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

Abstract

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 [(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.

Main outcome measures: 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.

Figure 1

Averaged Positron Emission Tomography Images for After Placebo and After Modafinil Averaged [¹¹C]raclopride and [¹¹C]cocaine binding potential (BP_ND) images at the level of the striatum (top row) and cerebellum (bottom row) after placebo and after modafinil. The color scale is a rainbow scale with red representing the highest value, which corresponds to a BP_ND of 4.4 in the [¹¹C]raclopride images and a BP_ND of 1.1 in the [¹¹C]cocaine images.

Figure 2

Plasma Modafinil Concentrations in Study Participants Who Received Either 200 mg or 400 mg of Modafinil Plasma modafinil concentrations were measured 2 hours after either 200 mg or 400 mg of modafinil was administered orally on day 1 and day 2. Lines connect the repeated measures for each participant, and horizontal bars indicate the mean modafinil concentration of the samples for each set.

Figure 3

Percentage Decrease in [¹¹C]Cocaine Binding Potential vs Plasma Modafinil Concentration Points on the plot correspond to individual participants where percentage of dopamine transporter decrease was paired with the value of the plasma modafinil concentration measured at the time of the beginning of the positron emission tomographic scan for both the caudate (R=0.87, P<.001) and the putamen (R=0.77, P=.01). BP_ND indicates binding potential. Curves were fit with linear regression.