Evidence suggests that one of our most widely prescribed herbs, ashwagandha, poses a risk to liver health. Withanolides have been implicated in hepatic injury and investigations have found adulteration of root supplies by withanolide-rich leaves. Simon Mills discusses findings and how we may responsibly engage with this information — How do we protect our patients? How do we protect the use of this herb in our practice?
Background and summary
The herbal sector has for decades been exposed to suspicions and some evidence that herbal remedies might cause liver problems, challenges that we have found hard to refute. Liver injury is most often not immediately apparent and so traditional experience is not a strong assurance that this does not happen. Already, because safety arguments have been ineffective, kava-kava has been widely banned around the world for this association, and variously black cohosh, germander, chaparral and shou wu (Polygonum multiflorum) have been seriously implicated; comfrey, ragworts and borage are very widely restricted for their pyrrolizidine alkaloids; now even fennel is threatened, and there is new evidence implicating curcumin-rich extracts of turmeric (1). Indeed the relative incidence of herb-related reports relative to conventional medicines is rising, perhaps as more attention is being paid to this possibility (2).
Ashwagandha (Withania somnifera) is one of the most widely used remedies in the herbalist’s dispensary, so new challenges to its safety are concerning. Since 2017 a cluster of reports, from the USA, Iceland and elsewhere, have suggested that it may be implicated in cases of liver injury. Now for the first time, cases have emerged from India, the land of its origin and most widespread use. In the most challenging report so far, a thorough review of cases obtained from just three Indian hospitals has identified serious adverse effects on liver function, including death, most of which were ‘probably’ associated with taking ashwagandha. Even allowing for the declared bias against Ayurvedic medicine by the lead author of the paper, these findings could signal a significantly wider health issue, not least in the likely spread of the message that ashwagandha is dangerous for the liver.
In this review of the evidence, we look closely at these reports, and consider some of the wider issues linked to liver injury following the intake of herbs. Three recommendations then emerge for the practitioner who wishes to use ashwagandha with minimum risk and proactively to engage with any threat to its use.
- Ensure supplies of ashwagandha are assured as root only, without added leaf, and otherwise to avoid high withanolide products.
- Avoid prescribing ashwagandha in patients with severe liver disease such as cirrhosis or liver cancer.
- Avoid ashwagandha if the patient is regularly taking paracetamol (Tylenol).
India report findings
Members of a research group of liver specialists collaborated on a paper published in 2023 reporting significant cases of liver injury associated with ashwagandha (3). The lead author, Cyriac Philips, has a taken a prominent position in India as a critic of Ayurvedic and other alternative medicines both in social media and published papers (4,5) but in this review the authors were scrupulous in their presentation and in ruling out confounding factors. A total of 23 suspected cases were identified in the medical records from three hospitals in the four years up to December 2022. The authors excluded 15 of these where ashwagandha use could be complicated by other herbs or medicines, those with active alcohol use and with other potential causes of acute liver injury. They finally identified 8 cases of liver injury where ashwagandha use without these other factors was implicated.
All eight patients underwent detailed follow-up to fully exclude other known causes of liver injury. The evaluation included laboratory investigations, viral serologies for acute and chronic hepatotropic viruses (including Hepatitis E, Herpes simplex, cytomegalovirus, Epstein-Barr, Dengue, and Covid), and other pertinent non-viral infectious agents, such as malaria parasite, Rickettsia, and Leptospira. Biomarkers for autoimmune liver disease and diagnostic cross-sectional imaging were also performed in all patients.
Six of the patients included in the study were males, and two were females. Their ages ranged between 31 to 75. Three patients had diabetes or hypertension and had been on medications for the same for decades without any significant prescription drug modifications pertinent to current events. Three patients presented with pre-existing chronic liver disease, while two patients were so diagnosed during evaluation. One patient had a history of non-Hodgkin lymphoma in remission for four years. Five patients presented with acute hepatitis and eventually recovered between one and three months later. The three patients who presented with chronic liver disease were then diagnosed with acute-on-chronic liver failure (ACLF): all of these died.
The standard Roussel Uclaf Causality Assessment Method (RUCAM) for assessing drug-induced liver injury (DILI) was applied to determine whether the association with ashwagandha intake was highly probable, probable, possible, and unlikely. By this means six cases were judged as ‘probable’ and two as ‘possible’.
