Gambir

Gambir (Uncaria gambir Roxb.): A Comprehensive Reference

1. Identity and Botanical Classification

Botanical and Common Names

Uncaria gambir, commonly known as gambier or gambir, is a species of plant in the genus Uncaria found in Southeast Asia, mainly Malaysia and Indonesia. It belongs to the family Rubiaceae. The accepted botanical authority is Uncaria gambir (W. Hunter) Roxb., with a widely used synonym being Ourouparia gambir (Hunter) Baill. The extract is also known as pale catechu, white catechu, or Japan Earth, and it is often confused with other forms of catechu. In Malaysia the plant is called gambir, gambier, or kancu; in Indonesia it is most widely known simply as gambir.

This species is frequently confused with other related species, particularly Uncaria callophylla, Uncaria acida, and Uncaria elliptica, which have been reported to have been incidentally used in gambier production.

Morphology and Natural Distribution

Gambir is a climbing or straggling shrub, with square young stems bearing horizontal branches with recurved hooks (which are actually modified peduncles of the inflorescences) that help the plant cling on to supports. It is cultivated in Peninsular Malaysia and Indonesia (Sumatra, Java, Bali, Kalimantan, Moluccas), and plants that are probably truly wild have been collected in Sumatra and Borneo. Gambir is generally cultivated on land with an altitude from 650 m to 800 m above sea level, with a flat to hillside topography.

Commercial Forms and Preparations

The resinous substance extracted from the leaves and young branches of gambier is crystallized and traded in small cubes or blocks. Gambir is a dry extract from the stems and leaves of the plant; one form of extraction is dried gambir, a dry extract obtained by steaming, extracting, freezing, printing, and drying the gambir extract. Raw gambir, a traditionally processed product of dried gambier produced by growers, has a high catechin composition ranging from 40% to 60%. A product containing up to 80% catechin (pure gambier) can be produced through further extraction.

The extract has three major uses: for tanning leather; as a stimulant chewed with betel nut (Areca catechu L.), lime, and the leaf of Piper betle L.; and as a medicine. Minor uses are as a dye in the traditional batik industry and for dyeing silk black; as a clearing agent for beer, and as a remover of scale from boilers.

Indonesia dominates the global production and export of gambier extract, accounting for approximately 80% of the world's supply, with the majority originating from smallholder plantations in Sumatra, particularly West Sumatra, which contributes 80–90% of the national output. After the Second World War, gambier lost most of its importance as an export product, and in tanneries in Europe and the United States it was largely replaced by other vegetable tanning materials.

2. Traditional and Historical Use

Betel Quid Chewing

Gambir is prepared by boiling the leaves and barks of Uncaria gambir in water; the liquid extracted from the plant is dried and molded into large-size pellets. As part of the betel quid, gambir is used together with betel leaves and areca nut in ratios documented among Malaysian communities; the betel quid was prepared using betel leaves, areca nut, and gambir in the proportion of 46:3:1, while the version containing calcium hydroxide was prepared using the proportion 43:3:1:3 for betel leaves : areca nut : gambir : calcium hydroxide respectively.

Gambier production began as a traditional occupation in the Malay archipelago; by the middle of the seventeenth century it was established in Sumatra, western Java, and the Malay peninsula. It was initially used as medicine and chewed with betel; local Chinese also began to use gambier to tan hides.

Gambier extract was also used by native people as a medical treatment or prevention of diseases believed to be spread by the now obsolete medical theory of miasma. The Indians invented paan, a gambir paste, that was believed to help prevent miasma; it was considered the first antimiasmatic application.

By the late 18th century, gambir entered international trade, exported from Indonesian ports such as those in Sumatra and Riau to Europe and Asia, often under the name "terra japonica" due to its earthy appearance, which initially led traders to mistake it for a mineral soil. This nomenclature reflected early misconceptions but facilitated its commerce as a versatile extract valued for dyeing and preservation.

