Ashwagandha (Withania somnifera) in Medicine, Mood and Neuropsychiatry

The botanical Withania somnifera is widely known as “Ashwagandha,” a Sanskrit name deriving from its use in traditional medicine in India. Withania somnifera (WS) enjoys a formidable reputation in Ayurvedic medicine as a Rasayana herb, i.e., one that can rejuvenate the body and promote the health of all tissues. Since ancient times, it has traditionally been used to strengthen the nervous system. [1] It is classified as a tonic-adaptogen and is often called the “Indian Ginseng,” although not botanically related. The paradoxical meaning of the names of ashwagandha gives away its’ adaptogenic qualities. The common name, “ashwagandha,” means “strong as a horse,” while the botanical name, “somnifera,” means restful sleep.[2]

WS has been used for over 2500 years as a valuable medicinal plant to improve disease defense, prevent aging, rejuvenate the body in a vulnerable situation, and generate a feeling of mental well-being. A recent extensive literature review found that WS mitigates various neurological disorders, including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, tardive dyskinesia, stroke, and anxiety. [3]

WS is classified as an adaptogen: an agent that promotes homeostasis of the whole body not only by one specific pharmacological mechanism but by eliciting complex responses as well. This popularity has elicited increased scientific study of its biological effects, including a potential application for neuropsychiatric and neurodegenerative disorders. The reputed properties of WS include improving concentration, memory, and mood and providing resilience against pathogens and disease.[4] WA mitigates age-related decline and has demonstrated gero-protective properties in vivo using the Drosophila model.[5]

WSE contains therapeutic molecules with a “disease-modifying” effect and can simultaneously modulate multiple synergistic targets.[6]

The Pleotropic Benefits of Ashwagandha

[7]

Depression is associated with the dysfunction of different neurotransmitters, such as serotonin, noradrenaline, and dopamine. At the tissue level, alterations in brain regions such as frontal lobes and the hypothalamus have been evidenced.[8], [9],[10] It is now believed by many leading researchers that the core of depression is a disorder of metabolism and energy regulation (i.e., allostasis overload) with sensory consequences of that regulation (i.e., altered interoception), which results in a relatively ‘locked-in’ depressed brain. This seems to be a valid integration under the paradigm of interoception as modeling and allostasis as control.[11],[12] In fact, previous studies have shown that the greater the allostatic load, the more severe the depressive symptoms in older adults.[13]

Considering these neurophysiological changes during the development of depression, it is essential to evaluate the biological mechanisms of adaptation to stressors. The most adequate model for this is allostasis, a predictive regulation model.[14]

It is important to emphasize that repeated exposure to a stressor leads to the so-called allostatic load, which must be necessary to facilitate adaptation and prevent the disruption of systemic regulators (thresholds depend on each biological system).[15],[16] The allostatic load is defined as the additional energetic burden the organism must bear to adapt and survive.[17]

Clinical improvements of adaptogens on depressive symptoms are probably due to the positive impact of secondary metabolites (e.g., terpenoids, alkaloids, glycosinolates, and phenols) on cellular allostasis.[18]

Overall, adaptogens trigger pleiotropic genes, molecular mechanisms, and cellular signaling pathways that mediate adaptive and defense responses, resulting in multitarget modes of action simultaneously and, therefore, in nonspecific pleiotropic pharmacological activity.

Pleiotropy results from the effect of adaptogen on a single gene that impacts multiple signaling pathways, biological processes, physiological functions, and phenotype characteristics. Various cells use the gene transcription mechanism to trigger numerous downstream signaling pathways and molecular networks that collectively affect multiple molecular targets, resulting in many pharmacological activities (nonspecific effect).

The rationale of specific and nonspecific pleiotropic actions of adaptogens.

The specific molecular targets and adaptive stress response signaling mechanisms involved in adaptogens’ nonspecific modes of action are identified.[19]

A recent paper highlighted the beneficial effects that adaptogens have on stress and depression. According to this meta-analysis review paper,[20] there was significantly better performance of adaptogens over placebo, and this may be due to the reduction of allostatic load via the action of secondary metabolites on brain-derived neurotrophic factor (BDNF) regulation.

BDNF is an essential protein influencing brain response and the peripheral nervous system. BDNF influences various functions, including preventing the death of existing brain cells, inducing the growth of new neurons (neurogenesis) and synapses, and supporting cognitive function.[21]

Adaptogens as an antidepressant non-pharmacological strategy. The core of depression is a disorder of metabolism and energy regulation (i.e., allostasis overload) with sensory consequences of that regulation (i.e., altered interoception), which results in a relatively ‘locked-in’ depressed brain.

