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Withania somnifera  (L.) Dunal, popularly known as Ashwagandha or Indian ginseng, is well acclaimed for its health-enhancing effects, including its potent immunomodulatory, anti-inflammatory, neuroprotective, and anti-tumorigenic properties. The prime biological effectors of these attributes are a diverse group of ergostane-based steroidal lactones termed withanolides. Withanones and withanosides are distributed differentially across the plant body, whereas withanolides and withanones are known to be more abundant in leaves, while withanosides are found exclusively in the roots of the plants. Standardized  W. somnifera  extract is Generally Recognized as Safe (GRAS)-affirmed, however, moderate to severe toxic manifestations may occur at high dosages. Withaferin A, which also happens to be the primary bioactive ingredient for the effectiveness of this plant. There have been contrasting reports regarding the distribution of withaferin A in  W. somnifera . While most reports state that the roots of the plant have the highest concentrations of this phytochemical, several others have indicated that leaves can accumulate withaferin A in proportionately higher amounts. A comprehensive survey of the available reports suggests that the biological effects of Ashwagandha are grossly synergistic in nature, with many withanolides together mediating the desired physiological effect. In addition, an assorted formulation of withanolides can also neutralize the toxic effects (if any) associated with withaferin A. This mini-review presents a fresh take on the recent developments regarding the safety and toxicity of the plant, along with a critical assessment of the use of roots against leaves as well as whole plants to develop therapeutic formulations. Going by the currently available scientific evidence, it is safe to infer that the use of whole plant formulations instead of exclusively root or leaf recipes may present the best possible option for further exploration of therapeutic benefits from this novel medicinal plant.HighlightsTherapeutic potential of withanolides owes to the presence of α,β unsaturated ketone which binds to amines, alcohols, and esters and 5β, 6β epoxy group which react with side chain thiols of proteins.At concentrations above NOAEL (no observed adverse effect level), the same mechanisms contribute towards toxicity of the molecule.Although withanosides are found exclusively in roots, whole plants have higher contents of withanones and withanolides.Whole plant-based formulations have other metabolites which can nullify the toxicity associated with roots.Extracts made from whole plants, therefore can holistically impart all therapeutic benefits as well as mitigate toxicity. Therapeutic potential of withanolides owes to the presence of α,β unsaturated ketone which binds to amines, alcohols, and esters and 5β, 6β epoxy group which react with side chain thiols of proteins. At concentrations above NOAEL (no observed adverse effect level), the same mechanisms contribute towards toxicity of the molecule. Although withanosides are found exclusively in roots, whole plants have higher contents of withanones and withanolides. Whole plant-based formulations have other metabolites which can nullify the toxicity associated with roots. Extracts made from whole plants, therefore can holistically impart all therapeutic benefits as well as mitigate toxicity.

toxicology mechanisms and methods

A critical assessment of the whole plant-based phytotherapeutics from  Withania somnifera  (L.) Dunal with respect to safety and efficacy vis-a-vis leaf or root extract-based formulation