Paullinia cupana

Paullinia cupana (of the family Sapindaceae) is a plant commonly referred to as 'Guaraná' or 'uaraná' and has its seeds used or psychostimulatory actions. Guarana powder is derived from the seeds and used in Amazonian medicine (Maues Indians traditionally^[1]) for its stimulant activity ^{[2] [3]} but is now commonly sold in soft drinks and other functional food products such as energy drinks, ^[4] with soft drinks being responsible for up to 50% of guarana raw ingredient usage.^[1] Guarana seeds are a large source of caffeine (more than other plants that are sources of caffeine^[5] and thought to be the highest naturally occurring source ^[6] ), and is claimed but not yet demonstrated to have a longer lasting stimulatory effect due to association between tannin structures and caffeine. ^[4]

The seeds are taken from guarana fruits, which after 2-3 days of fermentation are removed from the insides of the fruits and then heated to achieve a moisture content of approximately 9% where they are then ground into powder.^[1]

Somewhat similar to Yerba Mate, Guarana is a south american plant with a caffeine content and a history of use as a psychostimulatory agent

The seeds tend to contain:

• Caffeine at 3.2–7.0% dry weight (usually at the lower end of that range),^[5] thought to be the main bioactive; other xanthines such as theobromine (6.733mg/g ^[7] ) and theophylline are also detectable. ^{[8] [9] [5]} This is higher than that seen in black tea leaves (2-3%) and coffee seeds (0.5-1.2%) and leaves (1.0-1.2%)^[5] and higher than the caffeine found in yerba mate ^[8]

• Tannins ^[10]

• Catechin and epicatechin (4.336mg/g; or 0.4% total for dry weight ^[7] )

• Procyanidins B1–B4, A2 and C1^{[11] [10]}

• Polysaccharides rich in glucose and xylose ^[3]

• Dietary fibers including pectins and xylans ^[3] which appear to be 6% of the seed weight^[5]

The seeds of guarana tends to contain mostly xanthines and phenolics, the phenolics being divided into catechins (procyanidins being catechin and epicatechin chains) and tannins. The tannins are not structurally characterized yet, but are thought to play an important role

The essential oil portion of guarana seeds contain:

• Carvacol at 5-15% ^[12]

• Caryophyllene ^[12]

• Limonene ^[12]

• α-copaene ^[12]

• Estragole ^[12]

• Anethole (found in high levels in Fennel) ^[12]

• 4-(dimethylpropyl)-phenol ^[12]

The antioxidant activity of guarana appears to be correlated with the procyanidin, catechin, and tannin content. ^{[13] [10] [14]}

A semipurified fraction of guarana tends to have lower catechins and caffeine (the latter being 300.87μg/kg ^[15] ) and more of a procyanidin content.^{[11] [10]} This semipurified fraction has been cleared of toxic effects of up to 30mg/kg in rats, with 150-300mg/kg reducing weight gain and kidney weight gain (total and relative). ^[2] The semipurified extract appears to be a acetone:water (70:30) extract that is subject to turbo extraction and subsequently lyophilized and then extracted with ethyl acetate.^[16]

Semipurified extracts of guarana appear to have lower caffeine content, and on some neurological parameters are more effective than guarana basic seed extract (unidentified bioactive being increased in quantity)

It appears to be claimed that the chemical classes of methoxy/methylenedioxyphenylpropyl compounds can be metabolized into amphetamines in the body following oral ingestion and condensation with a secondary amine; the main molecules of concern as it pertains to Guarana (estragole and anethole) could be converted into 4-methoxyamphetamine and urinary 4-methoxyamphetamine has not been detected following oral consumption of Guarana. ^[12]

It has been claimed that guarana can produce amphetamine compounds after metabolism in the body; this has not been proven and may not be true according to one study

Guarana has been found to reduce systemic availability of Amiodarone (an anti-arrythmic drug ^[17] with a narrow clinical serum range of 0.5-2.0μg/mL^{[18] [19]} ) with a single dose of 821mg/kg guarana (12% caffeine content) reducing availability by 57.8%; 14 days of guarana failed to modify amiodarone kinetics. ^[20]

May reduce exposure to amiodarone, a cardioprotective pharmaceutical, and thus may be contraindicted

0.312-0.625mg/mL guarana in dopaminergic cells treated with rotenone (neurotoxin) noted that the lower dose of 0.312mg/mL was able to reduce LDH leakage and preserve cell integrity. ^[21]

High concentrations of guarana are neuroprotective, lower concentrations (in a more practical range) not yet tested

Guarana at 30mg/kg (but not 60mg/kg nor 10mg/kg caffeine) has been found to reduce escape latency in rats after 40 days of ingestion, while scopolamine treated rats had no such benefit from any group.^[22] This appears to hold true for 2mg/kg, but not 4mg/kg, of a semipurified extract with a high procyanidin content.^[22]

