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A Standardized Withania Somnifera Extract Significantly Reduces Stress-Related Parameters in Chronically Stressed Humans: A Double-Blind, Randomized, Placebo-Controlled Study

Authors:
  • Regional Ayurveda Research Institute Ranikhet

Abstract

Withania somnifera (WS) has historically been used in Asia for treating stress-related health conditions. In this study, we investigated the effects of standardized WS root and leaf extract (WSE) in chronically stressed humans in a modern clinical trial. Participants were randomly assigned to WSE (125 mg QD, 125 mg BID, or 250 mg BID) or placebo groups. Stress levels were assessed at Days 0, 30, and 60 using a modified Hamilton anxiety (mHAM-A) scale. Biochemical and clinical variables were measured at Days 0 and 60. Of 130 subjects enrolled, 98 completed the study. Between Days 0 and 60, the WSE 125 mg QD group decreased significantly more than placebo for mean mHAM-A score, serum cortisol, serum C-reactive protein, pulse rate and blood pressure, and increased significantly for mean serum DHEAS and hemoglobin. Other WSE treat- ment groups had greater dose-dependent responses in these parameters and had significantly greater responses com- pared to placebo in mean fasting blood glucose, serum lipid profiles and cardiac risk ratios. Participants and dropouts reported no adverse effects. Therefore, this study provides evidence that the consumption of WSE significantly reduces experiential and biochemical indicators of stress without adverse effects.
JANA Vol. 11, No. 1, 2008 51
O RIGINAL R ESEARCH
A Standardized Withania Somnifera Extract
Significantly Reduces Stress-Related
Parameters in Chronically Stressed Humans:
A Double-Blind, Randomized,
Placebo-Controlled Study
Biswajit Auddy, PhD
1
*
; Jayaram Hazra, PhD
2
; Achintya Mitra, MD
2
;
Bruce Abedon, PhD
3
; Shibnath Ghosal, PhD
1
1. Research and Development Center, Natreon Inc., Salt Lake City, Kolkata, India
2. Central Research Institute (Ayurveda), Ministry of Health and Family Welfare,
Govt. of India, Bidhan Nagar, Kolkata, India
3. Director of Scientific Affairs, NutraGenesis LLC, Brattleboro, Vermont
ABSTRACT
Withania somnifera (WS) has historically been used in
Asia for treating stress-related health conditions. In this
study, we investigated the effects of standardized WS root
and leaf extract (WSE) in chronically stressed humans in a
modern clinical trial. Participants were randomly assigned
to WSE (125 mg QD, 125 mg BID, or 250 mg BID) or
placebo groups. Stress levels were assessed at Days 0, 30,
and 60 using a modified Hamilton anxiety (mHAM-A)
scale. Biochemical and clinical variables were measured at
Days 0 and 60. Of 130 subjects enrolled, 98 completed the
study. Between Days 0 and 60, the WSE 125 mg QD group
decreased significantly more than placebo for mean
mHAM-A score, serum cortisol, serum C-reactive protein,
pulse rate and blood pressure, and increased significantly
for mean serum DHEAS and hemoglobin. Other WSE treat-
ment groups had greater dose-dependent responses in these
parameters and had significantly greater responses com-
pared to placebo in mean fasting blood glucose, serum lipid
profiles and cardiac risk ratios. Participants and dropouts
reported no adverse effects. Therefore, this study provides
evidence that the consumption of WSE significantly
reduces experiential and biochemical indicators of stress
without adverse effects.
Key words: Withania somnifera, antistress, withanolides,
sitoindosides, cortisol, C-reactive protein.
INTRODUCTION
Stress is a major component of modern life, causing
adverse physiological conditions such as cognitive deficien-
cies, impaired glucose and lipid homeostasis, immunosup-
pression, sexual dysfunction, gastric ulceration, and alter-
ation in serum cortisol and dehydroepiandrosterone sulfate
(DHEAS) levels.
1
Development of active management and
treatment protocols that control stress-related symptoms
with minimum adverse effects would be of great benefit.
Withania somnifera Dunal (Solanacea) (WS) has tradi-
tionally been used in Asia for safely managing and treating
stress. Also known as Ashwagandha, Indian ginseng and
winter cherry, it belongs to a rasayana (vitalizer) group of
medicinal plants that stabilize and revitalize systemic func-
tions. The Ayurvedic system of medicine claims that it pro-
motes stress relief, health and longevity by potentiating the
immune system, arresting premature aging, restoring
homeostasis and increasing resistance to adverse environ-
* Correspondence:
Biswajit Auddy, PhD
Research and Development Center, Natreon Inc.
CL 18A, Sector II
Salt Lake City, Kolkata 700 091, India
E-Mail: natr1910@dataone.in
3rd Proof
JANA Vol. 11, No. 1, 2008 52
mental factors, collectively known as the antistress-adapto-
genic effect.
2-4
However, its healing effects on chronically
stressed individuals have never been evaluated in a random-
ized, controlled clinical trial.
Several bio-actives, including withanolide glycosides
(also known as sitoindosides) and withanolide aglycones,
are considered to be responsible for the medicinal proper-
ties of WS.
5,6
Traditional medicinal use of WS has
employed root powder derived from wild plants,
7
which are
relatively low in concentration of bioactives.
