Supplements

Ashwagandha to Combat Cognitive Impairment

Ashwaghanda Root | MCI 911 Mild Cognitive Impairment

by Ari Magill, MD

Ashwagandha (ASH), also known as Indian ginseng, is a root that has been used for medicinal purposes for more than 3000 years. According to ayurvedic medicine, the traditional medicine practiced in India and the Indian subcontinent, the root has anti-aging properties, promoting well-being, both physical and mental, in the young and the elderly.1 It also shows promise as an agent to combat cognitive decline and dementia, although rigorous scientific research on its benefits has only recently started.

The Takeaway:

Ashwagandha might have cognitive protective effects through antioxidant, cholinergic, and other mechanisms of action.

Benefits to Nerves of Lab Rodents

Kuboyama et al investigated the impact of an ASH extract on the structure and function of neurons, the primary cells of the nervous system, when they were damaged by beta amyloid (one of the key pathologic proteins associated with Alzheimer’s disease [AD]).2,3 They found that the extract induced the growth and repair of connections between such injured neurons.

Connection between neurons results from outgrowths of them, called dendrites (the receiving apparatus) and axons (the sending apparatus). The site where chemical messengers are transmitted from the terminal end of the axon to the dendrite is called the synapse. Administration of ASH extract placed in drinking water increased the density of axons, dendrites, and synapses in neuronal tissue taken from the rat cortex (the outer layer of the brain). It also functionally improved the spatial memory of mice in a water maze test after injecting their brains with beta amyloid.

Mouse Memory Boosted

Sehgal et al investigated the effects of a 30-day oral treatment with the extract on a genetically engineered mouse model of AD.4 They found that it significantly boosted memory performance.

Amyloid Clearance Improved

It also decreased the amount of beta amyloid plaques, a pathologic hallmark of AD. This was accomplished through enhanced clearance mediated by a transporter protein called low-density lipoprotein receptor-related protein (LRP). The ASH extract also increased neprilysin, an enzyme that breaks down beta amyloid. Both processes initially started in the liver but later were found in the brain.

Other Benefits

Other mechanisms by which ASH exerts neuroprotection have been found. In a cell culture study, Shah et al examined the protective effect on both neurons and neuronal helper cells, known as glia, under stressed conditions.5 A low dose of ASH extracts and one isolated constituent, called withanone, provided defense against oxidative stress and excitotoxicity, the excessive stimulation of neurons by glutamate. The extracts also helped the cells develop into fully matured neurons and glia. Combining multiple extracts and withanone produced stronger therapeutic effects.

Other animal studies suggest a cognitive benefit from oral ASH administration. Shivamurthy et al investigated the impact of protein extracts of the herb on the memory function of albino rats (those that don’t produce pigmentation).Researchers assessed the rats’ recall ability using a water maze and avoidance learning tasks. They were co-administered scopolamine (an anti-cholinergic medication that blocks the activity of acetylcholine). Acetylcholine is a key neurotransmitter (brain chemical messenger) involved in memory formation.a

The investigators found that the ASH protein extract improved learning and memory performance compared to rats treated with scopolamine alone and rats treated with a combination of scopolamine and piracetam.b

In an attempt to clarify the exact mechanism by which ASH extracts reverse scopolamine-induced memory loss in mice, Konar et al investigated the molecular target of an ASH extract using an albino mouse model.7 They focused on a particular acetylcholine receptor, M1 muscarinic, which induces cellular changes that enhance learning and memory. After giving mice the ASH extract by mouth for a week, they examined two regions of the brain—the cerebral cortex and the hippocampus (the brain’s memory center). They also harvested hippocampal cells from neonatal mice and directly applied the ASH extract.

They found that it promoted the formation and growth of neuronal dendrites and blunted the negative effects on these processes by scopolamine. A known muscarinic receptor blocker, dicyclomine, prevented growth and generation of dendrites by the ASH extract, and pilocarpine, a known muscarinic receptor activator, enhanced the effects of the extract. Thus, ASH does appear to exert its cognitive enhancing effects, at least in part, through the acetylcholine M1 muscarinic receptor.

Studies in Humans

Rigorous scientific studies on the cognitive impact of ASH in humans are scarce. Pingali et al examined the effects on cognitive performance tasks in 20 healthy males between the ages of 20 and 35.8 This was a crossover study in which half of the subjects were given two 250-mg capsules of an ASH extract two times per day and half were given placebo for two weeks. Cognitive testing took place before study start and on day 15. There was a “washout period” of no capsules for two weeks, after which each study arm received the alternative capsules for two weeks. These tests were then administered a third time.

