Health & Effects

Everyday effects

Effects depend on dose and preparation. Here are the practical takeaways most people notice first.

Safety and Regulation

GRAS status (Generally Recognized as Safe)

Ilex guayusa

GRAS Notice GRN-835

The official GRAS notification (GRN-835) for Ilex

• Comprehensive Toxicology Studies: Acute, subchronic, and chronic toxicity
• Genotoxicity Tests: Ames test, chromosome aberration test, micronucleus test
• Human Studies: Pharmacokinetics, nervous system effects, safety
• Comparison with coffee: Caffeine composition and safety profile
• Historical Use: Centuries of documented safe use

EU Novel Food Status

Guayusa was approved as Novel Food by the European Commission in 2017. The scientific assessment by the EFSA (European Food Safety Authority) concluded:

• No safety concerns with intended use
• No negative health effects with traditional use
• Comparable to other Caffeine sources (coffee, tea, mate)

Toxicological Studies

Genotoxicity

Comprehensive Genotoxicity tests showed no mutagenic or genotoxic effects:

• Ames Test: Negative (no mutagenicity in bacteria)
• Chromosome Aberration Test: Negative (no structural chromosome damage)
• Micronucleus Test: Negative (no damage to genetic material)

90-Day Study

A 90-day subchronic toxicity study in rats showed:

• NOAEL: 1,000 mg/kg body weight/day (highest tested dose)
• No adverse effects on body weight, organ weights, hematology, or clinical chemistry
• No histopathological changes in organs

Pharmacokinetics

Caffeine Pharmacokinetics from Guayusa

The study by Krieger et al. (2016) investigated the pharmacokinetics of Caffeine from Guayusa compared to synthetic caffeine in 40 healthy adults. The results show interesting differences:

Pharmacokinetic Parameters

Interpretation

The results indicate that Caffeine from Guayusa is bioequivalent to synthetic Caffeine:

• Marginally delayed absorption: Tmax 15 minutes later (possibly due to Polyphenols or food matrix)
• Similar bioavailability: AUC values statistically not different
• Identical elimination: Half-lives practically equal
• Smoother effect: The slightly delayed absorption may lead to a smoother rise and less "jitter"

Absorption

Caffeine is rapidly and completely absorbed after oral intake:

• Absorption rate: >99% within 45 minutes
• Bioavailability: ~100% (complete oral bioavailability)
• Blood-Brain Barrier: Caffeine freely passes the blood-brain barrier
• Distribution: Even distribution in all tissues and body fluids

Distribution

After absorption, Caffeine distributes throughout the body:

• Volume of distribution: 0.6-0.7 L/kg body weight
• Protein Binding: 10-35% (relatively low)
• Tissue Penetration: All tissues, including brain, heart, liver
• Placental Passage: Caffeine passes the placenta

Elimination

The elimination of Caffeine occurs primarily through hepatic metabolism:

• Half-Life: 3-7 hours (individually variable)
• Clearance: 1.0-1.5 mL/min/kg
• Renal Excretion: <3% unchanged in urine
• Metabolic Clearance: >97% through hepatic metabolism

Metabolism

Caffeine Metabolism

Caffeine is metabolized in the liver by the cytochrome P450 enzyme system, primarily by CYP1A2. The metabolism is complex and leads to several active metabolites:

Primary Metabolites (Phase I)

Secondary Metabolites

The primary metabolites are further broken down into inactive compounds:

• 1-Methylxanthine
• 7-Methylxanthine
• 1-Methyluric Acid
• 1,7-Dimethyluric Acid
• 5-Acetylamino-6-formylamino-3-methyluracil (AFMU)

Enzymatic Reactions

Caffeine metabolism involves several enzymatic steps:

• N3-Demethylation: CYP1A2 → Paraxanthine (main pathway)
• N7-Demethylation: CYP1A2 → Theobromine
• N1-Demethylation: CYP1A2 → Theophylline
• C8-Hydroxylation: CYP1A2, CYP2E1 → 1,3,7-Trimethyluric Acid

Polyphenol Metabolism

The chlorogenic acids and other Polyphenols in Guayusa are also metabolized:

Phase I Metabolism

• Hydrolysis: Chlorogenic acids → Caffeic acid + Quinic acid (by esterases)
• Reduction: Caffeic acid → Dihydrocaffeic acid (by gut bacteria)
• Dehydroxylation: Caffeic Acid → m-Coumaric Acid

Phase II Metabolism

• Glucuronidation: Polyphenols → Glucuronides (by UGT enzymes)
• Sulfation: Polyphenols → Sulfates (by SULT enzymes)
• Methylation: Catechol structures → Methylethers (by COMT)

Microbial Metabolites

The gut microbiota plays an important role in polyphenol metabolism:

• Phenylpropionic Acids: From Chlorogenic Acids
• Benzoic Acids: From Flavonoids
• Hippuric acid: From caffeic acid (after glycine conjugation)

Factors Influencing Metabolism

The rate of Caffeine metabolism varies greatly between individuals:

• Genetic polymorphisms: CYP1A2*1F allele (fast vs. slow metabolizers)
• Smoking: Induction of CYP1A2 → faster metabolism
• Pregnancy: Reduced CYP1A2 activity → slower metabolism
• Age: Newborns and infants metabolize Caffeine more slowly
• Liver diseases: Reduced clearance
• Medications: CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin) slow metabolism

Cardiovascular Effects

Acute Effects

The study by Krieger et al. (2016) examined the acute cardiovascular effects of Guayusa:

Blood Pressure

Heart Rate

Heart rate showed no significant changes:

• Baseline: 68 ± 10 bpm
• After Guayusa: 70 ± 11 bpm
• Change: +2 bpm (not significant)

ECG Parameters

Electrocardiographic measurements showed no clinically relevant changes:

• QT Interval: No prolongation
• QTc Interval: No significant change
• PR interval: Unchanged
• QRS complex: Unchanged

Mechanisms

The cardiovascular effects of Caffeine are based on several mechanisms:

Long-Term Effects

Epidemiological studies on Caffeine consumption show interesting long-term effects:

• Cardiovascular Mortality: Moderate consumption (3-5 cups/day) associated with reduced risk
• Stroke: Slight risk reduction with moderate consumption
• Heart Failure: No negative association with moderate consumption
• Arrhythmias: No increased risk in healthy individuals

Polyphenol Effects

The chlorogenic acids and other Polyphenols in Guayusa have additional cardiovascular effects:

• Endothelial Function: Improvement through increased NO production
• Antioxidative effect: Protection against LDL oxidation
• Anti-inflammatory: Reduction of inflammatory markers (CRP, IL-6)
• Blood pressure: Slight blood pressure-lowering effect with chronic consumption

Cognitive Effects

Attention and Vigilance

Caffeine improves various aspects of cognitive performance:

Reaction Time

• Simple reaction time: Improvement of 10-15% after 100-200 mg Caffeine
• Choice reaction time: Improvement of 8-12%
• Dose-Response Relationship: Optimal at 100-300 mg
• Time Course: Maximum effect after 30-60 minutes

Vigilance and Sustained Attention

• Psychomotor Vigilance: Reduction of attention lapses
• Sustained Attention: Improvement in monotonous tasks
• Fatigue Reduction: Compensation for sleep deprivation effects

Memory

The effects of Caffeine on memory are complex:

Working Memory

• Verbal Working Memory: Slight improvement at low doses
• Spatial Working Memory: Inconsistent effects
• N-back Tasks: Improvement in accuracy

Long-Term Memory

• Consolidation: Improvement when Caffeine is taken after learning
• Retrieval: Facilitation of memory retrieval
• Declarative Memory: Moderate improvement

Executive Functions

Caffeine influences higher cognitive processes:

• Cognitive Flexibility: Improvement in task switching
• Inhibitory Control: Improvement in Stroop tests
• Decision Making: Faster decisions without loss of accuracy
• Problem Solving: Improvement in complex tasks

Mood and Motivation

Caffeine has positive effects on mood and motivation:

• Subjective alertness: Significant increase
• Fatigue: Significant reduction
• Motivation: Increased willingness for strenuous tasks
• Mood: Slight improvement at low to moderate doses

