Modafinil (M) is a psychostimulant drug that has been used clinically for a number of years in the treatment of narcolepsy and idiopathic hypersomnia (8,30). In healthy subjects, modafinil is also an effective treatment to sustain alertness and ameliorate the cognitive performance impairments that occur as a function of sleep deprivation (2–4,11,12). More recently it has been shown that M offers significant potential as a cognitive enhancer in normal, healthy, nonsleep-deprived subjects (38).
Other known cognitive enhancers include d-amphetamine (3,11,35) and caffeine (25,26,39). Both have been compared with M in controlled trials (35,39) with the conclusion that M is as effective as amphetamine or caffeine at maintaining cognitive functioning during sleep deprivation. It is thought that amphetamine and caffeine exert a stimulatory effect on the arousal centers of the CNS via the monoaminergic centers in the brain (20,30). The biochemical mechanism of action of M is not yet clearly identified. However, it has been suggested that M acts centrally as an β1-adrenergic agonist (16). More recent evidence has shown that modafinil inhibits γ-aminobutyric acid (GABA) release in the cerebral cortex through the possible involvement of serotonergic (5-HT3) receptors (18) leading to secondary increases in dopamine levels (17,19). Lin et al. (28) proposed a hypothesis of cerebral disinhibition to account for the action of M in increasing vigilance and wakefulness. Such a mechanism of action would inhibit sleep mechanisms originating in the anterior hypothalamus, the same area of the CNS where amphetamine and caffeine-mediated effects on alertness are pronounced.
Acute ingestion of amphetamine and caffeine can acutely improve physical performance (5,6,13,15,23,29,34,36,37). In light of mechanisms of action for these ergogenic aids that are similar to those underlying the effects of M, the current study was designed to test the hypothesis that acute ingestion of M would lead to enhanced exercise performance.
METHODS
Subjects.
Fifteen healthy males (mean ± SD age 29 ± 6 yr, body mass 78.8 ± 8.8 kg, height 178 ± 7 cm, maximal aerobic power (V̇O2max) during cycle exercise 47 ± 8 mL·kg−1·min−1) volunteered for this study. The subjects were fully informed of the details, discomforts, and risks associated with the experimental protocol and provided written informed consent. Subjects were asked to refrain from heavy exercise and alcohol for 24 h before each trial. The subjects were familiar with exhaustive exercise but were not trained athletes. This study protocol was reviewed and approved by the human ethics review committee of Defence R&D Canada–Toronto. At the time the study was carried out, modafinil was an investigative new drug, and approval for its use in this study was obtained from the appropriate federal regulatory agency.
Procedures.
During the study the subjects visited the laboratory on four separate occasions. During visit 1, they were medically screened and had their V̇O2max determined during exercise on an electronically braked cycle ergometer (Siemens Ergomed RE 930™, Elmas, Sweden). This test involved beginning exercise at a very light intensity, 60 W, with progressive 30-W increases in exercise intensity every 3 min until the subject could no longer maintain a pedaling cadence of 60 rev·min−1. Oxygen consumption was measured continuously during exercise using an automated metabolic cart (OCM-2, AMETEK, Pittsburgh, PA). The peak oxygen consumption measured was considered the V̇O2max. The relationship between the rate of oxygen consumption and power output for each subject was determined from this ride and used to calculate the linear regression equation between these variables. The equation was used to derive power output equivalents of 50 and 85% V̇O2max for each subject. These exercise intensities were used for all subsequent tests of exercise time to exhaustion trials (TE), as described below.
During visit 2, labeled the control trial (C), the subjects were familiarized with the experimental procedures and the TE test. The TE consisted of exercising for 5 min at the power output calculated to elicit 50% V̇O2max, followed immediately by a step increase to the intensity calculated to initially correspond to about 85% V̇O2max, and exercise to exhaustion at that intensity. The subjects were instructed to maintain pedaling rate between 60 and 80 rev·min−1 during all trials. The electronically braked ergometer adjusted the resistance in accordance with pedaling rate to maintain power output at the desired intensity. The ride ceased when the pedaling rate dropped below 50 rev·min−1. During this ride, oxygen uptake was measured continuously. To facilitate comparisons, oxygen uptake values were compared across trials after 5 and 10 min of exercise at the 85% V̇O2max and during the final 30 s of exercise. Heart rate was monitored throughout the exercise (Vantage XL Polar, Port Washington, NY) and recorded every 5 min. Subjects were also asked to rate their perceived exertion (RPE) after 5 and 10 min exercise at 85% V̇O2max and again at exhaustion using a 10-point scale (9).
