Caffeine, Nicotine, Ethanol, THC and Exercise Performance
Caffeine, Nicotine, Ethanol, THC and Exercise Performance
Apart from water, tea and coffee are among the most popular beverages worldwide. The main pharmacologically active substance in both is the purine alkaloid of the xanthines class, 1,3,7,-trimethylxanthine or caffeine. According to European and North American statistics, ~90% of the adult population consider themselves as daily coffee users with an average daily caffeine consumption of about 200 mg or 2.4 mg/kg/day (about 2 cups of coffee). It is therefore considered the world's most widely consumed pharmacologically active substance. Caffeine is both water and fat soluble and is quickly distributed in the body after absorption mainly by the small intestine and the stomach with peaking plasma levels after 15–120 min and a half-life of about 5–6 hours with individual variation. Due to its lipophilic nature, caffeine also crosses the blood–brain barrier, and is metabolized by the liver into paraxanthine, theophylline, and theobromine.
Caffeine most likely exerts its performance enhancing effect on the human body mainly by five mechanisms:
As for many pharmacological substances, there is generally more than one potential mechanism explaining the ergogenic effects. This is also true for caffeine which might affect both the central nervous system (CNS) and skeletal muscle. Although questionable, a potential downside is that caffeine also has diuretic properties which can exert ergolytic effects during prolonged endurance events. Caffeine intake at very high doses (>500–600 mg or four to seven cups per day) can cause restlessness, tremor and tachycardia.
Caffeine reduces fatigue and increases concentration and alertness, and athletes regularly use it as an ergogenic aid. Caffeine-induced increases in performance have been observed in aerobic as well as anaerobic sports (for reviews, see). Trained athletes seem to benefit from a moderate dose of 5 mg/kg, however, even lower doses of caffeine (1.0–2.0 mg/kg) may improve performance. Some groups found significantly improved time trial performance or maximal cycling power, most likely related to a greater reliance on fat metabolism and decreased neuromuscular fatigue, respectively. Theophylline, a metabolite of caffeine, seems to be even more effective in doing so. The effect of caffeine on fat oxidation, however, may only be significant during lower exercise intensities and may be blocked at higher intensities. Spriet et al. found that ingestion of a high dose of caffeine before exercise reduced muscle glycogenolysis in the initial 15 min of exercise by increasing free fatty acid (FFA) levels which inhibits glycolysis and spares glycogen for later use. Caffeine's effect of inhibition of glycogen phosphorylase has also been shown in vitro as well as its effect on increasing HSL activity. The effect of caffeine on adipose triglyceride lipase has not been studied and warrants investigation. Following caffeine administration prior to and after the onset of cycling, Ivy et al. found that plasma free fatty acid levels were increased 30% compared to placebo. This action might be mediated by inhibition of the enzyme phosphodiesterase, thereby yielding higher levels of cAMP, which has been identified as important molecule for glycogen metabolism and lipolysis. Phosphodiesterase inhibition has been observed only at high concentrations. When direct Fick measurements were applied, Graham et al. did not find altered CHO or fat metabolism, at least in the monitored leg. Further research is needed to evaluate the effect of caffeine on lipolysis, especially during higher exercise intensities.
Augmented post-exercise recovery by increased rates of muscle glycogen resynthesis has been observed. Pedersen et al. found higher rates of muscle glycogen accumulation after the co-ingestion of caffeine with CHO during recovery in highly trained subjects. This might, at least in part, be mediated by the activation of AMP-activated protein kinase (AMPK) as it is involved in the translocation of glucose transporter 4 (GLUT4) to the plasma membrane. This mechanism enables the cell to take up glucose from the plasma and store it as glycogen. Not only does caffeine impact endurance, it has also been reported to benefit cognitive function and fine motor skills. While the performance enhancing effects of caffeine in moderate-to-highly trained endurance athletes are quite clear and well documented, its effects on anaerobic, high-intensity tasks are less well investigated. Whereas caffeine supplementation did not yield significant performance increases in a Wingate test in untrained subjects, Mora-Rodriguez et al. report that caffeine ingestion of 3 mg/kg could counter reductions in maximum dynamic strength and muscle power output on the morning (2.5–7.0%) thereby increasing muscle performance to the levels found in the afternoon. Especially with regard to anaerobic performance caffeine's adenosine receptor blocking effect in the CNS may be important. A possible explanation for the diverging effect of caffeine on anaerobic performance is that caffeine seems to benefit trained athletes who show specific physiological adaptations whereas performance gains in untrained subjects might be lost or masked by a high variability in performance.
