Withanolides are thought to be the primary bioactive compounds in ashwagandha. As a result, many ashwagandha supplements are standardized to contain a certain withanolide concentration in order to increase the degree of effects.
In this article, we’ll go over the benefits of withanolides, their mechanism of action, dosing guidelines, and other considerations.
Table of Contents
Withanolides Overview:
Withanolides are a group of naturally occurring steroidal lactones found in a number of species in the Solanaceae genera, most notably ashwagandha (Withania somnifera). For the purpose of this article, we will be looking mainly at the withanolides in ashwagandha.
Among the withanolides, withaferin A is the most well-studied, although there are several others with potential health effects, including:
- Withanolide D
- Withanolide A
- Withanolide sulfoxide
- Vicosalactone B
- Sominone
- And more
The withanolides act on various systems in the body and seem to exert a variety of anti-inflammatory, antioxidant, immunomodulatory, and adaptogenic effects.
Withanolides Benefits:
Research has discovered many potential health benefits of withanolides when studied in isolation and when standardized within ashwagandha extracts.
The main benefits of withanolides are:
- Stress & Anxiety Management
- Anti-Inflammatory Effects
- Immune Support
- Neuroprotection
- Anti-Carcinogenic Activity
- Muscle & Exercise Support
Note: Most of the studies listed below are not clinical trials. This is because isolated withanolides are typically studied using in vitro or in vivo methods, whereas clinical trials use the herb itself, standardized for withanolides. So, while the clinical trials are of course the most important overall, the pre-clinical trials give a better view into the isolated actions of withanolides themselves.
1. Stress & Anxiety Management
Research shows that withanolides seem to modulate the hypothalamic-pituitary-adrenal (HPA) axis, which helps the body return to balance when dealing with stressors.
In a study done on rats exposed to stress, withanolide isolated from ashwagandha decreased corticosterone levels, and also reduced various enzymes that are markers of stress in the body.
In another study done on rats, withaferin A showed anti-anxiety properties similar to diazepam (an anti-anxiety drug). Withaferin A also appeared to increase nitric oxide levels in the brain, which researchers believe may also promote anti-anxiety effects.
Another animal study found that isolated glycowithanolides led to similar anti-anxiety effects as lorazepam and comparable anti-depressive effects as imipramine (an antidepressant drug).
There are numerous clinical trials showing the benefits too, although these are used with ashwagandha extracts and not withanolide isolation. For example, one clinical trial on stressed individuals showed that 500mg of ashwagandha standardized to 2.5% withanolides led to significant reductions in stress, anxiety, and cortisol compared to the placebo.
Given the benefits seen from withanolides, it is likely that they play a key role in reducing cortisol and other stress hormones, while providing support for general stress and anxiety management.
Summary:
Lab studies have shown that withanolides may possess anti-anxiety properties and reduce stress markers in the body.
2. Anti-Inflammatory Effects
Numerous studies also highlight the potential anti-inflammatory and antioxidant effects of withanolides.
Research shows that withaferin A and other withanolides may decrease the development of various inflammatory-related diseases.
One study showed that withaferin A exhibited potent inhibitory effects on enzymes involved in inflammatory pathways, suggesting strong anti-inflammatory effects. The researchers noted this also has potential for reducing inflammatory-related issues, such as poor immune function.
In an in vitro study, withanolide extracts exhibited anti-inflammatory and protective effects on osteoarthritic cartilage cells, suggesting potential utility in arthritis and pain management.
Another in vitro study showed that various withanolides inhibited cyclooxygenase (COX)-1 and COX-2, which are enzymatic markers of inflammation. Additionally, several of these withanolides inhibit lipid peroxidation, suggesting further anti-inflammatory effects.
Summary:
In vitro studies show that withanolides may work to promote anti-inflammatory and antioxidant effects.
3. Immune Support
Withanolides also seem to support immunity. This is in part related to anti-inflammatory effects, although there may be other immunomodulatory mechanisms at play.
In one study, withanolides showed antiviral effects against Covid-19. They influenced several immune-related processes, including the control of certain proteins involved in viral severity.
A study done on mice showed that withanolide A was the most effective constituent in ashwagandha for activating T-helper cells, increasing cytokine production, and activating other important immune responses.
Another study looked into the effects of withanolide A on stress-induced immunity reductions in mice. The researchers found that withanolide A provided significant immune recovery effects, including an increase in T cells and cytokine production. Withanolide A also helped to restore glutathione levels and offered several other anti-stress activities, which resulted in improved immunity.