Visits 3 and 4 were the treatment trials. They followed the C trial by 1 wk and were separated from each other by a minimum of 1 wk. The order of the treatment trials was assigned in a balanced manner among the subjects and the trials were conducted double blind. After an overnight fast and having refrained from caffeine ingestion for 12 h, the subjects reported to the laboratory and ingested opaque gelatin capsules containing either placebo (P), which was a dietary fiber (Metamucil®), or 4 mg·kg−1 M (Draxis Canada, Inc., Mississauga, Ontario). One hour later, the subjects were given a standardized light meal consisting of one bran muffin (approximately 125 kcal) and 178 mL of orange juice (approximately 80 kcal). Two hours after the meal, the subjects performed the exercise test to exhaustion as described for visit 2.
Data analysis.
A one-way repeated measures ANOVA was used to compare the differences in TE across treatment trials. For all other variables, a two-way repeated measures ANOVA was used to compare the changes in the dependent variables across treatments and time. Values at exhaustion were used in the analysis, but the reader should note that those values correspond to varying times to exhaustion among the subjects. When a post hoc comparison was required a means comparison contrast technique was employed (21) and Huyn-Feldtepsilon factors were used to adjust degrees of freedom for multiple comparisons. Statistical significance was accepted at the P < 0.05 level.
RESULTS
Table 1 shows the TE values for all subjects for all trials. Modafinil ingestion was associated with a significant increase in TE compared with either the C or P trials. The C and P times to exhaustion were similar to each other. Mean ± SD in minutes for TE was 14.3 ± 2.8, 15.6 ± 3.8, and 18.3 ± 3.5 for the C, P, and M trials, respectively. There was no significant effect on time to exhaustion due to the order of the trials.
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TABLE 1: Times to exhaustion (minutes) for all subjects during cycle ergometry exercise at 85% V̇O2max.
Table 2 shows V̇O2 during the 85% V̇O2max ride to exhaustion. Modafinil ingestion resulted in a slight but significant increase in V̇O2 compared with C and P but only during the last 30 s of exercise, that is, close to exhaustion.
TABLE 2: Mean ± SD values for oxygen consumption (L·min−1) during exercise at 85% V̇O2max.
The HR response during the 85% V̇O2max ride to exhaustion is listed in Table 3. HR increased with time and was further increased by M.
TABLE 3: Mean ± SD values for heart rate (beats·min−1) during exercise at 85% V̇O2max.
Table 4 shows the RPE during the 85% V̇O2max TE test. M ingestion was associated with a significantly lower RPE compared with C and P but only after 10 min of exercise at 85%V̇O2max. The subjective RPE values were similar at exhaustion regardless of the treatment.
TABLE 4: Mean ± SD values for rating of perceived exertion during exercise at 85% V̇O2max.
DISCUSSION
The effectiveness of M as a cognitive enhancer during sleep deprivation is well documented (3,4,11,12). The results of the current study extend earlier observations by demonstrating that M can also enhance physical performance as reflected by the increased time to exhaustion during relatively high-intensity exercise. As far as we know, this is the first study to document such a finding.
The results of this study are particularly timely in light of recent controversies around world-class athletes who had traces of M in their urine. Until this study, there was no published evidence to document that M can enhance physical performance. The current study is the first to provide evidence that M can indeed enhance physical performance of a nature that would likely be advantageous during competitive sports where exercise to exhaustion is commonplace.
In this study, the acute ingestion of M resulted in a 22% improvement in time to exhaustion during cycle exercise. For purposes of comparison, it is interesting to note that the magnitude of relative performance improvements with acute caffeine ingestion has ranged from 19.5 to 35% (6,15,23,34) using similar modes and intensities of exercise. As M has a half-life of 10–13 h (33), twice that of caffeine, its use could possibly result in a more sustained efficacy than that reported for caffeine (6).
It is more difficult to compare M with the relative performance improvement caused by amphetamines because of the nature of the performance tests used. Early studies with amphetamines used tests of running, swimming, and throwing (36,37) in contrast with the controlled laboratory tests used in the current investigation. Chandler and Blair (13) reported that time to exhaustion during a maximal treadmill run was improved 4.5% after amphetamine ingestion. It is difficult, however, to compare this finding with the 22% improvement caused by M, because in the former study the intensity of exercise was described as 100% of maximum treadmill running capacity (13).
