Centella Asiatica - Scientific Review On Usage, Dosage, Side Effects - Examine

21/10/2017 Centella asiatica - Scientific Review on Usage, Dosage, Side Effects | Examine.
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Centella asiatica
Centella asiatica (Gotu Kola) is a traditional medicine mainly renowned for its cognitive enhancing properties (usually
alongside bacopa monnieri (/supplements/bacopa-monnieri/)) and its ability to regenerate wound healing. It
appears e ective on both parameters in preclinical evidence, and may also be anti-rheumatic.
This page features 149 unique references to scienti c papers.
History (/history/centella-asiatica/)
Discussion (/discussion/centella-asiatica/)
SUMMARY THINGS TO KNOW HOW TO TAKE HUMAN EFFECT MATRIX SCIENTIFIC RESEARCH
CITATIONS
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Summary
All Essential Bene ts/E ects/Facts & Information
Centella asiatica (Gotu Kola) is a traditional medicine that is mostly used and renowned in Ayurveda (/supplements/ayurveda/) but has
some usage in Traditional chinese usage (/contribute/supplements/Traditional+chinese+usage/) as well. It is most commonly known
as a cognitive enhancing supplement that is somewhat 'interchangeable' with Bacopa monnieri (/supplements/bacopa-monnieri/)
(insofar that the two share many of the same names) but has additional bene ts for cardiovascular health (in particular, chronic
venous insu ciency), skin regeneration rates and wound healing, and possible bene ts to anxiety and rheumatism.
In regards to its cognitive enhancing properties, it requires a few weeks to work and seems to cause an increase in neuronal growth
(not how many neurons there are, but how far their dendrites branch out). This is due to activating a class of proteins known as
MAPKs, which causes a release in a growth factor for neurons called Brain-derived Neurotrophic Factor (BDNF). This is a mechanism
https://examine.com/supplements/centella-asiatica/ 1/30
21/10/2017 Centella asiatica - Scientific Review on Usage, Dosage, Side Effects | Examine.com
somewhat similar to Bacopa monnieri (/supplements/bacopa-monnieri/) and the time-delay in improving cognition is also similar;
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however, currently there are no studies assessing whether they can be used alongside each other or which one is more potent.
It has another independent mechanism where it augments the release of an anti-in ammatory signalling molecule from immune
cells, in particular it enhances the secretion of the molecule known as IL-1 from the immune cells known as macrophages; it does
this at a remarkably low concentration (in the picomolar range) and is likely relevant to oral supplementation, and if so this could
partly explain bene ts to chronic venous insu ency (which are quite proven with human evidence) and its anti-rheumatic bene ts
(not as proven).
Finally, this plant may inhibit a group of enzymes that break down collagen while simultanously increasing the rate that collagen is
synthesized; this is thought to underlie the increase in wound healing rate (which is proven in animal research with preliminary
human research) and is thought to be the reason why centella asiatica is used as a skin tightening agent as any increase in collagen
synthesis (like with creatine (/supplements/creatine/)) should cause a rmness of the skin.
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Things to Know
Also Known As
Gotu kola, Indian Pennywort, Jal Brahmi and Mandookaparni, Brahmi, Tsubokusa
Do Not Confuse With

Kola Nut (a ca eine (/supplements/ca eine/) containing plant)
Things to Note
Centella asiatica is reported to be tasteless and scentless
Is a Form Of
Nootropic
Ayurveda
Goes Well With

Vitamin E (/supplements/vitamin-e/) (appears to increase the rate of vitamin E recycling and augment its antioxidant e ects)
()
Caution Notice
Examine.com Medical Disclaimer (/disclaimer)
How to Take
Recommended dosage, active amounts, other details
Most of the human studies (on Chronic Venous Insu ciency) on this herb have used a centella asiatica supplement two to three times
a day, and at each dose the total saponin dose (asiatic acid, madecassic acid, asiaticoside, and madecassoside) has totalled 30-60 mg
given a total daily range of 60-180 mg total saponins.
While there are currently no human studies on cognitive enhancement, rat studies have noted success with 200-300 mg per kilogram
of the overall plant extract (since the saponins may not be the only active ingredient for cognition); this suggests a human dose of 32-
48 mg/kg and thus:
2,100-3,300 mg for a 150lb person
The above dosages ranges are but estimates for cognitive enhancement. Currently, 500mg of centella asiatica twice daily has shown
anxiety reducing e ects in humans and 750mg of a 5% asiaticoside extract has enhanced mood state; while these doses are active on
the cognition, it is not yet demonstrated if they are the dose needed to boost learning.
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Human E ect Matrix
The Human E ect Matrix looks at human studies (it excludes animal and in vitro studies) to tell you what e ects centella
asiatica has on your body, and how strong these e ects are.
GRADE LEVEL OF EVIDENCE
()
Robust research conducted with repeated double-blind clinical trials
Multiple studies where at least two are double-blind and placebo controlled
Single double-blind study or multiple cohort studies
Uncontrolled or observational studies only
LEVEL OF OUTCOME MAGNITUDE OF EFFECT CONSISTENCY OF RESEARCH RESULTS NOTES

EVIDENCE
? ? ?
Chronic Venous
Symptoms of chronic venous insu ciency extending to poor
Insu ciency VERY HIGH
circulation, venous reactivity, and adverse side-e ects such as
(/topics/chronic- See all 8 studies
Notable edema and leg pain are all reliably reduced with oral ingestion
venous- (/rubric/e ects/view/973746d613fae676132aa06b3e9ad44c/4fc336884a0a0750a72150a761e52af56ad65363/all
of centella asiatica
insu ciency/)
There appears to be a notable improvement in microcirculation

Microcirculation VERY HIGH associated with oral ingestion of centella asiatica in the
(/topics/microcircul See all 8 studies treatment of chronic venous insu ciency; this may extend to
Notable
ation/) otherwise healt...
(/rubric/e ects/view/973746d613fae676132aa06b3e9ad44c/37771820a4b2771f780c1fae4cd117514f6cbc2a/all/
See more
VERY HIGH Blood ow appears to be increased alongside improvements in

Blood Flow
See all 4 studies microcirculation seen in persons with impaired venous
(/topics/blood- ow/) Minor
insu ciency being treated with centella asiatica
(/rubric/e ects/view/973746d613fae676132aa06b3e9ad44c/6018e927f5404b44585a385e5cc4 9c/all/)
VERY HIGH There appears to be a decrease in edema associated with

Edema
See all 5 studies chronic venous insu ciency (CVI), associated with the
(/topics/edema/) Minor
treatment of CVI by centella asiatica
(/rubric/e ects/view/973746d613fae676132aa06b3e9ad44c/c321a559dc755179f861938a7ad6e140/all/)
Leg Swelling VERY HIGH The leg swelling associated with chronic venous insu ciency
(/topics/leg- See all 5 studies appears to be signi cantly reduced secondary to treating the
Minor
swelling/) state of chronic venous insu ciency.
(/rubric/e ects/view/973746d613fae676132aa06b3e9ad44c/8473517cd320011194d711e09de23b4f/all/)
-
Alertness An increase in the self-rated sensation of alertness is noted in
See study
(/topics/alertness/) Minor older healthy adults supplementing with centella asiatica
(/rubric/e ects/view/973746d613fae676132aa06b3e9ad44c/430988c9a37ba486e74ca25f851d3c3b/all/)
There appears to be a reduction in anxiety symptoms that build

-
Anxiety up over time (reaching a quarter reduction after two months)
See study
(/topics/anxiety/) Minor associated with twice daily ingestion of 500mg of the plant
(/rubric/e ects/view/973746d613fae676132aa06b3e9ad44c/042f3f19742d86e6bbfa31ee9af3bfa6/all/)
extract
An increase in attention has been noted which may be

-
Attention secondary to the treatment of anxiety (or the reductions in
See study
(/topics/attention/) Minor stress and depression that also occured due to treating
(/rubric/e ects/view/973746d613fae676132aa06b3e9ad44c/d46b34c67 0f1d7b178cac09ef58f51/all/)
anxiety).
()
VERY HIGH
A reduction in fear and anxiety responses to an acute startle

Calmness
response (indicative of less responsiveness to alerting stimuli
(/topics/calmness/)
and more calmness) has been noted with this plant extract
Minor See 2 studies
(/rubric/e ects/view/973746d613fae676132aa06b3e9ad44c/ac87de33fc4973b9e65a3f64cdc102a6/all/)
Contentment -
An increase in self-rated perceptions of contentment is seen in
(/topics/contentme See study
Minor otherwise healthy adults given centella asiatica
nt/) (/rubric/e ects/view/973746d613fae676132aa06b3e9ad44c/eee2d7f479097efee9c81817791ea64e845 502/all/)
Depression -
A reduction in depressive e ects may be secondary to the
(/topics/depression/ See study
Minor treatment of anxiety.
) (/rubric/e ects/view/973746d613fae676132aa06b3e9ad44c/821f28d3c7fa09e434c519e4de576207/all/)
There are decreased in reaction time when otherwise healthy

Reaction Time MODERATE older adults take this supplement (youth not tested) which span
(/topics/reaction- See 2 studies to choice recognition, and spatial memory reaction time but not
Minor
time/) digit vigi...
(/rubric/e ects/view/973746d613fae676132aa06b3e9ad44c/5083fd00351203a9af3c78ab0163a4e9/all/)
See more
- There appears to be stress reducing properties associated with

