Non-medical use (NMU) of prescription stimulant medications is a continuing public health concern (1–3). Emergency department (ED) visits related to NMU of stimulant medications increased 200% from 2005 to 2010 (4). Between 2006 and 2011, despite no change in treatment visits for adults involving prescriptions of dextroamphetamine, amphetamine or methylphenidate, NMU of prescription stimulants increased 67% and ED visits increased 156% (5). College students are particularly likely to engage in NMU of prescription stimulants (5–10). Past-year NMU of prescription stimulants is more common among 18–25 year-olds (~7.5%) compared with younger and older age groups (both ≤ 2%) (11).

Stimulant medications prescribed for attention-deficit/hyperactivity disorder (ADHD) are widely available on college campuses (12). One longitudinal study (13, 14) followed a single cohort of college freshmen for 4 years. Over the follow-up period, nearly two-thirds were offered prescription stimulants for NMU and 31% reported NMU, a prevalence echoed by other surveys (15).

One motivation for stimulant NMU is enhanced academic performance (1, 16), despite evidence that stimulant NMU does not improve academic performance (7, 10, 17). Stimulant NMU is associated with other drug use and/or heavy drinking (18, 19).

While most stimulant NMU is by oral routes, non-oral NMU has been noted (6, 14, 20). Only a few studies of college students have evaluated non-oral ROAs of prescription stimulants (14, 20), usually snorting and less often injection and smoking (7, 21). Drugs taken via injection, smoking and snorting have a more rapid onset than oral ingestion, resulting in greater reinforcement for getting high and addictive potential (22). Non-oral routes also enhance the risk of cardiovascular failure, cardiac arrhythmia, high blood pressure, paranoia (10) as well as hospitalization and death (23). Levels of prescription stimulant smoking or injection (when reported) in the general population of adults (6) and among college students (20) have been low (<6%). Estimates of snorting by college students range from 17% (14) to ~40% (20, 21).

The Food and Drug Administration (FDA) has declared NMU of prescription stimulants a serious public health concern and has called for the assessment of the potential impact of abuse deterrent formulations (ADFs) for prescription stimulants (24). ADFs, designed to deter non-oral use, have demonstrated benefits in reducing abuse of prescription drugs and associated adverse consequences, especially for prescription opioids (25–27). Examination of non-oral ROAs of prescription stimulants by college students has been previously identified as useful for determining the potential value of abuse deterrent formulations (ADFs) (16, 19). Surprisingly, little research has considered the characteristics or practices of college students who use non-oral ROAs.

One such characteristic is polydrug use, which is the misuse of more than one class of psychoactive prescription drugs (28). Toward this end we examined prescription stimulant NMU in the context of polydrug use by college students. We sought to investigate, descriptively, pathways of non-medical use and abuse of other non-alcohol substances. This may be particularly important given that initial exposure to prescription stimulants may occur via legitimate treatment for ADHD symptoms, as opposed to the traditional “gateway hypothesis” (29) which posits that early experimentation with alcohol, tobacco or marijuana is associated in a causal way to increased substance involvement later in life.

The present cross-sectional study used a self-report, online survey to characterize a sample of college students reporting NMU of prescription stimulants to gain a preliminary view of respondents' routes of administration, factors contributing to the NMU, and pathways of initiation associated with specific patterns of non-oral use. We particularly sought to consider whether prescription stimulant NMU by college students is the only type of misuse/abuse of non-alcohol substances, is an initial foray into misuse/abuse of other substances or occurs within the context of ongoing polysubstance abuse. Finally, we sought to examine the associations among different ROAs, motivations for NMU and sources of procurement of the prescription stimulants being misused.

This cross-sectional, online survey evaluated prescription stimulant NMU among college students in the United States. Pathways of initiation of prescription stimulant NMU were presented, as well as characteristics of non-oral use.

All respondents to this survey engaged in NMU of stimulants, while nearly one in four (23%) reported non-oral use. Non-oral use was consistently associated with increased likelihood of serious, non-alcohol substance use. Although other studies have found ADHD diagnosis, gender, race, depression, anxiety, marijuana and alcohol use to be associated with prescription stimulant NMU (34), in this study age, race, recent alcohol binge drinking, and marijuana use did not differentiate oral and non-oral NMU. Univariate analyses revealed associations of major factors with reports of non-oral ROA, especially being male, lifetime diagnoses of ADHD, alcohol or other substance disorder as well as conduct/oppositional defiant disorder, and history of prescription opioid NMU.

