I thought some of you guys might be interested in this. It discusses the implications of Modafinil in exercise. There isn’t a whole lot of research on Modafinil, which is why it’s pretty short and goes into more detail. I didn’t copy the sources since there are a ton of them, but if anyone’s interested I can throw those up here as well.
Introduction
Modafinil is a eugeroic drug originally developed by L Lafon Laboratory of France, and is marketed by Cephalon in the United States as a wakefulness-promoting agent. In the United States it is indicated and FDA approved (Schedule IV) for narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work sleep disorder (FDA, 2004). It has been used off-label to treat fatigue and cognitive disabilities associated with depression (Debatista, 2004; Menza, 2000), Parkinson�??s disease (Nieves, 2002), cerebral palsy (Hurst, 2002), myotonic dystrophy (MacDonald, 2002), opiod induced sleepiness (Webster, 2003), attention deficit/hyperactivity disorder (Amiri et al., in press), and multiple sclerosis (Rammohan, 2002).
The pharmacokinetics and related cognitive enhancement capabilities of modafinil have been reviewed (Ballon & Feifel, 2006; Minzenberg & Carter, in press), but its effects on physical performance have not been. The primary focus of this review will be the physical enhancement capabilities of modafinil�??both the physical and mental enhancements of exercise performance.
Physical Implications in Exercise Performance Enhancement
Military Applications. As modafinil is banned in every major sporting league in the world, the only applicable non-medical use for performance enhancement is military operations. The United States Air Force currently has two �??go-pills,�?? modafinil and Dexedrine, used to promote wakefulness during prolonged combat missions (USAF Lt. Gen. R. E. Keys, personal communication, December 2, 2003), and the United States Army has performed research regarding modafinil�??s efficacy during sustained ground operations (Moran, 2007; Whitmore et al., 2006). Much modafinil research has been by published by Defense Research and Development Canada-Toronto, and the United Kingdom has interest in modafinil for sustained military operations as well (Sample & Evans, 2004; Wheeler, 2006).
Time to exhaustion. A study by Jacobs and Bell (2004) found acute modafinil administration significantly prolonged exercise time to exhaustion (p < .05). Fifteen healthy male participants (mean ± SD, age 29 ± 6 yr, body mass 78.8 ± 8.8 kg, height 178 ± 7 cm, VO2max 47 ± 8 mL·kg-1) exercised on a cycle ergometer for 5 min at 50% VO2max followed by 85% VO2max until exhaustion. The participants exercised once weekly for four weeks. The first session was used to determine VO2max. The second session was a control trial, with participants exercising until exhaustion with no treatment. The third and fourth sessions were the treatment trials with a balanced-order, double-blind administration of either placebo or modafinil.
The participants fasted overnight before the day of the test, and refrained from caffeine for 12 hours prior to reporting to the laboratory. The participants ingested either placebo or modafinil (4 mg·kg-1). One hour post-treatment ingested a light standardized meal, and two hour post-treatment performed the exercise test to exhaustion. Modafinil administration significantly increased the time to exhaustion by 22% compared to placebo at 9%. Heart rate increased with exercise time and was further increased by modafinil treatment. No side effects were reported with either modafinil or placebo treatment.
Timed aerobic activities. Whitmore et al. (2006) observed the effects of modafinil on sustained military ground operations. Among the performance tests were a 3-mile run, a 1500-meter swim, and a 15-item obstacle course. No significant changes were observed in any of these tests (p > .05). Participants were 12 male advanced special tactics military personnel, ages 24-37 years, six trained in medical rescue and six trained in combat control. The participants performed simulated combat conditions during two 72-hour sessions, separated by 5 days, while receiving either modafinil or placebo. The order of drug administration was randomly assigned and balanced. Participants were ground tested with modafinil to assess tolerance prior to participating in the study.
The 72-hour test was preceded by a 7-hour sleep session, and began at 7:00am. The participants�?? only sleep during the 72-hour test was a two hour nap on day 3 between 8:20-10:20am. Modafinil was administered at 200-mg at 12:00am, 100-mg at 7:15am, and 100-mg at 3:00pm during days 2, 3, and 4, for a cumulative dose of 1200-mg (400 mg·day-1) for the duration of the test. Heart rate was not affected by drug or drug by time interaction. Blood pressure was similarly unaffected. Modafinil was well tolerated with no difference in side effects reported compared to placebo.