The oxygen uptake and HR were greater at exhaustion in the M trials in the current study, commensurate with the longer duration of exercise. At the intensity of exercise employed in this study, it is known that both oxygen consumption and HR increase the longer an individual exercises. Thus it is unlikely that the ergogenic effects were due to an acute increase in V̇O2max or HRmax. The more probable mechanism for action of M is likely associated with the observation that RPE was lower at the same time point during exercise. Because RPE is a function of CNS sensory processing, the present data support the putative central cerebral mechanism as proposed by Lin et al. (28) to account for the action of M. Others have proposed that M may indirectly increase alertness through inhibition of cortical GABA release (18,19,31). Such an effect would permit dopaminergic neurons to become more active. Dopamine has been identified as a key regulator of the autonomic nervous system and physiological adaptations to training that lead to performance enhancement (22).
Our interest in ergogenic aids stems from a desire to provide such potential tools for use during military combat operations when a physical advantage can be of critical importance. In such a scenario, the issue of timing of drug ingestion would be important. Peak blood concentration levels are reached 2–4 h after M ingestion (33). For purposes of comparison, caffeine is absorbed more rapidly in about 1 h (27) and even faster when taken in the form of chewing gum (24). Other factors such as the duration of the ergogenic effect after drug ingestion, the interindividual variability of the response (6), and how soon it can be used again effectively (7) are already investigated for caffeine but remain unclear for M.
Another potentially important issue associated with M is that it increases core temperature (0.3–0.5°C) during rest (10,35) and exercise (32). This would be of concern to the military as initial elevated core temperature could have negative consequences for exertion in hot environments. Previous studies have shown that increased core temperature at the beginning of a heat stress exposure can decrease exercise time while wearing impermeable protective clothing by 10–35% (1,14,32). Thus, in certain military scenarios the use of M would be contraindicated such as those associated with wearing protective clothing in the heat.
The fact that M does not appear to disrupt sleep, that it is an effective cognitive enhancer, and that it may shorten the amount of recovery sleep needed after sleep deprivation (11) suggest that it could be part of an effective strategy to combat jet lag. Such an area of investigation would be of practical significance both to military personnel and athletes who often traverse many time zones and then are required to perform optimally. When considered together with the current finding that M is also an effective ergogenic aid, there is strong support for the potential for M to become an integral part of a military survival or combat kit for sustained operations.
The dose of M used in this study was 4 mg·kg−1. This dosage corresponds to an absolute dose ranging from 262 to 382 mg for our subjects. Doses at this level have been shown to cause increased urination and marginally higher incidence of headaches when used chronically (35). In the current study, no untoward physical side effects were reported by the subjects.
It was interesting to note, however, that unlike high doses of caffeine which caffeine-sensitive individuals perceive as inducing anxiety and heightened awareness, the subjects in the current study did not report to us any indication that they felt subjectively different before commencing exercise with any of the treatments. They were not, however, polled systematically as to what treatment they thought they were administered. Baranski and Pigeau (3) have shown a disruptive effect of M on the ability to self-monitor one’s own cognitive performance and have labeled it “overconfidence.” This observation of overconfidence in the study of Baranski and Pigeau (3) was particularly evident 2–4 h post-M ingestion. Whether there is an “overconfidence” about one’s physical performance capability after ingesting M has yet to be determined and may be a useful area of study. It begs the question whether the reduced RPE noted in our subjects during exercise is another reflection of the “overconfidence” noted by Baranski and Pigeau (3).
The question may be asked as to why pharmacological treatments associated with effects on alertness and cognition can enhance exercise performance. Such a discussion is well beyond the scope of the current investigation. However, both in the current investigation as well as in our earlier research with stimulants such as caffeine and ephedrine, reduced ratings of perceived exertion at the same absolute exercise intensity have been reported. We therefore speculate that it is the perception of fatigue that is masked by such treatments, although delayed fatigue could equally well be attributed to the release from the restraints of normal inhibitory mechanisms that are otherwise linked to physiological signals, such as is the case with hypnosis.
In conclusion, this report demonstrates, for the first time, that acute ingestion of modafinil can result in prolonged time to exhaustion during relatively high-intensity exercise. Such an effect would likely provide an advantage during sports involving such effort.
We thank Mrs. Ingrid Smith for her technical assistance.