5
Cultivated
WS varieties differ morphologically from wild WS,
8
and
have higher levels of bioactive components.
5,9
Methods to
further concentrate levels of bioactives in standardized WS
extracts (WSE) have also been developed.
9
The objective of this study was to investigate, in chron-
ically stressed adults, the impact of WSE on experiential
and biochemical indicators of stress and anxiety as well as
cardiovascular risk, and to evaluate WSE tolerance.
MATERIALS AND METHODS
This double-blind, randomized, placebo-controlled study
was conducted from November 2004 to October 2006 at the
Central Research Institute (Ayurveda), Ministry of Health
and Family Welfare, Bidhan Nagar, Kolkata, India (CRI), in
accordance with the World Health Organization's Guideline
for Good Clinical Practice and the World Medical
Association Declaration of Helsinki.
10, 11
The CRI Ethics
Committee approved the protocol. Patients identified as
stressed in the CRI outpatient department were assessed clin-
ically (blood pressure, resting heart rate, reflexes, and neuro-
logical and psychological status) and completed a question-
naire assessing the severity of stress symptoms (cognitive,
mood and behavioral) based on a Bengali version of a modi-
fied Hamilton anxiety (mHAM-A) scale for stress.
12, 13
In the questionnaire, patients rated symptoms of anxi-
ety (fatigue, flushing, perspiration, loss of appetite,
headache and muscle pain, feelings of impending doom,
palpitations, dry mouth, sleeplessness, forgetfulness, irri-
tability and inability to concentrate) on a 5-point scale (0 =
no symptoms; 1 = occasional; 2 = mild/poor; 3 = moderate;
4 = severe). The total score was calculated by adding the
score from individual questions.
Men and women aged 18 to 60 years were eligible for
the study if they had a mHAM-A score of 24 to 42.
Exclusion criteria were any concomitant serious physical
disorder(s) or antistress treatment (antidepressants, anxi-
olytic) that was ongoing or had occurred during the previ-
ous month. Exercise as well as drugs that lower serum
lipids, blood pressure or blood sugar were not considered
exclusion criteria, but this was not considered a significant
bias in the study because only two participants (1.5% of the
total) were taking drugs of this nature (hypertensive) and
they were allocated randomly into different treatment
groups. Participants provided written informed consent in
English and Bengali, the local language, and were random-
ly divided into four groups using a computer-generated ran-
dom number list: WSE 125 mg QD, WSE 125 mg BID,
WSE 250 mg BID, and placebo.
The WSE used in this study {trade names Sensoril
®
(Natreon Inc., New Brunswick, New Jersey) and Essentra
®
(NutraGenesis, LLC, Brattleboro, Vermont)} was derived
from a withaferin A and corresponding withanolide glyco-
side-predominant, genetically uniform chemotype, which
was cultivated in the central and northern provinces of
India. WS root and leaf material was processed using a
water-based extraction protocol and assessed using high
performance thin layer chromatography analysis of frac-
tions against standard references (CAMAG Linomat V
applicator, CAMAG TLC Scanner, and WinCats software
version 1.3.4; CAMAG, Sonnenmattstr. Muttenz,
Switzerland) in accordance with US Patent 6,713,092. The
single lot of WSE used in the study had a composition of
11.90% withanolide glycosides, 1.05% withaferin A,
40.25% oligosaccharides, 0.05% alkaloids, and 3.44%
polysaccharides with no scopolamine, pyrrolizidine alka-
loids or aristolochic acid.
WSE (125 mg or 250 mg) plus excipients or excipients
only (placebo) were placed in coded hard-gelatin capsules
identical in size, shape, color (opaque white) and texture.
Participants received two bottles of capsules and were told
to take one capsule from Bottle 1 before lunch and one cap-
sule from Bottle 2 before dinner for 60 days. Participants in
the WSE 125 mg QD group took a 125 mg WSE capsule
before lunch and a placebo capsule before dinner.
Participants in the other groups took two of the same cap-
sule (corresponding to the group name, e.g., the placebo
group took two placebo capsules, etc.) each day. At each of
four visits, participants received a 15-day supply of cap-
sules. Compliance was monitored by counting the remain-
ing pills at each follow-up visit and at the end of the study.
Information about tolerance (i.e., treatment-emergent
adverse effects) was obtained by questioning the partici-
pants and clinically examining them at each visit.
Experiential feelings of stress and anxiety were
assessed by calculating the sum of scores from the mHAM-
A questionnaire taken at baseline (Day 0), Day 30 and Day
60. To measure biochemical markers of stress and anxiety,
participants fasted overnight prior to visits at baseline and
Day 60 to avoid diurnal variations (particularly in serum
cortisol concentration
14
). Blood samples (6–10 mL) were
collected in vacutainer tubes (BD Vacutainer Systems
Medical Supplies, Plymouth Devon, UK) between 9 a.m.
and 11 a.m., stored at 4°C, and assayed for serum concen-
trations of cortisol, dehydroepiandrosterone sulfate
(DHEAS), C-reactive protein (CRP), fasting blood glucose
(FBG), total cholesterol (TC), triglycerides (TG), low-den-
sity lipoprotein cholesterol (LDL-C), very low-density
lipoprotein cholesterol (VLDL-C), high-density lipoprotein
cholesterol (HDL-C), and hemoglobin at a laboratory
(Doyen Diagnostic & Research Foundation, 59 Bhupen
Bose Avenue, Kolkata-700004) accredited by the National
Accreditation Board for Testing and Calibration
Laboratories, Dept. of Science and Technology,
Government of India. Pulse rate and blood pressure were
also determined.
