BaillieÁre's Clinical Endocrinology and Metabolism

Vol. 14, No. 1, pp. 79±88, 2000

doi:10.1053/beem.2000.0055, available online at http://www.idealibrary.com on

Central nervous system stimulants

Alan J. George BSc, PhD, M.I. Biol

Reader in Clinical Pharmacology
School of Pharmacy and Chemistry, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, UK

Three major types of CNS stimulant are currently abused in sport: amphetamine, cocaine and
ca€eine. Each drug type has its own characteristic mechanism of action on CNS neurones and
their associated receptors and nerve terminals. Amphetamine is widely abused in sports
requiring intense anaerobic exercise where it prolongs the tolerance to anaerobic metabolism.
It is addictive, and chronic abuse causes marked behavioural change and sometimes psychosis.
Major sports abusing amphetamine are cycling, American football, ice-hockey and baseball.
Cocaine increases tolerance to intense exercise, yet most of its chronic e€ects on energy
metabolism are negative. Its greatest e€ects seem to be as a central stimulant and the
enhancement of short-term anaerobic exercise. It is highly addictive and can cause cerebral
and cardiovascular fatalities. Ca€eine enhances fatty acid metabolism leading to glucose
conservation, which appears to bene®t long-distance endurance events such as skiing. Ca€eine
is also addictive, and chronic abuse can lead to cardiac damage. Social abuse of each of the
three drugs is often dicult to distinguish from their abuse in sport.

Key words: stimulants; cocaine; amphetamine; ca€eine; sporting performance.

NEUROPHYSIOLOGY

In order to have an action on the brain a drug must be able to pass from the cerebral
circulation, across the blood±brain barrier and enter the brain tissue spaces in an
amount sucient to produce a pharmacological e€ect. The majority of drugs that act
on the brain to produce changes in behaviour or cognitive and intellectual function or
to ameliorate mental illness, the so-called psychoactive drugs, do so by altering the
functioning of the neurones.
Neurones communicate by the spread of an electrical impulse along the axon (the
action potential). The action potentials, if they reach a certain threshold frequency,
depolarize the nerve terminal causing the release of a chemical substance (neuro-
transmitter) on to receptors that are usually on an adjacent neurone but sometimes on
another type of cell. Only a few drugs (principally some anti-epileptic drugs) interfere
with the electrical transmission in neurones.
Most psychoactive drugs in¯uence the process of neurotransmission at the nerve
terminal (Figure 1) and the principal mechanisms are: (1) increased neurotransmitter
release on to receptors (amphetamine and ephedrine); (2) direct stimulation of the
post-synaptic receptors (ephedrine, ca€eine); (3) inhibition of neurotransmitter re-
uptake (cocaine and amphetamine).
1521±690X/00/010079+10 $35.00/00 *
c 2000 Harcourt Publishers Ltd.
80 A. J. George

Blood

X Nerve Terminal

1 Neurotransmitter

2 X
3
Receptors
SITES OF ACTION OF CNS STIMULANTS

Amphetamine 1,2
Cocaine 2
Caffeine 3
Figure 1. Possible mechanisms of action of some CNS stimulants (modi®ed from George AJ. CNS
stimulants. In Mottram DR (ed). Drugs in Sport, 2nd ed, pp. 86±112. London: E and F Spon, 1996).1

Central nervous system (CNS) stimulants are thought to act mainly on the
dopamine (DA), noradrenaline (NA) and 5-hydroxytryptamine (5HT) (serotonin)
neurotransmitter systems. Ca€eine is thought to a€ect adenosine neurotransmission.1

