Licorice Root--Potential Early Intervention for Chronic Fatigue Syndrome

Reference: Baschetti R. Chronic fatigue syndrome and liquorice (Letter). New Zealand Med J 1995; 108:156-7.

Summary: In a letter to the editor, Mr. Baschetti from Padova, Italy, reports his success in treating his own case of chronic fatigue syndrome (CFS) with licorice. After unsuccessfully trying several different therapies over a 20 month period, Mr. Baschetti began using licorice. He adds that licorice dissolved in milk (2.5 g/500 ml/day) was the delivery form. There is no information as to the source of the licorice. After several days of use, he reports a return of physical and mental stamina. The only symptom that did not change was his enlarged lymph nodes (he does not give the location of these nodes).

Mr. Baschetti provides clear rationale for his choice of licorice to treat CFS. Citing the work of Dr. Mark Demitrack of the University of Michigan Medical Center, he points to the mild glucocorticoid insufficiency noted in CFS patients. Mr. Baschetti then cites the ability of licorice to potentiate glucocorticoid production. This provides the basis for using licorice in CFS patients with hypocortisolemia. He wisely points out that depressed patients may actually have hypercortisolemia and that licorice may worsen their symptoms. He also notes that clinical depression should be ruled out before prescribing licorice for CFS. He adds that the enlarged lymph nodes (usually anterior of posterior cervical), which are present in CFS patients and not depressed patients, may be one way to discriminate.

Comments/Opinions: Mr. Baschetti, a CFS patient who has clearly done his homework, brings to light a fascinating theory of CFS and then goes the extra step to provide a very rational and inexpensive treatment option in licorice. I have long been an advocate of addressing adrenal function in CFS patients and have been successful with an approach that uses herbal adaptogens like Panax ginseng (Asian ginseng) and Eleutherococcus senticosus (eleuthero), both of which help support normal hypothalamic-pituitary-adrenal (HPA) axis functioning. I must admit that Mr. Baschetti's argument for the use of licorice makes perfect sense -- particularly as an initial treatment option to be followed by long-term treatment with the adaptogens mentioned above.

Dr. Demitrack's work at the University of Michigan Medical Center is essential reading for any healthcare provider interested in CFS. Dr. Demitrack and his colleagues have shown that the central problem with CFS patients may be impaired activation of the HPA axis. This is based on a 1991 study that found CFS patients to have significantly reduced basal evening glucocorticoid levels and low 24-hour urinary free cortisol excretion.(1) These patients also showed elevated ACTH concentrations and an increased adrenocortical sensitivity to ACTH, but a reduced maximal response. In short, their data indicates a mild central adrenal insufficiency with a resulting mild glucocorticoid deficiency.

Dr. Demitrack and colleagues chose to focus on the HPA axis in CFS because of the fact that many CFS patients report the onset of their illness following a significant period of stress (e.g. infection, emotional trauma, overwork, sleep disruption), and that the course of CFS waxes and wanes with periods of physical or emotional stress.(2) The HPA axis is the prototypical hormonal stress system of the body. In CFS, we appear to be dealing with a failure in the central activation of the HPA axis. This results in a mild hypocortisolemia and resulting glucocorticoid insufficiency. In fact, the clinical features of CFS show considerable overlap with those noted in patients with glucocorticoid insufficiency. These include debilitating fatigue, arthralgias, myalgias, adenopathy post-exertional fatigue, exacerbation of allergic responses, and disturbances of mood and sleep. Glucocorticoid insufficiency may also explain the paradoxical immune profile that we see in many CFS patients.(3,4) One need venture no further than fibromyalgia to see the results of low glucocorticoid production.

As I've mentioned before in the QRNM and in the section on CFS in my new book, Herbal Prescriptions for Better Health (Prima Publishing, 1996), a model for CFS that focuses on adrenal function may have been established over 50 years ago. In the 1940s, Dr. John Tintera, a medical doctor living in New York, began to look more closely at patients in his practice complaining of chronic fatigue. He observed that many of these people had been experiencing recurring stress, and was able to make an argument for depleted adrenal function. He developed the term hypoadrenocorticism to describe their symptoms.(5) Among the chief complaints observed were excessive fatigue, nervousness and irritability, insomnia, post-exertional fatigue, increased allergies, generalized cervical lymphadenopathy, and postural hypotension. He also found low glucocorticoid levels in these patients! While Dr. Demitrack's work is certainly more refined, Dr. Tintera may very well have been the first person to recognize the condition that has become known as CFS today.

