Adrenal-related fatigue and hypotension.
Mechanism of Action
Glycyrrhiza contains steroidal saponins credited with many of the supportive effects on the adrenal glands and hypothalamic–pituitary–adrenal (HPA) axis. Many adaptogenic plants possess steroidal saponins shown to exert immunomodulating and anabolic activities.1 As a general group of plant steroid-like compounds, saponins have been shown to promote neurogenesis, restore monoaminergic tone, enhance neurotrophic factors, and protect the HPA axis from acute and long-term stress.2
One of the most studied compounds in Glycyrrhiza is the steroidal saponin glycyrrhizin (synonymous with glycyrrhizic acid), which acts directly on the adrenal cortex and increases blood corticoids in patents with suppressed pituitary adrenocorticotropin (ACTH).3 Glycyrrhizin administered at a dose of 75 mg/kg/day for 5 days in rats resulted in inhibition of 11β-hydroxysteroid dehydrogenase (HSD) activity and also a significant reduction in steady-state 11β-HSD mRNA levels in both mineralocorticoid (kidney and distal colon) and glucocorticoid (liver and pituitary) target tissues.4
A similar group of steroidal saponins found in Glycyrrhiza are referred to collectively as glycyrrhizinates. Glycyrrhizinates inhibit 11- and 17β-HSDs, a group of steroid-specific dehydrogenase enzyme responsible for catalyzing the interconversion of active and inactive corticosteroids, such as cortisol to cortisone. Inhibition of these enzymes will prolong the life of cortisol in general circulation and may support a weak adrenal gland by boosting the tissue cortisol levels when adrenal output is insufficient.
Glycyrrhizinates can induce mineralocorticoid-like effects in both animals and humans.5 Elevated cortisol, both endogenous and exogenous pharmaceutical, leads to elevated aldosterone due to agonism of the renal corticoid receptors, which triggers the release of aldosterone. Glycyrrhiza steroidal compounds elicit a similar phenomenon to what is called pseudoaldosteronism, whereby the steroids promote the release of renal aldosterone.6
Other steroid-like compounds in Glycyrrhiza have also been shown to inhibit 11β-HSD enzymes, including glycyrrhetinic acid7 and the metabolic product of glycyrrhizin, carbenoxolone.8,9,10 Doses of
500 mg or less of glycyrrhetinic acid inhibit the enzymes only transiently, whereas 1000 and 1550 mg may cause long-lasting cortisone-like effects.11 These compounds may also reduce new releases of cortisol by inhibiting the conjugation of the metabolic precursors deoxycorticosterone and dehydroepiandrosterone in the adrenal gland.7
Carbenoxolone is a glycyrrhetinic acid derivative with a steroid-like structure. It has also been found
to support mitochondrial function contributing to the adaptogenic actions of Glycyrrhiza, such as improving energy and stamina. Carbenoxolone promotes mitochondrial functions stimulating phosphorylation via specific effects on mitochondrial membranes.12 This may help improve general cellular energy metabolism without the need to rely on greater adrenergic stimulation or stress on the HPA axis.
Adrenoreceptors on vascular smooth muscle fibers help regulate vascular resistance and blood pressure. Vascular adrenoreceptors are linked to pannexin channels involved in the release of ATP from smooth muscle cells, leading to vasoconstriction.13 Pannexin proteins are increasingly being shown to be involved in many physiological and pathological processes, amplifying ATP release, Ca(2+) signals, or both. Carbenoxolone inhibits pannexin channels.14 In adrenal chromaffin cells, pannexin channels play a role in the release of the catecholamine adrenaline and noradrenaline.13
Glycyrrhiza can normalize adrenal responsiveness as well as help mitigate stress affecting the HPA axis, as evidenced by its effects on adrenal hormones. Glycyrrhiza supports adrenal function, in part, by effecting cortisol-metabolizing dehydrogenase enzymes,15 as evidenced by increased blood levels of cortisol and decreased urinary excretion demonstrated with both animal and human studies. Human laboratory investigations show that Glycyrrhiza can lower cortisol in some subjects,16 yet raise it in Addison’s disease patients where serum cortisol is low,17 exemplifying the definition of an adaptogen, which are herbs with many nonspecific actions on the hormonal regulation, adrenal response, and HPA axis feedback, capable of optimizing tone, response, and circadian rhythms of hormones whether excess or deficient.
