Ashwagandha (Stress)

BACKGROUND: Ashwagandha (Withania somnifera), as an important herbal medicine, has been increasingly recognized for its role in mental health management, particularly in reducing stress and anxiety, and reflects the growing relevance of complementary and alternative medicine in addressing psychological well-being. The present study aims to investigate its effectiveness by pooling the evidence from existing randomized controlled trials (RCTs). METHODS: Major medical databases of PubMed, Scopus, and Web of Science Core Collection were searched. Eligible studies were included. Meta-analysis, meta-regression, non-linear dose-response analysis, and subgroup analyses were conducted. Standardized mean differences (SMDs) were calculated. P-values < 0.05 were considered as statistically significant. The study protocol was registered in the PROSPERO database (CRD420251073134). RESULTS: Twenty-two studies met the eligibility criteria and were included. Meta-analysis revealed that supplementation with ashwagandha significantly improves stress (SMD = -5.88; 95 % CI: -8.15 to -3.60), depression (SMD = -5.68; 95 % CI: -8.43 to -2.94), and anxiety (SMD = -6.87; 95 % CI: -8.77 to -4.97). There was significant linear (coefficient = 0.005, P = 0.031) and non-linear (P-nonlinearity = 0.005) association between dosages of administered ashwagandha and stress levels. CONCLUSION: Current evidence suggests that ashwagandha supplementation holds promising potential in alleviating symptoms of stress, anxiety, and depression. However, to strengthen these findings and translate them into clinical recommendations, well-designed, high-quality trials are still needed to address existing heterogeneity and to establish the most effective dosages and intervention durations.

BackgroundThe global medicine market is projected to reach US$417 billion by 2033, reflecting rising demand for natural healthcare alternatives. Ashwagandha (Withania somnifera) is widely used in Ayurvedic medicine for stress management, but evidence supporting its efficacy remains inconsistent.AimThis systematic review and meta-analysis evaluated Ashwagandha's impact on cortisol levels (a biological stress marker) and perceived stress via Perceived Stress Scale (PSS) scores across randomized controlled trials (RCTs).MethodPRISMA guidelines were followed. Four databases (PubMed, CINAHL, Google Scholar, and Scopus) were searched for studies from January 2012 to February 2024, yielding seven studies on cortisol and six on perceived stress (n = 488 participants). Inclusion criteria were RCTs longer than or equal to two weeks, oral doses ≥250 mg/day, and reporting cortisol and PSS outcomes. The Cochrane Risk of Bias 2 tool was used to assess the risk of bias.ResultsThere was a statistically significant reduction in cortisol levels (-1.16 µg/dL, 95% CI: -1.64 to -0.69, P < 0.001). No significant impact was observed on perceived stress (SMD = -0.355, 95% CI: -1.188 to 0.47; P = 0.40). Heterogeneity was moderate (I2 = 50.9%). However, no statistically significant impact was observed on perceived stress (SMD = -0.355, 95% CI: -1.188 to 0.47; P-value = 0.40). The heterogeneity among studies was moderate (I2 = 50.9%). Risk of bias was generally moderate; most studies reported adequate randomization, but some lacked allocation concealment. No publication bias was detected.ConclusionFindings support Ashwagandha's role in lowering cortisol, but gaps remain regarding long-term safety, dosing, and effectiveness across diverse populations. The disconnect between cortisol and PSS outcomes highlights the need for longer treatment duration and broader demographic inclusion. Longitudinal research is recommended to validate Ashwagandha as a holistic stress management tool.

Clinical trial studies revealed conflicting results on the effect of Ashwagandha extract on anxiety and stress. Therefore, we aimed to evaluate the effect of Ashwagandha supplementation on anxiety as well as stress. A systematic search was performed in PubMed/Medline, Scopus, and Google Scholar from inception until December 2021. We included randomized clinical trials (RCTs) that investigate the effect of Ashwagandha extract on anxiety and stress. The overall effect size was pooled by random-effects model and the standardized mean difference (SMD) and 95% confidence interval (CIs) for outcomes were applied. Overall, 12 eligible papers with a total sample size of 1,002 participants and age range between 25 and 48 years were included in the current systematic review and meta-analysis. We found that Ashwagandha supplementation significantly reduced anxiety (SMD: -1.55, 95% CI: -2.37, -0.74; p = .005; I2 = 93.8%) and stress level (SMD: -1.75; 95% CI: -2.29, -1.22; p = .005; I2 = 83.1%) compared to the placebo. Additionally, the non-linear dose-response analysis indicated a favorable effect of Ashwagandha supplementation on anxiety until 12,000 mg/d and stress at dose of 300-600 mg/d. Finally, we identified that the certainty of the evidence was low for both outcomes. The current systematic review and dose-response meta-analysis of RCTs revealed a beneficial effect in both stress and anxiety following Ashwagandha supplementation. However, further high-quality studies are needed to firmly establish the clinical efficacy of the plant. © 2022 John Wiley & Sons Ltd.

