Accurate Education – Ashwagandha

Ashwagandha (Withania somnifera (L.) Dunal) is a small shrub that grows in dry regions of South Asia, Central Asia, and Africa. It has been used as an herbal medicine for centuries in Ayurveda, an ancient Hindu system of medicine. Over 50 chemical constituents have been identified in the various parts of the ashwagandha plant, including various compounds and flavonoids that have antioxidant activity.

Ayurveda

Ayurveda, the traditional medical system of India, recognizes doshas, or functional principles. It is the combination of the doshas characteristics based on a five-element philosophy that drives mental and physical well-being. When the doshas are out of balance in quality or quantity, well-being is impaired and symptoms occur. Research suggests that some of the diagnoses established in Ayurveda overlap in many ways with western medical diagnoses, particularly related to anxiety and stress. As such, traditional Ayurveda treatment may offer benefit in the management of anxiety and stress.

In Ayurveda, disharmony among the doshas are managed by dietary and lifestyle interventions, including herbs, diet, massage, meditation, and yoga, paralleling contemporary western integrative medical management of anxiety and stress. Herbal treatments with Ashwagandha are frequently used to treat conditions associated with stress and anxiety in Ayurveda.

The History of Ashwagandha Use

Ashwagandha has been used for many different conditions  for centuries, but nevertheless there is still only limited research available for high-level evidence regarding its therapeutic benefits. Following this review that provides historic context for the use of Ashwagandha, there is an in-depth review of current scientific literature,

There is a great deal of experience with centuries of use in Ayurvedic medicine that has sparked a great deal of western interest in the potential benefits of Ashwagandha. Historically, it has been used for anxiety, stress, bipolar disorder, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), trouble sleeping, arthritis, back pain, fibromyalgia, hiccups, asthma, bronchitis, and Parkinson’s disease. Chronic treatment with Ashwagandha extract in animal studies has been suggested to reduce the development of tolerance to morphine.

Ashwagandha has also been reported to improve mental well-being and eating behaviors through its adaptogenic properties along with maintaining a normal hormone balance in conditions of stress. It has been reported to maintain an adequate range of testosterone, enhance cognitive abilities in people with mild cognitive impairment, and boost cardiorespiratory endurance.

Adaptogens and Stress Management

Adaptogens exert anti-fatigue effects that increase mental work capacity against a background of stress and fatigue by increasing tolerance to mental exhaustion and enhanced attention. They reduce stress-induced impairments related to the neuro-endocrine and immune systems. The adaptogen Ashwagandha is believed to exert its stress-protective effects primarily by regulating homeostasis via several mechanisms of action associated with the hypothalamic pituitary adrenal (HPA) axis.

Adaptogens also work by modulating key mediators of the stress response, such as cortisol, nitric oxide (NO), and molecular “chaperones” by regulating as many as 88 genes associated with adaptive stress response pathways. Adaptogens activate cellular adaptive systems by inducing the expression of genes, including those that encode neurohormones and neurotransmitters.  These adaptogen-activated cellular pathways may impact neuroinflammation and neuropathic pain as well as stress-induced aging-related disorders including chronic inflammation, cardiovascular diseases, neurodegenerative cognitive impairment and diabetes.

Because stress is known to impair the immune system,  by stabilizing the stress response it is believed that adaptogens strengthen the immune system during times of high stress. While a review of the pharmacologic basis for adaptogen’s activity is beyond the scope of this review, the reader may turn to:

Effects of Adaptogens on the Central Nervous System and the Molecular Mechanisms Associated with Their Stress—Protective Activity – 2010. 

Other botanicals commonly believed to be adaptogens include Siberian Ginseng (Eleutherococcus senticosus), Schisandra berry (Schisandra chinensis), licorice root, Rhodiola rosea and Bacopa.

2. Therapeutic benefits associated with Ashwagandha

Ashwagandha offers multiple therapeutic benefits across different organ systems. It is best known as an adaptogen, which focuses on the following benefits.

