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Abstract

Background: This study provides a path for many studies that may have been forgotten in the past to the use of modern-day knowledge supporting the use of traditional treatments, specifically Withania somnifera (ashwagandha). Primary study objective: The primary objective of this study was to bring back traditional therapy that could prove to be economically beneficial and possibly helpful to many clients with depression with few or no associated adverse events. Intervention: The key components of ashwagandha include 12 alkaloids and 35 withanolides, which have been proven in various studies to be beneficial in the treatment of anxiety and stress. While research supports that withanolides and alkaloides work as antidepressants and are the main reason ashwagandha is beneficial for depression, the mechanism of action in unknown. Studies also show that withanolides may bolster the immune system, increase stamina, fight inflammation and infection, combat tumors, reduce stress, revive the libido, protect the liver and soothe jangled nerves. Both of these molecules are steroidal and are similar in action and appearance. Ashwagandha stimulates the activation of immune system cells such as lymphocytes and has also been shown to inhibit inflammation and improve memory in animal experiments.
Introduction:
Several pharmaceutical industries have emerged in recent years to solve everyday
problems of the world which are usually hectic and fast-paced, so fast that everyone requires
solutions to their problems in seconds. So, what's a better solution than the use of drugs?
Especially in the field of mental illness, pharmaceutical industries have developed many
medicines like antipsychotics, antidepressants, anti-anxiety, mood-stabilizing, stimulant
medications1. These are the main types of drugs and if their subtypes are looked into, the
number of total drugs is tremendous. Research has shown multiple good things for people
around the globe. But to date, a large number of countries have difficulty buying these drugs
for economic reasons and more so for those who're using it. Over ⅓ of them would not
respond to these medications2. Researchers continue to look for a perfect cure to treat Major
Depressive Disorders (MDD) and this appears to be a mirage. Despite having so many options
of therapies and drugs that have been established by modern medicinal science, the generation
which has solutions on their fingertips has started looking for other options to treat MDD,
which has again opened up routes that point towards the path of alternative therapies.
Alternative therapy encompasses a variety of disciplines that includes everything from diet
and exercise to mental conditioning and lifestyle changes. Despite the presence of evidence for
traditional medicine, a lack of systematic research has made them much less likely to be used
by the patient with MDD. Maybe, this is the time to pause and review some of the alternative
medications that already exist for the treatment of depression. The findings of this literature
review will touch upon the antidepressant properties of ashwagandha, its side effects, and an
idea for future research.
Ashwagandha:
Ashwagandha (Withania somnifera
(L.) Dunal
) is a small shrub belonging to the Solanaceae
family. It is prolifically grown in dry regions of South Asia, Central Asia, and Africa, and is
regularly used in Ayurveda3. Withania Somnifera (WS) in today’s world is used for many
diseases which include, general debility and exhaustion, emaciation, memory loss, nerve
diseases, cough, anemia, and insomnia4, which are also a few of the symptoms of MDD. Modern
clinicians are most likely to employ it for chronic fatigue, anxiety, insomnia, and chronic heart
and vascular disorders. Study after study continues to confirm the stress tolerance, performance,
and endurance enhancing the benefits of this herb. The medicine was tested in rats against
chronic unpredictable stress behavior, depression, glucose metabolism, suppressed male sexual
behavior, suppressed immune function, and cognitive dysfunction. Stomach ulcer, adrenal gland
entropy, vitamin C level, and levels of stress hormones were also measured. Surprisingly, the
herb benefitted them all5.