The authors are grateful to Draxis Canada for providing the modafinil for this study.
The results of this study do not constitute endorsement of modafinil by the authors or the American College of Sports Medicine.
REFERENCES
1. Aoyagi, Y., T. M. McLellan, and R. J. Shephard. Effects of 6 versus 12 days of heat acclimation on heat tolerance in lightly exercising men wearing protective clothing.
Eur. J. Appl. Physiol. Occup. Physiol. 71:187–196, 1995.
2. Baranski, J. V., C. Cian, and D. Esquivie. Modafinil during 64 hr of sleep deprivation: effects on fatigue, alertness and cognitive performance.
Mil. Psychol. 10:173–193, 1998.
3. Baranski, J. V., and R. A. Pigeau. Self-monitoring cognitive performance during sleep deprivation: effects of modafinil, d-amphetamine and placebo.
J. Sleep Res. 6:84–91, 1997.
4. Batejat, D. M., and D. P. Lagarde. Naps and modafinil as countermeasures for the effects of sleep deprivation on cognitive performance.
Aviat. Space Environ. Med. 70:493–498, 1999.
5. Bell, D. G., I. Jacobs, and J. Zamecnik. Effects of caffeine, ephedrine and their combination on time to exhaustion during high-intensity exercise.
Eur. J. Appl. Physiol. Occup. Physiol. 77:427–433, 1998.
6. Bell, D. G., and T. M. McLellan. Exercise endurance 1, 3, and 6 h after caffeine ingestion in caffeine users and nonusers.
J. Appl. Physiol. 93:1227–1234, 2002.
7. Bell, D. G., and T. M. McLellan. Effect of repeated caffeine ingestion on repeated exercise endurance.
Med. Sci. Sports Exerc. 35:1348–1354, 2003.
8. Boivin, D. B., J. Montplaisir, D. Petit, et al. Effects of modafinil on symptomatology of human narcolepsy.
Clin. Neuropharmacol. 16:46–53, 1993.
9. Borg, G. A. V. Psychological bases of perceived exertion.
Med. Sci. Sports Exerc. 14:377–381, 1982.
10. Brun, J., G. Chamba, Y. Khalfallah, et al. Effect of modafinil on plasma melatonin, cortisol and growth hormone rhythms, rectal temperature and performance in healthy subjects during a 36 h sleep deprivation.
J. Sleep Res. 7:105–114, 1998.
11. Buguet, A., A. Montmayeur, R. Pigeau, and P. Naitoh. Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. II. Effects on two nights of recovery sleep.
J. Sleep Res. 4:229–241, 1995.
12. Caldwell, J. A., Jr., J. L. Caldwell, N. K. Smythe, 3rd, and K. K. Hall. A double-blind, placebo-controlled investigation of the efficacy of modafinil for sustaining the alertness and performance of aviators: a helicopter simulator study.
Psychopharmacology (Berl.) 150:272–282, 2000.
13. Chandler, J. V., and S. N. Blair. The effect of amphetamines on selected physiological components related to athletic success.
Med. Sci. Sports Exerc. 12:65–69, 1980.
14. Cheung, S. S., and T. M. McLellan. Heat acclimation, aerobic fitness, and hydration effects on tolerance during uncompensable heat stress.
J. Appl. Physiol. 84:1731–1739, 1998.
15. Costill, D. L., G. P. Dalsky, and W. J. Fink. Effects of caffeine ingestion on metabolism and exercise performance.
Med. Sci. Sports. 10:155–158, 1978.
16. Duteil, J., F. A. Rambert, J. Pessonnier, et al. Central alpha 1-adrenergic stimulation in relation to the behaviour stimulating effect of modafinil; studies with experimental animals.
Eur. J. Pharmacol. 180:49–58, 1990.
17. Ferraro, L., T. Antonelli, W. T. O’Connor, et al. Modafinil: an antinarcoleptic drug with a different neurochemical profile to d-amphetamine and dopamine uptake blockers.
Biol. Psychiatry 42:1181–1183, 1997.
18. Ferraro, L., S. Tanganelli, W. T. O’Connor, et al. The vigilance promoting drug modafinil decreases GABA release in the medial preoptic area and in the posterior hypothalamus of the awake rat: possible involvement of the serotonergic 5-HT3 receptor.
Neuro-sci. Lett. 220:5–8, 1996.
