For example, the antioxidant effects and anti-amyloid actions of Withaferin A (a steroidal lactone metabolite of ashwagandha) as well as its support for a healthy inflammatory response help to explain the neuroprotective effects observed in experimental models. Additionally, ashwagandha has been shown to increase levels of BDNF in model systems, though unfortunately no human clinical trials related to neurodegenerative conditions have been conducted. Similarly, no controlled clinical trials exist related to glucose control or insulin sensitivity, yet several mechanisms are suggested in the Pharmaceutics review, as well as one non-peer-reviewed clinical trial which hints at possible benefit.
An area for which more clinical trial data exists is related to stress, anxiety, and mental health. A systematic review published in 2022 included 12 randomized controlled trials (RCTs) and over 1,000 study participants found that supplementation at doses of 300-600 mg per day was associated with significant reductions in both stress and anxiety, with a dose-dependent effect (maxing out at around 12 g per day). Small clinical trials also suggest possible adjunctive benefits for stress and other related conditions when combined with SSRI treatment.
Given the general and wide-spectrum health-promoting effects that traditional practitioners attribute to ashwagandha, evidence that sleep may be supported with supplementation provides another possible mechanism, as good quality sleep has been associated with improved functioning of nearly every body system, including cardiometabolic, neurological, and cognitive health. A systematic review of 5 RCTs and 400 participants found a small but significant improvement in overall sleep with supplementation, with greater effects for each of the following: among participants with insomnia, at doses of 600 mg or more per day, or with treatment duration of 8 weeks or more. Improvements in sleep efficiency, latency, and overall sleep duration were reported.
Another notable effect of ashwagandha with good clinical data is related to physical health and performance. A systematic review of 12 clinical trials published in 2021 found that at doses between 120-1250 mg per day, supplementation was associated with improved physical performance in both men and women, including parameters such as strength/power, cardiorespiratory fitness, and fatigue/recovery, with benefits observed in athletes and non-athletes. It’s important to note that a 2020 systematic review of 4 RCTS specifically examining any impact on VO2max found that supplementation significantly increased VO2max among both athletes and non-athletes, at doses ranging from 300-500 mg per day, taken 1-2 times per day (total dose range of 300-1000 mg per day). Given the improvements in both sleep and physical health and performance, as well as a reduction in stress and anxiety, it could be speculated that many of the “adaptogenic” benefits of ashwagandha may be mediated through any or all of these influences.
Other clinical data indicative of benefit and not included in the above meta-analyses include a small randomized trial that enrolled participants with subclinical hypothyroidism, supplemented with either placebo or a root extract of ashwagandha at a dose of 600 mg per day (300 mg twice per day). Over an 8-week period, a significant increase in both T4 and T3 was observed compared to placebo, as well as a significant drop in TSH levels, with a normalization of thyroid indices over the 8-week period. The authors speculate this may be due to the regulation of the hypothalamic–pituitary–thyroid axis, as well as an antistress and cortisol-lowering effect of ashwagandha.
In another randomized and double-blinded clinical trial that enrolled healthy participants with high perceived stress levels at baseline, the same root extract of ashwagandha was found to both reduce perceived stress levels after 8 weeks, and also to reduce serum cortisol levels at both a 250 mg and 600 mg dose per day, suggesting possible modulation of the HPA axis. Other studies have also indicated cortisol- and DHEA-reducing effects of ashwagandha among stressed participants, both of which may be mediated via HPA axis effects (DHEA is stimulated by ACTH and GnRH, secreted by the anterior pituitary and hypothalamus, respectively), but there has been little investigation in humans to confirm this mechanism of action. A root extract of ashwagandha was also shown to help relieve perimenopausal symptoms, with modulation of FSH, LH, and estradiol levels.
Lastly, a leaf and root extract of ashwagandha (standardized for withanolide glycosides) was found to influence a variety of immune parameters in healthy adults at a dose of 60mg per day over a 30-day period. This included significant increases in multiple types of immunoglobulins (IgG, IgA, IgM, etc.), as well as markers related to T and B lymphocyte and natural killer cell activity. While not examined in this study, it suggests the possibility of broad immune-boosting potential by ashwagandha.
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