Ashwagandha

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ashwagandha

What is ashwagandha

Ashwagandha is botanically known as Withania somnifera Dunal, is a member of the Solanaceae family 1. Ashwagandha is commonly known as “Indian Winter cherry” or “Indian Ginseng” 2. This wild plant grows in dry and hot-semiarid climate such as southern Mediterranean region, Canary Islands, and northern Africa to northern India (Iran, Jordan, Sudan, Palestine, Afghanistan, and Egypt) 3. The small and greenish-yellow flowers can be single or in clusters. The fruit is smooth, round, and fleshy, with many seeds; it is orange-red when ripe and enclosed in a membranous covering 4. Different parts of this plant such as roots, leaves, flowers, seeds, stems, and fruits are used as remedy in traditional medicine of different countries 5, 6. Many phytochemicals have been extracted so far from Ashwagandha plant with possessing different pharmacologic and biological properties 7. Ashwagandha plant has been known to contain more than 80 types of phytochemicals such as steroidal and nonsteroidal alkaloids, steroidal lactones and saponins like isopelletierine, anaferin, anahygrine, hygrine, cuscohygrine, tropine, pseudotropine, withananine, ashwagandha, withaferins, withananinine, pseudowithanine, somnine, somniferine, somniferinine, 3-tropyltigloate, withanine, withasomine, visamine, mesoanaferine, sitoindoside (7–10), hentriacontane, amino acids such as aspartic acid, glycine, tryptophan, proline, alanine, tyrosine, hydroxyproline valine, cystine, glutamic acid, and cysteine, calcium, phosphorus, iron, flavonoids, starch, reducing sugars, proteolytic enzyme “chamase,” glycosides, dulcitol, and volatile oil. Of all these components, withaferin A and sitoindosides had the key role in Ashwagandha therapeutic effects 8, 9, 10.

The literal meaning of the word “Ashwagandha” is “smell of horse”. The ashwagandha herb is so named for two reasons. One reason is that the fresh roots of the herb emit the smell of horse. The second reason is that there is a commonly held belief that a person consuming extracts of the ashwagandha herb may develop the strength and vitality similar to that of a horse 11. Ashwagandha has a central and prominent place in Ayurvedic medicine (the traditional system of medicine in India). Ashwagandha is referred to as a “royal herb” because of its multifarious rejuvenative effects on the human body. Ashwagandha is a multipurpose herb that acts on various systems of the human body: the neurological system, the immune system, the energy-production system, the endocrinal system and the reproductive system 1.

Ashwagandha is the most commonly used and extensively studied adaptogen 12. Adaptogens are herbs that improve an individual’s ability to cope with stress. These herbs in times of increased stress, normalize the physiological process of the body and help the body adapt to changes 12. A recent definition of an adaptogen is, “a class of metabolic regulators which increase the ability of an organism to adapt to environmental factors and avoid damage from such factors.” Ideally, an adaptogen should: a) decrease stress-induced damage, b) be safe and produce a beneficial effect even if the number of administrations is more than required, c) be devoid of any negative effects such as withdrawal syndromes and d) not influence the normal body functions more than necessary 13. Ashwagandha is one adaptogen that possesses all of the characteristics listed above 1.

Ashwagandha has also been studied as antioxidant, anticancer, anxiolytic, antidepressant, cardioprotective, thyroid modulating, immunomodulating, antibacterial, antifungal, anti-inflammatory, neuroprotective, cognitive enhancing, hematopoietic agent, anti-hyperglycemic, neuropharmacological, immunomodulatory, cardioprotective, musculotropic, hepatoprotective, radiosensitizing, chemoprotective, anti-aging, macrophage-activating, diuretic, hypocholesterolemic, aphrodisiac and rejuvenating agent 14, 15, 16, 17, 18.

Ashwagandha leaves are used in the treatment of fever, tumors and ulcers 19. Medicinal importance of different parts of Ashwagandha is due to the presence of pharmaceutically active steroidal lactones withanolides including withanolide-A and withaferin-A and sitoindosides and other alkaloids as major bioactive molecules. These chemicals protect cells from oxidative damage and disease 20. Withaferin A appeared to be the most bioactive compound with anti-invasive, anti-angiogenic, anti-inflammatory and pro-apoptotic effects 21. Withaferin A is a natural steroidal lactone, rejuvenating tonifier, immunomodulator and a pre-dominant bioactive constituent obtained from Ashwagandha (Withania somnifera) which exhibits an array of potential biological activities including anti-leukemic, anti-invasive, anti-metastatic, apoptotic, anti-inflammatory, radiosensitizing and antidiabetic activity and also act as a potential leptin-sensitizer 22 and anti-inflammatory, pro-apoptotic, and anti-fibrotic effects 23. Withaferin A exhibits potent anti-inflammatory effect by downregulating central inflammatory mediator, nuclear factor kappa light chain enhancer of activated B cells (NF-κB) and other cytokines which has been well-elucidated in vitro and in vivo studies 24. Above all, Withaferin A is a pre-clinically proven vimentin and TGF-β inhibitor but its role in pulmonary fibrosis is not yet explored 25. Further studies are needed in order to establish Withaferin A as a promising therapeutic intervention for treatment of pulmonary fibrosis.

Grace et al. 26 studied the anti-oxidative and anti-inflammatory effects of two withanolide components, namely, Withanolide A and Withaferin A in microglial cells. Surprisingly, withanolide components not only abolished lipopolysaccharide (LPS) stimulated nitric oxide production and ROS generation, they also induced nuclear factor (erythroid-derived 2) like 2 (Nrf2) signaling followed by upregulation of hemeoxygenase-1 (HO-1) 26. Though both withanolide components displayed anti-oxidative and anti-inflammatory effects, Withaferin A was found to be 10 fold more effective than Withanolide A 26. In addition, ethanolic extract of Ashwagandha leaves significantly inhibited the proliferation of C6 rat glioma and YKG1 human glioma cell lines in a dose dependent manner 27.

Withanolide-A is a potential neurological, immunological and anti-stress agent 28. Roots of Ashwagandha plants are rich in withanolide-A, however withaferin-A is present in leaves in large amount and totally absent or present in traces in roots of Ashwagandha plant 29. Withanolides are terpenoids and synthesized in plants using the precursor isoprenoids which are synthesized via mevalonate and 2-C-methyl-D-erythritol-4-phosphate pathway. Genes encoding key enzymes of withanolide biosynthesis have been characterized 30 and consistent efforts are being made to increase the production of withanolides in roots as well as leaves. Biotechnological tools like genetic engineering are being focused for enhancing the withanolide production. Overexpression of squalene synthase, a key regulatory gene of withanolide biosynthesis in Ashwagandha could increase the content of withaferin A and withanolide A in the leaves up to 4–4.5 fold 31. Overexpression of cycloartenol synthase in Ashwagandha increased the withanolide content to the extent of 1.06 to 1.66 fold 32.

