Ashwagandha

Publication Details

OVERVIEW

Introduction

Ashwagandha is a popular Ayurvedic herb used as a general tonic, to improve health, increase energy and reduce stress and anxiety. Ashwagandha has not been implicated in causing serum enzyme elevations during therapy but recently has been implicated in cases of clinically apparent liver injury.

Background

Ashwagandha is an Ayurvedic herb that is derived from extracts of the roots of Withania somnifera, a low growing evergreen shrub that is native to India and Southeast Asia. Ashwagandha is a Sanskrit word meaning horse smell. Sometimes called “Indian ginseng”, it is purported to have neuroprotective and antiinflammatory activities and is used to treat stress, anxiety, insomnia, fatigue, pain, skin diseases, diabetes, arthritis, and epilepsy. It is also used as a general tonic to increase energy, reduce fatigue and counteract the effects of aging. Its efficacy in these conditions has not been shown in controlled prospective studies, but it has been used in Ayurvedic medicine for centuries and is currently the most frequently used Ayurvedic medication. Ashwagandha has recently become a popular herbal product in Western countries. Withania somnifera extracts have more than 100 different chemical constituents including alkaloids, steroidal lactones, saponins, withanolides, withaferins and iron. The ingredient responsible for its purported activities and side effects is not known but withanolides are suspected. Extracts of ashwagandha root are often supplied as capsules or tablets in concentrations of 150 to 600 mg, which are taken one to three times daily, the total daily dose varying widely. Side effects are uncommon and have not been clearly defined. Large doses can cause gastrointestinal upset, diarrhea, nausea and vomiting, probably because of direct irritation to the intestinal mucosa.

Hepatotoxicity

Despite widescale use, ashwagandha is considered generally safe and without major adverse effects. In clinical trials, there have been no reports of serum enzyme elevations occurring during therapy and no mention of serious adverse events or hepatotoxicity. Recently, however, cases of clinically apparent liver injury have been reported in patients taking commercial herbal products that are labelled as containing ashwagandha. Typically, the liver injury presented 2 to 12 weeks after starting ashwagandha usually with a cholestatic or mixed pattern of injury, jaundice, and pruritus. Immunoallergic and autoimmune features were not prominent. Occasional cases were hepatocellular initially, but in general the ensuing jaundice was protracted although it ultimately resolved completely. Rare instances of fatal liver injury or need for emergent liver transplantation have been reported particularly in patients with preexisting liver disease and cirrhosis. Because commercial herbal preparations are often mixtures of herbs and nutritional products and can be mislabeled and contain unknown herbs and medications, it is not always clear whether the reported cases were due to ashwagandha and one of its components or to a contaminant. In several reported cases, however, the commercial product being taken was tested and found to have ashwagandha without other contaminants. First reported in 2017, an increasing number of cases have been reported since. Thus, clinically apparent liver injury attributable to ashwagandha occurs although rarely, and its use should be avoided in patients with cirrhosis or advanced chronic liver disease.

Likelihood score: B (likely cause of clinically apparent liver injury).

Mechanism of Injury

The cause of hepatotoxicity from products containing ashwagandha is unclear. Among the many ingredients the withanolides have been most suspect. The possibility of mislabeling or adulteration with hepatotoxic herbal products is always an issue in commercial multiingredient dietary supplements.

Outcome and Management

Most cases of ashwagandha associated liver injury have been mild-to-moderate in severity and self-limited in course, but fatal cases due to acute liver failure or acute-on-chronic liver failure have been described. Protracted jaundice in not uncommon, but chronic liver injury and vanishing bile duct syndrome have not been described. In most instances, the liver injury subsides within 1 to 4 months of discontinuing the herbal product. Rechallenge with the same product should be avoided.

