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American Journal of Men’s Health
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Original Article
Fatigue is a common complaint among young and older
adults, presenting in approximately 20%–40% of indi-
viduals (Lerdal, Wahl, Rustoen, Hanestad, & Moum,
2005). It is one of the most common symptoms encoun-
tered in patients receiving primary care medical treat-
ment, reported by 14%–40% of patients (Cathebras,
Robbins, Kirmayer, & Hayton, 1992; Hickie et al., 1996).
While fatigue is a central symptom associated with sev-
eral medical and psychiatric conditions, idiopathic fatigue
also has a substantial impact on an individual’s self-care
(Rhodes, Watson, & Hanson, 1988) and overall quality of
life (Yoo et al., 2018). Fatigue is also a strong predictor of
future morbidity and mortality (Appels & Mulder, 1988;
Avlund, Schultz-Larsen, & Davidsen, 1998). Higher
fatigue levels in daily activities is also an early indicator
of aging as it is associated with several poor health out-
comes (Avlund, 2010).
The bulk of evidence suggests that rates of self-
reported fatigue increase with age (Loge, Ekeberg, &
Kaasa, 1998; Van Mens-Verhulst & Bensing, 1998). In a
835985JMHXXX10.1177/1557988319835985American Journal of Men’s HealthLopresti et al.
research-article2019
1School of Psychology and Exercise Science, Murdoch University,
Perth, Western Australia, Australia
2Clinical Research Australia, Duncraig, Western Australia, Australia
Corresponding Author:
Adrian L. Lopresti, 38 Arnisdale Rd, Duncraig, Western Australia
6023, Australia
Email: a.lopresti@murdoch.edu.au
A Randomized, Double-Blind,
Placebo-Controlled, Crossover Study
Examining the Hormonal and Vitality
Effects of Ashwagandha (Withania
somnifera) in Aging, Overweight Males
Adrian L. Lopresti1,2 , Peter D. Drummond1, and Stephen J. Smith1,2
Abstract
Ashwagandha (Withania somnifera) is a herb commonly used in Ayurvedic medicine to promote youthful vigor,
enhance muscle strength and endurance, and improve overall health. In this 16-week, randomized, double-blind,
placebo-controlled, crossover study, its effects on fatigue, vigor, and steroid hormones in aging men were investigated.
Overweight men aged 40–70 years, with mild fatigue, were given a placebo or an ashwagandha extract (Shoden beads,
delivering 21 mg of withanolide glycosides a day) for 8 weeks. Outcome measures included the Profile of Mood States,
Short Form (POMS-SF), Aging Males’ Symptoms (AMS) questionnaire, and salivary levels of DHEA-S, testosterone,
cortisol, and estradiol. Fifty-seven participants were enrolled, with 50 people completing the first 8-week period of
the trial and 43 completing all 16 weeks. Improvements in fatigue, vigor, and sexual and psychological well-being were
reported over time, with no statistically significant between-group differences. Ashwagandha intake was associated
with an 18% greater increase in DHEA-S (p = .005) and 14.7% greater increase in testosterone (p = .010) compared
to the placebo. There were no significant between-group differences in cortisol and estradiol. In conclusion, the intake
of a standardized ashwagandha extract (Shoden beads) for 8 weeks was associated with increased levels of DHEA-S
and testosterone, although no significant between-group differences were found in cortisol, estradiol, fatigue, vigor, or
sexual well-being. Further studies with larger sample sizes are required to substantiate the current findings.
Keywords
ashwagandha, Withania somnifera, DHEA, testosterone, hormones, fatigue, energy, herbal
Received November 30, 2018; revised January 29, 2019; accepted February 13, 2019
2 American Journal of Men’s Health
study of over 2,000 men between the ages of 18 and 92
years, an incremental increase in physical, mental, and
general fatigue was associated with increasing age
(Beute, Wiltink, Schwarz, Weidner, & Brahler, 2002).
Given the association between fatigue, disease, and qual-
ity of life, strategies to slow this decline are important.
Along with increasing fatigue, reductions in steroid
hormones commonly occur as men age. It is estimated
that males experience a decline in testosterone levels at
the rate of 1%–2% per annum after the age of 40 years
(Feldman et al., 2002; Stanworth & Jones, 2008).
Dehydroepiandrosterone sulfate (DHEA-S) concentra-
tions also decrease by an average of 1%–4% per year
between the ages of 40 and 80 years (Tannenbaum,
Barrett-Connor, Laughlin, & Platt, 2004; Walther,
Philipp, Lozza, & Ehlert, 2016). Testosterone and DHEA
have several important roles in the body as they influence
sexual health, lean body mass, mental health, cognition,
bone density, cardiovascular function, and metabolic
activity, just to name a few (Kelly & Jones, 2013;
Rutkowski, Sowa, Rutkowska-Talipska, Kuryliszyn-
Moskal, & Rutkowski, 2014). In men, testosterone can be
converted by the enzyme aromatase into estradiol.
Although estradiol is a hormone often associated with
women, it also tends to decline as men age (Orwoll et al.,
2006). It has several important roles in males, including
having a critical role in male sexual function, adiposity
levels, neurological activity, cardiovascular health, and
immunity (Cooke, Nanjappa, Ko, Prins, & Hess, 2017;
Schulster, Bernie, & Ramasamy, 2016).