Ashwagandha also contain a range of constituents like sitoindosides and other alkaloids that are pharmacologically and medicinally important. Results from a battery of tests, conducted to identify the anti-stress activity of sitoindoside VII and sitoindoside VIII implied that both sitoindosides produce anti-stress activity 33. Sitoindoside IX and X were tested in rats for immunomodulatory and central nervous system effects related to stress, memory and learning. A significant reduction was noticed in the incidence of stress-induced gastric ulcers 34.

Ashwagandha common names: Withania , aswaganda , winter cherry , Indian ginseng , ajagandha , kanaje Hindi , samm al ferakh , asgand (Hindi), amukkirag (Tamil), amangura (Kannada), asvagandha (Bengali), ashvagandha (Sanskrit), asundha (Gujarati), kuthmithi

Figure 1. Ashwagandha

ashwagandha

Figure 2. Ashwagandha root

ashwagandha root

Ashwagandha uses

Well-designed clinical studies in which ashwagandha or its extracts are used as a single agent are lacking.

Traditional Medicine Uses

Ashwagandha is an important herb of Ayurveda (the traditional system of medicine in India) used for millennia as a Rasayana for its wide ranging health benefits. Rasayana is described as an herbal or metallic preparation that promotes a youthful state of physical and mental health 2. These types of remedies are given to small children as tonics, and are also taken by the middle-aged and elderly to increase longevity 2. According to Ayurveda, ashwagandha improves the body’s defense against disease by improving the cell-mediated immunity. It also possesses potent antioxidant properties that help protect against cellular damage caused by free radicals. It is believed but not scientifically proven that ashwagandha enhances the function of the brain and nervous system and improves the memory. Ashwagandha is also believed to improve the function of the reproductive system promoting a healthy sexual and reproductive balance, again there is currently no clinical trials that showed these purported effects of ashwagandha. Being a powerful adaptogen, ashwagandha enhances the body’s resilience to stress, again we must emphasize clinical trials supporting its clinical use are limited. Ashwagandha is commonly available as a churna, a fine sieved powder that can be mixed with water, ghee (clarified butter) or honey.

Ashwagandha has been recommended for management of polyarthritis, lumbago, painful swellings, premature ejaculation, oligospermia, plague, asthma, vitiligo, general debility, impotency, ulcers, uterine infection, leucorrhoea, hemorrhoid, and orchitis in traditional Persian medicine 35, 36. All these therapeutic uses suggest its anti-inflammatory, aphrodisiac, semenogogue, and deobstruent features 37.

Ashwagandha and anxiety

Anxiety disorders are widespread and disabling conditions with a lifetime prevalence of nearly 30% in the United States 38. As the most common mental disorder, anxiety presents an urgent problem that affects people of all ages. Anxiety is often accompanied by stress, which is the body’s physiologic response to mental or physical threats. While brief exposure to the stress response is meant to be a beneficial coping mechanism, long-term stress is likely to result in the decline of overall health and the complication of existing diseases. Treatment protocols for the management of anxiety and the reduction of stress are continuously being sought to mitigate the effect of these prevailing health risks. Alternatives to benzodiazepines and other prescription medications are of great interest, with intentions to lessen exposure to harmful adverse effects affiliated with these drugs.

Ashwagandha has recently gained recognition as a treatment for anxiety and stress in the United States 39. Ashwagandha is also classified as an adaptogen, which indicates its ability to regulate physiologic processes and thereby stabilize the body’s response to stress 40. Ashwagandha exerts an anxiolytic effect in animals and humans 41. One study has examined the effects of a standardized Ashwagandha extract on chronic stress in rats exposed to a shock procedure; the researchers concluded that the rats treated with Ashwagandha extract responded better to the induced chronic stress symptoms 42. In a similar investigation, Ashwagandha increased stress tolerance among animals subjected to a cold water swimming stress test 43. Ashwagandha has even proven to have effects on anxiety similar to those of standard benzodiazepines. After experiencing a series of anxiety-producing events, Ashwagandha generated analogous effects compared with lorazepam in rats 44. The results of this particular study indicate that herbal supplementation is similarly effective in the management of anxiety as are standard prescription drugs, without the harmful adverse effects, in a rodent model.

A systematic review 45 aimed to collect and assess data from human randomized controlled trials on the effectiveness of ashwagandha as a treatment for anxiety and stress. Study design and outcomes varied widely among the five selected studies. The general finding among these studies was that Ashwagandha produced favorable results when compared with a placebo. The one study that approached, but failed to achieve, significance for its primary outcome measure had the shortest trial duration and smallest sample size 46. The remaining four trials showed significant differences between Ashwagandha and placebo when examining anxiety and stress relief outcomes.

However, the strength of trial results may be very limited by factors of potential bias. The methods of Cooley et al. 47 prevented blinding of the care providers, allowing greater chance for performance bias. Suggestion of reporting bias in Auddy et al. 48 was indicated by conflicts of interest between the authors and the company funding the trial. Another factor to consider in evaluating the results is that the primary outcomes for all included studies were classified as patient-reported measures. Future studies may benefit from adding blinded diagnostic intervieAshwagandha to gain non–patient-rated information as a comparison. Additionally, the use of such biomarkers as salivary amylase and serum cortisol levels would provide further objective measures and differentiation between the studied populations. None of the studies attained a low risk-of-bias rating according to Cochrane criteria 49 and the mildly favorable outcomes reported in that review should be understood in the context of an unclear, and probably moderate to high, risk of bias across these studies.

None of the trials in that review reported significant adverse effects of Ashwagandha. All effects reported by participants were mild and did not differ in duration or severity when compared with results in the placebo groups. The conclusion that Ashwagandha is a safe herbal supplement for general use agrees with findings from a recent evaluation of the tolerability and safety of Ashwagandha in human participants 50. While Ashwagandha appears to alleviate these prevalent conditions in these limited controlled trials, additional research in larger samples and in more clinical contexts is essential to validate its therapeutic capabilities for widespread use. Additional research is also needed to determine standardization of Ashwagandha supplements and dosage recommendations.

Effect of Ashwagandha on focal aspects of stress

In this study 1, the Ashwagandha group of subjects showed substantial reduction in all measures of stress (e.g., depression anxiety stress scale, anxiety and insomnia, general health questionnaire, perceived stress scale). The Ashwagandha group’s subjects had reductions of 69.7%, 64.2%, 75.6% and 44.0%, respectively, on these four measures. In contrast, the placebo group’s subjects saw reductions of only 11.6%, 10.4%, –4.3% and 5.5%, respectively. The differences are highly statistically significant, suggesting a substantial effect of Ashwagandha in improving the well-being of subjects with respect to these focal aspects of stress. This finding provides evidence of strong anti-stress adaptogenic activity of Ashwagandha 1. These results are consistent with the findings of previous in-vivo studies 51. Similar results were reported by Andrade et al. in anxiety patients 52.

