Withania Somnifera Monograph

Page 334 Alternative Medicine Review ◆ Volume 5 Number 4 ◆ 2000

Copyright©2000 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission

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: [email protected]

Betsy B. Singh, PhD – Dean of Research, LACC

Simon Dagenais, BA – Research Assistant, LACC

Scientific Basis for the Therapeutic Use ofWithania somnifera (Ashwagandha):

A ReviewLakshmi-Chandra Mishra, MD (Ayur), PhD,

Betsy B. Singh, PhD, Simon Dagenais, BA

IntroductionWithania somnifera Dunal (ashwagandha, WS) is widely used in Ayurvedic medicine,

the traditional medical system of India. It is an ingredient in many formulations prescribed fora variety of musculoskeletal conditions (e.g., arthritis, rheumatism), and as a general tonic toincrease 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-purposemedicinal agent. For example, anti-inflammatory properties have been investigated to validate

AbstractOBJECTIVE: The objective of this paper is to review the literature regarding Withaniasomnifera (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 andconsists of all publications relevant to ashwagandha that were identified by the authorsthrough a systematic search of major computerized medical databases; no statisticalpooling of results or evaluation of the quality of the studies was performed due to thewidely different methods employed by each study. RESULTS: Studies indicateashwagandha possesses anti-inflammatory, antitumor, antistress, antioxidant,immunomodulatory, hemopoetic, and rejuvenating properties. It also appears to exerta positive influence on the endocrine, cardiopulmonary, and central nervous systems.The mechanisms of action for these properties are not fully understood. Toxicity studiesreveal that ashwagandha appears to be a safe compound. CONCLUSION: Preliminarystudies have found various constituents of ashwagandha exhibit a variety of therapeuticeffects with little or no associated toxicity. These results are very encouraging andindicate this herb should be studied more extensively to confirm these results andreveal other potential therapeutic effects. Clinical trials using ashwagandha for a varietyof conditions should also be conducted.(Altern Med Rev 2000;5(4) 334-346)


Withania som

nifera (Ashw

agandha)

Alternative Medicine Review ◆ Volume 5, Number 4 ◆ 2000 Page 335

its use in inflammatory arthritis,3-6 and animalstress studies have been performed to investi-gate its use as an antistress agent.7-10 Severalstudies have examined the antitumor andradiosensitizing effect of WS.11-15 The purposeof this paper is to review the literature regard-ing WS and report on clinically relevant stud-ies, in an attempt to establish a scientific basisfor the therapeutic use of WS. Results of stud-ies investigating the chemistry and toxicity ofWS will also be discussed.

MethodsThis literature review was limited to

published articles and books in the Englishlanguage. Four computerized medical data-bases (MEDLINE, CINAHL, EMBASE, Man-tis) were searched for the entire duration ofeach database as available on the OVID com-puter search service. The following keywordswere used for the search: ashwagandha andcommon misspellings (ashwaganda,aswaganda, aswagandha), withania,

somnifera, dunal, withaferin,sitoindoside, solanaceae, Indian gin-seng, and winter cherry. Results ofthese searches were reviewed to iden-tify relevant articles.

ResultsA total of 58 articles were

found using the search method de-scribed above. Research revealsashwagandha possesses anti-inflam-matory, antitumor, antistress, antioxi-dant, immunomodulatory,hemopoetic, and rejuvenating prop-erties. Ashwagandha also appears tobenefit the endocrine, cardiopulmo-nary, and central nervous systems.Few articles were discovered on themechanism of action for these effects.Several preliminary studies have beenconducted on animals. A summary ofthe findings of these studies is pre-sented below.

ChemistrySince many of ashwagandha’s uses

have not been scientifically validated, skepti-cism can naturally be expected when presentedwith an herb purportedly useful in so manyailments. In Ayurvedic medicine there is a classof herbs, including WS, known as adaptogensor vitalizers. Adaptogens cause adaptive reac-tions to disease, are useful in many unrelatedillnesses, and appear to produce a state of non-specific increased resistance (SNIR)10,16 toadverse 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)

Page 336 Alternative Medicine Review ◆ Volume 5, Number 4 ◆ 2000


Figure 1: Chemical Structure of Withaferin A

CH3

CH3

CH3

CH3

O O

O

O

OH

OH

Withaferin A

anaferine), steroidal lactones (withanolides,withaferins), saponins containing an additionalacyl group (sitoindoside VII and VIII), andwithanolides with a glucose at carbon 27(sitoindoside IX and X). WS is also rich iniron. See Figure 1 for the chemical structureof withaferin A, and Figure 2 for sitoindosidesIX and X.