BACKGROUND: The adaptogenic effects of Ashwagandha root extract are evident. An earlier study showed the therapeutic effects of a once-daily sustained-release (SR) formulation (300 mg) of Ashwagandha root extract over an extended period. This study aimed to evaluate the efficacy and safety of Ashwagandha root extract sustained-release (AshwaSR) 150 and 300 mg capsules in reducing stress in healthy adult, stressed subjects. METHODS: In this double-blind, randomized, placebo-controlled trial, healthy subjects with Perceived Stress Scale score 14 to 26 were randomized (1:1:1) to AshwaSR 150 mg (group A) or 300 mg (group B) or placebo (group C). Change from baseline to day 60 was evaluated for stress levels, sleep quality, psychological well-being, eating behavior, and serum cortisol levels in all groups. RESULTS: Of 135 subjects randomized, 126 completed the trial (mean age, 34.79 ± 8.16 years). Mean Perceived Stress Scale scores significantly reduced from baseline to day 60 in group A and B (mean change, 38.6% and 41.6% respectively; P < .001). Sleep quality, psychological well-being, and eating behavior significantly improved from baseline to day 60 in groups A and B (P < .001). Serum cortisol levels in group B were significantly reduced on day 60 (P < .05). Both group A and B showed significant improvements in stress levels, sleep quality, psychological well-being, and eating behavior at day 60 (P < .05) compared to group C. No safety concerns were reported. CONCLUSION: AshwaSR 150 and 300 mg capsules reduced perceived stress and improved sleep quality, eating behavior, and psychological well-being and were safe in healthy adult, stressed subjects over 60 days of administration.

Stress and anxiety are interconnected, sharing both behavioural and neural foundations. Ashwagandha (Withania somnifera) helps reduce stress and anxiety. This study aimed to evaluate the efficacy and safety of a proprietary herbal extract of ashwagandha root (APB) in adult men and women with moderate stress and anxiety. This 8-week, randomized, double-blind, three-arm, placebo-controlled trial included 141 healthy men and women aged 18-65 years with stress and anxiety. Participants were randomized to receive either 300 mg of APB twice daily (n = 47), ashwagandha root extract (ARE, n = 47), or placebo (PL, n = 47) for 8 weeks. The primary endpoint was a change in serum cortisol levels at week 8. Secondary endpoints were the mean changes in Perceived Stress Scale (PSS), Hamilton Anxiety Rating Scale (HAM-A), Profile of Mood States (POMS), and Oxford Happiness Questionnaire (OHQ) scores. Safety was assessed through clinical adverse events (AEs) and laboratory parameters. Between-group comparisons were analyzed using one-way ANOVA with Tukey's post-hoc test, and within-group changes were assessed using paired t-tests. At 8 weeks, all groups have shown a significant reduction in serum cortisol, and improvements in PSS (P < 0.0001), HAM-A (P = 0.001), and POMS domain scores (tension, depression, and anger, P < 0.0001). In addition, the APB showed significant differences compared with ARE and PL for PSS, HAM-A total score, OHQ, and POMS (P < 0.05). The proprietary herbal extract of ashwagandha root (300mg twice daily) is considered an effective and safe intervention for reducing stress and anxiety. © 2026 The Author(s).

