Background: The coronavirus disease-2019 (COVID-19) pandemic has resulted in a surge in stress, anxiety, and depression worldwide. Ashwagandha, an ayurvedic adaptogen has been traditionally used to manage stress, anxiety, and general well-being.
Objective: We assessed the effect of Ashwagandha root extract (ARE-500 mg) standardized for 2.5% withanolides as per USP protocol with piperine (5 mg of 95% piperine) once daily for 60 days (12.5 mg withanolides/day) to alleviate stress and anxiety in healthy individuals with mild to moderate symptoms.
Methods: A randomized, double-blind, placebo-controlled study was conducted for 60 days using ARE (n = 27) and placebo (n = 27) once daily at night at Narayana Institute of Cardiac Sciences, Bangalore, and Vijaya Super Specialty Hospital, Nellore, in India. The objectives of this study were to assess an improvement in perceived stress scale (PSS), generalized anxiety disorder (GAD-7), quality of life (QOL), cognitive scores in the Cambridge Neuropsychological Test Automated Battery (CANTAB), changes in salivary cortisol, urinary serotonin, dopamine, serum levels of nitric oxide (NO), glutathione (GSH) and malondialdehyde (MDA) from baseline to end of the study. Safety was evaluated by laboratory parameters, and by monitoring any incidence of adverse events.
Results: 54 individuals were randomized and 50 of them completed the study. The PSS, GAD-7, and QOL scores improved significantly in all the participants taking ARE compared to the placebo. The CANTAB analysis revealed a significant improvement in multitasking, concentration, and decision taking time in ARE compared to placebo. ARE was also associated with a greater reduction in the morning salivary cortisol and an increase in urinary serotonin compared to placebo. Serum levels of NO, GSH, and MDA were not significantly different. Biochemical and hematological parameters remained in the normal range in all participants and ARE was well tolerated during the study.
Conclusion: In conclusion, the result of this study suggests that ARE (Shagandha, standardized for 2.5% withanolides) at 500 mg with 5 mg of 95% piperine once a day could induce positive effects on stress and anxiety and improve the quality of life in healthy individuals with mild to moderate stress. A significant improvement could be observed in cognitive tasks, multitasking, and concentration in comparison to placebo. ARE significantly reduced cortisol levels and increased serotonin suggesting its mechanism of action through the HPA axis. The results of the study were comparable to earlier studies conducted with ashwagandha extracts containing a higher quantum of withanolides. Future studies in different ethnic populations and longer duration would substantiate our results.
Keywords: anxiety, Ashwagandha root extract, CANTAB, cortisol, quality of life, serotonin, stress
A standardized Ashwagandha root extract alleviates stress, anxiety, and improves quality of life in healthy adults by modulating stress hormones Results from a randomized, double-blind, placebo-controlled study - Medicine (2023) 102:41 - Muhammed Majeed, Kalyanam Nagabhushanam, Lakshmi Mundkur

The experiment was conducted in male Wistar rats and observed for the reproductive performance studies. Both behavioral and biochemical assessments were carried out.
Results
●Non-estrous female rats were paired with males treated with a single dose of the formulation. There was an increase in the number of mounts significantly, indicating it is a very effective aphrodisiac
●Testosterone levels increased throughout the use of formulation, proving to be a safe and long-term solution for improved testosterone
●Androstenedione level increased in serum of treated animals after 1 hour of administration of the formulation
●An increase in cGMP and cGMP – PK1 concentration in serum of treated animals after 1 hr of administration of the formulation was observed. cGMP causes smooth muscles in the arteries to relax, increasing blood flow, thus playing a major role in maintaining the erection for a longer time
Conclusion Thus, the study proved that the formulation is very safe and exhibited an excellent aphrodisiac potential use for the management of male sexual dysfunction.

