Guarana for Cognitive Enhancement
June 1999; Volume 2: 67-70
By Michael D. Cirigliano, MD and Philippe O. Szapary, MD
As the pressures of modern life continue to increase, people are seeking "natural products"—often presumed to be safer than synthetic counterparts —to help them combat fatigue and enhance mental performance. The herbal remedy guarana, which has a high caffeine content and historical use as a "cerebral stimulant," is becoming more popular in the United States.
Despite guarana’s long history of use, especially in South America, few clinical studies have been undertaken to study its safety and efficacy. Those that do exist involve small numbers of patients and are of marginal quality. Despite this lack of clinical evidence, guarana’s use continues to grow. Clinicians must be aware of this herb’s actions and potential side effects.
History
Guarana is prepared from the dried crushed seed paste of the plant Paullinia cupana or Paullinia sorbilis (Family: Sapindaceae).1 These plants are native to the Amazon Basin in Brazil.2 Guarana was reportedly first discovered by the Maues-Sateres Indian tribe and has been used as a tonic and stimulant for thousands of years.3 Native peoples have used guarana during periods of fasting to tolerate dietary restrictions, for dysentery, and as an aphrodisiac.1 In the 19th century, guarana became popular as a stimulating drink in France,4 and in 1880 the product was introduced as an official drug in the U.S. Pharmacopoeia, where it remained listed until 1910.4 It later appeared in the National Formulary.
Pharmacology
Currently, guarana is classified as a food additive and dietary supplement. The herb’s pharmacological activity is primarily due to its content of methylxanthine alkaloids.5 Its phytochemical constituents include caffeine, hypoxanthine, saponins, tannins, xanthine, and timbonine.6 Related alkaloids, including theophylline and theobromine, have also been identified but are found only in the bark, flowers, and leaves of the plant and have not been found in the seeds.1 The high doses of saponins and tannins found in the plant have been demonstrated to have antioxidant properties.7
Some studies have noted guarana’s ability to inhibit platelet aggregation following IV or oral administration,8 possibly from decreased platelet thromboxane synthesis.9
Proposed Mechanisms of Action
It is thought that guarana’s major medicinal effects are due to its extremely high caffeine content.10 Guarana has been found to contain between 2.6-7% caffeine by dry weight.10 This compares to coffee beans which contain between 1-2% caffeine and dried tea leaves which contain between 1-4% caffeine.1
Some have speculated that the stimulant effect of guarana is more gradual and sustained than that given by an equivalent dose of caffeine,11 the duration of action of which ranges from one to three hours. Guarana has a caffeine-tannin complex that is postulated to affect the dissolution rate of caffeine from guarana in the GI tract and slow absorption by the gut wall. This theory remains unproven.11
Some researchers claim that part of the revitalizing effects of guarana may be due to its antioxidant action.12 These actions have been noted in vitro with inhibition of spontaneous lipoperoxidation.12
The use of guarana as a component in herbal weight loss preparations stems from numerous investigational studies showing the ability of the sympathetic stimulant ephedrine, when coupled with caffeine, to have a synergistic effect on increasing metabolic rates with subsequent increased energy expenditure (thermogenesis), and to have lipolytic effects.13 These effects have resulted in a modest but statistically significant weight loss in both animal and human trials when combined with diet.13
Animal Studies
Several animal studies have examined various aspects of the herb and its physiological effects. One study compared behavioral effects in rats and mice subsequent to acute and chronic guarana administration.12 These effects were compared with those produced by Panax ginseng administration. In this study, guarana was noted to have some antioxidant effects with resultant inhibition of spontaneous lipoperoxidation. Groups of animals treated with guarana in doses of 2,000 mg/kg showed no significant difference when compared to control groups for the parameters of motor activity, tremor, or salivation.
In another study, mice given a suspension of guarana in a dose of 0.3 mg/ml showed a significant increase in physical capacity when subjected to a stressful situation such as forced swimming after three to six months of guarana treatment.16
Clinical Trials
Despite its widespread use by the public, there are few human clinical trials looking at the safety and efficacy of guarana. Several small studies in humans have attempted to assess the effects of guarana on the cognition of normal volunteers with negative results. In one small study, three groups of normal volunteers ranging in age from 20 to 35 were given either placebo, 25 mg caffeine, or 1,000 mg of guarana containing 2.1% caffeine daily.14 Subjects were treated for three days. Neuropsychological testing, assessment of quality of sleep, and a State-Trait Anxiety Inventory (STAI) evaluation assessing level of anxiety were all performed before and after treatment. After four days, no reproducible improvement in cognition was noted in any group. Interestingly, no adverse effects on sleep or anxiety were noted either. The authors concluded that the negative results may have been due to the short duration of treatment.