Low serum testosterone levels in men are strongly
associated with increased morbidity (Maggi, Schulman,
Quinton, Langham, & Uhl-Hochgraeber, 2007) and com-
monly occur in men with major depressive disorder (Joshi
et al., 2010), cardiovascular disease (Corona et al., 2011),
obesity (Di Vincenzo, Busetto, Vettor, & Rossato, 2018;
A. M. Traish & Zitzmann, 2015), and type 2 diabetes
(Yao, Wang, An, Zhang, & Ding, 2018). Lower testoster-
one concentrations are also adversely associated with a
reduced quality of life (Khera, 2016). It has been reported
that DHEA levels predict longevity in men (Enomoto
et al., 2008), and higher concentrations are associated
with improvements in mood and reductions in fatigue
(Saad, Hoesl, Oettel, Fauteck, & Rommler, 2005). Given
the influence of steroid hormones such as testosterone
and DHEA on mental and physical well-being, health-
related quality of life, and disease morbidity and mortal-
ity, treatments options to slow their progressive decline as
men age may be prudent. Chronic and acute stress are
factors that can influence concentrations of steroid hor-
mones. Although research on the directional impact of
stress on DHEA concentrations is inconsistent, there is
strong evidence confirming that high stress, as indicated
by elevated cortisol, is regularly associated with lower
testosterone concentrations (Collomp et al., 2016). This
indicates that strategies to reduce stress, or cortisol con-
centrations, may be an effective way to optimize steroid
hormone concentrations in men. This is supported by
findings of increased DHEA-S and testosterone follow-
ing participation in a stress reduction program in men
(Antoni, 2003).
Adaptogens such as ashwagandha, Rhodiola rosea,
Siberian ginseng, and Bacopa monnieri are defined as
nontoxic substances, often of plant origin, that increase
the body’s ability to resist the damaging effects of stress
and promote or restore normal physiological function-
ing. Adaptogens exhibit neuroprotective, anti-fatigue,
antidepressant, anxiolytic, nootropic, and central ner-
vous system–stimulating activity (Panossian & Wikman,
2010). Many adaptogenic herbs demonstrated an anti-
fatigue effect, particularly during times of chronic or
acute stress (Panossian & Wikman, 2009). Ashwagandha
(also known as Withania somnifera, Indian ginseng, or
winter cherry) is an adaptogenic herb that is commonly
used in Ayurvedic medicine to promote “youthful
vigor,” enhance muscle strength and endurance, and
improve overall health. It is also believed to offer health-
restorative properties by counteracting chronic fatigue,
weakness, impotence, sterility, nervous exhaustion,
senility, and premature aging (Kulkarni & Dhir, 2008).
The mental and physical effects of ashwagandha have
been investigated in several research studies, with iden-
tified positive effects in reducing stress and anxiety
(Pratte, Nanavati, Young, & Morley, 2014) and increas-
ing memory and cognition (Choudhary, Bhattacharyya,
& Bose, 2017). In a recent meta-analysis comprising
four clinical trials, it was concluded that ashwagandha
supplementation was associated with significant
increases in sperm concentration, semen volume, and
sperm motility in oligospermic males. Increases in
serum testosterone and luteinizing hormone levels were
also identified (Durg, Shivaram, & Bavage, 2018). It
has been demonstrated in several animal studies that
ashwagandha can influence the hypothalamic–pitu-
itary–gonadal hormonal axis and increase testosterone
concentrations (Azgomi et al., 2018; Sengupta et al.,
2018). In a study on chronically stressed adults, ashwa-
gandha supplementation for 60 days was associated
with reductions in anxiety (as measured by the Hamilton
Anxiety Scale) and increases in serum DHEA-S (Auddy,
Hazra, Mitra, Abedon, & Ghosal, 2008).
The aims of this study were to identify the effects of
ashwagandha supplementation over an 8-week period
in overweight men aged 40–70 years with mild-to-
moderate, self-reported fatigue. Given the positive
association of steroid hormones such as testosterone
and DHEA-S on general well-being and quality of life,
the influence of ashwagandha on these hormones was
Lopresti et al. 3
also investigated. Since cortisol is consistently associ-
ated with stress and can have an adverse effect on
energy and androgenic hormones, the effects of ashwa-
gandha on this stress-related hormone was also exam-
ined. To help clarify the impact of ashwagandha
supplementation on hormonal pathways and enzymatic
activity in men (specifically aromatase), estradiol lev-
els were also measured.
Materials and Methods
Study Design
This was a 16-week, randomized, double-blind, placebo-
controlled, crossover trial evaluating the effect of an ash-
wagandha extract (Shoden beads) on salivary hormones
and symptoms of fatigue and vitality in healthy, overweight
men. No washout period was included in this crossover
trial as the aim in the second period of the trial was to
investigate the durability of changes after discontinuation
of the active treatment. The trial protocol was conducted in
accordance with the Declaration of Helsinki and approved
by the Human Research Ethics Committee at Murdoch
University, Western Australia, and was prospectively reg-
istered with the Australian New Zealand Clinical Trials
Registry (Trial ID. ACTRN12617000971336; date of reg-
istration 05/07/2017). Participants were recruited through
social media advertisements between December 2017 and
February 2018, across Western Australia, and they gave
their written informed consent for inclusion before they
participated in the study. Details of the study design are
outlined in Figure 1.
Participants were randomly and equally allocated into
two groups (placebo followed by ashwagandha or ashwa-
gandha followed by placebo) using a randomization calcu-
lator (http://www.randomization.com). The randomization
structure comprised seven randomly permuted blocks,
containing eight participants per block. Participant identifi-
cation number was allocated according to the order of par-
ticipant enrolment in the study. All tablets were packed in
identical containers labeled by intervention code numbers.
