Guarana (Paullinia cupana)
1. Identity
Botanical and Chemical Names
Guarana is an extract of roasted and pulverized seeds of the plant Paullinia cupana, which is indigenous to the Amazon Basin. It is a climbing plant in the family Sapindaceae. The species also appears under the variety name Paullinia cupana var. sorbilis in the scientific literature. The common name "guarana" derives from the Tupi–Guarani word used by indigenous peoples of the Amazon. In the local language, "guaraná" translates as "the beginning of all knowledge."
Natural Source and Botanical Description
Guarana is derived from the seeds of the plant Paullinia cupana, which is native to the Amazon Basin and is cultivated as a source of guarana and caffeine in South America. It is a climbing plant native to the Amazon basin, particularly Brazil, Venezuela, and Colombia, and is a member of the soapberry family that produces small, red fruit containing black seeds. The process of processing the fruit begins with sun drying; after the skin of the fruit opens, it reveals one to three white-black seeds, similar in appearance to a human eye. Due to optimal climatic conditions, the main area of cultivation in northern Brazil is the Amazon region as well as parts of Venezuela and Peru, as the plant usually does not survive drought or frost.
Common Preparations and Dosage Forms
Guarana is available in tablets and capsules, as liquid, and in multiple commercial multi-ingredient supplements, particularly weight loss products and energy drinks. Traditionally, the seeds are roasted and ground. The kernels are roasted in a fire and then ground like cocoa; the resulting guarana powder is mixed with freshwater and served as a kind of coffee, sometimes sweetened with honey. Paullinia cupana extract (from seed) is approved in the United States as a food additive and is considered a dietary supplement; it is also listed in the official Brazilian Pharmacopoeia. Today, guarana is found in a wide variety of drinks, foods, dietary/herbal supplements, and pharmaceuticals.
In the United States, guarana is Generally Recognized as Safe (GRAS), which allows for its incorporation into foods, energy drinks, and dietary supplements within notified limits. The European Food Safety Authority (EFSA) applies the same caffeine thresholds to guarana-fortified products across the European Union.
2. Traditional and Historical Use
Indigenous Amazonian Use
Guaraná had a rich cultural history long before European naturalists explored South America and even before the Portuguese arrived in Brazil in 1500. For the indigenous peoples living in the dense forests between the Rio Tapajós and the Rio Madeira in Brazil, the seeds of the plant known as guaraná are the cornerstone of their culture. For centuries, tribes like the Sateré-Mawé and the Guarani have selectively bred and carefully cultivated Paullinia cupana to produce the most potent seeds.
Father João Felipe Betendorf, a Jesuit missionary from Luxembourg, spoke of the significance of guaraná to the indigenous population when he first encountered it in 1669. A few decades later, in A Journey to Brazil (1869), French naturalist Louis Agassiz defined it as one of the "great staples" of the Amazonian settlements and described how indigenous peoples consumed its seeds.
Traditional Preparations and Therapeutic Applications
Guarana has been used as a stimulant and tonic to treat fatigue, decrease hunger and thirst, and for headaches and dysmenorrhea. As a medicine, guarana was used mainly to lower fever and relieve headaches, but also to produce a general stimulating effect. Its other chemical properties are used by indigenous peoples to treat a host of conditions, from migraine to dysentery to arteriosclerosis.
The indigenous people of the Amazon have traditionally used guarana in a variety of ways, including as a drink, a food, and a medicine. Guarana seeds are ground into a fine powder and mixed with water to create a paste that is then shaped into balls and roasted. The resulting balls are then grated and mixed with water to create a beverage. The tea is often sweetened with honey or sugar and is consumed to provide energy, relieve fatigue, and improve mental clarity.
Spread into Modern Use
Traditional practices spread beyond tribal boundaries during the European colonization of Brazil in the 16th century. Portuguese settlers recognized guarana's potential, leading to its initial commercialization and cultivation outside indigenous territories. By the 1900s, guarana had gained prominence in Brazilian urban areas, appearing in carbonated beverages and natural supplements. The most common current form of consuming it is through guarana drinks, among which Guarana Antarctica is considered the national drink of Brazil.
3. Key Constituents and Active Compounds
Methylxanthines
The seeds contain a high concentration of caffeine (2% to 8%), far higher than in coffee beans (1% to 3%). The seeds are also rich in other xanthine alkaloids such as theophylline and theobromine, as well as catechins, epicatechins, and procyanidins. The caffeine in guarana is sometimes referred to as "guaranine" in older literature, but it is chemically identical to caffeine from other sources. Concentrated guarana extracts can contain caffeine at levels of as much as 40–50% w/w.
