Withania Somnifera / Winter cherry / Ashwagandha

General features and historical background: The herb is extensively famed for its countless beneficial roles, holding ancient Ayurvedic name, Ashwagandha (in Sanskrit, meaning smelling like horse), also titled as ‘Indian Ginseng’, enabling to infuse invigorating actions on mind and health. In recent days none of the varieties carry any obnoxious odor that supplies the name. With most certainty, the plant is also unrelated to original Ginseng. As per legend, by consuming it, one may earn the strength and vigor of a stallion. The botanical designation is Withania Somnifera (WS) and in English it is called ‘Winter cherry’. The plant belongs to Solanaceae family (like tomatoes) and originally a native of India. The word ‘Somnifera’ in Latin, means, sleep inducer. The herb has been greatly revered over several millennia offering longevity, vitality and numerous health benefits. Historically, at the dawn of civilization it was introduced by a venerated Rishi (sage from the Vedic period) of India named Punarvasu Atriya around three to four thousand years ago. Its nature and uses have been eloquently described in the ancient Hindu pharmacology, Charaka & Sushruta Samhita, a part of Ayurveda. Rishi Punarvasu has been identified by historians being the original author of Charaka Samhita. The actions of WS / Ashwagandha are manifold. It acts as powerful aphrodisiac and additionally displays immense fortifying roles regarding health, for the sedative and adaptogenic behavior to relieve any mental and physical stress. Importantly, it offers countless restorative benefits too. In some places of India, each part of the plant is utilized for medicinal purposes. The fresh tender leaves are often consumed as a vegetable that also offers versatile healing effects, also counted appropriate for the elderly and children. The plant grows under sunny and dry sandy soil. It is perennial and 15 – 30 inches tall. The leaves are dull green, elliptic shape and about 4 – 5 inches in length. It produces small green bell shaped flowers and the orange-red berries like small tomatillos. It grows in Punjab, Sindh, Gujrat, Kerala, Rajasthan, and Madhya Pradesh and to a lesser extent in parts of West Bengal. Outside India it can be found in the neighboring Nepal, a few regions of China and in Eastern Yemen or North Africa and Mediterranean areas. The plant is prone to various pests and botanical diseases. Traditionally, its long tuberous roots are mainly used for the Ayurvedic medicines. The berries are encased within papery lantern shaped covering like that in tomatillos. It opens up when the fruits are ripen subsequently acquiring bright orange-red color. The red berries are often used in making the cheese replacing calf rennet. The roots and berries carry bitter-sweet and astringent taste. As per its medicinal function as folk medicine, it is normally used as anxiolytic, aphrodisiac, hypolipidemic, sedative, adaptogenic and nervine (therapeutic actions on nerve) substance.

Purpose to use as folk medicine: The herb secures its reputation for having the ability to provide strength and virility of a horse, an indication to its prominent aphrodisiac action, also simultaneously enhancing the support for stout health adding satisfactory sexual function for both sexes. Its use has been even mentioned in Kama Sutra, the ancient Indian literature explaining the human sexual behavior for enhancement of sexual pleasure. It is perhaps equally applicable to the adult women for boosting the libido. Besides acting as an aphrodisiac, it plays multiple role by functioning as a stimulating tonic providing strong antioxidant actions also exerting diuretic, anthelmintic and thermogenic effects. The treatment with WS / Ashwagandha frees emotional and physical stress or tensions or discomforts thereby helping establish the basis of mental stability. Traditionally, it is directed to treat any negative effects that include varieties of illnesses and stresses of life. It is often used against any fevers or inflammations. In African countries the leaves are smashed to prepare a paste for treating burns or wounds. It is occasionally used as sunscreen in many tropical nations. The berries are frequently used to treat the tumors, carbuncles or ulcers. The different kinds of ingredients produced in this herb make those versatile acts possible. The major active ingredients that have been identified are alkaloids, steroidal lactones, saponins (triterpenes with high glycosidic linkage) and withanolides. Due to strong anti-inflammatory effect, the herb can prevent the arthritis. It is a potent abortifacient and also applicable against hyperglycemia, hyperinsulinemia, insulin sensitivity type-2 diabetes. It is a good analgesic. Additionally it increases mental alertness, extends memory and concentration of mind, sooths nerve by relieving the stress thus promoting endurance.

