Gotu Kola

Scientific Name(s): Centella asiatica (L.) Urb. Family: Apiaceae (carrots).

Common Name(s): Gotu kola , hydrocotyle , Indian pennywort , talepetrako , spadeleaf , 1 Asiatic pennywort 2

Clinical Overview

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Uses of Gotu Kola

Traditionally used as treatment for a variety of ills and as an aphrodisiac, gotu kola has demonstrated efficacy for treating wounds, varicose veins, skin disorders, and venous insufficiency, as well as for enhancing memory. Limited evidence suggests gotu kola might have antifertility, hypotensive, and sedative effects.

Gotu Kola Dosing

Doses of gotu kola in crude form range from 1.5 to 4 g/day. Various extracts standardized to asiaticoside content also are available and have been studied in clinical trials in venous insufficiency and wound healing at doses of 30 to 90 mg/day. Wound-healing studies have involved topical application of a hydrogel ointment containing a titrated extract of C. asiatica (TECA).

Contraindications

Contraindications have not been identified.

Pregnancy/Lactation

Documented emmenagogue effects. Avoid use.

Gotu Kola Interactions

None well documented.

Gotu Kola Adverse Reactions

Gotu kola causes contact dermatitis in some individuals. Three cases of hepatotoxicity have been reported with patients using C. asiatica for 20 to 60 days.

Toxicology

No data.

Botany

C. asiatica is a slender, creeping plant that commonly grows in swampy areas of India, Sri Lanka, Madagascar, South Africa, and the tropics.

History

Gotu kola has been widely used to treat a variety of illnesses. Sri Lankans noticed that elephants, renowned for their longevity, ate the leaves of the plant. Thus the leaves were believed to promote long life, with a suggested ”dosage“ of a few leaves each day. Among the ailments historically purported to be cured or controlled by gotu kola are mental illness, high blood pressure, abscesses, rheumatism, fever, ulcers, leprosy, skin eruptions, nervous disorders, and jaundice; it has also been touted as an aphrodisiac. Gotu kola should not be confused with the dried seed of Cola nitida (Vent.) Schott. & Endl. (also known as kolanuts, kola, or cola), the plant used in cola beverages. C. nitida contains caffeine and is a stimulant. Gotu kola has no caffeine and has sedative properties. 3

Chemistry

Extracts of gotu kola contain the active principle madecassol, as well as asiatic acid and the glycoside asiaticoside. 4 Isothankuniside is also present. This compound has been used to derive another substance called BK compound (methyl 5-hydroxy-3,6-dioxo-23 (or 24)-nor-urs-12-ene-28-oate). 5 More than 70 constituents have been isolated from C. asiatica , including triterpenoid saponins, polyacetylenes, flavones, sterols, and lipids. 2 Below-ground parts of C. asiatica contain small amounts of at least 14 different polyacetylenes. The following molecular structures of 5 of these polyacetylenes have been determined: 2,9-pentadecadiene-4,6-diyn-1-ol, acetate; pentadeca-1,9-diene-4,6-diyne-3,8-diol, 8-monoacetate; pentadeca-1,9-diene-4,6-diyne-3,8 diol, diacetate; pentadeca-1,8-diene-4,6-diyne-3,10-diol, 10-monoacetate; and pentadeca (1,8)-diene-4,6-diyne-3,10-diol. Nine other polyacetylenes have been partially characterized. 6

A phytochemical study of C. asiatica revealed the presence of amino acids, flavonols, fatty acids, alkaloids, sterols, saccharides, and inorganic salts. The biostimulant activity is attributed to asiaticoside, asiatic acid, and madecassic acid. 7 A study of powdered gotu kola by microscopic and chemical identification methods has also been conducted. 8

