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Plant Profiler

Guarana (Paullinia cupana)


Guarana (Paullinia cupana) Image
Synonyms / Common Names / Related Terms
1,3,7-trimethyl-2, 6-dioxopurine, 1,3,7-trimethylzanthine, Brazilian cocoa, caffeine, caffeine-tannin complex, Dark Dog Lemon®, elixir of youth, gift of the gods, Go Gum®, guarana bread, guarana gum, guarana paste, Guarana Rush®, guarana seed paste, guaranin, guaranine, Guts®, Happy Motion®, Josta®, mysterious Puelverchen, pasta guarana, Paullinia, Paullinia cupana, Paullinia sorbilis, Sapindaceae (family), Superguarana, tetramethylxanthine, Uabano, Uaranzeiro, Zoom®.

Combination product examples: Euphytose® (Crataegus, Ballota, Valeriana, Passiflora, Cola, Paullinia); YGD (Yerbe mate, guarana, damiana).

Note: Guarana has one of the highest caffeine contents of all plants (up to 7%), and has been used by manufacturers for its caffeine content.

Mechanism of Action

Pharmacology:

  • Constituents: Guarana has been found to contain purine alkaloids, 3-10% caffeine, methylxanthine, <1% theophylline or theobromine, and 12% non-hyrolyzable tannins (catechin (5.98%) and epicatechin (3.78)).12,13,14,15,16,17 Guarana also contains trace amounts of timbonine, which is used as a fish poison. One sample of guarana contained 2.16, 1.10 and 36.78mg/g of theobromine, theophylline and caffeine, respectively.18
  • The main active ingredient of guarana is caffeine.19,20,18 Bellario found the caffeine content of 12 different guarana products (dried paste, commercial powder and ground tablets) to range between 0.76% and 3.75%; an aqueous extract contained 8.9% caffeine.15 Theophylline content was undetectable in five samples and was less than 0.2% in all other seven samples.15 In commercially available guarana capsules, powder, seeds and sticks of dried paste, Bempong et al., found that caffeine content ranged from 3.52 to 4.6% for all preparations, compared to 2.9% for tea and 3.18% for coffee.19
  • Avato et al. found that guarana seed oil contained cyanolipids and diestersacylglycerols, including 1-cyano-2-hydroxymethylprop-2-ene-1-ol, cis-11-octadecenoic (cis-vaccenic acid), cis-11-eicosenoic acids, paullinic acid and oleic acid.21
  • Benoni et al. analyzed the essential oil from guarana and identified methylbenzenes, cyclic monoterpene and cyclic sesquiterpene hydrocarbons, methoxyphenylpropenes and alkylphenol derivatives.22
  • Anti-carcinogenic effects: Guarana effects on mouse hepatocarcinogenesis have been investigated.23 Mice were treated with N-nitrosodiethylamine (DEN) received three different doses of Paullina cupana added to commercial food and were euthanized after 25 weeks. Gross lesions were quantified, and preneoplastic lesions (PNL) were histologically measured. Cellular proliferation was evaluated by immunoblotting for the proliferating cell nuclear antigen (PCNA). The incidence and multiplicity of macroscopic lesions were reduced. The PNL number and PCNA expression were reduced in the highest P. cupana dose.
  • Antioxidant effects: At low concentrations (1.2microg/mL), guarana inhibited the process of lipid peroxidation in an animal study.6
  • Carcinogenic effects: The tannins in guarana may be carcinogenic.
  • Cardiovascular effects: The extracts of Paullina cupana caused short-lived and dose-dependent rabbit corpus cavernosum relaxations.24 Incubations of rabbit corpus cavernosum with P. cupana extract (1mg/mL) increased the cAMP levels by 200% whereas higher doses (10 and 100mg/mL) caused smaller increases in the nucleotide levels (150% and 89%, respectively).
  • Cognitive effects: Espinola et al. found single doses (3mg/kg and 30mg/kg) as well as chronic administration (0.3mg/mL) of guarana to reverse the amnesic effect of scopolamine in mice and rats.25
  • Energy effects: Berube-Parent et al. compared the effect of a mixture of green tea and guarana extracts containing a fixed dose of caffeine and variable doses of epigallocatechin-3-gallate (EGCG) on 24-hour energy expenditure and fat oxidation.26 Fourteen subjects took part in this randomized, placebo controlled, double-blind, cross-over study. Each subject was tested five times in a metabolic chamber to measure 24-hour energy expenditure, substrate oxidation and blood pressure. During each stay, the subjects ingested a capsule of placebo or capsules containing 200mg caffeine and a variable dose of EGCG (90, 200, 300 or 400mg) three times daily, 30 minutes before standardized meals. Twenty-four hour energy expenditure increased significantly by about 750kJ with all EGCG-caffeine mixtures compared with placebo. No effect of the EGCG-caffeine mixture was observed on lipid oxidation. Systolic and diastolic blood pressure increased by about 7 and 5mmHg, respectively, with the EGCG-caffeine mixtures compared with placebo. This increase was significant only for 24-hour diastolic blood pressure.
