Topical steroid withdrawal (TSW) is a skin condition that emerges when some patients use an undetermined quantity of topical steroids, leading 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.

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.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, and 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 proinflammatory immune effects. However, the cellular and molecular mechanisms that mediate these effects are unknown to date.⁵

Is Gan Cao a Steroid?

Glycyrrhizin is the principal active ingredient in licorice, and its hydrolysed metabolite, 18β-glycyrrhetinic 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.⁴

This means 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 immune cells, the mechanism is quite different.

Does TSW Aarise 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.¹

Contrast that to the action of gan cao, which inhibits 11β-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: Isaldosterone excess safe?

How Much Gan Xao Is Ok?

Based upon existing data, the minimum level of glycyrrhizic acid required to produce the described symptoms of aldosterone excess is not yet known.⁷ 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.⁸

A few studies indicate that excessive and chronic doses of licorice lead to pseudoaldosteronism.² These cases appear to be alarming on a cursory level and probably further contribute to public concern. However, an excessive amount is not the norm and most likely not the amount used in TCM formulations.

A literature review yielded 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 eight weeks to 39 healthy female volunteers ages 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 10.⁹

This means consumption of 12 mg of glycyrrhizic acid/day for a person with a body weight of 60 kg is considered safe. Translated further, 6 grams of licorice a day for a 132-pound person, assuming the licorice contains 0.2 percent of glycyrrhizic acid, is acceptable.

Finally, it is important to note that all studies indicated gan cao's inhibitory effect on 11β-hydroxysteroid dehydrogenase is reversible; though noted, the depression of the reninangiotensin system can take several months to fully recover.

Impact On 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."

Clinical Recommendation

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, use 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 is always advised. However, the usage of 4-6 grams/day of gan cao should not pose a problem for the average TSW patient.

References & resources

1. Brown DA. "Adrenal Insufficiency: What Pharmacists Should Know."Pharmacy Times, Dec. 1, 2006.
2. Celik M, et al. Licorice induced hypokalemia, edema, and thrombocytopenia. Human & Exper Toxicol, 2012:1295-8.
3. Fung FY, et al. Steroids in traditional Chinese medicine: what is the evidence? Singapore Med J, 2017 Mar;58(3):115-120.
4. Isbrucker R, Burdock G. 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 Toxicol Pharmacol, 2006;46(3):167-192.
5. Muñoz-Durango N, et al. Modulation of immunity and inflammation by the mineralocorticoid receptor and aldosterone. BioMed Res Int, 2015.
6. Rasheed A, Qasim M. A review of natural steroids and their applications. Int J Pharmaceutical Sci and Res, 2017.
7. Størmer F, et al. Glycyrrhizic acid in liquorice - evaluation of health hazard. Food Chem Toxicol, 1993;31(4):303-12.
8. Su M, et al. [Content of active ingredient in Glycyrrhiza uralensis Fisch from different origins]. Central South Pharmacy, 2014:1022-4.
9. van Gelderen C, et al. Glycyrrhizic acid: the assessment of a no effect level. Human and Exper Toxicol, 2000;19(8):434-9.
10. What Is the Prevalence of RSS? International Topical Steroid Addiction Network, Feb. 10, 2019.

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Dr. Olivia Hsu Friedman is the owner of Amethyst Holistic Skin Solutions and specializes in resolving acne, eczema, psoriasis, and TSW by only using Chinese herbal medicine. When not in the office, Olivia serves on the board of directors of the American Society of Acupuncturists, the advisory board of LearnSkin, and faculty at the Chicago Integrative Eczema Support Group.

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