It has been shown that coffee, by containing phenolic compounds such as chlorogenic acids, elicits metabolic effects independent of caffeine. These compounds may have the potential to antagonize the physiological responses of caffeine. The question therefore remains whether ingesting the same amount of caffeine via a food source (e.g. energy bar or coffee) is as effective as ingesting isolated caffeine in the form of a tablet. As mentioned above, the performance enhancing effect of caffeine is very clear. Only a few studies, however, have shown a positive effect of coffee on performance. Whereas some studies found enhanced performance after coffee consumption, others did not.
One of the earlier works by Costill et al. reported increases in time trial performance of competitive cyclists only in the coffee trial group (containing 330 mg caffeine 1 h prior to exercise) but not in the decaffeinated coffee trial.
Graham et al. studied exercise endurance in runners after ingestions of a caffeine (4.45 mg/kg BW) or placebo capsule with water or either decaffeinated coffee, decaffeinated coffee with added caffeine or regular coffee. The authors found that only caffeine significantly improved running time to exhaustion at 75% VO2max but neither did regular coffee or decaffeinated coffee plus caffeine. Based on these results, the authors speculated that some component(s) in coffee possibly interfere with the ergogenic response of caffeine alone.
This is in opposition to Hodgson et al. who looked at time trial performance in trained subjects after administration of caffeine (5 mg caffeine/kg BW), coffee (5 mg caffeine/kg BW), decaffeinated coffee and placebo one hour prior to exercise. The authors report similar significant increases of ~5% in time trial performance in both the caffeine and the coffee supplemented group with no effects in the decaf or placebo group. The authors conclude that coffee consumed 1 h prior to exercise, at a high caffeine dose improved performance to the same extent as caffeine.
One reason for the disparity of the two studies mentioned above might be the different performance tests used. Whereas Graham et al. used a time to exhaustion test which reportedly can exhibit a coefficient of variation as high as ~27%, Hodgson et al. used a time trial which have been shown to be more reproducible. It has also been speculated by Hodgson et al. that due to lower statistical power, Graham et al. were not able to detect a difference between caffeine and coffee ingestion on performance. At this point, both coffee and caffeine exhibit a performance enhancing effect. Further research will hopefully extend our understanding on this issue.
Another reason for the widespread use of caffeine within the exercise community might be its small but significant analgesic effect, possibly mediated by augmenting plasma endorphin concentrations. It is also established that caffeine reduces the rate of perceived exertion during exercise, suggesting that athletes are able to sustain higher intensities but do not perceive this effort to be different from placebo conditions.
Some studies used caffeine-naïve whereas others used caffeine-habituated subjects. There seems to be a higher increase in plasma adrenalin in caffeine-naïves compared to caffeine habituated subjects after caffeine ingestion. However, no differences between habitual caffeine intake and 1500 m running performance or force of contraction could be observed. For both caffeine-naïve as well as caffeine-habituated subjects, moderate to high doses of caffeine are ergogenic during prolonged moderate intensity exercise. Although there is clearly the need to study caffeine habituation further, the differences between users and non-users do not seem to be major.
From 1962 to 1972 and again from 1984 to 2003 caffeine was on the WADA banned list, with a concentration >12 μg/ml in the urine considered as doping. Caffeine has been demonstrated to be ergogenic at doses lower than those doses that result in a urine concentration of 12 μg/ml, and higher doses appear to exhibit no additional performance-enhancing effect. During the second banned period, many athletes tested positive for caffeine. The sanctions ranged from warnings up to 2 year suspensions (maximum penalty, usually only 2–6 months). Since 2004, caffeine has been removed from the prohibited list, however, it is still part of WADAs monitoring program (stimulants - in competition only) in order to monitor the possible potential of misuse in sport. According to WADA, one of the reasons caffeine was removed from the Prohibited List was that many experts believe it to be ubiquitous in beverages and food and that having a threshold might lead to athletes being sanctioned for social or dietary consumption of caffeine. Furthermore, caffeine is metabolized at very different rates in individuals and hence urinary concentrations can vary considerably and do not always correlate to the dose ingested. In addition, caffeine is added to a wide range of popular food products such as coffee, tea, energy drinks and bars, and chocolate.