Intervention codes were held by the sponsor and a univer-
sity investigator not directly involved in study recruitment
and data collection. Participants and study investigators
were not informed of treatment group allocation until all
questionnaire data was collected.
As this was a pilot study, the sample size was a conve-
nience sample. Past studies have demonstrated that ash-
wagandha has an effect size of 0.8–1.2 on symptoms of
stress and anxiety in stressed adults (Auddy et al., 2008;
Chandrasekhar, Kapoor, & Anishetty, 2012). Assuming a
power of 80%, a type I error rate (alpha) of 5%, and a
10% dropout rate, the total number of participants to find
an effect was calculated as 57.
Participants
Participants were informed about the study and, if agree-
able, were assessed by the principal investigator for eli-
gibility based on the following inclusion/exclusion
criteria:
Inclusion criteria. Healthy males aged between 40 and 70
years reporting mild-to-moderate symptoms of fatigue or
reduced vitality were eligible to participate (as measured
by a Profile of Mood States [POMS] Fatigue-Inertia score
above the 50th percentile, or POMs total score or Vigor-
Activity score below the 50th percentile). Participants
were also required to be nonsmokers, be medication-free
for at least 3 months, and have a body mass index (BMI)
between 25 and 35. Participants were not planning to par-
ticipate in any weight-loss program or significant life-
style-related changes during the study.
Exclusion criteria. Participants were ineligible for partici-
pation in the study if they had a diagnosable mental health
disorder (e.g., depression, anxiety-related disorder, eating
disorder, psychosis/schizophrenia) or medical illness
including diabetes, autoimmune diseases, cardiovascular
disease, hypertension, chronic fatigue syndrome, or
asthma. Those suffering from an infection or illness over
the past month (including the common cold), those who
reported drinking greater than 14 standard servings of
alcoholic drinks per week, or those who reported a cur-
rent or history of illicit drug abuse were also ineligible to
participate. Additionally, current intake of any herbal
preparations or a known hypersensitivity to ashwa-
gandha, herbal supplements, or other herbs and spices
also resulted in ineligibility for study participation.
Eligibility was initially assessed via the completion of
an online questionnaire that screened for current medica-
tion use, energy/stamina levels, height and weight, physi-
cal and mental health, illnesses over the past month,
alcohol consumption, and nicotine intake. If deemed as
likely eligible, volunteers then participated in a phone
interview with the primary investigator. The phone inter-
view comprised a structured series of questions examin-
ing the eligibility criteria already specified.
Interventions
Tablets containing either an ashwagandha extract (Shoden
beads; Arjuna Natural Ltd., Aluva, Kerala, India), deliv-
ering 10.5 mg of withanolide glycosides, or a placebo
(roasted rice powder) were used for the intervention and
placebo periods, respectively. Shoden beads uses a pat-
ented Bioactive Ingredient Protection System (BIPS)
technology comprising an ashwagandha extract from
roots and leaves standardized to 35% withanolide
4 American Journal of Men’s Health
Figure 1. Systematic illustration of study design.
Lopresti et al. 5
glycosides. Both intervention and placebo were made
into tablets, each weighing 300 mg, and were produced in
a good manufacturing practice (GMP)–certified facility.
Participants were instructed to take two tablets once daily,
2 hours away from food (preferably after dinner). The
total daily intake of withanolide glycoside during the
treatment condition was 21 mg (two tablets). Tablets
were identical in appearance, shape, color, and packag-
ing, comprising round maroon-colored tablets.
Medication compliance was measured by participant
pill count at Weeks 4, 8, 12, and 16. Efficacy of partici-
pant treatment blinding was examined by asking partici-
pants to predict group allocation (placebo, ashwagandha,
or uncertain) at the completion of each phase of the study
(Weeks 8 and 16).
Outcome Measures
Outcome Measure 1: symptomatic changes
Aging Males’ Symptoms (AMS) self-report measure. The
AMS is a 17-item, self-report questionnaire measuring
psychological, somatic, and sexual symptoms. Items
are rated on a 5-point Likert scale from 1 (none) to 5
(extremely severe). The AMS is a commonly used and
reliable/valid measure of aging symptoms in men and
their impact on quality of life (Daig et al., 2003). The
AMS was completed at baseline, Week 4, Week 8, Week
12, and Week 16 after the commencement of tablet intake.
Profile of Mood States, Short Form (POMS-SF); Fatigue-
Inertia and Vigor-Activity subscale scores. The POMS-SF
is a 35-item, self-report questionnaire with subscales
including Anger-Hostility, Confusion-Bewilderment,
Depression-Dejection, Fatigue-Inertia, Tension-Anxiety,
Vigor-Activity, and Friendliness. Items are rated on a
5-point Likert scale from 0 (not at all) to 4 (extremely).
The POMS-SF is a commonly used and reliable/valid
questionnaire (Heuchert & McNair, 2012) with the
Fatigue-Inertia subscale demonstrating good validity in
a patient population (Fink et al., 2010). The POMS-SF
fatigue-inertia and Vigor-Activity subscale standardized
scores were used to examine symptomatic change over
time.
