REVIEW doi:10.1111/j.1360-0443.2009.02791.x Cognitive enhancement as a pharmacotherapy target for stimulant addictionadd_2791 38..48 Mehmet Sofuoglu Yale University, School of Medicine, Department of Psychiatry and VA Connecticut Healthcare System, West Haven, CT, USA ABSTRACT Background No medications have been proven to be effective for cocaine and methamphetamine addiction. Attenu- ation of drug reward has been the main strategy for medications development, but this approach has not led to effective treatments. Thus, there is a need to identify novel treatment targets in addition to the brain reward system. Aim To propose a novel treatment strategy for stimulant addiction that will focus on medications enhancing cognitive function and attenuating drug reward. Methods Pre-clinical and clinical literature on potential use of cognitive enhancers for stimulant addiction pharmacotherapy was reviewed. Results and conclusions Cocaine and methamphetamine users show significant cognitive impairments, especially in attention, working memory and response inhibition functions. The cognitive impairments seem to be predictive of poor treatment retention and outcome. Medications targeting acetylcholine and norepinephrine are particularly well suited for enhancing cognitive function in stimulant users. Many cholinergic and noradrenergic medications are on the market and have a good safety profile and low abuse potential. These include galantamine, donepezil and rivastigmine (cholinesterase inhibitors), varenicline (partial nico- tine agonist), guanfacine (alpha2-adrenergic agonist) and atomoxetine (norepinephrine transporter inhibitor). Future clinical studies designed optimally to measure cognitive function as well as drug use behavior would be needed to test the efficacy of these cognitive enhancers for stimulant addiction. Keywords Cognition, cognitive enhancers, pharmacotherapy, stimulants. Correspondence to: Mehmet Sofuoglu, Yale University, Department of Psychiatry, VA Connecticut Healthcare System, 950 Campbell Avenue, Building 36/116A4, West Haven, CT 06516, USA. E-mail: [email protected] Submitted 24 April 2009; initial review completed 29 June 2009; final version accepted 25 August 2009 INTRODUCTION A new strategy proposed in this review is to develop new science-based treatment targets that will broaden Stimulant addiction, most notably cocaine and metham- our screening methods for potential medications for phetamine, continues to be an important public health addictions. Converging evidence, especially from human problem, with an estimated 36 million current users neuroimaging and cognitive neuroscience studies, indi- world-wide [1]. Unfortunately, no medications have been cates that cognitive functions, particularly inhibitory proven to be effective for cocaine and methamphetamine cognitive control, are linked closely to addictive behaviors addiction in spite of the large number of compounds [6–9]. These cognitive functions, which are attributed to screened in randomized clinical trials [2–5]. For stimulant the prefrontal cortex (PFC), can also be improved by selec- addiction, the traditional medications development strat- tive medications known as cognitive enhancers. In this egy has been to identify medications that attenuate drug review, cognitive function in stimulant addiction will be reward [5], which is mediated by the dopaminergic overviewed, followed by examples of cognitive enhancers pathway from the ventral tegmental area (VTA) to the that may be used for the treatment of stimulant addicted nucleus accumbens (subcortical structures in the brain). individuals. An ideal cognitive enhancer for addiction This strategy, however, has not resulted in effective medi- pharmacotherapy should enhance cognitive function cation development.Thus, there is a clear need to examine and attenuate drug reward. Although such medications critically our medication development strategies and iden- remain to be identified, promising candidates for addic- tify new treatment targets for stimulant addiction. tion pharmacotherapy will be reviewed and future © 2010 The Author. Journal compilation © 2010 Society for the Study of Addiction Addiction, 105, 38–48 Cognitive enhancement for stimulant addiction 39 research directions will be discussed. This will be a selec- influenced greatly by the neurochemical environment of tive review of potential use of cognitive enhancers for the PFC to a greater degree than other brain regions [27]. stimulant addiction, with a focus upon medications This quality renders PFC functions very susceptible to development. Systematic reviews of medications under genetic and environmental influences, including stress. investigation for stimulant addiction can be found else- However, this sensitivity also