Glycyrrhizic acid in liquorice—Evaluation of health hazard

Abstract

Literature on case reports, clinical studies and biochemical mechanisms of the sweet-tasting compound glycyrrhizic acid in liquorice was critically reviewed to provide a safety assessment of its presence in liquorice sweets. A high intake of liquorice can cause hypermineralocorticoidism with sodium retention and potassium loss, oedema, increased blood pressure and depression of the renin-angiotensin-aldosterone system. As a consequence, a number of other clinical symptoms have also been observed. Glycyrrhizic acid is hydrolysed in the intestine to the pharmacologically active compound glycyrrhetic acid, which inhibits the enzyme 11β-hydroxysteroid dehydrogenase (in the direction of cortisol to cortisone) as well as some other enzymes involved in the metabolism of corticosteroids. Inhibition of 11β-hydroxysteroid dehydrogenase leads to increased cortisol levels in the kidneys and in other mineralocorticoid-selective tissues. Since cortisol, which occurs in much larger amounts than aldosterone, binds with the same affinity as aldosterone to the mineralocorticoid receptor, the result is a hypermineralocorticoid effect of cortisol. The inhibitory effect on 11β-hydroxysteroid dehydrogenase is reversible; however, the compensatory physiological mechanisms following hypermineralocorticoidism (e.g. depression of the renin-angiotensin system) may last several months. It is not possible, on the basis of existing data, to determine precisely the minimum level of glycyrrhizic acid required to produce the described symptoms. There is apparently a great individual variation in the susceptibility to glycyrrhizic acid. In the most sensitive individuals a regular daily intake of no more than about 100 mg glycyrrhizic acid, which corresponds to 50 g liquorice sweets (assuming a content of 0.2% glycyrrhizic acid), seems to be enough to produce adverse effects. Most individuals who consume 400 mg glycyrrhizic acid daily experience adverse effects. Considering that a regular intake of 100 mg glycyrrhizic acid/day is the lowest-observed-adverse-effect level and using a safety factor of 10, a daily intake of 10 mg glycyrrhizic acid would represent a safe dose for most healthy adults. A daily intake of 1–10 mg glycyrrhizic acid/person has been estimated for several countries. However, an uneven consumption pattern suggests that a considerable number of individuals who consume large amounts of liquorice sweets are exposed to the risk of developing adverse effects.