Caffeine 101 : The Most Widely Used Psychoactive Substance In The Western World

Caffeine is the most widely consumed psychoactive substance in the western world. In addition to being a CNS stimulant, it has a variety of peripheral effects relating to muscle contraction, diuresis, gastric secretion, and lipolysis. The average US citizen consumes 206 mg of caffeine daily (the equivalent of about two cups of coffee), and 10% of the adult population ingests more than 1000 mg of caffeine daily1. Despite this, there are many significant gaps in our understanding of the effects caffeine has on various systems2. This article will explore the application caffeine has for the athlete, as well as a myriad of other effects of caffeine.

Chemically, caffeine (1,3,7-trimethylxanthine) is a member of a class of drugs known as methylxanthines. The primary pharmacological effect of caffeine is selective antagonism of the adenosine A1 and A2A receptors3-4. Adenosine is a cellular constituent that modulates the release and activity of a variety of neurotransmitters, including norepinephrine, acetylcholine, dopamine, and GABA. It primarily inhibits the release of excitatory neurotransmitters, so increased concentrations of adenosine reduce arousal and suppress spontaneous behavioral activity3. Adenosine concentrations slowly increase during wakefulness, so adenosine antagonism is what causes caffeine's wake-promoting effect. Other effects of caffeine include inhibition of phosphodiesterase (PDE), GABA-A blockade, and mobilization of intracellular calcium. The relevance of these effects at normal doses is debatable.

After ingestion, caffeine is absorbed into the blood and other body tissues within 5 minutes, and peak concentration is reached in about half an hour, and the half-life is approximately 4 hours5. The ideal dosage for achieving various goals will be discussed further in the following sections.

Caffeine and exercise performance

The beneficial effect caffeine has on endurance exercise is well established, and has been confirmed in a multitude of studies. During submaximal exercise, caffeine in doses of 3-9 mg/kg (200-900 mg) delays fatigue considerably, increasing exercise time by 20-50%, with the 3-6 mg/kg range appearing to be ideal. Lower doses, such as 1.5 mg/kg, appear to offer at least some benefit. The magnitude of the beneficial effect depends on a variety of factors, such as type and intensity of exercise (the greatest effect is seen in exercise lasting 30-120 minutes), previous caffeine use (with greater and longer lasting effects among nonusers), training status, and individual variation3-4. Although many of these studies are conducted in the fasted state, which does not reflect realistic conditions, the benefit is still seen in studies in which the subjects are well fed6. Using caffeine to improve endurance performance is also quite safe. Doses as high as 10 mg/kg do not impair thermoregulation during exercise8, and exercise prevents the effects caffeine has on diuresis, so hydration status is not compromised.

Whether or not caffeine has a benefit for those engaged in short-term, high-intensity exercise (over 100% VO2max) such as strength training or sprinting is less clear, although the bulk of the evidence suggests a more modest benefit of a 10-25% increase in work output. However, this effect still appears to be more pronounced in exercise bouts lasting over 60 seconds. Few well-controlled studies have been done assessing whether or not caffeine has a benefit for strength trainers, but those that have been done have had positive results.

There are a few supplements which caffeine may interact with either positively or negatively. Caffeine and carnitine synergistically improve endurance exercise time12, and there is a wealth of data supporting the combination of caffeine and ephedrine for many types of training13. The issue of whether or not caffeine and creatine should be combined is controversial. Two studies indicate that they may be antagonistic. One study found that caffeine and creatine have opposing effects on muscle relaxation time11, but the importance of this is not clear. Another widely quoted study found that when caffeine and creatine were co-administered over a period of six days, caffeine prevented the beneficial effect of creatine10. On the other hand, when caffeine is administered acutely before exercise during creatine loading the effect caffeine has on athletic performance still remains10. This indicates that chronic caffeine consumption may interfere with the benefit of creatine, but that creatine does not interfere with the improvement of exercise performance from caffeine. Unfortunately, there is not yet enough research to draw any practical conclusions. It is doubtful that caffeine completely prevents the action of creatine, as creatine functions through multiple pathways, but whether or not there will be on balance a greater effect from creatine by itself or from creatine along with caffeine pre-exercise is unknown.