Chemical components: Either the intact dry roots or various forms of extracts are used for the medicinal purposes. The herb produces extensive number of chemical constituents in its roots which are broadly categorized as alkaloids, steroidal lactones, saponins and withanolides. At least twelve major alkaloids and its derivatives have been identified so far, for example, Anaferine, Anahygrine, Cuscohygrine, Pseudotropine, Somniferinine, Somniferiene, Tropanol, Withanine and Withananine.

Major alkaloids of Ashwagandha root

The alkaloid, Anaferine is a strong anti-viral agent acting as a powerful immunomodulators. The antiviral action mostly relies on the induction of interferon – α (IFN – α) whereas its immunomodulatory effect is exerted by the production of interferon – γ (IFN – γ). By acting through the interferon system, it induces anti-infectious responses. In that way, the compound offers broad spectrum antiviral effect. On the other hand Anahygrine acts as a neuronal acetyl choline receptor (nAChR) agonist improving neuronal communications also enhancing the cognitive functions that exerts beneficial effects by resisting several neurodegenerative diseases, particularly the Alzheimer’s disorder. Cuscohygrine, being a member of pyrrolidone alkaloid, acts as a strong CNS stimulant possibly effective against Parkinson’s disorder. It is known that tropane alkaloids induce CNS stimulation and a few also acts as local anesthetics as seen in the case of Cocaine. Majority of the tropane derivatives bind to the dopamine, serotonin or nor-epinephrine transport proteins thus inhibit their reuptake in pre-synaptic neurons helping accumulate the respective neuro-transmitters within synaptic cleft. In that way it increases the post-synaptic receptor activation. Actually, Cocaine follows that way by prohibiting the reuptake of those neurotransmitter amines resulting in the rise of their concentrations causing post-synaptic receptor activations. This imposes serious health effects. The local anesthetic role of tropane alkaloids occurs via its binding and subsequent blocking of the voltage-gated Na⁺ channels on the neuronal cell membrane. The other alkaloids of significant level is Pellertierine and its several analog which act as neuronal Nitric oxide synthase inhibitor (nNOS) in different degrees. It is considered to be a therapeutic agent.

Besides having large reserve of alkaloid, the root contains huge amount of withanolides which are steroidal lactones by nature. Among them Withanolides A and B exist in significant level. There are several acyl sterol glucosides have been identified. Among those Sitoindosides VII, VIII, and IX and X are found in the roots. The analogs VII and VIII are noticed to induce anti-stress effect whereas IX and X exert immune-modulatory actions. Withanolides have been reported to have the numerous biological role. Some of them show anti-inflammatory property by inhibiting the enzyme COX-2. Withanolide – A acts as an anti-angiogenic compound by inhibiting NF – κβ and Sp-1. Among the other derivatives, few members act as potent pesticide and insecticide. Some also show antitumor properties also. Below is shown the biologic effects of several Withanolides. Among the sterol contain, β – sitosterol was the prominent one which has the ability to reduce benign prostate hyperplasia and cholesterol level in circulation.

Pharmacological effects of few Withanolides from Withania Somnifera.

Withanolides	Pharmacological effects
3- p– hydroxy-2,3-dihydro-withanolide	Hepatoprotective, Antibacterial, Anti-tumor, Immunomodulatory & Anti-inflammatory.
Withania Somnifera -1	Hypnotic & Sedative.
Withania Somnifera – 2	Antibacterial.
Sitoindoside – IX & X	Immunomodulatory and selective serotonin Receptor inhibitory in CNS.
Sitoindoside – VII & VIII	Anti-stress.
Withanolide -D	Anti-tumor
Withanolide E	Antifeedant.
Withanone	Anti-tumor.
Withanolide – 5, 20a, (R)- Dihydroxy-6a,7a-epoxy -1-oxo-5a-2,24-di-enolide.	Immunomodulatory.