At initial presentation the liver injury was classified into hepatocellular (injury to the hepatocytes) or cholestatic (injury to the biliary system, resulting in inability to pass bile), or mixed type. This classification is based on ratios of liver function enzymes alanine aminotransaminase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP). Typically, elevated ALT and AST point to hepatocellular injury while elevated ALP (and gamma-glutamyl transferase GGT) suggest impaired bile flow or cholestasis. On this basis injuries were evenly spread between hepatocellular and cholestatic.
Percutaneous or transjugular liver biopsy was performed in six of the patients after informed consent (the other two had died). This showed that the portal area was the commonest site of inflammation, while the predominant type of inflammation was lymphocytic and eosinophilic. Half the biopsies showed hepatocellular necrosis.
The median time to symptom onset was 41 days, with four cases occurring within a month of taking ashwagandha and one outlier taking a year and a half of consuming a tea for symptoms to show.
The various types of ashwagandha formulations consumed by the patients included homemade powdered roots, herbal jam preparation (called lehyam), branded ashwagandha root formulations as powders, syrups, and tablets, non-branded Ayurveda practitioner-prepared tablets, and a ‘detox tea’. Five had been prescribed ashwagandha by Ayurvedic practitioners (these included two of those who died — both of whom initially presented with chronic liver failure), the other three were self-medicating. All patients claimed to have followed the practitioner’s advice or product labelling: the doses ranged from 500mg up to 20 g per day; most doses reported were at the higher range.
Five ashwagandha formulations from the patients were retrieved for further chemical and toxicology analysis. Heavy metal concentration was determined by plasma atomic emission spectrometry. One product was found to have trace amounts of lead (0.21 mg/kg), cadmium (0.038 mg/kg), and arsenic (0.089 mg/kg). Complete qualitative analyses were performed using gas chromatography with mass spectrometry. None of the formulations revealed potential hepatotoxic contaminants, adulterants, or other synthetic agents. Herb-based natural bioactive compounds were identified in all formulations, including glycosides, lactones, terpenes, saponins, and alkaloid groups.
The authors noted, though without elaboration, that an underlying mechanism for liver damage due to ashwagandha could be the presence of withanolides.
Interpretations of the India report: what may be going on here?
There are broadly four types of drug-induced liver injury (DILI)
- Directly related to the pharmacological effects of the drug
- Idiosyncratic immune-related reactions
- Problems associated with long-term use of a drug
- Delayed effects, such as carcinogenicity or teratogenicity
Of these, the first two are most relevant to this discussion (6). The direct, intrinsic, predictable injury is dose-related and occurs hours to days after exposure to an agent established as toxic to the liver. In the plant world such hepatotoxins include pyrrolizidine alkaloids (in which the damage is veno-occlusive), and also pulegone, safrole, with other examples of saponins, anthraquinones and triterpenoids, as well as common mycotoxin plant contaminants (7).
The second type of liver injury is idiosyncratic, indirect and unpredictable, and follows interaction with the substance of often unknown environmental and host, including immunological and genetic (8) factors. It is not dose-related and has a longer latency period (from a couple of weeks to several months). There are generally two stages in this process.
Drug activation
Most idiosyncratic reactions are not caused by the substance itself but by a reactive metabolite, for example formed by cytochrome P450 and other liver-based phase I detoxification enzymes, although usually in small quantities. However, genetic disposition (e.g., enhanced expression of the enzyme or deficiency of protective factors such as glutathione) or certain external conditions (e.g., co-medication with inducers of cytochrome P450 metabolism) may lead to toxic intermediates being generated in dangerous quantities. Certain functional groups (including those found in plant constituents), which are more readily oxidised to reactive metabolites, are associated with a higher incidence of adverse reactions (9). Risks are particularly high if biotransformation yields products with chemical substructures such as quinones, phenols, acyl halides, and aromatic and hydroxyl amines (10).
Adduct formation
The next step requires the reactive metabolite (occasionally the substance itself) irreversibly to bind to some structure – it forms covalent “adducts” with nucleic acids (DNA, RNA or their nucleosides) or a protein molecule. This new complex then assumes different antigenic properties to initiate an immunologic response which then completes the injury.