In another study, the effects of long-term administration of guarana on the cognition of normal, elderly volunteers were studied.15 Forty-five patients were divided into three groups either receiving 1,000 mg of guarana containing 2.1% caffeine, 25 mg of caffeine, or matching placebo for 150 days. All volunteers underwent immediate and recent memory assessment along with assessment of psychomotor performance at the beginning of the study, and at the third and fifth months of treatment. Volunteers were also evaluated using a sleep assessment scale and anxiety assessment scale. Results showed that guarana did not cause statistically significant memory effect. During the study, four patients taking guarana developed side effects including tachycardia, insomnia, and epigastric discomfort. One patient taking caffeine developed epigastric discomfort while one receiving placebo complained of insomnia.
Adverse Effects and Drug Interactions
Some researchers have raised the possibility that guarana may have dose-dependent genotoxic, mutagenic, and carcinogenic effects.17 Since guarana contains greater than 10% tannins, there is some concern of increased risk of carcinogenesis with long-term use.17 Increased incidence of cancers of the upper GI tract have been reported in some black tea drinking populations, a beverage with equally high tannin content.
Despite these concerns, no published reports describing severe toxicity from guarana have been noted.1 Much more is known about side effects of caffeine however. Caffeine effects typically include restlessness, nervousness, excitement, insomnia, diuresis, GI disturbances, tachycardia and even cardiac arrhythmias.18 Long-term use may exacerbate fibrocystic breast disease and may lead to a caffeine dependence and withdrawal syndrome.18 The one-time lethal dose for caffeine is estimated at 5-10 g, but fatal poisoning by caffeine is rare.19 Dosages greater than 1 g can lead to untoward effects; signs of intoxication can be seen at doses greater than 250 mg.20
In our own practices, side effects associated with the use of preparations containing guarana have included excessive nervousness and insomnia requiring discontinuation. In one such patient, herbal sedatives including valerian root and kava were self administered to counteract the stimulant effects noted with the use of guarana. Subsequent office visits resulted in discontinuation of all supplements and resolution of symptoms.
Drug Interactions/Contraindications
Given the high caffeine content found in guarana, a number of well-known drug interactions may occur. Cimetidine decreases caffeine clearance by 30-50% which may lead to increased side effects.21 Benzodiazepines may be rendered less effective.21 MAOIs combined with excessive caffeine ingestion have led to elevations in blood pressure. Lithium levels may be lower if caffeine is ingested in large doses.21 Certain quinolone antibiotics significantly inhibit caffeine elimination and may lead to increased caffeine side effects.21 Concomitant use with phenylpropanolamine and pseudoephedrine, ingredients commonly found in decongestants, has also led to significant increases in blood pressure.21 Verapamil also is noted to inhibit metabolism of caffeine.
Use of guarana is contraindicated in pregnancy and lactation21 and in children and adolescents. Patients with a history of anxiety or other psychological disorders, hypertension, and heart disease should avoid use of caffeine products.
Formulation and Dosage
Guarana preparations can be purchased with a wide range of dosages. Preparations may contain guarana alone or in combination with other nutritional supplements for weight loss including ma huang, Panax ginseng, bee pollen, gotu kola, and chromium. Dosages can range from 250-1,200 mg with caffeine content ranging from 20-200 mg. Prices range from $4.99 for 30 tablets of guarana to $44.99/month for combination products. Guarana adds a bitter taste when added to commercially available soft drinks. (See Table 1 for price comparison.)
| Table 1 | |||
| Sample guarana prices | |||
| Brand | Formulation | Recommended Dose | Price/Count |
| Excel | 455 mg guarana extract, 100 mg caffeine | 1 capsule daily | $14.99/60 capsules |
| Dr. Clayton’s | 425 mg Amazonian guarana per tablet | 1-2 tablets daily | $11.95/125 tablets |
| Source Naturals | 900 mg guarana per tablet (equivalent to 35 mg naturally occurring caffeine per tablet) | 1-4 tablets daily | $10.98/100 tablets |
| Natrol | 200 mg guarana extract 4:1 per capsule (equivalent to 32 mg caffeine per capsule) | 1-2 capsules daily | $7.95/90 capsules |
| Kal | 800 mg guarana per tablet | 3-6 tablets daily | $5.99/60 tablets |
|
Source: Online mail-order firms ____________________________________________________________________________________ |
|||
Regulation
Guarana is approved by the FDA as generally recognized as safe as a food additive for flavoring. It is not included in the Commission E monographs. Other herbal supplements for weight loss, including ma huang (ephedra), have been closely monitored by the FDA and have been associated with at least 44 deaths nationally, according to MedWatch.