Stress and Stress-Related Neuropsychiatric Disorders, Anxiety, Depression, and Insomnia

The adaptogenic activity of a WSE was investigated against a rat model of chronic stress (CS). The stress procedure was mild, unpredictable foot-shock, administered once daily for 21 days to adult male Wistar rats. CS-induced significant hyperglycemia, glucose intolerance, increase in plasma corticosterone levels, gastric ulcerations, male sexual dysfunction, cognitive deficits, immunosuppression, and mental depression. These CS-induced perturbations were attenuated by WS (25 and 50 mg/kg po) and by PG (100 mg/kg po), administered one hour before foot shock for 21 days. The results indicate that WS, like PG, has significant antistress adaptogenic activity.[22]

A 2014 systematic review of five human trials involving the anti-anxiety effects of WS extract (E) concluded that WSE intervention resulted in more significant score improvements (in most cases) than placebo in anxiety or stress scales outcomes.[23]

A recent review aims to provide a comprehensive summary of preclinical and clinical studies examining the neuropsychiatric effects of WS, specifically its application in stress, anxiety, depression, and insomnia.

Reports of human trials and animal studies of WS were collected primarily from the PubMed, Scopus, and Google Scholar databases.

• WS root and leaf extracts exhibited noteworthy anti-stress and anti-anxiety activity in animal and human studies.
• WS also improved symptoms of depression and insomnia, though fewer studies investigated these applications.
• WS may alleviate these conditions predominantly through modulation of the hypothalamic-pituitary-adrenal and sympathetic-adrenal-medullary axes and through GABAergic and serotonergic pathways.
• While some studies link specific withanolide components to its neuropsychiatric benefits, there is evidence of additional, unidentified, active compounds in WS.

[24]

Ashwagandha extract cuts the amount of non-restorative sleep

Five human studies have investigated WS’s effects on insomnia in adults aged 18-85. Overall, supplementation with WS improved various measures of insomnia across multiple study populations and age groups.

One possible mechanism by which WS may positively affect sleep is activating GABAergic neurotransmission. In old-aged rats, a hydroalcoholic leaf extract of WS restored the daily rhythms and phases of SIRT1 (a clock modulator) and NRF2, a transcription factor controlled by a clock regulating several endogenous antioxidant enzymes. It is likely that other mechanisms also contribute to the sleep-promoting effects of WS.[25]

According to these reviewed studies, WS clearly showed benefits for treating neuropsychiatric conditions.[26]

Data from a gold-standard randomized, double-blind, placebo-controlled trial show that daily supplementation with a standardized ashwagandha extract reduced the amount of nonrestorative sleep experienced by healthy adults.

In this study, 150 healthy subjects scoring high on non-restorative sleep measures were given 120 mg of the standardized ashwagandha extract (providing 42 mg per day of withanolide glycosides) or a placebo for six weeks.

Results showed that, for the 144 subjects who completed the study, participants in the Shoden group self-reported a 72% improvement in sleep quality, compared to 29% in the placebo group.

In addition, activity monitoring data revealed that the ashwagandha group showed statistically significant improvement in sleep efficiency, total sleep time, sleep latency, and wake after sleep onset, compared to placebo.

Improvements in scores for quality of life (QOL) relating to physical, psychological, and environmental domains were also observed for the ashwagandha. “Improving sleep may be related to a reduction in stress and especially a reduction in the stress hormone cortisol, which can disrupt the natural balance of the body,” wrote the researchers. “Previous studies have found that ashwagandha can reduce cortisol levels. In this study, the treatment could have improved sleep quality by decreasing cortisol and stress levels, although these measures were not included.”

In an earlier trial, reduced cortisol levels were reported using the same ingredient (but at a daily dose of 240 mg).[27]

WS extract (E) possesses GABAergic and other neurotransmitter modulatory effects. It reduces apoptosis and promotes synaptic plasticity. It improves cognition and reverses induced cognitive deficits. It attenuates stress indices. In human subjects, WSE enhances adaptogenesis in healthy adults. It modestly benefits generalized anxiety disorder and obsessive-compulsive disorder and symptom severity in schizophrenia, substance use disorders, and attention deficit hyperactivity disorder. It improves sleep quality.

WSE may confer modest benefits in certain neuropsychiatric conditions. Its benefits may arise from the induction of neuroplasticity, antioxidant and anti-inflammatory effects, and modulation of GABA, glutamate, and other neurotransmitters. The antioxidant and anti-inflammatory actions may also benefit neurodegenerative states.[28]

WSE efficacy in patients with generalized anxiety disorder: A randomized, double-blind placebo-controlled trial

This study aimed to investigate the effect of WSE as an alternative therapy to reduce standard generalized anxiety disorder (GAD) symptoms.