AMPHETAMINES

A number of drugs are referred to as `amphetamines' but in this chapter this term
refers only to the substance dextro amphetamine (Figure 2). After its introduction in
the 1920s amphetamine was prescribed unsuccessfully as a nasal decongestant, anti-
depressant and appetite suppressant. It is now a controlled drug in the UK and is used
only occasionally to treat attention de®cit disorder in children and narcolepsy.1
Amphetamine may produce its e€ects in four ways. These are: (1) release of
neurotransmitter ± DA, NA or 5HT ± from their respective nerve terminals; (2)
inhibition of monoamine oxidase activity; (3) inhibition of neurotransmitter re-uptake;
(4) direct action on neurotransmitter receptors. Of these four possibilities, neuro-
transmitter release appears to be the most important.2
Amphetamine stimulates DA release by reversing the neuronal membrane uptake
transporter system.3 It also inhibits the activity of the monoamine oxidase.3 It seems
that several major behavioural changes induced by amphetamine are most closely
 Central nervous system stimulants 81

NH2 H CH3
N
H C CH3
H C CH3

CH2
CH2

AMPHETAMINE METHAMPHETAMINE

CH3

C O O CH3
N
N N

N N
O O

C O CH3

CAFFEINE
COCAINE

Figure 2. The structures of some CNS stimulants (modi®ed from George AJ. CNS stimulants. In Mottram
DR (ed). Drugs in Sport, 2nd ed, pp. 86±112. London: E and F Spon, 1996).1

mimicked by the stimulation of central NA-releasing neurones. The increased alertness

and elevation of mood produced in humans is closely related to increases in nor-
adrenergic activity. Amphetamine is a potent anorectic and elevates plasma free fatty
acid levels. Body temperature is also elevated. The cardiovascular, gastrointestinal and
respiratory e€ects of amphetamine are sympathomimetic in nature. However, both
animal and clinical experiments suggest that the e€ects of amphetamine are mediated
by the release of at least two neurotransmitters, NA and DA, and that, in the rat, the
development of tolerance to amphetamine involves the release of 5HT. However, the
stereotyped behaviour induced in the rat by amphetamine administration appears to
depend on DA release. The euphoriant action of amphetamine can be abolished by the
DA receptor antagonist, pimozide. There is some evidence to suggest that the positive
behavioural e€ects of amphetamine may be mediated by DA, while the e€ect of
amphetamine on food intake may be mediated by NA. However, others have pro-
duced con¯icting evidence for this.4
Amphetamine is readily absorbed, mainly from the small intestine, and the peak
plasma concentration occurs 1±2 hours following administration. Absorption is usually
complete in 2.5±4 hours and is accelerated by food intake.
The metabolism of amphetamine has been dicult to investigate because of the wide
variation between species in its metabolic e€ects. The principal amphetamine metab-
olites are p-hydroxy ephedrine and p-hydroxy amphetamine. Both these metabolites
have similar pharmacological e€ects to the parent amphetamine. Amphetamine is lost
from the blood by renal ®ltration. Some secretion of amphetamine into the urine may
82 A. J. George

also occur. Amphetamine excretion is enhanced by an acid urine, and treatments that
increase the acidity of urine enhance amphetamine loss ± a reaction that is useful in the
treatment of amphetamine overdose.1