Conclusions
No published scientific data support the use of guarana for cognitive enhancement. Although there are some data suggesting that the combination of ephedrine and caffeine may have a modestly beneficial effect for short-term weight loss, short-term agents have a notorious history. Well-designed, long-term clinical trials are required. Given potential carcinogenesis from the concentrated tannin content and a highly variable caffeine content, guarana poses fundamental questions of safety and efficacy.
Recommendation
The use of guarana as a natural energizer and weight loss aid alone or in combination with other herbals, especially ma huang, cannot be recommended and should be discouraged as potentially harmful. A lack of significant scientific data proving safety and efficacy along with apparent potential for harm precludes its use. Patients using these products should be counseled regarding alternate, safer means for increased energy such as multidisciplinary lifestyle modification programs.
References
1. Guarana. In: The Review of Natural Products. St. Louis, MO: Facts and Comparisons; May 1991:1-2.
2. Der Marderosian AH, Liberti LE. Natural Product Medicine. Philadelphia, PA: G.F. Stickley Co.; 1988.
3. van Straten M. Guarana: The Energy Seeds and Herbs of the Amazon Rainforest. Essex, England: C.W. Daniel Co.; 1994.
4. Steinmetz EF. Guarana. Quart J Crude Drug Res 1965:749-751.
5. Carlson M, Thompson RD. Liquid chromatographic determination of methylxanthines and catechins in herbal preparations containing guarana. J AOAC Int 1998;81:691-701.
6. Duke JA. Paullinia Cupana "Guarana." In: Handbook of Phytochemical Constituents of GRAS Herbs and Other Economic Plants. Boca Raton, FL: CRC Press; 1992.
7. Yoshizawa S, et al. Antitumor promoting activity of Epigallocatechin gallate, the main constituent of tannin in green tea. Phytother Res 1987;1:44-47.
8. Bydlowski SP, et al. A novel property of an aqueous guarana extract (Paullinia cupana): Inhibition of platelet aggregation in vitro and in vivo. Braz J Med Biol Res 1988;21:535-538.
9. Bydlowski SP, et al. An aqueous extract of guarana (Paullinia cupana) decreases platelet thromboxane synthesis. Braz J Med Biol Res 1991;24:421-424.
10. Willard T, McCormick J. Textbook of Advanced Herbology. Calgary, Canada: Wild Rose College of Natural Healing, Ltd.; 1992.
11. Bempong DK, Houghton PJ. Dissolution and absorption of caffeine from guarana. J Pharm Pharmacol 1992;44:769-771.
12. Mattei R, et al. Guarana (Paullinia cupana): Toxic behavioral effects in laboratory animals and anti- oxidant activity in vitro. J Ethnopharmacol 1998; 60:111-116.
13. Breum L, et al. Comparison of an ephedrine/caffeine combination and dexfenfluramine in the treatment of obesity. A double-blind multi-centre trial in general practice. Int J Obes Relat Metab Disord 1994;18: 99-103.
14. Galduroz JC, Carlini E de A. Acute effects of the Paulinia cupana, "Guarana" on the cognition of normal volunteers. Rev Paul Med 1994;112:607-611.
15. Galduroz JC, Carlini E de A. The effects of long-term administration of guarana on the cognition of normal, elderly volunteers. Rev Paul Med 1996;114:1073-1078.
16. Espinola EB, et al. Pharmacological activity of Guarana (Paullinia cupana Mart.) in laboratory animals. J Ethnopharmacol 1997;55:223-229.
17. da Fonseca CA, et al. Genotoxic and mutagenic effects of guarana (Paullinia cupana) in prokaryotic organisms. Mutat Res 1994;321:165-173.
18. McGuffin M et al. eds. American Herbal Products Association’s Botanical Safety Handbook. Boca Raton, FL: CRC Press; 1997.
19. Curatolo PW, Robertson D. The health consequences of caffeine. Ann Intern Med 1983;98:641-653.
20. Sawynok J. Pharmacological rationale for the clinical use of caffeine. Drugs 1995;49:37-50.
21. Brinker F. Herb Contraindications and Drug Interactions. Sandy, OR: Eclectic Medical Publications; 1998.
The major active constituent of guarana is:
a. cocaine.
b. caffeine.
c. tannins.
Guarana has been shown to cause all of the following except:
a. fatigue.
b. inhibition of platelet aggregation.
c. tachycardia.
d. stimulation.
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