Gotu Kola Uses and Pharmacology

The glycoside madecassoside has anti-inflammatory properties, while asiaticoside appears to stimulate wound healing. Experiments with rats have established that wounds heal by a process involving dilation followed by contraction, which was prolonged in rats undergoing repeated experimental wounding. However, TECA 100 mg/kg accelerated healing time. 9 A study employing rats and mice found that topically applied TECA rapidly penetrated to subcutaneous tissues and abdominal muscle in high concentrations and had a greater effect on wound healing than oral administration. Asiatic acid was absorbed later than madecassic acid. The topical preparations of TECA were also able to penetrate to the plasma and deeper tissues. 10

Topical application of asiaticoside 0.2% solution to guinea pig punch wounds resulted in a 57% increase in tensile strength, an increase in collagen content, and improved epithelialization. Oral doses of the asiaticoside 1 mg/kg solution also appeared to promote wound healing in guinea pigs. 11

In another study, the effects of C. asiatica were assessed in rats receiving dexamethasone, a glucocorticoid known to suppress wound healing. Wistar albino rats were divided into 4 groups: group 1 contained rats with wounds treated with normal saline; group 2 contained rats with wounds treated with an ethanolic extract of C. asiatica ; group 3 contained rats with wounds treated solely with dexamethasone; and group 4 contained wounded rats that received C. asiatica extract and dexamethasone. Three different wound models were studied, including dead space, incision, and excision wounds. The type of wound dictated the duration of therapy with C. asiatica (ie, daily for 10 days of therapy for dead space and incision wounds, and daily until the day of epithelization for rats with excision wounds). Rats treated with C. asiatica experienced an increase in wound breaking strength, weight and dry tissue weight, and hydroxyproline content, suggesting an increase in collagen content. Those treated with dexamethasone only (ie, group 3) experienced a worsening of these parameters. However, rats in group 4 receiving dexamethasone and C. asiatica experienced an increase in these parameters. It was concluded that an ethanolic extract of C. asiatica promoted wound healing in rats because of the antioxidant properties of C. asiatica . 12

Because of the potential role in enhancing wound healing, the antioxidant effect of C. asiatica was studied in the wound-healing process in rats. A topical solution of asiaticoside 0.2% was applied twice daily for 7 days to cutaneous wounds in rats. The newly formed tissue had increased levels of antioxidants. However, antioxidant levels did not appear to differ from controls after 14 days of topical asiaticoside application. 13

C. asiatica extracts promote wound healing in humans. 9 There are 4 phases of wound healing: an initial period of vasoconstriction and hemostasis, followed by an inflammatory phase, a proliferative phase, and remodeling. C. asiatica appears to be effective in the proliferative phase through promotion of the production of type-1 collagen. 14 Other mechanisms by which C. asiatica may be beneficial in wound healing include a reduction in the inflammatory response and production of myofibroblasts. 15

Cell culture experiments have shown that the total triterpenoid fraction of the extracts, at a concentration of 25 mcg/mL, does not affect cell proliferation, total cell protein synthesis, or the biosynthesis of proteoglycans in human skin fibroblasts. However, the fraction does increase the collagen content of cell layer fibronectin, which may explain the action in wound healing. 16

TECA has been used as a scarring agent to stimulate wound healing in patients with chronic lesions, such as cutaneous ulcers, surgical wounds, fistulas, and gynecologic lesions. A clinical study evaluated TECA for treating bladder lesions in 102 patients with bilharzial infections. Injections of TECA 2% usually administered intramuscularly (IM) for 1 to 3 months produced cure or improvement in 75% of the cases, as determined from symptoms, urinary findings, and cystoscopic findings. Healing occurred with little scar formation, avoiding much of the loss of bladder capacity that can result from bilharzial infections. 17

Though studies are lacking, the use of gotu kola in combination with other herbal products, such as horse chestnut, butchers broom, witch hazel, or stone root, to improve the healing time of hemorrhoids has been considered. Gotu kola's ability to increase tensile strength and collagen content in the wound-healing process as well as its ability to enhance microcirculation may improve this condition. 18

There are no animal data regarding the use of gotu kola for stretch marks (striae gravidarum).