Anti-inflammatoryProperties

The effectiveness ofashwagandha in a variety ofrheumatologic conditionsmay be due in part to its anti-inflammatory properties,which have been studied byseveral authors. In a study byAnbalagan et al,3 powderedroot of WS (1 g/kgsuspended in 2% gumacacia, 50 mg/mL) wasgiven orally one hour beforethe induction ofinflammation by injection ofFreund’s complete adjuvantin rats and continued dailyfor three days;

phenylbutazone (100mg/kg) was given asa positive control. WS was found to causeconsiderable reduction in inflammation.Acute phase reactants of the bloodmonitored by crossed immuno-electrophoresis showed changes in theconcentration of many serum proteins(α2-glycoprotein, major acute phase α1-protein, and pre-albumin) in the WSgroup. The α2-glycoprotein found onlyin inflamed rat serum was decreased toundetectable levels in the WS group.Phenylbutazone, on the other hand,caused a considerable increase in the α2-glycoprotein in both arthritic and healthyrats. Another acute phase protein (peak2, α-1 major acute phase) whichincreased approximately 200 percent by

inflammation was brought back to normallevels by WS treatment but only to 132 percentof normal by phenylbutazone. WS influencedseveral modulator proteins in normal rats,suggesting that several plant chemicals in WSpossibly interact with the liver proteinsynthesis process. Another study by Anbalagan

Figure 2: Chemical Structures of Sitoindosides IX and X.

CH3

CH3

CH3

CH3

O O

O

O

OH

O O

OH

OHOH

RO

Sitoindoside IX, R=HSitoindoside X, R=palmitoyl

Withania som

nifera (Ashw

agandha)



et al4 found WS caused dose-dependentsuppression of α2-macroglobulin (an indicatorfor anti-inflammatory drugs) in the serum ofrats inflamed by sub-plantar injection ofcarrageenan suspension. The doses of WS rootpowder were 500, 1000, 1500, or 1200 mg/kggiven as suspension orally 3-4 hours prior toinduction of inflammation. Maximum effect(about 75%) was seen at 1000 mg/kg. Actualmeasurements of inflammation were notconducted.

In a study by Begum et al,20 air pouchgranuloma was induced by subcutaneousinjections of 4 mL of two-percent (w/v)carrageenan on the dorsum of male Wistar rats(150-200 g) which had been subcutaneouslyinjected one day prior with 6 mL of air on thedorsum. WS root powder (1000 mg/kg) wasgiven orally from day 7 to day 9. RadioactiveNa

232SO4/100 g was injected intraperitoneally

on day 9; 35S incorporation inglycosaminoglycan, oxidativephosphorylation (ADP/O ratio), Mg2+

dependent-ATPase enzyme activity, andsuccinate dehydrogenase activity weredetermined in the mitochondria of thegranuloma tissue. WS decreased theglycosaminoglycans content in the granulomatissue by 92 percent, compared with 43.6percent by hydrocortisone (15 mg/kg)treatment and no effect byphenylbutazone treatment (100mg/kg). WS also uncoupled theoxidative phosphorylation bysignificantly reducing the ADP/Oratio in mitochondria ofgranuloma tissue. It increased theMg2+ dependent-ATPase enzymeactivity and also reduced thesuccinate dehydrogenase activityin the mitochondria of thegranuloma tissue; no such effectwas produced by the referencedrugs. No physical measurementsof the inflammation were carriedout.

Another study by Begum et al21 exam-ined the effect of WS (root powder, 1000 mg/kg, orally daily for 15 days) on paw swellingand bony degenerative changes in Freund’s ad-juvant-induced arthritis in rats. WS caused sig-nificant reduction in both paw swelling anddegenerative changes as observed by radiologi-cal examination. The reductions were betterthan those produced by the reference drug, hy-drocortisone (15 mg/kg). No biochemical pa-rameters were reported in this study. A studyby al Hindawi et al22 found WS inhibited thegranuloma formation in cotton-pellet implan-tation in rats and the effect was comparable tohydrocortisone 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 andcontinued daily until the pellets were harvestedon day 4.

One clinical trial supports the possibleuse of WS for arthritis. In a double-blind,placebo-controlled cross-over study, 42patients with osteoarthritis were randomizedto receive a formula containing ashwagandha(see Table 1 for formula) or placebo for threemonths. Patients were evaluated for onemonth, pretreatment, during which time allprevious drugs were withdrawn. During boththe pretreatment and treatment phase, pain and

Table 1: Formula Used for Treatment of Osteoarthritis

Ingredient

Ashwagandha

Boswellia

Turmeric

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.



disability scores were evaluated weekly whileerythrocyte sedimentation (SED) rate andradiological studies were conducted monthly.The herbal formula significantly reduced theseverity of pain (p<0.001) and disability(p<0.05) scores, although no significantchanges in radiological appearance or SEDrate were noted.23

Few studies have been conducted onthe mechanism of action for the anti-inflam-matory properties of WS. In one study, ratsinjected with 3.5-percent formaline in the hindleg footpad showed a decrease in absorptionof 14C-glucose in rat jejunum.5 Glucose absorp-tion was maintained at the normal level by bothWS and the cyclooxygenase inhibitoroxyphenbutazone. Both drugs produced anti-inflammatory effects. Similar results wereobtained in parallel experiments using 14C-leu-cine absorption from the jejunum.6 These stud-ies suggest cyclooxygenase inhibition may beinvolved in the mechanism of action of WS.

