It is well documented that exercise performance is negatively influenced in high environmental temperatures (3,21). The capacity to exercise in the heat is thought to be primarily limited by thermoregulatory and fluid balance factors (9), and it has further been suggested that the central nervous system (CNS) may become important in the development of fatigue when body temperature is significantly elevated (16). Previous work conducted by Gonzalez-Alonso et al. (6) concluded that a high internal body temperature (Tcore) per se causes fatigue in trained subjects during prolonged exercise in uncompensable hot environments. Hyperthermia has been demonstrated to exert a profound effect on the CNS, with a reduction in maximal muscle activity (18), altered EEG brain activity (17), and increased perceived exertion (19) reported when body temperature is elevated. These factors could all contribute to the reduction in performance seen when exercise is undertaken in the heat.
In a series of studies, Piacentini and colleagues (13,23-25) failed to modify performance of a 90-min time trial in normal ambient temperatures (18°C), through the manipulation of central neurotransmission. However, the authors detected different hormonal responses depending on the neurotransmitter system triggered by the reuptake inhibitor. The neuroendocrine response to exercise suggested that the drugs did indeed produce a central effect, despite failing to influence performance. These data raise several questions: are the neurotransmitters targeted in these studies involved in fatigue during exercise, was the action of these drugs sufficient to bring about changes in performance, or was the protocol employed appropriate to detect changes in performance resulting from these interventions?
In a recent study, Watson et al. (31) examined the effects of bupropion (BUP; a dual dopamine/noradrenaline reuptake inhibitor) not only in temperate, but also in warm environmental conditions. The major finding was that subjects completed the time trial in the heat 9% faster when BUP was taken, an effect that was not apparent in 18°C. Seven out of nine subjects also attained body core temperatures exceeding 40°C, implying that BUP may dampen or override hyperthermia-induced inhibitory signals arising from the CNS to stop exercising, potentially increasing the risk on developing heat illness. Since the increase in central catecholaminergic neurotransmission may, in part, attenuate the loss of performance when exercise is performed in warm environmental temperatures (31) and dopamine (DA) is involved in both motor behavior and motivation (15), it would be interesting to elucidate the specific role of DA in this process. Amphetamines are known to increase extracellular DA and have been associated with flushing, sympathetic activation, increased metabolic rate, as well as clinical hyperthermia (4).
Methylphenidate (MPH), an amphetamine-like stimulant, is a well-known DA reuptake inhibitor (5) that is widely administered to treat children with Attention Deficit Hyperactivity Disorder (ADHD). MPH occupies the DA transporter (DAT; (29)) and has a fivefold-higher affinity for the DAT than for the noradrenaline (NA) transporter (NAT (10,20)). To our knowledge, there are no data available on the effects of MPH administration on exercise performance and thermoregulation during prolonged exercise in both normal and high ambient temperatures, even though it is administered to thousands of patients around the world (8). Therefore, the purpose of the present study is to examine the effect of MPH on exercise capacity and thermoregulation. We hypothesize that acute administration of the DA reuptake inhibitor MPH will enhance exercise performance and will influence metabolic heat production during exercise in temperate and hot environmental conditions.
Eight healthy males (age 26 ± 5 yr; height 1.82 ± 0.06 m; mass 77.9 ± 6.4 kg; maximal workload (Wmax) 361 ± 18 W) participated in this investigation. All subjects were well-trained cyclists or triathletes, but were not accustomed to exercise in a warm environment at the time of the study. Prior to the start of the study, all volunteers received written information regarding the nature and purpose of the experimental protocol. Following an opportunity to ask any questions, a written statement of consent was signed. The protocol employed was approved by the research council of the Vrije Universiteit Brussel, Belgium.
