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Ashwagandha

Scientific Name(s): Withania somnifera (L.) Dunal.
Common Name(s): Ajagandha, Amangura, Amukkirag, Asgand, Ashvagandha, Asundha, Asvagandha, Aswaganda, Indian ginseng, Kanaje Hindi, Kuthmithi, Samm al ferakh, Winter cherry, Withania

Clinical Overview

Use

Ashwagandha has been used as an adaptogen, diuretic, and sedative and is available in the United States as a dietary supplement. Trials supporting its clinical use are limited; however, many in vitro and animal experiments suggest effects on the immune, endocrine, and CNS systems, as well as in the pathogenesis of cancer and inflammatory conditions.

Dosing

Dosing information is limited. W. somnifera root powder has generally been used at daily dosages of 120 mg to 2 g in combination with other preparations.

Contraindications

Contraindications have not been identified.

Pregnancy/Lactation

Abortifacient properties have been reported for ashwagandha. Avoid use.

Interactions

None well documented.

Adverse Reactions

Limited clinical trials are available and case reports are lacking.

Toxicology

Acute toxicity of W. somnifera is modest; at reasonable doses, ashwagandha is nontoxic.

Botany

W. somnifera is an erect, greyish, slightly hairy evergreen shrub that grows to about 1.5 m in height and has fairly long tuberous roots. It is widely cultivated in India and throughout the Middle East and is found in eastern Africa. The small and greenish-yellow flowers can be single or in clusters. The fruit is smooth, round, and fleshy, with many seeds; it is orange-red when ripe and enclosed in a membranous covering.1 A synonym is Physalis somnifera L.

History

The root of W. somnifera is used to make the Ayurvedic tonic ashwagandha, which has been translated to "smells like a horse."2 Ashwagandha has been used as an adaptogen, diuretic, and sedative and is available in the United States as a dietary supplement. Other parts of the plant (eg, seeds, leaves) have been used as a pain reliever, to kill lice, and in making soap. The fresh berries have been used as an emetic.2, 3

Chemistry

The principal bioactive compounds of W. somnifera are withanolides, which are triterpene lactones. More than 40 withanolides, approximately 12 alkaloids and several sitoindosides have been isolated and identified from W. somnifera. The withanolides are structurally related to the ginsenosides of Panax ginseng, hence the common name "Indian ginseng."3, 4 Withanine and somniferine are among the alkaloids.67 Chemical constituents for the roots, fruits, seeds, and stem include withanone; withaferin A; withanolides A, D, an G; and sitoindosides IX, X, VII, and VIII. High performance liquid chromatography techniques to quantify constituents have also been established.2, 3, 4

Additional compounds, especially withanolides, have been described and evaluated, with variations dependent upon cultivation and varieties.5, 6, 7 Large amounts of iron are also found in the plant.4

Uses and Pharmacology

Well-designed clinical studies in which W. somnifera or its extracts are used as a single agent are limited.

Anti-inflammatory effects

In vitro and animal experiments suggest W. somnifera may possess anti-inflammatory properties. Cultures of cartilage from patients with osteoarthritis and rheumatoid arthritis have been used to demonstrate W. somnifera's protective effects on chondroplasts.8, 9, 10, 11 Related effects on cytokines and transcription factors, and suppression of nitric oxide have also been demonstrated.12 In experiments in rats with induced inflammation, decreased inflammation (paw volume), pain, and disability were noted, as well as an antipyretic effect after administration of W. somnifera root powder. The ulcerogenic effect of W. somnifera was lower than that of indomethacin.4, 13, 14, 15, 16 A small clinical study evaluating a combination therapy that included ashwagandha demonstrated decreased pain and disability in arthritis, while no changes were observed in the erythrocyte sedimentation rate.3, 4

