Clinical Evidence for the Use of Ashwagandha,Withania somnifera

Abstract

Ashwagandha, Withania somnifera, has been revered in Ayurvedic medicine for millennia and is considered a Rasayana herb, promoting both mental and physical health. Research has demonstrated an antioxidant and anti-inflammatory effect for ashwagandha, as well as an antistress effect. This article reviews clinical evidence for the use of ashwagandha, including in sports medicine, male and female health, stress adaptation, depression, anxiety, schizophrenia, and insomnia. Safety outcomes are also discussed, with the herbal extract generally shown to be well tolerated in clinical trials.

Introduction

Withania somnifera, commonly called ashwagandha, winter cherry, or Indian ginseng, has a long history of use in traditional Ayurvedic and Indian medicine. The roots, seeds, and leaves of the plant have been used for thousands of years for their medicinal properties.¹ Because of its broad therapeutic effects, ashwagandha has even been called the “Queen of Ayurveda” and is considered a Rasayana, or tonic/tonifying herb, in Ayurvedic medicine.^1,2

Ashwagandha is a member of the Solanaceae (nightshade) family. The Withania genus has 26 species, two of which are considered medicinally important (Withania somnifera, the focus of this article, and Withania coagulans, commonly known as rishyagandha). Two subspecies of Withania somnifera have been reported, W. somnifera Dunal and W. somnifera Kaul.¹ The plant grows in tropical and subtropical conditions and is native to parts of Africa, the Middle East, China, and India (where it is widely cultivated as a medicinal crop).³

Ashwagandha Constituents

Steroidal lactones

Withaferin-A, withanone, withanolides

Steroid compounds

β-sitosterol, stigmasterol, diosgenin, stigmastadien, sitoinosides

Flavonoids

Quercetin, Kaempferol, catechin

Nitrogen compounds

Withanol, somnisol, somnitol

Alkaloids

Withanine, withananine, withasomnine, somniferine, tropeltigloate, somniferinine, somninine, cuscohygrine, anahygrine, nicotine

The ashwagandha plant produces numerous chemical constituents, ranging from steroid compounds and steroidal lactones to alkaloids and flavonoids.^4,5 Of these, the principal bioactive constituents are considered to be the steroidal lactones withaferin A and withanolide D. These two compounds are thought to be largely responsible for the plant’s diverse effects on growth and transcription factors, structural proteins, receptors, and kinases, translating to the benefits demonstrated in the central nervous system (CNS), cardiovascular system, inflammatory processes, metabolic disorders, antioxidation, and cancer.⁴ Ashwagandha withanosides and withanolides can be extracted via aqueous methods as well as via a combination of water and alcohol extraction.^6,7

Ashwagandha and its constituents have been demonstrated preclinically to have a variety of therapeutic effects. They have been shown to have anti-inflammatory and antioxidant properties, to normalize apoptosis, and to promote synaptic plasticity. Ashwagandha appears to modulate glutamate and γ-aminobutyric acid (GABA). It attenuates laboratory and clinical markers of stress and improves sleep quality.⁸

Following oral administration, peak concentrations of ashwagandha constituents in healthy adult men occurred about 1.5 to 2.5 hours post-ingestion in one study (utilizing two commercially available W. somnifera extracts containing 185 mg total withanolides).⁹ In another study (again, in healthy adult men), maximum concentrations of ashwagandha constituents were seen at 0.903 ± 0.273 to 1.639 ± 0.993 hours post-ingestion of a single 500 mg dose containing at least 7.5 mg withanolides.¹⁰ These studies highlight that ashwagandha and its constituents are orally bioavailable and also rapidly absorbed from the gut.

Extracts with high withanolide content (i.e., 35% withanolide glycosides versus 2.5% withanolides) have longer serum residence times and half-lives, suggesting enhanced bioavailability. The half-life of various ashwagandha constituents in Kim et al.’s clinical study ranged from 1.882 ± 0.03 to 4.027 ± 0.266 hours for 2.5% withanolide extract, to 8.856 ± 1.152 to 10.954 ± 2.204 hours for 35% withanolide glycoside extracts.⁹ Studies on the metabolism of ashwagandha extracts are very limited, and in fact, no clinical trials appear to have investigated this subject. Studies in human liver microsomes and human isoenzymes have shown no significant inhibitory effect of Withania extract on cytochrome P450 (CYP) 3A4 or CYP2D6 activity in some cases, and moderate induction of CYP3A4 and inhibition of CYP2B6 in another.^11
–13 The clinical relevance of these findings has not been explored in the literature to this author’s knowledge. However, clinical trials looking at the coadministration of ashwagandha alongside various pharmaceutical agents (such as selective serotonin reuptake inhibitors [SSRIs] and antipsychotic medications, agents which are well-known to be CYP-metabolized) have not demonstrated any significant interactions or concerns (with more on these below).^14

