Modafinil, the ultimate stimulant?
by Robert Mason Ph.D

Modafinil is an eugeroic drug, (which simply means “good arousal”). This unique class contains only two at present, adrafinil and modafinil, both of which have been developed by Lafon Laboratories of France. Currently, their use and effectiveness is little known outside of Europe. The basis of their uniqueness lies in their ability to only “stimulate when stimulation is required.” As a result the “highs and lows” associated with other stimulants such as amphetamine are absent with eugeroics. Their initial use often produces comments such as “I can’t tell any difference.” But it is only several hours later when one realizes that attention and awakeness are the same as earlier, that one is aware of their benefits. Eugeroics have been designed to treat narcolepsy (sleeping in the day), hypersomnia (excessive sleep) and cataplexy (a condition of sudden muscular weakness or fatigue).
Yet eugeroics don’t affect normal sleep patterns, nor are they addictive and they have far fewer side effects than the current prescribed stimulants.

One study (5) on rats suggested that one possible vigilance enhancing property of modafinil was its ability to inhibit the release of GABA, through an action on 5HTP serotonin receptors. However, the doses used were far higher than normal therapeutic doses.

Meanwhile, most clinical studies point to modafinil as a unique and highly selective agonist of brain postsynaptic receptor sites called, alpha-1 adrenergic. (1,2,7,8,9,10)

These sites are receptive to the neurotransmitter- Norepinephrine (NE). The central function of norepinephrine is a fairly recent discovery, it appears to regulate alertness and the waking- sleep cycle and has a role in the maintenance of attention, memory, learning, cerebral plasticity and even has neuro-protection qualities (2).

Central nervous stimulants (CNS) such as amphetamine or pemoline are the most widely used drugs to treat narcolepsy, hypersomnia and cataplexy, but these have a number of well documented problems, such as cardiovascular side effects, interference with sleep, psychiatric disturbances and addition.

Two studies (3, 10) directly compared the affects of modafinil and d-amphetamine on sleep. Both double blind controls involved about twelve individuals, one study was undertaken on individuals whose mean age was 68, the other on much younger volunteers. They utilized 100 mg or 200 mg of modafinil, or 10 mg or 20 mg of d-amphetamine or a placebo. All the drugs were administered orally and sleep scales, awakening quality and psychometric tests were completed in the morning.

The outcome of both tests showed that d-amphetamine caused a dose dependant impairment of sleep maintenance, but modafinil did not. Here in lies the problem for those who have difficulty staying alert and awake during the day. The use of “classic” stimulants such as amphetamines threaten to reduce total sleep time and REM sleep, this will ultimately mean higher and higher doses are required and thus creates a vicious circle.

as reported in Wired magazine

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On the other hand. modafinil has not been shown to interfere with night time sleep, thus clearly indicating that the two compounds operate by different methods.

Numerous studies on animals since the mid 1980’s have confirmed the ability of modafinil to increase awakeness and alertness without serious side effects, or dependency.

One test on rats (4) produced an interesting result. The researchers discovered that modafinil decreased feeding and reduced body-weight! The amounts of modafinil required were not dose dependant and there was no alteration in the drink- feed ratio. Their conclusion was a reference to the possible mechanisms that underlie the relation between sleep, feeding and metabolism. Various human trials have concentrated upon modafinil as a therapeutic agent to help maintain alertness and vigilance. A note worthy conclusion of one clinical trial (10) compared modafinil to amphetamine and described amphetamine as “vigilance increasing” but modafinil as “vigilance promoting.” This is an interesting comment because as we’ve seen, modafinil won’t prevent a person from sleeping if they want to but if they wish to remain awake they will do so with a far greater alertness. This was borne out in one clinical trial (11) where volunteers were subjected to 60 hours of sleep deprivation! During their continued wakefulness, their vigilance was assessed using questionnaires, analogue visual scales and sleep latency tests.

