The stimulants your patient is taking won't necessarily be in her chart under "medication history." Consumption of caffeine, ephedra, or another herbal stimulant may be an overlooked factor affecting your patient's health.
The stimulants your patient is taking won't necessarily be in her chart under "medication history." Consumption of caffeine, ephedra, or another herbal stimulant may be an overlooked factor affecting your patient's health.
A breastfeeding mother of a baby boy is concerned that her son has trouble sleeping and seems "wired." She tells you she drinks 1 to 2 quarts of green tea daily because it is a powerful antioxidant. She wants to know what effects, if any, green tea has on the infant's sleep. What do you say?
As the physician for the local high school football team, you are pleased when several players tell you they've stopped using anabolic steroids. However, they've now switched to a natural sport supplement containing ephedra. What do you do?
A mother of an obese teenage girl phones to tell you she found a bottle of herbal diet pills in her daughter's bathroom. She is very concerned that her daughter is taking "herbal speed" to lose weight. Should you be concerned too?
A growing number of children and adolescents are taking stimulants. Between 1987 and 1996,1 there was a four-fold increase in the prescribing of stimulants as a psychotropic medication to treat attention deficit hyperactivity disorder (ADHD). The rate of prescription stimulant use is highest among children age 6 to 14 years.
But not all stimulants are prescribedthe use of nonprescription stimulants has increased as well. Consumption of caffeinated beverages, particularly soft drinks and teas containing black tea, green tea, guarana, and maté, has risen. Other "natural" stimulant products, such as ginseng and ephedra, have also become more popular. Children and teenagers are now using herbal stimulants in everyday activities such as sports, as study aids, and to lose weight. Common childhood problems such as insomnia, agitation, and nervousness could be side effects of an herbal stimulant. In this article, we'll review the characteristics of some of the more popular nonprescription stimulant products, along with safety concerns.
The most commonly consumed psychoactive drug in the world, caffeine can be legally purchased by children throughout the US without a prescription. Children regularly consume caffeine in chocolate, coffee, tea, soft drinks and "energy" drinks such as Mountain Dew, Surge, and Jolt, and even caffeinated water (Table 1). Caffeine is also present in more than 1,000 over-the-counter and prescription medications. It is found in pain relievers, diuretics, cold remedies, weight control products, and sport supplements (Table 2).
A United States Department of Agriculture (USDA) survey showed that among children 6 to 9 years old, the mean daily caffeine intake was 20 mg.2 A survey of 8- to 11-year-olds in Massachusetts found the average daily caffeine intake was 18.9 mg, or 0.6 mg/kg, and that more than 50% of caffeine consumed was from carbonated beverages.3
In a two-week survey of 191 seventh, eighth, and ninth graders, average caffeine consumption was 52.7 mg/day. The authors noted that boys consumed more caffeine than girls and that soda accounted for 64% of caffeine-containing items. In subjects with higher caffeine intake, there was more disturbed sleep, and sleep was interrupted on the nights after increased caffeine use. The authors of the study called into question the availability of soda vending machines in schools and how it may be affecting the sleep habits of students.4
Caffeine, a member of the methylxanthine drug class, increases norepinephrine and epinephrine secretion and blocks central adenosine receptors. It increases heart rate and basal metabolic rate; promotes secretion of acid in the stomach; and acts as a diuretic, a vasoconstrictor, and a vasodilator. Subjectively, it provides a mental "lift" and enhances alertness.
Caffeine peaks in the blood plasma within 30 minutes after ingestion. It penetrates all tissues, crosses the placenta-fetal barrier, and is found in breast milk. Breast milk concentration of caffeine is approximately 50% of the maternal serum concentration, and excessive maternal consumption may cause irritability in a nursing infant. The half-life of caffeine varies from several hours to days, depending on the patient's age, sex, hormonal status, and medications. Newborns do not have the enzymes needed to metabolize caffeine until several days after their birth. The metabolic half-life of caffeine in a newborn is, on average, longer than three days. The half-life in children is approximately three hours and, in adults, three to seven hours. In pregnant women in their last trimester, the half-life of caffeine may be as long as 18 to 20 hours.