Medicinal Traditions

U. gambir Roxb. has many traditional uses, namely in the treatment of wounds, ulcers, asthma, headaches, bacterial/fungal infections, tooth pain, cancer, cirrhosis, diabetes, rheumatism, dysentery, and urinary tract inflammation. The plant has long been used in traditional medicine to treat diarrhea, sore throat, swollen gums, dysentery, arteriosclerosis, and obesity.

In Indonesia, Uncaria gambir Roxb. is commonly used as a component in mixed medications for burns, headaches, diarrhea, dysentery, gargles, canker sores, sore skin, and to support digestion in the stomach and intestines, as well as for tanners and textile dyes. The leaves are also used fresh for medicinal purposes.

3. Key Constituents and Active Compounds

Overview of Phytochemical Classes

Fifty compounds have been detected in the leaves, twigs, wood, bark, and stems of U. gambir. These compounds include flavonoids, free aromatics, alkaloids, glucose, dimeric compounds from these groups, and so forth. In addition to flavonoids, phenolics, and alkaloids, gambir also contains other chemical compounds such as sterols, terpenoids, saponins, carbohydrates, proteins, and amino acids. However, there have been no studies that have comprehensively determined the structure and amount of all these chemical compounds.

Catechins and Flavanols (Primary Bioactive Class)

The main bioactive compounds extracted from U. gambir are catechins. Catechins are the major compounds and determine the pharmacological activity in this plant extract. Quantitative analyses have established the typical composition of gambir extract: the biochemical compounds in gambir extract are catechins (7–33%), catechin tannic acid (20–55%), pyrocatechol (20–30%), fluorescent gambir (1–3%), red catechu (3–5%), quercetin (2–4%), certain oils (1–2%), wax (1–2%), and small concentrations of alkaloids.

The total flavan content in gambir samples ranged from 24 to 79%. Catechins have a lower limit of about 20% for quality management. Other flavonoids showed epicatechin at an average of 1.5%, and dimer compounds procyanidin B1, procyanidin B3, and gambiriin A1 at about 1% each. According to Viena & Nizar, the phytochemical test results of ethanol extract of gambir leaves showed total flavonoids and total phenolic content of 32.06 and 71.80%, respectively.

Key identified flavonoid-type monomers and dimers include (+)-catechin, (−)-epicatechin, quercetin, procyanidins B1 and B3, gambiriin A1, and a range of unique gambir-specific dimeric flavans. Two novel polyphenolic compounds, uncariagambiriine and gambircatechol, were isolated from Uncaria gambir leaves along with dehydrodicatechin A and several catechin dimers; three new dimeric flavans — catechin-(4α→8)-ent-epicatechin, gambirflavan D1, and gambirflavan D2 — were also isolated from gambir. Further research identified additional dimeric flavans: gambiriin C, procyanidin B1, procyanidin B3, dimeric proanthocyanidin, gambircatechol, dehydrodicatechin A, catechin-(8→6′)catechin, and catechin-(6→6′)-catechin.

Alkaloids

Phytochemically, this plant contains alkaloid compounds including gambirine, isorinkophylline, gambirdin, isogambirdine, and auroparin, as well as gambirtannine and its derivatives. Alkaloids (compounds 35–47) and dimeric catechin-alkaloid compounds (compounds 48–50) have been structurally characterized from Uncaria gambir Roxb. The compound (−)-uncariagambiriine was isolated from the leaves of Uncaria gambir collected in Indonesia; this compound contains a dihydrogambirtannine residue linked to the A ring of the flanol catechin.

Phenolic Acids and Other Constituents

Free phenolic compounds (compounds 23–33) and quinic acid (compound 34) have been structurally characterized from Uncaria gambir Roxb. LC-MS/MS analysis has revealed the presence of quinic acid as a major compound of gambir and betel quid.

4. Established and Proposed Mechanisms of Action

Antioxidant Activity

Among the individual ingredients of betel quid tested in laboratory conditions, gambir demonstrated the highest antioxidant activity (DPPH IC₅₀ = 6.4 ± 0.8 µg/mL, FRAP = 5717.8 ± 537.6 µmol Fe(II)/mg), total phenolic content (TPC = 1142.5 ± 106.8 µg TAE/mg), and cytoprotective activity (100.1 ± 4.6%). A positive correlation was observed between total phenolic content and radical scavenging (r = 0.972), reducing power (r = 0.981), and cytoprotective activity (r = 0.682).