Administration resulted in significant increases in processing speed performing all the cognitive tasks except finger tapping. This study suggests that ASH extracts have cognitive enhancing properties in healthy young adults.

Choudhary et al conducted a pilot study in which 50 subjects with mild cognitive impairment were enrolled.9 Participants received either 300 mg of an ASH extract twice daily or placebo for eight weeks. Cognitive testing revealed that those given the extract had significantly better cognitive scores in multiple domains including memory, executive function (decision making), persistent attention, and information processing speed compared to the placebo group.

Overall, results are preliminary but there is a scientific basis for thinking that ASH might have cognitive protective effects through antioxidant, cholinergic (acting through the acetylcholine messenger system), and other mechanisms of action. The herb is generally considered quite safe, and side effects are rare, but GI symptoms, including dyspepsia, diarrhea, nausea, and vomiting have been documented at higher doses.10 ASH root extracts are readily available in health food stores and online without a prescription. No consistent dosage has been established, but human studies have used doses in the 600-mg to 1000-mg (per day) range. Sprouts sells a bottle of 90 475-mg capsules (containing whole root and an extract) for $17. A 1-ounce liquid formulation sells for $12 and can be used to gradually titrate up the dose if side effects occur.

Notes

a In earlier times, scopolamine was used as a “truth serum” in espionage and criminal investigations, as subjects supposedly talked more freely and had no memory of being questioned.

b Piracetam is another agent frequently taken to enhance cognitive performance.

References

  1. Farooqui AA, et al. Ayurvedic medicine for the treatment of dementia: mechanistic aspects. Evid-Based Complement Alternat Med. 2018;2481076. doi: 10.1155/2018/2481076.
  2. Kuboyama T, Tohda C, Komatsu K. Neuritic regeneration and synaptic reconstruction induced by withanolide A. Br J Pharmacol. 2005;144(7):961-971. doi: 1038/sj.bjp.0706122.
  3. Kuboyama T, Tohda C, Komatsu K. Withanoside IV and its active metabolite, sominone, attenuate Aβ (25–35)‐induced neurodegeneration. Eur J Neurosci. 2006;23(6):1417-1426. doi: 1111/j.1460-9568.2006.04664.x.
  4. Sehgal N, et al. Withania somnifera reverses Alzheimer’s disease pathology by enhancing low-density lipoprotein receptor-related protein in liver. Proc Natl Acad Sci. 2012;109(9):3510-3515. doi: 1073/pnas.1112209109.
  5. Shah N, et al. Combinations of ASH leaf extracts protect brain-derived cells against oxidative stress and induce differentiation. PLoS One. 2015;10(3):e0120554. doi: 10.1371/journal.pone.0120554.
  6. Shivamurthy S, Manchukonda RS, Ramadas D. Evaluation of learning and memory enhancing activities of protein extract of Withania somnifera (ASH) in Wistar albino rats. Int J Basic Clin Pharmacol. 2016;5(2):453. doi: http://dx.doi.org/10.18203/2319-2003.
  7. Konar A, et al. M1 muscarinic receptor is a key target of neuroprotection, neuroregeneration and memory recovery by i-Extract from Withania somnifera. Sci Rep. 2019;9(1):1-15. doi: 1038/s41598-019-48238-6.
  8. Pingali U, Pilli R, Fatima N. Effect of standardized aqueous extract of Withania somnifera on tests of cognitive and psychomotor performance in healthy human participants. Pharmacognosy Res. 2014;6(1):12-18. doi: 4103/0974-8490.122912.
  9. Choudhary D, Bhattacharyya S, Bose S. Efficacy and safety of Ashwagandha (Withania somnifera (L.) Dunal) root extract in improving memory and cognitive functions. J Diet Suppl. 2017;14(6):599-612. doi: 10.1080/19390211.2017.1284970.
  10. National Institutes of Health. Livertox: clinical and research information on drug-induced liver injury. National Institutes of Health website. https://livertox.nih.gov.

About the Author

Dr. Ari Magill is a holistic neurologist and medical consultant based in Mesa, AZ. He received medical school training at University of Texas Southwestern in Dallas and residency training at the University of Arizona in Tucson. He is passionate about finding innovative treatments for cognitive impairment, emphasizing lifestyle change and natural supplements.