Withania somnifera

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Contents 1 Introduction 2 Description 3 Active Constituents 4 Mechanisms of Action 5 Clinical Indications 5.1 Anti-Aging 5.2 Immunomodulation and Hematopoiesis 5.3 Anxiety and Depression 5.4 Chronic Stress 5.5 Cardiovascular Protection 5.6 Hypothyroidism 5.7 Other Therapeutic Considerations 6 Drug-Botanical Interactions 7 Side Effects and Toxicity 8 Warnings and Contraindications 9 References

[edit] Introduction

Withania somnifera, also known as ashwagandha, Indian ginseng, and winter cherry, has been an important herb in the Ayurvedic and indigenous medical systems for over 3000 years. Historically, the plant has been used as an aphrodisiac, liver tonic, anti-inflammatory agent, astringent, and more recently to treat bronchitis, asthma, ulcers, emaciation, insomnia, and senile dementia. Clinical trials and animal research support the use of ashwaganda for anxiety, cognitive and neurological disorders, inflammation, and Parkinson's disease. Ashwaganda's chemopreventive properties make it a potentially useful adjunct for patients undergoing radiation and chemotherapy. Ashwaganda is also used therapeutically as an adaptogen for patients with nervous exhaustion, insomnia, and debility due to stress, and as an immune stimulant in patients with low white blood cell counts.

[edit] Description

Ashwagandha is a small, woody shrub in the Solanaceae family that grows about two feet in height. It can be found growing in Africa, the Mediterranean, and India. As a result of this wide growing range, there are considerable morphological and chemotypical variations in terms of local species. However, the primary alkaloids of both the wild and the cultivated species appear to be the same. The roots are the main portion of the plant used therapeutically. The bright red fruit is harvested in the late fall and seeds are dried for planting in the following spring. The berries have been shown to have an emetic effect.

[edit] Active Constituents

The major biochemical constituents of ashwaganda root are steroidal alkaloids and steroidal lactones in a class of constituents called withanolides. (1) At present, 12 alkaloids, 35 withanolides, and several sitoindosides from this plant have been isolated and studied. A sitoindoside is a withanolide containing a glucose molecule at carbon 27. Much of ashwaganda's pharmacological activity has been attributed to two main withanolides, withaferin A and withanolide D.

[edit] Mechanisms of Action

The withanolides serve as important hormone precursors that can convert into human physiologic hormones as needed. Ashwagandha is thought to be amphoteric; i.e., it can help regulate important physiologic processes. The theory is that when there is an excess of a certain hormone, the plant-based hormone precursor occupies cell membrane receptor sites so the actual hormone cannot attach and exert its effect. If the hormone level is low, the plant-based hormone exerts a small effect. Ashwagandha is also considered to be an adaptogen, facilitating the ability to withstand stressors, and has antioxidant properties as well. Other studies have shown ashwaganda to have an immunostimulatory effect.

[edit] Clinical Indications

[edit] Anti-Aging

In a double-blind clinical trial, ashwagandha was tested in a group of 101 healthy males, 50-59 years old, at a dosage of 3 grams daily for one year. A significant improvement in hemoglobin, red blood cell count, hair melanin, and seated stature was observed. Serum cholesterol decreased and nail calcium was preserved. Erythrocyte sedimentation rate decreased significantly and 71.4 percent reported improvement in sexual performance. (2)

[edit] Immunomodulation and Hematopoiesis

A series of animal studies show ashwagandha to have profound effects on the hematopoietic system, acting as an immunoregulator and a chemoprotective agent. (3,4) In a mouse study, administration of a powdered root extract from ashwagandha was found to enhance total white blood cell count. In addition, this extract inhibited delayed-type hypersensitivity reactions and enhanced phagocytic activity of macrophages when compared to a control group. (5) Recent research suggests a possible mechanism behind the increased cytotoxic effect of macrophages exposed to W. somnifera extracts. (6) Nitric oxide has been determined to have a significant effect on macrophage cytotoxicity against microorganisms and tumor cells. Iuvone et al demonstrated Withania somnifera increased NO production in mouse macrophages in a concentration-dependent manner. This effect was attributed to increased production of inducible nitric oxide synthase, an enzyme generated in response to inflammatory mediators and known to inhibit the growth of many pathogens. (7) Ashwagandha exhibited stimulatory effects, both in vitro and in vivo, on the generation of cytotoxic T lymphocytes, and demonstrated the potential to reduce tumor growth. (8) The chemopreventive effect was demonstrated in a study of ashwagandha root extract on induced skin cancer in Swiss albino mice given ashwagandha before and during exposure to the skin cancer-causing agent 7,12-dimethylbenz[a]anthracene. A significant decrease in incidence and average number of skin lesions was demonstrated compared to the control group. Additionally, levels of reduced glutathione, superoxide dismutase, catalase, and glutathione peroxidase in the exposed tissue returned to near normal values following administration of the extract. The chemopreventive activity is thought to be due in part to the antioxidant/free radical scavenging activity of the extract. (9)