19. Ferraro, L., S. Tanganelli, W. T. O’Connor, et al. The vigilance promoting drug modafinil increases dopamine release in the rat nucleus accumbens via the involvement of a local GABAergic mechanism.
Eur. J. Pharmacol. 306:33–39, 1996.
20. Fredholm, B. B., K. Battig, J. Holmen, et al. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use.
Pharmacol. Rev. 51:83–133, 1999.
21. Gagnon, J., J. M. Roth, W. F. Finzer, and R. Hofmann.
Superanova: Accessible General Linear Modeling. Berkeley, CA: Abacus Concepts Inc., 1989, pp. 175–216.
22. Gilbert, C. Optimal physical performance in athletes: key roles of dopamine in a specific neurotransmitter/hormonal mechanism.
Mech. Age. Dev. 84:83–102, 1995.
23. Greer, F., D. Friars, T. E. Graham. Comparison of caffeine and theophylline ingestion: exercise metabolism and endurance.
J. Appl. Physiol. 89:1837–1844, 2000.
24. Kamimori, G. H., C. S. Karyekar, R. Otterstetter, et al. The rate of absorption and relative bioavailability of caffeine administered in chewing gum versus capsules to normal healthy volunteers.
Int. J. Pharm. 234:159–167, 2002.
25. Kamimori, G. H., D. H. Penetar, D. B. Headley, et al. Effect of three caffeine doses on plasma catecholamines and alertness during prolonged wakefulness.
Eur. J. Clin. Pharmacol. 56:537–544, 2000.
26. Lieberman, H. R., W. J. Tharion, B. Shukitt-Hale, et al. Effects of caffeine, sleep loss, and stress on cognitive performance and mood during U. S. Navy SEAL training.
Psychopharmacology (Berl.) 164:250–261, 2002.
27. Liguori, A., J. R. Hughes, and J. A. Grass. Absorption and subjective effects of caffeine from coffee, cola and capsules.
Pharmacol. Biochem. Behav. 58:721–726, 1997.
28. Lin, J. S., D. Gervasoni, Y. Hou, et al. Effects of amphetamine and modafinil on the sleep/wake cycle during experimental hypersomnia induced by sleep deprivation in the cat.
J. Sleep Res. 9:89–96, 2000.
29. Lovingood, B. W., C. S. Blyth, W. H. Peacock, and R. B. Lindsay. Effects of d-amphetamine sulfate, caffeine, and high temperature on human performance.
Res. Q. 38:64–71, 1967.
30. Lyons, T. J., and J. French. Modafinil: the unique properties of a new stimulant.
Aviat. Space Environ. Med. 62:432–435, 1991.
31. Mattay, V. S., K. F. Berman, J. L. Ostrem, et al. Dextroamphetamine enhances “neural network-specific” physiological signals: a positron-emission tomography rCBF study.
J. Neurosci. 16:4816–4822, 1996.
32. McLellan, T. M., M. B. Ducharme, F. Canini, et al. Effect of modafinil on core temperature during sustained wakefulness and exercise in a warm environment.
Aviat. Space Environ. Med. 73:1079–1088, 2002.
33. Moachon, G., I. Kanmacher, M. Clenet, and D. Matinier. Pharmokinetic profile of modafinil.
Drugs of Today 32(Suppl. 1):23–33, 1996.
34. Pasman, W. J., M. A. van Baak, A. E. Jeukendrup, and A. de Haan. The effect of different dosages of caffeine on endurance performance time.
Int. J. Sports Med. 16:225–230, 1995.
35. Pigeau, R., P. Naitoh, A. Buguet, et al. Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. I. Effects on mood, fatigue, cognitive performance and body temperature.
J. Sleep Res. 4:212–228, 1995.
36. Smith, G. M., and H. K. Beecher. Amphetamine sulphate and athletic performance.
JAMA 170:542–557, 1959.
37. Smith, G. M., and H. K. Beecher. Amphetamine, secobarbital and athletic performance.
JAMA 172:1623–1629, 1960.
38. Turner, D. C., T. W. Robbins, L. Clark, et al. Cognitive enhancing effects of modafinil in healthy volunteers.
Psychopharmacology (Berl.) 165:260–269, 2003.
39. Wesensten, N. J., G. Belenky, M. A. Kautz, et al. Maintaining alertness and performance during sleep deprivation: modafinil versus caffeine.
Psychopharmacology (Berl.) 159:238–247, 2002.