Dr. Tintera's primary approach to CFS was to use intravenous adrenocortical extract (ACE) as well as a combination of B vitamins and vitamin C. While therapeutic protocols for CFS should always focus on pantothenic acid and vitamin C, current research may prove licorice root to be a more efficacious and certainly less-expensive (not to mention legal) alternative to ACE. Two of the active components of licorice root, glycyrrhizic acid and glycyrrhetinic acid, have both been shown to inhibit 11á-hydroxysteroid dehydrogenase (11á-HSD).(6) 11á-HSD is responsible for the conversion of the active steroids cortisol and corticosterone to inactive cortisone and 11-dehydrocorticosterone. This means that initial use of licorice root in CFS patients would result in greater levels of cortisol and corticosterone and some initial compensation for the glucocorticoid insufficiency noted above.

The ideal dose of licorice root for treatment of CFS is unclear. Mr. Baschetti's results with 2.5 grams daily seem significant. There is another report of a patient with Addison's disease finding improvement consuming 10 to 20 grams of licorice daily from candy.(7) The patient, who had actually been craving licorice, later was found to respond to treatment with fludrocortisone.

My recommendation would be to try 2 to 3 grams of licorice root twice daily for four to eight weeks. At four to six weeks, begin using either eleuthero or Asian ginseng. While the licorice root will help "kick-start" adrenal function and glucocorticoid production, these adaptogens will provide support for normal HPA axis function. If improvement is noted at six to eight weeks, begin withdrawing licorice over a period of 10 to 14 days. Eleuthero and Asian ginseng should be considered long-term therapies.

The recommended dosage for eleuthero is 2 to 3 grams of the dry, powdered root and rhizome daily. Alternative dosage forms include alcohol-based extracts (8-10ml daily) or a standardized, concentrated extract (300-400mg daily). Use eleuthero continuously for four to six weeks with a one-week break before resuming. I recommend an extract of Asian ginseng root standardized to 5 to 7% ginsenosides. The daily dose is 100 mg bid and should be taken for four weeks continuously with a one- to two-week break before resuming.

Nutritional supplement considerations include:

Vitamin B complex -- 50 to 100 mg daily

Pantothenic acid -- 250 mg daily

Vitamin C -- 2 to 3 grams daily

Chromium polynicotinate -- 200 mcg bid

While CFS patients are less likely to suffer mineralocorticoid hypertension with volume expansion and hypokalemia, it is still important to regularly check vital signs when administering the high doses of licorice root recommended. Also, please remember we're talking about licorice root not deglycyrrhizinated licorice (DGL). Licorice root has glycyrrhizic and glycyrrhetinic acids while DGL does not.

(1) Demitrack MA, Dale JK, Straus SE, et al. Evidence for impaired activation of the hypohthalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab 1991; 73:1224-34.

(2) Holmes GP, Kaplan JE, Gantz NM, et al. Chronic fatigue syndrome: a working case definition. Ann Intern Med 1988; 108:387-9.

(3) Klimas NG, Slavato FR, Morgan R, Fletcher MA. Immunologic abnormalities in chronic fatigue syndrome. J Clin Microbiol 1990; 28:1403-10.

(4) Lloyd A, Hickie I, Hickie C, et al. Cell-mediated immunity in patients with chronic fatigue syndrome, healthy control subjects and patients with major depression. Clin Exp Immunol 1992; 87:76-9.

(5) Tintera JW. The hypoadrenocortical state and its management. NY State Med J 1955; 55:1869-76.

(6) Whorwood CB, Sheppard MC, Stewart PM. Licorice inhibits 11á-hydroxysteroid dehydrogenase messenger ribonucleic acid levels and potentiates glucocorticoid hormone action. Endocrinology 1993; 132:2287-92.

(7) Cotterill JA, Cunliffe WJ. Self-medication in a patient with Addison's disease. Lancet 1973; i:294-5.