Antitumor PropertiesTo investigate its use in treating various

forms of cancer, the antitumor andradiosensitizing effects of WS have beenstudied. In one study, WS was evaluated forits anti-tumor effect in urethane-induced lungadenomas in adult male albino mice.11

Simultaneous administration of WS (ethanolextract of whole plant, 200 mg/kg daily orallyfor seven months) and urethane (125 mg/kgwithout food biweekly for seven months)reduced tumor incidence significantly (tumorincidence: untreated control, 0/25; urethanetreated, 19/19; WS treated, 0/26, and WS plusurethane treated, 6/24, p<0.05). Thehistological appearance of the lungs of animalsprotected by WS was similar to those observedin the lungs of control animals. Nopathological evidence of any neoplastic changewas observed in the brain, stomach, kidneys,heart, spleen, or testes of any treated or controlanimals. In addition to providing protectionfrom carcinogenic effects, WS treatment also

reversed the adverse effects of urethane on totalleukocyte count, lymphocyte count, bodyweight, and mortality.

The growth inhibitory effect of WSwas also observed in Sarcoma 180 (S-180), atransplantable mouse tumor.12 Ethanol extractof WS root (400 mg/kg and up, daily for 15days) after intra-dermal inoculation of 5x105

cells of S-180 in BALB/c mice produced com-plete regression of tumor after the initialgrowth. A 55-percent complete regression wasobtained at 1000 mg/kg; however, it was a le-thal dose in some cases. WS was also found toact as a radio- and heat sensitizer in mouse S-180 and in Ehrlich ascites carcinoma.12,14 Anti-tumor and radiosensitizing effects ofwithaferin (a steroidal lactone of WS) werealso seen in mouse Ehrlich ascites carcinomain vivo.15 Withaferin A from WS gave aradiosensitizer ratio of 1:5 for in vitro cell kill-ing of V79 Chinese hamster cell at a non-toxicconcentration of about 2 mM/L.12-14 Thesestudies are suggestive of antitumor activity aswell as enhancement of the effects of radia-tion by WS.

Antistress EffectTo evaluate the antistress effect of WS,

an alcohol extract from defatted seeds of WSdissolved in normal saline was given (100 mg/kg intraperitoneally as a single dose) to 20-25g mice in a swimming performance test inwater at 28º-30ºC.10 Controls were given sa-line. The extracts approximately doubled theswimming time when compared to controls.In another study, WS prevented both a weightincrease of the adrenals and a reduction inascorbic acid content of the adrenals normallycaused by this swimming test. The authorssuggested that WS induced a state of nonspe-cific increased resistance during stress.

Glycosides of WS (sitoindosides VIIand 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 som

nifera (Ashw

agandha)



auto-analgesia in rats, restraint stress effect onthermic response of morphine in rats, andmorphine-induced toxicity in aggregatedmice.24 The alcohol extract of WS (100 mg/kg, twice daily orally on day 1, 4 or 7) reducedstress-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 WSreversed the cold swimming-induced increasesin plasma corticosterone, phagocytic index,and avidity index to control levels. WS rootpowder (100 mg/kg orally as an aqueous sus-pension daily for seven days) given before theswimming test in water at 10ºC also increasedtotal swimming time, indicating better stresstolerance in rats.8 These results indicated a sig-nificant increase in plasma corticosteronelevel, phagocytic index, and avidity index incontrol rats, whereas these levels were nearnormal in WS rats subjected to the same test.

In a comparative study for antistressactivity, finely powdered roots of WS andPanax ginseng (PG), suspended in 2-percentacacia (100 mg/kg in 1.00 mL orally) weregiven 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 theswimming endurance test, was found for bothcompounds. The swimming time was 536.6minutes for PG, 474.1 minutes for WS, and163.3 minutes for controls; all differences be-tween groups were significant (p<0.05). Ana-bolic activity, measured as an increase in bodyweight, was significant for both herbal extractsbut was better in the WS group than in the PGgroup. If these results could be reproduced inhumans, it would support the use of WS innervous exhaustion due to stress and incachexia to increase body weight.