(2) Anxiety & Sleep

Although limited, research supports the benefit of Ashwagandha for the management of anxiety and insomnia. Positive anxiolytic effects of Ashwagandha in adults with generalized anxiety disorder have been identified in clinical studies.  Pharmacological studies have confirmed that Ashwagandha has anxiolytic and sleep-inducing properties. Most of the clinical studies on the anxiety benefits of Ashwagandha have been conducted in India so the impact of diet, economic conditions, and daily occupation may have had an influence on therapeutic outcomes as compared to western cultures.

A 2009 study performed in Canada compared a Naturopathic anxiety treatment regimen consisting of Ashwagandha (300 mg twice a day), dietary counseling, deep breathing relaxation techniques and a standard multi-vitamin versus a traditional psychotherapy model consisting of psychotherapy and matched deep breathing relaxation techniques, and placebo. The Naturopathic model proved to be safe and effective with superior benefit over standardized psychotherapy in the treatment of mild to severe generalized anxiety.

(4) Depression

• Summary – Evidncce:
  1. Ashwagandha improves depression scores by 77–79.2% (300–600 mg/day, 60 days) through serotonin and GABA modulation, enhancing mood in stressed or chronic pain patients [1, 7, 9].
  2. It reduces depressive symptoms in healthy and psychiatric populations, with RCTs showing significant reductions in Depression, Anxiety, and Stress Scale (DASS) scores.
  3. Its adaptogenic effects stabilize mood without sedation, making it a safe adjunct for pain-related depression.
  4. Systematic reviews confirm its efficacy, particularly in stress-induced depression, supporting its use in holistic pain management.
• Preclinical Evidence (Lab & Animal Studies):
  1. Reduces depressive-like behaviors in rodents via monoamine enhancement [3, 10].
• Clinical Evidence (Human Studies):
  1. RCTs (n=60, 60 days) show 600 mg/day KSM-66 reduces DASS scores by 77–79.2% [1, 7].
  2. A meta-analysis (9 RCTs) confirms mood improvements in stressed adults, with benefits comparable to antidepressants in some cases [9].
  3. Gannon et al. (2019) report reduced depression in schizophrenia patients (1,000 mg/day) [21].
  4. Effects are dose-dependent and consistent across populations 
• Level of Confidence: High
  1. Consistent RCTs; more depression-specific studies needed [9].

(5) Fatigue

(including combating fatigue, increasing stamina, and improving physical performance)

• Summary – Evidncce:
  1. Ashwagandha reduces fatigue and enhances energy and stamina, with 69% improvement in mood and perceived energy outcomes (240–1,250 mg/day), via cortisol reduction and mitochondrial support, critical for pain-related fatigue [3, 6, 10, 18].
  2. Ashwagandha improves physical performance in healthy and stressed adults, supporting endurance and recovery.
  3. RCTs show dose-dependent effects, with benefits most pronounced in stressed populations. Its adaptogenic properties enhance cellular energy production, reducing fatigue-driven pain exacerbation.
  4. Ashwagandha’s non-stimulant nature makes it suitable for chronic pain patients seeking sustained energy without jitters.
• Preclinical Evidence (Lab & Animal Studies):
  1. Increases endurance and reduces fatigue in rodents through antioxidant and HPA axis effects [3, 10].
• Clinical Evidence (Human Studies):
  1. RCTs (240–1,250 mg/day, 2 weeks–6 months) show 69% improvement in mood/energy outcomes [3, 6].
  2. Sandhu et al. (2010) report enhanced cardiorespiratory endurance in young adults (500 mg/day) [18].
  3. A scoping review confirms anti-fatigue effects via stress-response gene regulation [6].
  4. Benefits are consistent in stressed populations, supporting its role in pain-related fatigue management.
• Level of Confidence: Moderate. 
  1. RCTs support efficacy, but pain-specific fatigue data are limited [3, 6].

6. Ashwagandha’s Role in:

Pain and Pain-Related Conditions

There is little direct evidence for benefits for pain with ashwagandha although patient reports do mention pain benefits. Based on the mechanisms of action demonstrated for ashwagandha, however speculation does suggest the potential for benefits for pain, but these speculations will require definitive RCTs for further evaluation. Of note however, given the evidence for the therapeutic benefit of ashwagandha on oxidative stress and systemic information. it would be easier to speculate the potential benefits towards pain by reducing these driving forces behind chronic pain.

