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Gotu Kola

Scientific Name(s): Centella asiatica (L.) Urban
Common Name(s): Asiatic pennywort, Brahmi, Gotu kola, Hydrocotyle, Indian Pennywort, Jalbrahmi, Manduukaparani, Spadeleaf, Talepetrako, Tsubokusa

Clinical Overview

See also: Basaglar

Use

Gotu kola has potential cardiovascular and dermatological (eg, wound healing) effects. Clinical data are limited.

Dosing

The recommended daily dose of titrated extracts of C. asiatica standardized for asiaticoside, asiatic acid, and madecassic acid is 60 to 120 mg.

Contraindications

Hypersensitivity to C. asiatica or any of its components.

Pregnancy/Lactation

Avoid use during pregnancy and lactation; gotu kola may have emmenagogue effects.

Interactions

Gotu kola extract has been shown to inhibit cytochrome P450 (CYP-450) 3A4, 2C19, and 2B6, but the clinical significance is unknown. Gotu kola may have additive effects when coadministered with antiplatelet agents.

Adverse Reactions

Contact dermatitis has been documented in some clinical trials.

Toxicology

Three cases of hepatotoxicity have been reported with C. asiatica administration for 20 to 60 days.

Botany

C. asiatica is a perennial, herbaceous, creeping plant of the genus Centella (Apiaceae).Centella 2007, Zheng 2007 The plant grows abundantly in shady, moist, or marshy areas and is distributed widely in many parts of the world, including India, Sri Lanka, Madagascar, South Africa, Australia, China, Indonesia, and Japan.Centella 2007, Satake 2007, Zheng 2007

The common name "brahmi" has also been applied to Bacopa monniera (bacopa) and Merremia gangetica.6

History

Gotu kola has been used in traditional medicinal systems for centuries.Zheng 2007 In India, the plant has been used to treat dermatitis, diabetes, cough, cataracts and other eye conditions, and to improve memory. In Europe, an infusion of the aerial parts of the plant was used to purify the blood and treat wounds, ulcers, dermatitis, and hypertension. A similar infusion has been used in Indonesia and Brazil to help improve memory. In Malaysia, the plant was used to treat respiratory ailments such as bronchitis and asthma, as well as gastric complaints (including dysentery), kidney disorders, urethritis, and edema. In Malaya, an infusion from the plant is sold as a tonic and cold beverage to treat liver ailments, tuberculosis, and blood in the urine. Historically, Japan valued the plant for its diuretic and detoxicant properties.Centella 2007, Satake 2007, Zheng 2007 Sri Lankans noticed that elephants, known for their longevity, ate the leaves of the plant. Believing the leaves promoted long life, the suggested "dosage" was a few leaves each day.Natarajan 1973 In South China, the plant is used as a dietary supplement to promote health and immune system function.Li 2009 Traditionally, gotu kola has been used in Ayurvedic and Chinese medicine to relieve anxiety and promote relaxation.Wijeweera 2006 Preparations have been used in the management of hemorrhoids.Abascal 2005

Gotu kola should not be confused with the dried seed of Cola nitida (Vent.) Schott. and Endl. (also known as kolanuts, kola, or cola), the plant used in cola beverages. C. nitida contains caffeine and is a stimulant. Gotu kola does not contain caffeine and has sedative properties.Natarajan 1973

Chemistry

Triterpenoids are the major components responsible for the medicinal activity of the gotu kola plant.Li 2009, Zheng 2007 However, the plant species also contains more than 70 constituents, including polyacetylenes, flavonoids, flavones, sterols, and lipids.Rafamantanana 2009, Subban 2008, Yu 2006 While wound healing and vascular effects are primarily a result of triterpene saponins and sapogenins, CNS and uterorelaxant actions seem to be due to actions of its saponin glycosides brahmoside and brahminoside.Gohil 2010 Below-ground parts of the plant contain small amounts of at least 14 different polyacetylenes.Schulte 1973 A phytochemical study revealed the presence of amino acids, flavonols, fatty acids, alkaloids, sterols, saccharides, and inorganic salts.Castellani 1981 A study of powdered gotu kola by microscopic and chemical identification methods has also been conducted.Sappakun 1982

Uses and Pharmacology

Many studies focus on the triterpenoids asiaticoside, centelloside, madecassoside, and asiatic acid.Randriamampionona 2007 Asiaticoside has anxiolytic,Liang 2008 anti-inflammatory, antioxidant, antiulcer, and wound healing properties.Kimura 2008 Asiaticoside and madecassoside may be effective in treating arthritis.Liu 2008 Asiatic acid induces apoptosis and cell cycle arrest in several types of cancer in rats.Barbosa 2008