Clinical data are mixed as to whether caffeine consumption during pregnancy harms a newborn.5 Caffeine may retard growth in a developing fetus when given in a dose greater than 300 mg/day. Although animal studies link a high dose of caffeine, such as 1,000 mg daily, with increased incidence of birth defects, eight clinical trials that have looked at the incidence of birth defects in children and their mothers' caffeine consumption have found no association.
Several clinical studies have evaluated the effect of caffeine on children.6,7 A double-blind placebo study found that caffeine enhanced performance on two of four measures of a test of attention and a test of manual dexterity, and the subjects reported feeling significantly less "sluggish and slowed down," but more "anxious."8
Clinical studies looking at caffeine as a potential treatment for ADHD in children have had mixed results; some report a benefit, others do not. In children with ADHD, caffeine is not associated with significant negative effects on behavior or cognition.9 However, most physicians do not solely prescribe caffeine instead of stimulant medications for ADHD.
Many adults are familiar with the side effects of caffeine withdrawalirritability, depression, anxiety, fatigue, and headache. These are present in pediatric patients as well. Withdrawal symptoms can occur after only two weeks of daily caffeine use. In one study, children had a worse performance-reaction time on a task requiring sustained attention during caffeine withdrawal; this deterioration may persist for a week.10
Excessive caffeine consumption can also have side effects. Large amountsmore than 1,000 mg a daymay lead to caffeinism, the manifestations of which include anxiety, restlessness, delayed onset of sleep, headache, and palpitations.
Caffeine can interact with over-the-counter and prescribed stimulant analgesics and other medications. It should be used with caution with MAO inhibitors, methylphenidate, and serotonin reuptake inhibitors.
In addition to black tea, other herbal preparations that contain natural sources of caffeine include guarana, green tea, and yerba maté.
Guarana (Brazilian Cocoa, Paullinia, Zoom) is a dried paste made from the crushed seeds of the Paullinia cupana or Paullinia sorbilis, a plant native to Brazil and Uruguay. Historically, it has served as a tonic, stimulant, diuretic, aphrodisiac, and appetite suppressant and has been used to protect against malaria and dysentery. Today, it is used to enhance athletic performance, counteract mental and physical fatigue, and promote weight loss. Its most popular use, however, is as a flavoring for soda in Brazil, a use that is now becoming popular worldwide.
Guarana contains caffeine (2.6% to 7% of dried weight), theobromine, theophylline, tannins, and a trace amount of timbonine (which is a poison fisherman use to kill fish). Its pharmacologic effects, side effects, and toxicity are similar to those of caffeine and include increased blood pressure and heart rate, central nervous system stimulation, insomnia, diuresis, and other sympathetic reactions. There are no clinical data on the therapeutic effect of guarana.
Guarana is approved as a food flavoring in the US. It is also available as a supplement in tablet form, from 200 mg to 800 mg, but it is most commonly found in "energy drinks." In excessive amounts, guarana may cause agitation, painful urination, abdominal pain, anxiety, diarrhea, headache, nausea, arrhythmias, seizures, tachycardia, tremors, and vomiting. Combining ephedra with guarana may increase the risk of adverse effects related to the caffeine in both these products. Drug interactions follow the same lines as any caffeine-containing product. For example, concomitant use of guarana with a ß-agonist medication may increase the cardiac inotropic effects because of the caffeine constituent. No clinical studies have evaluated the safety of guarana in pregnancy and during lactation.
Several teas are made from the plant Camellia sinensis, a relative of the well-known flowering camellia. The leaves contain caffeine in varying amounts. When black tea is harvested, the leaves are rolled and exposed to air; this exposure stimulates oxidation of the main biologic ingredients. Green tea leaves, in contrast, are steamed and heated to remove the enzyme that promotes oxidation. The caffeine in green tea is mostly extracted in the first infusion of the leaves, and because green tea caffeine combines with catechin in the brewing water, its action is said to be milder than other caffeine-containing beverages. One cup of green tea contains 22 to 46 mg of caffeine.