Cancer

Despite more than 30 years of research into a potential role for W. somnifera extracts in the treatment of cancer, clinical trials are lacking. In vitro and animal experiments have been conducted using whole plant extract, ethanol root extracts, aqueous and methanolic leaf extracts, individual withanolides, and withaferin A. Human cancer cell line investigations include HL-60 leukemic and myeloid leukemia cell lines, and bladder, breast, prostate, colon, kidney, gastric, and lung cancer cell lines. Mechanisms of action described include antiproliferative effects, apoptosis, radio-sensitization, mitotic arrest, antiangiogenesis, and enhancement of cell defense mechanisms.4, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 Limited studies suggest withanone, withaferin A, and withanolide A have protective effects on glioma cell lines, as well as human fibroblasts, and thereby slow senescence.30, 31

Experiments in mice have demonstrated decreased lung adenoma tumor incidence with whole plant extract and complete regression of mouse sarcoma tumor with ethanol root extract, as well as radio-sensitizing of carcinomas and increased apoptosis of human breast cancer cells by withaferin A, a steroidal lactone of W. somnifera.4, 24

Damage to the bladder by cyclophosphamide was ameliorated by W. somnifera extract32 as was leukopenia induced by cyclophosphamide.33

CNS effects

Animal data

In vitro studies and experiments in animals suggest CNS effects, including modulation of acetylcholinesterase and butyrylcholinesterase activity, inhibition of calcium ion influx, blockade of gamma-aminobutyric acid receptors, modulation of 5-HT1 and 5-HT2 receptors, antioxidant activity, and regeneration of neurites4, 6, 11 with some researchers suggesting potential applications in Alzheimer and Parkinson diseases.3, 5, 6

Withania extract protected against pentylenetetrazol-induced seizures in a mouse anticonvulsant model when administered over a 9-week period.34 The same research group found the extract active in a rat status epilepticus model.35 A depressant effect on the CNS was indicated by potentiation of pentobarbital effects on the righting reflex in mice36 and a mild tranquilizing/relaxant effect in monkeys, cats, dogs, rats, and mice by a total alkaloid extract from the plant roots.4

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.37 A withanolide-containing fraction reversed morphine-induced reduction in intestinal motility and confirmed the previous finding of inhibition of development of tolerance to morphine.38 A role in the management of drug addiction has been suggested.11

An experiment supported the traditional Ayurvedic medicinal claim that the plant's use could be attributed to effects on learning and memory. Ibotenic acid-induced lesions in intact rat brain that led to cognitive deficit, as measured by performance in a learning task, were reversed by treatment with a withanolide mixture.39

Following animal studies that revealed significant serotonergic effects of W. somnifera root extract, Iranian researchers conducted a double-blind, randomized, placebo-controlled trial (n=30) to investigate its effects on symptoms of obsessive-compulsive disorder (OCD). All patients were being treated with selective serotonin reuptake inhibitors (SSRIs). A significant difference was observed in baseline OCD scores between the groups with a mean of 26 (range, 14 to 40) in the treatment group and 18 (range, 11 to 33) in placebo (P=0.038). After 6 weeks, a significantly greater reduction in mean OCD symptom scores was observed in the treatment group (−8) compared to placebo (−2) (P<0.001). W. somnifera root extract was administered as 30 mg capsules and titrated up to 4 capsules daily over approximately 2 weeks (to reduce likelihood of GI side effects), then after 2 weeks, the dose was tapered down again over an approximate 2-week period. No side effects were reported.67

Clinical data

Limited trials in elderly populations using traditional combination therapies showed mixed results. One study of 2 g of root extract twice daily (in combination) administered over 6 months made no difference in sleep onset times or duration.40 In another study, increased balance was determined in elderly patients with long-term progressive degenerative ataxia.41

A systematic review of human trial evidence for W. somnifera as treatment for anxiety and stress identified 5 randomized controlled trials (n = 64 to 130). Dosages ranged from 125 to 12,000 mg/day. In general, favorable results were observed compared with placebo, with 4 trials documenting significant differences. Additionally, no significant adverse effects were reported. However, the quality of results was very limited due to nonblinding, conflicts of interest, and only patient-reported outcomes; risk of bias was probably moderate to high.66 Adjunctive use of 500 mg/day in patients with bipolar disorder has demonstrated significant improvements in memory, reaction time, and social cognition in a preliminary study.69

