Ashwaganda
Scientific Name(s): Withania somnifera (L.) Dunal, also W. coagulans Dunal Family: Solanaceae (nightshade)
Common Name(s): Withania , Ashwagandha , Aswaganda , Winter Cherry , Indian ginseng , Ajagandha , Kanaje Hindi , Samm Al Ferakh , Asgand (Hindi), Amukkirag (Tamil), Amangura (Kannada), Asvagandha (Bengali), Ashvagandha (Sanskrit), Asundha (Gujarati), Kuthmithi , Clustered Wintercherry
Clinical Overview
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Uses of Ashwaganda
Ashwaganda has adaptogenic, immunomodulatory, and anti-inflammatory effects in animals; it also has been studied in animals as a cytotoxic agent and has different CNS applications. However, research reveals no clinical data regarding the use of ashwaganda for any condition.
Ashwaganda Dosing
Despite a large volume of basic scientific studies on the plant, there is minimal evidence for a proper dose of this herb. A single study in which W. somnifera was the principal component of a polyherbal mixture administered 450 mg of root powder 4 times per day for arthritis.
Contraindications
Contraindications have not yet been identified.
Pregnancy/Lactation
Documented abortifacient effects. Avoid use.
Ashwaganda Interactions
None well documented.
Ashwaganda Adverse Reactions
No data.
Toxicology
Acute toxicity of W. somnifera is modest. A 180-day study involving rats found unfavorable increases in catecholamine content of the heart and decreases in the adrenal glands.
Botany
W. somnifera is an erect, greyish, slightly hairy evergreen shrub with fairly long tuberous roots. It is widely cultivated in India and throughout the Middle East, and is found in eastern Africa. The flowers are small and greenish, single or in small clusters in the leaf axils. The fruit is smooth, round, fleshy, and has many seeds, orange-red when ripe, enclosed in a membranous covering.
History
The root of W. somnifera is used to make the Ayurvedic sedative and diuretic “Ashwagandha,” which is also considered an adaptogen. Other parts of the plant (eg, seeds, leaves) are used as a pain reliever, to kill lice, and to make soap. The fresh berries have been used as an emetic.
Chemistry
The principal bioactive compounds of W. somnifera are withanolides, highly oxygenated C-28 steroid derivatives. More than 40 withanolides have been isolated and identified from W. somnifera . Three chemotypes of the plant have been defined: 1 Indian (Ι), which contains withanone 2 and withaferin A 3 , 4 as major constituents; Israeli (ΙΙ), whose major withanolides are withanolide D 5 and 27-hydroxywithanolide D; 1 and Israeli (ΙΙΙ), containing principally withanolide E. 6 The biosynthesis of withanolides from the cholesterol pathway has been studied, 7 and the C-13 NMR spectra of withanolides have been assigned. 8 An HPLC separation of withanolides has been reported. 9
W. somnifera roots also contain nicotine and assorted piperidine and pyrrolidine alkaloids. 10 The leaves have been found to contain flavonol glycosides and phenolic acids. 11
Ashwaganda Uses and Pharmacology
The majority of studies of W. somnifera pharmacology have not related bioactivity to specific chemical constituents present. Given the noted variation in withanolides, it is obvious that this has limited reproducibility of results.
Adaptogenic EffectsAnimal Data
Pretreatment with the alcoholic extract of defatted seeds increased swimming endurance in mice and significantly reduced cold-, stress-, restraint-, and aspirin-induced ulcers in rats. 12 A combination of withaferin A and two sterol glucosides from roots of W. somnifera showed antistress activity in a panel of tests. 13 Aqueous suspensions from the roots of Ashwagandha and ginseng were compared in a mouse swimming model and for anabolic activity (weight gain) in rats, and both were found to possess oral activity when animals were treated for 7 days. 14 Ashwagandha extract given orally to rabbits and mice prevented stress-induced increases in lipid peroxidation. 15 Stress-induced increases in plasma corticosterone, phagocytic index, and avidity index were blocked by administration of W. somnifera to rats, while swimming time was increased. 16 Another study in rats and frogs found the extract to be adaptogenic when given as a pretreatment for up to 3 months, as measured by swimming tests, glycogen content of various tissues, coagulation time, and catecholamine content, among others. 17 The effect of W. somnifera extract on thyroid hormone levels 18 and corticosterone levels 19 in animals has been studied. A review of adaptogenic effects of W. somnifera and other Ayurvedic adaptogens has been published. 20
Clinical DataResearch reveals no clinical data regarding the use of ashwaganda for adaptogenic effects.