Effect of Ashwagandha on antecedents and consequences of stress

This study 1 also measured aspects of stress that can be seen as precursors or results of the focal phenomenon of stress. These correspond to either events and conditions that lead to stress or events and conditions that result from stress. In this study 1, Ashwagandha group’s subjects had reductions of 76.1%, 68.1%, 79.2%, 77.0%, 27.9%, respectively, on these five measures. In contrast, the placebo group’s subjects saw reductions of only 4.9%, –3.7%, –10.6% –5.2%, 7.9%. Once again, these differences are highly statistically significant, suggesting a substantial effect of Ashwagandha in improving the condition of the subjects.

Serum cortisol is a frequently cited correlate of stress and is therefore worth elaborating on in this discussion. Acute stress increases heart rate and arterial blood pressure, stimulates gluconeogenesis, glycogenolysis, lipolysis and hepatic glucose secretion. These in turn elevates the catecholamines and cortisol levels in the body 53. Stress, either physical or mental leads to enhancement of ACTH secretion, which in turn increases cortisol levels; at times, the level may increase even 20-fold 54. The results of this study 1 shows that high-concentration full-spectrum Ashwagandha root extract reduces levels of serum cortisol, which elevates in stressful conditions. Similar findings were observed in previous study by Auddy et al. 55 in patients with stress.

These two sets of effects collectively suggest that high-concentration full-spectrum Ashwagandha root extract mitigates not only the focal aspects of stress but also some of the precursors, consequences and associated symptoms of stress 1.

Anti-inflammatory effects

In test tube and animal experiments suggest Ashwagandha may possess anti-inflammatory properties. Cultures of cartilage from patients with osteoarthritis and rheumatoid arthritis have been used to demonstrate Ashwagandha’s protective effects on chondroplasts 56. Related effects on cytokines and transcription factors, and suppression of nitric oxide have also been demonstrated 57. In experiments in rats with induced inflammation, decreased inflammation (paw volume), pain, and disability were noted, as well as an antipyretic effect after administration of Ashwagandha root powder. The ulcerogenic effect of Ashwagandha was lower than that of indomethacin 58. A small clinical study evaluating a combination therapy that included ashwagandha demonstrated decreased pain and disability in arthritis, while no changes were observed in the erythrocyte sedimentation rate 59.

Cancer

Despite more than 30 years of research into a potential role for Ashwagandha extracts in the treatment of cancer, clinical trials are lacking. In test tube and animal experiments have been conducted using whole plant extract, ethanol root extracts, aqueous and methanolic leaf extracts, individual withanolides, and withaferin A. Human cancer cell line investigations include HL-60 leukemic and myeloid leukemia cell lines, and bladder, breast, prostate, colon, kidney, gastric, and lung cancer cell lines. Mechanisms of action described include antiproliferative effects, apoptosis, radio-sensitization, mitotic arrest, antiangiogenesis, and enhancement of cell defense mechanisms 58, 60, 61, 62. Limited studies suggest withanone, withaferin A, and withanolide A have protective effects on glioma cell lines, as well as human fibroblasts, and thereby slow senescence 63.

Experiments in mice have demonstrated decreased lung adenoma tumor incidence with whole plant extract and complete regression of mouse sarcoma tumor with ethanol root extract, as well as radio-sensitizing of carcinomas and increased apoptosis of human breast cancer cells by withaferin A, a steroidal lactone of Ashwagandha 58.

Damage to the bladder by cyclophosphamide was ameliorated by Ashwagandha extract 64, as was leukopenia induced by cyclophosphamide 65.

CNS effects

In vitro studies and experiments in animals suggest CNS effects, including modulation of acetylcholinesterase and butyrylcholinesterase activity, inhibition of calcium ion influx, blockade of gamma-aminobutyric acid receptors, modulation of 5-HT 1 and 5-HT 2 receptors, antioxidant activity, and regeneration of neurites 66, with some researchers suggesting potential applications in Alzheimer and Parkinson diseases 59.

Ashwagandha extract protected against pentylenetetrazol-induced seizures in a mouse anticonvulsant model when administered over a 9-week period 67. The same research group found the extract active in a rat status epilepticus model 68. A depressant effect on the CNS was indicated by potentiation of pentobarbital effects on the righting reflex in mice 69, and a mild tranquilizing/relaxant effect in monkeys, cats, dogs, rats, and mice by a total alkaloid extract from the plant roots 58.

A further study of the extract found that it inhibited the development of tolerance to morphine in mice, while suppressing withdrawal symptoms precipitated by naloxone 70. A withanolide-containing fraction reversed morphine-induced reduction in intestinal motility and confirmed the previous finding of inhibition of development of tolerance to morphine 71. A role in the management of drug addiction has been suggested 72.

An experiment supported the traditional Ayurvedic medicinal claim that the plant’s use could be attributed to effects on learning and memory. Ibotenic acid-induced lesions in intact rat brain that led to cognitive deficit, as measured by performance in a learning task, were reversed by treatment with a withanolide mixture 73. Limited trials in elderly populations using traditional combination therapies showed mixed results. One study of 2 g of root extract twice daily (in combination) administered over 6 months made no difference in sleep onset times or duration 74. In another study, increased balance was determined in elderly patients with long-term progressive degenerative ataxia 75.

Immune system effects

Withanolides inhibit murine spleen cell proliferation 76 and an extract of Ashwagandha reversed ochratoxin’s suppressive effect on murine macrophage chemotaxis 77. Withanolide glycosides activated murine macrophages and phagocytosis, and increased lysosomal enzymatic activity secreted by the macrophages, while also displaying antistress activity and positive effects on learning and memory in rats 78. Alpha-2 macroglobulin synthesis stimulated by inflammation was reduced by Ashwagandha extract 79. Similarly, the extract prevented myelosuppression caused by cyclophosphamide, azathioprine, or prednisolone in mice 80. In a clinical study, ashwagandha 6 mL root extract administered twice daily for 4 days resulted in increases in CD4 expression, as well as activation of natural killer cells 81. Additional effects on cytokines and the complement system, lymphocyte proliferation, and humoral and cell-mediated responses have been discussed 82.

Other uses

Animal experiments have been conducted to describe adaptogenic properties (increased swimming endurance and reduced stress response) of Ashwagandha . Clinical trials are lacking 83.

Effects on aging have been promoted, based on claims regarding increased hemoglobin, red blood cell count, hair quality, and melanin levels in a non-peer-reviewed study conducted among healthy men. Serum cholesterol was also reduced and seated-stature improved in this study 63.

Antimicrobial effects 84 and antivenom activity via hyaluronidase inhibition have been described 85.