Rat studies suggest that there may be a cognitive enhancing aspect of Guarana that is independent of the caffeine content

Acute ingestion in healthy adults ^[23] and chronic ingestion in elderly adults ^[24] does not appear to have cognitive altering properties; the latter study noted that caffeine ingestion also failed to alter cognition. ^[24] These studies are contrasted by later studies noting that 75mg guarana (9mg caffeine) was able to enhance cognitive scores related to memory and reaction time ^[25] with a subsequent dose-response study noting that 75mg was more effective than higher (150-300mg) and lower (37.5mg) doses. ^[26]

Studies to measure logical reasoning tend to note no significant effects with 75mg guarana ^[25] while accuracy of tests appears to be mostly unaffected even in the presence of increased reaction time; the increased reaction time is unlikely to occur due to the caffeine content, as it occurred following 9mg (commonly seen as an inactive dose of caffeine). ^[25] Although there is no significant influence on primary memory factors, there appears to be an increase in secondary memory (recognition and recall tasks). ^{[25] [26]}

Some cognitive enhancing effects have been associated with guarana ingestion (222.2mg), but are confounded with the inclusion of other nutrients in a multivitamin formulation. ^[27]

There appears to be a slight improvement in secondary memory performance and reaction time (not all measured reaction time parameters, only some) associated with guarana. This does not appear to be associated with the caffeine content, and is somewhat comparable to panax ginseng although the two do not appear complementary

8-16mg/kg of a semipurified extract of guarana (lower caffeine, higher procyanidin content) appears to possess anxiolytic effects associated with serotonergic and dopaminergic signalling ^[28] while the seed extract itself has failed to alter parameters of anxiety in rats. ^[29]

Depression has been noted to be reduced in rats following ingestion of 30mg/kg (or the range of 20-50mg/kg ^[30] ) of the seed extract, which was similar in potency to the reference drug of 20mg/kg imipramine; ^[29] this was replicated with 4mg/kg of a semipurified extract, and did not appear to be related to the caffeine content. ^[29] Elsewhere, the effects of high dose guarana (100mg/kg) have been found to not be abolished by an adenosine agonist suggesting alternate pathways of efficacy (caffeine primarily works via adenosine). ^[30]

Mixed effects on anxiety, and some anti-depressive effects. The anti-depressive effects are actually more potent than many other herbs (performing similarly to the reference drug imipramine) and do not appear to be related to the caffeine content. More research is needed to see if guarana has a role in depression

Guarana extracts have been shown to inhibit ADP and arachidonic acid induced platelet aggregation (no effects on collagen-induced aggregation) ^[31] and subsequent thromboxane production ^{[32] [33]} which is thought to be related to the catechin, epicatechin, and catechin dimers present in guarana. ^[33] These effects occur at around 100mg/mL, ^{[32] [31]} and have been noted to reduce aggregation to 27-31% of control and thromboxane synthesis to 50-78% of control. ^[32]

Possesses antiplatelet actions, but the potency of this does not appear to be overly remarkable (requires a high concentration of guarana) and may not be linked to guarana-exclusive molecules but rather common catechins

Guarana has been demonstrated in vitro to protect cells from sodium nitroprusside via antioxidative effects (in fibroblasts) and is thought to aid nitric oxide metabolism due to this. ^[7]

Older persons who habitually consume guarana products appear to have lower total cholesterol ^[34] and LDL oxidation (27%) than do age-matched controls that do not consume guarana; ^[35] the lower LDL oxidation rates were not associated with total cholesterol, LDL, nor conjugated dienes but was associated with polyphenolics. ^[35]

In vitro, 0.5-1μg/mL greatly attenuated and 1-5μg/mL guarana abolished copper-induced LDL oxidation over 180 minutes of testing. ^[35]

Appears to reduce LDL oxidation, and in vitro studies suggest that the effect is fairly potent; currently there is no human evidence to assess this reduction in LDL oxidation

Guarana appears to be able to increase fat oxidation, which is highly correlated with the methylxanthine content and caffeine. ^[36]

A few rat studies that measure weight tend to note that weight gain over time is suppressed in rats consuming guarana at 821mg/kg (14 days), ^[20]

Insufficient evidence to establish a role of guarana in weight loss

In vitro, guarana extract appears to reduce mast cell degranulation in the 12.5-200µg/mL range; ^[37] despite caffeine normally having an inhibitory effect on mast cell degranulation at very high levels (5-20mM) ^[38] it was not the causative agent in this study due to being inactive at the micromolar range tested. ^[37]

In mice subject to passive cutaneous anaphylaxis (model of skin allergic reactions ^[39] ) who consumed guarana seeds two hours prior to exposure to the allergin, 1g/kg (but not 100-300mg/kg) was able to reduce the allergic reaction as assessed by exudate levels with a potency comparable to ketotifen fumarate (200mg/kg). ^[37]