Difference scores were calculated by subtracting sum
values at 30 days from baseline, 60 days from baseline, and
60 days from 30 days for each variable individually and for
the total anxiety score. Difference scores were then com-
pared among groups using 1-way analyses of variance with
post hoc pairwise comparisons of the three treatment
groups with the placebo group using the least significant
difference method. Percent changes were expressed as the
difference between the means of the baseline and treatment
phases divided by the mean of the baseline phase multiplied
by 100. Cardiovascular risk ratios (TC:HDL-C and LDL-
C:HDL-C) were calculated as TC divided by HDL-C and
LDL-C divided by HDL-C, respectively. Values between 3.5
and 5 for TC:HDL-C and between 1.1 and 3.6 for LDL-
C:HDL-C indicate average risk of developing coronary
artery disease and heart disease.
15
Sample size calculations
were not done for this study. P < 0.05 was considered sta-
tistically significant.
RESULTS
Out of 160 eligible participants, 130 (95 men, 35
women; mean age= 39.8 years) initially enrolled in the study
(Table 1) and 32 (26 men, 6 women) dropped out (WSE 125
mg QD group, 11; WSE 125 mg BID group, 5; WSE 250 mg
BID group, 1; and placebo group, 15). Reasons for study
withdrawal were protocol violations, 6; being lost to follow-
up, 10; physician’s decision, 4; and lack of efficacy, 12. This
dropout rate (and the fact that lack of efficacy was the largest
category of dropouts) is fairly common in clinical trials of
psychiatric drugs and is well within professionally recog-
nized limits.
16
Because dropouts were not included in the
final analysis, per-protocol analysis was followed and intent-
to-treat analysis was not performed.
17
Participants in all WSE treatment groups experienced
improved well being at Day 30 and Day 60 (Figure 1). The
125 mg QD group decreased significantly (P<0.001) in
mean sum mHAM-A score from baseline (29.9) to Day 30
(18.1; -39.5%) and to Day 60 (11.3; -62.2%) compared to
the placebo group, which showed no significant mean
change in sum mHAM-A score throughout the study. Mean
sum mHAM-A scores for the other WSE groups decreased
even further than for the 125 mg QD group in a dose-
dependent manner. The mean sum mHAM-A score for the
placebo group at baseline, 27.6, was lower than those of the
WSE-treated groups (which ranged between 29.2-29.9), but
not significantly. Mean scores for individual questions on
the mHAM-A questionnaire also decreased significantly
(P<0.001) at Day 30 and Day 60 for all WSE treatment
groups versus the placebo group (Table 2).
Mean values (SD) of biochemical and clinical parame-
ters investigated for each treatment group are summarized
in Tables 3 and 4. Between baseline and Day 60, the WSE
125 mg QD group decreased significantly (P<0.05) more
than the placebo group for mean serum cortisol (-14.5%),
serum VLDL-C (-8.9%), systolic BP (-1.6%), diastolic BP
(-5.6%), and (P<0.001) serum CRP (-31.6%) and pulse rate
(-6.0%), and increased significantly (P<0.05) more than the
placebo group for mean serum DHEAS (13.2%) and hemo-
globin (6.3%). For the same period, the other WSE treat-
Table 1. Baseline demographic and clinical characteristics of study participants (N = 130).
z
Characteristic Group
WSE 125 mg QD
(n = 30)
WSE 125 mg BID
(n = 35)
WSE 250 mg BID
(n = 35)
Placebo
(n = 30)
Age, mean (SD), y 37.8 (12.4) 39.4 (12.6) 40.0 (9.9) 42.1 (9.6)
Sex, no. (%)
Men 22 (73.3) 27 (77.1) 23 (65.7) 23 (76.7)
Women 8 (26.7) 8 (22.9) 12 (34.3) 7 (23.3)
Weight, mean (SD), kg 58.9 (9.9) 60.5 (9.0) 59.1 (9.2) 59.1 (6.6)
Height, mean (SD), cm 161.8 (9.3) 161.5 (7.7) 162.7 (7.3) 159.4 (6.7)
WSE = Withania somnifera extract.
z
No significant between-group differences were found.
53JANA Vol. 11, No. 1, 2008
ment groups had even greater responses in these parameters
than the WSE 125 mg QD group in a dose-dependent man-
ner. In addition, the WSE 125 mg BID group had signifi-
cantly (P<0.05) greater reductions, compared to the place-
bo group, in mean FBG (-4.7%), serum TC (-7.0%), serum
TG (-9.5%), and serum LDL-C (-9.0%). The WSE 250 mg
BID group had similar to greater responses in mean FBG,
and serum TC, TG and LDL-C than the WSE 125 mg BID
group, and also had a significantly (P<0.001) greater
increase in mean serum HDL-C compared to the placebo
group (17.3%). Cardiac risk ratios, at the higher end of the
average risk range at Day 0 for all treatment groups,
improved for the two higher dosage WSE groups at Day 60
by decreasing significantly (P<0.05) compared to the place-
bo group (data not shown).