In summary, caffeine, even at physiological doses (3–6 mg/kg), as well as coffee are proven ergogenic aids and as such – in most exercise situations, especially in endurance-type events – clearly work-enhancing. It most likely has a peripheral effect targeting skeletal muscle metabolism as well as a central effect targeting the brain to enhance performance, especially during endurance events (see Table 1). Also for anaerobic tasks, the effect of caffeine on the CNS might be most relevant. Further, post-exercise caffeine intake seems to benefit recovery be increasing rates of glycogen resynthesis.
Caffeine
Overview
Apart from water, tea and coffee are among the most popular beverages worldwide. The main pharmacologically active substance in both is the purine alkaloid of the xanthines class, 1,3,7,-trimethylxanthine or caffeine. According to European and North American statistics, ~90% of the adult population consider themselves as daily coffee users with an average daily caffeine consumption of about 200 mg or 2.4 mg/kg/day (about 2 cups of coffee). It is therefore considered the world's most widely consumed pharmacologically active substance. Caffeine is both water and fat soluble and is quickly distributed in the body after absorption mainly by the small intestine and the stomach with peaking plasma levels after 15–120 min and a half-life of about 5–6 hours with individual variation. Due to its lipophilic nature, caffeine also crosses the blood–brain barrier, and is metabolized by the liver into paraxanthine, theophylline, and theobromine.
Mechanism of Action
Caffeine most likely exerts its performance enhancing effect on the human body mainly by five mechanisms:
Antagonism of adenosine. Due to its close chemical resemblance of adenosine, caffeine blocks adenosine receptors (mainly A1 and A2A receptor subtypes), thereby competitively inhibiting its action. Caffeine can decrease cerebral blood flow as well as antagonize A1, A2A and A2B adenosine receptors in blood vessels, thereby reducing adenosine-mediated vasodilatation and consequently decrease myocardial blood flow.
Increased fatty acid oxidation: increased lipolysis leads to decreased reliance on glycogen use. Caffeine switches the substrate preference from glycogen to fat by increasing hormone sensitive lipase (HSL) activity and inhibition of glycogen phosphorylase activity.
Caffeine acts as a nonselective competitive inhibitor of the phosphodiesterase enzymes. Phosphodiesterases hydrolyze the phosphodiesterase bond in molecules such as cyclic adenosine monophosphate (cAMP), inhibiting the breakdown of cAMP. cAMP activates lipolysis by activating HSL and is an important molecule in the epinephrine cascade. It further activates protein kinase A, which in turn can phosphorylate a number of enzymes involved in glucose and lipid metabolism.
Increased post-exercise muscle glycogen accumulation: enhanced recovery by increased rate of glycogen resynthesis following exercise. Battram et al. reported that caffeine ingestion has no effect on glycogen accumulation during recovery in recreationally active individuals. Pedersen et al. recently reported that caffeine (8 mg/kg body weight) co-ingested with carbohydrates (CHO) increases rates of postexercise muscle glycogen accumulation compared with consumption of CHO alone in well-trained athletes after exercise-induced glycogen depletion. Although this issue needs further study in different populations (untrained, trained) and at different time points (during exercise or recovery), caffeine added to postexercise CHO feeding seems to have the potential to improve glycogen resynthesis.
Mobilization of intracellular calcium: It has been shown that caffeine can enhance calcium release from the sarcoplasmic reticulum and can also inhibit its reuptake. Via this mechanism, caffeine can enhance contractile force during submaximal contractions in habitual and nonhabitual caffeine consumers. Intracellular calcium favors the activation of endothelial nitric oxide synthase, which increases nitric oxide. Some of the ergogenic effects of caffeine might therefore as well be mediated partly by effecting the neuromuscular system and increasing contractile force. There is, however, still controversy about the translation of results from in vitro studies on muscle preparations to caffeine dose and calcium release in vivo (see below).