It has antioxidant activity in the brain, which explains its effectiveness in problems including
the reported anti-stressor agent6. The constituents believed to be active in ashwagandha have
been extensively studied. Compounds known as withanolides are believed to account for the
multiple medicinal applications of ashwagandha. These molecules are steroidal and bear a
resemblance, both in their action and appearance. The main reason to consider ashwagandha
as an antidepressant is its phytochemicals and nutrients in the root of the herb, which includes
Alkaloids, Beta-sitosterol, Chlorogenic acid, Scopoletin, Withaferin, amino acids, and
choline7. Moreover, the major constituents of the root are steroidal alkaloids and steroidal
lactones: withanine, somniferine, somnine, somnifernine, withaninine, pseudo-withanine,
tropine, pseudo-tropine, ashwagandhanolide, cuscohygrine, anferine, anhydryine, sitoindoside
7 and 8, and a bunch of steroidal lactones in the leaves called withanolides8.
Potential mechanisms of ashwagandha's anxiolytic effects may be via its antioxidant and
anti-inflammatory effects. Inflammation and oxidative stress are increased, during times of
high stress and higher levels have been demonstrated in adults with depression and anxiety. In
preclinical studies, it was found that ashwagandha can also influence GABAergic and
serotonin activity, which has antidepressant and anxiolytic activity. Despite these
mechanisms discussed separately, their effects certainly do not occur in isolation and the
interaction of all these mechanisms may be responsible for the positive, mood-enhancing
effects of ashwagandha9. It has also been shown to influence neurological, endocrine, and
cardiovascular activity, which adds on to its anti-stressor activity. In animal stress models,
ashwagandha has been shown to possess anxiolytic, antidepressant, and neuroprotective
effects10. A study on anti-stressor properties of ashwagandha also claimed that it reduces
cortisol and DHEA-S, participants taking ashwagandha suggest it has a moderating effect on
hypothalamic-pituitary-adrenal (HPA) axis activity in stressed adults. This may be associated
with stress-lowering effects11. In the same study, it was also observed that anxiety levels
reduced by 41% in participants taking ashwagandha, which compared favorably to the 24%
reduction experienced in participants taking a placebo. Further confirmation of the
mood-enhancing effects of ashwagandha was provided by positive overall improvements in
the DASS-21, a measure of depressive, anxiety, and stress symptoms12.
In an animal study, laboratory animals were subjected to mild electrical shocks that produced
chronic stress, resulting in learning problems, immune suppression, high blood sugar levels,
increased level of stress hormones, stomach ulcers, and male sexual dysfunction13. But when
the animals were given ashwagandha before the shocks, their stress symptoms were
significantly reduced. Other studies agree and “support the use of ashwagandha as
anti-stress adaptogen"14. Also, animal studies show the herb's antioxidant action also helps
to protect the liver and kidneys.
In another animal study conducted by MK, Jayanti et. al, FST and TST models were used to
screen for depression. In FST, mice were forced to swim in a restricted area, which induced
a behaviour of immobility. In TST, mice were suspended by their tip of the tail from a metal
rod which also induced a state of immobility in animals like that in FST. This immobility
reflects a state of despair, similar to depression in humans15. Ashwagandha extract in the
dose of 20 and 40 mg/kg produced significant dose-dependent antidepressant-like effects in
behaviour despair tests (FST and TST), as they reduced the immobility time. This decrease
produced by the combination group (WS & imipramine 10mg/kg each) was comparable to
that produced by the standard imipramine (15 mg/kg). These results suggest that WS
enhances the effect of imipramine on stress induced immobility time.
In the same study, Reserpinised mice (2.5 mg/kg) were observed for ptosis, catatonia &
sedation at 1, 2, 3 & 4 hours & scored on a scale from 0-3. WS (40 mg/kg) and imipramine
(15mg/kg) significantly reduced reserpine induced ptosis, catatonia and sedation. Moreover,
combinations consisting of sub-therapeutic doses of WS and imipramine (10 mg/kg each)
also produced significant reserpine antagonism in mice16.