Animal and human blood assays indicate that Glycyrrhiza at doses of 100, 250, and 500 mg/kg will acutely decrease serum cortisol, ACTH, aldosterone, and K and increase renin and Na concentration in a dose-dependent manner.16,18 Glycyrrhiza may double urinary cortisol excretion in some human subjects similar to the levels seen in Cushing’s syndrome patients.19 Doses of 100 and 200 g/day will cause urinary cortisol to remain elevated for a week or more after Glycyrrhiza is withdrawn. A small pilot study showed serum cortisol levels in Addison’s disease patients on prescription cortisone acetate to increase when Glycyrrhiza is added, and cortisol delivery to all tissues is improved.17 These polar effects of raising serum cortisol in Addison’s patients and lowering it in other populations is evidence of the ability of Glycyrrhiza’s adaptogenic action on the HPA axis in a manner that optimizes tone and regulation, regardless of where the baseline cortisol lies—deficient or excess.
Blunting of responsiveness to glucocorticoids and the circadian rhythm of cortisol and dehydroepiandrosterone (DHEA) occurs in various diseases, as well as in general again where weakness in the HPA axis amplifies age-related changes in the neuroendocrine system.20,21 Aging is associated with a progressive decrease in the DHEA:cortisol ratio and a shift from anabolic-to-catabolic dominance, which is also linked to atherosclerotic progression and loss of cognitive and immune competence.20 One human clinical lab marker investigation found a low DHEA:cortisol to be associated with age in general, and in particular age combined with cognitive and mood disorders21,22 and a greater degree of anxiety and anger, depression and hostility, and age and age of onset/duration of illness in schizophrenic populations.23 Subtle signs of adrenal weakness, or blunting of the HPA axis include easy fatigue, poor stamina, poor memory, depression, irritability, and frequent infections—the same set up symptoms that indicate the use of adaptogenic herbs.
Glycyrrhiza in moderate doses primarily affects cortisol metabolism, and the androgens to a lesser degree. Animal studies suggest that Glycyrrhiza can reduce elevated androgens,24 and one human study showed Glycyrrhiza to decrease elevated serum testosterone in women as well;25 yet, normal DHEA and testosterone levels in healthy subjects have not been shown to be significantly depressed or impacted. Glycyrrhiza at a dose of 100 g supplying 150 mg of glycyrrhetinic acid was found to insignificantly reduce serum DHEA in men without affecting testosterone after 4 weeks.26 Human studies assaying the effects of Glycyrrhiza on salivary cortisol also report that no changes in testosterone levels could be seen in healthy men.27
Safety in Pregnancy and Breastfeeding
Glycyrrhiza is not considered to have the risk of inducing miscarriage or acting as an abortifacient, but it has been associated with an increased risk of preterm delivery. In general, Glycyrrhiza is demonstrated to have a spasmolytic action on the uterus.28 Tissue studies suggest Glycyrrhiza to possibly inhibit oxytocin, prostaglandin, and KCl-induced uterine contractions29 as well as those induced by calcium channel activation, nitric oxide synthase, or cyclooxygenase.30 However, several outcome studies have reported a higher incidence of threatened miscarriages and preterm labors among regular users of Glycyrrhiza compared with those women not exposed to these herbs during pregnancy, although the sample size was small and the confounding factors numerous and complex.31 “Heavy” Glycyrrhiza exposure (>500 mg of glycyrrhizin per week) was associated with a greater risk of preterm delivery in one outcome study,32 without evidence of effects on birth weight or maternal blood pressure.33 Another outcome study reviewed data on 185 pregnant women who used Glycyrrhiza-containing cough and cold formulas with a maximum dose of 2104 mg/day, anywhere between the 4th day and 25th week of gestation. The rate of stillbirths was marginally higher among women who took Glycyrrhiza than those who did not, and there was no evidence of teratogenic effects.34
Synthetic glucocorticoids administered during pregnancy to improve fetal lung maturity in threatened preterm birth have been shown to reduce birth weight and head circumference, but they have not been linked to gross changes in long-term health to date. 11β-HSD type 2 enzymes (11β-HSD2), discussed above, are also active in the placenta and may become up-regulated during pregnancy if a women is exposed to stress, as the enzymes promote glucocorticoid production.