The subjects received either 200 mg modafinil or a placebo every 8 hours. The modafinil group sustained a satisfactory level of vigilance with an absence of sleep episodes, unlike the placebo group who gradually declined and slipped into “micro-sleep” episodes, (as one might expect when awake for longer than 24 hours!) A French study (9) conducted over 3 years, discovered that modafinil reduced drowsiness in 83% of hypersomniac patients and 71% of narcoleptics. Modafinil did not produce peripheric side effects, disturb night sleep and it was never responsible for drug dependence. Another French study conducted with 149 patients over a period of 2 years (13), was treating patients with narcolepsy-cataplexy at 200 mg to 400 mg daily. The patients were then asked to score the benefit of modafinil themselves from 0 (no affect) to 3 (excellent affect), 64.1% of the subjects scored it as excellent.

An earlier study (17) with 123 patients, which also included those suffering with hypersomnia; physicians evaluated the patients on a scale of 1 (no affect) to 4 (excellent affect). The results? 17% excellent response, 63% good response, 17% fair and 3% no affect. The incidence of side effects were minimal (14 of the 123 patients had side effects, 11 of whose side effects disappeared when doses were reduced).

These results have been repeated in a number of smaller clinical trials (8, 12, 14, 15) and confirm modafinil’s excellent response to treating individuals suffering with narcolepsy, hypersomnia and cataplexy. Its efficacious use in conjunction with a virtual absence of side effects, non contraindication with normal sleep patterns and lack of drug dependence, certainly indicates that eugeroics are a breed apart from conventional stimulants.

It is fascinating to see that several countries armed forces have studied (and use!) modafinil for military operations. The use of stimulants to keep troops awake and alert is not a new one. It is known that British troops used them during the Falklands conflict and that USAF aircrews took amphetamines during the Libyan air strikes. More recently the French government admitted that its crack Corp- the Foreign Legion- used modafinil during covert operations inside Iraq during the Gulf war.

In fact. Professor Michel Jouvet, an authority on sleep, claimed during an international defense meeting in Paris that, “modafinil could keep an army on its feet and fighting for three days and nights with no major side effects.”
Not surprisingly then, we have heard that modafinil is in use in some sections of the Belgian, Dutch and US airforces.
Side effects in 3 years continuous studies of modafinil have been minimal and usually noted as nothing more than headache or nausea, at therapeutic dosages (17,18).

In rare cases there has been hyper-salivation (19) and moderate tachycardia (increased pulse rate- 20), this probably accounts for modafinil’s instruction sheet, which states that those suffering from a heart condition must consult their physician before use. However, blood and pulse rates usually remain unchanged at normal therapeutic doses. In fact, the relative safety of modafinil was demonstrated by a suicidal 21 year old female who ingested 4500 mg.

Her side effects were limited to tachycardia, excitation and insomnia (9). As is common with most drugs, modafinil should not be used by those with serious liver disorders, nor those women who are pregnant or nursing. The official insert for the modafinil package remains unclear as to the precise drug contraindications, but as it is an alpha-adrenergic agonist, those drugs that represent alpha-adrenergic antagonists should be avoided. These include prazosin, phentolamine or beta blockers such as propranolol (Inderal).

Furthermore, drugs that enhance norepinephrine activity (such as yohimbine) should only be used with care as there may be a synergistic affect. Adrafinil is noted as contraindicated with epilepsy and has been shown to enhance the potency of anti-epileptic drugs such as phenytoin (Dilantin/ Epanutin). Although this isn’t mentioned in any of the modafinil literature we have read, it is best being advised of. As for dosages, there seems to be little difference in doses and more importance placed upon regular administration (12). Those who simply wish to remain awake and alert will benefit from a single 100 mg dose. To remain on call all day, 100 mg in the morning and another 100 mg in the afternoon is probgably all that is required. For those wishing to remain awake during the night, then another 100 mg in the late evening (in other words approximately every 8 hours). Dosages for those suffering from narcolepsy, hypersomnia and catoplexy are 100-200 mg morning and afternoon. Some of the doses in trials have been as high as 600 mg to 700 mg daily (9) although doses over 500 mg daily may cause euphoria, slight motor excitation or even insomnia!