Immunomodulatory and Anti-inflammatory EffectsAnimal Data
W. somnifera extracts given IP suppressed rat paw edema induced by carrageenan, 21 as well as in a granuloma pouch assay. 22 Orally administered proprietary extracts of W. somnifera were found to have modest activity in an active paw anaphylaxis model and to suppress cyclophosphamide-induced delayed-type hypersensitivity. 23 Withanolides inhibit murine spleen cell proliferation, 24 and an extract of W. somnifera reversed ochratoxin's suppressive effect on murine macrophage chemotaxis. 25 Withanolide glycosides activated murine macrophages, phagocytosis, and increased lysosomal enzymatic activity secreted by the macrophages, while also displaying anti-stress activity and positive effects on learning and memory in rats. 26 Alpha-2 macroglobulin synthesis stimulated by inflammation was reduced by W. somnifera extract. 27 Similarly, the extract prevented myelosuppression caused by cyclophosphamide, azathioprine, or prednisolone in mice. 28
The stimulation of macrophages was invoked to explain activity versus experimental aspergillosis in mice. 29 Similar activity in other experimental infections was observed in rats. 30
Clinical DataResearch reveals no clinical data regarding the use of ashwaganda for immunomodulatory and anti-inflammatory effects.
CancerWithaferin A was first isolated as a cytotoxic agent, 3 and a considerable amount of investigation followed. The compound produced mitotic arrest in Ehrlich ascites carcinoma cells in vitro 31 while in vivo effects were mediated by macrophage activation. 26 , 32 Further investigations on peripheral blood lymphocytes determined that withaferin A destroyed spindle microtubules of cells in metaphase. 33
Animal DataMouse sarcoma cells showed similar effects, with additional effects on nuclear membranes of cells. 34 A structure-activity comparison of withaferin A analogues in P388 cells attributed reaction of its lactone and epoxide moieties with cysteine as important to its cytotoxicity. 35 Withaferin was synergistic with radiation treatment in a mouse Ehrlich ascites carcinoma model. 36 Recently, several withanolides were identified as inducers of differentiation of myeloid leukemia cells. 37
Clinical DataResearch reveals no clinical data regarding the use of ashwaganda for cancer.
CNSAnimal Data
Withania extract protected against pentylenetetrazol-induced seizures in a mouse anticonvulsant model when administered over a 9-week period. 38 The same research group found the extract active in a rat status epilepticus model. 39 A further study of the extract found that it inhibited the development of tolerance to morphine in mice, while suppressing withdrawal symptoms precipitated by naloxone. 40 A withanolide-containing fraction reversed morphine-induced reduction in intestinal motility and confirmed the previous finding of inhibition of development of tolerance to morphine. 41 A depressant effect on the CNS was indicated by potentiation of pentobarbital effects on the righting reflex in mice. 42 Effects on learning and memory attributed to the plant in Ayurvedic medicine were supported by an experiment in which ibotenic acid-induced lesions in intact rat brain which led to cognitive deficit, as measured by performance in a learning task, were found to be reversed by treatment with a withanolide mixture. 43
Clinical DataResearch reveals no clinical data regarding the use of ashwaganda for CNS effects.
Other UsesAnimal Data
W. somnifera seed extract was found to protect against carbon tetrachloride-induced liver damage in rats. 44 The leaf extract also showed a modest protective effect in a subacute model of liver damage, as well as an anti-inflammatory effect. 45 Damage to the bladder by cyclophosphamide was ameliorated by W. somnifera extract given IP, 46 as was leukopenia induced by cyclophosphamide. 47 The extract decreased arterial and diastolic blood pressure in normotensive dogs, while preventing the hypotensive effect of acetylcholine and increasing the hypertensive effects of adrenaline. 48
Clinical DataResearch reveals no clinical data regarding the use of ashwaganda for any condition.
Dosage
Despite a large volume of basic scientific studies on the plant, there is minimal evidence for a proper dose of this herb. A single study in which W. somnifera was the principal component of a polyherbal mixture administered 450 mg of root powder 4 times per day for arthritis. 49
Pregnancy/Lactation
Documented abortifacient effects. 50 Avoid use.
Interactions
None well documented.
Adverse Reactions
No data.
