The Interaction Of Liquorice And Diuretics

One of the side effects of licorice is hypermineralocorticoidism, which can lead to hypertension. The reason for this is the glycyrrhizic acid content. Once ingested, glycyrrhizic acid is hydrolysed to form glycyrrhetinic acid. This compound selectively inhibits 1-b-hydroxysteroid dehydrogenase (also known as 11-beta-HSD2). [1-4]. 

With this enzyme blocked, cortisol doesn’t convert to the inactive cortisone and is allowed to build up in the body. This eventually leads to hypertension through binding of cortisol to the mineralocorticoid receptors in the kidneys, which increases water retention, and blood volume over time [5], mainly through renal sodium retention and loss of potassium [3]. 

The herb may act to reduce the effectiveness of diuretics through direct sodium retention activity. This action may reduce the effectiveness of diuretic medications like Thiazide-based diuretic medications used in the management of heart disease and hypertension [6].

These diuretic medications are well known for causing potassium depletion [7, 8], which is likely to develop into serious hypokalemia [9].

When using Glycyrrhiza, careful attention should be given on drug history taking of the patient. If they are currently taking diuretic medications to manage cardiovascular disease, or hypertension, it is recommended to avoid liquorice and substitute for another herb.

 

References:

  1. Heilmann, P., Heide, J., Hundertmark, S., & Schöneshöfer, M. (1999). Administration of glycyrrhetinic acid: significant correlation between serum levels and the cortisol/cortisone-ratio in serum and urine. Experimental and clinical endocrinology & diabetes, 107(06), 370-378. 
  2. Krähenbühl, S., Hasler, F. E. L. I. X., Frey, B. M., Frey, F. J., Brenneisen, R. U. D. O. L. F., & Krapf, R. (1994). Kinetics and dynamics of orally administered 18 beta-glycyrrhetinic acid in humans. The Journal of Clinical Endocrinology & Metabolism, 78(3), 581-585.
  3. Serra, A, D.E. Uehlinger, P. Ferrari, B. Dick, B.M. Frey, F.J. Frey, & B. Vogt. (2002).  Glycyrrhetinic acid decreases plasma potassium concentrations in patients with anuria.  Journal of the American Society of Nephrologists 13 (1):191-196.
  4. Whorwood, C. B., Sheppard, M. C., & Stewart, P. M. (1993). Licorice inhibits 11 beta-hydroxysteroid dehydrogenase messenger ribonucleic acid levels and potentiates glucocorticoid hormone action. Endocrinology, 132(6), 2287-2292. Chicago.
  5. Guilliams, T. G., & Edwards, L. (2010). Chronic stress and the HPA axis. The standard, 9(2), 1-12.
  6. Musini, V. M., Rezapour, P., Wright, J. M., Bassett, K., & Jauca, C. D. (2012). Blood pressure lowering efficacy of loop diuretics for primary hypertension. The Cochrane Library.
  7. Fichman, M. P., Vorherr, H., Kleeman, C. R., & Telfer, N. A. N. C. Y. (1971). Diuretic-induced hyponatremia. Ann Intern Med, 75(6), 853-863.
  8. Spital, A. (1999). Diuretic-induced hyponatremia. American journal of nephrology, 19(4), 447-452.
  9. Strykers, P. H., Stern, R. S., & Morse, B. M. (1984). Hyponatremia induced by a combination of amiloride and hydrochlorothiazide. JAMA, 252(3), 389-389.

Is Liquorice Actually An Adaptogen?

The term "adaptogen" refers to plants or other substances that augment non-specific resistance in the body, and help the body to adapt to various situations, therefore protecting it from stressful events and factors. (Mendes, Elisaldo, Carlini., 2007). According to Brekhman II & Dardymov IV., (1969), there are 3 criteria that need to be met before a compound can be considered an adaptogen; 

It must produce a nonspecific response in the body
It must produce a normalising influence on physiology in the face of a stressor
It must be incapable of influencing normal body functions more than required to gain non-specific resistance

Glycyrrhiza glabra, and G. uralensis have both been used traditionally as an adaptogen, which mainly involved its addition to traditional Chinese formulas to strengthen the body overall (Zhu, Y. P. 1998). The traditional well-rounded and non-specific indications for this herb has provoked numerous studies around the mechanisms of action as an adaptogen. 

Licorice was shown to provide antidepressant activity when a study revealed licorice extracts ability to reverse diazepam, scopolamine, and ethanol induced amnesia in mice (Parle, Dhingra,  & Kulkarni, 2004). The actions are suggested to be due to the cholinergic improvements in the brain, which have been reported in separate studies in doses as low as 150 mg/kg (Sigurjonsdottir, Manhem, Axelson, & Wallerstedt, 2003). In addition, the hydrophobic flavonoids of licorice root have been shown to produce abdominal fat lowering and hypoglycemic effects (Nakagawa, Kishida, Arai, Nishiyama, Mae, 2004). Both of these actions suggest the potential for adaptogenic action in the body due to marked improvements and increased tolerance to external stresses and changes in homeostasis. 

There are a number of problems with the classification of licorice as an adaptogen, however, such as the influence it has on cortisol levels throughout the body. Most adaptogenic substances that buffer the stress response, act on the hypothalamus, pituitary, adrenal (HPA) axis. This is because this system is one of the key components of the “stress system” (Guilliams, & Edwards, 2010). In most cases, such as with the South American herb Pfaffia paniculata, the effects on hormones are bidirectional, allowing the herb to successfully balance the stress response in both overactive and underactive states (Masami & Gu. 2003).

In the case of licorice, the main constituent affecting the stress response is glycyrrhizin, which is structurally similar to endogenous corticosteroids. This constituent has been shown to block 11-beta-hydroxysteroid dehydrogenase which is the enzyme responsible for the conversion of cortisol to cortisone, thereby inactivating the molecule (Heilmann, Heide, Hundertmark, Schöneshofer., 1999; Krähenbühl, hasler, Frey, Frey, Brenneisen, Krapf., 1994; Whorwood, Sheppard, Stewart., 1993). As cortisol is prevented from breaking down in the body, levels will increase which can lead to a number of negative side effects over time including memory deficits (Lupien, de Leon, De Santi, Convit, Tarshish, Nair, & Meaney., 1998). This single direction activity has been shown to increase blood pressure in both healthy, and hypertensive patients to the same degree (Belinky, Aviram, Mahmood, & Vaya, 1998). The German Commission E suggests that liquorice extracts should not be taken for any longer than 6-8 weeks without professional supervision (German Federal Minister Of Justice, 1991).

The deglycyrrhizinated licorice extracts have this cortisol increasing component removed, and offers a much clearer benefit for those experiencing hypertension. This version of licorice is likely to be the better adaptogenic compound due to the reduction of the most major side effects of licorice. 

The adaptogenic qualities may be caused by other components in the plant. An example of which involves the isoflavonoid glabridin which has been shown to increase the fatigue resistance of mice pretreated with the extract over a 28 day period (Van Uum, Hermus, Sweep, Walker, Ross, De Leeuw, & Lenders., 2002). 

The classification of licorice as an adaptogenic medicine appears to be based mainly off traditional medical uses rather than current and concrete scientific evidence. The glycyrrhizin content and associated single direction activity and numerous negative side effects effectively eliminate it from the protocols set to determine adaptogenic compounds on the market as per the guidelines set by Brekhman, & Dardymov (1969). Licorice may have many useful attributes medicinally but is not recommended for adaptogenic uses due to lack of comprehensive research outcomes and authoritative suggestions against long-term use.