Outcome Measure 2: hormonal changes
Salivary testosterone, cortisol, DHEA-S, and estradiol. Par-
ticipants were required to collect a morning, fasting
saliva sample at baseline, Week 8 (end of Phase 1), and
Week 16 (end of Phase 2). Participants were instructed to
fill the collection tube with saliva (approximately 5 ml)
between 6 a.m. and 8 a.m. or within 30 min of rising.
They were asked to collect saliva samples before eating,
drinking liquids, or brushing teeth. Salivary hormones
were tested in duplicate using a fully automated enzyme-
linked immunosorbent assay (ELISA) platform.
Statistical Analysis
An independent samples t-test was used to compare
demographic variables across the two groups. To exam-
ine self-reported symptomatic changes, AMS total score,
and standardized subscale scores for the POMS-SF
Fatigue-Inertia and Vigor-Activity subscales were ana-
lyzed using a 2 × 2 crossover, two-sample t-test (Senn,
2002). There were no significant outliers in data as
assessed by the visual inspection of Q-Q plots. Hormonal
changes (i.e., salivary cortisol, DHEA-S, testosterone,
and estradiol) were analyzed (placebo-ashwagandha and
ashwagandha-placebo) for treatment effects using a 2 ×
2 crossover, two-sample t-test. Grubbs’ single-outlier test
and Rosner’s ESD many-outliers test for response vari-
ables were examined for Week 8 and Week 16 (Period 1
and Period 2) and outliers were eliminated. Shapiro–Wilk
test was used to test for normality. Carryover effects and
period effects were also calculated with no significant
effects being observed.
Data from participants were included in analyses if
questionnaire data were received on at least two time
points across the two treatment phases (intention to treat,
with last observation carried forward for missing values).
For all the tests, statistical significance was set at p < .05
(two-tailed). All data were analyzed using SPSS (version
24; IBM, Armonk, NY) and NCSS 12.
Results
Demographic Details and Baseline Data
Eighty-two people were screened for participation in the
study and 57 met inclusion criteria and were enrolled to
participate. Forty-three (75%) participants complied with
all necessary treatment requirements (i.e., consumed
>80% of capsules, completed self-report inventories on
at least two time points across the two treatment phases,
and collected salivary samples) over the 16-week trial.
Six participants (11%) dropped out of the placebo–ash-
wagandha condition, and 8 (14%) dropped out of the
ashwagandha–placebo condition. There were no signifi-
cant differences between the dropout rates across treat-
ment groups. Reasons for withdrawal included
inconsistent tablet intake (n = 8, 14%), failure to com-
plete questionnaires/collect saliva samples (n = 3, 5%),
commencement of new medical treatment (n = 2, 4%),
and unexpected overseas trip (n = 1, 2%). No participant
withdrew from the study due to self-reported adverse
effects from tablet intake.
6 American Journal of Men’s Health
Demographic characteristics are presented in Table 1
and indicate that the study population was homogeneous,
with no statistically significant differences between the
groups on baseline demographic characteristics.
Outcome Measure 1: symptomatic changes. Mean scores
in the AMS total score, POMS Fatigue-Inertia subscale
score, and POMS Vigor-Activity subscale score during
the crossover period for the two treatment groups are
detailed in Table 2 and Figure 2. There were nonsignifi-
cant between-group differences in AMS total score (T41
= 1.33, p = .192), POMS Fatigue-Inertia subscale score
(T41 = −1.26, p = .213), and POMS Vigor-Activity sub-
scale score (T41 = −0.12, p = .907). A within-group,
paired-samples t-test for Period 1 of the study demon-
strated that there were significant improvements in most
symptom scores from baseline to Week 8, in both the
placebo (AMS, p = .001; POMS Fatigue-Inertia, p =
.001; POMS Vigor-Activity, p = .005) and ashwagandha
(AMS, p = .002; POMS Fatigue-Inertia, p = .348;
POMS Vigor-Activity, p = .017) conditions.
Outcome Measure 2: hormonal changes. Mean salivary
hormone levels during each crossover period are detailed
in Table 3 and Figure 3. The 2 × 2 crossover, two-sample
t-test confirmed significantly higher levels of DHEA-S
(T37 = 2.97, p = .005) and testosterone (T36 = 2.74, p =
.010) during ashwagandha intake, compared to placebo
intake (18.0% and 14.7%, respectively). Nonsignificant
decreases in cortisol (T38 = −1.01, p = .319) and estra-
diol (T38 = −1.34, p = .189) were found during ashwa-
gandha intake, compared to placebo intake (7.8% and
11.6% lower, respectively).
To examine the durability of increases in DHEA-S
and testosterone from ashwagandha supplementation,
mean levels at Period 1 (ashwagandha) can be com-
pared to Period 2 (placebo). As demonstrated in Table
3, mean DHEA-S levels dropped from 9.98 nmol/L to
Table 1. Participant Baseline Demographic Characteristics.
Placebo to ashwagandha
(mean and SE)
Ashwagandha to placebo
(mean and SE)p value
Sample size (n) 29 28 Not applicable
Age 51.66 (1.19) 50.07 (1.26) .363a
BMI 27.93 (0.65) 26.72 (0.55) .164a
Shift workers/remote travel occupations 6 (21%) 6 (21%) .945b
Outcome measures
AMS total score 38.17 (1.85) 36.18 (1.46) .403a
POMS Fatigue-Inertia score 55.83 (1.75) 52.29 (1.36) .117a
POMS Vigor-Activity score 41.28 (1.78) 42.11 (1.81) .745a
Cortisol (nmol/L) 30.64 (2.87) 25.54 (1.79) .137a
DHEA-S (nmol/L) 8.57 (0.79) 8.96 (1.07) .772a
Testosterone (pmol/L) 346.56 (27.20) 354.22 (24.18) .834a
Estradiol (pmol/L) 35.44 (3.71) 29.37 (3.55) .242a
Note. AMS = Aging Males’ Symptoms; POMS = Profile of Mood States; SE = standard error.
aIndependent samples t-test. bPearson’s chi-square.