Stretch marks are a common phenomenon in pregnancy, affecting up to 90% of women by the third trimester. Topical administration of a cream containing C. asiatica extract, alpha tocopherol, and collagen-elastin hydrolysates was compared with placebo. Women who received treatment with the cream had fewer stretch marks compared with those treated with placebo (odds ratio, 0.41; 95% confidence interval, 0.17 to 0.99). From this small study, it appears that C. asiatica has a potential role in reducing stretch marks associated with pregnancy, 19 , 20 but confirmation by other studies is needed.

There are no animal data regarding the use of gotu kola for psoriasis.

C. asiatica has shown promise in the treatment of psoriasis. When creams containing oil and water extracts of the leaves were administered each morning to 7 psoriatic patients, 5 displayed complete clearance of lesions within 3 to 7 weeks. One patient experienced clearance of most lesions, and one demonstrated improvement without clearance. One patient demonstrated a mild recurrence 4 months after treatment. Although this study was not controlled, a placebo effect was considered unlikely. Experience indicated that the creams were nontoxic and cosmetically acceptable, making them suitable for long-term use. 3

Crude extract of C. asiatica , isothankuniside, and BK compound reduced the fertility of female Swiss albino mice when administered orally. The effective dosages were 20 to 80 mg of whole plant/kg body weight for the crude extract, 40 to 120 mg/kg for isothankuniside, and 5 mg/kg for BK compound. BK compound had the strongest effect. 5 Because this was a preliminary screening study, the mechanism for this effect was not investigated.

There are no clinical data regarding the use of gotu kola for antifertility effects.

There are no animal data regarding the use of gotu kola for antihypertensive effects.

C. asiatica has been used in patients with venous hypertension and microangiopathy to improve circulation. The efficacy of centellase from C. asiatica in the treatment of venous hypertension has been evaluated using a combined microcirculatory model. 21 The researchers conducted a single-blind, placebo-controlled, randomized study of the effects of the total triterpenoid fraction (centellase) in 89 patients with venous hypertension microangiopathy. The hypotensive effects of centellase differed from placebo in activity on all the microcirculatory parameters investigated. No adverse reactions were noted.

Another study conducted in 62 patients was divided into 4 groups: group 1 consisted of patients with venous hypertension (ie, ambulatory venous pressure more than 42 mm Hg) who received total triterpenic fraction of C. asiatica (TTFCA) 60 mg 3 times daily; group 2 consisted of patients with venous hypertension who received TTFCA 30 mg 3 times daily; group 3 consisted of patients with venous hypertension who received placebo; group 4 consisted of healthy patients who received TTFCA 60 mg 3 times daily. Patients received treatment for a period of 4 weeks. Various measures of venous hypertension, including ankle edema, ankle circumference, and capillary filtration rate, improved in groups 1 and 2 after 4 weeks of therapy. No change was noted in either group receiving placebo or in the healthy group. 22

In a similar study, patients with venous hypertension (ie, ambulatory venous pressure more than 42 mm Hg) were divided into 3 groups: group 1 received TTFCA 60 mg 3 times daily; group 2 received 30 mg 3 times daily; and group 3 received placebo. A fourth group of healthy patients served as a comparator group and received TTFCA 60 mg 3 times daily. Patients received treatment for a period of 4 weeks. Measures of venous hypertension (ie, capillary filtration rate, ankle edema, ankle circumference) were improved in patients receiving treatment with TTFCA, and the effects were greater in patients receiving higher-dose TTFCA (60 mg 3 times daily). Symptoms were also improved in subjects receiving TTFCA. 23

In a study involving 40 patients with severe venous hypertension, ankle swelling, and/or lipodermatosclerosis, patients were randomized to receive 8 weeks of treatment with either TTFCA 60 mg orally twice daily or placebo. At the end of this study, there was a decrease in flux at rest and rate of ankle swelling in patients receiving TTFCA compared with placebo ( P < 0.05). In addition, symptoms improved as a result of decreased capillary filtration in patients receiving TTFCA ( P < 0.05). The authors concluded that TTFCA was effective in improving venous microangiopathy. 24

There are no animal data regarding the use of gotu kola for varicose veins.