Mechanism of action

A number of mechanisms of action for the ergogenic effect of caffeine have been proposed in the literature; some hold up to scrutiny while others do not. The original theory, known as the metabolic theory, was that the effect was primarily due to mobilization of free fatty acids, which would preferentially promote fat as a fuel source during exercise and spare muscle glycogen. In recent years, a multitude of studies have indicated that this is an unlikely reason for the benefit, and this theory has been rejected3, 6. A number of more promising theories have arisen, primarily involving effects on both the central and peripheral nervous system.

A major role of the central nervous system (CNS) is supported in many ways. Intracerebroventricular administration of caffeine to rats, which results in high CNS levels and negligible peripheral levels, increases run time by 60%3. A primary role of adenosine antagonism is implicated in this area, since adenosine inhibits the release of dopamine and increases the serotonin/dopamine ratio, and both of these may play a role in central fatigue during exercise 3. In line with this theory, administration of a selective adenosine agonist reduced run time to fatigue in rats and caffeine reversed this effect3.

There are also a variety of ways in which caffeine may improve neuromuscular function. These include changes in the chemical composition of the muscle's environment, alteration of feedforward inhibition, or alteration in central processing of feedforward or feedback14. This is where potentiation of calcium release plays a possible role15-16. In vitro, potentiation of the release of calcium from the sarcoplasmic reticulum occurs at levels that are obtainable in ergogenic doses in humans15. In line with this, doses of caffeine from 4 to 7 mg/kg potentiate submaximal skeletal muscle contraction, with no effect of tolerance15. This mechanism of action would also explain why caffeine appears to be more effective at lower exercise intensities, as the level of calcium release from the sarcoplasmic reticulum is thought to play an important role in fatigue at these intensities, but not higher intensities15. Caffeine may also improve neuromuscular function via adenosine antagonism. Specifically, it may reduce the inhibitory action adenosine has on motor neuron firing frequency and raise the frequency of potentials in the motor end plate through acetylcholine release16. Finally, it has been suggested that caffeine reduces fatigue by preventing loss of potassium from skeletal muscle10. This would be achieved by increased Na2+/K+ ATPase activity, leading to increased potassium ion uptake10. However, there is little evidence to support this theory at this point.

A final mechanism of action for improvement of exercise performance by caffeine is analgesia. One of the effects of caffeine on exercise is a lower rating of perceived exertion (RPE). Caffeine increases the pain threshold and tolerance to pain17. It has also specifically been shown to have an analgesic effect during ischemic muscle contractions10. This is related to caffeine's ability to increase the release of beta-endorphins and other hormones and neurotransmitters that influence perception of pain10.

Caffeine and weight loss

Almost every weight loss pill in the market contains caffeine, and there is good reason for it. Caffeine has well known thermogenic properties in humans, increasing the rate of lipolysis and total energy expenditure, and it also decreases food intake18-20. However, caffeine by itself rarely results in statistically significant weight loss unless it is used in high doses (a gram or more daily). Luckily, there are a variety of substances that caffeine exhibits potent synergistic relationships with. In addition to oral administration, clinical studies indicate that caffeine is an effective topical fat loss agent, especially in "stubborn" areas, when the right carrier is used21. This may be a particularly effective route of administration, since caffeine induces insulin resistance in adipocytes2.

The mechanisms of action for fat loss are relatively well established. Adenosine is one of the negative feedback mechanisms that prevents the release of the lipolytic hormone norepinephrine (NE)5. Caffeine also inhibits PDE, which results in higher concentrations of cyclic AMP, and this potentiates the effect of NE19. The inhibition of these two negative feedback mechanisms makes caffeine particularly useful when used in conjunction with an agent that causes release of NE or other catecholamines, such as ephedrine, and this combination is very effective for fat loss13.