The finding that women students were less likely overall to report non-oral NMU practices, may be an underlying feature common to many of the other factors investigated. For instance, women are less likely to be diagnosed with ADHD and, women diagnosed with ADHD appear to exhibit lower levels of conduct problems than their male counterparts (35), both factors that were associated with non-oral ROA NMU in this survey. Women were significantly less likely to inject, even if they reported snorting prescription stimulants, however, oral-only ROA vs. snorting but not injection were not significantly different by gender. Injecting may be associated with higher risk-taking behavior in men with ADHD (35). On the other hand, other studies of gender differences in adults with ADHD (36) have found women with an ADHD diagnosis to be much more likely than women without one to express suicidal ideation, which may be a very different phenomenon than male risk-taking behavior.

Of those reporting non-oral prescription stimulant NMU, the large majority (88%) snorted the medication, with a quarter reporting smoking and 15% injecting. Our findings are consistent with those from the few studies investigating injection of prescription stimulants, suggesting that injection of these medications is relatively rare (6, 20, 23). Because the small number of college students who inject prescription stimulants in this sample resulted in point estimates that may not be stable, the findings reported for non-oral injection users should be considered preliminary and used to stimulate further research. However, even though injection may be rare, it is associated with much higher risk and understanding what motivates this behavior may inform prevention and treatment strategies.

Compared with oral-only users, respondents reporting any non-oral route were more likely to have more serious substance use histories and drug-use patterns. Non-oral use is consistently associated with serious adverse consequences (10), increased prevalence of overdose (37), addictive potential (38) and significant risk of morbidity and mortality (23). Note that in the current study, the large majority of those who reported NMU of prescription stimulants via non-oral routes snorted the drug. Further research into this type of non-oral prescription stimulant NMU is warranted, as such work may clarify a role that ADF formulations can have in reducing the serious adverse consequences of non-oral prescription stimulant NMU (16, 19, 23, 24).

Consistent with findings of earlier research (7, 10, 39), two-thirds of NMU respondents obtained the prescription stimulant from a family member or friend (either bought, given, or stolen). About 40% obtained the stimulant through a legitimate prescription. Non-oral users, on the other hand, endorsed other sources, especially getting the drug from a “dealer,” and online purchases, while also obtaining prescription stimulants through the usual sources of friends, family, and providers.

The motivation most often reported for NMU by oral routes and snorting was performance enhancement, as others have noted (3, 7, 10, 40). Such oral NMU of prescription stimulants for performance enhancement may signal the lack of adequate resources or supports for students in a highly artificial (e.g., memory-based performance testing), high stress environment, where academic outcomes can have life-altering consequences. NMU for performance enhancement by students with ADHD using oral routes also raises questions regarding the perceptions by these patients as to the adequacy of their treatment (16). It may also be relevant that learning problems often associated with an ADHD diagnosis may be more responsive to treatments other than medication (35). Although not among the most often reported motivations by those who inject, performance enhancement was reported as a motivation for NMU by nearly a quarter of those respondents. Those reporting snorting and injection were significantly more likely than the oral-only group to report motivations to get high or to enhance the effects of other drugs. These motivations and the higher likelihood of polysubstance use in non-oral users are indicative of higher risk behaviors often associated with having or developing significant substance use problems.

More than 90% of prescription stimulant NMU was observed in the context of polysubstance use (not including alcohol); a finding consistent with results of a population-based survey (41). Among polysubstance users, 18.7% reported marijuana as the only other drug used. While 80.6% of polysubstance users reported marijuana use, and 69.6% of those reported marijuana use prior to prescription stimulant NMU, marijuana was considered separately in this study, given its legal status in many states for use by at least some individuals in the examined age range as well as changing views of marijuana use by the public (42, 43). Nevertheless, it is noteworthy that prescription stimulant NMU preceded prescription opioid NMU 45% of the time and preceded illegal drug use 32% of the time. Our pathways analyses are conceptually similar to the so-called “gateway hypothesis” (29), which proposes that a child or adolescent's early experimentation with or exposure to alcohol, tobacco, or cannabis leads to more addictive illicit drugs later in adulthood (44, 45). Empirical examination of the gateway hypothesis has yielded conflicting and ambiguous results (45, 46), suggesting that a simple, causal role of early exposure to abusable or addictive substances is unlikely. Interpretation of early prescription stimulant NMU in the pathway toward use of illegal drugs, NMU of other prescription drugs or use by non-oral routes is complex. There is evidence from this survey and other research (47) that an ADHD diagnosis maybe a risk factor for later serious drug involvement (i.e., polysubstance use and non-oral ROA use). Specifically investigating exposure to ADHD medications in childhood and adolescence, McCabe et al. (48) found that children who initiated stimulant medication for ADHD early (aged 9 or less) and for longer duration (6 or more years) did not differ between population controls (youth without ADHD and unmedicated youth with ADHD).

