The Corpus Callosum

Context  Modafinil, a wake-promoting drug used to treat narcolepsy, is increasingly being used as a cognitive enhancer. Although initially launched as distinct from stimulants that increase extracellular dopamine by targeting dopamine transporters, recent preclinical studies suggest otherwise.

Objective  To measure the acute effects of modafinil at doses used therapeutically (200 mg and 400 mg given orally) on extracellular dopamine and on dopamine transporters in the male human brain.

Design, Setting, and Participants  Positron emission tomography with [11C]raclopride (D2 / D3 radioligand sensitive to changes in endogenous dopamine) and [11C]cocaine (dopamine transporter radioligand) was used to measure the effects of modafinil on extracellular dopamine and on dopamine transporters in 10 healthy male participants. The study took place over an 8-month period (2007-2008) at Brookhaven National Laboratory.

Main Outcome Measures  Primary outcomes were changes in dopamine D2 / D3 receptor and dopamine transporter availability (measured by changes in binding potential) after modafinil when compared with after placebo.

Results  Modafinil decreased mean (SD) [11C]raclopride binding potential in caudate (6.1% [6.5%]; 95% confidence interval [CI], 1.5% to 10.8%; P = .02), putamen (6.7% [4.9%]; 95% CI, 3.2% to 10.3%; P = .002), and nucleus accumbens (19.4% [20%]; 95% CI, 5% to 35%; P = .02), reflecting increases in extracellular dopamine. Modafinil also decreased [11C]cocaine binding potential in caudate (53.8% [13.8%]; 95% CI, 43.9% to 63.6%; P < .001), putamen (47.2% [11.4%]; 95% CI, 39.1% to 55.4%; P < .001), and nucleus accumbens (39.3% [10%]; 95% CI, 30% to 49%; P = .001), reflecting occupancy of dopamine transporters.

Conclusions  In this pilot study, modafinil blocked dopamine transporters and increased dopamine in the human brain (including the nucleus accumbens). Because drugs that increase dopamine in the nucleus accumbens have the potential for abuse, and considering the increasing use of modafinil, these results highlight the need for heightened awareness for potential abuse of and dependence on modafinil in vulnerable populations.

What they did: they gave modafinil to 10 healthy men, along with tracer compounds, and did PET scans.  What they found: modafinil interacts with dopamine transporters, causing dopamine to linger in the synapse.  This increases the amount of dopamine that transmits signals within the brain.

Why might this be important?  Because many drugs that are commonly abused share these properties, it might mean that there is a potential for modafinil to be abused.

Why am I not impressed?

For one, we already knew that modafinil increases dopamine, and that it interacts with the dopamine transporter.  Much of that information comes from studies in nonhuman animals, so it does add a bit for this to be demonstrated clearly in humans.  But we (clinicians) pretty much assumed that this would be true in humans, or that it could be true.  So any caution that might be warranted was already present.

For another, clinicians are already well advised to consider the abuse potential for anything they prescribe.  Some people abuse Benadryl.  Some people abuse Haldol.  Or Cogentin.  There are several instances of drugs that were released with the notion that they would have little or no abuse potential, with subsequent events disabusing us of that notion.  Stadol is an example of this.  So the idea that we ought to be cautious about modafinil is hardly news.  

For another, the FDA has classified modafinil as a controlled substance.  That might be a clue that one ought to be cautious.  

Most important, though, is the empirical evidence.  Modafinil has been on the market since December 1998.  I've worked in and around various substance abuse treatment facilities for that entire time.  I personally have never encountered a single patient who reported abusing modafinil.  Sure, there probable are some out there, somewhere, but it simply has not emerge as a blip on the clinical radar screen.  

My own experience is, admittedly, not representative of the entire universe.  But a Medline search on "modafinil abuse" turns up very little.  Most of the hits pertain to the potential for the use of modafinil in the treatment of persons with stimulant abuse and/or dependence.  Some of these papers describe studies in which modafinil was given to persons who abused cocaine.  I don't claim to have read all of the studies, but I did not encounter any that said "DON"T DO THIS.  YOU WILL UNLEASH A MONSTER."  [Example: The Search for Medications to Treat Stimulant Dependence, in Addiction Science and Clinical Practice (PDF)]

I have to think that if this were a problem with any appreciable frequency, it would show up in either my person experience, or the professional literature.  

The authors of the study were careful to phrase their conclusion carefully; they avoid drawing an excessively broad conclusion.  The problem is, persons who are not accustomed to reading these studies easily could draw unsupported conclusions.  For example, there is already an article on Bloomberg: Narcolepsy Pill Used as Smart Drug May Be Addictive.  We can anticipate that the word will spread, and the original precision of the conclusion will be lost.