The experimental protocol used in this study is identical to the protocol used by Watson et al. (31), therefore we will address it briefly. All subjects completed a preliminary maximal exercise test, a familiarization trial, and four experimental trials. The preliminary trial consisted of continuous incremental cycle exercise to volitional exhaustion and was used to determine the power output required to elicit 55 and 75% of Wmax. A familiarization trial was undertaken to ensure the subjects were accustomed to the procedures employed during the investigation and to minimize any potential learning or anxiety effects. This trial was performed in temperate environmental conditions and was identical to the experimental trials in all respects. Experimental trials were undertaken in either temperate (18°C) or warm (30°C) conditions (trials are referred to as placebo 18°C (PLA18), placebo 30°C (PLA30), methylphenidate 18°C (MPH18), and methylphenidate 30°C (MPH30)), with relative humidity maintained between 50-60% in both conditions. All subjects had to complete all experimental trials, which were separated by at least 7 d to minimize the development of heat acclimation and to ensure drug washout. Subjects were instructed to record dietary intake and physical activity during the 2 d before the first trial, and to replicate this in the 2 d before the subsequent experimental trials. No exercise or alcohol consumption was permitted in the 24 h before each trial.
Subjects entered the laboratory in the morning approximately 90 min after consuming a standardized breakfast that included 500 mL of plain water. Nude postvoid body mass was measured and an indwelling venous cannula was introduced into a superficial forearm vein to enable repeated blood sampling at rest and during exercise. Subjects inserted a rectal thermister (Gram Corporation LT-8A, Saitama, Japan) 10 cm beyond the anal sphincter for the measurement of core temperature. Surface skin temperature probes (Gram Corporation LT-8A, Saitama, Japan) were attached to four sites (chest, upper arm, thigh, and calf) to enable the determination of weighted mean skin temperature (26) and a heart rate telemetry band (Polar Accurex plus, Kempele, Finland) was positioned. Subjects were dressed in only cycling shorts, socks, and shoes for all trials.
Subjects then entered a climatic chamber maintained at the appropriate environmental conditions and rested in a seated position for 15 min. During this period temperatures and heart rate were recorded at 5-min intervals and a resting venous blood sample was drawn immediately before the start of exercise. The exercise protocol consisted of 60 min of constant-load exercise at a workload corresponding to 55% Wmax, followed by a time trial (TT) to measure exercise performance. There was a 1- to 2-min delay between the end of the constant load exercise and the beginning of the TT, to program the ergometer (Lode Excalibur Sport, Groningen, Holland). The TT required the subjects to complete a predetermined amount of work equal to 30 min at 75% Wmax as quickly as possible (11). Subjects began the TT at a workload corresponding to 75% Wmax, but were free to increase or decrease their power output as desired from the outset. During the TT a computer program displayed a bar indicating the percentage of total work completed to give the subject an indication of their progress. Throughout the protocol no feedback was provided regarding time lapsed, power output, pedal cadence, or heart rate. During exercise, subjects had ad libitum access to plain water.
Core and skin temperatures and heart rate were recorded at 5-min intervals during exercise. Ratings of perceived exertion (RPE (2)) and thermal stress (assessed using a 21-point scale ranging from unbearable cold to unbearable heat) were assessed every 15 min during the initial 60 min and at 10-min intervals during the TT. Venous blood samples were drawn after 60 min of constant-load exercise and at the end of the TT. Following the completion of the TT, subjects returned to a seated position where recovery was monitored for 15 min and a further blood sample was obtained. The probes and cannula were then removed, and nude body mass was then remeasured to allow the estimation of body weight losses.
Subjects ingested 20 mg of MPH or a placebo (PLA: lactose) 1 h before the start of exercise. This rather low dose (the maximum dose for an adult is 1.3 mg·kg−1 spread over an entire day) was chosen due to the unknown reactions to the combination of extreme heat stress and exercise. The treatment was randomized and administered in double-blind crossover manner. MPH and PLA capsules were prepared by an independent pharmacy to appear indistinguishable with regard to dimensions, weight, and color.
Blood collection and analysis.