Table 2. Symptom Scores After Each Crossover Period.
Placebo Ashwagandha
Placebo
mean (both
periods)
Ashwagandha
mean (both
periods)
Mean
differenceap value
Period Period
1 2 1 2
AMS total score n24 19 19 24
26.7 (1.36) 28.1 (1.39) 1.37 (1.03) .192Mean (SE) 27.79 (1.92) 25.79 (1.85) 29.11 (2.34) 27.21 (1.63)
POMS Fatigue-
Inertia score
n23 20 20 23
47.72 (1.37) 46.17 (1.56) –1.55 (1.23) .213Mean (SE) 49.78 (2.26) 45.6 (1.37) 46.20 (1.96) 46.13 (2.34)
POMS Vigor-
Activity score
n23 20 20 23
45.39 (1.53) 45.25 (1.68) –0.15 (1.24) .907Mean (SE) 44.13 (2.32) 46.65 (1.91) 45.10 (2.20) 45.39 (2.49)
Note. AMS = Aging Males’ Symptoms; POMS = Profile of Mood States; SE = standard error.
aTreatment effect: mean score during ashwagandha period minus mean score during the placebo period.
Lopresti et al. 7
8.24 nmol/L and mean testosterone levels dropped from
332.77 pmol/L to 295.41 pmol/L. Although the sample
size available was small (n = 19), the results of a
paired-samples t-test confirmed that the reduction in
DHEA-S was statistically significant (T17 = 2.28, p =
.035), and there was a tendency to suggest testosterone
levels were not sustained (T16 = 1.34, p = .198). This
indicates that the effects of ashwagandha supplementa-
tion on DHEA-S and testosterone were not sustained 8
weeks later.
Adverse Events and Treatment Compliance
At Weeks 4, 8, 12, and 16, participants were asked to list
any adverse effects, symptoms, or illnesses experienced
during the study period (whether they believed it was
associated with tablet intake or not). Ashwagandha was
well tolerated with no significant differences in reported
adverse events between placebo and active drug treat-
ment groups. Compliance with tablet intake was also
high, as 86% of participants consumed greater than 80%
Figure 2. Mean symptom scores after each crossover period.
Table 3. Hormonal Scores After Each Crossover Period.
Placebo Ashwagandha
Placebo mean
(both periods)
Ashwagandha
mean (both
periods)
Mean
differenceap value
Period Period
1212
Cortisol
(nmol/L)
n21 19 19 21
29.42 (2.46) 27.13 (1.90) –2.29 (2.27) .319Mean (SE) 30.95 (3.19) 27.9 (3.78) 25.06 (2.72) 29.2 (2.66)
DHEA-S
(nmol/L)
n21 19 19 21
8.27 (0.74) 9.76 (0.77) 1.49 (0.50) .005Mean (SE) 8.3 (0.98) 8.24 (1.12) 9.98 (1.18) 9.54 (1.00)
Testosterone
(pmol/L)
n21 19 19 21
309.99 (15.29) 355.57 (22.02) 45.58 (16.64) .01Mean (SE) 324.57 (18.44) 295.41 (25.25) 332.77 (35.59) 378.38 (27.22)
Estradiol
(pmol/L)
n21 19 19 21
23.95 (2.68) 21.18 (1.94) –2.78 (2.08) .19Mean (SE) 29.52 (4.37) 18.38 (2.91) 22.21 (2.28) 20.14 (3.06)
Note. SE = standard error.
aTreatment effect: mean score during ashwagandha period minus mean score during placebo period.
8 American Journal of Men’s Health
of allocated tablets (as measured by self-reported tablet
number at Weeks 4, 8, 12, and 16).
Efficacy of Participant Blinding
To evaluate the efficacy of condition concealment over
the study, participants were asked at the completion of
each phase of the study to predict condition allocation
(i.e., placebo, ashwagandha, or uncertain). Efficacy of
group concealment was high as only 35% of participants
correctly guessed treatment allocation, 30% of partici-
pants were uncertain of treatment allocation, and the
remaining 35% incorrectly guessed group allocation.
Discussion
In this 16-week, randomized, double-blind, crossover study,
the 8-week intake of an ashwagandha extract (Shoden
beads, delivering 21 mg of withanolide glycosides) was
associated with significant changes in salivary DHEA-S
and testosterone in healthy, overweight males aged between
40 and 70 years reporting mild-to-moderate symptoms of
fatigue or reduced vitality. No statistically significant
change in salivary cortisol or estradiol was observed.
Improvements in fatigue, vigor, and sexual and psychologi-
cal well-being were observed after both ashwagandha and
placebo supplementation with no statistically significant
group differences. Ashwagandha supplementation was well
tolerated with no reported adverse events or participant
withdrawal associated with its intake.