Antioxidant EffectThe brain and nervous system are rela-

tively more susceptible to free radical damagethan other tissues because they are rich in lip-ids and iron, both known to be important in

generating reactive oxygen species.26 The brainalso uses nearly 20 percent of the total oxy-gen supply.27 Free radical damage of nervoustissue may contribute to neuronal loss in cere-bral ischemia and may be involved in normalaging and neurodegenerative diseases, e.g.,epilepsy, schizophrenia, Parkinson’s,Alzheimer’s, and other diseases.28,29 Since tra-ditional Ayurvedic use of WS has includedmany diseases associated with free radicaloxidative damage, it has been considered likelythe effects may be due to a certain degree ofantioxidant activity. The active principles ofWS, sitoindosides VII-X and withaferin A(glycowithanolides), have been tested for anti-oxidant activity using the major free-radicalscavenging enzymes, superoxide dismutase(SOD), catalase (CAT), and glutathione per-oxidase (GPX) levels in the rat brain frontalcortex and striatum. Decreased activity of theseenzymes leads to accumulation of toxic oxi-dative free radicals and resulting degenerativeeffects. An increase in these enzymes wouldrepresent increased antioxidant activity and aprotective effect on neuronal tissue. Activeglycowithanolides of WS (10 or 20 mg/kg in-traperitoneally) were given once daily for 21days 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 WSdoes have an antioxidant effect in the brainwhich may be responsible for its diverse phar-macological properties.30 Further studies onother parts of the brain (e.g., cerebellum, me-dulla, and hypothalamus) may provide infor-mation with respect to the effects of WS oncognitive behavior and other functions of thebrain, in both healthy and diseased individu-als.

In another study, an aqueous suspen-sion of WS root extract was evaluated for itseffect on stress-induced lipid peroxidation(LPO) in mice and rabbits.9 LPO blood levelswere increased by IV administration of 0.2 mg/



kg of lipopolysaccharides (LPS) from Kleb-siella pneumoniae and 100 mg/kg ofpeptidoglycans (PGN) from Staphylococcusaureus. Simultaneous oral administration ofWS extract (100 mg/kg) prevented an increasein LPO. The authors indicated that the almostinnocuous doses of LPS and PGN used in thisstudy that induced elevated levels of LPO werecomparable to a mild bacteremia which mayfollow tooth extraction, streptococcal angina,etc.

Immunomodulatory PropertiesThe use of WS as a general tonic to

increase energy and prevent disease may bepartially related to its effect on the immunesystem. Glycowithanolides and a mixture ofsitoindosides IX and X (Figure 2) isolated fromWS were evaluated for their immuno-modulatory and central nervous system effects(antistress, memory, and learning) in Swissmice (15-25 g, 5-6 months old) and Wistarstrain albino rats (120-150 g and 250-300 g).31

Both materials produced statistically signifi-cant mobilization and activation of peritonealmacrophages, phagocytosis, and increasedactivity of the lysosomal enzymes. Both com-pounds (50-200 mg/kg orally) also producedsignificant antistress activity in albino miceand rats, and augmented learning acquisitionand memory retention in both young and oldrats.

Root extract of WS was tested forimmunomodulatory effects in threemyelosuppression models in mice: cyclophos-phamide, azathioprin, or prednisolone.32 Sig-nificant increases (p<0.05) in hemoglobin con-centration, red blood cell count, white bloodcell count, platelet count, and body weightwere observed in WS-treated mice comparedto untreated control mice. The authors alsoreported significant increases in hemolyticantibody responses toward human erythrocyteswhich indicated immunostimulatory activity.

The effect of WS was also studied onthe functions of macrophages obtained from

mice treated with the carcinogen ochratoxinA (OTA).33 OTA treatment of mice for 17weeks significantly decreased the chemotacticactivity of the macrophages. Interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-α)production was also markedly decreased.

Hemopoetic EffectAdministration of WS extract was

found to significantly reduce leukopenia in-duced by cyclophosphamide (CTX) treatmentin Swiss albino mice.34 Total white blood cellcount on the 12th day of the CTX-treated groupwas 3720/mm3; that of the CTX-plus-WSgroup was 6120/mm3. In the CTX-plus-WSmice, the cellularity of the bone marrow wassignificantly increased (13.1 x 106 /femur)(p<0.001) compared to the CTX-alone treatedgroup (8 x 106/femur). Similarly, the numberof alpha-esterase positive cells (1130/4000cells) 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 thestimulation of stem cell proliferation. Thesestudies indicated WS reduced CTX-inducedtoxicity and may prove useful in cancer che-motherapy. Further studies need to be con-ducted to confirm the hemopoetic effect withother cytotoxic agents and to determine itsusefulness as an adjuvant in cancer chemo-therapy.

Rejuvenating EffectThe growth-promoting effect of WS

was studied for 60 days in a double-blind studyof 60 healthy children, age 8-12 years, whowere divided into five groups of 12.35 Group 1was given purified and powdered WS 2 g/dayfortified in 100 cc of milk (no details aboutpurification and powdering methods weredisclosed). Similarly, Group 2 received 2 gdaily of a mixture of equal parts WS andpunarnava (Boerhaavia diffusa), Groups 3 and

Withania som

nifera (Ashw

agandha)



4 were given ferrous fumarate 5 mg/day and30 mg/day, respectively, and Group 5 receivedplacebo.