  • Gastrointestinal effects: Guarana (50 and 100mg/kg orally) pretreated animals showed a significant reduction in the severity of gastric lesions induced by absolute ethanol in a manner similar to caffeine (20 and 30mg/kg orally).27 Against indomethacin-induced gastric ulceration, guarana at a higher dose offered significant protection, but caffeine was ineffective at the doses tested. In four hour pylorus-ligated rats, both guarana and caffeine caused significant diminution in the gastric secretory volume as well as the total acidity. Gastrointestinal transit in mice was not significantly affected by either of these agents.
  • Genotoxic effects: Aqueous extracts of guarana were genotoxic as assessed by lysogenic induction in Escherichia coli.28 Addition of S9 microsomal fraction, catalase, superoxide dismutase or thiourea counteracted the genotoxic activity of guarana, suggesting that oxygen reactive species play an essential role in the genotoxicity of aqueous guarana extracts.
  • Hepatotoxic effects: The tannins in guarana may be hepatotoxic.
  • Hyperglycemic effects: The tonic action of water extract of guarana was investigated in normal, exercised, and epinephrine-induced glycogenolytic mice.5 A water extract of guarana (500mg/kg) increased the blood glucose level (p<0.001) and decreased the liver glycogen contents of mice 60 minutes after oral maltose administration (p<0.05). Guarana water extract also significantly suppressed exercise-induced hypoglycemia (60 minutes: p<0.05). However, guarana water extract did not affect the blood glucose in epinephrine-induced glycogenolytic and exercise mice.
  • Hypertensive effects: Berube-Parent et al. compared the effect of a mixture of green tea and guarana extracts containing a fixed dose of caffeine and variable doses of epigallocatechin-3-gallate (EGCG) on blood pressure.26 Fourteen subjects took part in this randomized, placebo controlled, double-blind, cross-over study. During each stay, the subjects ingested a capsule of placebo or capsules containing 200mg caffeine and a variable dose of EGCG (90, 200, 300 or 400mg) three times daily, 30 minutes before standardized meals. Systolic and diastolic blood pressure increased by about 7 and 5mmHg, respectively, with the EGCG-caffeine mixtures compared with placebo. This increase was significant only for 24-hour diastolic blood pressure.
  • Immunosuppressant effects: Aqueous and ethanolic extracts from the seeds of Paullinia cupana were shown to block human lymphocyte proliferation in vitro.29 Lymphocyte suppression was not due to a cytotoxic effect.
  • Mutagenic effects: Aqueous extracts of guarana induced mutagenesis in Salmonella typhimurium.28
  • Platelet aggregation effects: Aqueous extracts of guarana were studied in terms of effects on the aggregation of human and rabbit platelets. In human and rabbit platelets, guarana extracts have anti-aggregatory and de-aggregatory actions on platelet aggregation induced by ADP or arachidonic acid but not by collagen.9 The active material was shown to be water soluble and heat resistant and appeared to be different from salicylates, nicotinic acid or known xanthines. Guarana extracts inhibited platelet aggregation in rabbits following either intravenous or oral administration.
  • Guarana extract (100mg/mL) decreased platelet aggregation (37, 27 and 31% of control values, respectively) and platelet thromboxane formation from [14C]-arachidonic acid (78, 70 and 50% of control values, respectively).10
  • Psychoactivity effects: The alleged psychoactivity of the essential oil is presumably due to the identified constituents estragole and anethole.22 Any contribution of aminated metabolites of estragole/anethole to the alleged psychoactivity of the essential oil of guarana can be excluded. Neither the psychoactive 4-methoxyamphetamine nor tert-aminoketones could be traced in human urine after oral application of guarana..
  • Radioactivity effects: De Oliveira et al. evaluated the influence of a guarana extract on the labeling of blood elements with technetium-99m (Tc-99m).30 Blood was incubated with P. cupana, stannous chloride and Tc-99m. Samples were centrifuged and plasma and blood cells were separated and precipitated with trichloroacetic acid. Soluble and insoluble fractions were isolated. The morphology of the blood cells was evaluated under an optical microscope. The results showed a significant (p=0.05) decrease in the uptake of radioactivity for the red blood cells (97.93 +/- 0.74 to 36.90 +/- 4.71%), in insoluble fractions of plasma and insoluble fractions of blood cells due to P. cupana extract.