In the Indian cases, there were such delayed onsets which, with other observations, supports the conclusion that these were idiosyncratic liver injuries.
As specific biomarkers for DILI are still lacking its diagnosis relies on the exclusion of other aetiologies of liver disease. Hepatocellular injury shares features with viral hepatitis: it usually shows marked liver cell necrosis and inflammation with only mild bile stasis, at least in the early stages. Symptoms of fatigue and weakness predominate. Cholestatic injury can follow hepatocellular and can also be caused by viral infections among other causes. Biopsy shows bile stasis, portal inflammation and proliferation or injury of bile ducts and ductules. Clinically, symptoms of jaundice and itching predominate. Often with drug-induced damage the injuries are mixed, and this can even help distinguish DILI from other causes. Liver biopsy for mixed injuries shows prominent hepatocyte necrosis and inflammation accompanied by marked bile stasis. Symptoms may include both fatigue and itching (6). In the Indian reports seven out of the eight cases presented with jaundice, and five with itching, suggesting that cholestatic injury predominated, even though half the cases had hepatocellular injury as well. Such a pattern of mixed injury was further reflected in half the caseload having necrosis.
The biopsy results performed here also reduced the possibility of autoimmune hepatitis that can sometimes follow drug injury. There are standard markers (11) for this: interface hepatitis (the extension of portal inflammation into the adjacent lobule with damage and progressive loss of hepatocytes at the portal-lobular interface), and antinuclear, anti-smooth muscle and anti-liver-kidney-microsomal antibodies. All these were largely absent in the India reports.
It is always a challenge to exclude viral causes of liver injury in any of these cases, especially as acute viral infection most often leads to cholestatic damage and lymphocytic infiltration, as seen in many of these cases (12). The authors reported that laboratory investigations were conducted to check for common infective causes (though not confirmatory PCR tests for Hepatitis C and E – and the details of these investigations were not elaborated). They go on to state that viral hepatitis was considered very unlikely to have caused the pattern of liver injuries described, with only mild elevation in aminotransferases. However, given that many cases reported were also hepatocellular and mixed, there does remain a possibility that viral causes were missed.
The three patients presenting with acute-on-chronic liver failure (ACLF) all died. This is consistent with the poor prognosis generally associated with DILI in those with advanced cirrhosis.
Other reports linking ashwagandha to liver injury
There have been similar ashwagandha alerts since 2016, including nine single case studies, from the USA, Japan, Germany and Poland (all reviewed in the Indian paper (3)).
In a more substantial report from Iceland (13), five cases of liver injury that the authors attributed to ashwagandha-containing supplements were described; three collected in 2017–2018 from Iceland, and another two from the US-based Drug-Induced Liver Injury Network (DILIN) in 2016. Among the patients, three were males and the mean age was 43 years (age range 21 to 62). All patients developed jaundice and symptoms such as nausea, lethargy, pruritus and abdominal discomfort after a latency period of 2 to 12 weeks from taking ashwagandha. The liver injury was cholestatic or mixed. Pruritus and hyperbilirubinaemia were prolonged (5 to 20 weeks), but no patient developed hepatic failure.
Liver tests normalised within 1 to 5 months in four patients and one case was lost to follow-up. One biopsy was performed, showing acute cholestatic hepatitis. Chemical analysis by the authors identified ashwagandha in the supplements taken. No other toxic compounds were identified. No patient was taking potentially hepatotoxic prescription medications, although four were consuming additional supplements, and in one case, rhodiola was also deemed to be a ‘possible’ association. The role of ashwagandha in causing liver injury was judged as definite in one case, highly likely in two, probable in one and possible in one. Viral markers for acute hepatitis A, B and C as well as cytomegalovirus IgM were negative in all patients. However, hepatitis C virus (HCV) RNA PCR was performed in only one case (and was negative) and hepatitis E virus (HEV) testing was not undertaken.