No significant difference was observed in the placebo
group between baseline and Day 60 for any biochemical or
clinical parameter measured. In addition, no study partici-
pant or dropout experienced any adverse effects or with-
drawal effects, regardless of the dosage or frequency.
Table 2. Mean (SD) scores by treatment group for individual symptoms of stress and anxiety based on a modified Hamilton anx-
iety scale
z
at Day 0 (baseline) and after 30 and 60 days of treatment with Withania somnifera extract (WSE) or placebo (n = 98).
Symptom
Fatigue Flushing Perspiration Loss of appetite Headache and
muscle pain
Feelings of
impending doom
Group Day
0
Day
30
Day
60
Day
0
Day
30
Day
60
Day
0
Day
30
Day
60
Day
0
Day
30
Day
60
Day
0
Day
30
Day
60
Day
0
Day
30
Day
60
WSE 125 mg QD
(n = 19)
3.2
(0.7)
1.9
(0.7)
1.5
(0.7)
†‡
2.1
(1.0)
1.1
(0.8)
0.4
(0.6)
2.4
(1.2)
1.6
(0.8)
1.2
(0.7)
1.3
(0.6)
1.1
(0.8)
0.9
(0.7)
†‡
2.4
(1.0)
1.1
(0.8)
0.6
(0.6)
3.2
(0.8)
1.7
(0.7)
0.8
(0.6)
†‡
WSE 125 mg BID
(n = 30)
2.9
(0.9)
1.3
(1.0)
0.6
(0.6)
†‡
1.6
(1.1)
0.8
(0.9)
0.4
(0.6)
1.9
(1.1)
1.3
(0.6)
0.9
(0.4)
1.7
(1.1)
0.8
(0.7)
0.5
(0.6)
1.7
(1.1)
0.8
(0.7)
0.5
(0.6)
†‡
3.6
(0.6)
2.0
(0.9)
0.9
(0.8)
†‡
WSE 250 mg BID
(n = 34)
3.0
(1.0)
1.4
(0.8)
0.4
(0.5)
†‡
1.8
(1.0)
0.7
(0.7)
0.4
(0.5)
1.8
(1.3)
1.2
(0.4)
0.8
(1.3)
1.4
(0.7)
1.0
(0.4)
0.8
(0.4)
†‡
1.7
(1.0)
0.5
(0.6)
0.3
(0.5)
†‡
3.1
(0.7)
1.4
(0.6)
0.5
(0.7)
†‡
Placebo
(n = 15)
2.9
(1.0)
2.9
(0.9)
2.7
(0.8)
1.9
(1.0)
1.7
(1.2)
1.5
(0.9)
1.5
(0.9)
1.5
(1.1)
1.5
(0.7)
1.2
(0.6)
1.5
(0.5)
1.5
(0.5)
2.1
(0.8)
1.9
(0.8)
1.8
(0.8)
3.1
(1.0)
3.0
(1.0)
3.2
(0.9)
Symptom
Palpitations Dry mouth Sleeplessness Forgetfulness Irritability Inability to concentrate
Group Day
0
Day
30
Day
60
Day
0
Day
30
Day
60
Day
0
Day
30
Day
60
Day
0
Day
30
Day
60
Day
0
Day
30
Day
60
Day
0
Day
30
Day
60
WSE 125 mg QD
(n = 19)
1.9
(0.8)
1.1
(0.8)
0.6
(0.5)
1.4
(1.0)
0.8
(0.8)
0.5
(0.6)
3.1
(0.9)
1.9
(0.8)
0.9
(0.8)
†‡
2.7
(0.7)
1.8
(0.5)
1.4
(0.6)
†‡
3.1
(0.7)
1.9
(0.9)
0.9
(0.5)
†‡
3.2
(0.5)
2.1
(0.7)
1.6
(0.8)
†‡
WSE 125 mg BID
(n = 30)
2.2
(1.1)
0.9
(0.9)
0.6
(0.6)
1.5
(0.8)
0.7
(0.7)
0.4
(0.5)
3.1
(1.0)
1.9
(1.1)
1.0
(0.8)
†‡
2.8
(0.8)
1.8
(0.8)
1.2
(0.6)
†‡
3.4
(0.6)
1.9
(0.7)
0.8
(0.6)
†‡
3.3
(0.7)
1.6
(0.8)
0.8
(0.6)
†‡
WSE 250 mg BID
(n = 34)
2.2
(1.1)
0.8
(0.8)
0.6
(0.7)
1.5
(1.0)
0.4
(0.7)
0.0
(0.0)
3.2
(1.1)
1.6
(0.7)
0.5
(0.7)
†‡
2.8
(0.7)
1.1
(0.5)
0.9
(0.5)
†‡
3.2
(0.7)
1.7
(0.6)
0.4
(0.6)
†‡
3.1
(0.9)
1.5
(0.7)
0.5
(0.6)
†‡
Placebo
(n = 15)
2.2
(0.7)
2.1
(0.7)
1.9
(0.7)
1.5
(0.9)
1.5
(0.9)
1.4
(0.7)
2.7
(1.2)
2.7
(1.2)
2.7
(1.1)
2.8
(0.4)
2.5
(0.5)
2.5
(0.5)
2.7
(1.1)
2.8
(1.1)
2.9
(1.1)
3.0
(0.9)
3.0
(1.0)
3.0
(0.9)
z
Scale: 0 = never; 1 = occasional; 2 = mild/poor; 3 = moderate; 4 = severe.
