Ilex

Ilex: A Comprehensive Encyclopedic Reference

1. Identity: Botanical Classification, Species, and Common Preparations

The Genus

The family Aquifoliaceae, known as the holly family, comprises the single species-rich genus Ilex L. and more than 600 species, which are dioecious shrubs or trees. It is sub-cosmopolitan, but is best represented in mountainous areas of the tropics, especially in Asia, Central and South America. Although the genus has hundreds of members, relatively few have attracted significant scientific or commercial attention as dietary supplements or medicinal plants. The most globally prominent species are discussed below.

Principal Medicinal and Dietary Species

• Ilex paraguariensis A. St.-Hil. (Yerba Mate) — Known as yerba mate, it is a plant native to the subtropical regions of South America, traditionally cultivated and consumed in Brazil, Argentina, Paraguay, and Uruguay. Yerba Mate tea, an infusion made from the leaves of the tree Ilex paraguariensis, is a widely consumed nonalcoholic beverage in South America that is gaining rapid introduction into the world market, either as tea itself or as an ingredient in formulated foods or dietary supplements.
• Ilex kaushue S.Y. Hu / Ilex kudingcha C.J. Tseng (Kuding Tea) — An evergreen tree in the holly family, Aquifoliaceae, native to dense subtropical forests in southern China and northern Vietnam, where it grows at elevations between 1,000 and 1,200 meters; it has been utilized for over 2,000 years in traditional East Asian medicine as the primary source of kuding cha, a bitter, caffeine-free tea substitute.
• Ilex guayusa (Guayusa) — A species of tree in the holly family, Aquifoliaceae, native to the Amazon rainforest. One of four known caffeinated holly trees, the leaves of the guayusa tree are harvested fresh and brewed like a tea for their stimulative effects.
• Ilex vomitoria (Yaupon Holly) — Known as "Yaupon Holly," a caffeine-containing plant from North America.
• Ilex aquifolium (European Holly) — Plants of the genus Ilex are widespread throughout the world, with its best-known representative being Ilex paraguariensis from South America. The European species Ilex aquifolium shows similarities in its terpenoid, sugar, and phenolic acid profiles.

Common Botanical Names

Ilex paraguariensis carries the synonyms Ilex mate St.-Lag. and Ilex paraguayensis Hook. Yerba mate (Ilex paraguariensis) is a plant species of the holly genus Ilex native to South America and was named by the French botanist Augustin Saint-Hilaire. The taxonomy of Ilex kaushue places it within the genus Ilex, with synonyms including Ilex kudingcha and Ilex latifolia f. puberula, as accepted in major floras such as the Flora of China.

Common Forms and Preparations

Mate is a traditional nonalcoholic drink, an aqueous infusion prepared from dried leaves of the herb Ilex paraguariensis. The leaves are harvested; dried using sunshine, smoking, traditional wood fires, or modern heating technologies; and chopped and ground into a powdery mixture, which is steeped in hot water and served with a metal straw as "hot mate tea." The steeping process can be repeated 10–15 times. The leaves of the plant can be steeped in hot water to make a beverage known as mate. Brewed cold, it is used to make tereré. Newer industrialized forms include capsules, energy drinks, and extracts that often contain standardized doses of caffeine and other bioactive compounds.

For kuding tea, the two most common plants used to make kuding are the wax tree species Ligustrum robustum and the holly species Ilex kaushue (synonym: Ilex kudingcha), the former being more commonly grown in Sichuan and Japan while the latter is most commonly grown and used in the rest of China and Vietnam.

2. Traditional and Historical Use

Indigenous South American Traditions (Ilex paraguariensis)

The indigenous Guaraní and some Tupí communities, whose territory covered present-day Paraguay, first cultivated and consumed yerba mate prior to European colonization of the Americas. Mate was first consumed by the indigenous Guaraní people and also spread in the Tupí people in the departments of Amambay and Alto Paraná in the territory of Paraguay. Its consumption became widespread during European colonization, particularly in the Spanish colony of Paraguay in the late 16th century, among both Spanish settlers and indigenous Guaraní.