The mood-lifting and antianxiety effects of ashwa-
gandha have been investigated in several studies, con-
firming its positive antianxiety effects in stressed, healthy
adults (Auddy et al., 2008; Chandrasekhar et al., 2012);
stressed, overweight adults (Choudhary, Bhattacharyya,
& Joshi, 2017); and adults with a diagnosed anxiety dis-
order (Andrade, Aswath, Chaturvedi, Srinivasa, &
Raguram, 2000; Khyati & Anup, 2013). Anti-stress and
antidepressant effects of ashwagandha have also been
observed in animal studies comprised of unpredictable
foot shock, elevated plus-maze test, and the forced swim
test (Bhattacharya, Bhattacharya, Sairam, & Ghosal,
2000; Bhattacharya & Muruganandam, 2003). Although
an area of lesser focus, ashwagandha supplementation
also has demonstrated positive effects on energy and
fatigue as evidenced by greater exercise-induced muscle
recovery in adults undergoing resistance training
(Wankhede, Langade, Joshi, Sinha, & Bhattacharyya,
2015) and breast cancer patients undergoing chemother-
apy (Biswal, Sulaiman, Ismail, Zakaria, & Musa, 2013).
In the current study, significant improvements over
time in levels of vigor and emotional or sexual well-being
Figure 3. Mean hormonal scores after each crossover period.
Lopresti et al. 9
from ashwagandha supplementation were identified; how-
ever, this was not significantly different to the placebo.
This suggests that in the population examined (i.e.,
healthy, overweight males aged 40–70 years reporting
mild-to-moderate symptoms of fatigue or reduced vital-
ity), ashwagandha had no advantage over a placebo in
alleviating fatigue, increasing vigor, or enhancing sexual
vitality. There are several potential explanations for these
findings. Average pretreatment, self-reported levels of
fatigue, vigor, and sexual well-being were of only mild
intensity. This increases the likelihood of floor effects, and
as only moderate improvements are likely, larger sample
sizes would be required to identify statistically significant
differences. Nonsignificant between-group differences
may also be associated with the method of participant
recruitment. Volunteers were recruited via social media,
and this likely included individuals motivated to improve
their general well-being. While participants were encour-
aged to not engage in any dietary, exercise, or lifestyle
changes during the study, it is possible that these moti-
vated individuals may have implemented changes that had
positive effects on their energy, vigor, and general well-
being (e.g., changes in work, relationships, diet, and phys-
ical activity). Unfortunately, monitoring of changes in
these areas over the study duration was not undertaken. In
addition, a large portion of participants (approximately
20%) were engaged in shift work and/or were employed
in occupations requiring travel to remote, mining commu-
nities. This may moderate the therapeutic efficacy of ash-
wagandha due to ongoing sleep-related disturbances and
stresses associated with living away from home. Research
confirms that shift work is associated with a greater need
for recovery and a higher risk of disability (Gommans,
Jansen, Stynen, de Grip, & Kant, 2015). This hypothesis
was supported in the current study, as a post hoc analysis
of trial data revealed an average 4.8% improvement in
fatigue during the first phase of the study in shift/mine
workers compared to a larger improvement of 12.6% in
the remaining participants. Undertaking statistical analy-
ses by excluding shift workers was considered inappropri-
ate due to the small sample and increased potential for
type I errors. The nonsignificant findings may also result
from the high observed placebo effect (e.g., AMS total
score reduction of 25% in Period 1 of the study). This is
significantly higher than effects observed in most previ-
ously published studies on ashwagandha. This suggests
greater treatment expectations in the recruited population
of Australian participants. This may be culturally influ-
enced, as previous studies have mostly been conducted on
Indian populations.
In the current study, an examination of hormonal
changes over time demonstrated that ashwagandha supple-
mentation over an 8-week period was associated with 15%
higher levels of salivary testosterone and 18% higher levels
of DHEA-S compared to placebo. However, there were no
statistically significant differences in levels of salivary cor-
tisol or estradiol compared to the placebo. The effects of
ashwagandha in increasing levels of testosterone have been
demonstrated in men undergoing resistance training
(Wankhede et al., 2015), oligospermic males (Ambiye
et al., 2013), and infertile men (Gupta et al., 2013). Increases
in DHEA-S from ashwagandha supplementation were also
identified in chronically stressed males (Auddy et al., 2008).
In animal studies, ashwagandha has been consistently dem-
onstrated to have a lowering effect on corticosterone con-
centrations (Baitharu et al., 2013; Bhatnagar, Sharma, &
Salvi, 2009; Bhattacharya & Muruganandam, 2003).
Animal studies investigating its effects on sex hormones are
limited, although there are preliminary supportive findings
(Abdel-Magied, Abdel-Rahman, & Harraz, 2001; Rahmati
et al., 2016).
Findings from the current study are consistent with
previous findings, as significantly higher levels of testos-
terone and DHEA-S were identified from ashwagandha
supplementation compared to the placebo. It seems that
these increases are not sustained over time, as DHEA-S,
and to a lesser extent testosterone, was lower after 8
weeks of discontinued ashwagandha supplementation.
This suggests that ongoing ashwagandha intake is
required to sustain changes, or longer intake is required
for more enduring changes. The effects of DHEA-S and
testosterone in aging males have important health impli-
cations as lower levels are associated with increased mor-
bidity, reduced longevity, and lower quality of life
(Enomoto et al., 2008; Khera, 2016; Maggi et al., 2007;
Nagaya, Kondo, & Okinaka, 2012).