Important medicinal and pharmacological actions:

Anti-aging action – The long term human studies indicate that ~ 70 % of the subjects showed considerable improvement in hemoglobin level, RBC count, increased level of hair melanin, skin lowering of serum cholesterol also significant preservation of nail Ca. These signifies the ant-aging effects of WS.

Anticonvulsant action – The root extract has potent anticonvulsant effect which is evident from the reduction effect of Pentylene tetrazole induced convulsions when recorded by the EEG pattern. Seizures induced by electrical stimulation through bipolar electrodes in basolateral amygdaloid nuclear complex undergoes substantial reduction. The effect is reported to be mediated by GABAergic neurons.

Anti-inflammatory action – The compound Withanolide / Witherferin – A exerts potent anti-inflammatory and anti-arthritic effects. The compound is far more effective than any steroids. On the other hand it does not impose any toxic effects like in steroids. Normally, animals treated with hydrocortisone lose weight whereas on the contrary either Witherferin-A or Ashwagandha root extract showed gaining of body weight.

Anti-stress effect – Experiments regarding the effect of root extract of WS on chronic stress in rodents who are receiving mild electric shock for 21 days on the feet showed remarkable results. The stressed animals without the extract showed hyperglycemia, glucose intolerance, increased plasma corticosterone level, gastric ulcerations, male sexual dysfunction, cognitive deficits, immunosuppression and mental depressions. But to the contrary, treated animals showed significantly low level of stress enhancing the adaptogenic behavior overcoming those unfavorable effects. The extract produced GABA like activity which relates to its anti-anxiety action. Experiments further indicate that the antidepressant effect is very comparable to Imipramine (antidepressant drug) and anti-anxiety action is like Lorazepam. The root extract has been used in India as a known tranquilizer. It also has beneficial effect on stress induced ulcers which often causes sexual dysfunction, irregularities in glucose homeostasis and increased corticosterone level.

Anti-parkinsonian effect – Selective loss of dopaminergic neurons within substantia nigra in brain is a definite sign of Parkinson disorder. The exact cause that triggers the loss inflicting this debilitating disease is still unclear. Numerous animal studies using the model of neuroleptic catalepsy indicate the possible involvement of toxicity which manifests in the neural damage. Experiments supports the view that oxidative stress could be one of the responsible factors. The pretreatment with root extract prevent those effects within then experimental animals. The glycated withanolides in extract is identified to be liable component. Studies further reveal that introducing withanolides or WS extract after the onset of disease can reduce the progression of neuron loss and also attenuates the associated lesions and neuroleptic tardive dyskinesia, the notable sign of Parkinson’s disorder.

Nootropic / Neuronal effect – The word ‘Nootropic’ is directed to its role on cognitive function. It is noticed that Sitoindosides and Withanolides have different level of activities on cholinergic, glutaminergic and GABAergic receptors. Studies revealed that the compounds reduce enzyme actions of Acetylcholine-esterase (AchE) accompanied by the enhanced binding of Acetyl choline (Ach) to M₁ –muscarinic receptor in lateral and medial septum and also frontal cortices. Further Ach binding to M₂ – receptors are significantly enhanced in various cortical regions that includes cingulate, frontal, parietal and retro-spinal cortices. A large number of experiments suggest that either the WS / Ashwagandha extract root extract or the above compounds are preferentially influencing the cholinergic signaling in cortical and basal forebrain. This increase in Muscarinic receptor binding capacity could explain the memory improvement and simultaneous enhancement of cognitive functions by the WS / Ashwagandha extract within Alzheimer’s patients. Additional in vitro experiments showed that several Withanolides including the root extract can induce neurite outgrowth in cultured neurons. It has been noticed that oral administration of Withanolide IV substantially improves memory within dementia patients.

Aphrodisiac property – Historically, the herb has been acknowledged to be an aphrodisiac. It enhances sexual arousal time possibly by improving the vitality also promoting the tranquil state of mind. Biochemically, the extract produces NO that enables to dilate the blood vessel causing increase of blood flow in the penile tissues thereby helping the erectile function like in the case of commercial drug, Viagra. Besides male, the herb also exerts beneficial effects toward the female libido. In addition, root extract improves semen quality by altering the reproductive hormone levels within seminal plasma of the infertile subjects. Numerous reports showed that it is effective against infertility and impotency as well. It works by restoring any biochemical impairment observed in the seminal fluids. Reports also indicate that, it enhances the sperm count while enabling for fertility. The antioxidant effect and subsequent action of stress relief might assist in the overall process.