The pathway findings among the 90% of survey respondents reporting polydrug use in this study support other studies that suggest primary care physicians largely underestimate the potential for NMU and diversion of ADHD medications by their patients (16). Thus, the findings presented here suggest that prescription stimulant NMU coincided with a more general pattern of substance misuse/abuse. Prescribers should at least be cognizant of the potential for current or later escalation of substance use by their patients. This study shares the limitations of other online surveys, including self-selection bias, self-report of drug use and medical diagnoses, and the use of an online panel. Although efforts were made to establish a representative sampling frame from which to draw respondents, the final sample may not be representative of college students who engage in NMU. While many of the findings are consistent with those from other studies, generalization should be approached cautiously. Use of a cross-sectional survey to explore retrospective recall of pathways of drug initiation across time is, by definition, limited, and can only be considered suggestive. In agreement with other authors (9), our use of the Internet panel survey is intended to complement, not replace, national probability studies.

A number of authors have proposed policies and interventions to address college student prescription NMU that are often educational in nature, stressing legal and ethical concerns (i.e., is NMU “cheating?”) and combating the “misinformation” that prescription stimulant NMU is harmless (10). Over-estimation of the extent to which stimulant products enhance memory, attention and creativity for individuals outside the treatment of ADHD (49) may have important implications for educational interventions. Identifying and providing services to those at risk for mental health and substance use issues has also been proposed (10). A comprehensive strategic planning guide has recently been published online by the Drug Enforcement Administration (50) to address prescription stimulant NMU. The guide covers assessment, building capacity and programs, implementation, and evaluating the impact of interventions. Some authors have stressed viewing NMU as a “red flag” for possible involvement in other illicit drug use, poor academic performance, and mental health problems (18, 19) and called for better diagnostic practices for ADHD (7), which can present challenges in adults (51, 52).

Our finding that nearly a quarter of NMU involved non-oral routes highlights the importance of non-oral NMU of prescription stimulants. This concerning rate of non-oral NMU suggests that further work should explore methods to reduce such use and the deleterious outcomes associated with snorting or injecting the drugs. Promising efforts to reduce the prevalence and negative impacts of prescription stimulant NMU among college students likely include a range of preventive approaches addressing policy, education, diagnostic practices and detection of malingering, paired with treatment approaches utilizing cognitive behavior therapy (53, 54), interventions geared to patients' specific needs, such as personality-targeted interventions (55), sensitivity to the unique needs of women with ADHD, who, for instance, appear to be more impacted by parenting style (56) than male ADHD patients, use of therapies other than medications when learning problems are a major presenting complaint (35), and, possibly, medication formulations that present barriers to non-oral use (16, 19, 23, 24).

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by New England Institutional Review Board (NEIRB). The patients/participants provided electronic informed consent to participate in this study.

SB, SF, AR, JN, KA, and JG contributed to conception and design of the study. SB and RR performed the statistical analysis. SB wrote the first draft of the manuscript. SF, AR, JN, and JG wrote sections of the manuscript and provided specific edits/revisions. All authors contributed to the article and approved the submitted version.

SB is a consultant to Inflexxion, an IBH Company. Inflexxion contracts with FDA and multiple companies with interests in some of the products included in the compounds evaluated for this article. In the past year, SF received income, potential income, travel expenses continuing education support and/or research support from, Akili, Arbor, Genomind, Ironshore, Ondosis, Otsuka, Rhodes, Shire/Takeda, Sunovion, Supernus, Tris, and Vallon. With his institution, he has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. In previous years, he received support from: Alcobra, CogCubed, Eli Lilly, Enzymotec, Janssen, KemPharm, Lundbeck/Takeda, McNeil, Neurolifesciences, Neurovance, Novartis, Pfizer, and Vaya. In the past 2 years, JN is/has been an advisor and/or consultant for Adlon Therapeutics, Akili Interactive, Arbor, Enzymotec, Ironshore, Medice, NLS, OnDosis, Pfizer, Rhodes, Shire, and Supernus. He was a DSMB member for Pfizer and Sunovion, and received research funds from Enzymotec, Otsuka, Shire and Supernus. He also has received speaker fees from Shire for disease-state presentations and served as a consultant for the US National Football League. KA has current investigator-initiated research funding from Takeda Pharmaceutical Company and serves as an advisory board member for Arbor Pharmaceutical Company. AR reports book royalties (Routedge/Taylor Francis Group), scientific board honoraria (Shire/Takeda, Arbor), consultant honoraria (Tris Pharmaceuticals and National Football League), and CME presentations (APA, Shire/Takeda, Globala Medical Education, and US Psychiatric Congress). RR is a Senior Epidemiologist at Inflexxion, an IBH Company. Inflexxion contracts with FDA and multiple companies with interests in some of the products included in the compounds evaluated for this article. JG is the Chief Scientific Officer at Inflexxion, an IBH Company. Inflexxion contracts with FDA and multiple companies with interests in some of the products included in the compounds evaluated for this article. JG has served as an expert witness on behalf of two manufacturers of prescription opioid medications.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.