Group 1 experienced a slight increasein hemoglobin, packed cell volume, mean cor-puscular volume, serum iron, body weight, andhand grip, and significant increases in meancorpuscular hemoglobin and total proteins(p<0.01) at the end of 60 days when comparedto the initial level and the placebo group. Therewas an increase in body weight in all groupsover the control group.

Group 2, treated with WS andpunarnava, showed a significant increase in thelevel of hemoglobin at the end of 30 days com-pared to the initial value. Marked increases inthe levels of hemoglobin, packed cell volume,mean corpuscular volume, mean corpuscularhemoglobin, serum iron, and hand grip werealso 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 hadan increase in body weight, 10 children hadan increase in hemoglobin and packed cellvolume, and 11 children had an increase inserum iron.

Group 3 (5 mg ferrous fumarate) hadno significant change in any parameters, whileGroup 4 (30 mg ferrous fumarate) showed asignificant increase in hemoglobin (p<0.01),mean corpuscular hemoglobin (p<0.05), meancorpuscular hemoglobin concentration(p<0.01), serum iron, (p<0.05), and hand grip(p<0.05), and a marked increase in packed cellvolume. Group 5 (placebo) had no significantchange 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 purifiedpowder was given 3 g/day for one year to 101normal healthy male volunteers, age 50-59years.36 All subjects showed significantlyincreased hemoglobin and RBC count, and

improvement in hair melanin and seatedstature. They also showed decreased SED rate,and 71.4 percent of the subjects reportedimprovement in sexual performance. Insummary, these studies indicate WS may proveuseful in younger as well as older populationsas a general health tonic.

Nervous System EffectsTotal alkaloid extract

(ashwagandholine, AG) of WS roots has beenstudied for its effects on the central nervoussystem.37 AG exhibited a taming effect and amild depressant (tranquilizer) effect on thecentral nervous system in monkeys, cats, dogs,albino rats, and mice. AG had no analgesicactivity in rats but increased Metrazol toxicityin rats and mice, amphetamine toxicity in mice,and produced hypothermia in mice. It alsopotentiated barbiturate-, ethanol-, and ure-thane-induced hypnosis in mice.

Effects of sitoindosides VII-X andwithaferin isolated from aqueous methanolextract of roots of cultivated varieties of WSwere studied on brain cholinergic,glutamatergic and GABAergic receptors inmale Wistar rats.38 The compounds slightlyenhanced acetylcholinesterase (AChE) activ-ity in the lateral septum and globus pallidus,and decreased AChE activity in the verticaldiagonal band. These changes were accompa-nied by enhanced M

1-muscarinic-cholinergic

receptor-binding in lateral and medial septumas 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, andretrospinal 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.



Ashwagandholine, total alkaloids extractedfrom extract of WS roots, caused relaxant andantispasmodic effects against various agentsthat produce smooth muscle contractions inintestinal, uterine, tracheal, and vascularmuscles.39 The pattern of smooth muscle ac-tivity was similar to that of papaverine, butseveral-fold weaker, which indicated a directmusculotropic action. These results are con-sistent with the use of WS to produce relax-ation.

Effects on the Endocrine SystemBased on the observations that WS pro-

vides protection from free radical damage inthe mouse liver, studies were conducted todetermine the efficacy of WS in regulating thy-roid function.40,41 Mice were given WS rootextract (1.4 g/kg by gavage, daily for 20 days).The treatment significantly increased the se-rum levels of 3,3’,5-triiodothyronine (T3) andtetraiodothyronine (T4), while the hepatic con-centrations of glucose 6-phosphatase activityand hepatic iodothyronine 5’-monodeiodinaseactivity did not change significantly. WS sig-nificantly reduced hepatic lipid peroxidationand increased the activity of superoxidedismutase and catalase. The results suggest WSstimulates thyroidal activity and also promoteshepatic antioxidant activity.

A combination formula of WS,Tinospora cordifolia, Eclipta alba, Ocimiumsanctum, Picorrhiza kurroa, and shilajit wasfound to cause a dose-related decrease instreptozotocin-induced hyperglycemia.31 Noneof 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 thansingle herbs.

Effects on the CardiopulmonarySystem

WS may be useful as a general tonic,due in part to its beneficial effects on the

cardiopulmonary system, as reported in thefollowing studies. The effect of AG was studiedon the cardiovascular and respiratory systemsin dogs and frogs.42 The alkaloids had aprolonged hypotensive, bradycardiac, andrespiratory-stimulant action in dogs. The studyfound that the hypotensive effect was mainlydue to autonomic ganglion blocking action andthat a depressant action on the higher cerebralcenters also contributed to the hypotension.The alkaloids stimulated the vasomotor andrespiratory centers in the brain stem of dogs.The cardio-inhibitory action in dogs appearedto be due to ganglion blocking and directcardio-depressant actions. The alkaloidsproduced immediate predominant but short-lived cardio-depressant effects and a weak butprolonged cardiotonic effect in isolated normaland hypodynamic frog hearts. Thepharmacological actions of the total extract ofWS roots on the cardiovascular and respiratorysystems appeared to be due to its alkaloidcontent. The total alkaloids were more thantwice as active as the 70-percent alcohol extractof WS root. These studies were found to beconsistent with the use of WS as a tranquilizingagent.