Implicated ashwagandha constituents and plant parts
Many chemical constituents have been isolated from the various plant parts of Withania somnifera. These include
- Alkaloids – notably withanine and also including somniferine, somnine, somniferinine, isopelletierine, anaferine and withananine
- Steroidal lactones – ‘withanolides’ including withaferin A, withanone, withanolide A, and withanolides D–M. These are particularly prominent in the leaves
- Saponins (with an additional acyl group) – e.g. sitoindoside VII and VIII
Withaferin A is a particularly potent withanolide, the molecule having many sites of unsaturation and differential oxygenation that can interact with signalling pathways involved in inflammatory response, oxidative stress response, cell cycle regulation and synaptic transmission (14,15,16), tumorigenic pathways (17) and including binding to the viral spike (S-) protein of SARS-CoV-2 (18). There have been contrasting reports regarding the distribution of withaferin A. While most state that the roots of ashwagandha have the highest concentrations, others have indicated that leaves can accumulate withaferin A in proportionately higher amounts (19). However, there are few indications of any safety issues here and withaferin A is still generally regarded as a beneficial constituent of ashwagandha.
Withanone, structurally closely related to withaferin (20), on the other hand, has attracted some suspicion. It has multiple electrophilic groups, referred to as toxicophores or structural alerts, that are commonly associated with adverse drug reactions. Investigators found that withanone can form non-labile adducts, including with hepatocellular DNA. Withanone is detoxified by glutathione, but when this pathway is overwhelmed with excessive withanone intake, or glutathione is otherwise limited, DNA damage is more likely (21). Incidentally, this is a similar mechanism to the hepatotoxic effects of high doses of paracetamol (Tylenol) whose metabolite N-acetyl-p-benzoquinone imine (NAPQI) reduces liver glutathione levels. An obvious implication is that paracetamol could be contraindicated with withanone.
Generally, as expected for secondary metabolite levels, there is much variability in all ashwagandha constituents from batch to batch (22). However concentrations of withanone, withaferin A and withanolide A have been found appreciably higher in the leaves than in roots, with the root levels being almost undetectable in some samples (23).
It is worth noting that some of this evidence was cited in attempts to find plant parts that delivered higher levels of withanolides, these often considered to be the most effective parts of the ashwagandha plant (24,25,26). The use of ashwagandha leaves, and even their higher levels of withanone (27), have been promoted in the research literature for this reason.
However, the use of the leaf flies in the face of traditional use and official definitions of ashwagandha. It was bypassed in traditional medicine, in spite of it being the most plentiful part of the plant, and used only for
topical skin treatments. All pharmacopoeial monographs on ashwagandha, e.g. The Pharmacopoeia of India, US Pharmacopeia and British Pharmacopoeia, specify and describe the root only.
There are, however, additional economic reasons why leaf parts feature in ashwagandha materials: it is considerably cheaper than root (see below).
There is an interesting follow up to the three Iceland cases reported above. All involved consumption of the same US-manufactured supplement, including the only case rated as ‘definite’. My colleague Professor Kerry Bone purchased a sample of this supplement and initiated analysis using the relevant USP (United States Pharmacopeia) method. On this basis the product was found to contain a high percentage of ashwagandha leaf, despite the label claiming only root as the plant part (28).
Hepatoprotective effects of ashwagandha?
Ironically, ashwagandha has a reputation as a rasayana for helping with many causes of chronic illness and depletion, including liver disease. This may even have accounted for the Ayurvedic practitioner prescriptions above where the patients had chronic liver disease, though then sadly died.
There is some limited evidence for benefit. Several studies have evaluated the anti-inflammatory and hepatoprotective potential of ashwagandha in animal models of hepatic disorders (29), albeit in unrealistically high doses, and over the short term. Withaferin A has been the subject of particular focus here demonstrating a theoretical capacity to manage hepatic consequences in models of alcohol poisoning, non-alcoholic fatty liver disease, metabolic syndrome and diabetes and cancer (30).
More broadly, ashwagandha has had few safety concerns in the past (31). Overwhelmingly, the medical literature still reflects a consensus that ashwagandha is safe. It does seem that any links to liver injury are uncommon exceptions to the safety record.
Wider implications
These data emerged from scrutinising the records of three hospitals. India has up to 70,000 public and private hospitals (32), so the unreported incidence rates in India alone could be very significant. Both these reports and those from Iceland and the DILIN arose when researchers with an interest in drug-induced liver injury looked for connections, and it appears they have mainly done this since 2016. The India paper follows others by these authors looking for links between herbal products and liver injury. Nevertheless, we can assume more cases will follow and there is a risk of tighter regulatory action.