Abstract : As the COVID-19 pandemic is progressing, the therapeutic gaps in conventional management have highlighted the need for the integration of traditional knowledge systems with modern medicine. Ayurvedic medicines, especially Ashwagandha (Withania somnifera (L.) Dunal, WS), may be beneficial in the management of COVID-19. WS is a widely prescribed Ayurvedic botanical known as an immunomodulatory, antiviral, anti-inflammatory, and adaptogenic agent. The chemical profile and pharmacological activities of WS have been extensively reported. Several clinical studies have reported its safety for use in humans. This review presents a research synthesis of in silico, in vitro, in vivo, and clinical studies on Withania somnifera (L.) Dunal (WS) and discusses its potential for prophylaxis and management of COVID-19. We have collated the data from studies on WS that focused on viral infections (HIV, HSV, H1N1 influenza, etc.) and noncommunicable diseases (hypertension, diabetes, cancer, etc.). The experimental literature indicates that WS has the potential for 1) maintaining immune homeostasis, 2) regulating inflammation, 3) suppressing pro-inflammatory cytokines, 4) organ protection (nervous system, heart, lung, liver, and kidney), and 5) anti-stress, antihypertensive, and antidiabetic activities. Using these trends, the review presents a triangulation of Ayurveda wisdom, pharmacological properties, and COVID-19 pathophysiology ranging from viral entry to end-stage acute respiratory distress syndrome (ARDS). The review proposes WS as a potential therapeutic adjuvant for various stages of COVID-19 management. WS may also have beneficial effects on comorbidities associated with the COVID-19. However, systematic studies are needed to realize the potential of WS for improving clinical outcome of patients with COVID-19.
Keywords: Adjuvant; Ashwagandha; Ayurveda; Cytokine; Immunomodulation; Inflammation; Rasayana.
Withania somnifera (L.) Dunal: Opportunity for Clinical Repurposing in COVID-19 Management, Akash Saggam, Kirti Limgaokar, Swapnil Borse, Preeti Chavan-Gautam, Santosh Dixit, Girish Tillu, Bhushan Patwardhan, Front Pharmacol. 2021 May 3

Ashwagandha is used in Cosmetics and hair care because it relaxes blood vessels and stimulates circulation. It is a mild sedative, with anti-inflammatory properties.
For Anti-aging : In a double blind clinical trial, ashwagandha was tested in a group of 101 healthy males, 50-59 years old at a dosage of 3 gms daily of 1 year. A significant improvement in hemoglobin, red blood cell count, Hair melanin was observed. Serum cholesterol decreased and nail calcium was preserved. Erythrocyte sedimentation rate decreased significantly.
In Ayurveda, it is an important ingredient of some formulations, that are administered internally to improve complexion.
Other Cosmetic uses based on :
1. For Treatment of Inflammatory conditions.
2. For treatment Scabies and Lice infestations.
3. For Pain reduction.
4. It has therapeutic effects stronger than Penicillin as an antibiotic

OBJECTIVE: The objective of this paper is to review the literature regarding Withania somnifera (ashwagandha, WS) a commonly used herb in Ayurvedic medicine. Specifically, the literature was reviewed for articles pertaining to chemical properties, therapeutic benefits, and toxicity.
DESIGN: This review is in a narrative format and consists of all publications relevant to ashwagandha that were identified by the authors through a systematic search of major computerized medical databases; no statistical pooling of results or evaluation of the quality of the studies was performed due to the widely different methods employed by each study.
RESULTS: Studies indicate ashwagandha possesses anti-inflammatory, antitumor, antistress, antioxidant, immunomodulatory, hemopoetic, and rejuvenating properties. It also appears to exert a positive influence on the endocrine, cardiopulmonary, and central nervous systems. The mechanisms of action for these properties are not fully understood. Toxicity studies reveal that ashwagandha appears to be a safe compound.
CONCLUSION: 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 this herb 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.
Scientific Basis for the Therapeutic Use of Withania somnifera : A Review - Ashwagandha - Alternative Medicine Review,  August, 2000  by Lakshmi-Chandra Mishra,  Betsy B. Singh,  Simon Dagenais

ETHNOPHARMACOLOGICAL RELEVANCE: Ashwagandha is a reputed herb in traditional Ayurveda, used for various ailments and improving general well-being. Improved cardiorespiratory endurance can aid in attaining better physiological, metabolic, and functional abilities in humans. According to Ayurveda, Ashwagandha has such potential to improve human health.
AIM OF THE STUDY: This study aimed to evaluate the efficacy and safety of Ashwagandha root extract in enhancing cardiorespiratory endurance in healthy athletic adults. MATERIALS AND METHODS: Fifty healthy athletic adults were selected randomly and equally allocated to Ashwagandha and placebo groups. The Ashwagandha group received 300 mg of Ashwagandha root extract capsules, twice daily, for 8-weeks. Cardiorespiratory endurance was assessed by measuring the maximum aerobic capacity (VO2 max). Estimation of stress management was done through Total Quality Recovery Scores (TQR), Recovery-Stress Questionnaire for Athletes (RESTQ), and Daily Analysis of Life Demands for Athletes (DALDA) questionnaires along with the antioxidant level measurement.
RESULTS: At the end of the study, a significant improvement in VO2 max outcome was observed in the Ashwagandha group when compared to the placebo group (P = 0.0074). The subjects in the Ashwagandha group also displayed a statistically significant increase at the end of the study when compared to the baseline (P<0.0001). Significantly improved TQR scores were observed in the Ashwagandha group members compared to their placebo counterparts (P below 0.0001). DALDA questionnaire analysis in the Ashwagandha group was found statistically significant (P below 0.0001) compared to the placebo group. RESTQ assessment also yielded better outcomes, especially for fatigue recovery (P below 0.0001), lack of energy (P below 0.0001), and fitness analysis (P below 0.0001). The enhanced antioxidant level was significant (P below 0.0001) in the Ashwagandha group.
CONCLUSION: The present findings suggest that Ashwagandha root extract can successfully enhance cardiorespiratory endurance and improve the quality of life in healthy athletic adults. No adverse events were reported by any of the subjects in this study.
A double-blind, randomized, placebo-controlled trial on the effect of Ashwagandha (Withania somnifera Dunal.) root extract in improving cardiorespiratory endurance and recovery in healthy athletic adults. Tiwari S, Gupta SK, Pathak AK 15 février 2021 J Ethnopharmacol. 2021 Feb 15. 113929