General Toxicity StudiesAn important consideration when

investigating the medicinal properties of anunknown compound is diligent evaluation ofits potential for harmful effects, usuallyevaluated through toxicity studies. For WS, nosystematic study was found which includedacute, sub-acute, sub-chronic or chronictoxicity of WS root powder, whole plantpowder, or different extracts of the plant (e.g.,water, alcohol, petroleum ether, purifiedalkaloids, and glycosides). The acute toxicitydata found as a part of pharmacological studiesare summarized here. Although onepreliminary toxicity study of WS wasconducted, it was of insufficient quality tosupport its findings as too few animals wereused, body weight data was not collected, and

Withania som

nifera (Ashw

agandha)



survival data was not reported.43 In one centralnervous system study, a two-percentsuspension of ashwagandholine (totalalkaloids from the roots of WS) prepared inten-percent propylene glycol using two-percent gum acacia as suspending agent wasused to determine acute toxicity.39 The acuteLD

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

50in albino mice.10 The acute LD

50 was 1750 +/-

41 mg (p.o). In another antistress-effect study,aqueous-methanol extracts of the root fromone-year-old cultivated WS (SG-1) andequimolar combinations of sitoindosides VIIand 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 administrationin mice was 1076 +/- 78 mg/kg and 1564 +/-92 mg/kg, respectively.

In one long-term study, WS was boiledin water and administered to rats in their dailydrinking water for eight months while moni-toring body weight, general toxicity, well be-ing, number of pregnancies, litter size, andprogeny weight.44 The estimated dose givenwas 100 mg/kg/day. In the second part of thestudy, the estimated dose was 200 mg/kg/daygiven for four weeks as above while monitor-ing body temperature, body weight, cortisolvalue in heparinized plasma, and ascorbic acidcontent of the adrenals. The liver, spleen, lungs,kidneys, thymus, adrenals, and stomach wereexamined histopathologically and were allfound to be normal. The initial average bodyweights of the WS-treated group (100 mg/kg/day) and control group on day 1 were 91 gand 106 g which, after four weeks, increasedto 185 g (103%) and 178 g (67.9%), respec-tively. The WS-treated rats appear to havegained more weight than the control group (nop value given). The percent weight gain aftereight weeks on the same WS treatment was227 percent for the treated group and 145.3

percent in the control group. The relative bodyweight gain was significantly greater in theWS-treated group as compare to the controlgroup (p< 0.001). While it is not clear whenthe rats were mated, the average weights ofthe progeny at one month of age were 70 gand 45 g in the WS-treated and control groups,respectively, indicating healthier progeny inthe WS-treated group. Additional studies arenecessary to confirm these findings.

In the four-week study, the weight gainin the treated group was comparable to that ofthe control group. The body temperature in theWS treated group was 1.7ºC lower than thecontrols. The WS treatment caused an increasein lung and liver weights and a decrease inadrenocortical activity as was evident from thereduction in adrenal weight and a significantreduction in plasma cortisol (p<0.001). His-topathologically, all organs were normal. Theauthors attributed the increase in liver weightto an increase in glycogen storage because WScontains many steroids and glucocorticoidsknown 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 steroidmoieties in WS roots which may act like ex-ogenous adrenocortical steroids, lowering theACTH secretion and consequently, endog-enous steroid production. The authors con-cluded the decoction of WS promoted growthespecially during the active growth period andhelped produce healthier progeny. The WSgroup was devoid of any toxic effects aftereight months of daily dosing in this study.

DiscussionAs outlined above, results from various

studies indicate ashwagandha possesses manyqualities, including anti-inflammatory,antitumor, and immunomodulatory properties,as well as exerting an influence on theendocrine, nervous, and cardiopulmonarysystems. Further clinical studies should be



conducted, as well as studies in multipleanimal-based models using a variety ofsuitable biochemical markers (e.g., urinaryexcretion of pyridinoline anddeoxypyridinoline) to understand itsmechanism of action. Any protective orprophylactic effect it may have on thedevelopment of arthritis should also beinvestigated, as well as effects it may have oncartilage degradation or regeneration. As forits use in fighting cancer, confirmatory studiesin several other animal tumor systems mustbe conducted for more definitive findings.Studies should also be carried out to determinethe effects, if any, of WS on existing antitumoragents when given in combination with WS.Regarding the effects observed in animals onthe endocrine and cardiopulmonary systems,the therapeutic significance of thesebiochemical markers is not clear. Studies pointto a possible benefit of WS in central nervoussystem-related ailments. The lack ofsystematic toxicity studies is of some concern,as is the poor quality of the existing toxicitystudies.

