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Scientific basis for the therapeutic use of Withania somnifera (Ashwagandha): A Review

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Scientific basis for the therapeutic use of Withania somnifera (Ashwagandha): A Review

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The objective of this paper is to review the literature regarding Withania somnifera (ashwagandha, WS) a commonly used herb in Ayurvedic medicine. Specifically, the literature was reviewed for articles pertaining to chemical properties, therapeutic benefits, and toxicity. This review is in a narrative format and consists of all publications relevant to ashwagandha that were identified by the authors through a systematic search of major computerized medical databases; no statistical pooling of results or evaluation of the quality of the studies was performed due to the widely different methods employed by each study. Studies indicate ashwagandha possesses anti-inflammatory, antitumor, antistress, antioxidant, immunomodulatory, hemopoietic, and rejuvenating properties. It also appears to exert a positive influence on the endocrine, cardiopulmonary, and central nervous systems. The mechanisms of action for these properties are not fully understood. Toxicity studies reveal that ashwagandha appears to be a safe compound. Preliminary studies have found various constituents of ashwagandha exhibit a variety of therapeutic effects with little or no associated toxicity. These results are very encouraging and indicate this herb should be studied more extensively to confirm these results and reveal other potential therapeutic effects. Clinical trials using ashwagandha for a variety of conditions should also be conducted.
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Volume 5 Number 4 2000
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Lakshmi-Chandra Mishra, MD (Ayur), PhD – Professor of Research (Adj.) Los Angeles College of Chiropractic (LACC).
Correspondence address: 16200 E Amber Valley Dr, Whittier, CA 90609-1166. E-mail: lakshmimishra@lacc.edu
Betsy B. Singh, PhD – Dean of Research, LACC
Simon Dagenais, BA – Research Assistant, LACC
Scientific Basis for the Therapeutic Use of
Withania somnifera (Ashwagandha):
A Review
Lakshmi-Chandra Mishra, MD (Ayur), PhD,
Betsy B. Singh, PhD, Simon Dagenais, BA
Introduction
Withania somnifera Dunal (ashwagandha, WS) is widely used in Ayurvedic medicine,
the traditional medical system of India. It is an ingredient in many formulations prescribed for
a variety of musculoskeletal conditions (e.g., arthritis, rheumatism), and as a general tonic to
increase energy, improve overall health and longevity, and prevent disease in athletes, the eld-
erly, and during pregnancy.
1,2
Many pharmacological studies have been conducted to investi-
gate the properties of ashwagandha in an attempt to authenticate its use as a multi-purpose
medicinal agent. For example, anti-inflammatory properties have been investigated to validate
Abstract
OBJECTIVE: The objective of this paper is to review the literature regarding
Withania
somnifera
(ashwagandha, WS) a commonly used herb in Ayurvedic medicine.
Specifically, the literature was reviewed for articles pertaining to chemical properties,
therapeutic benefits, and toxicity. DESIGN: This review is in a narrative format and
consists of all publications relevant to ashwagandha that were identified by the authors
through a systematic search of major computerized medical databases; no statistical
pooling of results or evaluation of the quality of the studies was performed due to the
widely different methods employed by each study. RESULTS: Studies indicate
ashwagandha possesses anti-inflammatory, antitumor, antistress, antioxidant,
immunomodulatory, hemopoetic, and rejuvenating properties. It also appears to exert
a positive influence on the endocrine, cardiopulmonary, and central nervous systems.
The mechanisms of action for these properties are not fully understood. Toxicity studies
reveal that ashwagandha appears to be a safe compound. CONCLUSION: Preliminary
studies have found various constituents of ashwagandha exhibit a variety of therapeutic
effects with little or no associated toxicity. These results are very encouraging and
indicate this herb should be studied more extensively to confirm these results and
reveal other potential therapeutic effects. Clinical trials using ashwagandha for a variety
of conditions should also be conducted.
(
Altern Med Rev
2000;5(4) 334-346)
Copyright©2000 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
Withania somnifera (Ashwagandha)
Alternative Medicine Review
Volume 5, Number 4 2000 Page 335
its use in inflammatory arthritis,
3-6
and animal
stress studies have been performed to investi-
gate its use as an antistress agent.
7-10
Several
studies have examined the antitumor and
radiosensitizing effect of WS.
11-15
The purpose
of this paper is to review the literature regard-
ing WS and report on clinically relevant stud-
ies, in an attempt to establish a scientific basis
for the therapeutic use of WS. Results of stud-
ies investigating the chemistry and toxicity of
WS will also be discussed.
Methods
This literature review was limited to
published articles and books in the English
language. Four computerized medical data-
bases (MEDLINE, CINAHL, EMBASE, Man-
tis) were searched for the entire duration of
each database as available on the OVID com-
puter search service. The following keywords
were used for the search: ashwagandha and
common misspellings (ashwaganda,
aswaganda, aswagandha), withania,
somnifera, dunal, withaferin,
sitoindoside, solanaceae, Indian gin-
seng, and winter cherry. Results of
these searches were reviewed to iden-
tify relevant articles.
Results
A total of 58 articles were
found using the search method de-
scribed above. Research reveals
ashwagandha possesses anti-inflam-
matory, antitumor, antistress, antioxi-
dant, immunomodulatory,
hemopoetic, and rejuvenating prop-
erties. Ashwagandha also appears to
benefit the endocrine, cardiopulmo-
nary, and central nervous systems.
