Prescription stimulants in individuals with and without attention deficit hyperactivity disorder: misuse, cognitive impact, and adverse effects\

ADHD DRUGS

Abstract

Prescription stimulants are often used to treat attention deficit hyperactivity disorder (ADHD). Drugs like methylphenidate (Ritalin, Concerta), dextroamphetamine (Dexedrine), and dextroamphetamine-amphetamine (Adderall) help people with ADHD feel more focused. However, misuse of stimulants by ADHD and nonaffected individuals has dramatically increased over recent years based on students’ misconceptions or simple lack of knowledge of associated risks. In this review, we discuss recent advances in the use and increasing misuse of prescription stimulants among high school and college students and athletes. Given the widespread belief that stimulants enhance performance, there are in fact only a few studies reporting the cognitive enhancing effects of stimulants in ADHD and nonaffected individuals. Student athletes should be apprised of the very serious consequences that can emerge when stimulants are used to improve sports performance. Moreover, misuse of stimulants is associated with dangers including psychosis, myocardial infarction, cardiomyopathy, and even sudden death. As ADHD medications are prescribed for long-term treatment, there is a need for long-term safety studies and education on the health risks associated with misuse is imperative.Keywords: Amphetamine, athletes, attention deficit hyperactivity disorder, cognition, methylphenidate, misuse, performance, studentsGo to:

Introduction

Attention deficit hyperactivity disorder (ADHD) is a treatable neurobehavioral disorder that is defined by persistent and maladaptive symptoms of hyperactivity/impulsivity and inattention (American Psychiatric Association 2000). ADHD is one of the most common psychiatric conditions of childhood (Wilens et al. 2002). Based on the Heath Resources and Services Administration’s National Survey of Children’s Health, the percentage of children aged 4–17 years diagnosed with ADHD increased from 7.8% in 2003 to 9.5% in 2007, representing a 21.8% increase in just 4 years (Centers for Disease Control and Prevention 2010). ADHD is diagnosed in boys at a rate of two to four times that of girls, although this observation may be the result of referral patterns from teachers (Sciutto et al. 2004; Kutcher 2011). Although ADHD was once regarded as a disorder of childhood and adolescence, an estimated 50% of patients diagnosed with ADHD under the age of 18 years continue to have symptoms as an adult (Wilens et al. 2004). Overall, the prevalence of ADHD in adults ranges from 3.5% to 4.5% (Kessler et al. 2006). Differences across ethnic groups within the United States are sometimes found, but seem to be more of the function of social class than ethnicity (Bloom and Cohen 2007). ADHD is found in all countries surveyed with rates similar to, if not higher than, those found in North America (Faraone et al. 2007; Polanczyk et al. 2007). Thus, adult ADHD is one of the most common adult psychiatric disorders.

Individuals with ADHD often have substantial functional impairment in academic, family, and social settings. Youth with ADHD are at an increased risk for academic failure because of learning or language problems. Other consequences associated with ADHD include dangerous driving, impaired peer relationships, delinquent behavior, and impulsive sexuality (Putukian et al. 2011; Visser et al. 2012). Moreover, when ADHD is untreated, there is increased prevalence of certain psychological disorders (e.g., major depression, bipolar disorder, conduct disorder, oppositional-defiant disorder, antisocial personality, substance use, and anxiety) (Faraone et al. 1997; Rasmussen and Gillberg 2000; Kollins et al. 2005; Biederman et al. 2006). However, early treatment may decrease negative outcomes of ADHD including the rate of conduct disorder and adult antisocial personality disorder (Dopheide and Pliszka 2009).

There are both pharmacological and nonpharmacological (e.g., cognitive behavioral therapy [CBT]) treatments of ADHD. Stimulants, such as methylphenidate (MPH; Ritalin and Concerta) and dextroamphetamine-AMP (d-AMP; Adderall) are the most common pharmacologic treatments (The MTA Cooperative Group 1999) and abundant data support the potentially positive effects of prescription stimulants for the majority of children, adolescents, and adults with ADHD. Experts estimate that approximately 60% of children with ADHD are treated with prescription stimulants (Center for Disease Control and Prevention 2005a); therefore, approximately three million children in this country take stimulants for problems with focusing. At the same time, many studies have revealed the numerous adverse effects associated with prescription stimulants when they are used inappropriately.