  • Thermogenic effects: Methylxanthines contained in guarana combined with ephedrine are reported to induce a thermogenic response in obese mice, increasing their daily energy expenditure.11
  • Note: The mechanism of action of guarana is related to its significant caffeine content. Caffeine acts as a central nervous system stimulant, increases heart rate and contractility, increases blood pressure, inhibits platelet aggregation, stimulates gastric acid secretion, induces diuresis, and relaxes bronchial smooth muscle. The following trials have been carried out with caffeine. Their outcome therefore cannot be directly related to guarana.
  • cAMP effects: Caffeine acts as a catecholamine inhibitor31, thereby prolonging cyclic adenosine monophosphate (cAMP) in some cells32.
  • Cardiovascular effects: Nyska et al. report cardiac failure in 7 and 14 week-old male F344 rats exposed by gavage to ephedrine (25mg/kg) and caffeine (30mg/kg) administered in combination for 1 or 2 days.33 The ephedrine-caffeine dosage was approximately 1.2- and 1.4-fold, respectively, above average human exposure, based on a mg/m2 body surface-area comparison. Five of the 7 exposed 14 week-old rats died or were sacrificed in extremis 4-5 hours after the first dosing. In these hearts, changes were observed chiefly in the interventricular septum but also left and right ventricular walls. Massive interstitial hemorrhage, with degeneration of myofibers, occurred at the subendocardial myocardium of the left ventricle and interventricular septum. Immunostaining for cleaved caspase-3 and hyperphosphorylated H2A. X, a histone variant that becomes hyperphosphorylated during apoptosis, indicated multifocal generalized positive staining of degenerating myofibers and fragmenting nuclei, respectively. The Barbeito-Lopez trichrome stain revealed generalized patchy yellow myofibers consistent with degeneration and/or coagulative necrosis. In ephedrine-caffeine treated animals terminated after the second dosing, foci of myocardial degeneration and necrosis were already infiltrated by mixed inflammatory cells.
  • Diuretic effects: In a single blind, randomized, cross-over trial an increase in diuresis, urinary sodium, potassium and osmol excretion was observed within 1 hour of ingestion of 250mg caffeine.8
  • Endocrine effects: Acute caffeine ingestion may induce a rise in mean adrenaline levels, an effect that is lost with sustained intake.34
  • Systemic effects of caffeine include the stimulation of catecholamine release, particularly epinephrine. Adrenomedullary secretions have been measured to increase as plasma norepinephrine by 75%, and plasma epinephrine by 207%.32
  • Energy effects: Dulloo et al. found that 100mg caffeine administered every 2 hours over a 12-hour day period increased the energy expenditure of both lean and obese females.35 However, a significant difference of 8-11% was found only in lean patients (p<0.01) during a twelve hour day. This effect was not found when studied over a twelve hour night. A significant difference (p<0.02) was found in the net energy expenditure of 150 kcal in lean women and 79 kcal in post-obese women. Limitations of this study include the study design and lack of placebo.
  • Hypotensive effects: Caffeine, in moderate doses, can decrease insulin sensitivity in healthy humans by 15%, possibly as a result of elevated plasma epinephrine levels.31
  • Neurologic effects: Caffeine alters several neurotransmitter functions, possibly through antagonism of adenosine receptors and reducing extraneuronal uptake of catecholamines.36 Caffeine may desensitize neuron receptors to dopamine. Caffeine has been shown to enhance dopamine release during an initial two-hour interval but to ultimately decrease total dopamine turnover during a three to four hour study period (biphasic response).
  • Caffeine contains opiate receptor binding activity.37
  • Spermatozoal effects: In human studies, caffeine increased forward progression of sperm, increased longevity of spermatozoa, and made a greater number of ejaculated spermatozoa become motile.1,38 It is speculated that these effects may stem from caffeine's action in inhibiting cyclic nucleotide phosphodiesterases, thus preventing the breakdown of cAMP in the sperm cell.
  • Thermogenic effects: Bracco et al. conducted a small, crossover study to evaluate the effect of caffeine thermogenesis in 10 lean and 10 obese women.39 Obese women experienced less thermogenesis (4.9 + 2%) than the lean women (7.6 + 1.3%). Lipid oxidation also occurred to a lesser degree in obese women than in lean women (10% vs. 29%, respectively). However, the obese women had higher urinary excretions of theobromine, theophylline, and paraxanthine. Limitations of this study include the study design and small sample size.