Ashwagandha benefits

Ashwagandha benefits for men and women

Based on this study 86, it was shown that extracts of ashwagandha fruits, leaves, stems, and especially roots enhance sperm quality indices such as motility and count in men 87 and also decrease the effects of chemical toxins on gonads in both men and women 8. Ashwagandha can increase gonadal weight in both sexes, enhance folliculogenesis and spermatogenesis, and improve LH, FSH, and testosterone balances 88. Sexual behavior indices such as female sexual function index and female sexual distress index improve statistically significant after ashwagandha extract administration 89. Although some studies proposed that ashwagandha extract might have infertilizing and spermicidal effect too. Therefore, further studies are needed with higher population and more-structured methodology so a more precise and decisive conclusion can be made.

The mechanism of ashwagandha effect on the reproductive system is not known entirely yet, but this mechanism is proposed to be linked to the antioxidative features and ability to improve the hormonal balance of LH, FSH, and testosterone and improve detoxification process 86. Also, the GABA (gamma-aminobutyric acid) mimetic feature of ashwagandha extract is thought to play the main role in inducing gonadotropin releasing hormone secretion and improving hormonal balance 90. GABA is an inhibitory neurotransmitter in the brain. Its function is to decrease neuron activity and inhibit nerve cells from over firing. This action produces a calming effect. Excessive neuronal activity can lead to restlessness and insomnia, but GABA inhibits the number of nerve cells that fire in the brain, and helps to induce sleep, uplift mood, and reduce anxiety 91. In the male reproductive system, it is assumed that ashwagandha by providing metal ions facilitates enzyme activities, modifies oxidative stress, and prevents cell apoptosis 90. The root extract of ashwagandha has been shown to induce alanine transaminase activity which increases alanine in seminal fluid leading to a less oxidative stress index and improved semen quality 92. Normalizing lactate, phenylalanine, glutamine, citrate, and histidine in seminal fluid are another feature of Ashwagandha extract which improves enzymatic processes in tricarboxylic acid cycle and fatty acid metabolism 93. On the other hand, some animal studies have suggested that ashwagandha extract may cause reversible spermicidal and infertilizing effect in male and delayed puberty in both sexes; this might be due to the dose, preparation method, adjuvant components, and duration of use designated in mentioned studies 94.

Ashwagandha dosage

Dosing information is limited. Ashwagandha root powder has generally been used at dosages of 300 mg to 2 g in combination with other preparations.

  • Capsule: 1-6 g whole herb oral daily
  • Tea form: 3 cups daily (1-6g whole herb)
  • Tincture: 2-4 mL oral three times daily

Ashwagandha side effects

Nasal congestion (rhinitis), constipation, cough and cold, drowsiness and decreased appetite were seen in people who take 300 mg Ashwagandha root extract 1. An analysis of the adverse events recorded in this study 1 indicates that high-concentration full-spectrum Ashwagandha root extract is safe and well tolerated as there were no serious adverse events. The side effects that were observed were mostly mild in nature and no known causal mechanisms relate them to the study drug. Insignificant changes in laboratory values were observed in both the groups. The results on safety in this study are consistent with previous studies on Ashwagandha, where generally there were no adverse events leading to drop outs or withdrawal symptoms 55. Long-term administration of the roots of Ashwagandha was found to be safe also in animal studies 95. A word of caution, however, those allergic to herbs belonging to the Solanaceae family are contraindicated for treatment with Ashwagandha.

Pregnancy Category X: Do NOT use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

A case-report of Ashwagandha-associated thyrotoxicosis (hyperthyroidism) 96 and data from mice administered Ashwagandha that showed significant increases in thyroxine levels (T4 levels) 97, 98. The authors opined that Ashwagandha’s actions are mainly driven by stimulation of the thyroid gland to release thyroxine T4 98, though the precise mechanism(s) remains unknown. These explanations require further investigation. Interestingly, however, all three Ashwagandha-treated patients showed a rise in free T4 (although small changes) similar to the results in animal experiments 98, but replicative studies are required to confirm these early data. At best, this early report is suggestive of the T4 elevating actions of Ashwagandha. Future prospective studies that are hypothesis driven with an adequate sample size to demonstrate a thyroid promoting effect for Ashwagandha are required. Moreover, confirmatory and repeat laboratory testing of thyroid indices in future work will provide greater confidence of the results obtained in this study. Therefore, even though a single case of thyrotoxicosis associated with Ashwagandha has been reported in the literature, vigilance may be well advised when Ashwagandha is utilized in clinical practice. This highlights the importance of thyroid function testing before starting Ashwagandha among Ayurvedic or other healthcare practitioners and emphasizes that repeat testing may be required if there is clinical suspicion of hyperthyroidism during Ashwagandha treatment. The current report of Ashwagandha elevating T4, along with its anti-inflammatory, neuroprotective, anti-oxidant, and anti-depressant properties 99, suggest that Ashwagandha can be considered for treatment of sub-clinical hypothyroidism in mood disorders. Prospective controlled studies among patients with laboratory confirmed subclinical hypothyroidism (i.e. TSH and free T4 along with thyroid antibodies), and other risk factors may provide answers to whether Ashwagandha extracts are more specifically beneficial in persons with unipolar or bipolar disorders with treatment resistant depression or rapid cycling.

A toxicity study was performed in Wistar rats by oral administration 100. An acute toxicity study was done at the dose of 2000 mg/kg. In the sub-acute study, Wistar rats (10/sex/group) were administered via gavage 0 (control), 500, 1000, 2000 mg/kg body weight/day of Ashwagandha extract for 28 days. In acute toxicity studies, oral LD50 (lethal dose 50 means the dose where 50% of test subjects die) of Ashwagandha extracts in Wistar rats was greater than 2000 mg/kg body weight. Compared to the control group in sub-acute toxicity study, administration of extract did not show any toxicologically significant treatment related changes in clinical observations, ophthalmic examination, body weight gain, feed consumption, clinical pathology evaluation, and organ weight. Hematological and serum chemistry parameters were within the normal limits. Terminal necropsy did not reveal any treatment related gross or histopathological findings. Based on this study, the no-observed-adverse-effect-level of Ashwagandha extract is 2000 mg/kg body weight, the highest level tested 100. In summary, the results of sub-acute toxicity suggest that oral administration of Ashwagandha extract containing 4.5% of Withaferin A at level up to 2000 mg/kg/day does not cause adverse effects in male and female rats 100. Though exact extrapolation of animal toxicity data to humans is difficult, some hematological findings of this study such as decrease in the levels of triglyceride, cholesterol, and urea are also get to see in an exploratory clinical study of Ashwagandha in healthy human volunteers 101. The volunteer study demonstrates that Ashwagandha, when given in the form of aqueous extract in capsules with gradual escalating doses from 750 to 1250mg/day, was well tolerated 101.