Pedro de Montenegro, a Jesuit monk, in his Materia Medica Misionera described the use of the most important species for the Guarani people, in which yerba mate appeared on the top of the list. The Guarani name for yerba mate is ka'a, which means "a plant" or "a herb"; hence yerba mate has been considered by this group as the plant par excellence. Yerba mate was also known as Jesuit tea or Paraguayan tea and shipped as such to Europe.

The indigenous people have used it for centuries as a social and medicinal beverage. Traditional ethnobotanical records from the USDA document historical uses including as a stimulant, diuretic, astringent, purgative, sudorific (sweat-inducing), and remedy for rheumatism and scurvy.

The Paraguayan Mestizo people have the longest tradition of using the yerba mate beverage, apart from the indigenous Guarani people. Most medicinal plants are used as additives of the national beverage, "tereré" and "mate," a cold maceration and a hot infusion, respectively, of yerba mate (Ilex paraguariensis).

Traditional Chinese Medicine (Ilex kaushue / Ilex kudingcha — Kuding Tea)

The term "kudingcha" (苦丁茶) literally translates to "bitter spike tea" or "bitter nail tea" in English. This nomenclature underscores its historical significance as a caffeine-free beverage and medicinal preparation in southern China, with records of use of Ilex species tracing back to the Song dynasty (960–1279 CE), and kudingcha's traditional use documented in later historical texts. I. kudingcha and I. latifolia are used as a popular herbal tea called kudingcha and are known in traditional practice as a remedy for arteriosclerosis, common cold, eye infections, cancer, cardiovascular disorders, cerebrovascular diseases, diabetes, diarrhoea, dysentery, hypertension, pharyngitis, and rhinitis.

Other Traditional Uses within the Genus

Ilex pubescens is used in traditional practice for the treatment of bronchial asthma, coronary artery disease, hepatitis, high cholesterol, and hypertension. Its bioactive metabolites have been shown to have anticancer, analgesic, anti-inflammatory, anticlotting, and neuroprotective activities.

3. Key Constituents and Active Compounds

Ilex paraguariensis

Yerba mate stands out for its rich phytochemical profile and is considered a relevant source of bioactive compounds with well-recognized functional properties. The leaves of I. paraguariensis primarily contain polyphenols, flavonoids, phenolic acids, methylxanthines (such as caffeine, theobromine, and theophylline), and triterpene saponins, in addition to vitamins, minerals, and pigments.

Phenolic Acids and Chlorogenic Acids

Quantitative analysis has determined the total phenolic content (TPC) to be approximately 51 mg/g of the plant's dry weight. Among the 46 polyphenolic compounds identified in the tested extracts, the most abundant were chlorogenic acids: 3-caffeoylquinic acid (26.8–28.8%), 5-caffeoylquinic acid (21.1–22.4%), 4-caffeoylquinic acid (12.6–14.2%), and 3,5-dicaffeoylquinic acid (9.5–11.3%). Among phenolic compounds, chlorogenic acids, especially the 3-, 4-, and 5-caffeoylquinic acid isomers, are the most abundant, and these contribute significantly to antioxidant activity and are linked to anti-inflammatory and hypolipidemic effects.

Methylxanthines

The invigorating attributes of the beverage are attributed to the presence of methylxanthines, a class of purine alkaloids encompassing caffeine, theobromine, and theophylline. The dried extract of I. paraguariensis leaves contains a caffeine content ranging from 1% to 2% of the dry matter.

Flavonoids

The main compounds include caffeoyl derivatives (caffeic acid, mono- and dicaffeoylquinic acids), methylxanthines (caffeine and theobromine), and flavonoids (rutin, quercetin, and kaempferol). The predominant flavonoids include rutin, quercetin, and their glycosylated derivatives, which act as free radical scavengers and enzyme modulators in inflammatory and metabolic pathways.

Saponins (Triterpenes)

The presence of free triterpenes, including ursolic acid, oleanolic acid, rotundic acid, and derived saponins, along with chlorogenic acid, caffeine, and theobromine, have also been found in the fruit portion of the plant. Saponins present in yerba mate have been associated with cholesterol-lowering effects. Such high saponin content in concentrated mate extract not only affects the flavour of the extract, but also provides hypocholesterolaemic properties.

