Botanicals of Interest

The BENFRA Center examines two popular botanical dietary supplements in the U.S., Centella asiatica (L.) Urban (CA; family Apiaceae) and Withania somnifera (L.) Dunal (WS; family Solanaceae). Both are highly regarded in the Ayurvedic tradition as rejuvenating herbs1 (“rasayana”). The first is sold as gotu kola, the second as ashwagandha. Based on the number of registered labels,2 there are over 200 dietary supplements containing CA and over 400 dietary supplements containing WS available for purchase in the US. In one survey, WS was listed as the sixth top selling herb in US in 2017,3 up from eighth position in 2016.4 Scientific studies suggest the utility of CA and WS to support resilience to neurological changes experienced in aging such as cognitive decline, and sleep and mood disturbances. Both botanicals have been the subject of earlier clinical studies. However, the studies range widely in methodological quality, product characterization, justification of doses, subject population and end points. Well-designed clinical trials are critically needed to reliably evaluate the potential of these botanicals to support age-related neurological and functional changes.

Based on their widespread use in the US, and compelling evidence for biological activity, the BENFRA Center will conduct a battery of studies to support the design of optimum clinical trials of these two botanicals. We have been working with CA for several years and will build on those studies. We are eager to apply our collaborative expertise in relevant methods to WS, as a new candidate for our research.

Centella asiatica (CA)

Biological effects of Centella asiatica

The leaves and roots of the centella asiatica plant, arranged on a wooden bench
Centella asiatica, also known as "gotu kola"

A substantial body of literature supports the neurological and neurotropic effects of CA.5 CA improves cognition in rodent models of oxidative stress,6-8 and in mouse models of Alzheimer’s disease (AD) and aging as shown by studies in our lab.9-12 We have found that CA appears to work by improving antioxidant response, ameliorating mitochondrial dysfunction and increasing dendritic arborization,13-16 effects which are relevant to both pathological and normal aging. In clinical studies, CA extract or dried herb improved cognitive function of healthy middle-aged and elderly17,18 and as well as elderly subjects with mild cognitive impairment.19 Anxiolytic20-22 and antidepressant23,24 properties of CA have been reported in rodent models. CA treatment showed similar effects in humans.19,25 CA has been reported to be used for sleep disorders,26 but has not been investigated systematically for this use. CA prevented some of the behavioral changes in a mouse model of extreme sleep deprivation,22 and in a clinical study of cognition and mood, self-reported insomnia was decreased with CA treatment.19 

Phytochemical and known active compounds of CA

CA is most known for its high content of pentacyclic triterpenoids.27,28 The saponins, asiaticoside (AS) and madecassoside (MS), and their aglycones, asiatic acid (AA) and madecassic acids (MA), are the most abundant and widely studied pentacyclic triterpenoids in CA. Saponins account for up to 8% of the dry mass of the herb.29 Less abundant components of CA include chlorogenic acids, a diverse group formed by quinic acid esterified to cinnamic acid derivatives, including caffeoylquinic acids (CQAs).30 Several isomeric dicaffeoylquinic esters are commonly found in CA: 1,3-, 1,4- 1,5-, 3,4-, 3,5- and 4,5-diCQA,31 some of which have the trivial names isochlorogenic acid A, B or C. CA contains many phenolic constituents, including flavonoids, such as catechin, epicatechin, kaempferol, quercetin and related glycoside.30 Many of the neurotropic and neuroprotective properties of CA have been associated with the triterpene compounds AS and AA.5 However, we14,31 and others have discovered that CQAs found in CA also confer neurotropic and neuroprotective effects including cognitive effects. 32-35  

Withania somnifera (WS)

Biological effects of Withania somnifera

Exposed roots of the Withania somnifera plant
Withania somnifera roots (Photo credit: Roy Upton, American Herbal Pharmacopoeia, Scotts Valley, CA)

Neuropharmacological effects of WS root and WS leaf have both been studied in preclinical and clinical models and are the subject of recent reviews.36-38 Cognitive improvement has been seen in rodent models treated with WS root39 or leaf40-43 extracts, and also reported in humans44-46 taking WS products. Antidepressant and anxiolytic effect of WS are reported in mice47-49 and in multiple human studies.50-56 In rodents, WS extracts increased non-REM sleep,43 and ameliorated cognitive and motor deficits, and alterations in synaptic proteins43,57,58 and EEG and EMG patterns59 induced by sleep deprivation. Several clinical studies51,52,55,60 also report improved sleep quality for WS products.