Abstract: The immunomodulatory effect of Withania somnifera (WS) extract was tested in healthy adults. In this randomized placebo-controlled double-blinded study, subjects were allocated either 60 mg WS extract or placebo. It consists of a blinded 30-day period and an open-label extension study of another 30 days with crossover of only placebo to test. After the 30-day blinded study period, the WS test group reported significant increase (p max 0.05) in Ig’s (IgA, IgM, IgG, IgG2, IgG3 and IgG4), Cytokines (IFN- , IL4), TBNK (CD45+, CD3+, CD4+, CD8+, CD19+, NK cells) whereas in the placebo group TBNK cells showed significant decrease (p max 0.05) and Ig’s and cytokines showed no change (p min 0.05). In the extension period on day 60, the subjects on placebo who were crossed over to the WS test group showed significant increase (p max 0.05) in Ig’s, cytokines and TBNK cells and the subjects who continued on the WS group showed a further significant improvement (p max 0.05) in Ig’s, cytokines and TBNK cells. There were no adverse events reported in the study. WS extract significantly improved the immune profile of healthy subjects by modulating the innate and adaptive immune systems. Boosting the immune system of people at risk of infection and during widespread infections can be targeted with WS extract.
Conclusion : This pilot, randomized, and controlled clinical study demonstrates for the first time that the leaf and root extract of WS standardized with withanolide glycosides possesses potent immune-stimulatory properties. It establishes Th2 up-regulating activity as evidenced by enhanced secretion of IL4 along with the enhanced expression of Th1 (IFN- ) strongly suggesting the role of WS in conditions where Th1/Th2 modulation is required. WS enhanced the proliferation of CD4+/CD8+ without altering its ratio and NK cells along with an increased expression of CD3+/CD19+/CD45+ and increased the circulating antibody and antibody-forming cells. The results of this study demonstrate that WS of defined chemical signature with its immune-stimulatory activities is a valuable addition in the immunity-boosting herbal supplements. These effects span both innate and adaptive immunity, which may partially explain its traditional use as a Rasayana or rejuvenating herb with anti-stress properties.
Keywords: Withania somnifera; withanolide glycosides; immunomodulation; immunity; Th1–Th2 pathway
Immunomodulatory Effect of Withania somnifera (Ashwagandha) Extract - A Randomized, Double-Blind, Placebo Controlled Trial with an Open Label Extension on Healthy Participants - Ajit Tharakan, Himanshu Shukla, Irin Rosanna Benny, Matthan Tharakan , Lekha George and Santhosh Koshy, J. Clin. Med. 2021, 10, 3644