Article copyright Natural Product Research Consultants, Inc.

~~~~~~~~

By D. BrownReference: Baschetti R. Chronic fatigue syndrome and liquorice (Letter). New Zealand Med J 1995; 108:156-7.

Summary: In a letter to the editor, Mr. Baschetti from Padova, Italy, reports his success in treating his own case of chronic fatigue syndrome (CFS) with licorice. After unsuccessfully trying several different therapies over a 20 month period, Mr. Baschetti began using licorice. He adds that licorice dissolved in milk (2.5 g/500 ml/day) was the delivery form. There is no information as to the source of the licorice. After several days of use, he reports a return of physical and mental stamina. The only symptom that did not change was his enlarged lymph nodes (he does not give the location of these nodes).

Mr. Baschetti provides clear rationale for his choice of licorice to treat CFS. Citing the work of Dr. Mark Demitrack of the University of Michigan Medical Center, he points to the mild glucocorticoid insufficiency noted in CFS patients. Mr. Baschetti then cites the ability of licorice to potentiate glucocorticoid production. This provides the basis for using licorice in CFS patients with hypocortisolemia. He wisely points out that depressed patients may actually have hypercortisolemia and that licorice may worsen their symptoms. He also notes that clinical depression should be ruled out before prescribing licorice for CFS. He adds that the enlarged lymph nodes (usually anterior of posterior cervical), which are present in CFS patients and not depressed patients, may be one way to discriminate.

Comments/Opinions: Mr. Baschetti, a CFS patient who has clearly done his homework, brings to light a fascinating theory of CFS and then goes the extra step to provide a very rational and inexpensive treatment option in licorice. I have long been an advocate of addressing adrenal function in CFS patients and have been successful with an approach that uses herbal adaptogens like Panax ginseng (Asian ginseng) and Eleutherococcus senticosus (eleuthero), both of which help support normal hypothalamic-pituitary-adrenal (HPA) axis functioning. I must admit that Mr. Baschetti's argument for the use of licorice makes perfect sense -- particularly as an initial treatment option to be followed by long-term treatment with the adaptogens mentioned above.

Dr. Demitrack's work at the University of Michigan Medical Center is essential reading for any healthcare provider interested in CFS. Dr. Demitrack and his colleagues have shown that the central problem with CFS patients may be impaired activation of the HPA axis. This is based on a 1991 study that found CFS patients to have significantly reduced basal evening glucocorticoid levels and low 24-hour urinary free cortisol excretion.(1) These patients also showed elevated ACTH concentrations and an increased adrenocortical sensitivity to ACTH, but a reduced maximal response. In short, their data indicates a mild central adrenal insufficiency with a resulting mild glucocorticoid deficiency.

Dr. Demitrack and colleagues chose to focus on the HPA axis in CFS because of the fact that many CFS patients report the onset of their illness following a significant period of stress (e.g. infection, emotional trauma, overwork, sleep disruption), and that the course of CFS waxes and wanes with periods of physical or emotional stress.(2) The HPA axis is the prototypical hormonal stress system of the body. In CFS, we appear to be dealing with a failure in the central activation of the HPA axis. This results in a mild hypocortisolemia and resulting glucocorticoid insufficiency. In fact, the clinical features of CFS show considerable overlap with those noted in patients with glucocorticoid insufficiency. These include debilitating fatigue, arthralgias, myalgias, adenopathy post-exertional fatigue, exacerbation of allergic responses, and disturbances of mood and sleep. Glucocorticoid insufficiency may also explain the paradoxical immune profile that we see in many CFS patients.(3,4) One need venture no further than fibromyalgia to see the results of low glucocorticoid production.