Additional Constituents

The yerba mate samples contain at least five free sugars, five organic acids, eighteen fatty acids, one tocopherol, nine hydroxycinnamoyl derivatives, and two flavonols. Numerous active phytochemicals have been identified in yerba mate, including minerals (phosphorous, iron, and calcium) and vitamins (C, B1, and B2).

Effects of Processing on Chemical Composition

The industrial processing involves different stages (green leaves, zapecado, drying, forced or natural aging) which can modify the qualitative and quantitative composition and the pharmacological activities. The main compounds — caffeoyl derivatives, methylxanthines, and flavonoids — were studied by HPLC in extracts obtained by decoction during its industrial process stages. The comparative quantitative analysis indicated that those obtained after the zapecado, drying, and aging stages possess higher content of biologically active principles when compared with green leaves.

Phytochemistry of Other Ilex Species

Ilex paraguariensis possesses the richest profile of hydroxycinnamic acid derivatives in terms of component concentration and diversity among studied Ilex species. Tea produced from Ligustrum or many species of Ilex is caffeine-free, although not Ilex paraguariensis, the source of mate. Compared to green tea, catechins (about 1.7%) are reported to be less abundant in kuding, while rutin (about 0.4%) is more abundant. In addition, kuding is reported to contain more zinc, manganese, copper, and selenium, and less amino acids and ascorbic acid than green tea.

4. Mechanisms of Action

Antioxidant Activity

Yerba mate has been extensively studied for its functional and therapeutic potential, which is attributed to the synergistic action of secondary metabolites such as phenolic acids (particularly chlorogenic acids), flavonoids, methylxanthines (caffeine and theobromine), and saponins. These compounds confer to I. paraguariensis antioxidant, anti-inflammatory, hypolipidemic, neurostimulant, antimicrobial, and gastroprotective properties. The ability of yerba mate to neutralize free radicals has been widely documented and is primarily attributed to the presence of chlorogenic acids and flavonoids such as rutin. Research suggests that I. paraguariensis and its major chemical markers have strong free radical scavenging properties as well as important anti-inflammatory activity, and that these compounds in a plant extract may work based on several different mechanisms synergistically, resulting in moderating the immune system.

Anti-inflammatory Mechanisms

An aqueous infusion extract showed inhibition of NOx secretion (50.10 ± 8.97%) as well as inhibition of TNF-α (83.33 ± 4.01%). Regarding the chemical markers, all compounds showed strong inhibition of NOx secretion, especially theobromine, which was 200 times more potent than dexamethasone. Furthermore, TNF-α secretion was also significantly decreased by theobromine, neochlorogenic acid, cryptochlorogenic acid, chlorogenic acid, caffeine, and rutin at tested concentrations.

Thermogenic and Metabolic Mechanisms

The primary methylxanthine in I. paraguariensis is caffeine, which is a thermogenic agent that acts through the adenosine receptor to increase metabolic rates, induce fat oxidation, stimulate respiratory centers, and increase resting energy expenditure.

Lipid-Lowering Mechanisms

Saponins have been proposed as a key contributor to the cholesterol-lowering properties of yerba mate. Consumption of approximately 130 and 350 mg of saponins in yerba mate infusion provided a further decrease in LDL-cholesterol in subjects undergoing statin therapy. Chlorogenic acids in yerba mate have also been shown to contribute to hypocholesterolemic effects. Yerba mate is rich in bioactive compounds, especially chlorogenic acid, which has been shown as one of the major contributors to hypocholesterolemic effects.

Central Nervous System Stimulation

The compounds found in high quantities are purine alkaloids (methylxanthines such as caffeine and theophylline), polyphenols (chlorogenic acids and derivatives), saponins, and flavonoids. Among the popularly known and described biological properties of I. paraguariensis, antioxidant and diuretic activities, hepatoprotective and hypocholesterolemic effects, inhibition of LDL, central nervous system stimulation, and a beneficial effect on the cardiovascular system have been reported.

Monoamine Oxidase (MAO) Activity

Monoamine oxidase (MAO) is an enzyme responsible for the degradation of monoamines, such as serotonin, dopamine, and norepinephrine. The abnormal activity of this enzyme has been implicated in the pathophysiology of depression. Preclinical research in animal models has explored whether Ilex paraguariensis extracts may modulate MAO activity, contributing to potential antidepressant-like effects, though human data are lacking.