Appears to have anti-allergic properties when taken in relatively high doses, and this does not appear to be associated with the caffeine content

In rats treated with cadmium (testicular toxin in high concentrations via oxidative damage ^{[40] [41]} ), 2g/kg of guarana ingestion over 56 days was able to confer protective effects to the seminiferous tubules and intertubular space (as assessed by histological examination) without being able to reverse the decrease in testicular weight. ^[42] Protective effects against cadmium are also noted with pretreatment at the same oral dose. ^[43]

May protect the testicles at high concentrations of orally ingested guarana, but the potency of protection and the high dose used suggest that this protective effect is likely to not be practical or relevant following guarana supplementation

Guarana (50mg twice daily for a total dose of 100mg) in persons experiencing fatigue from breast cancer chemotherapy was able to reduce fatigue as assessed by the FACT-F and FACT-ES rating scales without adversely affecting sleep quality. ^[44] Conversely, a study using radiotherapy failed to find a fatigue reducing effect of guarana at 75mg daily. ^[45]

Mixed effects on reducing fatigue in chemotherapy patients

Guarana ingestion at 2g/kg has been demonstrated to reduce DNA damage ^[46] and lesions ^[47] associated with N-nitrosodiethylamine injections (hepatic carcinogen), which is thought to be secondary to induction of superoxide dismutase (SOD) ^[46] and subsequently the same dosage showed antiproliferative properties against lung tumor cells. ^[48] Protective effects have also been noted against Ehrlich ascites carcinoma tumor inoculation which noted that ingestion of Guarana (100-1000mg/kg for 7 days prior to inoculation and for 21 days subsequent) caused a dose-dependent reduction in tumor size, cell count, and hemhorrage and increased cell accumulation in the G0/G1 phase. ^[49]

High doses of guarana (1000-2000mg/kg in mice, 80-160mg/kg for humans) appear to have anti-proliferative effects in various models of tumor injection

Guarana (0.08%) has been used in a study where topical application and its effects on wrinkles was investigated (confounded with both glycerol and creatine at 8% and 0.02%) was able to significantly reduce jowl size and improve skin integrity and tightening effect; ^[50] this was attributed more to the creatine content, as it was shown in vitro to increase collagen and procollagen levels. ^[50] Guarana has been noted to be able to release caffeine and catechins transdermally, ^[51] and thus it is possible that the efficacy of those compounds underlie the effect of topical guarana.

Although guarana may have a role in promoting skin aesthetics when topically applied, this has not yet been demonstrated with guarana in isolation and may not be unique to guarana (mediated via caffeine and catechins, both of which have demonstrated aid when applied to the skin)

YGD capsules are a mixture of Yerba Mate, Guarana, and Damiana leaf in the doses of 112mg, 96mg, and 36mg (3.1:2.7:1.0 ratio) per tablet. ^[52]

YGD capsules appear to reduce appetite when taken prior to a meal by approximately 17.6% (3 tablets 15 minutes prior) outperforming 5g Inulin ^[52] and appears to be additive with Inulin, increasing a 17.6% reduction in food intake to 27%. ^[52]

YGD capsules may reduce weight secondary to reducing food intake (via slowing gastric digestion rates). The role of guarana in YGD capsules is not known

Catuama is a mixture of the herbs guarana, muira puama, Trichilia catigua, and ginger (their relative concentrations being 40.31%, 28.23%, 28.23%,, and 3.26% respectively). ^[53] This herbal combination therapy has been noted to have vasorelaxing effects in isolated endothelium via nitric oxide^[54] (which has also been noted in the corpus cavernosum ^[55] ) and has been noted to fully revert ventricular fibrillation in isolated rabbit hearts at 200µg/mL and protected from induced arrhythmia. ^[53] This study noted that ginger and guarana in isolation failed to have such effects on the myocardium, but muira puama showed some efficacy although Trichilia catigua at 25µg/mL showed similar potency to Catuama, which outperformed the reference drug of lidocaine at 3μg/mL. ^[53]

Catuama has also been associated with anti-depressive effects in rodents associated with preventing monoamine (noradrenaline, dopamine, serotonin) reuptake. ^[56]

Guarana is one of four herbs used in Catuama, but currently it has not been shown to have a significant role in the combination and synergy/complementation with other herbs has similarly not been demonstrated

Panax Ginseng (True ginseng) is a common adaptogen used in energy drinks alongside guarana. At 200mg panax ginseng (G115) or 75mg guarana (12% caffeine; 9mg total) alone or in combination, all treatments reduced digit vigilance reaction time (no effect on simple reaction time) to equal levels with speed of memory improving in ginseng groups only; logical reasoning was unaffected by all groups. ^[25]

Currently no evidence to support synergism between these two molecules

Due to the inclusion of caffeine in guarana products, Guarana carries some of the same toxicological concerns when taken by persons sensitive to caffeine ^[57] which has been noted in case studies. ^{[58] [59]} )