Chapter 12: Stimulants

As our society develops more interest in sports and athletics, we become more fixated on winning matches, races, or games. To win, athletes must be in top physical and mental condition every time they compete. A close analysis of most sports calendars indicates that, despite an increasing number of games, none of the sports-governing bodies want to encroach on another sport's season, so athletes in each sport are required to play more games in a shorter time period. This abbreviated schedule requires athletes to be ready to play almost daily in certain sports like basketball and baseball. For athletes, competing every day or almost every day can be both physically and mentally fatiguing.

To keep up with ongoing participation requirements, some athletes elect to use a drug, such as a stimulant, to increase their energy level. For the purposes of this book, the term stimulant is defined as "any agent temporarily increasing functional activity".³³ These drugs provoke a stimulating action on the central nervous system (CNS) through a number of different actions. Because this book cannot discuss every drug that can provoke a stimulatory effect on the athlete, this chapter focuses on the over-the-counter (OTC) drugs that appear to be most commonly used as stimulants by athletes. Because OTC stimulants are more available to athletes than prescription drugs, the athletes may choose to use these drugs to maintain energy during the playing season. Some also use prescription drugs that stimulate the CNS (such as methylphenidate/Ritalin). These drugs are available legally by prescription only, but can be obtained illegally and abused by an athlete. As with other products, the spectrum of available ways to achieve a stimulatory effect can broaden as new products or alternative uses for current drugs are discovered.

Sympathomimetics are drugs that produce a stimulation of the sympathetic nervous system that is similar to the normal excitation response by the body. They are available in different forms.

In this chapter we begin by discussing products containing the OTC formulation of ephedra, and conclude by summarizing the effects of caffeine on athletic performance. As you will read, many manufacturers are now combining ephedra and caffeine in their products because both are stimulatory in nature. Some of the other drugs that are used as stimulants are discussed in Chapter 14 because they are better classified as social drugs than as actual performanceenhancement drugs for athletes.

In the United States we have a variety of cultures. As our society continues to evolve, we see the impact of these different cultures on our choices of foods and nutritional supplements. An interesting evolution in the American society is the influence of Eastern medical philosophy and practice in our health-care system. One of the most visible signs of the Eastern health-care philosophy is the use of herbal preparations for a variety of reasons. More and more athletes are using herbal preparations, including stimulants, in their quest for enhanced athletic ability, and are suggesting the same to their teammates and friends. Most of the herbal stimulants come from the ma huang (pronounced "mawong") plant.

The ma huang plant is harvested and processed into two types of stimulants: ephedra and pseudoephedrine. These two drugs are classified as sympathomimetics because of their stimulatory effect on the sympathetic nervous system. This is the system that stimulates the heart, lungs, and blood vessels to promote the "fight or flight" mechanism. Ephedra is removed from the plant and processed into alkaloid form. This form, known as ephedrine, is preferred because of its improved water solubility, which makes it easier for the human body to readily assimilate and utilize. Ephedrine's basic effects on the human body are threefold. It dilates the bronchial muscles, contracts nasal mucosa, and increases blood pressure. All of these are stimulatory actions on the physiology of the body. Pseudoephedrine, an isomer of ephedra, is more commonly found in OTC oral decongestants. It is helpful in producing a vasoconstriction of the blood vessels in the nasal passages and upper respiratory tract. It is also used for the illegal production of methamphetamine, as explained later in this chapter.

As of early 2004, ephedra was banned for OTC sale in the United States by the FDA. However, it remains available via the Internet, as do many other drugs. Therefore it is important for the athletic trainer to have a good understanding of this drug. To locate the FDA laws that banned ephedra and products that contain ephedra, please visit http://www.fda.gov. Ephedra is a compound commonly found in OTC "metabolism boosters"; weight-loss agents; decongestants; and cold, flu, and asthma medications. The potential for serious adverse effects is greater with "natural" or unprocessed ma huang because the amount is not always accurately described on the product label. There are numerous reports of herbal products containing substances (such as lead, diazepam, and codeine) that are not listed on the packaging.^8,22 One such case involved a product labeled "Chinese ginseng" that had the words "no side effects" on the label, when it actually contained 45 mg of ephedrine in combination with 20 mg of caffeine. If the athlete were to use 5 tablets of this preparation, as suggested on the container, he or she would be consuming approximately 10 to 11 times the OTC recommended dosage for ephedrine. Obviously, this would be dangerous, and the athletic trainer must be aware of these issues.

