Translating the Nuanced Risk for Substance Use Among Adolescents Treated for ADHD into Clinical Practice: A Commentary on

Abstract

In their recent examination of the Monitoring the Future (MTF) data, McCabe and colleagues (2023) address the complex, longstanding, and clinically valuable questions of whether and how stimulant medication treatment for adolescents with ADHD relates to their risk for substance use. Here, we expand on the authors’ interpretations of their nuanced findings of increased risk for illicit stimulant use and non-prescribed stimulant medication use for youth with later age of medication treatment initiation and shorter treatment duration. We particularly focus on highlighting tangible clinical implications, and we recommend ways future research can build on the authors’ findings to further clarify this important issue.

Psychostimulant medication is the first-line treatment for ADHD, with decades of compelling evidence backing its effectiveness and suggesting generally negligible long-term side effects. However, an unsolved question in the literature that troubles prescribers and caregivers is whether ADHD medication increases risk for later harmful substance use. Numerous research teams have attempted to address this important question, with most findings indicating protection or no associations, and very few studies suggesting increased risk for substance use-related outcomes (Humphreys et al., 2013). The heterogeneity of ADHD samples has obscured implications for risk (e.g., longitudinal studies of children with ADHD versus adult samples diagnosed at older ages). Moreover, a specific concern that has been difficult to study due to power challenges is risk for harmful use of stimulant substances. The field therefore benefits from a recent paper by McCabe and colleagues (2023), which leverages the longitudinal Monitoring the Future (MTF) data with its unique strengths (large representative sample; variable history of treatment timing) to shed light on this deceptively complex question.

McCabe et al. (2023) compared the risk of using illicit stimulants (cocaine, methamphetamine) and misusing prescription stimulants among adolescents with varying ages of initiation and duration of prescribed ADHD medication treatment. Population controls (those without ADHD plus the presumably small portion of untreated adolescents with ADHD) were also included in comparisons. Focusing first on the issue of illicit stimulants, results showed that adolescents who began ADHD stimulant treatment early in life (operationalized as by age 9) and for a relatively long duration (more than 6 years) were at no higher or lower risk of using cocaine or methamphetamine than were population controls – either over the past year or across their lifetimes. In contrast, adolescents who started prescribed stimulants later (age 10 or after) and for shorter durations had increased risk of cocaine and methamphetamine use compared to population controls, with the greatest risk generally among those who started treatment latest (age 15 or after) and who had only been taking prescription stimulants for less than a year. Moreover, later and shorter prescribed stimulant use was associated with higher odds of cocaine (but not methamphetamine) use relative to earlier/longer prescribed stimulant use, indicating heightened risk among late-starting youth and possible protection associated with early, enduring treatment. Together, this set of findings highlights a critical clinical distinction that should be further investigated: differences between youth with ADHD who start treatment in childhood versus later.

The authors also address the notable public health concern of prescription stimulant misuse. All adolescents with prescription stimulant histories had higher risk than population controls for use without a doctor’s orders (the definition of “misuse” in the study), but this risk was significantly lower when treatment was initiated at younger ages and for longer duration versus older ages/shorter duration. These results help isolate who is driving non-prescribed use among the 10.4% of adolescents in the MTF who reported this behavior. While 5.6% of population controls reported non-prescribed use, 11.4% to 26.0% of ever-medicated adolescents reported it (again, lowest among those stimulant-treated by age 9 and for six or more years, and highest amongst those starting treatment at high school age). We see both the well-known ADHD-related risk for substance use reflected here, but also heightened vulnerability associated with “late” starting and brief treatment. Based on MTF data (Miech et al., 2020), less than half of all 10^th and 12^th graders reporting ADHD medication treatment in their lifetimes were still prescribed medication for ADHD at the time of survey (past 30 days). Thus, consistent with many longitudinal clinical studies, medication cessation is normative, which probably includes adolescents who resume medication on their own (non-prescribed use).