Venous blood samples were drawn directly into precooled vacutainer tubes (BD Vacutainer, Plymouth, UK). Ten-milliliter samples were collected into a plain tubes and left to clot for 1 h at room temperature before centrifugation. The resulting serum was stored at -20°C for the determination of prolactin (PRL; Roche Diagnostics, Mannheim, Germany), cortisol (Diasorin, Stillwater, MN), and growth hormone (GH; Pharmacia & Upjohn Diagnostics, Uppsala, Sweden). Samples for plasma adrenocorticotropic hormone (ACTH) and beta-endorphin (Nichols Institute Diagnostics, CA) were collected into 4.5-mL tubes containing K3EDTA. An additional 7.5 mL was added to lithium heparin. A 0.5-mL aliquot of whole blood was extracted and used for the determination of hematocrit, with these used to estimate percent changes in plasma volume relative to the preexercise sample. Sodium metabisulphate (5 mg) was then added to the remaining whole blood prior to centrifugation.
Data are presented as means ± standard deviation (SD). The one-sample-Kolmogorov-Smirnov test was used to examine whether the outcome variables had a normal distribution. To evaluate differences in TT performance, a paired t-test was employed. Data collected over time were analyzed using two-factor (drug × time) ANOVA with repeated measures. Statistical significance was accepted at P < 0.05. Paired t-test were used to identify pair wise differences. In this case, the significance level was set at 0.025 to decrease the possibility for making type I errors.
All subjects completed all the experimental trials. Subjects took longer to complete the predetermined amount of work in the heat. Acute MPH supplementation increased exercise performance in warm (P = 0.049) but not temperate (P = 0.397) conditions. Subjects finished 16% faster when MPH was ingested compared with the PLA (PLA30: 45 min 24s± 7 min 18 s, MPH30: 38 min 6 s ± 6 min 24 s; Fig. 1).
As the TT required the completion of a predetermined amount of work, the time taken to complete the protocol was directly related to the power output maintained throughout this period. In the 30°C trials a difference in power output was apparent between the PLA and MPH trial from the start of exercise until completion of the target amount of work (P = 0.028; mean power output in MPH30: 226 ± 37 W, in PLA30: 196 ± 35 W; Fig. 2).
Core temperature increased significantly after 5 and 10 min of rest following MPH administration in the heat (P = 0.013; Fig. 3B), while in temperate conditions no such effect was present (P = 0.360; Fig. 3A). Exercise produced a gradual increase in core temperature in all trials (P = 0.001; Fig. 3). Ambient temperature and MPH both influenced Tcore during exercise. Tcore rose higher in MPH30 then in the PLA30 during the TT, but only reached significance levels after 25 (P = 0.006; Fig. 3B) and 30 min (P = 0.006; Fig. 3B) and at the end of the TT (P = 0.014; Fig. 3B). During recovery Tcore was significantly higher at all time points in the MPH30 (rec5 P = 0.009, rec10 P = 0.011, and rec15 P = 0.018; Fig. 3B). Tcore rose until 40.0 ± 0.6°C at the end of exercise in MPH30. During the trials in temperate conditions no significant increases in Tcore were observed (Fig. 3A). No differences in weighted mean skin temperature were obvious between PLA and MPH. Skin temperature increased during exercise in all conditions, reaching a plateau after 15 min in PLA30 and MPH30 and after 20 min in PLA18 and MPH18.
Ambient temperature increased mean heart rates in the corresponding trials (PLA18: 145 ± 8 bpm; PLA30: 152 ± 10 bpm; MPH18: 151 ± 9 bpm; MPH30: 160 ± 9 bpm; Fig. 4). During the TT and recovery, drug treatment induced significant increases in heart rate at every time point during TT in the heat, except for the TTend and rec10 value (P = 0.046 for both; Fig. 4B), while no differences were apparent in the 18°C trials (P = 0.199; Fig. 4A).