Stimulants are classified as Schedule II drugs (i.e., providing positive medicinal effects but also considerable abuse potential). The nonmedical use of prescription stimulants represents the second common most form of illicit drug use in college, second only to marijuana use (Johnston et al. 2004). Indeed, many consider stimulants – whether obtained by prescription or illicitly – a convenient option to improve performance or to induce euphoria (get “high”). Major daily newspapers such as The New York Times have reported a trend toward growing use of prescription stimulants, commonly called “smart pills,” by high school and college students for enhancing school or work performance (Jacobs 2005). Unfortunately, media reports appear to condone this behavior as 95% of articles mentioned at least one possible benefit of using a prescription stimulant for neuroenhancement, but only 58% mentioned any risks/side effects (Partridge et al. 2011). Stimulant misuse is often predicted on individuals’ misconceptions or simple lack of knowledge of associated risks.

This review discusses recent studies regarding the use and misuse of stimulants among high school and college students, including athletes, with and without ADHD. Given the widespread belief that prescription stimulants are “smart pills,” we address if these drugs actually enhance cognition in a healthy individual. Athletes may see stimulants as a way to help maintain physical fitness for their competitive sport or to improve their concentration. Finally, we elaborate on the long-term effects of chronic stimulant use. Addiction and tolerance are major concerns, as are psychosis and cardiovascular effects. Surprisingly, these associated risks of stimulant misuse are not frequently addressed in the media and literature. Clearly, the widespread misuse of prescription stimulants represents an important public health issue faced by students, school officials, health centers, and parents.Go to:

Methods

This review was initiated with a PubMed search of the US National Library of Medicine with combinations of the following key words: “Adderall,” “amphetamine,” “methylphenidate,” “dexamphetamine,” “ADHD,” “misuse,” “illicit use,” “non-prescription use,” “non-medical use,” “diversion,” “students,” and “athletes.” A review of all titles was conducted to include only pertinent publications. A hand search of psychiatry journals was performed and reference lists from relevant studies were searched.Go to:

Prescription stimulant use in ADHD

It is estimated that about two-thirds of the children diagnosed with ADHD receive pharmacological treatment (Centers for Disease Control and Prevention 2010) and the majority of medications used are stimulants (Center for Disease Control and Prevention 2005b). The prescribed use of stimulant medications to treat ADHD in children age 18 and younger rose steadily from 1996 to 2008, from an estimated 2.4% in 1996 to an estimated 3.5% of US children in 2008 (Zuvekas and Vitiello 2011). Overall, prescription stimulant use among 6- to 12-year-olds is highest, going from 4.2% in 1996 to 5.1% in 2008; however, the fastest growth rate occurred among 13–18 year olds, going from 2.3% in 1996 to 4% in 2008. Prescription stimulant use remained consistently low in the West than in other US regions and in lower racial/ethnic minorities.

MPH and d-AMP are the most widely used prescription stimulants approved by the US Food and Drug Administration (FDA) for the treatment of ADHD. MPH is a short-acting stimulant drug. Generic MPH is available in many forms, and several versions of the long-acting MPH have been introduced, with Concerta getting the largest share of the market. According to the U.S. Drug Enforcement Administration (DEA), MPH has been the fourth most prescribed controlled substance in the United States since 2003, with over 58,000 Americans purchasing MPH in 2006 (Department of Justice: Drug Enforcement Administration 2008). Both the production and prescription of MPH has risen as the diagnosis of ADHD has concurrently increased. In addition, with the realization that ADHD is a lifelong disorder, MPH has become more commonly prescribed for adolescents and adults, and treatment duration has increased (Horrigan 2001). Both MPH and d-AMP are efficacious and well-tolerated medications and remain the first choice for short duration management in adolescent and adult ADHD (Faraone and Glatt 2010). Although the precise mechanisms underlying the action of these medications are not completely understood, they appear to increase the availability of dopamine, which could account for their therapeutic effects.