Pain Conditions

• Inflammatory Conditions: Limited direct evidence for osteoarthritis, rheumatoid arthritis, Crohn’s disease, or ulcerative colitis. Anti-inflammatory effects (15–25% reductions in CRP/IL-6) suggest potential benefits for inflammatory pain, but specific RCTs are needed to confirm efficacy [3, 6, 10].
• Neuropathic Pain Conditions: No studies on diabetic neuropathy, chemotherapy-induced neuropathy, sciatica, or multiple sclerosis. Neuroprotective effects (e.g., BDNF upregulation) are speculative for neuropathic pain relief [6, 23].
• Migraine Headaches: No data on migraine frequency, severity, or duration. Anxiolytic effects may reduce tension-related triggers, but this is speculative and requires further research [7, 9].
• Fibromyalgia (FM): Fibromyalgia is a chronic disorder characterized by widespread musculoskeletal pain, fatigue, sleep disturbances, and cognitive issues. Ashwagandha’s active compounds, including withanolides, modulate stress responses and improve sleep quality, which are key factors in FM management. Preclinical and preliminary clinical studies suggest benefits but evidence is limited, with most research focusing on stress, anxiety, and sleep rather than FM-specific pain. 
• Peripheral and Central Sensitization (Mechanisms amplifying chronic pain): No direct evidence. GABA and serotonergic modulation may theoretically reduce neural excitability, potentially mitigating pain sensitization, but studies are lacking [7, 10].

7. Other Conditions: 

• Neurodegenerative Diseases:
  1. Multiple Sclerosis: No direct evidence. Anti-inflammatory and neuroprotective effects suggest potential, but no RCTs confirm efficacy [3, 6, 23].
  2. Alzheimer’s: No human RCTs. Preclinical studies show BDNF enhancement and amyloid-β reduction, implying cognitive benefits, but human data are speculative [3, 6, 23].
  3. Parkinson’s: No studies. Vasomodulation from related adaptogens (e.g., Ginkgo biloba) suggests theoretical benefits, but evidence is absent [23].

• Immune System Modulation (innate and adaptive immunity):
  1. Ashwagandha’s moderate anti-inflammatory effects (15–25% cytokine reduction) enhance immune function by mitigating stress-induced immunosuppression, supporting overall health in chronic pain patients [3, 10].
• Hormonal Imbalance:

• 1. Stress Response: Reduces cortisol by 27.9–44%, stabilizing HPA axis activity, critical for stress management in chronic pain [1, 3, 7, 10].
  2. Sex Hormones: Increases testosterone and luteinizing hormone in males, supporting hormonal balance and vitality [3, 14].

• Physical Performance, Endurance, and Recovery:
  1. RCTs (240–1,250 mg/day) show improved stamina and reduced fatigue, enhancing physical performance in stressed adults, beneficial for pain-related activity limitations [3, 18].
• Gut Health:
  1. No direct studies. Theoretical anti-inflammatory benefits may support gut barrier function or dysbiosis, but evidence is lacking [3].
• Metabolic Health:
  1. RCTs demonstrate improved insulin sensitivity and fasting glucose, reducing diabetes risk in stressed populations [3].
• Cardiovascular Health:
  1. Reduces blood pressure and LDL cholesterol, supporting cardiovascular health in stressed individuals [3].
•  Other Pertinent Relevant Conditions (e.g., cancer prevention): 
  1. No direct evidence for cancer prevention. Antioxidant properties (e.g., reduced ROS) are speculative for oncoprotection [3].