–17

In terms of safety, numerous clinical trials have demonstrated the safe use of ashwagandha extracts. In a 2020 systematic review by Tandon and Yadav, there were no serious adverse events or changes in hematological or biochemical parameters reported in 30 human trials of ashwagandha supplementation. Side effects with use of this herb were generally mild and transient, and the most common of these were loose bowel movements, epigastric pain or discomfort, and somnolence. Preclinical toxicity studies up to 8 months in duration indicated root extracts of the plant to be safe, and there was no mutagenicity or genotoxicity reported. Additionally, there was no inhibition of CYP3A4 and CYP2D6 in vitro or in vivo.¹⁸

Ashwagandha in Sports Medicine

W. somnifera extracts have been demonstrated to have a number of effects that may contribute to ergogenic benefits. Ashwagandha improves endothelial function, regulates apoptosis, enhances mitochondrial function, and reduces reactive oxygen species (ROS), thus acting as an antioxidant. Its anti-inflammatory effects are probably also pertinent in the area of athletic training.¹⁹ Clinical trials of ashwagandha in sports medicine can be roughly grouped into two areas, the first being strength training adaptation and the second being cardiorespiratory fitness or endurance.

Beginning with strength training adaptation, Wankhede et al. randomized 57 healthy men (ages 18–50) without resistance training experience to either ashwagandha 300 mg twice daily (standardized to 5% withanolides) or a placebo group. Both groups then underwent an 8-week resistance training program (with a variety of proscribed exercises performed 3 days/week). At the completion of the trial, men who took the herb versus placebo had significantly greater increases in muscle strength on both bench press and leg extension (P = 0.001 and P = 0.04, respectively) as well as significantly greater muscle size at the arm and chest (P = 0.01 and P < 0.001, respectively). The ashwagandha group also experienced a significantly greater reduction of exercise-induced muscle damage (assessed via serum creatine kinase levels) and a significantly greater increase in testosterone levels (P = 0.03 and P = 0.004, respectively). The decrease in body fat percentage was also significantly greater for men taking the herbal intervention (placebo: −1.5%, 95% confidence interval [CI]: −0.4% to −2.6% vs. ashwagandha: −3.5%, 95% CI: −2.0% to −4.9%; P = 0.03). There were no serious side effects in either group.²⁰

In Ziegenfuss et al.’s double-blind randomized trial, recreationally active men (26.5 ± 6.4 years old) were assigned to either a placebo (N = 19) or 500 mg daily ashwagandha patented standardized extract (an aqueous extract of the roots and leaves of W. somnifera) (N = 19) for 12 weeks. During the trial, participants underwent a specific, progressive overload resistance-training program (4 days/week, upper body/lower body split). At the completion of the trial, the men who received ashwagandha extract had significantly greater improvements in squat and bench press than men in the placebo group (P = 0.009 and P = 0.048, respectively). Participants also underwent baseline and follow-up dual-energy X-ray absorptiometry (DEXA) to assess body composition. DEXA was then used to calculate the android/gynoid ratio, a measure of body fat distribution comparing abdominal (android) fat to hip and thigh (gynoid) fat. This ratio, considered a rough marker of visceral fat deposition, also improved more in men taking the herbal extract (P = 0.03). Ashwagandha use was found to be safe, as evidenced by hematologic values, a comprehensive metabolic panel, and lipid levels.²¹

In a 2024 clinical trial including both male and female participants, 80 healthy subjects (ages 18–45) who were regular exercisers were randomized 1:1 to either ashwagandha 300 mg twice daily (standardized to 5% withanolides) or a placebo group for 8 weeks. Both men and women saw greater improvements in bench press and leg press with ashwagandha compared to placebo (males P = 0.0084 and females P = 0.0005, and males P = 0.0049 and females P = 0.018, respectively). Both male and female subjects taking ashwagandha also experienced greater increases in chest, arm, and thigh circumference compared to placebo. Cardiorespiratory endurance (as assessed by VO₂max) also improved significantly more with the use of ashwagandha (males P <0.0001; females P <0.0001) than without. In the ashwagandha group, there was a statistically significant 9.5% and 7% increase in VO₂max for men (P <0.0001) and women (P <0.0001) respectively. No adverse events were reported.²²

VO₂max and Cardiorespiratory Fitness

VO₂max is the maximum volume of oxygen consumed per minute per kilogram of body weight at the individual’s maximum level of physical exertion (expressed in milliliters/minute).