Forty patients who met the inclusion criteria (with a confirmed diagnosis of GAD as stated in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) took part in this randomized, double-masked placebo-controlled trial and were randomly selected for participation in the treatment group (WSE, 1g/day; n = 22) or the placebo group (n = 18). All patients were under treatment with Selective Serotonin Reuptake Inhibitors (SSRIs) and were prescribed one capsule of the extract or placebo per day for six weeks. The Hamilton Anxiety Rating scale (HAM-A) was used to assess the severity of GAD symptoms at baseline and the second and sixth weeks of the trial.

Comparison of the HAM-A scores during the trial revealed a significant amelioration of HAM-A scores in the treatment group versus placebo (14 and 8 units reduction, respectively (P < 0.05)). Moreover, there was a significant difference in the reduction of GAD score between the second (P =0.04) and sixth week (P =0.02) in the treatment group. The extract was safe, and no adverse effect was observed during the trial.[29]

An alternative treatment for anxiety: a systematic review of human trial results

A systematic review of the literature, with searches conducted in PubMed, SCOPUS, CINAHL, and Google Scholar by a medical librarian. Additionally, the reference lists of studies identified in these databases were searched by a research assistant, and queries were conducted in the AYUSH Research Portal. Search terms included “ashwagandha,” “Withania somnifera,” and terms related to anxiety and stress. Inclusion criteria were human randomized controlled trials with a treatment arm that included WSE as a remedy for anxiety or stress. The study team members applied inclusion criteria while screening the records by abstract review.

Sixty-two abstracts were screened; five human trials met inclusion criteria. Three studies compared several dosage levels of WSE with placebos using versions of the Hamilton Anxiety Scale. Two demonstrated a significant benefit of WSE versus placebo, and the third demonstrated beneficial effects that approached but did not achieve significance (p=0.05).

A fourth study compared naturopathic care with WS versus psychotherapy by using Beck Anxiety Inventory (BAI) scores as an outcome; BAI scores decreased by 56.5% in the WSE group and decreased by 30.5% for psychotherapy (p<0.0001).

A fifth study measured changes in Perceived Stress Scale (PSS) scores in the WS group versus placebo; there was a 44.0% reduction in PSS scores in the WSE group and a 5.5% reduction in the placebo group (p<0.0001).

All studies exhibited unclear or high risk of bias, and heterogenous design and reporting prevented the possibility of meta-analysis.

All five studies concluded that WS intervention resulted in more significant score improvements (significantly in most cases) than placebo in anxiety or stress scale outcomes. Current evidence should be received with caution because of various study methods and cases of potential bias.[30]

A study used a sustained-release capsule containing WA extract (300 mg). Participants took one WSE capsule daily for 90 consecutive days. It was noted that treatment with WSE once daily with one capsule significantly improved memory and attention, sleep quality, and overall psychological well-being. A reduction in stress levels was also noted. The treatment appeared to be safe and well tolerated.[31]

Low thyroid, depression, and WSE

There is a link between hypothyroidism and depression, and recent research also demonstrates that improving the underlying hypothyroidism in people who have been diagnosed with depression is very beneficial.[32],[33] WSE Improves thyroid function in subclinical hypothyroid patients.[34]

WSE has been shown in a clinical study to improve sexual function in women.[35]

Neuroprotective – enhances memory and learning.

WSE confers modest benefits in certain neuropsychiatric conditions. Its benefits may arise from the induction of neuroplasticity, antioxidant and anti-inflammatory effects, and modulation of GABA and, glutamate, and other neurotransmitters. The antioxidant and anti-inflammatory actions may also benefit neurodegenerative states.[36] WS supplementation ameliorates middle cerebral artery occlusion-induced oxidative stress, mitochondrial dysfunctions, apoptosis, and cognitive impairments.[37]

A study was conducted on rats orally administered vitanon—an ingredient isolated from the root of WA. Significant improvements in cognitive function were observed as a result of the inhibition of amyloid β-42, and a reduction in pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and MCP-1, nitric oxide, and lipid peroxidation was also observed. There was also a decrease in the activity of β and γ-secretase, enzymes responsible for forming insoluble neurotoxic aggregates of β-amyloid.[38]

The effects of WSE on copper-induced lipid peroxidation and antioxidant enzymes in the aging spinal cord of Wistar rats were studied. The glutathione peroxidase (GPx) activity decreased significantly in the spinal cord from adult to aged mice. Treatment with WSE successfully attenuated GPx activity and inhibited lipid peroxidation in a dose-dependent manner. WSE inhibited both the lipid peroxidation and protein oxidative modification induced by copper. These effects were similar to those of superoxide dismutase and mannitol. The results indicate the therapeutic potential of WSE in aging and copper-induced neuro-pathophysiological conditions.[39]