Caffeine also may exhibit a synergistic relationship with EGCG, a component of green tea. This is because EGCG inhibits COMT, an enzyme that breaks down NE and other catecholamines22. The combination of caffeine, carnitine, and choline causes fat loss in rats23. Caffeine together with capsaicin increases thermogenesis in humans, but it is not known if this was due to additive or synergistic effects20. Finally, caffeine and nicotine make an effective combination for fat loss18. One study found that 100 mg of caffeine along with 1 mg of nicotine gum significantly increased thermogenesis and increased resting metabolic rate by 8.5%. Raising the nicotine dose to 2 mg had little added benefit but significantly increased side effects. Also, despite the fact that caffeine raises blood pressure, it protects against the blood pressure raise from nicotine1. However, the two substances may potentiate the addictive effect of one another24. If a synergistic substance is being used, the ideal dose of caffeine for fat loss seems to be in the range of 200-400 mg daily, with little added benefit from higher doses.

Fatigue, cognitive performance, and sleep

Caffeine, usually in doses in the 150-400 mg range, acutely improves cognitive function in a multitude of ways. These primarily involve simple intellectual tasks and rapid information processing5. Beneficial effects seen from caffeine include faster typing with fewer errors, improved simple reaction and choice reaction time, improved performance on simulations of driving and sentry duty, improved performance on digit symbol substitution and logical reasoning tasks, improved accuracy of time estimation, and improved cognitive performance in the post-exercise state5, 25-28. Chronic or lifetime consumption of caffeine is associated with improved cognitive function in some studies, primarily on the elderly25, 32. However, the effects caffeine has on more complex tasks are not clear, and caffeine has a negative impact on fine motor coordination5, 25.

Caffeine also effectively combats fatigue and the negative effects of sleep deprivation. Improved cognitive function from caffeine has been demonstrated for up to 64 hours of sleep deprivation, and one study indicates that it is as effective as the prescription drug modafinil in increasing alertness during sleep deprivation29-30. Improved marksmanship and driving ability during sleep deprivation have also been demonstrated5, 31. Caffeine also reduces cognitive impairment due to benzodiazapenes, alcohol, and illness 25. Numerous effects on sleep itself are also associated with caffeine. Acute administration increases sleep latency and decreases sleep duration. One study found that there was an inverse relationship between chronic caffeine intake and sleep duration, but no relationship with sleep satisfaction25. However, three other studies have found no relationship between chronic intake and sleep variables25.

An important consideration when discussing cognitive enhancement from caffeine is the effects of withdrawal. Headache is the most common symptom of caffeine withdrawal, but other effects noted include irritability, sleepiness, dysphoria, delerium, nausea, nervousness, restlessness, anxiety, and muscle tension 5, 34. According to some sources, caffeine does not improve cognition in and of itself, but the improvement seen in studies is due to reversal of caffeine withdrawal. This is known as the "withdrawal reversal hypothesis." In support for this hypothesis, studies find greater cognitive improvement from caffeine in regular users undergoing withdrawal than in nonusers33. This would indicate that the withdrawal reversal hypothesis is at least partially true. However, there are a number of flaws in this hypothesis. First, it does not account for the behavioral changes seen in animal studies or in non-consumers. Second, the studies cannot be considered to be blinded, since users are specifically told to abstain from caffeine. Also, despite the fact that caffeine withdrawal increases anxiety and depression, few studies indicate that it significantly decreases cognitive performance, and when it does the effects are mild25. Finally, certain individuals may not use caffeine because it is ineffective in their case (individual response varies considerably), so the nonusers used in withdrawal reversal studies may be predisposed to derive little benefit from caffeine to begin with33.