Few articles were discovered on the
mechanism of action for these effects.
Several preliminary studies have been
conducted on animals. A summary of
the findings of these studies is pre-
sented below.
Chemistry
Since many of ashwagandha’s uses
have not been scientifically validated, skepti-
cism can naturally be expected when presented
with an herb purportedly useful in so many
ailments. In Ayurvedic medicine there is a class
of herbs, including WS, known as adaptogens
or vitalizers. Adaptogens cause adaptive reac-
tions to disease, are useful in many unrelated
illnesses, and appear to produce a state of non-
specific increased resistance (SNIR)
10,16
to
adverse effects of physical, chemical, and bio-
logical agents. They are relatively innocuous,
have no known specific mechanism of action,
normalize pathological effects, and are usu-
ally glycosides or alkaloids of a plant.
17,18
The chemistry of WS has been exten-
sively studied and over 35 chemical constitu-
ents have been identified, extracted, and iso-
lated.
19
The biologically active chemical con-
stituents are alkaloids (isopelletierine,
Withania somnifera (Ashwagandha)
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Figure 1: Chemical Structure of Withaferin A
CH
3
CH
3
CH
3
CH
3
O
O
O
O
OH
OH
Withaferin A
anaferine), steroidal lactones (withanolides,
withaferins), saponins containing an additional
acyl group (sitoindoside VII and VIII), and
withanolides with a glucose at carbon 27
(sitoindoside IX and X). WS is also rich in
iron. See Figure 1 for the chemical structure
of withaferin A, and Figure 2 for sitoindosides
IX and X.
Anti-inflammatory
Properties
The effectiveness of
ashwagandha in a variety of
rheumatologic conditions
may be due in part to its anti-
inflammatory properties,
which have been studied by
several authors. In a study by
Anbalagan et al,
3
powdered
root of WS (1 g/kg
suspended in 2% gum
acacia, 50 mg/mL) was
given orally one hour before
the induction of
inflammation by injection of
Freund’s complete adjuvant
in rats and continued daily
for three days;
phenylbutazone (100mg/kg) was given as
a positive control. WS was found to cause
considerable reduction in inflammation.
Acute phase reactants of the blood
monitored by crossed immuno-
electrophoresis showed changes in the
concentration of many serum proteins
(α2-glycoprotein, major acute phase α1-
protein, and pre-albumin) in the WS
group. The α2-glycoprotein found only
in inflamed rat serum was decreased to
undetectable levels in the WS group.
Phenylbutazone, on the other hand,
caused a considerable increase in the α2-
glycoprotein in both arthritic and healthy
rats. Another acute phase protein (peak
2, α-1 major acute phase) which
increased approximately 200 percent by
inflammation was brought back to normal
levels by WS treatment but only to 132 percent
of normal by phenylbutazone. WS influenced
several modulator proteins in normal rats,
suggesting that several plant chemicals in WS
possibly interact with the liver protein
synthesis process. Another study by Anbalagan
Figure 2: Chemical Structures of Sitoindosides IX and X.
CH
3
CH
3
CH
3
CH
3
O
O
O
O
OH
O
O
OH
OH
OH
RO
Sitoindoside IX, R=H
Sitoindoside X, R=palmitoyl
Withania somnifera (Ashwagandha)
Alternative Medicine Review
Volume 5, Number 4 2000 Page 337
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et al
4
found WS caused dose-dependent
suppression of α2-macroglobulin (an indicator
for anti-inflammatory drugs) in the serum of
rats inflamed by sub-plantar injection of
carrageenan suspension. The doses of WS root
powder were 500, 1000, 1500, or 1200 mg/kg
given as suspension orally 3-4 hours prior to
induction of inflammation. Maximum effect
(about 75%) was seen at 1000 mg/kg. Actual
measurements of inflammation were not
conducted.
In a study by Begum et al,
20
air pouch
granuloma was induced by subcutaneous
injections of 4 mL of two-percent (w/v)
carrageenan on the dorsum of male Wistar rats
(150-200 g) which had been subcutaneously
injected one day prior with 6 mL of air on the
dorsum. WS root powder (1000 mg/kg) was
given orally from day 7 to day 9. Radioactive
Na
2
32
SO
4
/100 g was injected intraperitoneally
on day 9;
35
S incorporation in
glycosaminoglycan, oxidative
phosphorylation (ADP/O ratio), Mg
2+
dependent-ATPase enzyme activity, and
succinate dehydrogenase activity were
determined in the mitochondria of the
granuloma tissue. WS decreased the
glycosaminoglycans content in the granuloma
tissue by 92 percent, compared with 43.6
percent by hydrocortisone (15 mg/kg)
treatment and no effect by
phenylbutazone treatment (100
mg/kg). WS also uncoupled the
oxidative phosphorylation by
significantly reducing the ADP/O
ratio in mitochondria of
granuloma tissue. It increased the
Mg
2+
dependent-ATPase enzyme
activity and also reduced the
succinate dehydrogenase activity
in the mitochondria of the
granuloma tissue; no such effect
was produced by the reference
drugs. No physical measurements
of the inflammation were carried
out.
