldosteronism from chronic licorice ingestion is characterized by low serum and urinary aldosterone levels and decreased serum renin activity. This differs from true primary hyperaldosteronism caused by aldosterone-producing adenomas or primary adrenal hyperplasia, which is characterized by elevated urine and serum aldosterone levels.

Licorice can reduce the serum testosterone level, probably by blocking 17-hydroxysteroid dehydrogenase and 17,20 lyase. [19] Licorice has therefore been considered an adjuvant therapy of hirsutism and polycystic ovary syndrome. [20]

The exact amount of ingested GZA that produces mineralocorticoid toxicity is unclear. A meta-analysis to assess the effect of chronic ingestion of licorice found the mean daily dose of glycyrrhizic acid across 18 studies was 377.9 mg, which is approximately 189 g of black licorice a day, assuming 2.0 mg g−1 (0.2% w/w) glycyrrhizic acid in black licorice. However, the concentration of glycyrrhizic acid changes significantly dependent on the product. Licorice findings range between 0.26 and 7.9 mg g−1, while in health products the range was 0.30 to 7.9 mg g−1. A typical pack of Liquorice Allsorts was found to contain 91.0 mg, a serving of licorice tea contained 20.0 mg and a single licorice pipe contained 4.6 mg. With only limited and sporadic consumption of licorice, it would be difficult to ingest more than 500 mg of glycyrrhizic acid per day. Assuming an average concentration of 2.0 mg g−1 for black licorice confectionery, it would require consumption of 250 g per day to reach 500 mg of glycyrrhizic acid daily. While this quantity is relatively high, but as evidenced by numerous case reports, a small portion of the population does consume licorice at these levels. [21]