Stress
See study supplementation of this herb at 1g daily, although they may be
(/topics/stress/) Minor
secondary to anxiety reduction.
(/rubric/e ects/view/973746d613fae676132aa06b3e9ad44c/779e0c4c8151cfb76124bebbd1479620/all/)
Wound Healing - An increase in wound contraction rate has been noted with oral
(/topics/wound- See 2 studies supplementation of centella asiatica yet an impairment in
healing/) Minor wound granulation (formation of connective tissue).
(/rubric/e ects/view/973746d613fae676132aa06b3e9ad44c/619b05f0ecfa4cfb8c2008edf93046e079344b9d/all/)
Blood Pressure -
- No signi cant in uence on blood pressure in otherwise healthy
(/topics/blood- See study
persons given an acute dosage.
pressure/) (/rubric/e ects/view/973746d613fae676132aa06b3e9ad44c/c9578369658a996e3cc21dd06ed75dbc/all/)
-
Heart Rate - No signi cant in uence on heart rate with acute ingestion of
See study
(/topics/heart-rate/) the herb in healthy persons.
(/rubric/e ects/view/973746d613fae676132aa06b3e9ad44c/698f2ee95f5d5b1a12907b825f29b8ca/all/)
Processing Accuracy -
- No signi cant in uence on processing accuracy is seen with
(/topics/processing- See study
centella asiatica supplementation
accuracy/) (/rubric/e ects/view/973746d613fae676132aa06b3e9ad44c/c963830f5450a76157ee05918b840cb4/all/)
Subjective Well-
-
Being - Acute ingestion of this herb in otherwise healthy individuals
See study
(/topics/subjective- does not appear to alter subjective mood parameters.
(/rubric/e ects/view/973746d613fae676132aa06b3e9ad44c/0d3a9cf9f9fc0d1184b7b398fe00f3a1/all/)
well-being/)
Scienti c Research
Table of Contents:
1 Sources and Structure
()
1.1 Sources
1.2 Composition
1.3 Structure and Properties
1.4 Formulations
2 Pharmacology
2.1 Serum
2.2 Distribution
2.3 Phase I Enzymatica Interactions
3 Molecular Targets
3.1 MAPKs
3.2 Cytokines
3.3 Phospholipase A2
4 Neurology
4.1 Cholinergic Neurotransmission
4.2 Glutaminergic Neurotransmission
4.3 Neurogenesis
4.4 Neuroprotection
4.5 Anxiety
4.6 Analgesia
4.7 Depression and Mood
4.8 Attention
4.9 Memory and Learning
5 Cardiovascular Health
5.1 Cardiac Tissue
5.2 Blood Pressure
5.3 Clotting
5.4 Endothelium
5.5 Circulation
5.6 Chronic Venous Insu ciency
6 Interactions with Glucose Metabolism
6.1 Mechanisms
6.2 Diabetes
7 In ammation and Immunology
Macrophages
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7.1
7.2 Fever
7.3 Virology
7.4 Rheumatoid Arthritis
8 Interactions with Hormones
8.1 Testosterone
9 Interactions with Organ Systems
9.1 Stomach
9.2 Kidney
9.3 Testicles
10 Interactions with Aesthetics
10.1 Skin
10.2 Wound Healing
10.3 Stretch Marks
11 Interactions with Cancer Metabolism
11.1 Breast Cancer
11.2 Lung Cancer
11.3 Melanoma
11.4 Liver Cancer
11.5 Prostate
12 Nutrient-Nutrient Interactions
12.1 Vitamin E
13 Safety and Toxicology
13.1 General
13.2 Case Studies
1 Sources and Structure
1.1. Sources
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Centella asiatica (of the family Apiaceae, also known as Umbellifere[1]) is a rasayana herb from Ayurveda (/supplements/ayurveda/) that
is also referred to as Gotu kola (from Traditional Chinese Medicine (/supplements/traditional-chinese-medicine/)[1]), Indian Pennywort,
Jal Brahmi and Mandookaparni[2] as well as the Japanese term 'Tsubokusa'.[3] It is botanically synonymous with Hydrocotyle asiatica[4]
and a few of its names (Indian Pennywort and Brahmi) and ranks (Aindri, Medhya Rasayana) are used synonymously with Bacopa
monnieri (/supplements/bacopa-monnieri/), as the two have an intertwined medicinal history.[1]
This herb appears to be traditionally used for leprosy, varicose veins, a 'blood puri er', ulcers, lupus and certain eczemas, general
longevity, and of mental retardation[4][1] as well as one of its more popular usages being both internal and topical use for skin health
(wound, scar, and burn healing).[5] It is commonly used alongside bacopa monnieri for the purpose of cognitive enhancement, insofar
that the term 'Brahmi' (used to refer to bacopa monnieri) sometimes is used to refer to the combination of the two herbs.[6]
The herb itself has been reported to be tasteless and odorless with small fan-shaped green leaves with white or light purple-to-pink
or white owers; it bears small oval shaped fruits and grows in watery areas.[1]
Centella asiatica is an ayurvedic herb that is seen as a cognitive enhancer, with its past being fairly intertwined with that
of bacopa monnieri. Beyond neural regeneration, it appears to be used for purposes related to anti-in ammation (lupus
and eczema), skin regeneration, and circulation (varicose veins)
1.2. Composition
The aerial parts of centella asiatica tend to contain:
Asiatic acid (0.72-0.98% dry weight[7])[8] and its glycoside known as Asiaticoside (0.3% dry weight in chloroform, methanol, and ethyl
acetate fractions yet 0.04% in water and ethanolic[4] but much higher (1.63-2%) in the plant extract[7]). Asiatic acid consists of 26.7% of
the total triterpenoids[9]
Madecassic acid (0.72-0.95% dry weight[7]) and its glycoside Madecassoside (1.27-1.7%[7]); the isomer of Madecassoside being
Asiaticoside B (or Terminoloside as a synonym)[7] and madecassic acid saponins consist of 25.53% total saponins[9]
Madasiatic acid,[10] Asiaticoside F-G,[11] quadranoside IV,[11] and Sce oleoside A (0.0068%)[10]
Thankuniside and Isothankuniside (glycosides)[1]
Centellasaponins B (0.0063%), C (0.0084%), and D (0.0036%)[10] as well as Centellosides A and B[12]
Brahmoside and Brahminoside[1]
Ursolic acid (/supplements/ursolic-acid/) (Triterpenoid)[8]
Other triterpenoids such as 2,3,20,23-tetrahydroxyurs-28-oic acid,[13] 11,12-dehydroursolic acid lactone, pomolic acid, corosolic acid,
2,3-dihydroxyurs-12-en-28-oic acid, and 3-epimaslinic acid[8]
Centellin and Centellicin[14]
Rosmarinic acid (/supplements/rosmarinic-acid/)[8]
Ginsenosides Mc, Rk1, Rg5, Rd2, and Y[12]
(20R)-ginsenoside Rg3 and (20S)-ginsenoside Rg3[12]
Notoginsenoside ST-4 and Fe[12]
Gypenoside I and [12]
8-acetoxy-1,9-pentadecadiene-4,6-diyn-3-ol[8]
The alkaloid hydrochotine[1]
Apigenin (/supplements/apigenin/) at a comparable concentration as bacopa monnieri (/supplements/bacopa-monnieri/)[15]
Rutin (yet no Quercetin (/supplements/quercetin/) or Quercetrin content)[15]
Irbic acid (3,5-O-dica eoyl-4-O-malonilquinic acid)[16] and other phenolic acids including 3,5-Di-O-ca eoyl quinic acid, 1,5-di-O-ca eoyl
()
quinic acid, 3,4-di-O-ca eoyl quinic acid, and 4,5-di-O-ca eoyl quinic acid[3]
Kaempferol (/supplements/kaempferol/),[3] kaempferol-3-O--D-glucoside,[3] and Castilliferol (ie. kaempferol-3-p-coumarate)[17]
Quercetin (/supplements/quercetin/),[3] quercetin-3-O--D-glucoside,[3] and castillicetin (Quercetin-3-ca eate)[17]
Chlorogenic acid (/supplements/chlorogenic-acid/)[3] and Isochlorogenic acid[17]
Cadiyenol[18]
Vitamin C (/supplements/vitamin-c/) at 255.7mg/100g (0.25%)[19]
-carotene (42.5-73.7g/g of the leaves[20]), trans-lutein (82.6-133.5g/g[20]), trans-neoxanthin (5.9-14.2g/g[20]), trans-violaxanthin (20.5-
26.3g/g[20]), and other unidenti ed carotenoid structures[20] with total carotenoid reaching 17.58mg/100g[19]
Anthocyanins at up to 37.6mg/100g[19]
Chlorophyll at 29.91mg/100g[19]
Iron (29-74.3mg/100g[20]), potassium (3,079-6,295mg/100g[20]), copper (2.6-6.4mg/100g[20]), zinc (/supplements/zinc/) (11.3-