†P < 0.001 versus Placebo Group, ‡P < 0.05 versus 30 days of treatment.
DISCUSSION
Several studies have been carried out during the last
few decades on the chemical constituents of WS
18
and its
biological activities, mostly using powder (or non-standard-
ized extracts) derived from the roots of wild plants.
Experimental studies of WS have assessed its antistress,
19
antioxidant,
20
immunomodulatory,
21, 22
anticancer,
23
antitu-
mor,
24
cardioprotective,
25
antiosteoarthritis
26
and antiag-
ing
27
activities. Our study is the first to evaluate the thera-
peutic benefits of standardized WSE in human subjects
using modern clinical trials.
Our findings that WSE reduces experiential feelings of
stress and anxiety at all dosage levels tested supports the
traditional claims of WS’s antistress-adaptogenic effect. All
WSE-treated groups showed improvement in mHAM-A
stress and anxiety scores at both Day 30 and Day 60 as a
result of participants feeling less fatigue, flushing, perspira-
tion, loss of appetite, headache and muscle pain, feelings of
impending doom, palpitations, dry mouth, sleeplessness, for-
54 JANA Vol. 11, No. 1, 2008
getfulness, irritability and inability to concentrate. The place-
bo group did not display changes in mHAM-A score
throughout the study. Feelings of frustration that treatment
was not helping their stress may have contributed to the high-
er dropout rate in this group. The placebo group had nine par-
ticipants drop out due to lack of efficacy compared to three
for all WSE-treated groups combined (data not shown).
WSE’s therapeutic activity may be attributed, at least in
part, to its effect on the hypothalamic-pituitary-adrenal axis,
which regulates serum cortisol concentration.
28
The link
between adaptogenic effects and cortisol has previously
been described.
29
In fact, the mean serum cortisol concen-
tration in all three WSE-treated groups, while being in the
normal range throughout the study, declined between base-
line and Day 60. In individuals with normal circadian
rhythm, serum cortisol concentration is high in the morning
and tends to decrease throughout the afternoon, reaching its
lowest point around 11 p.m.
14
One of the effects of chronic
stress is that serum cortisol concentration peaks in the after-
noon, rather than becoming lower.
28
Supplementation with
WSE may offset this afternoon cortisol peak in stressed indi-
viduals, although future studies are needed to confirm this.
Many types of physical and emotional stress, particu-
larly those that are chronic in nature, reduce serum DHEAS
0
5
10
15
20
25
30
35
Day 0 Day 30 Day 60
Day of Treatment
mHAM - A Score
WSE 125 mg QD (n=19)
WSE 125 mg BID (n=30)
WSE 250 mg BID (n=34)
Placebo (n=15)
Figure 1. Mean sum (SD) total stress and anxiety scores
based on a modified Hamilton anxiety (mHAM-A) scale
z
by
group for Day 0 (baseline), Day 30 and Day 60 of treatment
with Withania somnifera extract (WSE) or placebo (n = 98).
z
Scale: 0 = never; 1 = occa-
sional; 2 = mild/poor;
3 = moderate; 4 = severe.
DHEAS = dihydroepiandrosterone sulfate; CRP = C-reactive protein; FBG = fasting blood glucose; TC = total cholesterol; TG = triglyc-
erides; LDL-C = low-density lipoprotein cholesterol; VLDL-C = very low-density lipoprotein cholesterol; HDL-C = high-density lipopro-
tein cholesterol. * P<0.05 versus Placebo Group, † P<0.001 versus Placebo Group, ‡ P<0.05 versus WSE 125 mg QD Group, # P<0.05
versus WSE 125 mg BID Group.
Table 3. Mean (SD) values and percentage changes by treatment group of biochemical variables measured at Day 0 (base-
line) and after 60 days of treatment with Withania somnifera extract (WSE) or placebo (n = 98).