Other names: Indian Ginseng, Winter Cherry, Poison Gooseberry

Drug Class: Herbal and Dietary Supplements

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Ashwagandha – Generic

DRUG CLASS

Herbal and Dietary Supplements

SUMMARY INFORMATION

Fact Sheet at National Center for Complementary and Integrative Health, NIH

CHEMICAL FORMULA AND STRUCTURE

ANNOTATED BIBLIOGRAPHY

References updated: 03 December 2024

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    (Expert review of hepatotoxicity published in 1999; several herbals are discussed, including comfrey, Jin Bu huan, germander, chaparral leaf, skullcap and valerian, but not ashwagandha).
  • Liu LU, Schiano TD. Hepatotoxicity of herbal medicines, vitamins and natural hepatotoxins. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 2nd ed. New York: Informa Healthcare USA, 2007, pp. 735.
    (Review of hepatotoxicity of herbal and dietary supplements [HDS]; ashwagandha is not discussed).
  • No authors listed. Ashwagandha. In, Natural Medicines: comprehensive database. http:​//naturaldatabase​.therapeuticresearch.com
    (Compilation of short monographs on herbal medications and natural products).
  • Sudhir S, Budhiraja RD, Miglani GP, Arora B, Gupta LC, Garg KN. Pharmacological studies on leaves of Withania somnifera. Planta Med 1986; 52: 61-3. [PubMed: 3703993]
    (In rat models of acute and chronic inflammation and carbon tetrachloride hepatotoxicity, alcohol extracts of Withania somnifera leaves decreased edema, inflammation and hepatic injury).
  • Mishra LC, Singh BB, Dagenais S. Scientific basis for the therapeutic use of Withania somnifera (ashwagandha): a review. Altern Med Rev 2000; 5: 334-46. [PubMed: 10956379]
    (Review of published literature on Withania somnifera, a commonly used herb in Ayurvedic medicine, said to have antiinflammatory, antitumor, antistress, antioxidant, immune modulatory, hemopoietic and rejuvenating properties; toxicity studies have been done largely in laboratory animals, but adverse effects have not been demonstrated).
  • Chopra A, Lavin P, Patwardhan B, Chitre D. A 32-week randomized, placebo-controlled clinical evaluation of RA-11, an Ayurvedic drug, on osteoarthritis of the knees. J Clin Rheumatol 2004; 10: 236-45. [PubMed: 17043520]
    (Controlled trial of a 32 week course of RA-11 versus placebo in 90 patients with osteoarthritis, found improvements in clinical symptoms, but no side effects or changes in serum ALT, AST or Alk P levels).
  • van der Hooft CS, Hoekstra A, Winter A, de Smet PA, Stricker BH. [Thyrotoxicosis following the use of ashwagandha]. Ned Tijdschr Geneeskd 2005; 149: 2637-8. Dutch. [PubMed: 16355578]
    (32 year old previously healthy woman developed poor appetite, weight loss, shakiness, and palpitations 6 weeks after starting an herbal preparation of ashwagandha and shortly after increasing the dose [TSH <0.01 mU/L, free T4 33.9 pmol/L: normal 11-22], symptoms and abnormal thyroid tests resolving spontaneously soon after stopping).
  • Chopra A, Saluja M, Tillu G, Venugopalan A, Narsimulu G, Sarmukaddam S, Patwardhan B. Evaluating higher doses of Shunthi - Guduchi formulations for safety in treatment of osteoarthritis knees: A Government of India NMITLI arthritis project. J Ayurveda Integr Med 2012; 3: 38-44. [PMC free article: PMC3326794] [PubMed: 22529679]
    (Among 92 patients with symptomatic osteoarthritis of the knees treated for 6 weeks with one of four herbal preparations [2 with ashwagandha], adverse events were uncommon and mild, and none of 45 patients developed serum ALT or AST elevations).
  • Kumar G, Srivastava A, Sharma SK, Rao TD, Gupta YK. Efficacy & safety evaluation of Ayurvedic treatment (Ashwagandha powder & Sidh Makardhwaj) in rheumatoid arthritis patients: a pilot prospective study. Indian J Med Res 2015; 141: 100-6. [PMC free article: PMC4405924] [PubMed: 25857501]
    (Among 86 patients with rheumatoid arthritis treated with ashwagandha [5 gm twice daily] for 3 weeks followed by “Sidh Makardhwaj” for 4 weeks, symptom scores improved with treatment while ALT and AST levels did not change, serum mercury levels increased 4-fold).
  • Palliyaguru DL, Singh SV, Kensler TW. Withania somnifera: From prevention to treatment of cancer. Mol Nutr Food Res 2016; 60: 1342-53. [PMC free article: PMC4899165] [PubMed: 26718910]