Human clinical study with water extract of Ashwagandha and an animal toxicity study with water extract of Ashwagandha and Ginseng reported the increase in body weight and appetite. But a hydro alcoholic extract of Ashwagandha and the extract used in the present study did not cause any organ or body weight gain. The appetite was also unchanged 102.

Summary

Preliminary studies have found various constituents of ashwagandha exhibit a variety of therapeutic effects with little or no associated toxicity. These results are very encouraging and indicate Ashwagandha should be studied more extensively to confirm these results and reveal other potential therapeutic effects. Clinical trials using Ashwagandha for a variety of conditions should also be conducted.

  1. Chandrasekhar K, Kapoor J, Anishetty S. A Prospective, Randomized Double-Blind, Placebo-Controlled Study of Safety and Efficacy of a High-Concentration Full-Spectrum Extract of Ashwagandha Root in Reducing Stress and Anxiety in Adults. Indian Journal of Psychological Medicine. 2012;34(3):255-262. doi:10.4103/0253-7176.106022. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3573577/[↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩]
  2. Singh N, Bhalla M, de Jager P, Gilca M. An Overview on Ashwagandha: A Rasayana (Rejuvenator) of Ayurveda. African Journal of Traditional, Complementary, and Alternative Medicines. 2011;8(5 Suppl):208-213. doi:10.4314/ajtcam.v8i5S.9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3252722/[↩][↩][↩]
  3. Kumar A., Kumar R., Rahman M. S., Iqubal M. A., Anand G., Niraj P. K., et al. Phytoremedial effect of Withania somnifera against arsenic-induced testicular toxicity in Charles Foster rats. Avicenna Journal of Phytomedicine. 2015;5(4):p. 355. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4587609/[↩]
  4. Withania somnifera (L.) USDA, NRCS. 2007. The PLANTS Database[↩]
  5. Sharma V, Sharma S, Pracheta., Paliwal R. Withania somnifera: a rejuvenating Ayurvedic medicinal herb for the treatment of various human ailments. Int. J. Pharmtech Res. 2011;3:187–192.[↩]
  6. Dar N. J., Hamid A., Ahmad M. Pharmacologic overview of Withania somnifera, the Indian Ginseng. Cellular and Molecular Life Sciences. 2015;72(23):4445–4460. doi: 10.1007/s00018-015-2012-1 https://www.ncbi.nlm.nih.gov/pubmed/26306935[↩]
  7. Saiyed A., Jahan N., Majeedi S. F., Roqaiya M. Medicinal properties, phytochemistry and pharmacology of Withania somnifera: an important drug of Unani Medicine. Journal of Scientific & Innovative Research. 2016;5(4):156–60.[↩]
  8. Sharma V., Sharma S., Pracheta, Paliwal R. Withania somnifera: A rejuvenating ayurvedic medicinal herb for the treatment of various human ailments. International Journal of PharmTech Research. 2011;3(1):187–192.[↩][↩]
  9. Shukla K. K., Mahdi A. A., Mishra V., et al. Withania somnifera improves semen quality by combating oxidative stress and cell death and improving essential metal concentrations. Reproductive BioMedicine Online. 2011;22(5):421–427. doi: 10.1016/j.rbmo.2011.01.010[↩]
  10. Shaikh N. H., Deshmukh V. M., Walvekar M. V. Alteration in testicular morphology and sperm count due to Glycowithanolides treatment during aging. Asian Journal of Pharmaceutical and Clinical Research. 2015;8(3):72–77[↩]
  11. Shastry JLN., Dr . Ayurvedokta oushadha niruktamala, Chaukhambha Orientalia. Ist ed. Varanasi, India: 2001. p. 10.[↩]
  12. Provino R. The role of adaptogens in stress management. Aust J Med Herbal. 2010;22:41–9.[↩][↩]
  13. Evidence-based efficacy of adaptogens in fatigue, and molecular mechanisms related to their stress-protective activity. Panossian A, Wikman G. Curr Clin Pharmacol. 2009 Sep; 4(3):198-219. https://www.ncbi.nlm.nih.gov/pubmed/19500070/[↩]
  14. Singh G, Sharma PK, Dudhe R, Singh S. Biological activities of Withania somnifera. Annals Biol. Res. 2010;1:56–63.[↩]
  15. Ahlawat P, Khajuria A, Bhagwat DP, Kalia B. Therapeutic benefits of Withania somnifera: An exhaustive review. Int. J. Pharma. Chem. Sci. 2012;1:491–496.[↩]
  16. Jain R, Kachhwaha S, Kothari SL. Phytochemistry, pharmacology, and biotechnology of Withania somnifera and Withania coagulans: A review. J. Med. Plants Res. 2012;6:5388–5399. doi: 10.5897/JMPR12.704.[↩]
  17. Sehgal N, et al. Withania somnifera reverses Alzheimer disease pathology by enhancing low-density lipoprotein receptor related protein in liver. Proc. Natl. Acad. Sci. USA. 2012;109:3510–3515. doi: 10.1073/pnas.1112209109[↩]
  18. Uddin Q, Samiulla L, Singh VK, Jamil SS. Phytochemical and pharmacological profile of Withania somnifera Dunal: A Review. J. Appl. Pharma. Sci. 2012;2:170–175.[↩]
  19. Gauttam VK, Kalia AN. Development of polyherbal antidiabetic formulation encapsulated in the phospholipids vesicle system. J. Adv. Pharm. Technol. Res. 2013;4:108–117. doi: 10.4103/2231-4040.111527 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696222/[↩]
  20. Sharma V, Sharma S, Pracheta, Paliwal R. Withania somnifera: A rejuvenating ayurvedic medicinal herb for the treatment of various human ailments. Int J PharmTech Res. 2011;3:187–92.[↩]
  21. Vanden Berghe W, Sabbe L, Kaileh M, Haegeman G, Heyninck K. Molecular insight in the multifunctional activities of Withaferin A. Biochem Pharmacol. 2012;84:1282–91 https://www.ncbi.nlm.nih.gov/pubmed/22981382[↩]
  22. Lee J, et al. Withaferin A is a leptin sensitizer with strong antidiabetic properties in mice. Nat. Med. 2016;22:1023–1032. doi: 10.1038/nm.4145 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892415/[↩]
  23. Withaferin A inhibits the proliferation of gastric cancer cells by inducing G2/M cell cycle arrest and apoptosis. Kim G, Kim TH, Hwang EH, Chang KT, Hong JJ, Park JH. Oncol Lett. 2017 Jul; 14(1):416-422. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494816/[↩]
