The present study is the first to directly compare the reinforcing and subjective effects of MPH in individuals with and without ADHD. Several noteworthy findings were observed. First, the reinforcing effects of MPH as measured by the PR task were significantly higher in adults diagnosed with ADHD compared to a group of nondiagnosed adults. Second, the only group differences that were observed for the subject rated effects measures were on items generally assessing cognitive status (Concentration and Confused items from the DEQ) or affect/arousal (Sedative subscale of the ARS; Irritable, Sad, Tired from the SEQ; Alert from the DEQ). Since other measures of subject-rated effects did not differ between groups, it is possible that the comparative reinforcing effects of MPH in ADHD versus non-ADHD adults may be more related to the effects of the drug on these endpoints rather than the euphoria-producing effects that are commonly associated with drug reinforcement. Finally, among healthy, non-ADHD adults in the present study, MPH doses as high as 60 mg failed to increase PR break points above placebo levels. This was observed in spite of the fact that robust main effects of MPH were found for typical stimulant subjective effects (e.g., Like Drug, Good Effects, Excited, Would Like to Take Again, ARCI A, and ARCI BG.). This suggests that the reinforcing effects of MPH are not isomorphic with the subjective effects of the drug.
These findings are consistent with previous work that showed children and young adults with ADHD reliably chose MPH over placebo, with a lack of significant effects for subjective effects (Fredericks and Kollins 2004
; MacDonald Fredericks and Kollins 2005
). In addition, other studies have reported that MPH failed to produce reinforcing effects in non-ADHD adults when administered under routine laboratory conditions, although when environmental conditions are manipulated (i.e., sleep deprivation, high demand tasks), MPH exhibits more robust reinforcing effects (Chait 1994
; Roehrs et al. 1999
; Stoops et al. 2005
ADHD is hypothesized to be the result of disrupted dopaminergic transmission in corticostriatal circuits, which in turn gives rise to the characteristic deficits in executive functioning observed in ADHD patients (Grace 2001
; Solanto 2002
). This hypothesis is supported by studies showing differences in dopamine transporter (DAT) density in relevant striatal areas in ADHD patients compared to controls (Cheon et al. 2003
; Dougherty et al. 1999
; Dresel et al. 2000
; Krause et al. 2000
; Larisch et al. 2006
; Spencer et al. 2005
; Volkow et al. 2007
). Although these studies have reported discrepant findings with respect to the direction of DAT density change (i.e., some report higher levels, some report lower levels in ADHD), collectively, they suggest associations of DAT density and its consequent effects on DA neurotransmission with the clinical condition of ADHD. Since MPH increases DA neurotransmission through blockade of the DAT, at the clinically relevant oral doses used in the present study, the drug may reinforce behavior more strongly in patients with ADHD not because it produces euphorigenic effects but rather because it restores DA activity to comparable rates as non-ADHD individuals. These effects are noticeable by observed changes in self-reported increases in concentration, alertness, and decreases in confusion. As such, the reinforcing effects of the drug in individuals with ADHD may be mediated most saliently by improvements in cognition and executive functioning. Preliminary support for this hypothesis comes from the differential pattern of correlations observed between items from the DEQ and PR task performance ().