45.3mg/100g[19][20]), calcium (/supplements/calcium/) (1,150.9-2,206.1mg/100g[20][19]), sodium (1,114.2-2,597.1mg/100g[20]), manganese
(54.5mg/100g[19]), magnesium (/supplements/magnesium/) (240.7-841.3mg/100g[20]), cobalt (1.34+/-0.03mg/100g[19])
-sitosterol 3-O-glucopyranoside[8] as well as both campesterol and stigmasterol[1]
The main bioactives appear to be the triterpenoid structures, with the two major triterpenoids being asiatic acid and
madecassic acid (those two and their glycosides being at around 2% of plant weight each and being a quarter of total
triterpenoids each). The ursolic acid and rosmarinic acid contents may also be bioactive, and oddly this plant seems to
contain ginsensosides that are not found in any species of ginseng
As a vegetable product, centella asiatica has an 83.43% moisture content.[19] The dry weight (overall weight minus moisture) is 13.26%
ash content, 8.24% ber, 6.13% protein, 0.66% fat and the remaining carbohydrate.[19]
Overall, centella asiatica appears to have a relatively low avonoid and phenolic content[21] although a high tannin concentration (20-
25%).[1] The total centelloside content ('Centelloside' being a term used to collectively refer to asiatic acid, madecassic acid, and their
glycosides) is concentrated in the leaf extracts[22]) at around 20-80mg/g (2-8%) in the leaves depending on age and nutrient supply.[23]
There may be a metal chelating property with centella asiatica, with the hexane fraction showing a peak metal chelating activity (IC50
of 90g/mL) in vitro with iron sulfate.[24]
Centella asiatica appears to have antioxidant properties with both the aqueous and ethanolic extracts as assessed by FRAP, DPPH,
iron reduction and nitric oxide (/topics/nitric-oxide/) scavenging; the water extract exceeding the ethanolic in potency[21] and being
comparable in potency to Grape seed extract (/supplements/grape-seed-extract/),[25]Vitamin C (/supplements/vitamin-c/),[25] and
bacopa monnieri (/supplements/bacopa-monnieri/).[21]
()
1.3. Structure and Properties
The two main components (asiatic acid and medecassic acid) are of the saponin class, but in particular they are pentacyclic ( ve
ringed) triterpenoid saponins of the ursane class; a structurally designation similar to corosolic acid and ursolic acid
(/supplements/ursolic-acid/).
Asiaticoside appears to be poorly soluble in both ethanol and water and more soluble in chloroform, ethyl acetate, and methanol.[4]
1.4. Formulations
ECa-233 is a standardized extract of centella asiatica (no less than 80% triterpenoid saponins with a ratio of madecassoside to
asiaticoside in the range of 1.5+/-0.5).[26][27]
2 Pharmacology
2.1. Serum
An oral intake of 100mg/kg madecassoside in rats appears to reach a maximum concentration (Cmax) of 303.75+/-28.53ng/mL at
(Tmax) 0.9 hours after ingestion, exhibiting a half-life of 3.47+/-0.68 hours.[28] A double peak was noted, suggesting variations in
intestinal absorption of enterohepatic circulation (cause not con rmed).[28]
In humans, 30-60mg of the total triterpenoid fraction taken twice daily over the course of six days (with measurements after the rst
dose and after the week of dosing) noted that 30mg was able to raise plasma levels to around 700+/-110ng/mL after a single dose
and chronic treatment rose this to 1.03+/-0.05g/mL (Tmax of 4.1-4.5 hours) whereas 60mg acutely rose plasma levels to
1.36+/-0.13g/mL and chronic treatment to 1.69+/-0.07g/mL (Tmax of 4.2 hours).[29]
The half life in humans was quite variable, with di ering values with acute intake of 30mg (2.20+/-0.30 hours) and 60mg (3.40+/-0.68)
as well as chronic intake of 30mg (6.33+/-1.82) and 60mg (10.28+/-1.8).[29]
Oral intake of madecassoside at high doses reaches a nanomolar concentration in the blood, while it appears that the
standard recommended doses of total triterpenoid saponins (30-60mg twice daily) reaches the 1-2g/mL range
2.2. Distribution
Asiatic acid is known to bind to human serum albumin, particularly the IIA subdomain, which was mostly a hydrophobic interaction
with a G of 6.36 kcal/M-1.[30]
2.3. Phase I Enzymatica Interactions

In vitro, the CYP2C19 enzyme is inhibited by centella asiatica extracts at 615.1g/mL (water extract), 30.2g/mL (dichloromethane),
61.2g/mL (ethanol) and 112.5g/mL (hexane) with inhibition being noted with isolated asiatic acid (117.5g/mL or 240.4M),
asiaticoside (408.3g/mL or 425.7M), madecassic acid (92.5g/mL or 183.3M) and rosmarinic acid (/supplements/rosmarinic-acid/)
(2265.5M).[31]
The inhibition on CYP2C19 appears to be signi cantly higher than serum levels, and so while there is technically
inhibition the practical relevance of this information is not known
3 Molecular Targets
()
3.1. MAPKs
The MAPKs are three proteins involved in cellular growth and proliferation known as ERK (or MAPK), JNK (or SAPK), and p38. Centella
asiatica has been noted to inhibit ERK and p38 activation in cardiomyocytes,[32] p38 in endothelial cells,[33] and all three in
macrophages.[34]
Asiaticoside has been noted to induce transcription of DUSPP and DUSP3 fairly rapidly after incubation at 30g/mL ( broblasts)[35]
which are known to be negative regulators of the MAPK family.[36][37] It was also noted that, in macrophages, all MAPKs were
successfully suppressed in the presence of LPS due to inhibiting the activation of Raf-1[34] which is known to mediate the induction of
MAPKs in response to LPS.[38][39]
In general, the MAPKs appear to be inhibited although which particular MAPK (p38, ERK, or JNK) that is inhibited
depends on the tissue in question; this can be traced back to either induction of DUSPP and DUSP3 genes (which
suppress MAPK activity) or dysregulating the ability of Ras/Raf-1 to increase MAPK activity
In neuronal cells exclusively, centella asiatica appears to phosphorylate (activate) ERK[26][40][41] which underlies the protective and
growth e ects of this herb on brain cells.
Activation of the BDNF receptor is known to increase ERK activity in neurons[42] and centella asiatica itself increases BDNF in vivo[43]
suggesting a plausible mechanisms that is exclusive to neurons. An alternate and more plausible hypothesis is seen where
asiaticoside stimulates CREB phosphorylation which then causes an increase in BDNF secretion[40] and this increase in CREB
phosphorylation is blocked by inhibiting the upstream regulator of ERK (a protein known as MEK1[40] which couples Ras/Raf-1
signalling to ERK[44]) and the asiaticoside induced neuronal growth is blocked by MEK1 inhibition.[41]
Another alternate explanation, enhancing the activities of NGF (another growth factor) at 1M asiaticoside, is also tied into this
pathway as it relies on MEK1 activation[41] so regardless of which growth factor is causative the protein of MEK1 and the overall
Ras/Raf-1/MEK1/ERK pathway is implicated.
ERK phosphorylation is increased due to MEK1 activation, and this is known to cause neuronal growth in vitro (and since
this has been observed in animals following oral ingestion of the plant, it is thought to be biologically relevant). While
the exact mechanisms are not fully elucidated, it seems that MEK1 activation (unknown how this is activated) causes an
increase in CREB phorphorylation and a greater production of BDNF
3.2. Cytokines
In isolated THP-1 macrophages, asiaticoside has been found to augment the MCP-1 induced release of the macrophage-derived
cytokine known as IL-1, which occurs at a remarkably low concentration of 10pM to 100nM.[45]
The increase in MCP-1 induced IL-1 concentrations appears to occur at incredibly low concentrations (picomolar
range) and thus this mechanism is most likely relevant to oral supplementation of centella asiatica; possibly related to
the anti-rheumatic properties of this herb
3.3. Phospholipase A2
Centella asiatica has also been shown to inhibit phospholipase A2 on cellular surfaces in vitro[46] in cerebellum slices in a
concentration dependent manner between 31.5500g/mL (250-500g/mL nearly abolishing activity of iPLA2 and 12.5g/mL being
the lowest dose e ective against cPLA2 whereas 1.25g/mL was ine ective).[47] While thought to be neuroprotective (since elevated
phospholipase A2 activity in the brain causes cellular changes associated with neurodegeneration[48]), it is uncertain what role this
()
plays since the more resistant variant (iPLA2) consists of up to 80% of phospholipase A2 in the brain[47] and serum levels of
asiaticoside are known to reach up to 1-2g/mL in humans[29] which is in the ine ective range for cPLA2.
While there may be a direct inhibitory e ect on phospholipase A2 variants in the brain, they both appear to occur at
concentrations that are above what is seen with oral supplementation of centella asiatica and they may not occur
following oral ingestion
4 Neurology
4.1. Cholinergic Neurotransmission

Young mice given 200mg/kg of centella asiatica for 15 days appear to have a modest increase in hippocampal acetylcholinesterase
activity[49] although 150-300mg/kg over 6 weeks in a model of aluminmum toxicity (which would normally increased
acetylcholinesterase) prevented such an increase.[50]
Concentrations of up to 250g/mL of the water extract (lacking the standard saponins) have failed to inhibit acetylcholinesterase
activity.[51]
Overall, there do not appear to be any signi cant or known interactions with cholinergic neurotransmission
4.2. Glutaminergic Neurotransmission