  24. Withaferin A inhibits NF-kappaB activation by targeting cysteine 179 in IKKβ. Heyninck K, Lahtela-Kakkonen M, Van der Veken P, Haegeman G, Vanden Berghe W. Biochem Pharmacol. 2014 Oct 15; 91(4):501-9. https://www.ncbi.nlm.nih.gov/pubmed/25159986/[↩]
  25. Withaferin-A reduces type I collagen expression in vitro and inhibits development of myocardial fibrosis in vivo. Challa AA, Vukmirovic M, Blackmon J, Stefanovic B. PLoS One. 2012; 7(8):e42989. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3416765/[↩]
  26. Sun GY, Li R, Cui J, Hannink M, Gu Z, Fritsche KL, Lubahn DB, Simonyi A. Withania somnifera and Its Withanolides Attenuate Oxidative and Inflammatory Responses and Up-Regulate Antioxidant Responses in BV-2 Microglial Cells. Neuromolecular Med. 2016;18:241–52 https://www.ncbi.nlm.nih.gov/pubmed/27209361[↩][↩][↩]
  27. Shah N, Kataria H, Kaul SC, Ishii T, Kaur G, Wadhwa R. Effect of the alcoholic extract of Ashwagandha leaves and its components on proliferation, migration, and differentiation of glioblastoma cells: combinational approach for enhanced differentiation. Cancer Sci. 2009;100:1740–7 https://www.ncbi.nlm.nih.gov/pubmed/19575749[↩]
  28. Malik T, Pandey DK, Dogra N. Ameliorative potential of aqueous root extract of Withania somnifera against paracetamol induced liver damage in mice. Pharmacologia. 2013;4:89–94. doi: 10.5567/pharmacologia.2013.89.94[↩]
  29. Siriwardane AS, Dharmadasa RM, Samarasinghe K. Distribution of withaferin A, an anticancer potential agent, in different parts of two varieties of Withania somnifera (L.) Dunal. grown in Sri Lanka. Pak. J. Biol. Sci. 2013;16:141–144. doi: 10.3923/pjbs.2013.141.144[↩]
  30. Dhar N, et al. A decade of molecular understanding of withanolide biosynthesis and in-vitro studies in Withania somnifera (L.) Dunal: Prospects and perspectives for pathway engineering. Front. Plant Sci. 2015;6:1031. doi: 10.3389/fpls.2015.01031 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661287/[↩]
  31. Patel N, Patel P, Kendurkar SV, Khan BM. Overexpression of squalene synthase in Withania somnifera leads to enhanced withanolide biosynthesis. Plant Cell Tiss. Organ Cult. 2015;122:409–420. doi: 10.1007/s11240-015-0778-3[↩]
  32. Mishra S, et al. RNAi and homologous over-expression based functional approaches reveal triterpenoid synthase gene cycloartenol synthase is involved in downstream withanolide biosynthesis in Withania somnifera. PLoS One. 2016;11:e0149691. doi: 10.1371/journal.pone.0149691[↩]
  33. Bhattacharya SK, Goel RK, Kaur R, Ghosal S. Anti-stress activity of sitoindosides VII and VIII, new acylsterylglucosides from Withania somnifera. Phytother Res. 1987;1:32–7. [↩]
  34. Ghosal S, Lal J, Srivastava R, Bhattacharya SK, Upadhyay SN, Jaiswal AK, et al. Immunomodulatory and CNS effects of sitoindosides IX and X, two new glycowithanolides from Withania somnifera. Phytother Res. 1989;3:201–6.[↩]
  35. Uddin Q., Samiulla L., Singh V. K., Jamil S. S. Phytochemical and pharmacological profile of Withania somnifera dunal: A review. Journal of Applied Pharmaceutical Science. 2012;2(1):170–175.[↩]
  36. Imtiyaz S., Ali S. J., Aslam M., Tariq M., Chaudhary S. S. Withania somnifera: a potent unani aphrodisiac drug. International Research Journal of Pharmaceutical And Applied Sciences. 2013;3:59–63.[↩]
  37. Tuhfat al-mu’minin D. T. The Present for the Faithful. Tehran, Iran: Research Center of Traditional Medicine: Nashre Shahr Press; 2007.[↩]
  38. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Arch Gen Psychiatry. 2005 Jun; 62(6):593-602. https://www.ncbi.nlm.nih.gov/pubmed/15939837/[↩]
  39. Pratte MA, Nanavati KB, Young V, Morley CP. An Alternative Treatment for Anxiety: A Systematic Review of Human Trial Results Reported for the Ayurvedic Herb Ashwagandha (Withania somnifera). Journal of Alternative and Complementary Medicine. 2014;20(12):901-908. doi:10.1089/acm.2014.0177. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270108/[↩]
  40. Provino R. The role of adaptogens in stress management. Aust J Med Herbal 2010;22:41–49[↩]
  41. Sarris J, McIntyre E, Camfield DA. Plant-based medicines for anxiety disorders, part 2: a review of clinical studies with supporting preclinical evidence. CNS Drugs 2013;27:301–19 https://www.ncbi.nlm.nih.gov/pubmed/23653088[↩]
  42. Bhattacharya S, Muruganandam A. Adaptogenic activity of Withania somnifera: an experimental study using a rat model of chronic stress. Pharmacol Biochem Behav 2003;75:547–555 https://www.ncbi.nlm.nih.gov/pubmed/12895672[↩]
  43. Archana R, Namasivayam A. Antistressor effect of Withania somnifera. J Ethnopharmacol 1998;64:91–93 https://www.ncbi.nlm.nih.gov/pubmed/10075127[↩]
  44. Bhattacharya SK, Bhattacharya A, Sairam K, Ghosal S. Anxiolytic-antidepressant activity of Withania somnifera glycowithanolides: an experimental study. Phytomedicine 2000;7:463–9 https://www.ncbi.nlm.nih.gov/pubmed/11194174[↩]
  45. Pratte MA, Nanavati KB, Young V, Morley CP. An Alternative Treatment for Anxiety: A Systematic Review of Human Trial Results Reported for the Ayurvedic Herb Ashwagandha (Withania somnifera). Journal of Alternative and Complementary Medicine. 2014;20(12):901-908. doi:10.1089/acm.2014.0177 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270108/[↩]
  46. Andrade C, Aswath A, Chaturvedi SK, Srinivasa M, Raguram R. A double-blind, placebo-controlled evaluation of the anxiolytic efficacy of an ethanolic extract of Withania somnifera. Indian J Psychiatry. 2000;42:295–301 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2958355/[↩]
  47. Cooley K, Szczurko O, Perri D, et al. Naturopathic care for anxiety: a randomized controlled trial ISRCTN78958974. PLoS One 2009;4:e6628 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2729375/[↩]
  48. Auddy B, Hazra J, Mitra A, Abedon B, Ghosal S. A standardized Withania somnifera extract significantly reduces stress-related parameters in chronically stressed humans: a double-blind, randomized, placebo-controlled study. J Am Neutraceut Assoc 2008;11:50–56[↩]