Polyphenols and Tannins
Besides the great content of xanthines such as caffeine, theophylline, and theobromine, guaraná seeds also contain saponins and polyphenols, especially tannins, and several other compounds in smaller concentrations. A high concentration of polyphenols including tannins, flavonoids, and catechins has been identified, and antioxidant actions have been linked to these polyphenols. The procyanidins (condensed tannins) are among the most pharmacologically investigated non-xanthine constituents.
Summary of Major Constituents
- Caffeine (guaranine): 2% to 8% by weight in seeds, far higher than in coffee beans.
- Theophylline and theobromine: Other xanthine alkaloids present alongside caffeine.
- Catechins and epicatechins: Flavan-3-ol polyphenols with antioxidant properties.
- Procyanidins (proanthocyanidins): Condensed tannins present in significant quantities.
- Saponins: Present alongside polyphenols and tannins.
4. Mechanisms of Action
Adenosine Receptor Antagonism
Through its methylxanthine content, guarana can block adenosine receptors, inhibit phosphodiesterase, and enhance the action of noradrenaline. Caffeine stimulates the sympathetic nervous system by acting as a nonspecific antagonist for the adenosine receptor, primarily the A1A subtype. This interaction leads to an increase in intracellular cyclic adenosine monophosphate (cAMP).
Phosphodiesterase Inhibition
Caffeine can inhibit the phosphodiesterase enzyme, which is responsible for converting cAMP into AMP, thereby further increasing intracellular cAMP. cAMP plays a crucial role in brown adipose tissue (BAT), as it is associated with the activation of protein kinase A, which subsequently triggers the activation of Ucp1, enhancing the thermogenesis of this tissue.
Anti-inflammatory Pathways
The anti-inflammatory effects of guarana arise from non-selective phosphodiesterase inhibition — mainly phosphodiesterase 4 (PDE4) — increasing intracellular cyclic adenosine monophosphate, impeding tumor necrosis factor-alpha (TNFα) and leukotriene production, and activating protein kinase A, which decreases inflammation.
Antioxidant Mechanisms
The flavonoids present in guarana seeds can activate the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, which subsequently increases the levels of superoxide dismutase (SOD), catalase (CAT), and heme oxygenase 1 (HO-1). Guarana polyphenols inhibit alpha-glucosidase, support insulin sensitivity, and reduce low-density lipoprotein (LDL) oxidation.
Central Nervous System Stimulation
Caffeine is a central nervous system stimulant through its blockage of adenosine receptors, mainly A1 and A2A subtypes, thus competitively antagonizing their action. The absorption of adenosine by CNS cells is one of the mechanisms that triggers sleep and sedation. Moreover, caffeine slightly increases the release of norepinephrine and dopamine, enhancing the neural activity of numerous brain areas. Flavonoids, including condensed tannins, may also act on the CNS because they can cross the blood-brain barrier.
Beyond Caffeine: Synergistic Effects
Although many effects have been proven, few studies have managed to identify a single active principle responsible. Most studies attribute bioactive effects to more than one substance. For example, the stimulant property on the central nervous system is mainly attributed to guarana's alkaloids because their mechanism of action is known, although catechins may also be involved, as these are present in high concentrations in guarana cotyledons. Several clinical studies have reported cognitive effects at doses of guarana too low to fully explain the observed effects via caffeine content alone, suggesting other constituents contribute meaningfully.
5. Scientific Evidence by Area of Use
5.1 Cognitive Performance and Mental Alertness
Recent reviews have examined the effects of chronic supplementation of guarana in clinical populations; however, the acute effects of guarana on cognitive tasks, while of interest, have produced mixed results. A systematic review coupled with a meta-analysis was performed to assess whether acute guarana ingestion improves human cognitive performance.
Eight placebo-controlled studies were identified and met the inclusion criteria, providing data on 328 participants. The dose of guarana ranged from 37.5 to 500 mg, with reported caffeine content of 4.3 to 100 mg. The effect sizes for guarana averaged across a variety of cognitive measures and outcome variables were less than trivial (Hedge's g = 0.076, p = 0.14). Using a subgroup meta-analysis, effect sizes indicating a faster response time for guarana versus a placebo (g = 0.202, p = 0.005) differed from the accuracy measures (g = −0.077, p = 0.4), which were non-significant.