During the late 1990s, the federal government attempted to stop the sale of OTC preparations containing the caffeine-and-ephedra mixture by proposing a law that would stop its sale.¹⁰ Ultimately, however, the government was not able to stop sales of these preparations, even though the FDA continues to receive reports of adverse reactions (over 17,000 reports as of April 2003), including deaths linked to the improper use of these products and similar preparations sold illegally on the street.^11,12 The deaths linked to caffeine and ephedra mixtures should now be reduced with the ban on ephedra sales in the United States.

Pseudoephedrine, an ephedrine isomer, can also be used to produce—legally or illegally—other drugs with stimulatory effects on the body, such as methamphetamine. This alternative use of ephedrine is an unfortunate fact that should be recognized by the general public. In an effort to prevent sales of OTC ephedra-based drugs to people with improper intentions, many states require pharmacies to report individuals purchasing large quantities of OTC cold tablets, diet pills, or similar drugs.

Pharmacokinetics

Ephedra is available via the Internet in both natural and synthetic formulations.¹⁸ The natural form has been reported to reach peak plasma levels in approximately 4 hours, whereas the synthetic form can reach peak plasma levels in 1 hour.²⁹ After absorption and delivery to the tissues, both natural and synthetic ephedra are excreted in the urine in a basically unchanged form. In the "natural" product formulation, it is difficult to determine how much ephedrine is consumed. The packaging of natural ma huang indicates only how much of the actual herb is present and does not provide a reliable indication of the amount of the ephedrine alkaloid in the product.

As pointed out by Winterstein and Storrs in their overview of herbal supplement use by athletes, the manufacturers of herbal supplements are not regulated like prescription pharmaceutical companies.⁴⁰ In Chapter 13 it is pointed out that these supplements are marketed as food and therefore do not have to comply with FDA guidelines. In the past 10 years, numerous organizations have studied the composition of many different herbal preparations for concentration and purity. The results of these investigations indicate that different companies produce a wide variety of concentrations and purities in herbal preparations, even when marketed under the same or similar names.

Therefore, athletes can unknowingly ingest more or less of the active ingredient than they expect when consuming an herbal supplement. Additionally, because of very limited regulation of the production of these supplements, there are numerous reports of product adulteration during manufacturing. When these products are tested in an independent laboratory, chemicals not listed on the packaging are often discovered in the tablets, powder, or liquid. Some of the unknown chemicals are not safe or may interact with other medications a person might be taking, resulting in unwanted side effects.

One of the claims made about ephedrine is that it is an energy booster. It is commonly touted as a drug that will not only decrease fatigue, but will also improve endurance, reaction time, and strength in all types of athletes. Another drug for which these claims are common is caffeine. Many companies believe that combining these two products will generate even greater stimulatory effects for the athlete. Bell et al. reported in 1998 that the combination of ephedrine and caffeine can be synergistic.² This means that the combined effects of the drugs are not just additive to one another, but one can potentiate the other. As a result, an athlete can get an extreme reaction from combining these two drugs. Not surprisingly, drug manufacturers promising an "energy boost" regularly combine these two drugs in their OTC preparations. Table 12–1 outlines some of the more common ephedra-containing OTC supplements used by athletes at all levels of competition.

Effect on Performance

Ephedrine has been demonstrated to be an effective CNS stimulant. However, the ergogenic (performance enhancement capability) effect of ephedra on athletic performance has not been proven in well-controlled scientific studies. Most of the research completed to date on ephedrine in university laboratories does not indicate an increase in an athlete's physical capabilities from ephedra or caffeine use. The lack of any results demonstrating an ergogenic effect has not stopped the sale and marketing of these supplements to recreational and competitive athletes alike.

Many companies are now marketing different types of drugs that include a primary compound and a stimulant as a "secondary" acting drug. The secondary action of the stimulant is sometimes intended to overcome the sedative effect of the main drug. It can also be used to enhance a person's energy level so that he or she thinks that the primary drug is more beneficial. Athletes might take a product that is designed to relieve symptoms of allergies and unknowingly also consume a stimulant or sympathomimetic agent. An antihistamine, taken to reduce a runny nose, can create a general sedative effect. To counteract this, the manufacturer often puts a stimulant, such as caffeine, in the preparation so that the consumer will not feel sleepy after taking the antihistamine.