Toxicology
Acute toxicity of W. somnifera is modest. In mice an LD-50 was determined to be 1750 mg/kg PO 12 in one study and 1260 mg/kg by the intraperitoneal route. 51 Subacute IP toxicity studies at 100 mg/kg/day for 30 days led to decreased spleen, thymus, and adrenal weights, but no mortality or hematological changes. 51 A longer-term study (180 days) in rats at a dose of 100 mg/kg PO found no lethality but unfavorable increases in catecholamine content of the heart and decreases in the adrenal glands. 17
Bibliography
1. Nittala S, et al. Chemistry and genetics of withanolides in Withania somnifera hybrids. Phytochemistry 1981;20:2741.2. Kirson I, et al. Constituents of Withania somnifera Dun. Part XII. The withanolides of an Indian chemotype. J Chem Soc (C) 1971;2032.
3. Kupchan S, et al. The isolation and structural elucidation of a novel steroidal tumor inhibitor from Acnistus arborescens . J Am Chem Soc 1965;37:5805.
4. Lavie D, et al. Constituents of Withania somnifera Dun. Part IV. The structure of withaferin A. J Chem Soc 1965;7517.
5. Lavie D, et al. Constituents of Withania somnifera . X. The structure of withanolide D. Isr J Chem 1968;6:671.
6. Lavie D, et al. Crystal and molecular structure of withanolide E, a new natural steroidal lactone with a 17-alpha-side-chain. Chem Comm 1972;877.
7. Lockley J, et al. Biosynthesis of steroidal withanolides in Withania somnifera . Phytochem 1976;15:937.
8. Gottlieb H, et al. 13C NMR spectroscopy of the withanolides and other highly oxygenated C28 steroids. Org Magn Res 1981;16:20.
9. Hunter I, et al. Separation of withanolides by high-pressure liquid chromatography with coiled columns. J Chromatogr 1979;170:437.
10. Schwarting A, et al. The alkaloids of Withania somnifera . Lloydia 1963;26:258.
11. Kandil F, et al. Flavonol glycosides and phenolics from Withania somnifera . Phytochem 1994;37:1215.
12. Singh N, et al. Withania somnifera (Ashwagandha), a rejuvenating herbal drug which enhances survival during stress (an adaptogen). Int J Crude Drug Res 1982;20:29.
13. Bhattacharya S, et al. Anti-stress activity of sitoindosides VII and VIII, new acylsterylglucosides from Withania somnifera . Phytother Res 1987;1:32.
14. Grandhi A, et al. A comparative pharmacological investigation of ashwagandha and ginseng. J Ethnopharmacol 1994;44:131.
15. Dhuley J. Effect of ashwagandha on lipid peroxidation in stress-induced animals. J Ethnopharmacol 1998;60:173.
16. Archana R, et al. Antistressor effect of Withania somnifera . J Ethnopharmacol 1999;64:91.
17. Dhuley J. Adaptogenic and cardioprotective action of ashwagandha in rats and frogs. J Ethnopharmacol 2000;70:57.
18. Panda S, et al. Withania somnifera and Bauhinia purpurea in the regulation of circulating thyroid hormone concentrations in female mice. J Ethnopharmacol 1999;67:233.
19. Singh A, et al. Adrenocorticosterone alterations in male, albino mice treated with Trichopus zeylanicus , Withania somnifera , and Panax ginseng preparations. Phytother Res 2000;14:122.
20. Rege N, et al. Adaptogenic properties of six rasayana herbs used in Ayurvedic medicine. Phytother Res 1999;13:275.
21. al Hindawi M, et al. Anti-inflammatory activity of some Iraqi plants using intact rats. J Ethnopharmacol 1989;26:163.
22. al Hindawi M, et al. Anti-granuloma activity of Iraqi Withania somnifera . J Ethnopharmacol 1992;37:113.
23. Agarwal R, et al. Studies on immunomodulatory activity of Withania somnifera (Ashwagandha) extracts in experimental immune inflammation. J Ethnopharmacol 1999;67:27.
24. Bähr V, et al. Immunomodulating properties of 5,20-alpha(R)-dihydroxy-6-alpha-7-alpha-epoxy-1-oxo-(5-alpha)-witha-2,24-dieno lide and solasodine. Planta Med 1982;44:32.
25. Dhuley J. Effect of some Indian herbs on macrophage functions in ochratoxin A treated mice. J Ethnopharmacol 1997;58:15.
26. Ghosal S, et al. Immunomodulatory and CNS effects of sitoindosides IX and X, two new glycowithanolides from Withania somnifera . Phytother Res 1989;3:201.
