Ashwagandha

• How It Works

  A few preliminary studies suggest ashwagandha may help reduce stress, anxiety, and fatigue, but larger studies are needed.

  Ashwagandha, also known as Indian ginseng, is a popular Ayurvedic herb and considered a tonic with multiple properties. In the lab, ashwagandha has been shown to have anti-inflammatory effects and relax the central nervous system in animals. Other experiments suggest it can enhance immune cells and impair or kill cancer cells, but more studies are needed to determine whether these effects can occur in humans. Clinical trials suggest ashwagandha may help reduce anxiety, stress, and fatigue, but larger studies are needed.

  Ashwagandha may affect certain lab tests that measure thyroid functioning and digoxin levels.
  Hemolytic anemia and abdominal pain were reported following ingestion of contaminated ashwagandha/mucuna pills.

• Purported Uses
  • To reduce stress and anxiety
    A few studies suggest ashwagandha may be helpful for anxiety and stress.
  • To reduce fatigue
    Results from a small study in patients with cancer-related fatigue suggest benefit. Additional studies are needed to confirm this.
  • As a sedative
    In animal studies, ashwagandha has a tranquilizing effect.
  • To reduce pain
    A clinical trial suggests that a standardized extract may help patients with knee joint pain. Mild side effects like nausea and stomach irritation were observed in a few patients.
  • To treat rheumatoid arthritis
    A clinical trial showed that a compound of herbs and minerals containing ashwagandha reduced rheumatoid arthritis pain. Because the formula contained multiple herbs and minerals, whether ashwagandha played a role in observed benefits is unclear.
  • To treat diabetes
    Lab studies suggest that ashwagandha may improve type 2 diabetes. Human studies are needed.
• Do Not Take If
  • You have hormone-sensitive prostate cancer: Ashwagandha may increase testosterone levels.
  • You are taking benzodiazepines, anticonvulsants, or barbiturates: Lab and animal studies suggest ashwagandha may also have both sedative and central nervous system effects.
  • You are pregnant: Ashwagandha may induce abortion at higher doses, so pregnant women should not use it.
• Side Effects

  Mild to moderate and of short duration: drowsiness, upper GI discomfort, loose stools

  Case reports

  • Nausea, headache, and stomach irritation: Occurred in one study and managed with standard therapies.
  • Overactive thyroid: In a 32-year-old woman following ingestion of ashwagandha capsules for chronic fatigue. Symptoms resolved after discontinuing ashwagandha.
  • Burning, itching, and discoloration of skin/mucous membrane: In a 28-year-old man after taking ashwagandha for decreased libido. Symptoms improved with conventional treatment.
  • Irregular heartbeat, dizziness: 2 cases were possibly associated with the use of herbomineral preparations that contained ashwagandha.
  • Elevation of liver enzymes, skin rash, fatigue, fever, edema, and diarrhea: In patients with advanced stage high-grade osteosarcoma, following use of Withaferin-A.
• Scientific Name

  Withania somnifera

• Clinical Summary

  A popular Ayurvedic herb, ashwagandha is often used in formulations prescribed for stress, strain, fatigue, pain, skin diseases, diabetes, gastrointestinal disease, rheumatoid arthritis, and epilepsy ⁽¹⁾. It is also used as a general tonic, to improve energy levels, health, and longevity ⁽²⁾, and topically as an analgesic ⁽³⁾. Active constituents include alkaloids, steroidal lactones, saponins, and withanolides.

  In vitro studies suggest that ashwagandha has neuroprotective ^(26) (37) and anti-inflammatory properties which may protect against cartilage damage in osteoarthritis ⁽⁴⁾. In addition, improvements in hyperglycemia, hyperinsulinemia, and insulin sensitivity have been detected in an animal model of type 2 diabetes ⁽⁵⁾. Other studies indicate cytotoxic, immunomodulating ⁽⁸⁾, chemopreventive ⁽¹⁾, and radiosensitizing effects ⁽¹⁰⁾, and enhancement in chromosomal stability ⁽¹¹⁾. Ashwagandha is also rich in iron ⁽²⁾.