BACKGROUND: Chronic stress is detrimental to the maintenance of the main response system - the hypothalamic-pituitary-adrenal (HPA) axis. The current study aimed to investigate the efficacy of two plant-based adaptogens, a formula containing Rhodiola, holy basil and Schisandra chinensis (VL-G-A57) and a full-spectrum ashwagandha (VL-G-E12), on stress and related symptoms in individuals with high stress. MATERIALS AND METHODS: The 60-day randomized, double-blind, placebo-controlled clinical study included individuals aged between 18 to 65 years with a body mass index (BMI) of 18 to 29.9 kg/m2. One hundred eighty-six participants were randomized to one of the adaptogens, VL-G-A57 or VL-G-E12, or to placebo. The primary outcome was a reduction in stress levels. Secondary outcomes were changes in sleep quality, fatigue, restorative sleep, mental alertness, mood dysregulation, and anxiety. A priori power analysis determined the required sample size. Efficacy was assessed by comparing mean changes in the primary endpoint at days 30 and 60 using ANCOVA, with baseline values as covariates. Dunnett's post hoc test identified significant differences versus placebo, and within-group changes were evaluated using paired t-tests. Normality was assessed visually and via Shapiro-Wilk/Kolmogorov-Smirnov tests as needed. Secondary outcomes were analyzed similarly. Analyses were conducted using R (v4.0.5) and XLSTAT (v2021.3.1). RESULTS: At day 60, both VL-G-A57 and VL-G-E12 significantly reduced Perceived Stress Scale (PSS) scores compared to placebo (p < 0.0001). Sleep quality, as measured by the Pittsburgh Sleep Quality Index (PSQI), improved significantly in both adaptogen groups (VL-G-A57: p = 0.0008, VL-G-E12: p < 0.0001). This corresponded well with the Restorative Sleep Questionnaire-Weekly (RSQ-W) results in the two IP arms when compared with placebo (p < 0.0001). Additionally, mood dysregulation (VL-G-A57: p = 0.0454), anxiety (VL-G-A57: p = 0.0004, VL-G-E12: p = 0.0015), and stress levels (VL-G-A57-VL-G-E12: p < 0.0001) showed significant improvements compared to placebo. No differences in mental alertness were observed. CONCLUSION: The study concluded that both VL-G-A5

The relationship between excess body weight and stress significantly impacts overall health. The current study evaluated the efficacy and safety of Ashwagandha (Withania somnifera) root extract (ARE) in altering stress biomarkers and its role in weight management. In this prospective, randomized, double-blind, placebo-controlled study, 100 participants (age: 19-65 years) were randomized to receive either ARE 300 mg twice daily (n = 50) or an identical placebo (PL, n = 50) for 24 weeks. The primary efficacy endpoints were changes in body weight and body mass index (BMI). Secondary endpoints included evaluation of stress (Perceived Stress Scale, PSS), quality of life (Short Form-12 Quality of Life Scale), subjective satisfaction (Subjective Satisfaction Scale, SSS), and food cravings (Food Cravings Questionnaire-Trait, FCQ-T). Clinical safety was assessed based on treatment-emergent adverse events (TEAEs) and laboratory parameters, including complete blood count, renal function tests, liver function tests, lipid profile, thyroid function tests, and glycemic parameters (plasma glucose and glycated hemoglobin). Efficacy was analyzed in 91 patients. ARE administration resulted in a significant reduction in body weight (-8.46 ± 3.86 kg; P < 0.0001) and BMI (-3.31 ± 1.57 kg/m2; P < 0.0001) compared to the PL (-2.41 ± 2.07 kg and -0.93 ± 0.79 kg/m2 for body weight and BMI, respectively). Compared with PL, ARE showed significant improvements (P < 0.05) in PSS, SF-12, SSS, and FCQ-T scores. A total of seven participants with ARE and six with PL reported mild adverse events (nausea, abdominal pain, and drowsiness), which were resolved without any intervention. Ashwagandha root extract may offer a safe and beneficial approach for stress reduction and weight management. © 2025 The Author(s).

Objectives: This study investigates the effects of 600 mg/day Ashwagandha root extract on physiological stress biomarkers, perception of recovery, muscle strength and aerobic capacity in team sports athletes during pre-season training, a period associated with elevated cortisol and accumulated training stress. Methods: Fifty-six athletes (26.8 ± 4.4 years, 1.74 ± 0.10 m, 79.4 ± 17.3 kg, 11.0 ± 7.1 career years) across rugby, water polo and football were randomly assigned to an Ashwagandha (ASH; n = 28, 14 males and 14 females) or placebo (PLA; n = 28, 14 males and 14 females) group for 42 days. Salivary biomarkers were assessed after training, muscle strength and aerobic capacity were measured during training, and perception of recovery was evaluated with Hooper Index (HI) the following day. Mixed ANOVA was used to determine group × time interactions and Bonferroni post hoc analyses were conducted for multiple pairwise comparisons. Results: In female athletes, salivary cortisol increased significantly in PLA (p = 0.001), while recovery parameters such as the overall HI score (p = 0.001), Delayed Onset Muscle Soreness (DOMS) (p = 0.008) and perception of fatigue (p = 0.026) scores improved significantly in ASH. In males, salivary cortisone increased significantly in PLA (p = 0.022), while Countermovement Jump (CMJ) improved significantly in ASH (p = 0.018). Pull-up performance increased in both PLA (p = 0.004) and ASH (p < 0.0001) in males. Conclusions: Supplementation with 600 mg/day of Ashwagandha root extract for 42 days may stabilise stress biomarkers, improve perception of recovery and enhance muscle strength in team sports athletes during pre-season training. The trial is registered on ClinicalTrials.gov with the ID NCT07041853.