Although ADHD is a multifactorial disorder, disrupted dopamine (DA) neurotransmission plays an important role in its pathophysiology. In addition, polymorphisms in the dopamine D1 receptor (DRD1) are associated with the disorder (Misener et al. 2004). MPH and d-AMP both enhance DA signaling in the brain. MPH increases DA by blocking dopamine transporters (DATs) and AMP by releasing DA from the nerve terminal using the DAT as carrier (Kuczenski and Segal 1997). In healthy controls and in adolescents and adults with ADHD (Rosa-Neto et al. 2005; Volkow et al. 2007), MPH significantly increased DA in the ventral striatum (VS) (Volkow et al. 2012), a crucial brain region involved with motivation and reward (Wise 2002). Moreover, intravenous MPH-induced increases in DA in the VS were correlated with improvement in symptoms of inattention after long-term oral MPH treatment. Historically, the core feature of ADHD has been characterized as one of attention deficit, but increasing evidence suggests that a reward and motivation deficit may be of equal importance. It has been proposed that increasing DA in the VS would enhance the saliency of the task, thus improving attention in ADHD (Volkow et al. 2012). Intravenous MPH also significantly increased DA in the prefrontal and temporal cortices that were associated with decreased ratings of inattention, which may be therapeutically relevant.

The widespread use of prescription stimulants for ADHD has not been without critics. In recent months, we have heard speculation about whether ADHD is a real disease, and if it is real, whether it is being grossly over-diagnosed. Disorders often become widely diagnosed after drugs come along that can alter a set of suboptimal behaviors. In this way, Ritalin and Adderall helped make ADHD a household name. If there is a pill that can clear up the wavering focus of sleep-deprived youth, then those rather ordinary states may come to be seen as syndrome. A recent opinion piece entitled “Ritalin Gone Wrong” in the New York Times (Sroufe 2012) by psychology professor L. Alan Sroufe argues that attention-deficit drugs do more harm than good over the long term, a conclusion other professionals in his field dispute. Studies have shown that children who take MPH can show reductions in ADHD symptomatology (inattention, hyperactivity, and impulsivity) and gains in social and classroom behaviors. Studies of adults with ADHD have confirmed its usefulness for this population as well. However, the benefits of prescription stimulants on ADHD symptomatology do not appear to last long.

The Multimodal Treatment Study of Children with ADHD (MTA) compared four distinct treatment strategies during childhood for children diagnosed with DSM-IV ADHD, Combined Type (The MTA Cooperative Group 1999). Children were randomly assigned to 14 months of (a) systematic medication management (MedMgt), which was initial placebo-controlled titration, three times a day dosing, 7 days a week, and monthly 30-min clinic visits, (b) multicomponent behavior therapy (Beh), which included 27-session group parent training supplemented with eight individual parent sessions, an 8-week summer treatment program, 12 weeks of classroom administered behavior therapy with a half-time aide, and ten teacher consultation sessions, (c) their combination (Comb), or (d) usual community care (CC). This randomized, six-site, controlled clinical trial featured rigorous diagnostic criteria at study entry and compared the relative effectiveness of treatments of well-established efficacy. The initial MTA findings reported that all groups showed improvement over baseline at the end of the 14-month treatment period; however, the Comb and MedMgt group participants showed significantly greater improvements in ADHD symptoms than did the Beh or CC participants. By the next follow-up, 3 years after enrollment, there were no longer significant treatment group differences in ADHD symptoms or functioning (Jensen et al. 2007). Molina et al. (Molina et al. 2009) reported the next two follow-up assessments of the MTA sample at 6 and 8 years after random assignment, when the sample ranged in age from 13 to 18 years and found similar findings.Go to:

Prevalence of prescription stimulant misuse

The misuse of a stimulant medication – taking a stimulant not prescribed by a physician or in a manner not in accordance with physician guidance – has been growing over the past two decades. In fact, in the past 10 years there has been a surge in prevalence rates of nonprescription stimulant use among both adolescents and young adults. In general, nonprescription use of MPH in 2000 was reported as 1.2% and in 2006 this number had risen to 2%. Breaking the sample down by age, nonprescription use among adolescents (ages 12–17) went from 2.2% to 1.8% between 2000 and 2006, a slight decrease. Among college-aged individuals (ages 18–25), however, usage increased significantly from 3.6% in 2000 to 5.4% by 2006. Finally, among those 26 and older, usage is the lowest of any group, but rates are rising. In 2000, only 0.7% reported any lifetime usage of MPH, but this number had doubled to 1.5% by 2006 (Bogle and Smith 2009).