Amphetamine action
In the short term, amphetamine increases the speed of learning of new tasks. The e€ects
of amphetamine on judgement are uncertain and several con¯icting studies have been
published. There is general agreement that amphetamines cause a mild distortion of
time perception that may lead to misjudgement in planning manoeuvres or in
manipulations, such as driving a car. Active avoidance learning is facilitated by
amphetamine. Although there is considerable inter-individual variation in the e€ects of
amphetamine on mood, the general e€ects are of positive mood enhancement. These
positive e€ects include an increase in physical energy, mental aptitude, talkativeness,
restlessness, excitement and good humour. Subjects taking amphetamine also report
that they feel con®dent, ecient, ambitious and that their food intake is reduced.
Amphetamines do not seem to improve intellectual performance unless the perfor-
mance of the task in question is degraded by boredom or fatigue.2
Improvements in sporting and athletic performance have been observed following
amphetamine administration but these occur in speci®ed situations and are discussed
later.
Some `negative' e€ects of amphetamine are anxiety, indi€erence, slowness in
reasoning, irresponsible behaviour, irritability and restlessness, dry mouth, tremors,
insomnia and, following withdrawal, depression. These e€ects of amphetamine on mood
are dose-dependent and are thought to be produced by the stimulation of DA and
nonadrenergic receptors.1,2
Tolerance develops rapidly to many of the e€ects of the amphetamines. Tolerance is
said to be present when, over a period of time, increasing doses of a drug are required
to maintain the same response. There is much evidence to show that amphetamines
induce drug dependence and the amphetamine-dependent person may become
psychotic, aggressive and anti-social. Withdrawal of amphetamines is associated with
mental and physical depression.2
The major side-e€ects of amphetamine administration (excluding those following
withdrawal of the drug) include (1) many of the negative e€ects described above; (2)
confusion, delirium, sweating, palpitations, dilation of the pupil and rapid breathing; (3)
hypertension, tachycardia, tremors, muscle and joint pain. Though amphetamine may
initially stimulate libido, chronic amphetamine use often leads to a reduction in sex
drive. Chronic amphetamine administration is also associated with myocardial path-
ology and with growth retardation in adolescents. Usually, the personality changes
induced by chronic low doses of amphetamine are gradually reversed after the drug is
stopped. However, high chronic doses may lead to a variety of persistent personality
changes, including the so-called amphetamine psychosis.5 The frightening array of
psychiatric symptoms described in patients presenting with amphetamine psychosis
include many commonly found in paranoid-type schizophrenics. An important distinc-
tion between amphetamine psychosis and schizophrenia is that amphetamine induces a
preponderance of symptoms of paranoid delusions and tactile hallucinations.5
Amphetamine toxicity is usually treated symptomatically, using anti-adrenergic
drugs to treat sympathomimetic problems and DA receptor antagonists to treat
behavioural e€ects.1
 Central nervous system stimulants 83

The e€ects of amphetamine in sport

Since the action of amphetamine on sporting performance was ®rst investigated in
19596, it has been concluded that it enhances anaerobic performance while having little
or no e€ect on aerobic activity. Many of these studies have been carried out on amateur
and professional cyclists since they can be investigated conveniently under `laboratory'
conditions on bicycle ergometers, and in Europe they are among the biggest abusers of
the drug.7 At least one study7,8 demonstrates clearly that amphetamine increases the
athlete's ability to tolerate higher levels of anaerobic metabolism. Exactly how this is
achieved is uncertain since the action of amphetamine on muscle glycogen has been
shown to be variable.9 The action of amphetamine on central and peripheral aspects of
fatigue needs to be explored further since this may be the major reason for amphet-
amine abuse in sport outside cycling.
As discussed by George1 amphetamine may be abused for di€erent reasons by
di€erent athletes. An American study10 showed that members of an American football
team would take di€erent doses of amphetamine according to their position and role
in the team: those involved in accurate passing took the lowest doses (5±15 mg) while
the `aggressive' defenders took the highest (30±150 mg).

Side e€ects of particular importance to athletes

Some side e€ects of amphetamine are particularly important in athletes, and have
often only been revealed in individuals undertaking extremely arduous training or
sporting schedules.
Amphetamine-induced heatstroke has caused a number of fatalities in cyclists, owing
to the intensity of their exercise, the endurance required and the high ambient
temperatures at which the exercise often occurs. Amphetamine induces a blood ¯ow
redistribution away from the skin, thus limiting the cooling of the blood. As a result of
this, two cyclists (Jenson and Simpson), who had both been taking amphetamine, died
of heatstroke and cardiac arrest, respectively, during gruelling road races.1
The ability of amphetamine to obscure painful injuries has enabled many American
footballers to play on and exacerbate injuries which would normally have resulted in
their withdrawal from play.8
The side e€ects of amphetamine on behaviour are also important in sport. A review
of amphetamine abuse amongst American footballers found extensive abuse, as
much as 60±70 mg average dose per man per game. In this sport, amphetamine was
administered apparently to promote aggression and weaken fatigue in the footballers.
However, there are several accounts in which the euphoriant e€ects of such doses have
rendered the takers unaware of the errors and misjudgements they were making on the
pitch.10,11