There was discordance in the present study between the reinforcing and subjective effects of MPH among the non-ADHD subjects. None of the active doses of MPH occasioned PR responding above placebo levels for the Control group. By contrast, even when considered independently of the ADHD group, a number of prototypical stimulant drug subjective effects showed main effects of MPH dose for the Control group (e.g., Good Effects, Like Drug, Take Again, ARCI A; data not shown). These findings highlight the fact that multiple behavioral indices of abuse liability are required to characterize the potential for a drug to be self-administered. A more fine-grained analysis of these data may be required to better understand the findings. For example, previous studies of drug reinforcement have conducted “responder analyses” by examining subjects who worked for drug administration versus those who did not to help identify those individual difference and drug factors that are most strongly associated with reinforcement (Perkins et al. 1997
). For example, several studies have shown that the personality trait of sensation seeking is positively associated with the reinforcing effects of amphetamine (Kelly et al. 2006
; Stoops et al. 2007
). Although not measured in the present study, similar personality traits may help to explain our lack of reinforcing effects in the control group and the observed between group differences
The lack of reinforcing effects of MPH in the non-ADHD individuals in the present study deserves comment given the well-established abuse potential of MPH (Kollins et al. 2001
). This observation is not unprecedented in the literature. Several previous studies have failed to show that MPH functions as a reinforcer under routine laboratory conditions (Chait 1994
; Roehrs et al. 1999
; Stoops et al. 2005
). In studies that have shown MPH to function as a reinforcer, it often occurs under specific environmental conditions, such as sleep deprivation or prior to a high demand task (Roehrs et al. 1999
; Stoops et al. 2005
). The methods for this study did not require any specific demands following the PR task, other than remaining in the laboratory for several hours and participating in sedentary activities. As such, the present findings are comparable to those studies that failed to report reinforcing effects of MPH in presumably non-ADHD adults. Participants in the present study were also stimulant naïve and were therefore receiving MPH for the first time in the laboratory. The reinforcing effects of MPH may have been different in the non-ADHD group if individuals who had recreational experience with stimulant drugs were included.
The present study had several limitations. First, we did not include objective measures of attention, concentration, or other executive functions, and thus, the interpretation that MPH reinforcement was mediated in individuals with ADHD by improvements in concentration and alertness is based solely on self-report. Moreover, the observed mediation is only a correlation and cannot be interpreted as causal. It will be important for future work to evaluate the association between improvements in cognitive functioning and drug reinforcement in individuals with ADHD. The dose range of MPH evaluated in the present study (20–60 mg) was also somewhat narrow and may explain the lack of reinforcing effects in the non-ADHD participants and, in general, the lack of dose-dependent effects across endpoints. Also, there were no explicit task manipulations following MPH administration, and this may have also led to lower reinforcing effects among non-ADHD subjects. Given that group differences in drug reinforcement were still observed, however, the dose range and post-administration tasks might best be viewed as independent variables to be manipulated in subsequent studies, rather than outright limitations of this study. Our sample ascertainment strategy may limit generalizability of the findings. We excluded those participants in both groups who exhibited any DSM-IV Axis I or II psychopathology, or who had any history of recreational or clinical stimulant use. Comorbidity in adult ADHD is common and among non-ADHD individuals, those with no psychiatric history may be least likely to misuse MPH (Kessler et al. 2006
). Epidemiological surveys suggest that illicit use of prescription stimulants like MPH is more likely to occur in individuals with more extensive drug use history (McCabe et al. 2005
). It would be interesting in future studies to include a more diverse sample of both ADHD and non-ADHD individuals to determine whether psychiatric comorbidity or stimulant use history moderate the reinforcing effects of the drug. We also did not apply any corrections to our statistical tests, and given the number of comparisons that were conducted, it is possible that some of the observed effects occurred by chance. However, since the majority of significant effects converged in a similar direction, this concern is mitigated to some degree. Finally, our use of immediate-release MPH precludes conclusions about the reinforcing or subjective effects of longer-acting formulations of MPH, which are commonly used. At least two studies have shown that longer-acting formulations produce lower magnitude subjective effects in non-ADHD individuals, and future work should clarify whether similar formulation differences are observed for reinforcing measures (Kollins et al. 1998
; Spencer et al. 2006
In spite of these limitations, the present study adds to the literature on abuse liability of MPH, especially in the context of clinical use of the drug for the management of ADHD in adults. Individuals with ADHD responded more for MPH capsules than their nondiagnosed peers, and these reinforcing effects were not related to euphorogenic subjective effects. MPH and other stimulants continue to be a mainstay of effective management of ADHD across the lifespan. Still, better understanding of the risk profile of the drug with respect to abuse liability will improve the care we are able to provide to our patients.