Both RPE and TS scores increased during exercise. Ratings of perceived exertion were similar between PLA and MPH treatment in temperate and warm conditions (Fig. 5), despite a higher RPE after 60 min in the warm placebo trial (P = 0.100 in 18°C and P = 0.386 in 30°C; Fig. 5B). The subjects' ratings of thermal stress were not influenced by the drug treatment. The loss of body mass after exercises, corrected for fluid intake and blood that was drawn, was significantly higher in the warm compared with the temperate trials (PLA18: 2.44 ± 0.50 kg; PLA30: 3.33 ± 0.62 kg; MPH18: 2.37 ± 0.27 kg; MPH30: 3.21 ± 0.58 kg; P = 0.004), but no effect of MPH on body weight losses was found.
All measured hormone concentrations rose significantly during exercise in all trials (P < 0.001). No differences of the drug treatment were detected; however, in both temperate and warm conditions there was a trend for the PRL concentration to be decreased at rest and after 60 min of fixed-intensity exercise (Fig. 6). No differences in cortisol, ACTH, GH, or beta-endorphin levels were detected between trials.
The current study investigated the effects of acute oral administration of MPH (a DA reuptake inhibitor) on exercise performance, thermoregulation and hormonal responses to prolonged exercise in both temperate and warm environments. The improved exercise performance in the heat and increased core temperature and heart rate in warm conditions are in line with the results previously found by Watson et al. (31) after BUP administration, which also enabled the maintenance of a higher power output during a TT in warm conditions. It appears that this response is accompanied by an increased core temperature and heart rate, but with the same perception of effort and thermal stress. Similarly, these and other studies that used nutritional and pharmacological manipulations of catecholaminergic neurotransmission confirmed the lack of performance improvements in 18°C (14,24,25,28,31), suggesting that dopaminergic neurotransmission may only have a significant role in fatigue when exercise is undertaken in warm environmental temperatures.
The combination of MPH (which has a potent dopaminergic activity) and high ambient temperatures increased core temperature at rest in the heat. The mechanism behind this increase is not completely clear; it is possible that an increase of the metabolic rate causes the increase in core temperature (4). Malberg and Seiden (12) reported that the effect of MDMA on body temperature was influenced by ambient temperatures; rats given MDMA in 20°C developed hypothermia, whereas those given MDMA in 26-30°C developed hyperthermia. Additionally, most studies investigating the effects of amphetamines point out its thermogenic effect (4,7).
In the present study, four out of eight subjects reached a core temperature above 40°C in the MPH30, with one subject even exceeding 41°C after exercise, while there was only one subject that had 40.0°C at the end of the TT in PLA30. Although significance could not be shown at all time points, there is a clear increase in metabolic heat production during the TT in MPH30, with a greater rate of rise in core temperature seen during this trial. This may have resulted from an increased motivation and drive, consequently enabling a higher power output throughout the TT in comparison with the PLA30 condition. This result appears remarkable as the dose of MPH administered in this study was low (20 mg), given that the maximal therapeutic dose is set at 60 mg·d−1. It is important to note that even at this low dose, this response may potentially increase the risk of developing heat illness when performing hard exercise in warm conditions.
Even more interesting is that the perceptional response to an increased core temperature and heart rate seems to be dampened by MPH, as no changes in RPE and thermal stress were found. This result is identical to the result of the BUP study (31). This finding might in part result from the increased drive to continue exercise following MPH administration, given the role of DA in feelings of arousal and motivation, as was previously stated by Volkow and colleagues (30). As in the BUP trial in the heat (31), it appears that MPH administration, even at low doses, might result in an inhibition of signals arising from the CNS to cease exercise because of hyperthermia, and enable subjects to maintain a high power output even at that time. These findings raise several questions, but it seems that the question, "Is it safe or not?" might very well be the one to start with. A drug that is widely administered and chronically taken by both children and adults (8) might not only have an ergogenic but also a potentially harmful effect, especially during prolonged exercise in warm environmental conditions, and even at doses that are only one third of the maximal therapeutic dose.