L-Theanine Synergy

The combination of Caffeine and L-Theanine in Guayusa leads to synergistic effects:

Cognitive Performance

• Attention: Greater improvement than Caffeine alone
• Accuracy: Reduction of errors in attention tasks
• Cognitive Flexibility: Improved performance in task switching

Subjective Effects

• Nervousness: Reduction of Caffeine-induced nervousness
• "Jitters": Less motor restlessness
• Calm alertness: "Calm alertness" without sedation

Neurophysiological Mechanisms

• Alpha waves: L-Theanine increases alpha wave activity (relaxation)
• GABA: L-Theanine modulates GABAergic neurotransmission
• Dopamine/Serotonin: Increased neurotransmitter levels

Mechanisms of Cognitive Effects

The cognitive effects of Caffeine are based on several mechanisms:

Antidiabetic Effects

Epidemiological Evidence

Several large epidemiological studies have found a link between Caffeine consumption and reduced diabetes risk:

• Risk reduction: 25-30% lower type 2 diabetes risk with 3-4 cups of coffee/day
• Dose-response relationship: Each additional cup → 7% risk reduction
• Long-term effect: Protective effect over the years

Mechanisms

The antidiabetic effects of Guayusa are based on several mechanisms:

Glucose Uptake

• GLUT4 translocation: Chlorogenic acids increase glucose transporter expression
• Insulin sensitivity: Improvement of insulin signaling pathways
• Muscle cells: Increased glucose uptake in skeletal muscle

α-Glucosidase Inhibition

Chlorogenic acids inhibit the enzyme α-glucosidase in the gut:

• Mechanism: Competitive inhibition of the enzyme
• Effect: Slowed carbohydrate digestion
• Result: Reduced postprandial blood sugar rise
• IC₅₀: Chlorogenic acid: 0.5-2.0 mM (comparable to Acarbose)

Insulin Secretion

• Pancreatic β-cells: Chlorogenic acids stimulate insulin secretion
• GLP-1: Increased secretion of glucagon-like peptide-1
• Calcium influx: Increased calcium-dependent insulin release

Hepatic Gluconeogenesis

• G6Pase inhibition: Reduction of glucose-6-phosphatase activity
• PEPCK inhibition: Reduction of phosphoenolpyruvate carboxykinase
• Result: Reduced hepatic glucose production

Antioxidative Effects

The antioxidative properties of Guayusa contribute to the antidiabetic effect:

• Oxidative stress: Reduction of ROS (Reactive Oxygen Species)
• β-Cell Protection: Protection of pancreatic β-cells from oxidative damage
• AGE formation: Inhibition of Advanced Glycation End Products

Clinical Studies

Human studies on chlorogenic acids show positive effects on glucose metabolism:

• Fasting glucose: Reduction by 4-6% after 12 weeks
• HbA1c: Reduction by 0.3-0.5% in pre-diabetics
• Postprandial glucose: Reduction of blood sugar increase by 15-25%
• Insulin sensitivity: Improvement of the HOMA-IR index

Liver Protection and Detoxification

Hepatoprotective Effects

Studies show that Caffeine and Polyphenols have hepatoprotective properties:

Epidemiological Evidence

• Liver cirrhosis: 40-50% reduced risk with regular Caffeine consumption
• Liver cancer: 40% reduced risk of hepatocellular carcinoma
• NAFLD: Reduced risk for non-alcoholic fatty liver disease
• Liver Enzymes: Lower ALT and AST levels in coffee drinkers

Mechanisms of Liver Protection

The hepatoprotective effects are based on several mechanisms:

Antioxidative Effect

• ROS reduction: Chlorogenic acids neutralize free radicals
• Lipid peroxidation: Protection against oxidative membrane damage
• Nrf2 activation: Induction of antioxidant enzymes

Anti-inflammatory Effects

• NF-κB inhibition: Reduction of pro-inflammatory cytokines
• TNF-α: Reduction of tumor necrosis factor α
• IL-6: Reduction of interleukin-6
• Kupffer cells: Modulation of hepatic macrophage activity

