Still Awake: An Examination of Recent Research Involving Modafinil
by Ricky Opaterny

In his 1934 essay "Sleeping and Waking" F. Scott Fitzgerald recounts his nightly battles with insomnia in which he finds, "[no] choice, no road, no hope–only the endless repetition of the sordid and the semi-tragic. Or to stand forever, perhaps, on the threshold of life unable to pass it and return to it. I am a ghost now as the clock strikes four" (Fitzgerald 67). By four o’clock in the morning, the typical human who remains awake will be mired in the period known as the circadian trough, in which the effects of fatigue and sleep deprivation become most severe–decreased body temperature, blood pressure, and heart rate as well as notably diminished cognitive ability and alertness. A corollary to insomnia is excessive daytime sleepiness, commonly known as EDS. It is a condition often associated with narcolepsy, but which can appear with depression and diseases such as multiple sclerosis and Parkinson’s disease. Moreover, fatigue is a common symptom among healthy individuals, a generalization that would seem to explain the popular success of William C. Dement’s 1999 study The Promise of Sleep. And it’s no surprise that use of the psychoactive stimulant caffeine is prevalent across the entire American population among whom morning coffee represents a ritual more common than evening prayer. Approved by the FDA in 1998 for the treatment of EDS associated with narcolepsy, 2-[(diphenylmethyl)sulfinyl]acetamide or modafinil is a stimulant that, like caffeine, enhances wakefulness. The drug, marketed in the United States by Cephalon as Provigil^®, has recently been tested for efficacy in many off-the-label functions linked to wakefulness and cognitive ability in subjects with various disorders and in healthy subjects. The DEA classifies modafinil as a schedule IV drug, which contrasts the unscheduled classification of most prescription drugs, while reflecting an abuse potential much lower than the amphetamines that doctors have traditionally used to treat narcolepsy.

The mechanism by which modafinil, whose chemical formula is C₁₅H₁₅NO₂S, works is not entirely understood. Rat studies have revealed increased release of serotonin (5-HT) in the frontal cortex caused by the administration of modafinil at the dose of 100 mg/kg. However, modafinil appears to produce this amplification by means that do not affect the reuptake of 5-HT (Ferraro et al. 2000). One study found the drug to be a possible inhibitor of the dopamine transporter (DAT), as DAT knock-out mice did not display heightened alertness levels with administration of the drug, while those with the DAT gene intact did (Wisor et al. 2001). Although the neurochemical mechanism that regulates sleep is still largely uncertain, this study suggests that the dopaminergic system plays some role. Furthermore, the drug’s effect on this system raises the possibility that its abuse potential may be higher than typically thought since the euphoric quality of dopamine can provide a source of addiction. In addition, modafinil administration was found to produce a decrease in GABA release in the brain, but the drug has not been shown to bind to any specific receptors (Ferraro et al. 1998 as cited in Ferraro et al. 2000). Cephalon does not note any drug interactions between GABA enhancing sedatives such as the barbituates and modafinil (WWW1). However, it appears that such interactions could be an area for future study. If modafinil is used to produce wakefulness in subjects whose fatigue results from insomnia, it is plausible that the same subjects may also attempt to use sedatives to alleviate their insomnia. Possible interactions with alcohol consumption present another piece of information that will be necessary for many users. Also, Modafinil has been shown to activate a -1 adrenergic receptor activity, but not through any direct action by the drug on the receptors (Wisor et al. 2001).