The effects of gotu kola extract on mucopolysaccharide metabolism were studied in subjects with varicose veins. 25 The total triterpenic fraction of the plant (60 mg/day for 3 months) elevated the basal levels of uronic acids and lysosomal enzymes, indicating an increased mucopolysaccharide turnover in varicose vein patients. These results confirm the regulatory properties of C. asiatica extract on the metabolism in the connective tissue of the vascular wall.

There are no animal data regarding the use of gotu kola for venous insufficiency.

A double-blind, placebo-controlled study of 94 patients with venous insufficiency of the lower limbs indicated that TECA produced clinical improvement in this condition. The patients received 12 or 60 mg/day for 8 weeks. Improvement occurred in subjective measures of sensation of heaviness and pain in the legs, edema, overall patient assessment of efficacy, and in the objective measure of vein distensibility. The researchers concluded that TECA stimulated collagen synthesis in the vein wall, thus increasing tonicity and reducing its capacity to distend. In contrast, patients receiving placebo exhibited an increase in vein distensibility. Although there was no statistically significant difference between the 2 TECA dosage groups, data trends suggested that the effect of TECA was dose related. 26

A study was conducted to assess the role of C. asiatica in the prevention of edema and changes in circulation measures for patients traveling on an airline flight of at least 3 hours' duration. Patients between 30 and 50 years of age with mild to moderate venous insufficiency and varicose veins were randomized to receive TTFCA 60 mg 3 times daily beginning 2 days before the flight, the day of the flight, and 1 day following the flight or to receive no treatment. Those receiving TTFCA had less edema, while those in the control group continued to experience an increase in edema and worsening of other measures of circulation. These findings were consistent in those patients on flights of up to 10 hours' duration. It was concluded that TTFCA presents an option for patients who are prone to edema, particularly on long flights. 27

There are no animal data regarding the antibacterial effects of gotu kola. However, an in vitro study in India was performed to determine the antibacterial effects of an extract of C. asiatica against enteric pathogens as an antidiarrheal product. Microorganisms studied included strains of Escherichia coli , Staphylococcus aureus , Pseudomonas aeruginosa , Vibrio cholerae , and Shigella . Antibacterial activity was noted with all concentrations of the extract (100, 200, 300, and 400 mg/mL); however, inhibitory effects were most prominent with the 400 mg/mL concentration. Bactericidal effects against the Shigella species, one of the V. cholerae species, and S. aureus were noted within 2 hours. Thus, this preliminary study suggests the potential effects of C. asiatica extract as an option for the treatment of diarrhea. 28

There are no clinical data regarding the use of gotu kola for antibacterial effects.

In a small study involving fasting rabbits, C. asiatica 2 g/kg and 4 g/kg were administered to assess its effects on blood glucose. Extract administration resulted in a 26% mean deviation in blood glucose levels for rabbits receiving 2 g/kg and 35% mean deviation for those receiving 4 g/kg ( P < 0.05). 29

Although extracts of C. asiatica have historically been used by the Haya tribe in Tanzania to lower blood glucose levels in people with diabetes, there are no clinical data regarding the use of gotu kola for diabetes.

There are no animal data regarding the use of gotu kola for diabetic microangiopathy.

A study was conducted in 50 patients with diabetic microangiopathy to assess the effects of C. asiatica . Thirty patients received oral TTFCA 60 mg twice daily for 6 months, 10 patients received placebo, and 10 patients received nothing. Measures of microcirculation improved in patients receiving C. asiatica after 6 months of treatment. No changes were noted in patients receiving placebo or in those receiving nothing. It was concluded that TTFCA has a potential role in improving microcirculation in patients with diabetic microangiopathy. 30

To assess the effects of C. asiatica on brain function and neuronal maturation following birth, an aqueous extract of C. asiatica was given orally to mice in weight-based doses during the postpartum period. Multiple behavioral tests were conducted, including the radial arm maze test that involves the selection of food and is used to test spatial memory. Three-month-old mice receiving C. asiatica showed a dose-dependent increase in performance of the radial arm maze, demonstrating that C. asiatica can improve cognitive function in young mice. Higher doses were associated with more correct entries compared with lower doses. However, mice receiving lower doses completed the radial arm maze more rapidly than those receiving higher doses, which may be explained by the depressant effects seen with higher-dose C. asiatica . 31