Amphetamine incentive
The advantage amphetamine gives the abuser appears to be small but in those athletic
events in which abuse occurs this small advantage may be paramount. It has been
calculated that the 1500 m world record has improved by only 1% for every 7 years since
1950. An athlete maintaining a 1% improvement in performance over his opponents
would be at a tremendous advantage.1,12
84 A. J. George

Table 1. The ca€eine content of some beverages, drinks and

medicines.

Ca€eine content
(mg)
Co€ee (per 5 oz cup)
Percolated 64±124
Instant 40±108
Filter 110±150
Deca€einated 2±5

Tea (per 5 oz cup)

1 minute brew 9±33
5 minute brew 25±50

Soft drinks (per 12 oz serving)

Pepsi Cola 38.4
Coca Cola 46

Proprietary medicines
Anadin tablet 15
Cephos tablet 10
Coldrex cold treatment tablet 25
Phensic tablet 50

Source: reproduced from George AJ. CNS stimulants. In

Mottram DR (ed). Drugs in Sport, 2nd ed, pp. 86±112. London:
E and F Spon, 1996.

CAFFEINE
This is one of the oldest stimulants known to mankind and is found in many beverages
and medicines (Table 1).

Pharmacology
The dose range over which ca€eine is e€ective is 85±200 mg. Its e€ects are a reduction
in drowsiness and in fatigue, elevation of mood, improved alertness, increased
productivity, more sustained intellectual e€ort and a clearer ¯ow of thought. At this
same dose, diuresis occurs together with relaxation of smooth muscle, increased gastric
acid secretion, an increase in heart rate and in arteriole diameter. At doses higher than
250 mg, ca€eine intoxication is said to occur and may be associated with headaches,
unstable mood, nervousness and anxiety. Ca€eine pharmacokinetics are complex13 and
are strongly in¯uenced by the nature of the medium in which the ca€eine is ingested.1
Oral administration of ca€eine results in virtually 100% absorption and it begins to
appear in the blood within 5 minutes of ingestion.1,13,14
Ca€eine absorption from soft drinks is slower than from tea and co€ee and is
strongly in¯uenced by age, genetics, exercise, smoking and drugs that interfere with
its metabolism such as oral contraceptives.13
A summary of the pharmacological e€ects of ca€eine is shown in Table 2.

Mechanism of action
Ca€eine inhibits phosphodiesterase isoenzymes but the central action is associated
with antagonisms of the three types of adenosine receptors (A1 , A2 and A3).15
 Central nervous system stimulants 85

Table 2. The pharmacological e€ects of ca€eine.

. Increased gastric acid and pepsin secretion, plus increased secretion into the small intestine
. Increased heart rate, stroke, cardiac output and blood pressure at rest
. Tachycardia
. Increased lipolysis
. Increased contractility of skeletal muscles
. Increased oxygen consumption and metabolic rate
. Increased diuresis
. Increased anti-nociceptive action of NSAIDS and exerts a mild anti-nociceptive action itself

Source: reproduced from George AJ. CNS stimulants. In Mottram DR (ed). Drugs in Sport, 2nd ed, pp.
86±112. London: E and F Spon, 1996.

Speci®c central e€ects

The wide variation in ca€eine's stimulatory e€ects has been catalogued and includes
increased vigilance and attention, and a reduction in the negative e€ect on performance
caused by boring or repetitive jobs.13,15 The e€ects of ca€eine on numerical reasoning,
verbal ¯uency, short-term memory and digital skill are less predictable and may indicate
a strong in¯uence of personality and conditioning on ca€eine's central actions.12
Ca€eine abstinence, after long-term consumption, can give rise to a withdrawal state
in which irritability, insomnia, muscle twitching and headaches occur.