  49. Higgins J, editor; , Green S, editor. , eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. The Cochrane Collaboration; 2017. http://training.cochrane.org/handbook[↩]
  50. Raut AA, Rege NN, Tadvi FM, et al. Exploratory study to evaluate tolerability, safety, and activity of Ashwagandha (Withania somnifera) in healthy volunteers. J Ayurveda Integr Med 2012;3:111–114 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3487234/[↩]
  51. Bhattacharya SK, Muruganandam AV. Adaptogenic activity of Withania somnifera: An experimental study using a rat model of chronic stress. Pharmacol Biochem Behav. 2003;75:547–55. https://www.ncbi.nlm.nih.gov/pubmed/12895672[↩]
  52. Andrade C, Aswath A, Chaturvedi SK, Srinivas M, Raguram R. A double blind, placebo- controlled evaluation of the anxiolytic efficacy of an ethanolic extract of Withania somnifera. Indian J Psychiatry. 2000;42:295–301 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2958355/[↩]
  53. Chrousos GP. Stress and disorders of the stress system. Nature reviews. Endocrinology. 2009;5:374–81.[↩]
  54. Guyton AC, Hall JE. Adrenocortical Hormones Textbook of Medical Physiology. 11th ed. Philadelphia: Saunders; 2006. pp. 944–60.[↩]
  55. Auddy B, Hazra J, Mitra A, Abedon B, Ghosal S. A standardized Withania somnifera extract significantly reduces stress-related parameters in chronically stressed humans: A double-blind, randomized, placebo-controlled study. J Am Nutraceutical Assoc. 2008;11:50–6.[↩][↩]
  56. Sumantran VN, Chandwaskar R, Joshi AK, et al. The relationship between chondroprotective and antiinflammatory effects of Withania somnifera root and glucosamine sulphate on human osteoarthritic cartilage in vitro. Phytother Res . 2008;22(10):1342-1348.[↩]
  57. Kaileh M, Vanden Berghe W, Heyerick A, et al. Withaferin a strongly elicits IkappaB kinase beta hyperphosphorylation concomitant with potent inhibition of its kinase activity. J Biol Chem . 2007;282(7):4253-4264.[↩]
  58. Mishra LC, Singh BB, Dagenais S. Scientific basis for the therapeutic use of Withania somnifera (ashwagandha): a review. Altern Med Rev . 2000;5(4):334-346.[↩][↩][↩][↩]
  59. Kulkarni SK, Dhir A. Withania somnifera : an Indian ginseng. Prog Neuropsychopharmacol Biol Psychiatry . 2008;32(5):1093-1105.[↩][↩]
  60. Senthil V, Ramadevi S, Venkatakrishnan V, et al Withanolide induces apoptosis in HL-60 leukemia cells via mitochondria mediated cytochrome c release and caspase activation. Chem Biol Interact . 2007;167(1):19-30.[↩]
  61. Al-Fatimi M, Friedrich U, Jenett-Siems K. Cytotoxicity of plants used in traditional medicine in Yemen. Fitoterapia . 2005;76(3-4):355-358.[↩]
  62. Kaur K, Rani G, Widodo N, et al. Evaluation of the anti-proliferative and anti-oxidative activities of leaf extract from in vivo and in vitro raised Ashwagandha. Food Chem Toxicol . 2004;42(12):2015-2020.[↩]
  63. Widodo N, Shah N, Priyandoko D, Ishii T, Kaul SC, Wadhwa R. Deceleration of senescence in normal human fibroblasts by withanone extracted from ashwagandha leaves. J Gerontol A Biol Sci Med Sci . 2009;64(10):1031-1038.[↩][↩]
  64. Davis L, Kuttan G. Effect of Withania somnifera on cyclophosphamide-induced urotoxicity. Cancer Lett . 2000;148(1):9-17.[↩]
  65. Davis L, Kuttan G. Suppressive effect of cyclophosphamide-induced toxicity by Withania somnifera extract in mice. J Ethnopharmacol . 1998;62(3):209-214.[↩]
  66. Choudhary MI, Nawaz SA, ul-Haq Z, et al. Withanolides, a new class of natural cholinesterase inhibitors with calcium antagonistic properties. Biochem Biophys Res Commun . 2005;334(1):276-287.[↩]
  67. Kulkarni SK, George B. Anticonvulsant action of Withania somnifera (Ashwaganda) root extract against pentylenetetrazol-induced kindling in mice. Phytother Res . 1996;10(5):447-449.[↩]
  68. Kulkarni SK, George B, Mathur R. Protective effect of Withania somnifera root extract on electrographic activity in a lithium-pilocarpine model of status epilepticus. Phytother Res . 1998;12(6):451-453.[↩]
  69. Ahumada F, Trincado MA, Arellano JA, Hancke J, Wikman G. Effect of certain adaptogenic plant extracts on drug-induced narcosis in female and male mice. Phytother Res . 1991;5(1):29-31.[↩]
  70. Kulkarni S, Ninan I. Inhibition of morphine tolerance and dependence by Withania somnifera in mice. J Ethnopharmacol . 1997;57(3):213-217.[↩]
  71. Ramarao P, Rao KT, Srivastava RS, Ghosal S. Effects of glycowithanolides from Withania somnifera on morphine-induced inhibition of intestinal motility and tolerance to analgesia in mice. Phytother Res . 1995;9(1):66-68.[↩]
  72. Lu L, Liu Y, Zhu W, et al. Traditional medicine in the treatment of drug addiction. Am J Drug Alcohol Abuse . 2009;35(1):1-11.[↩]
  73. Bhattacharya SK, Kumar S, Ghosal S. Effects of glycowithanolides from Withania somnifera on an animal model of Alzheimer’s disease and perturbed central cholinergic markers of cognition in rats. Phytother Res . 1995;9(2):110-113.[↩]
  74. Manjunath NK, Telles S. Influence of Yoga and Ayurveda on self-rated sleep in a geriatric population. Indian J Med Res . 2005;121(5):683-690.[↩]
  75. Sriranjini SJ, Pal PK, Devidas KV, Ganpathy S. Improvement of balance in progressive degenerative cerebellar ataxias after Ayurvedic therapy: a preliminary report. Neurol India . 2009;57(2):166-171.[↩]
  76. Bähr V, Hänsel R. Immunomodulating properties of 5,20-alpha(R)-dihydroxy-6-alpha-7-alpha-epoxy-1-oxo-(5-alpha)-witha-2,24-dieno lide and solasodine. Planta Med . 1982;44(1):32-33.[↩]
  77. Dhuley JN. Effect of some Indian herbs on macrophage functions in ochratoxin A treated mice. J Ethnopharmacol . 1997;58(1):15-20.[↩]
  78. Ghosal S, Lal J, Srivastava R, et al. Immunomodulatory and CNS effects of sitoindosides IX and X, two new glycowithanolides from Withania somnifera . Phytother Res . 1989;3(5):201-206.[↩]