Animal studies show long-term stress to alter the HPA axis and that Glycyrrhiza-like synthetic glucocorticoids can increase the occurrence of behavioral problems as a result.35 Glycyrrhizin, a natural constituent of Glycyrrhiza, potently inhibits 11β-HSD2, thereby reducing the fetoplacental barrier to the higher maternal cortisol levels. Maternal consumption of glycyrrhizin was shown to correlate to increased salivary cortisol levels in newborns, compared with newborns whose mother had zero exposure during pregnancy.36 Another human outcome study reported that prenatal exposure to Glycyrrhiza exerted detrimental effects on cognitive performance, as determined by standardized neuropsychological assessment tests and the report of psychiatric symptoms. Those with zero to low exposure (0–249 mg/week) scored better than those with high exposure (≥500 mg/week).37
One rat study reported Glycyrrhiza gavage at a dose of 100 mg/kg for 7 days to significantly increase the teratogenicity of cyclophosphamide by inducing cytochrome p450 enzyme conversion of the compound into toxic metabolites.38 Other human outcome studies however have not observed Glycyrrhiza to have teratogenic activity.
Thus, it may be concluded that Glycyrrhiza be avoided in pregnancy in anything greater than an occasional cup of tea. High doses, concentrated products, and daily consumption of Glycyrrhiza should be avoided during pregnancy.
Glycyrrhiza’s side effect of hypertension has been widely publicized, although the actual occurrence of this side effect is quite rare. Studies indicate that Glycyrrhiza may aggravate high blood pressure more often in those with a preexisting complex adrenal disorder involving altered potassium levels39,40,41,42,43 or those with a particular isoform of the 11β-dehydrogenase enzymes. Defects in the 11β-HSD2 enzyme contribute to hypertension and may make some people more sensitive to the hypertensive effects of salt and Glycyrrhiza because the kidneys express high levels 11β-HSD2 and are the principal source of cortisone in humans.44
Interestingly, Glycyrrhiza has in fact been reported to reduce blood pressure in animal models with metabolic syndrome.45 However, the side effect of elevated blood pressure remains unpredictable, so people using Glycyrrhiza supplements regularly should monitor their blood pressure. People with abnormally low potassium levels should avoid Glycyrrhiza due to the possibility of serious muscle weakness and high blood pressure. Do not consume more than 2 or 3 cups of Glycyrrhiza tea per day unless under a physician’s guidance. One clinical study investigating the benefits of Glycyrrhiza on mineralocorticoids in women taking spironolactone reported no subjects to experience hypertension as a side effect.46 There has been one anecdotal case report of acute urinary retention associated with severe hypokalemia possibly associated with Glycyrrhiza use in a pregnant woman.47 Various genotoxic studies have indicated that glycyrrhizin is neither teratogenic nor mutagenic and may possess antigenotoxic properties under certain conditions.5
Glycyrrhizin/glycyrrhizic acid may induce edema, hypertension, and hypokalemia in patients treated with higher doses and long-term administration, all as a side effect of pseudoaldosteronism due to the 11β-HSD inhibition. There are cases of Glycyrrhiza aggravating pseudohyperaldosteronism.48 Hypokalemic periodic paralysis, a rare disorder consisting of sudden episodes of muscle weakness with areflexia involving all four limbs that spontaneously resolves in several hours to several days, may be associated with heavy Glycyrrhiza ingestion in some people.49
Traditional medicines include teas, syrups, and powders at a wide variety of dosages, depending on whether it is being used as a lead or supportive herb within the formula.