    (Review of the concept of chemoprevention of cancer and the evidence that ashwagandha might be effective based upon in vivo studies of apoptosis, angiogenesis, stress response, inflammation, and cancer prevention in animal models).
  • Choudhary D, Bhattacharyya S, Bose S. Efficacy and safety of ashwagandha (Withania somnifera (L.) Dunal) root extract in improving memory and cognitive functions. J Diet Suppl 2017; 14: 599-612. [PubMed: 28471731]
    (Among 50 adults treated with ashwagandha [300 mg twice daily] or placebo for 8 weeks, measures of memory, attention and information processing improved more with ashwagandha, and tolerability was “excellent”; no mention of ALT elevations or hepatotoxicity).
  • Choudhary D, Bhattacharyya S, Joshi K. Body weight management in adults under chronic stress through treatment with Ashwagandha root extract: a double-blind, randomized, placebo-controlled trial. J Evid Based Complementary Altern Med 2017; 22: 96-106. [PMC free article: PMC5871210] [PubMed: 27055824]
    (Among 52 adults with chronic stress treated with ashwagandha or placebo for 8 weeks, scores for perceived stress decreased more with the herbal extract and adverse events were uncommon and mild).
  • Inagaki K, Mori N, Honda Y, Takaki S, Tsuji K, Chayama K. A case of drug-induced liver injury with prolonged severe intrahepatic cholestasis induced by Ashwagandha. Kanzo 2017; 58: 448-54. Not in PubMed
    (20 year old man developed jaundice a month after increasing the dose of ashwagandha [bilirubin 20.7 mg/dL, ALT 94 U/L, Alk P 343 U/L, INR 1.02], jaundice persisting for more than 2 months, but ultimately resolving).
  • Brown AC. Liver toxicity related to herbs and dietary supplements: online table of case reports. Part 2 of 5 series. Food Chem Toxicol 2017; 107: 472-501. [PubMed: 27402097]
    (Description of an online compendium of cases of liver toxicity attributed to HDS products does not list or discuss ashwagandha).
  • Medina-Caliz I, Garcia-Cortes M, Gonzalez-Jimenez A, Cabello MR, Robles-Diaz M, Sanabria-Cabrera J, Sanjuan-Jimenez R, et al.; Spanish DILI Registry. Herbal and dietary supplement-induced liver injuries in the Spanish DILI Registry. Clin Gastroenterol Hepatol. 2018;16:1495-1502. [PubMed: 29307848]
    (Among 856 cases of hepatotoxicity enrolled in the Spanish DILI Registry between 1994 and 2016, 32 were attributed to herbal products, the most frequent cause being green tea [n=8] and Herbalife products [n=6], no mention of ashwagandha).
  • Björnsson HK, Björnsson ES, Avula B, Khan IA, Jonasson JG, Ghabril M, Hayashi PH, Navarro V. Ashwagandha as a cause for liver injury. Liver Int. 2020;40:2035-2036. [PubMed: 32475004]
    (Five cases of liver injury associated with ashwagandha use, 3 from Iceland and 2 from the U.S. in adults ages 21 to 62 years, presenting with symptoms and jaundice 2 to 12 weeks after starting the herbal supplement, enzyme pattern being mixed or cholestatic, frequently with prolonged jaundice but resolving in all within 1 to 5 months, with no fatalities and no evidence of chronic injury).
  • Ireland PJ, Hardy T, Burt AD, Donnelly MC. Drug-induced hepatocellular injury due to herbal supplement ashwagandha. J R Coll Physicians Edinb. 2021;51:363-365. [PubMed: 34882134]
    (39 year old woman developed nausea and vomiting 6 weeks after starting ashwagandha [154 mg] on alternative days for anxiety [bilirubin 9.0 rising to 19.1 mg/dL, ALT 1514 U/L, Alk P 184 U/L, prothrombin time 14 sec], with slow recovery on ursodiol therapy).
  • Weber S, Gerbes AL. Ashwagandha-induced liver injury: self-reports on commercial websites as useful adjunct tools for causality assessment. Am J Gastroenterol. 2021;116:2151-2152. [PubMed: 34187981]
    (40 year old man developed jaundice and pruritus 20 days after switching to a new brand of ashwagandha [Now Ashwagandha 450 mg], with bilirubin rising from ~ 8.5 to 25.2 but with only modest elevations in serum ALT and AST; few details provided).
  • Ballotin VR, Bigarella LG, Brandão ABM, Balbinot RA, Balbinot SS, Soldera J. Herb-induced liver injury: Systematic review and meta-analysis. World J Clin Cases. 2021;9:5490-5513. [PMC free article: PMC8281430] [PubMed: 34307603]