Antimicrobial Activity

Catechins, the main components of gambir, can damage cell membranes or cell walls by interfering with the cell permeability of bacteria. Uncaria gambir extract has been shown to have antimicrobial activity against Gram-positive bacteria (Staphylococcus aureus) and Gram-negative (E. coli). Tannins have the ability to inhibit the mitochondrial electron transport chain and diminish the potential of cell membranes; they obstruct the proton pumps and reduce ATP synthesis, causing cell death. Gambir has been reported to be effective as an antifungal agent.

Anti-inflammatory Activity

The major flavan in Uncaria gambir, catechin, possesses activities suggestive of benefits in arthritis including: inhibition of the activity of cyclooxygenase-2 (COX-2), lipoxygenase (5-LOX), and pro-inflammatory cytokines TNF-α, IL-1, -2, -6, -8, and -12. Catechins affect the expression of inflammation-related genes and proteins such as TNF-α and IL-1, demonstrating their anti-inflammatory roles.

Anticancer / Cytotoxic Activity

Antioxidant activity, regulation of drug-metabolizing enzymes, induction of apoptosis, inhibition of cell proliferation and metastasis, anti-inflammatory effects, and regulation of the gut microbiota may all play roles in catechins' anti-cancer activity. In in vitro experiments, catechin hydrate produced a dose-dependent reduction in MCF-7 breast cancer cell viability, with 54.76% of cells dead at the highest concentration tested (160 µg/mL) and an IC₅₀ of approximately 127.62 µg/mL. A dose- and time-dependent increase in the induction of apoptosis was observed when MCF-7 cells were treated with catechin hydrate.

Antidiabetic / Anti-hyperglycemic Activity

Catechins isolated by ethyl acetate extraction have been studied as anti-hyperglycemic agents in vitro through α-glucosidase inhibition. Results showed that the IC₅₀ for α-glucosidase inhibition ranged from 40.45 to 52.43 µg/mL, qualifying the extract as a potentially good antidiabetic. Ethanolic and ethyl acetate extracts showed significantly higher α-glucosidase inhibitory activity than aqueous extracts, with IC₅₀ ranges of 15.2–49.5 µg/mL. Regarding α-amylase enzyme inhibition, the ethanol extract of gambir leaves showed α-amylase inhibitory activity of 88.22% at a sample concentration of 1000 ppm.

Antihyperlipidemic Activity

In silico study revealed the mechanism of action of catechin as antihyperlipidemic via two pathways: inhibition of the enzyme HMG-CoA reductase and increase of LDL receptors. In vitro studies showed that catechin is able to inhibit lipid absorption in the intestine through inhibition of pancreatic lipase activity, lipid hydrolysis and emulsification, and micelle cholesterol deposition; pre-clinical tests on animals showed that the ethyl acetate fraction of gambir leaves was able to reduce levels of total cholesterol, triglycerides, and LDL, and increase blood plasma HDL.

5. Scientific Evidence by Area of Use

5.1 Antioxidant and Cytoprotective Properties

The antioxidant activity of gambir has been extensively characterized using in vitro assays. A published study aimed to investigate the antioxidant and cytoprotective activities of each of the ingredients of betel quid, and to correlate their cytoprotective and antioxidant activities with phenolic content. Five samples — betel leaf, areca nut, gambir, betel quid, and betel quid containing calcium hydroxide — were extracted in deionized distilled water. Antioxidant activities were evaluated by DPPH radical scavenging, ferric reducing activity (FRAP), and lipid peroxidation inhibition (FTC) assays; total phenolic content was determined by Folin-Ciocalteu procedure; phenolic composition was analyzed by LC-MS/MS; and cytoprotective activity toward human gingival fibroblast cells was examined by MTT assay. All five samples showed good lipid peroxidation inhibition compared to vitamin E. Evidence level: in vitro only; no controlled human trials.