VO₂max reflects maximum aerobic capacity and therefore cardiorespiratory fitness and efficiency.

VO₂max naturally declines with aging.

Low VO₂max is also associated with increased mortality risk and a higher risk of cardiovascular disease (CVD).

Turning to VO₂max and cardiorespiratory fitness specifically, additional studies have confirmed a beneficial effect of ashwagandha supplementation. In a small 2020 meta-analysis, four randomized placebo-controlled clinical trials of ashwagandha were included, with 142 total participants. Doses of ashwagandha in the included trials ranged from 330 mg to 1000 mg per day, for durations ranging from 2 to 12 weeks. Studies were conducted in healthy adults or athletic adults. This analysis indicated a significant mean difference (MD) in VO₂max with the use of ashwagandha compared to placebo (P = 0.04). The MD in VO₂max between groups was 3.00 milliliters/minute for the 4 included studies (95% CI: 0.18 to 5.82). The herbal supplement was noted to be well tolerated and safe, with none of the included trials reporting side effects. Note that there was a high degree of heterogeneity in the included trials, and longer, larger studies examining ashwagandha’s effects on cardiorespiratory fitness would be helpful to confirm these findings.²³

Ashwagandha and Aging

In Wankhede et al.’s trial discussed above, use of ashwagandha supplementation was associated with an increase in testosterone levels in healthy adult men undergoing resistance training.²⁰ This finding may be of particular interest in aging men, as testosterone levels in this group are seen to decline by 1%–2% annually after the fifth decade of life, and the prevalence of low testosterone levels is estimated to be around 25% in men ages 40–70.^24,25

In a study by Lopresti et al., overweight men ages 40–70 with mild fatigue were randomized to either placebo or an ashwagandha extract (providing 21 mg withanolide glycosides daily) for 8 weeks. After the initial 8 weeks, the men were then crossed over to the opposite intervention for an additional 8 weeks. Hormone levels (dehydroepiandrosterone sulfate [DHEA-S], testosterone, cortisol, and estradiol) were assessed via saliva and were not significantly different between groups at baseline. At the completion of the trial, ashwagandha supplementation resulted in an 18% greater increase in DHEA-S (P = 0.005) and a 14.7% greater increase in testosterone (P = 0.010) compared to placebo. There were no significant differences between the groups for cortisol or estradiol levels. Note that in addition to its anti-inflammatory and antioxidant effects, ashwagandha has been found to improve the function of the hypothalamic–pituitary–gonadal axis and upregulate gonadotropin-releasing hormone (GnRH) in animal studies, and all of these mechanisms were mentioned by the authors of this trial as possible contributors to the effects seen in this trial.²⁶

Another concern related to aging is cognitive dysfunction. In Choudhary et al.’s pilot trial in adults with mild cognitive impairment (MCI), subjects (N = 50) were randomized to either placebo or ashwagandha root extract 300 mg twice daily for 8 weeks. At the completion of the trial, people in the ashwagandha group had significant improvements in a number of cognitive measures compared with the placebo group. This included better results for the Wechsler Memory Scale III subtest scores for logical memory, verbal paired associates, faces, and family pictures (P values ranging from P = 0.006 to P = 0.03). Ashwagandha group subjects also experienced significantly greater improvement in executive function, sustained attention, and information-processing speed (assessed via a variety of measures: Eriksen Flanker task, P = 0.002; Wisconsin Card Sort test, P = 0.014; Trail-Making test part A, P = 0.006; and Mackworth Clock test, P = 0.009).²⁷ Early clinical evidence such as this is encouraging, but to date, no studies have been conducted on ashwagandha in people with dementia.

