The neurobiology of modafinil as an enhancer of cognitive performance and a potential treatment for substance use disorders

Abstract

Rationale and objectives: Modafinil (MOD) and its R-enantiomer (R-MOD) are approved medications for narcolepsy and other sleep disorders. They have also been used, off-label, as cognitive enhancers in populations of patients with mental disorders, including substance abusers that demonstrate impaired cognitive function. A debated nonmedical use of MOD in healthy individuals to improve intellectual performance is raising questions about its potential abuse liability in this population.

Results and conclusions: MOD has low micromolar affinity for the dopamine transporter (DAT). Inhibition of dopamine (DA) reuptake via the DAT explains the enhancement of DA levels in several brain areas, an effect shared with psychostimulants like cocaine, methylphenidate, and the amphetamines. However, its neurochemical effects and anatomical pattern of brain area activation differ from typical psychostimulants and are consistent with its beneficial effects on cognitive performance processes such as attention, learning, and memory. At variance with typical psychostimulants, MOD shows very low, if any, abuse liability, in spite of its use as a cognitive enhancer by otherwise healthy individuals. Finally, recent clinical studies have focused on the potential use of MOD as a medication for treatment of drug abuse, but have not shown consistent outcomes. However, positive trends in several result measures suggest that medications that improve cognitive function, like MOD or R-MOD, may be beneficial for the treatment of substance use disorders in certain patient populations.

Figure 1

Chemical Structures of modafinil (MOD) and armodafinil (R-MOD).

Figure 2

Targets of MOD’s actions as a cognitive enhancer Brain areas and related neurotransmitter systems that are potentially involved in mediating the therapeutic actions of MOD as a cognitive enhancer. NE= norepinephrine; DA= Dopamine; GABA= gamma-amino-butyric-acid; GLU= glutamate; NET= norepinephrine transporter; DAT= dopamine transporter, 5-HT=serotonin; Ach= Acetylcholine. Solid lines indicate direct interactions, while dashed lines indicate observed effects that appear to be via indirect interactions or for which a mechanism has not yet been elucidated.

Figure 3

Targets of MOD’s actions as a potential medication for substance use disorders. Brain areas and related neurotransmitter systems that are potentially involved in mediating the actions of MOD related to its potential therapeutic effects on psychostimulant and opiate abuse. NE= norepinephrine; DA= Dopamine; GABA= gamma-amino-butyric-acid; GLU= glutamate; NET= norepinephrine transporter; DAT= dopamine transporter. Solid lines indicate direct interactions, while dashed lines indicate observed effects that appear to be via indirect interactions or for which a mechanism has not yet been elucidated.