Incubation of centella asiatica water extract (lacking the standard saponins) at concentrations up to 200g/mL have failed to protect
cells from glutamate induced cell death[51] whereas isolated asiatic acid has been shown to protect cells from glutamate induced cell
death at 10nM (100mg/kg oral intake in mice).[52]
The saponins (asiatic acid) appear to be protective against glutamate induced cell death, and the mechanisms
underlying this are not yet known
4.3. Neurogenesis
Neurotrophy (growth of neurons) appears to occur via activation of the MERK/ERK or the PI3K/Akt pathways,[53][54] which are
downstream of several neurotrophic factors such as BDNF, NT-3, and NGF acting on their receptors.[55][42]Centella asiatica saponins
have been found to phosphorylate ERK and Akt and abolishing either of these pathways prevents the neurotrophic actions of this
herb.[26]
In isolated IMR-32 neuroblastoma cells, a centella asiatica extract (52% madecassoside and 32% asiaticoside) at 1-100g/mL (but not
100nM) failed to proliferate neurons yet promoted neurite outgrowth in a time dependent but not concentration dependent manner
with a potency comparable to 100ng/mL BDNF.[26] Elsewhere, in the presence of NGF (another neuronal growth factor) ethanolic
extracts of centella asiatica were shown to augment NGF-induced neurite outgrowth thought to be mostly due to isolated asiatic acid
(active at 1M) which acted via ERK.[41]
The saponins in centella asiatica appear to promote neuronal growth
In a rat model of Parkinson's Disease (MPTP toxicity), it was noted that while neither control nor the toxin control experienced any
()
changes in BDNF levels the groups given oral madecassoside (15-60mg/kg) experienced a dose-dependent increase in BDNF
concentrations reaching about 1.5-fold at the highest tested dose.[43]
At least one study has traced back the increase in BDNF to CREB phosphorylation, and the CREB phosphorylation to the activation of
MAPKs.[40]
Centella asiatica may induce BDNF expression after oral, which is likely due to CREB being phosphorylation from MAPKs
in neurons
Oral ingestion of centella asiatica has been con rmed to increase dendritic arborization at 200mg/kg for 15 days in young mice
(apical, basal, and branching points),[49] at 1.58-4.74g/kg (dry leaf equivalent given via juice) for six weeks in rat pups in the amygdala,
[56] and in rat pups given the same dosage of juice but in the hippocampus.[57]
The aforementioned studies were in youth, although increased dendritic arborization has been noted in adult rat hippocampuses
given the leaf juice at the highest aforementioned dose (4.74mg/kg appeared to be signi cant whereas 1.58-3.16mg/kg were not)[58]
as well as the amygdala.[59] The increases also took six weeks to manifest, but reached a 47118% increase in apical dendritic
intersections (111% increase in branching points) and 4790% increase in basal intersections (105% increase in branching points).[58]
When investigating the number of dendritic interactions within a particular distance from the neuron, all dendritic interactions
between 20-100 microns in length appear to be enhanced.[57][49][56] Furthermore, there appears to be a time-related as well as dose-
related response with up to four weeks being required for increased dendritic arborization.[49][56][57] Adult subjects also experience
increases in most lengths of dendrites and have a time-related bene t, but the time may be more delayed (requiring six weeks for a
dosage that is e ective in four for youth).[58]
This increased growth of neurons appears to occur in living creatures who ingest the herb at reasonable dosages. While
this occurs in both youth and adults rats, adults seem a bit more resistant to the changes
4.4. Neuroprotection
Centella asiatica has shown neuroprotective e cacy at an oral intake of 150-300mg/kg in rats when ingested over six weeks alongside
aluminum (neurotoxic dose),[50] against a model of stroke when 100-300mg/kg of the water extract is preloaded for 21 days where
centella asiatica exerts a dose dependnet e ective with maximal e cacy in reducing infarct volume from 40% to 10%,[60] protects
mice against -amyloid toxicity,[51] monosodium glutamate,[61] and oral doses as low as 5mg/kg centella asiatica (8.08.6% saponins
and 0.8% asiaticoside) for 10 days prior to 3-NPA toxicity have shown some protective e ects.[62][63]
When looking at various toxic components, centella asiatica appears to be generally neuroprotective and with a potency
that isn't overly remarkable but still somewhat respectable. In particular, it has been noted to occur at low oral doses
suggesting that this is relevant to oral supplementation of centella asiatica
Seven days ingestion of madecassoside (15-60mg/kg) prior to an injection of MPTP (neurotoxin that mimicks early phase Parkinson's
Disease[64]) was able to dose-dependently reduce motor de cits as assessed by a ladder walking test, with 60mg/kg e ectively
normalizing performance relative to control.[43] 30-60mg/kg were also able to signi cantly preserve dopamine and attenuate changes
in oxidative (Glutathione and TBARS) and genetic (Bcl but not Bax) alterations, but neither dose exerted absolute protection.[43]
An increase in BDNF was seen with madecassoside[43] which is known to protect neurons from MPTP[65][66] via inducing Bcl-2 and
reducing cellular death[67][68] (more cell preservation causing a preservation of dopamine synthesis) suggesting that this is the
mechanism of action.
Centella asiatica is thought to be neuroprotective via the same mechanism that it induces neuronal growth, via inducing
BDNF protein levels
4.5. Anxiety
()
In non-stressed mice, 100-300mg/kg of the ECa-233 extract showed slightly anxiolytic properties[27] and a juice extract for 15 days in
otherwise normal mice has shown anxiolytic properties in a hole-board test.[49] When looking at various extracts of centella asiatica, it
seems that while the water extract (200mg/kg) is ine ective in reducing anxiety on an elevated plus maze test both the chloroform
and methanolic extracts at the same dose are e ective.[69]
In stressed mice, the increase in corticosterone is hindered with 10mg/kg and abolished by 30-100mg/kg (similar to 2mg/kg and
10mg/kg diazepam) whereas anxiety is abolished by 100mg/kg;[27] the isolated madecassoside (16mg/kg) and asiaticoside (10mg/kg)
in doses equivalent to the 30mg/kg dosage were signi cantly less e ective.[27]
Animal studies suggest anxiolytic properties somewhat comparable to diazepam albeit requiring a higher dosage, and
these may occur following a single dose of the supplement. They may occur even if the subject is not inherently
stressed, albeit to a lesser degree than anxious/stressed subjects
A 70% ethanolic extract of the aerial parts of centella asiatica at 500mg twice daily (1,000mg total) in persons with generalized anxiety
disorder over the course of 60 days noted time dependent reductions in anxiety that reached 13.1% at 30 days and 26% at the end of
the trial.[2]
Comparable reductions were noted in self-reported stress (12.5% at 30 days and 23.2% at trial end) and depression (10.2% and
21.8%, respectively).[2]
Anxiety reduction has been reported in humans given oral supplementation of the plant, and this appears to be due to
the saponin content
4.6. Analgesia
1-10mg/kg asiatic acid appears to have analgesic e ects against acetic-acid induced writhing, the late phase of the formalin test, and
a carrageenan test with 10mg/kg asiatic acid being comparable to 10mg/kg indomethacin. Other parameters measured such as
serum cytokines (TNF- and IL-1) and oxidative changes were identical between 10mg/kg asiatic acid or indomethacin yet asiatic
acid seemed more e ective at reducing COX-2 and NF-kB activation.[70]
Appears to have pain killing properties
4.7. Depression and Mood

Oral ingestion of 250-750mg centella asiatica extract (3% polyphenolics and 5% asiaticoside plus asiatic acid) given either acutely or
over the course of 1-2 months in otherwise healthy older adults there was a trend to increase P300 latency (failed to reach statistical
signi cance) and while P300 amplitide and N100 latency were wholly una ected there appears to be a signi cant increase in N100
amplitude after two months of supplementation to near doubling.[71] These changes were associated with an increase in calmness,
contentment, and alertness.[71]
4.8. Attention
An increase in attention has been noted with 1,000mg centella asiatica in two divided doses, reaching 13.4% after 30 days and 27.8%
after 60 days, which is thought to be secondary to reduced symptoms of anxiety and stress in persons with generalized anxiety
disorder.[2] Elsewhere, otherwise healthy older adults given 250-750mg of an extract containing 5% asiaticoside plus asiatic acid for
two months there was a signi cant reduction in choice, numerical working memory, and spatial memory reaction time but not simple
reaction nor digit vigilance time.[71]
The usage of centella asiatica for ADHD has only been tested in conjunction with a large amount of herbs (Paeoniae Alba,
Ashwagandha (/supplements/ashwagandha/), Spirulina (/supplements/spirulina/), Bacopa Monnieri (/supplements/bacopa-
monnieri/), and Lemon Balm (/supplements/melissa-o cinalis/)) which, while e ective, cannot be used to evaluate the e cacy of
centella asiatica itself.[72]
()
A single dose of 12g of centella asiatica (basic herb) was able to signi cantly attenuate the acoustic startle response (ASR) in otherwise
healthy persons at 30-60 minutes after ingestion without signi cantly a ecting mood state, suggesting anxiolytic and anti-fear
properties.[73]
4.9. Memory and Learning

