Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications.
BACKGROUND
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.


METHODS
Positron emission tomography with [(11)C]raclopride (D(2)/D(3) radioligand sensitive to changes in endogenous dopamine) and [(11)C]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.


METHODS
Primary outcomes were changes in dopamine D(2)/D(3) receptor and dopamine transporter availability (measured by changes in binding potential) after modafinil when compared with after placebo.


RESULTS
Modafinil decreased mean (SD) [(11)C]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 [(11)C]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.
Volkow
Nora D
ND
National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA. nvolkow@nida.nih.gov
Fowler
Joanna S
JS
Logan
Jean
J
Alexoff
David
D
Zhu
Wei
W
Telang
Frank
F
Wang
Gene-Jack
GJ
Jayne
Millard
M
Hooker
Jacob M
JM
Wong
Christopher
C
Hubbard
Barbara
B
Carter
Pauline
P
Warner
Donald
D
King
Payton
P
Shea
Colleen
C
Xu
Youwen
Y
Muench
Lisa
L
Apelskog-Torres
Karen
K
D000328:Adult; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D002250:Carbon Radioisotopes; D002421:Caudate Nucleus / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000494:pharmacology*; D003042:Cocaine; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077408:Modafinil; D009714:Nucleus Accumbens / Q000378:metabolism; D010865:Pilot Projects; D049268:Positron-Emission Tomography; D011699:Putamen / Q000378:metabolism; D020891:Raclopride; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000378:metabolism; D019966:Substance-Related Disorders; D055815:Young Adult
D001559:Benzhydryl Compounds; D002250:Carbon Radioisotopes; D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D020891:Raclopride; D003042:Cocaine; D000077408:Modafinil; D004298:Dopamine