Abstract / Summary
Saffron (Crocus sativus L.) and ashwagandha (Withania somnifera Dunal) are medicinal plants with emerging clinical evidence supporting their use for stress-related mental health conditions. This PRISMA 2020-compliant systematic review, prospectively registered with PROSPERO (CRD420261385134), synthesizes randomized controlled trial evidence for both plants across eight mental health outcomes, with the literature search updated to 31 August 2026. From 494 initial records, 452 remained after duplicate removal; 34 studies met eligibility criteria (19 saffron, 14 ashwagandha, 1 comprehensive review), comprising 31 randomized controlled trials. Saffron demonstrated efficacy for depression (10 randomized controlled trials [RCTs]), anxiety (9 RCTs), and sleep (8 RCTs) at 15-30 mg/day standardized extract. Ashwagandha showed efficacy for anxiety (10 RCTs), stress (8 RCTs), and sleep (3 RCTs) at 30-600 mg/day with a withanolide-standardized extract, with a pooled cortisol reduction of -3.27 µg/dL. Risk of bias was low in 10 of 31 trials and raised some concerns in most of the remainder, and GRADE certainty was moderate at best. Both plants exhibited favorable safety profiles, although ashwagandha-associated hepatotoxicity warrants liver enzyme monitoring during prolonged use. Critically, no RCTs exist for burnout or posttraumatic stress disorder in either plant, despite mechanistic evidence of hypothalamic-pituitary-adrenal axis normalization, reduced neuroinflammation, and monoaminergic and gamma-aminobutyric acid-ergic modulation; this evidence is predominantly preclinical and requires clinical confirmation. This systematic review identifies these conditions as priority targets for well-designed clinical trials. The bioactive constituents-crocin and safranal in saffron, and withanolides in ashwagandha-share overlapping mechanistic pathways highly relevant to these underserved, high-burden disorders.