Mechanistically, in vitro application of a centella asiatica extract has noted CREB phosphorylation in neuroblastoma cells at a
concentration range of 1-200g/mL with an EC50 of 26g/mL; this was due to the saponin content, where asiaticoside and
madecassoside possess EC50 values of 3.8M and 5.7M respectively.[40] This CREB phosphorylation was blocked with the MAPK
inhibitor PD98059 (MEK1 inhibitor, MEK1 mediating the in uence of Raf-1 on ERK[44]) and enhanced CREB phosphorylation was
shown in vitro to enhance BDNF secretion[40] which is thought to underlie the brain's arborization[57] and regeneration;[41] two
phenomena seen with centella asiatica.
It was con rmed that PKA, nitric oxide (/topics/nitric-oxide/), and the NMDA receptor (all known to stimulate CREB) were uninvolved
with the actions of centella asiatica and its components.[40]
Appears to enhance CREB phosphorylation, and this occurs at a low enough concentration that it is probably relevant to
oral supplementation (perhaps higher doses, however). This is secondary to MAPK activation, and ultimately results in
increased BDNF production
When looking at studies assessing the anti-amnesiac e ects of centella asiatica, it appears to have protective e ects against -amyloid
(as assessed by the Tg2576 genetic strain of mice) at 200mg/kg of the water extract,[51] against streptozotocin-induced cognitive
impairment (100-300mg/kg),[74] D-galactose induced amnesia,[75] and pentylenetetrazole-induced cognitive impairment with the 100-
300mg/kg dose.[76] When looking at studies investigating solely saponins, asiatic acid at 100mg/kg is able to reduce cognitive
impairment in a model of glutamate excitotoxicity.[52]
In looking at anti-amnesiac mechanisms, a bene cial trend in oxidation is seen[51][74][75][76] despite the water extract (used in some
studies and free of both asiatic acid and madecassic acid) not possessing direct antioxidative e cacy.[51]
In regards to the anti-amnesiac e ects of centella asiatica, there appears to be components in the water extract
(excludes the saponins) as well as the saponins themselves which have protective e ects on neurons. The anti-
amnesiac e ects are respectable but not absolute even at the highest e ective tested dose (300mg/kg in rats)
Mice (young and adult) given 200mg/kg centella asiatica daily for 15 days appeared to experience increased performance in a radial
arm maze[49] and elsewhere a study over 14 days using 200mg/kg of one of three extracts (water, methanolic, or chloroform) noted
that only the water extract was e ective and that while 200mg/kg was more e ective than 100mg/kg that it was equivalent to
300mg/kg (assessed via step through, step down, and shuttle box experiments).[69] Leaf extracts (water) have shown improvements
in adult rat cognitive elsewhere.[77]
Asiatic acid in isolation has shown cognitive enhancing properties, albeit at an oral dose of 30mg/kg in rats (1-10mg/kg inactive) as
assessed by active and passive avoidance tasks.[78]
The centella asiatica extract does appear to have inhernet cognitive enhancing properties, and while isolated
asiaticoside is implicated in cognitive enhancement it seems that the water extract (lacking saponins) is also e ective;
suggesting that there are multiple bioactive components
5 Cardiovascular Health
5.1. Cardiac Tissue
()
Madecassoside is known to have antiin ammatory e ects in immune cells[79] and this appears to extend to cardiomyocytes at a
concentration of 100-300M when preloaded before LPS by 2-4 hours.[32] This protective e ect in cardiomyocytes was associated
with activation of ERK and p38 (but not JNK) resulting in inhibition of NF-kB.[32]
The antiin ammatory properties of madecassoside appear to extend to cardiomyocytes
Oral ingestion of 20mg/kg madecassoside to rats for ve days with the nal dose two hours prior to LPS infusion is able to attenuate
the changes in blood pressure and heart rate.[32] 2-50mg/kg madecassoside prior to ischemia/reperfusion dose-dependently reduced
infarct size, with the higher two doses (10-50mg/kg) being comparable to the reference drug of 10mg/kg nifedipine.[80] This study also
noted less potency in normalizing markers of cell damage (LDH and CK) yet more potency in normalizing antioxidant biomarkers
(SOD and MDA).[80]
Madecassoside appears to be active when orally ingested in rodents, and can protect from cardiac stressors when
preloaded
5.2. Blood Pressure

Acute administration of 30mg/kg asiatic acid to rats (but not 1-10mg/kg) is able to slightly and acutely reduce systolic and diastolic
blood presure.[78]
5.3. Clotting
A slight inhibitory e ect on platelet reactivity is noted with oral ingestion of 3,5-di-O-ca eoyl quinic acid at 4mg/kg bodyweight twice
daily over 14 days in rats;[3] avonoids of centella asiatica and asiaticoside are ine ective.[3]
5.4. Endothelium
30-300M madecassoside (but not 10M) is able to attenuate the damage done by H2O2 attenuated the changes in glutathione and
MDA in a concentration dependent manner, but only up to around half restoration;[33] This was associated with inhibition of MAPK
phosphorylation (although ERK was una ected)[33] which is known to be an upstream regulator of caspase-3[81] and its reduction may
explain the increased mitochondrial integrity with madecassoside.[33]
5.5. Circulation
One trial has assessed the e ects of centella asiatica on normal controls, persons with moderate super cial venous hypertension, and
those with postphlebitic limbs and severe venous hypertension.[82] 60mg centella asiatica thrice daily was able to bene t
microcirculation in all subjects albeit it was signi cantly more e ective in those with more severe symptoms.[82]
In diabetics with microangiopathy, 60mg of the saponins from centella asiatica twice daily over the course of six months, there was a
signi cant improvement in microcirculation relative to both control and placebo.[83] This same dose for 12 months in diabetics with
both microangiopathy and diabetic neuropathy also noted bene ts to the degree of 38% (improved venous response) associated
with a reduction in edema in extremities approximately 28% less than placebo control;[84] those without neuropathy also bene tted
from 12 months of treatment, but to a lesser degree of 22.7% for venous responsiveness and 9.5% for edema.[84]
In subjects with mild to moderate super cial venous disease given triterpenoids from centella asiatica before a three hour ight
(60mg of saponins thrice daily for the two days preceding the ight), supplementation was associated with signi cantly less ankle and
leg swelling (relative to placebo).[85]
5.6. Chronic Venous Insu ciency

Chronic venous insu cieny is a circulatory disorder that is caused by the obstruction or re ux of blood ow in the veins due to
abnormalities of the venous wall and valves,[86] and tends to result in varicose veins (aesthetic) and venous ulcers (medically
important) as a side-e ect of high venous blood pressure[87] resulting in reduced quality of life.[88]Centella asiatica has been
traditionally used for circulatory disorders, and similar to some other supplements (Pycnogenol (/supplements/pycnogenol/) and
()
Horse Chestnut (/supplements/horse-chestnut/)) it has been investigated for its therapeutic usage in CVI.[89]
Mechanistically, centella asiatica and its saponins are known to inhibit elastase and hyaluronidase[90] with a potency greater than
horse chestnut.[91] Hyaluronidase is known to degrade hyaluronic acid (component of capillaries) and elastase degrades numerous
targets in the extracellular matrix (elastin, collagen, proteoglycans, bronectin) and it is thought their overactivity can augment
plasma leakage through the endothelial wall (which results in edema).[91][92]
Centella asiatica is known to be used to treat chronic venous insu ciency, a circulatory disorder primarily associated
with the veins.
One review[89] has noted eight trials that investgiated the role of centella asiatica in chronic venous insu cient, three of which
involved venous insu cient[93][94][95] and ve of which involved venous hypertension.[96][97][98][99][100] While one study used 60mg of
centella asiatica total saponins once daily only[93] and another studies used 30mg twice[96] or thrice[99] daily, most studies have used a
twice daily approach at 60mg[100][95][98][97][96] yet all studies note e cacy over placebo.
Relatively low oral doses of the saponins from centella asiatica appear to be reliable in the treatment of chronic venous
insu ciency and in improving microcirculation; other symptoms of chronic venous insu ciency, such as leg
pain/edema as well as varicose veins, appear to be reduced alongisde other symptoms
6 Interactions with Glucose Metabolism
6.1. Mechanisms
5-20mg/kg oral intake of asiatic acid over 45 days in streptozotocin-induced diabetic rats was able to dose-dependently reverse the
changes in blood glucose and insulin, although the highest dose was less potent than the refernece drug of 600g/kg
glibenclamide[101] aside from restoring HbA1c and enzymatic function (Hexokinase, G6P, and F-1,6-BP) where they were equal.[101]
Non-diabetic rats given 20mg/kg asiatic acid do not experience any changes in glucose or insulin concentrations.[101]
6.2. Diabetes
In diabetic patients with wounds, thrice daily supplementation of a centella asiatica supplement containing 100mg asiaticoside for 21
days seemed to be associated with a signi cantly faster rate of wound contraction yet suppression on the rate of granulation.[102]
7 In ammation and Immunology
7.1. Macrophages
Asiatic acid and asisaticoside at 30-120M were both able to suppress LPS-induced in ammation in RAW 264.7 macrophages as
assessed by cytokine secretion as well as both nitrite and PGE2 production, these were due to inhibition of NF-kB;[34] the inhibition of
NF-kB was secondary to inhibiting phosphorylation of p38, ERK1/2, and JNK (MAPKs) and this inhibition was due to preventing
phosphorylation of Raf-1 (60-120M abolishing phosphorylation)[34] which is known to stimulate the MAPKs.[38][39]
Madecassoside has also been con rmed to inhibit NF-kB activation in macrophages[79] although elsewhere 10-100M has failed to
reduce nitric oxide (/topics/nitric-oxide/) production in LPS activated macrophages.[103]
()
The triterpenoids appear to have antiin ammatory e ects at moderate to higher concentrations, and this is associated
with suppression of NF-kB activation
Asiaticoside, in vitro with THP-1 macrophages, appears to augment the MCP-1 induced secretion of IL-1 at concentrations of 10pM
to 100nM without inherently having an e ect in the absence of MCP-1; the increase in secretion was around 30%.[45]
Asiaticoside appears to augment a macrophage dependent release of IL-1, and this occurs at remarkably low
concentrations
7.2. Fever
In fevers, macrophages activation and induction of the COX enzymes will produce PGE2. This prostaglandin binds to its receptors in
the brain to suppress heat losses and augment heat retention[104][105] causing fever symptoms. Due to the traditional usage of
centella asiatica as an antipyretic and its ability to suppress COX expression elsewhere, it has been investigated in fevers.
Three days supplementation of isolated asiaticoside (5-45mg/kg) to rats the subject to lipopolysaccharide (LPS) infusion was able to
attenuate the rise in body heat seen with LPS induced fever, and pretreatment of 45mg/kg asiaticoside was as potent as an infusion
of 50mg/kg paracetamol given once after LPS.[106] These anti-fever e ects are associated with increases in serum IL-10 (which is
known to reduce fevers via inducing heme-oxygenase 1 or HO-1[107][108]) and HO-1 was con rmed to be increased with asiaticoside;
blocking HO-1 prevents the antipyretic e ects of asiaticoside.[109]
May have anti-pyretic (fever reducing) properties secondary to causing an increase in circulating IL-10, which then
causes an increase in HO-1 activity
7.3. Virology
Centella asiatica (methanolic extract) appears to have anti-viral properties against herpes simplex, with inhibitory properties against
HSV-1 (EC50 of 362.40g/mL) and HSV-2 (EC50 of 298.84g/mL), a potency signi cantly lesser than the reference drug (Acyclovir 0.14-
0.15g/mL) and the herbs Maclura cochinchinensis and Magnifera indica (both around 20g/mL).[110] This moderate level of potency
has been replicated elsewhere.[111]
This may be related to the asiaticoside content.[110]
Technically there are anti-herpes simplex properties, hindering viral replication, but the potency seems to be
signi cantly lesser than other herbs and the reference drugs. May still be useful for topical application, but the
concentrations may be too high for oral ingestion
7.4. Rheumatoid Arthritis