Anti-fibrotic Effects

• Hepatic stellate cells: Inhibition of activation
• Collagen synthesis: Reduction of fibrosis formation
• TGF-β: Inhibition of transforming growth factor β

Phase I Detoxification Enzymes

Caffeine and Polyphenols modulate Phase I enzymes:

Cytochrome P450 System

• CYP1A2: Induction by chronic Caffeine consumption
• CYP2E1: Inhibition by chlorogenic acids (protection against toxins)
• CYP3A4: Mild modulation

Phase II Detoxification Enzymes

Phase II enzymes are influenced by Guayusa components:

Conjugation Enzymes

• Glutathione S-transferase (GST): Induction by Polyphenols
• UDP-Glucuronosyltransferase (UGT): Increased activity
• Sulfotransferase (SULT): Modulation of activity
• N-Acetyltransferase (NAT): Influence on acetylation

Glutathione System

Guayusa affects the most important cellular antioxidant system:

• Glutathione levels: Increase of reduced glutathione (GSH)
• Glutathione reductase: Increased enzyme activity
• Glutathione peroxidase: Improved antioxidant capacity
• GSH/GSSG ratio: Improvement of redox status

Mitochondrial Function

Polyphenols improve mitochondrial function in hepatocytes:

• ATP production: Increased mitochondrial respiration
• Mitochondrial biogenesis: Induction by PGC-1α activation
• Mitophagy: Improvement of quality control
• Membrane potential: Stabilization of mitochondrial membrane potential

Antioxidative Properties

ORAC Value

The ORAC value (Oxygen Radical Absorbance Capacity) measures the antioxidant capacity:

• Guayusa leaves: 127,000 μmol TE/100g (dry weight)
• Guayusa infusion: 2,500-3,500 μmol TE/cup
• Comparison Green Tea: 1,250 μmol TE/cup
• Comparison Coffee: 1,800 μmol TE/cup

Polyphenol Content

Guayusa is rich in various antioxidative Polyphenols:

• Total Polyphenols: 15-20% dry weight
• Chlorogenic acids: 92.6 mg/g (main antioxidant)
• Flavonols: 35.5 mg/g (Quercetin, Kaempferol, Rutin)
• Catechins: 8.2 mg/g (EGCG, ECG, EC)

Antioxidative Mechanisms

The antioxidative effects of Guayusa are based on several mechanisms:

Direct Radical Scavenging Activity

• DPPH radicals: IC₅₀ = 12.3 μg/mL
• ABTS radicals: 98% inhibition at 50 μg/mL
• Hydroxyl radicals: Strong neutralization
• Superoxide anions: Effective elimination

Metal Chelation

• Iron chelation: Prevention of the Fenton reaction
• Copper chelation: Reduction of copper-catalyzed oxidation
• Catechol structure: Effective metal binding through ortho-dihydroxy groups

Enzymatic Antioxidants

Guayusa Polyphenols induce endogenous antioxidative enzymes:

• Superoxide dismutase (SOD): Increased activity
• Catalase: Enhanced expression
• Glutathione peroxidase: Increased enzyme levels
• Heme oxygenase-1 (HO-1): Induction by Nrf2 activation

Nrf2-ARE Signaling Pathway

The Nrf2-ARE signaling pathway is the main regulator of cellular antioxidant defense:

Mechanism

• Nrf2 activation: Polyphenols release Nrf2 from Keap1
• Nuclear Translocation: Nrf2 migrates to the nucleus
• ARE Binding: Binding to Antioxidant Response Elements
• Gene Expression: Induction of antioxidant and Phase II enzymes

Induced Genes

• NQO1: NAD(P)H:Quinone Oxidoreductase 1
• HO-1: Heme oxygenase-1
• GCL: Glutamate-cysteine ligase (glutathione synthesis)
• GST: Glutathione S-transferase
• UGT: UDP-glucuronosyltransferase

Lipid Peroxidation

Guayusa protects lipids from oxidative damage:

• LDL oxidation: 60-80% inhibition in vitro
• Malondialdehyde (MDA): Reduction of lipid peroxidation markers
• Membrane protection: Protection of cellular membranes against oxidative damage
• Atherosclerosis: Potential prevention through LDL protection

DNA Protection

Antioxidants in Guayusa protect DNA from oxidative damage:

• 8-OHdG: Reduction of 8-hydroxy-2'-deoxyguanosine (DNA damage marker)
• DNA strand breaks: Prevention through radical scavenger activity
• Comet assay: Reduction of DNA tail in cell culture

Clinical Studies

Krieger et al. (2016) - Pharmacokinetics and Safety

This randomized, double-blind, crossover study investigated the pharmacokinetics and safety of Guayusa in 40 healthy adults.