Modern encapsulations will use 250–1000 mg in a single dose that is repeated several times a day. As this herb has potential for toxicity symptoms, use caution if exceeding doses greater than 4 g/day continuously.
Based on the in vivo and clinical evidence, an acceptable daily intake of isolated glycyrrhizin, one that will not typically cause Na retention or hypertension, is 0.015–0.229 mg/kg body weight/day.5
Glycyrrhiza is a rhizome that has been used since ancient times in traditional Chinese medicine and in ancient Egyptian, Greek, and Roman healing traditions for numerous medicinal uses. In China it has been referred to as “the great harmonizer” because of the belief that it can go everywhere in the body and pull together the actions of other herbs in botanical formulas. Glycyrrhiza seems to deserve this reputation because it can be used for ulcers, allergy, viral infections, fatigue, hepatoprotection, adrenal disorders, infertility, and numerous hormonal problems. Several Glycyrrhiza-based medicines have been introduced including a Japanese glycyrrhizin preparation used clinically as an antiallergic and antihepatitis agent and a remedy for gastric ulcer marketed in the Netherlands in 1940s. Glycyrrhiza also has a long-standing reputation as an emergency remedy in China for acute pituitary failure such as postpartum Sheehan’s syndrome.50
Phytomedicine. 1994;1(1):63–76. Plant adaptogens. Wagner H, Nörr H, Winterhoff H.
2 Nat Prod Res. 2015;29(4):302–7. Saponins: the phytochemical with an emerging potential for curing clinical depression. Abbas G, Rauf K, Mahmood W.
3 Br Med J. 1970;3(5721):498–500. Plasma 11-hydroxycorticoid levels after carbenoxolone sodium. Mattingly D, Tyler C, Bilton E.
4 Endocrinology. 1993;132(6):2287–92. Licorice inhibits 11β-hydroxysteroid dehydrogenase messenger ribonucleic acid levels and potentiates glucocorticoid hormone action. Whorwood CB, Sheppard MC, Stewart PM.
5 Regul Toxicol Pharmacol. 2006;46(3):167–92. Risk and safety assessment on the consumption of Licorice root (Glycyrrhiza sp.), its extract and powder as a food ingredient, with emphasis on the pharmacology and toxicology of glycyrrhizin. Isbrucker RA, Burdock GA.
6 Yakugaku Zasshi. 2000;120(10):849–62. A drug over the millennia: pharmacognosy, chemistry, and pharmacology of licorice. Shibata S.
7 Mol Cell Endocrinol. 2011;336(1–2):102–9. Liquorice and glycyrrhetinic acid increase DHEA and deoxycorticosterone levels in vivo and in vitro by inhibiting adrenal SULT2A1 activity. Al-Dujaili EA, Kenyon CJ, Nicol MR, et al.
8 Vitam Horm. 2000;58:121–48. Steroid dehydrogenase structures, mechanism of action, and disease. Duax WL, Ghosh D, Pletnev V.
9 Steroids. 1997;62(1):95–100. Structure and function of steroid dehydrogenases involved in hypertension, fertility, and cancer. Duax WL, Ghosh D.
10 Proc Biol Sci. 2014;281(1786). A mechanism for rapid neurosteroidal regulation of parenting behaviour. Pradhan DS, Solomon-Lane TK, Willis MC, et al.
11 J Clin Endocrinol Metab. 1994;78(3):581–5. Kinetics and dynamics of orally administered 18 beta-glycyrrhetinic acid in humans. Krähenbühl S, Hasler F, Frey BM, et al.
12 Arch Biochem Biophys. 2014;558:87–94. Carbenoxolone induces permeability transition pore opening in rat mitochondria via the translocator protein TSPO and connexin43. Azarashvili T, Baburina Y, Grachev D, et al.