Another study by Begum et al
21
exam-
ined the effect of WS (root powder, 1000 mg/
kg, orally daily for 15 days) on paw swelling
and bony degenerative changes in Freund’s ad-
juvant-induced arthritis in rats. WS caused sig-
nificant reduction in both paw swelling and
degenerative changes as observed by radiologi-
cal examination. The reductions were better
than those produced by the reference drug, hy-
drocortisone (15 mg/kg). No biochemical pa-
rameters were reported in this study. A study
by al Hindawi et al
22
found WS inhibited the
granuloma formation in cotton-pellet implan-
tation in rats and the effect was comparable to
hydrocortisone sodium succinate (5 mg/kg)
treatment. Methanol extract of WS (10 mg/kg,
which is one-tenth the LD
50
dose) was given
one hour before the cotton-pellet implant and
continued daily until the pellets were harvested
on day 4.
One clinical trial supports the possible
use of WS for arthritis. In a double-blind,
placebo-controlled cross-over study, 42
patients with osteoarthritis were randomized
to receive a formula containing ashwagandha
(see Table 1 for formula) or placebo for three
months. Patients were evaluated for one
month, pretreatment, during which time all
previous drugs were withdrawn. During both
the pretreatment and treatment phase, pain and
Table 1: Formula Used for Treatment of Osteoarthritis
Ingredient
Ashwagandha
Boswellia
Tur meric
Zinc complex*
Plant part
root
oleo gum-resin
rhizome
Dosage/capsule
450 mg
100 mg
50 mg
50 mg
* an Ayurvedic zinc complex (Jasad Bhasma) prepared by the traditional
method described in Sharanghar Sambhita.
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disability scores were evaluated weekly while
erythrocyte sedimentation (SED) rate and
radiological studies were conducted monthly.
The herbal formula significantly reduced the
severity of pain (p<0.001) and disability
(p<0.05) scores, although no significant
changes in radiological appearance or SED
rate were noted.
23
Few studies have been conducted on
the mechanism of action for the anti-inflam-
matory properties of WS. In one study, rats
injected with 3.5-percent formaline in the hind
leg footpad showed a decrease in absorption
of
14
C-glucose in rat jejunum.
5
Glucose absorp-
tion was maintained at the normal level by both
WS and the cyclooxygenase inhibitor
oxyphenbutazone. Both drugs produced anti-
inflammatory effects. Similar results were
obtained in parallel experiments using
14
C-leu-
cine absorption from the jejunum.
6
These stud-
ies suggest cyclooxygenase inhibition may be
involved in the mechanism of action of WS.
Antitumor Properties
To investigate its use in treating various
forms of cancer, the antitumor and
radiosensitizing effects of WS have been
studied. In one study, WS was evaluated for
its anti-tumor effect in urethane-induced lung
adenomas in adult male albino mice.
11
Simultaneous administration of WS (ethanol
extract of whole plant, 200 mg/kg daily orally
for seven months) and urethane (125 mg/kg
without food biweekly for seven months)
reduced tumor incidence significantly (tumor
incidence: untreated control, 0/25; urethane
treated, 19/19; WS treated, 0/26, and WS plus
urethane treated, 6/24, p<0.05). The
histological appearance of the lungs of animals
protected by WS was similar to those observed
in the lungs of control animals. No
pathological evidence of any neoplastic change
was observed in the brain, stomach, kidneys,
heart, spleen, or testes of any treated or control
animals. In addition to providing protection
from carcinogenic effects, WS treatment also
reversed the adverse effects of urethane on total
leukocyte count, lymphocyte count, body
weight, and mortality.
The growth inhibitory effect of WS
was also observed in Sarcoma 180 (S-180), a
transplantable mouse tumor.
12
Ethanol extract
of WS root (400 mg/kg and up, daily for 15
days) after intra-dermal inoculation of 5x10
5
cells of S-180 in BALB/c mice produced com-
plete regression of tumor after the initial
growth. A 55-percent complete regression was
obtained at 1000 mg/kg; however, it was a le-
thal dose in some cases. WS was also found to
act as a radio- and heat sensitizer in mouse S-
180 and in Ehrlich ascites carcinoma.
12,14
Anti-
tumor and radiosensitizing effects of
withaferin (a steroidal lactone of WS) were
also seen in mouse Ehrlich ascites carcinoma
in vivo.
15
Withaferin A from WS gave a
radiosensitizer ratio of 1:5 for in vitro cell kill-
ing of V79 Chinese hamster cell at a non-toxic
concentration of about 2 mM/L.
12-14
These
studies are suggestive of antitumor activity as
well as enhancement of the effects of radia-
tion by WS.
Antistress Effect
To evaluate the antistress effect of WS,
an alcohol extract from defatted seeds of WS
dissolved in normal saline was given (100 mg/
kg intraperitoneally as a single dose) to 20-25
g mice in a swimming performance test in
water at 28º-30ºC.
10
Controls were given sa-
line. The extracts approximately doubled the
swimming time when compared to controls.
In another study, WS prevented both a weight
increase of the adrenals and a reduction in
ascorbic acid content of the adrenals normally
caused by this swimming test. The authors
suggested that WS induced a state of nonspe-
cific increased resistance during stress.
Glycosides of WS (sitoindosides VII
and VIII, 50 to 100 mg/kg) exhibited signifi-
cant antistress activity in forced swimming-
induced immobility in mice, restraint stress-
induced gastric ulcers in rats, restraint-induced
Withania somnifera (Ashwagandha)
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auto-analgesia in rats, restraint stress effect on
thermic response of morphine in rats, and
morphine-induced toxicity in aggregated
mice.