INTRODUCTION: Prolonged exposure to stress may lead to low mood, anxiety, depression, insomnia, and metabolic disorders. Ashwagandha, an established adaptogen, is known to combat stress. We studied the safety and efficacy of Ashwagandha formulation, Zenroot™ (ZEN), containing 1.5% total withanolides on stress, anxiety, mood, and sleep quality in human subjects with non-chronic mild to moderate stress. METHODS: This was a prospective, randomized, double-blind, parallel, placebo-controlled, clinical interventional study with supplementation duration of 84 days. Ninety subjects were randomly assigned in a 1:1 ratio to receive 125 mg of ZEN or placebo. We measured stress using the Perceived Stress Scale (PSS) score as a primary endpoint. Various secondary endpoints included Mindfield eSense Skin Response (SCR) and Mindfield eSense PULSE Heart Rate Variability (HRV)-Root Mean Square of Successive Differences (RMSSD), and standard deviation of normal NN interval (SDNN), Beck Anxiety Inventory (BAI), Profile of Mood States (POMS), Pittsburgh Sleep Quality Index (PSQI), stress biomarkers of serum cortisol, and salivary alpha amylase (sAA) levels and safety parameters. The study assessments were performed on days 0, 14, 28, 56, and 84. RESULTS: All 90 randomized subjects completed the study. Mean ± standard error (SE) age of subjects in the ZEN group was 35.5 ± 1.3 years and in the placebo group was 34.5 ± 1.2 years. ZEN 125 mg showed significant (p < 0.05) improvements in PSS, BAI, and PSQI scores on days 28, 56, and 84; SCR on days 14, 28, and 84 and trend (p < 0.1) on day 56; HRV-RMSSD and SDNN on day 14; and POMS on days 56 and 84. No significant differences were observed between the two groups for serum cortisol and sAA. The study product was well tolerated without any safety concerns. CONCLUSION: We observed significant reductions in both subjective and objective measures of stress with improvement in mood, sleep quality, and occasional anxiety symptoms. ZEN was well tolerated without any related adverse events. Future clinical studies are warranted to evaluate the effect of ZEN on chronically stressed adults. CLINICAL TRIAL REGISTRATION NUMBER: http://ctri.nic.in/

INTRODUCTION: Ashwagandha has multiple medicinal properties and is widely used as a supplement to address various health conditions including stress and anxiety. The bioavailability of Ashwagandha bioactives provide critical information on the biological effects in humans after oral supplementation. METHODS: A randomized, double-blind, single-dose, cross-over comparative oral bioavailability study was conducted in 20 healthy, adult human subjects under fasting conditions. All subjects consumed single dose of ZEN 1.5 (Zenroot™ Ashwagandha 1.5% 125 mg), ASH 5 (Reference product 1-Ashwagandha 5% 600 mg) and ASH 10 (Reference product 2-Ashwagandha 10% 500 mg) as per a randomization schedule. Blood samples were collected at 0.00 h, and at 00.25, 00.50, 00.75, 01.00, 02.00, 03.00, 04.00, 05.00, 06.00, 09.00, 12.00, and 24.00 h post-dose. Total withanolides (consisting of withanoside IV, withanolide A, 12-deoxywithastramonolide, and withaferin A) were quantified in plasma using the LC-MS/MS method and pharmacokinetics parameters like area under the curve, AUC0-t, Cmax, Tmax, t½ and test/reference (T/R) ratio for test product, ZEN 1.5, versus reference products, ASH 5 and ASH 10, were used for statistical comparisons. RESULTS: Subjects in the ZEN 1.5 group showed significantly (P < 0.05) higher total withanolides concentration in plasma at all post-dose time points except 12.00 and 24.00 h compared to ASH 5. In addition, subjects in Ashwagandha ZEN 1.5 group showed significantly higher (P < 0.05) total withanolides concentration in plasma at 0.25, 1.00, 2.00, 3.0, and 4.00 h compared to ASH 10. Further, ZEN 1.5 showed significantly higher bioavailability for total withanolides compared to ASH 5 and ASH 10 with significantly higher (P < 0.05) Cmax and AUC0-t parameters, T/R ratio, and 90% CI. ZEN 1.5 at 125-mg dose showed 2.1-fold higher bioavailability compared to ASH 5 at 600 mg, and 1.3-fold higher bioavailability compared to ASH 10 at 500 mg. ZEN 1.5 was well tolerated during the study period. CONCLUSION: A low dose of 125 mg of ZEN 1.5 showed greater total withanolides bioavailability compared to reference products. The Cmax and AUC parameters were significantly hig