Many of the observed effects linked to modafinil correspond to those of amphetamine. However, amphetamine’s mode of action is direct in increasing levels of monoamine neurotransmitters, while modafinil’s remains obscure. Unlike amphetamine, modafinil does not produce increased agitation, and it does not function as a sympathomimetic (Jasinski & Kovacevic-Ristanovic 2000). Excessive doses of modafinil have resulted in agitation, but those doses were twenty-times the normal daily dose of 200 mg, and patients recovered from them within a day (WWW1). Moreover, 400 mg doses were also used in many studies, further suggesting that reasonably elevated doses of the drug do not pose any grave threats to patients. The low toxicity and lack of sympathomimetic action contribute to the drug’s safety and its preferred status in the treatment of narcolepsy. Since the mechanism of modafinil in the central nervous system has not been definitively determined, treatment of overdoses associated with the drug, rare as they may be given its low toxicity, could prove to be a problem. Stimulant users tend to develop tolerance to the stimulants they use, but patients who have been using modafinil for periods of up to one year have not displayed such symptoms (Teitelman 2001). Chemically, modafinil has low solubility in water, and it cannot easily be maintained at temperatures greater than 180 degrees Celsius, properties that lower its potential for abuse by inhalation and intravenous injection (Jasinski & Kovacevic-Ristanovic 2000). Cephalon cited modafinil’s half-life in the body as being approximately fifteen hours (WWW1). Given these qualities, the drug has a clear appeal for sufferers of EDS, healthy subjects who want to maintain alertness for long stretches of time, and the United States military, whose ideal soldier could perform at peak levels for consecutive days without sleeping. The potential for such off-the-label uses have become so popular that the FDA rebuked Cephalon earlier this year for expanding the target of its advertising for modafinil beyond the treatment of narcolepsy, which is currently its only approved use in the United States.

The mention of Parkinson’s disease commonly evokes images of trembling muscles, perhaps a quivering hand. But the disease also entails EDS for a relatively significant portion of its sufferers–more than fifteen percent (Tandberg et al. 1999 as cited in Happe et al. 2001). A group of Austrian doctors led by Svenja Happe reported last year that modafinil was successful in treating EDS in a patient suffering from Parkinson’s disease (Happe et al 2001). The patient’s EDS in this case had nothing to do with lack of sleep; rather, it was a condition linked simply to Parkinson’s that caused the patient to randomly fall asleep during the day. The patient’s daily dose of modafinil throughout most of the eight-month period studied by the doctors was 100 mg. Parkinsonism corresponds to reduced levels of dopamine. And it may be worth noting that this particular patient’s drug treatment for Parkinsonism was not affected by her use of modafinil, which, as cited earlier, apparently relies to some degree on the brain’s dopaminergic system. Moreover, certain D₁ and D₂ receptor agonists used to treat Parkinsonism have been linked to EDS (Frucht et al. 1999 as cited in Happe et al. 2001). Therefore, it appears that treatment of EDS with modafinil should be coordinated with the treatment of Parkinsonism.

In addition to Parkinson’s disease, multiple sclerosis is often accompanied by fatigue, which affects most of the diseases patients on a daily basis (Rammohan et al. 2002). A team of researchers at Ohio State recently conducted a study in which such patients were given modafinil in either 200 mg or 400 mg daily doses, and they noted that the lower of the two doses was most effective in reducing fatigue among patients (Rammohan et al. 2002). The decreased efficacy of the 400 mg dose suggests that a ceiling at which the drug reaches its maximum efficacy may exist somewhere in between those two dose levels. The researchers additionally raised the possibility of a tolerance that may develop in patients taking the higher dose, a hypothesis that opposes the optimistic belief in users’ low chances of developing a tolerance for modafinil. Also, the most common side effects among this group of patients were headaches and nausea, which are thus far the ones most often reported by all patients who take the drug. While modafinil’s effect of reducing fatigue appears similar among patients with narcolepsy and multiple sclerosis, the notably decreased efficacy of the 400 mg dose among sufferers of the latter disease indicates that modafinil might function differently in each case.

In another published report, the EDS suffered by a depressive patient was treated successfully with modafinil at the 200 mg daily dose, and the eradication of depression corresponded to the amelioration of EDS (Holder et al. 2001). The dopaminergic affect on wakefulness associated with modafinil found in the study by Wisor et al. combined with the possible relationship between depression and low levels of monoamine neurotransmitters offers a potential connection between modafinil’s effects as a stimulant and its influence on depression. Like the case of the woman suffering from Parkinson’s disease, the depressive patient was given modafinil to help eliminate EDS, while also being treated with anti-depressant medications. In a similar combination of modafinil with an established treatment, one study revealed a clear improvement of EDS caused by obstructive sleep apnea when patients took modafinil and underwent nasal continuous positive airway pressure therapy (Pack et al. 2001).