A similar study by Whitmore (2004) assessed an escape and survive scenario with 24 United States Air Force Survival Training Specialists hiking 22-miles over two days and performing various cognitive performance tasks every three hours while sleep deprived. The participants took 100-mg 3 times daily, for 300 mg·day-1 dosing. There was no significant difference at any time during the test between modafinil and placebo regarding heart rate or blood pressure.
Thermal regulation. Many military operations involve protective clothing, and may also take place in warm environments. Exercising in heated environments while wearing protective clothing can reduce time to fatigue by 10-35% (Aoyagi, McLellan, & Shephard, 1995; Cheung & McLellan, 1998; McLellan et al., 2002). An Air Force study simulating sustained ground operations using 400 mg·day-1 modafinil for 3 days found a time effect with body temperature, but no drug or drug by time effects of modafinil were observed (Whitmore et al., 2006).
Baranski, Gil, and McClellan (2002) observed the effects of modafinil on core temperature with exercise and rest during 40-hours of sleep deprivation in a warm environment (30°C, 50% humidity). Six healthy males, ages 21-30 years, spent two 40-hour sessions in a heated environment, separated by 5 days. All participants participated in both treatments, and were randomly assigned either 100-mg modafinil or placebo three times daily (300 mg·day-1) during the trials. Rectal temperature was significantly raised by modafinil over control (p < .0001) and over placebo (p < .009) during both exercise and at rest. There was no drug by time interaction, which indicated an ability of the participants to maintain thermal homeostasis, albeit at a higher temperature than in thermoneutral conditions.
A similar study by McClellen et al. (2002) found that with a greater cumulative dose of modafinil during sustained wakefulness in a heated environment (30°C, 50% humidity), body temperature was elevated by 0.15-0.2°C over control, both at rest and during exercise. Ten men ingested 3 100-mg doses of modafinil each day (300 mg·day-1) during 38 hours of sustained wakefulness. During this 38-hour session they exercised during evenly spaced, 2-hour sessions at 60% VO2max. Elevated rectal temperature was the result of an increase in heat production during the first day and a decrease in evaporative heat loss during the second day.
Modafinil significantly elevated rectal and skin temperatures during 1.5 hours at rest in a heated environment (45°C, <15% humidity, .8m·s-1 wind speed). Ten males ingested 200-mg modafinil or placebo prior to the sweat test in the heated environment. Compared to placebo, modafinil treatment resulted in a greater increase in rectal temperature (.5 ± .04 vs. .24 ± .05 °C, p < .05) and skin temperature (3.64 ± .16 vs. 3.32 ± .16 °C, p < .05). Modafinil treatment also resulted in a decreased sweat rate throughout the heat exposure (p < .05) with no change in metabolic heat production (p < .05), resulting in a greater storage of body heat. Heart rate was elevated with modafinil treatment compared to placebo (17.95 ± 1.49 vs. 12.52 ± 1.24 beats·min-1, p < .01).
Bourdon, Bateman, and Ballerand (1994) tested the effects of modafinil on thermal balance at rest in neutral and cold environments. Nine participants each completed three trials�??two in a cold environment (10°C) with placebo or modafinil (200-mg), and one in a thermoneutral environment (29.3°C) with modafinil (200-mg). Treatment was administered .5 hours prior to each 3-hour trial. The cold environment resulted in decreased rectal and skin temperatures, and an increase in VO2. There was a non-significant tendency for a greater decrease in rectal temperature (.65 vs. .57 °C), and similarly with heat debt, which was greater with modafinil compared to placebo (16.1 ± .7 vs. 14.7 ± .6 kJ·kg-1, +9.5%, p = 0.11). Though not statistically significant, this demonstrates the possibility of modafinil treatment resulting in lower heat production and a greater dry heat loss during cold exposure. There was no difference between thermal or metabolic measures in the thermoneutral environment.
Whitmore et al. (2004) observed significantly higher oral temperatures with modafinil (cumulative 300 mg·day-1) compared to placebo during sleep deprivation. In both treatment groups oral temperature decreased from baseline in conjunction with circadian lows. Modafinil treatment resulted in consistently higher temperatures, though never above baseline.
Anaerobic Exercise Performance. In the previously mentioned study by Whitmore et al. (2006), no significant drug or drug by time effect of modafinil was observed in any of the anaerobic tests. Twelve male advanced special tactics military personal were subjected to 88 hours of sleep deprivation. During the session the participants ingested a cumulative modafinil dose of 400 mg·day-1, while performing cognitive and physical tasks. Measures of anaerobic performance included pushups, pull-ups, and standing jumps. The jump task involved 2 sets of 20 vertical jumps each, performed in place. Jump height, average work, and average power were observed. These tests were performed three times (once per day) throughout the session.