In collagen-induced arthritis in mice, oral ingestion of 10-40mg/kg for 20 days was able to dose-dependently reduce in ammation,
and this appears to be associated with reductions in anti-CII antibodies (21.1-62% reductions at 20-40mg/kg) and reduced immune
cell reactivity to said antibodies.[103] This has been replicated elsewhere with 10-30mg/kg madecassoside, where it was noted that
circulating in ammatory cytokines were reduced and the antiin ammatory IL-10 upregulated alongside improvements in arthritis
symptoms[112] and the potency of madecassoside (10-30mg/kg) appears comparable to indomethacin (10mg/kg)[112] yet lesser than
dexamethasone (1mg/kg).[103]
8 Interactions with Hormones

()
8.1. Testosterone
In rats who consumed centella asiatica at a dose that impairs fertility (10-100mg/kg aqueous extract), it appears that testosterone is
reduced in a dose dependent manner.[113]
9 Interactions with Organ Systems
9.1. Stomach
Oral ingestion of a centella asiatica extract (hot water extract) at 50-500mg/kg bodyweight prior to alcohol (/supplements/alcohol/)
ingestion if able to reduce ulcer formation by 58-82%[114] and a subsequent test using 200-600mg/kg of the leaf juice (twice daily for
ve days) was able to protect against all tested stressors (aspirin, ethanol, stress, and pyloric ligation) with a potency comparable to
250mg/kg sucralfate.[115]
Appears to have somewhat respectable anti-ulcer properties in the stomach
9.2. Kidney
Centella asiatica appears to be used in traditional chinese medicine (/supplements/traditional-chinese-medicine/) for the purposes of
being a kidney tonic and promoting diuresis.[116]
In rats subject to adriamycin-induced renal toxicity (a model for nephrotic syndrome), oral 8-32mg/kg asiaticoside for four weeks was
able to reduce protein losses in the urine with 16-32mg/kg being as potent as 25mg/kg prednisone;[116] these protective e ects were
thought to be related to the preservation in integrity of the podocytes (last barrier against protein losses in the urine[117]).[116]
Asiaticoside appears to be protective of the kidneys against animal models of nephrotic syndrome
9.3. Testicles
Water extracts of centella asiatica (200mg/kg) were able to nearly normalize adverse changes in lead-induced impairments in sperm
cell morphology, motility, and count[118] without inherently a ecting sperm function or enzymatic (3-HSD and 17-HSD) activity.[118]
It has been noted that centella asiatica extracts (aqueous extract of dry leaves) at 10-100mg/kg to rats have increased testicular
weight yet caused abnormal morphology of sperm cells[119] thought to be related to the glycosides isothankuniside and thankuniside.
[1] A later study noted a decrease in testicular weight alongside dose-dependent decreases in sperm cell viabiltiy, motility, and count
which were associated with increased apoptosis in sperm cells.[113] It is unclear why the results from this research group di er from
the other ones.
10 Interactions with Aesthetics
10.1. Skin
30g/mL asiaticoside has been noted to induce genes associated with skin cell proliferation and collagen synthesis[35] and to
()
promote skin cell migration, attachment, and growth in vitro[120] while collagen type I and III mRNA has been noted to be increased at
1-10M concentrations of both asiaticoside and madecassoside (the latter being more potent).[121]
In keloid broblasts (keloids refer to excessive skin proliferation and scar formation, and tend to be exacerbated by TGF-1 since it
plays a role in tissue regeneration[122] but is dysregulated in prolonged and impaired wound healing resulting in scar formation[123]),
asiaticoside at 100-500g/mL inhibits keloid proliferation in a concentration and time dependent manner over ve days of incubation
(without a ecting normal broblasts, reducing keloids to 35-63% of baseline) associated with increasing Smad7 expression and
downregulating TGF- receptors which suppressed collagen synthesis.[124]
When looking at what happens to skin cells, they appear to experience an increase in collagen synthesis and enhanced
growth and proliferation when they are subject to centella asiatica glycosides (asiaticoside and madecassoside); the
opposite seems to occur in scar tissue
When looking at the enzymes of elastase and hyaluronidase asiaticoside shows inhibitory potential against their activity with IC50
values of 19.45+/-0.25g/mL (elastase) and 18.63+/-0.33g/mL, a potency comparable to ursolic acid (/supplements/ursolic-acid/)[90]
and greater than other medicinal plants such as clitoria ternatea (/supplements/clitoria-ternatea/)[125] and horse chestnut
(/supplements/horse-chestnut/).[91]
Madecassoside showed an increase in TIMP-1 mRNA (which normally sequesters MMP-1[126] which would preserve collagen, this also
being seen with asiaticoside[35]) but the ratio of TIMP-1:MMP-1 was unaltered suggesting no change in collagen breakdown.[121]
Elsewhere, asiaticoside has been shown to reduce MMP-1 activity in vitro[90] with a potency comparable to oleanolic acid.
Both madecassoside (3-10M) and asiaticoside (10M) also stimulated TGF-1 and TRII mRNA and Smad3 protein levels while
downregulating Smad7; the aglycones were inactive[121] and this stimulation of collagen synthesis and TGF-1 mRNA is independent
of the TGF-1 receptor.[127]
There appears to be a bene cial trend in enzymes and proteins involved in skin synthesis, with a downregulation of
MMP-1, elastase, and hyaluronidase activiy with an increase in transforming growth factor mRNA levels
There appears to be an increase in macrophage (but not leucocyte) concentration as well as some cytokines (MCP-1, VEGF, IL-1) in
the wound exudate of rats topically treated with asiaticoside, and macrophages in vitro were the cause of the increased IL-1 when in
the presence of MCP-1 (but not inherently).[45]
There appears to be increased macrophage recruitment to wounds associated with asiaticoside
Elastase and hyaluronidase are both involved in loss of skin elasticity with sun exposure[128] and MMP-1 is involved in wrinkle
formation;[129] due to the inhibitory potential of asiatocisde against all three aforementioned proteins, it is investigated as a topical
agent against skin aging.[90]
Elsewhere, centella asiatica appears to suppress pro-apoptotic changes in mRNA that occurs following UVB exposure.[130][131]
Centella asiatica may possess anti-aging properties on the skin when topically applied, secondary to reducing the
damaging e ects of UV radiation. While not tested in a living model yet, it appears more potent than other supplements
at this goal
10.2. Wound Healing

