Ashwagandha (Withania somnifera)

Bioactive compounds such as withanolides have been shown to modulate GABA_A receptors, leading to increased inhibitory neurotransmission in the central nervous system. Ashwagandha demonstrates adaptogenic qualities, possibly by regulating the Hypothalamic-Pituitary-Adrenal (HPA) axis and modulating serum cortisol levels.

Literature Review

Taking ashwagandha orally has been shown in clinical research to help reduce levels of perceived stress. Additionally, there is evidence to suggest that oral ashwagandha may also help prevent weight gain that is associated with stress. Specific ashwagandha root extracts have been shown to significantly reduce perceived stress levels by 30% to 44% and cortisol levels by 22% to 28% in adults with chronic stress over a 60-day period compared to placebo.^{[i],[ii],[iii],[iv]}

Another specific slow-release ashwagandha root extract lowered perceived stress scores and cortisol levels and also improved recall memory over a 90-day period in adults reporting moderate to high stress. This was measured via CANTAB Scoring methods, lower perceived stress scores and cortisol levels (9.01 +/- 3.69 mcg/dL to 7.38 +/- 3.31 mcg/dL at visit 4) when compared with placebo, along with recall memory being significantly improved.^[v]

Taking ashwagandha root extract 500 mg twice daily may prevent stress-related weight gain compared to placebo.¹⁷⁴

Mechanism of Action

General: The applicable parts of ashwagandha are the root and berry. Ashwagandha contains several active constituents including alkaloids (isopelletierine, anaferine), lactones (withanolides, withaferins), and saponins.^[vi],[vii] It also contains salvigenin, withaperuvin 1, eucommiol, vicosalactone B, anamides D and E, and asomidienone.^[viii]

Anti-stress effects: Preliminary research suggests that ashwagandha suppresses stress-induced increases in dopamine receptors in the corpus striatum in the brain and reduces stress-induced increases in plasma corticosterone, blood urea nitrogen, and blood lactic acid.^[ix],[x]

Anxiolytic effects: Ashwagandha may have anxiety-reducing effects, possibly by acting as a GABA mimetic agent. It also seems to enhance serotonergic transmission and postsynaptic serotonergic (5-HT) receptors.^[xi]

Memory effects: Both animal and human studies indicate that ashwagandha improves memory function through various potential mechanisms including increased axonal density and increased myelin in the peripheral nervous system.^{[xii],[xiii],[xiv]}

Reproductive effects: Clinical research indicates that ashwagandha improves sperm count and motility, possibly related to increased levels of specific hormones like testosterone, LH, FSH, and prolactin.^[xv]

References

[i]Chandrasekhar K, Kapoor J, Anishetty S. A prospective, randomized double-blind, placebo-controlled study of safety and efficacy of a high-concentration full-spectrum extract of ashwagandha root in reducing stress and anxiety in adults. Indian J Psychol Med. 2012;34(3):255-62.

[ii]Choudhary D, Bhattacharyya S, Joshi K. Body weight management in adults under chronic stress through treatment with ashwagandha root extract: a double-blind, randomized, placebo-controlled trial. J Evid Based Complementary Altern Med. 2017 Jan;22(1):96-106

[iii]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. Medicine (Baltimore). 2019;98(37):e17186.

[iv]Salve J, Pate S, Debnath K, Langade D. Adaptogenic and anxiolytic effects of ashwagandha root extract in healthy adults: A double-blind, randomized, placebo-controlled clinical study. Cureus. 2019;11(12):e6466.

[v]Gopukumar K, Thanawala S, Somepalli V, Rao TSS, Thamatam VB, Chauhan S. Efficacy and safety of ashwagandha root extract on cognitive functions in healthy, stressed adults: a randomized, double-blind, placebo-controlled study. Evid Based Complement Alternat Med. 2021 Nov 30;2021:8254344.

[vi]Bhattacharya SK, Satyan KS, Ghosal S. Antioxidant activity of glycowithanolides from Withania somnifera. Indian J Exp Biol 1997;35:236-9.

[vii]Mishra LC, Singh BB, Dagenais S. Scientific basis for the therapeutic use of Withania somnifera (ashwagandha): a review. Altern Med Rev 2000;5:334-46.

[viii]Kumar S, Bouic PJ, Rosenkranz B. Investigation of CYP2B6, 3A4 and ß-esterase interactions of Withania somnifera (L.) dunal in human liver microsomes and HepG2 cells. J Ethnopharmacol. 2021;270:113766.

[ix]Archana R, Namasivayam A. Antistressor effect of Withania somnifera. J Ethnopharmacol 1999;64:91-3.

[x]Upton R, ed. Ashwagandha Root (Withania somnifera): Analytical, quality control, and therapeutic monograph. Santa Cruz, CA: American Herbal Pharmacopoeia 2000:1-25.

[xi]Jahanbakhsh SP, Manteghi AA, Emami SA, Mahyari S, et al. Evaluation of the efficacy of withania somnifera (ashwagandha) root extract in patients with obsessive-compulsive disorder: a randomized double-blind placebo-controlled trial. Complement Ther Med 2016 Aug;27:25-9. 

[xii]Ghosal S, Lal J, Srivastava R, and et al. Immunomodulatory and CNS effects of sitoindosides 9 and 10, two new glycowithanolides from Withania somnifera. Phytotherapy Research 1989;3(5):201-206.

[xiii]Chengappa KN, Bowie CR, Schlicht PJ, Fleet D, Brar JS, Jindal R. Randomized placebo-controlled adjunctive study of an extract of withania somnifera for cognitive dysfunction in bipolar disorder. J Clin Psychiatry. 2013;74(11):1076-83. 

[xiv]Tohda, C. [Overcoming several neurodegenerative diseases by traditional medicines: the development of therapeutic medicines and unraveling pathophysiological mechanisms]. Yakugaku Zasshi 2008;128(8):1159-1167.

[xv]Ahmad MK, Mahdi AA, Shukla KK, et al. Withania somnifera improves semen quality by regulating reproductive hormone levels and oxidative stress in seminal plasma of infertile males. Fertil Steril 2010;94:989-96.