In another study, WS (20 and 50 mg/kg) was administered orally once daily for 5 days and
the results were compared by those elicited by the benzodiazepine lorazepam (0.5 mg/kg,
i.p.) for anxiolytic studies, and by the tricyclic antidepressant, imipramine (10 mg/kg, i.p.),
for the antidepressant investigations. Both these standard drugs were administered once, 30
min prior to the tests. WSG induced an anxiolytic effect, comparable to that produced by
lorazepam, in the elevated plus-maze, social interaction and feeding latency in an unfamiliar
environment, tests. Further, both WSG and lorazepam, reduced rat brain levels of tribulin,
an endocoid marker of clinical anxiety, when the levels were increased following
administration of the anxiogenic agent, pentylenetetrazole. WSG also exhibited an
antidepressant effect, comparable with that induced by imipramine17.
In another research, treatment with the single dose of WS root extract in various dose
ranges of 25, 37.5, 50, 100 and 200 mg/kg i.p and a combination of WS (37.5 mg/kg, i.p.)
with that of either imipramine (2.5 mg/kg, i.p.) or fluoxetine (2.5 mg/kg, i.p.) produced
significant decrease in the MIT in FST. Also, single dose of WS (100 mg/kg) and its
combination group significantly reduced MIT in reserpinised mice suggesting that
antidepressant effects of imipramine as well as fluoxetine were enhanced by concomitant
administration of WS18.
A number of studies on WS, or its major active principles, have shown its antioxidant,
adaptogen, anxiolytic, antidepressant, memory enhancing, anti-inflammatory,
anti-ulcerogenic, anti-parkinsonian and anti-carcinogenic properties. Still further human
studies are needed for the safety and efficacy of WS and its effects on humans, which serves
as a great idea for future research.
When looked at the negative sides of this herb, ashwagandha goes with almost no side effects
when taken for a short time (weeks to a few months), but in the long run (7-10 yrs) it has some
mild to moderate side effects such as headaches and upset stomach19. In extremely rare cases
where the patient has an allergic reaction to ashwagandha, it can also result in rapid heartbeat20,
which makes this herb as an allrounder with very limited side effects.
When the economic aspects for ashwagandha are compared with other medications, a researcher
said that about 1kg of ashwagandha costs about Rs. 56 which converts to USD 0.7921. According
to the study done by Kennedy, Hart, and Seely, medicinal herbs are more cost-effective than the
medicine we use in regular life22. Hence, more research should be done on treating illness or
disorders through natural medicines which will be cost-effective and at the same time has fewer
side effects or even no side effects that affect regular life.
Methodology:
1. Selection Criteria:
The literature included in this study were research papers and texts that addressed the effects of
MDD and different methods of treating it. This study aimed to include all types of study
participants including the general population, professionals, and patients. This broad category
was limited after eliminating therapies and alternative medicines that did not affect. Literature
and texts which were in any other language other than English were excluded.
2. Search Strategy:
We searched online journal databases, indexes, and reference lists using the search terms
“depression”, “ways to treat depression”, “current treatments for depression”, “ashwagandha”,
“history of ashwagandha”, “different uses of ashwagandha”, “active components of
ashwagandha”, “why ashwagandha is good for depression”, “studies on ashwagandha”. These
databases reflect the multidisciplinary nature of the research, which involves the medical,
psychological, and social fields.
The authors of this paper targeted both original research papers and review articles indexed by
PubMed, EMBASE, PsycINFO, MEDLINE, ScienceDirect, Research Gate.
The texts for this study were obtained from the York Library (UK), King's College London
Library (UK), Princeton University Library (USA), Manchester Central Library (UK), and
Passaic Public Library (USA). The reference list of all review articles that were identified, were
screened to cross-check any missing articles of interest.
Results:
We retrieved 259 citations from the papers and texts and excluded 239 of them, which left 20
papers and texts for further analysis. The authors of this paper did not identify any
international guidelines related to alternative medicine. The main reasons for exclusion were
as follows:
1. The subject of the article was not directly talking about Ashwagandha but rather
about other medicinal herbs that were not used for mental health.