5.2 Anti-inflammatory and Analgesic Activity

The anti-inflammatory activity of U. gambir has been demonstrated in both in vitro and in vivo studies. One study described the anti-inflammatory and analgesic effect of UP3005, a composition containing a standardized blend of extracts from the leaf of Uncaria gambir and root bark of Morus alba, in carrageenan-induced rat paw edema, abdominal constriction (writhing), and ear swelling assays in mouse at oral dose ranges of 100–400 mg/kg. In vivo, statistically significant improvement in pain resistance and suppression of paw edema and ear thickness in animals treated with UP3005 were observed compared with vehicle.

Yimam et al. conducted a study on the anti-inflammatory effect of UP3005, a combination of two extracts from the leaf of U. gambir and root bark of Morus alba (1:1); in vitro study showed the enzymatic inhibitory activity of UP3005 on COX-1, COX-2, and lipoxygenase (5-LOX) enzymes with IC₅₀ values of 12.4 µg/mL and related measurements. In that study, UP3005 showed a significant improvement in the major cardinal signs of arthritis, including reduction in pain sensitivity and swelling. Importantly, all authors of the UP3005 study were Unigen employees, and therefore had financial interests. Evidence level: preclinical animal and in vitro data only; no independent human clinical trials specifically on U. gambir for inflammation have been identified.

5.3 Antimicrobial Activity

Multiple laboratory-based studies have assessed the antimicrobial properties of gambir. Various studies have shown that extracts and compounds obtained from U. gambir have medical uses for their antioxidant, antibacterial, anti-helminthic, anticancer, antifungal, anti-inflammatory, anti-hyperglycemic, anti-hyperuricemic, anti-lipid peroxidation, and antihyperlipidemic properties. The principal mechanism proposed for antibacterial activity involves membrane disruption by catechins and tannin-mediated inhibition of ATP synthesis. Reported studies have shown gambir extract to have antimicrobial activity against Staphylococcus aureus (Gram-positive) and E. coli (Gram-negative). Studies have also specifically aimed to evaluate purified gambier extracts for antifungal activity in vitro against Candida albicans. Evidence level: in vitro only; no controlled human clinical trials on infection treatment.

5.4 Anticancer Activity

U. gambir is one of the plants with high catechin content; recent research revealed that a U. gambir ethyl acetate extract contained 89.34% catechins, and catechin has known anti-cancer properties. Research has investigated whether nano-formulations of gambir extract can serve as chemopreventive agents against breast cancer cell lines. In vitro work has focused on the cytotoxic mechanism of catechin against cancer cell lines including MCF-7 (breast cancer): catechin hydrate effectively kills MCF-7 cells through induction of apoptosis, confirmed by TUNEL and real-time PCR assays. Cells exposed to 150 µg/mL CH and 300 µg/mL CH for 24 hours resulted in 40.7% and 41.16% apoptotic cells respectively; a 48-hour exposure to 150 µg/mL CH and 300 µg/mL CH resulted in 43.73% and 52.95% apoptotic cells, respectively.

Catechins are considered to be potent inducers of apoptosis and cytotoxicity to cancer cells; while the antioxidant properties of catechins may contribute to lowering the risk of cancer induction by impeding oxidative injury to DNA, these properties alone cannot account for the apoptosis induction and chemotherapeutic observations. Evidence level: entirely in vitro and animal model studies; no human clinical trial evidence for the use of gambir or its isolated catechins specifically in cancer treatment has been established.

5.5 Antidiabetic and Anti-hyperglycemic Activity

Several studies have been conducted to determine the effect of gambir extract on reducing blood sugar levels. Research has revealed that gambier possesses pharmacological properties including antioxidant, antibacterial, anti-inflammatory, anticancer, and xanthine oxidase inhibitor activities. A study by Arundita et al. in 2020 showed that purified gambier has alpha-glucosidase inhibitor activity with better potency compared to acarbose.