  79. Anbalagan K, Sadique J. Withania somnifera (Ashwagandha), a rejuvenating herbal drug which controls a-2 macroglobulin synthesis during inflammation. Int J Crude Drug Res . 1985;23(4):177-183.[↩]
  80. Ziauddin M, Phansalkar N, Patki P, Diwanay S, Patwardhan B. Studies on the immunomodulatory effects of Ashwagandha. J Ethnopharmacol . 1996;50(2):69-76.[↩]
  81. Mikolai J, Erlandsen A, Murison A, et al. In vivo effects of Ashwagandha ( Withania somnifera ) extract on the activation of lymphocytes. J Altern Complement Med . 2009;15(4):423-430.[↩]
  82. Rasool M, Varalakshmi P. Immunomodulatory role of Withania somnifera root powder on experimental induced inflammation: An in vivo and in vitro study. Vascul Pharmacol . 2006;44(6):406-410.[↩]
  83. Singh N, Nath R, Lata A, Singh SP, Kohli RP, Bhargava KP. Withania somnifera (Ashwagandha), a rejuvenating herbal drug which enhances survival during stress (an adaptogen). Int J Crude Drug Res . 1982;20(1):29-35.[↩]
  84. Girish KS, Machiah KD, Ushanandini S, et al. Antimicrobial properties of a non-toxic glycoprotein (WSG) from Withania somnifera (Ashwagandha). J Basic Microbiol . 2006;46(5):365-374.[↩]
  85. Machiah DK, Girish KS, Gowda TV. A glycoprotein from a folk medicinal plant, Withania somnifera , inhibits hyaluronidase activity of snake venoms. Comp Biochem Physiol C Toxicol Pharmacol . 2006;143(2):158-161.[↩]
  86. Nasimi Doost Azgomi R, Zomorrodi A, Nazemyieh H, et al. Effects of Withania somnifera on Reproductive System: A Systematic Review of the Available Evidence. BioMed Research International. 2018;2018:4076430. doi:10.1155/2018/4076430. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833251/[↩][↩]
  87. Mahdi AA, Shukla KK, Ahmad MK, et al. Withania somnifera Improves Semen Quality in Stress-Related Male Fertility. Evidence-based Complementary and Alternative Medicine : eCAM. 2011;2011:576962. doi:10.1093/ecam/nep138. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136684/[↩]
  88. Phytoremedial effect of Withania somnifera against arsenic-induced testicular toxicity in Charles Foster rats. Kumar A, Kumar R, Rahman MS, Iqubal MA, Anand G, Niraj PK, Ali M. Avicenna J Phytomed. 2015 Jul-Aug; 5(4):355-64. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4587609/[↩]
  89. Dongre S, Langade D, Bhattacharyya S. Efficacy and Safety of Ashwagandha (Withania somnifera) Root Extract in Improving Sexual Function in Women: A Pilot Study. BioMed Research International. 2015;2015:284154. doi:10.1155/2015/284154 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4609357/[↩]
  90. Shukla K. K., Mahdi A. A., Mishra V., et al. Withania somnifera improves semen quality by combating oxidative stress and cell death and improving essential metal concentrations. Reproductive BioMedicine Online. 2011;22(5):421–427. doi: 10.1016/j.rbmo.2011.01.010 https://www.ncbi.nlm.nih.gov/pubmed/21388887[↩][↩]
  91. Pharmacological effects of Withania somnifera root extract on GABAA receptor complex. Mehta AK, Binkley P, Gandhi SS, Ticku MK. Indian J Med Res. 1991 Aug; 94():312-5. https://www.ncbi.nlm.nih.gov/pubmed/1660034[↩]
  92. Gupta A., Mahdi A. A., Shukla K. K., et al. Efficacy of Withania somnifera on seminal plasma metabolites of infertile males: A proton NMR study at 800 MHz. Journal of Ethnopharmacology. 2013;149(1):208–214. doi: 10.1016/j.jep.2013.06.02 https://www.ncbi.nlm.nih.gov/pubmed/23796876[↩]
  93. Kyathanahalli C. N., Manjunath M. J., Muralidhara Oral supplementation of standardized extract of Withania somnifera protects against diabetes-induced testicular oxidative impairments in prepubertal rats. Protoplasma. 2014;251(5):1021–1029. doi: 10.1007/s00709-014-0612-5 https://www.ncbi.nlm.nih.gov/pubmed/24488064[↩]
  94. Mali P., Chouhan P., Chaudhary R. Evaluation of antifertility activity of Withania somnifera in male albino rats. Fertility and Sterility. 2008;90:p. S18. doi: 10.1016/j.fertnstert.2008.07.394.[↩]
  95. Sharma S, Dahanukar SA, Karandikar SM. Effects of long-term administration of the roots of ashwagandha and shatavari in rats. Indian Drugs. 1985;29:133–9.[↩]
  96. [Thyrotoxicosis following the use of ashwagandha]. van der Hooft CS, Hoekstra A, Winter A, de Smet PA, Stricker BH. Ned Tijdschr Geneeskd. 2005 Nov 19; 149(47):2637-8. https://www.ncbi.nlm.nih.gov/pubmed/16355578/[↩]
  97. Withania somnifera and Bauhinia purpurea in the regulation of circulating thyroid hormone concentrations in female mice. Panda S, Kar A. J Ethnopharmacol. 1999 Nov 1; 67(2):233-9. https://www.ncbi.nlm.nih.gov/pubmed/10619390/[↩]
  98. Changes in thyroid hormone concentrations after administration of ashwagandha root extract to adult male mice. Panda S, Kar A. J Pharm Pharmacol. 1998 Sep; 50(9):1065-8. https://www.ncbi.nlm.nih.gov/pubmed/9811169/[↩][↩][↩]
  99. Gupta GL, Rana AC. Withania somnifera (Ashwagandha): A review. Pharmacogn Rev. 2007;1:129–36.[↩]
  100. Patel SB, Rao NJ, Hingorani LL. Safety assessment of Withania somnifera extract standardized for Withaferin A: Acute and sub-acute toxicity study. Journal of Ayurveda and Integrative Medicine. 2016;7(1):30-37. doi:10.1016/j.jaim.2015.08.001. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910650/[↩][↩][↩]
  101. Raut AA, Rege NN, Tadvi FM, et al. Exploratory study to evaluate tolerability, safety, and activity of Ashwagandha (Withania somnifera) in healthy volunteers. Journal of Ayurveda and Integrative Medicine. 2012;3(3):111-114. doi:10.4103/0975-9476.100168. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3487234/[↩][↩]
  102. Prabu P.C., Panchapakesan S., Raj C.D. Acute and sub-acute oral toxicity assessment of the hydroalcoholic extract of Withania somnifera roots in Wistar rats. Phytother Res. 2013;27:1169–1178. https://www.ncbi.nlm.nih.gov/pubmed/22996349[↩]

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