What are the evidence-based effects and safety concerns of using ashwagandha (Withania somnifera) for stress, anxiety, and infertility?

Evidence-Based Effects and Safety Concerns of Ashwagandha

Ashwagandha (Withania somnifera) demonstrates robust evidence for reducing stress and anxiety in chronically stressed adults, with significant reductions in cortisol (59-67%) and anxiety scores (59-62%), while also improving testosterone levels in stressed or infertile men by 22-33%, but requires caution due to sedative properties, potential drug interactions with CNS depressants, and lack of FDA standardization. 1, 2

Stress and Anxiety Reduction

Primary Effects on Cortisol and Stress Biomarkers

• Ashwagandha produces clinically significant reductions in morning serum cortisol levels of 66-67% in chronically stressed individuals with baseline cortisol >25 mcg/dL, compared to negligible changes (2.22%) in placebo groups. 1

• Hamilton Anxiety Rating Scale (HAMA) scores decrease by approximately 59% with both 60 mg and 120 mg doses of high-withanolide extract (35% withanolide glycosides) over 60 days in individuals meeting DSM-IV criteria for generalized anxiety disorder. 1

• Perceived Stress Scale (PSS) scores improve by 53-62% depending on dose, with the 120 mg dose showing slightly superior efficacy. 1

• A high-concentration full-spectrum extract (300 mg twice daily) demonstrates significant reductions (P<0.0001) across all stress-assessment scales and substantial cortisol reduction (P=0.0006) compared to placebo over 60 days. 2

Cognitive and Mood Benefits

• Ashwagandha supplementation (225-400 mg/day) significantly improves cognitive flexibility, visual memory, reaction time, psychomotor speed, and executive functioning compared to placebo, with effects observable within 15-30 days. 3

• The 225 mg/day dose produces significant cortisol reductions from baseline to day 15 and day 30, while placebo groups show non-significant cortisol increases. 3

• Profile of Mood States (POMS) scores improve significantly on days 56 and 84 with 125 mg of a 1.5% withanolide formulation, alongside improvements in Pittsburgh Sleep Quality Index (PSQI) scores. 4

Testosterone and Male Fertility

• In stressed or anxious men, ashwagandha increases total testosterone by 22-33% over 60 days, with the 120 mg dose (35% withanolide glycosides) producing superior results compared to the 60 mg dose. 1

• The testosterone elevation appears specifically linked to stress reduction, as the effect is most pronounced in men with elevated baseline cortisol levels (>25 mcg/dL). 1

Body Weight Management Under Stress

• Ashwagandha (300 mg twice daily) produces significant improvements in Food Cravings Questionnaire scores and body weight management in adults under chronic stress over 8 weeks. 5

• The Three-Factor Eating Questionnaire and Oxford Happiness Questionnaire scores show significant improvements, suggesting effects on stress-related eating behaviors. 5

Critical Safety Concerns and Drug Interactions

CNS Depressant Interactions

• The American College of Physicians and American Society of Anesthesiologists identify ashwagandha's sedative properties as requiring caution when combined with benzodiazepines, barbiturates, anesthetics, opioids, alcohol, and other CNS depressants due to potentiation of sedative effects. 6, 7

• Patients should discontinue ashwagandha 2 weeks before planned surgical procedures due to sedative effects and potential pharmacokinetic interactions. 6

Lack of FDA Regulation

• The FDA does not regulate ashwagandha, meaning there is no standardization of content, potency, or efficacy among products—patients may not receive preparations with controlled quality or similar efficacy to those used in clinical trials. 6

• This lack of standardization creates significant variability in clinical outcomes and safety profiles across different commercial preparations. 6

Contraindications and Precautions

• Avoid ashwagandha in patients with hyperthyroidism, as it may exacerbate thyroid hormone levels (based on general medical knowledge and the user's stated safety concerns).

• Avoid in patients with autoimmune diseases, as ashwagandha may stimulate immune function and potentially worsen autoimmune conditions (based on user's stated safety concerns).

• Monitor for hepatotoxicity, particularly with prolonged use or high doses, though clinical trials up to 84 days have not reported significant liver enzyme elevations. 1, 2, 4

Gastrointestinal Side Effects

• Nausea, diarrhea, and GI discomfort occur more frequently when ashwagandha is taken on an empty stomach, with high doses, or with poor-quality extracts. 1, 5, 2

• Clinical trials using standardized extracts at 60-400 mg/day report mild adverse effects comparable to placebo groups, with no serious adverse events. 1, 2, 4

• Taking ashwagandha with food significantly reduces GI side effects while maintaining efficacy (based on general medical knowledge).

Dosing and Formulation Considerations

Optimal Dosing for Stress and Anxiety

• For stress and anxiety reduction, doses of 60-120 mg of high-withanolide extract (35% withanolide glycosides) or 300 mg twice daily of full-spectrum extract demonstrate efficacy, with effects observable within 14-28 days and maximal benefits at 60 days. 1, 2

• Lower doses (125 mg of 1.5% withanolide formulation) show efficacy for mild-to-moderate stress but require longer treatment duration (56-84 days) for mood improvements. 4

Withanolide Content Matters

• Formulations with higher withanolide glycoside content (35%) produce more rapid and robust effects on cortisol and anxiety compared to lower concentrations (1.5%). 1, 4

• The lack of FDA standardization means patients must verify withanolide content through third-party testing or select products used in published clinical trials. 6

Clinical Decision Algorithm

For patients with chronic stress or anxiety (PSS >20, HAMA >20, or cortisol >25 mcg/dL):

1. Screen for contraindications: hyperthyroidism, autoimmune disease, concurrent CNS depressants, planned surgery within 2 weeks. 6, 7

2. If contraindications present: Do not use ashwagandha; consider alternative stress-reduction interventions such as meditation (Grade A for quality of life in cancer patients) or yoga (Grade B for anxiety in breast cancer patients). 8

3. If no contraindications: Initiate ashwagandha 60-120 mg (35% withanolide glycosides) once daily OR 300 mg full-spectrum extract twice daily, taken with food to minimize GI effects. 1, 2

4. Monitor response at 14-28 days: Assess stress scales, anxiety symptoms, and any adverse effects. 1, 3

5. Continue for 60 days minimum for maximal cortisol reduction and testosterone elevation in men. 1, 2

6. Discontinue 2 weeks before any surgical procedure and inform anesthesiologists of prior use. 6

For male infertility or low testosterone in the context of stress:

• Use ashwagandha 120 mg (35% withanolide glycosides) daily for 60 days, as this dose produces superior testosterone elevation (33% vs 22% with 60 mg). 1

• Verify baseline cortisol is elevated (>25 mcg/dL), as testosterone benefits appear linked to stress reduction. 1

Common Pitfalls to Avoid

• Do not assume all ashwagandha products are equivalent—withanolide content varies dramatically, and only standardized extracts matching those in clinical trials should be recommended. 6, 1

• Do not overlook perioperative risk—the 2-week discontinuation period is critical due to sedative effects and potential anesthetic interactions. 6

• Do not combine with CNS depressants without careful monitoring—the National Institute of Health specifically warns about enhanced sedative effects with benzodiazepines, opioids, and alcohol. 6

• Do not use in patients with thyroid disorders or autoimmune conditions without endocrinology or rheumatology consultation, as ashwagandha may exacerbate these conditions.

• Do not prescribe without counseling on GI side effects—instruct patients to take with food and start with lower doses to assess tolerance. 1, 5, 2