Whitmore et al. (2004) used a similar jump task to measure anaerobic performance during a reduced-sleep escape and evasion military scenario. Participants, as previously described, performed 16 consecutive jumps in place. Jump height, ground dwell time, and explosive leg factor (a combination of jump height and ground dwell time) were measured. No significant outcomes were associated with modafinil treatment. Explosive leg factor was consistently higher and ground dwell time was consistently less with modafinil treatment, though not statistically significant from placebo.
Cerebral blood flow. A recent review suggests cerebral blood flow is associated with muscle fiber recruitment, and that the normal alterations in blood flow and cerebral oxygenation during intense exercise can result in hypoxia of the cerebrum, limiting the muscle fiber recruitment (Secher, Seifert, & Van Lieshout, in press). The data indicate that under these conditions there is a significant decrement in slow contractions, but no influence on fast movements, which suggests the motor neurons controlling slow twitch muscle fibers may be more susceptible to hypoxia than those controlling fast twitch fibers.
Research by Engber, Dennis, Jones, Miller, and Contreras (1998) showed enhanced brain activity (glucose metabolism) by modafinil within the cerebral cortex, though not in regions associated with motor control. Amphetamine was found to increase brain activity to a greater extent and in more regions of the brain, including those associated with motor control. Florence et al. (2000) found increased cerebral perfusion and blood flow with amphetamine treatment, but not with modafinil.
Psychological Implications in Exercise Performance Enhancement
Mood and exercise performance. Much research has been done indicating an improved exercise capacity during positive mood states, indicated by both less physiological stress for a given workload and an improved exercise time to exhaustion (Crews, 1992; Garcin et al., 2003; Parfitt & Gledhill, 2004 ;Williams, Krahenbuhl, & Morgan, 1991). Anaerobic performance is also improved with positive mood states and high motivation (Karaba-Jakovljevi�?, Popadi�?-Ga�?esa, Gruji�?, Barak, & Drapsin, 2007).
Modafinil can have a euphoric effect (FDA, 2004), though the data are inconclusive with regards to enhanced mood, vigor, and motivation (Baranski, Cian, Esquivie, Pigeau, & Raphel, 1998; Baranski et al., 2002; Whitmore et al., 2006). The authors of the two studies involving military personnel concluded there could be a population bias with the subjects�??highly trained and motivated volunteers�??that limited the capacity of performance or subjective mood improvements (Whitmore et al., 2002; Whitmore et al, 2004). Modafinil has been shown to reduce subjective feelings of tiredness, and increase alertness, during episodes of sleep deprivation (Baranski et al., 1998; Baranski et al., 2002; FDA, 2004; Walsh, Randazzo, Stone, & Schwetzer, 2003; Whitmore, 2004). The mood-enhancing effects of modafinil may be beneficial towards improving exercise performance.
Ratings of perceived exertion. Acute modafinil treatment has been shown to improve exercise time to exhaustion (Jacobs & Bell, 2004). Ratings of perceived exertion were significantly lower in the modafinil group after 10 minutes of exercise at 85% VO2max (7.2 ± 1.9 modafinil vs. 7.7 ± 1.3 control), but were similar during the first 10 minutes and at exhaustion (mean = 18.25-min). Due to the lack of physiological changes associated with the improved time to exhaustion, it is likely that the lowered perceived exertion accounted for the improvement.
Directions for future research
Modafinil has been shown to improve exercise time to exhaustion, though overall its effects on exercise performance are not well established. To date it has proven generally ineffective at improving anaerobic or aerobic exercise performance, though the majority of participants in these trials were already well trained and highly motivated. It would seem modafinil�??s greatest contribution to enhancing exercise performance would be its mood and cognitive performance enhancing effects, especially during sleep-deprived conditions. Modafinil increases resting and exercising body temperature, and results in a higher-temperature thermal homeostasis. It is well tolerated by participants, and data show either no or moderate effects on heart rate and blood pressure.
Due to the lack of research in general, and especially with untrained or moderately trained populations, much more research is necessary to draw conclusions regarding modafinil�??s efficacy in affecting exercise performance. Modafinil may be beneficial to populations such as emergency first responders: police officers, paramedics, and firefighters. Less-trained populations such as these would benefit from the enhanced physical and mental performance modafinil could potentially offer during high-stress, prolonged emergency situations.