2. There was no evidence to support the claims that were made by the author.
3. The article repeated the same information as the other articles
4. The articles included current treatments, including SSRIs, SNRIs, MAOIs.
Limitations:
A major limitation of this review is that the authors of this literature article are not able to
conduct any proper testing in a lab before writing this literature review. Another major
limitation of this article is that not all claims have been proven by other researchers, some
remain unclear due to a lack of evidence with regards to ashwagandha working for humans, as
only the claim of ashwagandha being an antidepressant has been experimented on lab mice
using mazes. There were no robust publications and there are limited randomized clinical trials
of alternative treatments especially ashwagandha. Furthermore, some functionalities and
properties of ashwagandha may be underreported due to the biased medicinal research in the
field. However, researchers will take interest in this drug for further studies.
Conclusion:
The area of traditional medicines has great potential to reach a wide and diverse population
who suffer from economic restraints, but its long term effects, including side effects, need to
be studied. Ashwagandha has a huge potential to revolutionize the field of mental health. The
findings of this literature review suggest some promising details about ashwagandha being an
extremely useful resource for depression, but this study has also found that there is still a lack of
evidence to support the use and effectiveness of ashwagandha, especially in Major Depressive
Disorders (MDD). The main reason to consider ashwagandha as an antidepressant are its
phytochemicals and nutrients in the root of the herb. Moreover, chemicals like alkaloids and
lactones, collectively known as withanolides, play a major role as antidepressants.
Pharmacological studies have confirmed that plant preparation of ashwagandha has
anti-inflammatory, antioxidant, anticancer, anxiolytic, and immunomodulatory effects23. It has
also been shown to influence neurological, endocrine, and cardiovascular activity. Research
also shows that withanolides may bolster the immune system, buck up stamina, fight
inflammation and infection, oppose tumors, reduce stress, revive libido, protect the liver, and
soothe savaged nerves24. This is a rapidly evolving field as increasing awareness of side effects
in this generation has led them to look for other alternatives but due to the lack of research, the
validity of ashwagandha is questioned. The findings of this literature review provide a plan for
some good research. The authors of this literature are willing to conduct a randomized control
trial of ashwagandha.
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Article
Full-text available
Background: Ashwagandha (Withania somnifera (L.) Dunal) is a herb traditionally used to reduce stress and enhance wellbeing. The aim of this study was to investigate its anxiolytic effects on adults with self-reported high stress and to examine potential mechanisms associated with its therapeutic effects. Methods: In this 60-day, randomized, double-blind, placebo-controlled study the stress-relieving and pharmacological activity of an ashwagandha extract was investigated in stressed, healthy adults. Sixty adults were randomly allocated to take either a placebo or 240 mg of a standardized ashwagandha extract (Shoden) once daily. Outcomes were measured using the Hamilton Anxiety Rating Scale (HAM-A), Depression, Anxiety, and Stress Scale -21 (DASS-21), and hormonal changes in cortisol, dehydroepiandrosterone-sulphate (DHEA-S), and testosterone. Results: All participants completed the trial with no adverse events reported. In comparison with the placebo, ashwagandha supplementation was associated with a statistically significant reduction in the HAM-A (P = .040) and a near-significant reduction in the DASS-21 (P = .096). Ashwagandha intake was also associated with greater reductions in morning cortisol (P < .001), and DHEA-S (P = .004) compared with the placebo. Testosterone levels increased in males (P = .038) but not females (P = .989) over time, although this change was not statistically significant compared with the placebo (P = .158). Conclusions: These findings suggest that ashwagandha's stress-relieving effects may occur via its moderating effect on the hypothalamus-pituitary-adrenal axis. However, further investigation utilizing larger sample sizes, diverse clinical and cultural populations, and varying treatment dosages are needed to substantiate these findings.