Ilex aquifolium — Lipid Metabolism

Using aqueous extracts of Ilex aquifolium as a supplement in Wistar rats showed that, despite the lack of caffeine, it had strong hypocholesterolemic effects. In addition, a reduction in oxidative lipid degradation and a decrease in hepatic steatosis in histopathological studies were observed. The results of this study suggest that extracts from the European species Ilex aquifolium may have potential as an alternative treatment for hyperlipidemia.

5. Scientific Evidence by Health Area

5.1 Antioxidant Activity

Yerba mate protects DNA from oxidation and in vitro low-density lipoprotein lipoperoxidation, and has a high antioxidant capacity. The yerba mate spray-dried extract presents high catalase-like activity, suggesting that it is a strong free-radical scavenger. The antioxidant activity as expressed as catalase-like activity was related to total polyphenol content.

Evidence strength: Considerable in vitro and animal evidence. Human studies confirm measurable increases in plasma antioxidant capacity after consumption, but clinical significance for disease prevention has not been established in large randomized controlled trials.

5.2 Lipid Profile and Cardiovascular Health

Yerba mate has been shown to be hypocholesterolemic, hepatoprotective, central nervous system stimulant, and diuretic, and to benefit the cardiovascular system.

A systematic review and meta-analysis examining randomized placebo-controlled trials identified only three studies meeting inclusion criteria for quantitative synthesis. The study showed that Ilex paraguariensis could improve HDL-cholesterol, but with no differences in total cholesterol and triglycerides, comparing to the placebo-controlled group.

In a randomized, double-blind, placebo-controlled crossover trial in 34 male volunteers aged 45–65 years at elevated cardiovascular risk, volunteers were assigned to consume an encapsulated dry maté extract for four weeks, providing 580 mg of caffeoyl quinic acid derivatives (CQAs) daily, or a placebo, with a two-week washout between intervention periods. A significant decrease in fasting glucose was observed between day 0 and day 28 for the maté group only (−0.57 ± 0.11 mmol/L, p < 0.0002). In subjects with an intermediate to high Framingham risk score, consumption of maté extract induced a 10% increase of high-density lipoprotein (HDL)-cholesterol from baseline. In a subgroup representative of the study population, significant decreases in the C-reactive protein (CRP) (−50%) and interleukin-6 (IL-6) (−19%) levels were observed. These clinical observations suggest that maté, naturally rich in chlorogenic acids, could improve some cardiometabolic markers in subjects with a higher predisposition to metabolic syndrome, even if that remains to be confirmed in new trials specifically targeting this population.

Evidence strength: Preliminary to moderate. Small number of qualifying randomized trials, modest effect sizes, and heterogeneity in preparations and populations limit firm conclusions. HDL improvement is the most consistently observed lipid benefit in clinical evidence reviewed to date.

5.3 Body Weight and Obesity

A systematic review with meta-analysis of clinical trials demonstrated the positive effects of I. paraguariensis consumption on the reduction of body weight, BMI, and waist circumference in patients, showing its anti-obesity potential. However, special attention must be given due to the high concentrations of caffeine found in this plant. Future clinical trials should evaluate the effects of I. paraguariensis on lipid profile and blood pressure, together with the evaluation of its consumption by healthy people.

A randomized, double-blind, placebo-controlled clinical trial investigated the efficacy and safety of Yerba Mate supplementation in Korean subjects with obesity. A decrease in free fatty acid was observed with Yerba Mate, although the difference from the placebo group was not significant. This trial population had a BMI ≥ 25 and the intervention was conducted over 12 weeks.

In vitro evidence shows that phenolic compounds from mate (Ilex paraguariensis) inhibit adipogenesis in 3T3-L1 preadipocytes.

Evidence strength: The meta-analytic data suggest a statistically significant but modest effect on body weight and BMI. Individual trials have yielded mixed results. Much of the observed thermogenic/anti-obesity effect is attributable to caffeine, making it difficult to distinguish from caffeine's known effects per se. Evidence is insufficient for strong clinical recommendations.