24
The alcohol extract of WS (100 mg/
kg, twice daily orally on day 1, 4 or 7) reduced
stress-induced increases in blood urea nitro-
gen levels, blood lactic acid, and adrenal hy-
pertrophy, but did not affect changes in thy-
mus weight and hyperglycemia in rats.
7
WS
reversed the cold swimming-induced increases
in plasma corticosterone, phagocytic index,
and avidity index to control levels. WS root
powder (100 mg/kg orally as an aqueous sus-
pension daily for seven days) given before the
swimming test in water at 10ºC also increased
total swimming time, indicating better stress
tolerance in rats.
8
These results indicated a sig-
nificant increase in plasma corticosterone
level, phagocytic index, and avidity index in
control rats, whereas these levels were near
normal in WS rats subjected to the same test.
In a comparative study for antistress
activity, finely powdered roots of WS and
Panax ginseng (PG), suspended in 2-percent
acacia (100 mg/kg in 1.00 mL orally) were
given to 18-20 g mice daily for seven days;
the swimming test was given on day 8.
25
Sig-
nificant antistress activity, as measured by the
swimming endurance test, was found for both
compounds. The swimming time was 536.6
minutes for PG, 474.1 minutes for WS, and
163.3 minutes for controls; all differences be-
tween groups were significant (p<0.05). Ana-
bolic activity, measured as an increase in body
weight, was significant for both herbal extracts
but was better in the WS group than in the PG
group. If these results could be reproduced in
humans, it would support the use of WS in
nervous exhaustion due to stress and in
cachexia to increase body weight.
Antioxidant Effect
The brain and nervous system are rela-
tively more susceptible to free radical damage
than other tissues because they are rich in lip-
ids and iron, both known to be important in
generating reactive oxygen species.
26
The brain
also uses nearly 20 percent of the total oxy-
gen supply.
27
Free radical damage of nervous
tissue may contribute to neuronal loss in cere-
bral ischemia and may be involved in normal
aging and neurodegenerative diseases, e.g.,
epilepsy, schizophrenia, Parkinson’s,
Alzheimer’s, and other diseases.
28,29
Since tra-
ditional Ayurvedic use of WS has included
many diseases associated with free radical
oxidative damage, it has been considered likely
the effects may be due to a certain degree of
antioxidant activity. The active principles of
WS, sitoindosides VII-X and withaferin A
(glycowithanolides), have been tested for anti-
oxidant activity using the major free-radical
scavenging enzymes, superoxide dismutase
(SOD), catalase (CAT), and glutathione per-
oxidase (GPX) levels in the rat brain frontal
cortex and striatum. Decreased activity of these
enzymes leads to accumulation of toxic oxi-
dative free radicals and resulting degenerative
effects. An increase in these enzymes would
represent increased antioxidant activity and a
protective effect on neuronal tissue. Active
glycowithanolides of WS (10 or 20 mg/kg in-
traperitoneally) were given once daily for 21
days to groups of six rats. Dose-related in-
creases in all enzymes were observed; the in-
creases comparable to those seen with deprenyl
(a known antioxidant) administration (2 g/kg/
day intraperitoneally). This implies that WS
does have an antioxidant effect in the brain
which may be responsible for its diverse phar-
macological properties.
30
Further studies on
other parts of the brain (e.g., cerebellum, me-
dulla, and hypothalamus) may provide infor-
mation with respect to the effects of WS on
cognitive behavior and other functions of the
brain, in both healthy and diseased individu-
als.
In another study, an aqueous suspen-
sion of WS root extract was evaluated for its
effect on stress-induced lipid peroxidation
(LPO) in mice and rabbits.
9
LPO blood levels
were increased by IV administration of 0.2 mg/
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kg of lipopolysaccharides (LPS) from Kleb-
siella pneumoniae and 100 mg/kg of
peptidoglycans (PGN) from Staphylococcus
aureus. Simultaneous oral administration of
WS extract (100 mg/kg) prevented an increase
in LPO. The authors indicated that the almost
innocuous doses of LPS and PGN used in this
study that induced elevated levels of LPO were
comparable to a mild bacteremia which may
follow tooth extraction, streptococcal angina,
etc.
Immunomodulatory Properties
The use of WS as a general tonic to
increase energy and prevent disease may be
partially related to its effect on the immune
system. Glycowithanolides and a mixture of
sitoindosides IX and X (Figure 2) isolated from
WS were evaluated for their immuno-
modulatory and central nervous system effects
(antistress, memory, and learning) in Swiss
mice (15-25 g, 5-6 months old) and Wistar
strain albino rats (120-150 g and 250-300 g).
31
Both materials produced statistically signifi-
cant mobilization and activation of peritoneal
macrophages, phagocytosis, and increased
activity of the lysosomal enzymes. Both com-
pounds (50-200 mg/kg orally) also produced
significant antistress activity in albino mice
and rats, and augmented learning acquisition
and memory retention in both young and old
rats.
Root extract of WS was tested for
immunomodulatory effects in three
myelosuppression models in mice: cyclophos-
phamide, azathioprin, or prednisolone.