The majority of research on the misuse of prescription stimulants has focused on undergraduate college students. The nonprescription use of stimulants has increased in this population, to the extent that the misuse of prescription stimulants is second only to marijuana as the most common form of illicit drug use among college students (Johnston et al. 2004). A 2001 nationwide self-reported survey of more than 10,000 students from 4-year universities in the United States reported a 6.9% lifetime prevalence of nonprescription stimulant misuse, including a past-year prevalence of 4.1% and a past-month prevalence of 2.1% (McCabe et al. 2005). Colleges with the highest past-year prevalence rates were typically located in the northeastern United States, which is corroborated by other reports (McCabe et al. 2005). A study by Teter et al. (2005) of 9161 undergraduates reported an 8.1% lifetime nonprescription stimulant misuse rate among college students, including 5.4% over the past year. According to a 2002 survey of a single US college, 35.5% of undergraduates reported using stimulants without a prescription, with greater frequency occurring in males compared with females (Low and Gendaszek 2002).

The majority of nonprescription stimulant users reported obtaining the drugs from a peer with a prescription – a process termed diversion. The diversion of stimulants is very common and can begin in childhood, adolescence, or young adulthood. A study conducted by Wilens et al. (2008) reported that lifetime rates of diversion ranged from 16% to 29% of students with stimulant prescriptions asked to give, sell, or trade their medications (Wilens et al. 2008). One survey reported that 23.3% of middle and high school students taking prescribed stimulants had been solicited to divert their medication to others at a rate that increased from middle school to high school (McCabe et al. 2004). A review of 161 elementary and high school students prescribed the stimulant MPH revealed that they had been asked to give or sell their medication to others (Musser et al. 1998). Data has shown that the diversion continues among college students. McCabe et al. found 54% of college students who were prescribed stimulants for ADHD had been approached to divert their medication (McCabe and Boyd 2005). Nearly 29% of 334 college students had sold or given their medication to others (Upadhyaya et al. 2005).

McCabe et al. (2005) examined the prevalence rates and correlates of nonprescription use of stimulants (Ritalin, Adderall, or Dexedrine) among US college students and found evidence that misuse is more prevalent among particular subgroups of US college students and types of colleges. The lifetime prevalence of nonprescription stimulant use was 6.9%, past-year prevalence was 4.1%, and past-month prevalence was 2.1%. Multivariate analysis indicated that nonprescription use was higher among college students who were male, white, members of fraternities and sororities and earned lower grade point averages. Wilens et al. (2008) reported similar findings. Rates were higher at colleges located in the northeastern region of the United States and colleges with more competitive admission standards. Nonprescription stimulant users were more likely to report use of alcohol, cigarettes, marijuana, ecstasy, cocaine, and other risky behaviors. Among college students, available evidence suggests that individuals who misuse MPH were more likely to be white, male, affiliated with a formally organized fraternity, and more likely to use other illicit and illegal substances (Bogle and Smith 2009).

A descriptive, nonexperimental, cross-sectional study examined the nonprescription use of stimulants among student pharmacists (Lord et al. 2003). Lifetime prevalence of stimulant misuse was 7% and was more likely in students who were white, older, and fraternity or sorority members, whereas past-year misuse was more likely in whites and low academic achievers. A recent survey found that the misuse of prescription stimulants is also rampant among dental and dental hygiene students (McNiel et al. 2011). The survey, which was mailed to dental education institutions in the south-central region of the United States, found that 12.4% of these students used a stimulant without a prescription and, of those, 70% took it to improve attention and/or concentration. The most commonly reported stimulant medication used was Adderall (77%). The majority (87%) of the students obtained the medication through friends, and 90% began using the drug in college. Interestingly, 17% of the students surveyed felt it was easy to obtain stimulant medication for use at their school, and 17% thought it was a problem within their institution. The use, misuse, and diversion of prescription stimulants among middle and high school students were also examined by McCabe et al. (2005). In this study, the odds for nonprescription stimulant use were lower among African American students and higher among those students with no plans for attending college. These students also had the highest rates of alcohol and other drug use.