The review indicates that WS may beuseful in many ailments, including arthritis andother musculoskeletal disorders, stress-in-duced nervous exhaustion, and hypertension.There are a few preliminary studies availableon the effects of WS on the immune system,central nervous system, hemopoetic system,and general growth promotion to form a basisfor further studies but not enough evidence toprovide a firm scientific basis for definitivetherapeutic uses.

ConclusionAlthough the results from this review

are quite promising for the use of ashwagandhaas a multi-purpose medicinal agent, severallimitations currently exist in the currentliterature. While ashwagandha has been usedsuccessfully in Ayurvedic medicine forcenturies, more clinical trials should beconducted to support its therapeutic use. It is

also important to recognize that WS may beeffective not only in isolation, but may actuallyhave a potentiating effect when given incombination with other herbs or drugs.

Acknowledgment: The authors ac-knowledge the technical support provided byFred Zarow, DC, MS in the preparation of thismanuscript.

References1. Chatterjee A, Pakrashi SC. The Treatise on

Indian Medicinal Plants 1995;4:208-212.

2. Bone K. Clinical Applications of Ayurvedicand Chinese Herbs. Monographs for theWestern Herbal Practitioner. Australia:Phytotherapy Press; 1996:137-141.

3. Anbalagan K, Sadique J. Influence of anIndian medicine (Ashwagandha) on acute-phase reactants in inflammation. Indian J ExpBiol 1981;19:245-249.

4. Anbalagan K, Sadique J. Role of prostaglan-dins in acute phase proteins in inflammation.Biochem Med 1984;31:236-245.

5. Somasundaram S, Sadique J, Subramoniam A.Influence of extra-intestinal inflammation onthe in vitro absorption of 14C-glucose and theeffects of anti-inflammatory drugs in thejejunum of rats. Clin Exp Pharmacol Physiol1983;10:147-152.

6. Somasundaram S, Sadique J, Subramoniam A.In vitro absorption of [14C]leucine duringinflammation and the effect of antiinflamma-tory drugs in the jejunum of rats. Biochem Med1983;29:259-264.

7. Dadkar VN, Ranadive NU, Dhar HL. Evalua-tion of antistress (adaptogen) activity ofWithania somnifera (Ashwagandha). Ind JClin Biochem 1987,2:101-108.

8. Archana R, Namasivayan A. Antistressor effectof Withania somnifera. J Ethnopharmacol1999;64:91-93.

9. Dhuley JN. Effect of ashwagandha on lipidperoxidation in stress-induced animals. JEthnopharmacol 1998;60:173-178.

10. Singh N, Nath R, Lata A, et al. Withaniasomnifera (ashwagandha), a rejuvenatingherbal drug which enhances survival duringstress (an adaptogen). Int J Crude Drug Res1982;20:29-35.

Withania som

nifera (Ashw

agandha)



11. Singh N, Singh SP, Nath R, et al. Prevention ofurethane-induced lung adenomas by Withaniasomnifera (L.) Dunal in albino mice. Int JCrude Drug Res 1986;24:90-100.

12. Devi PU, Sharada AC, Solomon FE, KamathMS. In vivo growth inhibitory effect ofWithania somnifera (Ashwagandha) on atransplantable mouse tumor, Sarcoma 180.Indian J Exp Biol 1992;30:169-172.

13. Devi PU. Withania somnifera dunal(ashwagandha): potential plant source of apromising drug for cancer chemotherapy andradiosensitization. Indian J Exp Biol1996;34:927-932.

14. Devi PU, Sharada AC, Solomon FE. In vivogrowth inhibitory and radiosensitizing effectsof withaferin A on mouse Ehrlich ascitescarcinoma. Cancer Lett 1995;95:189-193.

15. Sharad AC, Solomon FE, Devi PU, et al.Antitumor and radiosensitizing effects ofwithaferin A on mouse Ehrlich ascites carci-noma in vivo. Acta Oncol 1996;35:95-100.

16. Lazarev NV. Farmacol Toxicol 1958;21:81-86.As cited in Brekhman II, Dardymov IV. Newsubstances of plant origin which increase non-specific resistance. Annu Rev Pharmacol1969;9:419-430.

17. Brekhman II. Panax Ginseng. Med Sci Serv1967;4:17-26.

18. Brekhman II, Dardymov IV. New substancesof plant origin which increase non-specificresistance. Annu Rev Pharmacol 1969;9:419-430.

19. Rastogi RP, Mehrotra BN. Compendium ofIndian Medicinal Plants, Vol.6. Central DrugResearch Institute, New Delhi, 1998.

20. Begum VH, Sadique J. Effect of Withaniasomnifera on glycosaminoglycan synthesis incarrageenin-induced air pouch granuloma.Biochem Med Metab Biol 1987;38:272-277.

21. Begum VH, Sadique J. Long term effect ofherbal drug Withania somnifera on adjuvantinduced arthritis in rats. Indian J Exp Biol1988;26:877-882.