An earlier double-blind, placebo-controlled, multi-dose study provides important individual-study context. This double-blind, counterbalanced, placebo-controlled study (n=26) assessed the acute mood and cognitive effects throughout the day of four different doses (37.5 mg, 75 mg, 150 mg, and 300 mg) of a standardized guaraná extract (PC-102). Guaraná improved secondary memory performance and increased alert and content mood ratings. The two lower doses produced more positive cognitive effects than the higher doses. This research supports previous findings of cognitive improvements following 75 mg guaraná and provides the first exploration of different dose effects. The findings suggest that the effects cannot be attributed to caffeine alone.
A separate double-blind randomized controlled trial tested guarana in combination with a vitamin/mineral supplement. A double-blind, randomized, placebo-controlled, parallel groups study assessed the acute effects of either a vitamin/mineral/guaraná supplement or placebo drink in 129 healthy young adults (18–24 years). The vitamin/mineral/guaraná combination resulted in improved task performance, in comparison to placebo, in terms of both increased speed and accuracy of performing the RVIP task throughout the post-dose assessment. The increase in mental fatigue associated with extended task performance was also attenuated by the supplement. This research supports previous findings demonstrating guaraná's cognition-enhancing properties.
A more recent crossover study tested 500 mg guaraná (containing 130 mg caffeine) against 100 mg caffeine alone and placebo in 20 participants. There were no treatment, time, or time-by-treatment interaction effects for the following: fatigue, energy, vigor, exhaustion, and motivation (p > 0.05).
Evidence strength: Preliminary and mixed. The largest meta-analysis (8 studies, n=328) found overall cognitive effect sizes less than trivial, although response time showed a small but statistically significant improvement. Several individual studies suggest benefits at lower doses that may not be fully explained by caffeine. High-quality, adequately powered, long-term trials are lacking. Guarana seems to improve reaction time and accuracy of performance at tasks, but no significant effects were found when compared with caffeine. High-quality randomized controlled clinical trials with a low risk of bias are needed.
5.2 Cancer-Related Fatigue
Cancer-related fatigue (CRF) is one of the most studied clinical applications of guarana. An important early randomized clinical trial enrolled patients with breast cancer. In patients with breast cancer undergoing systemic chemotherapy, CRF is a common problem. A study evaluated the effectiveness of guarana extract on fatigue, sleep quality, anxiety, depression symptoms, and menopause in a group of breast cancer chemotherapy patients. Patients with progressive fatigue after their first cycle of chemotherapy were randomized to receive either guarana 50 mg by mouth twice daily (32 patients) or placebo (43 patients) for 21 days. After a 7-day washout period, patients were crossed over to the opposite experimental arm. Guarana significantly improved the FACIT-F, FACT-ES, and BFI global scores compared to placebo on days 21 and 49 (p < 0.01). The Chalder Scale improved significantly on day 21 (p < 0.01) but not on day 49 (p = 0.27). Guarana did not produce any Common Terminology Criteria for Adverse Events grades 2, 3, or 4 toxicities and did not worsen sleep quality or cause anxiety or depression. Guarana was characterized as an effective, inexpensive, and nontoxic alternative for the short-term treatment of fatigue in breast cancer patients receiving systemic chemotherapy.
A subsequent meta-analysis with updated methodology reached somewhat different conclusions. In total, 4 full articles and 1 abstract, encompassing 229 patients from 2009 to 2023, were included in the meta-analysis. Despite high heterogeneity between studies (I²=78%), the analysis revealed a significant benefit of using guaraná to alleviate cancer-related fatigue, with a standard mean difference of −0.77 (95% CI −1.34, −0.21). An earlier systematic review identified 7 studies of 383 patients and concluded that guarana and placebo had similar effects on fatigue, depression, sleep, anxiety, and quality of life, and both had similar rates of adverse events (tachycardia, insomnia, nausea, and anxiety).
Evidence strength: Conflicting. Individual RCTs show benefit; however, systematic reviews are inconsistent. The anti-inflammatory, antioxidant, anticancer, and hypocholesterolemic effects of guarana have been demonstrated and reviewed; however, a meta-analysis established that chronic supplementation of guarana did not reduce perceived fatigue in cancer patients and the quality of experimental evidence was rated as low. High heterogeneity between studies, small sample sizes, and differing patient populations limit firm conclusions.