At first glance there may appear to be little difference between the two. It is true that modafinil is more potent, “average” doses of adrafinil are in the region of 600 mg to 1200 mg daily, compared to modafinil’s 200 mg to 400 mg daily and this is self evident by the respective tablet sizes. However, if one was to compare adrafinil and modafinil on price then adrafinil would win hands down. So the question must be asked why did Lafon produce a newer analogue of adrafinil? The answer probably lies in two parts. Firstly, it is thought that adrafinil might not be such a highly selective alpha-1 adrenergic as originally thought and may also affect other alpha receptors, (albeit in a minute fashion. Secondly, adrafinil is attributed to some other possible side effects that have not been associated (to date) with modafinil, including, stomach pain, skin irritations, inner tension and in long term use (over 3 months usually), an increase in liver enzyme levels, (which is reversible by reduction or withdrawal).

It is our guess that it is this last potential side effect that lead to the development of modafinil. Clearly adrafinil requires regular blood testing to monitor liver enzyme levels and this may prove inconvenient, to those patients who would need to use eugeroics on a regular basis. As none of the clinical reports we have read indicate any such problem with modafinil, it would appear that the analogue has achieved its desired aim.

Modafinil the conclusion

We were going to reiterate and condense the above article into a few lines, but the conclusion of the Aerospace Medical Association article (16) on modafinil was so good we will leave the last words to them.

“The development of modafinil brings to light a crucial social question. What would be the impediment for its use, if a compound such as modafinil is more like caffeine than amphetamine in terms of safety, and yet, as effective as the amphetamines?”

Our answer? Only time will tell (although looking around the so-called civilized world and seeing the rapid disappearance of individual rights through centralized bureaucratic control, we wouldn’t bet on it! -ed.). These are changing and challenging times indeed.


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3. Saletu B, Frey R, Krupka M, Anderer P, Grunberger J, Barbanoj MJ “Differential effects of a new central adrenergic agonist- modafinil and d-amphetamine on sleep and early morning behaviour in elderly” Arzneimittelforschung Oct 1989 39 (10) 1268-73.

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8. Billiard M, Besset A, Montplasir J, Laffont F, Goldenberg F, Weill JS, Lubin S “Modafinil, a double blind multicentric study” Sleep 1994 Dec 17 (8) 5107-112.

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Modafinil (Provigil®) by Cephalon was approved by the FDA December 1998 for the treatment of narcolepsy. Modafinil is the first new drug treatment to be developed for narcolepsy in 30 years.

Sleep researchers at the University of Illinois at Chicago have found that Modafinil helps narcolepsy patients stay awake without being a stimulant. In their study, 273 narcoleptic patients in a nine-week study took Modafinil once a day in doses of 200 or 400 milligrams or received a placebo. Patients taking Modafinil stayed awake at least 50 percent longer than those receiving a placebo and had far fewer side effects than the current standard treatment of amphetamines.

“Modafinil is not a cure for narcolepsy,” says Sharon Merritt, associate professor of medical-surgical nursing and director of the Center for Narcolepsy Research. “But if you can find a drug that has as few side effects as Modafinil appears to have, then that allows people with narcolepsy to live more normal lives.”

Besides treating patients with narcolepsy, Merritt says, Modafinil may have potential safe uses as an anti-fatigue agent for truck drivers, airline pilots and others for whom wakefulness is a critical part of their jobs.

Narcolepsy affects approximately one in every one thousand people. Two primary narcoleptic symptoms are excessive daytime sleepiness and cataplexy, or the sudden loss of strength in voluntary muscles. Other symptoms include memory and concentration problems, sometimes resulting in poor performance at work or school. The exact cause of narcolepsy is still unknown, though researchers believe it is a biological disorder, possibly involving abnormalities of brain chemistry.

J Pharmacol 1986 Jan-Mar;17(1):37-52