Male Infertility

As Withania somnifera might impact both reproductive hormones and oxidative stress, a handful of studies have examined the question of whether or not it may also affect male fertility. In Gupta et al., 180 infertile male patients (ages 22–45) were given ashwagandha root powder at a dose of 5 grams daily for 3 months. Participants could be diagnosed with idiopathic infertility, oligospermia, or asthenospermia. Age-matched, healthy, and fertile men (N = 50) were utilized as a control. Proton nuclear magnetic resonance (NMR) spectroscopy was then used to assess seminal plasma metabolites. At the conclusion of the trial, seminal markers of infertility, including alanine, lactate, citrate, glutamate, glycerylphosphorylcholine (GPC), histidine, and phenylalanine levels, all improved with the use of ashwagandha (P < 0.05). Results were significant both for the comparison to the control group and for the comparison of baseline to post-treatment with ashwagandha. Additionally, sperm concentrations increased significantly post-treatment (P < 0.01), as did sperm motility and seminal lipid peroxidation (P < 0.01 for both).²⁸

In Ahmad et al., a trial was conducted in 75 men (ages 25–40) with diagnoses of idiopathic infertility, oligospermia, or asthenospermia, and 75 healthy fertile men served as controls. As in Gupta’s trial above, the infertile men were given ashwagandha root powder at a dose of 5 grams daily for 3 months. At baseline, serum levels of testosterone were suboptimal in the men with infertility. At the trial’s completion, use of ashwagandha resulted in improved sperm counts and sperm motility, reduced lipid peroxidation, and improved seminal plasma levels of vitamins A and C. Use of ashwagandha resulted in improvements in serum testosterone levels (P < 0.01), significant increases in luteinizing hormone (LH) levels, and reductions in follicle-stimulating hormone (FSH) and prolactin (P < 0.01 for all).²⁹

In a randomized trial in men with idiopathic infertility (Azgomi et al.), 100 participants were given either W. somnifera root 5 grams daily or pentoxifylline group 800 mg daily (with this medication thought to potentially address sperm oxidative stress) for 3 months. Both groups saw improvements in semen profiles at the completion of the trial. In the ashwagandha group, mean sperm count increased (by 12.5%) and sperm motility increased (21.42%) while sperm morphology was improved (25.56%) compared to baseline (P = 0.04, P = 0.001 and P = 0.000, respectively). Mean semen volume was unaffected by use of ashwagandha. In the pentoxifylline group, mean semen volume increased (by 16.46%), as did sperm motility (25.97%), and sperm morphology also improved (13.28%) compared to baseline (P = 0.02, P = 0.003 and P = 0.01 respectively). Pentoxifylline had no significant impact on mean sperm counts. Although the rate of conception was not a study outcome, the authors noted a higher pregnancy rate in the partners of patients taking ashwagandha (18%) compared to those taking pentoxifylline (12%). There were no adverse effects reported.³⁰

A 2018 meta-analysis for male infertility included 4 trials and found that treatment with ashwagandha resulted in significant improvements in semen volume (MD 0.28 mL; 95% CI: 0.12 to 0.43; P = 0.0004), sperm concentrations (MD 13.57 million/mL; 95% CI: 11.12 to 16.01; P < 0.00001) and sperm motility (MD, 8.50%; 95% CI: 7.36 to 9.63; P < 0.00001). Overall, the pregnancy rate in women with partners who were normozoospermic in this analysis was 14%. Ashwagandha also led to significant reductions in semen lipid peroxides (P < 0.00001), and significant increases in seminal plasma antioxidant levels, including vitamin A (P < 0.00001), vitamin C (P < 0.00001), and vitamin E (P = 0.0006). Of the 4 included trials, 3 utilized ashwagandha root powder at a dose of 5 grams daily, and 1 utilized ashwagandha root extract at 675 mg daily. All included trials were 3 months in duration. There were no adverse effects reported in men taking W. somnifera treatment.³¹

Women’s Medicine

Ashwagandha has been used in two clinical trials specific to women’s medicine. The first of these was a pilot study for the use of the herb in improving sexual function in healthy women. Women (N = 50) ages 21–50 with a diagnosis of sexual dysfunction (this could include hypoactive sexual desire disorder, female sexual arousal disorder, female orgasmic disorder, or combined genital and subjective arousal disorder) were randomized to either a high-concentration ashwagandha root extract 300 mg twice daily or a placebo for 8 weeks. Participants had to be willing to engage in sexual intercourse with the intent to achieve orgasm at least twice a week during the study.³²