  Small-scale human studies suggest that it may promote growth in children and improve hemoglobin level and red blood cell count ⁽²⁾. In adults, it may improve sexual performance ⁽²⁾ and male infertility ⁽²⁷⁾.

  Data also indicate that ashwagandha may be helpful for anxiety ⁽²³⁾. In patients with schizophrenia, adjunctive treatment with ashwagandha significantly improved symptoms and stress ^(43) (50), and affected markers of metabolic syndrome ⁽³⁴⁾. Ashwagandha also improved cognitive function in patients with bipolar disorder ⁽³⁵⁾, and is currently being evaluated to assess its effects on nonrestorative sleep ⁽⁴⁴⁾.

  Preliminary data suggest that ashwagandha may help to improve balance in patients with progressive degenerative cerebral ataxias ⁽²⁴⁾. An herbo-mineral formula containing ashwagandha was shown to benefit osteoarthritis ⁽¹³⁾. In a double-blind RCT, a standardized extract produced analgesic, anti-inflammatory, and chondroprotective effects in patients with knee joint pain ⁽⁴¹⁾.

  In laboratory studies, ashwagandha reduced growth of breast, central nervous system, colon, and lung cancer cells ⁽⁶⁾ without affecting normal cells ⁽⁷⁾, but was not effective against drug-resistant cancer stem cells ⁽³⁶⁾. The compound Withaferin A enhanced oxaliplatin effects in human pancreatic cancer cells ⁽³⁸⁾. Ashwagandha was also shown to prevent chemotherapy-induced neutropenia in mice ⁽¹²⁾.

  In a small study of breast cancer patients, ashwagandha alleviated chemotherapy-induced fatigue and improved quality of life ⁽³¹⁾. Larger trials are needed to confirm these observations.

  Ashwagandha may increase testosterone levels, and should be avoided in patients with hormone-sensitive prostate cancer ⁽⁴⁸⁾.

• Purported Uses
  • Anxiety
  • Diabetes
  • Digestive disorders
  • Epilepsy
  • Fatigue
  • Pain
  • Rheumatoid arthritis
  • Sleep
  • Stress
• Mechanism of Action

  Alkaloids, steroidal lactones, saponins, and withanolides are considered the biologically active components of ashwagandha. Anti-arthritic effects are attributed to cyclooxygenase (COX) inhibition.

  In animal studies, anti-inflammatory activity by ashwagandha was comparable to hydrocortisone ⁽¹⁵⁾. Brain antioxidant effects and CNS tranquilizing effects may be due to influences on GABA receptor function ^(2) (17). Withanolides in the roots and leaves are considered similar to steroids in their biological activities ⁽⁴¹⁾. Triethylene glycol, a compound isolated from the leaves, was identified as an active sleep-inducing component in a murine model, and may potentially be used to relieve insomnia ⁽⁴²⁾.

  Microarray analysis revealed that ashwagandha represses proinflammatory gene expression, including IL-6, IL-1β, IL-8, Hsp70, and STAT-2, and induces p38/MAPK expression in a prostate cancer cell line ⁽¹⁶⁾. Ashwagandha may inhibit tumor growth ^(1) (21) and increased cytotoxic T lymphocyte production ⁽⁸⁾. In vitro studies show that root extracts have cytotoxic properties against lung, colon, CNS, and breast cancer cell lines ⁽⁶⁾. Withaferin A induced reactive oxygen species (ROS) generation and disruption of mitochondrial function in a human leukemia cell line, thereby inducing apoptosis ⁽¹⁸⁾. In estrogen receptor-positive (ER+) and negative (ER-) breast cancer cells, withaferin A induced apoptosis and decreased tumor size ⁽¹⁹⁾. Apoptosis of cancer cells by withanone is mediated through p53 ⁽⁷⁾. Withianone also exerts anticancer activity by binding to the TPX2-Aurora A Complex ⁽²⁹⁾. Other studies show ashwagandha cytotoxicity is related to its structure. It enhances ATPase and inhibits succinate dehydrogenase activities, impairing oxidative phosphorylation.