As I've mentioned before in the QRNM and in the section on CFS in my new book, Herbal Prescriptions for Better Health (Prima Publishing, 1996), a model for CFS that focuses on adrenal function may have been established over 50 years ago. In the 1940s, Dr. John Tintera, a medical doctor living in New York, began to look more closely at patients in his practice complaining of chronic fatigue. He observed that many of these people had been experiencing recurring stress, and was able to make an argument for depleted adrenal function. He developed the term hypoadrenocorticism to describe their symptoms.(5) Among the chief complaints observed were excessive fatigue, nervousness and irritability, insomnia, post-exertional fatigue, increased allergies, generalized cervical lymphadenopathy, and postural hypotension. He also found low glucocorticoid levels in these patients! While Dr. Demitrack's work is certainly more refined, Dr. Tintera may very well have been the first person to recognize the condition that has become known as CFS today.

Dr. Tintera's primary approach to CFS was to use intravenous adrenocortical extract (ACE) as well as a combination of B vitamins and vitamin C. While therapeutic protocols for CFS should always focus on pantothenic acid and vitamin C, current research may prove licorice root to be a more efficacious and certainly less-expensive (not to mention legal) alternative to ACE. Two of the active components of licorice root, glycyrrhizic acid and glycyrrhetinic acid, have both been shown to inhibit 11á-hydroxysteroid dehydrogenase (11á-HSD).(6) 11á-HSD is responsible for the conversion of the active steroids cortisol and corticosterone to inactive cortisone and 11-dehydrocorticosterone. This means that initial use of licorice root in CFS patients would result in greater levels of cortisol and corticosterone and some initial compensation for the glucocorticoid insufficiency noted above.

The ideal dose of licorice root for treatment of CFS is unclear. Mr. Baschetti's results with 2.5 grams daily seem significant. There is another report of a patient with Addison's disease finding improvement consuming 10 to 20 grams of licorice daily from candy.(7) The patient, who had actually been craving licorice, later was found to respond to treatment with fludrocortisone.

My recommendation would be to try 2 to 3 grams of licorice root twice daily for four to eight weeks. At four to six weeks, begin using either eleuthero or Asian ginseng. While the licorice root will help "kick-start" adrenal function and glucocorticoid production, these adaptogens will provide support for normal HPA axis function. If improvement is noted at six to eight weeks, begin withdrawing licorice over a period of 10 to 14 days. Eleuthero and Asian ginseng should be considered long-term therapies.

The recommended dosage for eleuthero is 2 to 3 grams of the dry, powdered root and rhizome daily. Alternative dosage forms include alcohol-based extracts (8-10ml daily) or a standardized, concentrated extract (300-400mg daily). Use eleuthero continuously for four to six weeks with a one-week break before resuming. I recommend an extract of Asian ginseng root standardized to 5 to 7% ginsenosides. The daily dose is 100 mg bid and should be taken for four weeks continuously with a one- to two-week break before resuming.

Nutritional supplement considerations include:

Vitamin B complex -- 50 to 100 mg daily

Pantothenic acid -- 250 mg daily

Vitamin C -- 2 to 3 grams daily

Chromium polynicotinate -- 200 mcg bid

While CFS patients are less likely to suffer mineralocorticoid hypertension with volume expansion and hypokalemia, it is still important to regularly check vital signs when administering the high doses of licorice root recommended. Also, please remember we're talking about licorice root not deglycyrrhizinated licorice (DGL). Licorice root has glycyrrhizic and glycyrrhetinic acids while DGL does not.

(1) Demitrack MA, Dale JK, Straus SE, et al. Evidence for impaired activation of the hypohthalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab 1991; 73:1224-34.

(2) Holmes GP, Kaplan JE, Gantz NM, et al. Chronic fatigue syndrome: a working case definition. Ann Intern Med 1988; 108:387-9.

(3) Klimas NG, Slavato FR, Morgan R, Fletcher MA. Immunologic abnormalities in chronic fatigue syndrome. J Clin Microbiol 1990; 28:1403-10.

(4) Lloyd A, Hickie I, Hickie C, et al. Cell-mediated immunity in patients with chronic fatigue syndrome, healthy control subjects and patients with major depression. Clin Exp Immunol 1992; 87:76-9.

(5) Tintera JW. The hypoadrenocortical state and its management. NY State Med J 1955; 55:1869-76.

(6) Whorwood CB, Sheppard MC, Stewart PM. Licorice inhibits 11á-hydroxysteroid dehydrogenase messenger ribonucleic acid levels and potentiates glucocorticoid hormone action. Endocrinology 1993; 132:2287-92.

(7) Cotterill JA, Cunliffe WJ. Self-medication in a patient with Addison's disease. Lancet 1973; i:294-5.

Natural Product Research Consultants, Inc.

~~~~~~~~

By D. Brown

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