The traditional use of green tea began about 4,700 years ago in China, where it was often used as medicine. In the 8th century, tea was introduced to Japan and, in the 1500s, to Europe. Tea is the second-most consumed beverage in the world, after water, with an estimated 2.5 million tons of tea leaves produced annually. Green tea accounts for approximately 20% of all tea and is consumed primarily in Japan, China, India, and some parts of the Middle East and North Africa. (The typical amount of green tea consumed daily in Japan is approximately three cups.) Its popularity in the US is growing because of its antioxidant properties, and it is commonly found in grocery stores, pharmacies, and beverage chains such as Starbucks. Green tea is consumed to reduce the risk of various malignancies, such as colon, gastric, and renal cancer; to treat gastrointestinal disorders, headaches, and mental fatigue; to prevent cavities; as a diuretic; and to lose weight.
The active ingredients of green tea include caffeine, 2-amino-5-(N-ethylcarboxyamido)-pentanoic acid, catechins, and polyphenolic compounds. Epicatechin derivatives from green tea interact with hepatic cytochrome P450 and inhibit the P450-dependent mixed-function oxidase enzymes in skin and liver. In vitro studies show green tea to be antibacterial, antimutagenic, and anticarcinogenic.11
Green tea is marketed as a weight loss product. In a placebo-controlled trial, 10 healthy men were randomly assigned to receive either green tea extract, caffeine, or placebo. Green tea had thermogenic properties and promoted fat oxidation beyond that explained by its caffeine content. Green tea extract may play a role in the control of body composition via sympathetic activation of thermogenesis, fat oxidation, or both.12
Green tea can cause gastrointestinal upset and constipation, as well as the common side effects and drug interactions associated with caffeine. It may interact with anticoagulants due to its antiplatelet effects. Caffeine withdrawal symptoms may occur after green tea has been consumed for longer than two weeks.
No long-term studies exist on the safety of green tea during lactation and pregnancy. As with any caffeine product, excessive consumption should be avoided in pregnant or breastfeeding women; in those with cardiac arrhythmias, hypertension, gastrointestinal ulcers, anxiety, or renal disease; and in those taking antifungal medications or aminophylline. Use is precautionary in infants and young children. A retrospective trial noted that microcytic anemia can occur in infants who consume green tea daily.13
A member of the holly family, yerba maté (Ilex paraguariensis) is a widely cultivated, medium-size evergreen tree indigenous to Paraguay, Brazil, and other South American countries. The leaves are used as a stimulating tea. Maté bars are as prevalent in South America as coffee bars are in North America and Europe. Yerba maté is used in folk medicine as a diuretic; as a mild analgesic for headache and joint pains; as a laxative; for weight loss; and to treat heart conditions and depression. It is traditionally considered a tonic or adaptogen.
Yerba maté's primary active chemical constituents are caffeine (0.3% to 2.0%), theobromine, theophylline, saponins, tannins (4% to 16%), and chlorogenic acid. Maté leaves also contain antioxidant polyphenols, chlorophyll, vitamins, beta-carotene, niacin, pantothenic acid, vitamin C, minerals, and 15 amino acids.
Maté is thought to be safe when consumed in moderate amounts on a short-term basis. Like other caffeine-containing products, maté may cause insomnia, gastric irritation, nervousness, diuresis, and arrhythmias. No studies have evaluated the safety of yerba maté in children or in pregnant and lactating women.
Large amounts or prolonged use of maté are associated with an increased risk of cancer of the esophagus, mouth, larynx, kidney, bladder, and lung.14 Drug interactions and interactions with diseases and conditions follow the same lines as any caffeine-containing product.