It seems especially important to consider the clinical implications of the “misuse” findings. First, a key distinction is frequency and quantity. In the 2019 MTF, 4.5%, 1.1%, and 3.9% of 12^th graders reported past year non-prescribed use of amphetamines, Ritalin, and Adderall, but only 2.3%, .6%, and 1.5% reported use more than 1–2 times (.4 to 1.5% more than five times). Thus, the frequency of this behavior (in the general population) is on par with use of hallucinogens and LSD (versus marijuana, with 35.7% reporting past-year use with a more balanced frequency distribution) and suggests isolated experimentation by about half of those with non-prescribed use. Relatedly, it is unknown whether stimulant misuse stopped or declined once prescribed treatment started. Although “late-starting” ADHD treatment recipients show the highest rates of non-prescribed use, consideration should be given to the likelihood that many of these individuals may be misusing infrequently and, given knowledge of treatment-recommended dosage schedules, some may be self-medicating. Some research lends support to this possibility. The most frequently cited reason for stimulant misuse among college students is cognitive enhancement (e.g., Faraone et al., 2020), and stimulant misuse is correlated with worse ADHD symptoms even among young people who are not (yet) treated for ADHD (Arria et al., 2011). Indeed, having suspected or untreated ADHD is associated with an increased risk of using stimulants without a prescription (Faraone et al.). Research examining adolescents’ reasons for non-prescribed use of stimulants as a function of treatment history may help elucidate the prevalence of this pattern. If widespread self-medication is documented, then this would underscore the clinical need for earlier ADHD detection and treatment.

Additionally, we concur with McCabe and colleagues that careful monitoring of adolescents initiating stimulant treatment is imperative. Interestingly, once a medication has been prescribed, the need for “use without a doctor’s orders” becomes irrelevant. Thus, from the perspective of the clinician treating an adolescent with ADHD, discussion may need to focus on previous non-prescribed use as a red flag for other health risk behaviors (e.g., cannabis use; diversion of stimulants) and treatment adherence (e.g., using medication as prescribed). Physician training can aid these discussions (McGuier et al., 2022). Additional research that examines the roles of age of initiation/duration in taking stimulant medication more than prescribed--another form of prescription stimulant misuse not included in the current study--can further inform physician guidelines.

Across all analyses, the McCabe et al. (2023) findings clearly show an association between early, persistent stimulant treatment and lowered risk of substance use relative to later, shorter treatment – both for non-prescribed stimulant and cocaine use. Among adolescents who were persistently medicated for several years, we wonder how consistently youth took their prescribed stimulants for ADHD, and whether differences in consistency yield differential effects on either illicit stimulant use or prescription stimulant misuse. Groenman and colleagues (2019) found that early-starting long duration treatment was associated with lower risk of later SUD, but medication trajectories were variable, suggesting that the age of onset may be most important.

A valuable feature of McCabe et al.’s (2023) study design is its contrasts between adolescents treated with stimulants versus nonstimulants. Those who took nonstimulants had a higher risk for cocaine, methamphetamine, and prescription stimulant misuse than population controls, but no greater risk than those prescribed stimulants the earliest/longest. Nonstimulant medication is widely considered to be a safe alternative to stimulants with respect to the potential for prescription medication misuse; these findings suggest that while nonstimulant treatment does not appear to eliminate the risk relative to population controls, the risk is commensurate with that among adolescents who have been using stimulant medications since childhood. Given that age of initiation/duration was not measured among prescribed nonstimulant users, it is possible that most adolescents who took nonstimulant medication started it early and used it for a long duration, which might account for the comparable results to the early/long stimulant treatment groups. Research that examines age of initiation and duration of nonstimulant treatment can help clarify the picture.

This study’s focus on adolescence, before more entrenched patterns of substance use in adulthood are established, is crucial to inform targeted intervention. Given that early (i.e., adolescent) substance use forecasts escalation to more serious use, problems, and substance use disorder, identifying adolescents who are experimenting with illicit stimulants and misusing prescription stimulants is necessary to monitor for and disrupt long-term problematic substance use trajectories. The practical significance of the effect sizes in this study indicate the potential for meaningful intervention. For example, the latest/shortest stimulant treatment group were 2½ times more likely to misuse prescription stimulants than the earliest/longest group and nearly 4 times more likely than population controls, which amounted to a rate of 26% – a staggering 1 in 4 adolescents – versus just 11% and 5%, respectively. (However, we remind readers to remember considerations about frequency of, and motives for, use.) Effect sizes for cocaine and methamphetamine were similarly clinically meaningful, even in this large sample.