Antiulcer activity

Animal data

In a study in rats, antiulcer activity of C. asiatica was comparable with that of famotidine and sodium valproate.Chatterjee 1992

A 600 mg/kg dose of C. asiatica given to rats twice daily for 5 days protected against induced gastric ulceration. The effects were comparable to those of sucralfate 250 mg/kg given orally once a day for 5 days. C. asiatica increased gastric juice mucin secretion and mucosal cell glycoproteins and decreased cell shedding, which led to an increase in the mucosal barrier.Sairam 2001

Cancer

C. asiatica may protect against oxidative damage resulting from doxorubicin administration. C. asiatica's antioxidant properties are believed to result from its phenolic compounds. The antioxidant activity of the plant may also be beneficial in reducing radiation-induced toxicity.

Animal and in vitro data

Studies have been conducted in rodents to evaluate the effect of C. asiatica on chemotherapy-induced cardiotoxicity and gamma radiation, with a protective role reported (as measured by mitochondrial enzymes and respiratory marker enzymes).Gnanapragasam 2007, Joy 2009 Similarly, effects on taste aversion due to radiation therapy was evaluated in rats, with positive findings reported.Jagetia 2007, Shobi 2001

C. asiatica extract may be effective in killing cultured cancer tumor cells.Babu 1995 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. The triterpene asiaticoside from C. asiatica may induce apoptosis and enhance the anticancer activity of vincristine in several cancer cell lines.Huang 2004 An in vitro study documented that asiatic acid isolated from C. asiatica induced apoptosis and inhibited colon cancer cell growth by interfering with the mitochondrial membrane potential in a concentration- and time-dependent manner.Tang 2009

Cardiovascular effects

Animal data

Limited studies in rodents have demonstrated cardioprotective effects in reperfusion injury and chemotherapy-induced cardiotoxicity, possibly due to antioxidant activity of C. asiatica.Chandrika 2015

Rats fed C. asiatica powder had significantly (P<0.05) lower serum low-density lipoprotein and triglycerides and higher high-density lipoprotein compared with controls. However, cholesterol levels of rats fed either C. asiatica extract or powder were higher compared with controls.Hussin 2009 An in vivo rabbit study documented that madecassoside protected against myocardial ischemia reperfusion injury,Li 2007 possibly through antioxidant, antilipid, anti-inflammatory, and antiapoptosis activity.Bian 2008

Clinical data

In a study of patients with severe venous hypertension, ankle swelling, and lipodermatosclerosis (N=40), treatment with total triterpenic fraction of C. asiatica (TTFCA) 60 mg tablets twice daily for 8 weeks resulted in a decrease (P<0.05 vs placebo) in flux at rest and rate of ankle swelling at 8 weeks. The decrease in capillary filtration was associated with improvement in signs and symptoms (P<0.05).Cesarone 2001 A study by the same group of researchers compared use of TTFCA 60 mg twice daily with placebo or no treatment in patients with diabetic microangiopathy (N=50). After 6 months of treatment with TTFCA, there was a significant improvement in microcirculatory parameter and a decrease in capillary permeability compared with those receiving placebo or no treatment. Also, TTFCA demonstrated protection against deterioration of microcirculation due to diabetic microangiopathy.Cesarone 2001 In another study of 52 patients with venous hypertension, TTFCA doses of either 30 mg or 60 mg 3 times daily for 4 weeks decreased capillary filtration rate, ankle circumference, and ankle edema compared to placebo and healthy subjects; decreases were greater in the group receiving the higher 60 mg dose.Cesarone 2001, Cesarone 2001, De Sanctis 2001

A study assessing 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 reported findings supportive of a role for C. asiatica.Cesarone 2001

CNS effects

Animal data

Studies in rodents have evaluated anxiolytic properties of gotu kola.Mohandas 2009, Wijeweera 2006 One study reported a dose-dependent effect, with results dependent on the extraction process applied.Wijeweera 2006

Cognitive function was improved in other tests in mice; dose-dependent effects were observed, with higher doses exhibiting CNS depressant effects.Chen 2005, Mohandas 2005, Rao 2005

Suggested mechanisms of action include inhibition of acetylcholinesterase,Dhanasekaran 2009, Mukherjee 2007 effects on certain signalling pathways,Xu 2008 and increasing dendritic length (intersections) and branches of neurons of the amygdala, thereby enhancing learning and memory.Gadahad 2008, Lokanathan 2016, Mohandas 2006, Mohandas 2009, Rao 2005

In a Parkinson mouse model, asiatic acid from gotu kola was neuroprotective via activation of several signalling pathways.Nataraj 2017