Adverse reactions
Ca€eine's side e€ects have been classi®ed as acute (mild or severe) and chronic. Mild
acute e€ects include nervousness, irritability, insomnia and gastrointestinal distress;
severe acute e€ects include peptic ulcer, delirium, coma, seizures and various types of
arrhythmia. The major chronic e€ect is raised serum cholesterol.1
Ca€einism is a cluster of mental symptoms that includes periodic anxiety, mood
changes, sleep disruption and withdrawal symptoms16 and is now recognized in the USA
as a psychiatric disorder.17

E€ects on athletes
Roughly 35 years ago, ca€eine was suggested to improve endurance by enhancing fat
utilization and reducing glycogen breakdown.18 Experiments on professional cyclists in
1978 showed that ca€eine takers could exercise for 19.5% longer than a placebo group
and they also had signi®cantly higher fatty acid and blood glycerol levels.19
Several further studies conducted up to 1980 appear to support this view that ca€eine
enhances the release and subsequent metabolism of fatty acids and glycerol leading to
carbohydrate conservation.20 Not all studies concurred with these ®ndings and a major
review in 1991 concluded that the variable e€ects of ca€eine might be due to six key
factors: dose, exercise type, exercise intensity, pre-exercise fuel intake, previous ca€eine
use and training status.9 Ca€eine is also more e€ective in ca€eine abstaining subjects
who refrain from high carbohydrate diets.9 In 1993 it was suggested that ca€eine may
have its greatest e€ect on particular types of exercise.20 A ruthless analysis of the e€ects
of ca€eine on exercise shows that in only one type, long-term endurance exercise at
75±80% VO2 , is there evidence of a consistent positive enhancement of performance. A
new summary of the mechanisms of ca€eine enhancement of sporting performance
86 A. J. George

includes CNS stimulation, enhanced catecholamine release, mobilization of free fatty

acids, glycogen sparing in muscle and liver, and increased utilization of muscle
triglycerides thus further reducing muscle glycogen utilization.20,21

COCAINE

One of the ®rst clinicians to experiment meaningfully with cocaine, was Sigmund Freud.
He measured its e€ects on exercise using a simple `®nger ergometer', and testi®ed to its
e€ects on enhancing stamina. Some of the disastrous results of the use of cocaine for the
treatment of mental disorders were obtained by him and his colleagues.1

Pharmacology
It increases motor activity, talkativeness and is a strong euphoriant. Cocaine is thought
to be the most addictive agent known. For ethical and practical reasons most of our
knowledge of the pharmacology of cocaine comes from animal studies. It is a powerful
`reinforcing and rewarding agent' acting to stimulate the brain's so-called pleasure and
reward centres. These centres are associated with the mesocortical and mesolimbic
neuronal systems in which dopamine is one of the major neurotransmitters.22 Cocaine is
known to inhibit re-uptake of DA into the terminals of DA-releasing neurones (Figure 1)
and to bind strongly to the DA-transporter ± the protein concerned with DA re-
uptake.23

Pharmacokinetics
Cocaine may be administered by injection, orally, intra-nasally or by inhalation. Peak
e€ects occur at variable times with behavioural changes lasting up to 1 hour following
oral administration. The most popular route is nasal `snorting', which produces peak
e€ects from 5±15 minutes and lasting for up to 1 hour. Inhalation of `free-base' cocaine
produces peak e€ects in less than 1 minute, but also a short-lived physiological e€ect
measured in minutes. The most intense cravings follow inhalation.8