27. Anbalagan K, et al. Withania somnifera (Ashwagandha), a rejuvenating herbal drug which controls a-2 macroglobulin synthesis during inflammation. Int J Crude Drug Res 1985;23:177.
28. Ziauddin M, et al. Studies on the immunomodulatory effects of Ashwagandha. J Ethnopharmacol 1996;50:69.
29. Dhuley J. Therapeutic efficacy of Ashwagandha against experimental aspergillosis in mice. Immunopharmacol Immunotoxicol 1998;20:191.
30. Thatte U, et al. Immunotherapeutic modification of experimental infections by Indian medicinal plants. Phytother Res 1989;3:43.
31. Shohat B, et al. Effect of withaferin A on Ehrlich ascites tumor cells–cytological observations. Int J Cancer 1970;5:244.
32. Shohat B, et al. Effect of withaferin A on Ehrlich ascites tumor cells. II. Target tumor cell destruction in vivo by immune activation. Int J Cancer 1971;8:487.
33. Shohat B, et al. The effect of withaferin A on human peripheral blood lymphocytes. An electron-microscope study. Cancer Lett 1976;2:63.
34. Shohat B, et al. The effect of withaferin A, a natural steroidal lactone, on the fine structure of S-180 tumor cells. Cancer Lett 1976;2:71.
35. Fuska J, et al. Novel cytotoxic and antitumor agents. IV. Withaferin A: Relation of its structure to the in vitro cytotoxic effects on P388 cells. Neoplasma 1984;31:31.
36. Devi P, et al. In vivo growth inhibitory and radiosensitizing effects of withaferin A on mouse Ehrlich ascites carcinoma. Cancer Lett 1995;95:189.
37. Kuroyanagi M, et al. Cell differentiation inducing steroids from Withania somnifera L. (Dun.). Chem Pharm Bull 1999;47:1646.
38. Kulkarni S, et al. Anticonvulsant action of Withania somnifera (Ashwaganda) root extract against pentylenetetrazol-induced kindling in mice. Phytother Res 1996;10:447.
39. Kulkarni S, et al. Protective effect of Withania somnifera root extract on electrographic activity in a lithium-pilocarpine model of status epilepticus. Phytother Res 1998;12:451.
40. Kulkarni S, et al. Inhibition of morphine tolerance and dependence by Withania somnifera in mice. J Ethnopharmacol 1997;57:213.
41. Ramarao P, et al. Bioactive phytosterol conjugates. 8. Effects of glycowithanolides from Withania somnifera on morphine-induced inhibition of intestinal motility and tolerance to analgesia in mice. Phytother Res 1995;9:66.
42. Ahumada F, et al. Effect of certain adaptogenic plant extracts on drug-induced narcosis in female and male mice. Phytother Res 1991;5:29.
43. Bhattacharya S, et al. Bioactive phytosterol conjugates. 9. Effects of glycowithanolides from Withania somnifera on an animal model of Alzheimer's disease and perturbed central cholinergic markers of cognition in rats. Phytother Res 1995;9:110.
44. Singh N, et al. An experimental evaluation of protective effects of some indigenous drugs on carbon tetrachloride-induced hepatotoxicity in mice and rats. Quart J Crude Drug Res 1978;16:8.
45. Sudhir S, et al. Pharmacological studies on leaves of Withania somnifera . Planta Med 1986;36:61.
46. Davis L, et al. Effect of Withania somnifera on cyclophosphamide-induced urotoxicity. Cancer Lett 2000;148:9.
47. Davis L, et al. Suppressive effect of cyclophosphamide-induced toxicity by Withania somnifera extract in mice. J Ethnopharmacol 1998;62:209.
48. Ahumada F, et al. Withania somnifera extract. Its effect on arterial blood pressure in anaesthetized dogs. Phytother Res 1991;5:111.
49. Kulkarni RR, Patki PS, Jog VP, Gandage SC, Patwardhan B. Treatment of osteoarthritis with a herbomineral formulation: a double-blind, placebo-controlled, cross-over study. J Ethnopharmacol . 1991;33:91-95.
50. McGuffin M, Hobbs C, Upton R, Goldberg A, eds. American Herbal Products Association's Botanical Safety Handbook . Boca Raton, FL: CRC Press; 1997.
51. Sharada A, et al. Toxicity of Withania somnifera root extract in rats and mice. Int J Pharmacognosy 1993;31:205.
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