32
Sig-
nificant increases (p<0.05) in hemoglobin con-
centration, red blood cell count, white blood
cell count, platelet count, and body weight
were observed in WS-treated mice compared
to untreated control mice. The authors also
reported significant increases in hemolytic
antibody responses toward human erythrocytes
which indicated immunostimulatory activity.
The effect of WS was also studied on
the functions of macrophages obtained from
mice treated with the carcinogen ochratoxin
A (OTA).
33
OTA treatment of mice for 17
weeks significantly decreased the chemotactic
activity of the macrophages. Interleukin-1 (IL-
1) and tumor necrosis factor alpha (TNF-α)
production was also markedly decreased.
Hemopoetic Effect
Administration of WS extract was
found to significantly reduce leukopenia in-
duced by cyclophosphamide (CTX) treatment
in Swiss albino mice.
34
Total white blood cell
count on the 12
th
day of the CTX-treated group
was 3720/mm
3
; that of the CTX-plus-WS
group was 6120/mm
3
. In the CTX-plus-WS
mice, the cellularity of the bone marrow was
significantly increased (13.1 x 10
6
/femur)
(p<0.001) compared to the CTX-alone treated
group (8 x 10
6
/femur). Similarly, the number
of alpha-esterase positive cells (1130/4000
cells) in the bone marrow of the CTX-plus-
WS mice increased compared to the CTX-
alone mice (687/4000 cells).
The major activity of WS may be the
stimulation of stem cell proliferation. These
studies indicated WS reduced CTX-induced
toxicity and may prove useful in cancer che-
motherapy. Further studies need to be con-
ducted to confirm the hemopoetic effect with
other cytotoxic agents and to determine its
usefulness as an adjuvant in cancer chemo-
therapy.
Rejuvenating Effect
The growth-promoting effect of WS
was studied for 60 days in a double-blind study
of 60 healthy children, age 8-12 years, who
were divided into five groups of 12.
35
Group 1
was given purified and powdered WS 2 g/day
fortified in 100 cc of milk (no details about
purification and powdering methods were
disclosed). Similarly, Group 2 received 2 g
daily of a mixture of equal parts WS and
punarnava (Boerhaavia diffusa), Groups 3 and
Withania somnifera (Ashwagandha)
Alternative Medicine Review
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4 were given ferrous fumarate 5 mg/day and
30 mg/day, respectively, and Group 5 received
placebo.
Group 1 experienced a slight increase
in hemoglobin, packed cell volume, mean cor-
puscular volume, serum iron, body weight, and
hand grip, and significant increases in mean
corpuscular hemoglobin and total proteins
(p<0.01) at the end of 60 days when compared
to the initial level and the placebo group. There
was an increase in body weight in all groups
over the control group.
Group 2, treated with WS and
punarnava, showed a significant increase in the
level of hemoglobin at the end of 30 days com-
pared to the initial value. Marked increases in
the levels of hemoglobin, packed cell volume,
mean corpuscular volume, mean corpuscular
hemoglobin, serum iron, and hand grip were
also observed at the end of 60 days when com-
pared to initial levels. However, when com-
pared with the placebo group, only hemoglo-
bin and handgrip showed significant increase
(p<0.05). No change was seen in other param-
eters. It was noted that 13 of 15 children had
an increase in body weight, 10 children had
an increase in hemoglobin and packed cell
volume, and 11 children had an increase in
serum iron.
Group 3 (5 mg ferrous fumarate) had
no significant change in any parameters, while
Group 4 (30 mg ferrous fumarate) showed a
significant increase in hemoglobin (p<0.01),
mean corpuscular hemoglobin (p<0.05), mean
corpuscular hemoglobin concentration
(p<0.01), serum iron, (p<0.05), and hand grip
(p<0.05), and a marked increase in packed cell
volume. Group 5 (placebo) had no significant
change in any parameter. The study demon-
strated that WS may be useful as a growth pro-
moter and hematinic in growing children.
In another clinical trial, WS purified
powder was given 3 g/day for one year to 101
normal healthy male volunteers, age 50-59
years.
36
All subjects showed significantly
increased hemoglobin and RBC count, and
improvement in hair melanin and seated
stature. They also showed decreased SED rate,
and 71.4 percent of the subjects reported
improvement in sexual performance. In
summary, these studies indicate WS may prove
useful in younger as well as older populations
as a general health tonic.
Nervous System Effects
Total alkaloid extract
(ashwagandholine, AG) of WS roots has been
studied for its effects on the central nervous
system.
37
AG exhibited a taming effect and a
mild depressant (tranquilizer) effect on the
central nervous system in monkeys, cats, dogs,
albino rats, and mice. AG had no analgesic
activity in rats but increased Metrazol toxicity
in rats and mice, amphetamine toxicity in mice,
and produced hypothermia in mice. It also
potentiated barbiturate-, ethanol-, and ure-
thane-induced hypnosis in mice.
Effects of sitoindosides VII-X and
withaferin isolated from aqueous methanol
extract of roots of cultivated varieties of WS
were studied on brain cholinergic,
glutamatergic and GABAergic receptors in
male Wistar rats.