5.4 Glycemic Control and Diabetes

A 3-month, randomized, double-blind, placebo-controlled clinical study evaluated a nutraceutical containing Ilex paraguariensis leaf extract (standardized to 2% 1-deoxynojirimycin), white mulberry, and chromium picolinate in 148 non-diabetic subjects with dysglycemia. A reduction in fasting plasma glucose, postprandial glucose, and glycated hemoglobin was observed with the nutraceutical combination, both compared to baseline and placebo. Data suggested a decrease in the Homeostasis Model Assessment index with the nutraceutical, both compared to baseline and placebo. The M value, an index of insulin sensitivity, obtained after nutraceutical treatment was higher compared to baseline. However, this study was a combination product, and the individual contribution of Ilex paraguariensis cannot be separated from that of the other components.

Contradictory results were found on the hypoglycemic effects of Ilex paraguariensis, whereby rigorous long-term clinical trials are needed to confirm these data.

Evidence strength: Preliminary. The available combination-product trial shows promising signals for glycemic control, but isolating the effect of Ilex paraguariensis alone is not possible from current evidence. Independent RCTs with adequate power and duration are needed.

5.5 Anti-inflammatory Effects

In a randomized, double-blind, crossover clinical study in men predisposed to cardiovascular risk, consuming 580 mg/day of caffeoyl quinic acid derivatives from maté extract produced significant decreases in CRP (−50%) and IL-6 (−19%) levels in a representative subgroup. Preclinical studies support multiple anti-inflammatory mechanisms involving TNF-α and nitric oxide suppression (see Section 4 above).

Evidence strength: Promising in vitro and animal-model data with some early clinical corroboration, but the clinical evidence is from small, short-duration trials with limited populations. Larger confirmatory trials are needed.

5.6 Central Nervous System, Mood, and Cognitive Effects

Animal studies using the forced swim test in rats demonstrated antidepressant-like effects of Ilex paraguariensis extract, attributed partly to monoamine modulation. However, no rigorous human clinical trials specifically targeting mood or cognition have been published. The CNS stimulant effects are primarily attributed to caffeine and theobromine content, which are well-established in the broader literature on methylxanthines. The effects of the consumption of I. paraguariensis include central nervous system stimulation, increased antioxidant defense, antioxidant properties in vitro, and thermogenic properties.

Evidence strength: CNS stimulant effects are supported by well-established pharmacology of caffeine. Specific antidepressant or cognitive enhancement effects from Ilex beyond caffeine content have not been demonstrated in human RCTs.

5.7 Antimicrobial Properties

Plants from the Ilex genus are known for properties such as antimicrobial and anti-inflammatory activity. In vitro studies have demonstrated that aqueous extracts inhibit the growth of various bacterial and fungal species, though these results have not been translated into clinical trials.

Evidence strength: In vitro only. No human clinical data support therapeutic antimicrobial applications.

5.8 Hepatoprotective Effects

In the rat model, using aqueous extracts of Ilex aquifolium as a supplement in Wistar rats showed, despite the lack of caffeine, strong hypocholesterolemic effects. In addition, a reduction in oxidative lipid degradation and a decrease in hepatic steatosis in histopathological studies were observed.

Evidence strength: Animal/preclinical only for hepatoprotection. In vitro data also exist. Human evidence is absent.

6. Body Systems Associated with Ilex

• Cardiovascular system: Lipid modulation (particularly HDL elevation and LDL reduction), blood pressure, endothelial function, and anti-atherosclerotic effects have all been studied in preclinical and, to a lesser extent, clinical settings.
• Metabolic system: Glycemic control, insulin sensitivity, obesity and body weight management, and thermogenesis.
• Central nervous system: Stimulation, wakefulness, and possible mood modulation via methylxanthines and MAO-related pathways.
• Immune and inflammatory system: Modulation of TNF-α, IL-6, CRP, and nitric oxide pathways.
• Hepatic system: Antisteatotic effects observed in animal models.
• Digestive and gastrointestinal system: Traditionally used as a digestive aid; preclinical evidence for microbiota modulation via phenolics.
• Renal system: Traditionally documented as a diuretic.