Centella asiatica appears to be a commonly ingested or topically applied herb for the purpose of wound healing, similar to aloe vera
(/supplements/aloe-vera/).[5] Of the phases of wound healing (reducing bacterial contamination, reducing in ammation, and
promoting resynthesis) centella asiatica appears to be recommended for the speci c purpose of promoting resynthesis of tissue.[5]
()
Appears to be traditionally used both topically (applied to the skin) and internally (consumed) for the purpose of wound
regeneration
When looking at burn healing rates, rats subject to burns and then fed either the glycosides (6-24mg/kg) or the aglycones (3-12mg/kg)
noted accelerated burn healing rates with madecassoside relative to asiaticoside (although both were e ective) while the aglycones
were ine ective.[121] Elsewhere, isolated madecassoside (6-24mg/kg) in burned rats appears to cause dose and time dependent
bene ts to wound closure associated with increased angiogenesis[132]
Topically applied centella asiatica herb extract (0.002-0.005%) or lower concentrations of isolated asiaticoside (10pg to 100ng per
wound in rats) is able to reduce wound size from a burn over 20 days of observation.[45]
Appears to have the ability to enhance burn healing rates when orally ingested as well as topically applied
In a punch wound model, 0.2% topical asiaticoside is able to increase wound tensile strength (57%) and collagen content when 0.1%
or lower was ine ective and in diabetic rats (wound healing rate is attenuated[133]) a higher concentration of 0.4% was required to
reduce wound size by 42% and increase tensile strength by 66%.[134]
Oral intake of 1mg/kg asiaticoside was found to accelerate wound healing by reducing the wound area by 28% and increased
collagen content by 76%, but half this dose and 10-fold the dose were both ine ective.[134]
Appears to possess wound healing properties when tested in non-burn models (physical trauma)
10.3. Stretch Marks

Centella asiatica has been used alongside other nutraceuticals (Vitamin E (/supplements/vitamin-e/),[135] rosehip oil,[136] and
hydroxyprolisilane CN[136] which is hydroxyproline and silicium) for the treatment of striae gravidarum (stretch marks), which is a
condition caused by either suppression of broblast proliferation (glucocorticoid usage) or mechanical stretching that exceeds the
rate of rboblast proliferation.
While the combination therapy appears highly e ective,[135][136] there are currently no studies asssessing the e cacy of centella
asiatica in isolation.
May have a role in reducing stretch marks, although this is not yet ascertained
11 Interactions with Cancer Metabolism
11.1. Breast Cancer

In MCF-7 and MDA-MB-231 breast cancer cells, asiatic acid is able to induce S-G2/M phase arrest and induce apoptosis with IC50
values of 5.95M and 8.12M, respectively[137] and 10M of asiatic acid can induce 95% apoptosis over 48 hours in vitro.[138] This was
due to inhibition of two MAPKs (p38 and ERK) causing an increase in p21/WAF1 independent of p53 (as asiatic acid did not in uence
p53) and also independent of JNK and Fas/Fas Ligand.[137] The overall protein content of p38 and ERK are not in uenced, just their
phosphorylation status.[137]
The aforementioned apoptosis is a mitochondrial-dependent pathway, and while p38 was required for the phase arrest both p38 and
ERK played a role in mitochondrial-dependent apoptosis[137] ultimately causing DNA fragmentation in these cancer cells.[138]
()
Asiatic acid signals via p38 to cause cell cycle arrest in breast cancer cells, and via both p38 and ERK to cause cellular
apoptosis; these occur at a concentration probably relevant to oral supplementation
11.2. Lung Cancer

Asiatic acid appears to have antiproliferative e ects on A549 lung carcinoma cells with an IC50 of 44.95+/-5.14M and on PC9/G cells
with an IC50 of 58.04+/-2.90M.[139]
Possible antiproliferative e ects at higher than normal concentrations of asiatic acid
11.3. Melanoma
SK-MEL-2 cells appear to experience apoptosis with asiatic acid with an IC50 of around 40M (despite a clear drop to less than 20%
viability at 50M) which was associated with an increase in oxidative damage from the mitochondrial pathway yet no alterations in
p53.[140]
Appears to induce apoptosis, possibly similar to the mechanisms seen in breast cancer cells due to no p53 involvement
11.4. Liver Cancer

In isolated HepG2 cells (hepatoma), asiatic acid is able to cause intracellular calcium in ux at around an IC50 of 30M yet reaches 20%
cell viability at 40M.[141] This increase in calcium in ux is known to mediate apoptosis[142] via activating p53[143] and increased p53
was noted to be secondary to calcium in ux in these cells.[141] Elsewhere, asiatic acid has noted a similar IC50 for apoptosis at 45M
in HepG2 cells.[30]
As evidenced in prostatic cancer cells, this increased calcium in ux may be from disrupting the endoplasmic reticulum (an
intracellular storage of calcium).[144]
Appears to cause calcium in ux at moderate to higher concentrations, causing an increase in p53
11.5. Prostate
PPC-1 prostatic cancer cells incubated with asiatic acid is able to induce cell death with an LD50 of 42+/-3.5M peaking at eight hours
of incubation. This was associated with the mitochondrial dependent pathway (increasing levels of caspase 2, 3, and 8 but not 9)[144]
but there appears to also be a mitochondrial independent pathway causing apoptosis which involved calcium release from physically
disrupting the endoplasmic reticulum.[144]
Appears to induce apoptosis in prostatic cells via two independent mechanisms
12 Nutrient-Nutrient Interactions
12.1. Vitamin E
While both the ethanolic extract of centella asiatica and Vitamin E (/supplements/vitamin-e/) show concentration-dependent
()
antioxidant properties in vitro, the combination was highly synergistic as the theoretically additive IC50 values (gained by adding the
individual IC50 of vitamin E and centella asiatica and assuming they are complementary) was reduced from 594-15,394ng/mL
(depending on extraction process) down to 14.9-584.2ng/mL (2-3% of the theoretical value).[145] This was thought to be due to centella
asiatica recycling vitamin E in the same manner that Vitamin C (/supplements/vitamin-c/) does.[145]
On in vitro antioxidant tests, centella asiatica appears to be highly synergistic with Vitamin E
13 Safety and Toxicology
13.1. General
An acute oral dose of 10g/kg of the centella asiatica extract ECa-233 (80% saponins) failed to exert acute toxicity to mice when
observed over 14 days, and in a subchronic study doses of up to 1g/kg daily over the course of 90 days was not associated with any
clinically relevant toxicological symptoms.[146]
13.2. Case Studies

There is a case study of a 15 year old girl on lymecycline (acne medication) for eight weeks who took an undisclosed herbal
medication for her acne of which one ingredient was centella asiatica (dosage and other ingredients not disclosed); that being said,
injury occurred upon rechallenge suggesting the product in question was causative.[147] While the acne mediciation belongs to a class
of molecules (tetracyclines) that may induce liver damage, these tend to occur within 4-5 days of ingestion.[148]
Elsewhere, three women have had reactions to centella asiatica itself (jaundice alongside liver in ammation and apoptosis/necrosis)
and one women had a reaction to reintroduction of the same product; all subjects were successfully treated with ursodeoxycholic
acid.[149]
There are a few case studies that pinpoint causation on the products containing centella asiatica as symptoms reoccur with
reintroduction, this isn't fully causative to say the herb causes liver damage but reasonable to suspect it and it isn't
ascertained what made these particular women susceptable
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98. Cesarone MR, et al. Microcirculatory effects of total triterpenic fraction of Centella asiatica in chronic venous hypertension: measurement by laser Doppler, TcPO2-CO2, and leg volumetry
99. De Sanctis MT, et al. Treatment of edema and increased capillary filtration in venous hypertension with total triterpenic fraction of Centella asiatica: a clinical, prospective, placebo-controlled, randomized, dose-
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()
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103. Liu M, et al. Anti-rheumatoid arthritic effect of madecassoside on type II collagen-induced arthritis in mice (http://www.ncbi.nlm.nih.gov/pubmed/18652917). Int Immunopharmacol. (2008)
104. Inoue W, et al. Brain-specific endothelial induction of prostaglandin E(2) synthesis enzymes and its temporal relation to fever (http://www.ncbi.nlm.nih.gov/pubmed/12204293). Neurosci Res. (2002)
105. Ivanov AI, et al. Prostaglandin E(2)-synthesizing enzymes in fever: differential transcriptional regulation (http://www.ncbi.nlm.nih.gov/pubmed/12376404). Am J Physiol Regul Integr Comp Physiol. (2002)
106. Preventive effect of asiaticoside on lipopolysaccharides-induced fever and its influence on levels of inflammatory factors in rats (http://en.cnki.com.cn/Article_en/CJFDTOTAL-YLBS200703012.htm).
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108. Leon LR, et al. An antipyretic role for interleukin-10 in LPS fever in mice (http://www.ncbi.nlm.nih.gov/pubmed/9887180). Am J Physiol. (1999)
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110. Yoosook C, et al. Anti-herpes simplex virus activities of crude water extracts of Thai medicinal plants (http://www.ncbi.nlm.nih.gov/pubmed/10715843). Phytomedicine. (2000)
111. Zheng MS. An experimental study of the anti-HSV-II action of 500 herbal drugs (http://www.ncbi.nlm.nih.gov/pubmed/2550706). J Tradit Chin Med. (1989)
112. Li H, et al. Madecassoside attenuates inflammatory response on collagen-induced arthritis in DBA/1 mice (http://www.ncbi.nlm.nih.gov/pubmed/19135346). Phytomedicine. (2009)
113. Heidari M, et al. The inductive effects of Centella asiatica on rat spermatogenic cell apoptosis in vivo (http://www.ncbi.nlm.nih.gov/pubmed/21870191). J Nat Med. (2012)
114. Cheng CL, Koo MW. Effects of Centella asiatica on ethanol induced gastric mucosal lesions in rats (http://www.ncbi.nlm.nih.gov/pubmed/11104366). Life Sci. (2000)
115. Sairam K, Rao CV, Goel RK. Effect of Centella asiatica Linn on physical and chemical factors induced gastric ulceration and secretion in rats (http://www.ncbi.nlm.nih.gov/pubmed/11480209). Indian J Exp Biol.
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116. Wang Z, Liu J, Sun W. Effects of asiaticoside on levels of podocyte cytoskeletal proteins and renal slit diaphragm proteins in adriamycin-induced rat nephropathy (http://www.ncbi.nlm.nih.gov/pubmed/23871990).
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117. Kerjaschki D. Caught flat-footed: podocyte damage and the molecular bases of focal glomerulosclerosis (http://www.ncbi.nlm.nih.gov/pubmed/11733553). J Clin Invest. (2001)
118. Sainath SB, et al. Protective role of Centella asiatica on lead-induced oxidative stress and suppressed reproductive health in male rats (http://www.ncbi.nlm.nih.gov/pubmed/21843793). Environ Toxicol Pharmacol.
(2011)
119. Evaluating the effects of Centella asiatica on spermatogenesis in rats (http://www.jri.ir/en/showarticle.aspx?id=258).