13 Front Cell Neurosci. 2014;8:270. Pannexin 1 channels: new actors in the regulation of catecholamine release from adrenal chromaffin cells. Momboisse F, Olivares MJ, Báez-Matus X, et al.
14 Eur J Pharmacol. 2015;750C:43–51. Pannexin-1 channels do not regulate α1-adrenoceptor-mediated vasoconstriction in resistance arteries. Angus JA, Betrie AH, Wright CE.
15 J Hypertens. 2000;18(3):241–8. The role of the 11beta-hydroxysteroid dehydrogenase type 2 in human hypertension. Ferrari P, Lovati E, Frey FJ.
16 Clin Endocrinol (Oxf). 1996;45(5):605–11. Urinary free cortisone and the assessment of 11 beta-hydroxysteroid dehydrogenase activity in man. Palermo M, Shackleton CH, Mantero F, et al.
17 Eur J Endocrinol. 2011;165(5):761–9. Grapefruit juice and licorice increase cortisol availability in patients with Addison's disease. Methlie P, Husebye EE, Hustad S, et al.
18 Food Chem Toxicol. 2002;40(10):1525–7. Liquorice (Glycyrrhiza glabra) and the adrenal-kidney-pituitary axis in rats. Al-Qarawi AA, Abdel-Rahman HA, et al.
19 J Clin Endocrinol Metab. 1978;47(2):397–400. Licorice raises urinary cortisol in man. Epstein MT, Espiner EA, Donald RA, et al.
20 J Endocrinol Invest. 2004;27(6 Suppl):62–3. Neuroendocrine hypothesis of aging: The role of corticoadrenal steroids. Valenti G.
21 Arch Gerontol Geriatr Suppl. 2004;(9):171–82. Cognitive and affective disorders in the elderly: A neuroendocrine study. Ferrari E, Mirani M, Barili L, et al.
22 Brain Cogn. 2002;50(2):316–23. Cortisol and dehydroepiandosterone sulfate plasma levels and their relationship to aging, cognitive function, and dementia. de Bruin VM, Vieira MC, Rocha MN, et al.
23 Eur Neuropsychopharmacol. 2004;14(4):267–73. Elevation of the cortisol/dehydroepiandrosterone ratio in schizophrenia patients. Ritsner M, Maayan R, Gibel A, et al.
24 Int J Androl. 2009;32(4):417–22. Antiandrogenic activities of Glycyrrhiza glabra in male rats. Zamansoltani F, Nassiri-Asl M, Sarookhani MR, et al.
25 Steroids. 2004;69(11–12):763–6. Licorice reduces serum testosterone in healthy women. Armanini D, Mattarello MJ, Fiore C, et al.
26 Horm Res. 2006;65(2):106–10. Liquorice in moderate doses does not affect sex steroid hormones of biological importance although the effect differs between the genders. Sigurjonsdottir HA, Axelson M, Johannsson G, et al.
27 Lancet. 2001;358(9293):1613–4. Liquorice consumption and salivary testosterone concentrations. Josephs RA, Guinn JS, Harper ML, et al.
28 J Obstet Gynaecol Res. 2012;38(7):1004–10. Shakuyaku-kanzo-to inhibits smooth muscle contractions of human pregnant uterine tissue in vitro. Tsuji S, Yasuda K, Sumi G, et al.
29 Pharm Biol. 2013;51(6):744–8. Relaxative effect of core licorice aqueous extract on mouse isolated uterine horns. Jia J, Li Y, Lei Z, et al.
30 Phytother Res. 2012;26(9):1410–7. Analgesic and uterine relaxant effects of isoliquiritigenin, a flavone from Glycyrrhiza glabra. Shi Y, Wu D, Sun Z, et al.
31 Pharmacoepidemiol Drug Saf. 2010;19(11):1151–8. Use of herbal products among 392 Italian pregnant women: Focus on pregnancy outcome. Cuzzolin L, Francini-Pesenti F, Verlato G, et al.
32 Am J Epidemiol. 2002;156(9):803–5. Preterm birth and licorice consumption during pregnancy. Strandberg TE, Andersson S, Järvenpää AL, et al.
