Modafinil has potential for abuse and addiction because of increased dopamine levels

In a pilot study published in the Journal of the American Medical Association, investigators demonstrated that modafinil blocks dopamine transporters and increases dopamine levels in the brain, suggesting that this agent has the potential for abuse and addiction.

This study took place at Brookhaven National Laboratory in New York. Healthy, nonsmoking men aged 18 to 50 years were eligible for enrollment. Excluded from the study were men with urine samples positive for psychoactive drugs; those with clinically significant abnormal laboratory values, history of or current medical illness, or history of or current neurologic or psychiatric disease; men who had used psychotropic medications in the previous month; those who had experienced head trauma with loss of consciousness >30 minutes; and those with a history of or current substance abuse. Participants underwent 4 positron emission tomography (PET) scans, 2 with [¹¹ C]raclopride (a dopamine D₂/D₃ radiotracer used to show changes in extracellular dopamine) and 2 with [¹¹C]cocaine (used to show dopamine transporter availability). The scans were carried out over a 2-day period. On both days, the first scan took place 2 hours after administration of placebo, and the second scan took place 2 hours after administration of oral modafinil 200 or 400 mg; the modafinil dose was administered immediately after completion of the first scan. Heart rate, blood pressure, and behavioral effects were assessed throughout the study.

A total of 10 men (median age, 34 y) were included in the study. Modafinil doses were associated with significantly increased heart rate and systolic blood pressure (SBP), but no significant changes in behavioral measures were observed. Analysis demonstrated no significant dose effect on binding potential levels; therefore, results for the 200- and 400-mg modafinil doses were combined. Modafinil significantly reduced the mean [¹¹C]raclopride binding potential in caudate (6.1%; 95% CI, 1.5%–10.8%; P=.02), putamen (6.7%; 95% CI, 3.2%–10.3%; P=.002), and nucleus accumbens (19.4%; 95% CI, 5%–35%; P=.02); these reductions reflect increases in extracellular dopamine. Modafinil was also associated with significant reductions in mean [¹¹ C]cocaine binding potential in caudate (53.8%; 95% CI, 43.9%–63.6%; P<.001), putamen (47.2%; 95% CI, 39.1%–55.4%; P<.001), and nucleus accumbens (39.3%; 95% CI, 30%–49%; P=.001), reflecting occupancy of dopamine transporters.

The authors discussed several limitations of their study, including the small sample size, inclusion of only healthy male participants, and the lack of a clinical outcome measure. In addition, they pointed out that their method of using [¹¹ C]raclopride could lead to the conclusion that their results reflect down-regulation of D₂/D₃ receptors and changes in affinity rather than increases in dopamine. They suggested that further studies are needed. Based on the current study, however, they stated, "Because drugs that increase dopamine have the potential for abuse, and considering the increasing use of modafinil for multiple purposes, these results suggest that risk for addiction in vulnerable persons merits heightened awareness."

SOURCE

Volkow ND, Fowler JS, Logan J, et al. Effects of modafinil on dopamine and dopamine transporters in the male human brain: Clinical implications. JAMA. 2009;301:1148–1154.