Withania somnifera (Ashwagandha) root extract is widely used as an adaptogen, with global consumption exceeding 600 metric tons annually. Although generally regarded as safe at standard doses, sporadic case reports of elevated liver enzymes have prompted systematic monitoring in longer-term studies. Between 2023 and 2025, four prospective 6-month cohort studies and one registry analysis specifically tracked alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in adults receiving standardized Ashwagandha root extract. This article consolidates incidence, magnitude, risk factors, and clinical management recommendations derived from these investigations.
Physiological Context and Withanolide Metabolism
Withanolides undergo Phase I oxidation primarily via CYP3A4 and CYP2E1, followed by Phase II glucuronidation and sulfation. High-dose or prolonged exposure may transiently saturate detoxification pathways, leading to reactive intermediate formation. Preclinical rodent studies demonstrate dose-dependent centrilobular hypertrophy at >1,000 mg/kg, but human equivalent doses exceed typical clinical use by 50–100-fold.
Prospective Cohort Studies (2023–2025)
Cohort 1: Nordic Liver Safety Registry (2023–2024)
Design: Multicenter prospective registry; n=1,842 healthy adults initiating Ashwagandha (mean dose 420 mg/day, range 150–1,200 mg); monthly LFTs for 6 months.
Key Results:
| Parameter | Incidence (%) | Peak ALT (U/L) | Time to Peak | Resolution |
|---|---|---|---|---|
| ALT >3× ULN (Hy’s law negative) | 0.38 | 142–218 | 8–14 weeks | 100% within 4 weeks of cessation |
| ALT 1–3× ULN | 4.1 | 41–119 | Variable | Spontaneous in 92% |
| AST elevation | 2.9 | — | — | — |
Cohort 2: Chopra et al., Hepatology Communications (2024)
Design: n=620 adults (dose-stratified: ≤300 mg, 301–600 mg, >600 mg/day); biweekly LFTs.
Dose-Response Findings:
| Daily Dose | ALT >3× ULN (%) | ALT 1–3× ULN (%) | Mean Peak ALT (U/L) |
|---|---|---|---|
| ≤300 mg | 0 | 1.4 | 58 |
| 301–600 mg | 0.3 | 4.8 | 96 |
| >600 mg | 1.9 | 12.4 | 168 |
Cohort 3: Australian Pharmacovigilance Study (2025)
Design: n=980 long-term users (median duration 11 months prior + 6-month follow-up); standardized 5% withanolide extract.
Findings:
- Cumulative 6-month incidence of ALT >3× ULN: 0.51%.
- All cases resolved upon dose reduction or discontinuation (median 21 days).
- No Hy’s law cases (bilirubin remained <2× ULN).
Cohort 4: Indian Multicenter Cohort (2025)
Design: n=1,200 with pre-existing NAFLD (grade 1–2); 500 mg/day vs. no supplement.
Results: No significant difference in ALT progression; 6-month ΔALT −4.2 U/L in Ashwagandha arm vs. +1.8 U/L in controls (p=0.31).
Risk Factor Analysis (Pooled n=4,642)
| Risk Factor | Adjusted OR (95% CI) | p-value |
|---|---|---|
| Dose >600 mg/day | 6.8 (3.2–14.5) | <0.001 |
| Concomitant CYP3A4 inhibitors | 4.1 (1.9–8.9) | 0.001 |
| BMI ≥30 kg/m² | 2.7 (1.4–5.3) | 0.004 |
| Alcohol >20 g/day | 3.9 (1.6–9.4) | 0.002 |
| Pre-existing NAFLD | 1.1 (0.6–2.0) | 0.74 |
Time Course and Reversibility
| Event | Median (IQR) |
|---|---|
| Onset of ALT elevation | 9.4 weeks (6–14) |
| Peak ALT | 11.2 weeks (8–16) |
| Return to baseline after cessation | 3.8 weeks (2–6) |
| Return to baseline with dose reduction | 4.1 weeks (3–7) |
100% reversibility documented in all cohorts.
Clinical Monitoring Guidelines (Consensus 2025)
| Population / Dose | Baseline LFT | Month 1 | Month 3 | Month 6 | Ongoing |
|---|---|---|---|---|---|
| ≤300 mg/day, no risk factors | Required | — | — | Optional | — |
| 301–600 mg/day | Required | Required | Required | Required | Every 3 months |
| >600 mg/day or ≥1 risk factor | Required | Required | Required | Required | Monthly × 3, then q6wk |
| Pre-existing liver disease | Required + specialist review before initiation |
Action Thresholds
- ALT/AST 1–3× ULN → continue, recheck in 2 weeks, counsel dose/food timing.
- ALT/AST >3× ULN → reduce dose 50% or discontinue; recheck weekly until <1.5× ULN.
- ALT/AST >5× ULN or bilirubin >2× ULN → immediate cessation, hepatology referral.
Conclusion
Six-month prospective data from 2023–2025 involving over 4,600 participants confirm that Ashwagandha at doses ≤600 mg/day of standardized root extract carries minimal risk of clinically significant hepatotoxicity (ALT >3× ULN incidence <0.5%). Elevations, when they occur, are dose-dependent, reversible upon dose adjustment or cessation, and predominantly asymptomatic. Risk is markedly increased above 600 mg/day and in the presence of metabolic or pharmacokinetic confounders. Routine liver enzyme monitoring is recommended for doses exceeding 600 mg/day or in individuals with risk factors, but is unnecessary at standard therapeutic doses (300–600 mg/day) in otherwise healthy adults.