Effect of Modafinil on Dopamine

Today's edition of the Journal of the American Medical Association
contains a study that employed PET scans to determine the effect of
modafinil upon dopamine concentration and reuptake in the human central
nervous system.  They conclude with a caution that clinicians
should be mindful of the potential for abuse and dependence in persons
taking modafinil.



The problem with the study is that it adds very little, if anything, to
clinical practice.

href="http://jama.ama-assn.org/cgi/content/short/301/11/1148">Effects
of Modafinil on Dopamine and Dopamine Transporters in the Male Human
Brain

Clinical Implications

JAMA. 2009;301(11):1148-1154.

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 ( href="http://www.nida.nih.gov/pdf/ascp/vol4no2/Search.pdf">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: class="news_story_title"> href="http://www.bloomberg.com/apps/news?pid=20601124&sid=aL46apDPdJz8&refer=home">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.