Is Gan Cao (Licorice Root) Safe for Treating TSW?
Topical Steroid Withdrawal (TSW) is a skin condition treated by many western and Traditional Chinese Medicine (TCM) dermatologists. The condition appears when some patients use an undetermined quantity of topical steroids which leads to either decreasingly effective treatments or the need for increasingly stronger dosages. Once the patient stops using steroids, the skin erupts into extreme erythema, known as Red Skin Syndrome (RSS) which can then lead to further deterioration of the skin barrier as well as debilitating non-skin symptomatology that can require hospitalization in severe cases. To date, there is no known western cure for TSW.
Currently, there is great debate among western dermatologists whether TSW is a disease of its own or an extreme version of a preexisting skin condition (i.e. atopic dermatitis). As such, statistics of the TWS population base are unclear since most patients go undiagnosed by their practitioners. According to the International Topical Steroid Addiction Network, a TSW patient and public education advocacy group, the prevalence of TSW/RSS “is unknown, underreported, not well characterized, and more common than realized, but frequently goes unrecognized.” (What is the prevalence of RSS?, 2019)
However, because topical steroids are the most commonly prescribed pharmaceuticals for patients with any type of inflammatory skin disease, it is not unreasonable to say, the population base is likely larger than suspected.
TCM dermatology provides very successful herbal formula treatments for TSW. As a result, TSW patients often suspect steroid activity must be at play and fear that once they heal from herbal treatment, TSW will reappear upon cessation of treatment. One commonly used Chinese herb, gan cao, better known as licorice root has been implicated as having properties like steroids. (Fung FY, 2017 Mar;58(3)).
Given its ability to harmonize all other ingredients and mitigate other herbs’ harsh actions, gan cao is used in many Chinese herbal medicine formulas and, most TCM dermatology formulas. Therefore, it is worthwhile to examine the existing literature to better inform TCM dermatology treatments of TSW and to provide credible information for this patient population base.
What is a corticosteroid?
Corticosteroids are steroid hormones that are either produced by the body or are man-made. Naturally occurring corticosteroids like hydrocortisone and cortisone are produced by the outer portion of the adrenal gland known as the cortex, hence the name, corticosteroid. Corticosteroids are classified as:
- Glucocorticoids, such as corticosterone and cortisol. These steroids have numerous effects and can act on nearly all cells in the body. For example, glucocorticoids regulate carbohydrate, protein and fat metabolism, are anti-inflammatory and anti-allergic, play a role in repairing injury and managing stress.
The use of man-made glucocorticoids inhibits many inflammation-associated molecules such as cytokines, chemokines, arachidonic acid metabolites, and adhesion molecules. In contrast, anti-inflammatory mediators often are up-regulated by glucocorticoids.
- Mineralocorticoids, such as aldosterone. These steroids promote electrolyte and sodium balance in the body. Currently, there is growing evidence indicating that mineralocorticoid receptors are not restricted to vascular and renal tissues but can also occur in cells of the immune system. Additionally, aldosterone has been associated with pro-inflammatory immune effects. However, the cellular and molecular mechanisms that mediate these effects are unknown to date. (Muñoz-Durango, et al., 2015)
Is gan cao a steroid?
Glycyrrhizin is the principal active ingredient in licorice, and its hydrolysed metabolite, 18βglycyrrhetinic acid, has been found to inhibit the oxidative function of 11β-hydroxysteroid dehydrogenase, which then prevents the metabolism of cortisol. When excess cortisol is available, it can then bind to mineralocorticoid receptors, resulting in mineralocorticoid excess and manifesting as fluid retention, hypertension and hypokalemia. (Isbrucker & Burdock, 2006).
This means that gan cao does in fact promote steroid-like activities, however, it does not behave like a glucocorticoid, it acts like a mineralocorticoid. While both promote anti-inflammatory properties and influence on immune cells, the mechanism is quite different.
Does TSW arise from any kind of steroid?
According to an article in Pharmacy Times, the use of glucocorticoids results in suppression of the hypothalamic-pituitary-adrenal axis which causes a reduction in cortisol and androgen levels as well as plasma adrenocorticotropic hormone levels. Aldosterone levels typically remain normal because of stimulation from the renin-angiotensin-aldosterone system.(Brown, 2006).
Contrast that to the action of gan cao, which inhibits 11-beta-hydroxysteroid dehydrogenase, the enzyme that normally inactivates cortisol. If cortisol is not inactivated, the net effect leads to aldosterone excess. Therefore, ingesting gan cao does not lead to suppressed cortisol, it leads to activated cortisol. And unlike the action of glucocorticoids, it increases aldosterone instead of leaving it alone.
While this demonstrates a clear difference between the actions caused by glucocorticoids and gan cao, the question then becomes, is aldosterone excess safe?
How much gan cao is okay?
Based upon existing data, the minimum level of glycyrrhizic acid required to produce the described symptoms of aldosterone excess is not yet known. (Størmer, Reistad, & Alexander, 1993). Great variations of individual susceptibility to glycyrrhizic acid have been identified and there is also high variability of glycyrrhizic acid content among licorice products of different preparations and licorice roots harvested from different sources. (Su, M, Zhang, You, & et, 2014)
A few studies indicated that excessive and chronic doses of licorice led to pseudoaldosteronism.