A small study was conducted in 7-day-old Wistar rats to assess the effects of a C. asiatica fresh leaf juice on learning and memory during the neonatal period. Rats were divided into treatment groups of 2, 4, and 6 weeks' duration. From these groups, they were further divided into treatment arms that consisted of normal controls, saline controls, and rats receiving C. asiatica , which was further subdivided into doses of 2, 4, and 6 mL/kg. Overall, the learning measures of rats receiving the low dose of C. asiatica 2 mL/kg for 2 weeks did not differ from normal control rats. Additionally, rats receiving higher doses for the short duration improved their learning behaviors. Rats receiving all doses of C. asiatica for 4 or 6 weeks demonstrated improvement in learning behaviors. Memory retention also improved in rats receiving all 3 doses of the extract for all 3 time periods. It was concluded that administration of C. asiatica to neonatal rats can improve learning and memory. 32

There are no clinical data regarding the use of gotu kola for memory.

An extract of C. asiatica was given to 6-week-old male mice in doses of 200 to 330 mg/kg/day in drinking water. As a result, there was an increase in axonal regeneration with a 675% increase in the number of myelinated axons and a 250% increase in mean axonal areas. These findings suggest that C. asiatica extract is potentially beneficial for the acceleration of nerve regeneration. 33

There are no clinical data regarding the use of gotu kola for nerve regeneration.

An extract of C. asiatica was given orally prior to ethanol administration in doses of 0.05, 0.25, or 0.50 g/kg to rats. Premedication with C. asiatica resulted in a 58% to 82% dose-dependent reduction in the formation of gastric lesions. These results were believed to be attributed to strengthening of the gastric mucosa and a reduction in free radicals. 34

There are no clinical data regarding the use of gotu kola for ethanol-induced gastric ulceration.

Historically, gotu kola has been used in Ayurvedic and traditional Chinese medicine to relieve anxiety and promote relaxation. A study conducted in rats compared the impact of different phytochemicals in gotu kola with placebo. During one portion of the study protocol, rats were given either a commercial product from Madagascar that contained high levels of triterpene or placebo (ie, distilled water). The groups receiving gotu kola were tested using either 200 or 500 mg/kg of each product. Anxiolytic effects were noted in multiple measures assessed in both groups receiving high doses of gotu kola products; however, anxiolytic effects were not noted in either group at the lower dose. No differences were noted between the 2 commercial products. In another portion of this study, a hexane extract, ethyl acetate extract, and methanol extract were compared. Improvements in measures of behavior were noted in rats receiving ethyl acetate and methanol extracts. Rats receiving the hexane extract did not appear to have any improvement in behavioral symptoms. These findings are consistent with the fact that the asiaticoside concentration is lowest in the hexane extract and highest in the methanol extract. In a third portion of this study, dose-dependent assessments using pure asiaticoside found changes in behavioral and anxiety measures compared with controls. However, no differences between rats receiving asiaticoside and those receiving placebo were noted in locomotor activity, suggesting that gotu kola does not cause sedation in rats. 35

To determine gotu kola's effects on anxiety in humans, 40 healthy volunteers were randomly assigned to receive either a single oral dose of gotu kola 12 g (n = 20) or placebo (n = 20). Those patients receiving gotu kola experienced an attenuation in the peak acoustic startle response amplitude 30 and 60 minutes after treatment, suggesting the potential role for gotu kola as an anxiolytic in humans. 36

Centella extract is effective in killing cultured cancer tumor cells. 37 The extract, a 5:1 concentrate extracted with methanol, was effective at a level of 100 mcg/mL. In addition, no toxic effects were detected in normal human lymphocytes. A preliminary French study showed TECA to produce histologic improvement in 5 of 12 patients with chronic hepatic disorders. 38

The pharmacokinetics of the total triterpenic fraction of gotu kola have been studied after single and multiple administration to healthy volunteers. 39 Using a high-pressure liquid chromatography procedure for detection of asiatic acid, researchers found that after chronic treatment at 2 doses, the peak plasma concentration, area under the curve, and half-life were higher than those observed after the corresponding single-dose administration.

