Mechanism of Action and Side Effects of Ashwagandha
Ashwagandha (Withania somnifera) primarily works as an adaptogen by modulating the hypothalamic-pituitary-adrenal (HPA) axis, which explains its effectiveness in reducing stress and anxiety symptoms.
Mechanism of Action
Primary Mechanisms
- HPA Axis Modulation: Ashwagandha significantly reduces morning cortisol levels and regulates DHEA-S, demonstrating its ability to moderate stress responses through the HPA axis 1
- GABA-mimetic Activity: Acts as a sedative agent by inhibiting γ-aminobutyric acid (GABA) metabolism, similar to how valerian root functions 2
- Adaptogenic Properties: Helps the body maintain homeostasis during stress by normalizing physiological functions disturbed by chronic stress 3
Secondary Mechanisms
- Hormonal Effects:
- Autonomic Nervous System Regulation: Increases heart rate variability, indicating improved autonomic nervous system function 4
- Anti-inflammatory Actions: Similar to other adaptogens, may reduce inflammation associated with stress responses 3
Clinical Effects
Stress and Anxiety Reduction
- Multiple randomized controlled trials show significant reductions in stress as measured by the Perceived Stress Scale (PSS) compared to placebo 5
- Improves scores on the Hamilton Anxiety Scale (HAS) 5
- Reduces subjective and objective measures of stress 6
Sleep Improvement
- Significantly improves Pittsburgh Sleep Quality Index (PSQI) scores 6
- May help with insomnia through its sedative properties 2
Fatigue Reduction
- Demonstrates significant anti-fatigue effects as measured by the Chalder Fatigue Scale 4
Side Effects and Safety Concerns
Common Side Effects
- Mild gastrointestinal symptoms
- Drowsiness and sedation
- Headache
- Dizziness or confusion
Drug Interactions
- Anesthesia Interactions: May enhance the sedative properties of certain anesthetics by affecting the cytochrome P-450 pathway 2
- Benzodiazepine Potentiation: May potentiate the effects of benzodiazepines and barbiturates due to its GABA-mimetic properties 2
- Sedative Medications: Caution when combining with other sedative agents due to additive effects 2
Special Populations
- Perioperative Use: Recommended to discontinue ashwagandha perioperatively due to potential interactions with anesthetics 2
- Pregnancy and Breastfeeding: Insufficient safety data; caution is advised
Dosing Considerations
- Effective doses in clinical studies range from 125mg to 600mg daily of standardized extract
- Most recent studies show efficacy with 125mg daily of extract standardized to 1.5% withanolides 6
- Higher doses (240mg daily) have shown significant effects on stress biomarkers 1
Clinical Recommendations
When considering ashwagandha for stress or anxiety:
- Start with lower doses (125mg daily) of standardized extract
- Monitor for sedative effects, especially when combined with other medications
- Discontinue at least 2 weeks before surgical procedures
- Use caution when prescribing to patients on medications metabolized by CYP450 enzymes
Unlike St. John's wort, ashwagandha does not appear to have significant interactions with oral contraceptives, anticoagulants, or immunosuppressants 7, but caution is still warranted due to limited long-term safety data.