The resounding clinical message of McCabe and colleagues’ findings is that earlier and longer stimulant treatment for ADHD appears to be associated with lower risk of adolescent cocaine use and prescription stimulant misuse than later and shorter stimulant treatment, which certainly pushes providers and caregivers to consider starting children with ADHD on medication before adolescence. It is important, though, when translating these findings to clinical practice to not reify age 9 as a critical threshold by which stimulant treatment must be initiated to effect protection. Indeed, the authors acknowledge this cautionary point, noting the growing risk with increasingly later initiation and shorter duration, such that intermediate starting ages/durations were related to intermediate levels of substance use risk.

Likewise, this does not mean that adolescents with ADHD should avoid starting stimulant treatment if the need or openness only arises later, especially given evidence that stimulants can be effectively used even in the presence of adolescent SUD (Winhusen et al., 2011). Moreover, symptom escalation is known to accompany the transition to secondary school (Langberg et al., 2008), which may underlie late-starting treatment. Instead, youth taking ADHD medication, especially those who start stimulant medication later, should be carefully monitored for medication adherence and illicit substance use. Future research should delve into the heterogeneity within stimulant-treated individuals with ADHD. Importantly, most adolescents (and young adults) do not misuse their prescriptions or abuse illicit stimulants; identifying protective factors among these youth can help providers weigh the pros and cons of various treatment recommendations using a personalized medicine approach.

McCabe and colleagues (2023) appropriately caution that their design does not permit rigorous tests of causality. Indeed, one of the trickiest complications to studying how age of initiation and duration of ADHD medication relates to later substance use is the necessarily observational data, given the virtual impossibility of randomly assigning individuals to different years-long treatment patterns. As a result, confounding factors that make someone more likely to both use substances and start ADHD medication later/for a shorter duration pose significant challenges to causal inference regarding definitive protection or risk of ADHD medication. The authors are to be commended for covarying likely important confounders (e.g., sex, grade level, parent education, other substance use). However, other known and unknown factors that could be driving both late/short treatment and illicit stimulant use/stimulant misuse, such as ADHD symptom severity, past-year conduct problems (versus past-month truancy), and family factors (e.g., parental substance use) could be driving the observed associations. The authors point out that the substance use outcomes they examined may have occurred prior to rather than after starting stimulant medication in some cases. Indeed, a visibly poor clinical profile (increasing substance use, worsening grades, heightened ADHD symptoms, increasing detachment from school) may have temporarily catalyzed parents to take action. This highlights the importance of providers assessing the full clinical profile when prescribing and managing stimulants and especially when treating teens with psychostimulants for the first time. In future research, factors associated with late and short duration treatments need to be better understood. Statistically, causal inference methods, such as propensity score and marginal structural modeling, are useful for estimating the potential causal effects of stimulant treatment on outcomes such as substance use, especially when considering medication use across time.

Conclusion

Although complications remain, McCabe et al.’s (2023) MTF findings sharpen our understanding of how ADHD medication relates to risk for substance use by highlighting the importance of age of treatment initiation and duration. Whether these factors directly affect risk or serve as a marker for other processes (substance use risk and protection), or both, is unknown. Regardless, the findings help assure clinicians that early treatment is not associated with increased illicit stimulant substance use and encourage heightened monitoring of adolescents newly taking ADHD medications. The findings also pinpoint crucial remaining pieces of this clinically important puzzle for ADHD researchers to solve. For instance, what causal mechanisms drive later identification and treatment of ADHD? Does late-initiated stimulant treatment help prevent substance use from worsening in adulthood relative to no treatment? How should caregivers and healthcare providers evaluate the relative risks and benefits of starting a young person on ADHD medication at various ages? Does the cumulative amount and consistency of medication use matter? ADHD researchers are charged with building on McCabe et al.’s illuminating findings to address these and other remaining questions using prospective longitudinal designs, causal inference statistical methods, and precise, detailed measurement of ADHD medication and substance use/misuse across time. The resulting advances in our understanding must then be clearly communicated to families and providers and be effectively disseminated into the clinical settings where youth with ADHD may directly benefit.