Panax, or Asian ginseng, is one of the most popular herbs worldwide. Over six million people in the US use it because of its tonic or adaptogenic properties. Use of the herb dates back to the Chinese Han dynasty, during which time it was referred to as the "root of heaven." It is commonly used today to enhance physical and mental well-being, increase stamina, and boost the immune systemprimarily in older people and those with chronic disease. Clinical applications include the treatment of fatigue, weakness, mild depression, cancer, hyperlipidemia, diabetes, impotence, hangovers, and menopause. The German Commission E (a German governmentsponsored organization that evaluates herbs) approved ginseng as a tonic for invigoration and fortification for fatigue and debility, for declining capacity for work and concentration, and for use during convalescence.15
Ginseng contains a number of active constituents, including ginsenosides, a saponin, essential oils, phytosterols, and carbohydrates. Ginseng's mechanism of action is hypothesized to be a normalization of adrenal, thyroid, or pituitary hypothalamic adrenal axis function.16
Studies evaluating ginseng's effect on stamina and well-being have suffered from poor design and inadequate numbers of subjects, and the results have been conflicting. Double-blind clinical control trials investigating the ergogenic and anti-fatigue effects of ginseng extract on physical and psychological performance also have had mixed results. A number of early human studies found significant ergogenic effects with ginseng use among athletes, but these studies were small and poorly designed. More recent studies have not reproduced these results, and the overall evidence fails to demonstrate that ginseng has any direct impact on athletic performance.17 A comprehensive review of the clinical literature on ginseng concluded that there was no compelling evidence that ginseng had any positive effect on physical or cognitive performance, immune function, or any specific disease state.18
Ginseng is usually well tolerated. The most common side effect is insomnia; less frequently reported side effects include vaginal bleeding, mastalgia, amenorrhea, palpitations, hypertension, hypotension, edema, anorexia, diarrhea, pruritus, headache, vertigo, and mania. There are no long-term safety studies evaluating its use during pregnancy or lactation, or in infants or children.
Theoretically, ginseng interacts with warfarin and other medications that have anticoagulant and antiplatelet potential. In two case reports, ginseng apparently decreased the effectiveness of warfarin.19,20 Ginseng may potentiate the effects of caffeine and interfere with antipsychotic, immunosuppressant, and diuretic drugs. It may also lower the blood glucose level.21 Therefore, caution must be used in patients prone to hypoglycemia or taking medications to lower blood sugar.
There are 40 species of ephedra, the most popular of which are Ephedra sinica and Ephedra equisetina. Ephedra is known as Ma huang in traditional Chinese medicine (TCM) and is used to treat colds and flu, respiratory problems, fever, chills, headaches, allergic rhinitis, edema, and joint and bone pain, and as a diuretic. In TCM, ephedra is usually combined with other herbs. An estimated 12 million people in the US have used products containing ephedra,22 primarily for weight loss, athletic performance, energy enhancement, and, to a lesser extent, allergic disorders, nasal congestion, and respiratory conditions such as asthma.
Ephedra contains approximately 0.5% to 2.5% alkaloids including ephedrine (30% to 90%), pseudoephedrine, and phenylpropanolamine. Ephedra's primary chemical constituent, ephedrine, was isolated in 1887, and became a popular medication in the US during the 1920s as a decongestant and bronchodilator. In the last quarter of the 20th century, ephedrine was used as a mainstream therapy for asthma and to correct hypotension resulting from spinal or epidural anesthesia. Today, ephedrine is common in over-the-counter products (Table 3).
Among teenagers and young adults, ephedrine is known as "natural ecstasy." It is used as a starting material for the illegal manufacture of methamphetamine. The stimulant activity of ephedrine is one-fifth as strong as amphetamine. Some athletes use ephedrine to boost their performance; ephedrine is banned by the International Olympic Committee, however. Ephedrine and pseudoephedrine are both nonselective a- and ß-receptor agonists and can directly and indirectly stimulate the central nervous system. Ephedrine increases heart rate, blood pressure, and peripheral vasoconstriction; it also relaxes smooth muscle and causes bronchodilation. Ephedrine has diuretic effects, but can exacerbate urinary retention.
Most clinical studies have focused on the use of ephedrine as treatment for asthma or weight loss. Safer, more selective ß-agonist medications such as albuterol are now used in the treatment of asthma. Trials of ephedrine or ephedrine-caffeine combinations have not shown consistent or dramatic results on weight loss, but have shown significant adverse effects.23
Over 900 cases of possible ephedra toxicity were reported to the Food and Drug Administration (FDA) from 1937 to 1995, including 37 serious cardiovascular events, 11 sudden deaths, 16 strokes, and 10 heart attacks.24 In high doses, ephedra can cause tachyarrhythmias, hypertension, psychosis, collapse, and death. Dosages typically used to treat allergic symptoms and asthma may lead to mild tachycardia, hypertension, insomnia, jitteriness and decreased appetite, dizziness, restlessness, anxiety, irritability, insomnia, headache, flushing, difficulty urinating, heart palpitations, and increased blood pressure. Chronic use can result in dependence or tolerance.