5.3 Cardiovascular and Metabolic Effects
An observational epidemiological study examined habitual guarana consumption in an elderly Amazonian population. A controlled study was performed to analyze the association between habitual guaraná consumption and the prevalence of metabolic disease (obesity, hypertension, type 2 diabetes, and dyslipidemia) in an elderly population living in the Amazon's Riverine region (Maués-AM). The study observed a lower prevalence of hypertension, obesity, and metabolic syndrome in the subjects who self-reported habitual guaraná consumption than in subjects who reported never ingesting guaraná. Additionally, an association was found between habitual guaraná consumption and lower cholesterol (total and LDL) and advanced oxidative protein product (AOPP) levels. A significant association was found between lower levels of advanced oxidative protein product (AOPP) and habitual guaraná consumption. These results constitute the first epidemiological study to suggest a potentially protective effect of habitual guaraná ingestion against metabolic disorders in elderly subjects.
Regarding LDL oxidation, an in vitro and in vivo study using blood samples from 42 healthy elderly subjects found: guaraná consumption is associated with a lower prevalence of cardiovascular metabolic diseases and has positive effects on lipid metabolism, mainly related to low-density lipoprotein (LDL) levels. As LDL oxidation is an important initial event in the development of atherosclerosis, in vitro and in vivo studies were performed to observe the potential effects of guaraná on LDL and serum oxidation. The study observed a lower prevalence of hypertension, obesity, and metabolic syndrome in subjects with habitual guaraná consumption than in subjects who reported never ingesting guaraná.
Studies have suggested that guaraná exhibits a cardioprotective effect by inhibiting platelet aggregation.
Evidence strength: Preliminary. The main cardiovascular-metabolic evidence in humans consists of a single epidemiological study in a geographically specific elderly Amazonian population. Such observational data cannot establish causation and is subject to significant confounding. Animal and in vitro data are more extensive but cannot be directly applied to humans.
5.4 Thermogenesis, Weight Management, and Metabolism
Paullinia cupana-containing products are popular among athletes because of their ergogenic and "fat burning" effects. Some studies have shown that Paullinia cupana positively affects lipid metabolism, enhances weight loss, and increases basal energy expenditure. These data suggest that Paullinia cupana has anti-obesity effects. The compounds found in guarana, including caffeine, catechin, and epicatechin, can influence the sympathetic nervous system (SNS), thereby synergistically regulating energy expenditure, lipolysis, and BAT thermogenesis.
Guarana is a rich source of caffeine, which may stimulate the metabolism and enhance thermogenesis by acting as an ergogenic agent, assisting in the degradation of lipids and prevention of atherosclerosis.
Evidence strength: Weak in humans. Most evidence for weight management and thermogenesis comes from animal models and in vitro experiments. Human clinical trial data specifically for guarana (rather than caffeine or multi-ingredient products) are limited and generally not sufficient to draw strong conclusions independent of caffeine's well-established thermogenic properties.
5.5 Antioxidant Effects
Guarana has demonstrated antioxidant effects by inhibiting lipid peroxidation. Studies have shown that guaraná extract, rich in compounds like methylxanthines, theobromine, and theophylline, presents many beneficial effects to the organism, such as antioxidant capacity, modulation of nitric oxide intracellular levels, as well as anti-obesity and anti-inflammatory capacity.
Evidence strength: Largely in vitro and animal-model-based. Human evidence for antioxidant effects is derived primarily from observational data (e.g., the Maués epidemiological study). Controlled human trials specifically measuring antioxidant outcomes are lacking.
5.6 Mood and Anxiolytic Effects
Chronic exposure to guarana seed extract produced an anxiolytic effect involving dopaminergic and serotonergic neurotransmission systems. This finding comes from preclinical research and should not be extended to human applications without further clinical evidence.
Evidence strength: Preclinical only. No robust human clinical trials specifically examining guarana's anxiolytic potential have been identified in the peer-reviewed literature.
6. Body Systems and Health Areas Associated with Guarana
- Central Nervous System: Stimulation via adenosine receptor antagonism; acute cognitive performance, alertness, mood (human evidence — mixed).
- Cardiovascular System: Caffeine's effects include cardiac stimulation, increased blood pressure, and inhibition of platelet aggregation. Observational associations with lower prevalence of hypertension and metabolic syndrome.
- Metabolic System: Thermogenesis, lipolysis, and effects on lipid metabolism; anti-obesity potential (primarily preclinical evidence).
- Oncology / Supportive Care: Cancer-related fatigue (conflicting human RCT and meta-analysis evidence).