Although ashwagandha was associated with increases
in DHEA-S and testosterone, no statistically significant
effects on morning salivary cortisol levels (a nonsignifi-
cant 7.8% lower level compared to placebo) or estradiol
concentrations (a nonsignificant 11.6% lower level com-
pared to placebo) were identified. The effect of ashwa-
gandha on estradiol has not been previously investigated,
although there are several studies confirming its cortisol-
lowering effects in adults. The current findings, therefore,
contrast with the results from studies confirming ashwa-
gandha’s cortisol-reducing influence in chronically
stressed adults (Auddy et al., 2008), adults with an anxi-
ety disorder (Chandrasekhar et al., 2012), and over-
weight, stressed adults (Choudhary, Bhattacharyya, &
Joshi, 2017). These findings suggest that ashwagandha
was ineffective at lowering cortisol levels in the exam-
ined male population. However, in contrast to previous
studies, salivary cortisol was measured rather than serum.
Moreover, as mentioned previously, a significant portion
of the recruited population (approximately 20%) were
shift and mine workers. There is research confirming a
strong influence of shift work on diurnal cortisol
10 American Journal of Men’s Health
concentrations (Li et al., 2018; Ulhôa, Marqueze, Burgos,
& Moreno, 2015) and there is some evidence, albeit
inconsistent, suggesting a lowering effect on testosterone
concentrations (Deng, Haney, Kohn, Pastuszak, &
Lipshultz, 2018). Recruiting shift workers may have
therefore moderated the potential effects of ashwagandha
on cortisol and other steroid hormones. In addition, con-
trary to previous investigations on ashwagandha, a
stressed or anxious population, where higher cortisol lev-
els are commonly observed, was not specifically recruited.
Rather, a population with self-reported fatigue was
recruited. There is evidence to suggest lower cortisol con-
centrations in people with symptoms of burnout
(Lennartsson, Sjors, Wahrborg, Ljung, & Jonsdottir,
2015) and chronic fatigue syndrome (Nijhof et al., 2014).
Consequently, if the recruited sample presented with pre-
morbid low cortisol levels, further reductions would
unlikely occur. This hypothesis requires investigation in
future studies.
Understanding the mechanisms associated with ash-
wagandha’s influence on DHEA and testosterone produc-
tion requires further investigation although there are
several plausible mechanisms. DHEA is produced in the
zona reticularis of the adrenal cortex and is influenced by
activity of the hypothalamus–pituitary–adrenal (HPA)
axis, particularly circulating levels of adrenocorticotropic
hormone (ACTH; Klinge, Clark, & Prough, 2018). As
already discussed, in several studies ashwagandha low-
ered cortisol concentrations, suggesting a dampening
effect on HPA axis activity. Potentially via ashwagand-
ha’s influence on HPA axis activity, DHEA and testoster-
one concentrations may be elevated. However, this
mechanism was not confirmed in the current study as ash-
wagandha had no appreciable effect on cortisol concen-
trations. DHEA and testosterone are also produced by
Leydig cells in the testes, which are influenced by gonad-
otropin-releasing hormone (GnRH). It has been demon-
strated through in vitro and animal studies that
ashwagandha upregulates the activity of GnRH
(Al-Qarawi et al., 2000; Kataria, Gupta, Lakhman, &
Kaur, 2015). Therefore, through its effect on GnRH activ-
ity, increases in DHEA and testosterone concentrations
from ashwagandha intake may occur. A bidirectional
relationship between inflammation, oxidative stress, and
androgen hormones such as testosterone has also been
regularly observed in animal and human studies
(Mohamad et al., 2018; Tostes, Carneiro, Carvalho, &
Reckelhoff, 2016; A. Traish, Bolanos, Nair, Saad, &
Morgentaler, 2018; Wang, Chen, Ye, Zirkin, & Chen,
2017). Ashwagandha has demonstrated antioxidant and
anti-inflammatory activity, thereby potentially contribut-
ing to its influence on DHEA and testosterone (Ganguly,
Kumar, Ahmad, & Rastogi, 2018; Mishra, Singh, &
Dagenais, 2000). Finally, it is important to note that
although there was no statistically significant change in
estradiol concentrations from ashwagandha supplementa-
tion, there was a trend signifying reduced levels. This
contrasts with the increased levels of estradiol prohor-
mones, DHEA-S and testosterone. Elevated estradiol lev-
els would, therefore, be expected. As this did not occur, it
is hypothesized that ashwagandha may be an inhibitor of
aromatase, an enzyme required for the conversion of tes-
tosterone into estradiol. The aromatase-inhibiting effect
of a plant from the same Solanaceae family, Withania
coagulans, was identified in one study (Haq et al., 2013).
W. coagulans, like ashwagandha, contains high concen-
trations of withanolides. This very speculative observa-
tion requires investigation in future studies.
Study Limitations and Directions for Future
Research
There are several limitations associated with this study
that may have impacted on the findings and require con-
sideration in future research. The sample size recruited
was small, making it difficult to develop definitive con-
clusions. Future studies should, therefore, involve larger
samples. Participants were recruited via social media,
which may have biased the findings. It is expected that
such individuals comprise a motivated cohort of volun-
teers. Consequently, in addition to participating in a study
and taking supplements, these individuals may have
made dietary, occupational, lifestyle, and/or social
changes that contributed to the fatigue-lowering and
vigor-enhancing changes observed in both treatment con-
ditions. While participants were encouraged to maintain
regular lifestyle habits during the study, this was not ade-
quately monitored. It may be beneficial in future studies
to monitor such changes (e.g., diet, exercise, weight, life
stressors) through questionnaires and other monitoring
instruments. It is also important to consider the potential
impact of participant expectations. This is particularly
important when there are strong advertising campaigns
promoting the virtues of a product or drug. In the sample
of Australian participants recruited in this study, most
reported limited knowledge about ashwagandha and its
benefits. However, this will require consideration in
countries such as India and increasingly in the United
States, where knowledge about ashwagandha by health-
conscious individuals is increasing.