An aqueous extract of C. asiatica demonstrated anticonvulsant effects in mouse models of tonic-clonic and absence seizures at a dose of 400 mg/kg and in tonic-clonic seizures at a dose of 200 mg/kg.Deka 2017

Clinical data

In an 8-week, randomized, placebo-controlled, double-blind pilot study of 28 elderly patients, C. asiatica extract enhanced spatial and numeric working memory and attention and improved mood. Patients were administered 250, 500, or 750 mg of C. asiatica in capsule form or placebo. The most important changes occurred in patients treated with 750 mg/day. The underlying mechanism may involve C. asiatica modulation of dopamine and norepinephrine in the prefrontal cortex and acetylcholine and serotonin in the hippocampus, leading to improved numeric and spatial memory.Wattanathorn 2008

Dermatological applications

A review of potential applications of C. asiatica extracts has been published.Bylka 2014 The wound healing effect of the glycoside madecassoside may involve several mechanisms, including antioxidant activity and effects on collagen synthesis and angiogenesis. Asiaticoside appears to stimulate wound healing by inducing type 1 collagen synthesis and promoting angiogenesis.Bylka 2014

Animal and in vitro data

In vitro studies have demonstrated activity against certain human pathogens (including Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Vibrio cholerae, and Shigella), which may contribute to healing.Mamtha 2004, Zaidan 2005 Studies in rodents have evaluated the effects of gotu kola extracts on wound healing, including traumatic and burn-related injury and corticosteroid-induced changes; the majority of study findings were supportive of a place in therapy.Bylka 2014, Hong 2005 Proangiogenic changes and expression of cytokines have been described as possible mechanisms of action.Bylka 2014, Widgerow 2000

Clinical data

Clinical studies have evaluated the effects of various topical formulations and extracts of C. asiatica in wound healing.Brinkhaus 2000 In a study in patients with diabetes (n=200), 2 capsules of C. asiatica extract (50 mg of asiaticoside per capsule) taken 3 times a day resulted in improved wound healing and reduced scar formation compared to placebo.Bylka 2014

In a study of 75 patients referred to a hospital in Iran for burns, topical application of Centriderm ointment (a derivative of C. asiatica) was compared to silver sulfadiazine. All objective and subjective signs and mean of re-epithelialization and complete healing were significantly better in the Centriderm group compared to the silver sulfadiazine group (P<0.05).Saeidinia 2017

A small clinical study of 25 patients reported increased skin firmness and elasticity following application of an herbal gel extract containing C. asiatica.Sommerfeld 2007 Similar results were reported in other studies.Ahshawat 2008, Martelli 2000

Diabetes

Animal data

In a small study involving fasted rabbits, C. asiatica extract 2 and 4 g/kg was administered to assess effects on blood glucose. Extract administration resulted in a 26% and 35% mean deviation in blood glucose levels for rabbits receiving 2 g/kg and 4 g/kg, respectively (P<0.05).Chandrika 2015, Mutayabarwa 2003

In mice with alloxan-induced diabetes, asiaticoside, whole plant extracts, and saponin-rich fractions of C. asiatica decreased fasting glucose levels and glucose levels after oral glucose tolerance tests, while nonsaponin fractions had no effect. Hemoglobin A1c (HbA1c) was also significantly lower than controls, but only at the highest doses used.Fitrianda 2017

A dried ethanolic extract of gotu kola dosed at 300 mg/kg decreased glucose levels in diabetic rats.Maulidiani 2016 Lipid levels and other metabolic change markers also normalized with long-term treatment.

Ethanol-induced gastric ulceration

Animal data

An extract of C. asiatica was given orally to rats in doses of 0.05, 0.25, or 0.5 g/kg prior to ethanol administration. 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 attributable to strengthening of the gastric mucosa and to a reduction in free radicals.Cheng 2000

Insecticide

Experimental data

A topical form of C. asiatica had repellant activity against malarial vector Anopheles stephensi in studies conducted in mosquito cages.Rahuman 2008, Rajkumar 2007, Senthilkumar 2009

Joint disease

Animal and in vitro data

Asiaticoside reduced articular cartilage degeneration and inflammatory cell infiltration in mice with collagen-induced arthritis. The underlying mechanism may involve inhibiting lymphocyte proliferation and reducing cyclooxygenase-2 and cytokine expression.Li 2007, Yun 2008 Madecassoside also provided a protective effect in joint destruction by potentially regulating abnormal humoral and cellular immunity.Liu 2008 The results of an in vitro and in vivo study demonstrated that a standardized C. asiatica fraction inhibited zymosan-induced cartilage damage by potentially inhibiting nitric oxide productionHartog 2009; nitric oxide plays a role in cartilage degradation in osteoarthritis.