    (Systematic review of the literature on herb induced liver injury identified 446 references describing 936 cases due to 79 different herbal products, the most common being He Shou Wu [91], green tea [90] Herbalife products [64], kava kava [62] and greater celandine [48]; Ashwagandha is listed as having 9 cases [~1%] in the literature).
  • Bessone F, García-Cortés M, Medina-Caliz I, Hernandez N, Parana R, Mendizabal M, Schinoni MI, et al. Herbal and dietary supplements-induced liver injury in Latin America: experience from the LATINDILI Network. Clin Gastroenterol Hepatol. 2022;20:e548-e563. [PubMed: 33434654]
    (Among 367 cases of hepatotoxicity enrolled in the Latin American DILI Network between 2011 and 2019, 29 [8%] were attributed to herbal products, the most frequent being green tea [n=7], Herbalife products [n=5] and garcinia [n=3], none were attributed to ashwagandha).
  • Pusec CM, Wolsky R, Llerena C, Sura P. A case of supplement-induced hepatitis. Cureus. 2022;14:e30433. [PMC free article: PMC9671273] [PubMed: 36407193]
    (43 year old woman developed abdominal pain and fatigue followed by jaundice after taking ashwagandha in high doses [2100 mg daily] for a year and while also on ibuprofen [1200 mg daily] and modest alcohol intake, liver biopsy showing marked macro- and micro-steatosis [bilirubin 13.5 mg/dL, ALT 70 U/L, Alk P 422 U/L], improving after stopping the herbal supplement).
  • Patel AD, Pinsker BL, Wall A, Arbogast M, King LY, Sherzoy S. Itching to find a diagnosis. Clin Liver Dis (Hoboken). 2022;20:77-80. [PMC free article: PMC9512456] [PubMed: 36187371]
    (65 year old man developed abdominal pain and weight loss followed by jaundice while taking a dietary supplement with ashwagandha for an unknown duration in an unknown dose [bilirubin 2.0 rising to 21 mg/dL, ALT 126 U/L, Alk P 96 U/L], resolving over the following 2-3 months).
  • Siddiqui S, Ahmed N, Goswami M, Chakrabarty A, Chowdhury G. DNA damage by Withanone as a potential cause of liver toxicity observed for herbal products of Withania somnifera (Ashwagandha). Curr Res Toxicol. 2021;2:72-81. [PMC free article: PMC8320610] [PubMed: 34345852]
    (The ashwagandha metabolite withanone [“win”] can form non-labile adducts with nucleosides and DNA which may interfere with DNA transcription, replication, and repair and might be detoxified by glutathione in a manner similar to acetaminophen).
  • Casiano-Manzano S, Torres-Larrubia M, Masa-Caballero A, Jiménez-Colmenarez Z, Martín-Noguerol E, Fernández-Bermejo M, Solís-Muñoz P. Changing perspectives: unveiling the risks of ashwagandha-induced hepatotoxicity. Rev Esp Enferm Dig. 2023 Nov 20. Epub ahead of print. [PubMed: 37982556]
    (Short report of a 33 year old Spanish man who developed jaundice and pruritus two months after starting ashwagandha for anxiety [bilirubin 10.7 rising to 21.1, ALT and Alk P levels not provided], with resolution after stopping).
  • Philips CA, Valsan A, Theruvath AH, Ravindran R, Oommen TT, Rajesh S, Bishnu S, et al.; Liver Research Club India. Ashwagandha-induced liver injury—A case series from India and literature review. Hepatol Commun. 2023;7:e0270. [PMC free article: PMC10531359] [PubMed: 37756041]
    (8 cases of ashwagandha related liver injury from 3 hospitals in India from 2019 through 2022, included 6 men and 2 women, ages 31 to 75, 7 taking the herb for 2-12 weeks and one for more than a year, for stress or sleep, presenting with median bilirubin 13.8 mg/dL, ALT 173 U/L, Alk P 204 U/L, 5 having preexisting chronic liver disease, 3 having acute-on-chronic liver failure and dying, the remaining resolving although often after prolonged cholestasis).
  • Bokan G, Glamočanin T, Mavija Z, Vidović B, Stojanović A, Björnsson ES, Vučić V. Herb-induced liver injury by Ayurvedic ashwagandha as assessed for causality by the updated RUCAM: an emerging cause. Pharmaceuticals (Basel). 2023;16:1129. [PMC free article: PMC10459262] [PubMed: 37631044]
    (Two case reports; 36 year old man developed jaundice 6 months after starting ashwagandha [450 mg 3 times daily] for fertility [bilirubin 2.6 mg/dL, ALT 1396 U/L, Alk P 432 U/L, INR 0.98] and a 30 year old woman developing rash 3 weeks and jaundice 6 weeks after starting ashwagandha [450 mg once daily] for fertility [bilirubin 12.6 mg/dL, ALT 111 U/L, Alk P 147 U/L, INR 0.93], both cases resolving within 2 months of stopping).
