(Glycyrrhiza glabra) contains an ingredient called glycyrrhizin or
glycyrrhizic acid and has been used in the treatment of stomach ulcers,
bronchitis, sore throat and even viral hepatitis.1 It is available in a
number of dosage forms that include powdered forms, capsules, tablets and
liquid extracts.1 Unfortunately, licorice ingestion can lead to excess
mineralocorticoid activity that is manifested by suppressed renin levels,
sodium retention, hypokalemia, hypertension and edema.1-5 As it relates
to edema, it can be caused one or more of the following: things known to
influence vasculature oncotic pressures, vasomotor tone of the veins,
permeability of the capillary membranes, lymphatic flow and/or intravascular
volume. Of these various biologic mechanisms, the change in
intravascular volume appears to be the major contributor to the increased risk
in patients developing swelling or edema when taking licorice
is the mechanism by which the Glycyrrhiza glabra in licorice can increase the
The normal physiology for sodium-water retention is largely
influenced by the expression of mineralocorticoids. While aldosterone is
regarded as the main hormone binding to mineralocorticoid receptors involved in
the regulation of sodium reabsorption and potassium excretion in the distal
renal tubules of the kidney, cortisol also binds to this receptor with the same
binding affinity as aldosterone. Interestingly, even though cortisol
blood concentrations tend to be greater than aldosterone concentrations, the
effect of aldosterone dominates in terms of regulating sodium and water reabsorption
and blood volume.
cortisol concentrations are greater than aldosterone and both have equal
affinity for the mineralocorticoid receptor, why doesn't cortisol have a
greater influence on the overall mineralocorticoid activity?
The type 2 isoenzyme of 11 beta-hydroxysteroid dehydrogenase
(11 beta-HSD2) is normally involved in regulating corticosteroid specificity in
the gastrointestinal tract, kidney and salivary glands (see figure 1).6
Cortisol (not aldosterone) is metabolized by 11 beta-HSD2 to cortisone, which
does not bind to either the mineralocorticoid or glucocorticoid receptor.
Without this inactivation of cortisol, there would be mineralocorticoid
excess. In fact, there is an inherited disease called syndrome of
apparent mineralocorticoid excess in which the mineralocorticoid
receptor is overly activated thereby causing hypokalemia and hypervolemia due
to the excessive reabsorption of sodium and water at the expense of potassium
excretion. This is the same effect created by licorice use.
is a known inhibitor of 11 beta-HSD2 and thus prevents the inactivation of
cortisol, thereby causing a state of excess mineralocorticoid activity or
pseudohyperaldosteronism.2-6 The increase in mineralocorticoid activity
results in greater sodium and water reabsorption at the expense of potassium
excretion. This will eventually manifest as an increase in hydrostatic and
overall blood pressures thereby resulting in the development of edema.
Details for Those Interested:
- How does cortisol binding to the mineralocorticoid receptor in the distal
renal tubule increase sodium and water reabsorption at the expense of potassium
excretion? The increased cortisol resulting from licorice use increases gene expression
and availability of several enzymes. The first of these is the Na+ ion
permease enzyme, which allows for a greater number of sodium ions to cross from
the lumen to the inside of the renal tubular cell. Next is Na+/K+ATPase
on the basal-lateral side of the renal tubular cell which acts to transfer the
increased cytosolic Na+ into the peritubular fluid resulting in a lowering
of the intracellular electronegativity. Lastly, there is an increase in
citrate synthase activity within the mitochondria for the purpose of increasing
the number of ATP available to fuel the increase in Na+/K+ATPase activity on
the basal-lateral side of the renal tubular cell.7-9
Excess mineralocorticoid activity and resulting increases in blood volume are
clearly the main mechanisms by which licorice causes both edema and
hypertension. In fact, the increase in blood pressure and development of
hypertension can be significant and last several weeks before returning to
baseline despite the discontinuation of the licorice supplementation.2,4 Given
the documented increases in edema and blood pressure, the use of licorice
supplements should be taken into consideration for any patient with an
unexplained increase in blood pressure, worsening of hypertension that is being
adequately treated with antihypertensive medications and/or worsening of
previously controlled heart failure. There is some evidence that spironolactone
(Aldactone) may confer some benefit on blood pressure; however, stopping the
licorice would be the preferred recommendation for patients.10
- National Institute of Health: National Center for Complimentary and
Alternative Medicine. Herbs at a glance: Licorice root. June 2008.
Last accessed on 6/1/09.
- Wash LK, Bernard JD. Licorice-induced pseudoaldosteronism. Am J Hosp Pharm 1975;32:73-4.
MT, Espiner EA, Donald RA et al. Liquorice toxicity and the
renin-angiotensin-aldosterone axis in man. Br Med J 1977;1:209-10.
C, Salvade G, Crivelli PL et al. Body-sodium and blood volume in a
patient with licorice-induced hypertension. J Hypertens
EP, Gomez-Sanchez CE. Central hypertensinogenic effects of
glycyrrhizic acid and carbenoxolone. Am J Physiol 1992;263:E1125-30.
TC, Walker BR. Pathophysiology of modulation of local glucocorticoid
levels by 11beta-hydroxysteroid dehydrogenases. Trends Endocrinol
- Garty H. Mechanisms of aldosterone action in tight epithelia. J Membr Biol 1986;90:193-205.
F, Schaerer E, Zoerkler P et al. Regulation by aldosterone of
Na+,K+-ATPase mRNAs, protein synthesis, and sodium transport in cultured
kidney cells. J Cell Biol 1987;104:1231-7.
JR, Husted RF, Stokes JB. Cellular responses to steroids in the
enhancement of Na+ transport by rat collecting duct cells in culture.
Difference between glucocorticoid and mineralocorticoid hormones. J
Clin Invest 1992;90:1370-8.
RM, Mattox VR, Rosevear JW. Inhibition of the "mineralocorticoid"
activity of licorice by spironolactone. J Clin Endocrinol Metab