  In animal studies, ashwagandha enhanced radiation therapy effects ⁽²⁰⁾ by reducing tumor GSH levels ⁽¹⁰⁾, and reversed paclitaxel-induced neutropenia in mice ⁽¹²⁾.

  No significant interactions have been reported between ashwagandha and either CYP3A4 or CYP2D6 enzymes in human liver microsomes ⁽⁴⁰⁾.

• Warnings

  Hemolytic anemia and abdominal pain were reported following ingestion of contaminated ashwagandha/mucuna pills ⁽³²⁾.

• Contraindications
  • Ashwagandha may increase testosterone levels, and should therefore be avoided in patients with hormone-sensitive prostate cancer ⁽⁴⁸⁾.
  • Patients who take benzodiazepines, anticonvulsants, or barbiturates should likely avoid ashwagandha because this botanical may have both sedative and GABAnergic effects ⁽⁴⁹⁾.
  • Pregnant women should avoid ashwagandha as it may induce abortion at higher doses ⁽⁴⁹⁾.
• Adverse Reactions

  Mild to moderate and transient: drowsiness, upper GI discomfort, loose stools ⁽⁴³⁾

  Case reports

  • Nausea, headache, and gastritis: Occurred in one study and managed with standard therapies ⁽⁴¹⁾
  • Thyrotoxicosis: In a 32-year-old woman following ingestion of ashwagandha capsules for chronic fatigue. Symptoms resolved after discontinuing ashwagandha ⁽²⁵⁾.
  • Burning, itching, and discoloration of skin/mucous membrane: In a 28-year-old man after taking ashwagandha for decreased libido. Symptoms abated with conventional treatment ⁽³³⁾.
  • Ventricular tachycardia: 2 cases were possibly associated with the use of herbomineral preparations that contained ashwagandha ⁽⁴⁵⁾.
  • Elevation of liver enzymes, skin rash, fatigue, fever, edema, and diarrhea: In patients with advanced stage high-grade osteosarcoma, following administration of Withaferin-A ⁽⁴⁷⁾.
• Herb-Drug Interactions

  Anticonvulsants, barbiturates, and benzodiazepines: Lab and animal studies suggest ashwagandha also has sedative and GABAnergic effects ^(30) (49). Clinical relevance has yet to be determined.

• Herb Lab Interactions
  • May cause false elevation in digoxin immunoassay
  • May increase thyroxine levels
• References

  1. 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(1):91-97.

  2. 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.

  3. Dafni A, Yaniv Z. Solanaceae as medicinal plants in Israel. J Ethnopharmacol. 1994;44(1):11-18.

  4. 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.

  5. Anwer T, Sharma M, Pillai KK, et al. Effect of Withania somnifera on insulin sensitivity in non-insulin-dependent diabetes mellitus rats. Basic Clin Pharmacol Toxicol. 2008;102(6):498-503.

  6. Jayaprakasam B, Zhang Y, Seeram NP, et al. Growth inhibition of human tumor cell lines by withanolides from Withania somnifera leaves. Life Sci. 2003;74(1):125-132.

  7. Widodo N, Kaur K, Shrestha BG, et al. Selective killing of cancer cells by leaf extract of ashwagandha: identification of a tumor-inhibitory factor and the first molecular insights to its effect. Clin Cancer Res. 2007;13(7):2298-2306.

  8. Davis L, Kuttan G. Effect of Withania somnifera on CTL activity. J Exp Clin Cancer Res. 2002;21(1):115-118.

  9. Derogatis LR, Morrow GR, Fetting J, et al. The prevalence of psychiatric disorders among cancer patients. JAMA. 1983;249(6):751-757.