38
The compounds slightly
enhanced acetylcholinesterase (AChE) activ-
ity in the lateral septum and globus pallidus,
and decreased AChE activity in the vertical
diagonal band. These changes were accompa-
nied by enhanced M
1
-muscarinic-cholinergic
receptor-binding in lateral and medial septum
as well as in frontal cortices, whereas the M
2
-
muscarinic receptor-binding sites were in-
creased in a number of cortical regions includ-
ing cingulate, frontal, piriform, parietal, and
retrospinal cortex. The data suggest the com-
pounds preferentially affect events in the cor-
tical and basal forebrain cholinergic-signal-
transduction cascade. The drug-induced in-
crease in cortical muscarinic acetylcholine-
receptor capacity might partly explain the cog-
nition-enhancing and memory-improving ef-
fects of WS extracts in animals and in humans.
Page 342 Alternative Medicine Review
Volume 5, Number 4 2000
Copyright©2000 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
Ashwagandholine, total alkaloids extracted
from extract of WS roots, caused relaxant and
antispasmodic effects against various agents
that produce smooth muscle contractions in
intestinal, uterine, tracheal, and vascular
muscles.
39
The pattern of smooth muscle ac-
tivity was similar to that of papaverine, but
several-fold weaker, which indicated a direct
musculotropic action. These results are con-
sistent with the use of WS to produce relax-
ation.
Effects on the Endocrine System
Based on the observations that WS pro-
vides protection from free radical damage in
the mouse liver, studies were conducted to
determine the efficacy of WS in regulating thy-
roid function.
40,41
Mice were given WS root
extract (1.4 g/kg by gavage, daily for 20 days).
The treatment significantly increased the se-
rum levels of 3,3’,5-triiodothyronine (T3) and
tetraiodothyronine (T4), while the hepatic con-
centrations of glucose 6-phosphatase activity
and hepatic iodothyronine 5’-monodeiodinase
activity did not change significantly. WS sig-
nificantly reduced hepatic lipid peroxidation
and increased the activity of superoxide
dismutase and catalase. The results suggest WS
stimulates thyroidal activity and also promotes
hepatic antioxidant activity.
A combination formula of WS,
Tinospora cordifolia, Eclipta alba, Ocimium
sanctum, Picorrhiza kurroa, and shilajit was
found to cause a dose-related decrease in
streptozotocin-induced hyperglycemia.
31
None
of the herbs given individually, however, pro-
duced any effect on the hyperglycemia, indica-
tive perhaps of why Ayurvedic medicine gen-
erally prefers combinations of herbs rather than
single herbs.
Effects on the Cardiopulmonary
System
WS may be useful as a general tonic,
due in part to its beneficial effects on the
cardiopulmonary system, as reported in the
following studies. The effect of AG was studied
on the cardiovascular and respiratory systems
in dogs and frogs.
42
The alkaloids had a
prolonged hypotensive, bradycardiac, and
respiratory-stimulant action in dogs. The study
found that the hypotensive effect was mainly
due to autonomic ganglion blocking action and
that a depressant action on the higher cerebral
centers also contributed to the hypotension.
The alkaloids stimulated the vasomotor and
respiratory centers in the brain stem of dogs.
The cardio-inhibitory action in dogs appeared
to be due to ganglion blocking and direct
cardio-depressant actions. The alkaloids
produced immediate predominant but short-
lived cardio-depressant effects and a weak but
prolonged cardiotonic effect in isolated normal
and hypodynamic frog hearts. The
pharmacological actions of the total extract of
WS roots on the cardiovascular and respiratory
systems appeared to be due to its alkaloid
content. The total alkaloids were more than
twice as active as the 70-percent alcohol extract
of WS root. These studies were found to be
consistent with the use of WS as a tranquilizing
agent.
General Toxicity Studies
An important consideration when
investigating the medicinal properties of an
unknown compound is diligent evaluation of
its potential for harmful effects, usually
evaluated through toxicity studies. For WS, no
systematic study was found which included
acute, sub-acute, sub-chronic or chronic
toxicity of WS root powder, whole plant
powder, or different extracts of the plant (e.g.,
water, alcohol, petroleum ether, purified
alkaloids, and glycosides). The acute toxicity
data found as a part of pharmacological studies
are summarized here. Although one
preliminary toxicity study of WS was
conducted, it was of insufficient quality to
support its findings as too few animals were
used, body weight data was not collected, and
Withania somnifera (Ashwagandha)
Alternative Medicine Review
Volume 5, Number 4 2000 Page 343
Copyright©2000 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
survival data was not reported.
43
In one central
nervous system study, a two-percent
suspension of ashwagandholine (total
alkaloids from the roots of WS) prepared in
ten-percent propylene glycol using two-
percent gum acacia as suspending agent was
used to determine acute toxicity.
39
The acute
LD
50
was 465 mg/kg (332-651 mg/kg) in rats
and 432 mg/kg (299-626 mg/kg) in mice.
In an antistress-effect study, an alco-
hol extract from defatted seeds of WS dis-
solved in normal saline was used to study LD
50
in albino mice.
10
The acute LD
50
was 1750 +/-
41 mg (p.o). In another antistress-effect study,
aqueous-methanol extracts of the root from
one-year-old cultivated WS (SG-1) and
equimolar combinations of sitoindosides VII
and VIII and withaferin-A (SG-2) were stud-
ied for acute toxicity.
25
The acute LD
50
of SG-
1 and SG-2 by intraperitoneal administration
in mice was 1076 +/- 78 mg/kg and 1564 +/-
92 mg/kg, respectively.