Article
Full-text available
Withania somnifera (L.) Dunal, shows several pharmacological properties which are attributed mainly to the withanolides present in the root. The efficacy of medicinally active withanolides constituents depends on the absorption and transportation through the intestinal epithelium. We examined these characteristics by employing the Sino-Veda Madin-Darby canine kidney cells culture system, which under in vitro condition shows the absorption characteristics similar to the human intestinal epithelium. Thus, the aim of the present investigation was to assess the bioavailability of individual withanolides. Withanolides were diluted in Hanks buffered saline at a concentration of 2 μg/ml were tested for permeability studies carried out for 1 h duration. Permeability was measured in terms of efflux pump (Peff ) in cm/s. Peff values of withanolide A (WN A), withanone (WNN), 1,2-deoxywithastramonolide (1,2 DWM), withanolide B (WN B), withanoside IV-V (WS IV-V), and withaferin A were 4.05 × 10-5 , 2.06 × 10-5 , 1.97 × 10-5 , 1.80 × 10-5 , 3.19 × 10-6 , 3.03 × 10-6 and 3.30 × 10-7 respectively. In conclusion, the nonpolar and low molecular weight compounds (WN A, WNN, 1,2 DWM, and WN B) were highly permeable. As against this, the glycosylated and polar WS IV and WS V showed low permeability. Surprisingly and paradoxically, the highly biologically active withaferin A was completely impermeable, suggesting that further studies possibly using human epithelial colorectal adenocarcinoma (Caco-2) cells may be needed to delineate the absorption characteristics of withanolides, especially withaferin A. © 2015 Journal of Advanced Pharmaceutical Technology and Research.
Article
Full-text available
Health care spending in North America is consuming an ever-increasing share of Gross Domestic Product (GDP). A large proportion of alternative health care is consumed in the form of natural health products (NHPs). The question of whether or not NHPs may provide a cost-effective choice in the treatment of disease is important for patients, physicians and policy makers. The objective of this study was to conduct a systematic review of the literature in order to find, appraise and summarize high-quality studies that explore the cost effectiveness of NHPs as compared to conventional medicine. The following databases were searched independently in duplicate from inception to January 1, 2006: EMBASE, MEDLINE, CINAHL, BioethicsLine, Wilson General Science abstracts, EconLit, Cochrane Library, ABI/Inform and SciSearch. To be included in the review, trials had to be randomized, assessed for some measure of cost effectiveness and include the use of NHPs as defined by the Natural Health Products Directorate. Studies dealing with diseases due to malnutrition were excluded from appraisal. The pooled searches unveiled nine articles that fit the inclusion/exclusion criteria. The conditions assessed by the studies included three on postoperative complications, two on cardiovascular disease, two on gastrointestinal disorders, one on critically ill patients and one on urinary tract infections. Heterogeneity between the studies was too great to allow for meta-analysis of the results. The use of NHPs shows evidence of cost effectiveness in relation to postoperative surgery but not with respect to the other conditions assessed. In conclusion, NHPs may be of use in preventing complications associated with surgery. The cost effectiveness of some NHPs is encouraging in certain areas but needs confirmation from further research.
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The roots of Withania somnifera (WS) are used extensively in Ayurveda, the classical Indian system of medicine, and WS is categorized as a rasayana, which are used to promote physical and mental health, to provide defence against disease and adverse environmental factors and to arrest the aging process. WS has been used to stabilize mood in patients with behavioural disturbances. The present study investigated the anxiolytic and antidepressant actions of the bioactive glycowithanolides (WSG), isolated from WS roots, in rats. WSG (20 and 50 mg/kg) was administered orally once daily for 5 days and the results were compared by those elicited by the benzodiazepine lorazepam (0.5 mg/kg, i.p.) for anxiolytic studies, and by the tricyclic anti-depressant, imipramine (10 mg/kg, i.p.), for the antidepressant investigations. Both these standard drugs were administered once, 30 min prior to the tests. WSG induced an anxiolytic effect, comparable to that produced by lorazepam, in the elevated plus-maze, social interaction and feeding latency in an unfamiliar environment, tests. Further, both WSG and lorazepam, reduced rat brain levels of tribulin, an endocoid marker of clinical anxiety, when the levels were increased following administration of the anxiogenic agent, pentylenetetrazole. WSG also exhibited an antidepressant effect, comparable with that induced by imipramine, in the forced swim-induced 'behavioural despair' and 'learned helplessness' tests. The investigations support the use of WS as a mood stabilizer in clinical conditions of anxiety and depression in Ayurveda.