  10. Devi PU. Withania somnifera Dunal (Ashwagandha): potential plant source of a promising drug for cancer chemotherapy and radiosensitization. Indian J Exp Biol. 1996;34(10):927-932.

  11. Panjamurthy K, Manoharan S, Menon VP, et al. Protective role of withaferin-A on 7,12-dimethylbenz(a)anthracene-induced genotoxicity in bone marrow of Syrian golden hamsters. J Biochem Mol Toxicol. 2008;22(4):251-258.

  12. Gupta YK, Sharma SS, Rai K, et al. Reversal of paclitaxel induced neutropenia by Withania somnifera in mice. Indian J Physiol Pharmacol. Apr 2001;45(2):253-257.

  13. 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(1-2):91-95.

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  15. al-Hindawi MK, al-Khafaji SH, Abdul-Nabi MH. Anti-granuloma activity of Iraqi Withania somnifera. J Ethnopharmacol. 1992;37(2):113-116.

  16. Aalinkeel R, Hu Z, Nair BB, et al. Genomic analysis highlights the role of the JAK-STAT signaling in the anti-proliferative effects of dietary flavonoid -’Ashwagandha’ in prostate cancer cells. Evid Based Complement Alternat Med. 2010 Jun;7(2):177-87.

  17. Kulkarni SK, Akula KK, Dhir A. Effect of Withania somnifera Dunal root extract against pentylenetetrazol seizure threshold in mice: possible involvement of GABAergic system. Indian J Exp Biol. 2008;46(6):465-469.

  18. 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.

  19. Stan SD, Hahm ER, Warin R, et al. Withaferin A causes FOXO3a- and Bim-dependent apoptosis and inhibits growth of human breast cancer cells in vivo. Cancer Res. 2008;68(18):7661-7669.

  20. Devi PU, Sharada AC, Solomon FE. In vivo growth inhibitory and radiosensitizing effects of withaferin A on mouse Ehrlich ascites carcinoma. Cancer Lett. 1995;95(1-2):189-193.

  21. Devi PU, Sharada AC, Solomon FE. Antitumor and radiosensitizing effects of Withania somnifera (Ashwagandha) on a transplantable mouse tumor, Sarcoma-180. Indian J Exp Biol. 1993;31(7):607-611.

  22. Bhat J, Damle A, Vaishnav PP, et al. In vivo enhancement of natural killer cell activity through tea fortified with Ayurvedic herbs. Phytother Res. 24(1):129-35.

  23. Cooley K, Szczurko O, Perri D, et al. Naturopathic care for anxiety: a randomized controlled trial ISRCTN78958974. PLoS One. 2009;4(8):e6628.

  24. 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):166-71.

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  26. Kumar S, Harris RJ, Seal CJ, Okello EJ. An aqueous extract of Withania somnifera root inhibits amyloid β fibril formation in vitro. Phytother Res. 2012;26(1):113-7.

  27. Ahmad MK, Mahdi AA, Shukla KK, et al. Withania somnifera improves semen quality by regulating reproductive hormone levels and oxidative stress in seminal plasma of infertile males. Fertil Steril. 2010;94(3):989-96.

  28. Dasgupta A, Tso G, Wells A. Effect of Asian ginseng, Siberian ginseng, and Indian Ayurvedic medicine Ashwagandha on serum digoxin measurement by digoxin III, a new digoxin immunoassay. J Clin Lab Anal. 2008;22(4):295-301.

  29. Grover A, Singh R, Shandilya A, et al. Ashwagandha derived withanone targets TPX2-Aurora a complex: Computational and experimental evidence to its anticancer activity. PLoS ONE. 2012;7(1).

  30. Kumar A, Kulkarni SK. Effect of herbals on sleep and their interactions with hypnotic drugs. Indian J Pharm Sci. 2005;67(3):391-393.