BACKGROUND: Ashwagandha has been reported to reduce stress and attenuate cognitive decline associated with inflammation and neurodegeneration in clinical populations. However, the effects as a potential nootropic nutrient in younger populations are unclear. This study examined the effects of liposomal ashwagandha supplementation on cognitive function, mood, and markers of health and safety in healthy young men and women. METHODS: 59 men and women (22.7 ± 7 yrs., 74.9 ± 16 kg, 26.2 ± 5 BMI) fasted for 12 h, donated a fasting blood sample, and were administered the COMPASS cognitive function test battery (Word Recall, Word recognition, Choice Reaction Time Task, Picture Recognition, Digit Vigilance Task, Corsi Block test, Stroop test) and profile of mood states (POMS). In a randomized and double-blind manner, participants were administered 225 mg of a placebo (Gum Arabic) or ashwagandha (Withania somnifera) root and leaf extract coated with a liposomal covering. After 60-min, participants repeated cognitive assessments. Participants continued supplementation (225 mg/d) for 30 days and then returned to the lab to repeat the experiment. Data were analyzed using a general linear model (GLM) univariate analysis with repeated measures and pairwise comparisons of mean changes from baseline with 95% confidence intervals (CI). RESULTS: Ashwagandha supplementation improved acute and/or 30-day measures of Word Recall (correct and recalled attempts), Choice Reaction Time (targets identified), Picture Recognition ("yes" correct responses, correct and overall reaction time), Digit Vigilance (correct reaction time), Stroop Color-Word (congruent words identified, reaction time), and POMS (tension and fatigue) from baseline more consistently with several differences observed between groups. CONCLUSION: Results support contentions that ashwagandha supplementation (225 mg) may improve some measures of memory, attention, vigilance, attention, and executive function while decreasing perceptions of tension and fatigue in younger healthy individuals. Retrospectively registered clinical trial ISRCTN58680760.

BACKGROUND: Stress is a known causative factor in modulating cognitive health, which overall well-being and quality of life are dependent on. Long-term stress has been shown to disrupt the balance of the hypothalamic-pituitary-adrenal (HPA) axis. Adaptogens, such as Withania somnifera (ashwagandha), are commonly used in Ayurvedic medicine for stress relief and ameliorating HPA-axis dysfunction. The aim of this study was to support the role of a root and leaf water-extracted ashwagandha extract (WS) in stress reduction by confirming the lowest clinically validated dose for stress management (125 mg/day) in a dose-dependent clinical study in adults with self-reported high stress. METHODS: An 8-week, randomized, double-blinded, placebo-controlled study to compare the effects of three different WS extract doses (125, 250 and 500 mg) was performed. A total of 131 adults were enrolled, and 98 were included in the final analysis. Attenuation of chronic stress was measured using the 14-item Perceived Stress Scale (PSS) and biochemical-related stress parameters. RESULTS: We have shown that aqueous WS extract (roots and leaves) safely reduces mild to moderate chronic stress at doses of 125 mg, 250 mg, and 500 mg/day for 8 weeks. CONCLUSIONS: Our findings demonstrate the stress-reduction capabilities of this well-characterized aqueous extract of WS (root and leaf) at the low dose of 125 mg/day, in a dose-dependent manner, via the modulation of the HPA axis. TRIAL REGISTRATION: This study was registered with the Clinical Trials Registry-India (CTRI) with the registration number: CTRI/2019/11/022100.

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: The results of the study suggest that ARE with 2.5% withanolides can effectively improve stress and anxiety by reducing cortisol and increasing serotonin in healthy individuals with mild to moderate

It is important to understand the potential of botanical-drug interactions to ensure the safe use of botanical dietary supplements (BDS). Cytochrome P450 (P450) is one of the most abundant phase 1 drug-metabolizing enzymes and is accountable for a great deal of pharmacokinetic botanical-drug interactions. This problem is particularly acute for older adults who often consume BDS with multiple prescription medicines. The consequences of botanical-drug interactions can lead to lack of prodrug efficacy or drug toxicity from reduced drug clearance through inhibition of P450 metabolizing enzymes. In this study, a 7-in-1 cocktail P450 inhibition assay with 7 Food and Drug Administration-recommended P450s (CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2D6, and CYP3A4/5) including CYP2B6 recombinant enzyme was performed, minimizing substrate interactions with respect to specificity while maximizing assay sensitivity. High-performance liquid chromatography-mass spectrometry was used for quantitative determination of probe substrate metabolism. Withania somnifera L. Dunal (ashwagandha), a popular BDS in the United States with sales of ∼$16 million in 2021, is used to promote sleep and relieve stress and anxiety, especially in older adults. However, comprehensive studies of pharmacokinetic drug interactions with ashwagandha, especially with leaf extracts, have not been reported. Four extracts from ashwagandha root or leaf were evaluated for P450 inhibition, and no reversible inhibition was detected at IC50 > 100 μg/mL extract. SIGNIFICANCE STATEMENT: Ashwagandha is often consumed by older adults, who also often use multiple prescribed medications concomitantly. Polypharmacy, combined with age-related decline of drug metabolism and other changes in drug disposition in this population, increases the risk of adverse events due to botanical inhibition of drug metabolism, indicating the significance of evaluating ashwagandha for potential pharmacokinetic drug interactions. This study will support our understanding for the safe use of ashwagandha.

