To our knowledge, this is the first prospective follow-up study to examine the relationship between age of initiation of methylphenidate treatment for ADHD and subsequent development of SUD, as well as other disorders. Risk of developing SUD was significantly associated with age at methylphenidate treatment, specifically, the later the treatment, the greater the chances of developing SUD. The principal value of the finding is in disconfirming that early exposure to stimulants presents special risk to children with ADHD, at least with regard to SUD and antisocial personality disorder.
Unexpectedly, the development of antisocial personality disorder accounted for the association between age when first treated with methylphenidate and substance abuse. This association was not due to age-related differences in early conduct problems. Although findings are consistent with animal data that later preference for cocaine in rats is relatively decreased by exposure to methylphenidate early rather than late in development (16
), the relevance of animal neurodevelopmental models of stimulant exposure is not straightforward. The relationship between age at first stimulant exposure and later SUD has to take account of the observation that the relationship is mediated by the development of antisocial personality disorder.
It is unclear why age at initiation of stimulant treatment and the later development of SUD and APD appear related. Castellanos and colleagues (40
) reported that unmedicated children with ADHD had smaller brain white matter volume than medicated children with ADHD and non-ADHD comparisons. Early stimulant treatment might increase brain functional reserve by increasing (or normalizing) brain white matter volume during a developmental period of greatest plasticity, and greater brain functional reserve may be associated with decreased risk of SUD. We are presently conducting an adult follow-up study on the current sample, now age 40, in which MRI scans will examine whether there are structural differences in early-treated and late-treated cases.
The major limitation of this study is that it is an experiment of nature which relied on a referred clinical sample. The age at referral was not experimentally controlled, so that unidentified non-random factors related to treatment initiation, other than those examined, may have contributed to the relationship between age first treated and SUD and APD. For example, perhaps parenting-family factors mediated this association, such that failure to attend to the needs of the child led parents to delay treatment for their child. Parent psychopathology, in general, and parent APD and SUD, in particular, did not explain this relationship, but other features related to child rearing may be relevant. Therefore, replication is essential. Other limitations include the sample's ethnic homogeneity, exclusion of females, and the minimum age of 6, thus restricting generalizability of results to clinic referred 6–12 year old white males. Furthermore, we do not know whether findings apply to early stimulant exposure or to early referral for treatment, independent of methylphenidate administration. It could be that timing of interventions, regardless of their nature, affect long-term outcome. Thus, the duration of untreated ADHD in childhood, rather than stimulant treatment per se might the important variable. Put otherwise, we cannot differentiate presumed effects of stimulant medication from effects of age at referral, independent of stimulant exposure.
The use of stimulants in young children has generated considerable controversy. At the least, the study findings do not indicate that treatment relatively early in childhood increases risk for negative outcomes.