Ashwagandha | Supplementopedia

Overview

Ashwagandha (Withania somnifera) is a perennial, adaptogenic herb native to the Indian subcontinent and parts of the Middle East.

Its roots and berries contain a complex mixture of steroidal lactones (withanolides) and other phytochemicals.
These compounds modulate stress-responsive pathways.
Ashwagandha is a widely studied natural supplement for supporting physiological resilience and overall well-being.

Stress & anxiety reduction: Randomized, double-blind trials show 300–600 mg of standardized extract (≥5 % withanolides) can lower the Perceived Stress Scale score by 6–8 % versus placebo (e.g., Chandrasekhar et al., 2012).
Cognitive function: Meta-analyses of three trials (n≈210) report modest improvements in reaction time and working memory, particularly in younger adults.
Sleep quality: 8-week supplementation (600 mg) improved Pittsburgh Sleep Quality Index scores by ~1.5 points in adults with insomnia.
Physical performance: 12-week trials in resistance-trained men reported a 5–7 % increase in bench-press strength and a 10 % rise in VO₂max at 500 mg/day.
Metabolic health: In pre-diabetic participants, 500 mg/day for 12 weeks lowered fasting glucose by 6 % and reduced serum cortisol by 15 % in a dose-responsive manner.
Anti-inflammatory/antioxidant: Clinical data reveal reductions in C-reactive protein (≈30 %) and oxidative markers (MDA) after 8 weeks, supporting systemic inflammation control.

Process: Ashwagandha's primary bioactive compounds are the withanolides, which resemble endogenous steroid hormones.
Pathway:
- They bind to glucocorticoid receptors, attenuating cortisol synthesis via inhibition of 11β-hydroxylase in the adrenal cortex.
- They modulate the hypothalamic-pituitary-adrenal (HPA) axis, reducing corticotropin-releasing hormone (CRH) release.
- Withanolides also activate the Nrf2-Keap1 pathway, up-regulating antioxidant enzymes (e.g., superoxide dismutase, glutathione peroxidase) and lowering reactive oxygen species.
- In the brain, they enhance GABA-A receptor activity and increase brain-derived neurotrophic factor (BDNF) expression, supporting neuroplasticity and anxiety reduction.
- Additionally, they inhibit NF-κB signaling, curbing pro-inflammatory cytokine production (IL-6, TNF-α).
The net effect is a coordinated reduction in stress hormones, enhanced antioxidant defenses, and improved neuronal signaling that underlie the observed clinical benefits.

Standardized extracts (≥5 % withanolides) are most commonly studied at 300–600 mg daily.
Dosing:
- Split into two 150–300 mg doses taken with meals to improve absorption.
- For stress-reduction, 300 mg twice daily for 8–12 weeks is typical.
- For athletic performance, 500 mg once daily (or 250 mg twice) has shown efficacy.
- In trials targeting glycemic control, 500–600 mg daily for 12 weeks produced measurable benefits.
When using a high-potency (≥10 % withanolides) product, the dose can be halved (e.g., 250 mg/day) with similar outcomes.
Pregnant or lactating women should avoid >200 mg/day and consult a health professional.
Cyclodextrin-based formulations may allow lower dosing due to enhanced bioavailability; however, safety data at higher concentrations (>1 g/day) remain limited.

Ashwagandha is generally well-tolerated.
Mild gastrointestinal upset (nausea, diarrhea) occurs in ≈5 % of users at ≥600 mg/day.
Rare cases of rash or increased thyroid hormone (especially in hyperthyroid patients) have been reported.
Contraindications include:
- (i) pregnancy (potential abortifacient effects at high doses)
- (ii) autoimmune disorders (potential immunomodulation)
- (iii) concurrent use of sedatives, benzodiazepines, or thyroid-stimulating medications due to additive effects.
Notable drug interactions:
- (a) cytochrome P450 3A4 substrates (e.g., midazolam, statins) may have altered metabolism
- (b) immunosuppressants (e.g., cyclosporine) may have reduced efficacy.
People with severe liver disease, uncontrolled hypertension, or scheduled for surgery should discontinue use at least 2 weeks before the procedure.
Continuous use beyond 6 months is not recommended without medical supervision.

The principal active constituents are withanolides, a group of C-28 steroidal lactones.
The prototypic compound, withaferin A, has the molecular formula C₂₈H₃₈O₆ and IUPAC name (5β,6β,7β,22R)-5,6-dihydro-22-hydroxy-2,3-dihydro-1-oxo-7,21-epoxy-5,6-dihydromeroterpenoid.
Its structure features:
- A C-28 ergostane skeleton with a lactone ring at C-22–C-26.
- An epoxide bridge at C-5–C-6.
Other withanolides (e.g., withanolide A, withanolide B) share a Δ²⁻³ double bond and a 7-acetyl group, conferring lipophilicity and membrane permeability.
The molecules are moderately stable (pKa ≈ 4.5 for the hydroxyl group) and soluble in organic solvents (ethanol, methanol) but poorly water-soluble.
This drives the use of carrier-based extracts (e.g., phosphatidylcholine complexes) to improve bioavailability.
Their molecular weight (~450 Da) falls within the range for passive diffusion across the intestinal epithelium when formulated appropriately.

Commercial Ashwagandra is primarily cultivated in India’s Rajasthan, Gujarat, and Madhya Pradesh regions.
Soil and climate conditions favor high withanolide content.
Sustainable cultivation uses organic farming practices to avoid pesticide residues that can affect extract purity.
Extraction methods:
- (i) ethanol-water (70 % ethanol) maceration, yielding a broad spectrum of withanolides
- (ii) super-critical CO₂ extraction, which produces a more selective, high-purity extract with reduced solvent residues.
Standardization to ≥5 % withanolides is mandated by major supplement bureaus (e.g., USP, NSF).
Reliable supplements undergo third-party testing for:
- Heavy metals (<10 ppb)
- Microbial contamination (<10³ CFU/g)
- Pesticide residues.
When selecting a product, look for:
- GMP-certified manufacturers
- Clear labeling of extract strength
- Independent certification (e.g., NSF-Certified for Sport).