Insight on toxicity mechanisms of <i>Datura metel</i> L. seeds: a 28-day repeated dose study, <i>in-silico</i> studies, and effect of <i>Shodhana</i> a traditional detoxification method

<i>Datura metel</i> L., a poisonous medicinal plant is used safely after <i>Shodhana</i> in Ayurveda. It is listed in Schedule E1 of Drugs and Cosmetics Act, as a poisonous medicinal plant to be used with caution. Although known for its toxic effects and reduction of toxicity by <i>Shodhana</i>. However, the toxicity mechanism, effect of <i>Shodhana,</i> and toxicity profile after repeated dosing are missing. <i>Shodhita</i> and <i>Ashodhita Datura metel</i> seeds were subjected to extraction using 70% ethanol and phytochemicals analyzed by LC-MS. Acute and 28-day repeated-dose toxicity studies were conducted as per OECD 423 and OECD 407. Network pharmacology, molecular docking, and dynamics were used to predict the potential multicomponent multitarget interactions and toxicity mechanisms. <i>Ashodhita D. metel</i> exhibited toxicity viz., neurotoxicity and hepatotoxicity, characterized by weight loss, altered organ weights, disrupted hematological, biochemical, behavioral and histological abnormalities. On the contrary, <i>Shodhita D. metel</i> was found safe with NOAEL 100 mg/kg. Whereas it was found to be 25 mg/kg for <i>Ashodhita D. metel</i>. Atropine and Scopolamine are predicted to disrupt cholinergic function and cause inflammation mediated through NFK-β1 and MAPK-1, altering neurotrophin, cAMP, PI3K-AKT, NOD-like receptor, AGE-RAGE, and IL-17 pathways. Atropine and scopolamine major toxic chemicals of <i>D. metel</i> were predicted to disrupt cholinergic function and induce inflammation, potentially mediated through NFK-β1 and MAPK-1 pathways. The <i>Shodhana</i> purification process was found to be effective in mitigating toxicity.