An ashwagandha plant, planted in soil
Ashwagandha plant, photo credit Oregon’s Wild Harvest

Chemistry and known active compounds of WS

The best-known compounds of WS are a complex group of steroidal lactones known as withanolides, which also occur as glycosides (withanosides). Over 40–60 individual withanolide derivatives have been reported in WS leaf and root,61,62 with higher levels in the leaves than the roots.63 The existence of WS chemotypes has been reported.64 Withanolides are considered to be the main active compounds of WS65,66 including for neurological effects. For example, withanone67 and withanolide A,68 sominone68 and withanoside IV68 all improved memory in cognitively impaired rodents. In vitro, withanolide A and withanosides IV and VI and sominone were also associated with increased neuritic extension and markers of synaptic health.69, 70 WS also contains multiple steroidal alkaloids65,71 and phenolic compounds72 and sitoindosides (long chain acylsterylglucosides)71 which, by contrast, have received very little attention for their neurological activities. Triethylene glycol has been suggested to be the active compound for sleep induction in mice73 although the concentrations used seem high compared to the parent WS extract. Some withanolides contain electrophilic sites conferring thiol reactivity which may play important roles in mediating biological activity associated with antioxidant and heat-shock-inducing activity and/or targeting other electrophile sensors that modulate transcriptional or post-transcriptional responses.74


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5. Gray NE, Alcazar Magana A, Lak P, et al. Centella asiatica: phytochemistry and mechanisms of neuroprotection and cognitive enhancement. Phytochem Rev. 2017:1-34.

6. Veerendra Kumar MH, Gupta YK. Effect of Centella asiatica on cognition and oxidative stress in an intracerebroventricular streptozotocin model of Alzheimer's disease in rats. Clinical & Experimental Pharmacology & Physiology. 2003;30(5-6):336-342.

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8. Gupta YK, Veerendra Kumar MH, Srivastava AK. Effect of Centella asiatica on pentylenetetrazole-induced kindling, cognition and oxidative stress in rats. Pharmacology, Biochemistry & Behavior. 2003;74(3):579-585.

9. Gray NE, Harris CJ, Quinn JF, Soumyanath A. Centella asiatica modulates antioxidant and mitochondrial pathways and improves cognitive function in mice. J Ethnopharmacol. 2016;180:78-86.

10. Gray NE, Zweig JA, Caruso M, et al. Centella asiatica increases hippocampal synaptic density and improves memory and executive function in aged mice. Brain Behav. 2018;8(7):e01024.

11. Gray NE, Zweig JA, Caruso M, et al. Centella asiatica attenuates hippocampal mitochondrial dysfunction and improves memory and executive function in beta-amyloid overexpressing mice. Mol Cell Neurosci. 2018;93:1-9.

12. Soumyanath A, Zhong YP, Henson E, Wadsworth T, Bishop J, Gold BG, Quinn JF., . Centella asiatica Extract Improves Behavioral Deficits in a Mouse Model of Alzheimer's Disease: Investigation of a Possible Mechanism of Action. Int J Alzheimers Dis,. 2012:381974.

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20. Wanasuntronwong A, Tantisira MH, Tantisira B, Watanabe H. Anxiolytic effects of standardized extract of Centella asiatica (ECa 233) after chronic immobilization stress in mice. J Ethnopharmacol. 2012;143(2):579-585.

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22. Chanana P, Kumar A. Possible Involvement of Nitric Oxide Modulatory Mechanisms in the Neuroprotective Effect of Centella asiatica Against Sleep Deprivation Induced Anxiety Like Behaviour, Oxidative Damage and Neuroinflammation. Phytother Res. 2016;30(4):671-680.

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30. Ncube EN, Steenkamp PA, Madala NE, Dubery IA. Chlorogenic Acids Biosynthesis in Centella asiatica Cells Is not Stimulated by Salicylic Acid Manipulation. Appl Biochem Biotech. 2016;179(5):685-696.

31. Gray NE, Morré J, Kelley J, et al. Caffeoylquinic Acids in Centella asiatica Protect against Amyloid-β Toxicity. J Alzheimer's Dis. 2014;40:359–373.

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73. Kaushik MK, Kaul SC, Wadhwa R, Yanagisawa M, Urade Y. Triethylene glycol, an active component of Ashwagandha (Withania somnifera) leaves, is responsible for sleep induction. PLoS One. 2017;12(2):e0172508.

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