Patients with hypertension, heart problems, diabetes, depression, thyroid disease, anxiety disorders, insomnia, anorexia or bulimia, tremor, kidney stones, or urinary retention should be extremely cautious when considering taking ephedra. Ephedra also has many drug interactions, and should be avoided by patients taking MAO-inhibiting antidepressants, CNS stimulants or cardiovascular stimulants (for example, digoxin and cardiac glycosides), ß-blockers, methyldopa, decongestants, oral steroids, antidiabetic drugs, or halothane. Combining ephedra with methylxanthines or caffeine-containing products or herbs may increase the risk of adverse effects.
Ephedrine crosses the placenta and is found in breast milk, and can harm fetuses and infants. It may also cause uterine stimulation.
The safety of ephedra for the consumer is a hotly debated subject, and new information is being reviewed every day. Based on numerous reports of toxicity, in 1997 the FDA convened a special advisory committee on ephedrine-containing dietary supplements. It proposed a policy that ephedrine-containing products must be properly labeled to list all possible adverse effects, including death, and contain a warning that the product not be used for longer than seven days. The FDA further proposed, among other things, prohibiting the marketing of dietary supplements containing 8 mg or more of ephedrine alkaloids per "serving"; a ban on labeling that recommends a total daily intake of 24 mg or more; and a ban on the combination of ephedra and caffeine in products. However, the proposal was tabled after a hearing of the General Accounting Office at which the dietary supplement industry challenged the link between ephedra and serious side effects. They questioned the basic science behind the FDA dosing recommendations and how the FDA reviewed their adverse event reports.
Although the FDA has not implemented its restrictions on ephedra, 28 states have independently implemented varying restrictions. Ephedra is also banned in Canada and by the US National Collegiate Athletic Association. Four leading dietary supplement associations have banded together to create special labeling for ephedra products and are encouraging the FDA to adopt their labeling as a required national standard. Both the FDA and the herbal industry have clearly come out against the use of ephedra as a recreational drug, such as in Herbal Ecstasy. The FDA has announced that ephedra products marketed as recreational drugs are unproved and misbranded drugs subject to seizure and injunction.
In February 2003, two important events led the FDA to clamp down on ephedra and require warning labels on ephedra products. First, the death of Baltimore Orioles baseball pitching prospect Steve Bechler was linked to ephedra. Second, results of a RAND Corporation study to review ephedra, commissioned by the National Institutes of Health, provided additional evidence that ephedra may be associated with important health risks. After the study was released, FDA Commissioner Mark B. McClellan, MD, PhD, noted: "We are particularly concerned about the risks of using products containing ephedra during heavy workouts, with caffeine and other stimulants, in a diet program that stresses the cardiovascular system, or by people under the age of 18. We are also concerned about potential stresses to the body caused by the long-term use of ephedra."25 On the basis of new evidence, there are reasons for heightened concern that dietary supplements containing ephedra may present a significant and unreasonable risk of illness and injury.
To return to our cases: When discussing with the mother her frequent consumption of green tea, it is important to educate her that the caffeine in the green tea is passing through her breast milk, and that this could be responsible for her infant's irritability.
Next, we turn to the high school football team members' use of natural sport supplements. We would educate the team members of the dangers of ephedra's side effects and explain that ephedrine is banned in Olympic sports.
Last, herbal weight loss supplements are very popular with adolescent girls, but they are a dangerous "quick fix." We would recommend to this patient that she stop the supplements and instead change her diet and exercise daily for long-term success.
More children and teenagers are exposed to herbal stimulants and are using them in daily activities. Because these compounds are easy to purchase and widely available, parents are not always aware of the stimulant products their children consume. Insomnia, agitation, nervousness, and other common childhood problems could be side effects of an herbal stimulant. It is important that health-care providers routinely ask children about which supplements they are using and be aware of common side effects and risks. The box "Nonprescription stimulants: Web sites of note" lists resources of evidence-based information about herbs and dietary supplements.