7. Dosage Forms and Dosages Reported in Studies

The amount of yerba mate typically consumed can vary greatly depending on cultural practices and product format. In traditional forms such as chimarrão or tereré, intake can reach 1–2 L per day, which may correspond to approximately 100–300 mg of caffeine and 300–600 mg of total chlorogenic acids daily, depending on the strength of infusion and frequency of refilling.

In a published randomized crossover trial in men at cardiovascular risk, the trial aimed to evaluate the impact of maté chlorogenic acids consumed in a daily dose achievable through traditional maté beverages. Thirty-four male volunteers aged 45–65 years were recruited for a randomized, double-blind, placebo-controlled, crossover study. The volunteers were assigned to consume an encapsulated dry maté extract for four weeks, providing 580 mg of caffeoyl quinic acid derivatives (CQAs) daily.

In the dysglycemia trial, 148 patients orally administered I. paraguariensis leaves (1000 mg) once daily in combination with Morus alba (50 mg) and chromium picolinate (100 µg). After a period of 3 months, improved glycemic status was observed, in particular for reduced fasting plasma glucose, postprandial glucose, and glycated hemoglobin.

Newer industrialized forms such as capsules, energy drinks, and extracts often contain standardized doses of caffeine and other bioactive compounds. These formats may deliver concentrated levels in smaller volumes, making it easier to exceed traditional intake thresholds, particularly when consumed alongside other caffeine-containing products.

8. Safety Considerations and Drug Interactions

Esophageal and Upper Aerodigestive Tract Cancer Risk

Drinking mate is very common in several South American countries and has been associated with an increased risk of esophageal cancer. This increased risk may be attributed to drinking mate very hot, or to mate's potentially carcinogenic contaminants, such as polycyclic aromatic hydrocarbons (PAHs). Mate leaves are often dried via smoking, and therefore commercial samples may have high amounts of PAHs. Ten original articles measured PAHs in commercial dry samples, and nearly all found very high mass fractions. Most studies found benzo[a]pyrene mass fractions to be over 25 ng/g, and some found levels up to 600 ng/g. However, carcinogenic PAHs are often hydrophobic, and may not readily transfer into infusions. Seven articles studied transfer rates, and these rates varied from 1 to 50%, depending on the methods employed.

Mate drinking has also been associated with increased risk of other smoking-related cancers, including cancers of the lung, larynx, oral cavity and oropharynx, kidney, and bladder, after adjustment for smoking.

In 1990, the International Agency for Research on Cancer (IARC), an office of the WHO, classified the infusion of yerba mate as a possible carcinogen based on a series of publications that linked consumption with different types of cancer, mainly the oropharynx.

Studies also note that incidents of cancer overlap with the use of alcohol, tobacco, the presence of nutritional deficiencies, and poor oral hygiene — not mate use alone.

Caffeine-Related Adverse Effects

Special attention must be given to the high concentrations of caffeine found in yerba mate. As a significant source of caffeine (1–2% of dry weight), Ilex paraguariensis carries well-documented caffeine-related risks at high intakes, including cardiovascular stimulation, anxiety, insomnia, and dependency. These concerns are compounded by modern concentrated supplement forms.

Pharmacokinetic and Pharmacodynamic Interactions

Due to its caffeine and methylxanthine content, yerba mate may potentiate the effects of other stimulant agents. Drug interaction databases document that yerba mate increases the effects of caffeine-containing products by pharmacodynamic synergism. Additionally, documented pharmacodynamic interactions include additive stimulant effects when combined with stimulant medications such as amphetamines and methylphenidate.

The anti-inflammatory and antioxidant polyphenolic constituents of Ilex paraguariensis (particularly chlorogenic acid) may theoretically influence CYP450 enzyme pathways and thus the metabolism of co-administered drugs, though definitive human pharmacokinetic data on this interaction profile are limited in the peer-reviewed literature.

Absence of Hepatotoxicity (In Vitro)

The absence of hepatotoxicity in the extracts was confirmed in porcine liver primary cells. This in vitro finding does not substitute for comprehensive human safety trials.

Safety and Scientific Gaps

Current data highlight the potential of yerba mate as a functional and strategic ingredient for the development of safe and sustainable products, while also identifying relevant scientific gaps, such as the lack of comparative studies between cultivars and standardized extraction methods that need to be addressed to support health claims.

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