  31. Biswal BM, Sulaiman SA, Ismail HC, Zakaria H, Musa KI. Effect of Withania somnifera (Ashwagandha) on the development of chemotherapy-induced fatigue and quality of life in breast cancer patients. Integr Cancer Ther. 2013;12(4):312-22.

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  33. Sehgal VN, Verma P, Bhattacharya SN. Fixed-drug eruption caused by ashwagandha (Withania somnifera): a widely used Ayurvedic drug. Skinmed. 2012;10(1):48-9.

  34. Agnihotri AP, Sontakke SD, Thawani VR, Saoji A, Goswami VS. Effects of Withania somnifera in patients of schizophrenia: A randomized, double blind, placebo controlled pilot trial study. Indian J Pharmacol. 2013;45:417-418.

  35. Chengappa KN, Bowie CR, Schlicht PJ, Fleet D, Brar JS, Jindal R. Randomized placebo-controlled adjunctive study of an extract of Withania somnifera for cognitive dysfunction in bipolar disorder. J Clin Psychiatry. 2013;74:1076-1083.

  36. Maliyakkal N, Appadath Beeran A, Balaji SA, Udupa N, Ranganath Pai S, Rangarajan A. Effects of Withania somnifera and Tinospora cordifolia extracts on the side population phenotype of human epithelial cancer cells: Toward targeting multidrug resistance in cancer. Integr Cancer Ther. 2015;14:156-171.

  37. Shah N, Singh R, Sarangi U, et al. Combinations of ashwagandha leaf extracts protect brain-derived cells against oxidative stress and induce differentiation. PLoS One. 2015;10:e0120554.

  38. Li X, Zhu F, Jiang J, et al. Synergistic antitumor activity of withaferin a combined with oxaliplatin triggers reactive oxygen species-mediated inactivation of the PI3k/Akt pathway in human pancreatic cancer cells. Cancer Lett. 2015;357:219-230.

  39. Gannon JM, Forrest PE, Roy Chengappa KN. Subtle changes in thyroid indices during a placebo-controlled study of an extract of Withania somnifera in persons with bipolar disorder. J Ayurveda Integr Med. 2014;5:241-245.

  40. Savai J, Varghese A, Pandita N, et al. Investigation of CYP3A4 and CYP2D6 interactions of Withania somnifera and Centella asiatica in human liver microsomes. Phytother Res. May 2015;29(5):785-790.

  41. Ramakanth GS, Uday Kumar C, Kishan PV, et al. A randomized, double blind placebo controlled study of efficacy and tolerability of Withaina somnifera extracts in knee joint pain. J Ayurveda Integr Med. Jul – Sep 2016;7(3):151-157.

  42. Kaushik MK, Kaul SC, Wadhwa R, Yanagisawa M, Urade Y. Triethylene glycol, an active component of Ashwagandha (Withania somnifera) leaves, is responsible for sleep induction. PLoS One. 2017 Feb 16;12(2):e0172508.

  43. Chengappa KNR, Brar JS, Gannon JM, et al. Adjunctive Use of a Standardized Extract of Withania somnifera (Ashwagandha) to Treat Symptom Exacerbation in Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Study. J Clin Psychiatry. Jul 10 2018;79(5).

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  48. Lopresti AL, Drummond PD, Smith SJ. A Randomized, Double-Blind, Placebo-Controlled, Crossover Study Examining the Hormonal and Vitality Effects of Ashwagandha ( Withania somnifera) in Aging, Overweight Males. Am J Mens Health. Mar-Apr 2019;13(2):1557988319835985.

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  50. Gannon JM, Brar J, Rai A, et al. Effects of a standardized extract of Withania somnifera (Ashwagandha) on depression and anxiety symptoms in persons with schizophrenia participating in a randomized, placebo-controlled clinical trial. Ann Clin Psychiatry. May 2019;31(2):123-129.