While modafinil’s ability to treat EDS associated with various conditions has been well-demonstrated, less research has been conducted involving the drug’s potential advantages for healthy users. The most obvious application would be among people enduring sleep deprivation–those who simply want to stay awake longer without experiencing decreased alertness or performance. Researchers at the Walter Reed Army Institute of Research in Maryland conducted a comparison between such wakefulness enhancement as produced by caffeine and modafinil in subjects who stayed awake for 54.5 consecutive hours (Wesensten et al. 2002). They began with the problem of trying to determine whether modafinil might replace caffeine as the stimulant of choice among the general population. However, this possibility seems highly unlikely given the FDA’s regulation and scheduling of the drug as well as its current high cost; modafinil costs just under $200 for a one-month supply. Subjects in the Wesensten et al. research answered math problems and furnished self-evaluations of their mood and fatigue states. The researchers also measured the subjects’ reaction times to visual stimuli, and found that both caffeine given as a 600 mg dose and modafinil in 200 mg and 400 mg doses maintained alertness during the circadian trough–2:00 a.m. until 10:00 a.m.–while subjects given placebos displayed a distinct decline in alertness and cognitive ability during this time period. The vigilance-promoting effects of caffeine, unlike those of modafinil, do not depend on the dopaminergic system (Wisor et al. 2001). However, the comparable results produced by each drug in the Wesensten et al. research suggest that similar improvements of alertness can function by means that have rather different neurochemical mechanisms. Additionally, the side effects of modafinil in this study proved to be rather minor–headache was the most common–while the side effects of caffeine were more widespread.

When considering cognitive performance, no discernable advantage seems to exist for choosing modafinil over caffeine. Therefore, modafinil’s possible mass appeal that has been touted by the media recently lacks merit. Even if people are willing to pay extra for a drug with slightly fewer side effects, the chances of modafinil gaining wider general use seems unlikely and irrational considering its seemingly negligible advantages over caffeine. However, research comparing modafinil and caffeine could be essential to understanding the body’s regulation of alertness and fatigue on a neurochemical level. Both drugs show effectiveness in keeping people awake for long stretches of time, but this capacity has only been tested in subjects who were otherwise rested when they began the period of sleep deprivation. Nobody has tested the efficacy of modafinil on subjects who repeatedly endured long periods of sleep deprivation. The drug’s potential attraction to the general population seems to be in the possibility of increasing productivity on a regular basis, not just once in a long while. For example, tests might be performed in which subjects used modafinil during a 45-hour period of sleep deprivation, slept for nine hours, and then underwent another modafinil-aided period of sleep deprivation.

Nonetheless, being able to perform at normal levels for a single large block of time does hold significance for military personnel, especially pilots whose airplanes are now capable of flying for consecutive days. In the spring of 2000 a group led by John and Lynn Caldwell at the Aeromedical Research Laborator in Alabama published the results of a study in which sleep deprived pilots flew helicopter simulators (Caldwell et al. 2000). The performance during the circadian trough of pilots given modafinil was significantly greater than that of those given placebos. Subjects who were given modafinil consistently outperformed those given placebos on each of the simulator tests taken during this period of heightened sleep deprivation. The biggest disparity between the two groups’s performances came when they were asked to control the simulators during descents between 1 a.m. and 12 p.m. on the second day of the testing. The pilots who took modafinil achieved a level of performance relatively equal to what they had achieved before the deprivation period. Their performance levels during sleep deprivation were comparable to those realized with the use of dextroamphetamine; however, modafinil use is preferable since it does not carry the high rate of abuse that amphetamine does. Furthermore, the levels of the pilots’ self-reported vigor, fatigue, and confusion each revealed modafinil’s role in increasing alertness and mental functioning while improving the pilots’ overall moods. Moreover, while subjects who had taken modafinil did not display any increase in pulse rate or blood pressure during the first day of testing, they had higher levels of each than the pilots who had not taken modafinil during the deprivation period. Some participants in this study noted both nausea and dizziness, which may have resulted from the use of a simulator rather than a real helicopter. The hypothesis that using the simulator induced dizziness is likely since dizziness does not appear a common side effect in research conducted without simulators.