At the conclusion of the trial, women who took ashwagandha had significantly greater improvements in the Female Sexual Function Index (FSFI) total score (P < 0.001) and the FSFI domain scores for “arousal” (P < 0.001), “lubrication” (P < 0.001), “orgasm” (P = 0.004), and “satisfaction” (P < 0.001) compared to those taking placebo. Additionally, the Female Sexual Distress Scale (FSDS) score was significantly improved with ashwagandha compared to placebo (P < 0.001), as was the number of successful sexual encounters (P < 0.001). No adverse events were reported, and ashwagandha was well-tolerated.³²

A second trial pertinent to women’s medicine involved subjects with climacteric symptoms in perimenopause. Like the study above, this was an 8-week randomized trial comparing the use of 300 mg of ashwagandha root extract twice daily to a placebo. A total of 100 women enrolled, and 91 completed the study. Ashwagandha use resulted in a statistically significant reduction in the total menopause rating scale (MRS) score (P < 0.0001), as well as in the MRS domains for psychological (P = 0.0003), somato-vegetative (P = 0.0152), and urogenital (P < 0.0001) concerns. Women taking ashwagandha also experienced significant decreases in the total menopause-specific QoL (MENQoL) score (P < 0.0001). Additionally, serum estradiol significantly increased with the use of the herbal extract (P < 0.0001), while serum FSH (P < 0.0001) and LH (P < 0.05) significantly decreased compared to placebo. There was no significant difference in serum testosterone levels.³³

Sleep Function

One of the best known or most popular uses of ashwagandha is as a sleep aid. The effects of W. somnifera on sleep are even hinted at within its scientific name, which is derived from “somnus,” the Latin for sleep.

Just a handful of clinical studies have been conducted on the subject of ashwagandha’s effects on sleep. These appear to be largely captured by a 2021 systematic review and meta-analysis by Cheah et al. A total of 5 randomized controlled trials (RCTs) with 400 participants were included. Included trials ranged in duration from 6 to 12 weeks, and daily doses of ashwagandha ranged from 120 mg to 600 mg (all trials used root extract). In this analysis, ashwagandha had a small but significant effect on overall sleep function (standardized mean difference [SMD]: −0.59; 95% CI: −0.75 to −0.42). In terms of specific measures, ashwagandha provided a significant benefit compared to placebo for the Sleep Quality Scale (SMD: −1.16; 95% CI: −1.65 to −0.66; P < 0.001; 4 trials with 228 participants), sleep onset latency (SMD: −0.53; 95% CI: −0.77 to −0.29; P < 0.001; 3 trials with 281 participants), total sleep time (SMD: −0.45; 95% CI: −0.69 to −0.21; P < 0.001; 3 trials with 281 participants), wake time after sleep onset (SMD: −0.39; 95% CI: −0.62 to −0.15; P = 0.002; 3 trials with 281 participants), and sleep efficiency (SMD: −0.68; 95% CI: −1.07 to −0.29; P <0.001; 3 trials with 281 participants). Ashwagandha’s effects on sleep were stronger for subgroups of adults with an insomnia diagnosis, treatment dosages ≥600 mg/day, and treatment durations ≥8 weeks. All of the trials reported safety outcomes. There were no serious adverse effects reported in the 5 included RCTs. One trial reported mild adverse events, reported as 1 case of viral fever, 1 headache, 2 acid reflux, and 2 allergic dermatitis in the ashwagandha group.³⁴ As the popularity of this herb as a sleep aid has grown over time, it would be useful to see longer-term trials of >12 weeks duration in this area to help guide clinical decision-making and provide additional safety information.

Stress Adaptation and Cortisol Function

The hypothalamic-pituitary-adrenal (HPA) axis plays a primary role in the stress response by generating increased cortisol and DHEA in response to stressors. In turn, a regulatory negative feedback system ensures cortisol levels return to baseline following exposure to stress. There is evidence that this feedback system may become perturbed in some conditions, such as anxiety and depression, leading to more prolonged excess cortisol secretion. Ashwagandha is thought to attenuate the action of the HPA axis, modulating excess cortisol and DHEA, and in turn perhaps rendering the HPA axis less reactive to stress.³⁵

