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 12).

Ashwagandha is the most commonly used and extensively studied adaptogen 13). 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 14). 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 15). Ashwagandha is one adaptogen that possesses all of the characteristics listed above 16).

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 17), 18), 19), 20), 21).

Ashwagandha leaves are used in the treatment of fever, tumors and ulcers 22). 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 23). Withaferin A appeared to be the most bioactive compound with anti-invasive, anti-angiogenic, anti-inflammatory and pro-apoptotic effects 24). 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 25) and anti-inflammatory, pro-apoptotic, and anti-fibrotic effects 26). 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 27). Above all, Withaferin A is a pre-clinically proven vimentin and TGF-β inhibitor but its role in pulmonary fibrosis is not yet explored 28). Further studies are needed in order to establish Withaferin A as a promising therapeutic intervention for treatment of pulmonary fibrosis.

Grace et al. 29) 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) 30). Though both withanolide components displayed anti-oxidative and anti-inflammatory effects, Withaferin A was found to be 10 fold more effective than Withanolide A 31). 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 32).

Withanolide-A is a potential neurological, immunological and anti-stress agent 33). 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 34). 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 35) 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 36). Overexpression of cycloartenol synthase in Ashwagandha increased the withanolide content to the extent of 1.06 to 1.66 fold 37).

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 38). 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 39).

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 40). These types of remedies are given to small children as tonics, and are also taken by the middle-aged and elderly to increase longevity 41). 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 42), 43). All these therapeutic uses suggest its anti-inflammatory, aphrodisiac, semenogogue, and deobstruent features 44).

Ashwagandha and anxiety

Anxiety disorders are widespread and disabling conditions with a lifetime prevalence of nearly 30% in the United States 45). 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 46). Ashwagandha is also classified as an adaptogen, which indicates its ability to regulate physiologic processes and thereby stabilize the body’s response to stress 47). Ashwagandha exerts an anxiolytic effect in animals and humans 48). 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 49). In a similar investigation, Ashwagandha increased stress tolerance among animals subjected to a cold water swimming stress test 50). 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 51). 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 52) 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 53). 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. 54) prevented blinding of the care providers, allowing greater chance for performance bias. Suggestion of reporting bias in Auddy et al. 55) 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 56) 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 57). 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 58), 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 59). These results are consistent with the findings of previous in-vivo studies 60). Similar results were reported by Andrade et al. in anxiety patients 61).

Effect of Ashwagandha on antecedents and consequences of stress

This study 62) 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 63), 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 64). 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 65). The results of this study 66) 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. 67) 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 68).

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 69). Related effects on cytokines and transcription factors, and suppression of nitric oxide have also been demonstrated 70). 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 71). 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 72).

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 73), 74), 75), 76). 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 77).

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 78).

Damage to the bladder by cyclophosphamide was ameliorated by Ashwagandha extract 79), as was leukopenia induced by cyclophosphamide 80).

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 81), with some researchers suggesting potential applications in Alzheimer and Parkinson diseases 82).

Ashwagandha extract protected against pentylenetetrazol-induced seizures in a mouse anticonvulsant model when administered over a 9-week period 83). The same research group found the extract active in a rat status epilepticus model 84). A depressant effect on the CNS was indicated by potentiation of pentobarbital effects on the righting reflex in mice 85), and a mild tranquilizing/relaxant effect in monkeys, cats, dogs, rats, and mice by a total alkaloid extract from the plant roots 86).

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 87). A withanolide-containing fraction reversed morphine-induced reduction in intestinal motility and confirmed the previous finding of inhibition of development of tolerance to morphine 88). A role in the management of drug addiction has been suggested 89).

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 90). 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 91). In another study, increased balance was determined in elderly patients with long-term progressive degenerative ataxia 92).

Immune system effects

Withanolides inhibit murine spleen cell proliferation 93) and an extract of Ashwagandha reversed ochratoxin’s suppressive effect on murine macrophage chemotaxis 94). 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 95). Alpha-2 macroglobulin synthesis stimulated by inflammation was reduced by Ashwagandha extract 96). Similarly, the extract prevented myelosuppression caused by cyclophosphamide, azathioprine, or prednisolone in mice 97). 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 98). Additional effects on cytokines and the complement system, lymphocyte proliferation, and humoral and cell-mediated responses have been discussed 99).

Other uses

Animal experiments have been conducted to describe adaptogenic properties (increased swimming endurance and reduced stress response) of Ashwagandha . Clinical trials are lacking 100).

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 101).

Antimicrobial effects 102) and antivenom activity via hyaluronidase inhibition have been described 103).

Ashwagandha benefits

Ashwagandha benefits for men and women

Based on this study 104), it was shown that extracts of ashwagandha fruits, leaves, stems, and especially roots enhance sperm quality indices such as motility and count in men 105) and also decrease the effects of chemical toxins on gonads in both men and women 106). Ashwagandha can increase gonadal weight in both sexes, enhance folliculogenesis and spermatogenesis, and improve LH, FSH, and testosterone balances 107). Sexual behavior indices such as female sexual function index and female sexual distress index improve statistically significant after ashwagandha extract administration 108). 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 109). 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 110). 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 111). In the male reproductive system, it is assumed that ashwagandha by providing metal ions facilitates enzyme activities, modifies oxidative stress, and prevents cell apoptosis 112). 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 113). 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 114). 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 115).

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 116). An analysis of the adverse events recorded in this study 117) 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 118). Long-term administration of the roots of Ashwagandha was found to be safe also in animal studies 119). 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) 120) and data from mice administered Ashwagandha that showed significant increases in thyroxine levels (T4 levels) 121), 122). The authors opined that Ashwagandha’s actions are mainly driven by stimulation of the thyroid gland to release thyroxine T4 123), 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 124), 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 125), 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 126). 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 127). 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 128). 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 129). 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 130).

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 131).

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.

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