The prevalence of prescription stimulant misuse in medical students is also high. In fact, discussion based websites such as Facebook, Medical School Forum, and The Student Doctor Network are rife with Adderall “experts” and informal question-and-answer sessions on the drug. An anonymous survey was administered to 388 medical students (84.0% return rate) across all 4 years of education at a public medical college. More than 10% of medical students reported using stimulants to improve academic performance. ADHD was diagnosed in 5.5% of students and 72.2% of those students were diagnosed after the age of 18 years (Tuttle et al. 2010). This study suggests that medical students appear to be a relatively high-risk population for prescription stimulant misuse. Several officials now say the problem is increasing in medical schools (Harris 2009). “During the last few years, the number of requests for ADD evaluations has hugely increased,” Paula Stoessel, Ph.D., director of mental health services for physicians in training at the University of California, Los Angeles, David Geffen School of Medicine. “We make them [medical students] go through a lot before we hand out medication, but I’ve heard them talk about [obtaining Adderall prescriptions] in passing.” Clearly, the results emphasize the need for education about stimulants and their adverse side effects.Go to:

Why are prescription stimulants misused?

The reasons why prescription stimulants are misused are numerous and include achieving euphoria, and helping cope with stressful factors related to their educational environment. According to a survey of 334 ADHD-diagnosed college students taking prescription stimulants, 25% misused their own prescription medications to get “high” (Upadhyaya et al. 2005). Like cocaine, MPH inhibits the DAT, which increases synaptic levels of DA, and this is presumed to mediate MPH’s reinforcing effects and abuse potential. In laboratory studies, it has been shown that animals will repeatedly administer MPH as they do cocaine (Kollins 2003), and humans receiving both drugs indicate a similar “high” (Volkow et al. 1995). A frequent concern regarding the use of stimulants for ADHD is their mechanism of action, which increases DA and thus may increase the risk for overt, illicit drug use. However, research points to the conclusion that people of any age receiving a stimulant for ADHD have no greater risk for illicit substance abuse compared with the general population (Wilens 2003).

Stimulants are especially popular at the end of a school term when students will often use the drugs to stay awake through the night to study for exams or complete academic projects. In fact, prescription stimulants are most commonly misused to enhance school performance. According to a Web survey of 115 ADHD-diagnosed college students, enhancing the ability to study outside of class was the primary motive for misuse (Rabiner et al. 2009). Pressures such as a persistent desire to succeed academically, poor sleep habits due to large workloads, and the persistence of underlying social and financial demands may place students at an increased risk for misuse of various drugs, including stimulants (Kadison 2005; Teter et al. 2005). Students who misused ADHD medications generally felt that doing so was helpful. Thus, prescription stimulants developed to help children with ADHD improve their focus and attention are often misused by the patient, especially ADHD patients with conduct disorder or comorbid substance abuse (Kollins 2008). Moreover, students without ADHD misuse stimulants to improve performance or to induce euphoria. A web-based survey administered to medical and health profession students found that the most common reason for nonprescription stimulant use was to focus and concentrate during studying (93.5%) (Herman et al. 2011). In this study, approximately 10.4% of students surveyed (45.2% female; 83.9% male; 83.9% Caucasian) have either used a stimulant or are currently using prescription stimulants, and the most commonly abused stimulant (71.4%) was d-AMP. A recent survey found that 70% of dental and dental hygiene students used a prescription stimulant nonmedically to improve attention and/or concentration (McNiel et al. 2011). Student pharmacists (Lord et al. 2003) and medical students (Tuttle et al. 2010) are also using stimulants to improve concentration and academic performance.Go to:

Effects of prescription stimulants on cognition in ADHD

Neuropsychological studies of ADHD children and adults indicate impairments in many cognitive areas including selective attention, memory, reaction time, information processing speed, and executive control function such as set-shifting, and working memory. The benefits of prescription stimulants for enhancing classroom manageability and increasing attention and academic productivity in children are well established. Prescription stimulants may increase the quality of note taking, scores on quizzes and worksheets, writing output, and homework completion. Nevertheless, they do not normalize the ability to learn and apply knowledge (Advokat 2010). In fact, it has been recognized over 30 years that there is little evidence that prescription stimulants such as MPH and AMP improve the academic achievement of ADHD-diagnosed children. Children with ADHD have a consistently lower full-scale IQ than normal controls. They score significantly lower on reading and arithmetic tests, use more remedial academic services, and are more likely to be placed in a special education class, or repeat a grade compared with controls. They also take more years to complete high school and have lower rates of college attendance (Advokat 2010). Thus, prescription stimulants have only a modest impact on these outcomes.