In a 60-day double-blind RCT in healthy adults experiencing stress (N = 60), subjects received either a placebo or 240 mg standardized ashwagandha extract daily. Outcomes related to mood as well as cortisol, DHEA, and testosterone levels were assessed. At the completion of the trial, ashwagandha supplementation led to a statistically significant reduction in the Hamilton Anxiety Rating Scale (HAM-A) score (P = 0.040), as well as greater improvement in serum morning cortisol (P < 0 .001) and DHEA-S (P = 0.004) levels compared to placebo. Importantly, female subjects experienced no change in testosterone level, but testosterone did increase in male subjects from baseline to trial completion (P = 0.038), although the increase was not statistically significant compared to placebo (P = 0.158). There were no adverse events reported.³⁵

In another trial in adults experiencing chronic stress (N = 131, 98 of whom completed the study), different doses of a patented standardized ashwagandha extract were compared to placebo. Subjects took either the ashwagandha extract at a dose of 125, 250, or 500 mg, or the placebo, for 8 weeks. At the completion of the trial, people in the 3 ashwagandha groups experienced significant decreases in plasma cortisol level as well as plasma adrenocorticotropic hormone (ACTH) (P < 0.001 for both). People taking ashwagandha (at all 3 doses) also had significant decreases in stress level, as assessed by the perceived stress scale (PSS) (P < 0.001). There were no serious adverse events reported in the trial, although 48% of participants did report side effects. Note that reported adverse events did not differ between the ashwagandha groups and the placebo group. These largely consisted of heartburn, abdominal discomfort, and trouble sleeping.³⁶

Yet another trial found that ashwagandha supplementation led not only to improved stress levels but also to reductions in overeating and body weight in overweight adults with chronic stress (N = 52). Subjects were randomized to either 300 mg of a standardized (5% withanolide) ashwagandha root extract twice daily or a placebo for 8 weeks. The mean PSS score decreased significantly at the completion of the trial for people taking ashwagandha compared to placebo (P = 0.015). In the ashwagandha group, the PSS score decreased by about 33% by the end of the study. On the three-factor eating questionnaire (TFEQ), participants taking ashwagandha also had significant improvements in scores for “Uncontrolled Eating” and “Emotional Eating” compared to baseline, and these changes were also statistically significant compared to placebo (“Uncontrolled Eating,” P = 0.0247; “Emotional Eating,” P = 0.0135). Mean body mass index (BMI) decreased in both the placebo and ashwagandha groups during the trial, but the herbal intervention resulted in significantly greater reductions (BMI: −2.93% for the ashwagandha group and −1.4% for the placebo group; P = 0.0096). Subjects rated the tolerability of ashwagandha as excellent, and only 2 of the 52 subjects reported minor, temporary side effects (including blurry vision and hyperacidity).³⁷

Another RCT in overweight or obese adults (ages 40 to 75, N = 120) with self-reported stress and fatigue indicated that ashwagandha supplementation (200 mg twice a day for 12 weeks) led to non-significant reductions in the PSS score compared to placebo but significant improvement in fatigue. Per the Chalder Fatigue Scale, people taking ashwagandha had statistically significant decreases in fatigue symptoms compared to placebo (P = 0.016), while also experiencing a significant increase in heart rate variability (HRV, P = 0.003). Additionally, for male subjects in the trial, there was a significant increase in mean free testosterone levels (from 8.64 pg/mL at baseline to 9.75 pg/mL; P = 0.048) and LH (P = 0.002) with the use of ashwagandha compared to placebo. Female subjects taking ashwagandha experienced an increase in mean estradiol levels (from 90.94 pg/mL at baseline to 145.25 pg/mL, P = 0.029, with the increase being greater in those subjects who were perimenopausal versus those who were menopausal), with no alteration of testosterone concentrations. There were no serious adverse events reported, and no change in serum markers of hematologic, renal, or liver function.³⁸

Mental Health

The effects of chronic stress can also contribute to mood disorders. As ashwagandha may improve stress markers, it also stands to reason that this may translate to an effect on mood. In Akhgarjand et al.’s 2022 systematic review and meta-analysis of RCTs, trials that assessed the effect of ashwagandha supplementation on anxiety and stress were included. In total, 12 studies with 1002 participants ages 25 and 48 were included. Ashwagandha was found to significantly decrease anxiety (SMD: −1.55, 95% CI: −2.37 to −0.74; P = 0.005) and stress level (SMD: −1.75; 95% CI: −2.29, −1.22; P = 0.005) compared to placebo. The authors cautioned that the certainty of the evidence was low for both outcomes, so additional studies would be needed to confirm these effects.³⁹