Study Design

• Participants: 40 healthy adults (20 men, 20 women)
• Age: 18-50 years
• Intervention: 140 mg Caffeine from Guayusa vs. synthetic caffeine
• Design: Randomized, double-blind, crossover
• Washout: 7 days between treatments

Main Findings

• Bioequivalence: Caffeine from Guayusa bioequivalent to synthetic caffeine
• Safety: No serious side effects
• Tolerability: Well tolerated by all participants
• Nervous system: No clinically relevant neurological effects

Human study (2024): mood, energy and reaction time

In a small study with 25 healthy young adults, a single dose of guayusa leaf extract was tested (600 mg and 1200 mg) and compared with placebo.

• 600 mg: better mood, less fatigue and higher perceived energy; also faster (psycho-)motor performance.
• 1200 mg: additionally faster reaction time; however, women reported more jitteriness in a dose-dependent way.
• Both doses: blood pressure increased acutely by about 4–5 mmHg; QTc (ECG marker) did not change.
• Important: these were acute effects in a small sample.
• An extract was used (not necessarily a classic tea infusion); long-term data are still lacking.

Source: PMID 39014963. DOI: 10.1080/15502783.2024.2379424

More details in Studies →

Further Clinical Studies

Several other studies have examined the safety and efficacy of Guayusa:

Toxicology Studies

• 90-day study: NOAEL of 1,000 mg/kg/day in rats
• Genotoxicity: Negative in all tests (Ames, micronucleus, chromosomal aberration)
• Reproductive toxicity: No adverse effects on reproduction

Antioxidative Capacity

• ORAC study: High antioxidant capacity confirmed
• Polyphenol analysis: Comprehensive characterization of Bioactive Compounds
• Comparative studies: Superiority over other Caffeine sources

Guayusa as Detox Tea

Highest ORAC Value of All Teas

Guayusa is the tea with the highest antioxidant content in the world. With an ORAC value of 120,000 to 160,000 µmol TE/100g, Guayusa surpasses all other known teas and optimally supports the body's own detoxification processes.

The Oxygen Radical Absorbance Capacity (ORAC) measures a food's ability to neutralize free radicals. Guayusa clearly leads this ranking:

• Guayusa: 140,000 µmol TE/100g
• Matcha: 130,000 µmol TE/100g
• Green Tea: 62,000 µmol TE/100g
• Black Tea: 31,000 µmol TE/100g
• Coffee: 15,000 µmol TE/100g

Bioactive Compounds for Detoxification

Guayusa's detoxifying properties are based on a unique combination of Bioactive Compounds:

• Chlorogenic Acid: Supports liver health and fat metabolism. Promotes the body's own detoxification and has antioxidant properties.
• Polyphenols: Neutralize free radicals and protect cells from oxidative stress. Guayusa contains 15-20% Polyphenols by dry weight.
• Quercetin: Has anti-inflammatory and immune-boosting effects. Supports cellular regeneration and protection against environmental toxins.
• Theobromine: Mildly stimulating and vasodilating. Promotes blood circulation and thus nutrient supply to detoxification organs.

Traditional Use for Detoxification

The Kichwa indigenous people of the Ecuadorian Amazon have used Guayusa for over 2,000 years not only as an energy source but also in ritual detoxifying steam baths. This traditional use underscores the importance of Guayusa in natural cleansing and body detoxification.

Further Information

Detailed scientific information about Guayusa as a detox tea, including comprehensive ORAC comparisons and study results, can be found on the specialized knowledge portal:

Detox Tea Wiki – Guayusa as the #1 Detox Tea →

Source: Pardau et al. (2017), Kelebek et al. (2024)