Immune system effects

Withanolides inhibit murine spleen cell proliferation42 and an extract of W. somnifera reversed ochratoxin's suppressive effect on murine macrophage chemotaxis.43 Withanolide glycosides activated murine macrophages and phagocytosis, and increased lysosomal enzymatic activity secreted by the macrophages, while also displaying antistress activity and positive effects on learning and memory in rats.44 Alpha-2 macroglobulin synthesis stimulated by inflammation was reduced by W. somnifera extract.45 Similarly, the extract prevented myelosuppression caused by cyclophosphamide, azathioprine, or prednisolone in mice.46 In a clinical study, ashwagandha 6 mL root extract administered twice daily for 4 days resulted in increases in CD4 expression, as well as activation of natural killer cells.47 Additional effects on cytokines and the complement system, lymphocyte proliferation, and humoral and cell-mediated responses have been discussed.48

Other uses

Animal experiments have been conducted to describe adaptogenic properties (increased swimming endurance and reduced stress response) of W. somnifera. Clinical trials are lacking.49, 50, 51, 52, 53, 54, 55, 56, 57

Effects on aging have been promoted, based on claims regarding increased hemoglobin, red blood cell count, hair quality, and melanin levels in a non-peer-reviewed study conducted among healthy men. Serum cholesterol was also reduced and seated-stature improved in this study.30

A statistically significant decrease in triglycerides and fasting blood glucose was observed in a double-blind, randomized controlled trial in 25 schizophrenic patients who took a total daily dose of 1,200 mg W. somnifera extract for 1 month versus those on placebo.65

An 8-week double-blind, randomized, placebo-controlled pilot study in 50 treatment-naive adults with subclinical hypothyroidism (elevated TSH) found that ashwagandha root extract (containing 5% withanolides) 300 mg twice daily significantly improved thyroid parameters. Serum T3 and T4 levels were significantly increased with ashwagandha over baseline and compared to placebo at 4 and 8 weeks, while serum TSH was significantly decreased. Treatment was well tolerated.68

Antimicrobial effects58 and antivenom activity via hyaluronidase inhibition have been described.59

Dosing

Dosing information is limited.

In a study in which a polyherbal mixture was used for arthritis, W. somnifera 450 mg root powder was administered 4 times per day.60

In a sleep study with elderly subjects, Withania 2 g root powder was administered with other ingredients twice daily for up to 3 months.40

In elderly patients with long-term progressive degenerative ataxia, ashwagandha 500 mg tablets were administered 3 times a day for 1 month (in combination).41

Pregnancy / Lactation

Abortifacient properties have been reported for ashwagandha. Avoid use.61

In animal experiments, no fetal abnormalities were found in mice fed Withania root extract for 4 weeks. The progeny of experiment animals had a higher birth weight than those of controls.3 Because of the plant's antiangiogenic and cytotoxic properties, Withania should be avoided during pregnancy.

Interactions

Case reports are lacking.3 Animal studies report potentiation of phenobarbital-induced sleep3 while interactions with some digoxin immunoassays have been demonstrated and are thought to be caused by similarity in chemical structure.62, 63

Adverse Reactions

Limited clinical trials are available and case reports are lacking.

Toxicology

Acute toxicity of W. somnifera is modest; at reasonable doses ashwagandha is nontoxic.3, 4

In mice, an oral median lethal dose was determined to be 1,750 mg/kg in 1 study12 and 1,260 mg/kg by the intraperitoneal route.64

Subacute intraperitoneal toxicity studies at 100 mg/kg/day for 30 days led to decreased spleen, thymus, and adrenal weights, but no mortality or hematological changes were noted.64

A longer-term study (180 days) in rats at an oral dose of 100 mg/kg found no lethality, but did discover unfavorable increases in catecholamine content of the heart and decreases in the adrenal glands.17 At higher dosages (200 mg/kg/day), increases in lung and liver weight were observed.3, 4

In mice fed the extract of the entire plant as 25% of the total diet, microscopic lesions in the lung and liver were apparent, and vascular and tubular congestion were described.3