Ashwagandha might also be a useful complement to selective SSRI medications in this setting. In a small double-blind RCT in people with generalized anxiety disorder (GAD), subjects were randomized to either ashwagandha extract 1000 mg daily (N = 22) or a placebo (N = 18) for 6 weeks. All subjects were taking SSRI medication. The HAM-A score decreased significantly in the ashwagandha group compared to the placebo group (14- and 8-unit reductions, respectively, P < 0.05). Ashwagandha also had a progressive effect: there was a significant difference in the reduction of GAD scores between week 2 (P = 0.04) and week 6 (P = 0.02) of the trial for those taking the herbal extract. Ashwagandha was found to be safe, and no adverse events were noted during the trial.¹⁴

In another RCT in people with both anxiety and depression, 70 subjects were given either a placebo or ashwagandha root extract 500 mg standardized to 2.5% withanolides (12.5 mg withanolides) with 5 mg 95% piperine daily (added to improve bioavailability) for 90 days. Subjects had mild to moderate depression and anxiety and could not be utilizing either medication or psychotherapy for their condition at the time of the trial. At the completion of the trial, participants taking the herbal extract experienced significant improvements in the Hamilton Depression Rating Scale (HAM-D), HAM-A, Groningen Sleep Quality Scale (GSQS), and quality of life (QOL) scoring (P < 0.001 for all). Ashwagandha was well-tolerated, and the rate of mild side effects reported was the same for the herbal extract and placebo (18 people taking ashwagandha and 16 taking placebo, with symptoms including headache or gastrointestinal [GI] concerns). Blood biochemistry, hematological parameters, and urinalysis remained in the normal range in all participants. Of additional interest in this trial was the finding that serum levels of serotonin increased with use of ashwagandha but declined with placebo, with the difference being statistically significant (P < 0.001). Again, participants in this trial were not taking medication for their depression, and the authors did not mention or comment on the implications of this finding for people taking SSRIs.⁴⁰

Aside from depression and anxiety, a single trial of ashwagandha has been conducted in people with obsessive-compulsive disorder (OCD), and a few small trials have been conducted in people with schizophrenia. Table 1 details these trials.

Table 1.

Clinical Trials of Ashwagandha in People with OCD or Schizophrenia

Authors	Subjects	Intervention	Outcomes
Jahanbakhsh et al. 2016⁴¹	30 participants with OCD, all of whom were taking SSRIs	RDBPCT of W. somnifera extract 120mg/day or placebo for 6 weeks	Y-BOCS significantly improved with ashwagandha compared to placebo (P < 0.001); no adverse events reported.
Agnihotri et al. 2013¹⁷	30 people with schizophrenia and MetS, all of whom were taking second-generation antipsychotics. Trial specifically assessed metabolic outcomes related to medication use, rather than schizophrenia outcomes.	RDBPCT of W. somnifera extract 400mg/day or placebo for 1 month	Serum TGs and FBS significantly decreased in people taking ashwagandha compared to placebo (mean TGs from 165.6 ± 4.179 to 146.3 ± 3.487, and FBS from 106.0 ± 3.693 to 92.5 ± 1.734; P < 0.05 for both). No adverse reactions observed.
Chengappa et al. 2018¹⁶	66 people with schizophrenia or schizoaffective disorder already on antipsychotic medication and experiencing an exacerbation of symptoms	RDBPCT of ashwagandha patented standardized extract 1000mg/day or placebo for 12 weeks	Use of ashwagandha led to significantly greater reductions in PANSS general, total, and negative symptoms, but not positive symptoms, versus placebo (P ≤ 0.22 for all). PSS scores improved significantly with ashwagandha versus placebo (P = 0.012). CRP also decreased more in ashwagandha group but reduction was not significant compared to placebo. All adverse events were mild to moderate and transient (such as GI symptoms and somnolence).
Gannon et al. 2019¹⁵	Study by same group listed above (Chengappa et al.¹⁶) in 66 people with schizophrenia or schizoaffective disorder on antipsychotic agents and experiencing symptom exacerbation, this time assessing depression and anxiety	RDBPCT of ashwagandha patented standardized extract 1000mg/day or placebo for 12 weeks	Medium ES of 0.683 (95% CI: 0.16 to 1.21) and 0.686 (95% CI: 0.16 to 1.21) favoring ashwagandha over placebo for PANSS depression single-item and anxiety-depression cluster scores, respectively.