Some competitive organizations, including the National Hockey League, allow the use of many OTC stimulants. Other organizing bodies, such as the United States Olympic Committee, place stimulants on the "banned" list even though these drugs are available as OTC preparations. Between 1993 and 1996, stimulant use was reported on almost 65 percent of the positive drug tests in International Olympic Committee (IOC) drug testing laboratories.²⁵

In this chapter the street drugs that are used by some athletes are not discussed in detail. It is worth noting that drugs illegally sold on the street, such as the various cocaine preparations and methamphetamine, are also considered stimulants. They produce a stimulatory effect in much the same physiologic manner as other sympathomimetics. The street drugs are discussed in Chapter 14. For more information on natural or herbal stimulants, see Chapter 13.

Table 12–2 provides an overview of the supplement problems experienced by athletes in the 2002 Winter Olympics in Salt Lake City, Utah. The supplements, which were available free to the athletes, exceeded the minimum levels for certain banned substances. All testing was completed at the IOC's testing lab in Cologne, Germany.

Coffee is considered the most popular beverage in the world, and many believe that the caffeine in the drink is what makes it most appealing. The amount of caffeine in coffee varies according to the roasting and brewing technique. Caffeine is only one of many chemicals in coffee; however, it is caffeine that is most recognized by the general public. It can also be found in a variety of other beverages and is frequently an ingredient in food products and medications (cola and other soft drinks, chocolate bars, and medications such as NoDoz and Vivarin). It is well known that coffee and other caffeinecontaining beverages and foods have worldwide social acceptance. Additionally, caffeine is a component of many OTC energy-enhancement products.

For many years, caffeine has been documented as having an ergogenic benefit for endurance athletes.^{4,6,9,13,20,21} The enhancement effect of caffeine on endurance performance is being studied even today, and different theories exist as to why it might be advantageous to the athlete. Spriet outlines the different research lines being followed on the physiology of how caffeine may have an ergogenic effect on the athlete.³⁰ It is important to keep an open mind and realize that future research on the enhancement effects of caffeine may take us in a totally new direction.

Many suggest that the research that inspired this curiosity about the ergogenic effects of caffeine dates back more than 20 years, when a group of researchers was exploring the effect of caffeine on endurance performance.^6,9,20 Early studies were the basis for the long-held hypothesis that caffeine increases fat metabolism. Caffeine, through one or more metabolic processes, increases the free fatty acid (FFA) concentration in the blood, providing an available energy source in the bloodstream, which spares muscle glycogen during exercise. This glycogen sparing in the muscle was thought to be the reason for the test subject's ability to increase cycling endurance by as much as 20 percent.

After these reports, other researchers began to investigate the reason or reasons why caffeine might be ergogenic in nature, and specifically how it affected fat metabolism in the body. Consequently, many research reports have been published in the last 20 years investigating the mechanism that caffeine uses to produce an increase in athletic performance. However, even the most recent published research does not explain the specific mechanism by which caffeine has an ergogenic effect on athletic performance.^4,7,19,32,36 As mentioned, the ability of an athlete to maintain a high level of performance through the use of caffeine supplements has been verified by numerous authors. Figure 12–1 reveals that endurance performance is improved in cycling and treadmill efforts by athletes working at about 80 to 85 percent of their maximum oxygen consumed during each minute of near-maximal exercise (VO_2max).

The following section reviews the various ergogenic mechanisms of caffeine that have been postulated. The reader will have the opportunity to consider the results of the major research published on caffeine as a performance enhancement product. Readers particularly interested in this topic should review articles published by Nehling (184 references),²⁶ Spriet (56 references),³⁰ and Hawley (160 references)¹⁹ for excellent reviews of the literature and discussions of related research.

Mechanism of Action

Caffeine belongs to the xanthine class of drugs. The xanthines, as one of their actions in the body, act as a CNS stimulant. Caffeine is 99 percent bioavailable, and plasma concentrations peak within 15 to 45 minutes after oral ingestion. Its half-life has been reported to be 3.0 to 7.5 hours in nonexercising adults. The xanthines (e.g., theophylline) are sometimes prescribed by a physician to reduce the incidence of exercise-induced bronchospasm. However, caffeine is not the drug of choice for control of exerciseinduced bronchospasm.

There are three different theories that attempt to explain why caffeine has an ergogenic effect on endurance activity in the athlete. All three theories have subtheories, which make it difficult to discern why caffeine exhibits an ergogenic effect on endurance performance.

The metabolic theory postulates increases in free fatty acids and catecholamines, which decreases the use of muscle glycogen. One of the effects of caffeine ingestion is an increase in circulating epinephrine levels, which can lead to an increase in free fatty acids (FFAs) in the bloodstream. This could be an argument for enhanced endurance capability in the athlete. However, it is also documented that exercise in general increases circulating epinephrine levels.