BACKGROUND: Ashwagandha (Withania somnifera) is a well-established and reputed herb in Ayurvedic medicine. It has been used as a "Rasayana" (rejuvenator), nootropic, and as a powerful natural adaptogen. The herb extract is extensively used for general wellbeing and in specific ailments. However, only a few studies have investigated the safety and tolerability of Ashwagandha in humans. This study evaluated the safety of Ashwagandha root extract consumption in healthy adults.
METHODS: In this randomized, double-blind, placebo-controlled, and parallel-group study, 80 healthy participants (40 males, 40 females) were randomized in a 1:1 ratio to receive either Ashwagandha 300 mg or a starch placebo of the same dosage, twice daily, orally for 8 weeks. The study was conducted at MV Hospital, and King George Medical University, Lucknow, India. The primary safety outcomes considered were laboratory assessment of hematological parameters, serum biochemistry analysis including hepatotoxicity evaluation, and thyroid function parameters. The secondary outcomes of this study were the clinical adverse events and the vital parameters. The within and between the groups' datasets were compared using the Wilcoxon signed-rank test and the Mann Whitney U test, respectively.
RESULTS: A detailed evaluation of the vital signs such as body weight, body temperature, pulse rate, respiratory rate, systolic and diastolic blood pressure, and Body Mass Index (BMI) were conducted for each participant at the baseline and the end of the study for treatment and placebo groups. Similarly, hematological and biochemical parameters were evaluated at the baseline and the study termination. The outcome did not indicate any untoward effects in any of the treated volunteers. No statistically significant change or abnormality was observed in the considered parameters including thyroid hormonal profile in both the groups. No adverse events were reported by any of the participants in this study.
CONCLUSIONS: Ashwagandha is being consumed since time immemorial following the Ayurvedic medicine practices. Modern science requires evidence of the safety and efficacy of the Ashwagandha extract before mass consumption for various health issues and as a supplement. The present study revealed that the consumption of Ashwagandha root extract for 8 weeks was safe in both males and females volunteers. However, long term study and varying dosage ranges should be investigated in the future.
Keywords: Clinical study; Safety; Thyroid hormones; Thyroxine; Vital sign; Withania somnifera
Safety of Ashwagandha Root Extract: A Randomized, Placebo-Controlled, Study in Healthy Volunteers, Verma N, Gupta SK, Tiwari S, Mishra AK, Complement Ther Med. 2020 Dec 15. 102642

Abstract : Laboratory indices of thyroid function (TSH, Free T4, and T3) were measured in a randomized clinical trial in which Ashwagandha (ASW) was used to improve cognitive function in patients with bipolar disorder. This was done in light of a case‑report of ASW‑associated thyrotoxicosis, and data from mice administered ASW that showed significant increases in thyroxine levels. Ten (of the original 60) patients showed abnormal results in one of the thyroid measures either at the beginning or end of the 8‑week study. One ASW‑ treated patient had subclinical hypothyroidism (TSH ‑ 5.7 mIU/L) at baseline that normalized, and all three ASW treated patients experienced T4 increases from baseline (7%, 12%, and 24%). Six of 7 placebo‑assigned patients showed decreases in T4 from baseline (4% to 23%), and one patient’s TSH moved from the normal to subclinical hypothyroid range (6.96 mIU/L). As thyroid indices were done for safety, and not the primary goal of the original study, only 16.7% had abnormal thyroid indices, and as there was no sub‑stratification for treatment assignment by thyroid status, unequal numbers of subjects received ASW (n = 3) or placebo (n = 7). In spite of these limitations, the subtle laboratory changes noted in thyroid indices in an 8‑week study suggest that ASW may increase thyroxine levels, and therefore vigilance regarding hyperthyroidism may be warranted. Nonetheless, the thyroid enhancing properties of ASW may also represent a clinical opportunity for the treatment of subclinical hypothyroidism, and these results suggest the need for further study of the effects of ASW on thyroid indices, especially in those with bipolar and unipolar mood disorders.
Discussion : The current report of ASW elevating T4, along with its anti‑inflammatory, neuroprotective, anti‑oxidant, and anti‑depressant properties, suggest that ASW 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 ASW extracts are more specifically beneficial in persons with unipolar or bipolar disorders with treatment resistant depression or rapid cycling.
Key words: Ashwagandha, bipolar disorder, depression, thyroid functions, subclinical hypothyroidism
Subtle changes in thyroid indices during a placebo‑controlled study of an extract of Withania somnifera in persons with bipolar disorder, Jessica M. Gannon, Paige E. Forrest, K. N. Roy Chengappa - Journal of Ayurveda & Integrative Medicine, October-December 2014, Vol 5, Issue 4

Ashwagandha (Withania somnifera) is widely used in Ayurvedic medicine, and it is one of the ingredients in many formulations to increase energy, improve overall health and longevity, and prevent disease. The main objective of the study was to analyze the efficacy of Ashwagandha root powder with water and with milk in treatment of hypertension. The experiment was conducted on 51 stress-oriented hypertensive subjects in the age group of 40 to 70 years, selected by purposive sampling. Subjects were divided into group I and group II. Supplementation of 2gm of Ashwagandha root powder was given to group I and group II with milk and water respectively in morning. Blood pressure was also recorded over a period of three months. Overall decrease in systolic blood pressure was found though it was non- significant. Further, decrease in systolic blood pressure was significant in group I, whereas decrease in diastolic blood pressure was significant in both the groups.
Hence, supplementation of Ashwagandha with milk is recommended in treatment of stress- oriented hypertension.
Effect of Ashwagandha (Withania somnifera) Root Powder Supplementation in Treatment of Hypertension - Shalini Kushwaha, Agatha Betsy and Paramjit Chawla - Ethno Med, 6(2): 111-115 (2012) - Shalini Kushwaha, Agatha Betsy and Paramjit Chawla