ES, effect size; FBS, fasting blood sugar; MetS, metabolic syndrome; TGs, triglycerides; OCD, obsessive-compulsive disorder; PANSS, Positive and Negative Syndrome Scale; RDBPCT, randomized double-blind placebo-controlled trial; Y-BOCS, Yale-Brown Obsessive-Compulsive Scale.

These trials demonstrated various effects with the use of ashwagandha.^15
–17,41 Measures of symptom severity decreased in people with OCD supplementing ashwagandha for 6 weeks.⁴¹ Likewise, in people with schizophrenia, ashwagandha supplementation resulted in reduced disease symptomatology and improved MetS markers (such as TGs and FBS) that may be altered secondary to treatment with antipsychotic medication.^15
–17 Ashwagandha was generally well-tolerated in these short-term trials. This is an area where larger and longer trials and studies elucidating ashwagandha’s mechanisms of action would be exciting to see. Neuroinflammation may play a role in both schizophrenia and OCD (not to mention depression and anxiety).^42

–45 HPA axis dysregulation is also thought to increase glutamate neurotransmission, subsequently affecting hippocampal neurogenesis (a process that may be dysregulated in psychiatric disorders).^42,46 And of course, conditions like schizophrenia and mood disorders are linked to increased oxidative stress.⁴⁷ Natural substances that are anti-inflammatory, antioxidative, and HPA axis-regulating, such as ashwagandha, might be uniquely poised to address these factors in combination.

Discussion

In this article, clinical evidence for the use of Withania somnifera has been discussed. Clinical trials have been conducted in a wide range of areas. These include sports medicine, male infertility (with a number of trials demonstrating an increase in testosterone levels in men taking ashwagandha), female sexual dysfunction, perimenopause (for climacteric symptoms), insomnia, stress adaptation, OCD, and schizophrenia. While ashwagandha itself does not carry GRAS (Generally Recognized as Safe) status, two patented standardized ashwagandha extracts do.^48,49 No serious adverse events have been noted in clinical trials reviewed in this article, and for those that included serum markers of hematologic, renal, or hepatic function, there were no significant changes in these measures, pointing to a good safety profile. The most commonly cited mild-to-moderate side effects seen in clinical trials of ashwagandha appear to be GI symptoms and drowsiness/somnolence. Note that ashwagandha has also been shown to be safe in people with subclinical hypothyroidism (with thyroid stimulating hormone [TSH] levels between 4.5 and 10 μIU/L), and with 8 weeks of treatment even leads to modest declines in TSH level in these individuals (from a mean of 6.48 to 5.35 μIU/L).⁵⁰ Ashwagandha does not significantly affect TSH levels or other parameters of thyroid function in healthy individuals with normal thyroid hormone levels at baseline.⁵¹

Doses used in the clinical trials discussed throughout this article have varied widely, from 120 mg to 1000 mg per day for ashwagandha extracts. A dosing summary taken from the studies in this article is seen in Table 2. All of the trials discussed here have also involved smaller sample sizes and have been short in duration, with 3 months being the maximum duration seen in the clinical studies noted here. This (3 months) is the duration of use for ashwagandha supplements that is cited as safe by the National Center for Complementary and Integrative Health (NCCIH), with NCCIH resources stating, “there is not enough information to allow conclusions about its long-term safety to be reached.”⁵² For patients wishing to take ashwagandha longer-term, it would be helpful to see longer trials with larger sample sizes exploring the herb’s therapeutic effects and demonstrating safety.

Table 2.

Dosing of Ashwagandha from Clinical Trials

Clinical study or scenario	Dosing of ashwagandha used
MCI	600 mg daily
Sports medicine/exercise training	330–1000 mg daily
Male infertility	675–5000 mg daily
Doses specifically shown to improve testosterone levels in men	Effective doses have ranged widely in clinical trials, from 21 mg withanolide glycosides daily, to 240–5000 mg ashwagandha daily
Female sexual dysfunction	600 mg daily
Climacteric symptoms in perimenopause	600 mg daily
Insomnia	120–600 mg daily
Stress adaptation	125–600 mg daily
Anxiety and depression	500 mg daily
OCD	120 mg daily
Schizophrenia	4000–1000 mg daily

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.▪

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