The neurologic theory suggests that caffeine activity affects the perception of effort at the central nervous system level and reduces the athlete's ability to perceive exhaustion. The muscular theory postulates that caffeine has a direct effect on the skeletal muscle via cellular calcium activity during muscle contraction. The general principles of these three theories are presented in the following paragraphs with a brief overview of the history and research supporting each theory.

Metabolic Theory

A common finding in the earlier endurance-related studies found that caffeine enhances fat oxidation during exercise.^5,6,9 In the metabolic theory, the mechanism of action for caffeine to improve endurance performance is by enhancing fat oxidation in the body. This results in an increase in FFAs in the blood. These FFAs are circulating and can be broken down for use as energy by the muscles. When this happens, the enzymes that metabolize carbohydrates are also inhibited.³⁰

Because of this increase in FFA mobilization throughout the body, available muscle glycogen stores are spared during exercise. More total energy can be derived from a gram of fat than from a gram of carbohydrate; therefore, during aerobic exercise, the body prefers to gain its energy source from fat stores.²⁴ It is also known that fat can be stored in the body in much greater quantities than carbohydrates. If more fats are used for energy during aerobic exercise, it is hypothesized that: (1) overall energy production for the body is greatly increased, and (2) muscle glycogen stores are spared so that the system is able to utilize these fuel sources at a later time. When fats are used as an energy source for the body, a greater amount of oxygen is needed to liberate the fat from its storage site. Therefore there is less oxygen for use by the cells, which alters the utilization of the available oxygen in the body during exercise. This is one reason why the metabolic theory is limited in applicability to aerobic exercise (i.e., to times when oxygen is plentiful in the body during exercise).

The metabolic theory has not been as widely accepted recently as it had been in the 1990s as a result of follow-up studies by other researchers who were not able to specifically identify the ergogenic effect of FFAs on the endurance performance of athletes. Specifically, subsequent research projects were not able to positively discern the muscle glycogen-sparing effect of increased FFAs in the bloodstream.^4,14,21,36 The process of muscle glycogen sparing in endurance performance activities has been a basic question for many researchers since the initial metabolic theory information was published. Other researchers have two fundamental questions regarding the effects of caffeine on athletic performance. First, is there an increase in FFAs in the bloodstream with caffeine ingestion? Second, if muscle glycogen is spared in this process, what effect does that have on endurance performance by athletes? The common thought is that aerobic activity is fueled by FFAs and glycogen is not a primary fuel source in endurance activity. If this is true, what does sparing of glycogen do for the system in an endurance activity? Many of the studies published in the late 1990s and after indicate the possibility of a CNS link to the ergogenic effect of caffeine on endurance performance.

Neurologic Theory

Much of the recently published research suggests that caffeine supplementation has an effect on the central nervous system. Specifically, it masks the effects of fatigue.^3,4,21 Different researchers have speculated on how this is done. Bruce et al. suggest that the masking of fatigue occurs in the CNS via alterations in neurotransmitter function or possibly by overruling fatigue signals to the brain during exercise, thus not providing the athlete's brain with the correct information regarding the true level of fatigue.⁴ Figure 12–2 demonstrates exercise to exhaustion of well-trained athletes who were given three different dosages of caffeine. The athletes ran at approximately 85 percent of VO_2max and there was no significant difference in the time to exhaustion for any of the doses of caffeine administered.

It could also be reasoned that caffeine binds to adenosine receptors in the brain and other parts of the CNS. Normally, when adenosine binds to adenosine receptors, the result is drowsiness and a concomitant dilation of blood vessels (this dilation allows increased oxygen delivery to the brain during sleep). Caffeine looks like adenosine to a nerve cell and will attach to the adenosine receptor, but it has the opposite affect of adenosine in the CNS. Caffeine, in essence, fools the CNS and does not allow the system to become drowsy. Therefore the system remains stimulated and functions at a higher level of activity for a much longer period of time when, in fact, the muscles are tired and ready to slow down.²⁶ Figure 12–3 shows a typical perceived exertion chart that is used when someone is exercising to exhaustion. Charts like this are a way for exercising athletes to let the examiners know how tired they are getting. Perceived exertion may not match actual time to exhaustion when stimulatory supplements are being used.

