Modafinil: Not Just Another Stimulant

Modafinil, the active ingredient in the drug Provigil (produced by Cephalon), has received no small amount of attention. Columnists from several popular media sources (e.g. MSN Slate's David Plotz's Wake Up, Little Susy) describe Modafinil almost as if it's "too good to be true", almost as if it's a miracle drug that packs the punch of a strong cup of coffee without all the jitters.

Fortunately, I'm not here to talk about the hype. I'm here to discuss the research I've conducted in the past year, most of which was motivated originally by a presentation I gave in an undergraduate psychopharmacology class. Specifically, I'm going to discuss modafinil's mode of action in the context its similarity and dissimilarity with respect to another drug used for studying and/or wakefulness, amphetamine. My intent is simply to draw some conservative conclusions regarding modafinil's psychopharmacological profile. Please note that I am not a licensed psychiatrist and make no statements regarding the proper use of the drug as a treatment. I'm simply a graduate student discussing openly what I take to be the upshot of several months' worth of academic research.

In the U.S., modafinil is currently prescribed for sleep-related disorders, although it is sometimes used off-label as a life-style drug and/or as an alternative to conventional ADHD stimulants.

Modafinil is a CNS stimulant used in the treatment of narcolepsy and other sleep-related disorders. Its exact psychopharmacological profile is not fully understood, but its wakefulness-inducing properties suggest that it might share a similar psychopharmacological profile with other CNS stimulants.

One animal study (conducted by Cephalon in 1998) attempted to understand modafinil's mode of action by comparing data of its 2-deoxyglucose autoradiography with data from amphetamine's 2-deoxyglucose autoradiography. Amphetamine is the active substance in several CNS stimulants including Adderall (Shire Pharmaceuticals) and Dexedrine. If modafinil shares a similar profile with amphetamine, then areas which are characteristically activated in the presence of amphetamine ought to be similarly activated in the presence of modafinil.

Compared with amphetamine's activation patterns, modafinil appears to be relatively targeted, despite certain similarities. For example, both modafinil and amphetamine were associated with higher levels of glucose utilization in certain sub regions of the area thought crucially associated with memory, the hippocampus. Given modafinil's positive impact on performance in memory tests (as cited in this 2004 study by Steffenhagen et al.), tests mostly involving short-term memory, this association between modafinil and amphetamine makes sense.

However, only modafinil (and not amphetamine) was associated with higher levels of glucose metabolism in the amygdala, an area associated with a host of conditions, including Autism (though that association is by no means definite). The amygdala is characteristically discussed in terms of its influence and/or significance with respect to emotional memories or emotional behaviors. It is part of the limbic system and is thus-in evolutionary time-- older than higher-order areas such as the prefrontal cortex. Activation of the amygdala might influence a person's emotionality and/or behavioral tendencies.

In any event, modafinil's unique effect (unique with respect to amphetamine) on the amygdala appears to be the only such instance. Oppositely, there are several regions for which amphetamine is associated with increased activation where modafinil is not. Such examples are important; they have certain implications regarding our understanding of Modafinil's side effects as compared to the side effects characteristic of amphetamine. Fully appreciating these differences is a part of the overall evaluation of modafinil's efficacy and safety.

One such dissociation involves activation of an area thought to code for bodily movements (it codes for movement, it is not responsible for it). This area is highly dopaminergic (meaning that it has a high density of receptors for the neurotransmitter dopamine or a.k.a. DA): any alteration of this area, such as an upregulation or downregulation of DA receptors caused by the ingestion of a DA agonist, could impact a person's ability to move and/or partake in smooth, controlled movements. While Modafinil does not appear to influence dopaminergic activity in this area, amphetamine clearly does. In fact, other prescription psychostimulants (e.g. methylphenidate a.k.a. Ritalin) are noted for psychomotor effects. Children who are given amphetamine sometimes develop facial tics or other uncontrollable muscle spasms. Of course, influencing the activity of this structure leads to other problems. The basal ganglia is associated with other movement disorders, including Parkinson's disease, the essential mark of which is the death of DA receptors found in the basal ganglia.

All in all, it is important to remember that just because modafinil appears to effect fewer total areas does not mean it's somehow a better or more effective drug. In my research I have found studies indicating that, for instance, modafinil may not share all of the cognitive-enhancing effects that several decades of research with amphetamine and methylphenidate (Ritalin) have shown. Moreover, the safety of a drug is not merely a function of the number of brain areas it affects. The upshot of the information discussed here is simply that modafinil does not share a mode of action characteristic of other psychostimulants. It also appears to lack some of the side effects that conventional psychostimulants are famous for, including tics, among others (that I did not comment on presently). Finally, modafinil has an extremely good record with regard to its safety, but its efficacy in treating attention and/or memory-related conditions is not fully understood.

Use of the word "amphetamine" refers only to prescribed drugs such as Adderall or Dexedrine. I am not in any way referring to illegal drugs.