An in vitro study showed withanolides from Withania somnifera inhibited growth in human breast, central nervous system, lung, and colon cancer cell lines comparable to doxorubicin. Withaferin A more effectively inhibited growth of breast and colon cancer cell lines than did doxorubicin. These results suggest Withania somnifera extracts may prevent or inhibit tumor growth in cancer patients, and suggest a potential for development of new chemotherapeutic agents. (10)

[edit] Anxiety and Depression

In an animal study assessing the anxiolytic and antidepressive actions of ashwagandha compared to commonly prescribed pharmaceuticals, an extract of the root was administered orally to rats once daily for five days. The results were compared to a group administered the benzodiazepine lorazepam for anxiolytic activity, and the tricyclic antidepressant imipramine for antidepressant investigation. Both the ashwagandha group and the lorazepam group demonstrated reduced brain levels of a marker of clinical anxiety. Ashwagandha also exhibited an antidepressant effect comparable to that induced by imipramine in the forced swim-induced "behavioral despair" and "learned helplessness" tests. (11) Other similar studies confirm these results, lending support to the use of ashwagandha as an antistress adaptogen. (12-15)

[edit] Chronic Stress

Chronic stress (CS) can result in a number of adverse physiologic conditions including cognitive deficit, immunosuppression, sexual dysfunction, gastric ulceration, irregularities in glucose homeostasis, and changes in plasma corticosterone levels. In a rat model of chronic stress Withania somnifera and Panax ginseng extracts were compared for their ability to attenuate some effects of chronic stress. Both botanicals were able to decrease the number and severity of CS-induced ulcers, reverse CS-induced inhibition of male sexual behavior, and inhibit the adverse effects of CS on retention of learned tasks. Both botanicals also reversed CS-induced immunosuppression, but only the Withania extract increased peritoneal macrophage activity in the rats. The activity of the Withania extract was approximately equal to the activity of the Panax ginseng extract. Withania somnifera, however, has an advantage over Panax ginseng in that it does not appear to result in ginseng-abuse syndrome, a condition characterized by high blood pressure, water retention, muscle tension, and insomnia. (16)

[edit] Cardiovascular Protection

Hypoglycemic, diuretic, and hypocholesterolemic effects of ashwagandha root were assessed in human subjects, in which six type 2 diabetes mellitus subjects and six mildly hypercholesterolemic subjects were treated with a powder extract for 30 days. A decrease in blood glucose comparable to that of an oral hypoglycemic drug was observed. Significant increases in urine sodium, urine volume, and decreases in serum cholesterol, triglycerides, and low-density lipoproteins were also seen. (17)

[edit] Hypothyroidism

Animal studies reveal ashwaganda has a thyrotropic effect. (18,19) An aqueous extract of dried Withania root was given to mice via gastric intubation at a dose of 1.4 g/kg body weight daily for 20 days. Serum was collected at the end of the 20day period and analyzed for T3 and T4 concentrations, and lipid peroxidation was measured in liver homogenate via antioxidant enzyme activity. Significant increases in serum T4 were observed, indicating the plant has a stimulatory effect at the glandular level. No changes in T3 levels were observed. Withania may also stimulate thyroid activity indirectly, via its effect on cellular antioxidant systems. Withania extract significantly decreased lipid peroxidation in the liver homogenate and significantly increased catalase activity, promoting scavenging of free radicals that can cause cellular damage. These results indicate ashwaganda may be a useful botanical in treating hypothyroidism. (18)

[edit] Other Therapeutic Considerations

Studies show ashwagandha to be effective in the treatment of osteoarthritis, (20) inflammation, (21,22) stroke, (23) and tardive dyskinesia. (24) Studies also reveal ashwagandha to be a potential antimicrobial agent, with antifungal activity (25-26) and moderate antibacterial activity against Staphyloccus aureus and Pseudomonas Aeruginosa. (27)

[edit] Drug-Botanical Interactions

There are anecdotal reports that ashwagandha may potentiate the effects of barbiturates; therefore, caution should be used if taking this combination.

[edit] Side Effects and Toxicity

Ashwagandha is generally safe when taken in the prescribed dosage range. (28) Large doses have been shown to cause gastrointestinal upset, diarrhea, and vomiting. Dosage A typical dose of ashwagandha is 3-6 grams daily of the dried root, 300-500 mg of an extract standardized to contain 1.5 percent withanolides, or 6-12ml of a 1:2 fluid extract per day.

[edit] Warnings and Contraindications

Large doses of ashwagandha may possess abortifacient properties; therefore, it should not be taken during pregnancy. Since ashwaganda acts as a mild central nervous system depressant, patients should avoid alcohol, sedatives, and other anxiolytics while taking ashwagandha.

[edit] References

(1.) Elsakka M, Grigorescu E, Stanescu U, et al. New data referring to chemistry of Withania somnifera species. Rev Med Chir Soc Med Nat lasi 1990;94:385-387.

(2.) Bone K. Clinical Applications of Ayurvedic and Chinese Herbs. Monographs for the Western Herbal Practitioner. Australia: Phytotherapy Press; 1996:137-141.