120. Lee JH, et al. Asiaticoside enhances normal human skin cell migration, attachment and growth in vitro wound healing model (http://www.ncbi.nlm.nih.gov/pubmed/22939261). Phytomedicine. (2012)
121. Wu F, et al. Identification of Major Active Ingredients Responsible for Burn Wound Healing of Centella asiatica Herbs (http://www.ncbi.nlm.nih.gov/pubmed/23346217). Evid Based Complement Alternat Med. (2012)
122. Suppression of TGF-1/SMAD pathway and extracellular matrix production in primary keloid fibroblasts by curcuminoids: its potential therapeutic use in the chemoprevention of keloid
(http://link.springer.com/article/10.1007/s00403-010-1075-y).
123. Leask A, Abraham DJ. TGF-beta signaling and the fibrotic response (http://www.ncbi.nlm.nih.gov/pubmed/15117886). FASEB J. (2004)
124. Tang B, et al. Asiaticoside suppresses collagen expression and TGF-/Smad signaling through inducing Smad7 and inhibiting TGF-RI and TGF-RII in keloid fibroblasts
(http://www.ncbi.nlm.nih.gov/pubmed/21240513). Arch Dermatol Res. (2011)

125. Maity N, et al. Standardized Clitoria ternatea leaf extract as hyaluronidase, elastase and matrix-metalloproteinase-1 inhibitor (http://www.ncbi.nlm.nih.gov/pubmed/23112418). Indian J Pharmacol. (2012)
126. Keyszer G, et al. Circulating levels of matrix metalloproteinases MMP-3 and MMP-1, tissue inhibitor of metalloproteinases 1 (TIMP-1), and MMP-1/TIMP-1 complex in rheumatic disease. Correlation with clinical
activity of rheumatoid arthritis versus other surrogate markers (http://www.ncbi.nlm.nih.gov/pubmed/9972954). J Rheumatol. (1999)
127. Lee J, et al. Asiaticoside induces human collagen I synthesis through TGFbeta receptor I kinase (TbetaRI kinase)-independent Smad signaling (http://www.ncbi.nlm.nih.gov/pubmed/16557473). Planta Med. (2006)
128. Bissett DL, Hannon DP, Orr TV. An animal model of solar-aged skin: histological, physical, and visible changes in UV-irradiated hairless mouse skin (http://www.ncbi.nlm.nih.gov/pubmed/3671514). Photochem
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129. Yoon HS, Lee SR, Chung JH. Long-term Topical Oestrogen Treatment of Sun-exposed Facial Skin in Post-menopausal Women Does Not Improve Facial Wrinkles or Skin Elasticity, But Induces Matrix
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130. An IS, et al. Titrated extract of Centella asiatica provides a UVB protective effect by altering microRNA expression profiles in human dermal fibroblasts (http://www.ncbi.nlm.nih.gov/pubmed/22948173). Int J Mol
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131. An IS, et al. Centella asiatica protects against UVB-induced HaCaT keratinocyte damage through microRNA expression changes (http://www.ncbi.nlm.nih.gov/pubmed/23064234). Int J Mol Med. (2012)
132. Liu M, et al. Madecassoside isolated from Centella asiatica herbs facilitates burn wound healing in mice (http://www.ncbi.nlm.nih.gov/pubmed/18484522). Planta Med. (2008)
133. Meyer JS. Diabetes and wound healing (http://www.ncbi.nlm.nih.gov/pubmed/8716387). Crit Care Nurs Clin North Am. (1996)
134. Shukla A, et al. In vitro and in vivo wound healing activity of asiaticoside isolated from Centella asiatica (http://www.ncbi.nlm.nih.gov/pubmed/10350364). J Ethnopharmacol. (1999)
135. Mallol J, et al. Prophylaxis of Striae gravidarum with a topical formulation. A double blind trial (http://www.ncbi.nlm.nih.gov/pubmed/19291041). Int J Cosmet Sci. (1991)
136. Garca Hernndez J, et al. Use of a specific anti-stretch mark cream for preventing or reducing the severity of striae gravidarum. Randomized, double-blind, controlled trial
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137. Hsu YL, et al. Asiatic acid, a triterpene, induces apoptosis and cell cycle arrest through activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways in human breast cancer
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138. Babykutty S, et al. Apoptosis induction of Centella asiatica on human breast cancer cells (http://www.ncbi.nlm.nih.gov/pubmed/20162036). Afr J Tradit Complement Altern Med. (2008)
139. Wang L, et al. Antiproliferative, cell-cycle dysregulation effects of novel asiatic acid derivatives on human non-small cell lung cancer cells (http://www.ncbi.nlm.nih.gov/pubmed/23924616). Chem Pharm Bull (Tokyo).
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()
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Human E ect Matrix

GRADE LEVEL OF EVIDENCE

Single double-blind study or multiple cohort studies

Uncontrolled or observational studies only

LEVEL OF OUTCOME MAGNITUDE OF EFFECT CONSISTENCY OF RESEARCH RESULTS NOTES

There appears to be a notable improvement in microcirculation

VERY HIGH Blood ow appears to be increased alongside improvements in

VERY HIGH There appears to be a decrease in edema associated with

There appears to be a reduction in anxiety symptoms that build

An increase in attention has been noted which may be

A reduction in fear and anxiety responses to an acute startle

There are decreased in reaction time when otherwise healthy

- There appears to be stress reducing properties associated with

1 Sources and Structure

1.3 Structure and Properties

2.3 Phase I Enzymatica Interactions

4.1 Cholinergic Neurotransmission

4.2 Glutaminergic Neurotransmission

4.7 Depression and Mood

4.9 Memory and Learning

5.1 Cardiac Tissue

5.2 Blood Pressure

5.6 Chronic Venous Insu ciency

6 Interactions with Glucose Metabolism

7 In ammation and Immunology

7.4 Rheumatoid Arthritis

8 Interactions with Hormones

9 Interactions with Organ Systems

10 Interactions with Aesthetics

10.2 Wound Healing

10.3 Stretch Marks

11 Interactions with Cancer Metabolism

11.1 Breast Cancer

11.2 Lung Cancer

11.4 Liver Cancer

13 Safety and Toxicology

13.2 Case Studies

1 Sources and Structure

Thankuniside and Isothankuniside (glycosides)[1]

Centellasaponins B (0.0063%), C (0.0084%), and D (0.0036%)[10] as well as Centellosides A and B[12]

Brahmoside and Brahminoside[1]

Ursolic acid (/supplements/ursolic-acid/) (Triterpenoid)[8]

Centellin and Centellicin[14]

Rosmarinic acid (/supplements/rosmarinic-acid/)[8]

Ginsenosides Mc, Rk1, Rg5, Rd2, and Y[12]

(20R)-ginsenoside Rg3 and (20S)-ginsenoside Rg3[12]

Notoginsenoside ST-4 and Fe[12]

Gypenoside I and [12]

The alkaloid hydrochotine[1]

Apigenin (/supplements/apigenin/) at a comparable concentration as bacopa monnieri (/supplements/bacopa-monnieri/)[15]

Rutin (yet no Quercetin (/supplements/quercetin/) or Quercetrin content)[15]

Kaempferol (/supplements/kaempferol/),[3] kaempferol-3-O--D-glucoside,[3] and Castilliferol (ie. kaempferol-3-p-coumarate)[17]

Quercetin (/supplements/quercetin/),[3] quercetin-3-O--D-glucoside,[3] and castillicetin (Quercetin-3-ca eate)[17]