Other effects & precautions

Benefits - Caffeine is used to treat certain conditions including asthma, headache, and jet lag (along with melatonin)35-37. Some of its metabolites are antioxidants38. Interestingly, both topical and oral caffeine protect skin from DNA damage and tumors due to UV radiation in mice39-41, and it may have some other anticarcinogenic effects42-43. Low dose caffeine and alcohol is being researched as a treatment for acute ischemic stroke 44. Finally, caffeine has a well known neuroprotective effect in chronic, low doses. In line with earlier animal studies, caffeine intake has been associated with lower risk of Parkinson's and Alzheimer's45-46.

Hydration status - A common concern is that caffeine will compromise fluid balance. However, the effect caffeine has is minor, and it goes away with tolerance. A review of 10 studies found only small differences in fluid retention with caffeinated beverages (containing 100-680 mg) compared to an equal amount of water47.

Cardiovascular - Caffeine (and especially coffee) should be avoided by those with high blood pressure or at high risk for cardiovascular disease. Since adenosine is a vasodilator, adenosine antagonism raises blood pressure5. Tolerance develops to this effect, but it is incomplete26. Caffeine also raises homocysteine levels, but not as much as coffee48. In line with these effects, caffeine intake has been associated with increased risk of heart attack1.

Insulin resistance - Acute administration of caffeine (the equivalent of 3-4 cups of coffee, in other words 300-400 mg) causes insulin resistance in sedentary males with skeletal muscle as a major contributing factor, although this only occurs in the presence of above normal insulin levels2. Also, tolerance to this effect develops18. Possible mechanisms of action include adenosine antagonism in skeletal muscle, increase in FFAs, and increased epinephrine concentration (the most likely cause, since caffeine-induced insulin resistance is reversed by the beta blocker propranolol)2, 49. Caffeine does not impair exercise-induced increases in insulin sensitivity, indicating that the effects are independent of one another2. Although caffeine significantly improves athletic performance, if one is trying to gain appreciable amounts of muscle mass, using large doses of caffeine pre-workout may not be a good idea as inhibition of muscle glucose uptake may be counterproductive to that goal.

Anxiety/stress - Large doses of caffeine (over 300 mg) promote anxiety, but this effect does not cross over to small doses except in select individuals (such as caffeine naive individuals, in which even 150 mg can be anxiogenic, or those with anxiety sensitivity)17, 25, 50. Lower doses are usually neutral or decrease anxiety25. Also, exercise is antagonistic towards caffeine-induced anxiogenesis51. Chronic daily intake of over 1000 mg daily is associated with chronic anxiety or "caffeinism," but causality has not been determined – it could be that anxiety leads to high caffeine intake, and not vice versa25. Those who easily become anxious should avoid caffeine.

Tolerance & addiction - It is clear that tolerance does not develop to all of the effects of caffeine. According to one study, tolerance develops to the peripheral effects but not the central ones, while another study found that tolerance to both central and peripheral effects was incomplete 26. There is at least some degree of CNS tolerance, as regular caffeine administration causes upregulation of adenosine receptors in the brain4. It takes about 20 hours for caffeine tolerance to wear off26. Caffeine is also addictive, but chronic caffeine use is generally regarded as safe except in select populations. Of more concern is that caffeine can potentiate the addictive effect of other drugs by increasing dopamine receptor sensitivity 52.

Bone density - Caffeine is associated with lower bone mineral density, especially in elderly women. However, there is no association if calcium intake is over 75% of the RDA57.

Drug combinations - A number of drugs that inhibit the enzymes that metabolize caffeine may have negative interactions with caffeine. These include fluvoxamine, mexiletine, clozapine, psoralens, idrocilamide, phenylpropanolamine, furafylline, theophylline, and enoxacin53-54. Caffeine should also be used with caution when combined with large doses of other stimulants. Additionally, caffeine can exacerbate kidney and liver toxicity from some substances such as acetaminophen and alcohol55-56, but this primarily becomes an issue when these substances are used in excess.

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