1. Olfson M, Marcus SC, Weissman MM, et al: National trends in the use of psychotropic medications by children. J Am Acad Child Adolesc Psychiatry 2002;41:512
2. Ahuja J: Caffeine and theobromine intakes of children: Results from CSF II 1994-96, 1998 Family Economics and Nutrition Review 2001;13(2):47 http://www.barc.usda.gov/bhnrc/foodsurvey/pdf/fenrv13n2p47.pdf
3. Ellison R: Caffeine intake and salivary levels in children. Paper presented at the 7th International Caffeine Workshop, Greece, June 1993
4. Pollack CP, Bright D: Caffeine consumption and weekly sleep patterns in US seventh-, eighth-, and ninth-graders. Pediatrics 2003;111:42
5. Castellanos FX, Rapoport JL: Effects of caffeine on development and behavior in infancy and childhood: A review of the published literature. Food Chem Toxicol 2002;40:1235
6. Rapoport JL, Berg CJ, Ismond DR, et al: Behavioral effects of caffeine in children. Relationship between dietary choice and effects of caffeine challenge. Archives of General Psychiatry 1984;41(11):1073
7. Hughes JR, Hale KL: Behavioral effects of caffeine and other methylxanthines on children. Exp Clin Psychopharmacol 1998;6(1):87
8. Bernstein G: Caffeine effects on learning, performance, and anxiety in normal school-aged children. J Am Acad Child Adolesc Psychiatry 1994;33:407
9. Stein MA, Krasowski M, Leventhal BL, et al: Behavioral and cognitive effects of methylxanthines. A meta-analysis of theophylline and caffeine. Arch Pediatr Adolesc Med 1996;150(3):284
10. Bernstein GA, Carroll ME, Dean NW, et al: Caffeine withdrawal in normal school-age children. J Am Acad Child Adolesc Psychiatry 1998;37:858
11. Mukhtar H, Wang ZY, Katiyar SK, et al: Tea components: Antimutagenic and anticarcinogenic effects. Prev Med 1992;21:351
12. Dulloo AG, Duret C, Rohrer D, et al: Efficacy of a green tea extract rich in catechin polyphenols and caffeine in increasing 24-h energy expenditure and fat oxidation in humans. Am J Clin Nutr 1999;70(6):1040
13. Merhav H, Amitai Y, Palti H, et al: Tea drinking and microcytic anemia in infants. Am J Clin Nutr 1985; 41(6):1210
14. Mate Monograph, Natural Medicines Comprehensive Database, www.naturaldatabase.com , accessed Nov. 2002
15. Blumenthal M: The Complete German Commission E Monographs, American Botanical Council, Texas, 1998, pp 138-139
16. Newall C: Herbal Medicines, A Guide for Health Care Professionals, The Pharmaceutical Press, London, 1996, p 145
17. Omantauna D: Ginseng to enhance sports performance. Alt Med Alert 2001;4(7):78
18. Vogler BK, Pittler MH, Ernst E: The efficacy of ginseng: A systematic review of randomized clinical trials. European Journal Clinical Pharmacology 1999;55(8): 567
19. Cheng T: Ginseng warfarin interaction, ACC Current Journal Review 2000;9(1):84
20. Janetzky K: Probable interaction between warfarin and ginseng. American Journal Health System Pharmacy 1997;54:692
21. Sotaniemi EA, Haapakoski E, Rautio A: Ginseng therapy in non-insulin dependent diabetic patient. Diabetes Care 1995;18(10):1373
22. Haller C, Benowitz NL: Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med 2000;343:1833
23. Berman A: Ephedra for weight loss. Alternative Therapies in Women's Health., 2000;2(11):81
24. Samenuk D, Link MS, Homoud MK, et al: Adverse cardiovascular events temporally associated with ma huang, an herbal source of ephedrine. Mayo Clin Proc 2002;77(1):12
25. FDA News, US Food and Drug Administration: HHS acts to reduce potential risks of dietary supplements containing ephedra, Feb 2003. www.fda.gov/bbs/topics/NEWS/2003/NEW00875. html
US Food and Drug Administration
Center for Food Safety and Applied Nutrition Information on ephedra
The FDA's white paper on ephedra; links to RAND Report
The Longwood Herbal Task Forcehttp://www.mcp.edu/herbal
Center for Science in the Public Interest
Report on soft drinks
Where to report any adverse effects with your patients
Paula Gardiner, Cora Collette Breuner, Kathi Kemper. What's the buzz? Contemporary Pediatrics August 2003;20:63.