References

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2. Ganzera M, Choudhary MI, Khan IA. Quantitative HPLC analysis of withanolides in Withania somnifera. Fitoterapia. 2003;74(1-2):68-76.12628397
3. Kulkarni SK, Dhir A. Withania somnifera: an Indian ginseng. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(5):1093-1105.17959291
4. Mishra LC, Singh BB, Dagenais S. Scientific basis for the therapeutic use of Withania somnifera (ashwagandha): a review. Altern Med Rev. 2000;5(4):334-346.10956379
5. Zhao J, Nakamura N, Hattori M, Kuboyama T, Tohda C, Komatsu K. Withanolide derivatives from the roots of Withania somnifera and their neurite outgrowth activities. Chem Pharm Bull (Tokyo). 2002;50(6):760-765.12045329
6. Choudhary MI, Nawaz SA, ul-Haq Z, et al. Withanolides, a new class of natural cholinesterase inhibitors with calcium antagonistic properties. Biochem Biophys Res Commun. 2005;334(1):276-287.16108094
7. Xu YM, Marron MT, Seddon E, et al. 2,3-Dihydrowithaferin A-3beta-O-sulfate, a new potential prodrug of withaferin A from aeroponically grown Withania somnifera. Bioorg Med Chem. 2009;17(6):2210-2214.19056281
8. Sumantran VN, Chandwaskar R, Joshi AK, et al. The relationship between chondroprotective and antiinflammatory effects of Withania somnifera root and glucosamine sulphate on human osteoarthritic cartilage in vitro. Phytother Res. 2008;22(10):1342-1348.18697233
9. Sumantran VN, Kulkarni A, Boddul S, et al. Chondroprotective potential of root extracts of Withania somnifera in osteoarthritis. J Biosci. 2007;32(2):299-307.17435322
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24. Stan SD, Zeng Y, Singh SV. Ayurvedic medicine constituent withaferin a causes G2 and M phase cell cycle arrest in human breast cancer cells. Nutr Cancer. 2008;60(suppl 1):51-60.19003581
25. Mulabagal V, Subbaraju GV, Rao CV, et al. Withanolide sulfoxide from Aswagandha roots inhibits nuclear transcription factor-kappa-B, cyclooxygenase and tumor cell proliferation. Phytother Res. 2009;23(7):987-992.19003581
26. Malik F, Kumar A, Bhushan S, et al. Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic cell death of human myeloid leukemia HL-60 cells by a dietary compound withaferin A with concomitant protection by N-acetyl cysteine. Apoptosis. 2007;12(11):2115-2133.17874299
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32. Davis L, Kuttan G. Effect of Withania somnifera on cyclophosphamide-induced urotoxicity. Cancer Lett. 2000;148(1):9-17.10680587
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34. Kulkarni SK, George B. Anticonvulsant action of Withania somnifera (Ashwaganda) root extract against pentylenetetrazol-induced kindling in mice. Phytother Res. 1996;10(5):447-449.
35. Kulkarni SK, George B, Mathur R. Protective effect of Withania somnifera root extract on electrographic activity in a lithium-pilocarpine model of status epilepticus. Phytother Res. 1998;12(6):451-453.
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38. Ramarao P, Rao KT, Srivastava RS, Ghosal S. Effects of glycowithanolides from Withania somnifera on morphine-induced inhibition of intestinal motility and tolerance to analgesia in mice. Phytother Res. 1995;9(1):66-68.
39. Bhattacharya SK, Kumar S, Ghosal S. 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(2):110-113.
40. Manjunath NK, Telles S. Influence of Yoga and Ayurveda on self-rated sleep in a geriatric population. Indian J Med Res. 2005;121(5):683-690.15937373
41. Sriranjini SJ, Pal PK, Devidas KV, Ganpathy S. Improvement of balance in progressive degenerative cerebellar ataxias after Ayurvedic therapy: a preliminary report. Neurol India. 2009;57(2):166-171.19439847
42. Bähr V, Hänsel R. 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(1):32-33.7063559
43. Dhuley JN. Effect of some Indian herbs on macrophage functions in ochratoxin A treated mice. J Ethnopharmacol. 1997;58(1):15-20.9324000