As for many pharmacological substances, there is generally more than one potential mechanism explaining the ergogenic effects. This is also true for caffeine which might affect both the central nervous system (CNS) and skeletal muscle. Although questionable, a potential downside is that caffeine also has diuretic properties which can exert ergolytic effects during prolonged endurance events. Caffeine intake at very high doses (>500–600 mg or four to seven cups per day) can cause restlessness, tremor and tachycardia.
Effects on Performance
Caffeine reduces fatigue and increases concentration and alertness, and athletes regularly use it as an ergogenic aid. Caffeine-induced increases in performance have been observed in aerobic as well as anaerobic sports (for reviews, see). Trained athletes seem to benefit from a moderate dose of 5 mg/kg, however, even lower doses of caffeine (1.0–2.0 mg/kg) may improve performance. Some groups found significantly improved time trial performance or maximal cycling power, most likely related to a greater reliance on fat metabolism and decreased neuromuscular fatigue, respectively. Theophylline, a metabolite of caffeine, seems to be even more effective in doing so. The effect of caffeine on fat oxidation, however, may only be significant during lower exercise intensities and may be blocked at higher intensities. Spriet et al. found that ingestion of a high dose of caffeine before exercise reduced muscle glycogenolysis in the initial 15 min of exercise by increasing free fatty acid (FFA) levels which inhibits glycolysis and spares glycogen for later use. Caffeine's effect of inhibition of glycogen phosphorylase has also been shown in vitro as well as its effect on increasing HSL activity. The effect of caffeine on adipose triglyceride lipase has not been studied and warrants investigation. Following caffeine administration prior to and after the onset of cycling, Ivy et al. found that plasma free fatty acid levels were increased 30% compared to placebo. This action might be mediated by inhibition of the enzyme phosphodiesterase, thereby yielding higher levels of cAMP, which has been identified as important molecule for glycogen metabolism and lipolysis. Phosphodiesterase inhibition has been observed only at high concentrations. When direct Fick measurements were applied, Graham et al. did not find altered CHO or fat metabolism, at least in the monitored leg. Further research is needed to evaluate the effect of caffeine on lipolysis, especially during higher exercise intensities.
Augmented post-exercise recovery by increased rates of muscle glycogen resynthesis has been observed. Pedersen et al. found higher rates of muscle glycogen accumulation after the co-ingestion of caffeine with CHO during recovery in highly trained subjects. This might, at least in part, be mediated by the activation of AMP-activated protein kinase (AMPK) as it is involved in the translocation of glucose transporter 4 (GLUT4) to the plasma membrane. This mechanism enables the cell to take up glucose from the plasma and store it as glycogen. Not only does caffeine impact endurance, it has also been reported to benefit cognitive function and fine motor skills. While the performance enhancing effects of caffeine in moderate-to-highly trained endurance athletes are quite clear and well documented, its effects on anaerobic, high-intensity tasks are less well investigated. Whereas caffeine supplementation did not yield significant performance increases in a Wingate test in untrained subjects, Mora-Rodriguez et al. report that caffeine ingestion of 3 mg/kg could counter reductions in maximum dynamic strength and muscle power output on the morning (2.5–7.0%) thereby increasing muscle performance to the levels found in the afternoon. Especially with regard to anaerobic performance caffeine's adenosine receptor blocking effect in the CNS may be important. A possible explanation for the diverging effect of caffeine on anaerobic performance is that caffeine seems to benefit trained athletes who show specific physiological adaptations whereas performance gains in untrained subjects might be lost or masked by a high variability in performance.
It has been shown that coffee, by containing phenolic compounds such as chlorogenic acids, elicits metabolic effects independent of caffeine. These compounds may have the potential to antagonize the physiological responses of caffeine. The question therefore remains whether ingesting the same amount of caffeine via a food source (e.g. energy bar or coffee) is as effective as ingesting isolated caffeine in the form of a tablet. As mentioned above, the performance enhancing effect of caffeine is very clear. Only a few studies, however, have shown a positive effect of coffee on performance. Whereas some studies found enhanced performance after coffee consumption, others did not.