33 Am J Epidemiol. 2001;153(11):1085–8. Birth outcome in relation to licorice consumption during pregnancy. Strandberg TE, Järvenpää AL, Vanhanen H, et al.
34 Planta Med. 2013;79(2):97–101. Fetal and neonatal outcomes in women reporting ingestion of licorice (Glycyrrhiza uralensis) during pregnancy. Choi JS, Han JY, Ahn HK, et al.
35 Birth Defects Res C Embryo Today. 2012;96(4):315–24. Long-term effects of prenatal stress and glucocorticoid exposure. Painter RC, Roseboom TJ, de Rooij SR.
36 Psychoneuroendocrinology. 2010;35(10):1587–93. Maternal prenatal licorice consumption alters hypothalamic-pituitary-adrenocortical axis function in children. Räikkönen K, Seckl JR, Heinonen K, et al.
37 Am J Epidemiol. 2009;170(9):1137–46. Maternal licorice consumption and detrimental cognitive and psychiatric outcomes in children. Räikkönen K, Pesonen AK, Heinonen K, et al.
38 Birth Defects Res B Dev Reprod Toxicol. 2011;92(6):553–9. Licorice extract increases cyclophosphamide teratogenicity by upregulating the expression of cytochrome P-450 2B mRNA. Park D, Yang YH, Choi EK, et al.
39 Eur J Endocrinol. 2003;149(3):163–8. Tissue-specific Cushing’s syndrome, 11beta-hydroxysteroid dehydrogenases and the redefinition of corticosteroid hormone action. Stewart PM.
40 Ned Tijdschr Geneeskd. 2007;151(12):692–4. From gene to disease; 'apparent mineralocorticoid excess' syndrome, a syndrome with an apparent excess of mineral corticoids. Levtchenko EN, Deinum J, Knoers NV, et al.
41 Ann Med. 2010;42(6):465–74. Licorice-induced hypertension and common variants of genes regulating renal sodium reabsorption. Miettinen HE, Piippo K, Hannila-Handelberg T, et al.
42 Nihon Ronen Igakkai Zasshi. 2007;44(4):513–6. A 87-year-old woman with mineralocorticoid excess due to 11 beta-HSD2 deficiency. Inada M.
43 Semin Vasc Med. 2004;4(2):121–8. Cortisol, 11beta-hydroxysteroid dehydrogenases, and hypertension. van Uum SH, Lenders JW, Hermus AR.
44 Biochim Biophys Acta. 2010;1802(12):1178–87. 10. The role of 11β-hydroxysteroid dehydrogenase type 2 in human hypertension. Ferrari P.
45 J Nutr. 2003;133(11):3369–77. A licorice ethanolic extract with peroxisome proliferator-activated receptor-gamma ligand-binding activity affects diabetes in KK-Ay mice, abdominal obesity in diet-induced obese C57BL mice and hypertension in spontaneously hypertensive rats. Mae T, Kishida H, Nishiyama T, et al.
46 Eur J Obstet Gynecol Reprod Biol. 2007;131(1):61–7. Treatment of polycystic ovary syndrome with spironolactone plus licorice. Armanini D, Castello R, Scaroni C, et al.
47 Am J Med Sci. 2009;338(6):500–4. Bartter’s syndrome in pregnancy: Review of potassium homeostasis in gestation. Luqman A, Kazmi A, Wall BM.
48 Horm Res. 1999;52(5):253–5. Liquorice, growth retardation and Addison’s disease. Doeker BM, Andler W.
49 J Endocrinol Invest. 2007;30(4):341–5. Hypokalemic periodic paralysis in a patient with acquired growth hormone deficiency. Lanzi R, Previtali SC, Sansone V, et al.
50 Zhonghua Yi Xue Za Zhi. 1973;11:693–4. Successful treatment of postpartum hypopituitarism with decoction of Radix glycyrrhizae and Radix ginseng: Report of a case. Lei CC, Tang CC.