Being able to keep pilots flying at high level of accuracy for long periods of time will allow them to perform missions with much less risk. Safety, not just ability, is a relevant factor in the military studies involving modafinil, and that element seems to give such use of modafinil much more legitimacy than the use by business travelers to help them manage their crazy schedules as cited last month in the Washington Post (Vedantam 2002). While people who need to work long shifts such as military personnel, pilots, and emergency workers could receive real benefit from using a drug like modafinil on occasions that their work demands it, using it simply to cram one’s schedule full of meetings, travel, and work sounds like terribly misguided optimism. The mechanisms that regulate wakefulness and sleep may remain obscure, but the idea of a healthy person regularly self-medicating himself to artificially alter those mechanisms seems both wrong and unreasonably risky.

However, modafinil may have another use in healthy individuals that does not pose such a problem. A recent study conducted by a team of French researchers on lab mice revealed a significant improvement in alternation scores among mice who were given 64 mg/kg doses of modafinil and placed in a t-maze (Béracochéa et al. 2000). In the same study, the researchers also gave mice a hole-board to explore, but modafinil did not produce any change in their exploratory levels or behavior. And doses below 64 mg/kg did not show any effects in either test. Since no higher doses were given, uncertainty persists about how the amount of modafinil given to subjects affects their performance of various tasks. In healthy humans a 100 mg doses often produces little if any effect, while much research shows 200 mg doses as being more effective than 400 mg doses for certain elements. And yet the patient described in the research by Happe et al. continued to display alleviation of EDS despite the reduction of her daily modafinil dose from 200 mg to 100 mg. Short term memory improvement in humans could improve productivity in many work-related settings. Although modafinil has a half-life in the body of around fifteen hours, it doesn’t seem to prevent people from falling asleep when they want to sleep. The effect on short-term memory in mice substantiates the claim that modafinil has some effect on the hippocampus. Though it seems unlikely to be of much help, such a hypothesis may suggest the possibility of testing modafinil in a patient with Alzheimer’s, whose hippocampus functions as though it has not yet developed or myelinized.

The most significant effect of modafinil remains the heightened vigilance and wakefulness that it produces in patients. The distinction between fatigue that represents the product of a disease such as Parkinson’s and fatigue as it occurs in a completely healthy person may not be as easy as it appears since feeling tired put in simplest terms is feeling tired. Research relating to modafinil has shown that a medication can, in many cases, improve such a condition. However, the point at which a healthy patient should resort to using such medication or when a doctor should be willing to prescribe it will remain vague. Regardless of whether it is aided with medication, consistent sleep deprivation will probably present adverse neurochemical consequences. Moreover, in a society that seems content with medicating itself to improve everything from depression to sex, eagerness for a product like modafinil appears fully justified. If the purpose of medicine is to cure the sick, then it should be necessary to consider how much of a detrimental condition, be it fatigue or depression, must be treated on the neurochemical level. Fatigue is common and it does impair a person’s ability to function properly in just about any setting, but most people who suffer from fatigue can probably be treated by means other than drug prescriptions. Sleep therapy seems quite possible, and it represents a much cheaper alternative to using medication.

If research relating to modafinil reveals a shortcoming it may be one in Americans’ own reasoning about sleep and their constant desire for quick fixes. The existence of a wonder drug that could abolish a person’s need for sleep in order to feel as though he got a good night’s sleep should be just as impossible as it sounds. While the cost of traditional stimulants reveal themselves in high abuse potentials and increased chances of overdosing, modafinil does not yet appear to have these properties. However, a perfectly healthy person choosing to both use the drug and forgo sleep must pay some cost. Further research will invariably reveal that cost. And perhaps it will be relatively negligible, but then again, it might not. Despite the opportunity it provides for excessive optimism, modafinil research has become a useful track for advancing knowledge of neurochemical mechanisms involved in sleep’s effects on the body as well as what it means to be alert and feel rested. Although much remains uncertain in the field, testing of the drug in various settings can help reduce that uncertainty while offering further hope to sufferers of EDS whose only hope for improvement is likely to be such a medication. And modafinil use could offer distinct advantages to workers and pilots who have no choice but to work long shifts. Obviously, increased safety should be pursued if the risks to individuals taking the drug are minimal, as they have been throughout studies thus far. Since modafinil has already achieved a large amount of popularity, future research should seek to expand possible applications of the drug to those who may benefit from the drug, and it should also attempt to establish guidelines for safe and acceptable usage beyond the currently approved treatment of EDS associated with narcolepsy.