One of the earlier works by Costill et al. reported increases in time trial performance of competitive cyclists only in the coffee trial group (containing 330 mg caffeine 1 h prior to exercise) but not in the decaffeinated coffee trial.
Graham et al. studied exercise endurance in runners after ingestions of a caffeine (4.45 mg/kg BW) or placebo capsule with water or either decaffeinated coffee, decaffeinated coffee with added caffeine or regular coffee. The authors found that only caffeine significantly improved running time to exhaustion at 75% VO2max but neither did regular coffee or decaffeinated coffee plus caffeine. Based on these results, the authors speculated that some component(s) in coffee possibly interfere with the ergogenic response of caffeine alone.
This is in opposition to Hodgson et al. who looked at time trial performance in trained subjects after administration of caffeine (5 mg caffeine/kg BW), coffee (5 mg caffeine/kg BW), decaffeinated coffee and placebo one hour prior to exercise. The authors report similar significant increases of ~5% in time trial performance in both the caffeine and the coffee supplemented group with no effects in the decaf or placebo group. The authors conclude that coffee consumed 1 h prior to exercise, at a high caffeine dose improved performance to the same extent as caffeine.
One reason for the disparity of the two studies mentioned above might be the different performance tests used. Whereas Graham et al. used a time to exhaustion test which reportedly can exhibit a coefficient of variation as high as ~27%, Hodgson et al. used a time trial which have been shown to be more reproducible. It has also been speculated by Hodgson et al. that due to lower statistical power, Graham et al. were not able to detect a difference between caffeine and coffee ingestion on performance. At this point, both coffee and caffeine exhibit a performance enhancing effect. Further research will hopefully extend our understanding on this issue.
Another reason for the widespread use of caffeine within the exercise community might be its small but significant analgesic effect, possibly mediated by augmenting plasma endorphin concentrations. It is also established that caffeine reduces the rate of perceived exertion during exercise, suggesting that athletes are able to sustain higher intensities but do not perceive this effort to be different from placebo conditions.
Some studies used caffeine-naïve whereas others used caffeine-habituated subjects. There seems to be a higher increase in plasma adrenalin in caffeine-naïves compared to caffeine habituated subjects after caffeine ingestion. However, no differences between habitual caffeine intake and 1500 m running performance or force of contraction could be observed. For both caffeine-naïve as well as caffeine-habituated subjects, moderate to high doses of caffeine are ergogenic during prolonged moderate intensity exercise. Although there is clearly the need to study caffeine habituation further, the differences between users and non-users do not seem to be major.
WADA Status
From 1962 to 1972 and again from 1984 to 2003 caffeine was on the WADA banned list, with a concentration >12 μg/ml in the urine considered as doping. Caffeine has been demonstrated to be ergogenic at doses lower than those doses that result in a urine concentration of 12 μg/ml, and higher doses appear to exhibit no additional performance-enhancing effect. During the second banned period, many athletes tested positive for caffeine. The sanctions ranged from warnings up to 2 year suspensions (maximum penalty, usually only 2–6 months). Since 2004, caffeine has been removed from the prohibited list, however, it is still part of WADAs monitoring program (stimulants - in competition only) in order to monitor the possible potential of misuse in sport. According to WADA, one of the reasons caffeine was removed from the Prohibited List was that many experts believe it to be ubiquitous in beverages and food and that having a threshold might lead to athletes being sanctioned for social or dietary consumption of caffeine. Furthermore, caffeine is metabolized at very different rates in individuals and hence urinary concentrations can vary considerably and do not always correlate to the dose ingested. In addition, caffeine is added to a wide range of popular food products such as coffee, tea, energy drinks and bars, and chocolate.
Summary
In summary, caffeine, even at physiological doses (3–6 mg/kg), as well as coffee are proven ergogenic aids and as such – in most exercise situations, especially in endurance-type events – clearly work-enhancing. It most likely has a peripheral effect targeting skeletal muscle metabolism as well as a central effect targeting the brain to enhance performance, especially during endurance events (see Table 1). Also for anaerobic tasks, the effect of caffeine on the CNS might be most relevant. Further, post-exercise caffeine intake seems to benefit recovery be increasing rates of glycogen resynthesis.
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