Relapse to drug-seeking after abstinence is the most challenging problem in treating drug addiction. Therefore, the demand for anti-relapse medications is high. Clinical trials have reported that modafinil, a wake-promoting agent used to treat sleep disorders such as narcolepsy, is effective in treating cocaine dependence. Although a weak stimulant, sites of action and behavioral effects of modafinil appear to be different from those of cocaine or amphetamine. Modafinil blunts the reinforcing as well as cardiovascular effects of cocaine. More importantly, modafinil decreases cocaine use and relapse rates in cocaine addicts (Dackis et al, 2005; Hart et al, 2008). Larger multi-center clinical trials of modafinil have found modestly positive outcomes (Anderson et al, 2009). In addition, modafinil showed promise in a small group of methamphetamine-dependent subjects and in pathological gamblers with high impulsivity. However, it appears that modafinil may only be effective in cocaine addicts without alcohol dependence (Anderson et al, 2009). Modafinil also is reported to increase negative affect and withdrawal symptoms associated with nicotine dependence. These findings indicate consideration of smoking and alcohol abuse in using modafinil as an anti-relapse medication.

In addition to this possible glutamate-mediated mechanism, modafinil is reported to affect other neurotransmitter systems such as catecholamines, serotonin, GABA, orexin, and histamine. The mild stimulant properties of modafinil may also be involved in its ability to reduce withdrawal symptoms of stimulant abuse. In a recent human PET study, modafinil was shown to block DA transporters and increase dopamine in the human brain including the nucleus accumbens (Volkow et al, 2009), in line with previous animal data. These and other findings highlight a potential for abuse of modafinil, although available data suggest a much lower potential for abuse and dependency than amphetamine-like stimulants (Myrick et al, 2004).

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