In addition, withaferin A extracted from Ashwagandha appears to be a promising ingredient in terms of Alzheimer’s disease treatment. It works by reducing β-amyloid aggregation and inhibiting τ protein accumulation. In addition, withaferin A is responsible for inhibiting oxidative and pro-inflammatory chemicals and regulating heat shock proteins (HSPs), the expression of which increases when cells are exposed to stressors. However, more medical studies are needed to assess the safety of withaferin A and to confirm its neuroprotective effects in the treatment of Alzheimer’s disease.[40]

Withaferin A from Ashwagandha extract significantly inhibits the production of amyloid β and the gene expression of neuroinflammatory molecules related to NF-κB.[41]

A study was also conducted in transgenic mice with a half-purified WAE containing mainly withanolides for 30 days. After this time, it was noted that Ashwagandha offset the negative effects of Alzheimer’s disease by increasing the number of the LDL receptor-related protein LRP1 (low-density lipoprotein-related protein 1) in the liver.[42]

Synergy of plants and nutritional compounds

WSE, like most plant extracts, is best suited for combination formulations. I use WSE in several compounded formulas, including a blended formula to support mood, combat stress, and enhance cognitive function. The herbal extracts combined in this formula include St. John’s Wort (Hypericum perforatum), Magnolia (Magnolia officinalis), and Bark Ext, together with the amino acids N-Acetyl-L-Tyrosine and L-Tryptophan.

L-tyrosine can help improve mood and mental performance when in stressful situations.[43] In one study, participants who performed a test that measured their cognitive flexibility did better when taking an L-tyrosine supplement versus a placebo. Another study involving people who worked on a mentally demanding task saw their working memory improve while taking L-tyrosine.[44]Relieves stress and improves cognition while significantly under environmental stress. One study demonstrates cold exposure degrades cognitive performance, and supplementation was alleviated by taking L-tyrosine.[45]

Tyrosine helps the body produce the mood-influencing chemical dopamine. Because people who are depressed often have low levels of tyrosine, tyrosine supplementation can help to improve mood, memory, and performance under psychological stress.[46],[47]

Tyrosine is also a part of the molecular structure of the thyroid hormones. Because the thyroid gland is directly involved in establishing the body’s metabolic rate by directing mitochondrial energy production, tyrosine is essential to energy production. The thyroid participates in improving mood health as well.[48]

N-Acetyl-L-tyrosine, converted in the body to L-tyrosine, is 20 times as soluble in water as tyrosine. For this reason, it serves as an efficient supplement for raising tyrosine levels in the body. Un-dissolved substances are not absorbed from the digestive tract.[49]

I find this combination very effective, and these particular plant compounds have a long traditional usage, backed by immense scientific research for their ability to optimize health, supporting mood, cognition, and adaptation. WSE and N-Acetyl-L-tyrosine improve energy, stress, response, and mental capacity.[50],[51],[52]

A recent experiment found that a combination of herbal extracts, including Hypericum perforatum (Serratula coronata and Valeriana officinalis), exhibited a more pronounced effect in reducing cytokine (TNF-α, IL-6, and IL-10) levels in stressed animals compared to the individual plant extracts.[53]

I have written several blogs on St. John’s wort, my favorite plant for mood support and general wellness. Here is a nice one to review – “Antidepressants May Be No More Effective Than Placebo: But What About St. John’s Wort and Other Herbal Medicines?” athttps://www.donnieyance.com/antidepressants-may-be-no-more-effective-than-placebo-but-what-about-st-johns-wort-and-other-herbal-medicines/. I also did a blog entitled “Botanical Support for Anxiety” https://www.donnieyance.com/botanical-support-anxiety/.

According to a recent meta-analysis of randomized clinical trials that assessed the efficacy and safety of St. John’s wort extract in depression compared to Selective serotonin reuptake inhibitors (SSRIs) in adults found that St. John’s wort extract was highly effective at reducing the number of depressive patients according to the Hamilton Depression Rating Scale score rating system, while having fewer risks and side effects than conventional medications.

Fourteen clinical trials with a total of 2270 depression patients were included in accordance with the inclusion criteria. All analyzed papers were published between 2000 and 2022.

.[54]

St. John’s wort extract contains many biological compounds, such as flavonoids, hyperforin, and hypericin, and no one compound is superior to the whole plant extract.[55]

Closing Thoughts

No amount of technological progress can cure the deep ailments that now face humankind, but we can. We cannot allow ourselves to make the mistake of viewing the world as some gloomy, hopeless place even though if all you do is listen to the media, it will depress you and draw you away from the silence and solitude we must seek. The more we remove ourselves from “information overload” the more we are able to full fill our spiritual path leading us to live in harmony with each other, loving in a way that truly reflects a response of the “will of God.”

“May the Lord bless you

and keep you;

May the Lord make

His face shine upon you,

and be gracious to you.”

Numbers 6:24-25

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