BACKGROUND: Sorafenib (Sora), a multi-target tyrosine kinase inhibitor, is widely recognized as a standard chemotherapy treatment for advanced hepatocellular carcinoma (HCC). However, drug resistance mechanisms hinder its anticancer efficacy. Derived from Withania somnifera, Withaferin A (WA) exhibits remarkable anti-tumor properties as a natural bioactive compound. This study aimed to examine the mechanisms that underlie the impacts of Sora and WA co-treatment on HCC. METHODS: Cell proliferation was evaluated through colony formation and MTT assays. Flow cytometry was employed to determine cellular apoptosis and reactive oxygen species (ROS) levels. The evaluation of apoptosis-related protein levels, DNA damage, and endoplasmic reticulum stress was conducte utilizing IHC staining and western blotting. Moreover, the caspase inhibitor Z-VAD-FMK, ATF4 siRNA, ROS scavenger N-acetyl cysteine (NAC), and TrxR1 shRNA were used to elucidate the underlying signaling pathways. To validate the antitumor effects of Sora/WA co-treatment, in vivo experiments were ultimately executed using Huh7 xenografts. RESULTS: Sora/WA co-treatment demonstrated significant synergistic antitumor impacts both in vivo and in vitro. Mechanistically, the enhanced antitumor impact of Sora by WA was achieved through the inhibition of TrxR1 activity, resulting in ROS accumulation. Moreover, ROS generation induced the activation of DNA damage and endoplasmic reticulum (ER) stress pathways, eventually triggering cellular apoptosis. Pre-treatment with the antioxidant NAC significantly inhibited ROS generation, ER stress, DNA damage, and apoptosis induced by Sora/WA co-treatment. Additionally, the inhibition of ATF4 by small interfering RNA (siRNA) attenuated Sora/WA co-treatment-induced apoptosis. In vivo, Sora/WA co-treatment significantly suppressed tumor growth in HCC xenograft models and decreased TrxR1 activity in tumor tissues. CONCLUSION: Our study suggests that WA synergistically enhances the antitumor effect of Sora, offering promising implications for evolving treatment approaches for HCC.

ETHNOPHARMACOLOGICAL RELEVANCE: Withania somnifera popularly known as Aswagandha or Indian Ginseng/Poison Gooseberry have thousands years of history of use in Indian traditional medicine. Besides, finding place root of the plant as Indian Ginseng, Ayurveda also uses root of this plant as general health tonic, adaptogenic, nootropic, immunomodulatory etc. With its widespread and growing use, it becomes prudent to scientifically evaluate and document both the efficacy and safety of this plant in humans. AIM OF THE STUDY: Aswagnadha root is rapidly gaining popularity abroad for use as medicine. Current article attempts to primarily review the human efficacy and safety of Aswagandha generated through clinical trials. METHODS: A systematic search both for indexed and non-indexed literature was made for W. somnifera using various search engines and databases and the details of research articles pertaining to all clinical trials/human studies, animal studies addressing safety issues of CNS, CVS, general toxicity, mutagenicity, genotoxicity, reproductive safety and herb-drug interactions were reviewed and compiled comprehensively from full texts. RESULTS: A total of 69 (39 pre-clinical and 30 clinical) studies documenting efficacy and safety aspects were identified and the desired information of these studies is comprehensively presented in this review. Retrieved thirty(30) human studies demonstrated reasonable efficacy of root preparations in subclinical hypothyroidism (1), schizophrenia (3), chronic stress (2), insomnia (2), anxiety (1), memory and cognitive improvement (2), obsessive-compulsive disorder (1), rheumatoid arthritis (2), type-2 diabetes (2), male infertility (6), fertility promotion activity in females (1), adaptogenic (3), growth promoter in children (3) and chemotherapy adjuvant (1). Reasonable safety of root preparations of Aswagandha has been established by these retrieved 30 human trials. No serious adverse events or any changes in haematological, biochemical or vital parameters were reported in these human studies. Only mild and mainly transient type adverse events of somnolence, epigastric pain/discomfort and loose stools were reported as most com