An animal-model study investigated purified gambier's effects on markers of oxidative stress and inflammation in diabetic rats: findings suggested that purified gambier has antioxidant-related anti-inflammation actions and blood sugar-lowering activity (p<0.05); the plasma malondialdehyde (MDA) and TNF-α level of the treatment group were significantly reduced (p<0.05) compared to the diabetes control group; at doses of 2.5–10 mg/kg body weight administered for 14 days on a diabetic rat model, purified gambier reduced plasma levels of MDA and TNF-α. Evidence level: in vitro enzyme inhibition and animal models only; no published human clinical trials specifically evaluating gambir for diabetes management have been identified.

5.6 Antihyperlipidemic Activity

Research results show a very strong potency of gambir plants in the treatment of hyperlipidemia with catechin as the bioactive compound. Evidence for the antihyperlipidemic effect rests on in silico, in vitro, and animal experiments. A review of 12 publications concluded that the Uncaria gambir isolates tested were catechin and ethyl acetate, used primarily for lesions, pain, edema, and diabetes in experimental Wistar rats; Uncaria gambir is an herbal plant that contains flavonoids and can potentially be applied in the medical field as adjuvant therapy. Evidence level: in vitro and preclinical only.

5.7 Oral Health (Anti-dental Plaque and Antimicrobial in the Oral Cavity)

The main compound of gambir extract, (+)-catechin, has been studied and described as having anti-dental plaque, antioxidant, antibacterial, and antihyperlipidemic properties. In silico studies have proposed a mechanism for catechin's antibacterial action against Streptococcus mutans: research aimed to observe the interaction of the active compound catechin from U. gambir against UDP-N-acetylenol pyruvylglucosamine reductase (MurB enzyme), which plays a role in the formation of peptidoglycan in S. mutans, through an in silico approach using molecular docking modeling. Evidence level: in silico and in vitro only; no clinical oral health trials on gambir extract as a standalone intervention have been identified.

6. Body Systems and Health Areas Associated with Gambir

• Gastrointestinal system: Traditionally used for burns, headaches, diarrhoea, dysentery, canker sores, and skin pain medication.
• Immune and inflammatory system: Anti-inflammatory activity has been demonstrated in vitro and in in vivo animal studies.
• Metabolic system (glucose regulation): Catechins isolated from gambir have been studied as anti-hyperglycemic agents through α-glucosidase inhibition in vitro.
• Cardiovascular and lipid metabolism: In vitro and animal studies have linked gambir catechins to inhibition of pancreatic lipase activity and reductions in total cholesterol, triglycerides, and LDL with increases in HDL.
• Oncology (preclinical): Proposed anti-cancer mechanisms of catechins include antioxidant activity, regulation of drug-metabolizing enzymes, induction of apoptosis, and inhibition of cell proliferation and metastasis.
• Oral cavity: It has been claimed that chewing betel quid (of which gambir is a component) could strengthen teeth and gums and maintain oral hygiene.
• Skin and wound healing: U. gambir Roxb. has traditional uses in the treatment of wounds and ulcers.
• Anti-uricemic: Gambier has been reported to exhibit xanthine oxidase inhibitor activity relevant to gout/hyperuricemia.

7. Dosage Forms and Reported Dosages

Gambir is produced and consumed in several physical forms. The resinous substance extracted from the leaves and young branches is crystallized and traded in small cubes or blocks. Gambir is also currently being developed as raw material for tea bags and as a refreshing material. Research has also explored nanosized formulations to improve bioavailability: catechin extraction produces catechin crystals; nano-sized particles have chemical and physical properties that are superior to micro-sized particles, and the rate of absorption of active compounds can be increased by using nanoscale particles.

The following dosages are reported solely as they appear in scientific publications and do not constitute recommendations:

• In the UP3005 animal study combining U. gambir leaf and Morus alba root bark extracts, oral dose ranges of 100–400 mg/kg were used in carrageenan-induced rat paw edema and related assays.
• In the diabetic rat model study, purified gambier was administered at doses of 2.5–10 mg/kg body weight for 14 days.
• In MCF-7 cell in vitro experiments, cytotoxic effects of catechin hydrate were assessed at concentrations up to 160 µg/mL, with an IC₅₀ of approximately 127.62 µg/mL.
• For in vitro α-glucosidase inhibition, IC₅₀ values for catechin fractions from gambir ranged from 40.45 to 52.43 µg/mL.