Dosing

Gotu kola is available in numerous doseforms, including capsules, creams, powders, liquids,Wongfhun 2009 and teas. Commercial manufacturers list numerous dosage regimens for gotu kola.

The recommended daily dose of titrated extracts of C. asiatica standardized for asiaticoside, asiatic acid, and madecassic acid is 60 to 120 mg.Brinkhaus 2000, Centella 2007

Topical formulations and C. asiatica extracts at various concentrations have been used in clinical trials evaluating its dermatological and wound healing effects.Ahshawat 2008, Martelli 2000, Saeidinia 2017, Sommerfeld 2007 In a clinical trial of diabetic patients, 2 capsules of C. asiatica extract (50 mg of asiaticoside per capsule) taken 3 times a day resulted in improved wound healing and reduced scar formation compared to placebo.Bylka 2014

In clinical studies of patients with venous hypertension or diabetic microangiopathy, 60 mg of TTFCA 2 to 3 times daily (treatment duration, 4 weeks to 6 months) has been used.Cesarone 2001, Cesarone 2001, De Sanctis 2001

The pharmacokinetics of the total triterpene fraction of gotu kola have been studied after single- and multiple-dose administration to healthy volunteers.Grimaldi 1990 Using a high-pressure liquid chromatography procedure for detection of asiatic acid, researchers found that after multiple-dose administration (2 doses), peak plasma concentration, area under the curve, and half-life were higher than those observed after single-dose administration. Pharmacokinetic studies have also been conducted in animals.Zheng 2009 Bioavailability of both madecassoside and asiaticoside are increased when given in a standardized gotu kola extract, compared to when given as sole ingredients.Hengjumrut 2017

Pregnancy / Lactation

Avoid use during pregnancy and lactation; gotu kola may have emmenagogue effects.Ernst 2002

Interactions

An in vitro study using human CYP isoforms demonstrated that the standardized C. asiatica extract ECa233 inhibited CYP3A4, 2C19, and 2B6, but not CYP1A2, 2C9, 2D6, or 2E1. The clinical relevance of this inhibition is unknown.Seeka 2012

No changes were observed in phase II drug metabolizing enzymes UDPGT, SULT, GST, and NQOR with varying Eca233 doses for 90 days.Seeka 2017

An in vitro study demonstrated antiplatelet aggregation activity of both unpurified and purified C. asiatica extracts.Lestari 2016 Activity was unconfirmed and clinical significance was not determined, but additive effects increasing bleeding risk are possible.

Antiepileptics

Theoretically, gotu kola may interact with drugs in the antiepileptic class. In a study investigating the interaction between oral C. asiatica ethyl acetate fraction and intraperitoneal antiepileptic drugs, the median effective doses of phenytoin, valproate, and gabapentin were 13, 104, and 310 mg/kg body weight, respectively; in the presence of C. asiatica ethyl acetate fraction, the corresponding values were 5, 29, and 79 mg/kg body weight, respectively.Vattanajun 2005 In an in vitro experiment, 1 mg/mL extracts from C. asiatica stimulated glutamic acid decarboxylase activity by more than 40%.Awad 2007

A beneficial interaction may exist with valproic acid; in rats, asiatic acid reduced the detrimental effects of valproic acid on spatial memory.Umka 2016

Adverse Reactions

Contact dermatitis has been reported by some patients using preparations of fresh or dried parts of the plant.Eun 1985 Patients who received subcutaneous injections rather than intramuscular injections experienced pain at the injection site and blackish discoloration of the subcutaneous tissues.

Sedative effects of C. asiatica extract in small animals have been attributed to its brahmoside and brahminoside constituents or saponin glycosides.Gohil 2010

Toxicology

Avoid use if hypersensitivity occurs with C. asiatica or any of its components.

Three cases of hepatotoxicity have been reported in patients using C. asiatica for 20 to 60 days. After the product was discontinued, improvement was noted. Two patients were unintentionally rechallenged with C. asiatica, which resulted in recurrent liver damage. Hepatotoxicity caused by apoptosis and alteration in the cell membrane due to the active constituents pentacyclic triterpenic saponosides was suspected.Jorge 2005

Several studies examined the protective effect of C. asiatica against several toxins, including lead,Ponnusamy 2008, Saxena 2006 arsenic,Flora 2007 and cyproterone acetate (genotoxic- and tumor-promoting agent).Siddique 2008 Other studies have reviewed the neuroprotective role of the plant species against neurotoxins.Shinomol 2008, Shinomol 2008

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