  • Tóth M, Benedek AE, Longerich T, Seitz HK. Ashwagandha-induced acute liver injury: a case report. Clin Case Rep. 2023;11:e7078. [PMC free article: PMC10014511] [PubMed: 36937644]
    (65 year old man living in Germany developed jaundice within 4 weeks of starting ashwagandha for “troubled thoughts” [bilirubin 17.3 mg/dL, ALT 54 U/L, Alk P 298 U/L], resolving within 5 months of stopping).
  • Lubarska M, Hałasiński P, Hryhorowicz S, Mahadea DS, Łykowska-Szuber L, Eder P, Dobrowolska A, et al. Liver dangers of herbal products: a case report of ashwagandha-induced liver injury. Int J Environ Res Public Health. 2023;20:3921. [PMC free article: PMC10002162] [PubMed: 36900932]
    (23 year old Polish man developed fatigue and jaundice approximately 3 months after starting ashwagandha [bilirubin 11.5 rising to 28.1 mg/dL, ALT 490 U/L, Alk P 227 U/L, INR 1.24], resolving within 3.5 months of stopping).
  • Suryawanshi G, Abdallah M, Thomson M, Desai N, Chauhan A, Lim N. Ashwagandha-associated acute liver failure requiring liver transplantation. Am J Ther. 2023;30:e80-e83. [PubMed: 36321995]
    (41 year old woman developed fatigue 2 months after starting ashwagandha and progesterone and stopped therapy but continued to have symptoms and then jaundice one month later [bilirubin 10.4 rising to 24.6 mg/dL, ALT 3400 U/L, Alk P 102 U/L] and 10 days later with progressive hepatic failure [encephalopathy and INR 6.2], undergoing successful emergency liver transplantation).
  • Vazirani S, Kothari A, Fujimoto J, Gomez M. Supplements are not a synonym for safe: suspected liver injury from ashwagandha. Fed Pract. 2023;40:315-319. [PMC free article: PMC10984693] [PubMed: 38562158]
    (48 year old man with severe alcohol use disorder started taking “TestBoost” [containing 8 ingredients including ashwagandha, long jack, eleuthero, ginseng, mushroom extract, bindi and horny goat weed] for alcohol withdrawal symptoms and developed jaundice 3 days later [bilirubin 13.6 mg/dL, ALT 49 U/L, AST 58 U/L Alk P 98 U/L, INR 1.1], with slow recovery and relapse in alcohol use in follow up).
  • Almuzghi F, Abdelmalik A, Abuhlaiga M. Ashwagandha-induced hepatic injury: a case report. Cureus. 2024;16:e71576. [PMC free article: PMC11564894] [PubMed: 39553154]
    (22 year old Libyan female developed itching and fatigue after 2 days followed by jaundice after 7 days of starting ashwagandha for anxiety [bilirubin 2.6 rising to 12.8 mg/dL, ALT 186 to 315 U/L, Alk P 119 to 150 U/L, INR 1.0], resolving 2 months after stopping).
  • Likhitsup A, Chen VL, Fontana RJ. Estimated exposure to 6 potentially hepatotoxic botanicals in US adults. JAMA Netw Open. 2024;7:e2425822. [PMC free article: PMC11301549] [PubMed: 39102266]
    (Analysis of a database of the U.S. adult population during 2023 and 2024 found that ashwagandha was one of the most frequently used herbal supplements).
  • Philips CA, Theruvath AH. A comprehensive review on the hepatotoxicity of herbs used in the Indian (Ayush) systems of alternative medicine. Medicine (Baltimore). 2024;103:e37903. [PMC free article: PMC11029936] [PubMed: 38640296]
    (Review of the literature on liver injury attributed to Ayurvedic medicines, mentions 23 cases of clinically apparent liver injury due to ashwagandha have been reported, with typical onset of cholestatic hepatitis after a month of use, most cases resolving spontaneously, but occasional instances of fatal liver failure or chronic injury).
  • Vaidya VG, Gothwad A, Ganu G, Girme A, Modi SJ, Hingorani L. Clinical safety and tolerability evaluation of Withania somnifera (L.) Dunal (Ashwagandha) root extract in healthy human volunteers. J Ayurveda Integr Med. 2024;15:100859. [PMC free article: PMC10784694] [PubMed: 38154316]
    (Among 18 healthy adult men treated with ashwagandha 500 mg twice daily for 1 month, therapy was well tolerated and there were no changes in body weight, blood counts, serum ALT or AST, with minor elevation in Alk P [140 to 164 U/L] and decrease in total bilirubin levels [0.84 to 0.65 mg/dL]).