Biochemical Variables
Serum Cortisol
µg/dL
Serum DHEAS
µg/dL
CRP
mg/L
FBG
mg/dL
Serum TC
mg/dL
Group Day
0
Day
60 %∆
Day
0
Day
60 %∆
Day
0
Day
60 %∆
Day
0
Day
60 %∆
Day
0
Day
60 %∆
WSE 125 mg
QD (n = 19)
13.1
(3.0)
11.2
(2.1)
–14.5
*
167.4
(37.8)
189.5
(40.8)
13.2
*
3.8
(1.2)
2.6
(1.1)
–31.6
88.1
(12.5)
87.6
(11.7)
–0.6
176.4
(30.0)
173.5
(27.6)
–1.6
WSE 125 mg
BID (n = 30)
12.8
(3.9)
9.7
(2.4)
–24.2
152
(48.9)
200.7
(54.6)
32.2
†‡
4.1
(1.0)
2.6
(1.0)
–36.6
94.4
(16.5)
90.0
(13.6)
–4.7
*
176.0
(33.4)
163.7
(30.9)
–7.0
*
WSE 250 mg
BID (n = 34)
14.1
(3.3)
9.8
(2.4)
–30.5
†‡
159.6
(61.7)
212.1
(74.7)
32.5
†‡
5.4
(1.4)
3.5
(2.6)
–35.2
91.9
(11.2)
86.3
(8.7)
–6.1
*
193.5
(27.2)
168.1
(27.5)
–13.1
†‡#
Placebo
(n = 15)
13.5
(3.2)
14.1
(3.3)
4.4 166.7
(32.9)
149.3
(35.6)
–10.8 6.4
(3.7)
6.0
(3.7)
–6.3 91.2
(12.2)
93.1
(11.1)
2.1 171.1
(18.6)
172.7
(22.7)
0.9
Serum TG
mg/dL
Serum LDL-C
mg/dL
Serum VLDL-C
mg/dL
Serum HDL-C
mg/dL
Group Day
0
Day
60 %∆
Day
0
Day
60 %∆
Day
0
Day
60 %∆
Day
0
Day
60 %∆
WSE 125 mg
QD (n = 19)
119.4
(45.5)
114.2
(41.6)
–4.4 122.7
(25.0)
114.9
(18.3)
–6.4 25.9
(8.9)
23.6
(6.0)
–8.9* 37.9
(4.9)
39.0
(5.0)
2.9
WSE 125 mg
BID (n = 30)
135.3
(40.5)
122.4
(34.9)
–9.5
*
118.1
(26.2)
107.5
(22.7)
–9.0
*
32.5
(12.2)
27.1
(10.4)
–16.6
37.3
(6.4)
39.0
(5.2)
4.6
WSE 250 mg
BID (n = 34)
132.8
(46.0)
117.3
(35.7)
–11.7
†‡
134.7
(20.4)
111.2
(14.0)
-17.4
†‡#
32.7
(7.8)
24.9
(7.0)
–23.9
†‡
34.6
(7.0)
40.6
(6.4)
17.3
*‡#
Placebo
(n = 15)
127.9
(31.4)
133.9
(33.3)
4.7
119.5
(28.6)
118.8
(26.9)
–0.6
27.1
(7.8)
29.4
(8.8)
8.5
39.3
(4.9)
39.1
(5.5)
–0.5
JANA Vol. 11, No. 1, 2008 55
concentration, which can be used as a marker of stress.
30
In
the present study, the WSE-treated groups displayed
increased serum DHEAS concentrations by the end of the
study, compared to the placebo group. The normalizing
action of WSE may also be due to neuroprotective proper-
ties of withanolide glycosides and withaferin A that help
reduce the stress-induced generation of reactive oxygen
species in various parts of the brain.
22, 31-33
Chronic stress has been found to be associated with
higher than normal levels of serum CRP, a systemic marker
of inflammation that is associated with increased risk for a
host of chronic diseases.
34
Use of WSE at all doses and fre-
quencies in this study resulted in a decrease in mean serum
CRP concentration, indicating that systemic inflammation
may have declined in members of each WSE-treated group.
Ingestion of WS root powder has decreased inflammation in
animal models.
35
Together these findings suggest that WSE
use might contribute to decreased risk of chronic disease, an
idea meriting further investigation.
Reduction in fasting blood glucose concentration in the
two highest dosage WSE-treated groups was also found.
This finding may be related to the observed concomitant
reduction in serum cortisol concentration. Cortisol is a glu-
cocorticoid hormone that performs several functions,
including regulation of blood sugar levels.
36
CONCLUSIONS
This study determined that daily consumption of stan-
dardized WSE at three dosages (125 mg QD, 125 mg BID,
and 250 mg BID) reduced experiential feelings of stress and
anxiety, serum concentrations of cortisol and CRP, pulse
rate and blood pressure; and increased serum concentration
of DHEAS in the chronically stressed adults who complet-
ed the study. The WSE 125 mg BID and WSE 250 mg BID
dosages also improved fasting blood glucose levels and
lipid profiles for study participants in those groups. Cardiac
risk ratios improved for the two higher dosage WSE groups.
Although the 25% dropout rate may have partially skewed
results, the observed dose-dependent, significant trends in
most variables evaluated support the view that daily use of
WSE would benefit people suffering from the effects of
stress and anxiety without any adverse effects.
ACKNOWLEDGMENT
We would like to thank Natreon Inc. (New Brunswick,
New Jersey) for financial support of this study.
POTENTIAL CONFLICTS OF INTEREST
Dr. Auddy is an employee of Natreon Inc., which is the
patent holder of Withania somnifera extract sold under the
trade names Essentra
®
and Sensoril
®
.
Dr. Abedon is an employee of NutraGenesis LLC,
which sells Withania somnifera extract exclusively under
the trade names Essentra
®
and Sensoril
®
.
Dr. Ghosal was an unpaid adviser to Natreon Inc. at the
time the study was conducted.
Table 4. Mean (SD) values and percentage changes by treatment group of clinical variables measured at Day 0 (baseline)
and after 60 days of treatment with Withania somnifera extract (WSE) or placebo (n = 98).