44. Ghosal S, Lal J, Srivastava R, et al. Immunomodulatory and CNS effects of sitoindosides IX and X, two new glycowithanolides from Withania somnifera. Phytother Res. 1989;3(5):201-206.PubMedID
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46. Ziauddin M, Phansalkar N, Patki P, Diwanay S, Patwardhan B. Studies on the immunomodulatory effects of Ashwagandha. J Ethnopharmacol. 1996;50(2):69-76.8866726
47. Mikolai J, Erlandsen A, Murison A, et al. In vivo effects of Ashwagandha (Withania somnifera) extract on the activation of lymphocytes. J Altern Complement Med. 2009;15(4):423-430.19388865
48. Rasool M, Varalakshmi P. Immunomodulatory role of Withania somnifera root powder on experimental induced inflammation: An in vivo and in vitro study. Vascul Pharmacol. 2006;44(6):406-410.16713367
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50. Bhattacharya SK, Goel RK, Kaur R, Ghosal S. Anti-stress activity of sitoindosides VII and VIII, new acylsterylglucosides from Withania somnifera. Phytother Res. 1987;1(1):32-37.
51. Grandhi A, Mujumdar AM, Patwardhan B. A comparative pharmacological investigation of Ashwagandha and Ginseng. J Ethnopharmacol. 1994;44(3):131-135.7898119
52. Dhuley JN. Effect of ashwagandha on lipid peroxidation in stress-induced animals. J Ethnopharmacol. 1998;60(2):173-178.9582008
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54. Dhuley JN. Adaptogenic and cardioprotective action of ashwagandha in rats and frogs. J Ethnopharmacol. 2000;70(1):57-63.10720789
55. Panda S, Kar A. Withania somnifera and Bauhinia purpurea in the regulation of circulating thyroid hormone concentrations in female mice. J Ethnopharmacol. 1999;67(2):233-239.10619390
56. Singh A, Saxena E, Bhutani KK. Adrenocorticosterone alterations in male, albino mice treated with Trichopus zeylanicus, Withania somnifera, and Panax ginseng preparations. Phytother Res. 2000;14(2):122-125.10685111
57. Bucci LR. Selected herbals and human exercise performance. Am J Clin Nutr. 2000;72(2 suppl):624S-636S.10919969
58. Girish KS, Machiah KD, Ushanandini S, et al. Antimicrobial properties of a non-toxic glycoprotein (WSG) from Withania somnifera (Ashwagandha). J Basic Microbiol. 2006;46(5):365-374.17009292
59. Machiah DK, Girish KS, Gowda TV. A glycoprotein from a folk medicinal plant, Withania somnifera, inhibits hyaluronidase activity of snake venoms. Comp Biochem Physiol C Toxicol Pharmacol. 2006;143(2):158-161.16513428
60. 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(1-2):91-95.1943180
61. Ernst E. Herbal medicinal products during pregnancy: are they safe? BJOG. 2002;109(3):227-235.11950176
62. Dasgupta A. Herbal supplements and therapeutic drug monitoring: focus on digoxin immunoassays and interactions with St. John's wort. Ther Drug Monit. 2008;30(2):212-217.18367983
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64. Sharada AC, Solmon FE, Devi PU. Toxicity of Withania somnifera root extract in rats and mice. Int J Pharmacognosy. 1993;31(3):205-212.
65. Agnihotri AP, Sontakke SD, Thawani VR, Saoji A, Shishir V. Effects of Withania somnifera in patients of schizophrenia: a randomized, double-blind, placebo controlled pilot trial study. Indian J Pharmacol. 2013;45(4):417-418.24014929
66. Pratte MA, Nanavati KB, Young V, Morley CP. An alternative treatment for anxiety: a systematic review of human trial results reported for the ayurvedic herb ashwagandha (Withania sominfera). J Altern Complement Med. 2014;20(12):901-908.25405876
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68. Sharma AK, Basu I, Singh S. Efficacy and safety of ashwagandha root extract in subclinical hypothyroid patients: a double-blind, randomized placebo-controlled trial. J Altern Complement Med. 2018;24(3):243-248.28829155
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