Cardiovascular, hypolipidemic and anti-hyperglycemic effect – Studies on canines and frogs identified the actual beneficial role on cardiopulmonary system which are duly exerted by the alkaloids produced in the plant. It has produced hypotensive, bradycardia and respiratory stimulation. Its hypotensive effect is due to the blocking of autonomic ganglion. Additionally the depressing effect on higher cerebral centers also contributes to that event. The Cardioprotective action is provided due to superb antioxidant effects of the extract. The WS / Ashwagandha root extract lowers total lipids, cholesterol and triglycerides in experimental hypocholesteremic animals also concomitantly enhances the plasma HDL-cholesterol level, enzyme HMG-CoA reductase and bile acid content of the liver. Experiments also reveals that it significantly lowers the lipid-peroxidation in hypocholesteremic animals. The use of Ashwagandha fruit extracts also produced identical positive results. Besides hypolipidemic action, the herb exerts considerable degree of hypoglycemic activity comparable to any commercially available oral glucose lowering medications. In these acts the plant wields its effects by lowering the serum cholesterol, triglyceride, LDL, VLDL, glucose simultaneously enhancing the diuretic action while increasing the level of Na in urine and also urine volume.

Anti-carcinogenic effect – The herb was recorded to have anti-carcinogenic effect when tested on animals. As per cell culture studies, it decreases NF – κβ and potentiates apoptotic signaling. Its ability to reduce the existing tumor volume has been recorded in the mice. The prolong administration even wiped out the tumor in the lung of experimental mice.

Immunomodulatory action – It has been established that the extracts of Ashwagandha prevents myelosuppression induced by the immunosuppressive drugs, cyclo-phosphamide, azathioprine or prednisolone. It has hematopoietic role while significantly increasing the RBC, platelets and white cell counts. In that way it prevents anemia.

Antibiotic action – The antibiotic action of root and leaf extracts have been known for a long time. The compound, Withanolide – A in the extract potently inhibits most gram-positive bacteria, aerobic bacilli and pathogenic fungi. It is also seen to be active against Micrococcus pyrogens and Bacillus subtilis. The extract or Withanolide-A is also effective against Vaccinia virus, Entamoeba histolytica, Aspergillus infection and Ranikhet / Newcastle disease.  The protective effect is due to the activation of macrophages while increasing the phagocytosis actions. The existence of unsaturated lactone ring in Withanolide – A is somewhat responsible for the act indicating its therapeutic effect which is seen often more powerful than the Penicillin.

Anti-oxidant effect – The herb is a potential source of antioxidants. The effective components are Sitoindosides (mostly VII – X) and Withanolide – A which act as powerful free radical scavengers. Simultaneously they enhance the enzyme actions of superoxide dismutase, catalase and glutathione peroxidase even in the brain. This event indicates its neuroprotective role against neurodegenerative diseases like migraine, epilepsy, schizophrenia, Parkinson’s and Alzheimer’s etc. The extract also inhibits stress induced lipid peroxidation and various, means of hepatotoxicity.

Effect on thyroid – The herb helps increase the secretion of thyroid hormones from thyroid gland. The exact reason is not so clear. It is very effective in treating hypothyroidism. Uniquely it stimulates the production of T4 and simultaneously stabilizes the level of TSH for patients suffering from hypothyroidism which often creates depression, sluggishness and nervousness. It is noteworthy that excess production of T4 produces oxidative stress. But the herb has the distinctive ability to control the T4 level also scavenge free radicals thereby lowering the oxidative stress preventing lipid peroxidation and its consequent damaging effects.

Important cautionary facts:

1. The herb or any of its extract should not be taken by pregnant women because of its abortifacient action.
2. It should not be consumed along with any sedatives since it has its potential sedative action which could be drastically enhanced especially in the case of using barbiturates.
3. It suddenly increases the thyroid hormone level for women taking it as a supplement for relieving fatigue syndrome.

 

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