In one long-term study, WS was boiled
in water and administered to rats in their daily
drinking water for eight months while moni-
toring body weight, general toxicity, well be-
ing, number of pregnancies, litter size, and
progeny weight.
44
The estimated dose given
was 100 mg/kg/day. In the second part of the
study, the estimated dose was 200 mg/kg/day
given for four weeks as above while monitor-
ing body temperature, body weight, cortisol
value in heparinized plasma, and ascorbic acid
content of the adrenals. The liver, spleen, lungs,
kidneys, thymus, adrenals, and stomach were
examined histopathologically and were all
found to be normal. The initial average body
weights of the WS-treated group (100 mg/kg/
day) and control group on day 1 were 91 g
and 106 g which, after four weeks, increased
to 185 g (103%) and 178 g (67.9%), respec-
tively. The WS-treated rats appear to have
gained more weight than the control group (no
p value given). The percent weight gain after
eight weeks on the same WS treatment was
227 percent for the treated group and 145.3
percent in the control group. The relative body
weight gain was significantly greater in the
WS-treated group as compare to the control
group (p< 0.001). While it is not clear when
the rats were mated, the average weights of
the progeny at one month of age were 70 g
and 45 g in the WS-treated and control groups,
respectively, indicating healthier progeny in
the WS-treated group. Additional studies are
necessary to confirm these findings.
In the four-week study, the weight gain
in the treated group was comparable to that of
the control group. The body temperature in the
WS treated group was 1.7ºC lower than the
controls. The WS treatment caused an increase
in lung and liver weights and a decrease in
adrenocortical activity as was evident from the
reduction in adrenal weight and a significant
reduction in plasma cortisol (p<0.001). His-
topathologically, all organs were normal. The
authors attributed the increase in liver weight
to an increase in glycogen storage because WS
contains many steroids and glucocorticoids
known to enhance liver glycogen stores. Re-
duction in metabolic rate also leads to under-
utilization of glycogen stores in the liver, lead-
ing to its accumulation. The reduced adreno-
cortical activity may be attributed to steroid
moieties in WS roots which may act like ex-
ogenous adrenocortical steroids, lowering the
ACTH secretion and consequently, endog-
enous steroid production. The authors con-
cluded the decoction of WS promoted growth
especially during the active growth period and
helped produce healthier progeny. The WS
group was devoid of any toxic effects after
eight months of daily dosing in this study.
Discussion
As outlined above, results from various
studies indicate ashwagandha possesses many
qualities, including anti-inflammatory,
antitumor, and immunomodulatory properties,
as well as exerting an influence on the
endocrine, nervous, and cardiopulmonary
systems. Further clinical studies should be
Page 344 Alternative Medicine Review
Volume 5, Number 4 2000
Copyright©2000 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
conducted, as well as studies in multiple
animal-based models using a variety of
suitable biochemical markers (e.g., urinary
excretion of pyridinoline and
deoxypyridinoline) to understand its
mechanism of action. Any protective or
prophylactic effect it may have on the
development of arthritis should also be
investigated, as well as effects it may have on
cartilage degradation or regeneration. As for
its use in fighting cancer, confirmatory studies
in several other animal tumor systems must
be conducted for more definitive findings.
Studies should also be carried out to determine
the effects, if any, of WS on existing antitumor
agents when given in combination with WS.
Regarding the effects observed in animals on
the endocrine and cardiopulmonary systems,
the therapeutic significance of these
biochemical markers is not clear. Studies point
to a possible benefit of WS in central nervous
system-related ailments. The lack of
systematic toxicity studies is of some concern,
as is the poor quality of the existing toxicity
studies.
The review indicates that WS may be
useful in many ailments, including arthritis and
other musculoskeletal disorders, stress-in-
duced nervous exhaustion, and hypertension.
There are a few preliminary studies available
on the effects of WS on the immune system,
central nervous system, hemopoetic system,
and general growth promotion to form a basis
for further studies but not enough evidence to
provide a firm scientific basis for definitive
therapeutic uses.
Conclusion
Although the results from this review
are quite promising for the use of ashwagandha
as a multi-purpose medicinal agent, several
limitations currently exist in the current
literature. While ashwagandha has been used
successfully in Ayurvedic medicine for
centuries, more clinical trials should be
conducted to support its therapeutic use. It is
also important to recognize that WS may be
effective not only in isolation, but may actually
have a potentiating effect when given in
combination with other herbs or drugs.
Acknowledgment: The authors ac-
knowledge the technical support provided by
Fred Zarow, DC, MS in the preparation of this
manuscript.
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Copyright©2000 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
... The predominant mechanism by which medicinal herbs act in avian rations is to improve the metabolism by combating stress and regulating hormones (46). Numerous field studies on medicinal herbs from all over the world have revealed promising outputs in improving weight gain (WG) and feed efficiency, reducing mortality, elevating livability, and maintaining health among different avian species (47)(48)(49). ...
... Ashwagandha roots include steroids that act as exogenous adrenocortical steroids and decrease adrenocorticotropic hormone (ACTH) secretion and, consequently, endogenous steroid production. Therefore, W. somnifera is considered a growth promoter, particularly during development (49). ...