Muscular Theory

During the late 1990s, a number of authors suggested that caffeine has a direct effect at the cell level in producing its ergogenic benefit.^4,21,32 Recently, Tarnopolsky published a study that concluded that there was a direct link between the ergogenic effect of caffeine and the ability of the muscle to perform endurance activity.³³ The subjects in this study were able to increase the contractibility of their muscles with as little as 6 mg/kg of caffeine ingestion. In this study of skeletal muscle force, it was concluded that the endurance effect of the caffeine is via a potentiation of an increase in the calcium release from the sarcoplasmic reticulum. This increase in calcium enhances the ability of the muscle to contract over longer periods of time, thus providing an increase in endurance performance during aerobic activity.

Endurance vs. High-Intensity Exercise

Originally, the majority of the research on the ergogenic effect of caffeine was directed at increasing performance during endurance activities (e.g., activities lasting an hour or more). Trice and Haymes concluded in 1995 that caffeine can have a glycogen-sparing effect during high-intensity moderate-length (30 minutes) stationary cycling.³⁴ They reported a 29 percent increase in stationary cycling time to exhaustion. The 29 percent increase was attributed to an increase in plasma FFAs, indicating an increase in fat mobilization. In 1996 Jackman et al. published a study that indicated caffeine can be ergogenic in intense activity (lasting approximately 5 minutes).²¹ Jackman et al. did not indicate that the caffeine had a glycogen-sparing effect, but they did suggest that there may be a CNS or muscular connection to the increased performance after caffeine ingestion.²¹ Similarly, Doherty determined similar findings regarding the effect of caffeine on brief, intense activity. The author suggested that the improvement in short-term, high-intensity treadmill running appeared to be from caffeine either having some type of influence on the CNS or acting directly on the muscle cell.⁷ Shortly thereafter, other studies were published that contradicted these results, challenging the general theory that caffeine provides an ergogenic effect during short-duration exercise.^2,17 Essentially, the most recent evidence suggests that caffeine does not provide any ergogenic assistance to the athlete during brief, high-intensity activities.^28,35 Figure 12–4 demonstrates the results of a study in which anaerobic capacity was measured over three different bouts of exercise on a stationary bicycle with caffeine and creatine ingestion by trained athletes.

Habitual Caffeine User vs. Nonuser

The effect of caffeine in the habitual user was questioned early in the search for the most efficient use of caffeine as an ergogenic aide. Tarnopolsky outlined much of the early research and questioned the physiologic responses to exercise of the habitual caffeine-consuming athlete.³³ Earlier results indicted that habitual caffeine users did not experience a metabolic or neuromuscular benefit during exercise following the consumption of caffeine.³³ Nor were any detrimental effects from the caffeine ingestion noticed in the performance of the subjects. However, in his most recent work on the subject, published in 2000, Tarnopolsky concludes that there is an increase in muscle contraction in both habitual users and nonusers of caffeine. It now appears that caffeine ingestion can be ergogenic to both the regular user and the nonuser of caffeine. This is definitely an area that will be researched in much more detail in the future. Figure 12–5 demonstrates that cyclists in endurance-to-exhaustion tests show a similar result to that in runners.

Athletes using different sources of caffeine seem to have various results in their ability to maintain exercise endurance. Capsules appear to be slightly more effective than beverages in producing this change.¹⁴ The reason why capsules appear to be more effective is also unknown. See Figure 12–6 for a comparison of types of caffeine ingestion and time to exhaustion during exercise.

Athletes need to understand that some of the supplements they can use might contain both caffeine and ephedra.

1. Ephedra and pseudoephedrine can be found in "natural," OTC, and prescription medications.

   True  False

2. The production and marketing of herbal supplements is regulated by the Food and Drug Agency in the United States.

   True  False

3. Ephedra will NOT enhance the performance of a sprint athlete.

   True  False

4. Wrestlers who are trying to lose weight will lose more weight using ma huang.

   True  False

5. To what group of drugs does caffeine belong?

   1. Amphetamines

   2. Xanthines

   3. Decongestants

   4. Appetite suppressants

6. Caffeine has multiple effects on the physiology of the body.

   True  False

7. Which of the following is NOT a theory of how caffeine works on the body?

   1. Muscular

   2. Neurologic

   3. Metabolic

   4. Stimulatory

8. Which caffeine theory is the original argument for how caffeine works to provide an ergogenic benefit to athletes?

   1. Muscular

   2. Neurologic

   3. Metabolic

   4. Stimulatory

9. What effect does caffeine have on an endurance-type of activity?

   1. Increases reaction times

   2. Increases total exercise time

   3. Decreases reaction times

   4. Decreases total exercise time

10. What effect does caffeine have on a short-term type of activity?

    1. No difference in exercise time

    2. Increases total exercise time

    3. Decreases reaction time

    4. Decreases total exercise time