(3.) Kuttan G. Use of Withania somnifera Dunal as an adjuvant during radiation therapy. Indian J Exp Biol 1996;34:854-856.

(4.) Ziauddin M, Phansalkar N, Patki P, et al. Studies on the immunomodulatory effects of Ashwagandha. J Ethnopharmacol 1996;50:69-76.

(5.) Davis L, Kuttan G. Immunomodulatory activity of Withania somnifera. J Ethnopharmacol 2000;71:193-200.

(6.) Iuvone T, Esposito G, Capasso F, Izzo A. Induction of nitric oxide synthase expression by Withania somnifera in macrophages. Life Sci 2003;72:1617-1625.

(7.) Bogdan C. Nitric oxide and the immune response. Nature Immunol 2001;2:907-916.

(8.) Davis L, Kuttan G. Effect of Withania somnifera on CTL activity. J Exp Clin Cancer Res 2002;21:115-118.

(9.) Prakash J, Gupta SK, Dinda AK. Withania somnifera root extract prevents DMBA-induced squamous cell carcinoma of skin in Swiss albino mice. Nutr Cancer 2002;42:91-97.

(10.) Jayaprakasam B, Zhang Y, Seeram N, Nair M. Growth inhibition of tumor cell lines by withanolides from Withania somnifera leaves. Life Sci 2003;74:125-132.

(11.) Bhattacharya SK, Bhattacharya A, Sairam K, Ghosal S. Anxiolytic-antidepressant activity of Withania somnifera glycowithanolides: an experimental study. Phytomedicine 2000;7:463-469.

(12.) Bhattacharya A, Ghosal S, Bhattacharya SK. Antioxidant effect of Withania somnifera glycowithanolides in chronic footshock stress-induced perturbations of oxidative free radical scavenging enzymes and lipid peroxidation in rat frontal cortex and striatum. J Ethnopharmacol 2001;74:1-6.

13.) Singh B, Saxena AK, Chandan BK, et al. Adaptogenic activity of a novel, withanolide-free aqueous fraction from the root of Withania somnifera. Phytother Res 2001;15:311-318.

(14.) Archana R, Namasivayam A. Antistressor effect of Withania somnifera. J Ethnopharmacol 1999;64:91-93.

(15.) Dhuley JN. Adaptogenic and cardioprotective action of ashwagandha in rats and frogs. J Ethnopharmacol 2000;70:57-63.

(16.) Bhattarcharya SK, Muruganandam AV. Adaptogenic activity of Withania somnifera: an experimental study using a rat model of chronic stress. Pharmacol Biochem Behav 2003;75:547-555.

(17.) Andallu B, Radhika B. Hypoglycemic, diuretic and hypocholesterolemic effect of winter cherry (Withania somnifera) root. Indian J Exp Biol 2000;38:607-609.

(18.) Panda S, Kar A. Withania somnifera and Bauhinia pupurea in the regulation of circulating thyroid hormone concentrations in female mice. J Ethnopharmacol 1999;67:233-239.

(19.) Panda S, Kar A. Changes in thyroid hormone concentrations after administration of ashwaganda root extract to adult male mice. J Pharm Pharmacol 1998;50:1065-1068.

(20.) Kulkarni RR, Patki PS, Jog VP, et al. Treatment of osteoarthritis with a herbomineral formulation: a double-blind, placebo-controlled, cross-over study. J Ethnopharmacol 1991;33:91-95.

(21.) Angalagan K, Sadique J. Influence of an Indian medicine (ashwagandha) on acute-phase reactants in inflammation. Indian J Exp Biol 1981;19:245-249.

(22.) Begum VH, Sadique J. Long-term effect of herbal drug Withania somnifera on adjuvant-induced arthritis in rats. Indian J Exp Biol 1988;26:877-882.

(23.) Chaudhary G, Sharma U, Jagannathan N, Gupta Y. Evaluation of Withania somnifera in a middle cerebral artery occlusion model of stroke in rats. Clin Exp Pharmacol Physiol 2003;30:399-404.

(24.) Bhattacharya SK, Bhattacharya D, Sairam K, Ghosal S. Effect of Withania somnifera glycowithanolides on a rat model of tardive dyskinesia. Phytomedicine 2002;9:167-170.

(25.) Abou-Douh AM. New withanolides and other constituents from the fruit of Withania somnifera. Arch Pharm 2002;335:267-276.

(26.) Choudhary MI, Dur-e-Shahwar, Parveen Z, et al. Antifungal steroidal lactones from Withania coagulance. Phytochemistry 1995;40:1243-1246.

(27.) Ali NA, Julicch WD, Kusnick C, Lindequist U. Screening of Yemeni medicinal plants for antibacterial and cytotoxic activities. J Ethnopharmacol 2001;74:173-179.

(28.) Aphale AA, Chhibba AD, Kumbhaakarna NR, et al. Subacute toxicity study of the combination of ginseng (Panex ginseng) and ashwagandha (Withania somnifera) in rats: a safety assessment. Indian J Physiol Pharmacol 1998;42:299-302.