To increase compliance and reduce the demands on
participants, hormonal concentrations were evaluated via
fasting salivary collections rather than in serum. It has
been confirmed in several studies that salivary measure-
ments of testosterone, DHEA-S, cortisol, and estradiol
correlate well with serum levels (Arregger, Contreras,
Tumilasci, Aquilano, & Cardoso, 2007; Francavilla et al.,
2018; Lood et al., 2018). However, their accuracy as an
Lopresti et al. 11
outcome measure can be compromised by their rapid
diurnal variability (Wood, 2009). Although participants
were instructed to collect saliva samples within 15 min of
waking, and in a fasting state, sample collection times
could not be adequately monitored as they were under-
taken in participants’ homes. Inconsistency in such col-
lections will have a negative impact on the accuracy and
reliability of measurements. In future studies, to enhance
the robustness of findings, it would be important to con-
trol for or accurately monitor such variables. Measuring
hormonal concentrations in both saliva and serum may
also be advantageous. Measurement methods and stan-
dardization must also be considered due to increasing
concerns around the accuracy and variability associated
with testosterone measurements (Vesper & Botelho,
2010).
As previously noted, approximately 20% of volun-
teers were either shift or mine workers. Given the limited
sample size, subgroup analyses could not be adequately
undertaken to examine the effect of shift work on mea-
sured outcomes. However, there is research confirming
the adverse effects of shift work on general well-being,
morbidity, and hormonal concentrations such as cortisol
and testosterone. It will be important in future studies to
control for the recruitment of shift workers and/or to spe-
cifically examine the effects of ashwagandha in this
group of individuals. Given their variable sleep and daily
routines, an examination into the impact of variable dos-
ing and timing may also be helpful.
Increases in steroid hormones such as testosterone and
DHEA-S in men are commonly considered to have posi-
tive health-enhancing effects. However, this may not
always be the case. For example, there is evidence to sug-
gest that testosterone replacement therapy may be associ-
ated with adverse effects in men with high cardiovascular
risk, preexisting prostate disease, and sleep apnea (Bhasin
et al., 2010; Grossmann, 2011; Snyder et al., 2016). While
these risks are specifically associated with testosterone
replacement therapy (and continue to be debated particu-
larly in relation to cardiovascular risk), the safety of ash-
wagandha in such populations requires further
consideration and evaluation. However, serious adverse
effects seem unlikely with ashwagandha, as a moderate
15% increase in testosterone level, which remained
within normal endogenous concentrations, was observed
in this study. Previous studies have also confirmed that
ashwagandha is not associated with withdrawal effects
and has not been associated with abuse (Durg et al., 2018;
Pratte et al., 2014). In the current study, ashwagandha
intake was not associated with any significant adverse
events and was well tolerated by participants. This strong
safety profile is supported by previously conducted stud-
ies where systematic reviews confirmed that ashwa-
gandha intake was not associated with significant adverse
reactions in stressed and anxious adults (Pratte et al.,
2014) or infertile males (Durg et al., 2018). However,
most studies have been of short duration, so safety and
efficacy over longer term administration are required.
Finally, in this study, we used a patented ashwagandha
extract, Shoden beads, standardized to withanolide glyco-
sides. This extract is manufactured in a GMP-certified
facility (Arjuna Natural Ltd.). The quality of herbal extracts
and the manufacturing practices used can vary signifi-
cantly, likely impacting on therapeutic potency. Therefore,
generalizing the findings from this study to alternative ash-
wagandha extracts should be done cautiously.
In conclusion, the findings from this study demon-
strated that 8 weeks of supplementation with an ashwa-
gandha extract (Shoden beads, 600 mg daily delivering
21-mg withanolide glycoside) was associated with sig-
nificant improvements in salivary DHEA-S and testos-
terone, but not cortisol and estradiol, in healthy males
aged between 40 and 70 years. Furthermore, supple-
mentation had no significant effect on symptoms of
fatigue, vigor, or sexual or psychological well-being.
The robustness and generalizability of the findings are
moderated by the small sample size and the high num-
ber of shift and mine workers recruited. Future investi-
gations utilizing larger sample sizes, varying treatment
doses and duration, and divergent study populations,
including both males and females, are necessary to fur-
ther understand the potential therapeutic and adapto-
genic effects of ashwagandha.
Acknowledgments
The authors gratefully acknowledge Arjuna Natural Ltd. for
funding the project and supplying Shoden® for use in this study.
Author Contributions
AL, PD, and SS contributed to the study design, data collec-
tion, writing, statistical analyses, and data interpretation of the
clinical trial of the present research. All the authors read and
approved the final draft of the manuscript.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article. Arjuna Natural Ltd. was not involved in the design of
the research, analysis of data, or in the writing of the report.
Funding
The author(s) disclosed receipt of the following financial sup-
port for the research, authorship, and/or publication of this arti-
cle: This study was funded by Arjuna Natural Ltd.
ORCID iD
Adrian L. Lopresti https://orcid.org/0000-0002-6409-7839
12 American Journal of Men’s Health
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