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Clinical Implications

Nora D. Volkow, MD; Joanna S. Fowler, PhD; Jean Logan, PhD; David Alexoff, BSE; Wei Zhu, PhD; Frank Telang, MD; Gene-Jack Wang, MD; Millard Jayne, RN; Jacob M. Hooker, PhD; Christopher Wong, BA; Barbara Hubbard, RN; Pauline Carter, RN; Donald Warner, AA; Payton King, BA; Colleen Shea, MS; Youwen Xu, MS; Lisa Muench, BA; Karen Apelskog-Torres, AA

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.

Author Affiliations: National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (Drs Volkow and Telang, Mr Jayne, and Ms Muench); National Institute on Drug Abuse, Bethesda (Dr Volkow); Brookhaven National Laboratory, Upton, New York (Drs Fowler, Logan, Wang, and Hooker; Messrs Alexoff, Wong, Warner, and King; and Mss Hubbard, Carter, King, Shea, Xu, and Apelskog-Torres); Mount Sinai School of Medicine, New York, New York (Drs Fowler and Wang); and Departments of Chemistry (Dr Fowler) and Applied Mathematics and Statistics (Dr Zhu), State University of New York at Stony Brook.

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