Clinical Variables
Hemoglobin
g/dL
Pulse rate
Beats/min
Systolic
Blood Pressure (BP)
mm Hg
Diastolic
Blood Pressure (BP)
mm Hg
Day
0
Day
60
%∆
Day
0
Day
60
%∆
Day
0
Day
60
%∆
Day
0
Day
60
%∆
WSE 125 mg
QD (n = 19)
12.7
(1.2)
13.5
(1.5)
6.3
*
76.4
(4.6)
71.8
(1.4)
–6.0
121.6
(11.7)
119.6
(7.0)
–1.6
*
83.5
(10.1)
78.8
(5.8)
–5.6
*
WSE 125 mg
BID (n = 30)
12.6
(1.3)
13.1
(1.4)
4.0
*
80.7
(6.4)
74.1
(3.7)
–8.2
126.3
(13.6)
122.0
(8.6)
–3.4
82.8
(7.1)
78.7
(4.4)
–5.0
*
WSE 250 mg
BID (n = 34)
12.1
(1.2)
13.2
(1.1)
9.1
78.8
(7.7)
73.6
(4.3)
–6.6
120.0
(15.2)
116.1
(9.8)
–3.3
81.6
(9.5)
76.4
(7.1)
–6.4
Placebo
(n = 15)
12.7
(1.2)
12.5
(1.2)
–1.6
78.4
(2.3)
80.0
(3.4)
2.0
118.7
(11.4)
125.6
(8.0)
5.8
83.5
(6.7)
86.3
(4.5)
3.4
* P<0.05 versus Placebo Group, † P<0.001 versus Placebo Group.
56 JANA Vol. 11, No. 1, 2008
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Supplementary resource (1)

... Six studies evaluated the use of WS for anti-stress activity in adults aged 18-75 years [57][58][59][60][61][62] (Table 1). Study populations included participants who were healthy [61], stressed [57,60], overweight, or obese, experiencing chronic work stress [58], diagnosed with anxiety [62], and diagnosed with schizophrenia or schizoaffective disorder [59]. ...
... Six studies evaluated the use of WS for anti-stress activity in adults aged 18-75 years [57][58][59][60][61][62] (Table 1). Study populations included participants who were healthy [61], stressed [57,60], overweight, or obese, experiencing chronic work stress [58], diagnosed with anxiety [62], and diagnosed with schizophrenia or schizoaffective disorder [59]. The number of participants in each study ranged from 52 to 130 participants. ...
... It is worth noting that the literature description of KSM-66 as an "aqueous" extract differs from the product website [71], describing the use of a traditional process involving milk (except for a vegan version), which may extract more lipophilic molecules due to its fat content. Two other studies used Sensoril®, an aqueous extract of WS leaf and root standardized to ≥10% withanolide glycosides [59,62]; and one study used Shoden®, a hydroalcoholic (70:30) root and leaf extract of WS standardized to 35% withanolide glycosides [61]. In addition, Auddy et al. (2008) included Es-sentra®, a version of Sensoril® created for the food and beverages market [62]. ...
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Background Withania somnifera (WS), also known as Ashwagandha, is commonly used in Ayurveda and other traditional medicine systems. WS has seen an increase in public use worldwide due to its reputation as an adaptogen. This popularity has elicited increased scientific study of its biological effects, including a potential application for neuropsychiatric and neurodegenerative disorders. Objective This review aims to provide a comprehensive summary of preclinical and clinical studies examining the neuropsychiatric effects of WS, specifically its application in stress, anxiety, depression, and insomnia. Methods Reports of human trials and animal studies of WS were collected primarily from the PubMed, Scopus, and Google Scholar databases. Results WS root and leaf extracts exhibited noteworthy anti-stress and anti-anxiety activity in animal and human studies. WS also improved symptoms of depression and insomnia, though fewer studies investigated these applications. WS may alleviate these conditions predominantly through modulation of the hypothalamic-pituitary-adrenal and sympathetic-adrenal medullary axes, as well as through GABAergic and serotonergic pathways. While some studies link specific withanolide components to its neuropsychiatric benefits, there is evidence for the presence of additional yet unidentified active compounds in WS. Conclusion While benefits were seen in the reviewed studies, significant variability in the WS extracts examined prevents a consensus on the optimum WS preparation or dosage from treating neuropsychiatric conditions. WS generally appears safe for human use; however, it will be important to investigate potential herb-drug interactions involving WS if used alongside pharmaceutical interventions. Further elucidation of active compounds of WS is also needed.
... 5,14 The stress response is known to play an important role in hair loss pathology and is intrinsically linked to alopecia areata and telogen e uvium, with recent studies indicating that cortisol and microin ammation at the level of the hair follicle also plays a role in AGA. 5,15,16 Ashwagandha is a botanical that contains steroidal lactones which modulate and reduce cortisol levels. In a randomized, double-blind, placebo-controlled study of 98 patients, daily supplementation with 10% withanolide ashwaghanda showed statistically signi cant reductions in serum cortisol, serum C-reactive protein, blood pressure, and subjective feelings of stress compared to placebo. ...
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This study concluded that the combining extracts of Hibiscus rosa sinensis, Withania somnifera, Eclipta alba, Olea europea and Nigella sativa were used in different composition to get multipurpose effects on scalp and hair such as antimicrobial, prevent hair fall and increased hair growth and prevent greying of hair.