Article
The antidepressant-like effect of the hydroalcoholic extract obtained from aerial parts of Siphocampylus verticillatus, a Brazilian medicinal plant, was investigated in two models of depression in mice and against synaptosomal uptake of serotonin, noradrenaline and dopamine. The immobility times in the forced swimming test (FST) and in the tail suspension test (TST) were significantly reduced by the extract (dose range 100-1000 mg/kg, i.p.), without accompanying changes in ambulation when assessed in an open-field. In addition when given orally the extract was also effective in reducing the immobility time in the TST. The efficacy of extract in the TST was comparable to that of the tricyclic antidepressant imipramine (15 mg/kg, i.p.) and with fluoxetine (32 mg/kg, i.p.). The anti-immobility effect of the extract (600 mg/kg, i.p.) assessed in the TST was not affected by pre-treatment with naloxone (1 mg/kg, i.p., a non-selective opioid receptor antagonist) or L-arginine (750 mg/kg, i.p., a nitric oxide precursor). In contrast, the extract (600 mg/kg, i.p.) antidepressant-like effect was significantly reduced by pre-treatment of animals with p-chlorophenylalanine (PCPA, 100 mg/kg, i.p., an inhibitor of serotonin synthesis), sulpiride (50 mg/kg, i.p., a selective D2 receptor antagonist), prazosin (62.5 microg/kg, i.p., an alpha1 adrenoreceptor antagonist) or by guanosine 5'-monophosphate (GMP, 250 mg/kg, i.p., a nucleotide known to block some actions elicited by NMDA). The biochemical data show that the extract of S. verticillatus inhibited in a graded manner the uptake of monoamines. However, at the IC50 level, the extract was approximately 3.2 to 3.4-fold more potent and also more efficacious in inhibiting the synaptosomal uptake of noradrenaline and serotonin than dopamine. Taken together these data demonstrate that the extract of S. verticillatus elicited a significant antidepressant-like effect, when assessed in the TST and FST in mice. Its action seems to involve an interaction with adrenergic, dopaminergic, glutamatergic and serotonergic systems.
Introduction to Depression. Psych Central
  • J M Grohol
Grohol JM. Introduction to Depression. Psych Central. https://psychcentral.com/depression/introduction-to-depression/. Published January 9, 2017.
Depression Definition and DSM-5 Diagnostic Criteria. Psycom.net -Mental Health Treatment Resource Since
  • J Truschel
Truschel J. Depression Definition and DSM-5 Diagnostic Criteria. Psycom.net -Mental Health Treatment Resource Since 1986. https://www.psycom.net/depression-definition-dsm-5-diagnostic-criteria/.
The Way of Ayurvedic Herbs: The Most Complete Guide to Natural Healing and Health with Traditional Ayurvedic Herbalism
  • Kps Khalsa
  • M Tierra
Khalsa KPS, Tierra M. The Way of Ayurvedic Herbs: The Most Complete Guide to Natural Healing and Health with Traditional Ayurvedic Herbalism. Twin Lakes, WI: Lotus; 2008.
The Essential Herbs Handbook: More than 100 Herbs for Well-Being, Healing, and Happiness
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Bremness L. The Essential Herbs Handbook: More than 100 Herbs for Well-Being, Healing, and Happiness. London: Duncan Baird Publishers; 2009.
The New Healing Herbs: The Essential Guide to More than 130 of Natures Most Potent Herbal Remedies
  • M Castleman
Castleman M. The New Healing Herbs: The Essential Guide to More than 130 of Natures Most Potent Herbal Remedies. New York: Rodale; 2017.