renders PFC cognitive func- where [2–5]. For a broader perspective of cognitive reme- tions amenable to treatment with selective cognitive diation in stimulant addiction, the reader is referred to an enhancers. Secondly, inhibitory control is not a circum- excellent review by Vocci [9]. scribed function of the PFC. Rather, many PFC areas con- tribute to inhibitory function including the orbitofrontal cortex, anterior cingulate cortex, dorsolateral PFC, COGNITIVE FUNCTION AND dorsomedial PFC and inferior frontal gyrus [28,29]. More- ADDICTION over, inhibitory control is linked closely to other Many studies have demonstrated that chronic use of PFC functions, most notably to attention and working cocaine and methamphetamine is associated with deficits memory. For example, lapses in attention during early in cognitive functioning, including decision-making, abstinence have been linked to relapse, possibly by reduc- response inhibition, planning, working memory and ing behavioral inhibition [30]. Similarly,working memory attention [10–15]. In a recent meta-analysis [12], function is essential for optimum inhibitory control. cocaine users (n = 481) showed greater impairment in Under high working demand, cocaine users have reduced attention, visual memory, design reproduction and inhibitory control measured by impaired suppression of working memory compared to healthy controls pre-potent responses compared to healthy controls [31]. (n = 586). These deficits seem to be correlated with the As these examples suggest, optimum inhibitory control severity of cocaine use, suggesting a dose-related effect of function depends on other PFC functions including atten- drug use [13]. Similarly, methamphetamine-dependent tion and working memory. One possible, as yet untested, individuals showed deficits in memory, attention, set- treatment implication of these findings is that in stimulant shifting, response inhibition and decision-making abili- users, medications improving attention and working ties [16–20]. The severity of impairments in verbal memory may lead to better inhibitory control. memory and psychomotor function for methamphet- amine users were correlated with loss of dopamine trans- COGNITIVE DEFICITS AND TREATMENT porters in the striatum and nucleus accumbens [21,22]. OUTCOME The neural substrates of these deficits have been exam- ined in functional imaging studies. A recent PET study Despite evidence supporting the presence of cognitive demonstrated low glucose metabolism in the anterior cin- deficits in drug users including decision-making, gulate and high glucose metabolism in the lateral orbito- response inhibition, planning, working memory and frontal area, middle and posterior cingulate, amygdala, attention, the clinical implications of these findings have ventral striatum and cerebellum of recently abstinent received limited attention, due perhaps to the subtle methamphetamine abusers [23]. These and many other nature of these deficits and observations that at least studies point to a dysfunction in the PFC in stimulant some may be reversible following cessation of drug use. users [24]. The PFC serves many functions that are However, former amphetamine users have shown cogni- highly relevant for addiction, including attention, tive impairments similar to current users, suggesting that working memory, response inhibition and decision- these cognitive impairments were not reversible after making [8,25]. short-term abstinence [32]. Similarly, in a longitudinal Among PFC functions, disruptions in inhibitory study of methamphetamine-dependent individuals par- control of the PFC have been the centerpiece in many ticipating in an out-patient treatment program [33], the theories of addiction [6–8]. The inhibitory function of the group continuing to use methamphetamine performed PFC is especially important when the individual needs to best in cognitive tests, followed by the recent relapse override a reflexive pre-potent response, such as drug- group, and the abstinent group (6 months) performed the taking behavior in response to drug cues. In fact, compul- poorest overall. In addition, recent cocaine use seems to sive drug use, the hallmark of drug addiction, is mask underlying cognitive deficits in cocaine users [34], characterized by behavioral inflexibility and more specifi- further indicating a possible decrease in cognitive func- cally a decreased ability to inhibit responses to drug- tioning during early abstinence from stimulant use. related cues, also commonly called impulsivity [26]. Several lines of evidence link cognitive function to From a treatment perspective, the inhibitory control treatment outcome in stimulant users. In a series of function of the PFC has two unique features. First, inhibi- studies, Aharonovich