... 6 Biologically Ashwagandha constitutes many medical rich constituents that includes alkaloids, steroidal lactores and saponins, the sitoindosides and acylsterylglucosides present in ashwagandha are anti stress agents. 7 The ayuvedic medicines are natural with a innumerable number of medical benefits as they are consumed natural with no added preservatives they helps in boosting the immunity functions of the human, relives stress, avoids premature ageing, 8 that are the common symptoms in the employees working in the information technology companies. Many studies have proved that the physiological consumption of the ashwanganda has proved itself work as an ayurvedic medicine in reducing the effect of stress among the humans. ...
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... Five trials that met the pre-specified inclusion criteria were selected for this systematic review and meta-analysis. We had to exclude five trials from this review due to: one study protocol [48], one trial non-randomized [49], two trials with outcomes not related to sleep [50,51], and one trial due to non-English language [52]. ...
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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.
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Withania somnifera (Hindi - Ashwagandha, English - winter cherry) is used in Ayurvedic formulations for a variety of health-promoting effects. Several mono- and poly-herbal products commercially available in the Indian market were quantitatively analysed for a number of chemical constituents. The results revealed wide variations in the content of all seven constituents tested. More than 70-fold variation in the daily intake of withaferin A (the main active constituent of Ashwagandha) was found in the products. The study thus emphasizes the need for stringent phytochemical standardization of herbal products.
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Ayurvedic medicines prepared in India consist of Withania somnifera roots as one of the main ingredients. It is consumed as a dietary supplement around the world. The leaves of W. somnifera were used in the treatment of tumors and inflammation in several Asian countries. We have isolated twelve withanolides such as withaferin A (1), sitoindoside IX (2), 4-(1-hydroxy-2, 2-dimethylcyclpropanone)-2, 3-dihydrowithaferin A (3), 2, 3-dihydrowithaferin A (4), 24, 25-dihydro-27-desoxywithaferin A (5), physagulin D (1-->6)-beta-D-glucopyranosyl- (1-->4)-beta-D-glucopyranoside (6), 27-O-beta-D-glucopyranosylphysagulin D (7), physagulin D (8), withanoside IV (9), and 27-O-beta-D-glucopyranosylviscosalactone B (10), 4, 16-dihydroxy-5beta, 6beta-epoxyphysagulin D (11), viscosalactone B (12) from the leaves of this species. Compounds 1-12 and diacetylwithaferin A (13) were tested for their antiproliferative activity on NCI-H460 (Lung), HCT-116 (Colon), SF-268 (Central Nervous System; CNS and MCF-7 (Breast) human tumor cell lines. The inhibitory concentration to afford 50% cell viability (IC50) for these compounds was determined by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay. Withaferin A and its derivatives exhibited inhibitory concentrations (50%) ranging from 0.24 +/- 0.01 to 11.6 +/- 1.9 microg/mL. Viscosalactone B (12) showed the 50% inhibition at concentrations ranging from 0.32 +/- 0.05 to 0.47 +/- 0.15 microg/mL whereas its 27-O-glucoside derivative (10) exhibited IC50 between 7.9 +/- 2.9 and 17.3 +/- 3.9 microg/ml. However, Physagulin D type withanolides showed either weak or no activity at 30 microg/mL. Therefore, incorporation of withanolides in the diet may prevent or decrease the growth of tumors in human.
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Two new glycowithanolides, sitoindoside IX (1) and sitoindoside X (2), isolated from Withania somnifera Dun., were evaluated for their immunomodulatory and CNS effects (anti-stress, memory and learning) in laboratory animals, because the plant extract is used by practitioners of the Indian systems of medicine for similar purposes. The two compounds, in doses of 100–400 μg/mouse, produced statistically significant mobilization and activation of peritoneal macrophages, phagocytosis and increased activity of the lysosomal enzymes secreted by the activated macrophages. Both these compounds (50–200 mg/kg p.o.) also produced significant anti-stress activity in albino mice and rats and augmented learning acquisition and memory retention in both young and old rats. These findings are consistent with the use of W. somnifera, in Ayurveda, to attenuate cerebral function deficits in the geriatric population and to provide non-specific host defence.
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The clinical efficacy of a herbomineral formulation containing roots of Withania somnifera, the stem of Boswellia serrata, rhizomes of Curcuma longa and a zinc complex (Articulin-F), was evaluated in a randomized, double-blind, placebo controlled, cross-over study in patients with osteoarthritis. After a one-month single blind run-in period, 42 patients with osteoarthritis were randomly allocated to receive either a drug treatment or a matching placebo for a period of three months. After a 15-day wash-out period the patients were transferred to the other treatment for a further period of three months. Clinical efficacy was evaluated every fortnight on the basis of severity of pain, morning stiffness, Ritchie articular index, joint score, disability score and grip strength. Other parameters like erythrocyte sedimentation rate and radiological examination were carried out on a monthly basis. Treatment with the herbomineral formulation produced a significant drop in severity of pain (P less than 0.001) and disability score (P less than 0.05). Radiological assessment, however, did not show any significant changes in both the groups. Side effects observed with this formulation did not necessitate withdrawal of treatment.