Hormonal responses to exercise after manipulation of catecholaminergic neurotransmission have been studied previously. BUP has been reported to influence ACTH, cortisol, and beta-endorphin concentrations at rest and during prolonged exercise (24); these changes were, in part, attributed to the noradrenergic properties of the drug. Watson et al. (31) reported increased plasma ACTH and cortisol concentrations at rest and ACTH levels during exercise after BUP administration, but no influence on GH and PRL. Changes in circulating PRL concentrations have previously been employed in defining serotonergic activity, but its reliability has been questioned (13). Ben-Jonathan (1) established that hypothalamic DA release inhibits PRL secretion from the anterior pituitary. Slattum et al. (27) also found (+)-amphetamine suppressed PRL secretion in human subjects, and a rat study by Piacentini et al. (22) resulted in decreased PRL concentrations after BUP administration, indicating an important role for the DA system. The present study agrees with these findings, since PRL concentrations showed a trend to decrease at rest and after 60 min of fixed-intensity exercise, in both normal and warm environmental temperatures. However, caution should be taken since no statistical significance was detected. These findings, plus the higher ACTH concentration during exercise observed in this study, might be meaningful, but because of large intrasubject variations no significance could be proven.
Limitations to this study include the facts that this research was done in adults and not children, and the number of subjects that participated. Eight healthy subjects, a very common number of subjects in this kind of research, is a low number; as a result, the statistical power is low, and results might not always be generalized. A further limitation is that the hormonal data could not be corrected for hemoconcentration because of a failure in the measurement of hemoglobin.
In conclusion, acute MPH administration resulted in a significant improvement in the time to complete a predetermined amount of work in a warm environment. This ergogenic effect was not apparent at 18°C. Core temperature in MPH30 increased to a mean of 40.0 ± 0.6°C, with four out of eight subjects reaching core temperatures above 40°C and one subject attaining 41°C after exercise. However, no differences between PLA and MPH were apparent in the subjects' RPE and perceived thermal stress. These results not only suggest that MPH exerts equal or greater effects on exercise performance, metabolic heat production, and hormonal responses than previously demonstrated with BUP; they also raise questions over the possible harmful effects of this drug can affect when combined with hard exercise undertaken in warm environmental conditions. Given that many thousands of patients (8), many of whom are children diagnosed with ADHD, take methylphenidate on a daily basis, this finding raises some obvious concerns. These data appear to suggest that a combination of dopamine reuptake inhibition and exercise under conditions of heat stress may limit an individuals perception of effort and thermal stress and consequently increase the risk of developing potentially serious heat illness.
This study was supported by research funding from the Vrije Universiteit Brussel (OZR 607, 990, and 1236). We want to acknowledge the assistance of Prof. Dr. Ilse Smolders for the preparation of the treatments and Arjan De Nijs, Dorine Brusselmans and Marco Fonzo for their hard work during the experiments.
1. Ben-Jonathan N. Dopamine: a prolactin-inhibiting hormone. Endocr Rev
2. Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc
3. Cheung S, McLellan T. Heat acclimation, aerobic fitness, and hydration effects on tolerance during uncompensable heat stress. J Appl Physiol
4. Freedman R, Johanson C, Tancer M. Thermoregulatory effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans. Psychopharmacology
5. Fukui R, Svenningsson P, Matsuishi T, et al. Effect of methylphenidate on dopamine/DARPP signalling in adult, but not young, mice. J Neurochem
6. Gonzalez-Alonso J, Teller C, Andersen SL, Jensen FB, Hyldig T, Nielsen B. Influence of body temperature on the development of fatigue during prolonged exercise in the heat. J Appl Physiol
7. Green A, Mechan A, Elliot J, O'Shea E, Colado M. The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "ecstacy"). Pharmacol Rev
8. Greydanus DE, Pratt HD, Patel DR. Attention deficit hyperactivity disorder across the lifespan: the child, adolescent and adult. Dis Mon
9. Hargreaves M, Febbraio MA. Limits to exercise performance in the heat. Int J Sports Med
. 1998;19(Suppl. 2):S115-6.