8. Recommended Dosing

1. Dietary Sources: Rare in foods. Ayurvedic teas or powders (1–2 tsp/day) have variable withanolide content, less reliable for therapeutic dosing [3, 9]. In general, dosing for therapeutic benefit should not rely on dietary intake due to the poor bio availability.
2. Supplements:

   The recommended daily dosing of withanolides (the primary active compounds in ashwagandha) varies based on the standardization of the extract and the intended use (e.g., stress reduction, sleep, or general wellness). Most supplements are standardized to 2.5%–10% withanolides, and evidence-based recommendations from reliable sources like NIH, Mayo Clinic, and Examine.com suggest the following:

   • Standard Dose: 7.5–30 mg of withanolides per day. This is typically achieved with 300–600 mg of ashwagandha root extract standardized to 2.5%–5% withanolides (e.g., 300 mg at 5% = 15 mg withanolides).
   • Higher Dose: Up to 50–100 mg per day for more intensive support, from 500–1,000 mg of extract standardized to 5%–10% withanolides, though this is less common and should be monitored for side effects.
   • Minimum Effective: At least 6 mg per day (per Mayo Clinic guidelines for safety and potential benefits).

   Start with lower doses (e.g., 7.5–15 mg withanolides) and consult a doctor, especially if combining with medications, as ashwagandha may interact with thyroid drugs or sedatives.  Current evidence is preliminary; long-term use (>12 weeks) lacks robust data. It has been suggested also that one cycle their dosing with intermittent breaks off the supplement:

   1. Cycling: 8 weeks on, 2 weeks off to prevent potential tolerance, based on expert recommendations [24].

Some authorities recommend dosing based on therapeutic goals:

1. 1. Suggested dosing:
      1. Stress/Anxiety/Sleep: 300–600 mg/day standardized extracts (e.g., KSM-66, ≥5% withanolides), taken twice daily with food; evening doses enhance sleep benefits [1, 2, 4, 5, 7, 9, 11].
      2. Cognitive Function: 120–1,000 mg/day, split doses, for 2–16 weeks [6, 13].
      3. General Use: 240–1,250 mg/day for 2 weeks–6 months, depending on condition [3, 18].
      4. Cycling: 8 weeks on, 2 weeks off to prevent potential tolerance, based on expert recommendations [24].

9. Ashwagandha Products

1. Suggested dosing:
   1. Stress/Anxiety/Sleep: 300–600 mg/day standardized extracts (e.g., KSM-66, ≥5% withanolides), taken twice daily with food; evening doses enhance sleep benefits [1, 2, 4, 5, 7, 9, 11].
   2. Cognitive Function: 120–1,000 mg/day, split doses, for 2–16 weeks [6, 13].
   3. General Use: 240–1,250 mg/day for 2 weeks–6 months, depending on condition [3, 18].
   4. Cycling: 8 weeks on, 2 weeks off to prevent potential tolerance, based on expert recommendations [24].

10. Bioavailability and Recommended Formulations

• Bioavailability: Moderate
  1. Enhanced by root-only extracts like KSM-66 (≥5% withanolides).
  2. Absorption is better on an empty stomach, but food reduces gastrointestinal side effects [3, 9].
• Formulations:
  1. Capsules: Preferred for standardized dosing (300–600 mg KSM-66), ensuring consistent withanolide content [3, 9].
  2. Powders: Effective if standardized, mixed with water or milk; less precise dosing [3].
  3. Liposomal/Nanoformulations: Limited data; may improve absorption but not widely studied [3, 16].
  4. Teas/Decoctions: Less standardized, with variable potency, less suitable for clinical use [3].
• Practical Tips:
  1. Choose root-only extracts (e.g., KSM-66) for consistency and safety
  2. Avoid heavy meals for optimal absorption. 
  3. Store in a cool, dry place.
  4. Cycle use (8 weeks on, 2 weeks off) to maintain efficacy [24].