Interestingly, another study done on arthritic rats showed that withanolides from ashwagandha showed immunosuppressive activities, including T cell proliferation, humoral immunity, and cell-mediated immunity.
Essentially, withanolides seem to modulate the immune system depending on what is needed at that time, which is reflective of their general adaptogenic effects in the body as a whole.
Summary:
Studies indicate that withanolides may aid in immune system modulation, making this effective for immune support.
4. Neuroprotection Support
Withanolides may also have neuroprotective effects (protective effects in the brain and nervous system).
In a rat study, two different withanolide compounds showed anti-stress activity in the brain and appeared to increase learning acquisition and memory retention in both young and old rats.
In a combined in vitro and in vivo study, withanoside IV attenuated several effects resulting from beta-amyloid induced neurodegeneration. For example, withanoside IV helped to regenerate axons, dendrites, and synapses (which are all key components of nerve cells). The same study found that withanolide IV significantly improved memory deficits from beta-amyloid (a harmful protein), while also preventing nerve cell damage.
In another animal study, ashwagandha and its withanolides provided neuroprotective effects against rats with Parkinson’s disease. They showed that withanolides reduced oxidative stress in the brain and helped to regenerate dopamine (which is an important neurotransmitter).
These results likely explain some of the benefits that ashwagandha has for cognitive function, including its ability to help people with cognitive impairment, schizophrenia, and certain mood disorders.
Summary:
Withanolides may have potential benefits for protecting the brain, supporting the nervous system, and improving cognitive function.
5. Anti-Carcinogenic Activity
Withanolides have also been shown to have anti-carcinogenic activity. Of course, this area is in particular need of clinical trials before any claims can even start to be initiated. But at the very least, withanolides do show certain promising anti-carcinogenic effects.
In one study, researchers found that withaferin A reduced lung cancer cell proliferation and increased apoptosis (cell death) of lung cancer cells in vitro. They also showed that mice treated with withaferin A had decreased lung tumor size and increased apoptosis compared to the control mice.
An in vitro study showed that withanolide led to apoptosis in leukemia cells, in part by disrupting cell DNA, while also increasing caspase activation.
A study also found that withaferin A and other withanolides inhibited cell proliferation in lung, colon, central nervous system, and breast tumor cells.
Summary:
Although additional clinical research is required in order to confirm these findings, withanolides may have anti-carcinogenic effects.
6. Muscle & Exercise Support
Withanolides may have benefits for muscle health and related factors, such as exercise performance.
In one study, withaferin A and withanone seemed to protect muscle protein from stress while also improving muscle cell activity, suggesting a role in muscle repair.
In a mice study, withaferin A enhanced energy expenditure and improved metabolism by improving mitochondrial function in fat and muscle cells. It appeared to help promote brown fat as opposed to white fat, which is important since brown fat is used for energy whereas white fat is stored fat.
These effects likely explain at least part of the reason why ashwagandha is beneficial for exercise performance for both men and women. A review of the research shows that ashwagandha supplements (which are standardized for withanolides) improved various markers of exercise performance, such as strength and endurance.
Summary:
Withanolides may possess possible benefits for improving exercise performance, strength, and endurance.
Are Withanolides Safe?
In general, withanolides seem to be safe when consumed in reasonable amounts. Clinical research has generally used 250 to 1,000mg of ashwagandha per day, which is typically standardized with 2.5 to 10% withanolides. Therefore, a range of anywhere from 6.25 to 100mg of withanolides per day seems reasonable, based on clinical research. Evidently, this provides a wide range to choose from, although it’s best to start low and work your way up if needed. And going beyond this range may increase the risk of side effects and other issues.
There isn’t a whole lot of information on the side effects of withanolides themselves since the clinical research is based on ashwagandha rather than isolated withanolides. Nonetheless, withanolides may have similar possible side effects as ashwagandha, including:
- Upset stomach
- Headache
- Mood changes
- Liver toxicity (rarely, and only in high amounts)
- Allergic reactions
Click here to learn more about the safety and dosage of ashwagandha.
Conclusion:
Withanolides are important compounds with several bioactive effects. Many studies show that withanolides extracted from ashwagandha exert anti-stress, anti-anxiety, immunomodulatory, neuroprotective, anti-carcinogenic, and muscle-supportive properties.
These effects likely underlie many of ashwagandha’s benefits for stress, anxiety, sleep, athletic performance, brain function, and overall vitality.
Of course, there are several other constituents in ashwagandha that are likely involved in these benefits too. But the withanolides seem to provide many of these benefits. As a result, it is wise to choose ashwagandha supplements standardized to at least 2.5% withanolides in order to increase the likelihood of health benefits.