Adverse e€ects
Cocaine is more highly addictive than amphetamine and the abuser may experience
acute psychotic symptoms and become irrational, in addition to the adverse e€ects
produced by euphoria. Chronic symptoms include a paranoid psychosis similar to
amphetamine, plus delirium and confusion. Other CNS side e€ects include epilepto-
genesis. This adverse e€ect is particularly dangerous because the epileptogenic e€ect
increases with frequency of cocaine abuse, a process known as reverse tolerance.24 This
is important when the powerful reinforcing properties of the drug are considered. The
epileptogenic e€ect can be produced even by repeated small doses of the drug.8
Cocaine abuse is strongly associated with cerebrovascular accidents arising either
from the rupture or spasm of cerebral blood vessels. Some of these incidents may be due
to pre-existing vascular pathologies, but there are several cases where no predisposing
cause has been found at autopsy. Cocaine is also associated with cardiovascular side
e€ects and the increase seen in these in recent years is probably due to the rise in abuse
of `crack' cocaine, which is rapidly absorbed and produces a concentrated e€ect on
cerebral and cardiac arterioles.1
 Central nervous system stimulants 87

E€ects in athletes
Much of our recent knowledge of the e€ects of cocaine on exercise has been obtained
from animal studies.9,24 Cocaine experimentation in humans is severely restricted for
ethical reasons.1
Many studies have demonstrated that cocaine has no bene®cial e€ect on running
times with a dose range of 0.1±20.0 mg/kg body weight, and at doses above 12.5 mg/kg
the cocaine actually reduces running time. At all doses used, cocaine signi®cantly
increases glycogen degradation while increasing plasma lactate concentration without
producing consistent changes in plasma catecholamine levels.9,25 Experiments in rats
exercising voluntarily demonstrated that cocaine increases glycogen metabolism and
enhances the exercise-induced sympathetic responses.25 None of these studies have
explained how cocaine reduces endurance performances.24 Three possible mechanisms
to explain cocaine's action that could operate in parallel are: (1) cocaine releases
catecholamines that increase glycogenolysis and lactate production leading to early
fatigue; (2) cocaine may induce skeletal muscle vasoconstriction, reducing oxygen
delivery, oxidative metabolism, strength and reaction time, and stimulating glycogen
breakdown; (3) cocaine may have a direct e€ect on muscle glycogen breakdown.
Mechanism (2) is less likely since cocaine-induced reduction of myocardial blood¯ow is
not associated with increased myocardial glycogen breakdown.9
Despite these apparently detrimental e€ects cocaine continues to be abused in sport.
It may be that cocaine only has a positive ergogenic e€ect on activities of short duration
requiring a burst of high intensity energy output such as basketball.1 The activities
associated with the drug's central stimulatory e€ect may be more important than its
action on peripheral metabolism. It has been suggested that it is precisely for these
central heightened arousal and increased alertness e€ects, achieved principally at `low'
doses, that cocaine is used in sport.1

Side e€ects in athletes

A number of dramatic fatalities associated with coronary occlusion have occurred in
cocaine abusing athletes, usually those who have been exercising intensely following
drug administration.9,26 Many sports people who abuse cocaine complain of negative
central e€ects such as perceptual misjudgements and time disorientation that some-
times reduced their athletic performance.1
Some bizarre fatalities have occurred when cocaine abuse has been mixed with
alcohol or anabolic steroids. A possible novel metabolite may result from the joint
abuse of alcohol and cocaine, which is extremely cardiotoxic.27

SUMMARY

. CNS stimulants improve sporting performance only in particular exercise regimes.

. Amphetamine and cocaine induce serious chronic side e€ects that may sometimes
prove to be fatal.
. Ca€eine, amphetamine and cocaine may disrupt CNS functioning while improving
sporting performance.
. All three drugs are associated with habituation.
Further research is needed on the following:
. To establish the `over¯ow' between social and sporting abuse of CNS stimulants.
. To investigate the abuse of CNS stimulants in the aspiring young athlete.
 88 A. J. George

. To investigate whether particular personality types are associated with CNS

stimulant abuse in sport.
. The e€ects of stimulants on fatigue in sport should be investigated more intensively.

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