10. Ihalainen J, Tanila H, Scheinin M, Riekkinen P. α2C
-Adrenoceptors modulate the effect of methylphenidate on response rate and discrimination accuracy in an operant test. Brain Res Bull
11. Jeukendrup A, Saris WH, Brouns F, Kester AD. A new validated endurance performance test. Med Sci Sports Exerc
12. Malberg J, Seiden L. Small changes in ambient temperature cause large changes in 3,4-methylenedioxymethamphetamine (MDMA)- induced serotonin neurotoxicity and core body temperature in the rat. J Neurosci
13. Meeusen R, Piacentini MF, Van Den Eynde S, Magnus L, De Meirleir K. Exercise performance is not influenced by a 5-HT reuptake inhibitor. Int J Sports Med
14. Meeusen R, Roeykens J, Magnus L, Keizer H, De Meirleir K. Endurance performance in humans: the effect of a dopamine precursor or a specific serotonin (5-HT2A/2C) antagonist. Int J Sports Med
15. Meeusen R, Watson P, Hasegawa H, Roclands B, Piacentini MF. Central fatigue. The serotonin hypothesis and beyond. Sports Med
16. Nielsen B. Heat stress causes fatigue! Exercise performance during acute and repeated exposures to hot, dry environments. In: Marconnet P, Komi P, Saltin B, Sejersted O, editors. Muscle Fatigue Mechanisms in Exercise and Training
. S Karger, Basel, Schweiz: 1992. p. 207-17.
17. Nielsen B, Hyldig T, Bidstrup F, Gonzalez-Alonso J, Christoffersen G. Brain activity and fatigue during prolonged exercise in the heat. Pflugers Arch
18. Nybo L, Nielsen B. Hyperthermia and central fatigue during prolonged exercise in humans. J. Appl. Physiol
19. Nybo L, Nielsen B. Perceived exertion is associated with an altered brain activity during exercise with progressive hyperthermia. J Appl Physiol
20. Pan D, Gatley S, Dewey S, et al. Binding of bromine-substituted analogs of methylphenidate to monoamine transporters. Eur J Pharmacol
21. Parkin JM, Carey MF, Zhao S, Febbraio MA. Effect of ambient temperature on human skeletal muscle metabolism during fatiguing submaximal exercise. J Appl Physiol
22. Piacentini MF, Clinckers R, Meeusen R, Sarre S, Ebinger G, Michotte Y. Effect of bupropion on hippocampal neurotransmitters and on peripheral hormonal concentrations in the rat. J Appl Physiol
23. Piacentini MF, Meeusen R, Buyse L, De Schutter G, De Meirleir K. No effect of a selective serotonergic/noradrenergic reuptake inhibitor on endurance performance. Eur J Sports Sci
24. Piacentini MF, Meeusen R, Buyse L, De Schutter G, De Meirleir K. Hormonal responses during prolonged exercise are influenced by a selective DA/NA reuptake inhibitor. Br J Sports Med
25. Piacentini MF, Meeusen R, Buyse L, et al. No effect of a noradrenergic reuptake inhibitor on performance in trained cyclists. Med Sci Sports Exerc
26. Ramanathan LM. A new weighting system for mean surface temperature of the human body. J Appl Physiol
27. Slattum P, Venitz J, Barr W. Comparison of methods for the assessment of central nervous system stimulant response after dextroamphetamine administration to healthy male volunteers. J Clin Pharmacol
28. Struder HK, Hollmann W, Platen P, Donike M, Gotzmann A, Weber K. Influence of paroxetine, branched-chain amino acids and tyrosine on neuroendocrine system responses and fatigue in humans. Horm Metab Res
29. Volkow N, Wang G, Fowler S, et al. Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain. J Neurosci
30. Volkow N, Wang G, Fowler S, et al. Evidence that methylphenidate enhances saliency of a mathematical task by increasing dopamine in the human brain. Am J Psychiatry
31. Watson P, Hasegawa H, Roelands B, Piacentini MF, Loovrie R, Meeusen R. Acute dopamine/noradrenaline reuptake inhibition enhances human exercise performance in warm, but not temperate conditions. J Physiol
. 2005;565(Pt. 3):873-83.