(Celik, et al., 2012). These cases appear to be alarming on a cursory level and probably further contribute to public concerns, however an excessive amount is not the norm and most likely not the amount used in TCM formulations
A literature review finds one study that used healthy volunteers to investigate varying doses of licorice to ascertain what amount constituted a “safe” dose. Doses of 0, 1, 2 and 4 mg of glycyrrhizic acid/kg body weight were administered orally for 8 weeks to 39 healthy female volunteers aged 19-40 years. The experiment lasted 12 weeks including an adaptation and a “wash-out” period. The study found that a daily dose of 2 mg/kg of glycyrrhizic acid did not have any effect on aldosterone level, blood pressure, potassium and fluid retention. The researchers determined there was a no-effect level of 2 mg/kg making a daily intake (ADI) of 0.2 mg/kg body weight extrapolated with a safety factor of 10. (van Gelderen, Bijlsma, van Dokkum, & Savelkoul, 2000)
This means that the consumption of 12 mg of glycyrrhizic acid/day for a person with a body weight of 60 kg is considered safe. Translated further, this indicates that 6 grams of licorice a day for a 132-pound person, assuming the licorice contains 0.2% of glycyrrhizic acid, is acceptable.
Lastly, it is important to note that all studies indicated that gan cao’s inhibitory effect on 11 betahydroxysteroid dehydrogenase is reversible; though noted, the depression of the reninangiotensin system can take several months to fully recover.
How this impacts TCM treatment
As a rule, the quantity of gan cao used in TCM herbal formulations is between 1.5 and 9 grams per day. The higher end represents formulas utilizing gan cao for its ability to promote and restore circulation whereas the lower end generally utilizes gan cao for its harmonizing effects. By and large, TCM dermatology formulations use gan cao for its harmonizing features and thus, 4-6 gram per day is the norm. In this way, gan cao usage stays within the quantitatively determined “safe zone.”
In my own clinic, several TSW patients have been treated with herbal formulations that include 6 grams per day of gan cao. Upon completing treatment and discontinuing all usage of herbal formulas, no patients to date have rebounded with TSW symptoms and no patients have reported signs of aldosteronism. Additionally, gan cao has been included in all our clinic formulas treating atopic dermatitis patients, a population that is most sensitive to all ingredients. To date, this has not caused any issues as well.
While not at all an exhaustive study, colleagues who also specialize in TCM dermatology have also reported these same results with their TSW and atopic dermatitis cases. Anecdotally, this would further suggest that gan cao is not typically a problem with dermatology cases.
Further research would be helpful to quantify exactly how much gan cao is needed to impact aldosterone levels since other TCM formulas include higher amounts. It would also be helpful to examine the various sources of the gan cao supply chain to ascertain the percentage differences in glycyrrhizic acid. However, for TSW, it appears that gan cao, used at current levels from various sources does not warrant further concern.
While gan cao does promote anti-inflammatory effects and can influence immune cell activity much like a corticosteroid, its biomechanism mimics a mineralocorticoid not a glucocorticoid. Instead of suppressing cortisol production, it activates cortisol which can lead to aldosterone excess.
While aldosterone excess occurs with excessive ingestion of gan cao, the typical dosage of gan cao in TCM dermatology formulations is not considered excessive and is within safe limits. Therefore, the usage of gan cao is unlikely to promote concerning issues and any minor issues are reversed within a few months after treatment ends. While individual variances may apply, careful observation of unique responses are always advised. However, the usage of 4-6 grams/day of gan cao should not pose a problem for the average TSW patient.
Brown, D. A. (2006, December 1). Adrenal Insufficiency: What Pharmacists Should Know.
Retrieved from Pharmacy Times: https://www.pharmacytimes.com/publications/issue/2006/2006-12/2006-12-6101
Celik, M., Karakus, A., Zeren, C., Demir, M., Bayarogullari, H., Duru, M., & Al, M. (2012). Licorice induced hypokalemia, edema, and thrombocytopenia. Human & Experimental Toxicology, 1295–8.
Fung FY, L. Y. (2017 Mar;58(3)). Steroids in traditional Chinese medicine: what is the evidence? Singapore Med J., 115-120.
Isbrucker, R., & Burdock, G. (2006). 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. Regulatory Toxicology and Pharmacology, 167–192.
Muñoz-Durango, N., Vecchiola, A., Gonzalez-Gomez, L. M., Simon, F., Riedel, C., Fardella, C.
E., & Kalergis, A. M. (2015, June 3). Modulation of Immunity and Inflammation by the
Mineralocorticoid Receptor and Aldosterone. Retrieved from BioMed Research
Rasheed, A., & Qasim, M. (2017). A Review of Natural Steroids and Their Applications.
Retrieved from International Journal of Pharmaceutical Sciences and Research: http://ijpsr.com/bft-article/a-review-of-natural-steroids-and-theirapplications/?view=fulltext
Størmer, F., Reistad, R., & Alexander, J. (1993). Glycyrrhizic acid in liquorice–evaluation of health hazard. Food Chemical Toxicology, 303-12.
Su, M, Zhang, J., You, Y., & e. a. (2014). Content of active ingredient in Glycyrrhiza uralensis Fisch from different origins]. Central South Pharmacy, 1022–4.
van Gelderen, C., Bijlsma, J., van Dokkum, W., & Savelkoul, T. (2000). Glycyrrhizic acid: the assessment of a no effect level. Human and Experimental Toxicology, 434–9.
What is the prevalence of RSS? (2019, February 10). Retrieved from International Topical Steroid Addiction Network: itsan.org
About the Author
Dr. Olivia Hsu Friedman, DACM, LAc, Dipl.OM, is the owner of Amethyst Holistic Skin Solutions and treats eczema, TSW, psoriasis, and acne patients throughout the US in person and via video conferencing using only herbal medicine. Olivia earned a Doctorate in Acupuncture and Chinese Medicine as well as a diploma in Traditional Chinese Medicine Dermatology. Outside of the office, Olivia serves on the Board of Directors of the American Society of Acupuncturists, the Advisory Board of LearnSkin and the faculty of the Chicago Integrative Eczema Support Group sponsored by the National Eczema Association.