26. Ann Agric Environ Med. 2026 Mar 25;33(1):3-11. doi: 10.26444/aaem/213417. Epub 2025 Dec 9. Clinical evidence for the adaptogenic effects of Withania somnifera and Rhodiola rosea - A systematic review with molecular interpretation of psychometric outcomes. Łuszczak J(1), Kocki J(2). Author

BACKGROUND: Ashwagandha (Withania somnifera) is an adaptogenic herb used to prevent and treat psychosomatic disorders. This systematic review and meta-analysis evaluated the effects and safety of Ashwagandha on psychosomatic functions related to stress and anxiety among patients. METHODS: A comprehensive search was conducted in MEDLINE, EMBASE, PubMed, PsychINFO, and the Cochrane Library for articles published from January 2000 to January 2022. Randomized controlled trials that examined the effects of Ashwagandha on stress and anxiety were included. Two authors independently extracted all relevant data from the included studies. Both subjective and objective measures of stress and anxiety were assessed as outcome variables. RESULT: Nine randomized controlled trials involving 558 patients were eligible for this study. The findings of the meta-analysis showed a significant effect of Ashwagandha formulations on the Perceived Stress Scale (PSS) (MD = -4.72, 95 % CI = [-8.45 to -0.99]), Hamilton Anxiety Scale (HAS) (MD = -2.19, 95 % CI = [-3.83 to -0.55]), and serum cortisol levels (MD = -2.58, 95 % CI = [-4.99 to -0.16]) compared to the placebo group. Among the included studies, four reported mild to moderate adverse events. CONCLUSION: The findings from the included studies indicate that Ashwagandha formulations have beneficial effects on stress and anxiety. The adverse effects associated with Ashwagandha are limited; however, further information is required to determine its safety with long-term administration.

166. Altern Ther Health Med. 2024 Sep;30(9):54-64. Therapeutic Evaluation of Unani Medicine, Including Single Drugs and Polyherbal Formulations with Special Reference to Neurodegenerative Disorders. Imran S, Ahmad W, Saltanat S. ETHNOPHARMACOLOGICAL RELEVANCE: Unani remedies are considered safe and can be utilized as a healthcare resource due to the adverse effects of conventional pharmaceuticals. For instance, Donepezil, used to treat alzhemier's disease exerts many adverse effects such as dizziness, vertigo, dryness of mouth. Similarly, Memantine used to slow the neurotoxicity involved in alzhemier's disease also exerts adverse effects like vomiting, tremors and sleep disturbance. Over sixty percent of drugs are derived from synthetic basis, highlighting the potential benefits of natural Unani treatments as a safer alternative. Neurodegenerative disorders are illnesses characterized by structural and functional deterioration due to abnormal protein aggregation, resulting in inflammation and oxidative stress in the central nervous system. In unani system of medicine all current brain ailments, including alzheimer's disease, parkinson's disease, mania, anxiety, melancholia and others are classified under the general category of neurodegenerative disorders Their pathogenic variables and soociated symptoms and therapeutic modalities are similar. This study focuses on evidence-based Unani herbs and polyherbal formulations for the treatment of various neurodegenerative disorders. It reveals that 43 ethnomedicinal plants can be employed to treat the symptoms of neurodegenerative disorders. The material was gathered from several sources that tabulated the specific details of individual herbs and polyherbal formulations and highlighted the importance of various phytoconstituents on neuroprotective action. The research provides in vivo and scientific evidence to support the use of ethnomedicine in treating neurodegenerative disorders. AIM OF THE STUDY: This study aims to validate the efficacy of Unani medicines, traditionally used for neurodegenerative diorders through evidence-based research. METHODS: To scan single and polyherbal formulations for neurodegenerative

This study systematically reviewed the scientific literature on natural remedies for male sexual dysfunction (MSD), including conditions like erectile dysfunction, premature ejaculation, and reduced libido. Limited scientific evidence exists regarding the efficacy and safety of these natural products. To ensure an objective assessment, the study used the Scopus database, followed the PRISMA guidelines, and employed a comprehensive search strategy involving relevant vital concepts, controlled vocabularies, and specific inclusion/exclusion criteria. The analysis included 1504 documents from 624 journals, spanning from 1967 to 2023. The literature showed an annual growth rate of 2.46%, with an average document age of 10.2 years and an average of 23.54 citations per document. India had the highest publication count (319), followed by the United States (164). Conceptual Mapping categorized themes into basic, motor, niche, emerging, and declining categories, including nitric oxide, oxidative stress, phytotherapy, herbal medicine, Asparagus racemosus, and dopamine. This mapping provided a holistic understanding of the field, identified research gaps, and guided the development of new interventions or treatment strategies for MSD. Trend topics include molecular coupling, Ashwagandha, phytochemistry, phosphodiesterase-5, and arginase. The study findings will assist healthcare professionals in making informed decisions when recommending or advising patients about the use of these remedies.