11. Synergies

• Other Adaptogens:
  1. Ashwagandha + Rhodiola rosea: Enhances stress resilience and energy, reducing cortisol by ~30% through complementary HPA axis and sympatho-adrenal system (SAS) modulation, ideal for chronic pain patients [10, 24, 32]. RCTs suggest additive effects on stress and fatigue [24, 32].
  2. Ashwagandha + Bacopa monnieri: Amplifies cognitive and anxiolytic benefits via shared GABAergic pathways, improving memory and reducing anxiety [13, 25, 33]. Limited RCTs support synergy for stress-related cognitive deficits.
  3. Ashwagandha + Panax ginseng: Improves fatigue and energy by enhancing mitochondrial function and stress response [10, 25, 30]. Clinical data suggest complementary effects in stressed populations.
  4. Ashwagandha + Schisandra chinensis/Holy Basil: Reduces oxidative stress and inflammation, potentially synergistic for pain-related comorbidities [10, 30, 33]. Mechanistic overlaps suggest benefits, but RCTs are limited.
• Prescription & OTC Medications: No direct data on synergies with opioids or NSAIDs. May complement anxiolytics like gabapentin for anxiety-related pain, but monitor for CNS depression due to additive GABAergic effects [7, 9].
• Nutraceuticals: Synergies with chamomile (400–2,000 mg/day), green tea (200–800 mg/day L-theanine/EGCG), or dark chocolate (0.25–100 g/day flavanols) enhance sleep, mood, and cognition via complementary pathways [6, 23, 31].
• Cannabinoids: No studies; theoretical synergy with CBD for anxiolytic effects due to shared GABA pathways, potentially beneficial for pain-related anxiety [7].
• Terpenes: No data; potential synergy with linalool (e.g., lavender, 1–4 g/day) for relaxation, inferred from anxiolytic effects [6]. 
• Acupuncture: No studies; stress reduction may enhance acupuncture’s benefits for pain and anxiety, particularly in chronic pain patients [10].

 12. Safety: Side Effects and  Drug Interactions

Ashwagandha is generally considered safe when taken orally for short-term use, but the safety of long-term  use of Ashwagandha is not known. The studies have demonstrated only mild side effects including loss of appetite and sedation. Large doses of Ashwagandha might cause stomach upset, diarrhea, and vomiting. Ashwagandha may be sedating.

• Ashwagandha is safe at 300–1,250 mg/day for 3–6 months, with mild side effects (e.g., gastrointestinal upset, drowsiness) comparable to placebo in RCTs [1, 3, 4, 7, 9, 11, 18].
• No serious adverse events reported.
• Long-term safety data (>6 months) are limited;
• Cycling (8 weeks on, 2 weeks off) is recommended to prevent potential tolerance [24].
• Discontinue if rare signs of liver issues (e.g., yellowing skin, dark urine) or severe dizziness occur, and consult a physician [3, 16].

Contraindications include

1. 1. Solanaceae allergies (e.g., tomatoes, eggplants)
   2. pregnancy
   3. lactation
   4. autoimmune diseases (e.g., lupus) without medical guidance.

Drug Interactions

Monitor for interactions with CNS depressants (e.g., sedatives), thyroid medications, or blood thinners due to potential synergistic effects [3, 9, 11]:

Immunosuppressants

Because Ashwagandha may increase the immune response, taking Ashwagandha with medications purposed to decrease the immune system might decrease the effectiveness of these medications. Medications are used to suppress the immune system in conditions such as auto-immune disorders, rheumatoid arthritis, lupus, psoriasis and cancer. Commonly used immune suppressants include azathioprine (Imuran), basiliximab (Simulect), cyclosporine (Neoral, Sandimmune), daclizumab (Zenapax), muromonab-CD3 (OKT3, Orthoclone OKT3), mycophenolate (CellCept), tacrolimus (FK506, Prograf), sirolimus (Rapamune), prednisone (Deltasone, Orasone), corticosteroids (glucocorticoids), and others. Do not take Ashwagandha if you are prescribed any of these medications without discussing it with your prescribing physician.

Sedatives

Due to its sedative properties, Ashwagandha should be used with caution when also taking sedatives such as sleeping medicines, antidepressants and anxiolytic drugs like benzodiazepines.

Diabetic medications

There is preliminary evidence suggesting that Ashwagandha might lower blood glucose levels thus Ashwagandha might have additive effects when used with antidiabetes drugs and increase the risk of low sugar.

Thyroid hormones

Preliminary research suggests that Ashwagandha increases thyroid hormone synthesis and secretion. In one clinical study, Ashwagandha increased triiodothyronine (T3) and thyroxine (T4) levels by 41.5% and 19.6%, respectively, and reduced serum TSH levels by 17.4% from baseline. Combined use of Ashwagandha with thyroid hormones may cause additive therapeutic and adverse effects.

14. How Does Ashwangandha Work?