22. al Hindawi MK, al Khafaji SH, Abdul-NabiMH. Anti-granuloma activity of Iraqi Withaniasomnifera. J Ethnopharmacol 1992;37:113-116.

23. Kulkarni RR, Patki PS, Jog VP, et al. Treat-ment of osteoarthritis with a herbomineralformulation: a double-blind, placebo-con-trolled, cross-over study. J Ethnopharmacol1991;33:91-95.

24. Bhattacharya SK, Goel RK, Kaur R, Ghosal S.Antistress activity of sitoindosides VII andVIII, new acylsterylglucosides from Withaniasomnifera. Phytotherapy Res 1987;1:32-39.

25. Grandhi A, Mujumdar AM, Patwardhan B. Acomparative pharmacological investigation ofAshwagandha and Ginseng. J Ethnopharmacol1994;44:131-135.

26. Halliwell B, Gutteridge JMC. Free Radicals inBiology & Medicine. 2nd ed. Oxford:Clarendon Press; 1989.

27. Ames BN, Shigenaga MK, Hagen TM.Oxidants, antioxidants, and the degenerativediseases of aging. Proc Natl Acad Sci U S A1993;90:7915-7922.

28. Jesberger JA, Richardson JS. Oxygen freeradicals and brain dysfunction. Int J Neurosci1991;57:1-17.

29. Scarfiotti C, Fabris F, Cestaro B, Giuliani A.Free radicals, atherosclerosis, ageing, andrelated dysmetabolic pathologies: pathologicaland clinical aspects. Eur J Cancer Prev1997;6:S31-S36.

30. Bhattacharya SK, Satyan KS, Chakrabarti A.Effect of Trasina, an Ayurvedic herbal formu-lation, on pancreatic islet superoxidedismutase activity in hyperglycaemic rats.Indian J Exp Biol 1997;35:297-299.

31. Ghosal S, Lal J, Srivastava R, et al.Immunomodulatory and CNS effects ofsitoindosides IX and X, two newglycowithanolides from Withania somnifera.Phytotherapy Res 1989;3:201-206.

32. Ziauddin M, Phansalkar N, Patki P, et al.Studies on the immunomodulatory effects ofashwagandha. J Ethnopharmacol 1996Feb;50:69-76.

33. Dhuley JN. Effect of some Indian herbs onmacrophage functions in ochratoxin A treatedmice. J Ethnopharmacol 1997;58:15-20.

34. Davis L, Kuttan G. Suppressive effect ofcyclophosphamide-induced toxicity byWithania somnifera extract in mice. JEthnopharmacol 1998;62:209-214.

35. Venkataraghavan S, Seshadri C, SundaresanTP, et al. The comparative effect of milkfortified with aswagandha, aswagandha andpunarnava in children – a double-blind study. JRes Ayur Sid 1980;1:370-385.



36. Kuppurajan K, et al. J Res Ayu Sid 1, 247,1980. As cited in Bone K. Clinical Applica-tions of Ayurvedic and Chinese Herbs.Monographs for the Western Herbal Practitio-ner. Australia: Phytotherapy Press; 1996:137-141.

37. Malhotra CL, Mehta VL, Das PK, Dhalla NS.Studies on Withania-ashwagandha, Kaul. V.The effect of total alkaloids (ashwagandholine)on the central nervous system. Indian J PhysiolPharmacol 1965;9:127-136.

38. Schliebs R, Liebmann A, Bhattacharya SK, etal. Systemic administration of defined extractsfrom Withania somnifera (Indian Ginseng) andShilajit differentially affects cholinergic butnot glutamatergic and GABAergic markers inrat brain. Neurochem Int 1997;30:181-190.

39. Malhotra CL, Mehta VL, Prasad K, Das PK.Studies on Withania ashwagandha, Kaul. IV.The effect of total alkaloids on the smoothmuscles. Indian J Physiol Pharmacol1965;9:9-15.

40. Panda S, Kar A. Evidence for free radicalscavenging activity of ashwagandha rootpowder in mice. Indian J Physiol Pharmacol1997;41:424-426.

41. Panda S, Kar A. Changes in thyroid hormoneconcentrations after administration ofashwagandha root extract to adult male mice. JPharm Pharmacol 1998;50:1065-1068.

42. Malhotra CL, Das PK, Dhalla NS, Prasad K.Studies on Withania ashwagandha, Kaul. III.The effect of total alkaloids on the cardiovas-cular system and respiration. Indian J Med Res1981;49:448-460.

43. Arseculeratne SN, Gunatilaka AA, PanabokkeRG. Studies of medicinal plants of Sri Lanka.Part 14: Toxicity of some traditional medicinalherbs. J Ethnopharmacol 1985;13:323-335.

44. Sharma S, Dahanukar S, Karandikar SM.Effects of long-term administration of the rootsof ashwagandha (Withania somnifera) andshatavari (Asparagus racemosus) in rats.Indian Drugs 1986;23:133-139.


Documents

Withania Somnifera Monograph