No standardized or pharmacopoeia-approved human clinical dosage for gambir as a medicine or dietary supplement has been identified in the peer-reviewed or institutional literature reviewed.

8. Safety Considerations and Interactions

Preclinical Safety Data

Long-term use of gambir leaves has been demonstrated to be safe in animal models, with no mutagenicity, no hematological or clinical biochemical abnormalities, and no abnormalities in the vital organs of the tested animals. This finding, however, is limited to animal models and may not directly translate to human safety at equivalent doses.

Betel Quid — Carcinogenicity Concern (Context of Gambir Use)

An important safety consideration is the context in which gambir is most commonly consumed: as part of the betel quid complex. Gambir itself is only one component; however, the overall mixture carries well-documented carcinogenic risks primarily attributable to areca nut rather than to gambir per se. The International Agency for Research on Cancer (IARC) has disclosed that betel quid substances, with and without tobacco additives, have been classified as Group I carcinogens in humans, with elevated risks for oral and pharyngeal cancers. The IARC review concluded that areca nut is carcinogenic in humans and that it is linked to cancers of the oral cavity, pharynx, oesophagus, liver and biliary tracts, and the uterus.

Epidemiological investigations have revealed that prolonged betel quid use confers an increased risk of esophagus cancer, hepatocellular carcinoma, liver cirrhosis, metabolic syndromes, and likely contribution to type 2 diabetes mellitus and high blood pressure. These risks are attributed to the betel quid as a composite preparation; no peer-reviewed study has isolated carcinogenicity specifically to the gambir fraction.

Distinction Between Gambir and Areca Nut

Available scientific literature consistently implicates areca nut alkaloids (such as arecoline and related compounds) rather than gambir catechins as the primary drivers of betel quid carcinogenicity. Potential biomarkers of betel quid carcinogens, such as areca nut alkaloids and 3-methylnitrosaminopropionitrile (MNPN), are closely associated with human health toxicology; molecular mechanisms involving autophagy, hypoxia, COX-2, NF-κB activity, and stemness are known to be induced by betel quid ingredients and are closely related to the carcinogenesis of oral and pharyngeal cancers. The catechins in gambir have conversely been investigated for potentially protective, antioxidant, and anti-inflammatory effects; however, in the context of the full betel quid mixture these any potential protective effects do not offset the carcinogenic risks of the whole preparation.

Potential Interactions and Considerations

Phytochemical studies identify biologically active constituents in gambir such as flavonoids, phenolics, and alkaloids; various studies have shown anti-hyperglycemic, antihyperlipidemic, anti-inflammatory, and other pharmacological properties. Based on this pharmacological profile, interactions are theoretically plausible with anticoagulant drugs (given the phenolic and tannin content), antidiabetic medications (given demonstrated α-glucosidase and α-amylase inhibitory activity), and lipid-lowering drugs; however, no direct human pharmacokinetic or interaction studies have been published in the peer-reviewed literature reviewed here.

No studies have comprehensively determined the structure and precise amounts of all chemical compounds present, which limits the ability to fully characterize the safety and interaction profile of gambir preparations. The existing safety data remain largely confined to animal models.

9. Evidence Summary

The keywords characterizing current research on Uncaria gambir Roxb. are catechin, flavonoids, alkaloids, and antioxidant. The plant is from Southeast Asia and is widely used as an alternative medicine with various applications; it has been widely used in traditional medicine. The scientific evidence base as of the peer-reviewed literature reviewed is characterized by a predominance of in vitro and animal-model studies. No large-scale, randomized, placebo-controlled human clinical trials of gambir extract as an isolated therapeutic agent have been identified in the peer-reviewed literature; the majority of mechanistic work has been conducted with isolated catechin fractions rather than with whole gambir preparations. U. gambir, which is commonly used in traditional medicine, is a potential plant for many therapeutic applications and prospects for drug development, as well as for other applications such as adsorbent and corrosion inhibition, but robust clinical evidence for most of these applications remains to be established.

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