Taste aversion can be an undesired result of radiation therapy. Male rats were exposed to low-dose, whole-body gamma irradiation and received either an aqueous extract of C. asiatica 100 mg/kg or ondansetron 1 mg/kg. Rats treated with ondansetron had more protection against conditioned taste aversion (CTA) on the first postirradiation day. However, both ondansetron and C. asiatica appeared equally effective on the second postirradiation day. Additionally, rats receiving C. asiatica continued to experience a decline in CTA up to 5 days postirradition. This pattern was unlike that in rats treated with ondansetron. Thus, it was concluded that C. asiatica offers a potential option in the prevention of radiation-induced taste aversion. 40

There are no clinical data regarding the use of gotu kola for radiation-induced taste aversion.

Doxorubicin is a cancer chemotherapeutic agent that produces dose-dependent toxicity in the heart, limiting the total cumulative dose allowable. This effect is in part caused by oxidative damage on membrane lipids. Mitochondrial dysfunction is believed to also play a role in doxorubicin-associated cardiotoxicity. Thus, agents with potential antioxidant activity, such as C. asiatica , have been suggested to protect against oxidative damage resulting from doxorubicin administration. C. asiatica antioxidant properties are believed to result from its phenolic compounds.

A study was conducted in adult male albino rats. The rats were divided into the following 4 groups: group 1 received placebo; group 2 received doxorubicin 2.5 mg/kg in 6 equal injections over 2 weeks; group 3 received an extract of C. asiatica (200 mg/kg); and group 4 received both doxorubicin and the extract of C. asiatica . The extract was given 1 week prior to doxorubicin and for 2 weeks during doxorubicin administration. At the end of this study, cardiac enzyme markers were significantly lower in rats treated with doxorubicin compared with placebo ( P < 0.05). However, the rats in group 4, who received pretreatment and simultaneous administration of C. asiatica and doxorubicin, did not have a significant change in cardiac enzyme markers ( P < 0.05). The same was also true for mitochondrial enzymes and respiratory marker enzymes in the respective groups. Additionally, morphological changes, such as severe swelling of the mitochondria and nucleus, were noted in group 2 rats. However, rats receiving doxorubicin in combination with C. asiatica appeared to have normal morphology and mitochondrial ultrastructure. C. asiatica was concluded to be potentially effective in reducing the dose-dependent effect of cardiotoxicity associated with doxorubicin therapy because of its antioxidant properties. 41

There are no clinical data regarding the use of gotu kola for chemotherapy-induced cardiotoxicity.

Dosage

Doses of gotu kola in crude form range from 1.5 to 4 g/day. Various extracts standardized to asiaticoside content are available and have been studied in clinical trials in venous insufficiency and wound healing at doses of 30 to 90 mg/day. Wound-healing studies have involved topical application of a hydrogel ointment containing TECA. 42 , 43

Pregnancy/Lactation

Documented emmenagogue effects. 44 Avoid use.

Interactions

None well documented.

Adverse Reactions

Contact dermatitis has been reported in some patients using preparations of fresh or dried parts of the plant. 4 Patients who received subcutaneous injections rather than IM injections experienced pain at the injection site with blackish discoloration of the subcutaneous tissues.

Relatively large doses of extract have been found to be sedative in small animals; this property is attributed to 2 saponin glycosides, brahmoside and brahminoside.

Three cases of hepatotoxicity have been reported with patients using C. asiatica for 20 to 60 days. Once the product was discontinued, improvement was noted. Two patients unintentionally rechallenged with C. asiatica , which resulted in recurrent liver damage. Hepatotoxicity from apoptosis and alteration in the cell membrane due to the active constituents pentacyclic triterpenic saponosides is suspected. 45

Toxicology

No data.

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