... The hematinic activity of W. somnifera root powder is attributed to direct and indirect action on the hematological parameters. A direct positive impact of W. somnifera was noticed on hemopoiesis in broiler chicks via stimulation of stem cell proliferation and improved bone marrow cellularity (49,144). Also, W. somnifera root powder protected red blood cells from oxidative stress in broiler chickens through its antioxidant effect and improvement in the erythrocytic enzyme activity (133). ...
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Poultry production contributes markedly to bridging the global food gap. Many nations have limited the use of antibiotics as growth promoters due to increasing bacterial antibiotic tolerance/resistance, as well as the presence of antibiotic residues in edible tissues of the birds. Consequently, the world is turning to use natural alternatives to improve birds’ productivity and immunity. Withania somnifera, commonly known as ashwagandha or winter cherry, is abundant in many countries of the world and is considered a potent medicinal herb because of its distinct chemical, medicinal, biological, and physiological properties. This plant exhibits antioxidant, cardioprotective, immunomodulatory, anti-aging, neuroprotective, antidiabetic, antimicrobial, antistress, antitumor, hepatoprotective, and growth-promoting activities. In poultry, dietary inclusion of W. somnifera revealed promising results in improving feed intake, body weight gain, feed efficiency, and feed conversion ratio, as well as reducing mortality, increasing livability, increasing disease resistance, reducing stress impacts, and maintaining health of the birds. This review sheds light on the distribution, chemical structure, and biological effects of W. somnifera and its impacts on poultry productivity, livability, carcass characteristics, meat quality, blood parameters, immune response, and economic efficiency.
... In overweight and obese adults with chronic stress, Ashwagandha root extract has been reported to improve the mental well-being, eating behaviours and reduce stress through its adaptogenic properties along with maintaining the normal endocrinological balance . In addition, it was also reported to maintain an adequate range of testosterone, enhancing cognitive abilities in people with mild cognitive impairment, and boosting cardiorespiratory endurance ( Chemical Composition-The biologically active chemical constituents of Withania somnifera (WS) include alkaloids (isopelletierine, anaferine, cuseohygrine, anahygrine, etc.), steroidal lactones (withanolides, withaferins) and saponins (Mishra, 2000(Mishra, et al., 2000. Sitoindosides and acylsterylglucosides in Ashwagandha are anti-stress agents. ...
... In overweight and obese adults with chronic stress, Ashwagandha root extract has been reported to improve the mental well-being, eating behaviours and reduce stress through its adaptogenic properties along with maintaining the normal endocrinological balance . In addition, it was also reported to maintain an adequate range of testosterone, enhancing cognitive abilities in people with mild cognitive impairment, and boosting cardiorespiratory endurance ( Chemical Composition-The biologically active chemical constituents of Withania somnifera (WS) include alkaloids (isopelletierine, anaferine, cuseohygrine, anahygrine, etc.), steroidal lactones (withanolides, withaferins) and saponins (Mishra, 2000(Mishra, et al., 2000. Sitoindosides and acylsterylglucosides in Ashwagandha are anti-stress agents. ...
... Ashwagandha root extract mostly used for the treatment of nervous and immunological disorders, adaptogen /stress, sexual disorders, cancer, diabetes, infectious diseases, ulcer, arthritis, etc. It acts as a tonic to arrest the aging process, rejuvenate the body, and boosts the immune system against infection as well as to promote the longevity of life [2][3][4][5][6]. Ashwagandha root extract contains the major active phytoconstituents like withanolides, withanamides, alkaloids, sitoindosides, reducing sugars, starch, peroxidases, glycosides, withanicil, benzyl alcohol, dilcitol, 2-phenyl ethanol, 3,4,5-trihydroxy cinnamic acid, phenyl acetic acid, benzoic acid, etc [7][8][9]. ...
... Ashwagandha root extract contains the major active phytoconstituents like withanolides, withanamides, alkaloids, sitoindosides, reducing sugars, starch, peroxidases, glycosides, withanicil, benzyl alcohol, dilcitol, 2-phenyl ethanol, 3,4,5-trihydroxy cinnamic acid, phenyl acetic acid, benzoic acid, etc [7][8][9]. Withanolides have various pharmacological activities in the body include immunomodulating, anti-inflammatory, neuroprotective, memory loss, hepatoprotective, antioxidant, hypoglycaemic, gastrointestinal issues, constipation, antiarthritic, antimicrobial, anticancer, insomnia, skin conditions, Alzheimer's, Huntington's, and Parkinson's disorders, etc. [3][4][5][6][10][11][12]. Therefore, ashwagandha root extract used in many nutraceutical and pharmaceutical formulations as a supplement for the prevention and treatment of various human disorders. ...
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... Withania somnifera is a traditional plant applied in Ayurvedic medicine that grows in large parts of Africa but also India. Withanone, withaferin, withanolides with asomidi-enone and withanolide are among the steroidal lactones found in the root extract [95]. These substances have been shown to decrease metastasis and quinone reductase activity, and to selectively impact the cortical and basal forebrain's cholinergic signal transduction cascade, suggesting that they might be useful in the PD treatment ( Fig. 2) [90]. ...
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... 21,22 Withania somnifera (also known as ashwagandha, Indian ginseng, or winter cherry) is a medicinal plant that has been safely used for thousands of years in India and its neighboring countries as remedies against various diseases. 23,24 WifA and win ( Figure 1C) are two major components of W. somnifera. 25,26 Structurally, both wifA and win are C22 steroidal lactones with a withanolide-type A skeleton. ...
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