Can traditional paths such as ashwagandha be beneficial for treating Depression?

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.

Full text

❖ 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
medications1. 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 medications2. 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 Ayurveda3. 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 insomnia4, 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 all5.
It has antioxidant activity in the brain, which explains its effectiveness in problems including
the reported anti-stressor agent6. 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
choline7. 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 withanolides8.
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 ashwagandha9. 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
effects10. 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 effects11. 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 symptoms12.
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 dysfunction13. 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 humans15. 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 mice16.
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 imipramine17.
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 WS18.
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 stomach19. In extremely rare cases
where the patient has an allergic reaction to ashwagandha, it can also result in rapid heartbeat20,
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 0.7921. According
to the study done by Kennedy, Hart, and Seely, medicinal herbs are more cost-effective than the
medicine we use in regular life22. 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 effects23. 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 nerves24. 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.

Bibliography
1. Grohol JM. Introduction to Depression. Psych Central.
https://psychcentral.com/depression/introduction-to-depression/. Published January 9,
2017.
2. 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/.
3. 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.
4. Bremness L. The Essential Herbs Handbook: More than 100 Herbs for Well-Being,
Healing, and Happiness

. London: Duncan Baird Publishers; 2009.
5. Castleman M. The New Healing Herbs: The Essential Guide to More than 130 of Natures
Most Potent Herbal Remedies

. New York: Rodale; 2017.
6. Gaby A, Ackerson A. The Natural Pharmacy Complete A-Z Reference to Alternative
Treatments for Common Health Conditions

. New York: Three Rivers Press; 2006.

7. Balch PA. Prescription for Nutritional Healing: The A-to-Z Guide to Supplements

. New
York: Penguin Group; 2010.
8. Buhner SH. Herbal Antibiotics Natural Alternatives for Treating Drug-Resistant
Bacteria

. North Adams, MA: Storey Pub.; 2012.
9. Duke JA. The Green Pharmacy Herbal Handbook: Your Comprehensive Reference to the
Best Herbs for Healing

. New York: St. Martins Paperbacks; 2002.
10. Devkar ST, Kandhare AD, Sloley BD, et al. Evaluation of the bioavailability of major
withanolides of Withania somnifera using an in vitro absorption model system. Journal of
advanced pharmaceutical technology & research.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630722/0. Published 2015.
11. Lopresti AL, Smith SJ, Malvi H, Kodgule R. An investigation into the stress-relieving
and pharmacological actions of an ashwagandha (Withania somnifera) extract: A
randomized, double-blind, placebo-controlled study.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750292/. Published September 2019.
12. Bhattacharya SK, Bhattacharya A, Sairam K, et al. Anxiolytic-antidepressant activity of
Withania somnifera glycowithanolides: an experimental study. Phytomedicine
2000;7:463–9
13. Faravelli C;Lo Sauro C;Lelli L;Pietrini F;Lazzeretti L;Godini L;Benni L;Fioravanti
G;Talamba GA;Castellini G;Ricca V; The role of life events and HPA axis in anxiety
disorders: a review. Current pharmaceutical design.
https://pubmed.ncbi.nlm.nih.gov/22632471/.

14. Watt GVD, Laugharne J, Janca A. Complementary and alternative medicine in the
treatment of anxiety and depression. Current Opinion in Psychiatry

. 2008;21(1):37-42.
DOI:10.1097/yco.0b013e3282f2d814.
15. Rodrigues AL;da Silva GL;Mateussi AS;Fernandes ES;Miguel OG;Yunes RA;Calixto
JB;Santos AR; Involvement of monoaminergic system in the antidepressant-like effect of
the hydroalcoholic extract of Siphocampylus verticillatus.
https://pubmed.ncbi.nlm.nih.gov/11885577/.
16. (PDF) Anti-depressant effects of Withania somnifera fat (Ashwagandha Ghrutha) extract
in experimental mice. ResearchGate.
https://www.researchgate.net/publication/249656563_Anti-depressant_effects_of_Withan
ia_somnifera_fat_Ashwagandha_Ghrutha_extract_in_experimental_mice.
17. S; BSKBASKG. Anxiolytic-antidepressant activity of Withania somnifera
glycowithanolides: an experimental study. Phytomedicine : international journal of
phytotherapy and phytopharmacology. https://pubmed.ncbi.nlm.nih.gov/11194174/.
18. SHAH PC. EFFECT OF WITHANIA SOMNIFERA ON FORCED SWIMMING TEST
INDUCED IMMOBILITY IN MICE AND ITS INTERACTION WITH VARIOUS
DRUGS. semantic scholar.
https://pdfs.semanticscholar.org/039a/885f9ab5afc9b3713510dc2aae1df9ad762a.pdf.
Published 2006.

19. What are the side effects of ashwagandha supplements? ConsumerLab.com.
https://www.consumerlab.com/answers/side-effects-of-ashwagandha-supplements/ashwa
gandha-side-effects/.
20. Verma, Kartar & Thakur, N S. (2010). Economic analysis of ashwagandha (Withania
somnifera L.) based agroforestry land use systems in mid hills Western Himalayas.. Indian
Journal of Agroforestry. 12. 62-70.
21. A; KSKD. Withania somnifera: an Indian ginseng. Progress in
neuro-psychopharmacology & biological psychiatry.
https://pubmed.ncbi.nlm.nih.gov/17959291/.
22. Kennedy DA, Hart J, Seely D. Cost effectiveness of natural health products: a
systematic review of randomized clinical trials. Evidence-based complementary and
alternative medicine : eCAM. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2722206/.
Published September 2009.
23. Ashwagandha. LiverTox: Clinical and Research Information on Drug-Induced Liver
Injury [Internet].
https://www.ncbi.nlm.nih.gov/books/NBK548536/#Ashwagandha.PRODUCT_INFORM
ATION. Published May 2, 2019.
24. Delgado JL. The Buena Salud Guide to Overcoming Depression and Enjoying Life

.
New York: Newmarket Press; 2011.