OBJECTIVE: Despite the historical neurological use of Withania somnifera, limited evidence supports its efficacy for conditions like anxiety and insomnia. Given its known anti-stress properties, this review evaluated its safety and efficacy for anxiety and insomnia. METHODS: We searched Medline, Cochrane Library, and Google Scholar until August 2023 for randomized controlled trials (RCTs) comparing W. somnifera to placebo in patients with anxiety and/or insomnia. Outcome measures included changes in anxiety levels via the Hamilton Anxiety Scale (HAM-A), Sleep Onset Latency (SOL), Total Sleep Time (TST), Wake After Sleep Onset (WASO), Total Time in Bed (TIB), Sleep Efficiency (SE), and Pittsburgh Sleep Quality Index (PSQI) score. We utilized a random-effect model for pooling Mean Differences (MD) with a 95% Confidence Interval (CI). Heterogeneity was assessed through sensitivity and subgroup analysis, and the quality of RCTs was evaluated using the Cochrane revised risk of bias tool. RESULTS: Pooled results from five RCTs (n = 254) demonstrated that W. somnifera significantly reduced HAM-A scores (MD = -5.96; [95% CI -10.34, -1.59]; P = 0.008; I2 = 98%), as well as sleep parameters such as SOL, TST, PSQI, and SE, but not WASO and TIB. CONCLUSION: While W. somnifera extracts yielded promising results, further research with larger sample sizes is needed to confirm its effects on anxiety and insomnia. © 2024 John Wiley & Sons Ltd.

BACKGROUND: Withania somnifera (WS), a popular medicinal plant of the Solanaceae family, contains active ingredients with antioxidant, anti-inflammatory, immunomodulatory, and anti-stress activities. However, its precise mechanisms of action and optimal use as a supplement are not yet fully understood. The objective of this systematic review is to assess the impact of WS supplementation on cortisol levels in stressed humans by analyzing clinical trials conducted prior to May 2023. METHODS: The assessment was carried out following the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) by exploring the databases of EMBASE, PubMed, Google Scholar, CENTRAL, and Scopus. RESULTS: Of the 4788 articles identified, only 9 studies met the selection criteria. The selected studies varied in terms of design, results, formulations, dosages, and treatment duration (30-112 days), and involved subjects with varying degrees of stress. WS supplementation decreases cortisol secretion with no significant adverse effects. Nonetheless, none of the studies evaluated the potential impact of cortisol reduction on adrenal function and long-term effects. CONCLUSIONS: Brief-term supplementation with WS appears to have a stress-reducing effect in stressed individuals. However, since the long-term effects of WS supplementation are not yet fully understood, WS supplements should be used under medical supervision.

PURPOSE OF REVIEW: Withania somnifera (L.) Dunal (Ws) is a common herb plant that has been used for centuries to treat a wide range of conditions, particularly certain chronic diseases due to its antidiabetic, cardioprotective, antistress, and chondroprotective effects, among many others. No conclusive evidence, however, exists about the potential health effects of Ws in adults without chronic conditions. We aimed to evaluate the current evidence on the health benefits of Ws supplementation in healthy adults. RECENT FINDINGS: Based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we systematically reviewed studies indexed in Web of Science, Scopus, and PubMed to assess the effects of Ws on hematological and biochemical markers, hormonal behavior, and oxidant response in healthy adults. Original articles published up to March 5, 2022, with a controlled trial design or pre-post intervention design, in which supplementation of Ws was compared to a control group or data prior to intervention were included. Among 2,421 records identified in the search, 10 studies met the inclusion criteria. Overall, most of the studies reported beneficial effects of the Ws supplementation, and no serious adverse events were reported. Participants supplemented with Ws displayed reduced levels of oxidative stress and inflammation, and counterbalanced hormone levels. No evidence of the beneficial effects of Ws supplementation on hematological markers was reported. Ws supplementation appears to be safe, may regulate hormone levels, and has potent anti-inflammatory and antioxidant effects. However, further studies are needed to elucidate the relevance of its application. © 2023. The Author(s).