Pharmacodynamics/Kinetics:

  • Caffeine is the major active component of guarana and is rapidly absorbed from the gastrointestinal tract and distributed into most tissues.40,41,42 Although there is a suggestion that guarana would have a prolonged stimulatory effect when taken orally4, in an earlier study, there was no difference in absorption or dissolution between caffeine capsules and guarana capsules3. Obese males have a significantly higher absorption rate constant (Ka 0.0757 vs. 0.0397, p<0.05) than lean males.43
  • Note: The mechanism of action of guarana is related to its significant caffeine content. The following trials have been carried out with caffeine. Their outcome therefore cannot be directly related to guarana.
  • The plasma half-life of caffeine was found to be variable, ranging from 2.7 to 9.9 hours.41 However, in term newborn infants, plasma half-life ranges from 31-132 hours (mean 81).44,7 Aldridge et al. reported the plasma half-life of caffeine in the newborn to be four days.45
  • The volume of distribution for caffeine is lower in elderly males.40 Caffeine is approximately 35% protein bound in males regardless of age.46 Caffeine was found to have rapid distribution into the semen of male patients administered 200 or 400mg of caffeine (blood/semen concentration ratio =0.97).47
  • Absorbed caffeine is metabolized by the cytochrome P450 (CYPIA2) hepatic enzyme system, N-acetyltransferase, and xanthine oxidase into 25 metabolites, including theophylline.48 Caffeine is demethylated to I-methylxanthine.49
  • Caffeine clearance is slower during pregnancy50,51, increases in infancy, and reaches adult rates within the first three months of life7. Clearance of caffeine is significantly greater in smokers as compared to nonsmokers (p<0.05).52
  • Urine metabolites are highly variable after administration of oral caffeine.53
  • Acute Plasmodium falciparum infection may not affect the pharmacokinetics of caffeine.2

References

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