The first review to describe the general academic functioning of adults with ADHD summarized the results from 23 studies (Weyandt and DuPaul 2006). ADHD-diagnosed college students were found to have significantly lower grade point averages, report more “academic problems” and to be less likely to graduate from college. Nevertheless, ADHD-diagnosed college students did not differ in IQ from those without ADHD, and were shown to be able to meet the demands of college courses. On psychological tests, they showed significant deficits in attention, but were not different from normal students on other measures, such as the ability to be flexible and to maintain performance, as task demands varied (Weyandt and DuPaul 2006). More recent reports have reached similar conclusions. Interestingly, like elementary and high school students, college students with ADHD are less likely to reach the same academic level as their non-ADHD counterparts, even when they use stimulant medications. Thus, stimulant medications do not necessarily equalize academic achievement in the typical adult with ADHD.

A recent controlled, cross-sectional study evaluated the effects of stimulants on cognition in adults with ADHD and found that treated ADHD subjects had significantly better scores on measures of IQ than did untreated patients (Biederman et al. 2012). Thus, either good cognitive functioning may be a determinant of seeking treatment or stimulant treatment may improve cognition in adults with ADHD. When ADHD studies address the issue of cognition, they usually demonstrate that treated patients perform better than untreated patients on neuropsychological tests or measures after they are treated. Whether treatment normalizes neurocognitive performance is rarely addressed. In fact, adults with ADHD are less likely to attain the same educational levels as those without the diagnosis relative to what would be predicted based on their IQ, and this outcome does not appear to be improved by stimulant medication. In one recent study, for example, although 84% of ADHD-diagnosed adults were statistically expected to be college graduates, only 50% reached this level of education (Biederman et al. 2008a,b). Gualtieri and Johnson (2008) conducted a cross-sectional study of ADHD patients treated with different ADHD drugs (Adderall XR, atomoxetine, Concerta) (Adderall XR is an extended-release formulation with duration of action of approximately 10–12 h. This is significantly longer than the duration of action of most methylphenidate formulations, with the exception of Concerta. Immediate-release methylphenidate lasts at most for 6 h). Patients’ performance on a computerized neurocognitive screening battery was compared with untreated ADHD patients and normal controls. Significant differences were detected between normal and untreated ADHD patients. Treated patients performed better than untreated patients but remained significantly impaired compared with normal subjects. Thus, even after optimal treatment, neurocognitive impairments persisted in the ADHD patients.

It has never been established that the cognitive effects of stimulant drugs are central to their therapeutic utility. In fact, although ADHD medications are effective for the behavioral components of the disorder, little information exists concerning their effects on cognition. Barkley and Cunningham (1978) summarized 17 short-term research studies ranging from 2 weeks to 6 months, and found stimulant medications produced little improvement in the academic performance of hyperkinetic ADHD children. The drugs appeared to reduce disruptive behavior rather than improve academic performance. Stimulant drugs do improve the ability (even without ADHD) to focus and pay attention. One function, which is reliably improved by stimulant medications, is sustained attention, or vigilance. Stimulants improve sustained, focused attention, but “selective attention” and “distractibility” may be worsened, possibly because of a drug induced increase in impulsivity. Both AMP and MPH do not improve (and may even impair) short-term acquisition of information. In addition, AMP and MPH do not improve, and may impair “cognitive flexibility” as assessed with tests such as the Wisconsin Card Sort and Attentional Set-Shifting tasks. MPH has been shown to improve performance on an auditory arithmetic task, the Paced Auditory Serial Addition Task, in adults with ADHD relative to control subjects (Schweitzer et al. 2004). AMP and MPH might improve long-term retention of information, if the drugs are active during a period in which memory is being “consolidated.” However, this may only occur in situations where retention is already suboptimal.