- Oxidative Stress / Inflammation: Antioxidant and anti-inflammatory mechanisms identified in vitro and in animal models; limited human evidence.
- Endocrine/Metabolic: Guarana polyphenols inhibit alpha-glucosidase and support insulin sensitivity. Preclinical data only.
7. Dosage Forms and Doses Reported in Studies
Daily doses range from 200 to 1000 mg daily in the clinical literature. More specific doses from individual studies include:
- Four doses of 37.5 mg, 75 mg, 150 mg, and 300 mg of a standardized guaraná extract (PC-102) were assessed in a double-blind, placebo-controlled study of 26 participants.
- Guarana 50 mg by mouth twice daily (100 mg/day) was administered in a cancer-related fatigue crossover trial.
- Doses of guarana across the identified cognitive performance trials ranged from 37.5 to 500 mg, with reported caffeine content of 4.3 to 100 mg.
- A crossover trial used a guarana dose of 125 mg/kg in 25 participants alongside cognitive and exercise testing.
- A double-blind crossover experiment used 500 mg guarana (containing 130 mg caffeine) in 20 participants.
A recent report showed that among five commercial products analyzed (three brands of capsules and two of tablets containing guarana), all differed in terms of the presence of chemical markers of the drug, both on dissolution test as well as in relation to pharmacotechnical aspects. Reported caffeine and flavonoid levels can vary widely between different guarana extracts, with label inaccuracies of up to 30% and differing bioactive profiles that alter absorption.
8. Safety Considerations and Drug Interactions
General Safety Profile
In conventional doses, guarana has few side effects and has not been linked to episodes of liver injury or jaundice. In small studies on guarana, there were no reports of liver injury or serum enzyme elevations during treatment. In high doses, guarana can cause tremor, jitteriness, agitation, confusion, hypertension, and dehydration. Most of its beneficial effects as well as its side effects can be explained by its caffeine content.
Adverse Effects
Common side effects include a fast heartbeat, an increased need to urinate, nervousness, irritability, an upset stomach, and trouble sleeping. Guarana intoxication produces water loss, gastric irritation, nausea, vomiting, metabolic acidosis, hyperglycemia, ketosis, chest pain, syncope, tachydysrhythmia (a risk that is increased in the case of structural heart disease), shortness of breath, insomnia, nervousness, restlessness, tremors, anxiety, mania, seizures, and even sudden death.
Preclinical toxicological data in rodents showed: Acute toxicity tests in male Swiss mice produced acute mortality with an oral LD50 of 1.825 g/kg. In the repeated-dose toxicity test, a semi-purified extract was administered orally daily to male and female Wistar rats at doses of 30, 150, and 300 mg/kg/day for 90 days. No rats died during the tests; however, males dosed at 150 or 300 mg/kg gained weight more slowly and lost kidney weight compared to the control group.
Caffeine Accumulation and Multi-Product Use
The use of multiple herbal products containing guarana and other sources of caffeine can result in caffeine toxicity. This is a particularly relevant concern given that guarana is widely used in energy drinks and multi-ingredient supplements that may contain additional caffeine from other sources.
Drug Interactions
Research in rats has identified a pharmacokinetic interaction with the antiarrhythmic drug amiodarone. Taking into account the great diversity of components present in Paullinia cupana extract, especially methylxanthines (caffeine) and large quantities of tannins, a physical-chemical interaction between those compounds and amiodarone in the gastrointestinal tract of rats was hypothesized to explain the considerable decrease in the systemic exposure/bioavailability of amiodarone observed after simultaneous coadministration with Paullinia cupana extract. This interaction has not yet been characterized in human studies. Caffeine's effects include skeletal muscle, CNS, and cardiac stimulation, diuresis, increased blood pressure, inhibition of platelet aggregation, and hyperglycemia. These pharmacological properties are relevant to potential interactions with antiplatelet agents, antihypertensives, and stimulant medications.
Pregnancy and Lactation
Caffeine in guarana passes into breast milk and can affect a nursing baby. Excessive guarana should not be used if breastfeeding.
Regulatory and Quality Variability
In the United States, guarana is GRAS, which allows for its incorporation into foods, energy drinks, and dietary supplements within notified limits. The EFSA applies the same caffeine thresholds to guarana-fortified products across the European Union. Paullinia cupana is also listed in the official Brazilian Pharmacopoeia. Standardization of extracts remains an issue, as commercial products differ substantially in their chemical composition and dissolution characteristics.
References
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