Already there are restrictive moves in some European member states, quite unrelated to any questions of liver harm. In 2020, the Technical University of Denmark (DTU) Food Institute carried out a risk assessment of ashwagandha for the Danish Veterinary and Food Administration (DVFA or Fødevarestyrelsen in Danish) (33). Building on a previous negative assessment in 2008, DTU noted some studies that had shown harmful effects to thyroid and sexual function as a result of eating unspecified extracts of the root and extracts of other parts of the plant. In spite of concerted arguments to the contrary, DVFA concluded it could not establish a safe lower limit for intake for the root or extract of the root and, as a result, ashwagandha has been banned in Denmark. Other EU states have indicated that they have been influenced by the Danish decision. This regulatory pressure can be expected to increase as reports of liver injury are more widely cited.
More constructively, in October 2021 India’s Ministry of AYUSH released a statement that advised against the use of ashwagandha leaves in Ayurveda and products for therapeutic purposes. The ministry said this was because classical Ayurveda texts do not specify leaf use but that some of the existing OTC formulations sold in the markets contain ashwagandha leaves. AYUSH noted:
No substantial evidence and literature is available to endorse the efficacy of crude drug/extract of Withania somnifera leaves. Considering this, it would not be appropriate to consider the Withania somnifera leaves as ASU (Ayurveda, Siddha, Unani) medicine at this stage. Extensive studies are required to establish the safety and efficacy of leaves of Withania somnifera for different indications. Till then, the usage of leaves may not be considered for therapeutic purpose in ASU systems (34).
Very presciently in January 2019, before the latest spate of reports, the ABC-AHP-NCNPR Botanical Adulterants Prevention Program (BAPP) released a Botanical Adulterants Prevention Bulletin on ashwagandha (Withania somnifera) root and root extract (35). It listed as known adulterants ‘undisclosed non-root parts of W. somnifera, such as leaves, stem, and aerial parts of ashwagandha, which are rich in withaferin A as well as other withanolides.’
Mark Blumenthal, founder and executive director of the American Botanical Council (ABC) commented at the time:
The inappropriate and unethical practice of increasing the amount of withanolides in ashwagandha root powder and extract by adding undisclosed, lower-cost dry leaf material and/or its extracts has been confirmed. This type of adulteration will fool only those companies and laboratories that do not use adequate analytical efforts to properly test their ashwagandha materials.
As the BAPP report above also noted:
The motivation behind adulteration in commercial products is financial gain. Since ashwagandha has seen a steady increase in sales, there is more global demand for its roots. This has led to a considerable increase in costs of roots, compared to the lower-cost aerial parts, which, as noted above, also contain withanolides. Larger amounts of aerial parts can be collected in a comparatively short time, which then can be made into extracts at a fraction of the cost of producing root extracts and can be priced below the market rates of authentic root extracts while providing a substantial profit for the producer/seller. Accidental adulteration can happen at harvesting stage by the farmers as some may not be aware of differences in the constituents and the importance of using roots only rather than aerial parts. While cutting aerial parts during the root harvesting process, they may cut the roots too far above ground, leading to raw materials that contain a small portion of aerial parts.
So what is a prudent practitioner to do?
These new challenges to ashwagandha safety remind us that these are battles we have tended to lose. It has been difficult to prove safety in the cases of unpredictable liver injury. The consequences are not consistent nor usually close enough to the consumption of the herb for the connection to be made unless forensic examinations of reported cases are made by those with the tools and inclination to look. Since 2016, people have been alerted to look and this is unlikely to stop. To avoid further unwelcome restrictions on the use of one of our most popular remedies it will be useful to be proactive and show that we are taking responsible precautions to make the unusual problem vanishingly rare.
From the evidence we have seen above three measures should be reassuring. They are not too demanding or intrusive on everyday practice and if stated firmly enough when needed may defray further challenges to the use of ashwagandha.
We may assert that we
- ensure our supplies of ashwagandha are assured as root only, without added leaf, and otherwise we will avoid products marketed as high in withanolides;
- avoid prescribing ashwagandha in patients with chronic liver disease such as cirrhosis or liver cancer even when these otherwise fit the indications for this wonderful rasayana;
- avoid prescribing ashwagandha if the patient is taking frequent daily doses of paracetamol (Tylenol).
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